Diagnostic Accuracy of On-line Quantitative Flow Ratio. Functional Assessment by Virtual Online Reconstruction (The FAVOR II Europe-Japan Study)
Conditions: Coronary Artery Disease
Sponsor: Aarhus University Hospital Skejby

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!'#G'"#'
'
Diagnostic Accuracy of On-line Quantitative Flow Ratio 
Functional Assessment by Virtual Online Reconstruction 
 
The FAVOR II study  
 
$%&'(')*+,(&,%-*.%'-,/%'0&+10-,(*%-*.&-.,'0&23&$'.415&6%,7*.5,-3&8/59,-'0:&;*%+'.<&
&
H>.&5'3B?5>=F'D#&?I'JKI'E">?B"8'>=(.5$>FB$#"'
L>"F>$$.'M"#F5FBB"7'0=7."5.=I'JNI'%##"7>=B$>=F'>=(.5$>FB$#"'
O(B&7'DPQ'R-">5$>B=5.=I'JKI'!-KI'%#:>=(.5$>FB$#"'
S'
N-.=FT>B=',6I'E"#G.55#"I'!-KI'U/3'7.(.&#E."'
V>&&>B?'V>Q=5I'E"#G.55#"'JKI'!-KI'%#:>=(.5$>FB$#"'
DB=5'3.>W."I'E"#G.55#"'!-KI'%#:>=(.5$>FB$#"'
X*)+Y);+*<'
'
0B"-65'C=>(."5>$8'D#5E>$B&I'NA.QW8'
K.E)'RB"7>#&#F8'
!B&&.'Z66&:Z.=5.=5'L#6&.(B"7'[[I'\;++'0B"-65'HI'K.=?B"A 
 
 
CONFIDENTIAL 
Property of PCI-Research, Aarhus University Hospital. Denmark

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'"'#G'"#'
'
 
Study group 
 
Primary investigator  
Niels Ramsing Holm1, MD, AUH - niels.holm@clin.au.dk  
Scientific coordinator  
Birgitte Krogsgaard Andersen1, AUH - birgitte.krogsgaard@clin.au.dk 
Co-investigator  
Evald Høj Christiansen1, MD PhD, AUH - 
evald.christiansen@dadlnet.dk 
Co-investigator 
Mai-Britt Vestergaard, AUH - mai-britt.vestergaard@post.au.dk 
Co-investigator  
Professor Hans Erik Bøtker1, MD, PhD, AUH - heb@dadlnet.dk  
Co-investigator 
Professor William Wijns, MD, The Lambe Institute for Translational 
Medicine and Curam, National University of Ireland, Galway and Saolta 
University Healthcare Group, Galway, Ireland. - 
william.wyns@gmail.com 
Co-investigator 
Professor Hans Reiber3 PhD -HansR@medis.nl    
Site PI 
Gianluca Campo, MD, associate professor, consultant cardiologist, 
Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, 
Ferrara, Italy 
Marco Götte, MD, PhD, consultant cardiologist, Department of 
Cardiology, Haga Teaching Hospital, Leyweg 275, 2545 CH The Hague, 
Netherlands 
Marco 
Barbierato, 
MD 
PhD, 
consultant 
cardiologist, 
Ospidale 
dell´angelo, Mestre, Italy 
Cristoph Naber, MD PhD, professor, Elizabeth Krankenhaus Essen, 
Essen, Germany 
Hitoshi Matsuo, MD PhD, director of Gifu Heart Center, Tokyo, Japan 
 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'='#G'"#'
'
QFR developer 
Professor Shengxian Tu2 PhD, Biomedical Instrument Institute, School 
of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 
China - sxtu@sjtu.edu.cn 
QFR distributor  
Professor Hans Reiber3 PhD -HansR@medis.nl    
QFR training , support 
Gerhard Koning4 PhD - gkoning@medis.nl  
Study secretary  
Helle Bargsteen, AUH Skejby - hellbarg@rm.dk 
Project coordinator 
Lars Peter Jørgensen, AUH Skejby - larsjoer@rm.dk 
Data management, eCRF Jakob Hjort, AUH, Skejby - j.hjort@clin.au.dk 
QFR core lab 
Interventional Coronary Imaging Core Laboratory, Aarhus University -  
intvcorelab@clin.au.dk 
FFR core lab  
Coronary Physiology Core Laboratory, AUH Skejby - jelwes@rm.dk 
Statistician 
Morten Madsen, Dep. Clinical Epidemiology, AUH, Skejby - 
morten.madsen@clin.au.dk 
Budget, funding 
Niels Ramsing Holm, AUH, Skejby – niels.holm@clin.au.dk 
Legal advisor 
Susanne Kudsk, TTO, Aarhus University - sfk@au.dk 
 
1) Dep. Cardiology, Aarhus University Hospital, Skejby. Phone +45 78452254 Fax: +45 78452260 
Palle Juhl Jensens Boulevard 99, 8200 Aarhus N, Denmark 
2) Biomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong 
University, Shanghai, China 
3) Division of image processing, Leiden University Medical Centre, Leiden, The Netherlands 
4) Medis medical imaging, Leiden, The Netherlands 
 
 
Abbreviations 
AMI 
 
Acute Myocardial Infarction 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'>'#G'"#'
'
AP 
 
Angina Pectoris 
AS 
 
Area Stenosis 
CABG 
 
Coronary Artery Bypass Grafting 
CCS 
 
Canadian Cardiovascular Society Angina Grading System 
CK-MB 
 
Creatinine Kinase MB 
CRF 
 
Case Report Form 
 FFR 
 
Fractional Flow Reserve 
GCP 
 
Good Clinical Practice  
IHD 
 
Ischemic Heart Disease 
LBBB 
 
Left bundle branch block 
MACE 
Cardiac Death, Myocardial Infarction, Stent Thrombosis or Target 
Vessel Revascularization 
MI 
Myocardial Infarction 
MV 
 
Main Vessel 
PCI 
 
Percutaneous Coronary Intervention 
QCA 
 
Quantitative Coronary Analysis 
QFR 
 
Quantitative Flow Ratio 
TNI 
 
Troponin I 
TNT 
 
Troponin T 
TLR 
 
Target Lesion Revascularization 
TVR 
 
Target Vessel Revascularization 
TLF 
 
Target Lesion Failure 
TVF 
 
Target Vessel Failure 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'?'#G'"#'
'
 
 
1. Background 
Patients in high risk of having one or more coronary stenoses are evaluated routinely by invasive 
coronary angiography (CAG) and often in combination with measurement of fractional flow reserve 
(FFR) during the procedure1. Stenosis identified by angiography is considered to cause ischemia if 
the narrowing results in a lumen reduction of more than 90% diameter stenosis by visual estimate. 
If the lumen reduction is between 30% and 90% it is indicated to measure FFR to assess if the flow 
is reduced more than 20% by the stenosis. Such a reduction in flow is correlated to ischemia in the 
downstream myocardium2,3. FFR is assessed during CAG by advancing a wire with a pressure 
transducer towards the stenosis and measuring the ratio in pressure between the two sides of the 
stenosis during maximum blood flow (hyperaemia). Hyperaemia is induced by adenosine infusion 
during the measurement.  
This strategy of FFR-guided intervention in coronary artery disease is well established by solid 
clinical evidence and has gained the highest guideline recommendations in Europe1. In Denmark 
FFR is measured in an estimated 4000 patients a year. 
Pros and cons of FFR 
The solid evidence for FFR evaluation of coronary stenosis and the relative simplicity in performing 
the measurements have supported wide spread adoption of the technology. However, the need for 
interrogating the stenosis by a pressure wire carries the risk of dissecting or even perforating the 
vessel. The wire can also dissect a plaque and cause plaque rupture and thrombus can form around 
the catheter. These complications are relatively rare but may be detrimental. Another factor is the 
price where pressure wires and adenosine adds substantially to the procedural costs. Cost-
effectiveness analysis has shown that an FFR guided strategy is cost-effective compared to an 
angiographic guided strategy as fewer stents are implanted per patient4. Still, if the cost of doing 
FFR could be reduced or alleviated it would definitely benefit the economically restrained health 
care systems.    
Wire-free FFR 
A new method (QFR by Medis medical imaging) for evaluation of the functional significance of 
coronary stenosis is based on computer calculation of the FFR value. This calculation is performed 
by analysing the coronary angiogram and thus reduces or potentially eliminates the need for 
measuring FFR by pressure wires. The QFR method combines a 3D reconstruction of the target 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'@'#G'"#'
'
vessel based on two angiographic projections and the contrast flow velocity to compute the “FFR 
value”. In the presented FAVOR study, QFR was shown to be very promising and results on in-
procedure analysis from the WIFI I trial are imminent. Development of similar methods is ongoing 
in multiple companies and academic groups5-7  and at present we are not aware that similar 
methods are tested for in-procedure computation of FFR.  The FAVOR study evaluating the QFR 
technology showed good diagnostic accuracy in comparison to FFR when QFR was based on 
angiographic views acquired with and without induced hyperaemia.  
The available version of the method is capable of assessing QFR during CAG but is not yet CE-
marked and has not received FDA approval for clinical decision-making, but it allows evaluation of 
the feasibility and diagnostic precision of this novel method.  
1.1 Purpose 
To evaluate the feasibility and diagnostic precision of QFR during CAG in comparison to QCA with 
FFR as gold standard for physiological lesion evaluation. 
1.2 Hypothesis 
QFR has superior sensitivity and specificity for detection of functional significant lesions in 
comparison to QCA with FFR as gold standard  
2. Materials and methods 
2.1 Design 
Prospective, observational, multicenter study with inclusion of 310 patients.  
2.2 Patients 
Consecutive patients referred for diagnostic angiography are screened for eligibility.  
2.2.1 Inclusion criteria 
- Stable angina pectoris or secondary evaluation of stenosis after acute MI 
- Age > 18 years 
- Able to provide signed informed consent  
2.2.2 Angiographic inclusion criteria 
- 
Indication for FFR in at least one stenosis: 
o Diameter stenosis of 30%-90% by visual estimate 
o Reference vessel size > 2 mm in stenotic segment by visual estimate'

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'#'#G'"#'
'
'
 
2.2.3 Exclusion criteria 
- Myocardial infarction within 72 hours 
- Severe asthma or severe chronic obstructive pulmonary disease 
- Severe heart failure (NYHA!III) 
- S-creatinine>150"mol/L or GFR<45 ml/kg/1.73m2 
- Allergy to contrast media or adenosine 
- Atrial fibrillation 
2.2.4 Angiographic exclusion criteria 
Lesion specific 
- Below 30% and above 90% diameter stenosis by visual estimate. 
- Reference size of vessel below 2 mm by visual estimation. 
- Ostial LMCA lesions 
- Ostial RCA lesions 
- Distal LMCA lesions in combination with proximal Cx lesions 
- Other bifurcation stenosis with lesions on both sides of a major shift (>1mm) in reference 
diameter 
Angiographic quality 
- Poor image quality precluding contour detection 
- Good contrast filling not possible 
- Severe overlap of stenosed segments 
- Severe tortuosity of target vessel 
2.3 Endpoints 
2.3.1.1 Primary endpoint 
Sensitivity and specificity of QFR in comparison to QCA with FFR as gold standard 
2.3.1.2 Secondary endpoints 
A) Feasibility of TIMI-flow based QFR in FFR assessed lesions 
B) Diagnostic performance of TIMI-flow based QFR in comparison to FFR reported as 
1) Sensitivity 
2) Specificity 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'A'#G'"#'
'
3) Positive predictive value 
4) Negative predictive value  
5) Positive and negative Likelihood ratio 
C) Diagnostic grey zone. QFR limits for achieving 95% sensitivity and specificity in comparison to 
FFR 
D) Diagnostic accuracy of TIMI-flow based QFR in comparison to 2D QCA (>50% diameter 
stenosis) as area under the curve 
E) Diagnostic accuracy of three different methods for computing QFR 
1) Fixed hyperemic flow rate (online computed) 
2) TIMI flow based without hyperaemia (online computed) 
3) TIMI flow based with hyperaemia (core laboratory computed) 
F) Reproducibility of QFR 
1) Fixed hyperemic flow rate (online computed vs core laboratory computed) 
2) TIMI flow based without hyperaemia (online computed vs core laboratory computed) 
 
2.3.2 Procedural endpoints 
1) Procedural safety 
2) Procedure time to FFR 
3) Procedure time to QFR 
4) Time to QFR after receiving angiographic images 
5) Contrast use  
6) Fluoroscopy time  
2.4 Study procedure 
2.4.1 Enrollment and angiographic based exclusion 
Patients fulfilling clinical inclusion criteria and fulfills no clinical exclusion criteria are enrolled by 
providing written informed consent before the procedure (see section 6.3). During angiography 
patients enters the QFR cohort if fulfilling angiographic inclusion criteria. If patients have 
angiographic exclusion criteria, they are excluded before attempting QFR. All enrolled patients are 
entered in the study eCRF. If excluded, reasons are entered in the eCRF. 
2.4.2 Study procedure flow 
The CAG procedure with FFR assessment is performed as normal best practice. QFR is calculated 
for all the vessels in which FFR assessment is planned. Angiographic projections are acquired 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'B'#G'"#'
'
ensuring minimal overlap of the investigated vessels. Two projections of each vessel to be assessed 
are obtained at least 25 degrees apart. After initial diagnostic angiography the images are 
transferred to a workstation for calculation of the QFR-value. Not awaiting the result hereof, the 
operator continues the procedure by measuring standard FFR during I.V. hyperaemia. The FFR 
trace is recorded from before inducing hyperaemia to verification of drift not exceeding 
prespecified limits (section 2.4.3). The procedure is finalized as by normal practice according to the 
results of angiography and standard FFR. The QFR value is calculated in parallel and the results 
noted before knowing the measured FFR values. The QFR value may not be used for diagnosing the 
patient.
 
2.4.2.1 Coronary angiography, detailed 
Two good projections at least 25 degrees apart are required for the 3D vessel reconstruction. 
Angiographic procedure:  
• 
Inject I.C. nitro-glycerine as early as possible 
• 
Use framerate of at least 12.5/15 frames/sec  
• 
Make sure that the catheter is filled with contrast before the injection (i.e. after 
administration of nitro-glycerine)' 
• 
Use brisk, continuous and fast contrast injections. Aim for full 3 cardiac cycles 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!C'#G'"#'
'
• 
Minimize overlap of target segments 
• 
Avoid foreshortening of the vessel  
• 
Avoid zooming 
• 
Avoid moving the table early after injection 
• 
Aim projections perpendicular to the target vessel 
• 
Make sure that the entire vessel is visible in both projections. Both the proximal end and 
the potential position of the FFR pressure transducer should be visible in the same frame.  
 
Suggested projections are found in table 1. 
 
 
If only one good projection is identified, consider to use the Acquisition Guide tool in the Medis 
Suite QAngio XA 3D/QFR solution to identify the second projection: 
1. Transfer first good projection to QFR computer (see section 2.4.2.2). 
2. Right-click on the good projection and start QAngio3D. 
3. Choose Acquisition Guide (Figure 1, red box). The yellow line on the angiography indicates 
the new projection angle, and should be approximately perpendicular to the target vessel at 
the lesion site. 
a. If several lesions are located on the same vessel, a compromise must be made to 
ensure that most and the most severe lesions can be seen in the same projection.  
4. Move the projection line by moving the yellow spot (Figure 1, arrow) in the Acquisition 
Guide indicator. Aim to keep the yellow spot inside the green area.  
5. Position the C-arm as proposed by the guide. 
6. In case of excessive overlap of the target segments and other vessels, rotate the C-arm 5 
degrees around the axis of the target vessel. 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!!'#G'"#'
'
a. If needed, use the Acquisition guide indicator again by maintaining the angulation of 
the yellow line and move the yellow spot just outside the green area – away from the 
red area. Move the C-arm accordingly. 
Figure 1 Acquisition Guide. Red box: Acquisition guide. White arrow: Yellow spot indicating position of C-arm.  
2.4.2.2 Image transfer 
The angiographic runs are transferred to the QFR-computer using an angiographic equipment 
specific protocol.   
2.4.2.3 Angiographic run selection 
Optimal projections are chosen according to the following criteria: 
• 
Minimal overlap of the target vessel 
• 
Good contrast injection, filling the entire vessel 
• 
Includes both most proximal stenosis and most distal potential location of the pressure 
transducer of the subsequent FFR assessment 
2.4.3 Detailed description of FFR recording: 
The pressure wire is prepared and calibrated according to instructions for use. The pressure wire is 
advanced in the engaged guiding catheter and the pressure transducer positioned just outside the 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!"'#G'"#'
'
tip of the catheter and equalized. After equalization, the wire is advanced to a position with the 
transducer in a stable position distal to the stenosis. In case of long healthy segments distal to the 
lesion, do not advance the FFR wire to a very distal position as this increases the complexity of 
acquiring appropriate angiographic views. 
I.V. FFR recording: Recording of FFR during I.V. adenosine induced hyperemia is performed by 
femoral or brachial vein infusion of adenosine at 140 "gL-1min-1. The infusion rate is increased to 
200 "gL-1min-1 if a stable FFR value is not achieved. At least 20 seconds of the lowest stable value is 
documented before obtaining an angiographic projection during hyperemia, which should at least 
be 25 frames/sec. 
The entire FFR interrogation is recorded from before equalization and until a potential drift has 
been checked after retracting the pressure wire. 
FFR is calculated as the ratio of distal mean pressure (Pd) measured by the pressure-wire to the 
proximal mean pressure (Pa) during hyperemia. The FFR cut-off for identification of a flow 
limiting stenosis is # 0.80 for all lesions. The wire location is documented angiographically for all 
measurements. A pressure-wire pullback is performed to check for pressure-drift. A drift-value 
from 0.96-1.04 is accepted; otherwise, the procedure is repeated. For FFR values of 0.76-0.84, a 
drift with a narrower range of 0.98-1.02 is accepted. 
St. Jude FFR systems are recommended, but Volcano FFR systems can be used as well. iFR 
recordings and Acists FFR system are not allowed. It is mandatory that complete FFR traces can be 
exported for documentation and core lab analysis. If using the St. Jude Quantien system it is 
crucial to finalize the recordings and session correctly on the console to avoid loss of FFR data. FFR 
systems integrated in physiology systems or angiographic equipment are only allowed if a complete 
trace can be reanalyzed by the FFR core laboratory. 
2.4.4 Detailed description of QFR computation 
The Medis Suite QAngio XA-3D/QFR solution (Medis medical imaging system bv, Leiden, The 
Netherlands) is used for computation of QFR. The Medis Suite QAngio XA-3D/QFR solution is 
installed on a windows based computer. The analysis is performed as described in the manual 
provided with the software and in a step-by-step study specific standard operating procedure 
(Appendix A)  
2.4.4.1 Documentation of QFR analysis 
After finishing the QFR analysis, it is saved by two steps for the study purpose.  

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!='#G'"#'
'
1. A screenshot is acquired and saved in a folder named ”Patient X”, X indicating the patient’s 
study ID.  
2. The QFR analysis is saved in the Medis Suite QAngio XA 3D/QFR solution by clicking Done 
in the lower right corner (Figure 2, white arrow) and clicking Save in the upper panel 
(Figure 2, red arrow). 
 
 
Figure 2 Documentation. How to save the analysis in the Medis Suite QAngio 3D-/QFR solution.  
After a session is made and saved, Medis Suite QAngio XA 3D/QFR solution will create a Report 
(summarizing the analysis, including 2D images of the vessel reconstruction, the 3D 
reconstruction, results etc.). You can easily change which parts of the analysis the report includes 
by clicking on the different parameters (Figure 3, left panel).  

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!>'#G'"#'
'
 
Figure 3 Report 
2.4.5 Endpoint definition 
2.4.5.1 Feasibility 
Fraction of lesions with FFR where QFR was computed 
Time to QFR: Time from first image evaluation on QFR computer until TIMI frame count 
based QFR is obtained. 
Time to FFR: Time from starting preparations to do FFR (e.g. ordering assistants to 
prepare pressure wire, adenosine infusion) FFR value is obtained AND drift has been 
verified to be within the prespecified limits 
2.4.5.2 Endpoint definitions: 3D Quantitative Coronary Angiography (3D-QCA) 
• 
Percentual diameter stenosis: (Reference diameter ÷ minimal luminal 
diameter)/reference diameter in percent  
 
 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!?'#G'"#'
'
2.4.6 Definitions of clinical endpoints (procedural)  
2.4.6.1 Cardiac death 
Encompasses death due to coronary heart disease including fatal myocardial infarction, sudden 
cardiac death including fatal arrhythmias and cardiac arrest without successful resuscitation, death 
from heart failure including cardiogenic shock, and death related to a cardiac procedure or surgery 
within 28 days from the procedure. If death is not clearly attributable to other non-cardiac causes, 
it will be adjudicated as cardiac death. 
2.4.6.2 All-cause mortality (total death)  
Total death includes cardiac death and other fatal categories such as cerebrovascular death, death 
from other cardiovascular disease (i.e. pulmonary embolism, dissection aortic aneurism will be 
included in this category), death from malignant disease, death from suicide, violence or accident, 
or death from other reasons.  
2.4.6.3 Non-procedure related target lesion myocardial infarction  
The term myocardial infarction should be used when there is evidence of myocardial necrosis in a 
clinical setting consistent with myocardial ischemia. Under these conditions any one of the 
following criteria meets the diagnosis for myocardial infarction: 
1) Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value 
above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial  
ischemia with at least one of the following (MI types 1 or 2): 
a. 
Symptoms of ischemia 
b. 
ECG changes indicative of new ischemia (new ST-T changes or new LBBB) 
c. 
Development of pathological Q waves in the ECG 
d. 
Imaging evidence of new loss of viable myocardium or new regional wall  
 
motion abnormality 
2) Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of 
myocardial ischemia, and accompanied by presumably new ST elevation, or new LBBB, and/or 
evidence of fresh thrombus by coronary angiography and/or at autopsy, but death occurring before 
blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the 
blood (MI type 3). 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!@'#G'"#'
'
3) Pathological findings of an acute myocardial infarction. 
2.4.6.4 Procedure related biochemical release of markers (Myocardial infarction 
related to the index procedure) 
The following biomarkers may be used in the study: CK-MB mass and/or Troponin-T/-I. For 
percutaneous coronary interventions (PCI) in patients with normal baseline biomarker values, 
elevations of CK-MB greater than 5 X 99th percentile URL are designated as defining PCI-related 
myocardial infarction (MI type 4a). Similar rise or higher by TnT or TnI will be reported. If cardiac 
biomarkers are elevated before the procedure and not stable for at least two samples 6 hours apart, 
there are insufficient data to recommend biomarker criteria for the diagnosis of peri-procedural 
myocardial infarction. If the values are stable or falling, criteria for re-infarction by further 
measurement of biomarkers can be applied; that is 20% or more increase of the value in the second 
sample after the procedure. This value should also exceed the 99th percentile URL. 
 
2.4.6.5 Target lesion revascularization 
Coronary artery bypass grafting or PCI of index lesion. 
2.4.6.6 Target vessel revascularization 
Coronary artery bypass grafting or PCI of index vessel. 
2.4.6.7 Target lesion failure 
Target lesion failure is defined as objective evidence for in-segment occlusion (symptomatic or 
asymptomatic) or stenosis causing ischemia.  
2.4.6.8 Target vessel failure 
Target vessel failure is defined as objective evidence for in-vessel occlusion (symptomatic or 
asymptomatic) or stenosis causing ischemia. '
2.4.6.9 Stent thrombosis 
Stent thrombosis is recognized when documented by angiography and/or autopsy and when 
meeting the criteria for spontaneous myocardial infarction occurring in the territory of the treated 
vessel.  Stent thrombosis is categorized as acute, sub-acute, late and very late and as definite, 
probable and possible according to the ARC-criteria8. 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!#'#G'"#'
'
2.4.7 FFR core lab analysis 
The recorded FFR traces are analyzed by experienced observers at the Coronary Physiology Core 
Laboratory, Aarhus University, Denmark. The observers are blinded to any other procedural 
information. FFR recordings are analyzed for achievement of maximal hyperemia, no reversed 
gradient during hyperemia, no loss of Pa or Pd signal and acceptable drift.  
2.4.8 QFR core lab 
The angiograms are reanalyzed by two observers blinded to any procedural results and FFR results. 
Analysis is performed using the three flow models; fixed hyperemic flow rate (HFR), TIMI flow 
based without hyperaemia and TIMI flow based with hyperaemia. Analysis is performed applying 
same principles as during on-line computation. Analysis is performed at the core laboratory for 
interventional imaging at Aarhus University Hospital, Denmark 
3. Statistics and sample size 
3.1 Statistics 
Baseline characteristics and procedural characteristics are presented as count and percentages, or 
if continuous variables are analyzed by mean and standard deviation if Gaussian distributed, else 
reported as medians and inter-quartile range. If more than one vessel is assessed pr patient it is 
analysed on a per vessel level. Feasibility is calculated as the number of successful QFR/number of 
standard FFR times 100. The primary endpoint is calculated as superiority for sensitivity and 
specificity of QFR in comparison to QCA. The QCA value in analysis is the lesion site 3D QCA value 
obtained on-line during QFR analysis. Secondary endpoints include positive predictive value, 
negative predictive value, together with their 95% confidence intervals (CIs). The area under the 
curve by receiver-operating characteristic analysis is used to assess the diagnostic accuracy of QFR 
and QCA with FFR as gold standard. The diagnostic performance of QFR compared to 2D QCA is 
performed by one-tailed paired comparison of ROC curves (Hanley test). Pearson correlation is 
used to quantify the correlation between QFR and FFR. Agreement between QFR and FFR is 
assessed by Bland-Altman plot. Intra- and inter-patient variation in paired QFR and FFR values 
are compared to detect clustering. Analysis is performed using STATA 13. 
3.2 Sample size 
The study is an observational study designed to assess the diagnostic accuracy of QFR with FFR as 
gold standard. Estimates for the sample size calculation are based on the results from the FAVOR 
study, where a sensitivity of 0.74 and a specificity of 0.91 for QFR was found. The null hypothesis is 
H0: Sensitivity(QFR) = Sensitivity(DS50). H1: Unequal sensitivities for the two methods. 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!A'#G'"#'
'
Calculated with SAS version 9.4 with proc power for paired frequency, to do a sample size analyses 
for McNemar’s test for paired proportions.  
We did a normal-approximate McNemar test with the Connor method;  
Proportion1=0.48; proportion2=0.74; correlation=-0.1  
We did similar for specificity (H0: Specificity(QFR) = Specificity(DS50). H1: Unequal specificities 
for the two methods. 
Proportion1=0.75; proportion2=0.91; correlation=0.4 
With power=0.90, alpha=0.05 and a rate of true positives in the population of estimated 30% a 
total of 274 patients with paired QFR and FFR are required to reject the null hypothesis for 
sensitivity and 257 for specificity. To accommodate for insufficient angiographic quality or failed 
FFR a total of 310 patients should be enrolled.   
4. Notifications 
The study is notified to the Central Denmark Region Committees on Biomedical Research Ethics. 
Notification to local or national medical ethics committees is performed by the local or national 
coordinating investigators as required for the individual sites. The study is initiated center wise 
when full final approval is obtained covering the specific center.  
The study does not require notification to the respective National Board of Health as the tested 
QFR technology is not in contact with the patient (simple file transfer from angiographic 
equipment to a standard personal computer (PC)) and the obtained measurements are not used for 
diagnosing the patient during, or at any point after the individual study procedures.  
The study is notified to the Danish Data Protection Agency. Data is transferred to the Danish Data 
Archive before termination of the data controller permission and deletion of all the related study 
material at Aarhus University Hospital. Data is handled, processed and stored according to the 
regulations set forth in the “Persondataloven” and published guidelines by the Danish Data 
Protection Agency. Any additional use or transfer of data is only done pending permission by the 
Danish Data Protection Agency and by signed data processor agreement if applicable. The 
notification to the Danish Data Protection Agency covers the handling, processing, storage and 
transmission for all participating sites in all EC countries. All sites and investigators are required to 
obey the data protection regulations as referred to in the site contract. Sites outside the EC zone 
should obtain permission from local or national data protection authorities if required by law. 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'!B'#G'"#'
'
 
5. Data management 
5.1 Data obtained in the study 
Patient data recorded in the study database includes: 
Site data entered in eCRF, data entered in the study CRF (CPR no. (only Denmark), patient 
identifier, hypertension, diabetes, prior PCI or CABG, indication for CAG, creatinine, GFR rate, 
hemoglobin, blood pressure, pulse, symptoms during adenosine infusion, adenosine infusion rate, 
FFR-result, time to QFR, time to FFR, QFR result (fixed and TIMI-flow based),  clinical decision, 
treatment.   
Site data transferred for documentation and analysis 
1. Angiographic runs and documentation for the FFR wire position to be transferred in 
DICOM format (anonymized but marked with patient id, date, site, study name)  
 
2. FFR traces:   
Volcano systems 
All raw study files are archived on DVD's (not USB memory sticks). 
1) Locate the patient in the Volcano database. 
 
2) Select the Archive button and then choose storage location (DVD). 
 
3) Mark "Archive the study anonymously” 
 
All cases should contain a dir. and SDY. file. Further, all screenshots that may have been 
acquired should be included.  
 
St. Jude QUANTIEN systems 
Find the patient in archive and select the export function. 
1) Mark “to USB memory”, “Internal”, “Spreadsheet” and “Bitmap”.  
2) Select “Export all recordings in study” 
3) Click the green export arrow 
 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'"C'#G'"#'
'
A typical filename for the raw data file (.DAT) may be:  
{7DDB22A7-DEB9-49FA-B420-3AAE68CD870A}.dat 
Do not rename the files.  
 
St. Jude OPTIS (ILUMIEN/Integrated) systems 
Find the patient and select the specific FFR traces. Click “export”. 
 
1) Select native “RAW” 
2) Select “anonymize” and “alternate patient ID” to type the patient-identifier 
3) Identify export destination (USB/CD/DVD) and click export. 
 
If there prior to export are cases stored on the selected storage device, the QUANTIEN and 
OPTIS systems asks if the selected case may be added to the existing database.    
 
Transfer all the files from the CD or USB sticks to a separate folder on a hard drive, ZIP it 
(not by a Mac) and upload it to our trial system (TrialPartner).  
 
3. Screen shot of final screen after each QFR computation 
Missing data is verified as missing and indicated by unique coding.   
 
5.2 Monitoring of the study 
The study is monitored according to the Good Clinical Practice (GCP) rules by internal 
professionals at Aarhus University Hospital. During the study period, internal monitors ensures 
that the trial is conducted in compliance with the protocol, GCP and applicable regulatory 
requirements. 
The site investigator is responsible for accuracy of data submitted for the study organization and 
for storing source documents for verification of consistency with the data recorded in the e-CRF.  
5.3 Data monitoring committee (DMC) 
The safety of the study is monitored by the study PI. No data safety monitoring board is formed as 
the study is observational and participation is not associated with any relevant increased risk.  

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'"!'#G'"#'
'
5.4 Access to source documentation 
The investigator(s)/institution(s) will permit study-related monitoring, audits and regulatory 
inspection(s), to get passed on necessary information from source data/hospital records. The 
investigator is responsible and verifies that each patient has consented in writing to the outlined 
information to be passed on from hospital records to the study database. Data to be passed on 
includes: Patient related data (Weight, Height, Smoker status, Blood pressure), Biochemistry 
(Creatinine, GFR). Relevant measures for heart disease (Ejection fraction, Angina CCS-class, 
NYHA class,  atrial fibrillation) Relevant disease / former disease (Microvascular disease, 
Hypertension, Hypercholesterolemia, Diabetes, History of PCI, History of CABG, Severe asthma or 
COPD); Procedure related data (Access site, Catheter sizes, Lesion description, Procedure time, 
Fluoroscopy time, Contrast use, Medical treatment during angiography), and descriptions of any 
complication potentially related to the study investigation. 
5.5 Source data verification 
During indicated monitoring, the data recorded in the e-CRF by the investigator is controlled for 
consistency and correctness with the source data/hospital records. 
6. Ethical aspects 
6.1 Ethical conduct of the study 
The study is conducted in accordance with the protocol, applicable regulatory requirements and 
the ethical principles of the Declaration of Helsinki as adopted by the 18th World Medical 
Assembly in Helsinki, Finland in 1964 and subsequent versions. 
It is the responsibility of the coordinating investigator to obtain approval of the study 
protocol/protocol amendments, the patient information and the informed consent form from the 
Ethical Committee for all patients included in the study.  
6.2 Risks, side effects, advantages and disadvantages in participating in the 
study  
QFR-computation is performed using the initial angiographic recordings. The recordings need to 
be of good quality to make sure that the QFR-measurements are carried out properly. In individual 
cases a need of making 1-2 extra angiographic recordings per vessel interrogated by FFR would be 
necessary. For each vessel undergoing FFR measurement, and therefore also QFR calculation, the 
potential extra amount of contrast is estimated to be up to 15mL and the radiation exposure can in 
total increase by up to 0.1 mSv.  This extremely low extra contrast load and radiation exposure is 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'""'#G'"#'
'
not supposed to cause any measurable increased risk for the patient. Interventional cardiologists 
and support staff at the participating sites are well trained to manage and reduce any procedural 
risks.   
The study group finds no reason to believe there should be any ethical problems connected to this 
study.  
There are no firm advantages related to participating in the study.  
6.3 Patient information and informed consent 
The patient is included in the study after a signed informed consent form is obtained according to 
the guidelines given by the local scientific medical ethics committee. 
Before signing the informed consent form, eligible patients are provided with full and adequate 
verbal and written information by the professionals responsible for the study. This information is 
given when a patient is admitted to the department of cardiology or at a visit at the outpatient 
clinic. Eligible patients will on request be provided with sufficient time for consideration after 
initial oral information, where the written information is handed out. If the patient wishes so, study 
participation can be discussed with a third person; as well a third person can be present during the 
process of information. The investigator and assistants will help arrange that a third person can be 
present if requested. 
It is the responsibility of the investigator to provide each patient with full and adequate verbal and 
written information about the objectives, procedures and possible risks and benefits from the 
study. The written patient information must not be changed without prior discussion with the 
coordinating investigator and notification of the medical ethics committee. 
The patients are notified of their voluntary participation and of their right to withdraw from the 
study at any time and without giving any particular reason. The patients are also informed that 
withdrawing from the study does not influence their future treatment. The investigator is 
responsible for obtaining written informed consent from all patients prior to enrolment into the 
study. 
6.4 Withdrawal 
A patient can be withdrawn from the study at any time if it is the wish of the patient or if it is 
medically indicated. In any circumstance, every effort should be made to document patient 
outcome, if possible. 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'"='#G'"#'
'
A patient's participation in the study is discontinued if any of the following criteria applies: 
The patient's general condition contraindicates continuing the study, as judged by the investigator. 
Non-eligible patient. 
Protocol violation. 
If the patient decides to withdraw from the study, he/she is contacted in order to, if he/she agrees, 
obtain information about the reason(s) for discontinuation. The date and reason for the withdrawal 
is recorded in the CRF. 
6.5 Biological material 
Biological material will not be drawn or stored in the study. 
7. Study plan 
7.1 Steering committee 
The steering committee consists of Dr. Niels Ramsing Holm, MD  (primary investigator), fellow 
Birgitte Krogsgaard Andersen, professor Hans Erik Bøtker, MD, PhD and senior consultant Evald 
Høj Christiansen, MD, PhD (Senior supervisor), Aarhus University Hospital, Skejby 
All participating site PI are members of the steering committee: 
Gianluca Campo, Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, 
Italy 
Marco Götte, Department of Cardiology, Haga Teaching Hospital, Leyweg 275, 2545 CH The 
Hague, Netherlands 
Marco Barbierato, Ospidale dell´angelo, Mestre, Italy 
Cristoph Naber, Elizabeth Krankenhaus Essen, Essen, Germany 
Hitoshi Matsuo Gifu Heart Center, Tokyo, Japan 
 
 
All steering committee members oversees the safety of the study, and are participating in the 
interpretation of data. 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'">'#G'"#'
'
7.2 Study procedure training 
Participating sites are requested to have operators and dedicated staff trained for the QFR 
computation. The staff receives instructions and training from Medis medical imaging. Only staff 
that has been trained by Medis can perform the study computation of QFR. Sites are required to 
have performed at least 20 supervised cases before study enrollment. 
7.3 Case by case feedback 
Site PI´s receives confidential case by case core lab feedback on QFR computation throughout the 
study for continuous optimization of operator and QFR observer skills. The feedback relates to the 
quality of angiographic acquisitions and QFR computation. On-line feedback is provided in special 
cases or on request. 
7.4 Progress of the study 
The progress of the study is checked on a monthly basis by the steering committee. They will 
receive and evaluate data on inclusion rate.  
The steering committee receive data by e-mail and answer by e-mail with copy to all members. On 
basis on comments from the steering committee members, the coordinating investigators draws 
preliminary conclusions required to be approved by the steering committee members. 
8. Economy 
The study is an academic conceived investigator study conducted by interventional cardiologists at 
Aarhus University Hospital. The study is designed, conducted and reported independent of 
commercial interests. The study is funded by surplus research funding at the Department of 
Cardiology, Aarhus University Hospital, Skejby.  Funding from external sources is applied for. The 
manufacturer and distributor of the QFR software (Medis Medical Imaging, Leiden, NL) is not 
involved in design, conduct, or reporting of the study and provides no funding for the study except 
for making the Medis Suite solution available for free in the study period and provide training for 
participating sites. 
The patients will not receive any remuneration for participating in the study. 
8.1 Insurance 
Sponsor is liable for the design of the study as outlined in the protocol. Patients are covered by 
hospital liability insurance or national health insurance as this is an observational academic study.   

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'"?'#G'"#'
'
Sponsor shall approve the insurance coverage as outlined in the signed site contract for all 
participating centers before enrollment.   
9. Publication and ownership of data 
9.1 Ownership of data 
The source data itself (patient files, imaging data, blood samples) remains the property of the 
participating centers. All data and information transferred as by protocol and data generated in 
association with this study will be held in strict confidence and remains the sole property of PCI-
Research, Dep. Cardiology, Aarhus University Hospital.  
9.2 Publication 
Positive, neutral as well as negative or inconclusive result, are published in an international 
cardiovascular journal without delay. Publication and author issues are decided by the steering 
committee on basis of general involvement in the study (drafting of protocol, core laboratory 
function, analysis, drafting of manuscript etc.) and of number of included patients. Subsequent 
publications of results from the study are coordinated by the steering committee. 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 reviewed by the steering committee. 
9.3 Authorship requirements 
Requirements for co-authorship on center level includes at least 1) critical appraisal/revision of the 
protocol 2) inclusion of at least 15 patients and 3) critical revision of the main manuscript. 
10. 
Disputes 
In the unlikely event of disputes regarding any study related matter, 1) the study organization will 
do its outmost to resolve the issue to the satisfaction of all parties, 2) the steering committee will be 
asked for positions and recommendations, or lastly 3) the PI has the final decision by acting on 
behalf of the responsible sponsor, Aarhus University, Denmark.   
 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'"@'#G'"#'
'
11. Reference list 
1. Authors/Task Force members, Windecker S, Kolh P, et al. 2014 ESC/EACTS guidelines on 
myocardial revascularization: The task force on myocardial revascularization of the european 
society of cardiology (ESC) and the european association for cardio-thoracic surgery 
(EACTS)developed with the special contribution of the european association of percutaneous 
cardiovascular interventions (EAPCI). Eur Heart J. 2014;35(37):2541-2619. doi: 
10.1093/eurheartj/ehu278 [doi]. 
2. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the 
functional severity of coronary-artery stenoses. N Engl J Med. 1996;334(26):1703-1708. doi: 
10.1056/NEJM199606273342604 [doi]. 
3. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding 
percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224. doi: 
10.1056/NEJMoa0807611; 10.1056/NEJMoa0807611. 
4. Fearon WF, Bornschein B, Tonino PA, et al. Economic evaluation of fractional flow reserve-
guided percutaneous coronary intervention in patients with multivessel disease. Circulation. 
2010;122(24):2545-2550. doi: 10.1161/CIRCULATIONAHA.109.925396; 
10.1161/CIRCULATIONAHA.109.925396. 
5. Tu S, Barbato E, Koszegi Z, et al. Fractional flow reserve calculation from 3-dimensional 
quantitative coronary angiography and TIMI frame count: A fast computer model to quantify the 
functional significance of moderately obstructed coronary arteries. JACC Cardiovasc Interv. 
2014;7(7):768-777. doi: 10.1016/j.jcin.2014.03.004 [doi]. 
6. Morris PD, Ryan D, Morton AC, et al. Virtual fractional flow reserve from coronary angiography: 
Modeling the significance of coronary lesions: Results from the VIRTU-1 (VIRTUal fractional flow 
reserve from coronary angiography) study. JACC Cardiovasc Interv. 2013;6(2):149-157. doi: 
10.1016/j.jcin.2012.08.024 [doi]. 
7. Papafaklis MI, Muramatsu T, Ishibashi Y, et al. Fast virtual functional assessment of 
intermediate coronary lesions using routine angiographic data and blood flow simulation in 
humans: Comparison with pressure wire - fractional flow reserve. EuroIntervention. 2014. doi: 
20140526-01 [pii]. 

!"#$#%#&'()'*)+'
,-.'/0123'44'5$678'
7)'+9:*+:;+*<'
=>.&5)-#&?@A>)B6)7A'
0B"-65'C=>(."5>$8'D#5E>$B&'
!BF.'"#'#G'"#'
'
8. Applegate RJ, Sacrinty MT, Kutcher MA, et al. Comparison of drug-eluting versus bare metal 
stents on later frequency of acute myocardial infarction and death. Am J Cardiol. 2007;99(3):333-
338.