Maintenance Of aNtiplatElet Therapy in Patients With Coronary Stenting Undergoing Surgery
Conditions: Coronary Disease
Sponsor: Italian Society of Invasive Cardiology

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 1 of 45 
 
 
 
 
1
                                                        
 
The MONET registry 
 
Study Title: Maintenance Of aNtiplatElet Therapy in patients with coronary stenting 
undergoing surgery 
 
Sponsor: Fondazione GISE Onlus 
 
Date and Version No: 20.07.2017 1.0 
              
Principal Investigators: 
Roberta Rossini, MD, PhD Division of Cardiology, Ospedale 
Santa Croce e Carle, Cuneo Italy 
Dominick J Angiolillo, MD, PhD, University of Florida College 
of Medicine-Jacksonville 
 
 
 
 
 
 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 2 of 45 
 
 
 
 
2
 
 
Study Coordinators 
 
Department: ………………………………………… 
A.O. S.Croce e Carle di Cuneo 
Via Michele Coppino, 26 – 12100 – Cuneo (CN) 
 
Name and Surname: Roberta Rossini 
 
Signature: ...........................................................  date: ........../........../..........  
 
 
 
 
Department: .................................................................. 
University of Florida College of Medicine-Jacksonville 
653 W 8th St, Jacksonville, FL 32209, U.S. 
 
Name and Surname: Dominick J Angiolillo 
 
Signature: ...........................................................  date: ........../........../..........  
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 3 of 45 
 
 
 
 
3
Principal Investigator 
 
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. 
 
 
Department: Reparto di Cardiologia 
Centre:  
Address:  
 
          
                                                                                     
Signature: 
Name and Surname:  
date: 26/09/2017 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 4 of 45 
 
 
 
 
4
 
 
 
 
 
Confidentiality Statement: This document contains confidential information that must not be 
disclosed to anyone other than the Sponsor, the Investigator Team, regulatory authorities, and 
members of the Research Ethics Committee       
 
 
 
   
 
 
 
 
 
 
 
 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 5 of 45 
 
 
 
 
5
Contents 
1. 
ABBREVIATIONS ................................................................................................................ 7 
2. 
BACKGROUND AND RATIONALE ...................................................................................... 9 
3. 
OBJECTIVES ..................................................................................................................... 15 
3.1  
Primary Objective ........................................................................................................ 15 
3.2  
Secondary Objectives ................................................................................................. 15 
4.  
STUDY DESIGN ............................................................................................................. 16 
4.1  
Summary of Study Design ........................................................................................... 16 
4.2  
Primary endpoint ......................................................................................................... 16 
4.3  
Secondary endpoints .................................................................................................. 16 
4.4 Participants ...................................................................................................................... 17 
4.4.1  
Inclusion Criteria ...................................................................................................... 17 
4.4.2  
Exclusion criteria ..................................................................................................... 18 
4.4.3 Enrollment time ............................................................................................................. 18 
4.5 
Study Procedures ........................................................................................................ 18 
4.5.1 
Informed Consent .................................................................................................... 18 
4.5.2 
Screening ................................................................................................................ 18 
4.5.3 
In-hospital assessments .......................................................................................... 18 
4.5.4 
Follow-up ................................................................................................................. 21 
4.6 
Source Data ................................................................................................................ 21 
5.  
TREATMENT OF PARTICIPANTS ................................................................................. 23 
6.  
DEFINITIONS OF THE ENDPOINT COMPONENTS ..................................................... 24 
6.1  
Antiplatelet therapy discontinuation ............................................................................. 24 
6.2  
Death .......................................................................................................................... 24 
6.3  
Myocardial Infarction ................................................................................................... 25 
6.3  
Stent thrombosis ......................................................................................................... 26 
6.4  
Bleeding Classification ................................................................................................ 26 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 6 of 45 
 
 
 
 
6
7. STATISTICS ......................................................................................................................... 29 
7.1 
The Number of Participants ......................................................................................... 29 
7.2 
Description of Statistical Methods ............................................................................... 29 
8. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ................................ 31 
8.1  
Main platform characteristics of the eCRF system ....................................................... 31 
8.2  
Security of data ........................................................................................................... 32 
8.3  
Help desk and investigator training ............................................................................. 32 
9. 
ETHICS .............................................................................................................................. 33 
9.1 
Declaration of Helsinki................................................................................................. 33 
9.2 
ICH Guidelines for Good Clinical Practice ................................................................... 33 
9.3 
Approvals .................................................................................................................... 33 
9.4 
Participant Confidentiality ............................................................................................ 33 
10. DATA HANDLING AND RECORD KEEPING ...................................................................... 34 
11. 
STUDY COMMITTEES ................................................................................................... 35 
11.1 
Steering Committee .................................................................................................... 35 
11.2 
Event-adjudication Committee ..................................................................................... 35 
12. 
PUBLICATION POLICY .................................................................................................. 36 
13. 
STUDY COORDINATING CENTER AND DATA RESPONSIBILITY............................... 37 
14. FINANCING ........................................................................................................................ 38 
16. 
REFERENCES ............................................................................................................... 39 
 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 7 of 45 
 
 
 
 
7
1. 
ABBREVIATIONS 
ACC  
American College of Cardiology 
ACS   
Acute Coronary Syndrome 
AE 
 
Adverse event 
AR  
 
Adverse reaction 
ARC  
Academic Research Consortium 
BARC  
Bleeding Academic Research Consortium 
BMS  
Bare Metal Stent 
BP 
 
Blood Pressure 
CABG  
Coronary Artery Bypass Graft 
CCU  
Coronary Care Unit 
CK-MB  
Creatine Kinase-MB  
CRO   
Contract Research Organisation 
CT 
 
Computerised Tomography 
e-CRF  
electronic Case Report Form 
DAPT   
Dual antiplatelet therapy 
DES 
 
Drug Eluting Stent 
EAC  
Event adjudication Committee 
EC 
 
Ethics Committee 
ECG  
Electrocardiogram 
ESC 
 
European Society of Cardiology 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
eGFR  
estimated Glomerular Filtration Rate 
ICH 
 
International Conference of Harmonisation 
MI 
 
Myocardial infarction 
NSTE  
Non ST Elevation 
PCI 
 
Percutaneous Coronary Intervention 
SAE 
 
Serious Adverse Event 
ST 
 
Stent Thrombosis 
STE 
 
ST Elevation 
Tn 
 
Troponin 
ULN  
Upper Limit of Normal Range 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 8 of 45 
 
 
 
 
8

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 9 of 45 
 
 
 
 
9
2. 
BACKGROUND AND RATIONALE 
Every year more than 1 million PCIs are performed in United States and similar numbers in 
Europe
1,2. In more than 85% of cases a coronary stent is implanted
3, with the ensuing need for 
prolonged antiplatelet therapy in order to prevent stent thrombosis (ST). The international 
Practice Guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 
receptor antagonist for at least one month after bare metal stent (BMS) implantation and for 6 
months after drug eluting stent (DES)
4,5. In patients with acute coronary syndrome (ACS), DAPT 
should be prolonged up to 12 months. 
Premature discontinuation of antiplatelet therapy is associated with a significant increase in 
the risk of ST
6-9, an infrequent but lifethreatening event which occurs most of the times as acute 
myocardial infarction (MI), with a mortality rate of 10-40%. The single most important predictor 
of ST is the cessation of antiplatelet therapy
,10-12. Previous studies demonstrated that premature 
discontinuation of antiplatelet therapy (permanent or transitory) after stent implantation occurs in 
10-50% of patients
7,13, most frequently due to surgical interventions
13.  
It has been estimated that 4-8% of patients submitted to stent implantation undergo surgery 
within the first year
3. The perioperative management of antiplatelet therapy represents a relevant 
issue, not only as it is epidemologically relevant, but also because it may have significant clinical 
consequences
17. A patient who experiences a perioperative MI has an inhospital mortality of 15-
25%
18-20.  
Perioperative management of antiplatelet therapies raises important challenges and safety 
concerns. On one hand, withholding therapy to reduce the risk of bleeding complications is 
associated with a heightened risk of ischemic events, including life-threatening stent thrombosis 
(ST), myocardial infarction (MI) and stroke [8-10]. Surgery leads to inflammatory, 
hypercoagulable and hypoxic states which are associated with plaque instability and perioperative 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 10 of 45 
 
 
 
 
10
arterial thrombosis
3,14. Thus, the perioperative risk of ST and other cardiac ischemic events is 
high, particularly if antiplatelet therapy is discontinued
15,16. On the other hand, maintaining 
antithrombotic therapy may increase the risk of bleeding and the need for transfusions, which are 
both known determinants of poor prognosis [3-10]. 
Defining the trade-off between ischemia and bleeding requires not only an understanding of 
the thrombotic risk of the individual patient, typically defined by the cardiologist, but also a clear 
understanding of the hemorrhagic risk specific to each surgical procedure, which requires the 
expertise of the surgeon. Although guidelines provide recommendations with respect to the 
perioperative management of antiplatelet and anticoagulant drugs, these have been developed 
primarily by cardiologists who may be less informed of the inherent bleeding risk of specific 
surgical procedures [11, 12]. Therefore, the surgical point of view is essential when it comes to 
issuing recommendations on how to manage antithrombotic therapies in the perioperative period. 
However, characterization of the perioperative bleeding risk of each surgical procedure is an area 
not addressed by current guidelines [11, 12].  
On this background, the Italian Society of Interventional Cardiology (GISE) has previously 
promoted the creation of a task force integrating the expert opinions from a multidisciplinary 
collaboration between cardiologists, anesthesiologists, hematologists and surgeons, providing 
recommendations on the antithrombotic treatment regimen to be used in patients treated with 
coronary stents undergoing surgical and endoscopic procedures [13]. In particular, this led to the 
creation of a consensus document, called Surgery after Stenting (SAS), which provided practical 
recommendations for standardizing the approach to antithrombotic therapy management with 
respect to various types of surgery based on the predicted individual risk of thrombotic 
complications against the anticipated risk of surgical bleeding complications. A national registry 
surveyed the applicability of the recommendations in real-world clinical practice and supported 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 11 of 45 
 
 
 
 
11
the relative merit of a risk stratification approach for both ischemia and bleeding in patients with 
coronary stents undergoing cardiac and NCS [21]. However, the landscape of devices, 
antithrombotic drugs, and surgical techniques has changed over the past years. In particular, the 
advent of the newer generation of DES has been associated with a remarkable risk reduction of 
ST, potentially allowing for a safe shorter DAPT duration, particularly in low ischemic risk 
patients [12, 22, 23]. On the other hand, data have shown potential for a protective effect of 
prolonged DAPT duration in high-risk settings [12, 22, 23]. The POISE-2 trial, investigating the 
effects of perioperative aspirin use, showed that this had no significant effect on the combined 
risk of death or nonfatal MI in patients undergoing non-cardiac surgery [24]. Nevertheless, it is 
important to note that only one patient out of four in this study had a history of coronary artery 
disease and only 4% of randomized patients had previously received coronary stents. Moreover, 
patients with implantation of DES within 1 year and BMS <6 weeks were excluded. Due to this 
limitation, the results of the POISE-2 trial should not be applied to patients with previous 
coronary stent implantation. Thus, while being an important study, it should not be considered 
when managing perioperative antiplatelet therapy in patients with coronary stents undergoing 
surgery. 
The SAS 2 Consensus Document derives from a multidisciplinary collaboration and provides 
practical recommendations on the perioperative management of antithrombotic therapy in 
patients treated with coronary stents. These recommendations are summarized in the present 
document and can be accessed through a workable web application, which can be downloaded at 
https://itunes.apple.com/us/app/stent-surgery/id551350096?mt=8. The Writing Committee was 
composed of cardiologists, surgeons, anesthesiologists, and hematologists. Overall, the 
recommendations summarized in this document were finally endorsed by 23 scientific societies, 
including interventional cardiology (n=1), anesthesiology (n=1), hematology (n=1), and a number 
of surgical specialties (n=20). 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 12 of 45 
 
 
 
 
12
Cardiologists defined the thrombotic risk based on a series of clinical features and procedural 
characteristics. In particular, the definition of thrombotic risk (low, intermediate or high) was 
derived after careful revision of the literature which led to the formulation of a tables which 
summarized the information obtained. All Cardiology members of the Writing Committee 
provided their feedback until a consensus was reached. Surgeons classified all interventions 
according to the inherent hemorrhagic risk (low, intermediate, or high) of each specific surgery. 
In particular, bleeding risk was not solely based on the amount of blood loss, but mostly 
according to the anticipated difficulty in achieving adequate local hemostasis. The bleeding risk 
was defined in a total of about 250 surgical procedures. Finally, the most appropriate 
antithrombotic treatment regimen in the perioperative phase was defined for each procedure 
taking into consideration both the thrombotic and bleeding risk profiles. Ultimately, a consensus 
agreement was reached which involved not only cardiologists and surgeons, but also 
anesthesiologists and hematologists. Importantly, the recommended antithrombotic treatment 
regimen was not standard to a given thrombotic/bleeding risk profile, but was specific to each 
individual surgical specialty.  
In general, if surgery cannot be delayed, it should be performed after the first month and 
ideally after at least 3 months from PCI [25, 32, 46, 49]. The vast majority of procedures may be 
performed while on aspirin, with the possible exception of surgeries at extremely high risk of 
bleeding (e.g., neurosurgery). When a wash-out of P2Y12 inhibiting therapy is required, this 
should be performed judiciously according to the timing of surgery: 5 days for clopidogrel and 
ticagrelor and 7 days for prasugrel. Recent data from a large observational study in CABG 
patients demonstrated that discontinuation 3 days before surgery, as opposed to 5 days, did not 
increase the incidence of major bleeding complications with ticagrelor (OR 0.93 (95% CI 0.53-
1.64), p=0.80), but increased the risk with clopidogrel (OR 1.71 (95% CI 1.04 – 2.79), p=0.033 
[71]. On the basis of these findings, in selected cases, surgery might be performed after 3 days of 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 13 of 45 
 
 
 
 
13
ticagrelor discontinuation.  
In selected cases, according to the SAS 2 recommendations, a bridging of antiplatelet therapy 
should be considered. A bridge therapy indicates a strategy of temporary transition with an 
intravenous antiplatelet agent in patients on oral antiplatelet therapy typically consisting of 
aspirin and a P2Y12 inhibitor. This strategy is usually reserved for patients deemed at high 
thrombotic risk (who thus cannot safely interrupt oral antiplatelet therapy) undergoing non-
deferrable surgery at high risk of bleeding, which requires a predictable interruption of platelet 
inhibition at the time of the intervention [3-6].  
The only intravenous antiplatelet agents available for clinical use, and thus of potential utility 
for antiplatelet bridging, include cangrelor and glycoprotein IIb/IIIa inhibitors (GPI). Cangrelor is 
an intravenous analog of adenosine triphospate with a potent, selective and specific affinity for 
P2Y12 receptors [63]. Given that cangrelor is not renally cleared, there is no need for dose 
adjustment in patients with impaired renal function. Reversible binding to P2Y12 receptors of 
this agent along with its very short half-life (3-6 minutes) allows for resumption of platelet 
function within 60 minutes of infusion cessation [64]. Cangrelor was recently approved for the 
reduction of thrombotic cardiovascular events in patients with CAD undergoing PCI who have 
not received an oral P2Y12 inhibitor prior to the PCI [65]. Cangrelor has also been specifically 
tested against placebo as a bridging agent among thienopyridine-treated patients undergoing 
coronary artery bypass grafting surgery (CABG) in the Bridging Antiplatelet Therapy With 
Cangrelor in Patients Undergoing Cardiac Surgery (BRIDGE) trial [66]. In conclusion, in line 
with the BRIDGE trial approach, if intended as a bridging agent, cangrelor can be commenced 
any time between the next expected dose of the P2Y12 inhibitor and within 72 hours from P2Y12 
inhibitor discontinuation, and stopped up to 1 hour before the start of surgery. 
         Alternatively, small molecule GPI’s (eptifibatide or tirofiban) may be considered for 
bridging therapy [67]. Compared with cangrelor however, these agents have a slower offset of 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 14 of 45 
 
 
 
 
14
action and they do not target the P2Y12 receptor. In addition, since they are renally cleared, dose 
adjustments are required among patients with impaired renal function. There are no randomized 
trials on bridging with small molecule GPIs and data derive from observational studies. Infusion 
should be commenced three days prior to surgical intervention, whereas clopidogrel and 
ticagrelor should be discontinued five days prior to surgery and seven days with prasugrel. GPI 
infusion should be interrupted at least four hours prior to surgery (eight hours in patients with 
creatinine clearance <30 ml/min). 
P2Y12 inhibitors resumed within 24-48 hours after the intervention after confirmation of 
successful hemostasis, and with a loading dose. In patients with an increased bleeding risk in the 
post-operative period, clopidogrel should be preferred over prasugrel or ticagrelor. If 
gastrointestinal function has not yet recovered (e.g., abdominal surgery), intravenous infusion of 
antiplatelet agents (cangrelor or GPI) should be restarted after the surgical procedure, after 
careful evaluation of the bleeding risk. After complete intestinal recanalization, therapy with 
P2Y12 inhibitors should be resumed with a loading dose, after which the infusion of intravenous 
antiplatelet agents can be stopped. Because thrombotic complications occur most frequently soon 
after surgery, close post-operative clinical and electrocardiographic monitoring is strongly 
encouraged.  
Notably, the impact of the application of the SAS 2 document on perioperative antiplatelet 
therapy in clinical practice has not been evaluated. 
 
 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 15 of 45 
 
 
 
 
15
3. 
OBJECTIVES 
3.1  
Primary Objective 
 To assess outcomes associated with the application of the Consensus Document “Stent 
and Surgery-2” on perioperative antiplatelet therapy in patients with coronary stenting 
undergoing surgery. 
3.2  
Secondary Objectives 
 To assess ischemic and hemorrhagic events in relation to the application of the Consensus 
Document. Length of any antiplatelet discontinuation and delay in performing surgical 
procedures will also be evaluated.  

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 16 of 45 
 
 
 
 
16
4.  
STUDY DESIGN 
4.1  
Summary of Study Design 
The SAS registry will include any patient with previous coronary stenting undergoing any 
type of surgery or operative endoscopic/endovascular procedure at the participating Centers. 
Centers will be divided into two groups: Centers that routinely follow the recommendations of 
the SAS 2 Document and Centers that do not. The relevant clinical, procedural and outcome data 
(within index admission and at 30 days) will be entered in a specifically designed electronic case 
record form (eCRF).  
4.2  
Primary endpoint 
 Rate of discontinuation of P2Y12 inhibitors and/or aspirin (without bridging) in the first 3 
months after PCI with low risk characteristics and 6 months after PCI with high risk 
characteristics or any antiplatelet therapy discontinuation without bridging therapy   
4.3  
Secondary endpoints 
Patients undergoing non cardiac surgery: 
• 
The composite of death, myocardial infarction, probable/definite stent thrombosis 
according the Academic Research Consortium definition44 and bleeding events of Bleeding 
Academic Research Consortium (BARC) grad
 
• 
The composite of death, myocardial infarction and probable/definite stent at 30 days  
• 
The incidence of bleeding events of Bleeding Academic Research Consortium (BARC) 
grade  3 at 30 days 
• 
The type and the length of discontinuation of any antiplatelet therapy in patients 
undergoing non cardiac surgery according to time from PCI to surgery  
• 
Rate of non cardiac surgical procedures within 12 months from PCI divided into quartiles 
(0-3, 3-6, 6-9, 9-12 months) 
• 
Delay in performing non cardiac surgical procedure  
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 17 of 45 
 
 
 
 
17
Patients undergoing cardiac surgery: 
• 
The composite of death, myocardial infarction, probable/definite stent thrombosis 
according the Academic Research Consortium definition44 and bleeding events of Bleeding 
Academic Research Con
 
• 
The composite of death, myocardial infarction and probable/definite stent at 30 days  
• 
The incidence of bleeding events of Bleeding Academic Research Consortium (BARC) 
grade  4 at 30 days 
• 
The type and the length of discontinuation of any antiplatelet therapy in patients 
undergoing cardiac surgery according to time from PCI to surgery  
• 
Rate of cardiac surgical procedures within 12 months from PCI divided into quartiles (0-3, 
3-6, 6-9, 9-12 months)  
•           Delay in performing cardiac surgical procedure 
 
4.4 Participants 
4.4.1  Inclusion Criteria 
Eligible will be male and female patients > 18 years of age. 
Eligible will be patients with previous coronary stenting undergoing any kind of surgical or 
operative endoscopic procedure at the participating Centers, irrespective of the distance in time 
between stenting and surgery.  
Both candidates to elective and urgent/emergent surgical procedures will be included in the 
MONET registry.  
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 18 of 45 
 
 
 
 
18
4.4.2  Exclusion criteria 
Unwillingness/inability to sign the Informed Consent Form (ICF). Patients with an active 
bleeding requiring discontinuation of one or both antiplatelet agents will be also excluded. There 
are no other exclusion criteria.  
 
4.4.3 Enrolment time  
The enrolment period is 12 months after authorization of respective Ethics Committee. 
4.5 
Study Procedures 
4.5.1 Informed Consent 
Patients will be asked to sign an ICF for participation in the Registry.  
4.5.2 Screening 
Screening for inclusion into the registry will be made at the time of preoperative evaluation: this 
will be made by the consultant cardiologist in cooperation with the anaesthesiologist and/or 
surgeon/endoscopist in charge of the operation. 
4.5.3 In-hospital assessments 
The MONET registry does not imply any assessments additional to routine treatment. The 
following clinical and laboratory variables will be captured by the eCRF: 
Clinical characteristics 
- 
Age, gender, body weight. 
- 
Selected coronary risk factors, such as diabetic status, smoking, hypertension, 
dyslipidemia. 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 19 of 45 
 
 
 
 
19
- 
Cardiovascular status: prior MI, PCI (date of latest stenting), CABG, heart failure, atrial 
fibrillation, latest left ventricular ejection fraction. 
Laboratory tests  
- 
Baseline serum creatinine (eGFR will be automatically calculated by the eCRF using the 
Cockroft-Gault formula) and peak serum creatinine during hospital stay.  
- 
Baseline haemoglobin/haematocrit and nadir values during hospital stay.  
- 
CKMB and troponin values should be checked at 6-hour intervals for 24 hours after any 
suspect ischemic symptoms and/or ischemic ECG changes in the perioperative period, 
unless otherwise recommended by local practice. The peak value of CKMB will be 
recorded in the eCRF. 
Electrocardiogram  
A standard 12-lead ECG will be taken preoperatively, in the case of ischemic symptoms and at 
discharge.  
Concomitant Medications 
The following medications will be captured by the eCRF: 
- 
Aspirin 
- 
P2Y12 inhibitors (further subdivided as ticlopidine, clopidogrel, prasugrel, ticagrelor) 
- 
Betablockers 
- 
Statins 
- 
ACEI, ARBS 
- 
Oral 
anticoagulants 
(warfarin, 
acenocumarol, 
apixaban, 
dabigatran, 
edoxaban, 
rivaroxaban) 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 20 of 45 
 
 
 
 
20
- 
Low-molecular weight heparin 
- 
Tirofiban or eptifibatide 
- 
Cangrelor 
The dates and times of perioperative discontinuation and reinstitution (if any) will also be 
captured. 
Drug therapy at discharge and at the 30-day contact will be captured by the eCRF. 
 
Index PCI and surgical procedure details 
Details of PCI and surgical procedures will obtained from interrogation of the medical 
records and hospital charts.  
The delay from stenting to surgery and the type of stent (BMS, first or second generation 
DES), stent number, length and diameter will be recorded. Surgeries will risk-stratified according 
to the American College of Cardiology/American Heart Association classification [11]. 
Moreover, the American Society of Anaesthesiologists (ASA) physical status will be assessed for 
each patient [21].  
For each patient, surgical hemorrhagic and thrombotic risk (according to the SAS 2 
Consensus Document definitions) will be identified at the time of data analysis according to 
clinical and angiographic characteristics that will be captured in the eCRF.  
 
Outcome Events 
The following outcome events will be captured by the eCRF: 
 Death 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 21 of 45 
 
 
 
 
21
 Myocardial infarction, recurrent ischemia, heart failure, ventricular tachycardia, 
ventricular fibrillation. 
 Major bleeding 
 Transfusions 
 Reoperation due to bleeding 
See point 8 for definitions 
4.5.4 Follow-up 
A follow-up contact visit is planned at 30 days (± 7 days) after the surgical procedure using 
hospital records, outpatient visits, or telephone contact. A standard questionnaire will be used to 
collect information on the medications the patients were taking and the occurrence of any adverse 
events. Each site will have a designated individual who entered raw data into an electronic case 
report form, allowing immediate and continuous monitoring of its completeness and accuracy. 
Unscheduled visits can also take place whenever necessary.  
Relevant information to be inquired and collected in the e-CRF will include:  
 check of items describing the primary and secondary study endpoints, with special 
reference to new hospitalizations;  
 ongoing medications 
 compliance with medication prescribed at discharge 
 adverse events 
4.6 
Source Data 
When required for the adjudication of endpoint clinical events, original documents, data, and 
records from which participants’ CRF data are obtained will be electronically uploaded in the 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 22 of 45 
 
 
 
 
22
eCRF (see point 9).  These include, but are not limited to, hospital records (from which medical 
history and previous and concurrent medication may be summarised into the CRF), clinical and 
office charts, laboratory and pharmacy records, diaries, radiological images. 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 23 of 45 
 
 
 
 
23
5.  
TREATMENT OF PARTICIPANTS 
The Registry will record actual perioperative management strategies in patients with previous 
stent implantation undergoing surgical and operative endoscopic/endovascular procedures. A 
guidance for the perioperative management of antiplatelet therapy is provided by the Consensus 
Document SAS 2 issued by GISE. The document is enclosed as an Appendix to the present 
protocol. The recommendations can be accessed by the Investigators through a workable web application, 
which can be downloaded at https://itunes.apple.com/us/app/stent-surgery/id551350096?mt=8.   
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 24 of 45 
 
 
 
 
24
6.  
DEFINITIONS OF THE ENDPOINT COMPONENTS 
6.1  
Antiplatelet therapy discontinuation  
Antiplatelet discontinuation is defined as P2Y12 inhibitors and/or aspirin withdrawal for 
>5 days at the time of surgical procedure without bridging therapy with antiplatelet agents in the 
first 3 months after PCI with low risk characteristics and 6 months after PCI with high risk 
characteristics or any any antiplatelet therapy discontinuation without bridging therapy at any 
time after PCI. A detailed description on the perioperative management of oral antiplatelet 
therapy will be obtained for both aspirin and P2Y12 inhibitors (ticlopidine, clopidogrel, prasugrel, 
and ticagrelor). This includes the time delay from drug interruption to surgery as well as the time 
from surgery to reintroduction of therapy. The use of any bridging strategy will also be recorded. 
According to the SAS 2 Consensus Document, in selected patients at high risk for both bleeding 
and ischemic events, when withdrawal of oral antiplatelet therapy is required, bridging with 
cangrelor or with a short-acting intravenous glycoprotein IIb/IIIa inhibitor (GPI) (tirofiban or 
eptifibatide) can be considered. 
6.2  
Death  
All-cause mortality will be considered for the primary analysis. All-cause mortality includes all 
deaths, regardless of whether the cause of death is determined.  
For the secondary analysis, death will be classified in two primary categories, cardiovascular or 
non-cardiovascular.  
 Cardiovascular death is defined as death due to atherosclerotic coronary heart disease, 
cerebrovascular accident or (complication of) peripheral embolization, and includes 
deaths due to acute MI, stroke, sudden death, non-sudden death, unwitnessed death, and 
procedure-related deaths.  

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 25 of 45 
 
 
 
 
25
 Non cardiovascular death includes deaths due to all other causes.  
All deaths will be assumed cardiovascular in nature unless a non-cardiovascular cause can be 
clearly shown, with the exception of death without any additional information, which will be 
classified as unknown cause of death.  
6.3  
Myocardial Infarction  
All definite MIs will be counted as events whether they occurred spontaneously or as the direct 
consequences of a procedure or operation.  
The definition of perioperative MI includes cardiac marker evidence of MI with either troponin or 
CK-MB elevation greater than the ULN with a typical rise and fall44 and 1 or more of the 
following defining features45:  
 ischemic symptoms (such as chest, epigastric, arm, wrist, or jaw discomfort or shortness 
of breath),  
 development of pathologic Q waves in 2 contiguous leads during ECG,  
 ischemic changes detected with ECG (new or presumed-new ST-segment elevation or 
depression or T-wave inversion in at least 2 contiguous leads during ECG),  
 coronary artery intervention (such as percutaneous coronary intervention or coronary 
artery bypass graft surgery),  
 or evidence of MI on cardiac imaging (a new or presumed-new cardiac wall–motion 
abnormality on echocardiographic imaging or a new or presumed-new fixed defect on 
radionuclide imaging).  
 a patient’s autopsy findings demonstrated acute MI.  
According to the 3rd Universal Definition of MI44,  

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 26 of 45 
 
 
 
 
26
 following PCI, CK-MB elevation must be >5 x ULN.  
 Following CABG, the definition for an MI requires that cardiac markers are >10 x ULN.  
Outcome adjudicators evaluated all potential MIs, and their decisions will be used in the 
statistical analyses. The event adjudication committee should also consider the clinical features 
(eg, renal insufficiency), possible alternative diagnoses (eg, pericarditis), pattern of marker 
release (eg, absence of a rise and fall), and known sensitivity/specificity of the various cardiac 
markers in the adjudication of infarction, particularly when there is discordance in the results of 
multiple markers.  
6.3  
Stent thrombosis 
Probable/definite stent thrombosis will be defined according the Academic Research Consortium 
definition42. With regard to the primary endpoint of the study, the adjudication will follow a 
hierarchical order with death first, MI second and stent thrombosis third, mostly in the case of 
recurrent ischemia without enzyme elevation.  
6.4  
Bleeding Classification  
All bleeding events will be considered in patients undergoing cardiac and non cardiac surgery. 
Bleeding events will be classified according to BARC classification.  
 
Bleeding Academic Research Consortium Definition for Bleeding (Ref 43) 
 Type 0: no bleeding 
 Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional; may 
include episodes leading to self-discontinuation of medical therapy by the patient without 
consulting a healthcare professional 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 27 of 45 
 
 
 
 
27
 Type 2: any overt, actionable sign of hemorrhage (eg, more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) that 
does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following 
criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, (2) 
leading to hospitalization or increased level of care, or (3) prompting evaluation 
 Type 3 
Type 3a: overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided hemoglobin 
drop is related to bleed); any transfusion with overt bleeding 
Type 3b: overt bleeding plus hemoglobin drop >5 g/dL* (provided haemoglobin drop is 
related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control 
(excluding dental/nasal/skin/hemorrhoid); bleeding requiring intravenous vasoactive 
agents 
Type 3c: intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal); subcategories confirmed by autopsy or imaging 
or lumbar puncture; intraocular bleed compromising vision 
 Type 4: CABG-related bleeding, including perioperative intracranial bleeding within 48 h, 
reoperation after closure of sternotomy for the purpose of controlling bleeding, 
transfusion of >5 U whole blood or packed red blood cells within a 48-h period, chest 
tube output >2L within a 24-h period 
 Type 5: fatal bleeding 
Type 5a: Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
Type 5b: Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 28 of 45 
 
 
 
 
28
6.5  
Rate of non cardiac surgical procedures within 12 months from PCI  
The rate of cardiac and non cardiac surgical procedures performed within 12 months from 
PCI will be assessed. Time from PCI to surgery will be divided into 4 quartiles: from 0 to 3 
months, from 3 to 6 months, from 6 to 9, and from 9 to 12 months. 
 
6.6  
Delay in performing non cardiac surgical procedure 
 
The delay in performing cardiac and non cardiac surgical procedures will be defined as 
the time from the time of surgical indication to the time of surgical procedure. 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 29 of 45 
 
 
 
 
29
7. STATISTICS 
7.1 
The Number of Participants 
Consecutive patients will be enrolled over one year of time at the participating Centers. 
Cases and controls patients will be divided into those who will use Consensus Document “Stent 
and Surgery-2” (group 1) vs those who traditionally will be managed by local practice (group 2).  
On the basis of previous data reported SAS, a sample size of 1623 patients would be required to 
have a case-control matching 1:2, assuming a study power of 80% and 5% significance. Of those, 
324 case-patients (20% of group 1) vs 162 control-patients (ratio 1:2) would be required for 
enrollment within one-year after implanted stents. Two preplanned interim analyses will be 
performed by an independent statistician when 800 and 1500 of patients will be enrolled.   
 
7.2 
Description of Statistical Methods 
Continuous numeric variables will report as means with SD and compared using the Student’s t-
or Wilcoxon rank-sum test. Categorical variables will be presented as counts and percentages and 
will be compared using the chi-square or Fisher’s exact test. To examine the effect of significant 
factors on two different groups (Group 1 vs Group 2) the hazard ratio of the interaction term will 
be calculated.  To identify the independent predictors for in hospital NACE, 30day MACE and 
30-day BARC bleedings, first univariate and then multivariate logistic regression models will 
apply. The BARC bleedings will be considered according to type of surgery. Specifically, BARC 
bleedings grade >3  will be considered in patients undergoing cardiac surgery, and BARC 
bleedings grade >4 will be taken into account for non-cardiac surgery.  Covariates for 
multivariable models will be selected on the basis of a backward stepwise algorithm in a Cox 
proportional hazards model. Additionally, to minimise group differences on confounding 
covariates between patients who will be managed with consensus document (group 1) and those 
who will be received local practice (group 2), a 1:2 propensity score matching would be used. 
Propensity scores will be calculated with logistic regression, with multiple imputation and 
backwards elimination with a significance level to stay of 0.05. To ensure that the comparison 
between two groups (group 1 vs group 2 ) would not be bias, the proportion of patients  who will 
not received consensus document within center that traditionally used it, will be excluded. The 
results will be presented as ORs with 95% confidence intervals (CI) and p values. For all 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 30 of 45 
 
 
 
 
30
analyses, a two-sided P <0.05 will be required for statistical significance. All data will be 
analyzed using the Statistical Package of Social Sciences version 20 (IBM SPSS, Chicago, IL). 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 31 of 45 
 
 
 
 
31
8. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
An expert academic Clinical Research Organization especially expert in cardiovascular clinical 
trials (Advice Pharma, Italy) will be in charge of data management, control and quality assurance. 
Patients data will be collected using and electronic CRF using a centralized system for collecting 
data via the Web that can be operated via a simple web browser and an internet connection.  
8.1  
Main platform characteristics of the eCRF system 
 Compliance with FDA 21 CFR part 11 requirements and guidelines concerning security 
and data protection; 
 Full web: requirements are browser and Internet connections; 
 Compatible with Windows / SQL Server and Linux / MySQL and with main browsers 
(Internet Explorer, Mozilla Firefox, Google Chrome, Safari and Opera); 
 Access control and advanced user management; 
 Advanced user profiling management and customization; 
 Audit Trail: tracking all user operations (e.g. visited pages); user data audit, patients and 
centres audit, CRF data audit; 
 CRF source verified data locking at visit / page / single variable levels; 
 On-line control of data plausibility and consistency; 
 Automatic query generation; 
 Electronic upload of selected source data for evaluation by the Event Adjudication 
Committee; 
 Production of blank and annotated CRF; 
 SAS clinical data base 
 Exporting data to SAS and Excel format; 
 Graphic reports and descriptive statistics. 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 32 of 45 
 
 
 
 
32
8.2  
Security of data  
 Secure data transmission using 256-bit SSL (HTTPS) protocol and relative Certificate 
from Thawte Certification Authority. 
 Access with personal password with complexity requirements, password expiration are 
customizable, but at least quarterly; 
 Expiry of the session after 15 minutes of inactivity; 
 Hosting of data in web-farm monitored and controlled 7x24; 
 Redundant hardware; 
 Daily backups and redundant. 
8.3  
Help desk and investigator training 
 Help Desk technical support to investigators (5 days/7 - office hours - availability outside 
office hours); 
 Participation in meetings and training meetings for investigators on the characteristics and 
use of the e-CRF (if required); 
 Participation in periodic teleconference (if required); 
 Database data production for individual centres as CD / DVD 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 33 of 45 
 
 
 
 
33
9. 
ETHICS 
9.1 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in full conformity with the current 
revision of the Declaration of Helsinki. 
9.2 
ICH Guidelines for Good Clinical Practice  
The Investigator will ensure that this study is conducted in full conformity with the ICH 
Guidelines for Good Clinical Practice and all relevant local regulations (DL 211/2003; DL 
200/2007)  
9.3 
Approvals  
The protocol, informed consent form, participant information sheet and any proposed advertising 
material will be submitted to an appropriate Ethics Committee (EC) and competent authorities 
(CA) for written approval.   
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents.    
9.4 
Participant Confidentiality 
The trial staff will ensure that the participants’ confidentiality is maintained.  The participants 
will be identified only by initials and a participants ID number on the CRF and any electronic 
database.  All documents will be stored securely and only accessible by trial staff and authorised 
personnel. The study will comply with the Italian Law on the protection of personal data and with 
guidelines dated July 24th 2008.   
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 34 of 45 
 
 
 
 
34
10. DATA HANDLING AND RECORD KEEPING 
Data will be entered by the Investigators in the electronic CRF provided by the CRO. The 
Principal Investigator or Co-Investigator must ensure the accuracy and completeness of the 
recorded data. 
The entire 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 and international standards. The participants will be identified by a 
study specific participants number and/or code in any database. 
Security of the data will be ensured according to explanations given at point 9 of the present 
protocol.  
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 35 of 45 
 
 
 
 
35
11. 
STUDY COMMITTEES 
11.1 
Steering Committee  
The Steering Committee is listed in the “MONET_Annex 1 – Steering Committee”. 
The Steering Committee will be responsible for:  
 preparation of the protocol and preparation of the first draft of the CRF (the latter in co-
operation with Advice Pharma)  
 selection of the study centers conducting the investigator meetings (one at the beginning 
and one at the end of the study)  
 writing newsletters for the investigators 
 establishing a troubleshooting call-line for the investigators 
 negotiating the statistical analysis with the chief statistician  
 preparing the manuscript and taking care of the main study publication and its offsprings 
 appointing experts in charge of any substudies. 
11.2 
Event-adjudication Committee 
The following experts, designated by the Steering Committee and not involved in enrolment for 
the present study, will constitute the Event-Adjudication Committee.  
The Event-Adjudication Committee is listed in the “MONET_Annex 2 - Event-Adjudication 
Committee”. 
The Event-adjudication Committee will screen and adjudicate all critical adverse events based on 
the review of CRF, original source documents and films.  
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 36 of 45 
 
 
 
 
36
12. 
PUBLICATION POLICY  
The final manuscript of the study will be prepared by the Principal Investigators, reviewed and 
approved by the Steering Committee, presented in a final meeting to all of the Investigators (pre-
view by e-mail and Cyber-Session allowed) and published under the authorship of “The MONET 
Registry Investigators”. Dr Roberta Rossini will act as the corresponding author. Any sponsor 
must agree not to interfere on the interpretation and presentation of data. The data will remain 
property of the Steering Committee.  
Any substudies derived from subgroup analyses of the study will have to be decided in 
coordination with the Steering Committee of the study. 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 37 of 45 
 
 
 
 
37
13. 
STUDY COORDINATING CENTER AND DATA RESPONSIBILITY 
The study will be promoted by the Fondazione GISE Onlus.  
The Coordinating Center will act as the study sponsor and will therefore be responsible – among 
the other sponsor reponsibilites - for handling, managing and storing the data according to 
current regulations. (DL 196/2003: “Codice in materia di protezione dei dati personali, 30 
giugno 2003”). Some of the sponsor responsibilities will be delegated to the CRO Advice 
Pharma.   
 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 38 of 45 
 
 
 
 
38
14. FINANCING 
The study will be co-financed by liberal contributions and research grants from the 
pharmaceutical industry.  

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 39 of 45 
 
 
 
 
39
16. 
REFERENCES 
1. Roger VL, Go AS, Lloyd-Jones DM, et al. American Heart Association Statistics Committee 
and Stroke Statistics Subcommittee. Heart disease and stroke statistics - 2012 update: a report 
from the American Heart Association. Circulation 2012;125: e2-e220. 
2. Moschovitis A, Cook S, Meier B. Percutaneous coronary interventions in Europe in 2006. 
EuroIntervention 2010;6:189-94.  
3. Savonitto S, Caracciolo M, Cattaneo M, De Servi S. Management of patients with recently 
implanted coronary stents on dual antiplatelet therapy who need to undergo major surgery. J 
Thromb Haemost 2011;9: 2133-42. 
4. Wijns W, Kolh P, Danchin N, et al.; Task Force on Myocardial Revascularization of the 
European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic 
Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions 
(EAPCI). Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501- 55. 
5. Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 
appropriateness criteria for coronary revascularization: a report by the American College of 
Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular 
Angiography and Interventions, Society of Thoracic Surgeons, American Association for 
Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology 
endorsed by the American Society of Echocardiography, the Heart Failure Society of America, 
and the Society of Cardiovascular Computed To- mography. J Am Coll Cardiol 2009;53:530- 53. 
6. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after 
discontinuation of antiplatelet therapy. Lancet 2004;364:1519-21. 
7. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis 
after successful implantation of drug-eluting stents. JAMA 2005;293:2126- 30. 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 40 of 45 
 
 
 
 
40
8. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature 
discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the 
PREMIER registry. Circulation 2006;113:2803-9. 
9. van Werkum JW, Heestermans AA, Zomer AC, et al. Predictors of coronary stent thrombosis: 
the Dutch Stent Thrombosis Registry. J Am Coll Cardiol 2009;53:1399- 409. 
10. Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after 
drug-eluting stent implantation during long- term follow-up. Am J Cardiol 2006;98:352–6. 
11. Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE. Catastrophic outcomes of noncardiac 
surgery soon after coronary stenting. J Am Coll Cardiol 2000;35:1288–94. 
12. Akowuah E, Shrivastava V, Jamnadas B, et al. Comparison of two strategies for the 
management of antiplatelet therapy during urgent surgery. Ann Thorac Surg 2005;80:149–52. 
13. Rossini R, Capodanno D, Lettieri C, et al. Prevalence, predictors, and long-term prognosis of 
premature discontinuation of oral antiplatelet therapy after drug eluting stent implantation. Am J 
Cardiol 2011;107: 186-94. 
14.To AC, Armstrong G, Zeng I, Webster MW. Noncardiac surgery and bleeding after 
percutaneous coronary intervention. Circ Cardiovasc Interv 2009;2:213-21. 
15. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of 
multicenter coronary stent clinical trials. Circulation 2001;103:1967–71. 
16. Patrono C, Bachmann F, Baigent C, et al. Expert consensus document on the use of 
antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic 
cardiovascular disease of the European society of cardiology. Eur Heart J 2004;25: 166 – 81. 
17. Abualsaud A, Eisenberg M.  Perioperative management of patients with drug-eluting stents. J 
Am Coll Cardiol Intv 2010;3;131-142. 
18. Kumar R, McKinney WP, Raj G, et al. Adverse cardiac events after surgery: assessing risk in 
a veteran population. J Gen Intern Med 2001;16:507-18. 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 41 of 45 
 
 
 
 
41
19. Badner NH, Knill RL, Brown JE, Novick TV, Gelb AW. Myocardial infarction after 
noncardiac surgery. Anesthesiology 1998; 88:572-8. 
20. Shah KB, Kleinman BS, Rao TL, Jacobs HK, Mestan K, Schaafsma M. Angina and other risk 
factors in patients with cardiac diseases undergoing noncardiac operations. Anesth Analg 
1990;70:240-7. 
21. Srinivasan AK, Grayson AD, Pullan DM, Fabri BM, Dihmis WC. Effect of preoperative 
aspirin use in off-pump coronary artery bypass operations. Ann Thorac Surgery 2003;76:41–5. 
22. Ferraris VA, Ferraris SP, Moliterno DJ, et al. The Society of Thoracic Surgeons practice 
guideline series: aspirin and other antiplatelet agents during operative coronary revascularization 
(executive summary). Ann Thorac Surg 2005;79:1454 – 61. 
23. Purkayastha S, Athanasiou T, Malinovski V, et al. Does clopidogrel affect outcome after 
coronary artery bypass grafting? A meta-analysis. Heart 2006;92:531–2. 
24. Ascione R, Ghosh A, Rogers CA, Cohen A, Monk C, Angelini GD. In-hospital patients 
exposed to clopidogrel before coronary artery bypass graft surgery: a word of caution. Ann 
Thorac Surg 2005;79: 1210 – 6. 
25. Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary artery bypass 
surgery. Crit Care Med 2001;29:2271–5. 
26. Chu MW, Wilson SR, Novick RJ, Stitt LW, Quantz MA. Does clopidogrel increase blood 
loss following coronary artery bypass surgery? Ann Thorac Surg 2004;78:1536–41. 
27. Leong JY, Baker RA, Shah PJ, Cherian VK, Knight JL. Clopidogrel and bleeding after 
coronary artery bypass graft surgery. Ann ThoracSurg 2005;80:928–33. 
28. Burger W, Chemnitius JM, Kneissl GD, Rücker G. Low-dose aspirin for secondary 
cardiovascular prevention - cardiovascular risks after its perioperative withdrawal versus bleeding 
risks with its continuation - review and meta-analysis. J Intern Med 2005; 257:399-414. 
29. Gurbel PA, DiChiara J, Tantry US. Antiplatelet therapy after implantation of drug-eluting 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 42 of 45 
 
 
 
 
42
stents: duration, resistance, alternatives, and management of surgical patients. Am J Cardiol 
2007;100:18M–25M. 
30. Chassot PG, Delabays A, Spahn DR. Perioperative antiplatelet therapy: the case for 
continuing therapy in patients at risk of myocardial infarction. Br J Anaesth 2007;99: 316-28. 
31. Brilakis ES, Banerjee S, Berger PB. Perioperative management of patients with coronary 
stents. J Am Coll Cardiol 2007;49: 2145-50.  
32. Riddell JW, Chiche L, Plaud B, Hamon M. Coronary stents and noncardiac surgery. 
Circulation 2007;116:e378-e382. 
33. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative 
cardiovascular evaluation and care for noncardiac surgery: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee 
to revise the 2002 guidelines on perioperative cardiovascular evaluation for noncardiac surgery) 
developed in collaboration with the American Society of Echocardiography, American Society of 
Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society 
for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, 
and Society for Vascular Surgery. J Am Coll Cardiol 2007;50:e159-e241. 
34. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary 
artery bypass graft surgery: a re- port of the American College of Cardiology/American Heart 
Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for 
Coronary Artery Bypass Graft Surgery). Circulation 2004; 110:1168-76. 
 
35. Grines CL, Bonow RO, Casey DE Jr, et al. Prevention of premature discontinuation of dual 
antiplatelet therapy in patients with coronary artery stents: a science advisory from the American 
Heart Association, American College of Cardiology, Society for Cardiovascular Angiography 
and Interventions, American College of Surgeons, and American Dental Association, with 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 43 of 45 
 
 
 
 
43
representation from the American College of Physicians. J Am Coll Cardiol 2007;49:734-9. 
36. Poldermans D, Bax JJ, Boersma E, et al.; Task Force for Preoperative Cardiac Risk 
Assessment and Perioperative Cardiac Management in Non-cardiac Surgery, European Society of 
Cardiology (ESC). Guidelines for preoperative cardiac risk assessment and perioperative cardiac 
management in non-cardiac surgery. Eur Heart J 2009;30:2769-812. 80.  
37. Cardiac Society of Australia and New Zealand. Guidelines for the management of antiplatelet 
therapy in patients with coronary stents undergoing non-cardiac surgery. Heart Lung Circ 
2010;19:2-10. 
39. Samama CM, Bastien O, Forestier F, et al.; French Society of Anesthesiology and Intensive 
Care. Antiplatelet agents in the perioperative period: expert recommendations of the French 
Society of Anesthesiology and Intensive Care (SFAR) 2001 - summary statement. Can J Anaesth 
2002;49:S26-S35.  
40 Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative Management of 
Antithrombotic Therapy and Prevention of Thrombosis. 9th ed: American College of Chest 
Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141(2)(Suppl):e326S–
e350S 
41. Rossini R, Bramucci E, Castiglioni B, a nome della Società Italiana di Cardiologia Invasiva 
(GISE) e dell’Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO). Documento di 
consenso. Stent coronarico e chirurgia: la gestione perioperatoria della terapia antiaggregante nel 
paziente portatore di stent coronarico candidato a intervento chirurgico. Giornale Italiano di 
Cardiologia 2012;13:528-51 
42. Cutlip DE, Windecker S, Mehran R, et al, Academic Research Consortium. Clinical end 
points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51 
43. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular 
clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 44 of 45 
 
 
 
 
44
2011;123:2736-47 
44. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; the Writing Group 
on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of 
Myocardial Infarction. Third Universal Definition of Myocardial Infarction. Eur Heart J 2012 
Aug 24 [Epub ahead of print] 
45. Devereaux PJ, Xavier D, Pogue J, et al, on behalf of the POISE (PeriOperative ISchemic 
Evaluation) Investigators. Characteristics and Short-Term Prognosis of Perioperative Myocardial 
Infarction in Patients Undergoing Noncardiac Surgery: A Cohort Study.  Ann Intern Med. 
2011;154:523-8. 
 

Date and Version No: 1.0 
25.09.2017 
 
 
 
CONFIDENTIAL 
Page 45 of 45 
 
 
 
 
45
APPENDIX A: SCHEDULE OF PROCEDURES 
Procedures 
Screening 
 
Index admission 
Discharge 
1 month 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
X 
Concomitant medications 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
ECG 
X 
X 
X 
 
Laboratory tests: blood 
cell count 
X 
X 
X 
 
Eligibility assessment 
X 
 
 
 
Compliance with 
medications 
 
 
 
X 
Assessment 1 
 
 
Report 
of 
MACCE 
and 
bleeding 
during 
index admission 
 
Assessment 2 and 
following 
 
 
 
Report 
of 
MACCE 
and 
bleeding 
Adverse event 
assessments  
 
X 
X 
X