Definition of Intra-procedural Optical Coherence Tomography (OCT) Clinical Impact, Both in Terms of Revascularization Indication and Procedural Result.
Conditions: Acute Coronary Syndromes (ACS), Chronic Coronary Syndrome, MINOCA, INOCA (Ischemia With Non Obstructive Coronary Artery Disease), Percutaneous Coronary Intervention (PCI), Coronary Stent Implantation, Stent Restenosis, Stent Thrombosis, Clinical Outcome
Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

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STARRING OPTICAL COHERENCE TOMOGRAPHY DURING 
PERCUTANEOUS CORONARY INTERVENTIONS GUIDANCE: 
THE OCTAGEM REGISTRY  
 
 
 
 
 
 
I. NCT study number:     
 
II. Center: Fondazione Policlinico Universitario Agostino Gemelli, IRCCS 
 
 
    
    
    
 
  

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III. 
PROTOCOL SYNOPSIS 
Title 
Definition of intra-procedural optical coherence tomography 
(OCT) clinical impact both in terms of revascularization indication 
and procedural result.  
Design 
Observational ambispective cohort study. 
Single-centre, retrospective, observational registry (I phase) 
Single-centre prospective, observational registry (II phase) 
Objective 
To explore the role of intra-procedural OCT in order to optimize 
coronary revascularization in terms of procedural results and long-
term clinical outcome. 
Device/drug planned  
None 
Registration  
The study will be register on www.clinicaltrial.gov site after local 
Ethic Committee approval 
Study Population 
All subjects over 18 years who are undergoing an OCT coronary 
assessment during clinically indicated coronary angiogram 
regardless of the clinical syndrome (silent ischemia, effort angina 
or acute coronary syndrome). 
Estimated population size  
2200 (based on annual OCT-guided procedure rate of ~150) for the 
retrospective phase. 
1000 (based on annual OCT-guided procedure rate of ~150) for the 
prospective phase 
Statistical hypothesis 
On the basis of previous clinical studies testing clinical impact of 
OCT use during percutaneous coronary revascularization and 
preliminary experience of the steering committee, we estimated: 
 Non-interventional arm: a cumulative incidence of 5% for the 

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composite clinical end-point and of 20% for the OCT-defined 
vulnerable plaque are assumed. For the study purpose a sample 
size of 986 patients was computed assuming a HR of 0.80 favoring 
patients without OCT-defined plaque vulnerability, and aiming to 
a 2-sided alpha level of 0.05 and a power of 80%. To 
accommodate for possible missing investigations or withdrawals, 
sample size was increased to 1100 patients.  
Interventional arm: a cumulative incidence of 25% for the OCT-
defined suboptimal stent implantation and of 12% for the 
composite clinical end-point are assumed. For the primary study 
purpose a sample size of 1858 patients is computed assuming a 
HR of 0.85 favoring patients without suboptimal stent 
implantation OCT criteria, and aiming to a 2-sided alpha level of 
0.05 and a power of 80%. To accommodate for possible missing 
investigations, sample size will be increased to 2100 patients. 
The study enrolment will be considered complete when the 
required target population has been enrolled. A patient is 
considered enrolled in the study when he/she has signed the 
informed consent form (point of enrolment). 
  
Study Centre  
Fondazione Policlinico Universitario Agostino Gemelli, IRCCS 
Coordinating  
Clinical Investigator 
Dr. Enrico Romagnoli  
Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 
Rome, Italy  
 

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Primary Endpoints 
 
Predictive clinical value of vulnerable plaque OCT criteria at mid 
and long term outcome in patients with non-obstructive coronary 
artery disease (MINOCA/INOCA).  
Predictive clinical value of plaque/stent OCT parameters at mid 
and long term outcome in patients undergoing percutaneous 
coronary revascularization  
Clinical composite endpoint: cardiac death, target-vessel 
myocardial infarction, target lesion revascularization, and stent 
thrombosis 
Secondary Endpoints 
Non-interventional: clinical impact of the single pre-specified 
OCT features of plaque vulnerability: 
- Minimum lumen area <3.5 mm2; 
- Fibrous cap minimum thickness <65 µm; 
- Lipid arc extension >180°; 
- Presence of macrophages;  
- Superficial and deep calcified nodules 
- Ulceration/Erosion/Dissection 
- Layered tissue 
- Plaque burden (%) 
- Optical flow ratio (OFR) 
Interventional: clinical impact of the single pre-specified OCT 
features of the stented lesions:  
- Edge dissection with a width ≥200μm. 
- Reference narrowing: lumen area <4.5mm2 in presence of 
significant residual plaque adjacent to stent endings; 
- Malapposition >200μm;  
- In-stent minimum lumen area (MLA) <4.5mm2;  
- In-stent MLA <80% of the average reference lumen area;  
- Intrastent plaque/thrombus protrusion ≥500μm in thickness. 
- Stent deformation/geometry 
- Neo-carina shaping at bifurcation 
- Post-procedural optical flow ratio (OFR) 

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Selection Criteria 
 
Inclusion criteria 
 Age 18 years; 
 Patients with clinical indication to coronary angiography 
undergoing intra-procedural OCT regardless of the clinical 
syndrome; 
 Patients with at least one end-procedural OCT assessment 
with a sufficient acquisition length to address the whole 
length of plaque or stented segments plus the proximal and 
distal reference segments 
 Patient has been informed of the nature of the study, agrees to 
its provisions, and has provided written informed consent as 
approved by the Ethical Committee of the respective clinical 
site. 
 
Exclusion criteria 
 Female with childbearing potential or lactating; 
 Acute or chronic renal dysfunction (defined as creatinine 
greater than 2.0 mg/dl and/or GFR <30 ml/min); 
 Advanced heart failure (NYHA III-IV) 
 Previous heart transplantation 
 Co-morbidities that could interfere with completion of study 
procedures, or life expectancy less than 1 year; 
 Participating in another investigational drug or device trial 
that has not completed the primary endpoint or would 
interfere with the endpoints of this study; 
 Heavily calcified lesion or tortuous vessel which cannot be 
successfully imaged by OCT 
 Lesion located at the ostium or in angulated (>70°), sharp 
take-off vessel; 
Data source 
Data regarding procedures will be exported from the currently 
used cath-lab database (Suite ESTENSA), while data regarding 
clinical outcome (e.g. in-hospital course) will be exported from 
the general hospital database (Trackcare). 

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Safety/Adverse 
Event 
management 
All adverse events observed during the study will be collected and 
recorded. 
Adverse events involving medical devices can be classified as 
incidents and deficiency, the aforementioned, as identified by the 
following definitions, will be reported to the National Competent 
Authority and to the Manufacturer according to the provisions of 
current legislation for medical devices (EU Regulation 745/ 2017 
and Legislative Decree 5 August 2022, n.137 and subsequent 
communications from the Ministry of Health). 
In the case of a medical device, it means for 
• any untoward medical occurrence, unintended disease or injury 
or any untoward clinical signs, including an abnormal laboratory 
finding, in subjects, users or other persons, in the context of a 
clinical investigation, whether or not related to the investigational 
device.; 
• any inadequacy in the identity, quality, durability, reliability, 
safety or performance of an investigational device, including 
malfunction, use errors or inadequacy in information supplied by 
the manufacturer; 
• any incident, malfunction or alteration of the characteristics or 
performance of a device made available on the market, including 
the error of use caused by the ergonomic characteristics, as well as 
any inadequacy in the information provided by the manufacturer 
and any unwanted side effects. 
A serious incident is defined as any incident which, directly or 
indirectly, has caused, may have caused or may cause one of the 
following consequences: 

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a) death of the patient, user or other person 
b) serious deterioration, temporary or permanent impairment of 
the state of health of the patient, the user or another person; 
c) a serious threat to public health 
Data error control  
To limit the error in the assessment of OCT parameters and 
clinical outcome, only patients with adequate images quality (i.e. 
good OCT pullback quality), and complete clinical data 
collection (e.g. all clinical and procedural variables potentially 
affecting clinical course) will be enrolled in this study. These 
data will be recorded and used to perform a multivariable 
analysis for the study endpoints. 
Statistical analysis 
Continuous variables will be reported as mean (standard 
deviation) or median (interquartile range) and compared by 
means of paired t or Mann-Whitney tests, when appropriate. 
Categorical variables will be reported as raw numbers (%) and 
compared by means of Pearson chi-square, Fisher exact or log-
rank tests, when appropriate. Survival analysis will be conducted 
for the secondary clinical end-point by means of both Kaplan-
Meier method and/or Cox proportional hazard analysis. 
Multivariable logistic regression model will be used to identify 
independent outcome predictors and to calculate their adjusted 
hazard ratios (HRs) with associated 95% confidence intervals 
(CI). The Hosmer and Lemeshow goodness-of-fit test will be 

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used to assess model calibration. A two tailed, p value <0.05 has 
been established as the level of statistical significance for all 
tests.  
Study Timelines 
Enrolment start: September 2025  
Estimated last patient out: September 2031. 
Retrospective phase I:  
patients screening and data collection: 24 months 
Prospective phase II: 
Patients screening and data collection: 6 years (+5 follow up) 
Data analysis: 3 month 
Manuscript draft: 2 month 
 
 

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IV. STUDY FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCT features of plaque vulnerability: 
 
 Minimum lumen area <3.5 mm2; 
 Fibrous cap minimum thickness <65 µm; 
 Lipid arc extension >180°; 
 Presence of macrophages;  
 Superficial and deep calcified nodules 
 Ulceration/Erosion/Dissection 
 Layered tissue 
 Plaque burden (%) 
Non-interventional group 
Patients with medical therapy 
indication on the basis of 
angio/OCT results 
Interventional group 
Patients undergoing PCI on 
the basis of angio/OCT results 
Patients undergoing OCT coronary assessment 
during clinically indicated coronary angiogram 
regardless of the clinical syndrome 
Patients fulfilling inclusion/exclusion criteria 
with adequate intra-procedural OCT assessment  
Candidates 
Eligible  
Periodical follow up by means of scheduled direct visits (generally at six 
or twelve months) and phone contacts (after twelve months), to assess 
clinical outcome.                      
 
OCT features of the stented lesions:  
 
 Edge dissection with a width ≥200μm 
 Reference narrowing: lumen area <4.5mm2 in 
presence of significant residual plaque 
 Malapposition >200μm 
 In-stent minimum lumen area <4.5mm2 
 In-stent MLA <80% of the average reference 
lumen area 
 Intrastent plaque/thrombus protrusion 
≥500μm in thickness. 
 Stent deformation/geometry 

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V. CLINICAL STUDY SCHEDULE 
Baseline 
Follow-up 
Event 
Screen Enrolment Discharge Any contact 
Informed consent signed 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Physical examination 
X 
 
 
X* 
Medical and cardiac history 
X 
 
 
 
Diagnosis  
 
 
X 
X* 
Clinical status 
 
 
X 
X 
Clinical indication to coronary angiography  X 
 
 
 
ECG 
X 
 
X 
X* 
Medical regimen 
X 
X 
X 
X 
Adverse event monitoring 
 
 
X 
X 
Angiography (QCA)* 
 
X 
 
 
OCT 
 
X 
 
 
Phone call or e-mail 
 
 
 
X 
*To be performed in case of adverse event 

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VI. 
TABLE OF CONTENTS 
1. Title  
 
 
 
 
 
 
 
 
 
 
page 1 
2. Participating center 
 
 
 
 
 
 
 
 
page 1 
3. Protocol synopsis  
 
 
 
 
 
 
 
 
page 2 
4. Study flow chart  
 
 
 
 
 
 
 
 
page 9 
5. Clinical study schedule 
 
 
 
 
 
 
 
 
page 10 
6. Table of contents  
 
 
 
 
 
 
 
 
page 11  
7. Background and study rationale  
 
 
 
 
 
 
page 12 
8. Study Plan  
 
 
 
 
 
 
 
 
 
page 13 
9.1. Objective of the study 
 
 
 
 
 
 
 
page 13 
9.2. Study design  
 
 
 
 
 
 
 
 
page 13 
9.3. Study end-points 
 
 
 
 
 
 
 
 
page 14 
9.4. Number of patients  
 
 
 
 
 
 
 
page 16 
9.5. Patients selection criteria 
 
 
 
 
 
 
 
page 17 
9.6. Clinical Study schedule 
 
 
 
 
 
 
 
page 18 
9.7. Follow up procedures 
 
 
 
 
 
 
 
page 19 
9.8. Study duration 
 
 
 
 
 
 
 
 
page 20 
9.9. Patient withdrawal 
 
 
 
 
 
 
 
 
page 20 
9. Definitions 
 
 
 
 
 
 
 
 
 
page 21 
10. Materials and methods 
 
 
 
 
 
 
 
 
page 23 
10.1. Frequency-domain Optical Coherence tomography (FD-OCT)  
 
page 23 
10.2. Coronary angiography and quantitative coronary analysis (QCA) 
 
page 25 
11. Study organization 
 
 
 
 
 
 
 
 
page 26 
11.1. Clinical Events Committee 
 
 
 
 
 
 
page 26 
11.2. Statistical analysis  
 
 
 
 
 
 
 
page 26 
11.3. Ethics committee review and approval 
 
 
 
 
 
page 27 
11.4. Patient information and informed consent  
 
 
 
 
page 27 
11.5. Confidentiality and patient data protection 
 
 
 
 
page 27 
11.6. Source documents  
 
 
 
 
 
 
 
page 28 
11.7. Case report form 
 
 
 
 
 
 
 
 
page 28 
11.8. Final study report 
 
 
 
 
 
 
 
 
page 29 
11.9. Clinical data collection and management 
 
 
 
 
 
page 29 
11.9.1. Monitoring 
 
 
 
 
 
 
 
 
page 29 
11.9.2. Clinical Data Management 
 
 
 
 
 
 
page 29 
11.10. 
Publication policy 
 
 
 
 
 
 
 
page 30 
12. References 
 
 
 
 
 
 
 
 
 
page 31 
13. Figures 
 
 
 
 
 
 
 
 
 
 
page 37 
 
 
 

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VII. BACKGROUND AND STUDY RATIONALE 
 
The potential efficacy of intravascular imaging techniques in reducing adverse clinical outcomes after 
percutaneous coronary intervention (PCI) has been evidenced in several observational studies and large 
meta-analyses (1-4). Similarly, intravascular imaging could represent a valid help in proper assessment 
and management of intermediate/ambiguous lesions (5,7). 
In this context, frequency domain optical coherence tomography (FD-OCT) is the newest intracoronary 
imaging technique designed for a better definition of coronary atherosclerosis and its functional 
consequences (8-11). Indeed, OCT with its innovative high-resolution imaging (in the range of 10-15 
microns) system allows in vivo characterization of intraluminal and endothelial structures (8,9); in 
particular, it permits semi-automated accurate insights regarding plaque vulnerability, thrombus 
burden, stent apposition, struts coverage and neo-intimal growth.  
In terms of plaque assessment, the OCT allows not only the evaluation of pathogenetic mechanism 
underlying the clinical syndrome (i.e. plaque ulceration or erosion) (12,13) but consents an accurate 
individuation of vulnerable plaques, typically characterized by large superficial lipid pool, thin fibrous 
cap and variable local signs of inflammation (14-16). Identification of these plaque features with 
imaging modalities is potentially a valid approach to classify patients at increased risk of myocardial 
infarction (MI) (17). 
Moreover, OCT represents a new angle of view to address the adequacy of stent deployment. Besides 
enabling assessment of intravascular ultrasound (IVUS)-validated predictors of major adverse cardiac 
events (MACE), including minimum lumen area (MLA) and inflow/outflow disease, the high 
resolution of OCT technique permits detection of features that may be missed by IVUS, such as 
malapposition, intra-stent plaque/thrombus protrusion, or edge dissection.  

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The CLIMA and CLI-OPCI registries clearly disclosed that potential OCT clinical impact in a real-
world population: the CLIMA showed the predictive value of vulnerable plaque identification in non-
obstructive coronary artery disease; CLI-OPCI I demonstrated a lower rate of composite of cardiac 
death or non-fatal MI at 1-year in OCT-guided PCIs; while CLI-OPCI II showed that some end-
procedural OCT parameters were significantly associated with an increased MACE risk during follow 
up. Finally, OCT is capable to depict vessel/stent interaction in terms of malapposition, struts coverage 
(e.g. uneven healing) and neo-intima formation; this important information could allow the 
identification of stents at increased risk of thrombosis (e.g. vascular healing delay and incomplete 
endothelialisation) and the need for a prolonged dual antiplatelet therapy (DAPT) (9, 18-21). 
Thus, the purpose of the OCTAGEM registry is to confirm the utility of plaque/stent OCT 
assessment (i.e. OCT guidance) over the standard coronary angiography evaluation. In particular, this 
ambispective cohort study aims to validate the use of the predictive quantitative OCT criteria identified 
in the retrospective CLIMA/CLI-OPCI registries in order to optimize procedural and long-term clinical 
outcomes.  
 
VIII. STUDY PLAN  
 
9.1. Objective of the study 
The aim of the study is to relate presence of OCT-defined criteria of plaque vulnerability and 
suboptimal stent implantation with following clinical events. 
 
9.2. Study design  
This is an observational ambispective cohort study collecting all consecutive patients undergoing OCT 

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evaluation during a clinically indicated coronary angiography. Patients will be enrolled at the time of 
OCT assessment and prospectively investigated to evaluate clinical outcome. 
Clinical status leading to the index coronary angiography, exams and any specific documentation (e.g. 
previous cardiac history, 12-led electrocardiogram and medical therapy) at the time of OCT evaluation 
will be collected using a pre-specified dedicated database. In order to ensure a maximal quality of the 
records, data entry, variable definitions, end-points, and post–procedural follow up are standardized 
and agreed on by all operators. Moreover, research technicians periodically will verify completeness 
and accuracy of the database in order to assure <5% of missing data for each variable. Due to the 
exploratory nature of this project, no preliminary indication for OCT assessment will be recommended 
and intra-procedural techniques (e.g. PCI) will be left to each operator’s discretion.  
All patients fulfilling inclusion/exclusion criteria will be followed by means of scheduled direct visits 
(generally at six and twelve months) and phone contacts (after twelve months). in order to verify the 
clinical status of the patient. In case of any adverse event or new hospitalization, additional visits will 
be planned; source documents will be obtained and examined in detail by a specific clinical-event 
committee that adjudicated each event to a specific culprit lesion. Written informed consent will be 
obtained from all patients for data management and for phone/direct visit during follow-up.  
 
9.3. Study endpoints  
Primary endpoint 
Predictive value of OCT-defined plaque vulnerability (non-interventional arm) and suboptimal stent 
deployment (interventional arm) in terms of clinical composite endpoint: cardiac death, target-vessel 
myocardial infarction, target lesion revascularization, and stent thrombosis. 
 

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Secondary endpoints 
Individual incidence and clinical impact of the single pre-specified OCT features of plaque 
vulnerability including: 
- Minimum lumen area <3.5 mm2; 
- Fibrous cap minimum thickness <65 µm; 
- Lipid arc extension >180°; 
- Presence of macrophages;  
- Superficial and deep calcified nodules 
- Ulceration/Erosion/Dissection 
- Layered tissue 
- Plaque burden (%) 
 
Individual incidence and clinical impact of the single pre-specified OCT features of the stented 
lesions:  
- Edge dissection ≥200μm in width. 
- Reference narrowing (lumen area <4.5mm2 in presence of significant residual plaque adjacent to 
stent endings);  
- Malapposition >200μm in thickness;  
- In-stent minimum lumen area (MLA) <4.5mm2;  
- In-stent MLA <80% of the average reference lumen area;  
- Intra-stent plaque/thrombus protrusion ≥500μm in thickness. 
- Stent deformation/geometry 
- Neo-carina shaping at bifurcation 
 

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9.4. Number or patients 
This study is a spontaneous, not randomized, observational registry evaluating the role of intra-
procedural OCT. All consecutive subjects undergoing OCT assessment during coronary angiography 
will be screened for eligibility.  
On the basis of previous clinical studies testing clinical impact of OCT use during PCI and preliminary 
experience of the steering committee (3-5), we estimated:  
 Non-interventional arm: a cumulative incidence of 5% for the composite clinical end-point 
and of 20% for the OCT-defined vulnerable plaque are assumed. For the study purpose a 
sample size of 986 patients was computed assuming a HR of 0.80 favoring patients without 
OCT-defined plaque vulnerability, and aiming to a 2-sided alpha level of 0.05 and a power of 
80%. To accommodate for possible missing investigations or withdrawals, sample size was 
increased to 1100 patients.  
 Interventional arm: a cumulative incidence of 25% for the OCT-defined suboptimal stent 
implantation and of 12% for the composite clinical end-point are assumed. For the primary 
study purpose a sample size of 1858 patients is computed assuming a HR of 0.85 favoring 
patients without suboptimal stent implantation OCT criteria, and aiming to a 2-sided alpha level 
of 0.05 and a power of 80%. To accommodate for possible missing investigations, sample size 
will be increased to 2100 patients. 
A patient is considered enrolled in the study when he/she has signed the informed consent form (point 
of enrolment). 
 
 

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9.5. Patients selection criteria 
The patient enrolment will be carried out in an ambispective sequential way, so that all patients 
undergoing coronary artery assessment by OCT could participate in the study and therefore, be 
evaluated according to the selection criteria defined in the protocol. 
The patients enrolled in this clinical evaluation should have a clinical profile that fully meets the 
inclusion criteria listed below. Moreover, if even one of the exclusion criteria is present the Investigator 
must exclude the patient from the clinical evaluation.  
 
Inclusion criteria 
 Age 18 years; 
 Patients with clinical indication to coronary angiography undergoing intra-procedural OCT 
regardless of the clinical syndrome; 
 Patients with at least one end-procedural OCT assessment with a sufficient acquisition length to 
address the whole length of plaque or stented segments plus the proximal and distal reference 
segments 
 Patient has been informed of the nature of the study, agrees to its provisions, and has provided 
written informed consent as approved by the Ethical Committee of the respective clinical site. 
 
Exclusion criteria 
 Female with childbearing potential or lactating; 
 Acute or chronic renal dysfunction (defined as creatinine greater than 2.0 mg/dl); 
 Advanced heart failure (NYHA III-IV) 
 Previous heart transplantation 

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 Co-morbidities that could interfere with completion of study procedures, or life expectancy less 
than 1 year; 
 Participating in another investigational drug or device trial that has not completed the primary 
endpoint or would interfere with the endpoints of this study; 
 Heavily calcified lesion and/or tortuous vessel which cannot be successfully imaged by OCT 
 Lesion located at the ostium or in angulated (>70°), sharp take-off vessel; 
 
 
9.6. Clinical study schedule  
The study will be performed in accordance with the European Regulation ISO 14155 part 1 and 2 
(2009) and Good Clinical Practice (GCP). Respect of patient’s rights will be granted during the study 
phase according to the most recent version of the Helsinki Declaration. 
This clinical protocol requires that the Investigator perform an accurate evaluation of the patient prior 
to the enrolment phase. The Investigator also has the responsibility of assessing the patient's clinical 
status at the scheduled follow up. Subjects not completing at least 1 year follow up will not be 
considered enrolled in this study: a phone call should be scheduled in order to verify the clinical status 
of the patient and the occurrence of any adverse event. 
Data to be collected at the enrollment and during the clinical follow-up visits are:  
• 
Demographic data documentation; 
• 
Clinical examination: the patient must undergo a clinical examination during all follow-up visits 
required by this protocol, or when adverse events occur; 
• 
Blood analysis: The evaluation of CK, CK-MB and Troponin must be performed in all the cases 
in which an adverse event occurs, or when required by the Investigators; 

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• 
Electrocardiography (ECG): Twelve-lead electrocardiograms will be collected at the time of the 
procedure and will be repeated at the clinical visits and in case of any adverse event. 
• 
Angiography: the diagnostic coronarography performed at the time of OCT evaluation, must be 
collected to evaluate the location, to classify the coronary vessel stenosis and to assess the lesion. Any 
additional angiography should be also collected, for the proper end-point adjudication. It is important 
that all the coronary angiographies are performed in standard conditions and with a reproducible 
method, as they must provide images suitable for a quantitative analysis (QCA). The angiographic 
examination must be performed according to the guidelines provided by the Core-Lab to perform an 
accurate evaluation of QCA. 
• 
OCT: the OCT examination must be performed according to the guidelines provided by 
expert’s consensus documents 
 
9.7. Follow up procedures 
Patients will undergo a clinical visit, where an ECG will be performed to evaluate the patient status and 
the medication regimen and any adverse event occurred since the previous contact will be recorded. In 
case of additional coronary angiography, the exams will be used to assess target vessel patency. All 
patients will be required to adhere to the following schedule outlined below unless they have 
withdrawn their consent or died. The reason(s) the patient is not followed must be documented on the 
Case Report Form (CRF). The date of the study index procedure is considered day zero. All patients 
will undergo telephone/e-mail-based interviews and/or office-based direct visits for end-point 
adjudication according to standard institutional guidelines. During follow-up assessment, the following 
information are to be recorded: 
• Clinical status assessment; 
• Adverse Event assessment, including all cardiac events; 

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• Record cardiac medications (with specific focus on antiplatelet and antithrombotic therapy); 
If patient reports any adverse events, that in the opinion of the investigator, are considered serious, the 
patient should return to the investigator’s facility for a medical history and physical exam in order to 
further assess the event. 
Long-term follow up data will be obtained by means of phone-based interview in the following years.  
Any adverse event will be evaluated and adjudicated by a specific committee unware of the primary 
end-point results. 
 
 
9.8. Study duration 
The enrolment phase will terminate on September 2031or when 3200 patients will be enrolled.  
Retrospective phase. Patients screening and data collection will be completed in 24 months using 
available data sources.   
Prospective phase. Patients screening and data collection will be completed in 6 years.  Data analysis 
and manuscript draft will require 3 months each. The estimated total duration study is 11 years (6 
enrolment + 5 follow up). 
A minimum follow-up period of 1 year will be mandatory for all enrolled patients. Every effort must be 
made to ensure that all subjects will be contacted for their follow-up evaluations. These evaluations 
will be scheduled as close as possible to pre-specified intervals. If a subject will not be reachable and 
the follow-up could not be scheduled, the subject will be considered lost to follow-up and not included 
in the final analysis. 
 
9.9. Patient withdrawal  
Patients may withdraw from the study at any time and for any reason, without affecting their right to be 
followed by the Investigator. Every patient should be encouraged to remain in the study until they have 

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completed at least the1 year follow-up. If the patient prematurely discontinues from the study, for any 
reason, a final evaluation will be completed for that patient and the reason for withdrawal will be 
documented. All documentation concerning the patient must be as complete as possible and the patient 
will not be replaced in the study. A patient will be considered as completed his/her participation in the 
study if concluding at least 1-year follow-up period. 
 
IX. 
DEFINITIONS 
 
All outcomes were defined according to the Academic Research Consortium recommendations (22). 
Angiographic failure will be defined as revascularization with final TIMI <3 flow and/or residual 
stenosis >30%. 
Cardiac death was defined as any death due to cardiac cause, procedure-related deaths, and death of 
unknown cause. 
Target vessel new Myocardial infarction (MI) will be defined as an increase in the cardiac biomarker 
troponin at least 10 times above the normal value (according to the local lab range)  along with at least 
one of the followings: 1) symptoms of ischemia; 2) new or presumed new significant ST-segment or T-
wave changes or new left bundle branch block; 3) development of new pathologic Q waves on an 
electrocardiogram; 4) imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality; or 5) identification of an intracoronary thrombus by angiography or autopsy (23). 
Target lesion revascularization (TLR) will be defined as any revascularization procedure performed 
because of angiographic restenosis/thrombosis >70% at the site of the culprit lesion or restenosis >50% 
(core lab QCA assessment) associated with clinical or objective evidence of inducible myocardial 
ischemia. Any revascularization procedure performed on the stented vessel was defined as Target 
vessel revascularization (TVR). 

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OCT assessment of plaque/stent will be based on conventional definitions reported in expert consensus 
OCT documents (9,11,24-27) and utilizing the cut-off points identified in the previous CLI-OPCI 
registries (3,4,26-28).  In particular, the following were considered significant findings: 
Minimum lumen area <3.5 mm2: measured along the entire length of the assessed coronary segment 
(29); 
Fibrous cap minimum thickness <65 µm:  fibrous cap will be defined as a signal-rich homogeneous 
band overlying a lipid core. Fibrous cap thickness will be measured at the thinnest portion and TCFA 
will be diagnosed in presence of a lipid-rich plaque and a fibrous cap thickness of ≤65m (15,30) 
Lipid plaque with lipid arc extension >180°: a lipid plaque will be defined as a signal-poor region 
diffusely bordered by overlying signal-rich bands corresponding to a fibrous cap; a plaque will be 
defined as lipid-rich if containing 2 or more lipid quadrants (31); 
Presence of macrophages: inflammatory cells macrophages accumulations, will be characterized at 
visual estimation as signal-rich, distinct, or confluent punctate regions that exceed the intensity of 
background speckle noise (15,32). To identify more accurately local inflammation a two-step algorithm 
will be applied onto OCT ROIs in order to distinguish between inflamed and non-inflamed regions 
(12). 
Edge dissection: the presence of a linear rim of tissue with a width ≥200μm and a clear separation from 
the vessel wall or underlying plaque, that was adjacent (<5 mm) to a stent edge (4). 
Reference lumen narrowing: lumen area <4.5mm2 in presence of significant residual plaque adjacent 
to stent endings (4); 
Malapposition: stent-adjacent vessel lumen distance >200μm (4,24,25);  
In-stent minimum lumen area (MLA) <4.5mm2 (4,5);  
In-stent MLA <80% of the average reference lumen area (4,5);  

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Intra-stent plaque/thrombus protrusion: tissue prolapsing between stent struts extending inside a 
circular arc connecting adjacent struts or intraluminal mass ≥500μm in thickness with no direct 
continuity with the surface of the vessel wall or highly backscattered luminal protrusion in continuity 
with the vessel wall and resulting in signal-free shadowing (24,26,28).  
Stent thrombosis will be assessed utilizing the Academic Research Consortium (ARC) definition (22) 
as definite or probable, and as acute (<24 hours), subacute (>24 hours to 30 days), late (31 to 360 
days), or very late (>360 days). The definition of definite stent thrombosis required the presence of an 
acute coronary syndrome with angiographic or autopsy evidence of in-stent thrombus or occlusion. 
Probable stent thrombosis included unexplained deaths within 30 days after the procedure or acute MI 
involving the target-vessel territory without angiographic confirmation.  
 
X. MATERIALS AND METHODS 
 
Frequency-domain Optical Coherence tomography (FD-OCT)  
Imaging acquisition. FD-OCT will be performed with a validated non-occlusive technique (9). After 
intracoronary injection of nitroglycerin 200 µg, OCT images will be acquired with a commercially 
available system (Ilumien Optis or UltreonTM from St Jude Medical, Westford, MA, USA) after 
positioning of the Dragonfly OCT catheter (LightLab Imaging Inc/St Jude Medical, Westford, MA, 
USA) distal to the target segment. During OCT image acquisition, the blood will be displaced by 
means of angiographic contrast media injection through the guiding catheter with an automated power 
injector (Acist, Bracco, Milan, Italy). OCT pull-back speed will be set at 20 mm/sec and OCT images 
will be calibrated adjusting the Z-offset.  
Quantitative analyses and definitions. The acquired OCT coronary images will be analyzed off-line 
using a proprietary OCT console (St Jude Medical, Inc., USA) by expert readers blinded to patient 

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outcome. Readers will evaluate the image quality of each OCT pull-back, and only acquisitions that 
meet the pre-specified image-quality requirements will be eligible for analyses. OCT images will be 
deemed of good quality if they allow both an accurate measurement of lumen and a qualitative 
definition of the superficial plaque components. Images will be excluded if the boundary between the 
lumen and the vessel wall is not discernible along a continuous arc of at least 270˚ around the center of 
the lumen. 
Conventional definitions derived from expert consensus OCT documents (9) will be applied. In 
presence of atherosclerotic lesions, FD-OCT analysis will be performed at minimum lumen are (MLA) 
site (MLA site analysis) and along the entire plaque (plaque analysis) in every cross-section. At the 
MLA site the following measurements will be obtained: lumen area, minimal and maximal diameters, 
mean diameter, and asymmetric index calculated as (maximal diameter-minimal diameter)/maximal 
diameter. 
Plaque composition analyses. Atherosclerotic cross-sections will be distinguished into fibrous, lipid, 
and calcified by OCT according standardized definitions (9,33). Briefly, fibrous plaque exhibits 
homogeneous highly backscattering (i.e. signal-rich) regions; calcified plaque is identified by the 
presence of signal-poor regions with sharply delineated upper and/or lower borders; lipid-rich plaque 
shows diffusely bordered, signal-poor regions with overlying signal-rich bands, corresponding to 
fibrous cap. A non-diseased vessel cross-section is imaged as a three-layered structure by OCT (33). 
The analysis will include other anatomical features: presence of TCFA, lipid pool circumferential 
extension, local inflammation, and thrombus. The mechanism of local thrombosis will be categorized 
into ulceration vs erosion.  
Inflammatory cells quantification. Inflammatory cells will be evaluated applying tissue property 
indexes including signal attenuation (34), normalized standard deviation (35), and granulometry index 
(32,36). These indexes will be assessed using a custom developed software written using the Matlab 

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(MathWorks, Inc.) according to a validated methodology (32). Signal attenuation refers to the signal 
loss with depth in the OCT image and will be calculated by fitting exponential curves of OCT signal to 
the signal profile of the pixels. 
  
Coronary angiography and quantitative coronary analysis (QCA) 
Angiographic images will be acquired according to validated standards: the diagnostic angiographic 
examination should be performed in order to identify the presence of atherosclerotic lesions, in at least 
two views. QCA analysis will be performed with a validated edge detection system (CAAS Version 
5.9, Pie Medical Imaging, Maastricht, the Netherlands). The guiding catheter tip (6 F or greater) filled 
with contrast medium must be clearly visible in each recorded angiogram. Angiographic projections, 
which may lead to a foreshortening of the target vessel, should be avoided in order to obtain a more 
accurate evaluation of the QCA parameters. Reference vessel diameter, minimal lumen diameter, 
percentage of diameter stenosis (DS), and stenosis length will be measured in diastolic frames from 
orthogonal projections according to validated protocols for all identified lesions (37).  

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XI. 
STUDY ORGANIZATION 
12.1. Clinical Events Committee 
The Clinical Events Committee (CEC) is an independent adjudication body comprised of 
interventional and/or non-interventional cardiologists who are not participants in the clinical 
investigation. The CEC will review and adjudicate all cases of endpoint events (Composite 
endpoint). The Clinical Events Committee will meet regularly to review and adjudicate all clinical 
events in which the required minimum data is not available according to pre-specified CEC 
guidelines. The Committee will also review and rule on all deaths that occur throughout the trial. 
 
12.2. Statistical analysis  
Continuous variables will be reported as mean (standard deviation) or median (interquartile range) and 
compared by means of unpaired t or Mann-Whitney tests, when appropriate. Categorical variables will 
be reported as raw numbers (%) and compared by means of Pearson chi-square, Fisher exact or log-
rank tests, when appropriate. Survival analysis will be conducted for clinical end-points by means of 
both Kaplan-Meier method and/or Cox proportional hazard analysis. 
Combined adverse events will be evaluated on a per-patient hierarchical basis, thus each patient could 
provide only one hard event per event type. Intention to treat analysis will be used throughout, with 
end-points analysed at the patient level.  
Multivariable logistic regression model will be used to identify independent outcome predictors and to 
calculate their adjusted hazard ratios (HRs) with associated 95% confidence intervals (CI). The Hosmer 
and Lemeshow goodness-of-fit test will be used to assess model calibration.  
A two tailed, p value <0.05 has been established as the level of statistical significance for all tests. All 
statistical analyses will be carried out using SPSS software (SPSS inc., Chicago, Illinois). 

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12.3. Ethics committee review and approval 
Local Ethical Committee (EC) approval for the protocol has been obtained by investigators (ID 7262) 
and the study has been registered in the ClinicalTrial.gov registry (https://clinicaltrials.gov) 
 
12.4. Patients information and informed consent 
Informed consent for the procedure is mandatory for the participation in the study and must be obtained 
from all subjects and/or their legal representative(s) as per local regulations. The investigator must 
inform every subject in details about the nature of the study, its purpose, the treatments, the reasonably 
expected benefits, the expected duration and the approximate number of subjects involved and the 
subject’s responsibilities. Study subjects must additionally be informed that: 
1. Participation in this study is voluntary and that he/she may withdraw from this study at any time for 
any reason and that that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physicians. 
2. Any foreseeable circumstances and/or reasons under which the subject’s participation in the study 
may be determined. 
12.5. Confidentiality and patient data protection  
All information and data concerning subjects or their participation in this study will be considered 
confidential. Only those working on protocol, the independent Ethics Committee and regulatory 
authorities will have access to subject medical records and other study documents for verification of 
study procedures and data without violating the confidentiality of the subject. All data used in the 
analysis and reporting of this evaluation will not bear identifiable reference to the subjects.  
 

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12.6. Source documents 
All data will be exported from the currently used cath-lab database (ESTENSA Suite), while clinical 
data and in-hospital course will be obtained from the general hospital database (Trackcare). Source 
documents are original hospital records, clinical charts, screening log, patient identification 
list/enrolment log, original laboratory report, memoranda, pharmacy dispensing records, recorded data 
from automated instruments, transcriptions certified after verification as being accurate, magnetic or 
electronic media, xrays, subject’s files, and records kept at the laboratories and medico-technical 
departments involved in the study. The investigator must maintain source documents for each patient in 
the study. To limit the impact of confounding factors or selection bias, all clinical and procedural 
variables potentially affecting clinical outcome will be recorded and used to perform a multivariable 
analysis for the study endpoints. 
12.7. Case report form (CRF) 
Electronic Case Report Forms (CRFs) will be used to collect all patient data during the course of the 
study. Good Clinical Practice Guidelines require that Investigators maintain information in the study 
patient's medical records that corroborate data collected on the CRFs. The Investigator must complete 
and he appropriate CRFs; completed CRFs will be reviewed for accuracy verified with the source 
documentation and collected by the study monitor. The CRFs with incomplete or inaccurate data will 
require correction by the Investigator. 
The OCT core laboratory will provide the electronic CRFs for the study: 
1. 
Enrolment phase: form collecting demographic data including clinical status, clinical history 
and pharmacological treatment, risk factors, diagnostic angiography and OCT assessment. 
2. 
Follow-up visit scheduled or unscheduled: form collecting data related to the clinical status and 
pharmacological treatment of the patient collected during the scheduled follow-up visits or any visits 
that occurred outside of the required schedule (unscheduled follow-up). 
3. 
 Adverse event: section that must always be completed by reporting the occurred adverse 
events, as well as the treatment performed and the clinical outcomes (e.g. death of patient, surgical or 
percutaneous revascularization), during the entire period in which the patient participated in the study. 

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12.8 Final study report 
Upon completion or termination of the study, the principal investigator will submit a final written 
report to the Ethics Committee. The report must be submitted within 12 months of completion or 
termination of the trial.  
 
12.9. Clinical data collection and management  
12.9.1. Monitoring 
An initiation visit will be conducted to ensure that the investigator clearly understands and accepts the 
obligations incurred in undertaking the clinical investigation set forth in ICH-GCP, ISO 14155-1 
(2009), and that the facilities are suitable for the conduction of the clinical study. 
The coordinating centre will ensure proper clinical site monitoring, which includes but is not limited 
to review of CRFs, 100% of source data verification, parity checks with the source documentation 
(including operator work sheets retained with CRF documentation and hospital charts) and 
verification of the obtained patient informed consent. 
Periodic monitoring visits will be conducted frequently enough to ensure throughout the clinical 
investigation that the investigator’s obligations as set forth in ICH-GCP and ISO 14155-1 (2009) are 
being fulfilled and that the facilities continue to be acceptable. Personal contact between the monitor 
and the investigators will be maintained throughout the investigation, and the monitor will visit the 
investigators at the site of the investigation. 
A close-out visit will be conducted at the completion of the study to ensure that all patient data are 
properly documented. 
 
12.9.2. Clinical Data Management 
The clinical data obtained during this clinical study must be completed on the appropriate CRFs (or 
attached to these forms) provided by the coordinating centre. In order to collect mandatory missing 
data and to clarify unreadable or inconsistent data, clarifications will be requested to the Investigator 
through Data Clarification Forms (DCFs) and the database will be updated accordingly. The entire 

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process of the clinical data treatment (from the collection to the final statistical analysis) will be 
conducted following the internal standard operative procedures in accordance with the European 
regulations ISO 14155 (2009). 
 
12.10. Publication policy 
The coordinating clinical investigator and the principal investigators are committed to the publication 
and widespread dissemination of the results of the study. This study represents a joint effort all 
investigators, and as such, the parties agree that the recommendation of any party concerning 
manuscript or text shall be taken into consideration in the preparation of final scientific documents for 
publication or presentation. Authorship will include the investigators in order of patient recruitment. 
The number of authors will be determined according to the rules of the addressed scientific journal.  

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XIII. FIGURES   
1. Interventional group  
 
 
 

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2. Non-interventional group  
 
Panel A: acute thrombosis due erosions. OCT shows an acute thrombus on a regular surface without 
atherosclerotic plaque beneath the lumen. 
Panel B: acute thrombosis caused by ulceration. A superficial thrombus located at the shoulder of the 
plaque is shown. Plaque rupture connecting the lumen with lipid pool is appreciated at the shoulder 
site.  
Panel C: old thrombosis, likely due to erosion with a layered aspect at OCT. 
Panel D: old ulcerations with the plaque cavity in contact with lumen without superficial thrombosis.  
Panel E: Vulnerable plaque with thin fibrous cap and large lipid component. 
Panel F:  Atherosclerotic plaque with lipid necrotic core and high inflammatory content.