Verona Coronary Physiology Interventional Registry
Conditions: Coronary Artery Disease, Ischemic Heart Disease (IHD), Coronary Heart Disease (CHD)
Sponsor: Azienda Ospedaliera Universitaria Integrata Verona

 
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Version 1, 01/03/2025 
 
 
Verona coronary physiology interventional registry 
 
 
 
 
ACRONYM: VR-CP 
 
Ethical committee authorization code: 618-CET 
 
Sponsor: Azienda Ospedaliera Universitaria Integrata Verona – UOC Cardiologia 
 
Principal investigator: Roberto Scarsini, MD PhD 
Co-investigators:  
• Simone Fezzi MD 
• Gabriele Pesarini MD PhD 
• Flavio Ribichini MD 
 
 

 
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Version number 1 of March 1st 2025 
 
This protocol is the confidential intellectual property of Study Promotor. The use of any 
unpublished material presented in this document must be restricted to the recipient for the agreed 
purpose and must not be disclosed to unauthorized persons without the written consent of the 
investigators. 
 
 

 
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SIGNATURE PAGE, APPROVAL OF STUDY PROTOCOL 
 
I, the undersigned, have read and understand the protocol and agree that it contains all necessary 
information for conducting the study for my position in the study and I agree to conduct the trial as 
set out in this study protocol, the current version of the World Medical Declaration of Helsinki, 
ICH-GCP guidelines and the local legally applicable requirements. 
 
 
 
 
 
 
Study Principal Investigator 
__________________________   
 
______________________________ 
Date:  
 
 
 
 
 
 
Verona, 15/09/2025
Roberto Scarsini

 
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SUMMARY 
 
 
1. SYNOPSY ....................................................................................................................................................................... 6 
2. INTRODUCTION .......................................................................................................................................................... 8 
3. STUDY DESIGN .......................................................................................................................................................... 14 
4. STUDY OBJECTIVES ................................................................................................................................................ 15 
5. POPULATION ............................................................................................................................................................. 16 
6. DESCRIPTION OF THE DISEASE IN THE STUDY ............................................................................................ 17 
7. ENDPOINTS ................................................................................................................................................................. 18 
8. PLANNED PROCEDURES AND DATA COLLECTION ...................................................................................... 19 
9. DATA MANAGEMENT AND PROCEDURES TO ENSURE DATA CONFIDENTIALITY ........................... 22 
10. STUDY DURATION .................................................................................................................................................. 24 
11. SAMPLE SIZE CALCULATION ............................................................................................................................ 24 
12. STATISTICAL ANALYSIS ...................................................................................................................................... 25 
13. LIMITATIONS AND BIASES ................................................................................................................................. 26 
14. ADVERSE EVENTS .................................................................................................................................................. 27 
15. DEFINITIONS ........................................................................................................................................................... 29 
16. ETHICAL ASPECTS AND REGULATORY STANDARDS ................................................................................ 31 
17. DATA OWNERSHIP AND PUBLISHING AGREEMENTS ............................................................................... 32 
18. REFERENCES ........................................................................................................................................................... 33 
 
 
 

 
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Abbreviation 
AE: adverse event 
ACS: acute coronary syndrome 
CAD: coronary artery disease 
CCS: chronic coronary syndrome 
DES: drug-eluting stent 
eCRF: electronic clinical report form  
FCA: functional coronary angiography 
FFR: fractional flow reserve 
IVUS: intravascular ultrasound  
LDL: low density lipoprotein 
VLDL: very low-density lipoprotein 
MI: myocardial infarction 
MLA: minimum lumen area  
OCT: optical coherence tomography 
PCI: percutaneous coronary intervention  
SAE: serious adverse event 
SAQ: Seattle angina questionnaire 
TCFA: thin cap fibroatheroma 
TVR: target vessel revascularization  
VOCE: vessel-oriented cardiac adverse events 
 

 
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1. SYNOPSY 
Study title 
Verona coronary physiology interventional registry 
(VR-CP) 
Protocol version 
V1 
Date 
March, 1st 2025 
Study sponsor 
Azienda Ospedaliera Universitaria Integrata di Verona 
Study principal 
investigator 
Roberto Scarsini MD PhD 
Patient population  
The observational Verona Coronary Physiology Interventional Registry 
(VR-CP) study enrols patients with suspected coronary artery disease 
who underwent coronary angiography with functional assessment 
(coronary physiology).  
Primary objective 
The primary objective is to assess the functional characteristics of 
coronary lesions documented during coronary angiography and correlate 
them with the risk of cardiovascular events during follow-up. 
Secondary objective 
- 
To examine the prognostic value of physiological parameters 
(FFR and angiography-derived FFR). 
- 
To analyze the clinical, demographic, and angiographic 
characteristics of patients with coronary lesions assessed by 
coronary physiology parameters, in order to identify high-risk 
subgroups. 
- 
To correlate coronary physiology values with angina symptoms. 
- 
To compare invasive FFR with angiography-derived FFR.  
- 
To compare clinical outcomes between patients managed 
conservatively and those undergoing invasive interventions. 
Study design 
The VR-CP study is a single-center observational study enrolling 
consecutive patients with coronary stenoses documented during 
coronary angiography and functionally assessed with coronary 
physiology (fractional flow reserve [FFR] or angiography-derived FFR) 
performed for suspected ischemic heart disease. Follow-up is 
conducted, after obtaining informed consent, through telephone contact 
and/or outpatient visits. Adverse events are adjudicated by an 
independent clinical events committee, blinded to clinical data. 
Data source 
The selection of eligible patients is extracted from registries and the 
analysis of coronary angiographic studies performed from January 2010 
to December 2024. 
Sample size 
Enrollment will include approximately 1,000 patients evaluated with 
FFR or angiography-derived FFR. This sample size will allow for 
subgroup analyses stratifying lesions by functional severity based on 
FFR values. 
Inclusion criteria 
- 
Coronary angiography with functional assessment by FFR or 
angiography-derived FFR (index procedure) 
- 
Provision of written informed consent 
- 
Age ≥18 years old at the time of the index procedure 

 
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Exclusion Criteria 
- 
Inability to provide informed consent to participate in the study 
Informed Consent 
Patients identified as eligible for the protocol will be invited to provide 
informed consent for participation in the retrospective study through 
contact by telephone, e-mail, mail, or during an outpatient visit. 
Study Procedures 
Once eligibility for the protocol is confirmed, informed consent is 
requested and obtained. After enrolment, the angiographic images from 
the index coronary angiography are analysed by the investigators. Long-
term follow-up is performed by monitoring the clinical status and 
recording major adverse cardiac events through review of medical 
records, outpatient visits, or telephone contacts. 
Primary Endpoint 
Composite of vessel-oriented composite endpoint (VOCE), including 
target vessel revascularization (TVR), target vessel-related myocardial 
infarction (MI), and cardiovascular death. 
Secondary 
Endpoints 
- 
Individual components of the primary endpoint 
- 
Hospitalization for unstable angina 
- 
Angina status (Seattle Angina Questionnaire) 
- 
Number of prescribed antianginal medications 
Study Duration 
Patients are retrospectively enrolled from January 2010 to December 
2024. 
Clinical contact (medical records, outpatient visits, telephone 
communication) is periodically collected recording longitudinal data at 
12-month intervals. 
Clinical Event 
Adjudication 
Committee 
The following events are adjudicated by an independent committee 
blinded to clinical data: TVR, target vessel-related MI, cardiovascular 
death, and hospitalization for unstable angina. 
 
 
 
 
 
 
 
 
 
 

 
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2. INTRODUCTION 
 
Integrated assessment of lesion hemodynamic impact and high-risk plaque 
features: an unmet clinical need.   
 
Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality in developed 
countries [1]. Coronary angiography remains the gold standard for diagnosing CAD, however, its 
ability to differentiate ischemic from non-ischemic lesions is limited [2]. Relying solely on the 
anatomical evaluation through coronary angiography fails to reveal the hemodynamic significance 
of epicardial CAD [3]. The 2-dimensional representation of the arterial lesion provided by 
angiography is limited in distinguishing intermediate lesions that require stenting from those that 
simply need appropriate medical therapy [4]. In the current era of drug-eluting stents (DES), when 
percutaneous coronary revascularization is achieved with high success rates, low complication 
rates, and excellent long-term patency, it might be tempting to treat all suspect lesions with DES 
implantation [4]. However, procedural complications associated with percutaneous coronary 
intervention (PCI), the inherent risk of restenosis, and late stent thrombosis still exist. 
Histopathological studies have demonstrated that angiographic evidence of stenosis is usually not 
detected until the plaque’s cross-sectional area approaches 40% to 50% of the vessel’s total cross-
sectional area. The outer wall of the artery, encompassed by the external elastic membrane, enlarges 
to accommodate the growing plaque. This process of compensatory dilatation seems to be limited. 
When the plaque area exceeds 40% to 50% of the external elastic membrane area, the plaque begins 
to encroach upon the lumen. Only at this point the angiogram might reveal minimal luminal 
narrowing [4–7]. 
In this respect, coronary physiology, which consider the functional severity of coronary stenosis, 
outperforms the traditional diagnostic approach based solely on morphometric assessment. 

 
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Consequently, invasive wire-based solutions for physiological assessment were developed to 
identify ischemia-producing epicardial coronary stenoses [3, 8]. Current European guidelines 
emphasize the importance of performing physiological assessment for all intermediate coronary 
artery stenoses, including left main stenosis, side branch stenosis and serial stenoses, when 
functional information from non-invasive tests is lacking [9]. Moreover, in patients with multivessel 
CAD, PCI guided by fractional flow reserve (FFR) results in an improved outcome irrespective of 
available non-invasive functional test results [9]. The development of FFR and its use in guiding 
percutaneous intervention, has led to improved patient outcomes compared with angiography 
guidance alone [10]. New developments in wire-free functional coronary assessment derived from 
the angiogram, globally termed as functional coronary angiography (FCA), may contribute to a 
more widespread use of physiology to diagnose the cause of ischemia and to plan and guide 
coronary revascularization [11–16]. These systems are based on vessel lumen reconstructions from 
coronary angiography, with the aim of providing FFR-like estimates of stenosis severity, whilst not 
requiring pharmacological agents or intracoronary instrumentation. Different software approaches 
to FFR estimation derived from coronary angiography have been developed. Several studies 
demonstrated the good correlation between wire-based and Angiography-derived FFR with a cut-
off of 0.80. In a recent meta-analysis of 16 studies, 819 patients and 969 vessels with paired FFR 
and Angiography-derived FFR were included. Authors found an overall satisfactory agreement 
(mean difference 0.009 ± 0.068, I2 = 39.6) of angiography- and wire- derived FFR. The diagnostic 
performance was sensitivity 84% (95%CI: 77-90, I2 = 70.1), specificity 88% (95%CI: 84-91, I2 = 
60.1); positive predictive value 80% (95%CI: 76-85, I2 = 33.4), and negative predictive value 95% 
(95%CI: 93-96, I2 = 75.9) [15]. Several non-inferiority trials are ongoing to provide the data answer 
regarding Angiography-derived FFR clinical equivalence in comparison with wire-based FFR 

 
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(Tab.I). Angiography-derived FFR analyzability depends on quality of angiography, and it is 
feasible in around 80% of the cases. 
 
The Vulnerable Plaque: Pathophysiology of Coronary Artery Disease 
Progression 
 
Acute coronary syndromes (ACS) primarily result from the rupture or erosion of a vulnerable 
plaque [17]. After the first acute event, a residual risk of recurrent coronary events persists despite 
optimal medical therapy. Target lesion–related events mainly drive this risk during the first year. 
Thereafter, the risk stems from other lesions, which in most cases were only angiographically mild 
during the index procedure and were not considered at risk of rupture on initial coronary 
angiography, as demonstrated in several retrospective studies [17, 18].  
Indeed, even when non-obstructive and non–flow limiting on angiographic and/or functional 
assessment, a coronary lesion may harbor vulnerable features not detectable by angiography that 
increase the risk of rupture [19]. 
The concept of “vulnerable plaque” was first introduced in 1989 by Muller et al., referring to 
plaques associated with an increased risk of destabilization, rupture, and subsequent vessel 
occlusion. They observed that, in most cases, the culprit vessel displayed only mild stenosis, not 
angiographically critical, and that thrombosis was the main mechanism of vessel occlusion. Since 
then, several studies have focused on defining, detecting, and analyzing plaque vulnerability[20] 
In 2003, Naghavi et al. published the first consensus document to standardize definitions of 
vulnerable plaques, described as “all plaques prone to thrombosis and with a high likelihood of 
rapid progression, thereby becoming culprit plaques”. Five major vulnerability criteria were 
identified: 1) a thin fibrous cap with a large lipid core; 2) active inflammation within the plaque 

 
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(e.g., macrophage infiltration); 3) endothelial denudation leading to superficial platelet aggregation 
(e.g., plaque erosion); 4) a fissured plaque (mainly indicating recent rupture); 5) diameter stenosis 
>90%. Minor criteria included the presence of superficial calcific nodules, shiny yellow plaque on 
angioscopy, intraplaque hemorrhage, endothelial dysfunction, or outward remodeling. Multiple 
mechanisms contribute to plaque development and destabilization. Accumulation of low- and very-
low-density lipoproteins (LDL and VLDL), lipoprotein(a)-mediated inflammation, increased 
expression of adhesion molecules on endothelial cells, and active inflammation are key drivers of 
this process. Persistent elevation of circulating lipid levels promotes the formation of vulnerable 
plaques with a large necrotic core and a thin fibrous cap [20–22]. 
If the thin fibrous cap ruptures, the lipid-rich plaque releases its thrombogenic content into the 
bloodstream, leading to the formation of an occlusive (or sub-occlusive) intraluminal thrombus 
responsible for ACS. Thus, the thickness and quality of the fibrous cap influence the risk of rupture, 
although the triggering factors remain incompletely understood. Proposed triggers include changes 
in atherosclerotic plaque components, blood influx through the vasa vasorum, and the functional 
integrity of the arterial intima. Degradation of the extracellular matrix in the arterial wall by matrix-
degrading enzymes (e.g., matrix metalloproteinases) may further contribute. Perivascular adipose 
tissue (PVAT) may also be involved. Production of reactive oxygen species (ROS) and expression 
of intercellular and vascular adhesion molecules by endothelial cells promote active inflammation, 
activation of vascular smooth muscle cells, and increased release of proinflammatory cytokines and 
ROS. These factors activate PVAT, which responds by releasing proinflammatory adipocytokines, 
lipid mediators, and ROS, thus perpetuating a vicious cycle of active inflammation and 
atherosclerosis progression [19, 23]. 
The PROSPECT study, the first prospective natural-history investigation correlating plaque features 
with subsequent cardiovascular events, included nearly 700 patients undergoing percutaneous 

 
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coronary intervention for ACS who also underwent intravascular ultrasound (IVUS). The aim was 
to assess the incidence of major adverse cardiovascular events related to both the culprit lesion and 
an additional non-culprit lesion. It was observed that 20.4% of patients experienced an event at 3-
year follow-up, equally attributable to culprit and non-culprit lesions, with most non-culprit event-
related lesions being angiographically mild at baseline (mean diameter stenosis 32.3 ± 20.6%). 
Gray-scale and radiofrequency IVUS analysis showed that the presence of a thin-cap fibroatheroma 
(TCFA), together with a plaque burden >70% and a minimal luminal area (MLA) <4.0 mm², was a 
strong independent predictor for non-culprit lesions. Vulnerable non-culprit plaques are common in 
patients with multivessel disease. A secondary analysis of the COMPLETE trial showed that nearly 
50% of patients with ST-segment elevation myocardial infarction (STEMI) had at least one non-
culprit obstructive TCFA. Moreover, obstructive lesions (>70% diameter stenosis on visual 
assessment) more often contained vulnerability features than non-obstructive lesions. Another 
interesting study by Zhao et al. showed that, among STEMI patients who underwent optimal optical 
coherence tomography (OCT) imaging of all three coronary arteries, those with plaque progression 
at 12 months (defined as a ≥0.4 mm reduction in minimal luminal diameter) had more high-risk 
plaque features (47.4% vs. 33.3%; p = 0.036) and more non-culprit plaque ruptures (25.6% vs. 
4.5%, p = 0.036).  [18] 
 
 
 
The Vulnerable Plaque and the Vulnerable Patient: A Targeted Therapeutic 
Approach 
 
Atherosclerosis progresses through repeated cycles of plaque rupture and healing, driven by 
persistent active inflammation, ultimately leading to progressive luminal narrowing. This 

 
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phenomenon is particularly pronounced in vulnerable plaques compared to stable lesions. Since 
inflammation promotes atherosclerosis progression, plaque destabilization, and a prothrombotic 
state, targeted therapeutic strategies aimed at reducing both local and systemic inflammation have 
been proposed and tested to improve cardiovascular outcomes.[22] 
Ongoing studies are evaluating preventive strategies based on intensification of pharmacologic 
therapy in patients at high risk of cardiovascular events, or a combination of medical therapy with 
prophylactic revascularization of vulnerable plaques.[22] 
With regard to medical therapy, randomized clinical trials have demonstrated that intensive lipid-
lowering therapy stabilizes vulnerable plaques, either with high-dose statin therapy alone or in 
combination with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor [19] 
As for prophylactic revascularization of vulnerable lesions, robust evidence indicates that in chronic 
coronary syndromes (CCS), this strategy has not significantly improved long-term outcomes. 
Conversely, in patients with STEMI and multivessel disease—who exhibit a higher prevalence of 
vulnerable plaques than those with CCS—elective treatment of non-culprit obstructive lesions has 
been shown to reduce the 5-year incidence of myocardial infarction and future acute coronary 
syndromes in the COMPLETE trial [19, 24]. Following stenting, neointimal hyperplasia generates a 
new fibrous cap, thickening the pre-existing one. Moreover, the use of everolimus-eluting stents has 
been shown in animal models to reduce plaque macrophage content. Large-scale randomized 
clinical trials are underway to determine whether focal therapy of imaging-identified vulnerable 
plaques can improve overall patient outcomes. Recently published results from the PREVENT 
trial—randomizing more than 1,500 patients with CCS or ACS in a 1:1 ratio to medical therapy 
alone or medical therapy plus revascularization (using bioresorbable vascular scaffolds or second-
generation everolimus-eluting stents) of non–flow-limiting, non-culprit vulnerable plaques 
identified by IVUS, radiofrequency IVUS, or OCT—appear to support the interventional strategy. 

 
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At two years, the composite endpoint of cardiac death, target vessel myocardial infarction, 
ischemia-driven target vessel revascularization, or hospitalization for unstable or progressive angina 
was significantly lower in the PCI group (absolute difference –3.0%, 95% CI –4.4 to –1.8, 
p=0.0003) [25]. 
3. STUDY DESIGN 
 
The Verona Coronary Physiology Interventional Registry (VR-CP) study is a single-center, single-
arm, observational study with blinded event adjudication. VR-CP enrolls patients who underwent 
coronary angiography for suspected ischemic heart disease, in whom at least one coronary lesion 
was identified and functionally assessed by coronary physiology testing (fractional flow reserve 
[FFR] or angiography-derived FFR). 
Eligible patients are identified through registry data and review of coronary angiographic studies 
performed from January 2010 to December 2024. Patients meeting inclusion criteria are invited to 
provide written informed consent to participate in the observational study. Recruitment may occur 
through telephone, mail, email, or during outpatient visits. All study data are recorded in an 
anonymized electronic case report form (eCRF). 
The follow-up involves periodic recording of the clinical status and reporting of any adverse events 
through review of medical records, outpatient visits, or telephone communications, in order to 
ensure longitudinal data collection at 12-month intervals. 
Adverse events are adjudicated by an independent Clinical Event Committee (CEC) blinded to all 
patient clinical data. Investigators will provide the CEC with anonymized clinical documentation 
relating to the reported adverse event. The CEC will adjudicate events that are part of the study’s 
primary and secondary endpoints. Event definitions and adjudication rules are established by the 

 
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Principal Investigators and recorded in the Adjudication Committee Charter. The adjudication 
outcomes determined by the CEC will be used for the final statistical analysis. 
CEC members will be appointed by the Principal Investigator at the time of study activation. They 
will be selected among experienced cardiologists with no access to the clinical documentation of 
enrolled patients. 
4. STUDY OBJECTIVES 
 
Primary Objective  
The primary objective is to identify a risk profile for vessel-oriented composite endpoint (VOCE) 
associated with the functional characteristics of coronary lesions documented during coronary 
angiography. 
 
Secondary Objectives  
Secondary objectives include: 
- 
Assessing the prognostic value of physiological parameters (invasive FFR and angiography-
derived FFR). 
- 
Analysing the clinical, demographic, and angiographic characteristics of patients with 
coronary lesions evaluated by coronary physiology to identify high-risk subgroups. 
- 
Investigating the correlation between coronary physiology values and angina symptoms. 
- 
Comparing invasive FFR with angiography-derived FFR. 
- 
Comparing clinical outcomes between patients managed conservatively and those 
undergoing invasive interventions.  
 
 

 
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5. POPULATION 
 
Inclusion Criteria 
- 
Previous coronary angiography with assessment of FFR and/or angiography-derived FFR. 
- 
Age ≥ 18 years old* 
- 
Provision of written informed consent. 
* At the time of the index coronary angiography. 
 
Exclusion Criteria 
- 
Inability to provide informed consent to participate in the study. 
- 
Age < 18 years old* 
* At the time of the index coronary angiography. 
 
Vulnerable Populations 
The following subjects will not be eligible for inclusion: 
- 
Pregnant women 
- 
Women who are breastfeeding 
 
Criteria for Early Withdrawal from the Study 
Subject’s request to withdraw participation 
 
 
 

 
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6. DESCRIPTION OF THE DISEASE IN THE STUDY 
 
Ischemic Heart Disease and General Information on Coronary Angiography 
The selection of eligible patients is based on the review of hospital registries and the analysis of 
coronary angiography procedures performed from January 2010 to December 2024.  
Participants with suspected CAD undergo coronary angiography as part of the standard diagnostic 
and therapeutic pathway, in accordance with current guidelines for the management of ischemic 
heart disease. A patient is considered eligible if at least one mild or intermediate coronary stenosis 
is identified on angiographic assessment and subsequently evaluated with a coronary physiology 
test (fractional flow reserve [FFR] or angiography-derived FFR). These functional assessments 
guide the operator’s decision to proceed with or defer vessel revascularization. 
If a physiological evaluation of CAD is performed, the corresponding data — including FFR and/or 
angiography-derived FFR — are collected and recorded. The initial angiogram of all patients will 
be stored, anonymized, and kept locally for functional analysis (acceptable formats include CD, 
DVD, or digital files). 
 
 
 
 
 
 
 
 

 
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7. ENDPOINTS 
 
Primary Endpoint 
The primary endpoint is the composite risk of vessel-oriented composite endpoint (VOCE), 
including target vessel revascularization (TVR), vessel-related myocardial infarction (MI), and 
cardiovascular death. 
Secondary Endpoint 
• Individual components of the primary endpoint. 
• Hospitalization for unstable angina. 
• Angina status assessed using the Seattle Angina Questionnaire (SAQ). The SAQ will be 
used to evaluate patients' quality of life and the impact of angina symptoms over time. 
Scores from the main subscales (physical limitation, angina stability, angina frequency, 
treatment perception, and overall quality of life) will be analysed to correlate symptom 
severity with coronary physiology parameters (e.g., FFR/angiography-derived FFR). 
• Number of prescribed antianginal drugs. The number of prescribed antianginal medications 
will be monitored to assess the intensity of pharmacological treatment required during 
follow-up. This parameter will serve as a proxy for residual disease severity and will allow 
comparison between patients managed conservatively and those treated with invasive 
interventions. 
 
 
 
 

 
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8. PLANNED PROCEDURES AND DATA COLLECTION 
 
The VR-CP study is a retrospective observational study enrolling consecutive patients who 
underwent coronary angiography for suspected ischemic heart disease and were found on 
angiographic examination to have coronary lesions evaluated using coronary physiology testing 
(FFR or angiography-derived FFR). These physiology assessments guided the decision to proceed 
with or defer target vessel revascularization. 
Regardless of whether the lesion was treated invasively or managed conservatively, patients’ 
clinical status and any adverse events are periodically recorded. 
This retrospective follow-up is conducted through the collection of information from medical 
records, direct contact during outpatient visits, or via telephone communications, in order to ensure 
longitudinal data collection at 12-month intervals.    
  
 
 
 
 
 
 
Fig. 1 
Summary of Activities Performed 
 

 
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Flowchart 
Fig.2 Retrospective Observational Study Design 

 
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*at the time of index procedure 

 
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DATA MANAGEMENT AND PROCEDURES TO ENSURE DATA CONFIDENTIALITY 
The Sponsor commits to comply with Privacy Laws (as defined below), including provisions 
relating to security measures and confidentiality. The Sponsor guarantees, for itself and the 
Investigator, full awareness of all obligations arising from any applicable regulations concerning 
professional medical confidentiality and the protection of patients’ personal data, including but not 
limited to EU Regulation 2016/679, the Italian Privacy Code (Legislative Decree 196/03, as 
amended), the provisions, guidelines, and current general authorizations issued by the Italian Data 
Protection Authority (collectively “Privacy Laws”).  The Sponsor ensures that all personnel 
involved in the conduct of the study comply with Privacy Laws and the Sponsor’s instructions 
regarding the protection of personal data, including security and confidentiality aspects. This 
obligation includes, for example: (i) providing the patient with a complete and lawful privacy notice 
(in particular, EU Regulation 2016/679, Legislative Decree 196/2003 as amended, and the 
aforementioned guidelines dated July 24, 2008); (ii) obtaining the patient’s written informed 
consent before participation in the study; (iii) respecting the privacy rights of each data subject as 
established by applicable Privacy Laws; (iv) adopting all appropriate physical, logical, 
organizational, technical, and IT measures in compliance with applicable Privacy Laws. Due to the 
particular sensitivity of the data processed in the study, specific technical measures have been 
adopted to increase data security, without prejudice to any other minimum measures. These relate 
especially to the recording of data on persons involved in the study at the investigative sites, 
whether electronic or paper-based, their electronic transfer to a centralized database held by the 
Sponsor or third parties performing data validation and statistical processing on behalf of the 
Sponsor, and the management of this database. The Sponsor has taken appropriate measures to 
protect the recorded data from risks of unauthorized access, theft, or partial or total loss of paper 
documents, storage media, or fixed or portable processing systems. 

 
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Access to computers storing the data requires a username and password. Furthermore, access to the 
database for data entry sessions is protected by username and password. To ensure data 
confidentiality and to prevent data manipulation or loss, the following precautions are taken: 
Data access is restricted to authorized members only. The network is protected by a firewall. 
Internet connections are encrypted with a digital certificate (SSL technology). The database is 
hosted on a password-protected server, with passwords changed periodically. Database access is 
password protected and limited to responsible personnel at the center. Periodic backups are 
performed. 
Paper materials related to clinical assessments will be stored in locked cabinets, with keys held only 
by persons authorized by the study management. The Sponsor has adopted secure communication 
protocols based on cryptographic standards for the electronic transmission of data collected from 
investigative sites to the centralized database maintained by the Sponsor or third parties performing 
subsequent data validation and statistical processing. The Sponsor will require the adoption of 
secure communication protocols for the transmission of any paper documentation. Regarding the 
database, appropriate authentication and authorization systems are in place according to user roles 
and access needs, along with periodic procedures to verify the quality and consistency of 
authentication credentials and authorization profiles assigned to data handlers. The Investigator will 
adequately dissociate patient identifying data from study result data (e.g., by anonymizing results 
using randomly generated alphanumeric codes) so that only pseudonymized data are processed by 
the Sponsor. 
The Sponsor will allow access to clinical data (including medical records) and any other 
information relevant to the study, always in compliance with applicable Privacy Laws and 
respecting data security and confidentiality measures. Within the limits provided by the information 
given to study patients, personal data will be accessible only to employees, collaborators, monitors, 

 
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and auditors of the Sponsor, and/or to competent authorities in the exercise of their functions. The 
Sponsor and Investigator commit to clearly and fully inform each study patient about the processing 
of their personal data before participation in the study, according to applicable Privacy Laws. 
Before data acquisition, the Investigator will provide appropriate information to each patient 
regarding the nature, purpose, outcomes, consequences, and risks of the study. Prior to patient 
enrollment, the Investigator or authorized delegate will obtain written informed consent from the 
patient for: (a) participation in the study; (b) communication of related confidential information; (c) 
processing of personal data; (d) transfer of documentation containing the patient’s personal data, 
including sensitive health data, to the Sponsor and/or competent authorities and/or other 
institutions, including those outside the European Union, in accordance with legal requirements and 
applicable Privacy Laws. The Sponsor commits to retaining original paper documentation (e.g., 
informed consent forms) for at least 7 years in compliance with Legislative Decree 200/2007. 
10. STUDY DURATION 
 
Recruitment: Once eligibility for the protocol is confirmed, informed consent is requested and 
obtained, and the patient is then enrolled in the study. 
Patient involvement: Enrollment includes patients undergoing coronary angiography from January 
2010 to December 2024.  
Follow up: Follow-up will be maintained until all patients have completed a clinical evaluation at 
10 years. 
 
 
 
 

 
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11. SAMPLE SIZE CALCULATION 
In contemporary clinical trials on coronary physiology indices, the composite adverse event rate at 
12 months follow-up is relatively low, ranging from 6.1% in the SWEDEHEART-IFR study to 
6.7% in the DEFINE-FLAIR study. Therefore, assuming a type I error of 0.05 and a statistical 
power of 80%, the study should include 1000–1200 patients to generate a sufficient number of 
evaluable events. This sample size will also allow for subgroup analyses stratifying lesions by 
functional severity based on FFR values. 
12. STATISTICAL ANALYSIS 
 
Continuous variables will be tested for normal distribution using the Kolmogorov-Smirnov test. 
Variables with a normal distribution will be presented as mean ± standard deviation and compared 
using t-tests and one-way ANOVA. Otherwise, median [interquartile range] will be used, and 
comparisons will be performed using the Mann-Whitney U and Kruskal-Wallis tests. Categorical 
variables will be summarized as absolute and relative frequencies (percentages) and compared using 
the χ² test. Correlations between variables will be evaluated using linear and logistic regression 
analyses. The level of statistical significance will be set at α = 0.05. Kaplan-Meier curves will be 
plotted to describe event-free survival, and differences between groups will be tested using the log-
rank test. The primary analysis will be based on events occurring during the entire follow-up period 
for each patient at database lock. Any confounding factors will be tested using Cox regression 
models. Variables with a p-value < 0.1 in univariate analysis will be included in a multivariate 
analysis to identify independent predictors. When appropriate, 95% confidence intervals will be 
calculated. 
 

 
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13. LIMITATIONS AND BIASES 
 
The VR-CP retrospectively enrols patients who underwent coronary angiography documenting at 
least one mild to intermediate coronary lesion assessed by coronary physiology tests (FFR or 
angiography-derived FFR). The retrospective enrolment may not be fully representative of the 
general population or could be influenced by prior clinical decisions, thus introducing selection 
bias. To mitigate this issue, consecutive patients are enrolled, ensuring a more representative and 
generalizable sample. This approach minimizes the influence of selection bias, investigator bias, 
and temporal bias, improving the logistical simplicity and scientific rigor of the study. Our goal is 
to ensure that the sample reflects the typical patient population encountered in routine clinical 
practice. 
Another limitation is that historical data might reflect medical practices or diagnostic techniques 
that are no longer routinely used or have evolved over time, limiting the generalizability of the 
results. 
An independent Clinical Event Committee (CEC) evaluates all endpoints. The CEC members and 
management team are fully blinded to patients’ identifying information. The CEC adjudicates 
events based on predefined definitions. Additional measures to prevent or minimize bias include the 
use of objective criteria for endpoint classification. Finally, unlike prospective randomized studies, 
this retrospective study does not include randomization, which may lead to uneven distribution of 
risk factors. 
 
 
 

 
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14. ADVERSE EVENTS 
Definitions 
Adverse Events (AEs) / Serious Adverse Events (SAEs) / Incidents: 
Any undesirable medical occurrence in a clinical study during which a patient receives the study 
treatment, and which does not necessarily have a causal relationship with such treatment or with 
any device malfunction. An AE can therefore be an unintended and accidental manifestation, 
represented by a sign (including an abnormal laboratory result), a symptom, or a disease, whose 
onset is temporally associated with the study treatment or with any device malfunction, whether 
related or unrelated to the study treatment. 
Serious Adverse Event (SAE): 
Any undesirable medical event or device malfunction that results in one or more of the following 
outcomes: 
- 
Death 
- 
Life-threatening condition 
- 
Hospitalization or prolongation of existing hospitalization 
- 
Persistent or significant disability/incapacity 
- 
Congenital anomaly/birth defect 
- 
Medically significant event or one that requires intervention to prevent any of the above 
outcomes. If an event meeting the SAE definition occurs after signing the informed consent 
form but before patient inclusion, it should not be reported as an SAE. Such an event may be 
reported in the appropriate section of the Case Report Form (CRF). 
For medical devices and active implantable medical devices, an incident is defined as: 
a) Any malfunction or deterioration in the characteristics or performance of a medical 
device/active implantable medical device, as well as any inadequacy in labeling or 

 
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instructions for use, which may have caused or contributed to death or serious deterioration 
in the health condition of a patient or user; 
b) Any technical or medical reason related to the characteristics or performance of a medical 
device/active implantable medical device that leads to the systematic recall of devices of the 
same type by the manufacturer for reasons described in point (a). (Decree Legislative 24 
February 1997, n. 46 – Implementation of Directive 93/42/EEC concerning medical devices, 
amended by D. Lgs. 25.01.2010, n. 37). 
 
Monitoring of Adverse Events, Serious Adverse Events, and Incidents 
As established by the Investigator, patients who experience Adverse Events (AEs), Serious Adverse 
Events (SAEs), or Incidents will be evaluated using relevant clinical assessments and laboratory 
analyses. Any actions taken and the outcomes of follow-up must be recorded in the patient’s 
original documentation and in the appropriate sections of the Case Report Form (CRF). 
To obtain evidence of adverse events throughout the entire case series, the patient will be 
interviewed and/or examined by the Investigator or an authorized delegate. Questions asked to 
patients regarding the possible occurrence of adverse events should be as non-specific as possible. 
However, since the center is responsible for conducting follow-up for all cases of AEs, specific 
questions regarding previously reported AEs, SAEs, and Incidents must be included concerning 
their resolution or continuation.  
For treatment-related AEs/SAEs/Incidents, relevant clinical evaluations and laboratory analyses will 
be repeated until the event is fully resolved, stabilized, or its cause explained.  
SAEs not related to treatment that remain unresolved at the completion of the case series must be 
followed for a maximum period of one month after the case series completion. 
 

 
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Reporting of Adverse Events, Serious Adverse Events, and Incidents 
The reporting of an incident (whose definition is included within that of “serious adverse effect” 
used in clinical trials – see technical standard UNI EN ISO 14155-11) involving medical devices 
under post-marketing investigation must be carried out similarly to the reporting for medical 
devices used in routine clinical practice, through the completion of the Ministry’s form for MD/IVD 
(Medical Devices/Active Implantable Medical Devices) — which requires indicating the study code 
number — or the form related to IVDs (In Vitro Diagnostics). A copy of the report must also be 
sent to the relevant Ethics Committee. 
15. DEFINITIONS 
Ischemia-driven target vessel revascularization (TVR)  
All ischemia-driven revascularizations refer to the target lesion that led to enrollment into the study.  
Requires the following criteria: 
- 
Ischemic symptoms consistent with CCS class ≥ 3 angina despite optimal medical therapy 
AND 
- 
PCI or CABG of either the target that led to enrollment into the study PLUS at least ONE of 
the following: 
- 
Positive functional study (Exercise or myocardial perfusion imaging or stress or 
dobutamine echo) demonstrating clear evidence of reversible ischemia corresponding to 
a stenosis in the target vessel; 
- 
New ischemic ECG changes (ST-segment depression ≥ 1 mm, ST-segment elevation ≥ 1 
mm or T wave inversion ≥ 2 mm) at rest or with exertion in a distribution consistent with 
a stenosis in the target vessel; 
- 
FFR ≤0.80, iFR≤0.89, cFFR≤0.85, Angiography-derived FFR≤0.80 in the target vessel. 
 

 
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Vessel-related myocardial infarction (MI) 
MI is defined according to the 4th universal definition of myocardial infarction. The leading 
symptom that initiates the diagnostic and therapeutic cascade in patients with suspected MI is 
chest pain. Based on the electrocardiogram (ECG), two groups of patients should be differentiated: 
Patients with acute chest pain and persistent (>20 min) ST-segment elevation. This condition is 
termed ST-elevation ACS and generally reflects an acute total coronary occlusion. Most patients 
will ultimately develop an ST-elevation myocardial infarction (STEMI). The mainstay of treatment 
in these patients is immediate reperfusion by primary angioplasty or fibrinolytic therapy.  
Patients with acute chest pain but no persistent ST-segment elevation. ECG changes may include 
transient ST-segment elevation, persistent or transient ST-segment depression, T-wave inversion, 
flat T waves or pseudo-normalization of T waves or the ECG may be normal. The clinical spectrum 
of NSTE-MI may range from patients free of symptoms at presentation to individuals with ongoing 
ischemia, electrical or hemodynamic instability or cardiac arrest. 
The pathological correlate at the myocardial level is cardiomyocyte necrosis. A small proportion of 
patients may present with ongoing myocardial ischemia, characterized by one or more of the 
following: recurrent or ongoing chest pain, marked ST depression on 12-lead ECG, heart failure and 
hemodynamic or electrical instability. Due to the amount of myocardium in jeopardy and the risk of 
malignant ventricular arrhythmias, immediate coronary angiography and, if appropriate, 
revascularization are indicated. The clinical definition of MI denotes the presence of acute 
myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute 
myocardial ischaemia.  
Any MI without a clearly identifiable culprit vessel is counted as target vessel related.  
 
Cardiovascular death 

 
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Deaths are classified as cardiovascular, non-cardiovascular, or of undetermined cause according to 
ARC-2 criteria. Deaths of undetermined cause are classified as cardiovascular but as a separate 
subcategory of cardiovascular deaths to indicate this uncertainty. Deaths due to procedural 
complications or concomitant treatments are classified as cardiovascular. Only deaths due to a 
documented non-cardiovascular cause (e.g., cancer) are classified as non-cardiovascular. 
Cardiovascular deaths in patients with multivessel disease are assigned to each affected vessel.  
16. ETHICAL ASPECTS AND REGULATORY STANDARDS 
Good clinical practice 
The latest version of the Declaration of Helsinki and the Oviedo Convention are the fundamental 
references for the clinical conduct of the study.  
The study protocol is designed and it will be conducted to ensure the adherence to the principles 
and the procedures of Good Clinical Practice and to comply with the Italian laws, as described in 
the following documents and accepted with their signature by the investigators of the study:  
- 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
- 
Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. 
- 
D. L.vo n.211 del 24 giugno 2003. 
- 
D. L.vo n.200 6 Novembre 2007. 
- 
D.M. 21 Dicembre 2007. 
- 
Determinazione AIFA 20 Marzo 2008. 
All the essential clinical documents will be stored in order to prove the validity and the integrity of 
the data collected.  

 
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According to the responsibilities provided from the rules of Good Clinical Practice (d.lgs 211/2003) 
and the applicable laws and regulations in the field of data protection including the European Data 
Protection Regulation 2016/679, the Promotor of the study will process the personal data, 
exclusively with the aim of the realization of the study and for the purpose of pharmacovigilance or 
medical device vigilance. 
17. DATA OWNERSHIP AND PUBLISHING AGREEMENTS 
 
The data are exclusively owned by the Promotor of the study and by Azienda Ospedaliera 
Universitaria Integrata di Verona. Published data refers to the following protocol.   
 
 

 
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