Randomized Trial Of Hybrid Coronary Revascularization Versus Percutaneous Coronary Intervention
Phase: NA
Conditions: Coronary Artery Disease
Sponsor: Emilia Bagiella

Randomized Trial Of Hybrid Coronary Revascularization Versus 
Percutaneous Coronary Intervention
PI: Emilia Bagiella, PhD
NCT03089398
Document Date: July 25, 2017

Hybrid Coronary Revascularization Trial 
CONFIDENTIAL 
Protocol Rev 2.1 
July 2017 
InCHOIR 
RANDOMIZED TRIAL OF HYBRID CORONARY 
REVASCULARIZATION VERSUS PERCUTANEOUS 
CORONARY INTERVENTION 
Trial Protocol 
Sponsored By NHLBI 
Data Coordinating Center 
InCHOIR 
Mount Sinai School of Medicine 
New York 
Version 2.1 
CONFIDENTIAL 

Hybrid Coronary Revascularization Trial 
CONFIDENTIAL 
Protocol Rev 2.1 
InCHOIR 
July 2017 
2 
 
Trial Principal Investigators 
Clinical Coordinating Center: John Puskas, MD; Gregg W. Stone, MD  
Data Coordinating Center: Emilia Bagiella, PhD, Alan Moskowitz, MD 
Steering Committee 
John D. Puskas, MD; Mount Sinai School of Medicine (Chair)  
Gregg W. Stone, MD; Columbia University Medical Center (Chair) 
Emilia Bagiella, PhD; InCHOIR, Mount Sinai School of Medicine (Chair)  
Alan Moskowitz, MD; InCHOIR, Mount Sinai School of Medicine (Chair)  
Michael Argenziano, MD; Columbia University Medical Center 
Joseph J. DeRose, MD; Montefiore-Einstein Heart Center (Co-chair Surgical Management 
Committee) 
Patrick O'Gara, MD; Cardiothoracic Surgical Trials Network 
Annetine C. Gelijns, PhD; InCHOIR, Mount Sinai School of Medicine 
Michael E. Halkos, MD; Emory University (Co-chair Surgical Management Committee)  
Steve J. Hoff, MD; Orlando Heart Hospital 
Ajay Kirtane, MD; Columbia University Medical Center (Co-Chair Cardiology Clinical 
Management Committee) 
Henry Liberman, MD; Emory University 
Donna Mancini, MD; InCHOIR, Mount Sinai School of Medicine  
William H. Matthai, Jr., MD; University of Pennsylvania 
David Zhao, MD; Wake Forest School of Medicine 
Clinical Coordinating Center 
Icahn School of Medicine at Mount Sinai: John Puskas, MD; Stella Palencia, RN 
Columbia University: Gregg Stone, MD 
Data Coordinating Center 
International Center for Health Outcomes and Innovation Research (InCHOIR), Icahn School of 
Medicine at Mount Sinai: Emilia Bagiella, PhD; Alan Moskowitz, MD; Helena Chang, MS, Susan 
Comninel, BSN, MPH;  Edlira Dobrev, MS; Vincent Dobrev, BS; Rami Habas, MS; Annetine 
Gelijns, PhD; Lopa Gupta, MPH;  Brittany Kalosza, MPH; Donna Mancini, MD; Ellen Moquete, 
RN, BSN; Karen O’Sullivan, MPH; Terry Ye, BS. 
Trial Sponsor 
National Heart Lung and Blood Institute (Marissa Miller, DVM MPH; Wendy Taddei-Peters, PhD; 
Catherine Burke, MA) 

Hybrid Coronary Revascularization Trial 
CONFIDENTIAL 
Protocol Rev 2.1 
InCHOIR 
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3 
 
TABLE OF CONTENTS 
OBJECTIVES ................................................................................................................................. 11 
BACKGROUND AND SIGNIFICANCE ...................................................................................... 11 
STUDY DESIGN............................................................................................................................ 13 
ENDPOINTS .................................................................................................................................. 14 
STUDY POPULATION ................................................................................................................. 14 
TREATMENT ASSIGNMENTS ................................................................................................... 17 
RANDOMIZATION....................................................................................................................... 18 
TREATMENT INTERVENTIONS................................................................................................ 19 
DEFINITIONS AND MEASUREMENT OF ENDPOINTS ......................................................... 22 
UNANTICIPATED ADVERSE DEVICE EFFECTS.................................................................... 27 
CLINICAL CENTERS ................................................................................................................... 28 
INVESTIGATORS ......................................................................................................................... 28 
SITE INITIATION ......................................................................................................................... 29 
DATA COLLECTION ................................................................................................................... 30 
DATA MANAGEMENT................................................................................................................ 37 
ANALYTICAL PLAN ................................................................................................................... 38 
ORGANIZATION OF THE STUDY ............................................................................................. 42 
APPENDIX I:  Canadian Cardiovascular Society Classification ................................................... 47 
Appendix II:  Quality of Life Measures .......................................................................................... 48 
Appendix III: New York Heart Association (NYHA) Classification ............................................. 53 

Hybrid Coronary Revascularization Trial 
CONFIDENTIAL 
 
Protocol Rev 2.1  
 
 
 
 
 
 
 
 
InCHOIR 
July 2017 
 
 
 
 
4 
 
TABLE OF CHANGES 
 
Rev. 
Section 
Change 
Reason 
Page 
2.0 
Abstract /Study Design and 
throughout 
Delete mention of CathPCI registry 
Not using CathPCI registry 
7, 13 
2.0 
Abstract /Study Design and 
throughout 
Change “extracted directly” to “partially extracted” 
Clarification, CathPCI registry will 
not be used, most but not all sites 
will use STS 
7, 13 
2.0 
Abstract /Study Design 
Wording added, “When allowed by local IRB/REBs…” 
Canadian IRBs may require 
Canadian sites perform all follow 
up calls 
7, 13 
2.0 
Abstract, Rx arms 
“sternal sparing, off-pump” added to hybrid arm 
Definition clarification 
7 
2.0 
Abstract, Endpoints 
The word “repeat’ has been removed from “…unplanned 
repeat revascularization”    
Definition clarification 
7,14  
2.0 
Abstract, Endpoints 
“post-procedure” added after “Measured at 30 days” 
Specify time point 
7, 14 
2.0 
Abstract, Endpoints 
“and non-cardiovascular” added to secondary endpoint 
Secondary endpoints include all-
cause mortality 
7, 14, 
25 
2.0 
Inclusion criteria 
#3) Delete “multivessel” before coronary revascularization 
Clarification 
8, 15 
2.0 
Inclusion criteria 
Note added under coronary revascularization criterion 
Clarification 
8, 15 
2.0 
Exclusion criteria 
#4) Delete the word “territories” after LAD 
Clarification 
9, 15 
2.0 
Exclusion criteria 
Added exclusion of bare metal stents use in past year 
Protocol update 
9, 15 
2.0 
Exclusion criteria 
Deleted mention of bare metal stents 
Protocol update 
9, 15 
2.0 
Exclusion criteria 
Update sentence on pregnancy exclusion 
Clarification 
9, 16 
2.0 
Data Collection Schedule 
Change 30 day visit window to +/- 7 days 
Protocol update 
10 
2.0 
Data Collection Schedule 
Remove NYHA 30 day visit 
Protocol update 
10 
2.0 
Data Collection Schedule 
Delete “X” where CathPCI registry was indicated 
Not using CathPCI registry 
10 
2.0 
Randomization table 
“minimally invasive” added throughout 
For trial, hybrid must be off-pump 
minimally invasive procedure 
18 
2.0 
Randomization 
Wording updated to describe specific vessels to be treated 
Clarification 
18 
2.0 
Hybrid Coronary 
Revascularization 
Deleted non-sternal sparing from definition of minimally 
invasive approach.  Wording updated to indicate only off-
pump, sternal sparing procedures to be planned.   
Protocol update 
19 
2.0 
Hybrid Coronary 
Revascularization 
Sentence added to indicate that planned open sternotomy is 
not permitted but conversion is acceptable for patient safety 
Protocol update 
20 
2.0 
Hybrid Coronary 
Revascularization 
Sentence added to define LIMA-LAD anastomosis during 
TECAB 
Clarification 
21 
2.0 
Treatment Interventions 
Revised reference vessel diameter measurement from 2.0 mm 
to 2.25 mm 
To align with available delivery 
systems 
21 
2.0 
Additional HCR 
Considerations 
Added two paragraphs regarding possible open sternotomy 
protocol violation  
Clarification 
21 
2.0 
Unplanned 
Revascularization 
Wording changed/added to define ischemia-driven unplanned 
revascularization  
Update and clarify definition 
24 
2.0  
Secondary Endpoints 
Words “post procedure” added after “MACCE (defined 
above) at 30 days” 
Specify time point 
25 
2.0 
Secondary Endpoints 
Ischemia-driven repeat revascularization paragraph deleted. 
Ischemia-driven revascularization (adjudicated)” bullet point 
added. 
This was described in previous 
section 
25 
2.0 
Unexpected Adverse Device 
Effects 
Section added after endpoints 
Defines what to do in the event of 
serious adverse events and 
unexpected adverse device effects 
27 
2.0 
Clinical Centers,  
Investigators, Site Initiation 
and throughout 
“PIPEDA” and “REBs” added where HIPAA and IRB are 
mentioned 
Include Canadian privacy law and 
ethics board  
28, 29 
2.0 
Data Collection 
Sentence added regarding collection of STS data 
Sites not using STS registry will be 
required to collect and submit data 
30, 
33,34 
2.0 
Data Collection 
“Pre-Implant” deleted from heading Screening /Pre-Implant 
Data Collection 
“Pre-Implant” not needed  
30 
2.0 
Data Collection 
Pre-Screening Failure Form changed to Screening 
Registration Form 
More accurate description of form 
30 
2.0 
  Data Collection 
“race’ added to description of data collected  
Clarification 
30 
2.0 
Data Collection 
Planned Revascularization changed to Revascularization Plan 
Clarification 
31 
2.0 
  Data Collection 
Revascularization plan updated and Note added to define  
Clarification 
31 
2.0 
  Data Collection 
Sentence deleted regarding Quality of Life data collection 
Protocol update 
32 

Hybrid Coronary Revascularization Trial 
CONFIDENTIAL 
Protocol Rev 2.1 
InCHOIR 
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5 
 
2.0 
Data Collection 
Deleted first, middle, and last initial collected for 
Demographics  
Protocol update 
32 
2.0 
Treatment Intervention 
Wording changed to reflect that medication data during and 
within 24 hours after the revascularization procedure will be 
collected by the sites 
Protocol update 
33 
2.0 
Laboratory Assessment 
Subheading added to note that lab value will be extracted 
from STS database after index coronary revascularization 
Protocol update 
33 
2.0 
PCI Procedure 
Reworded to exclude mention of CathPCI registry and to state 
data that will be collected by site coordinators 
Protocol update, CathPCI registry 
will not be used 
33 
2.0 
Hospitalization and 
MACCE Events 
Reworded to describe limited information that will be 
collected from the STS registry 
Clarification 
33,34 
2.0 
Post-Intervention Site 
Activities 
Follow-up window changed from two weeks to one week; 
phrase added: …following all procedures “that occur within 
90 days of the first revascularization procedure.”  
Protocol update 
34 
2.0 
Medications 
Phrase “since the date of index hospital discharge” deleted 
from regarding medication use collection 
Protocol update 
34 
2.0 
NYHA 
Section deleted.  NYHA will be captured only at baseline 
Protocol update 
34 
2.0 
Quality of life 
Sentence regarding QOL checklist deleted 
Protocol update 
34 
2.0 
Long-term Patient-Reported 
MACCE & QoL 
Wording added to reflect that site coordinators will conduct 
telephone follow ups in the event that local IRB/REBs will 
not allow centralized DCC follow up and to make clear that 
follow up window is plus or minus one month. 
Canadian REBs may only allow 
site coordinators to conduct 
telephone follow ups. 
35 
2.0 
Long-term Patient-Reported 
MACCE & QoL 
Missed Visit - event driven section deleted. 
Data will be captured on an event 
driven form instead of a missed 
visit form 
35 
2.0 
Patient Retention Strategies 
DCC nurse “or local site coordinator” added regarding 
building relationships with participants; phrase regarding 
giving gifts and cards to patients deleted 
Canadian REBs may only allow 
site coordinators to conduct 
telephone follow ups. Cards and 
gifts will not be sent to participants 
due to budgetary constraints 
38 
2.0 
Analytical Plan 
Individual components of MACCE changed to delete “all 
cause unplanned and repeat revascularizations” and to include 
“ischemia-driven revascularizations, cardiovascular and non 
cardiovascular mortality, re-hospitalization (all-cause and 
cardiovascular), health status and …” 
Protocol update 
38 
2.0 
Cardiovascular Events 
The words “and bleeding” deleted from sub heading. 
Wording changed to clarify MACCE components 
Protocol update 
40 
2.0 
Data Coordinating Center 
(DCC) 
The following has been added:” The DCC holds the study-
specific IDE with the FDA and will be responsible for 
reporting UADEs to the FDA according to 21CFR812.150.  
In addition, the DCC will be responsible for submitting the 
required progress reports to the FDA.” 
Protocol update 
42 
2.0 
Abstract /Study Design and 
throughout 
Delete mention of CathPCI registry 
Not using CathPCI registry 
7, 13 
2.1 
Title page and footer 
Revised to Version 2.1, July 2017 
Protocol update to reflect 
administrative changes 
All 
pages 
2.1 
Abstract 
Added “Selected” to Exclusion Criteria 
Correction 
9 
2.1 
Study Population 
Added as criterion 16, “Allergy or hypersensitivity to any of 
the study drugs or devices used in the trial” and renumbered  
Correction 
16 
2.1 
Treatment Interventions 
In the subsection, Percutaneous Interventions (HCR Group & 
PCI-only Group) revised to state, “Only commercially 
available metallic drug-eluting stents may be used in this 
protocol.  Because the use of DES in PCI on patients with left 
main disease or with three-vessel disease, both of which are 
off-label uses for DES, is considered investigational, this trial 
will be conducted under an Investigational Device Exemption 
(IDE).”  
Correction
21 
2.1 
Investigators 
Added “As stated in the Investigator agreement form, they will 
conduct the investigation in accordance with the agreement, 
the investigational plan, Part 812 and other applicable FDA 
regulations, and conditions of approval imposed by the 
reviewing IRB and FDA.”  Also added FDA to parties that 
may review source documentation. 
Correction 
29 

Hybrid Coronary Revascularization Trial 
CONFIDENTIAL 
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DEFINITIONS, ACRONYMS & ABBREVIATIONS 
AE 
Adverse event 
BMS 
Bare metal stent 
CABG 
Coronary artery bypass grafting 
CAD 
Coronary artery disease 
CCSC 
Canadian Cardiovascular Society Classification  
CEC 
Clinical Events Committee 
CK MB 
Creatine kinase- myocardial band 
CFR 
Code of Federal Regulations 
DCC 
Data Coordinating Center 
DES 
Drug eluting stent 
DSMB 
Data & Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture system 
EuroQOL 
European Quality of Life Scale 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practices  
HCR 
Hybrid coronary revascularization 
HIPAA 
Health Insurance Portability and Accountability Act 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
LAD 
Left anterior descending (coronary artery) 
LBBB 
Left bundle branch block 
LIMA 
Left internal mammary artery  
LM 
Left main (coronary artery) 
MACCE 
Major adverse cardiac and cerebrovascular events  
MI 
Myocardial infarction 
NHLBI 
National Heart, Lung and Blood Institute 
PCI 
Percutaneous coronary intervention 
PIPEDA 
Personal Information Protection and Electronic Documents Act 
RBC 
Red blood cells 
REB 
  Research Ethics Board 
SAE 
Serious adverse event 
SF-12 
Short Form 12 Health Survey  
STS 
Society of Thoracic Surgeons 
SVG 
Saphenous vein graft 
UADE 
Unanticipated Adverse Device Effect 
UB 
Uniform Billing 
UHC 
University HealthSystem Consortium  
ULN 
Upper limit of normal 
URL 
Upper reference limit 

Hybrid Coronary Revascularization Trial 
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ABSTRACT 
Objectives 
To evaluate the effectiveness and safety of hybrid coronary revascularization (HCR) compared to 
multi–vessel percutaneous cardiac intervention (PCI) with metallic drug-eluting stents (DES) in 
patients with multi-vessel coronary artery disease (CAD) involving the Left Anterior Descending 
(LAD) and/or Left Main (LM) arteries. The primary objective of this trial is to determine whether 
hybrid coronary revascularization is associated with a reduction in Major Adverse Coronary and 
Cerebrovascular Events (MACCE) compared to PCI with DES. 
Study Design 
Prospective, randomized, multi-center, comparative effectiveness trial; patients randomized with 
equal allocation (1:1). Baseline and peri-procedural data collection will be partially extracted from 
the Society of Thoracic Surgeons (STS) Data Registry.  Limited additional data will be collected 
to assess coronary anatomy, pharmacology specific to the procedure, device usage, etc.  When 
allowed by local IRB/REBs, follow-up data collection, with the exception of data collection at 
post-intervention clinical visits, will be collected centrally via phone follow-up by the Hybrid Trial 
Data Coordinating Center (DCC), and will focus on patient-reported MACCE and QOL, 
supplemented by limited supporting documentation to verify MACCE events, and cost data 
collected from the University Health Consortium (UHC) and directly from hospitals for non-UHC 
members.  All MACCE events will be adjudicated by a Clinical Events Committee (CEC). The 
estimated enrollment period is 24 months and all patients (n = 2354) will be followed for 5 years 
following randomization. 
Target 
Population 
Patients with multi-vessel CAD involving the LAD distribution with a clinical indication for 
revascularization and eligible for both HCR and multi-vessel PCI with DES. 
Rx arms 
o
HCR with sternal-sparing, off-pump Left Internal Mammary Artery (LIMA) to LAD + PCI
with metallic drug eluting stents (DES) of non-LAD vessels
o
Multi-vessel PCI with metallic DES, including the LAD and or LM.
Sample Size 
2354 patients; assuming an estimated event rate of approximately 25% in the PCI group at 5 years; 
0.05 type I error (2-sided) and assuming: (a) minimum follow-up of 5 years, (b) 80% power, (c) 
drop-in and drop-out rates of approximately 0.5% and 2% respectively, annually, and (d) 15% loss 
to follow-up by end of the study, 530 events will need to be observed (or 2354 patients) to detect a 
relative decrease in MACCE of ≥ 20% in the HCR compared to the PCI group.  Estimates of loss 
to follow-up, and cross-over rates are conservative and justify fixing the power at 80%. 
Duration 
Accrual over 2 years; accrual will terminate when 530 events have occurred or 2354 patients are 
randomized, whichever comes first. All patients will be followed for 5-years. 
1 Endpoints 
The occurrence of MACCE defined as all-cause mortality, myocardial infarction (MI), stroke, or 
unplanned revascularization  over 5-year follow-up after randomization or at the time when 530 
events have accrued. 
2 Endpoints 
Measured at 30 days post procedure, 12, 24, 36, 48, 60 months, unless otherwise specified: 
Cardiovascular Events 
o
MACCE at each data collection time point
o
Individual components of MACCE
o
All-cause mortality
o
Unplanned revascularization
o
Stroke
o
Myocardial infarction (MI)
o
Ischemia-driven revascularization
o
Cardiovascular and non-cardiovascular mortality
Hospitalizations
o
Re-hospitalization (all-cause and cardiovascular)

Hybrid Coronary Revascularization Trial 
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Health Status 
o
Angina Score (Canadian Cardiovascular Society Classification [CCSC])
o
Quality of Life (SF-12 and EuroQOL)
Cost-effectiveness
o
Costs
Selected 
Inclusion 
Criteria 
o
Signed informed consent, release of medical information, and HIPAA documents  (US sites)
o
Age ≥ 18 years
o
Clinical indication for coronary revascularization
o
Coronary anatomy requiring revascularization as follows1:
- Multivessel CAD involving the LAD (proximal or mid) and/or LM (ostial, mid-shaft or
distal) with at least 1 other epicardial coronary artery requiring treatment (LCX or RCA),
OR
- Single vessel disease involving the LAD and a major diagonal, with both requiring
independent revascularization with at least one stent if randomized to HCR and stents for
both the LAD and diagonal if randomized to multivessel PCI
Note:  If the patient qualifies based only on a LM lesion, then there must be involvement
of the distal bifurcation (Medina 1,1,1) intended for treatment with a 2-stent approach
(separate stents into the LAD and LCX) if randomized to PCI. However, if the patient
also has non-LM disease in the RCA and/or non-ostial LAD and/or non-ostial LCX that
requires separate treatment, any LM lesion is a valid criterion for enrollment, whether
LM ostial, shaft or distal bifurcation disease, and any strategy of treating the LM may be
employed, including not treating the ostial LCX, a provisional approach or a planned 2-
stent strategy as appropriate.  Similarly, if the patient qualifies based only on LAD-Dg
disease, whether a bifurcation lesion or separate lesions in the LAD and Dg, without
RCA or LCX disease, then both the LAD and Dg must be true lesions intended for stents
(planned 2-stent approach). However, if the patient has LAD-Dg disease and a lesion in
the RCA or LCX that also requires treatment, the LAD-Dg disease can then be treated in
any fashion (2-stents, a provisional approach, or the Dg not even dilated if it is small),
according to operator preference
o
Suitable candidate for both PCI with metallic DES and HCR as determined by clinical
assessment and angiogram review by an interventional cardiologist and a cardiac surgeon at
the site
o
Ability to tolerate and no plans to interrupt dual anti-platelet therapy for ≥ 6 months if
presentation with stable CAD, or ≥ 12 months if presentation with biomarker positive acute
coronary syndrome (ACS)

Hybrid Coronary Revascularization Trial 
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Selected 
Exclusion 
Criteria 
o
Previous cardiac surgery of any kind, including CABG
o
Previous thoracic surgery involving the left pleural space
o
Previous LM or LAD stent (a) with evidence of in-stent restenosis or (b) within 1 cm of a
qualifying lesion
o
Previous PCI of the LM and/or LAD within 12 months prior to randomization
o
PCI with bare metal stent (BMS) within 12 months prior to randomization
o
Any complication or unsuccessful revascularization with PCI within 30 days prior to
randomization
Note: A patient may be considered eligible for enrollment if PCI with DES in non-LM 
and non-LAD territories  was performed within 30 days prior to randomization, as long as 
revascularization was successful and uncomplicated, or has been performed any time 
more than 30 days prior even if unsuccessful or complicated.  
o
Planned treatment with bioresorbable vascular scaffold(s) after randomization
o
Total occlusion (TIMI 0 or 1 flow) of the LM, LAD or LCX.
o
Cardiogenic shock at time of screening
o
STEMI within 72 hours prior to randomization
o
Need for concomitant vascular or other cardiac surgery during the index hospitalization
(including, but not limited to, valve surgery, aortic resection, left ventricular aneurysmectomy,
or carotid endarterectomy or stenting)
o
Indication for chronic oral anticoagulation therapy at the time of randomization
o
Extra-cardiac illness that is expected to limit survival to less than 5 years
o
Therapy with an investigational drug, device or biologic within 1 year prior to randomization,
or plan to enroll patient in additional investigational study during participation in this trial
o
Unable to give informed consent or potential for noncompliance with the study protocol in the
judgment of the investigator
o
Pregnant at time of screening or  unwilling to use effective birth control measures while
dual antiplatelet therapy is required
1 Enrollment is based on the initial coronary anatomy. If PCI was already performed enrollment is still possible if the initial angiogram 
demonstrated anatomy that qualified under these criteria. 

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Hybrid Coronary Revascularization Trial 
CONFIDENTIAL 
DATA COLLECTION SCHEDULE 
Screening & 
Randomization 
Surg/PCI 
Procedure 
Hosp 
D/C 
30  (±7) 
Days Post 
Interv
6 
(±1) 
Mo 
12 
(±1) 
Mo 
18 
(±1) 
Mo 
24 
(±1) 
Mo 
30 
(±1) 
Mo 
36 
(±1) 
Mo 
42 
(±1) 
Mo 
48 
(±1) 
Mo 
54 
(±1) 
Mo 
60 
(±1) 
Mo 
Event 
Driven 
Description 
Clinical 
Site 
Registry 
Data* 
Informed Consent 
X 
Angiogram 
X 
X 
Eligibility 
X 
Demographics 
X 
X 
Medical History 
X 
X 
Medications 
X 
X 
X 
X 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
Laboratory Assessment
X 
X 
Randomization 
X 
PCI Procedure Data 
X 
X 
Surgical Procedure Data 
X 
X 
X 
Hospitalization 
C 
CCSC Angina Class 
X 
X 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
NYHA 
X 
QoL (SF-12 & EuroQoL) 
X 
X 
C 
C 
C 
C 
C 
MACCE 
X 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
X1/C 
Cost Data 
X 
X 
X 
X 
X 
X 
Study Completion/ Early 
Termination 
X1/C 
End of Study/Inv. Statement 
X/C 
X= Site coordinator activity; X= STS registry data or site coordinator; X = University HealthSystem Consortium/Uniform Bill-forms; C = DCC phone follow-up (when allowed by local IRB/REBs) 
* For sites participating in the STS registry
 1If ≤ 30 days post-index intervention (STS data terminates thereafter); thereafter, collected by DCC phone follow-up 

Hybrid Coronary Revascularization Trial 
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OBJECTIVES 
The overall objective of this trial is to evaluate the effectiveness and safety of Hybrid Coronary 
Revascularization (HCR) compared to multi–vessel percutaneous coronary intervention (PCI) 
with metallic drug-eluting stents (DES) in patients with multi-vessel coronary artery disease 
involving the Left Main and/or Left Anterior Descending arteries. 
 
The primary objective of the trial is to determine whether hybrid coronary revascularization is 
associated with a reduction in Major Adverse Cardiac and Cerebrovascular Events [MACCE] 
compared to PCI with DES. 
 
The secondary objectives are to determine the impact of HCR compared to PCI on health status 
and quality of life. 
 
BACKGROUND AND SIGNIFICANCE 
Importance of the Study 
The increasing prevalence of coronary artery disease (CAD), advances in coronary artery bypass 
grafting (CABG), PCI, and concomitant medical therapy, and the costs of revascularization have 
resulted in rising interest regarding the appropriate indications and alternatives for coronary 
revascularization. The 2009 ACCF/SCAI/STS/AATS/ AHA/ASNC Appropriateness Criteria for 
Coronary Revascularization document that for patients with 3-vessel disease requiring 
revascularization, CABG is rated as appropriate while revascularization by PCI is rated as 
uncertain. 1 Moreover, the recent SYNTAX trial demonstrated that CABG was superior to PCI 
with first generation drug eluting stents (DES) for patients with 3- vessel disease and/or left main 
coronary artery (LM) disease.2 However, the SYNTAX trial results were driven by the repeat 
revascularization component of the primary composite endpoint (lower for CABG), and 
divergence with the outcomes of the stroke component (higher for CABG) has led to differences 
in interpretation of the overall results. 
 
These differences in interpretation, coupled with strong patient preferences for the lower level of 
invasiveness, a potentially lower stroke risk, and faster recovery have driven the widespread 
adoption of PCI. At the same time, CABG has been shown to provide improved long-term 
durability, superior long term symptom relief, fewer repeat interventions and higher rates of 
survival.2-4 Integrating the positive features of both PCI and CABG has been the fundamental 
rationale of “hybrid” coronary revascularization. 
 
Hybrid coronary revascularization is the intended combination of CABG and PCI. The HCR 
strategy combines grafting of the left anterior descending artery (LAD) coronary artery using the 
left internal mammary artery (LIMA) and PCI of non-left anterior descending coronary artery 
(LAD) coronary stenoses.  Essentially, stents are substituted for saphenous vein grafts (SVG) for 
non-LAD lesions, and the surgical LIMA to LAD bypass is performed, ideally through a limited 
access, minimally traumatic approach. The rationale for choosing HCR over PCI or CABG 
alone stems from a number of observations: 
(1) The LAD is the most important of the three coronary branches, supplying 50% to 60% of the 
ventricular mass and twice the mass of the circumflex or right coronary distributions; 

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(2) The LIMA has been shown to be more effective than PCI with respect to event-free survival,
relief of angina, and long term patency;4,5
(3) The LIMA to LAD bypass graft contributes the vast majority of the survival advantage
provided by CABG and the value of additional arterial grafts to non-LAD targets is limited
and difficult to demonstrate;6-9
(4) The early restenosis rate of non-LAD vessels after PCI with drug eluting stents (DES) may
not be significantly different from the early occlusion rate of saphenous vein grafts.10,11
Perrault and colleagues12 found the 3-month occlusion rates of saphenous vein grafts to be 
between 14.8% and 15.6%. Similar results were found by Yun and colleagues13 with vein graft 
occlusion rates between 17.6% and 21.7% at 6 months. 
Unfortunately, the published data to date on HCR must be considered limited and hypothesis 
generating. Over a ten-year period, the collective published work constitutes only 500 patients in 
twelve small series (See Table 1)14-22 Nonetheless, the data from these uncontrolled studies suggest 
that HCR (1) can potentially provide a higher degree of durability, symptom relief and 
survival relative 
to three-vessel 
stenting by 
virtue of 
incorporating a 
LIMA to LAD 
graft as part of 
the overall 
therapy, (2) 
afford a stroke 
 Table 1.  Contemporary HCR Results 
Author 
Year 
Patients
Surgical 
Procedure 
LIMA 
patency 
Mortality 
(%) 
Target 
Vessel 
Event-free 
Survival 
(%) 
Revasc (%) 
(%) 
Bonatti14 
2008 
5 
TECAB 
100 
0 
0 
100 
Holzhey15
2008 
107 
MIDCAB 
99 
1.9 
4.2 
86 
10 
TECAB 
Kiaii16 
2008 
58 
Robotic-assist 
93 
0 
10.3 
NR 
Reicher17 
2008 
13 
MIDCAB 
93 
0 
7 
86 
Vassiliades18 
2009 
91 
EndoACAB 
100 
0 
5.5 
NR 
Zhao19 
2009 
112 
Sternotomy 
100 
2.6 
6 
88 
Gao20 
2009 
10 
Robotic-assist 
100 
NR 
NR 
NR 
Srivastava21 
2010 
50 
TECAB 
98.2 
0 
NR 
NR 
Bonatti22 
2012 
226 
TECAB 
- 
1.3
16.9 
75 
rate comparable to PCI and lower than standard CABG by not manipulating the ascending aorta, 
and (3) offer a very low infection rate, transfusion rate and recovery time, by minimizing chest 
wall trauma and completely avoiding a median sternotomy. To date, no randomized trial 
comparing HCR to either CABG or PCI has been performed. Preliminary observational data 
suggest that HCR has the potential to disseminate widely and become the third major 
interventional alternative for patients with multi-vessel CAD. Without sound data from a clinical 
trial, there will be insufficient evidence to guide dissemination of this potentially important 
procedure for a major patient population. 
In short, clinicians, payers, and patients are interested in the specific benefits of revascularization 
alternatives. HCR as a scientifically validated approach would have a major healthcare impact. The 
ability to deliver a new therapy for CAD that provides durability, but without the obligatory trauma 
and prolonged recovery time characteristic of conventional CABG would be a major advance in 
the field of cardiovascular medicine. Candidates in whom HCR would be particularly 
advantageous would be several subgroups of CAD patients that are increasing in numbers: the 
elderly, patients with a high predicted risk of mortality and/or morbidity for CABG, deconditioned 
patients or patients with significant disabilities and patients in whom treatment durability is 
important, but a significantly invasive approach is not an option. Moreover, HCR is likely to 
bridge the divide in treatment philosophies and approaches that exist between 

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Figure 1:  Risk-Adjusted MACCE-free Survival 
cardiologists and cardiac surgeons. Collaboration rather than competition between 
these specialties will ultimately benefit patients, hospitals, payers and healthcare 
providers. 
The National Heart, Lung, and Blood 
Institute (NHLBI)-funded Hybrid 
Observational Study (RC1 HL100951-01, 
Principal Investigators, J. Puskas, D. 
Ascheim) was the first multicenter 
prospective cohort study of practice 
patterns and outcomes of patients 
undergoing HCR, and informed the design 
of this trial. The 200 HCR and 98 HCR-
eligible, multi-vessel PCI with DES 
patients enrolled at 11 U.S. sites in the 
Hybrid Observational Study, demonstrated 
similar risk-adjusted MACCE rates over 
the first 12 months following intervention, 
with rates diverging over approximately 18 
months of total follow up (see Figure 1).23 The study further confirmed that there is strong 
concordance between cardiac surgeons and interventional cardiologists regarding anatomic 
eligibility for HCR, with disagreement in only 3.0% of cases.24 Such consensus supports the 
feasibility of conducting a much needed comparative effectiveness trial of this emerging 
new coronary revascularization paradigm. 
Thus, the NHLBI-funded Hybrid Observational Study demonstrated that equipoise exists between 
the two coronary revascularization paradigms; however, a rigorously designed randomized 
clinical trial is now needed to provide sufficient evidence to guide clinical decision making for 
this important patient population. 
STUDY DESIGN 
This trial is a prospective, multi-center randomized comparative effectiveness trial of HCR 
compared to multi-vessel PCI with metallic DES in patients with multi-vessel CAD involving the 
LAD or LM territories. The trial is designed as a “large, simple” trial, and some baseline, 
procedure-related and short-term outcomes data collection will be extracted from existing registry 
data from the Society of Thoracic Surgeons [STS] Data Registry. By incorporating existing 
clinical data collected by sites for reporting to STS registry, the design greatly reduces trial-
specific data collection at the sites participating in STS. When allowed by local Institutional 
Review Boards (IRBs) or Research Ethics Boards (REBs), follow-up data collection, with the 
exception of data collection at post-intervention clinical visits, will be collected centrally via 
phone follow-up by the Hybrid Trial Data Coordinating Center (DCC). All follow-up data 
collection will focus on patient-reported MACCE events and QOL, and will be supplemented by 
limited supporting documentation to verify MACCE events. All MACCE events will be 
adjudicated by a Clinical Events Committee (CEC). Health care costs will be collected 

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electronically through Uniform Billing (UB) medical claim forms and the University 
HealthSystem Consortium (UHC) operational database system. This design decreases (1) 
duplication of effort, (2) the burden on participating patients and sites, and (3) the cost of 
conducting the trial, while maintaining the rigor of traditional RCTs. The estimated enrollment 
period is 24 months (n = 2354), and all patients will be followed for a minimum of 5 years 
following randomization. 
ENDPOINTS 
Primary Endpoint 
The primary endpoint of this trial is MACCE over 5 years following randomization. For the 
purpose of this trial, the components of MACCE include (1) all-cause mortality, (2) myocardial 
infarction, (3) stroke, and (4) unplanned revascularization. The primary objective of this trial is 
to determine whether hybrid coronary revascularization is associated with a reduction in 
MACCE compared to PCI with metallic DES. 
Secondary Endpoints 
The secondary endpoints of the trial (measured at 30 days post procedure, 12, 24, 36, 48, and 60 
months, unless otherwise specified) include: 
Cardiovascular Events 
o MACCE at 30 days post procedure, and 12, 24, 36, 48 months
o Individual components of MACCE: All-cause mortality, myocardial infarction, stroke,
unplanned revascularization
o Ischemia-driven revascularization
o Cardiovascular and non-cardiovascular mortality
Hospitalizations 
o Re-hospitalization (all-cause and cardiovascular)
Health Status 
o Angina Score (Canadian Cardiovascular Society Classification [CCSC])
o Quality of Life (QoL) (Short Form 12 Health Survey [SF-12}, European Quality of Life Scale
[EuroQoL])
Cost-effectiveness 
o
Costs
o
Quality-adjusted life expectancy
STUDY POPULATION 
The patient population for this trial consists of adult patients with multi-vessel coronary artery 
disease involving the Left Main (LM) and/or Left Anterior Descending (LAD) arteries, and a 
clinical indication for revascularization, who are candidates for both HCR and PCI with metallic 
DES. 
Eligibility Criteria 
All patients who meet all inclusion criteria and no exclusion criteria will be eligible for the trial 

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regardless of gender, race, or ethnicity. 
Inclusion Criteria 
1. Signed informed consent, inclusive of release of medical information, and Health Insurance
Portability and Accountability Act (HIPAA) documentation (US sites)
2. Age ≥ 18 years
3. Clinical indication for coronary  revascularization
4. Coronary anatomy requiring revascularization as follows(2)

Multivessel CAD involving the LAD (proximal or mid) and/or LM (ostial, mid-shaft or
distal) with at least 1 other epicardial coronary artery requiring treatment (LCX or RCA),
OR

Single vessel disease involving the LAD and a major diagonal, with both requiring
independent revascularization with at least one stent if randomized to HCR and stents for
both the LAD and diagonal if randomized to multivessel PCI
Note:  If the patient qualifies based only on a LM lesion, then there must be
involvement of the distal bifurcation (Medina 1,1,1) intended for treatment with a 2-
stent approach (separate stents into the LAD and LCX) if randomized to PCI.
However, if the patient also has non-LM disease in the RCA and/or non-ostial LAD
and/or non-ostial LCX that requires separate treatment, any LM lesion is a valid
criterion for enrollment, whether LM ostial, shaft or distal bifurcation disease, and any
strategy of treating the LM may be employed, including not treating the ostial LCX, a
provisional approach or a planned 2-stent strategy as appropriate.  Similarly, if the
patient qualifies based only on LAD-Dg disease, whether a bifurcation lesion or
separate lesions in the LAD and Dg, without RCA or LCX disease, then both the LAD
and Dg must be true lesions intended for stents (planned 2-stent approach). However, if
the patient has LAD-Dg disease and a lesion in the RCA or LCX that also requires
treatment, the LAD-Dg disease can then be treated in any fashion (2-stents, a
provisional approach, or the Dg not even dilated if it is small), according to operator
preference
5. Suitable candidate for both PCI with metallic DES and HCR as determined by clinical
assessment and angiogram review by an interventional cardiologist and a cardiac surgeon at
the enrolling clinical site
6. Ability to tolerate and no plans to interrupt dual anti-platelet therapy for ≥ 6 months if
presentation with stable CAD, or ≥ 12 months if presentation with biomarker positive acute
coronary syndrome (ACS)
7. Willing to comply with all protocol required follow-up
Exclusion Criteria 
1. Previous cardiac surgery of any kind, including CABG
2. Previous thoracic surgery involving the left pleural space
3. Previous LM or LAD stent (a) with evidence of in-stent restenosis or (b) within 1 cm of a
qualifying lesion
4. Previous PCI of the LM and/or LAD within 12 months prior to randomization
5. PCI with bare metal stent (BMS) within 12 months prior to randomization
6. Any complication or unsuccessful revascularization with PCI within 30 days prior to
randomization.
Note: A patient may be considered eligible for enrollment if PCI with DES in non-

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LM and non-LAD territory was performed within 30 days prior to randomization, as 
long as revascularization was successful and uncomplicated, or  has been performed 
any time more than 30 days prior even if unsuccessful or complicated 
7. Planned treatment with bioresorbable vascular scaffold(s) after randomization
8.
Total occlusion (TIMI 0 or 1 flow) of the LM, LAD or LCX.
9.
Cardiogenic shock at time of screening
10. STEMI within 72 hours prior to randomization
11. Need for concomitant vascular or other cardiac surgery during the index hospitalization
(including, but not limited to, valve surgery, aortic resection, left ventricular
aneurysmectomy, and carotid endarterectomy or stenting)
12. Indication for chronic oral anticoagulation therapy at the time of randomization
13. Any prior lung resection
14. ESRD on dialysis
15. Patients who could not be switched from prasugrel or ticagrelor to clopidogrel, should that be
needed prior to a CABG,  during reverse HCR
16. Extra-cardiac illness that is expected to limit survival to less than 5 years
17. Allergy or hypersensitivity to any of the study drugs or devices used in the trial
18. Therapy with an investigational drug, device or biologic within 1 year prior to
randomization, or plan to enroll patient in additional investigational study during
participation in this trial
19. Unable to give informed consent or potential for noncompliance with the study protocol in
the judgment of the investigator
20. Pregnant at time of screening or unwilling to use effective birth control measures while
dual antiplatelet therapy is required.
(2) Enrollment is based on the initial coronary anatomy. If PCI was already performed enrollment is still possible if 
the initial angiogram demonstrated anatomy that qualified under these criteria. 
Recruitment Strategies 
The Hybrid Observational Study previously described, demonstrated that 44% of the 6,669 
patients who underwent diagnostic cardiac catheterization over the course of the study had 
normal or non-obstructive CAD, and that among patients with obstructive CAD, 55% had multi- 
vessel disease, 24% had at least three vessel disease, and 12% had significant left main disease. 
Surgeons and interventional cardiologists exhibited a high degree of concordance in decisions 
regarding anatomic eligibility for HCR (LIMA to LAD combined with PCI of at least one 
additional vessel). Of the 3,715 patients with any obstructive CAD, 12% were deemed 
anatomically eligible for HCR; in only 3% of patients did the surgeon and cardiologist disagree 
regarding anatomic eligibility. 
We plan to enroll 2354 patients in the Hybrid Coronary Revascularization Trial through active 
screening and recruitment by the multidisciplinary Heart Teams at the clinical sites.  The 
strategies used to successfully enroll this trial will build on the momentum achieved over the last 
several years in the formation of Heart Teams at participating hospitals, consisting of 
interventional cardiologists and surgeons who work collaboratively to provide unified treatment 
recommendations for patients with complex CAD and valvular heart disease. The strategies will 
include: frequent presentations by the site Principal Investigators regarding the trial in weekly 
interventional cardiology and cardiac surgery conferences, as well as the combined multi- 

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disciplinary conferences; review of consecutive patients with multi-vessel disease by the site 
participating Heart Teams prior to recommending treatment options; regular Grand Rounds 
presentations at clinical sites as well as referring hospitals, mailings to referring physicians of the 
study hospitals, symposia and health care events targeted towards this population; as well as 
telephone calls to neighboring health care facilities. The DCC will regularly assess actual 
enrollment in relation to pre-specified goals, and additional interventions directed by the Clinical 
Coordinating Center (CCC) to increase enrollment, will be implemented as needed. The Pre- 
Screening Failure Form will identify numbers of patients screened and reasons for non- 
enrollment in the study. 
 
Inclusion of Women and Minorities 
The inclusion of women and minorities in clinical trials is critical for scientific, ethical, social 
reasons, and for the generalizability of trial results. The Hybrid Trial investigators are strongly 
committed to ensuring a balanced recruitment of patients regardless of sex or ethnicity, and 
intend to recruit at least 30% women and 25% minorities. The following measures will be 
employed to ensure adequate representation of these groups: (1) documentation of the number of 
women and minorities screened and enrolled via screening/exclusion logs; (2) monitoring of 
such logs from each clinical center on a regular basis; and (3) if necessary, the development and 
implementation of additional outreach programs designed to recruit adequate numbers of women 
or minorities. 
 
 
TREATMENT ASSIGNMENTS 
All patients enrolled in this trial will undergo coronary artery revascularization. Patients will be 
randomly assigned to the following treatment groups: 
 
Hybrid Coronary Revascularization (HCR Group) 
LIMA to LAD + PCI with metallic DES of non-LAD vessel(s) 
 
Multi-vessel PCI (PCI-only Group) 
Multi-vessel PCI with metallic DES, including the LAD and or LM 
 
 
 

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RANDOMIZATION 
Qualifying 
angiogram type 
Time from the 3- 
vessel qualifying 
angiogram until 
randomization 
Time from 
randomization to 
1st procedure 
Sequence options if 
randomized to HCR 
Sequence options 
if randomized to 
multi-vessel PCI 
If staged: Time from first 
revascularization 
intervention after 
randomization until final 
planned revascularization 
intervention 
3-vessel 
angiogram only 
(PCI not 
performed) 
Anytime within 90 
days 
≤14 days after 
randomization 
1. Off-pump 
minimally 
invasive CABG 
first followed by 
staged PCI 
(recommended) 
2. PCI first followed 
by staged Off- 
pump minimally 
invasive CABG 
3. Concomitant Off- 
pump minimally 
invasive CABG 
and PCI (same 
calendar day) 
1. Single 
procedure 
multi-vessel 
PCI 
2. Staged PCI 
procedures 
No longer than 90 days (≤60 
days recommended) 
3-vessel 
angiogram 
followed by PCI 
of a non-LM or 
non-LAD lesion in 
the same or 
subsequent 
procedure within 
90 days prior to 
randomization 
Anytime within 90 
days 
≤14 days post 
randomization 
1. If only untreated 
LM or LAD 
lesion remains: 
Off-pump 
minimally 
invasive CABG 
2. If non-LM or non- 
LAD lesion(s) 
remain: Same 3 
options as above 
1. If only 
untreated LM 
or LAD lesion 
remains: 
single PCI 
procedure 
2. If non-LM or 
non-LAD 
lesion(s) 
remain: Same 
2 options as 
above 
No longer than 90 days (≤60 
days recommended) 
 
Patients will be randomly assigned (1:1) to HCR or multi-vessel PCI. The randomization 
procedure will be performed after patient eligibility is confirmed. 
 
For patients identified in the setting of a qualifying 3-vessel diagnostic angiogram without a 
PCI performed during or subsequent to the diagnostic angiogram, randomization must occur 
within 90 days following the qualifying angiogram. The first study revascularization 
intervention is recommended to be performed within 72 hours post randomization and must be 
performed within 14 days following randomization (see above Table for possible procedure 
options). 
 
For patients identified in the setting of a 3-vessel qualifying diagnostic angiogram and 
successful PCI of a non-LM or non-LAD vessels in the same or subsequent procedure, 
randomization into the trial must occur within 90 days following the initial qualifying 
angiogram. The first “study” intervention must be performed within 14 days following 
randomization (see above Table for possible procedure options). 
 
Randomization will be stratified by center, PCI of non-LM or non-LAD vessels within the prior 
90 days, and  type of vessels treated (1) LAD and Diagonal only; 2) LAD (or Left Main) and 
LCX or RCA; 3) LAD (or Left Main) and both LCX and RCA). The randomization scheme 
will be in random blocks of 4 and 6 within each stratum to maintain balance. 
 
Randomization will be generated centrally and performed through a Web-based data collection 
system that automates the delivery of the randomization codes. The treatment assignment will be 

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sent to the site coordinator electronically, in a secure fashion, and electronic verification of the 
treatment assignment will be required before proceeding with the treatment intervention. From 
that point on, primary efficacy will be analyzed by intention-to-treat; that is, the patients will be 
grouped by their assignment at randomization whether or not they actually received the treatment 
to which they were assigned. 
 
MASKING 
Neither patients nor investigators will be blinded to treatment assignment due to the nature of 
treatment interventions. Clinical and CCC investigators will, however, be blinded to all data 
from other clinical sites, except serious unexpected adverse events (SAEs) for IRB/REB 
reporting purposes. The DCC Research Nurse will be blinded to treatment assignment during 
follow-up telephone calls and will be blinded to aggregate outcomes data. MACCE events will 
be adjudicated by the independent CEC and trial oversight will be provided by an independent 
Data & Safety Monitoring Board (DSMB). 
 
TREATMENT INTERVENTIONS 
By design, patients in the HCR group will undergo planned staged procedures, and patients in 
the PCI group may or may not undergo planned staged procedures. The treatment strategy for 
staged procedure will be collected at the time of the first index procedure. Regardless of 
treatment assignment (HCR or PCI group), the revascularization strategy for staged procedures 
must be completed (in all cases) within 90 days after the first revascularization intervention after 
randomization, with ≤60 days recommended. Unplanned ischemia-driven procedures at any 
time, and all procedures performed >90 days after the first post-randomization revascularization 
intervention will be considered endpoint events. 
 
To minimize ascertainment bias in the identification of peri-procedural MI, baseline cardiac 
biomarkers (CK-MB and/or Troponin T or I) and an electrocardiogram (ECG) must be 
performed in all patients prior to CABG and PCI. For patients with stable CAD, the baseline 
biomarkers may be sent at the time of the first procedure, before revascularization. An ECG must 
be repeated once within 24 hours after each revascularization procedure, and the biomarkers 
must be repeated at least twice within 24 hours after each procedure (at 12 ± 4 hours and at 24 ± 
4 hours, or at discharge if sooner than 24 hours). 
 
Hybrid Coronary Revascularization 
HCR is defined, for the purposes of this trial, as a planned off-pump, minimally invasive 
(sternal-sparing) isolated LIMA-LAD revascularization, combined with percutaneous 
revascularization of at least one non-LAD target. The revascularization targets and procedural 
timing strategy to be utilized should be outlined prior to the initial revascularization procedure. 
Three possible timing strategies may be used: surgery followed by PCI on separate calendar 
days, PCI followed by surgery on separate calendar days, or concomitant (simultaneous) PCI 
and surgery (defined as: a. PCI followed by CAGB in the same room on the same day, or b. 
CABG followed by PCI in the same room on the same day, or c. PCI followed by CABG in 
different rooms on the same day, or d. CABG followed by PCI in different rooms on the same 
day). The specific strategy adopted will be collected and categorized. The complete 
revascularization strategy, if staged, must be completed within 90 days of the first 
revascularization intervention (≤ 60 days preferred). 
 

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Note: Whenever PCI is performed after the LIMA-LAD revascularization, LIMA angiography 
must be performed prior to the PCI to assess the graft and distal anastomosis. Please see the 
Procedural Treatment Guidance Document for further recommendations as to when and how to 
intervene if the distal anastomosis appears abnormal and/or antegrade flow is reduced. 
 
In most surgical specialties, minimally invasive surgery refers to the access the operator takes to 
the surgical field. Minimally invasive cardiac surgery, however, aims to ameliorate two 
potentially invasive surgical components: the cardiopulmonary bypass machine and the 
sternotomy incision. For the purpose of this trial, acceptable minimally invasive approaches to 
LIMA-LAD revascularization are sternal sparing off-pump procedures. 
 
Listed below are definitions of the beating heart, sternal sparing minimally invasive operations 
that are acceptable for patients enrolled in this trial and randomly assigned to the HCR group. 
The selection of the HCR strategy below remains at the discretion of the surgical investigator. 
The chosen approach will be documented and reported for each patient in the trial. 
 
Surgical Interventions 
 
Off-Pump CABG  
An off-pump CABG will be defined as an isolated LIMA-LAD revascularization 
performed on the beating heart without the use of cardiopulmonary bypass. Additional 
bypass grafts to other targets (including the diagonal) are not allowed in this study as part 
of an HCR procedure. For the trial, the planned minimally invasive approach to the 
LIMA – LAD revascularization must be a sternal sparing off-pump procedure. 
Planned open sternotomy will not be allowed in this study. However, after 
randomization, conversion of a planned sternal-sparing procedure to an open sternotomy 
procedure is acceptable if required to safely and successfully complete the 
revascularization procedure. Such conversions will be tracked. 
 
The planned sternal-sparing, off-pump LIMA-LAD revascularization may be performed 
by Mid-CAB, Robotic- Assisted CAB, or TECAB as described below 
 
1. Minimally Invasive Direct Coronary Artery Bypass (Mid-CAB) 
A mid-CAB will be defined as any operation in which LIMA mobilization is 
undertaken in an open fashion through a limited anterior or lateral thoracotomy 
incision.  The anastomosis will be performed by hand on the beating heart. 
 
2. Robotic-Assisted Coronary Artery Bypass 
A robotic mid-CAB or endo-ACAB will be defined as a procedure in which the 
LIMA is mobilized with the use of robotics through a port access approach. Both 
directed non-rib spreading and small rib spreading thoracotomies can be used for 
surgical access to the LAD. The anastomosis will be performed by hand on the 
beating heart. Planned surgery performed with cardiopulmonary support will not 
be allowed in this study. 
 
3. Beating Heart Totally Endoscopic Coronary Artery Bypass Graft (TECAB) 
Beating heart TECAB will proceed in a fashion similar to robotically assisted 
CABG in terms of vessel identification and LIMA takedown. Target mobilization, 

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LAD arteriotomy and anastomosis will be performed endoscopically with the 
robot. The LIMA-LAD anastomosis will be constructed by robotic/endoscopic 
techniques on the beating heart, utilizing sutures, U-clips or facilitated anastomotic 
connectors, according to surgeon preference.  Planned beating heart endoscopic 
operations on cardiopulmonary bypass as well as planned arrested heart TECAB 
are not allowed in this study. 
Additional HCR Considerations 
Anastomotic Patency 
Whenever possible, anastomotic patency should be confirmed with intra-operative transit 
time Doppler flow prior to closure. The data derived from the Doppler graft assessment 
will be documented and reported for all patients in whom Doppler assessment is 
performed; the printout of each patient’s data will be provided to the DCC for analysis 
and correlation with angiographic findings. These data points will include the graft flow 
(ml/min), the pulsatility index, the diastolic fraction and the presence/absence of 
backwards flow. 
If open sternotomy is required after an unsuccessful or complicated minimally invasive 
approach, only a LIMA to LAD should be performed; PCI, as per protocol, should be done 
in non-LAD territories. Unplanned sternotomy is not a protocol violation if required to 
safely and successfully complete the revascularization procedure. Bypassing a non-LAD 
vessel, however, is a protocol violation unless there is evidence of ongoing ischemia in the 
non-LAD territories, in which case bypass of the ischemic vessels will not be considered a 
protocol violation. 
Percutaneous Interventions (HCR Group & PCI-only Group) 
Only commercially available metallic drug-eluting stents may be used in this protocol.  Because 
the use of DES on patients with left main disease or with three-vessel disease, both of which are 
off-label uses for DES, is considered investigational, this trial will be conducted under an 
Investigational Device Exemption (IDE).  PCI should be performed using standard techniques at 
the discretion of the operator. In general PCI should be performed of lesions in vessels with 
visually estimated reference vessel diameter ≥2.25 mm with evidence of a) plaque rupture or 
thrombosis, or b) with an angiographic diameter stenosis ≥80%, or c) with evidence of ischemia 
on either non-invasive testing or by fractional flow reserve ≤0.80 or iFR ≤0.90. Which of these 
criteria are met will be categorized. The specific adjunctive devices used (e.g. atherectomy, 
cutting/scoring balloons, or aspiration) and techniques (e.g. 1- vs. 2-stent and technique for 
treatment of bifurcation lesions) will be collected. Bioresorbable vascular scaffolds may not be 
used in this study. 
Procedures may be staged at the discretion of the operator, but the intention to stage procedures 
must be specified within 24 hours after completion of the first procedure, should ideally be 
completed within 60 days of the first procedure, and in all cases must be completed within 90 of 
the first procedure after randomization. 
For patients randomized to HCR, if off-pump CAB is performed first, prior to the staged PCI 
procedure a diagnostic angiogram of the LIMA-LAD graft must be performed, irrespective of the 

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surgical approach chosen for HCR. Please see the Anticoagulation Guidance Document for 
further recommendations as to when and how to intervene if the distal anastomosis appears 
abnormal and/or antegrade flow is reduced. 
Optimal Medical Management 
All patients should be managed according to guideline-directed medical therapy (GDMT) by 
clinicians at each clinical site according to generally accepted societal recommendations. Details 
of GDMT are included in the MOP. Information will be collected about adherence to GDMT. 
DEFINITIONS AND MEASUREMENT OF ENDPOINTS 
Primary Endpoint 
The primary endpoint for this trial is a composite of MACCE over 5 years following 
randomization. 
All MACCE events will be adjudicated by an independent CEC. For the purpose of this trial 
MACCE is defined as a non-weighted composite score comprised of the following components: 
o All-cause mortality
Death from any cause
o Stroke
Stroke (ischemic or hemorrhagic) is defined as the rapid onset of a new neurological
deficit attributed to an obstruction in cerebral blood flow and/or cerebral hemorrhage
with no apparent non-vascular cause (e.g., trauma, tumor, or infection) that i) persists
beyond 24 hours, or ii) less than 24 hours if: a) associated with infarction or hemorrhage
on an imaging study, or b) treated with pharmacologic or mechanical intervention, or c)
results in death. Patients with non-focal global encephalopathy will not be reported as a
stroke without unequivocal evidence based upon neuroimaging studies. In most cases a
vascular neurologist or stroke specialist will determine whether a stroke has occurred.
Available neuroimaging studies will be considered to support the clinical impression and
to determine if there is a demonstrable lesion compatible with an acute stroke. Strokes
will be classified as ischemic, hemorrhagic, or unknown. Hemorrhagic conversion of an
ischemic stroke should be classified as ischemic.
o Myocardial Infarction
A. Non-Procedure Related Myocardial Infarction 3
The Third Universal Definition of Myocardial Infarction will be used to define Non-
Procedure Related Myocardial Infarction. This definition applies to an event
occurring >48 hours after any revascularization procedure as follows:
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least
one value above the 99th percentile of the upper reference limit (URL) of the assay
together with evidence of myocardial ischemia with at least one of the following:
o
Symptoms of ischemia;
o
ECG changes indicative of new ischemia (new ST-T changes or

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new left bundle branch block [LBBB]); 
o Development of pathological Q waves in the ECG; 
o Imaging evidence of new loss of viable myocardium or new 
regional wall motion abnormality. 
In the absence of knowledge of the URL, the local laboratory upper limit of 
normal (ULN) may be substituted. 
Note: Sudden unexpected cardiac death, involving cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, and accompanied by presumed new 
ST elevation or new LBBB, and/or evidence of fresh thrombus by coronary 
angiography and/or autopsy, with death occurring before blood samples obtained, 
or at a time before the expected appearance of cardiac biomarkers in blood will be 
classified as a mortality due to spontaneous MI. 
 
B. Peri-PCI and Peri-CABG Myocardial Infarction4 
The SCA&I definition of a clinically relevant peri-procedural myocardial infarction 
(MI) will be used for this definition. CK-MB is the preferred biomarker for post 
revascularization assessment of myonecrosis, but cardiac troponin I or T may be used 
as described below. A baseline pre-procedure value should be measured in all patients, 
and 2 additional biomarker measurements must be measured post procedure at 12±4 
hours and 24±4 hours post- procedure. If any measurement is elevated, serial measures 
should be repeated until the peak is reached and the levels are returning toward 
baseline. This definition applies to an event occurring ≤48 hours after any 
revascularization procedure as follows: 
 
a. In patients with normal baseline CK-MB: The peak CK-MB measured within 
48 hours of the procedure rises to ≥10x the local laboratory ULN, or to ≥5x 
ULN with new pathologic Q-waves in ≥2 contiguous leads or new persistent 
LBBB, OR in the absence of CK-MB measurements and a normal baseline 
cTn, a cardiac troponin (cTn) I or T level measured within 48 hours of the 
PCI rises to ≥70x the local laboratory ULN, or ≥35x ULN with new 
pathologic Q- waves in ≥2 contiguous leads or new persistent LBBB. If 
baseline CK-MB or cTn is unavailable in a patient with stable CAD, they will 
be assumed to be normal. 
b. In patients with elevated baseline CK-MB (or cTn) in whom the biomarker 
levels are stable or falling: The CK-MB (or cTn) rises by an absolute  
c. increment equal to those levels recommended above from the most recent 
pre- procedure level. 
d. In patients with elevated CK-MB (or cTn) in whom the biomarker levels 
have not been shown to be stable or falling, or in the patients with ACS 
without a baseline CK-MB or cTn measure: The CK-MB (or cTn) rises by 
an absolute increment equal to those levels recommended above plus new 
ST-segment elevation or depression plus signs consistent with a clinically 
relevant MI, such as new onset or worsening heart failure or sustained 
hypotension. 
 
    3Joint ESC/ACCF/AHA/WHF Task for the Redefinition of Myocardial Infarction, Circulation. 2007;116:0-0. 
4 Moussa ID, Klein LW, Shah B, et al. Consideration of a New Definition of Clinically Relevant Myocardial 
Infarction After Coronary Revascularization: An Expert Consensus Document From the Society for Cardiovascular 

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Angiography and Interventions (SCAI). J Am Coll Cardiol. 2013;62:1563-70. 
 
Note: Sudden unexpected cardiac death, involving cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, and accompanied by new ST- 
segment elevation or new LBBB, and/or evidence of fresh thrombus by coronary 
angiography and/or autopsy, with death occurring before blood samples obtained, 
or at a time before the expected appearance of cardiac biomarkers in blood will be 
classified as a mortality due to peri-procedural MI. 
 
o Unplanned Revascularization (adjudicated) 
(a) An unplanned revascularization procedure is defined as any PCI or CABG procedure 
performed that is an entirely new procedure due to ischemia not included in the pre-
specified revascularization strategy, or (b) was included in the pre-specified 
revascularization strategy as a planned staged procedure, but was performed >90 days 
after the first revascularization procedure after randomization, or (c) that is a repeat 
intervention of a previously performed study-related revascularization. Determination 
as to whether the revascularization procedure involves an original target vessel and 
lesion or a new (non-target) vessel and lesion will be made by the CEC whenever 
possible. 
 
 
Ischemia-driven Unplanned Revascularization 
Ischemia-driven unplanned revascularization procedures will be assessed. All unplanned 
revascularization procedures will be reviewed and adjudicated by the CEC to determine if 
they are ischemia-driven. Revascularization will be considered ischemia-driven if the 
diameter stenosis of the revascularized coronary segment is ≥50% or new thrombus 
and/or ulceration is present, and if any of the following criteria for ischemia are met: i) A 
positive functional study corresponding to the area served by the target lesion; or ii) 
Ischemic ECG changes at rest in a distribution consistent with the target vessel; or iii) 
Typical ischemic symptoms referable to the target lesion; or iv) IVUS of the target lesion 
with a minimal lumen area (MLA) of ≤4 mm2 for non-left main lesions or ≤6 mm2 for  
left main lesions; or v) FFR of the target lesion ≤0.80 or iFR of the target lesion <0.90 . A 
target lesion revascularization for a diameter stenosis less than 50% might also be 
considered ischemia-driven by the CEC if there was a markedly positive functional study 
or ECG changes corresponding to the area served by the target lesion. 
 
Planned staged procedures which are declared within 24 hours of the first 
revascularization procedure or post randomization and are performed within 90 days of 
the first post- randomization revascularization procedure will not be considered an 
unplanned  revascularization. Staged procedures performed >90 days after the first post- 
randomization revascularization procedure, even if originally pre-specified, will be 
considered an endpoint unplanned revascularization. Intervention on the LIMA, LIMA- 
LAD distal anastomosis or LAD triggered by routine LIMA angiography prior to a 
planned staged PCI will not be considered an unplanned revascularization. However, if 
anterior ischemia occurs after CABG necessitating LIMA angiography prior to the 
planned staged PCI with subsequent intervention on the LIMA, LIMA- LAD distal 
anastomosis or LAD, this event will be adjudicated as an unplanned revascularization.  
 
 

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Secondary Endpoints 
The secondary endpoints for the trial (each measured at 30 days post procedure, 12, 24, 36, 48, 
and 60 months, unless otherwise specified) of the trial include: 
 
Cardiovascular Events (adjudicated) 
o MACCE (defined above) at 30 days post procedure, and 12, 24, 36, 48 months 
o Individual components of MACCE (adjudicated, as defined above): 
 All-cause mortality 
 Stroke 
 Myocardial infarction 
 Unplanned  revascularization 
 
o Ischemia-driven revascularization (adjudicated) 
 
o Cardiovascular and Non-cardiovascular Mortality (adjudicated) 
Cardiovascular mortality, as adjudicated by the CEC, will be assessed. Cardiovascular 
death includes sudden cardiac death, death due to acute MI, heart failure or cardiogenic 
shock, stroke, other cardiovascular causes, or bleeding. Non- cardiovascular death is 
defined as any death with known cause not of cardiovascular causes. Any deaths in 
which the cause is unknown or undetermined will be considered cardiovascular. 
 
o Stent thrombosis (adjudicated) 
Stent thrombosis will be adjudicated according to the Academic Research Consortium 
scale.25 Stent thrombosis will be considered to be present if criteria for definite or 
probable stent thrombosis are met. According to its timing, stent thrombosis will be 
further classified as acute <24 hours), subacute (24 hours – 30 days), early (≤30 days), 
late (>30 days – 1 year), or very late (>1 year). 
 
o Symptomatic graft stenosis or occlusion (adjudicated) 
Symptomatic graft stenosis or occlusion requires angiographic confirmation of a DS 
≥50%, and the presence of at least one of the following criteria: i) A positive functional 
study corresponding to the area served by the target lesion; or ii) Ischemic ECG changes 
at rest in a distribution consistent with the target vessel; or iii) Typical ischemic 
symptoms referable to the target lesion; or iv) IVUS of the target lesion with a minimal 
lumen area (MLA) of ≤4 mm2; or v) FFR of the target lesion ≤0.80 or iFR of the target 
lesion ≤0.90. 
Intervention on the LIMA, LIMA-LAD distal anastomosis or LAD triggered by routine 
LIMA angiography prior to a staged PCI will also be considered to meet the criteria for 
symptomatic graft stenosis or occlusion. 
The adjudicated rates of symptomatic graft stenosis or occlusion of the LIMA to the LAD 
in the HCR arm will be compared to the rate of angiographic definite stent thrombosis of 
LAD stents in the PCI arm. 
 
Hospitalizations (non-adjudicated) 
o Re-hospitalization will be assessed and classified as all-cause or cardiovascular (further 
subdivided as due to cardiac arrest, acute MI, heart failure or cardiogenic shock, other 
cardiovascular causes, or bleeding). 

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Bleeding (non-adjudicated) 
o Site assessed bleeding complications will be reported using the Bleeding Academic 
Research Consortium (BARC) Scale26: 
o Type 0: no bleeding 
o 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 
o 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 (this does not apply to routine evaluation of chest 
tube drainage). 
o Type 3 
 Type 3a 
 Overt bleeding plus hemoglobin drop of 3 to 5 g/dL (corrected for 
transfusion: 1 U packed red blood cells or 1 U whole blood = 1 g/dL 
hemoglobin or 3% hct), OR 
 Any transfusion with overt bleeding 
 Type 3b 
 Overt bleeding plus hemoglobin drop 5 g/dL (corrected for 
transfusion: 1 U packed red blood cells or 1 U whole blood = 1 g/dL 
hemoglobin or 3% hct), OR 
 Cardiac tamponade, OR 
 Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid), OR 
 Bleeding requiring intravenous vasoactive agents outside routine care 
 Type 3c 
 Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal), OR 
 Subcategories confirmed by autopsy or imaging or lumbar puncture, 
OR 
 Intraocular bleed compromising vision 
o Type 4: CABG-related bleeding 
 Perioperative intracranial bleeding within 48 h, OR 
 Reoperation after closure of sternotomy for the purpose of controlling 
bleeding, OR 
 Transfusion of 5 U whole blood or packed red blood cells within a 48- 
hr period (excluding cell saver products), OR 
 Chest tube output 2L within a 24-h period 
 
o Type 5: fatal bleeding 
 Type 5a 
 Probable fatal bleeding; no autopsy or imaging confirmation but 

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clinically suspicious 

Type 5b

Definite fatal
o
Transfusion of blood products (number of units of whole blood, pRBCs, fresh frozen
plasma, platelets, cryoprecipitate and other, excluding auto-transfused blood) will be
recorded. Relationships between anti-platelet medication regimens and transfusion
requirement will be analyzed.
o
Total chest tube drainage will also be reported for HCR patients at 48 hours postop or
prior to chest tube removal, whichever is earlier.
Health Status 
o Angina class
Health status will be assessed by angina class measured by the Canadian Cardiovascular
Society Classification (CCSC).  The CCSC guidelines are detailed in Appendix I.
o Quality of Life
The change in quality of life (QOL) from baseline will be measured, using the Short
Form-12 (SF-12) general health status index and EuroQol 5-D (EuroQoL) which
measures health state preference from the individual and societal perspective. The SF-12
instrument examines 8 quality of life dimensions (physical activity, social activity,
role/physical, body pain, general mental health, role/emotional, vitality and general health
perception). The EuroQoL 5-D is a standardized instrument for measuring health-related
quality of life. This questionnaire provides a simple descriptive profile that consists of 5
dimensions.  The 5 domains are anxiety/depression, pain/discomfort, usual activities,
self-care, and mobility.  The instrument also has a self-assessment of health status.
o Cost-effectiveness
Cost-effectiveness will be evaluated using a microsimulation model, which will predict
the accrued health care costs and quality-adjusted life expectancy for each subject at the 
end of the trial follow-up period and in addition over a lifetime horizon. 
For this trial, the SF-12 is available in English, Spanish and French, and the EuroQol is available 
in English and French.  Inability to read and complete these instruments in the available 
languages does not preclude a patient from enrollment in the trial (a family member may assist in 
completing the QOL questionnaires).  Copies of these instruments can be found in Appendix II. 
UNANTICIPATED ADVERSE DEVICE EFFECTS 
Reporting of Serious Adverse Events and Unanticipated Adverse Device Effects  
All unanticipated adverse device effects (UADEs) must be reported to the DCC and the clinical 
center’s IRB/REB within 24 hours of knowledge of the event. 
The DCC will notify the NHLBI program officer of any UADEs via e-mail within 24 hours of 
receipt of the event.  The program officer will report these events to the DSMB chair within 72 
hours of notification.   

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DCC Reporting to FDA  
The DCC will report UADEs to FDA according to Code of Federal Regulations 21CFR812.150 
for this Investigational Device Exemption (IDE) trial. 
 
 
CLINICAL CENTERS 
The study will be conducted in between 50 and 125 U.S. and non-U.S. clinical sites with 
extensive experience in minimally invasive surgical coronary revascularization and multi-vessel 
PCI, as well as expertise in hybrid revascularization. The sites will be selected by the multi- 
disciplinary Hybrid Trial Steering Committee with particular focus on procedural expertise and 
evidence of a functioning multi-disciplinary heart team. An average recruitment of 98 patients 
monthly (2 patients/month/site) is anticipated. 
 
Each clinical center will be required to obtain IRB/REB approval for the initial protocol and 
informed consent document and any subsequent revisions in a timely fashion, to recruit patients, 
to collect data and enter it accurately into the electronic data capture (EDC) system, to faithfully 
follow the protocol and adhere to the standards of Good Clinical Practice (GCP) and HIPAA or 
Personal Information Protection and Electronic Documents Act (PIPEDA) regulations. In 
addition, centers will be required to provide the DCC the information necessary for interim, 
annual, and final reports, to provide source documents, data and regulatory documents to study 
monitors, to respond promptly to DCC inquiries, and, to participate in analyses and reporting of 
study results. 
 
Site Approval 
The following documents are required for all sites approved to participate in the trial: 
o Clinical Study Agreement with the CTSN DCC: InCHOIR, Department of Health Policy, 
Icahn School of Medicine at Mount Sinai 
o Signed Conflict of Interest Statements 
o Signed and dated CVs for all staff on Delegation of Authority Log 
o Completed Delegation of Authority Log 
o HIPAA/PIPEDA and Human Subjects/GCP training documentation (as required by local 
institutional guidelines) for all staff on Delegation of Authority Log 
o Current licenses for all staff on Delegation of Authority Log 
o IRB/REB roster 
o IRB/REB approval for protocol, informed consent document, HIPAA authorization (US 
sites) 
o NIH Stroke Scale Training Certification for appropriate staff 
o Laboratory Normal Ranges 
o Certification forms for Surgeons and Interventional Cardiologists 
o Signed Document Approval Form for protocol 
o Study-specific training documents 
 
 
INVESTIGATORS 
All surgeons, cardiologists, coordinators and other investigators involved in the trial must 
complete the Investigator Contact Form with their hospital affiliation, address, contact 
numbers (phone, fax, cell, pager), and email address. All investigators must send their CV, 

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Clinical Study Agreement/Conflict of Interest Statement, Good Clinical Practice Certificate 
and HIPAA or PIPEDA certification to the DCC.  As stated in the Investigator agreement 
form, they will conduct the investigation in accordance with the agreement, the 
investigational plan, Part 812 and other applicable FDA regulations, and conditions of 
approval imposed by the reviewing IRB and FDA. 
 
 
Qualifications and Training 
Clinical investigators will be cardiothoracic surgeons with expertise in minimally invasive 
coronary revascularization and interventional cardiologists with expertise in multi-vessel PCI, as 
well as experience with HCR.  To qualify, the surgical and interventional cardiology 
investigators must have demonstrated proficiency in HCR procedures and be approved by the 
Hybrid Trial Site Selection Committee. Surgical and interventional cardiology qualifications for 
all participating investigators will be collected on the Certification Form and faxed to the DCC 
prior to accreditation.  The clinical site Surgical and Interventional Co-Principal Investigators 
will be responsible for overseeing the ongoing performance of the other participating surgical 
and cardiology investigators at that site over the course of the study. 
 
All clinical site investigators and coordinators will be trained by the DCC in the specifics of the 
protocol the electronic data capture system. 
 
Good Clinical Practices (GCP) Certificate 
All investigators and coordinators who are involved in care of study patients, and/or research 
data collection must provide certification that they have successfully completed their local 
institutional GCP course. 
 
Conflict of Interest 
A conflict of interest statement will be collected from all study investigators to ensure that no 
investigator may exert undue influence that may bias the trial. Any conflict of interest identified 
will be reviewed by the NIH and managed in compliance with 21 CFR 54 and 42 CFR 50(f). 
Conflict of interest statements will be updated as changes occur and no less than annually. 
 
Patient Confidentiality 
Confidentiality of all patient records will be maintained according to HIPAA or PIPEDA 
guidelines. Study Investigators, site IRBs/REBs, the DCC (InCHOIR), the CEC, the FDA and 
the NHLBI may review source documentation for enrolled patients as necessary, but all unique 
patient and hospital identifiers will be removed prior to review. If the results of this study are 
published, the data will be presented in aggregate, with all patient identifiers removed. 
 
HIPAA or PIPEDA Certification 
All investigators and coordinators must provide documentation that they have successfully 
completed the institutional requirements to ensure patient rights, privacy and security under 
HIPAA or PIPEDA. 
 
 
SITE INITIATION 

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IRB/REB approval and the clinical study agreement between the clinical site and the DCC must 
be signed and executed prior to the site initiation.  Additionally, applicable CVs and other 
regulatory documentation must be on file with the DCC prior to site initiation. A representative 
from the DCC will conduct a site initiation teleconference prior to enrollment of the first patient. 
The surgeon(s), interventional cardiologist(s), and study coordinator will be required to attend 
the initiation. 
 
DATA COLLECTION 
For clinical sites participating in the STS registry, data collection will be done using the STS 
registry dataset. For clinical sites that are not part of the STS registry, and for patients randomized 
to PCI, data collection will be done at the site. 
 
Screening Data Collection 
 
Screening Registration Form 
Prior to informed consent 
Prior to approaching a patient to begin the informed consent process, the study personnel will 
review data on prospective patients to determine eligibility for inclusion in the trial.  All pre- 
screened patients (patients who are not consented) who are not enrolled are recorded in the 
Screening Registration  form in the EDC. The data collected is HIPAA compliant and does not 
include patient identifiers but does include screening quarter, screening year, age, gender, race 
and reason not eligible or not enrolled. 
 
Informed Consent 
Prior to screening data collection and all protocol defined procedures 
The site co-principal investigators are responsible for ensuring that the informed consent process 
is conducted and documented appropriately by trained study staff. A signed informed consent 
form, which has been approved by the DCC and the individual IRB/REB s, is required. The 
consent form must incorporate HIPAA (US sites only) clinical research authorization and 
Release of Medical Information that authorizes both transfer of specified STS Registry data to 
the DCC, release of medical records and release of billing information from all hospitalizations 
and outpatient services to the trial investigators, monitors, sponsor (NIH) and the DCC. The 
consent form will also permit analysis of all angiographic films at a central angiographic core 
laboratory. The investigators or a designated individual, will provide a thorough explanation of 
the objectives, patient responsibilities, risks and benefits of the study, and will fully address all 
concerns raised by the patient and/or family. After all issues have been adequately resolved, and 
the investigator has confirmed that the patient has been fully consented, the patient will be asked 
to sign the informed consent. The consent process must be documented in the medical chart, and 
a signed copy of the consent must be given to the patient. 
 
For the purpose of primary analysis, patients meeting the eligibility criteria are considered 
enrolled in the study at time of randomization. 
 
Anatomic Eligibility 
Prior to proceeding with the following trial-specific activities, the coronary angiogram will be 
reviewed by both an interventional cardiologist and a cardiothoracic surgeon to establish 
consensus that the patient is an appropriate candidate for hybrid revascularization as well as 

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multi-vessel PCI with metallic DES. The clinical inclusion and exclusion criteria will be 
documented on the Eligibility Form (see below). 
 
Once consensus regarding eligibility for HCR and multi-vessel PCI with DES is established, the 
following activities should be undertaken. 
 
Screening & Baseline Site Activities 
 
Eligibility Evaluation 
Prior to randomization 
This checklist of inclusion and exclusion criteria will be completed and signed by the 
investigator to verify that the patient meets all eligibility requirements for this trial. 
 
Randomization Procedure 
A DCC representative will be available to discuss any questions regarding patient eligibility. 
Once the site investigator has confirmed  that  the patient  meets  all  eligibility criteria for 
participation in the trial, and has completed the eligibility forms in the EDC, randomization 
will be performed electronically. 
 
Randomization 
Must be completed 
(a) within 90 days of the 3-vessel qualifying angiogram for patients identified in the setting 
of a diagnostic angiogram, or 
(b) within 90 days following the qualifying 3-vessel angiogram for patients also 
undergoing a PCI of a non-LAD and non-LM vessel prior to randomization. (See table 
under Randomization Section) 
 
The first study intervention is recommended to be performed within 72 hours post 
randomization and must be performed within 14 days following randomization. 
Randomization to the treatment assignment will be generated by the EDC system once the 
checklist of inclusion and exclusion criteria has been completed and verified and the planned 
revascularization strategy form has been completed. For the purpose of the primary analysis, 
patients are considered enrolled in the study once they are randomized and an identification 
code is generated. 
 
Revascularization Plan 
Prior to randomization 
The surgical and percutaneous revascularization plan will be described for both HCR and 
PCI-only revascularization prior to randomization. This plan may be revised within 24 
hours of the first procedure after randomization to reflect procedural complications, should 
they occur. Any revascularization procedures deviating from the final revascularization plan 
in place 24 hours after the first procedure will be considered unplanned revascularization 
procedures. 
Note: Any revascularization procedure that is done during a planned revascularization 
procedure will NOT be considered an unplanned procedure. E.g.: planned minimally 
invasive LIMA-LAD procedure becomes complicated by inferior ischemia requiring 
conversion to an open procedure and RCA bypass; or planned PCI after minimally invasive 

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LIMA-LAD procedure demonstrated LIMA-LAD graft occlusion requiring PCI; or planned 
PCI of the LCX results in a LM dissection requiring a LM stent. However, CABG 
complications that result in separate unplanned PCI or CABG procedures, and PCI 
complications that result in separate unplanned PCI or CABG procedures, will be 
considered unplanned procedures and endpoint events. 
Angina Class - Canadian Cardiovascular Society Classification (CCSC) 
Following determination of eligibility and within 14 days prior to randomization 
The presence of angina will be assessed, and when present, classified according to the CCSC 
scale and documented on this form.  CCSC classification scheme is detailed in Appendix I. 
NYHA Class 
Following determination of eligibility and within 14 days prior to randomization 
The presence of heart failure will be assessed, and when present, classified according to the 
NYHA scale. NYHA classification will be determined by investigative center personnel and 
documented on the “New York Heart Association Classification” form. The NYHA 
classification scheme is detailed in Appendix III. 
Quality of Life 
Following determination of eligibility and within 14 days prior to randomization 
The SF 12 and EuroQol (Appendix II) questionnaires will be completed by the patient to 
assess quality of life. 
Pre-intervention Existing STS Registry Data Extraction (collected by sites if not 
participating in STS or for patients randomized to PCI group) 
Angiogram 
Data partially extracted from the STS Registry database 
Data regarding the coronary anatomy, including the number of lesions, degree of coronary 
obstruction and SYNTAX score will be extracted from the STS registry database. 
Demographics 
For all patients screened, the  date of birth, race, ethnicity, sex, and insurance will be 
captured. 
Medical History 
Data partially extracted from the STS Registry database  
Information pertaining to the medical history, with particular focus on cardiovascular history, 
will be extracted from the STS registry database. The data collection includes, but is not 
limited to previous myocardial infarction and coronary revascularization, AICD and 
pacemaker therapy, stroke and other comorbidities such as diabetes, dialysis and peripheral 
vascular disease. Information regarding the current cardiac condition is also captured, 
including symptoms and severity of cardiac disease and the patient’s current height and 
weight. 
Laboratory Assessment 
Data partially extracted from the STS Registry database 
Data regarding the following laboratory values prior to index coronary revascularization will 

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be extracted from the clinical registry databases: 
 
o CK MB (creatine kinase- myocardial band) and/or Troponin I or T (ng/mL) 
o Hematocrit (%) 
o Creatinine (mg/dl) 
 
Treatment Intervention 
The assigned study coronary revascularization intervention (or first revascularization 
intervention, for staged procedures) are recommended to be performed within 72 hours post 
randomization, and must be performed within 14 days following randomization. (See 
Randomization section) 
 
Procedural and Peri-Procedural STS Registry Data Extraction (collected by sites if not 
participating in STS or for patients randomized to PCI group) 
 
The following will be collected for all hospitalizations required to complete the original planned 
revascularization strategy, if staged. 
 
Medications 
Data regarding medication use within 24 hours prior to, during the revascularization 
procedure or within 24 hours after the procedure, including antiplatelet and antithrombin 
agents, beta blocker, and ACE inhibitors, ARBs, aldosterone antagonists, and statins, will 
be collected at the sites. This data will be collected whenever possible for all subsequent 
revascularization procedures. 
 
Laboratory Assessment 
Data partially extracted from the STS Registry database 
Data regarding the following laboratory values after the index coronary revascularization 
will be extracted from the clinical registry databases: 
 
o CK MB and/or Troponin I or T (ng/mL) 
 
PCI Procedure 
 
Data regarding the index PCI procedure(s) will be  provided by the site coordinators. 
Information to be collected includes, but is not limited to, the status of the procedure (e.g., 
elective, urgent, emergency, salvage), indications for the procedure, the percutaneous 
intervention(s) performed, and intra and post-procedural events.  
 
Index Surgical Procedure 
Data partially extracted from the STS registry database; HCR Group ONLY. Additional 
data to be supplied by cardiac surgical investigator 
Data regarding the surgical intervention for the HCR procedure will be extracted from the 
STS dataset, including but not limited to the status of the procedure (e.g., elective, urgent, 
emergent, and emergent salvage), details regarding the anesthesia and intra-operative 
interventions, bypass pump use, conduit and harvest technique, anastomoses, concomitant 
procedures, and intra-operative blood use and complications if applicable. Modest additional 

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data will be provided by the surgical investigator, including surgical technique such as 
MIDCAB, EndoCAB or TECAB. 
 
Hospitalization & MACCE Events 
Limited information about the index revascularization procedure(s) and hospitalization will 
be extracted from the STS registry dataset including length of stay, transfusion 
requirements, repeat procedures, and discharge disposition when possible. Information 
regarding MACCE events that occur during study-procedure related hospitalizations will 
also be extracted from the STS registry when possible. Limited source documentation 
pertaining to the MACCE event will be collected and uploaded into the EDC as detailed in 
the trial Manual of Procedures (MOP). 
 
 
Index Hospital Costs 
Data extracted from UHC database and UB forms for all hospitalizations required to 
complete the original planned revascularization strategy (if staged) 
 
Medical costs are defined as hospital costs and physician fees incurred during the index 
revascularization procedure(s) and hospitalization. Cost data will be extracted from the UHC 
operational database system for member sites, and from UB medical claims forms for sites 
without UHC membership. Dates of charges and revenue codes will be used to match the 
cost data with data on study-procedure related hospitalization from the STS registry. UB 
medical claims will be converted to costs using the same methodology as used by UHC to 
estimate costs including center-specific ratios of cost to charges. These ratios will be based 
on the annual Medicare costs reports submitted annually by participating study sites to 
Medicare. Physician fees will be based on collected length of stay data and the Medicare fee 
schedule. Physician fees for HCR and PCI procedures will include those for the primary 
surgeon, surgical assistant, and anesthesiologist. Non procedure-related physician fees 
regarding the index hospitalization(s) will be based on collected length of stay data and the 
Medicare fee schedule. The patient-specific cost data downloaded from the UHC operational 
database system and electronic UB data will be de-identified and coded with the unique 
study ID, and subsequently transferred by the participating clinical site to the DCC via a 
secure FTP website. 
 
Post-Intervention Site Activities 
 
Follow-up must be performed at 30 (±7) days following all procedures (index and staged) 
that occur within 90 days of the first study revascularization procedure.. However, if a 
staged procedure occurs <45 days after the first procedure, it will not be considered a 
protocol violation if a 30-day follow-up visit was not performed after the first procedure. 
 
Medications 
This form captures medication use, including antiplatelet and anticoagulant agents, beta 
blocker, and ACE inhibitors, ARBs, aldosterone antagonists and statins. 
 
Angina Class - Canadian Cardiovascular Society Classification (CCSC) 
The presence of angina will be assessed, and when present, classified according to the CCSC 

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scale and documented on this form.  CCSC classification scheme is detailed in Appendix I. 
 
Quality of Life 
The SF-12 and EuroQol (Appendix II) questionnaires will be completed by the patient to 
assess quality of life.  
 
MACCE and Other Cardiovascular and Bleeding Events 
Information regarding MACCE, other cardiovascular and bleeding events will be recorded. 
Limited source documentation pertaining to the MACCE event will be collected and 
uploaded into the EDC as detailed in the trial Manual of Procedures (MOP). 
 
Long-term Patient-Reported MACCE & QoL 
 
MACCE and Other Cardiovascular and Bleeding Events 
Follow-up must be performed at 6 (±1), 12 (±1), 18 (±1), 24 (±1), 30 (±1), 36 (±1), 42(±1), 
48 (±1), 54 (±1), and 60 (±1) months post-randomization, via centralized DCC telephone 
follow-up (when allowed by local IRB/REBs) 
Follow-up MACCE and other cardiovascular and bleeding event assessments will be 
conducted via telephone contact with patients by the DCC research nurse.  Site coordinators 
will conduct follow-up via telephone at sites where the IRB/REB does not approve of 
centralized DCC follow-up.  Vital status and the occurrence of any MACCE and other 
cardiovascular and bleeding event events since the last follow-up will be ascertained. 
Information regarding MACCE and other cardiovascular and bleeding event events will be 
recorded by the DCC research nurse or local site coordinator. In addition, limited source 
documentation pertaining to the MACCE and selected other cardiovascular events will be 
collected by the site coordinator and uploaded into the EDC for review by the Clinical Events 
Committee. 
 
For patients who have completed their planned revascularization procedure(s) as documented 
on the Planned Revascularization form, including planned staged procedures, any subsequent 
PCI or CABG performed will be considered an unplanned revascularization, and treated as a 
MACCE event. As noted in the Definition and Measurement of Endpoints section, this 
excludes an additional planned staged revascularization if it is declared by the end of the 
prior planned study intervention procedure. 
 
Medications 
At 6 (±1), 12 (±1), 18 (±1), 24 (±1), 30 (±1), 36 (±1), 42(±1), 48 (±1), 54 (±1), and 60 (±1) 
months post-randomization, via centralized DCC telephone follow-up (when allowed by local 
IRB/REBs) 
 
Patient reported medication use since the last follow-up, specifically, antiplatelet and 
anticoagulant agents, beta blocker, ACE inhibitors, ARB, aldosterone antagonists and statin 
use will be recorded by the DCC research nurse or local site coordinator. 
 
Angina Class - Canadian Cardiovascular Society Classification (CCSC) 
At 6 (±1), 12 (±1), 18 (±1), 24 (±1), 30 (±1), 36 (±1), 42(±1), 48 (±1), 54 (±1), and 60 (±1) 
months post-randomization, via centralized DCC telephone follow-up (when allowed by local 

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IRB/REBs) 
The presence of angina will be assessed by the DCC research nurse, and when present, 
classified according to the CCSC scale and documented on this form. CCSC classification 
scheme is detailed in Appendix I. 
 
Quality of Life 
At 12 (±1), 24 (±1), 36(±1), 48 (±1), and 60 (±1) months post-randomization, via centralized 
DCC telephone follow- up (when allowed by local IRB/REBs) 
 
The SF-12 and EuroQoL will be administered annually, either by phone from the DCC 
research nurse or site coordinator, or via electronic patient portals, including electronic QoL 
surveys that can be utilized for all patients with computer, tablet or smart phone capability. 
The electronic forms will also be accessible for patient reporting via a password protected 
portal on the HCR Trial website. 
 
Costs 
Collected at 12 (±1), 24 (±1), 36 (±1), 48 (±1), and 60 (±1) months post-randomization, via 
electronic transfer from UHC database and UB forms 
Medical costs were defined as hospital costs, physician fees, outpatient procedure costs, the 
cost of prescription drugs, and the cost of rehabilitation incurred after the index 
hospitalization. Medical claims associated with any hospital stay and outpatient service in 
participating sites are collected annually. Cost data will be extracted from the UHC 
operational database system for member sites, and from UB medical claims forms for sites 
without UHC membership. UB medical claims will be converted to costs using the same 
methodology as used by UHC to estimate costs using center-specific ratios of cost to charges. 
These ratios will be based on the annual Medicare costs reports submitted by participating 
study sites to Medicare. Multivariable imputation algorithms will be used to impute costs for 
patient-reported out of network hospital stays. Physician fees will be based on collected 
MACCE and length of stay data and the Medicare fee schedule. Resource use associated with 
prescribed medication and the rehabilitation of myocardial infarction and stroke will be 
estimated based on patient-reported information and will be converted into dollars using 
reimbursements from Centers for Medicare and Medicaid Services costing reports 
 
Event Driven Data Collection 
 
Major Adverse Cardiac and Cerebrovascular Events (MACCE) and Other Cardiovascular 
and Bleeding Events (when allowed by local IRB/REBs) 
Patient reported via electronic patient portal or phone call to DCC (when allowed by local 
IRB/REBs) 
Patients will be encouraged to report interim MACCE and other cardiovascular and bleeding 
events between the annual phone follow-ups. Follow-up MACCE and other cardiovascular 
and bleeding event reporting will be conducted either via telephone contact to the DCC 
research nurse or the site coordinator, or via one of the electronic patient portals (e.g., 
electronic QoL surveys for all patients with computer, tablet or smart phone capability. The 
electronic forms will also be accessible for patient reporting via a password protected portal 
on the HCR Trial website). 
 

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Information regarding MACCE and other cardiovascular and bleeding events reported via 
telephone will be recorded by the DCC research nurse or site coordinator. In addition, limited 
source documentation pertaining to the MACCE and other selected cardiovascular events will 
be collected by the site coordinator. 
End of Study 
Study Completion/Early Termination 
Event Driven 
This form records the date and reason for study completion or early termination. 
Investigator Statement 
At the end of study after electronic case report form (eCRF) data completion and review 
After a complete review of the eCRFs and patient summaries, the investigator will sign this 
form to attest to the accuracy and completeness of the data collected. 
DATA MANAGEMENT 
In order to capture the highest quality data, we will use a web-based system with electronic 
validation. In addition, we will cross-validate the data for complex errors. Ongoing review of 
data collection by the DCC will ensure that the quality and completeness of the data will be 
reflective of the state of the art in clinical trials. 
Electronic Data Capture 
All study data will be entered in the EDC system. Study personnel requiring access will have 
their own Login/Password. Access to clinical study information will be based on individuals' 
roles and responsibilities. The EDC application provides hierarchical user permission data entry, 
viewing, and reporting options. For optimum security, the system operates Secure Socket Layer 
128-bit encryption protocol over Virtual Private Networks. This application is designed to be in
full compliance with the International Conference on Harmonization and Good Clinical
Practices (ICH-GCP), the FDA’s CFR21 Part 11 Electronic Record and Electronic Signatures,
the FDA's "Guidance: Computerized Systems Used in Clinical Trials,” and the Privacy Rule of
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).
EDC supports efficient data collection and management and facilitates rapid data closure. A 
strong advantage of web-based design is that the DCC has immediate and ongoing access to the 
data from all clinical centers so that queries can be generated and distributed to the sites in real- 
time, the frequency of missing data can be reduced by two mechanisms, the coordinators will 
receive a list of queries generated by the study monitors upon logging into the system, and any 
data required during a visit is immediately evident through the system and can be collected 
before closure of the visit window. The EDC will be a vital part of the centralized monitoring 
planned for this study. 
Monitoring 
The DCC will employ a risk-based approach to monitoring for this study. This will be 
accomplished via centralized or remote monitoring of data via the EDC with a focus on safety, 

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study endpoints, data completion and data outliers. Clinical centers will provide source 
documentation to the DCC for remote monitoring via upload to the EDC or remote access to 
electronic medical records. The DCC will also centrally monitor study logs including the 
Informed Consent Log, the Protocol Violation/Deviation Log and the Serious Adverse Event/ 
Investigational Device Exemption (IDE) Safety Report Log periodically to ensure that the sites 
are adhering to the study protocol and procedures. The DCC will generate performance metrics 
to analyze site characteristics such as recruitment rates and timeliness of data entry. This will 
allow the DCC to identify trends across sites and to address low-performing sites appropriately. 
The monitors will also conduct a review of the regulatory documents for the study. 
 
Through the combination of centralized monitoring, the EDC system, instantaneous electronic 
validation, and visual cross-validation by the DCC to detect complex errors, it is anticipated that 
the best possible quality and most complete data will be collected. 
 
Patient Retention Strategies 
The DCC nurse or local site coordinator will build relationships with each participant, beginning 
immediately after discharge from the index hospitalization, to maximize data completion and 
participant retention. Tools to enhance the patient/DCC relationship will include 24 hour phone 
access for study questions and clinical referrals, quarterly newsletters (electronic and paper 
based). 
 
 
ANALYTICAL PLAN 
The primary objective of this trial is to determine whether hybrid coronary revascularization 
(HCR) is associated with a reduction in MACCE defined as all-cause mortality, myocardial 
infarction (MI), stroke, or unplanned revascularization over a minimum of 5 years follow-up 
after randomization, compared to PCI with metallic DES. Secondary outcomes of this study will 
include MACCE at each data collection time point, individual components of MACCE,  
ischemia-driven revascularizations, cardiovascular and non-cardiovascular mortality, Re-
hospitalization (all-cause and cardiovascular)  health status, and the comparative cost-
effectiveness of HCR vs. PCI. 
 
Power and Sample Size 
Sample size for this study was determined based on the following operating characteristics: (a) 
two sided type I error fixed at 0.05, (b) 80% power, (c) minimum follow-up of 5 years, 2-year 
enrollment period with uniform enrollment (d) 5-year MACCE rate in the PCI group of 
approximately 25%, (e) expected 5-year MACCE relative rate reduction in the HCR group of ≥ 
20%, (f) drop-in (HCR to PCI) and drop-out (PCI to HCR) rates of approximately 0.5% and 2% 
respectively, and (g) loss to follow-up by the end of the study of 15%.Under the above 
assumptions it is estimated that 530 events (or 2354 patients) will be required to detect a 
relative decrease in MACCE of ≥ 20% in the HCR compared to the PCI group. This is a 
reasonable improvement based on estimates from recent studies.25-28 
 
Interim Monitoring Guidelines 
The objectives of interim monitoring are to (1) monitor for safety, (2) track participant accrual 
rates, and (3) monitor the primary and secondary outcomes for early evidence of efficacy, harm 
or futility. To accomplish this, summaries of data quality, accrual, adherence, distribution of 

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baseline factors, safety, study endpoints and other analyses as requested will be prepared for 
review by the DSMB. A single interim analysis and one final analysis are planned for this trial, 
for a total of two analyses. The interim analysis will be conducted when 0.5 fraction of the total 
number of events have been observed. This interim analysis will evaluate the composite rate of 
adjudicated death, stroke or MI (excluding unplanned repeat revascularization), as the endpoint is 
being conducted for safety, rather than efficacy, purposes.  We will use an alpha-spending 
O’Brien-Fleming sequential procedure as a guideline for decision-making. At the interim 
analysis the value of the test statistic will be compared with the alpha spending function critical 
value. The p-values for the interim monitoring analysis and the final analysis are, 0.0031, and 
0.05, respectively. 
 
Stopping Rule 
We do not anticipate stopping the trial for evidence of early efficacy or futility at the time of the 
interim analysis. The collection of 5-year follow-up information on all patients enrolled in the 
trial is necessary to provide a comprehensive overview of the relative safety and effectiveness of 
the two randomized strategies. 
 
A decision to stop the trial for safety reasons will be based on the result of the interim analysis 
as well as other supporting evidence that either arm of the trial poses unacceptable risk to 
patients. Should the data suggest that the composite rate of death, stroke or MI is significantly 
higher in one group than the other at the interim analysis (with a p-value of ≤ 0.0031), additional 
analyses and sub-group analyses will be conducted to supplement this information including 
investigation of site effects, adherence to the guideline-directed medical therapy, and other ad-
hoc pertinent analyses as discussed and agreed upon with the DSMB. 
 
Analysis Plan 
The primary analysis will be an intent-to-treat analysis that will include all randomized 
participants regardless of treatment actually received or follow-up schedule. All hypothesis 
testing will be conducted using two sided tests at  =0.05. 
 
Univariate Analysis 
All outcome measures will be described in a univariate analysis. For continuous variables means 
and standard deviations will be calculated. For discrete and dichotomous variables, contingency 
tables will be used. 
 
Analysis of Primary Endpoint 
The primary endpoint of this study will be MACCE defined as all-cause mortality, myocardial 
infarction (MI), stroke, or unplanned revascularization over a minimum of 5 years of follow-
up after randomization. Overall time to first event will be estimated using Kaplan-Meier 
curves. Survival time will be defined as the time (in months) between randomization and the 
occurrence of MACCE. To compare the HCR arm with the PCI arm we will use a stratified 
log-rank statistic using the stratification variables from the randomization procedure. A Cox 
proportional hazards model with treatment and stratification factors as covariates will be used 
for the multivariate analysis of the time to first MACCE. The assumption of proportionality 
will be tested prior to fitting the model. If the proportional hazards assumption is not met, the 
extended Cox model will be used. Hazard ratios and their 95% confidence intervals will be 
computed. Survival will be included in the analysis as censored if they are alive and free of 

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MACCE at the end of the study. Although we do not anticipate interactions between treatment 
and stratification factors, formal tests for interactions will be assessed using proportional 
hazards models. 
 
Analysis of Secondary End-points 
Secondary outcomes of the study will be analyzed as follows: 
 
Cardiovascular Events 
Secondary cardiovascular events include MACCE at each data collection time point; individual 
components of MACCE (all-cause mortality, stroke, myocardial infarction, unplanned 
revascularization,); cardiovascular and non-cardiovascular mortality, ischemia-driven 
revascularization, and other cardiovascular events.  
 
MACCE at each time point, individual components of MACCE, cardiovascular and non-
cardiovascular mortality, , ischemia-driven revascularization other cardiovascular endpoints such 
as stent thrombosis and symptomatic graft stenosis or occlusion, and bleeding events will be 
analyzed using the stratified log-rank statistic in the manner of the primary outcome. Unplanned 
revascularization, stroke, MI, and cardiovascular mortality may not occur because death from 
any cause precedes the event, thus it is possible that censoring patients from all-cause mortality 
may lead to biased estimates when analyzing time to first event of these outcomes. As a 
sensitivity analysis, competing risks analysis using the methods of Gray29 and Fine and Gray30 
will be used to calculate cause-specific cumulative incidence. Gray and Fine’s test will be 
compared with the log-rank test for the treatment group effect, and the cumulative incidence 
curve will be compared to the Kaplan-Meier curve. 
 
For unplanned and ischemia-driven revascularizations, a Poisson regression model will be used 
to assess differences in the rate of revascularization between groups. Time to death will be 
described by Kaplan-Meier curves and differences between randomization groups assessed via 
the stratified log-rank test. Mortality analyses will be conducted for both cardiovascular and 
non-cardiovascular mortality. 
 
Hospitalizations 
All cause and cardiovascular re-admissions will be recorded. A Poisson regression model will 
be used to compare the rate of readmission between groups for any cause, and specifically for 
cardiovascular hospitalizations. 
 
Health Status 
Health status will be measured by Angina Score (Canadian Cardiovascular Society 
Classification [CCSC]) and by QoL surveys (SF-12 and EuroQOL). The distribution of CCSC 
angina class will be presented for each randomization arm and compared using a chi-squared test 
at each time point. Quality of life will be measured using the SF-12 and EuroQol. Quality of life 
will be analyzed longitudinally using mixed effects models. 31, 32, 33 Log-transformations will be 
used, if necessary to normalize the variables or stabilize the variance. These models will be used 
to predict outcome given treatment group and time. The interaction between treatment and time 
will be used to determine the difference between the two arms over time. 
 
Cost-effectiveness 

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A cost-effectiveness analysis will be performed from an overall healthcare system perspective. 
Costs associated with hospitalizations and outpatient services will be estimated from collected 
medical claim data using center-specific ratios of cost to charges. Multivariable imputation 
algorithms will be used to impute costs for patient-reported out of network MACCE related 
hospitalizations. Community-based health state preferences will be estimated from the trial’s 
EuroQOL data using an algorithm developed for the U.S. general population.34 
 
We will subsequently develop an individual-level decision model, which will predict and 
extrapolate the overall survival, quality of life, and costs per trial participant as a function of 
randomization and MACCE. With the decision model we will compare the two scenarios: HCR 
vs. PCI by rerunning the randomized trial “in silico”. In this re-simulated trial, each of the 2354 
patients will be virtually exposed to both scenarios. Subsequently, each patient’s life course 
according to an intention-to-treat principle is modeled by microsimulation while individualizing 
event rates, quality of life and costs. 
 
For the base case analysis, we will use the trial duration as time horizon and in addition an 
extended lifetime horizon. The modeled future costs and quality-adjusted life years (QALYs) 
will be discounted at the annual rate of 3% and averaged for the two scenarios. To take into 
account patient heterogeneity and parameter uncertainty, the decision model’s equations for 
event rates, quality of life, and costs will be regenerated in bootstrap datasets, each with the same 
size of 2354 patients. Using the decision models’ output of each bootstrap (probabilistic cost- 
effectiveness analysis), we will construct incremental cost effectiveness (ICE) scatterplots. 
Second, we will calculate average net health benefits for HCR and PCI. The net health benefit is 
defined as the difference between the health effect in QALY associated with the chosen 
intervention and the minimum health effect that society would demand in return for the 
investment: QALY – QALY/cost-effectiveness threshold .35 Recently recommended cost- 
effectiveness thresholds of $50,000, $100,000, and $200,000 per QALY will be considered.36 In 
addition, 95% confidence intervals will be calculated for the difference in mean QALYs, costs 
and net health benefits by comparing the two scenarios across bootstraps. Deterministic 
sensitivity analyses will be performed to explore the robustness of the findings, including 
variations in discount rates, different time horizons, and changes in costs, survival and QoL due 
to increased use and experience. 
 
Missing Data 
For participants who are lost to follow-up we will use all the information available up to the 
time of loss to follow-up. If the data are missing at random (MAR), that is, the probability of 
being missing depends only on observed values, then likelihood-based methods such as mixed-
effects models will be used for analysis without bias.37 If the fraction of missing data is small 
we expect that even non-ignorability will have a negligible effect on the final estimates. If the 
extent of missingness is large compared to the effect size, we will use the multiple imputation 
procedure proposed by Rubin and Little.38, 39 
 
Safety Analysis 
The DSMB will receive regular reports on MACCE and the individual components of MACCE, 
as well as other cardiovascular and bleeding events for all participants in the trial. As part of the 

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safety analysis, mortality data will also be provided. Exact 95% confidence intervals (based on 
the Poisson distribution) for the risk ratios for individual components of MACCE for HCR 
versus PCI will be computed. 
  ORGANIZATION OF THE STUDY 
This section describes the overall study organization. The study is conducted in at least 50 
clinical sites selected by the Hybrid Trial Steering Committee. The following committees and 
institutions will be involved in the administration of the study. 
Clinical Events Committee (CEC) 
The charge of the CEC is to review source documents and to adjudicate all MACCE events 
according to their pre-specified definitions. The individuals who will serve on the committee 
will be appointed by the DCC, and will be independent of the DCC, CCC, clinical centers and 
the investigators. The committee will consist of, at least, a cardiothoracic surgeon with HCR 
experience, an interventional cardiologist, and a neurologist. The CEC will meet via 
teleconference, and when possible, Skype, every 6 months or as needed to adjudicate outcomes 
data for each subject enrolled. 
Data and Safety Monitoring Board (DSMB) 
To meet the study's ethical responsibility to its subjects, an independent DSMB will monitor 
results during the study. The board consists of physicians, biostatisticians, and ethicists, who 
have no formal involvement or conflict of interest with the subjects, the investigators, the DCC, 
CCC, or the clinical sites, and will be appointed by the NHLBI. The DSMB will act in a senior 
advisory capacity to the DCC, CCC, Steering Committee, and the NHLBI regarding data and 
safety matters throughout the duration of the study. These data include adverse events (e.g., 
MACCE) and mortality. They will communicate their findings directly with the DCC and the 
NHLBI. The clinical centers will have no contact with the members of DSMB and no voting 
member of the committee may participate in the study as an investigator. 
Data Coordinating Center (DCC) 
A university-based DCC (InCHOIR) will collaborate with the CCC, Steering Committee, and 
clinical investigators to finalize and revise the study protocol as necessary, and bears 
responsibility for monitoring interim data, and analyzing the study's results in conjunction with 
the CCC, Steering Committee, investigators and the sponsor. The DCC will coordinate and 
monitor the trial, and will administrate the DSMB. The DCC holds the study-specific IDE 
with the FDA and will be responsible for reporting UADEs to the FDA according to 
21CFR812.150.  In addition, the DCC will be responsible for submitting the required progress 
reports to the FDA. 
Clinical Coordinating Center (CCC) 
The clinical coordination for the Hybrid Trial will be directed by a CCC, co-chaired by an 
interventional cardiologist (Gregg W. Stone) and cardiac surgeon (John Puskas).  The CCC will 
collaborate with the DCC, Steering committee and clinical investigators to optimize the close 
collaboration between the interventional cardiologists and surgeons within the clinical site 
Heart Teams. The charge of the CCC will be to (1) maximize enrollment, (2) monitor the 
appropriateness of enrollment, (3) mentor site investigators, and (4) facilitate communication 

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between site investigators and the DCC, (5) interpreting and disseminating the study results in 
collaboration with the DCC, Steering Committee and clinical investigators. The CCC will 
oversee the medical and surgical management committees with site investigators, and monitor 
respective surgical and medical literature and other knowledge sources to assure state-of-the-art 
patient management standards are integrated into the protocol. 
 
Steering Committee 
The Steering Committee will provide the overall scientific direction for the Hybrid Trial. The 
committee will consist of the surgical and interventional cardiology Principal Investigators from 
the two highest enrolling centers, representatives of the DCC and CCC, and the NHLBI project 
officer. The responsibilities of the Steering Committee are to: (a) maintain contact with study 
investigators to ensure high quality data collection; (b) approve and implement major protocol 
changes in response to advice from the DSMB; (c) collaborate in data analysis, interpretation, 
and publication; (d) establish criteria for authorship on all manuscripts, publications and 
presentations that arise from the study. 
 
NIH 
This trial is funded by the National Heart, Lung, and Blood Institute (NHLBI). The NHLBI has 
appointed an independent DSMB to provide oversight of this trial. NHLBI program officials 
will serve as members of the Steering Committee. 

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APPENDIX I:  Canadian Cardiovascular Society Classification 
Overview: 
The Canadian Cardiovascular Society Classification of angina pectoris separates patients with 
anginal symptoms into groups based on the severity of their symptoms. The classification uses 
the extent of limitation on daily activities and the kind of physical activity which precipitates the 
anginal episode. 
Clinical Findings 
Features 
Grade 
No limitation of ordinary 
activity 
Ordinary physical activity (such as walking or climbing stairs) 
does not cause angina. Angina may occur with strenuous 
rapid or prolonged exertion at work or recreation. 
I 
Slight limitation of 
ordinary activity 
Angina may occur with 
•
Walking or climbing stairs rapidly;
•
Walking uphill;
•
Walking or stair climbing after meals or in the cold in
the wind or under emotional stress, or only during the
few hours after awakening.
•
Walking more than 2 blocks on the level at a normal
pace and in normal conditions
•
Climbing more than 1 flight of ordinary stairs at a
normal pace and in normal conditions
II 
Marked limitation of 
ordinary physical 
activity 
Angina may occur after 
•
Walking 1-2 blocks on the level or
•
Climbing 1 flight of stairs in normal conditions at a
normal pace
III 
Unable to carry on any 
physical activity without 
discomfort 
Angina may be present at rest. 
IV 
Campeau L. Grading of angina pectoris (Letter to the Editor). Circulation. 1976; 54: 522-523. 

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Appendix II:  Quality of Life Measures 
SHORT FORM – 12 (SF-12 version 2) 

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EURO QoL 5-D QUESTIONNAIRE 
 
 
Check one box for each of the following six health dimensions. 
Mobility 
I have no problems in walking about 

I have some problems in walking about 

I am confined to bed 

Self-Care 
I have no problems with self-care 

I have some problems washing or dressing myself 

I am unable to wash or dress myself 

Usual Activities (e.g. work, study, housework, family or leisure activities) 
I have no problems with performing my usual activities 

I have some problems with performing my usual activities 

I am unable to perform my usual activities 

Pain/Discomfort 
I have no pain or discomfort 

I have moderate pain or discomfort 

I have extreme pain or discomfort 

Anxiety/Depression 
I am not anxious or depressed 

I am moderately anxious or depressed 

I am extremely anxious or depressed 

Compared with my general level of health over the past 12 months, my 
health state today is: 
Better 

Much the same 

Worse 


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To help people say how good or bad a health state is 
we have drawn a scale (rather like a thermometer) on 
which the best state you can imagine is marked by 100        
and the worst state you can imagine is marked by 0. 
 
We would like you to indicate on this scale how good or  
bad is your own health today, in your opinion. 
Please do this by drawing a line from the box below                                       
to whichever point on the scale indicates how good or                                 
bad your current health state is.                                                                   
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
                              
 
 
 
 
 
 
 
 
 
 
Best 
imaginable 
health state 
Your own 
health state 
today 
 
Worst 
imaginable 
health state 

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Appendix III: New York Heart Association (NYHA) Classification 
Class 
Patient Symptoms 
Class I (Asymptomatic) 
No limitation of physical activity. Ordinary physical activity 
does not cause undue fatigue, palpitation, or dyspnea 
(shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or 
dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, 
but less than ordinary activity causes fatigue, palpitation, or 
dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical 
activity is undertaken, discomfort is increased.