Single-arm Trial Evaluating the Effectiveness of PCI of de Novo 3-vessel Disease Applying the SYNTAX Score II With Pressure Wire Functional Assessment and IVUS Guidance, Using an Everolimus-eluting Stent With Biodegradable Abluminal Coating
Conditions: Heart Diseases, Cardiovascular Diseases, 3 Vessel Coronary Artery Disease
Sponsor: ECRI bv

 
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ECRI-002 
 
 SYNTAX-II Clinical Investigational Plan 
 
 
 
 
 
A single-arm trial to evaluate the effectiveness of PCI of de novo 3-vessel disease 
applying the SYNTAX Score II with pressure wire functional assessment and 
IVUS guidance, using an everolimus-eluting stent with biodegradable abluminal 
coating  
 
 
 
 
 
 
 
 
 
 
 
 
Version 2.0, November  27th, 2013 
 
 
 
 
 
Sponsor: 
 
 
 
 
 
 
 
 
CRO: 
European Cardiovascular Research Institute (ECRI) 
 
 
Cardialysis  
Westblaak 92   
 
 
 
 
 
 
 
Westblaak 92  
3012 KM Rotterdam   
 
 
 
 
 
 
3012 KM Rotterdam  
The Netherlands  
 
 
 
 
 
 
 
The Netherlands  

 
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Protocol approval page  
 
A single-arm trial to evaluate the effectiveness of PCI of de-novo 3-vessel disease applying the 
SYNTAX Score II with pressure wire functional assessment and IVUS guidance, using an 
everolimus-eluting stent with a biodegradable abluminal coating  
 
Protocol version: 2.0, dated 27 November 2013 
 
We, the undersigned, have read and approved the protocol specified above, and agree upon the 
contents:  
 
 
 
 
 
____ 
Patrick W. Serruys, Erasmus MC Rotterdam 
 
 
 
Date 
Steering Committee Member,  
Chairman 
 
 
 
 
 
____ 
Javier Escaned, Hospital San Carlos Madrid  
 
 
 
Date 
Steering Committee Member,  
Principal Investigator 
 
 
 
 
 
____ 
Adrian Banning, John Radcliffe Hospital, Oxford 
 
 
 
Date 
Steering Committee Member,  
Principal Investigator 
 
 
 
 
 
____ 
Vasim Farooq, Manchester Royal Infirmary  
 
 
 
Date 
Steering Committee Member,  
Deputy Study Chair 
 
 
 
 
 
____ 
Gerrit-Anne van Es 
 
 
 
 
 
 
 
Date 
Managing Director, ECRI-Trials B.V. 
 
 
 
 
 
 
 
 

 
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Other Steering Committee members: 
 
Arie-Pieter Kappetein, Erasmus MC Rotterdam, Co-Principal Investigator 
 
David Taggart, John Radcliffe Hospital, Oxford, Co-principal Investigator 
 
Robert-Jan van Geuns, ErasmusMC, Rotterdam, The Netherlands 
 
Hector Garcia, Cardialysis, Rotterdam The Netherlands 
 

 
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TABLE OF CONTENTS 
1 
PROTOCOL SYNOPSIS ....................................................................................................... 7 
2 
INTRODUCTION ................................................................................................................ 11 
3 
OBJECTIVE ......................................................................................................................... 17 
4 
STUDY DESIGN.................................................................................................................. 18 
4.1 
Risk Factor Modification ................................................................................................ 20 
5 
ENDPOINTS ........................................................................................................................ 21 
5.1 
Primary Endpoint ............................................................................................................ 21 
5.2 
Secondary endpoints ....................................................................................................... 21 
5.3 
Exploratory endpoint ...................................................................................................... 21 
6 
SUBJECT SELECTION ....................................................................................................... 22 
6.1 
Inclusion Criteria ............................................................................................................ 22 
6.2 
Exclusion Criteria ........................................................................................................... 23 
7 
STUDY PROCEDURES ...................................................................................................... 24 
7.1 
Patient Information and Informed Consent..................................................................... 24 
7.2 
Baseline evaluation ......................................................................................................... 24 
7.3 
Anatomical, residual and functional SYNTAX Scores .................................................. 25 
7.3.1 
EuroSCORE and EuroSCORE II ............................................................................. 25 
7.4 
Patient Allocation............................................................................................................ 25 
7.5 
MSCT .............................................................................................................................. 26 
7.5.1 
MSCT and angiographic SYNTAX Score: Exploratory Endpoint .......................... 26 
7.5.2 
MSCT and non-invasive FFRCT: Exploratory Endpoints ........................................ 27 
7.6 
Index Procedure .............................................................................................................. 27 
7.6.1 
iFR/FFR ................................................................................................................... 27 
7.6.2 
Stent implantation .................................................................................................... 30 
7.6.2.1 
Treatment of Bifurcations ................................................................................. 30 
7.6.2.2 
Treatment of Total Occlusions.......................................................................... 31 
7.6.3 
Intravascular Ultrasound (IVUS) ............................................................................. 31 
7.6.4 
Staged procedures .................................................................................................... 33 
7.7 
Concomitant Medications ............................................................................................... 33 
7.7.1 
Anti-Platelet Medication .......................................................................................... 33 
7.7.2 
Other medication ...................................................................................................... 34 
7.7.3 
PCI Statin therapy .................................................................................................... 35 
7.8 
Hospital Discharge (post-PCI to hospital discharge) ...................................................... 35 
7.9 
Follow-up Period ............................................................................................................ 36 
7.9.1 
Hospital visits........................................................................................................... 36 
7.9.2 
Telephone contacts................................................................................................... 36 
7.10 
Withdrawal from the Study ......................................................................................... 36 
8 
STATISTICAL DESIGN AND ANALYSIS ....................................................................... 38 
8.1 
Introduction ..................................................................................................................... 38 
8.2 
Patient Selection.............................................................................................................. 38 
8.3 
Assumptions for comparative analysis ........................................................................... 39 
8.4 
Sample size ..................................................................................................................... 39 
8.4.1 
Superiority testing (PCI) for the primary endpoint .................................................. 39 
8.4.2 
Non-inferiority testing (CABG) for the exploratory endpoint ................................. 40 

 
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8.4.3 
Sample size justification .......................................................................................... 40 
8.5 
Analytical plan ................................................................................................................ 40 
8.5.1 
Descriptive statistical methodology ......................................................................... 40 
8.5.2 
Comparative statistical methodology ....................................................................... 40 
8.6 
Validation of SYNTAX Score II .................................................................................... 41 
9 
SAFETY REPORTING ........................................................................................................ 42 
9.1 
Serious Adverse Events (SAEs) Definitions................................................................... 42 
9.2 
Anticipated Adverse Device Effects ............................................................................... 43 
9.3 
Reporting to Ethics Committee (EC) .............................................................................. 43 
9.4 
Data Safety Monitoring Board (DSMB) ......................................................................... 44 
9.5 
Risk Analysis .................................................................................................................. 45 
10 QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 47 
10.1 
Compliance to Standards and Regulations .................................................................. 47 
10.2 
Data Recording ............................................................................................................ 47 
10.3 
Quality Assurance and Monitoring ............................................................................. 47 
10.4 
Quality Assurance and Data management ................................................................... 48 
10.5 
On-site Audits .............................................................................................................. 49 
11 ORGANISATION ................................................................................................................ 50 
11.1 
Sponsor ........................................................................................................................ 50 
11.2 
Steering Committee ..................................................................................................... 50 
11.3 
Clinical Event Committee (CEC) ................................................................................ 50 
11.4 
Data Safety Monitoring Board (DSMB) ..................................................................... 50 
11.5 
Data Management ........................................................................................................ 50 
11.6 
Site Management and Monitoring ............................................................................... 50 
11.7 
Safety Reporting .......................................................................................................... 51 
11.8 
Statistical Analysis ...................................................................................................... 51 
12 DATA HANDLING AND RECORD KEEPING ................................................................ 52 
12.1 
Source Documentation (SD) ....................................................................................... 52 
12.2 
Case Report Form Completion .................................................................................... 52 
12.3 
Record Retention ......................................................................................................... 52 
13 PUBLICATION POLICY .................................................................................................... 54 
14 INVESTIGATOR RESPONSIBILITIES ............................................................................. 55 
14.1 
Investigator Responsibility/Performance .................................................................... 55 
14.2 
Required Documents ................................................................................................... 55 
14.3 
Ethics Committee (EC) / Institutional Review Board (IRB) Approval ....................... 56 
14.4 
Informed Consent ........................................................................................................ 56 
14.5 
Protocol Deviation ....................................................................................................... 57 
14.6 
Reporting Requirements .............................................................................................. 57 
14.7 
Audits / Inspection ....................................................................................................... 58 
15 SPONSOR RESPONSIBILITIES ........................................................................................ 59 
15.1 
Role of ECRI ............................................................................................................... 59 
15.2 
Supplemental Applications .......................................................................................... 60 
15.3 
Submitting Reports ...................................................................................................... 60 
15.4 
Maintaining Records ................................................................................................... 60 
15.5 
Audit ............................................................................................................................ 61 

 
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15.6 
Confidentiality ............................................................................................................. 61 
16 REFERENCES ..................................................................................................................... 62 
17 APPENDIX I: SCHEDULE OF EVENTS ........................................................................... 71 
18 APPENDIX II: PROPORTION OF 3VD PATIENTS SUITABLE FOR PCI ..................... 73 
19 APPENDIX III: SYNTAX SCORE II .................................................................................. 74 
20 APPENDIX IV: IVUS CRITERIA ....................................................................................... 76 
21 APPENDIX V: BIFURCATION MANAGEMENT CRITERIA......................................... 78 
22 APPENDIX VI: DEFINITIONS........................................................................................... 80 
23 APPENDIX VI: MSCT ACQUISITION GUIDELINES ..................................................... 91 
 
 
 

 
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1 
PROTOCOL SYNOPSIS 
 
Protocol Number 
ECRI-002 
Title 
A single-arm trial to evaluate the effectiveness of PCI of de novo 3-vessel 
disease applying the SYNTAX Score II with pressure wire functional 
assessment and IVUS guidance, using an everolimus-eluting stent with a 
biodegradable abluminal coating. 
  
Objective 
• To evaluate the effectiveness of contemporary PCI treatment of de 
novo 3-vessel disease following the heart team selection applying the 
SYNTAX Score II with pressure wire functional assessment and 
IVUS guidance (SYNTAX II strategy) 
• To establish superiority of the SYNTAX II strategy compared to the 
PCI arm of the SYNTAX I study (Primary endpoint) 
• To prospectively assess the effectiveness of the SYNTAX Score II for 
heart team decision making 
• To prospectively validate the SYNTAX Score II for all-cause death at 
1 and 2 year and 5 year follow-up; 
• To retrospectively validate the residual SYNTAX Score (academic 
research) 
 
Treatment 
SYNTAX II strategy consists of contemporary PCI of de novo 3-vessel 
disease following the heart team consensus applying the SYNTAX Score 
II for the heart team selection of patients, pressure wire functional 
assessment of lesions and IVUS optimization of DES implantation. 
 
Study design 
The SYNTAX II Trial is a multicenter, 3-vessel disease, all-comers, open-
label, single-arm trial of approximately 450 patients in approximately 25 
interventional cardiology centres in Europe. All patients will be treated 
with an everolimus-eluting stent with a biodegradable abluminal coating. 
 
Comparisons will be undertaken using the completed SYNTAX I Trial as 
a control: Primary endpoint: comparison with PCI (TAXUS Express2);. 
 
Number of Subjects 
450 subjects in total 
 
Investigational Sites 
Up to approximately 25 sites in Europe 
 
Follow-up 
In-hospital and additional follow-up visits at 1 month, 6 months and 12 
months after enrolment.  

 
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In addition, patients will be contacted annually by telephone up to 5 years 
to check survival status and other MACCE components (patient reported). 
 
Primary Endpoint 
The primary endpoint is a composite of MACCE rate (all-cause death, 
cerebrovascular event (stroke), documented myocardial infarction, or all-
cause revascularization) at 1 year follow-up (SYNTAX I definition) 
compared to PCI arm of the SYNTAX I Trial (Patient Oriented Clinical 
Endpoint).  
 
Secondary Endpoints 
• Composite of all-cause death, cerebrovascular event (stroke), 
documented myocardial infarction at 1 year follow-up compared 
to the  PCI arm of SYNTAX I; (Safety Endpoint) 
• Composite of cardiovascular death, documented target-vessel 
myocardial infarction and repeat target lesion revascularization at 
1 year follow-up compared to the  PCI arm of SYNTAX I; 
(Device Oriented Clinical Endpoint) 
• Rates of individual components of MACCE (all-cause death, 
cerebrovascular event (stroke), documented myocardial infarction 
and repeat revascularization) at 1 year;  
• The composite of MACCE and its individual components at 2-5 
years follow-up (patient reported);  
• Myocardial Infarction – according to Universal MI definition 2012 
at all timepoints;  
• Stent Thrombosis – according to ARC definitions at all 
timepoints; 
 
Exploratory Endpoint 
• Composite of MACCE (all-cause death, cerebrovascular event 
[stroke], documented myocardial infarction or all-cause 
revascularization) at 5 years follow-up compared to CABG arm of 
the SYNTAX I Trial. 
 
General Inclusion and 
Exclusion Criteria 
Inclusion Criteria: 
1. 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 without left main involvement; 
(Patients with ostial LAD or ostial CX - Medina 0,0,1 or Medina 0,1,0 – 
may be enrolled) 
 
 

 
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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 
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; 
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 for initial screening 
with the SYNTAX Score II; 
6. 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; 
7. Signed Heart Team Decision Form between local cardiologist and 
surgeon that the selected case meets all of the inclusion and 
exclusion criteria; 
 
Exclusion Criteria: 
Candidates will be ineligible for enrolment in the study if any of the 
following conditions apply: 
1. Under the age of 21 years; 
2. 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; 
  
3. Prior PCI or CABG; 
4. Ongoing acute myocardial infarction and enzymes CKMB >2x 
upper limit of normal; 
5. Concomitant cardiac valve disease requiring surgical therapy 
(reconstruction or replacement); 
6. Single or two-vessel disease (at time of Heart Team consensus); 
 

 
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7. Participation or planned participation in another cardiovascular 
clinical study before one year follow up is completed; 
8. Mental condition (psychiatric or organ cerebral disease) rendering 
the subject unable to understand the nature, scope, and possible 
consequences of the study or mental retardation or language 
barrier such that the patient is unable to give informed consent and 
potential for non-compliance towards the requirement in the study 
protocol. 
Antiplatelet 
Medication 
Dual Antiplatelet treatment is mandatory for at least 6 months; aspirin 
indefinitely. 
Loading dose: 
• All patients must receive aspirin ≥300 mg/day starting 12-24 hours 
prior to the procedure (even if the subject is on chronic aspirin 
therapy). 
• Clopidogrel loading dose must be 600 mg, starting 12-24 hours 
prior to the procedure (even if the subject is on chronic clopidogrel 
therapy). 
Alternatively: 
• Prasugrel 60 mg >1 hr before PCI; or 
• Ticagrelor 180 mg >1 hr before PCI if approved by the local 
regulatory authorities during the enrolment period of this protocol. 
 
Maintenance dose: 
Starting from the day after the procedure, aspirin 75-100 mg/day will be 
prescribed to all patients indefinitely. 
Additionally, all patients must receive platelet aggregation inhibition 
therapy for at least 6 months as currently recommended by the 
ESC/AHA/ACC guidelines which includes: 
• Clopidogrel 75 mg once daily. 
Alternatively: 
• Prasugrel 10 mg once daily; or 
(The dose of prasugrel may be decreased to 5mg od in patients with a weight 
<60 kg or age >75 years).  
• Ticagrelor (90mg bid) 

 
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2 
INTRODUCTION 
 
 
The anatomical-based SYNTAX Score (http://www.syntaxscore.com) has established itself as a 
tool to aid the Heart Team consensus in determining the optimal revascularization modality in 
patients with unprotected left main coronary artery (ULMCA) disease or de novo three vessel 
disease (3VD).1-10 The anatomical based SYNTAX Score was designed and implemented in the 
landmark SYNTAX Trial,4, 7, 10 as an instrument to force the interventional cardiologist and 
cardiac surgeon to examine the coronary angiogram, and agree that equivalent anatomical 
revascularisation could be achieved. Only after the publication of the SYNTAX Trial did the 
importance of the anatomical SYNTAX Score become clear. Namely, in appropriately guiding 
decision making between coronary artery bypass graft (CABG) surgery and percutaneous 
coronary intervention (PCI) for the treatment of complex coronary artery disease. Since 
publication of the SYNTAX Trial, the anatomical-based SYNTAX Score, has been validated in 
multiple studies, and has recently been advocated in both the US and European revascularization 
guidelines, as a tool to guide the clinician in determining the optimal revascularization modality 
(CABG or PCI) in patients with complex coronary artery disease.8, 9, 11-13 
 
Dedicated studies in the post SYNTAX Trial era investigating 3VD remain scarce. As of present, 
current revascularization guidelines recommend that a low SYNTAX Score (0-22) may offer 
similar clinical outcomes between percutaneous coronary intervention (PCI) with drug eluting 
stents (DES) and coronary artery bypass graft (CABG) surgery.11-13  
Diabetes 
Outcomes in diabetic patients have historically lacked suitably powered randomized trials. Meta-
analyses of trials comparing CABG against PCI in the pre-DES era (balloon angioplasty and bare 
metal stents) have shown a potential prognostic advantage of CABG compared to PCI.14, 15 A 
major limitation of these studies were however that the studies were not all-comers in design, 
with patients ‘cherry-picked’ for randomisation based on restrictive inclusion and exclusion 
criteria, making application to clinical practice questionable.16, 17 

 
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In the DES era, the Future Revascularization Evaluation in Patients with Diabetes Mellitus: 
Optimal Management of Multivessel Disease (FREEDOM) Trial,18, 19 consisting of 1900 patients 
with two or 3VD, randomised to CABG or PCI with first generation DES, showed a prognostic 
advantage for CABG at a median follow up of 3.8 years. At 5 years follow up, only 678/1900 
patients reached this time point, with 197 deaths recorded. In this subset of patients, there was no 
interaction between the SYNTAX Score and treatment (p=0.58). There was however a stepwise 
increase in death, MI, or stroke in patients that underwent PCI (low SYNTAX Score: 19.4%, 
intermediate SYNTAX Score: 22.2%, high SYNTAX Score: 31.0%), but not in those treated 
with CABG (low SYNTAX Score: 20.1%, intermediate SYNTAX Score: 21.5%, high SYNTAX 
Score: 16.0%). The FREEDOM Trial was however underpowered to assess the SYNTAX Score 
at 5 years.9, 20 
Conversely, diabetics in the SYNTAX Trial (a pre-stratified powered subgroup), has shown that 
low SYNTAX Scores to be associated with comparable long term mortality and composite 
clinical outcomes (major adverse cardiac and cerebrovascular events [MACCE]).20-22  
Left Main Coronary Artery Disease 
Based on the results of the SYNTAX Trial, in which short and long term outcomes were similar 
between CABG and PCI in subjects with unprotected left main coronary artery (ULMCA) 
disease with an anatomical SYNTAX Score <33,4, 7, 10 the EXCEL (Evaluation of Xience Prime 
versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial 
was conceived (ClinicalTrials.gov Identifier: NCT01205776). EXCEL is an ongoing, 
international, multicentre trial, aiming to recruit 2600 patients with ULMCA disease and a 
SYNTAX Score <33 – randomized to surgical (n=1300) or percutaneous (with the XIENCE 
PRIME or XIENCE V DES [n=1300]) revascularization.23 Notably the US Food and Drug 
Administration (FDA) mandated the anatomical-based SYNTAX Score as entry criteria within 
the EXCEL Trial. 
 
 

 
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SYNTAX Score II 
The category based risk approach of the anatomical-based SYNTAX Score – i.e. “low”, 
“intermediate,” or “high” SYNTAX Scores – to guide decision making between CABG or PCI, 
has been shown to be potentially misleading in a post hoc analysis of the SYNTAX Trial.24 
Within this study, it was shown that low and high risk subjects existed in higher and lower 
SYNTAX Score tertiles, which appeared to have implications for the most appropriate 
revascularisation modality (CABG and PCI); e.g. there was a doubling of 3-year mortality in 
subjects with 3VD – with a low SYNTAX Score (<23) and a high additive EuroSCORE (≥6) – 
who underwent PCI compared to CABG.24 In addition, a recent study pooling over 6000 PCI 
subjects treated with DES, demonstrated that the addition of clinical variables to the anatomical 
SYNTAX Score, substantially increased the accuracy of identifying low (and high) risk patients 
compared to the anatomical SYNTAX Score alone.25 
 
The SYNTAX Score II26, 27 was designed to improve decision making between CABG and PCI, 
by allowing for a long term, individualized risk assessment of patients with complex coronary 
artery disease. The SYNTAX Score II combined the anatomical based SYNTAX Score with 
clinical variables, that were shown to alter the threshold value of the SYNTAX Score so that 
equipoise was achieved between CABG and PCI for long term mortality. These included the 
presence of unprotected left main coronary artery disease, female gender,28 chronic obstructive 
pulmonary disease, age and left ventricular ejection fraction. The SYNTAX Score II was 
developed in the randomized SYNTAX Trial (n=1800), and validated in the multicentre Drug 
Eluting stent for LefT main coronary Artery disease (DELTA) Registry (n=2891).29 Importantly 
the DELTA Registry was a multinational, non-randomised, all-comers registry, conducted in 14 
centres in Europe, US and South Korea. The study population was heterogeneous, and included 
complex coronary artery disease – anatomical SYNTAX Score ≥33 existed in 30%, and 3VD in 
26%, of the DELTA Registry. 
During development and validation of the SYNTAX Score II, it was shown that diabetes did not 
improve decision making between CABG and PCI. Findings that were consistent with a previous 
study of over 6000 patients treated with DES, where it was shown that the presence of diabetes 
minimally affected long term mortality predictions after PCI with DES, when age, kidney 

 
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function and left ventricular ejection fraction were accounted for.25 Subsequent 
epidemiology/population based studies have further supported these findings.30, 31  
By utilizing the individualized approach of the SYNTAX Score II, in contrast to the anatomical-
based SYNTAX Score tertiles, a subset of patients with low, intermediate or high SYNTAX 
Scores were identified, that would have lower, similar, or higher 4-year mortality predictions for 
CABG or PCI. Specifically for 3VD, approximately 80%, 60% and 30% of patients in the 
respective low, intermediate and high SYNTAX Score tertiles of the randomised SYNTAX 
population would have similar long-term mortality between CABG and PCI (Appendix II).  
Contemporary PCI Practice and the SYNTAX Trial 
Overall, the amount of information gathered in the SYNTAX Trial has helped shape both clinical 
practice and international guidelines in the management of complex coronary artery disease.  The 
conclusions drawn in the SYNTAX Trial since its publication do however not take into account 
areas in which the progress has been made in more contemporary interventional practice. Some 
of these are discussed in the following paragraphs: 
1) Chronic total occlusion recanalization: In SYNTAX, the presence of a (chronic) total 
occlusion (C)TO was identified to be the strongest independent predictor of incomplete 
revascularisation in the PCI arm of the SYNTAX Trial.32, 33 Over the last 10 years the practice of 
(C)TO recanalization has been largely modified by the systematisation in the approach to (C)TO 
recanalization and the development of new devices. Although acquaintance with these 
techniques is still limited among interventional cardiologists, international registries have 
consistently reported that skilled, dedicated (C)TO operators have success rates of 85-95%, a 
much higher success rate that that observed in SYNTAX operators (approximately 50%).34 
Major technical improvements include the development of new coronary wires, dedicated 
intracoronary cathethers (Corsair,Ⓡ Tornus,Ⓡ CrossBossTM) and re-entry devices (The 
Stingray™ CTO Re-Entry System).35 Contemporary (C)TO procedures are performed both in 
anterograde or retrograde fashion (through collateral channels), frequently with the concourse of 
IVUS imaging. Virtually all these developments were not applied to (C)TO recanalization in 
SYNTAX. It will therefore be encouraged that each participating centre should select an expert 

 
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in (C)TO revascularisation who should be involved in the procedure whenever a (C)TO is 
involved. 
2) Ischemia-driven revascularisation: A large body of evidence, largely based on the use of 
fractional flow reserve (FFR), has demonstrated that, compared with angiography, decision 
making of coronary revascularisation based on physiological assessment of stenosis severity 
results in improved patient outcomes.36-39 Recalculation of the SYNTAX score by incorporating 
FFR-derived information of stenosis severity (functional SYNTAX score40) may decrease the 
number of higher-risk patients with multivessel disease undergoing PCI and contribute to a better 
discrimination of risk for adverse events in this subset of patients. A new pressure-derived index, 
instantaneous wave-free ratio (iFR), that allows faster adenosine-free assessment may be more 
ideally suited for multiple measurements performed in the context of multivessel disease.41  
3) Imaging guidance of PCI procedures: While the proposal of using intravascular ultrasound 
(IVUS) to tackle restenosis made in the bare metal stent (BMS) era was virtually abandoned with 
the arrival of drug eluting stents (DES), a growing body of evidence suggests that DES 
implantation with IVUS guidance in complex anatomical subsets may contribute to better patient 
outcomes. Specifically, a recent meta-analysis of IVUS guided DES implantation in almost 20 
000 subjects has reported significantly reductions in stent thrombosis and mortality.42, 43 
 
4) Newer generation DES: Compared to first generation DES, newer generation DES have 
proven reductions in stent thrombosis and other clinical outcomes. This has largely been through 
the design of more biocompatible polymers, biodegradable polymers, limus based drugs, thinner 
stent struts through the incorporation of metallic alloys with greater radial strength, and increased 
deliverability of the devices.44-49 Outcomes of the SYNTAX Trial related to newer generation 
DES are therefore unknown and will be investigated in the current study. 
 
 

 
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Purpose of Study 
The purpose of the planned SYNTAX II Trial is to investigate the management of de-novo 3VD 
in order to prospectively assess which patients would have at least comparable short and long 
term clinical outcomes between CABG and PCI, using contemporary PCI practice. In SYNTAX 
II the effectiveness of a contemporary stent (the new generation SYNERGYTM DES, designed 
with thinner struts, biocompatible and biodegradable polymer, and a limus based drug50, 51), the 
use of pressure wire assessment of lesions to allow for ischemia-driven revascularisation, IVUS 
guidance to optimise DES deployment, and the treatment of (C)TO lesions with contemporary 
techniques, will be compared against PCI practice in the original SYNTAX trial. The proposed 
study would involve the SYNTAX Score II to prospectively recruit subjects on the grounds of 
patient safety.26, 27  
 
 

 
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3 
OBJECTIVE  
 
• To evaluate the effectiveness of contemporary PCI treatment of de novo 3-vessel disease 
following the heart team selection applying the SYNTAX Score II with pressure wire 
functional assessment and IVUS guidance (SYNTAX II strategy). 
• To establish superiority of the SYNTAX II strategy compared to the PCI arm of the 
SYNTAX I study (Primary Endpoint). 
• To prospectively assess the effectiveness of SYNTAX Score II for heart team decision 
making. 
• To prospectively validate the SYNTAX Score II for all-cause death at 1 and 2 year and 5 
year follow-up. 
• To retrospectively validate the residual SYNTAX Score (academic research)52, 53. 
 
Comparisons will be undertaken using the completed SYNTAX I Trial as a historical control:4 
Primary Endpoint – PCI cohort (TAXUS Express2); 

 
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4 
STUDY DESIGN  
 
 
The SYNTAX-II Trial is a multicenter, 3-vessel disease, all-comers, open-label, single arm trial 
of approximately 450 patients in approximately 25 interventional cardiology centres in Europe. 
All patients will be treated with the Boston Scientific SYNERGY™ Everolimus-Eluting 
Platinum Chromium Coronary Stent System. 
 
 
Heart Team Discussion
Confirm SYNTAX Score II calculation, and that recruitment of patients for PCI is based on 
safety (long term mortality comparisons between CABG and PCI)
SYNTAX Trial II 
Inclusion: All-Comers, angiographic, de-novo 3-vessel disease without 
left main involvement (visual % diameter stenosis ≥50%)
Screening according to
SYNTAX Score II
Low (0-22) anatomical 
SYNTAX Score
Interm (23-32) anatomical 
SYNTAX Score
High (≥33) anatomical 
SYNTAX Score
Patient ‘Signed Off’ by Heart Team for PCI
SYNTAX Score II 
Favours CABG*
*Index revascularisation
procedure type collected (CABG, 
PCI or medical or refusal).. 
SYNTAX Score II 
Offers equipoise for PCI and CABG
YES
NO
Can ‘equivalent’ anatomical revascularisation be 
achieved*
*Surgeon and interventional cardiologist in agreement
Exploratory study: MsCT scan →non-invasive computation of FFRCT
Not 
“eligible”
for PCI
 
Study Flowchart: Part-1: Heart Team algorithm  
 

 
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1. All patients with de-novo 3-vessel disease (DS ≥50%), with no left main involvement, 
will be screened by the local Heart Team (interventional cardiologist and cardiac 
surgeon). Initial enrolment criteria will be unrestrictive and similar to the SYNTAX 
Trial.3, 4 As per the original SYNTAX Trial, prior CABG or PCI will be one of the very 
few exclusion criteria. 
2. All patients will have anatomical SYNTAX Scores and EuroSCOREs (I and II)54-58 
undertaken, and will undergo further assessment by the Heart Team for enrolment in the 
study. 
3. All patients will have the SYNTAX Score II prospectively determined by the Heart Team 
using an online calculator (Appendix III). The SYNTAX Score II will be used to 
objectively determine if the patient is suitable for PCI, CABG, or both revascularization 
modalities. Based on SYNTAX Score II in the SYNTAX Trial, approximately 80%, 60% 
and 30% of patients in the low, intermediate and high SYNTAX Score tertiles 
respectively, would have at least similar long-term mortality between CABG and PCI 
(Appendix II). Patients not suitable for PCI based on the SYNTAX Score II assessment 
will undergo CABG, unless contraindicated. In patients not eligible for SYNTAX II trial, 
the index revascularisation procedure type will be collected (i.e. CABG, PCI, medical 
treatment or refusal). 
 
Equivalent Anatomical Revascularization 
As per the SYNTAX Trial, patients must be able to undergo “equivalent anatomical 
revascularization,” based on the SYNTAX Trial definition of 1.5 mm vessels being 
revascularised, as agreed by the cardiac surgeon and interventional cardiologist during the Heart 
Team meeting.3 Patients not suitable for equivalent anatomical revascularization will undergo 
CABG, unless contraindicated. For patients not eligible for SYNTAX II trial, the index 
revascularisation procedure type will be collected (i.e. CABG, PCI, or medical treatment or 
refusal). 
 
 
 

 
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Exploratory sub-study 
After the Heart Team consensus, but prior to PCI procedure, a multislice computed tomography 
(MSCT) scan should be obtained (documentary only). MSCT will not be used in process of 
Heart Team discussion. The MSCT scan will be processed by HeartFlow Inc. (Redwood city, 
California, USA). HeartFlow’s technology enables the computation of FFRCT in a non-invasive 
manner.8, 59-62 Results will only become available after completion of the SYNTAX II study.  
 
Reporting of Study Endpoints 
The primary endpoint will be reported at 1 year. At 2-5 years follow-up, all patients will be 
contacted by telephone to check survival status and other MACCE components (patient reported). 
From all screened patients the index treatment type (i.e. CABG, PCI, medical, other) will be 
collected. 
 
Clinical data will be adjudicated by an independent Clinical Event Committee (CEC). Ongoing 
safety monitoring will be performed by a Data Safety Monitoring Board (DSMB). 
 
4.1 
Risk Factor Modification 
 
Tight control of risk factors will be mandated in line with the European and US revascularisation 
guidelines.11, 12 Cholesterol reduction, with a LDL ≤1.8, will be an additional protocol defined 
target the operator will be recommended to record and control.  
In summary, patients (de-novo 3VD) will be treated according to ACC/AHA/ESC guidelines, i.e. 
Heart Team discussion (Ia); functional evaluation for diagnosis in absence of objective evidence 
of ischemia (Ia); and LDL levels ≤1.8mmol (Ia). 
 
 
 
 
 
 
 

 
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5 
ENDPOINTS 
 
5.1 
Primary Endpoint 
 
The primary endpoint is a composite of MACCE at 1 year follow-up compared to PCI arm of the 
SYNTAX I Trial (acting as a historical control) (Patient Oriented Clinical Endpoint) 
MACCE is defined as: all-cause death; cerebrovascular event (stroke); documented myocardial infarction or all-
cause revascularization). 
 
5.2 
Secondary endpoints 
 
Secondary endpoints of this study are to assess: 
• Composite of all-cause death, cerebrovascular event (stroke), documented myocardial 
infarction at 1 year follow-up compared to the  PCI arm of SYNTAX I; (Safety Endpoint) 
• Composite of cardiovascular death, documented target-vessel myocardial infarction and 
repeat target lesion revascularization at 1 year follow-up compared to the  PCI arm of 
SYNTAX I; (Device Oriented Clinical Endpoint) 
• Rates of individual components of MACCE (all-cause death, cerebrovascular event 
(stroke), documented myocardial infarction and repeat revascularization) at 1 year;  
• The composite of MACCE rate and its individual components at 2-5 years follow-up 
(patient reported);  
• Myocardial Infarction – according to Universal MI definition 2012 at all timepoints;  
• Stent Thrombosis – according to ARC definitions at all timepoints; 
 
5.3 
Exploratory endpoint 
• Composite of MACCE (all-cause death, cerebrovascular event (stroke), documented 
myocardial infarction or all-cause revascularization) at 5 years follow-up compared to 
CABG arm of the SYNTAX I Trial 
 
 
 

 
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6 
SUBJECT SELECTION   
 
Patient selection will be from all-comers de novo 3VD patients. Anatomical SYNTAX and 
SYNTAX II Scores, will be undertaken to objectively determine if CABG or PCI offer a least 
similar long term mortality.  
 
Approximately 450 3-vessel disease all-comers patients will be enrolled. The recruitment will be 
competitive. 
 
6.1 
Inclusion Criteria 
 
1. 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 without left main involvement; 
(Patients with ostial LAD or ostial CX - Medina 0,0,1 or Medina 0,1,0 – may be enrolled) 
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 
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; 
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 for initial screening with the SYNTAX 
Score II; 
6. 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; 
7. Signed Heart Team Decision Form between local cardiologist and surgeon that the 
selected case meets all of the inclusion and exclusion criteria; 
 
 
 

 
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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 21 years; 
2. 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; 
3. Prior PCI or CABG; 
4. Patients with ongoing acute myocardial infarction and enzymes CKMB >2x upper limit of 
normal;  
5. Concomitant cardiac valve disease requiring surgical therapy (reconstruction or replacement); 
6. Single or two-vessel disease at the time of Heart Team consensus; 
7. Participation or planned participation in another cardiovascular clinical study before one year 
follow up is completed; 
8. Mental condition (psychiatric or organ cerebral disease) rendering the subject unable to 
understand the nature, scope, and possible consequences of the study or mental retardation or 
language barrier such that the patient is unable to give informed consent and potential for non-
compliance towards the requirement in the study protocol. 

 
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7 
STUDY PROCEDURES 
 
7.1 
Patient Information and Informed Consent 
 
All potential subjects must be consented prior to undergoing any study-specific procedures. Once 
the subject’s general eligibility for the study is met, the background of the proposed study and 
the benefits and risks of the procedures and study must be explained to the subject prior to 
obtaining informed consent. Only those subjects who sign the Ethics Committee approved 
informed consent form prior to any study-specific procedures are candidates for actual enrolment 
in the study. Failure to provide written informed consent renders the subject 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.  
 
7.2 
Baseline evaluation 
 
The following routine tests will be performed: 
a) Routine laboratory tests prior to the procedure according to local hospital practice. 
Creatinine and creatinine clearance (Cockcroft and Gault63) are mandated to be 
performed prior to procedure. Cardiac enzymes must be sampled prior to the PCI 
procedure in order to detect acute myocardial infarction (AMI) patients. Prior to the PCI 
procedure the cardiac enzymes (CK-MB or Troponin) must be less than 2-times the upper 
limit of normal (<ULN). 
b) 12-lead electrocardiogram pre, and post procedure and at discharge 
 
 
 
 

 
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7.3 
Anatomical, residual and functional SYNTAX Scores  
 
The baseline anatomical SYNTAX Score and SYNTAX Score II will be recorded in the eCRF. 
All procedural coronary angiograms will be collected and allowances made for the export of this 
data to Cardialysis, Rotterdam. No analyses will be performed by the Core Laboratory. At a later 
stage post hoc analysis of the baseline anatomical SYNTAX Score, residual SYNTAX Score52, 53 
and functional SYNTAX Score40 will be undertaken (academic research).  
7.3.1 EuroSCORE and EuroSCORE II 
 
EuroSCORE and EuroSCORE II will be collected and recorded in the eCRF. 
 
7.4 
Patient Allocation  
 
Calculation of the  SYNTAX Score II and prognostic outcomes (mortality predictions) following 
CABG or PCI will be determined at 4 years using the SYNTAX Score II online calculator. 
Individual mortality predictions for CABG and PCI that can be separated with 95% confidence 
(ie, that can be statistically separated, p<0•05) will have a treatment recommendation for either 
CABG alone or PCI alone. Individual mortality predictions for CABG and PCI that cannot be 
separated with 95% confidence (i.e., could not be statistically separated, p>0•05) will have a 
treatment recommendation for either CABG or PCI. 
Comparisons of 4 year mortality predictions will be undertaken using the SYNTAX Score II 
online calculator, which will incorporate statistical comparisons of mortality predictions for 
CABG and PCI (as previously highlighted). The online calculator will provide the heart team 
with an objective treatment recommendation, namely, CABG is recommended, PCI is 
recommended, or either CABG or PCI is recommended. 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. Reasons for undertaking this should be clearly 
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Having established that the patient could be potentially recruited based on the SYNTAX Score II 
on the grounds of patient safety, subjects will be assessed by the heart team as to whether 
“equivalent anatomical revascularization” could be potentially achieved between CABG and 
PCI. Secondly, the heart team must clearly establish that both CABG and PCI would be equally 
offered to the patient. If the patient fulfils both criteria then the patient may be recruited in the 
SYNTAX II Trial.  
The decision for the subject’s inclusion into SYNTAX II will be documented and ‘signed off’ by 
both members of the local Heart Team (Heart Team Worksheet) - subsequently investigator will 
receive patient allocation number. 
 
7.5 
MSCT  
 
After Heart Team consensus, but prior to the planned PCI procedure, a MSCT scan should be 
obtained (documentary only). Refer to Appendix VI for MSCT acquisition protocol. The MSCT 
results and results of MSCT-derived FFR will only become available after completion of the 
SYNTAX II study, and therefore investigators will be blinded to its results during the study. 
Furthermore, the analysis of MSCT and FFRCT will be performed by analysts blinded to 
iFR/FFR and angiographic data.  
 
7.5.1 MSCT and angiographic SYNTAX Score: Exploratory Endpoint 
 
• To prospectively examine the value of an objective anatomic SYNTAX Score based on 
non-invasive MSCT imaging - compared to conventional angiographic SYNTAX Score 
as visually assessed by the Heart Team. 
 
 
 
 
 

 
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7.5.2 MSCT and non-invasive FFRCT: Exploratory Endpoints 
 
• To prospectively compare, in a population of patients with multi-vessel disease, 
functional stenosis severity assessed with non-invasive FFRCT with invasive functional 
assessment with iFR/FFR, using per-vessel comparisons. Per vessel analysis will be 
performed to calculate the percentage of vessels properly classified by MSCT-FFR, in 
terms of haemodynamic stenosis severity, compared to invasive iFR/FFR measurements. 
• To prospectively compare, in a population of patients with multi-vessel disease, 
functional SYNTAX scores calculated from a) multi-slice computed tomography 
coronary angiography and non-invasive FFR, and b) conventional angiography and 
iFR/FFR. In both a) and b), functional SYNTAX score is defined as anatomical 
SYNTAX scoring limited to vessels with haemodynamically significant stenoses (as 
estimated by HeartFlow [non-invasive functional SYNTAX score] or iFR/FFR [invasive 
functional SYNTAX score]) 
 
7.6 
Index Procedure 
 
7.6.1 iFR/FFR 
 
All centres must be experienced in PCI of complex coronary artery disease, utilizing functional 
(iFR/FFR) and IVUS guidance. 
 
iFR is a recently introduced pressure-derived index for the assessment of coronary stenosis 
severity that, at difference to FFR, does not require adenosine administration and provides an 
estimation of stenosis severity a few seconds after crossing the stenosis with the pressure guide- 
wire.41 These characteristics make iFR a more ideal method to apply ischemia driven 
revascularisation in patients with 3VD, in whom multiple measurements are required.   
The subject will undergo invasive adenosine-free iFR® assessment of all 3 major epicardial 
vessels. All lesions intended to be treated should be interrogated, including side-branches. Total 
occlusions and culprit lesions of acute coronary syndromes64-66 preclude iFR measurements. iFR 
values will be collected with the PrimeWire Prestige Plus with AccuesenseTM technology. In 

 
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place of the PrimeWire Prestige Plus wire, the VerrataTM wire will be permitted to be used in the 
study once the wire has received an expected CE-mark. 
In SYNTAX II ischemia driven revascularisation will be performed following a hybrid decision-
making strategy of coronary revascularisation with iFR and FFR.67 The use of a hybrid iFR/FFR 
approach, currently undergoing testing in the ADVISE II study (ClinicalTrials.gov Identifier: 
NCT01740895) has the potential of significantly reducing the need for adenosine administration, 
whilst maintaining a 95% classification agreement to the FFR-only strategy.67 
iFR in all intended to treat vessels 
iFR <0.86*
Implantation of 
SYNERGYTM stent(s)
iFR >0.93
No stent implantation
in lesion
Optimization by IVUS 
guidance (modified MUSIC 
Criteria) 
Optimal medical therapy with a strict control of LDL (≤1.8 mmol)
Patient ‘Signed Off’ by 
Heart Team for PCI
* Consider FFR pullback with sequential lesions
iFR 0.86-0.93
FFR
FFR≤0.80
FFR>0.80
 
Study Flowchart: Part-2: PCI procedure  
 
iFR values will be collected with the PrimeWire Prestige Plus (or VerrataTM wire) with 
AccusenseTM technology.  

 
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In case of iFR <0.86 the lesion will be treated by PCI. If iFR is ≥0.86 and ≤0.93, FFR is 
mandated to be measured using i.v. or i.c. adenosine, and the decision to treat will be based on an 
FFR cutoff of 0.80. iFR >0.93 the stenosis should not be treated.  
In subjects with contraindications to adenosine administration, revascularisation will be 
performed using iFR as a dichotomous index, using most recently reported cutoff value of iFR 
<0.89 for haemodynamic significance.67 
In case of sequential lesions, the procedure depicted in the flowchart should be followed. 
Treat visually most severe lesion
Sequential Lesions:
iFR <0.86 or FFR <0.80 in distal vessel beyond all lesions 
Reassess vessel with iFR
iFR <0.86*
Implantation of further 
SYNERGYTM stent(s)
iFR >0.93
No further stent 
implantation
Optimization by IVUS 
guidance (modified MUSIC 
Criteria) 
iFR 0.86-0.93
FFR
FFR≤0.80
FFR>0.80
FFR hyperaemic pullback to guide sequential lesion 
treatment can be alternatively performed at the 
discretion of the operator
 Study Flowchart: Part-2a: PCI procedure (sequential lesions) 

 
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iFR/FFR values will be recorded in the eCRF. No analysis will be performed by the core 
laboratory. Export of recordings to Cardialysis will be performed for post hoc analysis at a later 
stage (academic research). 
7.6.2 Stent implantation 
 
Stent implantation will be performed according to routine local clinical practice using the 
femoral, brachial or radial approach with the intention of achieving equivalent anatomical 
revascularization to CABG. The radial approach, although not mandated, will be strongly 
recommended.68 
Patients will exclusively be implanted with the SYNERGYTM stent.50, 51 Stenting should be 
attempted for each lesion in a vessel with a >1.5 mm in diameter as assessed on the diagnostic 
angiogram and agreed to be revascularised by the Heart Team in order to achieve equivalent 
anatomical revascularization. 
IVUS use at pre-PCI is left to the discretion of the investigator. IVUS assessment post stent 
implantation for optimisation of stent deployment is mandated (see part 7.5.3). 
If the implantation of the SYNERGY stent was not successful, the reason should be recorded in 
the CRF. 
 
7.6.2.1 Treatment of Bifurcations 
 
All types of bifurcation may need stenting of the main vessel, and/or the side branch, followed 
by kissing balloon post-implantation if a two stent approach is adopted. The treatment goal is to 
avoid gaps whenever more than one stent is used. Bifurcation techniques will be selected 
depending on the anatomy and morphology, although it is expected that most lesions would 
require a simple (provisional) approach, in keeping with recommendations from the European 
Bifurcation Club.69, 70  
 

 
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Stent sizing in bifurcation stenoses should take into account vessel diameter mismatch between 
mother and daughter vessels, following the recommendations of the European Bifurcation Club69, 
70 (see also Appendix V for detailed treatment of bifurcations – mandated and recommended 
strategies). 
 
7.6.2.2 Treatment of Total Occlusions 
 
It has recently been shown that the presence of a total occlusion (TO) to be the strongest 
independent predictor of incomplete revascularisation in the PCI arm of the SYNTAX Trial.32, 33 
Operator skill and use of specific techniques and devices are key determinants PCI success in 
CTOs.34 A dedicated chronic total occlusion (CTO) operator is recommended to be made 
available in all participating centres. Staging of the revascularisation procedure should be 
encouraged, to ensure CTOs are appropriately revascularised. CTO recanalization can be 
performed using the antegrade or retrograde approach, as well as using specific re-entry 
techniques such as the StingRay device 71 Selection of stent length can be based on IVUS 
imaging. Viability assessment of total occlusions will be left at the discretion of the operator.72-77  
A tolerant attitude, refraining stenting towards moderate stenoses located distal to the occluded 
segment should be followed, on the grounds of important vessel diameter shift after vessel 
recanalization.78  
 
7.6.3 Intravascular Ultrasound (IVUS) 
 
In SYNTAX II Trial, mechanical IVUS catheters (Revolution® Rotational Imaging Catheter / 
Volcano Therapeutics or AtlantisTM SR Pro or SR Pro2 Imaging Catheter or OpticrossTM / 
Boston Scientific Corp) or phase array IVUS catheters (EagleEye®  Platinum Digital IVUS 
Catheter / Volcano Therapeutics) will be used to guide SYNERGY implantation. Use of either 
motorised or manual IVUS pullback will be allowed, although motorised pullback is 
recommended. 
 

 
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Both Boston and Volcano IVUS consoles have incorporated simplified software algorithms into 
their consoles to allow for the operator to undertake these calculations, and allow export of the 
data for post hoc analysis at a later stage. The following are the recommendations made on the 
grounds of evidence collected in the DES era:  
• Plaque preparation based on pre-procedural IVUS. Rotational atherectomy or cutting 
balloon should be considered if a >270° arc of superficial calcium is evident in IVUS.79 
Pre-procedural IVUS is left to the discretion of the investigator (not mandatory). 
• Selection of SYNERGY dimensions. Separate recommendations are given for selecting 
SYNERGY stent diameter in bifurcation and non-bifurcation stenoses.  
o In non-bifurcation stenoses: stent diameter matching distal vessel diameter or 
area (See table in Appendix IV). 
o In bifurcation stenoses: stent diameter matching distal (daughter) branch, with 
mandatory post-dilation of the proximal (mother) segment and polygon of 
confluence (POC) with a larger balloon size according to IVUS imaging. 
Regarding stent length, IVUS can be useful in outlining the presence of 
significant neighbour stenoses that might cause in-flow or out-flow narrowing 
after DES implantation, a very common finding in cases of DES thrombosis that 
is believed to be causative.  
o Incomplete stent expansion: See IVUS criteria Appendix IV. 
o Incomplete stent apposition. A non-compliant balloon sized with IVUS to vessel 
luminal diameter or area will be used in segments with malapposition (See table 
in Appendix IV) 
 
No analyses will be performed by the Core Laboratory. However, allowances will be made 
for export of IVUS data to Cardialysis, Rotterdam for potential post hoc analysis at later 
stage (academic research). 
The operator will record the numerical values of the IVUS targets in the eCRF. 
 
 
 

 
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7.6.4 Staged procedures 
 
Staged procedures are permitted, and will be encouraged for more complex cases – e.g. 
revascularization of total occlusions – to increase the likelihood of complete revascularization 
and to decrease the risk of contrast induced nephropathy. 
The recommended timing of a planned elective staged second PCI procedure is within 2 weeks 
post index procedure (with an upper limit allowed for 4 weeks in exceptional circumstances). 
The need for staging, and all specific lesions planned to be treated during the staged procedure 
should be captured beforehand in the eCRF. Staged procedures are only allowed in non-target 
vessels. Stented index segments or immediately adjacent segment(s), including adjacent branch 
segment(s) should not be manipulated again. The staged procedures will not affect the original 
follow-up schedule. Staged procedures should be performed in the exact same manner as the 
index procedure, including iRF/FFR, IVUS, medications, etc. 
 
7.7 
Concomitant Medications 
 
Optimal medical therapy will be mandated in all patients and will be assessed at clinical follow-
up visits.  
 
7.7.1 Anti-Platelet Medication 
 
Dual antiplatelet (aspirin + clopidogrel/ticagrelor/prasugrel) will be mandated for at least 6 
months, aspirin indefinitely. Ticagrelor therapy will be encouraged to be continued in patients 
already receiving this therapy, based on this regime having been shown to have the best safety to 
efficacy ratio.80, 81  
Loading dose: 
• All patients must receive aspirin ≥300 mg/day starting 12-24 hours prior to the procedure 
(even if the subject is on chronic aspirin therapy). 
• Clopidogrel loading dose must be 600 mg, starting 12-24 hours prior to the procedure 
(even if the subject is on chronic clopidogrel therapy). 

 
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On the rare occasion of a patient not receiving aspirin or clopidogrel as outlined above, the 
procedure is to be deferred until appropriate administration of antiplatelet therapy has been 
attained. Loading of antiplatelet therapy immediately prior to PCI should be discouraged, 
since lack of pre-procedural anti-platelet therapy was linked to creatine kinase (CK) cardiac 
enzyme rises >2 x upper limit of normal post PCI and adverse mortality in the SYNTAX 
Trial.28, 82 
Alternatively: 
• Prasugrel 60 mg >1 hr before PCI; or 
• Ticagrelor 180 mg >1 hr before PCI if approved by the local regulatory authorities during 
the enrolment period of this protocol. 
Maintenance dose: 
Starting from the day after the procedure, aspirin 75-100 mg per will be prescribed to all patients 
indefinitely. 
Additionally, all patients must receive platelet aggregation inhibition therapy for at least 6 
months as currently recommended by the ESC/AHA/ACC guidelines which includes: 
• Clopidogrel 75 mg once daily. 
Alternatively: 
• Prasugrel 10 mg once daily; or 
(The dose of prasugrel may be decreased to 5mg od in patients with a weight <60 kg or age >75 years).  
• Ticagrelor (90 mg bid) 
 
7.7.2 Other medication 
 
- Unless contraindicated, peri-procedural IIb/IIIa inhibitor will be given according to the 
guidelines.11-13  
- The use of other medications (e.g. beta-blockers, ACE inhibitors) should be given in 
accordance to the guidelines.11-13  
 

 
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7.7.3 PCI Statin therapy 
 
Optimal medical therapy with strict control of LDL (target of ≤1.8 mmol/l) is strongly 
recommended, along with optimization of all medical therapy – rosuvastatin/atorvastatin 
(according to the guidelines). Strict control of LDL levels is recommended  
aiming for a target of ≤1.8 mmol. 
Several randomized trials have demonstrated that high dose statin therapy decreases PCI-related 
myonecrosis in subjects undergoing stent implantation, whether or not the subject is already 
taking chronic statin therapy.83-87 Therefore, in the absence of absolute contraindications to statin 
use (e.g. severe allergy with prior use), one of the following statin regimens must be 
administered at least 12 hours (at least one dose) before the PCI, regardless of LDL level and 
history of prior statin use. 
• atorvastatin 80 mg daily 
• rosuvastatin 40 mg daily 
Risk Factor Modification 
Tight control of risk factors will be mandated in line with the European and US revascularisation 
guidelines.11-13 Cholesterol reduction, with a LDL ≤1.8, will be an additional protocol defined 
target the operator will be recommended to record and control.  
In summary, patients (de novo 3VD) will be treated according to ACC/AHA/ESC guidelines, i.e. 
Heart Team discussion (Ia); functional evaluation for diagnosis in absence of objective evidence 
of ischemia (Ia); and LDL levels ≤1.8mmol (Ia). 
 
 
7.8 
Hospital Discharge (post-PCI to hospital discharge) 
At discharge from the hospital where the index procedure took place, an assessment of the 
patient’s clinical status will be performed. Assessment of the cardiovascular drug use and any 
Serious Adverse Events will be recorded. An ECG will be performed and an anonymised copy of 
the ECG (showing patient ID and recording date) should be sent to the CRO. 
 
 

 
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7.9 
Follow-up Period 
 
7.9.1 Hospital visits at 1 month (± 7 days), 6 months (± 14 days) and 1 year (± 30 days) 
post-procedure 
 
An assessment of the angina status, cardiovascular drug use and any Serious Adverse Events 
will be recorded during clinical follow-up visits.  
An anonymised copy of the ECG (showing patient ID and recording date) should be sent to 
the CRO. 
 
7.9.2 Telephone contacts at 2 years (± 30 days), 3 years (± 30 days), 4 years (± 30 days) and 
5 years (± 30 days)  
 
During these telephone contacts information from the patient will be gathered on any Major 
Adverse Cardiac or Cerebrovascular Events (MACCE). Patients will also be asked for 
angina status and cardiovascular drug use. 
 
7.10 Withdrawal from the Study 
After entering into the study, the patients are asked to complete all scheduled follow-up visits. 
Patients will be exempt from follow-up only if they withdraw their consent. 
  
All subjects should be encouraged to remain in the study until he/she has completed the protocol 
requirements during the 5-year follow-up period.  
 
Possible reasons for premature discontinuation may include, but are not limited to, the following:  
• Withdrawal of consent: Patient decides to withdraw from the study. The decision must be an 
independent decision that is documented in the patient study files.  
• Physician discretion: The investigator may choose to withdraw a patient from the study if 
he/she considers follow-up too burdensome for the patient.  
• Lost to follow-up: All patients should be encouraged to return for all scheduled follow-up 
visits, and to provide appropriate contact information to accommodate completion of required 
telephone follow-ups. The investigator will attempt to contact the patient at each follow-up 

 
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visit, independent of any missed follow-ups. The investigator should make 3 documented 
attempts per required follow-up visit.  
 
Patients who have discontinued the trial prematurely will not be replaced.   

 
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8 
 STATISTICAL DESIGN AND ANALYSIS 
 
 
8.1 
Introduction 
 
This trial is a non-randomized single arm study that aims to perform a comparative analysis with 
historical controls. Patient recruitment in the current trial will be using the SYNTAX Score II, 
and the historical control will be with similarly selected patients from the randomised SYNTAX 
Trial.  
The analytical plan will be split into two sections: 
1. Descriptive statistical methodology: to describe the results of the current trial by itself.  
2. Comparative statistical methodology: to describe the comparison between the SYNERGYTM 
Everolimus Eluting Stent (EES) results of this trial and similar selected patients from the PCI 
and CABG cohorts of the randomised SYNTAX Trial. 
 
8.2 
Patient Selection  
 
Patients will be prospectively recruited in the current trial with the SYNTAX Score II.  Similarly 
selected subjects (using the SYNTAX Score II) will be undertaken from the PCI and CABG 
cohorts of the randomised SYNTAX Trial and will act as control groups for the current trial. 
The study populations of SYNTAX II and the de-novo 3-vessel disease patients of SYNTAX I 
will be ‘matched’ based on the SYNTAX Score II. During the recruitment of the SYNTAX II 
study it will be monitored whether the populations sufficiently overlap. 
No reference data for multivessel disease can be found in the published literature for the 
SYNERGY EES; thus the data is inferred from the Italian EXECUTIVE Pilot Trial (Ribichini et 
al)88 in which the XIENCE EES was compared to the Taxus Liberte (paclitaxel eluting stent 
[PES]) in multivessel coronary disease. In the current trial, EES will be compared to the selected 
PES arm (superiority) and the selected CABG arm (non inferiority) of the SYNTAX Trial. 
 

 
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8.3 
Assumptions for comparative analysis 
 
In the EXECUTIVE Trial, the PES arm had an event rate for MACE (major adverse cardiac 
events) at 1 year of 16.5%, and 11.1% for the EES arm. This implies a ratio of 11.1/16.5 i.e. 
0.67. 
We assume the same ratio as the margin of effect of the new device in the current trial. We 
assume the incidence of stroke will be low and unchanged in the current trial as compared to the 
SYNTAX Trial, therefore the outcome of major adverse cardiac and cerebrovascular events 
(MACCE) will be assessed in order to allow comparisons with the CABG arm. The incidence of 
MACCE at 1 year for the selected PES arm was 17.1%; assuming a ratio of 0.67, we estimate 
11.5% as the incidence of MACCE in the current trial. The incidence of MACCE at 1 year for 
the selected CABG arm was 10.8%. In our assumptions - as factor of benefit - we only 
considered the hazard ratio of Synergy vs. Taxus. We did not introduce reduction in the hazard 
ratio due to functional/IVUS assessment. 
 
SYNTAX II will not consider CABG as a separate arm and therefore we need to define the 
uncertainty margins in advance. The point estimate of 10.8% for the selected CABG arm is 
accompanied with a 95% confidence interval of 7.7-14.6% (Clopper-Pearson Exact Test). It is 
assumed that there have been minimal changes of CABG over the time since the recruitment of 
the SYNTAX Trial. 
 
8.4 
Sample size 
 
8.4.1 Superiority testing (PCI) for the primary endpoint 
 
A sample size of 416 patients will guarantee a power of 90% to show superiority of the EES arm 
of the current trial to the historical PES control group. The assumptions used are: 
1) a 5% 2-sided level of significance (alpha) 
2) a 11.5% MACCE rate at 360 days for the EES arm, compared to the historical control of 
17.1% in the selected patients from the PES arm of the SYNTAX Trial. 

 
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8.4.2 Non-inferiority testing (CABG) for the exploratory endpoint 
 
A sample size of 416 patients will guarantee a power of 80% to show non-inferiority of the EES 
arm of the current trial to the historical CABG control group. The assumptions used are: 
1) a 5% 1-sided level of significance (alpha) 
2) a 11.5% MACCE rate at 360 days for the EES arm, compared to the historical control of 
10.8% in the selected patients from the CABG arm of the SYNTAX Trial 
3) a non-inferiority margin of 5%, as was used in the SYNTAX Trial. 
8.4.3 Sample size justification 
 
For the comparison with the selected PCI arm a sample size of 450 patients is chosen to obtain a 
power of at least 90%. 
8.5 
Analytical plan 
 
The primary analysis will be based on the intention-to-treat principle. More details will be 
described in the statistical analysis plan. 
All statistical analyses will be done using the SAS System software, version 9.2 or above (SAS 
Institute Inc., SAS Campus Drive, Cary, North Carolina 27513, USA. All rights reserved). 
 
8.5.1 Descriptive statistical methodology 
 
Continuous variables will be presented using mean, standard deviation, median, minimum and 
maximum. Discrete variables will be presented in terms of frequencies and percentages. 
 
8.5.2 Comparative statistical methodology 
 
For the primary endpoint (MACCE at 360 days) the log rank test will be applied to compare the 
SYNTAX II with the historical control of the selected PCI arm. 
For the comparison to the selected CABG arm a 90% CI for the incidence of MACCE at 360 
days will be constructed. If the upper limit of 90% CI in the current trial is less than 15.8%, the 
SYNERGY EES will be declared non-inferior to the selected CABG arm. 

 
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For the current trial day 0 will be the day of patient allocation, i.e. the day of patient “signed off” 
by the Heart Team.  
8.6 
Validation of SYNTAX Score II 
 
Prospective validation of the SYNTAX Score II for all-cause death at 1, 2 and 5 year will be 
undertaken. 
 
 
 

 
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9 
SAFETY REPORTING 
 
The investigator will monitor the occurrence of Serious Adverse Events (SAEs) for each subject 
during the course of the study. For the purpose of this protocol, the reporting of SAEs begins 
directly after patient has signed Informed Consent.  
An SAE form should be completed within 24 hours of the investigator’s and study staff’s 
awareness of the event. 
 
9.1 
Serious Adverse Events (SAEs) Definitions 
An AE is defined as any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, 
whether or not related to the investigational medical device.  
 
An AE is classified as “serious” if the event: 
• 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. 
All SAEs will be followed until the event has been resolved (with or without sequelae). 
 
 
 
 
 

 
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9.2 
Anticipated Adverse Device Effects 
 
Anticipated adverse device effects for Synergy, IVUS, iFR/FFR procedures are described in the 
Instructions For Use (IFU).  
 
If the investigator observes device malfunctions that led or might have led to a death or serious 
deterioration in health of a patient, user or other person or has complaints with regard to defects 
in the medical devices, the investigator shall, within 24 hours of such observation, report such 
device malfunction or complaint to the device company. Company shall be responsible for 
handling all complaints and reported device malfunctions in respect of the quality of medical 
devices, for determining the measures to be taken due to such observations or complaints and for 
ensuring that all necessary actions are taken including, but not limited to, any necessary action in 
connection with the recall of the medical devices or the reporting of incidents to competent 
authorities if deemed appropriate by the Company. Discussions regarding such device 
malfunction or complaints will be held between the Company and the Participating Site. 
 
9.3 
Reporting to Ethics Committee (EC)  
Safety reporting to local ECs will be in accordance with the “guidelines on a medical device 
vigilance system” by the European Commission (MEDDEV2.12 rev 6, Dec 2009) and in 
compliance with local country law.  
 
If an event fulfils the criteria for SAE, then this shall be reported in the eCRF within 24 hours of 
the clinic study staff having become aware of this. At the time the event is reported in the eCRF, 
no event-supporting source documentation needs to be sent. Event supporting source documents 
will be requested by the sponsor (via monitoring organisation and/or CRO) for the purpose of 
clinical event adjudication. 
 
Clinical study staf must report device malfunctions directly to the manufacturer, who will then 
perform vigilance reporting to Competent Authorities, if applicable. 
 
. 

 
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All (S)AEs will be MedDRA coded by the Safety Group. This allows categorising them by body 
system, which facilitates their reporting as frequency counts to local ethics committees, as well 
as to the Data Safety Monitoring Board (DSMB). 
 
9.4 
Data Safety Monitoring Board (DSMB) 
Serious adverse events (events leading to serious disability or admission to hospital, life-
threatening events or death) will be periodically reviewed and analysed by an independent 
DSMB. Members of this board are not affiliated with any (interventional) cardiology site 
enrolling patients into the trial, are not participating in the trial, and will declare any conflicts of 
interest should they arise. 
 
The composition, guiding policies, and operating procedures governing the DSMB are described 
in a separate DSMB Charter. Based on safety data, the DSMB may recommend that the Steering 
Committee modify or stop the clinical trial. All final decisions regarding clinical 
trial/investigation modifications, however, rest with the Steering Committee.  
 
All analyses are carried out aiming to protecting the safety of the trial participants. If the data at 
hand suggests a substantial safety concern about the experimental treatment strategy, the DSMB 
will carefully balance the observed risk profile against possible signs of improved efficacy.  
 
 
 
 
 
 
 
 

 
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9.5 
Risk Analysis 
There is extensive clinical and commercial experience worldwide with cardiac catheterization 
and interventional procedures and it is expected that the procedural risks in this study and 
existing stenting procedure will not be significantly different. Known adverse events that may 
result from stent intervention (incorporating IVUS/FFR assessments) include but may not be 
limited to: 
• 
Allergic reaction or hypersensitivity to device material and its degredants (everolimus, 
platinum, chromium, poly-lactide-co-glycolide (PLGA)) 
• 
Shortness of breath/dyspnea 
• 
Distal embolism (air, tissue, or thrombotic) 
• 
Nausea/Vomiting 
• 
Coronary and stent thrombosis 
• 
Coronary and stent embolism 
• 
Coronary dissection 
• 
Total coronary occlusion 
• 
Abrupt coronary closure/threatened abrupt closure 
• 
Coronary injury 
• 
Coronary spasm 
• 
Coronary perforation 
• 
Coronary rupture 
• 
Pseudoaneurysm 
• 
Angina (stable or unstable) 
• 
Urgent or non-urgent coronary artery bypass graft surgery 
• 
Vascular complications including at the entry site which may require vessel repair and 
vessel dissection 
• 
Hematoma 
• 
Respiration cease 
• 
Hypertension 
• 
Death 

 
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• 
Bleeding 
• 
Bleeding complication (that may require transfusion) 
• 
Shock 
• 
Myocardial ischemia 
• 
Cardiac enzyme level elevation 
• 
Myocardial infarction 
• 
Cardiac tamponade 
• 
Cardiac arrest 
• 
ECG change 
• 
Heart failure 
• 
Renal failure 
• 
Stent implanted in unintended location 
• 
Restenosis of lesion/vessel treated with stent 
• 
Access site infection or pain 
• 
Access site hematoma or bleeding 
• 
Cerebral stroke/cerebral vascular accident (CVA) 
• 
Hypotension 
• 
Palpitation 
• 
Aneurysm 
• 
Arteriovenous fistula 
• 
Pulmonary edema 
• 
Fever 
• 
Arrhythmia (atrial or ventricular) 
• 
Peripheral ischemia (due to vascular injury) 
• 
Adverse reaction to drug (to everolimus, antiplatelets or contrast agent) 
 
 

 
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10 
QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 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.  
 
10.2 Data Recording 
It is the expectation of the Sponsor that all data entered into the eCRF has source documentation 
available at the clinical site. The site must implement processes to ensure this happens.   
 
10.3 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).  
 
A baseline monitoring visit will be scheduled when first patients have been enrolled and data 
have been entered into the eCRF. This serves to confirm the quality of site study execution and 
to discuss practicalities with the site study staff. During on-site monitoring, the Informed 
Consent Forms will be checked and a sample of clinical data will be verified against eCRF data. 
Subject confidentiality will be maintained at all time. Emphasis will be on the complete reporting 
by the study staff of SAEs as well as the availability of baseline angiograms, iFR, IVUS 
recordings and per protocol required 12-lead ECGs. 
 
Each clinical site will be visited several times during the study to ensure a high degree of data 
quality. These site monitoring visits will be conducted to verify that the data are authentic, 
accurate and complete, that the safety and rights of subjects are protected, that the study is 
conducted according to the protocol, and that any other study agreements, GCP and all 

 
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applicable regulatory requirements are met. The investigator and the head of the medical 
institution (where applicable) agree to allow the CRA direct access to all relevant documents. It 
is important that the investigator and the study staff are available during the monitoring visit and 
possible audits and that sufficient time is devoted to the process. Findings from the review and 
source documents will be discussed with the investigator. The number of monitoring visits will 
depend on Key Performance Indicators (KPI) derived from data management. 
 
Remote site monitoring will also be performed to ensure complete quality study data and patient 
adherence to the protocol. On a regular basis, the monitoring organisation will contact each site 
to discuss the progress of the study with respect to patient enrolment, timely attendance of 
patients to their follow-up visits and other relevant study aspects such as data query resolution.  
 
Each participating clinic will receive a close-out visit to resolve any outstanding issues and to 
perform the final source data verification. 
 
There will be regular teleconferences between the Sponsor and the monitoring organisation to 
discuss site management issues. 
 
10.4 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 
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, ECGs, 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. 
 

 
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10.5 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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11 
ORGANISATION  
11.1 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 18. 
 
11.2 Steering Committee 
The Steering Committee is responsible of the overall management of the study at the highest 
level. The Steering Committee is comprised of a Chairman, Deputy Study Chair, PIs, Co-PIs, 
ECRI). Their names, roles and responsibilities are described in a separate Steering Committee 
Charter. 
 
11.3 Clinical Event Committee (CEC) 
The composition, events to be adjudicated, the minimum amount of data required, and the 
algorithm followed in order to classify the events are described in a separate CEC Charter.  
 
11.4 Data Safety Monitoring Board (DSMB) 
The composition, guiding policies and operating procedures governing the DSMB are described 
in a separate DSMB Charter.  
 
11.5 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). 
 
11.6 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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11.7 Safety Reporting 
Sites are responsible for reporting of incidents, including device malfunctions, to the 
manufactures. Manufacturers are responsible for vigilance reporting of device malfunctions to 
competent authorities according to the “guidelines on medical devices vigilance system” by the 
European Commission (MEDDEV2.12 rev 6, Dec 2009). 
No expedited safety reporting is foreseen. 
The CRO Cardialysis (Cardialysis B.V., PO Box 2125, 3000 CC Rotterdam, The Netherlands) is 
responsible for event reporting to the EC/IRB  according to local  and national requirements. 
 
11.8 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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12 
DATA HANDLING AND RECORD KEEPING 
12.1 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; 
• Adverse events reported and their resolution, including supporting documents such as 
discharge summaries, cath lab reports, ECGs, lab results; 
• Study patient’s condition upon completion of or withdrawal from the study.  
 
12.2 Case Report Form Completion 
All required data will be accurately recorded by authorised personnel documented on the 
authorised signature log in the eCRF.  
 
12.3 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 

 
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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.  
 
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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13 
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 II trial is an investigator-initiated and scientifically driven study nested within the 
European Cardiovascular Research Institute (ECRI) and set up in collaboration with Boston 
Scientific and Volcano. All public presentations and manuscript generation and submissions will 
be led under the auspices of the Principal Investigators 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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14 
INVESTIGATOR RESPONSIBILITIES 
14.1 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.  
 
14.2 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 Principal Investigator and co-
investigators of the clinical site. These CVs should clearly show the investigator’s and co-
investigators’ 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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14.3 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.  
 
Serious Adverse Event (SAE) reports will be submitted to the EC/IRB as requested by the 
Sponsor, EC/IRB and/or local regulations. Annual and final reports will be provided to the 
EC/IRB as required.  
 
14.4 Informed Consent 
Study subjects must provide written informed consent using an EC/IRB-approved informed 
consent form. The study must be explained to the study subjects in lay language. The 
investigator, or representative, must be available to answer all of the study subject’s study-
related questions. Study subjects will be assured that they may withdraw from the study at any 
time for any reason and receive alternative conventional therapy as indicated.  
 

 
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14.5 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.  
 
14.6 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. The same procedure will be applied to 
Competent Authority where required.  
 
Site responsibilities for submitting data and reports:  
Type of CRF/Report  
Completed by Site Within  
Process  
Serious Adverse Event Notification 
eCRF (including death, MACE)  
24 hours  
Enter eCRF pages within 
24 hours of knowledge of 
event  
 
 
 
eCRF (Baseline, In-hospital summary, 
Follow-up, Patient Withdrawal)  
Ongoing basis  
Collected in the eCRF 
Angiographic Films, ECGs, IVUS and 
iFR/FFR recordings. 
MSCT scans (if applicable). 
Ongoing basis  
Collected by site and 
shipped to Core lab 
within 7 days  
Device malfunctions 
Ongoing basis 
Collected by site and 
provided to manufacturer 
Annual Reports  
Forward as requested by 
EC/IRB  
Copy  provided by 
Sponsor to be send to 
EC/IRB  
Final Report  
Forward within 3 months of 
study completion or 
termination  
Copy  provided by  
Sponsor to be send to 
EC/IRB  

 
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14.7 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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15 
SPONSOR RESPONSIBILITIES  
 
15.1 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 
competent 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 will select qualified investigators and 
facilities which have 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  
• Records of any Serious Adverse Events (SAEs) reported to the Sponsor during the clinical 
investigation  
• Any statistical analyses and underlying supporting data  
• Final report of the clinical investigation  
 
 
15.2 Supplemental Applications 
As appropriate, the Sponsor will submit changes to the study protocol to the investigators to 
obtain EC/IRB re-approval. 
 
15.3 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. 
 
15.4 Maintaining Records 
The Sponsor will maintain copies of correspondence, data,  SAEs 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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15.5 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.  
 
15.6 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 subjects’ 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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16 REFERENCES 
 
1. 
SYNTAX score calculator: www.syntaxscore.com. SYNTAX working-group. Launched 
19th May 2009. 
2. 
Sianos G, Morel MA, A.P. K, Morice MC, Colombo A, Dawkins K, van den Brand M, 
Dyck NV, Russell ME, Mohr FW, Serruys PW. (2005 ) The SYNTAX Score: an angiographic 
tool grading the complexity of coronary artery disease. EuroIntervention. 
3. 
Ong AT, Serruys PW, Mohr FW, Morice MC, Kappetein AP, Holmes DR, Jr., Mack MJ, 
van den Brand M, Morel MA, van Es GA, Kleijne J, Koglin J, Russell ME. The SYNergy 
between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) study: 
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4. 
Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Stahle E, 
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Serruys PW, Onuma Y, Garg S, Sarno G, van den Brand M, Kappetein AP, Van Dyck N, 
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Es GA, Morel MA, Mohr FW. Assessment of the SYNTAX score in the Syntax study. 
EuroIntervention 2009;5(1):50-6. 
6. 
Morice MC, Serruys PW, Kappetein AP, Feldman TE, Stahle E, Colombo A, Mack MJ, 
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with de novo left main disease treated with either percutaneous coronary intervention using 
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Kappetein AP, Feldman TE, Mack MJ, Morice MC, Holmes DR, Stahle E, Dawkins KD, 
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stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the 
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Head SJ, Farooq V, Serruys PW, Kappetein AP. The SYNTAX score and its clinical 
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Mukherjee D, Nallamothu BK, Ting HH. 2011 ACCF/AHA/SCAI Guideline for Percutaneous 
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Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, Cigarroa JE, Disesa 
VJ, Hiratzka LF, Hutter AM, Jr., Jessen ME, Keeley EC, Lahey SJ, Lange RA, London MJ, 
Mack MJ, Patel MR, Puskas JD, Sabik JF, Selnes O, Shahian DM, Trost JC, Winniford MD. 
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American College of Cardiology Foundation/American Heart Association Task Force on 
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Coll Cardiol 2011;58(24):e123-210. 
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Clayton TC, Danchin N, Flather M, Hamm CW, Hueb WA, K‰hler J, Kelsey SF, King SB, 
Kosinski AS, Lopes N, McDonald KM, Rodriguez A, Serruys P, Sigwart U, Stables RH, Owens 
DK, Pocock SJ. Coronary artery bypass surgery compared with percutaneous coronary 
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Hoffman SN, TenBrook JA, Wolf MP, Pauker SG, Salem DN, Wong JB. A meta-
analysis of randomized controlled trials comparing coronary artery bypass graft with 
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Farooq V, Serruys PW. "Cherry-picking" patients for randomized, controlled trials-
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Farkouh ME, Dangas G, Leon MB, Smith C, Nesto R, Buse JB, Cohen DJ, Mahoney E, 
Sleeper L, King S, 3rd, Domanski M, McKinlay S, Fuster V. Design of the Future 
REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of 
Multivessel disease (FREEDOM) Trial. Am Heart J 2008;155(2):215-23. 
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Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, Yang M, Cohen 
DJ, Rosenberg Y, Solomon SD, Desai AS, Gersh BJ, Magnuson EA, Lansky A, Boineau R, 
Weinberger J, Ramanathan K, Sousa JE, Rankin J, Bhargava B, Buse J, Hueb W, Smith CR, 
Muratov V, Bansilal S, King S, 3rd, Bertrand M, Fuster V. Strategies for multivessel 
revascularization in patients with diabetes. N Engl J Med 2012;367(25):2375-84. 
20. 
Serruys PW, Farooq V. Revascularization strategies in patients with diabetes. N Engl J 
Med 2013;368(15):1454-5. 
21. 
Banning AP, Westaby S, Morice MC, Kappetein AP, Mohr FW, Berti S, Glauber M, 
Kellett MA, Kramer RS, Leadley K, Dawkins KD, Serruys PW. Diabetic and nondiabetic 
patients with left main and/or 3-vessel coronary artery disease: comparison of outcomes with 
cardiac surgery and paclitaxel-eluting stents. Journal of the American College of Cardiology 
2010;55(11):1067-75. 
22. 
Kappetein AP, Head SJ, Morice MC, Banning AP, Serruys PW, Mohr FW, Dawkins KD, 
Mack MJ. Treatment of complex coronary artery disease in patients with diabetes: 5-year results 

 
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comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX 
trial. Eur J Cardiothorac Surg 2013;43(5):1006-13. 
23. 
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Serruys PW, Farooq V, Vranckx P, Girasis C, Brugaletta S, Garcia-Garcia HM, Holmes 
DR, Jr., Kappetein AP, Mack MJ, Feldman T, Morice MC, Stahle E, James S, Colombo A, 
Pereda P, Huang J, Morel MA, Van Es GA, Dawkins KD, Mohr FW, Steyerberg EW. A global 
risk approach to identify patients with left main or 3-vessel disease who could safely and 
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Farooq V, Vergouwe Y, Raber L, Vranckx P, Garcia-Garcia H, Diletti R, Kappetein AP, 
Morel MA, de Vries T, Swart M, Valgimigli M, Dawkins KD, Windecker S, Steyerberg EW, 
Serruys PW. Combined anatomical and clinical factors for the long-term risk stratification of 
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Farooq V, van Klaveren D, Steyerberg EW, Meliga E, Vergouwe Y, Chieffo A, 
Kappetein AP, Colombo A, Holmes DR, Jr., Mack M, Feldman T, Morice MC, Stahle E, Onuma 
Y, Morel MA, Garcia-Garcia HM, van Es GA, Dawkins KD, Mohr FW, Serruys PW. 
Anatomical and clinical characteristics to guide decision making between coronary artery bypass 
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validation of SYNTAX score II. Lancet 2013;381(9867):639-50. 
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Farooq V, van Klaveren D, Steyerberg EW, Serruys PW. SYNTAX score II - Authors' 
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28. 
Farooq V, Serruys PW, Bourantas C, Vranckx P, Diletti R, Garcia Garcia HM, Holmes 
DR, Kappetein AP, Mack M, Feldman T, Morice MC, Colombo A, Morel MA, de Vries T, van 
Es GA, Steyerberg EW, Dawkins KD, Mohr FW, James S, Stahle E. Incidence and multivariable 
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revascularization in the synergy between percutaneous coronary intervention with taxus and 
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Margey R, Agnihotri A, Marra S, Capodanno D, Leon MB, Moses JW, Fajadet J, Lefevre T, 
Morice MC, Erglis A, Tamburino C, Alfieri O, Serruys PW, Colombo A. Drug-Eluting Stent for 
Left Main Coronary Artery Disease: The DELTA Registry: A Multicenter Registry Evaluating 
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Tonelli M, Muntner P, Lloyd A, Manns BJ, Klarenbach S, Pannu N, James MT, 
Hemmelgarn BR. Risk of coronary events in people with chronic kidney disease compared with 
those with diabetes: a population-level cohort study. Lancet 2012;380(9844):807-14. 

 
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32. 
Farooq V, Serruys PW, Garcia-Garcia HM, Zhang Y, Bourantas CV, Holmes DR, Mack 
M, Feldman T, Morice MC, Stahle E, James S, Colombo A, Diletti R, Papafaklis MI, de Vries T, 
Morel MA, van Es GA, Mohr FW, Dawkins KD, Kappetein AP, Sianos G, Boersma E. The 
negative impact of incomplete angiographic revascularization on clinical outcomes and its 
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Head SJ, Mack MJ, Holmes DR, Jr., Mohr FW, Morice MC, Serruys PW, Kappetein AP. 
Incidence, predictors and outcomes of incomplete revascularization after percutaneous coronary 
intervention and coronary artery bypass grafting: a subgroup analysis of 3-year SYNTAX data. 
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34. 
Thompson CA, Jayne JE, Robb JF, Friedman BJ, Kaplan AV, Hettleman BD, Niles NW, 
Lombardi WL. Retrograde techniques and the impact of operator volume on percutaneous 
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Whitlow PL, Burke MN, Lombardi WL, Wyman RM, Moses JW, Brilakis ES, Heuser 
RR, Rihal CS, Lansky AJ, Thompson CA. Use of a novel crossing and re-entry system in 
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FAST-CTOs (Facilitated Antegrade Steering Technique in Chronic Total Occlusions) trial. 
JACC Cardiovasc Interv 2012;5(4):393-401. 
36. 
Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, Maccarthy 
PA, Van't Veer M, Pijls NH. Angiographic versus functional severity of coronary artery stenoses 
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of the American College of Cardiology 2010;55(25):2816-21. 
37. 
Pijls NH, Fearon WF, Tonino PA, Siebert U, Ikeno F, Bornschein B, van't Veer M, 
Klauss V, Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, De Bruyne B. 
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):177-84. 
38. 
De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, Jagic N, Mobius-
Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engstrom T, Oldroyd KG, Mavromatis K, 
Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Juni P, Fearon WF. Fractional flow 
reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 
2012;367(11):991-1001. 
39. 
Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V, 
Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF. Fractional 
flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 
2009;360(3):213-24. 
40. 
Nam CW, Mangiacapra F, Entjes R, Chung IS, Sels JW, Tonino PA, De Bruyne B, Pijls 
NH, Fearon WF. Functional SYNTAX score for risk assessment in multivessel coronary artery 
disease. J Am Coll Cardiol 2011;58(12):1211-8. 
41. 
Sen S, Escaned J, Malik IS, Mikhail GW, Foale RA, Mila R, Tarkin J, Petraco R, Broyd 
C, Jabbour R, Sethi A, Baker CS, Bellamy M, Al-Bustami M, Hackett D, Khan M, Lefroy D, 
Parker KH, Hughes AD, Francis DP, Di Mario C, Mayet J, Davies JE. Development and 
validation of a new adenosine-independent index of stenosis severity from coronary wave-

 
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intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis 
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Takkenberg JJ, Kappetein AP, Steyerberg EW. The role of EuroSCORE II in 21st 
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Gimple L, Watson DD, Beller GA, Barringhaus KG. Fractional flow reserve of infarct-related 
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Leesar MA, Abdul-Baki T, Akkus NI, Sharma A, Kannan T, Bolli R. Use of fractional 
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66. 
Ntalianis A, Sels JW, Davidavicius G, Tanaka N, Muller O, Trana C, Barbato E, Hamilos 
M, Mangiacapra F, Heyndrickx GR, Wijns W, Pijls NH, De Bruyne B. Fractional flow reserve 
for the assessment of nonculprit coronary artery stenoses in patients with acute myocardial 
infarction. JACC Cardiovasc Interv 2010;3(12):1274-81. 
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Petraco R, Park JJ, Sen S, Nijjer SS, Malik IS, Echavarria-Pinto M, Asrress KN, Nam 
CW, Macias E, Foale RA, Sethi A, Mikhail GW, Kaprielian R, Baker CS, Lefroy D, Bellamy M, 
Al-Bustami M, Khan MA, Gonzalo N, Hughes AD, Francis DP, Mayet J, Di Mario C, Redwood 

 
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S, Escaned J, Koo BK, Davies JE. Hybrid iFR-FFR decision-making strategy: implications for 
enhancing universal adoption of physiology-guided coronary revascularisation. EuroIntervention 
2013;8(10):1157-65. 
68. 
Rao SV, Cohen MG, Kandzari DE, Bertrand OF, Gilchrist IC. The transradial approach 
to percutaneous coronary intervention: historical perspective, current concepts, and future 
directions. J Am Coll Cardiol 2010;55(20):2187-95. 
69. 
Hildick-Smith D, Lassen JF, Albiero R, Lefevre T, Darremont O, Pan M, Ferenc M, 
Stankovic G, Louvard Y. Consensus from the 5th European Bifurcation Club meeting. 
EuroIntervention 2010;6(1):34-8. 
70. 
Stankovic G, Lefevre T, Chieffo A, Hildick-Smith D, Lassen JF, Pan M, Darremont O, 
Albiero R, Ferenc M, Finet G, Adriaenssens T, Koo BK, Burzotta F, Louvard Y. Consensus from 
the 7th European Bifurcation Club meeting. EuroIntervention 2013;9(1):36-45. 
71. 
Werner GS, Schofer J, Sievert H, Kugler C, Reifart NJ. Multicentre experience with the 
BridgePoint devices to facilitate recanalisation of chronic total coronary occlusions through 
controlled subintimal re-entry. EuroIntervention 2011;7(2):192-200. 
72. 
Baks T, van Geuns RJ, Duncker DJ, Cademartiri F, Mollet NR, Krestin GP, Serruys PW, 
de Feyter PJ. Prediction of left ventricular function after drug-eluting stent implantation for 
chronic total coronary occlusions. Journal of the American College of Cardiology 
2006;47(4):721-5. 
73. 
Kwon DH, Hachamovitch R, Popovic ZB, Starling RC, Desai MY, Flamm SD, Lytle BW, 
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revascularization versus medical therapy: association with end-systolic volume and viability. 
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74. 
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Vancraeynest D, Pasquet A, Vanoverschelde JL. Prognostic value of myocardial viability by 
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75. 
Camici PG, Wijns W, Borgers M, De Silva R, Ferrari R, Knuuti J, Lammertsma AA, 
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76. 
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77. 
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78. 
Galassi AR, Tomasello SD, Crea F, Costanzo L, Campisano MB, Marza F, Tamburino C. 
Transient impairment of vasomotion function after successful chronic total occlusion 
recanalization. J Am Coll Cardiol 2012;59(8):711-8. 
79. 
Mosseri M, Satler LF, Pichard AD, Waksman R. Impact of vessel calcification on 
outcomes after coronary stenting. Cardiovasc Revasc Med 2005;6(4):147-53. 

 
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80. 
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, 
Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, 
Harrington RA, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute 
coronary syndromes. N Engl J Med 2009;361(11):1045-57. 
81. 
Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, 
Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF. 
Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of 
ticagrelor versus clopidogrel in patients with stable coronary artery disease: the 
ONSET/OFFSET study. Circulation 2009;120(25):2577-85. 
82. 
Farooq V, Serruys PW, Holmes DR, Kappetein AP, Mack M, Feldman T, Dawkins KD, 
Mohr FW, James S, Ståhle E. Abstract: The long term (4-year) prognostic significance of 
abnormal cardiac enzyme rises in patients treated with surgical or percutaneous 
revascularisation: a substudy from the SYNTAX Trial. Presented at: Congress of the European-
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Journal 2012;33(suppl 1):500. 
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Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G. Randomized trial of 
atorvastatin for reduction of myocardial damage during coronary intervention: results from the 
ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study. 
Circulation 2004;110(6):674-8. 
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Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, Montinaro A, Di 
Sciascio G. Atorvastatin pretreatment improves outcomes in patients with acute coronary 
syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS 
randomized trial. J Am Coll Cardiol 2007;49(12):1272-8. 
85. 
Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A. Efficacy of 
atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary 
intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial 
Damage During Angioplasty) Randomized Trial. J Am Coll Cardiol 2009;54(6):558-65. 
86. 
Briguori C, Visconti G, Focaccio A, Golia B, Chieffo A, Castelli A, Mussardo M, 
Montorfano M, Ricciardelli B, Colombo A. Novel approaches for preventing or limiting events 
(Naples) II trial: impact of a single high loading dose of atorvastatin on periprocedural 
myocardial infarction. J Am Coll Cardiol 2009;54(23):2157-63. 
87. 
Briguori C, Colombo A, Airoldi F, Violante A, Focaccio A, Balestrieri P, Paolo Elia P, 
Golia B, Lepore S, Riviezzo G, Scarpato P, Librera M, Bonizzoni E, Ricciardelli B. Statin 
administration before percutaneous coronary intervention: impact on periprocedural myocardial 
infarction. Eur Heart J 2004;25(20):1822-8. 
88. 
Ribichini I, Romano M, Rosiello R, Vecchia LL, Cabianca E, Caramanno G, Milazzo D, 
Loschiavo P, Rigattieri S, Musarò S, Pironi B, Fiscella A, Amico F, Indolfi C, Spaccarotella C, 
Bartorelli A, Trabattoni D, Rovere FD, Rolandi A, Beqaraj F, Belli R, Sangiorgio P, Villani R, 
Berni A, Sheiban I, Quijada MJL, Cappi B, Ribaldi L, Vassanelli C. A Clinical and 
Angiographic Study of the XIENCE V Everolimus Eluting Coronary Stent System in the 
Treatment of Patients with Multi-Vessel Coronary Artery Disease. The EXECUTIVE Trial. 
JACC Interventions (In Press) 2013. 
89. 
Serruys PW, Unger F, Sousa JE, Jatene A, Bonnier HJ, Schonberger JP, Buller N, Bonser 
R, van den Brand MJ, van Herwerden LA, Morel MA, van Hout BA. Comparison of coronary-

 
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artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 
2001;344(15):1117-24. 
90. 
de Jaegere P, Mudra H, Figulla H, Almagor Y, Doucet S, Penn I, Colombo A, Hamm C, 
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Hausmann D, Rowe S, Rabinovich S, Sunamura M, van Es GA. Intravascular ultrasound-guided 
optimized stent deployment. Immediate and 6 months clinical and angiographic results from the 
Multicenter Ultrasound Stenting in Coronaries Study (MUSIC Study). Eur Heart J 
1998;19(8):1214-23. 
 
 

 
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17 APPENDIX I: SCHEDULE OF EVENTS 
 
Event 
Screen 
Procedure 
Post -
Procedure 
to Hospital 
D/c 
1 Mo 
±7 days 
6 Mo 
±14 days
1 Yrs 
±30 days
2-5Yrs 
±30 days
Type of contact 
 
 
 
Visit 
Visit 
Visit 
Phone 
Local Heart Team 
conference 
- Inclusion/ 
exclusion Criteria  
-  SYNTAX Score II  
- EuroSCORE 
- EuroSCORE II 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
Medical and Cardiac 
history 
X 
 
 
 
 
 
 
Anginal Status 
X 
 
X 
X 
X 
X 
X 
1CBC, blood 
chemistry, lipids 
X 
 
 
 
 
 
 
CK-MB  
X2 
 
X3 
 
 
 
 
Troponin 
X2 
 
X3 
 
 
 
 
12 lead ECG7 
X4 
 
X5 
X 
X 
X 
 
Medication regimen 
X 
X 
X 
X 
X 
X 
X 
Angiography6, 7 
 
X 
 
 
 
 
 
IVUS7 
 
X 
 
 
 
 
 
FFR/(iFR)7 
 
X 
 
 
 
 
 
MSCT7 
X 
 
 
 
 
 
 
Serious Adverse Event 
monitoring 
 
X 
X 
X 
X 
X 
X 
1 within 7 days prior to procedure 
2 CK-MB/Troponin is drawn at least 24 hours prior to PCI. 
3 CK-MB/Troponin is determined pre-discharge or within 48 hours whatever comes first 
4  ECG at time of screening should be at least 24 hours prior to PCI 
5  within 24 hours post-procedure or at discharge, whichever comes first 

 
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6  In 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. 
7  Collect and forward to central Core Lab (material collection only).  
 
 
 

 
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18 APPENDIX II: PROPORTION OF 3VD PATIENTS SUITABLE FOR PCI 
 
 
Mortality predictions for CABG versus PCI for each individual patient in the randomised 
SYNTAX trial (n=1800). Scatter plots illustrating mortality predictions for the left main (upper 
panel) and 3VD (lower panel) cohorts separated by conventional tertiles of the SYNTAX Score. 
The diagonal line represents identical mortality predictions for CABG and PCI. Individual 
predictions plotted to the left of the diagonal line favour CABG (actual percentages shown in top 
left corner), and to the right favour PCI (actual percentages shown in bottom right corner). 
Individual mortality predictions for CABG or PCI that could be separated with 95% confidence 
(p<0·05) are coloured black (actual percentage shown in parentheses in respective corners). 
Mortality predictions that could not be separated with 95% confidence (p>0·05) are highlighted 
in grey, and identify patients with similar 4-year mortality. Percentages of patients in each 
category are shown. CABG=coronary artery bypass surgery. PCI=percutaneous coronary 
intervention. LMS=left main stem. 3VD=three-vessel disease. Adapted and reproduced from 
Farooq et al.26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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19 APPENDIX III: 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).1 
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,54 long-term use of bronchodilators or steroids for 
lung disease. PVD defined according to ARTS I definition,89 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.26 
 
 
 
 

 
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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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20 APPENDIX IV: IVUS CRITERIA 
 
IVUS Criteria (Modified MUSIC Criteria90): for evaluation of appropriate stent apposition: 
1). Complete apposition against the vessel wall of the entire stent AND 
2). 
a) ≥90% of the average reference lumen area or ≥100% of lumen area of the 
 
reference segment with the lowest lumen area; or 
 
b) MLA >between 5.5 mm2; or 
 
c) MLA ≥80% of the average reference lumen area or ≥90% of lumen area of the 
 
reference segment with the lowest lumen area. AND 
3). Symmetric stent expansion. 
 
ISA
No
ISA
Yes
Symmetry >0.7-No
Symmetry >0.7-Yes
LD 
min
LD 
max
LD 
min
LD 
max
LD 
min
LD 
max
LD 
min
LD 
max
Malapposition area
Malapposition area
Reference
Reference
Reference
Reference
Reference
Reference
Reference
Reference
A
C
B
D
Figure: Stent Symmetry, Expansion and Apposition
ISA: Incomplete Stent Apposition
 
 
 

 
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A. Symmetry check: LD min/LD max is close to 1, thus is symmetric; Expansion check: The 
minimum lumen area within the stent should be compared to that of the reference 
segments; Apposition check: there is a space behind the struts, thus the stent is not lying 
on the vessel luminal wall and therefore is not well apposed. We recommend 
postdilation, preferably with a non compliant balloon according the inflation chart. 
B. Symmetry check: LD min/LD max is far from 1, thus is asymmetric. We recommend 
postdilation preferably with a non compliant balloon according the inflation chart; 
Expansion check: The minimum lumen area within the stent should be compared to that 
of the reference segments; Apposition check: there is a space behind the struts, thus the 
stent is not lying on the vessel luminal wall and therefore is not well apposed. We 
recommend postdilation, preferably with a non compliant balloon according the 
inflation chart.  
C. Symmetry check: LD min/LD max is 1, thus is symmetric; Expansion check: The 
minimum lumen area within the stent should be compared to that of the reference 
segments; Apposition check: there is NO space behind the struts, thus the stent is lying on 
the vessel luminal wall and therefore is well apposed and therefore no extra actions are 
needed. 
D. Symmetry check: LD min/LD max is far from 1, thus is asymmetric. We recommend 
postdilation, preferably with a non compliant balloon according the inflation chart.; 
Expansion check: The minimum lumen area within the stent should be compared to that 
of the reference segments; Apposition check: there is NO space behind the struts, thus the 
stent is lying on the vessel luminal wall and therefore is well apposed and therefore no 
extra actions are needed.  
 
 
 

 
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21 APPENDIX V: BIFURCATION MANAGEMENT CRITERIA 
 
Principals - consistent with European Bifurcation club 
1) Provisional T is preferred strategy 
2) 2 wires from the outset are recommended when branch is of sufficient size for the 
lesion to be considered a bifurcation and it has some disease 
3) Probable 2 stents (operators choice of technique) when disease is in a suitably sized 
side branch and branch disease extends >5mm  
4) When 2 stents are used kissing balloon post dilatation is mandatory at completion 
5) When  1 stent used-  kissing balloon post dilatation is not mandatory at completion 
6) Large side branch with proximal disease and very challenging access should be 
stented once accessed - (no iFR/FFR required of branch before treatment) - these are 
exceptional cases. 
 
Performance/technique- pre stent 
7) Plan to perform iFR/FFR to main vessel prior to PCI – mandatory  
8) When performing elective 2 stents strategy-  iFR/FFR to main vessel prior to PCI – 
mandatory and branch iFR/FFR at operators discretion 
9) Plan to perform provisional approach and branch appears diseased and may require 
stenting – iFR/FFR of branch recommended 
10) In 0,0,1 lesion iFR/FFR of main vessel mandatory and branch recommended  
 
Performance/technique- post stent 
11) Post stent deployment in main vessel iFR/FFR recommended of main vessel  
12) Post stent deployment in main vessel – treatment of branch vessel 
a. Normal flow in branch with discrete pinched ostium – operators discretion 
either leave it or iFR/FFR prior to stenting – mandatory 
b. Reduced flow / dissection in significant branch - bail out strategy at operators 
discretion- can do  iFR/FFR at completion at operators discretion. If 2 stents 
placed final kissing is mandatory. 
 
 
Angiographically 1,1,0 LAD D1 bifurcation 
iFR/FFR of the LAD confirms need for stent  
stent placed, discrete ostial pinch of D1 but normal flow 
iFR/FFR mandatory if further stent to D1 considered 
iFR/FFR of LAD at completion 
 
Angiographically 1,1,0 LAD D1 bifurcation 
iFR/FFR of the LAD confirms need for stent  
LAD stent placed , but TIMI II flow in D1 
wire with any wire chosen by operator and proceed as per usual practice including additional 
stent if considered necessary  
iFR/FFR of LAD at completion and D1 if possible 
 

 
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Angiographically 1,0,1 LAD D1 bifurcation 
iFR/FFR of the LAD confirms need for stent  
unable to comment on D1 ostium in presence of proximal stenosis using iFR/FFR 
if disease >5mm in D1- 2 stent strategy of operators choice with kissing to complete procedure 
if disease <5mm in D1- stent LAD and then iFR/FFR of D1 is further stent considered 
iFR/FFR of LAD at completion 
 
Angiographically 0,0,1 LAD D1 bifurcation 
iFR/FFR of the LAD confirms no requirement for LAD stent  
iFR/FFR of the D1 confirms requirement for stent (unusual)  
stent strategy of operators choice 
iFR/FFR of LAD and D1 at completion 
 
Angiographically 0, 1, 0  LAD D1 bifurcation 
iFR/FFR of the LAD confirms requirement for LAD stent  
stent to LAD – will usually cover bifurcation 
stent strategy of operators choice 
discrete ostial pinch of D1 but normal flow iFR/FFR mandatory if further stent to D1 considered 
iFR/FFR of LAD and ideally D1 at completion 
 
 
 
 
 
 
 
 
 
 
 

 
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22 APPENDIX VI: DEFINITIONS 
 
 
I. According to SYNTAX I Trial, MACCE is defined as: 
 
• All cause death 
• Cerebrovascular event (stroke) 
• Documented myocardial infarction 
• Repeat revascularization (PCI and/or CABG). 
 
DEATH 
All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. 
Cardiac Death: any death due to immediate cardiac causes (e.g. MI, low-output failure, fatal 
arrhythmia). Unwitnessed death and death of unknown cause will be classified as cardiac death. 
Vascular Cause death: death due to cerebrovascular disease, pulmonary embolism, ruptured 
aortic aneurysm, dissecting aneurysm, or other vascular cause. 
Non-Cardiovascular death: any death not covered by the above definitions, including death due 
to infection, sepsis, pulmonary causes, accident, suicide or trauma. 
 
STROKE 
A focal neurological deficit of central origin lasting more than 72 hours and results in 
irreversible brain damage or permanent body impairment. Type and severity of symptoms is 
dependent on the location and extent of brain tissue whose circulation has been involved. Strokes 
will be further classified as ischemic or hemorrhagic based on imaging studies. When blood flow 
to the brain is interrupted because of rupture of a vessel causing bleeding into or around the brain, 
it is considered hemorrhagic. When a vessel that supplies the brain is blocked, the event is 
considered ischemic. 
 
 
 
 

 
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MYOCARDIAL INFARCTION 
A myocardial infarction will be considered whether it occurred spontaneously or in association 
with angioplasty or coronary bypass graft surgery procedures. A definite diagnosis of myocardial 
infarction is made: 
 
Definition I: Within the first 7 days post intervention: 
New Q-waves (*) and one plasma level of CKMB 5x upper limit for normal. 
 
Definition II: At least 7 days after any intervention procedure: 
Either a. New Q-waves (*) 
Or one plasma level of CKMB 5x upper limit for normal  
 
(*) development of new abnormal Q-waves not present on the patient’s baseline (i.e. before 
allocation) ECG. The Minnesota Code for pathological Q-waves will be used. 
(*) In cases of ECG diagnosis of MI in the presence of a complete left bundle branch block, peak 
CKMB levels should be obtained locally. 
 
TLR 
Target Lesion Revascularization is defined as any ischemia-driven repeat percutaneous 
intervention of the target lesion or bypass surgery of the target vessel due to any of the 
following: 
1. the patient had a positive functional study corresponding to the area served by the target lesion. 
2. ischemic ECG changes at rest in a distribution consistent with the target vessel 
3. ischemic symptoms referable to the target lesion. 
 
TVR 
Target Vessel Revascularization is defined as any ischemia-driven repeat percutaneous 
intervention of the target vessel or bypass surgery of the target vessel due to any of the 
following: 
1. the patient had a positive functional study corresponding to the area served by the target vessel 
2. ischemic ECG changes at rest in a distribution consistent with the target vessel 
3. ischemic symptoms referable to the target lesion. 

 
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II. 
Contemporary definitions 
 
Death (Per ARC Circulation 2007; 115: 2344-2351) 
 
The deaths will be adjudicated per the ARC definition. All deaths are considered cardiac unless 
an unequivocal non-cardiac cause can be established. Specifically, any unexpected death even in 
patients with coexisting potentially fatal non-cardiac disease (e.g. cancer, infection) should be 
classified as cardiac.  
 
• Cardiac death: 
Any death due to proximate cardiac cause (e.g. MI, low-output failure, fatal arrhythmia), 
unwitnessed death and death of unknown cause, all study procedure related deaths including 
those related to concomitant treatment. 
 
• Vascular death: 
Death due to non-coronary vascular causes such as cerebrovascular disease, pulmonary 
embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular cause. 
   
• Non-cardiovascular death: 
Any death not covered by the above definitions such as death caused by infection, 
malignancy, sepsis, pulmonary causes, accident, suicide or trauma. 
 
Stroke 
1. Duration of a focal/global neurological deficit  ≥24 hours or<24 hours if any of the 
following conditions exist: 
i. 
at least one of the following therapeutic interventions: 
a. Pharmacologic (i.e., thrombolytic drug administration) 
b. Non-pharmacologic (i.e., neurointerventional procedure such as 
intracranial angioplasty) 
ii. 
Available brain imaging clearly documents a new hemorrhage or infarct 
iii. 
The neurological deficit results in death 
2. No other readily identifiable non-stroke cause for the clinical presentation (e.g., brain 
tumor, trauma, infection, hypoglycemia, other metabolic abnormality, peripheral 
lesion, or drug side effect). Patients with non-focal global encephalopathy will not be 
reported as a stroke without unequivocal evidence based upon neuroimaging studies. 
3. Confirmation of the diagnosis by a neurology or neurosurgical specialist and at least 
one of the following: 
a. Brain imaging procedure (at least one of the following): 
i. 
CT scan 
ii. 
MRI scan 
iii. 
Cerebral vessel angiography 
b. Lumbar puncture (i.e. spinal fluid analysis diagnostic of intracranial hemorrhage) 

 
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A. If the acute focal signs represent a worsening of a previous deficit, these signs must have 
either 
1. Persisted for more than one week, or 
2. Persisted for more than 24 hours and were accompanied by an appropriate new CT or 
MRI finding 
B. Strokes may be sub-classified as follows:  
1. Ischemic (Non-hemorrhagic):  a stroke caused by an arterial obstruction due to 
either a thrombotic (e.g., large vessel disease/atherosclerotic or small vessel 
disease/lacunar) or embolic etiology. 
2. Hemorrhagic:  a stroke due to a hemorrhage in the brain as documented by 
neuroimaging or autopsy.  This category will include strokes due to primary 
intracerebral hemorrhage (intraparenchymal or intraventricular), ischemic strokes 
with hemorrhagic transformation (i.e., no evidence of hemorrhage on an initial 
imaging study but appearance on a subsequent scan), subdural hematoma,* and 
primary subarachnoid hemorrhage. 
*All subdural hematomas that develop during the clinical trial should be recorded 
and classified as either traumatic versus nontraumatic. 
3. Unknown:  the stroke type could not be determined by imaging or other means (e.g., 
lumbar puncture, neurosurgery, or autopsy) or no imaging was performed. 
C. Stroke Disability 
All strokes with stroke disability of Modified Rankin Scale (mRS) ≥1 will be included 
in the primary endpoint. All diagnosed strokes (even with mRS 0) will also be tabulated. 
Stroke disability will be classified using an adaptation of the modified Rankin Scale.  
 Scale 
Disability 
0 
No stroke symptoms at all.  (May have other complaints) 
1 
No significant disability; symptoms present but no physical or other limitations. 
2 
Slight disability;  limitations in participation in usual social roles, but 
independent for activities of daily living (ADL) 
3 
some need for assistance but able to walk without assistance 
4 
Moderately severe disability; need for assistance with some basic ADL, but not 
requiring constant care  
5 
Severe disability requiring constant nursing care and attention. 
 
 
Stroke: Modified Rankin score  ≥1 and increase by ≥1 from baseline 
D. Transient Ischemic Attack (as compared to stroke) is defined as: 
• New focal neurologic deficit with rapid symptom resolution, usually 1-2 hours, 
always within 24 hours 
• Neuroimaging without tissue injury 

 
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Myocardial Infarction 
 
New Universal Definition 2012 
 
Type 1: Spontaneous myocardial infarction 
Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, 
erosion, or dissection with resulting intraluminal thrombus in 
one or more of the coronary arteries leading to decreased myocardial blood flow or distal platelet 
emboli with ensuing myocyte necrosis. The patient may have 
underlying severe CAD but on occasion non-obstructive or no CAD. 
 
Type 2: Myocardial infarction secondary to an ischemic imbalance 
In instances of myocardial injury with necrosis where a condition other than CAD contributes to 
an imbalance between myocardial oxygen supply and/or demand, 
e.g. coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-/brady-
arrhythmias, anemia, respiratory failure, hypotension, and 
hypertension with or without LVH. 
 
Type 3: Myocardial infarction resulting in death when biomarker values are unavailable 
Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic 
ECG changes or new LBBB, but death occurring before blood 
samples could be obtained, before cardiac biomarker could rise, or in rare cases cardiac 
biomarkers were not collected. 
 
Type 4a: Myocardial infarction related to percutaneous coronary intervention (PCI) 
Myocardial infarction associated with PCI is arbitrarily defined by elevation of cTn values>5 x 
99th percentile URL in patients with normal baseline values (≤99th percentile URL) or a rise of 
cTn values >20% if the baseline values are elevated and are stable or falling. In addition, either 
(i) symptoms suggestive of myocardial ischemia, or (ii) new ischemic ECG changes or new 
LBBB, or (iii) angiographic loss of patency of a major coronary artery or a side branch or 
persistent slow- or no-flow or embolization, or (iv) imaging demonstration of new loss of viable 
myocardium or new regional wall motion abnormality are required. 
 
Type 4b: Myocardial infarction related to stent thrombosis 
Myocardial infarction associated with stent thrombosis is detected by coronary angiography or 
autopsy in the setting of myocardial ischemia and with a rise and/ 
or fall of cardiac biomarkers values with at least one value above the 99th percentile URL. 
 
Type 5: Myocardial infarction related to coronary artery bypass grafting (CABG) 
Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac 
biomarker values >10 x 99th percentile URL in patients with normal 
baseline cTn values (≤99th percentile URL). In addition, either (i) new pathological Q waves or 
new LBBB, or (ii) angiographic documented new graft or new 
native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or 
new regional wall motion abnormality. 

 
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Revascularization 
 
The revascularizations will be adjudicated per the ARC definition. 
 
• Location of Revascularization: 
 
• Target Lesion Revascularization (TLR)  
TLR is defined as any repeat percutaneous intervention of the target lesion or bypass 
surgery of the target vessel performed for restenosis or other complication of the target 
lesion. The target lesion is defined as the treated segment from 5 mm proximal to the 
stent and to 5 mm distal to the stent. 
 
• Target Vessel Revascularization (TVR) 
TVR is defined as any repeat percutaneous intervention or surgical bypass of any 
segment of the target vessel. The target vessel is defined as the entire major coronary 
vessel proximal and distal to the target lesion which includes upstream and downstream 
branches and the target lesion itself  
 
• Non Target Lesion Revascularization (Non-TLR) 
Any revascularization in the target vessel for a lesion other than the target lesion is 
considered a non-TLR. 
 
• Non Target Vessel Revascularization (Non-TVR) 
Revascularization of the vessel identified and treated as the non-target vessel at the time 
of the index procedure.  
 
 
Stent Thrombosis (Per ARC Circulation 2007; 115: 2344-2351) 
 
Stent thrombosis should be reported as a cumulative value at the different time points and with 
the different separate time points. Time 0 is defined as the time point after the guiding catheter 
has been removed and the subject left the catheterization lab.  
 
• Timing:  
• Acute stent thrombosis*:  
 
0 - 24 hours post stent implantation  
• Subacute stent thrombosis*:   
>24 hours . 30 days post stent implantation  
• Late stent thrombosis†:  
 
30 days - 1 year post stent implantation  
• Very late stent thrombosis†:   
>1 year post stent implantation  
 
*  Acute/subacute can also be replaced by early stent thrombosis. Early stent thrombosis (0 - 
30 days) - this definition is currently used in the community.  
† Including “primary” as well as “secondary” late stent thrombosis; “secondary” late stent 
thrombosis is a stent thrombosis after a target segment revascularization.  
 
 

 
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• Categories: 
• Definite 
• Probable 
• Possible 
 
Definitions of each category are as follows. 
 
• Definite stent thrombosis 
Definite stent thrombosis is considered to have occurred by either angiographic or 
pathologic confirmation. 
 
 
Angiographic confirmation of stent thrombosis* 
The presence of a thrombus† that originates in the stent or in the segment 5 mm proximal 
or distal to the stent and presence of at least one of the following criteria within a 48-hour 
time window:  
o Acute onset of ischemic symptoms at rest  
o New ischemic ECG changes that suggest acute ischemia  
o Typical elevation or depression in cardiac biomarkers (refer to definition of 
spontaneous MI)  
o Nonocclusive  thrombosis 
o Thrombus Intracoronary thrombus is defined as a (spheric, ovoid, or 
irregular) noncalcified filling defect or lucency surrounded by contrast 
material (on 3 sides or within a coronary stenosis) seen in multiple 
projections, or persistence of contrast material within the lumen, or a 
visible embolization of intraluminal material downstream.  
o Occlusive thrombus  
o TIMI 0 or TIMI 1 in-stent or proximal to a stent up to the most adjacent 
proximal side branch or main branch (if originates from the side branch).  
 
    * 
The incidental angiographic documentation of stent occlusion in the absence of 
clinical signs or symptoms is not considered a confirmed stent thrombosis. 
 
    † 
Intracoronary thrombus. 
 
Pathological confirmation of stent thrombosis  
Evidence of recent thrombus within the stent determined at autopsy or via examination of 
tissue retrieved following thrombectomy.  
 
• Probable stent thrombosis 
Either of the following occurred after stent implantation will be considered a probable 
stent thrombosis: 
o Any unexplained death within the first 30 days  
o Irrespective of the time after the index procedure, any MI that is related to 
documented acute ischemia in the territory of the implanted stent without 
angiographic confirmation of stent thrombosis and in the absence of any other 
obvious cause  

 
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• Possible stent thrombosis 
Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death from 30 days following intracoronary stenting until end of trial follow 
up. 
 
 
III. 
Other definitions 
 
ACUTE SUCCESS DEFINITIONS 
 
Clinical Device Success (Lesion Basis) 
Successful delivery and deployment of the assigned device at the intended target lesion and 
successful withdrawal of the delivery system with attainment of final in-stent residual stenosis of 
< 30% by QCA (by visual estimation if QCA unavailable).  
 
Clinical Procedure Success (Patient Basis) 
Achievement of final in-stent residual stenosis of < 30% by QCA (by visual estimation if QCA 
unavailable) with successful delivery and deployment of the assigned device at the intended 
target lesion and successful withdrawal of the delivery system without the occurrence of 
MACCE during the hospital stay (maximum of 7 days), and with or without use of other 
therapeutic device. 
 
In multiple target lesion setting all lesions must meet clinical procedure success criteria to have a 
patient level procedure success. 
 
 
 
 
 
 
 
 

 
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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. 
 
Adverse Device Effect 
 
Adverse device effects include issues related to its specifications, product experiences and device 
malfunctions, insufficient contents of instruction for use and adverse device effects. It also 
includes inevitable adverse events potentially occurs even if a device is properly used. This 
means that an adverse device effect is defined as any adverse event that is related to the study 
device, or whose relationship to the study device is unknown. 
 
 
 
 
 
 

 
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Unanticipated Adverse Device Effect (UADE) 
 
An unanticipated adverse device effect is an adverse device effect (including infection that is 
suspected to relate to use of the device) of which occurrence and the occurrence trend such as 
number and frequency of the occurrences, and conditions on the occurrence cannot be predicted 
from the Investigator’s Brochure of the investigational device. 
 
 
Angina Pectoris 
 
• Braunwald Classification of Unstable Angina: 
I. New onset of severe or accelerated angina. Patients with new onset (≤ 2 months in 
duration) exertional angina pectoris that is severe or frequent (> 3 episodes/day) or patients 
with chronic stable angina who develop accelerated angina (that is, angina distinctly more 
frequent, severe, longer in duration, or precipitated by distinctly less exertion than 
previously) but who have not experienced pain at rest during the preceding 2 months. 
II. Angina at rest, subacute. Patients with one or more episodes of angina at rest during the 
preceding month but not within the preceding 48 hours. 
III. Angina at rest, acute. Patients with one or more episodes of angina at rest within the 
preceding 48 hours. 
 
• Canadian Cardiovascular Society [CCS] Classification of Stable Angina: 
I. 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. 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. 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. Inability to carry on any physical activity without discomfort - angina syndrome may be 
present at rest. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TIMI (Thrombosis in Myocardial Infarction) Flow Grades 
 
0. No contrast flow through the stenosis. 
 
 
1. A small amount of contrast flows through the stenosis but fails to fully opacify the artery 
beyond. 
2. Contrast material flows through the stenosis to opacify the terminal artery segment. 
However, contrast enters the terminal segment perceptibly more slowly than more 
proximal segments. Alternatively, contrast material clears from a segment distal to a 
stenosis noticeably more slowly than from a comparable segment not preceded by a 
significant stenosis. 
3. Anterograde flow into the terminal coronary artery segment through a stenosis is as 
prompt as anterograde flow into a comparable segment proximal to the stenosis. Contrast 
material clears as rapidly from the distal segment as from an uninvolved, more proximal 
segment. 
 
 

 
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23 APPENDIX VI: MSCT ACQUISITION GUIDELINES 
 
[Optimizing Imaging Quality for MSCT and FFRCT] 
 
Introduction 
• Please utilize 64 Slice CT Scanner. 
• Imaging the entire coronary tree allows for the most accurate FFRCT computation. 
 
Preparation 
• Assess heart rate and rhythm. Heart rate control (below 60 beats per minute) reduces 
misregistration and 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 3 times. 
o Contraindications: conduction delays, hypotension, severe asthma, allergy to 
betablockers. 
o Consider ivabradin or calcium antagonist for patients with contra-indications to 
betablockers. 
• 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 
• ask patients not to take any nitrates 12-14 hours prior to CT acquisition 
• additional Beta blockade may be given after nitroglycerin to counteract the reflex tachycardia 
 
o Confirm absence of allergy to contrast media (consider prophylaxis for patients with 
doubtful or mild reactions to contrast in the past). 
o No caffeine (coffee, tea, energy drinks, and most soda) products <12h pre-scan. 
o No smoking 5 minutes prior to scan. 
 
Patient installation 
o Attach ECG leads, avoid respiratory muscles, check signal stability during breath hold. 
o Placement of an IV catheter that allows a flow of at least 4 ml/s. 
 

 
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Data acquisition 
o Overview/scout of the entire chest. 
o Contrast enhancement:  
o ≥300 g/L iodine contrast medium. 
o Injection rate: 4-6 ml/s. 
o Total amount depends on the patient size, the scan mode and the scan duration.  
o Contrast-scan timing: 
o Test bolus acquisition: 15-20 ml of contrast is injected, preferably followed by a 
bolus chaser. The time of (maximum) enhancement is used as the delay of the 
data acquisition after start of contrast injection.   
o Bolus tracking: arrival of the (entire) bolus is monitored in the ascending aorta. 
To avoid premature triggering of the scan the ROI should be sufficiently large and 
placed away form the superior vena cava. 
o A saline bolus of ≈50 ml is injected after the contrast medium at the same rate. 
o Scan mode (depending on the available CT equipment and local experience): 
o ECG-gated spiral scan mode. ECG-triggered tube modulation: use and nominal 
output width depending on the heart rate and rate stability. Full-output window 
wider, to include both end-systolic and diastolic phase, for heart rates >70/min.   
o ECG-triggered sequential (step-and-shoot) scan mode can be used by experienced 
sites for patients with a modest heart rate (<70-75/min) without rhythm 
irregularities. Scan window preferably widened to allow reconstruction of more 
phases, wider for faster heart rates (>65/min).  
o High-pitch spiral scans (Definition Flash®) not recommended.  
o Acquisition parameters: 
o Thinnest detector width. 
o Tube current (mA), depending on the size of the patient.  
o Tube voltage 120 kV, 100 kV can be considered for (very) small patients (<70 kg).  
o Scan range: from 1-2 cm below the carina until the caudal border of the heart. 
 
Image reconstruction (appropriately labelled): 
1) Standard reconstructions: 
o Standard medium-sharp convolution kernel. 
o ECG-editing, if necessary. 
o Field-of-view enclosing the entire heart (cover inferior carina to lower heart border) 
(approx. 18 x 18 cm). 
o Reconstructed slice thickness equal or slightly wider than the individual detector 
width. In case of noisy images (obesity), thicker-slice reconstructions may be added.  
o Reconstructions of at least three different phases. Depending on the scan protocol 
both diastolic and systolic reconstructions should be performed.  

 
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o Reconstructions should be optimized for the segments of interest (ROI). In case of 
suboptimal image quality other phases should be explored.  
o In case of slab artifacts at the level of the lesions/segments of interest, ECG editing 
may improve image quality.  
2) Sharp-kernel reconstructions:  
o Thinnest slice thickness 
o One or two reconstructions at the best phase for each of the one or two stented 
segments, based on the standard reconstructions. 
 
DVD recording:  
o Topogram. 
o ECG file. 
o Scan protocol file containing: scan mode, mA, kV, DLP, etc.  
o Standard kernel reconstructions, at least one (or the same) optimal phase for each 
diseased coronary segment, preferably three or more datasets including both systolic and 
diastolic phases. 
o Sharp kernel reconstructions (dedicated stent reconstruction), at least one (or the same) 
optimal phase for each diseased segment.  
 
 
 
 
 
Summary 
 
• FFRCT is derived from precise modelling of the coronary tree, not just areas of 
disease 
 
• cCTA best practices = best practices for FFRCT data 
J Cardiovasc Comput Tomogr. 2009 May-Jun;3(3):190-204 
 
• Scan optimization is essential in unlocking the potential of FFRCT