PERcutaneouS Coronary intErventions in Patients Treated With Oral Anticoagulant Therapy
Conditions: Acute Myocardial Infarction, Unstable Angina, Chronic Stable Angina
Sponsor: Italian Society of Invasive Cardiology

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PERSEO Registry: 
PERcutaneouS coronary intErventions in 
patients treated with Oral anticoagulant 
therapy 
 
 
 
 
 
Version: 3.0 
Date: 25/10/2017 
 

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Principal Investigator 
Alessandro 
Sciahbasi, 
Sandro 
Pertini 
Hospital, ASL RM2, Rome 
Co-Principal Investigator 
Andrea 
Rubboli, 
Ospedale 
Maggiore, 
Bologna 
Steering Commettee 
Battistina Castiglioni, Alessio La Manna, 
Ugo Limbruno, Alfredo Marchese, Ciro 
Mauro, 
Giuseppe 
Musumeci, 
Stefano 
Rigattieri, 
Giuseppe 
Tarantini, 
Fabio 
Tarantino, Ferdinando Varbella 
Clinical Events Commettee 
Salvatore De Rosa, Dionigi Fischetti, Guido 
Parodi 
 
Signatures confirm that this protocol has been carefully read and fully understood, and that 
there is agreement to comply with the conduct and terms of the trial specified herein in 
compliance with Good Clinical Practice and all other regulatory requirements. 
 
Role 
Name and Title 
Principal Investigator 
Alessandro Sciahbasi 
Signature 
 
--------------------- 
Date 
 
------------------------- 
 
 
 
Role 
Name and Title 
Co-Principal Investigator 
Andrea Rubboli 
Signature 
 
--------------------- 
Date 
 
------------------------- 
 
 
 
 

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Table of Contents 
Protocol Summary…………………………………………………….  
 
Pag. 4 
1 Introduction……………………………………………………….....  
 
Pag. 6 
1.1 Background………………………………………………. 
 
 
Pag. 6 
2 
Study Objectives………………………………………………….  
 
Pag. 8 
3 
Study Design…………………………………………………….. 
 
 
Pag. 8 
4 
Patient Selection and Follow up……………………………….. 
 
 
Pag. 8 
4.1 Inclusion Criteria……………………………………………. 
 
 
Pag. 8 
4.2 Exclusion Criteria…………………………………………… 
 
 
Pag. 8 
4.3 Informed Consent…………………………………………… 
 
 
Pag. 9 
4.4 Procedure and treatment regimen………………………… 
 
 
Pag. 9 
4.5 Follow up…………………………………………………….. 
 
 
Pag. 9 
4.6 Data collection……………………………………………… 
 
 
Pag. 9 
5.  Endpoints…………………………………………………………. 
 
 
Pag. 10 
5.1 Primary endpoint…………………………………………... 
 
 
Pag. 10 
5.2 Secondary endpoints……………………………………… 
 
 
Pag. 11 
5.3 Subgroups analysis……………………………………….. 
 
 
Pag. 11 
6  Sample size calculation…………………………………………. 
 
 
Pag. 11 
7. Data Management………………………………………………. 
 
 
Pag. 12 
7.1 Data recording…………………………………………….. 
 
 
Pag. 12 
7.2 Record retention………………………………………….. 
 
 
Pag. 12 
8.  Adjudication of events………………………………………….. 
 
 
Pag. 12 
9.  Editorial Policy………………………………………………….. 
 
 
Pag. 13 
10. References……………………………………………………. 
 
 
Pag. 14 

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Protocol Summary 
Title 
Percutaneous coronary interventions in patients treated 
with oral anticoagulant therapy 
Acronym 
PERSEO 
Background 
Percutaneous coronary interventions with stent (PCI-S) 
in patients requiring chronic oral anticoagulant therapy 
are associated with an increased risk of bleeding and 
ischemic complications. Limited data are available on 
the management of these patients, especially when 
oral anticoagulation is carried out with non-vitamin K 
antagonist (NOAC) which only recently have been 
introduced in clinical practice. 
Objective 
To evaluate in a “real world” setting the management 
and outcome of the different antithrombotic strategies 
used in patients with an indication for oral anticoagulant 
therapy, especially focusing on NOAC 
Study Design 
Prospective, multicenter, observational, controlled 
study 
Sample size 
At least 1080 patients treated with PCI-s and requiring 
oral anticoagulant therapy 
Study sites 
Approximately 30 or more Interventional Cardiology 
Centers across Italy  
Co-Primary end-point 
In the study there are two co-primary end-points:  
1. Describe the current management of 
antithrombotic therapy after the introduction of 
NOAC in patients requiring oral anticoagulant 
therapy undergoing PCI-S. 
2. A combined measure of efficacy and safety 
endpoints, the so-called Net Adverse Clinical 
Event (NACE) end-point including major 
bleeding events + major adverse cardiac and 

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cerebral events (MACCE) at one year follow up 
in patients treated with NOAC (and various 
combinations of antiplatelet therapy) compared 
to the corresponding strategies of vitamin K 
antagonists. 
Secondary end-points 
a. The individual components of the primary endpoint 
b. Major bleedings according to the International 
Society on Thrombosis and Haemostasis (ISTH) 
classification  
Inclusion criteria 
All patients undergoing percutaneous coronary 
interventions with stent and an indication for chronic 
anticoagulant therapy. 
Exclusion criteria 
- Patients of age < 18 years old 
- Lack of written informed consent to participate in the 
study 
Contact 
Principal Investigator: 
Alessandro Sciahbasi, UOC Cardiologia, Ospedale 
Sandro Pertini ASL RM2 
Tel.3472968314 
E-mail: alessandro.sciahbasi@fastwebnet.it 
 
Co-Principal Investigator: 
Andrea Rubboli, UOC Cardiologia, Ospedale Maggiore 
di Bologna 
Tel: 335477354 
E-Mail: andrearubboli@libero.it 
 

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1. INTRODUCTION 
1.1 Background 
Approximately 5 to 8% of patients undergoing percutaneous coronary interventions 
requires chronic anticoagulant therapy due to atrial fibrillation or other clinical entities (1-2). 
These patients pose particular problems when undergo percutaneous coronary 
intervention with stent implantation (PCI-S), because of the different antithrombotic and 
oral anticoagulant (OAC) strategies required after the procedure when dual antiplatelet 
therapy is recommended. Indeed dual antiplatelet therapy with clopidogrel and aspirin is 
superior to oral anticoagulation in term of stent thrombosis reduction (3) but OAC is 
superior to antiplatelet therapy for ischemic stroke reduction in patients requiring chronic 
OAC therapy for atrial fibrillation (4). Consequently, this scenario requires careful 
consideration balancing bleeding, stroke and acute coronary syndrome risks (5).  
Recent guidelines on atrial fibrillation (6) suggest combined OAC and antiplatelet 
therapy to be modulated during follow up to prevent both thromboembolism and recurrent 
coronary events and/or stent thrombosis. In particular, a short period (1 month) of triple 
therapy (OAC, aspirin, clopidogrel) is recommended, followed by a period of dual therapy 
(OAC plus a single antiplatelet). However, in case of an acute coronary syndrome with 
stent implantation in atrial fibrillation patients at risk of stroke, a combination of triple 
therapy with aspirin, clopidogrel and an oral anticoagulant should be considered for 6 
months to prevent recurrent coronary and cerebral ischemic events. For the first time 
these guidelines do not exclude the possible use of the new oral anticoagulants (NOAC) 
over warfarin and when NOAC are used, the consensus recommendation is that the 
lowest dose effective for stroke prevention in atrial fibrillation should be considered.  
NOAC have been compared to warfarin for stroke prevention in the setting of atrial 
fibrillation and all these drugs showed a similar or improved efficacy over warfarin in term 

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of ischemic events as well as bleeding complications reduction (7-10). In particular, an 
important safety issue is the reduction of intracranial bleeding compared to warfarin. 
Currently, four different NOAC have been approved for the treatment of patients with atrial 
fibrillation: apixaban, edoxaban, rivaroxaban and dabigatran. The first three drugs are anti 
Xa inhibitors whereas the last one is a direct thrombin inhibitor.  
A previous meta-analysis including all randomized phase II and III studies of NOAC 
in acute coronary syndromes showed that the combination of low dose NOAC and dual 
antiplatelet therapy is associated with a significant reduction in cardiovascular events at 
the price, however, of an increased risk of bleeding (11). Unfortunately, these studies did 
not include patients requiring chronic anticoagulant therapy. 
Data regarding the combination of NOAC and antiplatelet therapy after PCI-S in 
patients requiring chronic anticoagulant therapy are currently scarce. Only recently, the 
randomized PIONEER study (12) showed the safety of the use of Rivaroxaban over 
warfarin in this setting of patients. In particular, the use of Rivaroxaban 15 mg combined 
with a single antiplatelet agent (mostly clopidogrel) was associated with a lower rate of 
clinically significant bleeding compared to standard therapy with a vitamin K antagonist 
plus dual antiplatelet therapy for 1, 6, or 12 months. However, the sample size of this study 
was not large enough to test accurately the efficacy in term of ischemic events prevention. 
Moreover, real world data on the use of the NOAC in combination with antiplatelet therapy 
after PCI-s in patients requiring chronic anticoagulant therapy are currently lacking.  
Few years ago, in a previous observational Italian Registry (13), we presented the 
real world treatment of patients who underwent PCI-S and concomitant oral anticoagulant 
therapy with vitamin K antagonists. The study enrolled more than 400 patients and showed 
that there were no significant difference in term of ischemic events with triple therapy 
(vitamin K antagonist and dual antiplatelet therapy) or dual therapy (vitamin K antagonist 
and single antiplatelet agent) but all major bleeding episodes except one were detected in 

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the group of patients treated with triple (warfarin, aspirin and clopidogrel) therapy. 
However, in this Registry data on the association of antiplatelet and NAOC therapy were 
lacking because at that time these drugs were not available yet.  
 
2. Study Objectives 
The primary objectives of the study are:  
1. To describe the contemporary antithrombotic management during and post PCI-S in 
patients treated with oral anticoagulant therapy  
2. To evaluate, in this context, the efficacy and safety of the different NAOC compared 
to warfarin regimens.  
 
3. Study design 
Prospective, multicenter, observational, controlled study designed on patients requiring 
chronic anticoagulant treatment with either vitamin K antagonists or NOAC undergoing 
PCI-S for concomitant coronary disease.  
 
4. Patient selection and follow up 
4.1 Inclusion criteria 
Patients with chronic disease requiring oral anticoagulant therapy (atrial fibrillation, 
prosthetic valves, previous pulmonary embolism, venous thrombosis) undergoing 
either elective, urgent or emergency percutaneous coronary interventions with stent 
implantation for acute or chronic coronary disease. 
 
4.2 Exclusion criteria 
Patients are not eligible if any of the following applies: 

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- 
Patients of age < 18 years old 
- 
Lack of written informed consent to participate in the study 
 
4.3 Informed Consent 
The Principal Investigator, Sub-investigator, or designee, who has been trained on 
the protocol, will explain the nature and scope of the study, potential risks and 
benefits of participation, and to answer questions of the subjects. All subjects or 
legally authorized subjects’ representatives must sign the Ethics Committee (EC) 
approved informed consent prior to inclusion in the study. The signed informed 
consent will be kept in the subject’s medical records and a copy will be given to the 
subject or the legally authorized representative. 
4.4 Procedure and treatment regimen 
According to the observational design of the study, anticoagulant therapy (vitamin 
antagonists or new oral anticoagulant drugs), other pharmacological therapy as 
well as procedural device utilized, before, during the procedure and at follow-up will 
be left to the physician decision.  
4.5 Follow up 
After the index event each subject will be followed with office follow-up visit at 30 ± 
7 days and 12 ± 1 months. All follow-up visits are preferably scheduled as a visit to 
outpatient clinic. If patients are unable or unwilling to visit the outpatient clinic, the 
scheduled visit can be replaced by a telephone call.  
Medication prescriptions are recorded at each follow-up visit. In case of an 
ischemic or bleeding event, the patient will be asked to provide documentation of 
the event as well as the troponin and hemoglobin values (when available).  
4.6 Data collection 
Patients are informed that data are collected at scheduled follow-up as well as at 

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unscheduled visits. The pre-procedural data to be collected include medical history, 
cardiac medications pre-PCI-S indication for PCI-S (elective, non-STEMI, or 
STEMI) and the reason for chronic anticoagulant therapy. The procedural details of 
the index PCI-S include location of treated lesions, number of stents, stent length, 
stent diameter, type of stents used and complications, the anticoagulant employed 
and its dose. The post-procedural medication is evaluated as well as clinical events 
(MACE and bleeding) that have occurred. INR is recorded if the patient is on 
chronic OAC with warfarin. 
At each visit, the following information is collected: 
- 
Medication prescription 
- 
Major adverse cardiac and cerebral events 
- 
Vital status 
- 
Potential acute coronary syndrome 
- 
Potential stroke of any etiology (ischemic, haemorrhagic and indeterminate) 
- 
Stent thrombosis 
- 
Any clinically overt bleeding events 
- 
Coronary revascularization (PCI-S or coronary artery bypass grafting) 
 
5. Endpoints 
5.1 Primary end-point 
In the study there are two co-primary end-points:  
1. 
Describe the current management of antithrombotic therapy after the 
introduction of NOAC in patients requiring oral anticoagulant therapy undergoing 
PCI-S. 
2. 
A combined measure of efficacy and safety endpoints, the so-called Net 
Adverse Clinical Event (NACE) end-point including major bleeding events + major 

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adverse cardiac and cerebral events (MACCE) at one year follow up comparing 
patients treated with warfarin or NOAC. 
Major bleedings are defined according to the Bleeding Academic Research 
Consortium (BARC) (14) including BARC 2, 3 and 5 events. 
Major adverse cardiac and cerebral events include target vessel revascularization, 
myocardial infarction, stent thrombosis, stroke or transient ischemic attack and 
death.  
Stent thrombosis is defined according to the Academic Research Consortium 
(ARC) definition (15) including definite, probable and possible stent thrombosis. 
5.2 Secondary end-points  
The secondary end-points include: 
a. The individual components of the primary endpoint 
b. Major bleedings according to the International Society on Thrombosis and 
Haemostasis (ISTH) classification (16)  
5.3 Subgroups analysis 
A full subgroup analysis of the primary end-point and of the secondary end-points 
will be performed comparing:  
c. The different NOAC used 
d. The different anticoagulant strategies (i.e. uninterrupted therapy anticoagulant 
therapy versus bridging or interrupted anticoagulant therapy) during the PCI-S.  
e. Transradial versus transfemoral access for PCI-S 
f. Patients with prosthetic heart valves 
g. Drug eluting stents versus bare metal stents. 
 
6. Sample size calculation 

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The sample size was estimated on the basis of the primary end-point (the rate of NACE at 
1 year follow up) according to a previous observational study performed in Italy (13) with a 
rate of NACE of 27% in the warfarin group and according to the results of the PIONEER 
trial that showed a 10% reduction of NACE with rivaroxaban (12). 
Consequently assuming a 25% incidence of NACE in the warfarin group, in order to detect 
a difference of 7% with a power of 80% and an alpha error of 0.05 the number required 
was calculated to be at least 540 patients per group (totally 1080 patients). 
 
7. Data Management 
7.1 Data recording 
The Case Report Forms (CRFs) in this study are implemented electronically using 
a dedicated electronic system. All data entered into the eCRF must be traceable to 
source documents available at the clinical site. In exceptional cases where data are 
recorded directly in the eCRF (i.e. no other source documentation exists), this must 
be explicitly documented (e.g. in a note to file). In such a case, eCRF should be 
printed out, signed, dated and filed with source document.  
7.2 Record retention 
The Investigator/Site will maintain all records pertaining to this study for at least five 
years following study completion or as otherwise instructed by the Coordinating 
Investigator (or designees) or per local regulations if longer. 
 
8. Adjudication of events 

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The events are adjudicated by the clinical event committee (CEC) comprised of 
qualified physicians. The CEC is responsible for adjudicating all potential endpoint 
events, including death, bleeding, myocardial infarction, stent thrombosis, stroke, and 
coronary revascularization 
 
9. Editorial Policy 
At the conclusion of the study, a multicenter abstract reporting the primary results will be 
prepared by the Coordinating Investigator (in collaboration with the Executive Steering 
Committee) and presented at an annual scientific meeting. The first 15 top enroller 
Centers will have the local principal Investigator included in the list of authors (or a 
different collaborator indicated by the principal investigator). After the publication of the 
main paper, the local principal Investigators of each center that enrolled at least 15 
patients and not included in the main study will be included in the secondary papers that 
will be published. Moreover, after the publication of the main paper all the co-authors 
aiming to perform further analysis for possible sub-studies will have access to the 
database (after the presentation of a specific protocol that should be approved by the 
Steering Committee). Submission of all abstracts and publications regarding the primary 
endpoint and secondary endpoints from the study requires approval by the Coordinating 
Investigator after review by the Executive Steering Committee. 

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Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, 
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myocardial revascularization: The Task Force on Myocardial Revascularization of 
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European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur 
Heart J. 2014; 35: 2541-2619 
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Popescu BA, Schotten U, Van Putte B, Vardas P. 2016 ESC guidelines for the 
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Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin 
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JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, 
Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais 
P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L. Apixaban versus warfarin in 
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11. Oldgren J, Wallentin L, Alexander JH, James S, Jönelid B, Steg G, Sundström J. 
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atrial fibrillation undergoing PCI. N Engl J Med 2016, ahead of print. DOI: 
10.1056/NEJMoa1611594. 
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Calabrò P, Palmieri C, Rizzi A, Imperadore F, Sangiorgi GM, Valgimigli M, Carosio 
G, Steffenino G, Galvani M, Di Pasquale G, La Vecchia L, Maggioni AP, Bolognese 
L. Outcome of patients on oral anticoagulation undergoing coronary artery stenting: 
data from discharge to 12 months in the Warfarin and Coronary Stenting (WAR-
STENT) Registry. J Invasive Cardiol. 2014; 26: 563-9. 
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SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik 
JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding 
definitions for cardiovascular clinical trials: a consensus report from the Bleeding 
Academic Research Consortium. Circulation. 2011; 123: 2736-47 
15. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, 
Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, 
Serruys PW. Clinical end points in coronary stent trials: a case for standardized 
definitions. Circulation 2007; 115: 2344-51 
16. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the 
Scientific and Standardization Committee of the International Society on 

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Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations 
of antihemostatic medicinal products in non surgical patients. J Thromb Heamost 
2005; 3: 692-694 
 
 
 
 
 
Local Principal Investigator at study site*: 
I have read and understood this trial protocol and agree to conduct the trial as set out in 
this study protocol, the current version of the World Medical Association Declaration of 
Helsinki, ICH-GCP guidelines and the local legally applicable requirements. 
 
Site:  
Address: 
Principal investigator: 
 
 
___________________________                 ____________________________ 
Place/Date  
                                       Signature