Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization.
Phase: NA
Conditions: Chronic Coronary Occlusion, Unprotected Left Main Coronary Artery Disease, Stent Thrombosis, Vascular Disease, Myocardial Ischemia, Coronary Artery Stenosis, Coronary Disease, Coronary Artery Disease, Coronary Restenosis
Sponsor: Abbott Medical Devices

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PROTOCOL 10-389 
 
EXCEL Clinical Trial 
 
Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main 
Revascularization 
 
Principal Investigators 
Gregg W. Stone, MD 
Columbia University Medical Center 
New York, NY, USA 
 
Patrick W. Serruys, MD 
Erasmus Medical Center 
Rotterdam, The Netherlands 
 
Joseph Sabik, MD 
Cleveland Clinic Main Campus 
Cleveland, OH, USA 
 
A. Pieter Kappetein, MD 
Erasmus Medical Center 
Rotterdam, The Netherlands 
 
Planned Number of Sites and 
Region 
 
Approximately 165 sites in USA, Canada, Europe, 
South America, South Korea and Australia 
 
Sponsor 
Abbott Vascular (“Abbott”) 
3200 Lakeside Drive 
Santa Clara, CA 95054, USA 
 
Trial Type 
Randomized Clinical Trial: Prospective, unblinded, 
randomized multicenter trial of approximately 1900 
subjects with unprotected left main coronary artery 
(ULMCA) disease and treatment groups of stenting 
with commercially approved XIENCE Family Stent 
System (inclusive of XIENCE PRIME®, XIENCE 
V®, XIENCE Xpedition™ and XIENCE PRO [for 
use outside the United States only]) versus coronary 
artery bypass grafting. 
 
Universal Registry: Approximately 1000 subjects who 
have angiographically significant left main disease but 
are not eligible for the randomized trial. 
 
Data Monitoring 
Novella Clinical 
Morrisville, NC  27560, USA 
 

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Data Management 
Cardialysis 
3012 KM, Rotterdam, The Netherlands 
 
Data Analysis 
The Cardiovascular Research Foundation 
New York, NY 10022, USA 
 
Angiographic Core Laboratory 
The Cardiovascular Research Foundation 
New York, NY 10022, USA 
 
Electronic Data Capture 
Medidata RAVE 
New York, NY 10003, USA 
 
Quality of Life and U.S. Health 
Economics Analysis 
 
Health Economics and Technology Assessment Group 
Mid America Heart Institute 
Saint Luke’s Health System 
Kansas City, MO64134, USA 
 
Randomization Service 
ICON Clinical Research, L.P. 
North Wales, PA19454, USA 
 
Clinical Events Committee 
The Cardiovascular Research Foundation 
New York, NY 10022, USA 
 
Data Safety Monitoring Board 
Lars Wallentin, MD, Chair 
University Hospital 
Uppsala, Sweden 
 
Protocol Contact 
Jennifer Jones-McMeans, PhD 
Associate Director Clinical Research 
 
 
 
 
Version 10.0 
08 February 2016 

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Table of Contents 
COMPLIANCE STATEMENT ...................................................................................................................... 11 
PROTOCOL SUMMARY .............................................................................................................................. 12 
1.     INTRODUCTION .................................................................................................................................. 21 
2.     BACKGROUND .................................................................................................................................... 21 
2.1. 
Evolution in Surgical Revascularization ......................................................................................... 21 
2.2. 
Percutaneous Coronary Intervention ............................................................................................... 22 
2.3. 
The SYNTAX Trial – Influence of Anatomic Complexity ............................................................. 24 
2.4. 
Other Studies Comparing PCI and CABG for Unprotected Left Main Coronary Artery 
(ULMCA) Disease ...................................................................................................................................... 26 
2.5. 
Quality of Life and U.S. Health Economics Sub-Studies ................................................................ 27 
2.6. 
Justification for a Contemporary Large-Scale Trial Comparing ............................................... 28 
PCI and CABG for LMCA Disease ............................................................................................................. 28 
2.7. 
Device Overview ............................................................................................................................ 31 
2.7.1. 
XIENCE V EECSS Clinical Experience ................................................................................. 31 
2.7.2. 
XIENCE V Stent in Unprotected Left Main Coronary Artery ................................................ 32 
(ULMCA) Disease Background .............................................................................................................. 32 
2.7.3. 
XIENCE V Stenting in Multiple and Complex Lesions.......................................................... 33 
2.7.4. 
XIENCE V Stenting in Medically Treated Diabetics .............................................................. 34 
2.7.5. 
XIENCE V Everolimus Eluting Coronary Stent System (EECSS) ........................................ 34 
2.7.6. 
XIENCE PRIME Everolimus Eluting Coronary Stent System (EECSS) ............................ 35 
2.7.7. 
XIENCE XPEDITION STENT SYSTEM .............................................................................. 36 
2.7.8. 
XIENCE PRO Everolimus Eluting Coronary Stent System (EECSS) ................................... 37 
3.     STUDY OBJECTIVE ............................................................................................................................. 38 
4.     STUDY DESIGN .................................................................................................................................... 38 
4.1. 
Study Design ................................................................................................................................... 38 
4.2. 
Subject Follow-up ........................................................................................................................... 39 
4.3. 
Treatment Strategy .......................................................................................................................... 39 
5.     ENDPOINTS .......................................................................................................................................... 40 
5.1. 
Primary Endpoint and Key Secondary Endpoints ........................................................................... 40 
5.2. 
Other Secondary Endpoints ............................................................................................................. 40 
5.3. 
Pre-Specified Sub-Groups ............................................................................................................... 42 

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6.     SELECTION AND WITHDRAWAL OF SUBJECTS ........................................................................... 42 
6.1. 
Subject Population .......................................................................................................................... 42 
6.2. 
Subject Screening ............................................................................................................................ 42 
6.3. 
Stroke Assessment .......................................................................................................................... 42 
6.4. 
Informed Consent ............................................................................................................................ 43 
6.5. 
Eligibility Criteria ........................................................................................................................... 44 
6.5.1. 
Inclusion Criteria ..................................................................................................................... 44 
6.5.2. 
Clinical Exclusion Criteria ...................................................................................................... 45 
6.5.3. 
Angiographic Exclusion Criteria ............................................................................................. 46 
6.6. 
Subject Flow ................................................................................................................................... 46 
6.7. 
Subject Discontinuation .................................................................................................................. 49 
7.     TREATMENT OF SUBJECTS ............................................................................................................... 50 
7.1. 
Schedule of Events – Randomized Trial ......................................................................................... 50 
7.2. 
Baseline and Pre-Procedure............................................................................................................. 51 
7.2.1. 
Demographics and Medical History ........................................................................................ 51 
7.2.2. 
Pre-PCI Medication ................................................................................................................. 51 
7.2.3. 
Pre-CABG Medication ............................................................................................................ 52 
7.2.4. 
12-Lead ECG .......................................................................................................................... 53 
7.2.5. 
Laboratory Tests ...................................................................................................................... 53 
7.2.6. 
Left Ventricular Ejection Fraction ........................................................................................... 53 
7.2.7. 
Angiography ............................................................................................................................ 53 
7.2.8. 
IVUS / FFR ............................................................................................................................. 53 
7.2.9. 
TIA/Stroke Questionnaire ....................................................................................................... 54 
7.2.10. 
QoL Questionnaire .................................................................................................................. 54 
7.2.11. 
Resource Utilization ................................................................................................................ 55 
7.2.12. 
IVRS Randomization .............................................................................................................. 55 
7.3.         Procedure- PCI ............................................................................................................................. 55 
7.3.1. 
General Considerations ........................................................................................................... 55 
7.3.2. 
Optimal ULMCA PCI – General Considerations .................................................................... 56 
7.3.3. 
Left Main Ostial and Shaft Lesions ......................................................................................... 58 
7.3.4. 
Left Main Distal Bifurcation Lesions ...................................................................................... 58 
7.3.5. 
Optimal PCI of Other Coronary Lesions ................................................................................. 59 
7.3.6. 
Intra-procedure Adjunctive Pharmacology ............................................................................. 60 

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7.3.7. 
GP IIb/IIIa inhibitors ............................................................................................................... 61 
7.4.  
Procedure – CABG ......................................................................................................................... 61 
7.4.1 
Optimal CABG Requirements ................................................................................................. 61 
7.5. 
Completeness of Revascularization ................................................................................................ 64 
7.6. 
Post-Procedure Assessments and Medications ................................................................................ 64 
7.6.1. 
Laboratory Assessments .......................................................................................................... 64 
7.6.2. 
Post-PCI Medications .............................................................................................................. 64 
7.6.3. 
Post-CABG Medications ......................................................................................................... 65 
7.6.4. 
Post-Operative Atrial Fibrillation – CABG ............................................................................. 65 
8.     EVALUATION OF SAFETY AND EFFECTIVENESS ........................................................................ 66 
8.1. 
Laboratory Tests, ECGs, and Other Measures ................................................................................ 66 
8.2. 
Clinical Follow-up .......................................................................................................................... 66 
8.3. 
Guidelines for Follow-up Non-Invasive Testing, Angiography and .............................................. 67 
Reintervention ............................................................................................................................................. 67 
8.3.1. 
Follow-up Non-Invasive Testing ............................................................................................. 67 
8.3.2. 
Follow-up Angiography .......................................................................................................... 68 
8.3.3. 
Repeat Intervention (PCI or CABG) ....................................................................................... 68 
8.4. 
Adverse Events ............................................................................................................................... 69 
8.4.1. 
Serious Adverse Event Reporting ........................................................................................... 70 
8.4.2. 
Unanticipated Serious Adverse Device Effects (USADE) ...................................................... 71 
8.4.3. 
Device Relationship ................................................................................................................ 71 
8.5. 
Safety Monitoring – Data Safety Monitoring Board (DSMB) ........................................................ 71 
8.6. 
Event Adjudication – Clinical Events Committee (CEC) ................................................................ 72 
9.     STATISTICAL DESIGN AND ANALYSIS .......................................................................................... 72 
9.1. 
Randomized Cohort ........................................................................................................................ 72 
9.1.1. 
Primary Endpoint .................................................................................................................... 72 
9.1.2. 
Major Powered Secondary Endpoints ..................................................................................... 73 
9.1.3. 
Other Secondary Endpoints ..................................................................................................... 73 
9.1.4. 
Subgroup Analyses .................................................................................................................. 75 
9.1.5. 
Analysis Populations ............................................................................................................... 75 
9.1.6. 
Sample Size Calculations and Assumptions ............................................................................ 75 
9.1.7. 
Statistical Analysis .................................................................................................................. 78 
9.1.8. 
Procedures for Accounting for Missing Data .......................................................................... 79 

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9.1.9. 
Measures Taken to Minimize Bias .......................................................................................... 79 
9.1.10. 
 Pooling Strategy ..................................................................................................................... 79 
9.1.11. 
Interim Analysis ...................................................................................................................... 80 
9.2. 
Universal Registry........................................................................................................................... 80 
9.3. 
Health-Related Quality of Life (HRQoL) and Treatment Costs ...................................................... 80 
9.3.1. 
Endpoints................................................................................................................................. 80 
9.3.2. 
Quality of Life ......................................................................................................................... 80 
9.3.3. 
Economic Outcomes/Cost-Effectiveness ................................................................................ 81 
9.4. 
Other Analysis ................................................................................................................................ 81 
10.   DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................................................................... 82 
11.   QUALITY CONTROL AND QUALITY ASSURANCE ....................................................................... 82 
11.1. 
Selection of Clinical Sites and Investigators ................................................................................... 82 
11.2. 
Protocol and Informed Consent Approval ....................................................................................... 82 
11.2.1. 
Protocol Amendments ............................................................................................................. 83 
11.3. 
Protocol Deviations......................................................................................................................... 83 
11.4. 
Training ........................................................................................................................................... 83 
11.4.1. 
Site Training ............................................................................................................................ 83 
11.4.2. 
Training of Sponsor’s Monitors .............................................................................................. 83 
11.5. 
Monitoring ...................................................................................................................................... 84 
11.6. 
Quality Assurance Assessments ...................................................................................................... 84 
11.7. 
Regulatory Agency Inspection ........................................................................................................ 84 
11.8. 
Executive Operations Committee .................................................................................................... 84 
12.   DATA HANDLING AND RECORD KEEPING ................................................................................... 85 
12.1. 
Source Documentation .................................................................................................................... 85 
12.2. 
Electronic Case Report Form (eCRF) Completion .......................................................................... 85 
12.3. 
Record Retention ............................................................................................................................ 86 
12.4. 
Investigational Device Management ............................................................................................... 86 
12.5. 
Maintenance of Randomization Codes ............................................................................................ 86 
13.   ETHICAL CONSIDERATIONS ............................................................................................................ 86 
14.    PUBLICATION POLICY ................................................................................................................... 87 
14.1. 
Publication Policy ........................................................................................................................... 87 
14.2. 
Publication Committee .................................................................................................................... 87 
15.   RISK ANALYSIS ................................................................................................................................... 88 

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15.1. 
Potential Risks - PCI ....................................................................................................................... 88 
15.1.1. 
Risks from Cardiac Catheterization, Stenting, and PTCA ....................................................... 88 
15.1.2. 
 Associated Risks of Everolimus ............................................................................................. 89 
15.1.3. 
Drug Interactions with Everolimus ......................................................................................... 91 
15.1.4. 
Associated Risks of XIENCE Polymer ................................................................................... 91 
15.1.5. 
Genotoxicity, Carcinogenicity and Reproductive Toxicity of XIENCE .................................. 92 
15.1.5.1. 
Pregnancy/Fertility .............................................................................................................. 92 
15.2. 
Potential Risks – CABG .................................................................................................................. 92 
15.3. 
Major Adverse Event Rates in Left Main Studies ........................................................................... 93 
15.4. 
Gender/ Race Specific Prevalence .................................................................................................. 93 
15.4.1. 
Gender-specific and Race-specific Diagnosis and Treatment Patterns .................................... 95 
15.4.2. 
Proportions of Women Included in Past Trials........................................................................ 95 
15.4.3. 
Clinically Significant Gender Differences in Outcomes Related to ....................................... 96 
Safety or Effectiveness ............................................................................................................................ 96 
15.5. 
Risk Management Procedures ......................................................................................................... 97 
15.5.1. 
Post PCI ................................................................................................................................... 97 
15.5.2. 
Post CABG .............................................................................................................................. 97 
15.5.3. 
Gender-specific ....................................................................................................................... 97 
15.6. 
Potential Benefits ............................................................................................................................ 98 
15.6.1. 
Potential benefits of stenting. .................................................................................................. 98 
15.6.2. 
Potential benefits of CABG. .................................................................................................... 99 
16. 
APPENDIX A: DEFINITIONS, ABBREVIATIONS, AND ACRONYMS ..................................... 100 
16.1. 
Primary and Major Secondary Endpoint Definitions ..................................................................... 100 
16.1.1. 
Definition of Death ................................................................................................................ 100 
16.1.2.        Definition of Myocardial Infarction ................................................................................... 102 
16.1.3. 
Definition of Stroke ............................................................................................................... 105 
16.1.4. 
Definition of Coronary Revascularization Procedures .......................................................... 107 
16.2.       Other Definitions ........................................................................................................................ 109 
16.3 
 Abbreviations and Acronyms ....................................................................................................... 116 
17. 
APPENDIX B: QUALITY OF LIFE AND U.S. HEALTH ECONOMICS SUB-STUDIES .......... 118 
17.1. 
Study Objectives ........................................................................................................................... 118 
17.1.1. 
Cost Studies ........................................................................................................................... 118 
17.1.2. 
Quality of Life Studies .......................................................................................................... 118 

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17.1.3. 
Cost-effectiveness Studies ..................................................................................................... 118 
17.2. 
Subject Population ........................................................................................................................ 119 
17.3. 
Quality of Life Assessment ........................................................................................................... 119 
17.3.1. 
Disease-specific measures ..................................................................................................... 119 
17.3.2. 
Generic quality of life measures ............................................................................................ 120 
17.3.3. 
Mental Health/Depression ..................................................................................................... 120 
17.3.4. 
Utility measurement .............................................................................................................. 120 
17.3.5. 
Economic Data Collection ..................................................................................................... 121 
17.4. 
Cost Measurement ........................................................................................................................ 122 
17.4.1. 
Procedural Costs .................................................................................................................... 122 
17.4.2. 
Non-procedural Hospitalization Costs ................................................................................... 122 
17.4.3. 
Other costs ............................................................................................................................. 124 
17.5. 
Analytic Plan ................................................................................................................................. 125 
17.5.1. 
Quality of Life Endpoints ...................................................................................................... 125 
17.5.2. 
Exploratory Analyses:  Impact of Events on Quality-Adjusted Life ................................... 126 
Expectancy ............................................................................................................................................ 126 
17.5.3. 
Cost and Resource Use Comparisons .................................................................................... 126 
17.5.4. 
Cost-Effectiveness Analyses ................................................................................................. 127 
17.5.5. 
Lifetime Cost-Effectiveness .................................................................................................. 127 
17.5.6. 
Evaluation of Heterogeneity by Country ............................................................................... 127 
17.5.7. 
Subgroup Analyses ................................................................................................................ 128 
17.6. 
Approach to Unanticipated Protocol Modifications ...................................................................... 128 
17.7. 
Independence of Research ............................................................................................................. 128 
18.    APPENDIX C: IVUS SUBSTUDY ..................................................................................................... 129 
19.   APPENDIX D: OPTIMAL REVASCULARIZATION DEFINITIONS ............................................... 130 
19.1. 
Principles: ..................................................................................................................................... 130 
19.2. 
Anatomic revascularization: ......................................................................................................... 131 
19.3. 
Ischemic revascularization: ........................................................................................................... 131 
20.   APPENDIX E: IVUS AND FFR RECOMMENDATIONS ................................................................. 133 
20.1. 
Pre-Revascularization Assessment of Intermediate ULMCA Lesions ......................................... 133 
20.1.1. 
Prior to Randomization ......................................................................................................... 133 
20.1.2. 
IVUS Criteria ........................................................................................................................ 133 
20.1.3. 
FFR Criteria........................................................................................................................... 134 

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20.2. 
IVUS for PCI Guidance of ULMCA PCI ...................................................................................... 137 
20.3. 
IVUS and FFR for Guidance of Non-ULMCA Lesion PCI .......................................................... 138 
20.3.1. 
Pre-intervention non-ULMCA lesion assessment ................................................................. 138 
20.3.2. 
IVUS guidance of non-ULMCA stenting ............................................................................. 138 
20.4. 
Follow-up ...................................................................................................................................... 139 
20.5. 
Technical Considerations .............................................................................................................. 139 
21. 
APPENDIX F:  PROPOSED ANALYSES FOR SECONDARY PUBLICATIONS....................... 140 
21.1. 
Other Endpoints ............................................................................................................................ 140 
21.2. 
Pre-specified subgroups ................................................................................................................ 140 
22.   APPENDIX G: OPTIMAL MEDICAL THERAPIES .......................................................................... 142 
22.1. 
General Recommendations and Goals ........................................................................................... 143 
22.1.1. 
Smoking ................................................................................................................................ 143 
22.1.2. 
Dietary and Weight Goals ..................................................................................................... 143 
22.1.3. 
Physical Activity ................................................................................................................... 143 
22.1.4. 
Influenza Vaccination ........................................................................................................... 143 
22.1.5. 
Diabetes ................................................................................................................................. 143 
22.1.6. 
Lipid Goals ............................................................................................................................ 144 
22.1.7. 
Hypertension ......................................................................................................................... 144 
22.2. 
Pharmacologic Therapy ................................................................................................................. 144 
22.2.1. 
Antiplatelet Therapy .............................................................................................................. 145 
22.2.2. 
Treatment of Hypertension .................................................................................................... 145 
22.2.3. 
Lipid Lowering Therapy ........................................................................................................ 145 
22.2.4. 
Anti-anginal Therapy ............................................................................................................ 146 
22.2.5. 
Vitamin Supplementation ...................................................................................................... 146 
23. 
APPENDIX H: ANGIOGRAPHIC CORE LABORATORY ........................................................ 147 
INSTRUCTIONS .......................................................................................................................................... 147 
24.  
APPENDIX I: EXCEL Insulin Protocol for Glycemic Control ..................................................... 149 
25.  
APPENDIX J:  Transient Ischemic Attack (TIA)/Stroke Questionnaire ........................................... 153 
26. 
APPENDIX K: REFERENCES ........................................................................................................ 156 

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LIST OF TABLES 
 
Table 2-1    SYNTAX  Trial:    Components of  Major  Adverse  Cardiac  and  Cerebrovascular 
 
Events at 3 Years in the Left Main Subgroup with the Highest SYNTAX Score  
 
Tertile (SYNTAX Scores ≥ 33) ................................................................................25 
 
Table 2-2    SYNTAX  Trial:    Components of  Major  Adverse  Cardiac  and  Cerebrovascular 
 
Events at 3 Years for the Left Main Subgroup in Subjects with the Lowest and 
 
Intermediate SYNTAX Score Tertiles (SYNTAX Scores 0-32) ..............................26 
 
Table 2-3 
XIENCE V EECS Product Sizes .............................................................................. 35 
 
Table 2-4 
XIENCE PRIME EECS Product Sizes ..................................................................... 36 
 
Table 2-5 
XIENCE Xpedition Product Sizes ............................................................................ 37 
 
Table 2-6 
XIENCE PRO EECS Product Sizes ......................................................................... 38 
 
Table 15-1 Proportions of Women Included in Past Trials...........................................................97 
 
Table 22-1 Risk Factor Modification Goals............................................................................. 142 
 
Table 22-2 Waist Circumference Thresholds for Abdominal Obesity..................................... 142 
 
Table 22-3 Pharmacologic Therapy Indications ...................................................................... 144 
 
Table 22-4 Lipid Lowering Recommendations........................................................................ 145 
 
 
 
LIST OF FIGURES 
 
Figure 2.1 
SPIRIT III Trial: Major Adverse Cardiac Events at 3 Years (n=1,002) ............... .23 
 
Figure 2.2 
SPIRIT IV Trial: Target Lesion Failure at 1 Year (n=3,690) ................................ 23 
 
Figure 2.3       SYNTAX Trial:  Major Adverse Cardiac and Cerebrovascular Events at 3 Years 
 
in the Left Main Subgroup with the Highest SYNTAX Score Tertile 
 
(SYNTAX Scores≥ 33) 
................................................................................. 24 
 
Figure 2.4       SYNTAX Trial:  Major Adverse Cardiac and Cerebrovascular Events at 3 Years  
  
 for the Left Main Subgroup in Subjects with the Lowest and Intermediate  
  
 SYNTAX Score Tertiles (SYNTAX Scores 0-32) .................................................25 
 
Figure 2.5 
SYNTAX Trial: Quality of Life Measures Comparing PCI and CABG .............. 30 
 
Figure 6.1 
Subject Flow ......................................................................................................... 49

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COMPLIANCE STATEMENT 
 
This trial will be conducted in accordance with this Protocol/Clinical Investigational Plan, the 
Declaration of Helsinki, applicable good clinical practices and regulations (e.g., US 21 CFR Part 
50, 21 CFR Part 56, and 21 CFR Part 812, OUS ISO14155) and the appropriate local 
legislation(s). The most stringent requirements, guidelines or regulations must always be 
followed.   The conduct of the trial will be approved by the appropriate Institutional Review 
Board (IRB)/ Medical Ethics Committee (MEC) of the respective investigational site and by the  
applicable regulatory authorities (e.g., FDA, PMDA, MHRA, etc.

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PROTOCOL SUMMARY 
Trial Name 
and 
Number 
EXCEL Clinical Trial: 10-389 
Evaluation of XIENCE versus Coronary Artery Bypass Surgery for 
Effectiveness of Left Main Revascularization 
Objectives 
To establish the safety and efficacy of the commercially approved XIENCE 
Family Stent System (inclusive of XIENCE PRIME, XIENCE V, XIENCE 
Xpedition and XIENCE PRO [for use outside the United States [OUS] only]) in 
subjects with unprotected left main coronary artery disease (either isolated to 
the left main trunk or associated with disease in other coronary arteries) by 
demonstrating that compared to coronary artery bypass graft surgery, treatment 
of the left main stenosis ± other significant coronary lesions with the XIENCE 
stent will result in non-inferior or superior rates of the composite measure of 
all-cause mortality, myocardial infarction or stroke at an anticipated median 
follow-up duration of three years. 
Study 
Device 
Commercial XIENCE Family Stent Systems, including: 
• Commercial XIENCE PRIME EECSS: 
Stent diameter: 2.25*, 2.5, 2.75, 3.0, 3.5 and 4.0 mm 
Stent lengths: 8, 12, 15, 18, 23, 28, 33 and 38 mm 
• Commercial XIENCE V EECSS : 
Stent diameter: 2.25, 2.5, 2.75, 3.0, 3.5, 4.0 mm 
Stent lengths: 8, 12, 15, 18, 23, and 28 mm 
• Commercial XIENCE Xpedition Stent System: 
Stent diameter: 2.25*, 2.5, 2.75, 3.0, 3.25, 3.5, 4.0 mm 
Stent lengths: 8, 12, 15, 18, 23, 28, 33 and 38 mm 
• Commercial XIENCE PRO EECSS (for OUS use only): 
Stent diameter: 2.25*, 2.5, 2.75, 3.0, 3.5, 4.0 mm 
Stent lengths: 8, 12, 15, 18, 23, 28, 33 and 38 mm 
* 2.25 mm diameter stents do not include stent lengths of 33 and 38 mm 

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Study 
Design 
Randomized Clinical Trial (RCT) 
Prospective, unblinded, randomized multicenter trial of about 1900 subjects at 
approximately 165 U.S. and international centers. 
Following diagnostic angiography demonstrating significant left main disease 
and consensus of the local Heart Team that the subject meets the study entry 
criteria, subjects will be consented and randomized 1:1 to: 
a) PCI using XIENCE (N~950),or  
b) CABG (N~950) 
Follow-up for all randomized subjects will continue for five years with an 
option for additional follow-up to 10 years  
Universal Registry 
An additional group of approximately 1000 subjects who are not eligible 
for randomization or for other reasons are not randomized will be consented 
for the Universal Registry.  All patients with left main disease without prior 
CABG in whom the visual estimated diameter stenosis is greater than or 
equal to 50% will be eligible for entry into EXCEL registry. These subjects 
will be consented for the Universal Registry, and followed through the time 
of initial treatment per standard of care with either PCI, CABG or medical 
therapy. Approximately 100 consecutive subjects from the Universal Registry 
with a ≥50% and <70% visually estimated angiographic diameter stenosis 
who otherwise meet all eligibility criteria, but without significant ischemia by 
noninvasive testing consistent with significant left main disease, and in whom 
IVUS shows a MLA >6.0 mm2  and/or a FFR >0.80, will be analyzed 
separately as intermediate lesion subjects, and followed through the time of 
initial treatment per standard of care with either PCI, CABG or medical 
therapy.  

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Primary 
and Key 
Secondary 
Endpoints 
RCT 
• Primary Endpoint: 
Composite measure of all-cause death, myocardial infarction (MI) or stroke 
(modified Rankin Scale (mRS) ≥1 and increase by ≥1 from baseline) at 3 
years post randomization.  The primary endpoint will be estimated via 
Kaplan-Meier failure rate. The primary endpoint analysis will be conducted 
at the time when approximately 50% of the patients have reached the 3-year 
follow-up AND all patients have reached the 2-year follow-up, whichever 
time point is latest. All available data through 3-year follow-up will be used. 
• Major Powered Secondary Endpoints: 
• Composite measure of all-cause mortality, MI or stroke (mRS≥1 and 
increase by ≥1 from baseline) at 30 days 
• Composite measure of all-cause mortality, myocardial infarction, stroke 
(mRS≥1 and increase by ≥1 from baseline) or unplanned revascularization 
for ischemia at 3 years post randomization. This powered endpoint will be 
estimated via Kaplan-Meier failure rate. The analysis will be conducted at 
the time when approximately 50% of the patients have reached the 3-year 
follow-up AND all patients have reached the 2-year follow-up, whichever 
time point is latest. All available data through 3-year follow-up will be used. 
Quality of 
Life (QoL) 
and Health 
Economics 
Health-related quality of life (HRQoL) and treatment costs will be assessed in 
1800 randomized patients alongside the core clinical trial to evaluate the impact 
of the PCI and CABG strategies on a range of relevant quality of life (QoL) 
domains and also to evaluate the cost-effectiveness of the two treatment 
strategies. 
HRQoL and functional status will be assessed using a combination of generic 
and disease-specific measures selected to cover a broad range of health domains 
that may be affected by coronary artery disease, its treatment, and its 
complications.  Disease-specific QoL will be assessed using the Seattle Angina 
Questionnaire (SAQ) and the London School of Hygiene Dyspnea 
Questionnaire.  Mental health and depression will be assessed using the Patient 
Health Questionnaire-9 (PHQ-9).  Generic health status will be assessed using 
the Medical Outcomes Study 12-item Short Form (SF-12), and health utilities 
will be assessed using the EuroQoL (EQ-5D) with U.S.-specific weights. These 
measures will be assessed using standardized, written questionnaires at baseline 
(prior to randomization), 1 month, 12 months, 3 years, and 5 years. 
 
Data on cardiovascular-specific resource utilization will be collected 
prospectively for the index hospitalization and the full follow-up period for all 
subjects using standardized case report forms.  Procedural costs will be assessed 

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using a resource-based approach to convert standard measures such as 
procedural duration and utilization of items into costs.  Other hospital costs will 
be assessed using an “event-driven” approach in which specific complications 
and outcomes are assigned standard costs based on external data.  The cost and 
quality of life data will be integrated in order to perform a formal cost- 
effectiveness analysis.  The primary analysis will be performed from the 
perspective of the U.S. healthcare system using a lifetime time horizon. 
Secondary analyses will be performed from the perspective of other health care 
systems with the collaboration of a local health economist. 
Targeted 
Number of 
Subjects to 
Receive 
Study 
Device 
A total of about 2900 subjects, as outlined below, will be targeted at up to 
approximately 165 U.S. and international sites. 
RCT: Approximately 1900 subjects will be randomized. 
Universal Registry: Approximately 1000 consecutive subjects will be 
registered, which includes approximately 100 consecutive subjects with 
intermediate lesions. 
Subject 
Follow-Up 
RCT: 
Clinical follow-up at in-hospital, 30 days, 6 months, 1 year, 2 years, 3 years, 4 
years, and 5 years, with an option for additional follow-up to 10 years. 
Universal Registry: 
Follow up through the time of initial treatment as per standard of care with PCI, 
CABG or medical therapy. 
Treatment 
Strategy 
• All subjects participating in this clinical trial will have informed consent 
obtained after diagnostic angiography and prior to randomization. “Ad hoc” 
unprotected left main PCI is not permitted. 
• It is strongly recommended that the timing from randomization to treatment 
(PCI or CABG) be ≤1 week. It is mandatory that revascularization be 
performed ≤2 weeks after randomization in all cases in both treatment arms. 
Reasons for delay beyond 2 weeks will be tracked. 
• Target lesion(s) will be treated in accordance with the randomization 
schedule after satisfying the general and angiographic inclusion and 
exclusion criteria as defined in the protocol.  If more than one target lesion 
will be treated, all lesions must receive the treatment that has been assigned 
as per the randomization. 

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Inclusion 
Criteria for 
RCT 
 
Inclusion criteria (following criteria must be present): 
• Unprotected left main coronary artery (ULMCA) disease with angiographic 
diameter 
stenosis 
(DS) 
≥70% 
(visually 
estimated) 
requiring 
revascularization as assessed by both a participating interventional 
cardiologist and cardiac surgeon (local Heart Team), 
OR 
• ULMCA disease with angiographic DS ≥50% but <70% (visually estimated) 
requiring revascularization as assessed by both a participating interventional 
cardiologist and cardiac surgeon (local Heart Team), with one or more of the 
following present: 
◦ 
Non-invasive evidence of ischemia referable to a hemodynamically 
significant left main lesion (large area of ischemia in both the LAD and 
LCX territories, or in either the LAD or LCX territory in the absence of 
other obstructive coronary artery disease to explain the LAD or LCX 
defect), or stress-induced hypotension, or stress-induced fall in LVEF, or 
stress-induced transient ischemic dilatation of the left ventricle, or stress-
induced thallium/technetium lung uptake, and/or 
◦ 
IVUS MLA ≤6.0 mm2, and/or 
◦ 
FFR ≤0.80 
OR 
• Left Main Equivalent Disease: Left main Medina classification 0,1,1 
bifurcation disease (diameter stenosis of both the true ostial LAD and LCX 
[within 5 mm of the left main distal bifurcation]) ≥50%, in the absence of 
significant angiographic stenosis in the left main coronary artery, may also 
be randomized if one of the two following conditions are present: 
◦ 
Both the ostial LAD and ostial LCX stenoses are ≥70% stenotic 
by visual estimation, or 
◦ 
If one or both of the ostial LAD and ostial LCX stenoses are ≥50% and 
 
<70% stenotic by visual estimation, then this lesion(s) is demonstrated 
 
to be significant either by 
    a) non-invasive evidence of ischemia in its myocardial distribution; 
 
and/or 
    b) FFR ≤0.80; and/or 
    c) IVUS MLA ≤4.0 mm2 (FFR is preferred). 
Note: if both the ostial LAD and ostial LCX stenoses are ≥50% and 
<70% stenotic by visual estimation, then both lesions must be significant 
by these criteria for the patient to be eligible for randomization. 
 
 

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Inclusion 
Criteria for 
RCT 
(continued) 
• Clinical and anatomic eligibility for both PCI and CABG as agreed to by the 
local Heart Team 
◦ 
Interventionalist determines PCI appropriateness and eligibility 
◦ 
Surgeon determines surgical appropriateness and eligibility 
• Silent ischemia, stable angina, unstable angina or recent MI 
◦ 
If recent MI, CK-MB must have returned to normal prior to 
randomization 
• Ability to sign informed consent and comply with all study procedures 
including follow-up for at least three years 
• The subject must be ≥18 years of age 
Exclusion 
Criteria for 
RCT 
Clinical exclusion criteria (the subject is not eligible for randomization if any 
of the following are present): 
• Prior PCI of the left main trunk at any time prior to randomization 
• Prior PCI of any other (non-left main) coronary artery lesions within one 
year prior to randomization 
• Prior CABG at any time prior to randomization 
• Need for any concomitant cardiac surgery other than CABG (e.g. valve 
surgery, aortic repair, etc.), or intent that if the subject randomizes to 
surgery, any cardiac surgical procedure other than isolated CABG will be 
performed 
• CK-MB greater than the local laboratory upper limit of normal, or recent MI 
with CK-MB levels still elevated 
Note: A subject with a recent MI in whom the troponin levels are 
still elevated but falling and in whom the CK-MB has returned to 
within normal range may be randomized, with the CK-MB levels 
used to assess peri-procedural MI. 
• Subjects unable to tolerate, obtain or comply with dual antiplatelet therapy 
for at least one year 
• Subjects requiring or who may require additional surgery (cardiac or non- 
cardiac) within one year 
• The presence of any clinical condition(s) which leads the participating 
interventional cardiologist to believe that clinical equipoise is not present 
(i.e. the subject should not be treated by PCI, but rather should be managed 
with CABG or medical therapy [reasons will be documented in the Heart 
Team worksheet] 
• The presence of any clinical condition(s), which leads the participating 
cardiac surgeon to believe that clinical equipoise is not present (i.e. the 
subject should not be treated by CABG, but rather should be managed with 
PCI or medical therapy (reasons will be documented in the Heart Team 
worksheet) 

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Exclusion 
Criteria for 
RCT 
Clinical exclusion criteria (the subject is not eligible for randomization if any 
of the following are present): 
• Prior PCI of the left main trunk at any time prior to randomization 
• Prior PCI of any other (non-left main) coronary artery lesions within one 
year prior to randomization 
• Prior CABG at any time prior to randomization 
• Need for any concomitant cardiac surgery other than CABG (e.g. valve 
surgery, aortic repair, etc.), or intent that if the subject randomizes to 
surgery, any cardiac surgical procedure other than isolated CABG will be 
performed 
• CK-MB greater than the local laboratory upper limit of normal, or recent MI 
with CK-MB levels still elevated 
Note: A subject with a recent MI in whom the troponin levels are 
still elevated but falling and in whom the CK-MB has returned to 
within normal range may be randomized, with the CK-MB levels 
used to assess peri-procedural MI. 
• Subjects unable to tolerate, obtain or comply with dual antiplatelet therapy 
for at least one year 
• Subjects requiring or who may require additional surgery (cardiac or non- 
cardiac) within one year 
• The presence of any clinical condition(s) which leads the participating 
interventional cardiologist to believe that clinical equipoise is not present 
(i.e. the subject should not be treated by PCI, but rather should be managed 
with CABG or medical therapy [reasons will be documented in the Heart 
Team worksheet]) 
• The presence of any clinical condition(s) which leads the participating 
cardiac surgeon to believe that clinical equipoise is not present (i.e. the 
subject should not be treated by CABG, but rather should be managed with 
PCI or medical therapy (reasons will be documented in the Heart Team 
worksheet) 
 

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Exclusion 
Criteria for 
RCT 
(continued) 
• Pregnancy or intention to become pregnant (female subjects of child bearing 
potential must have a negative pregnancy test within 7 days of the index 
procedure) 
• Non cardiac co-morbidities with life expectancy less than 3 years 
• Other investigational drug or device studies that have not reached their 
primary endpoint 
Angiographic exclusion criteria (the subject is not eligible for randomization 
if any of the following are present): 
• Left main diameter stenosis <50% (visually assessed by the consensus of 
the local Heart Team), unless left main equivalent disease is present 
• SYNTAX score ≥33, as determined by the consensus of the local Heart 
Team 
• Visually estimated left main reference vessel diameter <2.25 mm or >4.25 
mm (post dilatation up to 4.5 mm is allowed) 
• The presence of specific coronary lesion characteristics or other cardiac 
condition(s) which leads the participating interventional cardiologist to 
believe that clinical equipoise is not present (i.e. the subject should not be 
treated by PCI, but rather should be managed with CABG or medical 
therapy reasons will be documented) 
• The presence of specific coronary lesion characteristics or other cardiac 
condition(s) which leads the participating cardiac surgeon to believe that 
clinical equipoise is not present (i.e. the subject should not be treated by 
CABG, but rather should be managed with PCI or medical therapy - reasons 
will be documented) 
Primary 
Analytical 
Population 
For the RCT, the primary analysis of the composite endpoint of all-cause 
mortality, MI and stroke will be performed on the intent-to-treat (ITT) 
population. 

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Statistical 
Method 
For the RCT, the primary endpoint is a composite of all-cause mortality, MI 
or stroke (mRS≥1 and increase by ≥1 from baseline) at 3 years post 
randomization. The primary endpoint will be estimated via Kaplan-Meier 
failure rate and Greenwood’s formula for estimating the standard error. The 
primary endpoint analysis will be conducted at the time when approximately 
50% of the patients have reached the 3-year follow-up AND all patients 
have reached the 2-year follow-up, whichever time point is latest. All 
available data through 3-year follow-up will be used. 
 
The study is powered for sequential non-inferiority and superiority testing. If 
the non-inferiority of PCI to CABG test is met for the primary endpoint, then 
superiority testing will be performed. 
 
The primary endpoint will be evaluated using the difference in Kaplan-
Meier failure rates in the intent-to-treat population using all available data.   
The hypothesis test is designed to show non-inferiority of PCI to CABG for 
the primary endpoint with a one-sided alpha of 0.025. 
 
Assuming the following: 
•   
primary endpoint event rate is 11% in each treatment arm at 3 years 
 
(using 3-year event rates from the SYNTAX trial, the most 
 
contemporary reference dataset) 
•   
minimum time to follow-up is years 
•    
median time to follow-up is approximately 3 years 
•    
8% lost to follow-up at 3 years 
•    non-inferiority margin ∆ = 4.2% 
•    one-sided alpha = 0.025 
•    accrual time of 29 months 
 
then a sample size population of 1900 subjects (~950 per arm) will provide 
80% power to demonstrate non-inferiority. 
 
If non-inferiority is met, superiority testing will be performed with a one-
sided alpha of 0.025. The trial will have 80% power to demonstrate 
superiority with a difference of 3.84% of PCI arm to CABG arm (e.g. 7.16% 
in PCI arm vs. 11% in CABG arm). 
 
 
 
 
 
 
 
 
 
 

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1.     INTRODUCTION 
 
The primary objective of this study is to evaluate the safety and efficacy of the commercially 
approved XIENCE Family Stent System (inclusive of XIENCE PRIME, XIENCE V, XIENCE 
Xpedition and XIENCE PRO [for OUS use only]) in selected subjects with unprotected left main 
coronary artery disease (either isolated to the left main trunk or associated with disease in the 
other coronary arteries) by testing the principal hypothesis that compared to coronary artery 
bypass graft surgery, treatment of the left main stenosis and other significant coronary lesions 
with the XIENCE stent will result in non-inferior or superior rates of the composite measure of 
all-cause mortality, myocardial infarction or stroke at an anticipated median follow-up duration 
of three years. 
 
All subjects will be screened per the protocol inclusion and exclusion criteria and randomized 
subjects will have clinical follow-up at 30 and 180 days, and 1, 2, 3, 4, and 5 years with potential 
follow-up continuing annually to 10 years. 
2.     BACKGROUND 
 
2.1. 
Evolution in Surgical Revascularization 
 
Coronary artery bypass grafting (CABG) was introduced in 1967 and rapidly became the 
accepted standard treatment for subjects with obstructive coronary artery disease who were 
deemed necessary for coronary revascularization.1 
The Coronary Artery Surgery Study (CASS) trial in the 1970’s2 showed that obstructive left 
main disease was best treated with CABG compared to medical treatment.   Mortality was 
reduced by CABG in these subjects and thus has been the standard of care for over 30 years. 
 
Recent advances in coronary surgery include improvements in pre-operative risk assessment and 
management, anesthesia, the use of arterial grafts, and improvement in post-operative care.3, 4, 5,6 
 
These have resulted in further improvements with reduced hospital morbidity and mortality. 
Furthermore, with the use of arterial grafts the occlusion rate of bypass graft has been reduced 
and improved quality of life. 
 
With the introduction of drug-eluting stents (DES), long-term outcomes after percutaneous 
coronary  intervention  (PCI)  have  markedly  improved  in  patients  with  complex  coronary 
anatomy, justifying randomized trials of PCI vs. CABG. This resulted in the recent 1800 
randomized patient Synergy between PCI with TAXUS and Cardiac Surgery (SYNTAX) trial, 
which showed that PCI with paclitaxel-eluting stents (PES) in a cohort of subjects with three 
vessel disease and left main disease with few other exclusion criteria was inferior to CABG for the 
composite primary endpoint of death, MI, stroke or unplanned revascularization at 1 year. 
However, post-hoc and subgroup analysis from the 705 left main stem subjects according to the 
anatomic SYNTAX score demonstrated that those subjects with low and intermediate SYNTAX 
scores had comparable or improved results with PCI compared to CABG. 7 However, as an 
underpowered subgroup analysis, this observation is considered hypothesis generating. 
 
 

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Most large-scale comparative trials of surgery vs. PCI have found higher rates of stroke in those 
undergoing CABG. 8 , 9 , 10 In  the  SYNTAX  trial,  the  incidence  of  stroke  at  one  year  was 
significantly higher in the CABG cohort than with PCI (2.2% vs. 0.6%, respectively, 
P=0.003).11This has been perceived by many surgeons as possibly not representative of current 
surgical results. The surgical community believes that the stroke incidence may be further 
reduced by selective screening of the cerebral circulation, a shorter waiting time from 
randomization to CABG, more careful management of the ascending aorta, and improved 
adjunctive pharmacotherapy. 
 
 
2.2. 
Percutaneous Coronary Intervention 
 
PCI was introduced into clinical practice in 1977, almost 10 years later than CABG, and was 
initially considered appropriate only for subjects with single-vessel disease. 12  However, as 
experience and technology have advanced, the indication has been expanded to treat subjects 
with multivessel and more complex disease. 
 
In the last decade, several randomized controlled trials (ARTS I, MASS II, ERACI-II) examined 
the relative benefits of PCI and CABG in subjects with single or multivessel coronary artery 
disease.13, 14  The validity of these conclusions has been questioned because of (1) subsequent 
improvements in both percutaneous and surgical techniques as well as (2) strict inclusion criteria 
limiting relevance to subjects treated in the ‘real world’. 
 
Re-evaluation  may  be  especially  important  in  the  case  of  PCI  as  stenting  is  applied  to 
increasingly complex subjects. Moreover, the durability of the benefit of stenting to 5 years has 
been challenged. 15 The most appropriate treatment for left main disease subjects remains a 
matter of considerable debate, especially since the introduction of drug-eluting stents (with 
sirolimus or paclitaxel).16, 17, 18, 19, 20  More recently, the second generation everolimus-eluting 
stent,  XIENCE V,  has  shown  superiority  in  angiographic  outcomes  compared  to  the  first 
generation PES in the SPIRIT III trial. The clinical outcomes for the XIENCE V stent compared 
to the first generation PES were superior at both three years in the SPIRIT III trial and at one 
year in the SPIRIT IV trial as shown in Figure 2.1 and Figure 2.2, respectively. The COMPARE 
randomized trial also showed marked improvements in both safety and efficacy with the 
everolimus-eluting stent compared to the paclitaxel DES in an 1800 patient randomized trial 
which randomized patients with unprotected left main stem disease.21 Thus, clinical outcomes 
may be further improved with left main and multivessel stenting with the XIENCE V stent 
compared to drug-eluting stents used in earlier randomized trials. 

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Figure 2.1 
SPIRIT III Trial: Major Adverse Cardiac Events at 3 Years (n=1,002) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* MACE = cardiac death, MI, or ischemia-driven TLR 
 
Figure 2.2 
SPIRIT IV Trial: Target Lesion Failure at 1 Year (n=3,690) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Target lesion failure = cardiac death, target vessel MI, or ischemia-driven TLR

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2.3. 
The SYNTAX Trial – Influence of Anatomic Complexity 
 
The potential influence of anatomic complexity in the SYNTAX trial was evaluated by examining 
the outcomes of TAXUS DES vs. CABG in different subgroups from this trial according to the 
SYNTAX score.7  Subjects within the highest SYNTAX tertile (score of 33 or greater) had 
superior overall clinical outcomes (including lower mortality) when treated with CABG. (Figure 
2.3 and Table 2-1).  Conversely, the approximately two-thirds of the left main subjects with a 
SYNTAX score of 32 or below had comparable or superior clinical overall outcomes 
(including lower mortality) achieved with PCI at 3years follow-up which may justify the use of 
PCI with DES in these subjects (Figure 2.4 and Table 2-2).  However, these subgroup analyses 
were post hoc and underpowered, and as such must be considered hypothesis- generating.  It is 
also possible that, based on the recent data on XIENCE V from the SPIRIT Trials, the new 
second-generation DES would have competed more favorably with CABG. 
 
 
Figure 2.3      SYNTAX Trial: Major Adverse Cardiac and Cerebrovascular Events at 3 
Years in the Left Main Subgroup with the Highest SYNTAX Score Tertile 
(SYNTAX Scores ≥33) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cumulative KM Event Rate = 1.5 SE; log-rank P value; site-reported data; ITT population 

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Table 2-1        SYNTAX Trial:  Components of Major Adverse Cardiac and Cerebro 
vascular Events at 3 Years in the Left Main Subgroup with the Highest 
SYNTAX Score Tertile (SYNTAX Scores ≥33) 
Outcome 
CABG 
(N=149) 
TAXUS 
(N=135) 
P-value 
Death 
7.6% 
13.4% 
0.10 
CVA 
4.9% 
1.6% 
0.13 
MI 
6.1% 
10.9% 
0.18 
Death, CVA, or MI 
15.7% 
20.1% 
0.34 
Revascularization 
9.2% 
27.7% 
<0.001 
 
 
Figure 2.4       SYNTAX Trial:  Major Adverse Cardiac and Cerebrovascular Events 
at 3 Years for the Left Main Subgroup in Subjects with the Lowest and 
Intermediate SYNTAX Score Tertiles (SYNTAX Scores 0-32) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cumulative KM Event Rate = 1.5 SE; log-rank P value; site-reported data; ITT population 

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Table 2-2          SYNTAX Trial:  Components of Major Adverse Cardiac and Cerebro 
vascular Events at 3 Years for the Left Main Subgroup in Subjects with 
the Lowest and Intermediate SYNTAX Score Tertiles (SYNTAX Scores 
0-32) 
Outcome 
CABG 
(N=196) 
TAXUS 
(N=221) 
P-value 
Death 
9.0% 
3.7% 
0.02 
CVA 
3.3% 
0.9% 
0.09 
MI 
2.6% 
4.6% 
0.33 
Death, CVA, or MI 
13.2% 
8.7% 
0.12 
Revascularization 
13.7% 
15.7% 
0.61 
 
2.4. 
Other Studies Comparing PCI and CABG for Unprotected Left 
Main Coronary Artery (ULMCA) Disease 
 
Other studies specifically examining PCI for ULMCA disease include: 
• The LEMANS randomized trial, while only studying 105 patients, demonstrated a benefit of 
PCI compared to CABG in the primary endpoint of LVEF after left main revascularization: a 
significant increase in LVEF at 12-month follow-up was noted only in the PCI group (mean 
3.3% vs. 0.5% with CABG, P=0.047).22   Moreover, the LeMANS trial reinforced the 
well-known benefits of PCI compared to CABG in reducing peri-procedural and short-term 
morbidity.  In this trial, major adverse events within 30 days (including death, myocardial 
infarction, stroke, major bleeding, major arrhythmia, unstable angina, acute heart failure, 
unplanned surgery or revascularization, renal failure, infection, post-cardiotomy syndrome, 
and sternal refixation) occurred in 8% of PCI patients versus 28% of CABG patients 
(P=0.006).  Subjects undergoing PCI compared to CABG also had significantly shorter 
hospitalization (mean 6.8 days vs. 12.0 days; P=0.0007). 
• The LEMANS Registry and the large scale LEFT MAIN-COMPARE registry demonstrated 
that stenting of ULMCA is feasible and offers good long-term outcome.   Implantation of 
DES for ULMCA decreased the risk of long-term Major Adverse Cardiac and 
Cerebrovascular Events (MACCE), and particularly improved survival in subjects with distal 
ULMCA disease.23,24 
• The ISAR-LEFT MAIN randomized trial demonstrated that implantation of either paclitaxel 
eluting stent (PES) or sirolimus eluting stent (SES) in ULMCA lesions is safe and effective; 
both of these drug-eluting stents provide comparable clinical and angiographic outcomes.25 
• Recent meta-analysis26 of multiple trials among selected subjects with first generation DES 
showed that death, myocardial infarction, or stroke (major adverse cardiovascular or 
cerebrovascular events) were similar in the PCI and CABG subjects at 1 year (odds ratio 
[OR]: 0.84 [95% confidence interval: 0.57 to 1.22]).   Target vessel revascularization was 
significantly higher in the PCI group at 1 year (OR: 4.36 [95% CI: 2.60 to 7.32]), 2 years 
(OR: 4.20 [95% CI: 2.21 to 7.97]), and 3 years (OR: 3.30 [95% CI: 0.96 to 11.33]).  
There was no difference in mortality in PCI versus CABG subjects at 1 year (OR: 1.00 
[95% CI: 0.70 to 1.41]), 2 years (OR: 1.27 [95% CI: 0.83 to 1.94]), and 3 years (OR: 1.11  

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[95% CI: 0.66 to 1.86]).  The meta-analysis concluded that most studies demonstrate no 
significant difference in mortality or the composite of mortality, MI, or stroke, for up 
to 3 years, between PCI and CABG for the treatment of ULMCA stenosis in selected 
subjects. However, PCI subjects have a significantly higher risk of target vessel 
revascularization.  In selected subjects with ULMCA stenosis (especially in those without 
complex concomitant coronary artery disease, as seen in the SYNTAX trial), PCI is 
emerging as an acceptable option. Reflecting these findings, PCI for stenting of non-
complex ULMCA disease has recently been given a class IIb recommendation in the 
guidelines of the American College of Cardiology and American Heart Association.27 
2.5. 
Quality of Life and U.S. Health Economics Sub-Studies 
 
Until very recently, most physicians viewed the field of medical economics as an academic 
exercise that was irrelevant to daily practice (see also Section 17, Appendix B). Typically, new 
therapeutic strategies and medical technologies were adopted by practitioners prior to any 
definitive evaluation of their effectiveness.  Such is no longer the case.  As health expenditures 
have continued to grow, it is no longer sufficient for a therapeutic strategy to simply demonstrate 
improved efficacy in order to be accepted into the mainstream of medical practice.  Today, 
physicians, payers, and policy-makers have become increasingly interested in understanding the 
value of therapies by evaluating their cost-effectiveness.  Such economic evaluations assume 
particular importance when the disease under consideration is either highly prevalent or very 
costly. 
 
Since the earliest days of health economic studies, there has been interest in understanding the 
relative costs and benefits of percutaneous coronary intervention (PCI) and bypass surgery 
(CABG).  These  studies  have  been  motivated  by  both  the  frequency  and  costs  of  these 
procedures, which currently account for more than $20 billion in annual health care expenditures 
in the U.S. alone.28   In the early 1980’s, Weinstein and Stason29 first used data from the VA 
Cooperative Study and the European Coronary Surgery Study to develop projections of life- 
expectancy and symptomatic status for subjects with coronary disease treated with CABG or 
medical therapy.  They estimated that for subjects with multivessel CAD, the cost-effectiveness 
ratio for CABG (compared with medical therapy) ranged from $15,000 - $70,000 per quality- 
adjusted year of life (QALY) gained (costs adjusted to 1997 dollars).  Lower ratios were 
associated with treatment of subjects with more extensive disease and more severe anginal 
symptoms.  More recently, Wong and colleagues30 used a Markov simulation model to predict 
long-term medical care costs and quality-adjusted life expectancy for subjects with chronic stable 
angina treated with either medication or coronary revascularization.  In contrast to Weinstein, 
they also considered balloon angioplasty (PTCA) as a potential form of revascularization. Since 
their model was developed in the late 1980s, they did not incorporate the results of any of the 
more recent randomized trials of PTCA vs. either medical therapy 31 , 32 , 33  or CABG.19, 34 , 35 
Nonetheless, based on observational data regarding the symptomatic and survival benefits of  
PTCA, they estimated that for subjects with one- or two-vessel disease and moderate to severe 
angina, PTCA was economically attractive with a cost-effectiveness ratio of $10,000 - $40,000 
per quality-adjusted year of life gained (costs in 1997 dollars).   For subjects with mild or no 
symptoms, however, PTCA did not appear particularly attractive, with a cost-effectiveness ratio of 
$140,000-$200,000/QALY. 

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Currently, the best long-term data regarding the cost-effectiveness of PCI vs. CABG are from the 
Bypass Angioplasty Revascularization Investigation (BARI).  Within BARI, Hlatky and 
colleagues performed a prospective cost-effectiveness substudy among 934 of the 1829 trial 
participants.36 Based on 12-year follow-up data, they estimated that the mean cumulative cost of 
CABG was $123,000 vs. $121,000 for PCI. 37 Despite these higher costs, however, after 
accounting for the greater overall life expectancy with CABG (8.48 vs. 8.42 years) the 
incremental cost-effectiveness ratio for CABG vs. PCI was highly favorable at $14,300 per year 
of life gained.  Given the substantial differences in subject populations (BARI specifically 
excluded subjects with left main disease) and revascularization techniques (BARI pre-dated the 
use of either stents or drug-eluting stents as well as contemporary use of high dose statins and 
dual antiplatelet therapy), however, these results provide only limited insight into the cost- 
effectiveness of PCI with DES vs. CABG for subjects with left main disease. 
 
To date, the only available data regarding the cost-effectiveness of PCI for left main disease are 
derived from the 1-year follow-up of the SYNTAX trial (Cohen DJ, ACC Scientific Sessions 
2009).   For the overall population of subjects with either 3-vessel or left main disease, initial 
revascularization costs were ~$6000/subject greater with CABG than with PCI.   Over the 
subsequent 12 months, repeat revascularization was significantly more common with initial PCI 
such that follow-up costs were ~$2500/subject greater with PCI.   Thus, at 12 months, total 
medical care costs remained greater with CABG, by approximately $3500/subject.   Because 
there were no differences in overall survival yet short-term quality of life was better with PCI, 
quality adjusted life expectancy was also slightly greater with PCI at this early timepoint. 
Consequently, PCI with DES was an economically dominant strategy at this relatively early 
timepoint. Results were even more favorable for the subgroup of subjects (n=701) with left main 
disease.  Among this subset, 1-year costs were $6300/subject higher with CABG and quality- 
adjusted life expectancy also favored PCI (by 0.03 QALYs) rendering PCI a highly dominant 
strategy at this relatively early timepoint.  Although these results suggest that PCI could be a 
highly attractive strategy from both a clinical and economic perspective for subjects undergoing 
revascularization for left main CAD, longer term follow-up and additional confirmatory data will 
be required to determine the durability and reproducibility of these findings. 
 
2.6. 
Justification for a Contemporary Large-Scale Trial Comparing 
PCI and CABG for LMCA Disease 
 
The SYNTAX trial is the largest contemporary trial of DES vs. CABG in patients with complex 
coronary artery disease, and with a primary endpoint of death, MI, stroke or repeat 
revascularization at one year, confirmed the superiority of CABG compared to PES.  As a result 
the SYNTAX investigators concluded that “CABG remains the standard of care for patients with  
three-vessel or left main coronary artery disease, since the use of CABG, as compared with PCI, 
resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular  
events at one year.”7   However, SYNTAX was not powered to examine the outcomes of patients 
only with left main coronary artery disease (with or without other diseased coronary vessels).  
 
Indeed, the results of SYNTAX, as well as the numerous other trials discussed above suggest 
equipoise between PCI with first generation DES and CABG for the composite of mortality, 

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myocardial infarction or stroke, albeit with higher rates of repeat revascularization for PCI. 
 
Although the importance of mortality, MI and stroke as essential endpoints is universally 
accepted, no single trial has been adequately powered to examine whether CABG has superior, 
comparable, or non-inferior rates of the composite endpoint of mortality, MI, or stroke compared 
expressed that the inclusion of unplanned revascularization into the primary SYNTAX endpoint 
(which was necessitated for sample size requirements) biased the trial against PCI, as many other 
endpoints of equal or more important impact to patient well-being might have been selected 
instead.  As discussed above, most trials (including SYNTAX) have shown that stroke rates are 
higher after CABG than PCI, an endpoint significantly more important to physicians and subjects 
than repeat revascularization.  Peri-procedural bleeding is significantly more common after 
CABG compared to PCI, and is a powerful independent predictor of early and late mortality in 
this setting.38, 39, 40Subjects undergoing CABG compared to PCI have prolonged hospital stays 
(for example, mean 3.4 days after PCI vs. 9.5 days after CABG, P<0.001),7  greater  and prolonged 
incisional chest pain, and delayed return to work and activities of daily life. The impact of all 
of these adverse events, including the benefits from the greater prevention of recurrent ischemia 
and repeat revascularization with CABG compared to PCI, may be captured in quality of life 
measures. As reported from the One-Year Quality of Life SYNTAX Substudy,41 
 
PCI as compared to CABG had superior measures of quality of life in most measures at one 
month, though these outcomes had equalized by 6 and 12 months (Figure 2.5). 

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Figure 2.5        SYNTAX Trial: Quality of Life Measures Comparing PCI and CABG 

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Moreover, as described above, the SYNTAX trial had few exclusion criteria, and post hoc 
analyses using the SYNTAX score have demonstrated a clear advantage of CABG for those 
subjects with the highest risk SYNTAX tertile (score ≥33). In contrast, for subjects randomized 
to PES vs. CABG with a SYNTAX score of ≤32 (approximately two thirds of the left main 
cohort), mortality was lower with PCI at 3 years, and a trend was present for reduced composite 
death, MI or stroke with PCI, with nonsignificantly different rates of unplanned revascularization 
between PCI and CABG.   However, as a post hoc, subgroup analysis, these findings must be 
considered hypothesis-generating, warranting testing in an appropriately powered randomized 
trial.  Furthermore, the primary endpoint of SYNTAX was measured at one year, a period which 
may be too early to capture the intermediate term outcomes between PCI and CABG. 
 
In addition, as described below, the XIENCE V stent has been shown to be superior to the PES, 
with lower rates of stent thrombosis, MI and target lesion revascularization demonstrated in four 
randomized trials (SPIRIT II, SPIRIT III, SPIRIT IV and COMPARE).  Use of XIENCE V may 
therefore further improve outcomes in the PCI arm.  Since the SYNTAX trial was conducted, 
improvements in PCI technique and adjunct pharmacotherapy have occurred (e.g. strategies to 
manage the bifurcation, use of intravascular ultrasound and fractional flow reserve, bivalirudin 
and optimal thienopyridine use), as well as improvements in CABG (optimal use of arterial 
conduits, screening for and management of peri-procedural stroke risk, e.g., with epi-aortic 
ultrasound, and optimal use of pre-, intra-, and post-procedural pharmacotherapy). 
 
Thus, an appropriate trial to evaluate PCI vs. CABG in subjects with disease of the left main 
stem is justified, and would: 
 
• be restricted to those patients in whom clinical equipoise is present between PCI and CABG 
(SYNTAX score ≤32); 
 
• utilize optimal interventional and surgical techniques (allowing for acceptable variation 
between centers); 
 
• be adequately powered for a primary endpoint of mortality, MI or stroke, and at a later 
endpoint than one year (e.g. at 3 years); and 
• evaluate other important secondary endpoints including not only revascularization, but also 
in-hospital, short-term and as well as late outcomes, and quality of life and cost-effectiveness at 
different intervals so a complete assessment of the risks vs. the benefits of PCI compared to 
CABG may be appreciated. 
 
2.7. 
Device Overview 
2.7.1. XIENCE V EECSS Clinical Experience 
 
After a small first-in-man trial, SPIRIT FIRST, in which the XIENCE V stent was shown to 
reduce angiographic late loss in comparison with the bare-metal MULTI-LINK VISION stent,42 
the safety and efficacy of the XIENCE V stent was further studied in larger randomized trials of 
subjects with noncomplex lesions in which XIENCE V stent was compared to the widely used  
 
TAXUS stent (Boston Scientific).  In both the 300-subject randomized SPIRIT II trial and the 
1002-subject randomized SPIRIT III trial, XIENCE V stent proved superior to TAXUS stent in 

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terms of the primary end point of in-stent late loss at 6 months (SPIRIT II)43 and in-segment late 
loss at 8 months (SPIRIT III).44   In the SPIRIT III trial, XIENCE V stent was also found to be 
non-inferior to TAXUS stent for the co-primary end point of ischemia-driven target vessel failure 
(cardiac death, myocardial infarction [MI] or ischemia-driven target vessel revascularization 
[TVR]) at 9 months.45  In a pooled analysis from the 1302 subjects in the SPIRIT II and SPIRIT 
III trials, XIENCE V stent resulted in reduced rates of major adverse cardiac events (MACE; 
cardiac death, MI or ischemia-driven target lesion revascularization [TLR]: 5.2% vs. 10.0%, 
P=0.02) at 1 year, driven by a significantly reduced rate of TLR (3.1% vs. 5.8%, P=0.02)and a 
trend toward less cardiac death or MI (2.7% vs. 4.5%, P=0.10), with nonsignificantly different 
rates of stent thrombosis (0.7% vs. 0.8%, P=0.90).46   These findings have been robust to three 
years.  In SPIRIT III, treatment with XIENCE V stent compared with TAXUS stent resulted in a 
28.5% reduction in target vessel failure (14.3% vs. 20.0%) and a 40.9% reduction in MACE 
(9.7% vs. 16.4%) at 3 years.47   However, neither SPIRIT II nor SPIRIT III were powered for 
statistical superiority testing in clinical end points, nor were they adequately sized to elicit 
potential differences in low frequency safety events between the two stent platforms.  Of note, 
routine angiographic follow-up was prespecified in all subjects at 6 months in SPIRIT II and in 
564 subjects at 8 months in SPIRIT III, a protocol-specific process which may artificially 
enhance the absolute difference in TLR between the two stents by provoking angiographically 
induced revascularization procedures, the so-called “oculostenotic reflex”. 48 , 49 Although this 
process may not affect the relative difference in clinical efficacy between two stents,47, 50 routine 
angiographic follow-up should ideally not be performed prior to the primary clinical end point if 
an accurate and realistic assessment of treatment related differences is to be obtained.51  
 
Thus, the SPIRIT IV trial was performed with clinical endpoints only and represents an 
adequately-powered, single- blind, multicenter prospective trial comparing the XIENCE V stent to 
the TAXUS EXPRESS stent in 3690 subjects (2:1 ratio of XIENCE V to TAXUS EXPRESS). The 
primary endpoint was target lesion failure (TLF) defined as the composite of cardiac death, target 
vessel MI and ischemia-driven target lesion revascularization (TLR), and was superior for 
XIENCE V stent compared to TAXUS EXPRESS stent (TLF 3.9% vs. 6.6%, respectively, 
P=0.0008).50  In addition, both TLR (2.5% vs. 4.6%, P=0.001), MI (1.9%. vs. 3.0%, P=0.02), and 
ARC definite or probable stent thrombosis (ST) (0.29% vs. 1.06%, P=0.003) favored the XIENCE 
V stent group.  These results were duplicated in the investigator-sponsored COMPARE trial (also 
performed without routine angiographic follow-up), in which 1800 subjects were randomized to 
the XIENCE V stent vs. the TAXUS Liberté stent.21 Compared to TAXUS at one year, XIENCE 
V stent resulted in statistically lower rates of the primary composite endpoint of death, MI or TVR 
(6.2% vs. 9.1%, P=0.02), as well as MI (2.8% vs. 5.4%, P=0.007), ARC definite or probable ST 
(0.7% vs. 2.6%, P=0.002), TLR (1.7% vs. 4.8%, P=0.0002). 
2.7.2. XIENCE V Stent in Unprotected Left Main Coronary Artery 
(ULMCA) Disease Background 
 
The French multicenter prospective observational LeMAX study assessed 1-year outcomes in 
174 subjects treated with the XIENCE V stent who had ULMCA disease and were treated with 
protocol mandated provisional T-stenting.  The subjects represented a high-risk cohort with a 
mean EuroSCORE of 4.67, mean SYNTAX score of 25.1, and the presence of multi-vessel 
disease in 46% of subjects. 76.2% of subjects had a SYNTAX score 0-32 and left ventricular 

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function was well preserved.  Importantly, despite 81% of lesions involving the distal left main 
stenosis (74% bifurcation, 7% trifurcation), a mean of only 1.2 stents were implanted, and final 
kissing balloon inflation was used in 95% of lesions. The rate of MACCE, death, MI, stroke and 
target lesion revascularization was 14.7%, 4.1%, 2.5%, 1.6% and 2.5% respectively. The rate of 
MACCE-free survival at 1-year stratified according to SYNTAX score tertiles <22, 23-32 and 
≥33 was 90%, 88.4% and 72.4%.  MACCE is defined as the composite of all-cause death, MI, 
TLR and cerebrovascular events.52 
 
2.7.3. XIENCE V Stenting in Multiple and Complex Lesions 
 
There is evidence that event rates with the XIENCE V stent are lower than with TAXUS stent in 
subjects with multiple vessels treated.  Data from the SPIRIT III trial suggest numerically lower 
rates for XIENCE V stent in dual vessel treatment compared to TAXUS stent53.  In the 
SPIRIT IV trial, subgroup analysis demonstrated that the relative benefits of XIENCE V stent 
compared to TAXUS stent in reducing Target Lesion Failure rates (TLF: cardiac death, target 
vessel myocardial infarction, or target lesion revascularization) were consistent in most subgroups 
examined, although the absolute differences were greater in complex subjects, such as those with 
long lesions, small reference vessel diameter, and multiple lesions54. 
 
In a recent pooled analysis of the SPIRIT II (n=300), SPIRIT III (n=1002) and SPIRIT IV 
(n=3687) trials in which XIENCE V stent was compared to TAXUS stent (randomized 3:1 or 
2:1) in 4689 subjects, clinical outcomes atone year were analyzed in subjects with either a single 
vessel treated (n=4152), or two or more treated vessels (n=1648)55. 
 • Single treated vessel: Adverse outcomes trended lower in XIENCE V stent vs. TAXUS 
stent subjects with a single treated vessel for major adverse cardiac events (MACE: cardiac 
death, MI or TLR) (4.1% vs. 6.5%) and TLF (4.0% vs. 6.3%).  Stent thrombosis rates were 
comparable between the XIENCE V single vessel treated subgroup and the TAXUS subgroup 
for both protocol and ARC-defined 
• Multiple treated vessels: The observed TLF and MACE rates trended toward lower rates in 
the XIENCE V subgroup compared to the TAXUS subgroup. The one year observed rates for 
TLF were 6.1% for the XIENCE V subgroup and 13.0% for the TAXUS subgroup. The 
observed rates at one year for MACE were 6.3% for the XIENCE V subgroup and 13.4% for 
the TAXUS subgroup. The observed difference in overall stent thrombosis rates at one year 
was 1.3% (protocol defined) and 1.5% (ARC defined) between the XIENCE V subgroup and 
the TAXUS subgroup, in favor of the XIENCE V subgroup. 
• In summary, for the one-year results of the SPIRIT II, III, and IV pooled analysis, the 
XIENCE V arm consistently showed numerically lower event rates for composite clinical 
endpoints than the TAXUS arm. 
 
Finally, in the SPIRIT V single-arm study of 2700 real-world subjects receiving an XIENCE V 
stent, the composite rate of cardiac death, target vessel MI and TLR (i.e. TLF) was predictably 
higher in subjects with multiple vessels treated, compared to single vessel treatment, driven by a 
numerically higher TLR rate with multiple vessels treated; yet, the absolute TLF rate of 7.79% 
was low in this complex subject population, confirming the efficacy and safety of the XIENCE V 
stent in these subjects56. 

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2.7.4. XIENCE V Stenting in Medically Treated Diabetics 
 
In both the SPIRIT III44 and SPIRIT IV50 trials, a significant interaction was observed between 
stent type and diabetes mellitus.  In this regard, with a pre-specified stratified randomization of 
1,185 diabetic subjects in SPIRIT IV (a larger cohort than the entire SPIRIT III trial), SPIRIT IV 
represents the largest comparative experience to date evaluating the outcomes of different DES in 
subjects with diabetes mellitus.  The relative reduction in TLF with XIENCE V stent compared to 
TAXUS stent in subjects with diabetes mellitus was 6% (0.5% absolute reduction), compared to 
53% (3.6% absolute reduction) in subjects without diabetes mellitus.   While the point estimate 
for the primary endpoint favored XIENCE V stent compared to TAXUS stent in both diabetic and 
non-diabetic subjects, the differences in relative effect size suggests that the mechanisms of 
restenosis and/or response to antiproliferative agents may vary in subjects with insulin resistance 
or deficiency 57.  Longer-term follow-up is required to determine whether differences between 
XIENCE V stent and TAXUS stent in subjects with diabetes mellitus emerge over time. 
 
In the COMPARE trial, in a stratified analysis of the primary endpoint (all death, non-fatal MI and 
TVR) that was not pre-specified in the protocol, there was no difference between the everolimus-
eluting and the PES among subjects with diabetes mellitus (RR 1.00 [95% CI, 0.53-1.89], 
P=0.99) but confidence intervals were wide, and the results of a test of interaction were not 
significant.58  Thus, as in the SPIRIT IV trial, in the COMPARE trial as well, the XIENCE V stent 
and TAXUS stent appear to have similar clinical outcomes in the population of subjects with 
diabetes mellitus. In the SPIRIT V single-arm study of 2700 real-world subjects receiving a 
XIENCE V stent, composite rates of all death, MI and TVR were predictably higher in subjects 
with diabetes mellitus as compared to subjects without diabetes mellitus at one year, but composite 
rates of cardiac death, target vessel MI and TLR (i.e., TLF) were no different (5.73% vs. 4.80, 
P=0.3285).56   Overall, SPIRIT V confirms low event rates with everolimus-eluting coronary stent 
in real world subjects with diabetes mellitus. 
 
2.7.5. XIENCE V Everolimus Eluting Coronary Stent System (EECSS) 
 
2.7.5.1.  Indication 
 
The XIENCE V EECSS is indicated for improving coronary luminal diameter in subjects with 
symptomatic heart disease due to de novo native coronary artery lesions (length ≤ 28 mm) with 
reference vessel diameters of 2.25 mm to 4.25 mm. 
 
2.7.5.2.  Description of XIENCE V Stent System 
 
The XIENCE V EECSS is comprised of the XIENCE V EECS, a delivery system, and a drug 
eluting coating.  The coating is composed of two polymers and the anti-proliferative drug 
everolimus.  Both polymers have been previously CE Marked and FDA/MHLW approved for 
blood contacting applications. Zortress®, the oral formulation of everolimus developed by 
Novartis Pharmaceuticals Corporation, has been evaluated in clinical trials and is approved in the 
United States for the prevention of organ rejection in adult kidney transplant recipients at the 
dose of 1.5 mg/day. 

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Outside the U.S., Zortress is sold under the brand name, Certican®, in more than 70 countries. 
Everolimus is also approved in the United States under the name of Afinitor® for patients with 
advanced renal cell carcinoma (cancer) at doses of 5 to 20 mg/day when taken by mouth. 
 
Table 2-3          XIENCE V EECS Product Sizes 
Diameter→ 
Length ↓ 
2.25 mm 
2.5 mm 
2.75 mm 
3.0 mm 
3.5 mm 
4.0 mm 
8 mm 
X 
X 
X 
X 
X 
X 
12 mm 
X 
X 
X 
X 
X 
X 
15 mm 
X 
X 
X 
X 
X 
X 
18 mm 
X 
X 
X 
X 
X 
X 
23 mm 
X 
X 
X 
X 
X 
X 
28 mm 
X 
X 
X 
X 
X 
X 
 
The everolimus-eluting coronary stent (EECS, manufactured and distributed by Abbott Vascular, 
Santa Clara, CA, as XIENCE V) is a medical grade L-605 cobalt chromium (CoCr) alloy 
MULTI-LINK VISION or MULTI-LINK MINI VISION balloon-expandable stent with 0.0032- 
in strut thickness which is coated with a conformal coating of a non-erodible polymer loaded 
with 100 µg/cm2  of everolimus [40-O-(2-hydroxyethyl)-rapamycin], a semisynthetic macrolide 
immunosuppressant, inhibits growth factor-stimulated cell proliferation by causing cell-cycle 
arrest in the late G1 stage, thereby suppressing neointimal formation.59, 60Comparative analysis in 
an in vivo rabbit aortoiliac model has shown more rapid endothelialization with the EECS 
compared to sirolimus eluting stents, paclitaxel eluting stents, and zotarolimus eluting stents.61 
Clinical trials are required, however, to determine whether this finding translates into improved 
human safety or efficacy. 
 
2.7.6. XIENCE PRIME Everolimus Eluting Coronary Stent System 
(EECSS) 
 
While the data in Section 2.7.1 to 2.7.4, were obtained using the XIENCE V stent, the next 
iteration of this stent XIENCE PRIME, is now commercially available in the U.S., EU and some 
Asia-Pacific countries and includes stent lengths of 33 and 38 mm. A U.S. single arm trial, 
 
SPIRIT PRIME, of 500 subjects is currently ongoing under an investigational device exemption  
(IDE) from the FDA (IDE # G090068). 
 
2.7.6.1. Indication 
 
The XIENCE PRIME stent system is indicated for improving coronary luminal diameter in 
subjects with symptomatic heart disease due to de novo native coronary artery lesions (length 
≤ 32 mm) with reference vessel diameters of ≥2.25 mm to ≤4.25 mm. 
 

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2.7.6.2. Description of XIENCE PRIME Stent System 
 
The XIENCE PRIME stent system is composed of a drug coated stent and balloon expandable 
delivery system. The drug coating is composed of two polymers and the anti-proliferative drug 
everolimus, which are identical to XIENCE V stent.  The delivery system used in this trial 
utilizes the same principle of operation as other Abbott Vascular Rapid Exchange (RX) coronary 
stent systems and coronary dilation catheters. 
 
Table 2-4 
XIENCE PRIME EECS Product Sizes 
Diameter → 
Length ↓ 
2.25 mm 
2.5 mm 
2.75 mm 
3.0 mm 
3.5 mm 
4.0 mm 
8 mm 
X 
X 
X 
X 
X 
X 
12 mm 
X 
X 
X 
X 
X 
X 
15 mm 
X 
X 
X 
X 
X 
X 
18 mm 
X 
X 
X 
X 
X 
X 
23 mm 
X 
X 
X 
X 
X 
X 
28 mm 
X 
X 
X 
X 
X 
X 
33 mm 
n/a 
X 
X 
X 
X 
X 
38 mm 
n/a 
X 
X 
X 
X 
X 
 
The everolimus-eluting coronary stent (EECS, manufactured and distributed by Abbott Vascular, 
Santa Clara, CA, as XIENCE PRIME) is a balloon expandable stent manufactured from a 
flexible cobalt chromium alloy with a multicellular design and 0.0032-in strut thickness which is 
coated with a thin non-adhesive, durable, biocompatible acrylic polymer and fluorinated 
copolymer releasing everolimus. 
 
2.7.7. XIENCE XPEDITION STENT SYSTEM 
 
The XIENCE Xpedition Stent System is a new iteration of XIENCE PRIME with a new stent 
delivery system. XIENCE Xpedition is now commercially available in the U.S., EU and some 
Asia-Pacific countries. The stent and stent contacting balloon materials, and the drug coating 
formulation and drug dose density (100 ug/cm²) are identical to the XIENCE PRIME EECSS. 
XIENCE Xpedition also includes stent lengths of 33 and 38 mm and stent diameter of 3.25 mm. 
 
2.7.7.1. Indication 
 
The XIENCE Xpedition stent system is indicated for improving coronary artery luminal diameter 
in patients with symptomatic heart disease due to de novo native coronary artery lesions (length 
≤32 mm) with reference vessel diameters of ≥2.25 mm to ≤4.25 mm. 
 
2.7.7.2. Description of XIENCE Xpedition Stent System 
The XIENCE Xpedition stent systems are device/drug combination products consisting of a drug-
coated stent and a balloon expandable delivery system.  The stent is coated with a formulation 

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containing everolimus, the active ingredient, embedded in a non-erodible polymer, which is 
identical to the FDA approved XIENCE V and XIENCE PRIME EECSS.  The XIENCE 
Xpedition Stent System is available in two delivery system configurations: Rapid Exchange (RX) 
and Over-the-Wire (OTW). 
 
Table 2-5 
XIENCE Xpedition Product Sizes 
Diameter → 
Length ↓ 
2.25 mm 
2.5 mm 
2.75 mm 
3.0 mm 
3.25 mm 
3.5 mm 
4.0 mm 
8 mm 
X 
X 
X 
X 
X 
X 
X 
12 mm 
X 
X 
X 
X 
X 
X 
X 
15 mm 
X 
X 
X 
X 
X 
X 
X 
18 mm 
X 
X 
X 
X 
X 
X 
X 
23 mm 
X 
X 
X 
X 
X 
X 
X 
28 mm 
X 
X 
X 
X 
X 
X 
X 
33 mm 
n/a 
X 
X 
X 
X 
X 
X 
38 mm 
n/a 
X 
X 
X 
X 
X 
X 
 
2.7.8. XIENCE PRO Everolimus Eluting Coronary Stent System (EECSS) 
 
The XIENCE PRO EECSS is a rebranding (re-labeling) of the commercially approved XIENCE 
V EECSS and the XIENCE PRIME LL EECSS. XIENCE PRO is only approved for use outside 
the U.S.  It is not commercially available in the U.S. 
 
2.7.8.1. Indication 
 
The XIENCE PRO EECSS (with stent length up to 28 mm) is indicated for improving coronary 
luminal diameter in patients with symptomatic ischemic heart disease due to discrete de novo 
native coronary artery lesions (length ≤28 mm) with a reference vessel diameter of 2.25 mm 4.0 
mm. 
 
The XIENCE PRO LL EECSS (with 33 mm and 38 mm stent length) is indicated for improving 
coronary luminal diameter in patients with symptomatic ischemic heart disease due to discrete de  
novo native coronary artery lesions.  The treated lesion length should be less than the nominal 
stent length (33 mm or 38 mm) with a reference vessel diameter of ≥2.50 mm and ≤4.25 mm. 
 
2.7.8.2. Description of XIENCE PRO EECSS 
The XIENCE PRO is comprised of a balloon-expandable everolimus eluting stent pre-mounted 
on a dedicated delivery system.  The XIENCE PRO utilities the identical stent, delivery system, 
drug coating as the commercially approved XIENCE V EECSS and XIENCE PRIME LL 
EECSS. 
 

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Table 2-6 
XIENCE PRO EECS Product Sizes 
Diameter → 
Length ↓ 
2.25 mm 
2.5 mm 
2.75 mm 
3.0 mm 
3.5 mm 
4.0 mm 
8 mm 
X 
X 
X 
X 
X 
X 
12 mm 
X 
X 
X 
X 
X 
X 
15 mm 
X 
X 
X 
X 
X 
X 
18 mm 
X 
X 
X 
X 
X 
X 
23 mm 
X 
X 
X 
X 
X 
X 
28 mm 
X 
X 
X 
X 
X 
X 
33 mm 
n/a 
X 
X 
X 
X 
X 
38 mm 
n/a 
X 
X 
X 
X 
X 
3.     STUDY OBJECTIVE 
 
The primary objective of this study is to establish the safety and efficacy of the XIENCE Stent 
System in subjects with unprotected left main coronary artery (ULMCA) disease (either isolated to 
the left main trunk or associated with disease in  other coronary arteries) by demonstrating that 
compared to coronary artery CABG, treatment of the left main stenosis ± other significant 
coronary lesions with the XIENCE stent will result in non-inferior or superior rates of the 
composite measure of all-cause mortality, myocardial infarction or stroke at the anticipated 
median follow-up of three years. 
4.     STUDY DESIGN 
 
4.1. 
Study Design 
 
A total of approximately 2900 subjects will be targeted in the study. 
 
The prospective, unblinded, randomized multicenter trial will randomize about 1900 subjects at 
approximately 165 U.S. and international centers.  Following diagnostic angiography 
demonstrating significant ULMCA disease and the consensus of the local Heart Team (qualified 
participating interventional cardiologist and cardiac surgeon) that the subject meets all the study 
entry criteria, subjects will be consented and randomized 1:1 to: a) PCI using the XIENCE stent, or 
b) CABG.  Follow-up for all randomized subjects will continue for 5 years with a potential for 
additional follow-up to 10 years. 
 
An additional group of approximately 1000 subjects who are not eligible for randomization or 
for other reasons are not randomized will be consented for the Universal Registry.  All patients 
with left main disease without prior CABG in whom the visual estimated diameter stenosis is 
greater than or equal to 50% will be eligible for the EXCEL registry.  These subjects will be 
consented for the Universal Registry, and followed through the time of initial treatment as per 

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standard of care with either PCI, CABG or medical therapy.  No adverse event data will be 
collected for Universal Registry subjects. 
 
Approximately 100 consecutive subjects from the Universal Registry with a ≥50% and <70% 
visually estimated angiographic diameter stenosis who otherwise meet all enrolment criteria, but 
without significant ischemia by noninvasive testing consistent with significant ULMCA disease, 
and in whom IVUS shows a MLA >6.0 mm2 and/or a FFR >0.80 will be analyzed separately as 
intermediate lesion subjects, and followed through the time of initial treatment as per standard of 
care with either PCI, CABG or medical therapy. 
 
4.2. 
Subject Follow-up 
 
All randomized subjects will be followed for at least a five-year period post-procedure.  All 
randomized subjects will have a follow-up telephone contact or office visit (preferred) at 30 days, 
at 6 months, and then at 1, 2, 3, 4, and 5 years post procedure.  To support the 3 year endpoint 
analysis, clinical sites will be asked to obtain the 3 year adverse event status on all subjects.  
Therefore, at the time the last subject reaches the minimal follow-up duration, an additional 
adverse event (AE) check will be performed in order for data up to 3 years (365 days*3=1095 
days) from date of randomization to be established equally in both arms (see Section 8.2 for further 
details).   
 
The randomized subject consent form will also contain the potential for possible follow-up for a 
total of 10 years, with data collected from subject telephone contact or office visits at 6, 7, 8, 9 
and 10 years.  Follow-up after 5 years and for up to 10 years will be performed at the sole 
discretion of the Sponsor, if funding is available.  Prior to the 5 year follow-up visit date for the 
first randomized subject, all sites will be notified if follow-up will continue for 5 or 10 years. 
 
4.3. 
Treatment Strategy 
 
The treatment strategy for all subjects randomized in the trial is as follows: 
• All subjects participating in the randomized portion of clinical trial will have informed 
consent obtained after diagnostic angiography and prior to randomization.  “Ad hoc” ULMCA 
PCI is not permitted (with one exception – see Section 20.1.3.). 
• It is strongly recommended that the timing from randomization to treatment (PCI or CABG) 
be ≤1 week, but it is mandatory that revascularization be performed ≤2 weeks after 
randomization in all cases in both treatment arms.  Reasons for delay beyond 2 weeks will be 
tracked. 
• Target lesion(s) will be treated in accordance with the randomization schedule after satisfying 
the general and angiographic inclusion and exclusion criteria as defined in the protocol.  If 
more than one target lesion will be treated, all lesions must receive the treatment that has 
been assigned as per the randomization. 

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5.     ENDPOINTS 
 
5.1. 
Primary Endpoint and Key Secondary Endpoints 
 
Primary Endpoint. The primary endpoint of the randomized trial is the composite measure of all- 
cause mortality, myocardial infarction, or stroke (modified Rankin Scale (mRS) ≥1 and increase 
by ≥1 from baseline) at 3 years post randomization.  The primary endpoint will be estimated via 
Kaplan-Meier failure rate measured from randomization and Greenwood’s formula for estimating 
the standard error. The primary endpoint analysis will be conducted at the time when 
approximately 50% of the patients have reached the 3-year follow-up AND all patients have 
reached the 2-year follow-up, whichever time point is latest. All available data through 3-year 
follow-up will be used. 
 
Major Powered Secondary Endpoints:  
1. The composite of all-cause mortality, MI and stroke (mRS≥1 and increase by ≥1 from 
baseline) at 30 days post randomization. This powered endpoint will be estimated via Kaplan-
Meier failure rate defined from randomization and Greenwood’s formula for estimating the 
standard error. 
 
2. The composite measure of all-cause mortality, MI, stroke (mRS≥1 and increase by ≥1 from 
baseline), or unplanned revascularization for ischemia at 3 years post randomization. This powered 
endpoint will be estimated via Kaplan-Meier failure rate defined from randomization and 
Greenwood’s formula for estimating the standard error. The analysis will be conducted at the time 
when approximately 50% of the patients have reached the 3-year follow-up AND all patients 
have reached the 2-year follow-up, whichever time point is latest. All available data through 3-
year follow-up will be used. 
 
5.2. 
Other Secondary Endpoints 
 
The primary endpoint composite event rate (all-cause death, MI or stroke) and powered secondary 
endpoints at all time points other than median of 3 years will be other secondary endpoints. 
 
Time points for all other secondary endpoints, unless specified otherwise, are in-hospital, 
30 days, 6 months, 1, 2, 3, 4, and 5 years post-procedure. The other secondary endpoints are: 
• All-cause mortality 
o Cardiac death 
o Non-cardiac death 
• All MI (peri-procedural, spontaneous, Q-wave and non Q-wave) including large and small 
 
MIs 
•   Protocol-defined MI 
•   MI adjudicated per Universal MI Definition 
•   Stroke (all, ischemic, and hemorrhagic) 
•   Disability following stroke event at 90 days± 2 weeks 

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•   Ischemia-driven revascularization 
o Ischemia-driven target lesion revascularization (TLR) 
o Ischemia-driven target vessel revascularization (TVR) 
o Ischemia-driven non target vessel revascularization (Non-TVR) 
•   All revascularization (ischemia driven and non-ischemia driven) 
◦ 
All target lesion revascularization (TLR) 
◦ 
All target vessel revascularization (TVR) 
◦ 
All non-target vessel revascularization (non-TVR) 
• Complete revascularization at baseline procedure, anatomic and functional (see Section 19. 
Appendix D). 
•   Stent thrombosis (ARC definition) symptomatic or asymptomatic 
• Symptomatic graft stenosis or occlusion (since this requires angiographic documentation, this 
endpoint will be compared to symptomatic ARC definite stent thrombosis) 
•   Bleeding complications 
o Requirement for blood product transfusion 
o TIMI scale (major or minor) 
o BARC scale 
•   Requirement for blood product transfusion 
• Time from randomization to procedure; time from procedure to discharge; ICU days; time 
from procedure to return to work 
 
• Major adverse events (MAE) defined as composite of the following components.  MAE will 
be assessed in-hospital and at 30 days only. 
◦ 
death 
◦ 
myocardial infarction 
◦ 
stroke 
◦ 
Transfusion of ≥2 units of blood 
◦ 
TIMI major or minor bleeding 
◦ 
major arrhythmia 
◦ 
unplanned coronary revascularization for ischemia 
◦ 
any unplanned surgery or therapeutic radiologic procedure 
◦ 
renal failure 
◦ 
sternal wound dehiscence 
◦ 
infection requiring antibiotics for treatment 
◦ 
intubation for >48 hours 
◦ 
post-pericardiotomy syndrome. 
 
Definitions of terms and endpoints are located in Sections 16.1 and 16.2.  Acronyms and 
abbreviations are defined in Section 16.0.  Other secondary endpoints are included in the QoL 
sub-study. 

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5.3. 
Pre-Specified Sub-Groups 
 
The present trial is underpowered for comparative assessment of PCI vs. CABG in any subgroup. 
Proposals for analysis that could lead to publications and hypothesis generation are included in 
Section 21.2. 
 
 
6.     SELECTION AND WITHDRAWAL OF SUBJECTS 
 
6.1. 
Subject Population 
 
Subjects randomized into this trial will be comprised of male and female subjects from the 
general 
interventional 
cardiology 
population. The randomized 
trial will randomize 
approximately 1900 subjects who meet all eligibility criteria and provide written informed 
consent.  Each site should randomize a minimum of one subject, and may not randomize more 
than a maximum of 250 subjects. 
 
6.2. 
Subject Screening 
 
Once local IRB or ethics committee approval is obtained, potential subjects will be identified by 
qualified investigators in this trial and screened for study eligibility by the local Heart Team. 
Subjects eligible for randomization per the general inclusion and exclusion criteria will be asked to 
sign an informed consent for the randomized trial.  Subjects who do not satisfy inclusion and 
exclusion criteria or who are otherwise not randomized will be documented on the Heart Team 
Worksheet, and asked to sign a consent form for data collection for the Universal Registry. 
 
6.3. 
Stroke Assessment 
 
All patients to be randomized into the Excel RCT will have a modified Rankin Scale (mRS) 
assessment conducted by mRS trained personnel at baseline and each visit and telephone 
interview. Additionally, the site research coordinator will evaluate each subject at 30 days, 6 
months 1, 2, 3, 4 and 5 Y follow-up time points and at the primary endpoint follow up time point 
(either at annual follow up or at subject contact for primary endpoint AE check) using a Transient 
Ischemic Attack (TIA)/Stroke Questionnaire (Appendix J) and mRS disability questions. This 
questionnaire is a National Institute of Health Stroke Scale (NIHSS) validated questionnaire used in 
the CREST clinical trial. The disability questions are adapted from a structured interview 
developed for stroke patients.1 If the responses to this questionnaire indicates a possible stroke or a   
 
1 Wilson JTL, Hareendran A, Grant M, Baird  T, Shultz UGR, Muir KW, and Bone I.  “Improving the Assessment 
of Outcomes in Stroke:   Use of a Structured Interview to Assign Grades on the Modified Rankin Scale.” Stroke. 
2002; 33; 2243-46. 
 
change in the mRS, then a vascular neurologist or stroke specialist or a mRS certified personnel 
blinded to the treatment type will confirm the mRS scale, determine whether a stroke has occurred 

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and determine the stroke severity using the NIHSS TIA/Stroke questionnaire.  If a new stroke is 
diagnosed at the site, the investigators at the site will prepare a short narrative that describes the 
findings that support the diagnosis.  All stroke events will be adjudicated by the Clinical Events 
Committee (CEC). Furthermore, if there is an increase in the mRS by one or more points noted 
at any visit, then an evaluation will be carried out to determine if a stroke or other outcome event 
has occurred. 
 
Post-procedure, if a patient is diagnosed and adjudicated with a stroke event by the Clinical 
Events Committee (CEC), a disability assessment must be performed at 90 days ±2 weeks after 
the diagnosis of stroke using the mRS assessment instrument. 
6.4. 
Informed Consent 
 
Trial-specific subject procedures will not be started until a signed informed consent has been 
obtained.  The Investigator and/or a person designated by the Investigator who has been trained 
on the protocol, will explain the nature and scope of the trial, potential risks and benefits of 
participation, and answer questions for the subjects.  If the subject agrees to participate, the 
informed consent form must be signed and personally dated by the subject or legally authorized 
representative.  The Investigator or a person designated by the Investigator must also sign the 
informed consent form, prior to subject participation in this trial.  Any additional persons 
required by the local Institutional Review Board (IRB) or Ethics Committee (EC) to sign the 
informed consent form will also do so as required by the IRB/EC.  No subjects belonging to a 
vulnerable population will participate in the trial.  A copy of the executed informed consent form 
will be provided to the subject.  In addition, the signed informed consent must be kept in the 
subject’s medical records.  A statement from the IRB/EC as to the requirements of additional 
signatures is to be provided to the Sponsor. 
 
All subjects must provide informed consent in accordance with the local IRB/EC, using an 
IRB/EC-approved informed consent form.  The final eligibility for the trial will be confirmed 
based on the pre-intervention angiography. 
 
For trials with investigational product: 
 
For live cases at congresses, the subject needs to sign a specific Live Case ICF, approved by the 
IRB/EC and by AV, as well as by the competent authorities (e.g., FDA), as applicable. The 
investigator must request AV approval prior to performing a Live Case. 
 
For trials with commercial product: 
 
For live cases at congresses, the subject needs to sign a specific Live Case ICF approved by the 
IRB/EC. The investigator must notify AV prior to performing a Live Case. 
 
At U.S. sites, an authorization for use and disclosure of the subjects’ protected health 
information as that term is defined by the Health Insurance Portability and Accountability Act 
(HIPAA) shall be obtained. Per individual site procedures, this authorization may be included as 
part of the subject informed consent. 

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6.5. 
Eligibility Criteria 
Assessment for general eligibility criteria is based on medical records of the site and interview  
with a candidate subject. If some of the clinical and laboratory tests are not included in site 
standard tests, they must be done but after written informed consent is obtained. Subjects must 
meet ALL of the inclusion criteria to be considered for the clinical evaluation. If ANY of the 
exclusion criteria are met, the subject is excluded from the clinical evaluation and cannot be 
randomized. 
 
The subjects who do not meet the eligibility criteria for the randomized clinical trial can 
participate in the Universal Registry. 
6.5.1. Inclusion Criteria 
• Unprotected left main coronary artery (ULMCA) disease with angiographic diameter stenosis 
(DS) ≥70%  (visually estimated) requiring revascularization as assessed by both a 
participating interventional cardiologist and cardiac surgeon (local Heart Team), 
or 
• ULMCA disease with angiographic DS ≥50% but <70% (visually estimated) requiring 
revascularization as assessed by both a participating interventional cardiologist and cardiac 
surgeon, with one or more of the following present: 
◦ 
Non-invasive evidence of ischemia referable to a hemodynamically significant left main 
lesion (large area of ischemia in both the LAD and LCX territories, or in either the LAD 
or LCX territory in the absence of other obstructive coronary artery disease to explain the 
LAD or LCX defect), or stress-induced hypotension or stress-induced fall in LVEF, or 
stress-induced transient ischemic dilatation of the left ventricle or stress-induced 
thallium/technetium lung uptake, and/or 
◦ 
IVUS minimum lumen area (MLA) ≤6.0 mm2, and/or 
◦ 
Fractional Flow Reserve (FFR) ≤0.80 
 Note: IVUS is strongly preferred to FFR for ULMCA interrogation unless there is no 
other disease in both the LAD and LCX territories (i.e. isolated left main disease), in 
which case either is acceptable (see Section 18. Appendix C.) 
or 
• Left Main Equivalent Disease: Left main Medina classification 0,1,1 bifurcation disease 
(diameter stenosis of both the true ostial LAD and LCX [within 5 mm of the left main distal 
bifurcation]) ≥50%, in the absence of significant angiographic stenosis in the left main 
coronary artery, may also be randomized if one of the two following conditions are present: 
◦ 
Both the ostial LAD and ostial LCX stenoses are ≥70% stenotic by visual estimation, or 
◦ 
If one or both of the ostial LAD and ostial LCX stenoses are ≥50% and <70% stenotic by 
visual estimation, then this lesion(s) is demonstrated to be significant either by 
 a) non-invasive evidence of ischemia in its myocardial distribution; and/or 
 b) FFR ≤0.80; and/or 
 c) IVUS MLA ≤4.0 mm2 (FFR is preferred). 

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Note: if both the ostial LAD and ostial LCX stenoses are ≥50% and <70% stenotic by visual 
estimation, then both lesions must be significant by these criteria for the patient to be 
eligible for randomization. 
• Clinical and anatomic eligibility for both PCI and CABG as agreed to by the local Heart 
Team 
◦ 
Interventionalist determines PCI appropriateness and eligibility 
◦ 
Surgeon determines surgical appropriateness and eligibility 
• Silent ischemia, stable angina, unstable angina or recent MI 
◦ 
If recent MI, CK-MB must have returned to normal prior to randomization. 
• Ability to sign informed consent and comply with all study procedures including follow-up 
for at least three years 
• The subject must be ≥18 years of age 
 
6.5.2. Clinical Exclusion Criteria 
• Subject is part of a vulnerable population who, in the judgment of the investigator, is unable 
to give Informed Consent for reasons of incapacity, immaturity, adverse personal 
circumstances or lack of autonomy.  This may include:  Individuals with mental disability, 
persons in nursing homes, children, impoverished persons, persons in emergency situations, 
homeless persons, nomads, refugees, and those permanently incapable of giving informed 
consent. Vulnerable populations also may include members of a group with a hierarchical 
structure such as university students, subordinate hospital and laboratory personnel, 
employees of the Sponsor, members of the armed forces, and persons kept in detention. 
• Prior PCI of the left main trunk at any time prior to randomization 
• Prior PCI of any other (non-left main) coronary artery lesions within 1 year prior to 
randomization 
• Prior CABG at any time prior to randomization 
• Need for any concomitant cardiac surgery other than CABG (e.g. valve surgery, aortic repair, 
etc.), or intent that if the subject randomizes to surgery, any cardiac surgical procedure other 
than isolated CABG will be performed 
• CK-MB greater than the local laboratory upper limit of normal or recent MI with CK-MB 
levels still elevated. 
 Note: A subject with a recent MI in whom the troponin levels are still elevated but 
falling and in whom the CK-MB has returned to within normal range prior to 
randomization may be randomized, with CK-MB levels used to assess peri- 
procedural MI. 
• Subjects unable to tolerate, obtain or comply with dual antiplatelet therapy for at least 1 year 
• Subjects requiring or who may require additional surgery (cardiac or non cardiac) within 1 
year 

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• The presence of any clinical condition(s) which leads the participating interventional 
cardiologist to believe that clinical equipoise is not present (i.e. the subject should not be 
treated by PCI, but rather should be managed with CABG or medical therapy - reasons will 
be documented in the Heart Team worksheet) 
• The presence of any clinical condition(s) which leads the participating cardiac surgeon to 
believe that clinical equipoise is not present (i.e. the subject should not be treated by CABG, 
but rather should be managed with PCI or medical therapy - reasons will be documented in 
the Heart Team worksheet) 
 
• Pregnancy or intention to become pregnant (female subjects of child bearing potential must 
have a negative pregnancy test within 7 days of the index procedure) 
 
Note: Female patients should be instructed to use safe contraception (e.g. intrauterine devices,  
hormonal contraceptives: contraceptive pills, implants, transdermal patches, 
hormonal vaginal devices, injections with prolonged release. It is accepted in certain cases to 
include subjects having a sterilized regular partner or subjects using a double barrier 
contraceptive method. However, this should be explicitly justified in special circumstances 
arising from the study design, product characteristics and/or study population. 
•   Non cardiac co-morbidities with life expectancy less than 3 years 
•   Other investigational drug or device studies that have not reached their primary endpoint 
6.5.3. Angiographic Exclusion Criteria 
• Left main diameter stenosis <50% (visually assessed), unless left main equivalent disease is 
present 
 
• SYNTAX score ≥33, as determined by the consensus of at least one participating 
interventional cardiologist and one surgeon of the local Heart Team 
 
• Visually estimated left main reference vessel diameter <2.25 mm or >4.25 mm (post 
dilatation up to 4.5 mm is allowed) 
• The presence of specific coronary lesion characteristics or other cardiac condition(s) which 
leads the participating interventional cardiologist to believe that clinical equipoise is not 
present (i.e. the subject should not be treated by PCI, but rather should be managed with 
CABG or medical therapy - reasons will be documented) 
• The presence of specific coronary lesion characteristics or other cardiac condition(s) which 
leads the participating cardiac surgeon to believe that clinical equipoise is not present (i.e. the 
subject should not be treated by CABG, but rather should be managed with PCI or medical 
therapy - reasons will be documented) 
6.6. 
Subject Flow 
Every subject who presents with ULMCA or left main equivalent disease to any qualified 
interventional cardiologist or cardiac surgeon participating in this trial will be evaluated by the 
local Heart Team including detailed assessment of the inclusion and exclusion criteria, the  
SYNTAX score calculated from diagnostic angiogram, history, physical examination and 
laboratory evaluations. If the information is not adequate for the local Heart Team to make their 
decision, then further testing and/or an angiogram will be performed after informed consent is 
obtained from the subject. 

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The Study Coordinators should facilitate the local team conference.  Each site will take minutes 
of each conference for the investigators sites.  The members will review the collected baseline 
information e.g. the angiogram (including the SYNTAX score), and demographic characteristics.  
During the local Heart Team conference, the members will jointly decide whether the subject is 
eligible for randomization or for the Universal Registry. 
 
If both members of the local Heart Team determine that the subject meets the eligibility criteria 
of the Randomized Study, the subject will be deemed meeting randomization criteria and enters 
the “Randomized Clinical Trial” (Figure 6.1). 
• Note: If all the eligibility criteria are met except that the diagnostic angiography demonstrates a 
ULMCA lesion or left main equivalent lesion(s) which either the interventional cardiologist 
and/or cardiac surgeon of the local Heart Team believes is ≥50% but <70% in diameter 
stenosis by visual estimate, the subject is not yet eligible for randomization without further 
evaluation.  If non-invasive evidence of ischemia referable to a hemodynamically significant 
ULMCA lesion as defined in Section 6.5.1 is not present, the subject must have IVUS 
(preferably) or FFR assessment of the ULMCA lesion.  In this case, the subject will be 
consented for randomization prior to the invasive IVUS/FFR procedure.  If the IVUS/FFR 
procedure demonstrates that the ULMCA lesion is significant, the subject may be 
randomized at that point in the catheterization laboratory, and PCI performed if the 
randomization is to PCI. If the randomization is to CABG, the catheterization laboratory 
procedure is terminated and CABG performed as per standard of care. 
 
The local Heart Team may also decide that the subject does not meet randomization criteria. The 
reasons for this will be documented in a worksheet (Heart Team Worksheet). These subjects will 
be approached for inclusion into the Universal Registry (Figure 6.1). 
• The purpose of the Universal Registry is to assess the proportion and reasons for which 
subjects with angiographically significant ULMCA disease requiring revascularization 
during the time course of this study are not randomized; to compare the baseline 
characteristics (including the SYNTAX score) of the randomized and non-randomized 
subjects, and between those in the registry who undergo PCI versus CABG; and to assess the 
site to site variability in randomization eligibility and treatment patterns. 
• Up to 100 consecutive subjects with a visually estimated angiographic left main diameter 
stenosis of ≥50% but <70% but who did not meet the ischemia, IVUS, or FFR criteria will 
be entered into the Universal Registry but evaluated separately as intermediate lesion 
subjects.  The purpose of the evaluation of intermediate lesion subjects is to document the 
proportion and characteristics of subjects with an angiographically intermediate lesion 
(visually estimated angiographic left main diameter stenosis of ≥50% but <70%) in whom 
ischemia cannot be demonstrated and/or the lesion does not appear significant by IVUS using 
standard accepted criteria, and to assess the treatments these subjects undergo 
 
The decision for the subject’s inclusion into the Randomized Clinical Trial or the Universal 
Registry must be documented and signed by both members of the local Heart Team (Heart Team 
Worksheet). 
 
Figure 6.1 outlines the screening and randomization process and illustrates the point where 
informed consent should be obtained.

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Figure 6.1 
Subject Flow 
 
Any patient with a visually estimated left main (or left main equivalent) diameter 
stenosis of ≥50% taken care of by any qualified participating interventional 
cardiologist or cardiac surgeon at an EXCEL center 
 
 
 
Screening by Local Heart Team to determine subject eligibility using available 
diagnostic measurements 
 
 
 
Informed Consent for either 
• 
Randomized Clinical Trial (if all eligibility criteria met or could be met 
with additional testing) 
-OR- 
• 
Universal Registry (if eligibility criteria not met) 
 
 
 
 
Additional laboratory testing and/or additional angiogram if required 
to meet eligibility criteria 
 
 
 
Does not meet Criteria 
Meets All Criteria 
 
 
 
 
 
Universal Registry 
N=1000 subjects 
Subset of Patients with 
Intermediate Lesions 
N=100 subjects 
Randomized Clinical Trial 
 
(RCT) 
 
N=1900 subjects 
 
 
 
Baseline Stroke Questionnaire 
(RCT subjects) Baseline 
QoL Questionnaire (1800 
subjects) 
 
 
 
Randomize 
 
 
 
Patient is registered

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6.7. 
Subject Discontinuation 
 
Every subject should remain in the trial until completion of the required follow-up period. 
However, a subject’s participation in any clinical trial is voluntary and the subject has the right to 
withdraw at any time without penalty or loss of benefit.  Should this occur, the reason for 
withdrawal must be recorded in the source documentation. Conceivable reasons for 
discontinuation may include, but not be limited to, the following: 
 
 
• 
Subject Withdrawal:  Subject participation in a clinical trial is voluntary and the subject 
may discontinue participation (refuse all subsequent testing/follow-up) at any time without loss of 
benefits or penalty. 
 
• 
Lost-to-Follow-up:   Subject does not complete the scheduled follow-up visits but has not 
officially withdrawn from the trial (does not apply to missed visits).  Site personnel should make 
all reasonable efforts to locate and communicate with the subject, including the following, at each 
contact time point: 
◦ 
A minimum of two telephone calls to contact the subject should be recorded in the source 
documentation, including date, time, and initials of site personnel trying to make contact. 
◦ If these attempts are unsuccessful, a letter should be sent to the subject. 
◦ If  the  subject  misses  two  consecutive  scheduled  contact  time points  and  the  above 
mentioned attempts at communicating with the subject are unsuccessful, the subject will 
be considered lost-to-follow-up. 
 
Note: If a subject misses one or more of the follow-up contact time points this will be 
considered a missed visit. Subject may then return for subsequent visits. 
 
All subjects have the right to withdraw at any point during the course of the study without 
prejudice. It will be documented whether or not each subject completed the clinical study.  If the 
study treatments or observations are discontinued in any subject, the reason will be recorded and 
the Sponsor must be notified promptly. It is imperative to obtain complete follow-up data for all 
subjects (other than those who withdraw their consent), whether or not they receive their 
assigned treatments.  Every attempt should be made to collect follow-up information on all 
subjects randomized in the study through the entire five years of follow-up (or up to ten years 
optional). All procedures and laboratory specimens or tests requested for evaluation following 
administration of the study device/CABG surgery should be carried out when possible, whether 
or not a subject continues to receive treatment according to the protocol. 
 
If a subject withdraws from the study due to problems related to the investigational device safety or 
performance, the investigator shall ask for the subject's permission to follow his/her 
status/condition outside of the clinical investigation. 
 
A Study Completion Form must be completed: 
 
•   when the subject is considered lost to follow-up (per the above definition) 
•   when the subject withdraws from the study 
•   upon study completion 

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The Sponsor must be notified of the reason for subject discontinuation. The site will provide this 
information on the Study Completion Form.  Investigators must also report this to their IRB/EC 
as defined by their institution’s procedure. Subjects will not be replaced. 
7.     TREATMENT OF SUBJECTS 
7.1. 
Schedule of Events – Randomized Trial 
 
Screening 
Pre-procedure / 
Baseline 
Procedure 
Post-procedure 
visit preferred 1 
1M ± 7d 
Phone or office visit 
6M ± 14d 
visit preferred 1 
1Y (-30d, +60d) 
visit preferred 1 
2Y (-30d, +60d) 
visit preferred 1 
3Y,4Y, 5Y 
(-30d, +60d) 
possible visits 
6Y, 7Y, 8Y, 9Y, 10Y 
(-30d, +60d) 
Local Heart Team meeting 
x 
Estimate LM disease severity 
x 
Angina status 
x 
x 
x 
x 
x 
x 
x 
x 
Eligibility criteria 
x 
SYNTAX score 
x 
Physical examination 
x 
LVEF (echo, MRI or cath)10 
x 
Informed consent 
x 
FFR / IVUS(if DS ≥50 and <70%)2 
x 
Demographics, Medical History 
x 
12 lead ECG 
x3 
x3 
x4 
Laboratory tests 
HgbA1c (required), hsCRP & 
BNP (recommended) 
x 
Hgb, WBC, Platelets 
x 
CK / CK-MB 
x5 
x6 
Serum creatinine 
x 
mRS assessment 
x7 
X9 
X9 
X9 
X9 
X9 
Stroke Assessment 
(TIA Questionnaire)* 
X9 
X9 
X9 
X9 
X9 
Cardiac medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
QoL questionnaire 
x 
x 
x 
x8 
x 
Treatment assignment 
x 
Safety assessment & reporting 
---------------------- (S)AE AND Study event REPORTING-------------------------- 
Event related source docs 
----------------------collecting source documents related to events-------------------------- 
CABG / PCI treatment 
x 
Document resource utilization 
x 
x 
x 
x 
x 
x 
x 
1 Office visits are strongly recommended.   If that is not possible, phone contact with subject or subject’s local physician is acceptable.   As a last 
resort, notification of death by civil registry will be accepted. 
 
 

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2 For an intermediate left main lesion (≥50 - <70% visual DS) without non-invasive evidence of a hemodynamically significant ULMCA lesion; prior 
to randomization, a cath lab procedure must document left main IVUS ≤6mm2 (preferred) or FFR ≤0.80. 
3  ECGs to be collected for independent core lab assessment at baseline, within 24 hours post procedure (ideally at the same time as the first CK-MB draw), 
at discharge, and during any adverse cardiac event. 
4  ECG to be collected for independent core lab assessment at 1Y visit.  If the 1Y contact is by phone, the ECG must be done at a local institution and 
submitted to investigative site. 
5 CK/CK-MB is required at baseline and to assess peri-procedural MI; troponin levels are optional. At baseline prior to randomization, the CK-MB must be 
within normal limits, or if recent MI and troponin is still elevated, the CK-MB must have returned within the laboratory normal range prior to randomization. 
6 For assessment of post procedural myocardial damage, CK-MB must be drawn at 12h (±2 hrs; i.e. 10-14 hrs) and 24h (±2 hrs; i.e. 22-26 hrs) post 
procedure or at discharge if sooner. Additional serial troponins or CK-MBs should be drawn in hospital or at any time during follow-up to assess any 
adverse cardiac event. 
7. At baseline assessment is performed using mRS scale 
8. QoL questionnaire is not done at 4 year follow-up. 
9.Stroke Assessment: performed using Stroke/TIA and mRS stroke assessment. In case of an event of stroke, a mRS questionnaire disability assessment 
will also be done at 90 days±2 weeks after the event 
10.LVEF must be assessed at baseline within 14 days prior to randomization. 
 
Schedule of Events – Universal Registry 
Screening 
Pre-Treatment 
Estimate LM disease severity 
x 
Local Heart Team meeting 
x 
Angina status 
x 
Eligibility criteria 
x 
SYNTAX score 
x 
Informed consent 
X 
FFR / IVUS(if DS ≥50 and <70%)1 
x 
Demographics, Medical Hx, Physician exam, intended LVEF 
(recommended), basic labs (Hgb, creatinine) 
x 
CABG / PCI / medical treatment 
x 
 
1 Intermediate lesion (visually estimated left main diameter stenosis ≥50 - <70%) registry only; no evidence of any of the following: 1) non-invasive 
ischemia consistent with hemodynamically significant ULMCA disease; 2) FFR ≤0.8; 3) IVUS MLA ≤6mm2 
 
7.2. 
Baseline and Pre-Procedure 
 
Subject preparation will occur in accordance with standard hospital policy for the care of 
interventional cardiology or CABG subjects. 
 
7.2.1. Demographics and Medical History 
 
In all study subjects (randomized or registry), demographics and medical history will be captured 
in the eCRF. 
 
7.2.2. Pre-PCI Medication 
 
Aspirin. Preloading with aspirin 300 to 325 mg at least 2 hrs before the PCI is mandatory.  For 
subjects already receiving chronic aspirin therapy, the loading dose of 300 to 325 mg of aspirin 
must still be given.  Either chewable or intravenous aspirin is mandatory for the loading dose in  
subjects not on chronic aspirin who will receive only one dose of aspirin before the ULMCA 
PCI. 
 

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ADP antagonists. ADP antagonist pre-loading therapy is mandatory. In patients undergoing PCI, 
the ADP antagonist must be given prior to the start of the interventional procedure according to 
the timing for the selected agent below. For subjects already receiving chronic ADP antagonist 
therapy, pre-loading is still mandatory. The choice of either clopidogrel, prasugrel or ticagrelor is 
left to the discretion of the investigator. The one exception where ADP antagonist loading may 
be first given after the procedure is in the case of the patient who qualifies for randomization 
except for the presence of a visually estimated 50% - <70% diameter stenosis of the left main in 
whom IVUS or FFR will be performed for confirmation of lesion severity. In this case, since the 
patient will be randomized in the catheterization laboratory after IVUS or FFR, ADP antagonist 
pre-loading is permitted but is not mandatory; if the patient randomizes to PCI, however, and had 
not been preloaded, ADP antagonist preloading must be administered within 2 hours post PCI. In 
case of preloading, the following schedule is recommended: 
 
• clopidogrel 600 mg >6 hrs before PCI, or 300 mg >12 hrs before PCI (even if the subject is 
on chronic ADP antagonist therapy); or 
•   prasugrel 60 mg >1 hr before PCI (even if the subject is on chronic ADP antagonist therapy); 
or 
• ticagrelor with dosing per labeling >1 hr before PCI (even if the subject is on chronic ADP 
antagonist therapy) if approved by the local regulatory authorities during the randomization 
period of this protocol. 
Pre-PCI statin therapy. Recent randomized trials62, 63,64, 65, 66 have demonstrated that high dose 
statin therapy decreases PCI-related myonecrosis in subjects undergoing stent implantation, 
whether or not the subject is already taking chronic statin therapy.  Therefore, in the absence of 
absolute contraindications to statin use (e.g. severe allergy with prior use), it is strongly 
recommended to give the statins 12 hours in advance (at least one dose), but in all cases at least 1 
hour  before the PCI, regardless of LDL level and history of prior statin use. 
•   atorvastatin 80 mg 
•   rosuvastatin 40 mg 
The above statin regimens are required per the protocol. In certain circumstances, sites may not 
be able to follow the protocol required statin regimen.  In these cases, the site must agree to an 
alternative regimen with the sponsor in writing prior to randomizing any patients.  Failure to 
prospectively document and obtain approval of the alternative therapy will lead to the assessment of 
a protocol deviation. 
 
Other medications.  The use of other medications prior to PCI (e.g. beta-blockers, ACE inhibitors) 
is left to the discretion of the treating physicians. 
 
7.2.3. Pre-CABG Medication 
It is strongly recommended that subjects are treated with aspirin, statins, and antihypertensive 
medications prior to surgical revascularization. For subjects on clopidogrel, prasugrel, or  
ticagrelor prior to CABG, these agents should be discontinued and CABG postponed for at least 
5 days, 7 days or 5days, respectively, if the subject is stable. Subjects receiving amiodarone  
prophylaxis should be loaded prior to surgery, and have their treatment continued for a minimum 
of five days after surgery. It is strongly recommended that ACE inhibitors be stopped sufficiently 
before surgery to ensure they are no longer effective at the time of surgery. 

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7.2.4. 12-Lead ECG 
 
12-lead ECGs must be collected only in the randomized cohort, at pre-procedure, within 24 
hours post procedure, at discharge, and at one year follow-up. If the one year follow-up is 
performed through phone contact, the mandatory ECG must be performed at a local institution 
and submitted to the investigative site.  In addition, 12-lead ECG should be recorded during 
clinical episodes of ischemia or other adverse cardiac event and included in the event source 
documentation of the subject. 
 
7.2.5. Laboratory Tests 
 
In the randomized cohort, the following lab tests will be required pre-procedure: HbA1c, CK- 
MB, hemoglobin, WBC, platelet count and serum creatinine, whereas hsCRP and BNP are 
highly recommended. 
 
Initial screening must show that CK-MB is within normal limits.  If the subject has had a recent 
MI and the troponin level is still >ULN, the CK-MB must have fallen to within normal limits to 
qualify the subject for randomization. If the CK-MB is still elevated the subject is not eligible for 
randomization until the CK-MB has fallen to <ULN. Cardiac markers must be measured in all 
subjects at baseline and twice within 24 hours following the revascularization procedure: at 12 ± 
2 hours (i.e. 10-14 hours) and at 24 ± 2 hours (i.e. 22-26 hours) post procedure or at discharge if 
sooner. In addition, with any significant new clinical episodes of angina or adverse cardiac 
events, cardiac markers should be repeated and followed for 6-18 hours post ischemia. CK-MB 
levels must be used to assess baseline entry criteria and post procedure myonecrosis. Either CK- 
MB or Troponin I or T levels may be used to assess myonecrosis >48 hours post procedure. 
 
Note: Discharge is considered when subject leaves the treating or referral hospital. 
 
7.2.6. Left Ventricular Ejection Fraction 
 
Left ventricular ejection fraction (LVEF) must be assessed at baseline within 14 days prior to 
randomization, either by echocardiography, MRI, or contrast left ventriculography. For registry 
patients this is only recommended. 
7.2.7. Angiography 
 
Baseline angiography of the target vessel(s) will be completed as per the Angiographic Core Lab 
Protocol. (Refer to Section 23, Appendix H.) 
7.2.8. IVUS / FFR 
 
Prior to randomization, all subjects with an angiographically intermediate left main lesion (≥50 -
<70 DS% by consensus visual assessment by the Heart Team) without noninvasive evidence of a 
hemodynamically significant left main lesions must undergo additional invasive investigation 
after informed consent such as IVUS (preferred) or FFR to document lesion severity. If these 
tests provide data that the patient meets the inclusion criteria, the subject may be randomized; if 
not, the subject should be included in the Universal Registry. (Refer to Section 18, Appendix C.) 

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7.2.9. TIA/Stroke Questionnaire 
 
All patients randomized into the EXCEL RCT will have a modified Rankin Scale (mRS) 
assessment conducted by mRS-trained personnel at baseline and each visit and telephone 
interview.  Additionally, the site research coordinator will evaluate each subject at 30 days, 6 
months, 1, 2, 3, 4 and 5 Y follow-up time points and at the primary endpoint follow-up time 
point (either at annual follow-up or at subject contact for primary endpoint AE check) using a 
Transient Ischemic Attack (TIA)/Stroke Questionnaire and mRS disability questions (Appendix J).   
This questionnaire is the National Institute of Health Stroke Scale (NIHSS) validated 
questionnaire used in Abbott Vascular’s CREST clinical trial.  The disability questions are 
adapted from a structured interview developed for stroke patients.  If a subject’s response to this 
questionnaire indicates a possible stroke or a change in the mRS, then a vascular neurologist/ 
stroke specialist/mRS certified personnel blinded to the treatment type will confirm the mRS 
scale, determine whether a stroke has occurred and determine the stroke severity using the 
NIHSS TIA/Stroke Questionnaire.  If a new stroke is diagnosed at the site, the investigators at 
the site will prepare a short narrative that describes the findings that support the diagnosis.  All 
stroke events will be adjudicated by the Clinical Events Committee (CEC). Furthermore, if there is 
an increase in the mRS by one or more points noted at any visit, then an evaluation will be carried 
out to determine if a stroke or other outcome event has occurred. 
 
Post procedure, if a patient is diagnosed and adjudicated with a stroke event by the Clinical 
Events Committee (CEC), a disability assessment will be performed at least 90 days after the 
diagnosis of stroke using the mRS assessment instrument. 
 
7.2.10. QoL Questionnaire 
 
Subjects in the QoL substudy of the randomized trial should complete the Quality of Life (QoL) 
questionnaires after being determined to be eligible for randomized study participation but prior to 
randomization.  Subjects who have intermediate lesions who require an additional angiogram to 
determine eligibility should complete the QoL questionnaire prior to the additional angiogram in 
case the randomization assignment is to PCI and the angiogram procedure continues into the PCI 
treatment without leaving the catheterization laboratory. 
 
Disease-specific QoL will be assessed using the Seattle Angina Questionnaire (SAQ) and the 
London School of Hygiene Dyspnea Questionnaire in 1800 selected patients.  Mental health and 
depression will be assessed using the Patient Health Questionnaire-9 (PHQ-9).  Generic health 
status will be assessed using the Medical Outcomes Study 12-item Short Form (SF-12), and 
health utilities will be assessed using the EuroQoL (EQ-5D) with U.S.-specific weights.  These 
measures will be assessed using standardized, written questionnaires at baseline (prior to 
randomization), 1 month, 12 months, 3 years, and 5 years.  Questionnaires will be presented in 
each subject’s native language using culturally-validated translations.  When an appropriate 
translation does not exist for the instrument, it will be omitted from the specific country but the 
remainder of the questionnaires will still be administered. Data entry for each questionnaire into 
the study database will be the responsibility of an appropriate contract research organization 
(CRO). 
 
See Section 17, Appendix B. for details regarding Quality of Life and U.S. Health Economics 
Sub-Studies. 

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7.2.11. Resource Utilization 
 
Data on cardiovascular-specific resource utilization will be collected prospectively for each 
randomized U.S. subject for the index hospitalization and the full follow-up period for all 
subjects using standardized case report forms. 
 
7.2.12. IVRS Randomization 
 
After informed consent has been obtained and all eligibility criteria have been confirmed, the 
central allocation service (Interactive Voice Response System:  IVRS) should be contacted 
(ICON Clinical Research, L.P.). Prior to randomization, the IVRS will prompt the study 
coordinator to provide the subject’s SYNTAX score and diabetes status (whether or not medically 
treated for stratification purposes). The IVRS will randomize the subject to either PCI with the 
XIENCE stent (depending on availability) or CABG treatment on a one to one basis using a 
randomized block design.  Randomization will be stratified by the presence vs. absence of 
medically treated diabetes, SYNTAX score <23 vs. ≥23, and study center. Patients with 
significant ULMCA disease who are otherwise not eligible for randomization should be entered 
into the Universal Registry through the IVRS, ideally prior to revascularization. 
 
7.3.         Procedure- PCI 
 
It is recommended that the treatment for subjects randomized to PCI will be according to the 
product labeling and instructions for use as well as the following instructions: 
 
7.3.1. General Considerations 
 
• 
Procedural “staging” in PCI subjects is defined as a planned elective second PCI procedure 
at a separate setting to optimally complete the PCI.  Given the complexity of the ULMCA 
subjects randomized in this clinical trial, it is anticipated that a substantial proportion of PCI 
subjects may fall into the category of staged procedures.  The criteria for staging are left to 
the operator’s best judgment, and there is expected variability among operators and sites.  In 
general, the decision to stage is based on the overall extent and complexity of coronary  
 
 
disease, the case complexity (intra-procedure difficulty encountered by the operator), the 
duration of the procedure, assessment of radiation exposure, the total volume of contrast 
utilized, the clinical stability of the subject, and other subject-related factors (diabetes, renal 
function, etc.). The recommended timing of a planned elective staged second PCI procedure 
is optimally within 2 weeks post index procedure, but in all subjects it is strongly 
recommended that it be completed within 4 weeks post index procedure. 
 
The reason(s) for the staged procedure must be documented in the eCRF and source 
documents. Furthermore, the need for staging, and all specific lesions planned to be treated 
during the staged procedure should be declared beforehand in the eCRF at the time of initial 
baseline procedure. 
 
Unless otherwise planned, stented segment(s) treated during the initial baseline procedure 

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should not be treated again during the staged procedure. If the e-CRF from the first procedure 
did not indicate that such re-intervention was planned, the re-PCI will be considered to be 
clinically indicated, and will be analyzed as an event (although not necessarily ischemia- 
related – the Clinical Events Committee will make this determination). 
 
Only randomized study stents should be used during staged procedures, if possible. During a 
staged  procedure  the  same  study  assessments  (such  as  ECG  and  cardiac  biomarker 
collection) apply as during the baseline procedure. All subjects must be taking the protocol 
required post ULMCA medications (such as aspirin and ADP antagonists) prior to staged 
procedure. The staged procedures will not affect the original follow-up schedule. 
• 
Hemodynamic support for PCI subjects with ULMCA lesions is usually not required but 
there is significant variability in the perceived need for hemodynamic support among 
experienced operators and sites.  Criteria for required hemodynamic support may include 
systemic hypotension, severe pulmonary hypertension, severely reduced ejection fraction, 
extreme anatomic complexity (e.g. severely calcified left main lesion with intended use of 
rotational atherectomy), and/or subject instability before or during the procedure.  The 
decision regarding the use hemodynamic support, either elective and planned or urgently 
required due to subject instability, and the type of support device is left to the operator’s best 
judgment. 
 
• 
The choice of vascular access for PCI (e.g. femoral or radial) is left to the operator’s best 
judgment. 
• 
The choice and use of vascular closure devices is left to the operator’s best judgment. 
 
7.3.2. Optimal ULMCA PCI – General Considerations 
 
• 
Determination of ULMCA lesion severity. At the time of the PCI procedure, all ULMCA 
lesions which appear visually to be <70% stenotic (even if the angiographic stenosis 
appeared to be ≥70% in severity on the earlier qualifying angiogram), should not be treated 
with PCI unless there is evidence of ischemia or morphologic severity defined as either: 
◦ 
noninvasive functional evidence of ischemia in the territory of the lesion (not explained 
by another coronary stenosis), and/or 
◦    IVUS minimal luminal area ≤6.0 mm2 (see IVUS procedural guidelines), and/or 
◦    FFR ≤0.80 (see FFR procedural guidelines). 
 
If the subject has been randomized to PCI and the ULMCA stenosis is no longer believed to 
be significant by these criteria, PCI should in most cases be performed of other significant 
lesions, but the ULMCA should not undergo intervention. Exceptions might include cases in 
which there is ostial LAD or LCX disease abutting the borderline left main lesion which 
must be treated; when the left main stenosis is rapidly progressive on the basis of serial 
angiograms; or when the left main lesion is irregular or disrupted in appearance or has other 
high risk features for continued medical therapy. Whether or not the ULMCA is treated, once 
randomized, the subject will remain in the randomized trial by intention to treat. 
 
• 
In subjects with “other coronary disease” outside of the ULMCA complex, the following 
treatment sequences are recommended: 
◦ 
If LAD and/or LCX disease is present, treat the LAD and/or LCX first (distal to proximal, 

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as per usual PCI practice), unless the severity of the LM stenosis (e.g. >70% stenosis) 
requires primary treatment of the LM first. 
◦ If the ULMCA lesion is critical (e.g. >90% visually assessed stenosis or clinical 
instability), treat the ULMCA first, either with balloons or definitive stenting as 
randomized to insure subject safety. 
◦ 
If the RCA has a severe culprit lesion in a large vessel and the ULMCA stenosis is <70%, 
the operator may choose to treat the RCA before the ULMCA lesion; otherwise the 
ULMCA lesion should usually be treated before the RCA. 
◦ 
Chronic total occlusions (CTOs) should usually be treated after completion of the 
ULMCA lesion (frequently as a planned second staged procedure). 
• 
Left main lesion preparation, defined as pre-treatment with balloons or other approved 
devices (including rotational atherectomy for heavily calcified vessels), of the ULMCA 
complex is left to the operator’s best judgment, but is strongly recommended.  Direct stenting 
of the ULMCA is strongly discouraged. 
• 
Adequate lesion pre-dilatation requires dilatation with a balloon no smaller than 0.5 mm 
smaller than the distal RVD. Furthermore, when moderate or greater calcification is evident 
by either angiography or IVUS, all possible steps should be taken to ensure that full balloon 
expansion with the anticipated final stent size is achievable before the stent is implanted. 
This might require pre-dilatation with a non-compliant balloon sized 1:1 to the distal RVD 
(either alone or in conjunction with a cutting/scoring balloon and/or high-speed rotational 
atherectomy), and/or successful passage of an IVUS catheter after pre-dilatation 
demonstrating adequate lumen dimensions.  Strong consideration should be given to 
additional pre-dilatation or lesion preparation if an IVUS catheter will not cross the lesion 
prior to stent implantation. 
• 
To provide continuous branch vessel access and to ensure subject safety, two separate 
guidewires must always be in place in both the LAD and LCX during treatment of a distal 
LM bifurcation lesion. 
• 
In subjects randomized to PCI, only the commercially available XIENCE stent can be used –  
 
this is mandatory. The XIENCE DES should be used if it is available in the appropriate 
diameter and length. The XIENCE PRIME DES is available in diameters from 2.25 mm to 
4.0 mm and lengths from 8 mm to 38 mm (see Table 2-4 for size matrix).  The XIENCE V 
DES is available in diameters from 2.25 mm to 4.0 mm and lengths from 8 mm to 28 mm 
(see Table 2-3 for size matrix).  The XIENCE Xpedition is available in diameters from 2.25 
mm to 4.0 mm and lengths from 8 mm to 38 mm (see Table 2-5 for size matrix). The 
XIENCE PRO DES (for OUS use only) is available in diameters from 2.25 mm to 4.0 mm 
and lengths from 8 mm to 38 mm (see Table 2-6 for size matrix).  The 4.0 mm diameter 
XIENCE stent can be post-dilated up to 4.5 mm diameter using appropriately sized balloons. 
It is strongly recommended not to overlap XIENCE V stents due to the absence of longer 
XIENCE V stent lengths to match the XIENCE PRIME, XIENCE Xpedition or XIENCE 
PRO (for OUS use only) 33 and 38 mm stent lengths. 
• 
The following techniques are strongly recommended to optimally deploy the XIENCE DES: 
◦    good lesion preparation with balloons or other approved devices as above 
◦    selection of the stent diameter according to the distal reference vessel diameter (1.0 – 
1.1 : 1.0 ratio) 

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◦ 
deployment of the XIENCE PRIME (at 8 to 18 atm), XIENCE Xpedition (at 8 to 18 atm), 
XIENCE PRO (at 8 to 18 atm, for OUS use only) or XIENCE V DES (at 8 to 16 atm) 
◦ 
optional post-dilation using properly sized non-compliant balloons at  high pressures 
contained within the stent margins, especially if there is an area of incomplete expansion 
(noted by IVUS or as a “waist” on the deployment balloon or angiographic narrowing 
post-deployment). 
 
In the rare case where a XIENCE stent is not available in the size and/or length needed, or 
the XIENCE stent cannot be delivered to the target site, subjects should be managed per the 
standard of care at the hospital site in the best interest of the subject. 
 
IVUS guidance for ULMCA PCI is found in Section 20.2 
• 
Devices not approved by the FDA may not be used during the procedure. 
 
7.3.3. Left Main Ostial and Shaft Lesions 
 
• 
After adequate lesion preparation and in the optimal deployment view, a single stent should 
be implanted in the ULMCA, beginning at the ostium (placed 1-2 mm in the aorta to ensure aorto-
ostial coverage) and ending in either the ULMCA segment if the ULMCA length is >8 mm, or 
“crossing-over” to end in either the LAD (usually) or LCX (less commonly) if the ULMCA length 
is <8 mm. 
• 
Post-dilatation with short high pressure (≥18 atm) non-compliant balloons within the stent 
margins is strongly recommended unless IVUS guidance indicates flush apposition and 
appropriate CSA (minimum CSA >8.5 mm2). 
 
7.3.4. Left Main Distal Bifurcation Lesions 
 
• 
A single stent crossover provisional technique is strongly recommended whenever possible 
with the stent size selected to match the distal branch reference vessel (usually the LAD). If the 
side branch origin (usually the ostial LCX) has a residual stenosis <50% with TIMI 3 flow, and 
without a significant dissection, the decision to dilate the side branch is left to the discretion of 
the operator.   If the decision is made not to dilate the side branch, a short (usually 8 mm) 
non-compliant balloon contained within the left main segment should be used to fully expand the 
stent in the left main.  If there is uncertainty concerning the adequacy of side branch patency, an 
FFR determination is recommended, with a value of ≤0.80 indicating that side branch dilatation 
should be performed.67, 68  If there is significant (>50%) stenosis or other signs of sub-optimal 
side branch appearance (e.g. dissection or FFR ≤0.80), it is strongly recommended to utilize 
kissing balloons after a single stent crossover technique, with long inflations of 60 seconds or 
more if tolerated by the subject to attempt to manage the ostial LCX without additional stent 
implantation. The technique of post-stent kissing balloons in this circumstance includes the use of 
non-compliant short balloons in both branches with balloon sizing according to the distal  
reference  vessel  diameters,  initial dilation of the side branch balloon at moderate pressures (8 to 
12 atm), followed by simultaneous inflation/deflation of both balloons (8 to 12 atm). 
 
• Guidelines for a provisional second stent: After single stent crossover stent placement, if the 
branch vessel origin appears sub-optimal based upon angiographic, FFR or IVUS 

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assessment, subsequent kissing balloon angioplasty is strongly recommended as above. If 
the side branch is still suboptimal in appearance despite multiple balloon inflations, based 
upon the following criteria: severe dissection (≥grade B), TIMI flow <3, or “severe stenosis” 
>70% DS (visual estimate) or IVUS MLA ≤4.0 mm2 with plaque burden >60%, or FFR ≤0.80 
– a provisional second stent should be strongly considered. 
• The technique for a provisional second stent is left to the operator’s best judgment and may 
include any the following: T-stent, TAP, mini-crush (reverse crush), or culotte bifurcation 
stent techniques. The use of kissing balloons after provisional second stents is strongly 
recommended. The technique of post-stent kissing balloons in this circumstance includes the 
use of non-compliant short balloons in both branches with balloon sizing according to the 
distal  reference  vessel  diameters,  initial  dilation  with  the  side  branch  balloon  at  high 
pressures (≥18 atm), followed by simultaneous inflation and deflation of both balloons 
(8-12 atm). 
• The decision to use a primary two stent technique strategy rather than a single crossover 
stent technique should be considered when the side branch (usually the LCX) is large 
(>3 mm), with significant disease (by angiographic or IVUS assessment) and lesion length 
>5 mm, or when there are other special anatomic considerations (e.g. heavy calcification). 
Considering the anatomic variability of the distal LM bifurcation, the final decision to select 
a primary two stent technique strategy is left to the operator’s best judgment. The choice of a 
particular distal bifurcation stent strategy is also left to the operator’s best judgment and may 
include T-stenting, TAP, crush, or culotte stent techniques. A “V-stent” distal bifurcation 
stent approach is discouraged unless the ULMCA segment is very short, or there is focal 
ULMCA distal bifurcation disease which extends into the branch vessel origins and the 
procedure can be completed with a short segment (<3 mm) of two stents in the distal 
ULMCA segment. 
• The use of kissing balloons after primary two stent technique is strongly recommended. The 
technique of post-stent kissing balloons in this circumstance includes the use of non- 
compliant short balloons within the margins of the stents in both branches with balloon sizing 
according to the distal reference vessel diameters, initial dilation of the side branch balloon at  
 
high pressures (≥18 atm), followed by simultaneous inflation/deflation of both balloons (8- 
 
12 atm). 
 
7.3.5. Optimal PCI of Other Coronary Lesions 
 
• For all “borderline or intermediate non left main lesions” (40-70% diameter stenosis by 
angiographic visual estimate), it is strongly recommended to confirm the lesion significance 
before treatment using FFR evaluation (preferred) or IVUS assessment (alternate).  In the 
case of FFR this may need to be performed after successful stenting of the left main stenosis. 
(See Section 20)  Non left main lesions which are not severe either by angiographic, IVUS or 
FFR assessment should not undergo PCI. 
• For all non-left main lesions, IVUS guidance pre-treatment and assessment post-treatment 
to optimize lumen dimensions is recommended (especially for LAD lesions, with exceptions 
including distal lesions, tortuous vessels, or focal proximal lesions in large vessels).  IVUS 
guidance 
to 
optimize 
the 
results 
of 
intervention 
in 
the 
left 
main 
segment 

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is strongly recommended. (See Section 20. Appendix E.) 
 
• The liberal use of additional guidewires to protect side branches during complex angioplasty is 
recommended as per the operator’s best judgment. 
 
• Lesion preparation using balloons or any approved device is left to the operator’s best 
judgment to be able to deliver the stent to the lesion and achieve full stent expansion. 
• It is mandatory that only a XIENCE stent is used for all non left main coronary lesions 
which are stented. If the XIENCE stent is either unavailable or cannot be delivered to lesion 
site, it is recommended to follow standard of care at the site. 
• Liberal use of short non-compliant post-dilation balloons (≥18 atm) within the stent margins 
of all stents is recommended to optimize luminal results, unless IVUS otherwise shows 
optimal expansion and lumen dimensions. 
• Criteria for optimal PCI of ULMCA and non LM lesions are as follows: visual diameter 
stenosis <10% is acceptable (0% stenosis is strongly preferred), and there should be no edge 
dissections > type A, with no residual edge stenosis >20% by angiography. 
• Specific lesion categories, such as chronic total occlusions, bifurcation disease, diffuse 
lesions, thrombus-containing lesions or heavily calcified lesions should be treated according to 
the operator’s best judgment using acknowledged best PCI practices. In situations of 
diffuse disease or tandem lesions it is recommended to use single long stents rather than 
either two shorter side-by-side or overlapping stents. A liberal staging strategy should be 
used, especially for subjects with complex double vessel or triple vessel disease, or if high 
doses of radiation and/or contrast are used in the first procedure. Refer to Section 7.3.1. 
7.3.6. Intra-procedure Adjunctive Pharmacology 
• Either bivalirudin, unfractionated heparin or low molecular weight heparin is acceptable 
(according to proper dose guidelines, adjusted for renal insufficiency). Bivalirudin is 
recommended for this protocol based on a recent large scale study in more than 127,000 
subjects demonstrating a reduction in mortality with bivalirudin compared to heparin + 
GPIIb/IIIa inhibitors across a broad cross section of subjects undergoing PCI.69 Moreover, 
two additional recent studies in more than 1.5 million patients and 13,500 patients have 
 
shown that bivalirudin results in a marked reduction in major bleeding compared to other 
 
anticoagulants,  especially  when  used  in  concert  with  vascular  closure  devices. 70 , 71 
 
Bivalirudin should be administered as an intravenous bolus of 0.75 mg/kg and an infusion of 
 
1.75 mg/kg/hr, started 5 minutes before PCI.  In patients with an estimated creatinine 
 
clearance <60 ml/min (as calculated by the Cockcroft-Gault formula), the bolus dose of 
 
bivalirudin is unchanged, but the infusion dose should be reduced as follows: 
 
 
Calculated Clcr 
(ml/min) 
Bivalirudin 
Half-life (min) 
Reduction in Infusion 
Dosage (%) 
>90 
25 
0 
60-90 
22 
0 
30-59 
34 
20 
10-29 
57 
60 
<10 
210 
90 

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As a direct thrombin inhibitor, bivalirudin increases the activated clotting time (ACT). 
However, use of the ACT level to guide bivalirudin dosing has not been found to be helpful; 
i.e. high ACT levels have not correlated with bleeding, and low ACT levels have not 
correlated with lack of efficacy with bivalirudin. ACT levels are therefore not required in this 
protocol. However, it is recommended that an ACT is drawn just to be certain that the 
bivalirudin bolus and infusion have been delivered. 
 
 
In  nearly  all  cases,  the  bivalirudin  infusion  should  be  discontinued  at  the  end  of  the 
procedure. If manual compression is to be used, femoral sheaths may be removed in 2 hours 
without checking an ACT or a PTT level. Of course, hemostasis may be obtained at any 
earlier time by use of a vascular closure device, the use of which is per operator discretion. 
 
• 
If unfractionated heparin is used as a procedural anticoagulant, it is recommended that an 
initial bolus of 60 U/kg be administered, with subsequent boluses titrated to an ACT of 
250 seconds. However, the exact manner of use of unfractionated heparin is left to the 
discretion of the operator and local practice. Low molecular weight heparin may be used as a 
procedural anticoagulant as per local practice and expertise, but is not recommended in 
subjects with an estimated creatinine clearance <60 ml/min. Fondaparinux is not permitted as 
a procedural anticoagulant. Procedural anticoagulants should usually be discontinued at the 
end of the procedure, but in rare cases may be continued at low dose as per physician 
discretion (e.g. for subjects with an indwelling intra-aortic balloon pump). The routine use of 
post procedural low molecular weight heparin for prophylaxis of deep venous thrombosis is 
not permitted. 
7.3.7. GP IIb/IIIa inhibitors 
 
GP IIb/IIIa inhibitors are strongly discouraged in subjects adequately pre-loaded with an ADP 
antagonist (clopidogrel, prasugrel, or ticagrelor), especially if bivalirudin is used. GP IIb/IIIa 
inhibitors may be used, however, in subjects with large amounts of thrombus, or for thrombotic 
or ischemic complications arising during the procedure (provisional or bail-out use) – e.g. for 
refractory thrombus or no reflow resistant to repeat balloon dilatation and intracoronary use of 
nitroprusside or calcium channel blockers in the absence of a mechanical complication. 
Provisional GP IIb/IIIa inhibitors may not be used for “soft” indications such as lesion haziness 
or a small dissection as their use in these situations will increase bleeding complications, without 
clear benefit. 
7.4.  Procedure – CABG 
 
The treatment for subjects randomized to CABG is as follows: 
 
7.4.1 Optimal CABG Requirements 
 
• Conduct of Surgery.  Coronary artery bypass grafting may be performed with or without the 
assistance of cardiopulmonary bypass, depending on the expertise of the center. Robotic 
surgery techniques may not be used. 
 
On-pump, surgical revascularization may be performed with an arrested heart or beating 

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heart strategy.  Cannulation for cardiopulmonary bypass should be ascending aortic for 
arterial return, unless there is ascending aortic atherosclerosis or dilatation (>4 cm in 
diameter), and right atrial for venous drainage. In cases of aortic atherosclerosis or dilatation, 
an alternate arterial cannulation strategy must be performed (see below).  Cardiopulmonary 
bypass blood flow should be maintained at least at 2.0 liters/m2/minute.  Systemic arterial 
blood pressure should be at maintained at a minimum of 60 mm Hg during cardiopulmonary 
bypass, and should be increased in the elderly and in those with cerebrovascular disease to 
ensure adequate cerebral blood flow. During cardiopulmonary bypass the subject’s 
temperature may be cooled or allowed to drift down as determined by local practice. Use of a 
single cross-clamp technique for subjects undergoing CABG on CPB is strongly 
recommended and multiple applications of an aortic clamp is strongly discouraged. When 
weaning from cardiopulmonary bypass it is recommended that the subject be normothermic. 
 
Sites will be advised to follow their own insulin protocols for glucose level management 
intra-and postoperatively if these are consistent with the STS practice guidelines. If no 
guidelines exist, then sites will be advised to follow an insulin protocol similar to the one 
included in Appendix I. 
 
In off-pump and on-pump beating heart surgery, coronary stabilization devices must be used. 
Coronary artery exposure and cardiac manipulation may be performed with apical suction 
positioners and/or pericardial sutures. Intravascular shunts may be used to prevent ischemia 
and allow for hemostasis during performance of the distal anastomoses.  Proximal vessel 
loops may be used to obtain hemostasis during construction of the distal anastomoses or 
placement of intravascular shunts.  Distal vessel loops are to be avoided whenever possible. 
The use of a humidified blower during the performance of the distal anastomoses to improve 
visibility is highly recommended.  Every effort should be made to keep the subjects 
normothermic during off-pump revascularization. 
 
After completion of proximal and distal anastomoses, graft patency assessment is strongly 
recommended with either transit time Doppler flow measurements or with intra-operative 
angiography with immunofluorescence or standard radiographic angiography.  If a bypass graft 
is determined to be functioning poorly, the graft should be evaluated and revised. 
• Aortic Assessment.  It is strongly recommended that intra-operative assessment of the 
ascending aorta by transesophageal echocardiography and/or epi-aortic echocardiography be 
performed.  Aortic assessment should be performed prior to manipulation, cannulation, or 
clamping of the ascending aorta.  If ascending aortic atherosclerosis or dilatation is identified, a 
surgical strategy must be used that does not manipulate, cannulate, or clamp the 
atherosclerotic or dilated aorta.  For on-pump revascularization a strongly recommended 
option is alternate site arterial cannulation (axillary or femoral artery) with no ascending 
clamping, and for off-pump revascularization a strategy with a no-touch aortic technique 
should be implemented.  Hypothermic circulatory arrest with ascending aortic replacement 
should be used as a last resort for subjects with ascending aortic atherosclerosis. Locally 
approved proximal aortic connectors and facilitators (that do not involve aortic clamping) 
may be used to perform proximal anastomoses. 
• Cardioplegia for On-Pump, Arrested Heart Surgery. Intermittent, cold blood cardioplegia is 
the preferred myocardial protection strategy for on-pump, arrested heart surgery.  However, 
intermittent cold crystalloid cardioplegia or continuous warm blood cardioplegia is allowed if 
local standard of care.  Cold blood cardioplegia should be administered initially at 10 to 15 

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cc/kg to arrest and protect the heart, and then re-administered every 20 to 30 minutes at a 
minimum of 5 cc/kg.  Delivery of cardioplegia should be initially antegrade to arrest the heart 
in the absence of important aortic insufficiency.  If important aortic insufficiency is present 
and antegrade delivery of cardioplegia is not feasible, cardioplegia should be administered 
retrograde to arrest the heart and additional right ventricular protection methods should be 
performed, such as ice slush to the surface of the right ventricle and cardioplegia administered 
via the completed bypass graft to the right coronary artery system.  During the remainder of 
the cross-clamp period, cardioplegia may be administered antegrade, retrograde via a coronary 
sinus catheter, and/or via completed saphenous vein grafts.  If available, a nutrient rich hot 
shot given prior to removing the aortic cross-clamp is highly recommended. 
◦ 
Conduit Selection. Arterial grafts are the preferred conduits for coronary revascularization. It 
is strongly recommended for all subjects to have the left internal thoracic artery used to 
graft the left anterior descending coronary artery system. In most cases this may be the left 
internal thoracic artery. In subjects less than seventy years of age, additional arterial grafts are 
highly recommended. The right internal thoracic artery is the preferred second arterial graft, 
and should be used to graft the next most important and stenotic coronary artery system. It 
may be used as an in-situ graft or free graft. Other arterial grafts that may be used in this study 
include the radial, in-situ gastroepiploic, and free inferior epigastric arteries. When using the 
radial artery as a bypass graft, it should be preferentially used to revascularize a left coronary 
artery system branch with severe (>70%) stenosis. The in-situ gastroepiploic artery may be 
used to graft severely stenotic (preferentially occluded) branches of the right coronary artery 
or posterior descending of a left dominant system. The inferior epigastric artery is best used as 
a “Y” or “T” graft. 
 
Saphenous vein grafts may be used for coronary revascularization in the study. Since 
internal thoracic artery grafting of the left anterior descending is standard of care for surgical 
revascularization, saphenous veins may be used to bypass the left anterior descending only 
when the left internal thoracic is an inadequate conduit. 
 
Although arterial grafts are the preferred conduit, each center should use a conduit 
revascularization strategy that they are experienced and comfortable performing. When selecting 
conduits, the effects of native coronary competitive blood flow must be considered. 
 
Details of non-use of arterial grafts and non-use of internal mammary artery grafts including the 
reasons for such non- use will be recorded in the EXCEL trial eCRF. 
 
• Intraoperative Transesophageal Echocardiography Assessment. It is highly recommended 
that intraoperative transesophageal echocardiography be performed prior to cannulation to 
assess left ventricular function, cardiac valves, and ascending aorta. For subjects with 
intraoperatively identified important valve dysfunction or aortic aneurysmal disease, the 
surgeon may repair or replace the valve or aorta as deemed necessary. Intraoperatively, after 
coronary revascularization is complete, it is strongly recommended that transesophageal 
echocardiography be used to assess for new ventricular wall abnormalities. If new ventricular 
wall abnormalities are identified, then the bypass graft supplying that myocardial area should 
be evaluated and revised if necessary. 
 

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7.5. 
Completeness of Revascularization 
 
All ischemic myocardial areas, such as those subtended by coronary arteries with visually 
assessed ≥50% diameter stenosis, should be revascularized. 
 
For subjects randomized to PCI:  In prior PCI vs.  CABG trials, the determination of and 
execution of “completeness of revascularization” strategy has been an important consideration. 
In this trial, the philosophical approach is to perform PCI of all significant ischemia-
producing lesions as opposed to all lesions which appear to be significant by angiographic visual 
assessment, especially if the angiographic lesions are 40-70% diameter stenosis.  Moreover, it is 
strongly recommended that PCI is performed only in ischemia-producing lesions, in most cases 
not treating non ischemia-producing lesions. Ischemia-producing lesions are defined as those 
which (1) are ≥70% angiographic diameter stenosis (visually assessed), or if <70% diameter 
stenosis, are either (2a) associated with noninvasive functional evidence of ischemia in the 
territory of the lesion (not explained by another coronary stenosis), and/or (2b) intra-procedure 
FFR ≤0.80 (note FFR procedure guidelines), and/or (2c) IVUS minimal luminal area ≤4.0 mm2 
(for non left main lesions) with plaque burden >60% (note IVUS procedure guidelines). 
 
For subjects randomized to CABG: Since all subjects in this study have important ULMCA 
stenosis, according to contemporary surgical standards, all subjects should have at least one 
bypass graft to the left anterior descending coronary artery system and a second graft to 
circumflex coronary artery system. All coronary arteries with ≥50% stenosis and ≥1.5 mm in 
diameter should be revascularized. 
7.6. 
Post-Procedure Assessments and Medications 
 
Following the procedure, mandated medication is specified below; beyond that, the subject will 
be treated in accordance with hospital standard of care. 
 
7.6.1. Laboratory Assessments 
 
The laboratory assessments need to be obtained according to the Schedule of Events included in 
Section 7.1. 
 
7.6.2. Post-PCI Medications 
 
Aspirin. Mandatory dosing with aspirin will be ≥75 mg post-PCI per day in the hospital, and 
then aspirin ≥75 mg per day indefinitely.  Daily aspirin must be given for the duration of the 
trial. Aspirin must not be discontinued for CABG or other reasons unless absolutely necessary. 
 
ADP antagonists. Chronic daily ADP antagonist therapy is mandated for at least one year after 
PCI in subjects who received a ULMCA DES, with the choice of agent left to the discretion of 
the investigator, either: 
 
 
• 
clopidogrel 75 mg per day, or 150 mg per day for 7-30 days then reduced to 75 mg per day, 
unless clopidogrel hyporesponsive; 
 
• 
prasugrel 10 mg per day (5 mg per day may be used in patients <60 kg in body weight or in 
other circumstances, but in general  the 5 mg per day prasugrel dose is discouraged given 

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minimal clinical experience with this prescribed amount); 
 
 
• 
ticagrelor per labeling and recommended guidelines if approved by the local regulatory 
authorities during the treatment period of this protocol. 
 
“Hypo-responders” to anti-platelet therapy based on point of care testing are managed according to 
local standard of care.  A daily ADP antagonist must be given for at least one year in the 
absence of major complications, and is recommended for the duration of the trial in the absence of 
major bleeding or other complications. 
 
ADP antagonists must not be discontinued within the first year after DES implantation unless 
absolutely necessary for major bleeding, major trauma, or major surgery necessitating 
discontinuation of antiplatelet therapy (e.g. intracranial surgery).  Many surgeries can safely be 
performed while the subject is on dual antiplatelet therapy.  If a subject on dual antiplatelet 
therapy requires surgery, strong consideration should be given to performing the surgery without 
antiplatelet agent discontinuation.  If a particular dual antiplatelet therapy must be discontinued, a 
GP IIb/IIIa bridging strategy up until the time of surgery may be considered, followed by re- 
loading of the ADP antagonist as soon as possible post surgery. 
 
Statin therapy. See Section 22.2 for recommendations for statin use after PCI. 
 
Other medications. For medication use post PCI, see Section 22.2. 
 
7.6.3. Post-CABG Medications 
 
Aspirin (≥75 mg) must be given within six hours after surgery intravenously, orally, rectally, or 
via a nasogastric tube if there is no important bleeding (≤50 cc/hr), and daily for the duration of 
the trial.  All subjects should be treated postoperatively with daily statins and beta-blockers, 
unless contraindicated, see Section 22.2. 
 
Beta-blockers are recommended for prophylaxis of post-operative atrial fibrillation.  Amiodarone 
may be considered for subjects in whom beta-blockers are contraindicated and as therapy for 
postoperative sinus rhythm control.  For subjects receiving amiodarone prophylaxis for atrial 
fibrillation, amiodarone should be continued for five days postoperatively. 
 
It is recommended that ACE inhibitors be given in subjects with depressed left ventricular 
function. 
 
Clopidogrel is not required but may be administered as per local standard of care in subjects with 
saphenous vein grafts or in those who underwent off-pump surgery. 
 
7.6.4. Post-Operative Atrial Fibrillation – CABG 
 
Post-operative atrial fibrillation should be treated with either rate control and anticoagulation, or 
chemical or electrical cardioversion.  Subjects being treated with rate control and anticoagulation 
should be treated with warfarin and may be bridged with heparin as per local protocol.  Subjects 
undergoing cardioversion may undergo cardioversion without anticoagulation if the duration of 
atrial fibrillation is less than 36 hours.  Subjects undergoing cardioversion where the duration of 
atrial fibrillation is greater than 36 hours should be adequately anticoagulated with either heparin 
or warfarin as per local practice.  If atrial fibrillation recurs or is resistant to cardioversion, 

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anticoagulation with warfarin with or without heparin bridging is strongly recommended. 
Warfarin anticoagulation should be continued as per local practice, but at a minimum until atrial 
fibrillation has resolved.  Subjects on warfarin anticoagulation for atrial fibrillation should be 
maintained with an INR of 2.0 to 2.5. 
8.     EVALUATION OF SAFETY AND EFFECTIVENESS 
 
Safety and efficacy will be evaluated at several timepoints throughout the trial as described in the 
Schedule of Events. 
 
8.1. 
Laboratory Tests, ECGs, and Other Measures 
 
Tests will be performed periodically on all subjects as follows (Section 7.1, Schedule of Events): 
 
8.2. 
Clinical Follow-up 
 
Subjects will have clinical follow-up as a telephone contact or office visit, at the time points listed 
below.  Day 0 is the date of the randomization assignment which can be on the same date or 
earlier than the date of the randomized procedure.  All adverse events (AE) will be recorded 
from Day 0.  Patient follow-up will occur from the day of randomized procedure as shown below. 
Office visits are strongly recommended for the annual clinical follow-up.  If that is not possible, 
phone contact with subject or subject’s local physician is acceptable.  As a last resort, notification 
of death by civil registry will be accepted. 
•   30 ± 7 days (office visit preferred) 
•   6 months ± 14 days (telephone contact or office visit) 
•   Visits at 1, 2, 3, 4, and 5 years with windows of -30 days, +60 days (office visit preferred) 
•   Potential visits: 
 
◦ 
Yearly visits at 6, 7, 8, 9, and 10 years with window of-30 days, +60 days (office visit 
 
preferred) 
 
All efforts must be made to obtain follow-up information on subjects who have visited a clinic or 
hospital, underwent procedures or have been treated for adverse events in a non-study-related 
hospital(s).  Non study hospital related material will be collected and reviewed at the study 
coordinating centers.  All follow-up angiograms must be collected (whether at the study hospital or 
an outside hospital) and sent to the angiographic core laboratory for independent analysis. 
 
The following data will be collected at 30 days, 6 mo, 1 year, 2 years, 3 years, 4 years and 5 
years follow-up time points (and potential 6-10 year visits).  
 
 
• 
Data regarding adverse events (with related laboratory tests results), including but not limited 
 
to death, MI, stroke, TIA, bleeding, renal insufficiency, repeat revascularization procedures, 
 
repeat hospitalization for any reason, ECGs, details of any subsequent repeat coronary 
 
angiography and results of such, if applicable. 

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• 
Details of any subsequent coronary interventions (for example, repeat PCI or CABG).  The 
 
physician must record in the source documents whether a revascularization was carried out 
 
during the period between the index procedure and the follow-up visit.  The physician must 
 
then document whether the revascularization was based on clinical signs and symptoms and 
 
available ancillary data and whether the procedure was ischemia driven according to the 
 
definition specified in this protocol (Refer to Section 16, Appendix A). 
•   Compliance to protocol-required medications 
•   Use and changes in chronic concomitant medications (Refer to Section 16, Appendix A). 
 
Additional Follow-up Visits 
 
Additional subject visits may occur as clinically warranted.  The same information as specified in 
Section 8.2, Clinical Follow-up, will be collected. 
 
To support the 3 year endpoint analysis, clinical sites will be asked to obtain the 3 year adverse 
event status on all subjects.  Therefore, an adverse event (AE) check should be performed in order 
for data up to 3 years (365 days*3=1095 days) from date of randomization to be established 
equally in both arms.  The AE check will commence the day after the 2 year follow-up of the last 
subject enrolled.  At this time, all clinical sites must contact subjects to collect AE information if 
one of the following has occurred: 
•   Subject had a 3 year visit >28 days prior to 1095 days; or 
•   Subject has completed their 2 year visit but has not yet completed the 3-year visit, and follow-
up is beyond 730+28 days. 
 
For subjects who have completed visits at ≥ (1095 – 28= 1067) days, no further contact is needed 
concerning the AE check. 
 
8.3. 
Guidelines for Follow-up Non-Invasive Testing, Angiography and 
 
Reintervention 
 
8.3.1. Follow-up Non-Invasive Testing 
 
The decision whether to perform routine stress testing after ULMCA treatment should depend on 
the symptomatic state of the subject, as follows: 
 
 
• 
The asymptomatic subject.  Routine stress testing is strongly discouraged in the asymptomatic 
 
subject. 
 
• 
The subject with atypical symptoms.  Routine stress testing may be performed in the subject 
 
with atypical symptoms according to the discretion of the treating physicians, or such 
 
subjects may be treated conservatively. 
 
• The subject with typical angina or other progressive cardiac symptoms or signs.  Subjects 
with typical cardiac symptoms or evidence of progressive heart disease should in most cases 
undergo repeat cardiac catheterization; stress testing should not be performed, especially in 
the subject with possible recurrent disease in the left main stem. 

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Because of the risk of exercise-induced stent thrombosis, in no case should routine follow-up 
exercise stress testing be performed within 8 weeks after stent implantation. 
 
Follow-up echocardiography (without exercise) is not mandated by protocol but may be 
performed at any time during follow-up per the discretion of the treating physicians.  Similarly, 
multislice CT scanning but may be performed at any time during follow-up per the discretion of 
the treating physicians.  However, the use of MSCT in accurately determining in-stent restenosis 
has not been validated, and thus should in general not be used to guide decision making.  MSCT 
may be useful, however, in determining bypass graft patency. 
 
8.3.2. Follow-up Angiography 
 
Routine follow-up angiography in the asymptomatic subject is not permitted in this study.  Prior 
studies have not demonstrated a benefit of routine follow-up angiography after ULMCA disease, 
and routine follow-up angiography can result in non clinically indicated revascularization 
procedures (the “oculostenotic reflex”).48,49  In the SYNTAX trial, routine follow-up angiography 
was performed at 15 months in 268 surviving asymptomatic subjects with ULMCA disease 
randomized to PCI with TAXUS PES vs. CABG.  In the PCI group, the mean late loss in the left 
main stem with PES was only 0.2 mm, and thrombus was present in only 2 subjects (1%).  The 
composite rate of death, MI, stroke or repeat revascularization among PCI subjects undergoing 
routine angiography was 13% at 15 months (compared to 15.8% in all PCI subjects at 12 months, 
including those who were symptomatic).  Numerous prior studies of drug-eluting stents in subjects 
with ULMCA disease have demonstrated very low rates (<0.5%) of left main stent thrombosis,25, 
72 , 73 and no prior study of routine angiographic follow-up has been shown to improve 
outcomes after drug-eluting stents.  Routine angiographic follow-up after left main intervention is 
not recommended by the current ACC/AHA PCI guidelines.27 
 
 
For subjects who develop atypical chest pain or other symptoms that might reflect ischemia, it is 
strongly recommended that a nuclear stress test, echocardiographic stress test, or MSCT scan be 
performed, with subsequent angiography only for positive non-invasive results.  Valid indications 
for follow-up angiography in the present study include any of the following: 
•   the recurrence of typical angina; 
 
• a positive noninvasive study indicating moderate or severe ischemia, a significant decline in 
 
left ventricular function or progressive valve disease; 
•   progressive heart failure or unstable arrhythmias; 
•   cardiac arrest; 
•   or other clinical conditions for which the treating physician believes follow-up angiography is 
indicated. 
The reasons for follow-up angiography will be closely tracked in the case report form. 
 
8.3.3. Repeat Intervention (PCI or CABG) 
 
In subjects who do undergo follow-up angiography, repeat PCI or CABG may only be performed 
with evidence of ischemia, requiring one of the following to be present: 

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•   ≥70% diameter stenosis of the treated or new lesions by visual angiographic assessment 
•   In the case of a visually estimated diameter stenosis of ≥50% to <70%, either 
 
 
◦ 
evidence of definite ischemia in the territory of the diseased vessel by prior non-invasive  
 
 
stress testing with imaging evaluation showing ischemia in the questioned myocardial  
 
 
territory, and/or 
 
 
◦ 
IVUS minimal stent area ≤6.0 mm2 (see IVUS procedure guidelines) for left main lesions 
 
 
or ≤4.0 mm2 for non-left main lesions, and/or 
 
◦ 
intra-procedure FFR ≤0.80 (see FFR procedure guidelines). 
 
IVUS is preferred for assessment of left main lesions, and FFR is preferred for assessment of 
non-left main lesions. In particular, after left main stent implantation, the ostial LCX may often 
appear significantly or even severely stenosed in the absence of symptoms or ischemia (“pseudo- 
stenosis”). All subjects with a suspected ostial LCX stenosis, regardless of the degree of 
angiographic severity (unless occluded), are highly recommended to have demonstrated an FFR 
≤0.80 in the LCX prior to repeat revascularization, unless there is unequivocal evidence of lateral 
wall ischemia on non-invasive stress testing. 
 
If repeat revascularization is to be performed, the decision whether to perform PCI or CABG 
should be made according to the discretion of the treating physicians, ideally by local Heart 
Team consensus. 
8.4. 
Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. 
 
NOTE 1: This definition includes events related to the investigational medical device or the 
comparator. 
 
NOTE 2: This definition includes events related to the procedures involved. 
 
NOTE 3:  For users or other persons, this definition is restricted to events related to investigational 
medical devices. 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
 
Stable, chronic, pre-existing conditions are not to be reported as AEs.  However, worsening of a 
pre-existing condition that occurs after a subject’s participation in the trial is considered an AE 
and must be reported as such. 
 
Planned procedures (scheduled prior to the index procedure) that occur after the index procedure 
are not considered AEs and are not to be reported as such.  Complications from such procedures, 
however, are considered AEs and must be reported. 
 
Non-cardiac related abnormal laboratory values will not be considered AEs unless: 
• 
the investigator determined that the value is clinically significant, 

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• 
the abnormal lab value required intervention, or 
• 
the abnormal lab value required subject termination from the study. 
 
The investigator should report the event(s) to the IRB/EC according to the institution’s reporting 
requirements.  
 
Adverse Event Reporting 
 
The Investigator will monitor the occurrence of adverse events for each subject during the course of 
the study.  For the purpose of this protocol, the reporting of adverse events begins directly after 
randomization.   All adverse events (AEs) reported by the subject, observed by the Investigator, or 
documented in medical records will be listed on the Adverse Event Case Report Forms. 
 
Adverse events will be monitored throughout the course of the 
study. Serious Adverse Events 
If the adverse event meets any of the criteria below, it is regarded as a serious adverse event 
(SAE): 
 
a) Led to a death, 
b) Led to a serious deterioration in health that either: 
    1) Resulted in a life-threatening illness or injury, or 
  2) Resulted in a permanent impairment of a body structure or a body function, or 
  3) Required in-patient hospitalization or prolongation of existing hospitalization, or 
    4) Resulted in medical or surgical intervention to prevent life threatening illness or injury or                        
 
permanent impairment to a body structure or a body function. 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
d) An important medical event that may not result in death, be life-threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical judgment, 
may jeopardize the patient or subject and/or may require intervention to prevent one of the 
outcomes listed in this definition. 
NOTE 1: This includes device deficiencies that might have led to a serious adverse event if 
a) suitable action had not been taken or b) intervention had not been made or c) if 
circumstances had been less fortunate. These are handled under the SAE reporting system. 
NOTE 2: A planned hospitalization for pre-existing condition, or a procedure required by 
the Clinical Investigation Plan, without a serious deterioration in health, is not considered 
to be a serious adverse event. 
 
The investigator will report serious adverse events to the IRB/EC according to the institution’s 
reporting requirements. 
 
8.4.1. Serious Adverse Event Reporting 
 
Serious adverse events and device deficiencies must be reported no later than 3 calendar days from 

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the site becoming aware of the event or as per the investigative site’s local requirements if the 
requirement is more stringent than those outlined. The date the site staff became aware of the 
serious adverse event must be recorded in the source document. The Investigator will further report 
the event to the local IRB/EC according to the institution’s IRB/EC reporting 
requirements. 
 
Serious adverse events should be reported on the SAE Notification Form in the occurrence that 
the electronic data capture (EDC) system is not available.  This does not replace the EDC 
reporting system.  All information must still be entered in the EDC system once the system is 
back to normal function. 
 
Serious adverse events that occurred in the user or persons other than the study subject should 
not be entered in the EDC system, however they need to be reported on the fax notification form 
titled SAE Notification Form. 
 
8.4.2. Unanticipated Serious Adverse Device Effects (USADE) 
 
Unanticipated serious adverse device effect (USADE) refers to any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 
 
Abbott Vascular requires the Investigator to report any USADE to the sponsor within 3 calendar 
days of the investigator’s knowledge of the event and to the IRB/EC per IRB/EC requirements. 
8.4.3. Device Relationship 
 
Determination of whether there is a reasonable possibility that an investigational product or 
device caused or contributed to an adverse event is to be determined by the Investigator and 
recorded on the appropriate CRF form.  Determination should be based on assessment of 
temporal relationships, biologic plausibility, association (or lack of association) with underlying 
disease, and presence (or absence) of a more-likely cause. 
8.5. 
Safety Monitoring – Data Safety Monitoring Board (DSMB) 
 
The Data Safety Monitoring Board (DSMB) is useful to ensure safety by reviewing cumulative 
data from the clinical trial at pre-scribed intervals for the purpose of safety guarding the interest 
of trial participants.  The DSMB will serve as an advisory role.  The composition, guiding 
policies, and operating procedures governing the DSMB are described in a separate DSMB 
charter.  Based on safety data, the DSMB may recommend a modification to the protocol or that 
the sponsor stops the clinical trial/investigation.  All final decisions regarding clinical trial/ 
investigation modifications, however, rest with the Sponsor. 

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8.6. 
Event Adjudication – Clinical Events Committee (CEC) 
 
The Clinical Events Committee is comprised of qualified physicians who are not investigators in 
the trial.  The Clinical Events Committee is responsible for adjudicating specified clinical 
endpoints based on the specific criteria used for the categorization of clinical events in the trial. 
The composition, guiding policies, and operating procedures governing the CEC are described in a 
separate CEC Manual of Operations. 
9.     STATISTICAL DESIGN AND ANALYSIS 
 
This section describes the statistical considerations and analysis plans for the EXCEL trial.  The 
study is powered for both the primary and the 2 major secondary endpoints through an 
anticipated median follow-up of three years. 
 
In general, binary variables will be summarized using counts, percentages, and exact 95% 
confidence intervals. For continuous variables, percentiles, means, standard deviations, and 95% 
confidence intervals for the mean using the Gaussian approximation will be calculated.  Time to 
event data will be summarized using Kaplan-Meier estimates and 95% confidence intervals. 
Kaplan-Meier curves will be constructed for the primary and major secondary endpoints and 
differences in treatment will be tested using the difference in Kaplan-Meier failure rates on all 
available data through 3-year follow-up at the time of the analysis (event driven analysis).  All 
primary analyses will be measured from randomization onward and will be by intention to treat 
according to randomized assignment, regardless of what therapy was actually received.  A 
sensitivity analysis will be performed on the primary endpoint defined from the index procedure 
date.  The composite of all-cause mortality, MI, stroke (mRS≥1 and increase by ≥1 from baseline), 
or unplanned revascularization for ischemia at 3 years post randomization will also be classified as 
a sensitivity analysis.  Secondary analyses will be performed for the per protocol (PP) population 
(see also Section 9.1.5.2). 
 
9.1. 
Randomized Cohort 
9.1.1. Primary Endpoint 
 
The primary endpoint is a composite of all-cause mortality, MI or stroke (mRS≥1 and increase 
by ≥1 from baseline) at 3 years post randomization.  The primary endpoint will be estimated via 
Kaplan-Meier failure rate measured from randomization and Greenwood’s formula for estimating 
the standard error.  The primary endpoint analysis will be conducted at the time when 
approximately 50% of the patients have reached the 3-year follow-up AND all patients have 
reached the 2-year follow-up, whichever time point is latest.  All available data through 3-year 
follow-up will be used. 
 
The analysis will also be performed at 3 years post index procedure, as a sensitivity analysis. 
 

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9.1.2. Major Powered Secondary Endpoints 
 
The major powered secondary endpoints are:  
 
• The composite of all-cause mortality, MI, or stroke (mRS≥1 and increase by ≥1 from 
baseline) at 30 days post randomization. This powered endpoint will be estimated via 
Kaplan-Meier failure rate measured from randomization and Greenwood’s formula for 
estimating the standard error. 
 
• The composite of all-cause mortality, MI, stroke (mRS≥1 and increase by ≥1 from 
baseline), or unplanned revascularization for ischemia at 3 years post randomization.  This 
powered endpoint will be estimated via Kaplan-Meier failure rate measured from 
randomization and Greenwood’s formula for estimating the standard error.  The analysis will 
be conducted at the time when approximately 50% of the patients have reached the 3-year 
follow-up AND all patients have reached the 2-year follow-up, whichever time point is 
latest.  All available data through 3-year follow-up will be used. 
 
Sensitivity analyses will also be performed on all of the endpoints above from the index procedure 
date.  The composite of all-cause mortality, MI, stroke (mRS≥1 and increase by ≥1 from 
baseline), or unplanned revascularization for ischemia at 3 years post randomization will also be 
classified as a sensitivity analysis. 
 
9.1.3. Other Secondary Endpoints 
 
The primary endpoint composite event rate (all-cause death, MI or stroke) and powered secondary 
endpoints at all time points other than median of 3 years will be analyzed as other secondary 
endpoints. 
 
Time points for all other secondary endpoints, unless specified otherwise, are in-hospital, 30 and 
180 days, 1, 2, 3, 4 and 5 years post-procedure.   
 
Survival analysis techniques will be used to analyze the time-to-event variables. All of these 
analyses will be performed for these endpoints with time defined from date of randomization and 
(as a sensitivity analysis) from date of index procedure. 
 
The other secondary endpoints are: 
•   All-cause mortality 
 
◦ 
Cardiac death 
 
◦ 
Non-cardiac death 
 
 
• All myocardial infarctions (periprocedural, spontaneous, Q-wave and non Q-wave) including 
 
large and small MIs 
•   Protocol-defined MI 
•   MI adjudicated per Universal Definition 
•   Protocol-defined stroke 

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•   All stroke (all, ischemic and hemorrhagic) 
•   Disability following stroke event at 90 days± 2 weeks 
•   Ischemia-driven revascularization 
o Ischemia-driven target lesion revascularization (TLR) 
o Ischemia-driven target vessel revascularization (TVR) 
o Ischemia-driven non target vessel revascularization (Non-TVR) 
•   All revascularization (ischemia driven and non-ischemia driven) 
 
◦ 
All target lesion revascularization (TLR) 
 
◦ 
All target vessel revascularization (TVR) 
 
◦ 
All non target vessel revascularization (non-TVR) 
•   Complete revascularization at baseline procedure, anatomic and functional (see Section 19. 
 
Appendix D) 
•   Stent thrombosis (ARC definition) symptomatic or asymptomatic 
• Symptomatic graft stenosis or occlusion (since this requires angiographic documentation, this 
endpoint will be compared to symptomatic ARC definite stent thrombosis) 
•   Requirement for blood product transfusion 
•   Bleeding complications 
o Requirement for blood product transfusion 
o TIMI scale (major or minor) 
o BARC scale 
 
• Time from randomization to procedure; time from procedure to discharge; ICU days; time 
from procedure to return to work 
• Major adverse events (MAE) defined as composite of the following components.  MAE will 
be assessed in-hospital and at 30 days only. 
◦ 
death 
◦ 
myocardial infarction 
◦ 
stroke 
◦ 
transfusion of ≥2 units of blood 
◦ 
TIMI major or minor bleeding 
◦ 
major arrhythmia 
◦ 
unplanned coronary revascularization for ischemia 
◦ 
any unplanned surgery or therapeutic radiologic procedure 
◦ 
renal failure 
◦ 
sternal wound dehiscence 
◦ 
infection requiring antibiotics for treatment 
◦ 
intubation for > 48 hours 
◦ 
post-pericardiotomy syndrome 

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9.1.4. Subgroup Analyses 
 
Subgroup analysis will be performed in the intent-to-treat population.  However, these  
comparisons are not powered for hypothesis testing, and the analysis results are considered 
exploratory.  The proposed subgroups are listed in Section 21.2. 
 
9.1.4.1. 
Gender-specific Subgroup Analysis 
 
In particular, the primary and powered secondary endpoints will be further examined for 
differences between males and females.  A test for interaction will be performed to evaluate the 
potential differences in treatment effect for these two groups.  Details of the analysis will be 
specified in the SAP. 
9.1.5. Analysis Populations 
 
Hypothesis testing for the primary endpoint and the major powered secondary endpoints will be 
performed based on the intent-to-treat (ITT), the as-treated and per-protocol (PP) populations. 
Other endpoints, including the Economic Outcomes/Cost-Effectiveness Analysis will be 
performed on both the ITT and PP populations. Adverse events collected for safety will be 
summarized for the ITT population only. 
 
9.1.5.1. 
Intent-to-Treat Population 
 
The intent-to-treat population will consist of all subjects randomized to the study, regardless of 
the treatment actually received.  Subjects will be analyzed in the treatment group to which they 
were randomized.  This is the primary analysis population. 
 
9.1.5.2. 
Per-Protocol Population 
 
The per-protocol population consists of subjects with the following characteristics: 
• subjects who received the initial treatment to which they were randomized   
• assigned treatment must have been for their first revascularization 
• no major protocol violations (defined in the statistical analysis plan) 
 
9.1.5.3. 
As-Treated Population 
 
The as-treated population consists of subjects who received a protocol defined treatment. Subjects 
will be included in the treatment arm corresponding to the first study treatment actually received.   
 
9.1.6. Sample Size Calculations and Assumptions 
 
Sample size calculations for the Com-Nougue approach74, which utilizes the difference in Kaplan-
Meier estimates, were derived using simulations. Sample size calculations were performed  using 
the PASS 2008 software.75 
 
 

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9.1.6.1. 
Primary Endpoint: Composite of All-Cause Mortality, MI, 
 
or Stroke (mRS≥1 and increase by ≥1 from baseline) at 3 
 
years 
 
The primary endpoint of all-cause mortality, MI or stroke will be evaluated using the difference in 
Kaplan-Meier failure rates measured from randomization in the intent-to-treat population using 
all available data.  The hypothesis test is designed to show non-inferiority of PCI to CABG for 
the primary endpoint with a one-sided alpha of 0.025.  The null (H0) and alternative (HA) 
hypotheses are: 
 
H0: FPCI-PE(T) - FCABG-PE(T) ≥ ∆PE 
 
HA: FPCI-PE(T) - FCABG-PE(T) < ∆PE. 
 
FPCI-PE and FCABG-PE are the Kaplan-Meier estimates of failure rate of the primary endpoint at 3 
years in the PCI and CABG arms, respectively. ∆PE is the non-inferiority margin for the primary 
endpoint. 
The sample size calculation is based on the following assumptions: 
 
 
• 
primary endpoint event rate is 11% in each treatment arm at 3 years (using 3-year event rates 
 
from the SYNTAX trial, the most contemporary reference dataset) 
• 
minimum time to follow-up is 2 years 
• 
median time to follow-up is approximately 3 years 
• 
8% lost to follow-up at 3 years 
• 
non-inferiority margin ∆PE = 4.2% 
• 
one-sided alpha = 0.025 
• 
accrual time of 29 months 
 
A sample size population of 1900 subjects (~950 per arm) will provide approximately 80% 
power to demonstrate non-inferiority of PCI to CABG. 
 
For the PCI arm to pass the non-inferiority test for the primary endpoint of the composite of 
death, MI and stroke at 3 years, the maximum allowable event rate would be approximately 
12.1%.  Comparing to the 11% event rate of the CABG arm, the average difference per year is 
only ~ 0.4%.  The criteria for an acceptable non-inferiority delta has been carefully considered 
by the  principal investigators, executive committee, PCI  and  surgical committees and  
country leaders of this protocol, representing more than 100 physicians not related to the study 
Sponsor, 50% of whom are interventional cardiologists and 50% of whom are cardiac surgeons. 
A non- inferiority margin of 4.2% for the primary endpoint in this protocol has been agreed upon 
by this balanced study leadership to represent clinical therapeutic interchangeability76 between PCI 
and CABG, given the substantially lower peri-procedural morbidity of PCI, the likelihood for 
fewer strokes with PCI, especially in the first 30 days to 1 year (which in most cases is a 
clinically more important endpoint than MI, although the trial will not be powered to demonstrate 
a reduction in stroke), and the likely higher rate of subsequent unplanned revascularization for 
PCI. 
 
If non-inferiority is met, superiority testing will be performed with a one-sided alpha of 0.025. 

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The null (H0) and alternative (HA) hypotheses for the superiority test are: 
H0: FPCI-PE(T) - FCABG-PE(T) ≥ 0 
 
HA: FPCI-PE(T) - FCABG-PE(T) < 0. 
 
Using a one-sided alpha of 0.025, assuming 8% lost to follow-up at 3 years, the trial will have 
approximately 80% power to demonstrate superiority with a difference of 3.84% of PCI arm to 
CABG arm (e.g. 7.16% in PCI arm vs. 11% in CABG arm). 
 
9.1.6.2. 
Major Powered Secondary Endpoints 
Composite of All-Cause Mortality, MI, or Stroke (mRS≥1 
and increase by ≥1baseline) at 30 Days 
 
The first major powered secondary endpoint of all-cause mortality, MI or stroke at 30 days will 
be evaluated using the difference in Kaplan-Meier failure rates measured from randomization in 
the intent to treat population using all available data.  Loss to follow-up is considered to be 
minimal at this time point.  This endpoint is a major powered secondary endpoint, based on data 
from the SYNTAX trial, and has historical relevance.  The hypothesis is designed to show non-
inferiority of PCI to CABG with a one-sided alpha of 0.05.  The null (H0) and alternative (HA) 
hypotheses for non- inferiority of this powered secondary endpoint are: 
 
H0: FPCI-PE(T) - FCABG-PE(T) ≥ ∆PE 
 
HA: FPCI-PE(T) - FCABG-PE(T) -PCI < ∆PE. 
 
FPCI-PE(T) - FCABG-PE(T) are the Kaplan-Meier estimates of failure rates measured from 
randomization at 30 days between CABG and PCI and∆PE is the non-inferiority difference for 
this powered secondary endpoint. 
 
The power calculation is based on the following assumptions: 
•   composite rate is 3.0% in each treatment arm at 30 days 
•   non-inferiority ∆PE = 2% 
•   one-sided alpha = 0.05 
•   accrual time = 29 months 
 
A sample size population of 1900 subjects (~ 950 per arm) will provide approximately 80% 
power to demonstrate non-inferiority between the two treatment groups. 
 
The second major powered secondary endpoint has been defined to provide direct comparison 
to the results of the SYNTAX trial. 
 
Composite of All-Cause Mortality, MI, Stroke (mRS≥1 and increase by 
≥1 from baseline), or Unplanned Revascularization for Ischemia at 3 
Years 
 
The powered secondary endpoint of the composite of all-cause mortality, MI, stroke, or unplanned 
revascularization for ischemia will be evaluated using the difference in Kaplan-Meier failure rates 
from randomization to 3 years between CABG and PCI in the intent to treat population using all 

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available data.  This endpoint is a powered endpoint, based on data from the SYNTAX trial, and 
has historical relevance, although in terms of clinical relevance is not necessarily considered 
weighted greater than is quality of life measures or other secondary endpoints.  The hypothesis is 
designed to show non-inferiority of PCI to CABG with a one-sided alpha of 0.05.  The null (H0) 
and alternative (HA) hypotheses for non-inferiority of this powered secondary endpoint are: 
 
H0: FCOMP-PCI(T) – FCOMP-CABG(T) ≥ ∆COMP 
 
HA: FCOMP-PCI(T) – FCOMP-CABG(T) < ∆COMP. 
 
FCOMP-PCI(T) – FCOMP-CABG(T) is the difference in failure rates at 3 years between CABG and PCI 
and ∆COMP is the non-inferiority margin for this powered secondary endpoint.  
 
Assuming the following: 
 
 
 
• major secondary endpoint event rate is 22% in each treatment arm at 3 years (using 3-year 
 
event rates from the SYNTAX trial) 
•   median time to follow-up is approximately 3 years 
•   minimum time to follow-up is 2 years 
•   8% lost to follow-up at 3 years 
•   non-inferiority ∆COMP = 8.4% 
•   one-sided alpha = 0.05 
•   accrual time of 29 months 
 
then a sample size of 1900 subjects (~950 per arm) will provide an approximately 99% power to 
demonstrate non-inferiority of CABG to PCI using the Com-Nougue approach. 
 
9.1.7. Statistical Analysis 
 
9.1.7.1. 
Analysis of Primary and Major Powered Secondary 
 
Endpoints 
 
The primary and the two major powered secondary endpoints will be analyzed for the intent-
to-treat population, the as-treated population and the per-protocol population.  Formal hypothesis 
testing will be based on the intent-to-treat population.  Hierarchical testing will be employed 
following the order below: 
 
• Primary endpoint-All cause mortality, MI or Stroke from randomization to  median follow-up 
of 3 years (non-inferiority) 
• First major powered secondary endpoint-All cause mortality, MI or Stroke from randomization to  
30 days 
• Second major powered secondary endpoint-All cause mortality, MI, Stroke or Unplanned 
 
Revascularization for Ischemia from randomization to median of 3 years 
• 
Primary endpoint – All cause mortality, MI, or stroke from randomization to median follow-up 
of 3 years  (superiority) 

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Formal hypothesis testing of the first major powered secondary endpoint will occur only if non-
inferiority for the primary endpoint is met.  Simultaneous formal hypothesis testing of the second 
major powered secondary endpoint and the superiority test of the primary endpoint will occur 
only if non-inferiority for the first major powered secondary endpoint is met.  
 
9.1.7.2. 
Analysis of Other Endpoints 
 
For binary variables, counts, percentages, and exact 95% confidence intervals will be calculated. 
For continuous variables, percentiles, means, standard deviations, and 95% confidence intervals 
for the mean using the Gaussian approximation will be calculated.  P values will be reported for 
descriptive purposes only.  Logistic regression and ANOVA models will be used to determine if 
the data exhibit any trends.  For time-to-event variables, such as stent thrombosis, survival 
curves will be constructed using Kaplan-Meier estimates, and log-rank test or Cox proportional 
hazard model results will be displayed for hypothesis-generating purposes only. 
 
9.1.8. Procedures for Accounting for Missing Data 
 
Although every effort will be made to minimize the amount of missing data, some loss to follow- 
up is unavoidable.  For time-to-event hypothesis tests, subjects will be censored at their last  
known follow-up.  The percentage of subjects with follow-up in each treatment arm will be 
summarized.  The reasons for loss to follow-up will be collected and summarized.  All of these 
comparisons will be performed using descriptive analyses only. 
9.1.9. Measures Taken to Minimize Bias 
 
9.1.9.1. 
Randomization 
 
Assessment of eligibility must be done prior to randomization.  Suitable subjects will be 
randomized to procedure with PCI or CABG in a ratio of 1:1.  Randomization will be stratified 
by medically treated diabetes mellitus (diabetic vs. non-diabetic), SYNTAX score (<23 vs. ≥23) 
and by center. 
 
The randomization will be managed by a central IVRS randomization.  See Section 7.2.12 for 
randomization details.  Once randomized the subject is analyzed as part of the intent-to-treat 
(ITT) population. 
9.1.9.2. 
Clinical Events Committee and Angiographic Core 
Laboratory 
 
In order to minimize bias, the clinical events committee (CEC) will assess specified clinical events 
per the Manual of Operation and independent core laboratories will assess imaging data. 
9.1.10.  
Pooling Strategy 
 
Analyses will be performed pooling data across study sites, study regions, and study stents. 
Additional analyses will be conducted to evaluate the potential differences in treatment effect for 
different sites/regions/study stents for the primary and powered secondary endpoints. Details 
of the analyses will be specified in the SAP. 

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9.1.11. 
Interim Analysis 
 
No formal interim analysis is planned for this study.  Interim study reports with descriptive 
analysis may be produced for regulatory or reimbursement purposes. 
 
9.2. 
Universal Registry 
 
The key baseline characteristics including reasons for exclusion from randomization, SYNTAX 
score and clinician treatment allocation will be summarized descriptively.  For binary variables, 
percentages, and exact 95% confidence intervals will be calculated.  For continuous variables, 
percentiles, means, standard deviations, and 95% confidence intervals for the mean using the 
Gaussian approximation will be calculated.  The baseline features and treatment allocation of  
subjects in the registries will be compared to those in the randomized trial for descriptive 
purposes. 
 
9.3. 
Health-Related Quality of Life (HRQoL) and Treatment Costs 
 
Health-related quality of life (HRQoL) and treatment costs will be assessed alongside the core 
clinical trial in about 1800 patients to evaluate the impact of the PCI and CABG strategies on a 
range of relevant quality of life (QoL) domains and also to evaluate the cost-effectiveness of the 
two treatment strategies. Details regarding the QoL and U.S. Health Economics Sub-Studies can 
be found in Section 17, Appendix B. 
 
9.3.1. Endpoints 
 
Quality of life will be assessed using five patient reported outcome instruments administered at 
the following time points: baseline, 1 month, 1 year, 3 years, and 5 years.  Score ranges for each 
instrument are as follows: SAQ: 0-100; PHQ-8: 0-24; SF-12: 0-100; EQ-5D: 0-1; Rose Dyspnea: 
0-4.  Means and standard deviations for these scores will be presented. 
 
9.3.2. Quality of Life 
 
HRQoL and functional status will be assessed using a combination of generic and disease- 
specific measures selected to cover a broad range of health domains that may be affected by 
coronary artery disease, its treatment, and its complications in about 1800 patients.  Disease- 
specific QoL will be assessed using the Seattle Angina Questionnaire (SAQ)77, 78 and the London 
School of Hygiene Dyspnea Questionnaire.79, 80   Mental health and depression will be assessed 
using the Patient Health Questionnaire-9 (PHQ-9).81   Generic health status will be assessed using 
the Medical Outcomes Study 12-item Short Form (SF-12),82 and health utilities will be assessed 
using the EuroQoL (EQ-5D) with U.S.-specific weights. 83 , 84   Further details regarding the 
rationale for selection of these instruments and specific analytic approaches are detailed in 
Section 17.  These measures will be assessed using standardized, written questionnaires at 
baseline (prior to randomization), 1 month, 12 months, 3 years, and 5 years. 
 

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9.3.3. Economic Outcomes/Cost-Effectiveness 
 
Data on cardiovascular-specific resource utilization and will be collected prospectively for the 
index hospitalization and the full follow-up period for 1800 subjects using standardized case  
report forms.  Procedural costs will be assessed using a resource-based (e.g., “bottom up”) 
approach to convert standard measures such as procedural duration and utilization of “big ticket” 
items (e.g., stents, balloons, wires, contrast, etc.) into costs.  Other hospital costs will be assessed 
using an “event-driven” approach in which specific complications and outcomes (e.g. myocardial 
infarction, bleeding complications, post-operative infection, etc.) are assigned standard costs based 
on external data.  Additional costs will be assigned for follow-up hospitalizations and repeat 
revascularization procedures, emergency room visits, outpatient diagnostic testing, cardiovascular 
medications, and rehabilitation services (including skilled nursing services).  In each case, costs 
will be assessed from the perspective of the U.S. healthcare system.  Finally, the cost and quality 
of life data will be integrated in order to perform a formal cost-effectiveness analysis.  The 
primary analysis will be performed from the perspective of the U.S. healthcare system using a 
lifetime time horizon.  Secondary analyses will be performed from the perspective of other health 
care systems with the collaboration of a local health economist. 
 
If there are no significant differences in prognostically important endpoints (e.g., death, non-fatal 
MI, non-fatal stroke) between the two groups then the analysis will be based on the observed 
cost and QoL data from the trial itself (under the assumption that long-term survival would be 
comparable for the two groups).  If there are differences in one or more of these endpoints (or 
their composite), however, then it will be important to account for differences in long-term 
survival between the two groups in the analysis. In this case, the data from the trial itself will be 
used along with external data in order to project long-term survival for each trial participant and 
use these estimates in order to estimate differences in quality-adjusted life expectancy over each 
subject’s lifetime.  Consistent with current guidelines for health economic analyses, the trial data 
will be used to calculate an incremental cost-effectiveness ratio (cost per quality-adjusted year of 
life gained) for the more expensive technique compared with the less expensive technique, and 
by comparing this ratio with those for other medical interventions, determine whether one 
treatment strategy is preferred on economic grounds.85   Additional analyses will be performed 
using intermediate, disease-specific endpoints including cost per major adverse cardiovascular 
event avoided and cost per repeat revascularization avoided.86 
 
The primary cost-effectiveness and quality of life analyses will be performed when all 
randomized subjects have completed a minimum of 3-years of follow-up.  Although this time 
frame is slightly different from that for the main clinical endpoint, the longer follow-up duration 
for the economic analysis will minimize the need for extrapolation beyond the observed data. 
 
Additional details of the approaches to U.S.-specific costing and the formal cost-effectiveness 
analysis are provided in Section 17.4 and Section 17.5. 
 
9.4. 
Other Analysis 
 
An IVUS substudy (Section 18) is planned (see Appendix C). 
 

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10.   DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The Investigator/institution will permit direct access to source data/documents in order for trial- 
related monitoring, audits, IRB/EC review and regulatory inspections to be performed. 
 
Subjects providing informed consent are agreeing to allow the Sponsor access and copying rights to 
pertinent information in their medical records concerning their participation in this trial, both at 
the study hospital and subsequent hospitals where the subject may receive subsequent care after 
randomization. The Investigator will obtain, as part of the informed consent, permission for trial 
monitors or regulatory authorities to review, in confidence, any records identifying the subjects in 
this trial.   This information may be shared with regulatory agencies; however, the Sponsor 
undertakes not to otherwise release the subject's personal and private information. 
 
11.   QUALITY CONTROL AND QUALITY ASSURANCE 
 
11.1. Selection of Clinical Sites and Investigators 
 
The Sponsor will select Investigators who are qualified by training and experience and are 
legally entitled to perform clinical research and to participate in the investigation of the study 
device.  Sites will be selected based upon review of a recent site assessment and the qualifications 
of the Primary Investigator at the site.  Each site will have an interventional cardiologist and 
cardiac surgeon as “joint” principal investigators.  All participating investigators will be trained to 
the protocol and study procedures prior to enrolling subjects. 
 
11.2. Protocol and Informed Consent Approval 
 
Institutional Review Board (IRB) or Ethics Committee (EC) approval for the protocol, informed 
consent form, and other study related documents will be obtained by the Primary Investigator at 
each investigational site prior to participation in this trial.  The approval letter must be signed by 
the IRB/EC chairman or authorized representative prior to the start of this trial and a copy for 
U.S. sites must be provided to the Sponsor.  In addition, the investigator or designee will provide 
the Sponsor with all required documentation necessary for initial and ongoing study approval at 
their site. 
 
In accordance with the investigational site IRB/EC requirements, the investigator will (a) advise 
the IRB/EC of the progress of this trial on a regular basis until study completion; (b) obtain 
written IRB/EC approval at predetermined timepoints to continue the trial as required by country 
regulations; and (c) submit any amendments to the protocol as well as associated informed 
consent form changes and obtain written IRB/EC approval obtained prior to implementation. 
 
No investigative procedures other than those defined in this protocol will be undertaken on the 
study subjects without the written agreement of the IRB/EC and the Sponsor. 
 

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11.2.1. Protocol Amendments 
 
Approved protocol amendments will be provided to the Investigators by the Sponsor prior to 
implementing the amendment.  The Primary Investigator will be responsible for notifying the 
IRB/EC of the protocol amendment (administrative changes) or obtaining IRB/EC approval of 
the  protocol  amendment (changes  in  subject  care  or  safety),  according  to  the  instructions 
provided by the Sponsor with the protocol amendment. 
 
Acknowledgment/approval by the IRB/EC of the protocol amendment must be documented in 
writing prior to implementation of the protocol amendment.  Copies of this documentation must 
also be provided to the Sponsor. 
 
11.3. Protocol Deviations 
 
It is the Investigator's responsibility to ensure that there are no deviations from the protocol and 
to stay in full compliance with all established procedures of the IRB/EC.  The Investigator will 
not deviate from the protocol for any reason except in cases of medical emergencies, when the 
deviation is necessary to protect the life or physical well-being of the subject. All deviations must 
be reported to the Sponsor.  Protocol deviations are determined by the Sponsor.  In subject- 
specific deviations from the protocol, a protocol deviation eCRF will be completed. The 
occurrence of protocol deviations will be monitored by the Sponsor. Investigators will inform 
their IRB/EC of all protocol deviations in accordance with their specific IRB/EC reporting 
policies and procedures. 
 
In the event that an Investigator does not comply with the Investigator Agreement or protocol, 
the Sponsor will notify the Investigator of the site’s non-compliance. Continued non-compliance 
may result in further escalation in accordance with the Sponsor’s SOP. 
11.4. Training 
11.4.1. Site Training 
 
All Investigators/trial personnel are required to attend Sponsor training sessions, which may be 
conducted at an Investigator's meeting, a site initiation visit or other appropriate training sessions. 
Also, training by telephone may take place as required. Training of Investigators/trial personnel 
will include, but is not limited to, the investigational plan, investigational device usage, protocol 
requirements, electronic case report form completion and trial personnel responsibilities.   All 
Investigators/trial personnel that are trained must sign a training log (or an equivalent) upon 
completion of the training.  Prior to being trained, Investigator/trial personnel must not perform 
any trial-related activities that are not considered standard of care at the site. 
 
11.4.2. Training of Sponsor’s Monitors 
 
The Sponsor’s monitors or designee will be trained to the protocol, electronic case report forms 
and investigational device usage, if appropriate.  The Sponsor or designee is responsible for the 
training. Training may be conducted in accordance with the Sponsor’s SOP. 

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11.5. Monitoring 
 
Sponsor and/or designee will monitor the study over its duration according to the pre-specified 
monitoring plan.   The study monitor will visit each site at appropriate intervals to review 
investigational data for accuracy and completeness and ensure compliance with the protocol. 
 
Medical records/source documents (office, clinic or hospital) will be reviewed for 100% of 
subjects looking for primary end-point events. 
 
In cases of all-cause mortality and SAE, the study monitor will perform inspection for pertinent 
documents and records for these events. The monitor will be assisting sites to resolve any data 
queries and ensuring that relevant source documents related to study events are being retrieved 
from the sites. The Investigator/site will permit access to such records. Source documentation must 
be available to substantiate proper informed consent procedures, adherence to protocol procedures, 
adequate reporting and follow-up of adverse events, accuracy of data collected on case report 
forms, and device information.  A monitoring visit sign-in log will be maintained at the site.  The 
Investigator and/or research coordinator will be available for monitoring visits.  It is expected that 
the Investigator will provide the study monitor with a suitable working environment for review of 
study-related documents. 
 
11.6. Quality Assurance Assessments 
 
The Sponsor/designee may conduct periodic compliance assessments (on-site audits) at various 
study sites.  A  Sponsor representative or designee may request access to all trial records, 
including source documentation, for inspection and duplication during a compliance assessment.  
 
The Investigator and research coordinator must be available to respond to reasonable requests 
and queries made during the compliance assessment process. 
 
11.7. Regulatory Agency Inspection 
 
In the event that an Investigator is contacted by a Regulatory Agency in relation to this study, the 
Investigator will notify the Sponsor immediately.   The Investigator and research coordinator 
must be available to respond to reasonable requests and inspection queries made during the 
inspection process.  The Investigator must provide the Sponsor with copies of all correspondence 
that may affect the review of the current study (e.g., Form FDA 483, Inspectional Observations, 
and warning letters).  The Sponsor will provide any needed assistance in response to regulatory 
inspections. 
11.8. Executive Operations Committee 
 
The Executive Operations Committee (EOC) is responsible of the overall management of the 
study at the highest level. The EOC is comprised of four voting members who are the Co-PIs, as 
well of non-voting members: representatives from the Sponsor, the heads of the PCI and CABG 
committees, a neurology expert as well as representative from both Cardialysis and CRF. 

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12.   DATA HANDLING AND RECORD KEEPING 
 
For the trial duration, the Investigator will maintain complete and accurate documentation 
including but not limited to medical records, trial progress records, laboratory reports, case report 
forms, signed informed consent forms, device accountability records, correspondence with the 
IRB/EC and trial monitor/Sponsor, adverse event reports, and information regarding subject 
discontinuation or completion of the trial. 
 
12.1. Source Documentation 
 
Regulations require that the Investigator maintain information in the subject’s medical records that 
corroborates data collected on the case report forms.  In order to comply with these regulatory 
requirements the following information should be included in the subject record at a minimum: 
 
 
• 
Medical history/physical condition of the subject before involvement in the trial sufficient to 
 
verify protocol entry criteria 
 
• 
Dated and signed notes on the day of entry into the trial referencing the Sponsor, protocol 
 
number, subject ID number, treatment assigned and a statement that informed consent was 
 
obtained 
•    Dated and signed notes from each subject visit (for specific results of procedures and exams) 
• 
Adverse  events  reported  and  their  resolution  including  supporting  documents  such  as 
discharge summaries, catheterization laboratory reports, ECGs, and lab results, including 
 documentation of site awareness of SAEs and of investigator device relationship assessment 
 of SAEs 
•  Study required lab reports and 12-lead ECGs, signed and dated for review and annotated 
 for clinical significance of out of range results 
•  Notes regarding protocol-required and prescription medications taken during the trial 
(including start and stop dates) 
•  Subject’s condition upon completion of or withdrawal from the trial 
•  Any other data required to substantiate data entered into the CRF 
 
Source documents will be requested for events that require adjudication.  Source documents 
requested for adjudication must be redacted of all protected health information prior to 
submission. 
 
12.2. Electronic Case Report Form (eCRF) Completion 
 
Primary data collection based on source-documented hospital chart reviews will be performed 
clearly and accurately by research coordinators (RC) at each clinical site trained on the protocol 
and case report form completion. The eCRF data will be collected for all subjects that are 
randomized. This data will be monitored by the Sponsor’s Site Monitors. The Sponsor will 
provide clinical monitoring to include review of case report forms and parity checks with the 
source documentation, including operator worksheets retained with case report form 
documentation and hospital charts. 

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12.3. Record Retention 
 
The sponsor will archive and retain all documents pertaining to the trial as per the applicable 
regulatory record retention requirements. The Primary Investigator will maintain all records 
pertaining to this study until instructed by the Sponsor. Investigator will be notified by the 
Sponsor of the date of marketing approval or discontinuation of the study.  The Investigator will 
obtain permission from the Sponsor in writing before destroying or transferring control of any 
study records. 
 
12.4. Investigational Device Management 
 
Sites will use only commercially available XIENCE stents. 
 
12.5. Maintenance of Randomization Codes 
 
The Sponsor will maintain a complete record of randomization codes for all subjects randomized 
in the trial. 
 
13.   ETHICAL CONSIDERATIONS 
 
This study will be conducted in accordance with the Declaration of Helsinki ISO 14155-2011(E) 
standards, as well as with applicable country specific requirements. 
 
All subjects must provide written informed consent in accordance with the site’s IRB/EC for the 
respective Countries, using an IRB/EC-approved informed consent form. The final eligibility for 
the study will be confirmed based on the decision of the local Heart Team. Study-specific 
procedures must not be performed until a signed informed consent has been obtained. The  
 
Investigator or designee, who has been trained on the protocol, will explain the nature and scope 
of the study, potential risks and benefits of participation, and answer questions for the subject. If 
the subject agrees to participate, the informed consent form must be signed and personally dated by 
the subject or legally authorized representative. The Investigator or a person designated by the 
Investigator must also sign the informed consent form.  The informed consent must be completed 
by both the subject and Investigator prior to any protocol specified testing and prior to subject 
participation. Any additional persons required by the site’s IRB/EC to sign the informed consent 
form must also comply. In addition, for U.S. sites an authorization for use and disclosure of the 
subjects’ protected health information (PHI) according to the Health Insurance Portability and 
Accountability Act (HIPAA) may be included as part of the subject informed consent process in 
accordance with individual site procedures. 
 
Figure 6.1 outlines the screening and randomization process and illustrates the point where 
informed consent should be obtained. 
 

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14.    PUBLICATION POLICY 
 
14.1. Publication Policy 
 
The  Executive  Operations  Committee,  Sponsor  and  Investigators  are  committed  to  the 
publication and widespread dissemination of the results of the study. Data from this study will 
not be withheld regardless of the findings. The Excel Clinical Trial is a scientifically driven 
study sponsored by Abbott Vascular. All public presentations and manuscript generation and 
submissions will be led under the auspices of the four Principal Investigators who will organize 
and lead a Publications Committee. However, this Study represents a joint effort between 
investigators and Sponsor, and as such, the parties agree that the recommendation of any party 
concerning manuscripts or text shall be taken into consideration in the preparation of final 
scientific documents for publication or presentation. 
 
Copies of the final locked database will be housed at both Cardialysis and CRF. Neither CRF nor 
Cardialysis will publicly release any data or study related material, presentations, or manuscripts 
without the express permission of both organizations as well as agreement of the four Principal 
Investigators. All four Principal Investigators will be listed as authors on all abstracts and 
publications, and as such must agree to their submission. The publication and/or presentation of 
results from a single trial site are not allowed until publication and/or presentation of the multi- 
center results. All single site data for public dissemination must be generated from the central 
database – local database projects are not permitted. All proposed publications and presentations 
resulting from or relating to the study (whether from multicenter data or single site analysis) 
must be submitted to the Publications Committee for review and approval prior to submission for 
publication or presentation. 
 
The Sponsor will receive any proposed publication and/or presentation materials prior to 
submission of the presentation or the initial submission of the proposed publication in order for 
the materials to be reviewed by the Sponsor. If any such proposed publication or presentation 
contains patentable subject matter which in Sponsor's sole discretion, warrants intellectual 
proprietary protection, the Sponsor may delay any publication or presentation for up to sixty (60) 
days  after  Executive  Operations  Committee  approval  for  the  purpose  of  pursuing  such 
protection. The prior notwithstanding, however, the results of the study will not be considered 
confidential or patentable information after the multicenter primary endpoint data is presented, 
and the Investigators’ rights to present and publish such data representing the scientific results of 
this study will not be restricted. 
 
The primary endpoint presentation and publication will state that the study has been performed in a 
selected patient population with left main disease. 
 
14.2. Publication Committee 
 
The Publication Committee is composed of the Principal Investigators, representatives from 
Abbott Vascular Clinical Research, and other personnel as determined by the committee 
Chairperson and approved by the Executive Operations Committee. This team will oversee 
presentation and/or publication aspects of the study. The Publication Committee will determine 

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policy and strategies regarding individual presentations and/or publications arising from study 
generated data. The committee will also review all external requests for accessing study related 
data and strategies aligning with Abbott Vascular presentation and publication team expectations. 
The committee will also follow Abbott Vascular applicable policies and standard operating 
procedures regarding Abbott Vascular-sponsored clinical studies. 
 
15.   RISK ANALYSIS 
 
15.1. Potential Risks - PCI 
 
15.1.1. Risks from Cardiac Catheterization, Stenting, and PTCA 
 
There is extensive clinical and commercial experience worldwide with cardiac catheterization 
and interventional procedures and it is expected that the surgical and procedural risks will not be 
significantly different in this clinical trial.   For a list of anticipated adverse events from each 
stent system, refer to XIENCE PRIME, XIENCE V, XIENCE Xpedition and XIENCE PRO (for 
OUS use only) device IFU. 
 
 
Some of the complications of stenting procedure are: 
• Death, stroke, shock, kidney failure, squeezing of the heart due to accumulation of blood in 
the sac around the heart (cardiac tamponade), access site infection,  decreased blood supply to 
a part of the heart muscle, arms or leg, inadvertent injury to the aorta and/or its branches may 
occur in <2% of the patients. 
• Vascular complications at the access site that might need vessel repair including hematoma or 
hemorrhage, blockage of the coronary artery. 
• Rapid/ slow heartbeat, heart attack, development of blood clots, abnormal connection between 
an artery and a vein next to it (arterio-venous fistula), abnormal blood pressure, fluid 
development in the lungs (pulmonary edema), emergency or non-emergency surgery may 
occur in 2-5% of the patients. 
• Chest pain or discomfort, access site pain, allergic reaction or hypersensitivity to contrast agent 
or cobalt, chromium, nickel, tungsten, acrylic and fluoropolymers and drug reactions to 
antiplatelet drugs or contrast agent, repeat closure of the coronary artery over time may occur 
in 5-10% of the patients. 
• The rates of surgical and procedural risks for patients being treated for LM disease or Left 
Main Equivalent disease may be higher than the experience worldwide with cardiac 
catheterization and interventional procedures. 
• The adverse events and potential device issues associated with the particular techniques (e.g., 
T- stent, TAP, mini-crush (reverse crush) or culotte bifurcation)) associated with the treatment 
of Left Main disease and allowed for in this study may result in adverse events or device issues 
not previously identified.  As the study progresses and the experience with these techniques are 
better understood, the protocol may be updated with additional risks. 
 
 

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15.1.2.  
Associated Risks of Everolimus 
 
The risks of everolimus when used in a blood vessel (as in the Trial) are unknown. Zortress®, the 
oral formulation of everolimus developed by Novartis Pharmaceuticals Corporation, has been 
evaluated in clinical trials and is approved in the United States for the prevention of organ 
rejection in adult kidney transplant recipients at low-moderate immunologic risk, at the dose of 
1.5 mg/day. 
 
Outside the U.S., Zortress is sold under the brand name, Certican®, in more than 70 countries. 
Everolimus is also approved in the United States under the name of Afinitor® for the treatment of 
patients with advanced renal cell carcinoma (cancer) after failure of treatment with sunitinib or 
sorafenib, at doses of 5 to 20 mg/day when taken by mouth.  The amount of drug in the blood 
from the XIENCE stent is several folds lower than obtained with oral doses (1.5 mg to 20 
mg/day). 
 
The list below includes the known risks of everolimus at the oral doses indicated above.  There 
may be other potential adverse events that are unforeseen at this time. 
• Abdominal pain (including upper abdominal pain) 
• Anemia 
• Angioedema 
• Anorexia 
• Asthenia 
• Constipation 
• Cough 
• Delayed wound healing/fluid accumulation 
• Diarrhea 
• Dyslipidemia (including hyperlipidemia and hypercholesterolemia) 
• Dyspnea 
• Dysgeusia 
• Dyspepsia 
• Dysuria 
• Dry skin 
• Edema (peripheral) 
• Epistaxis 
• Fatigue 
• Headache 
• Hematuria 
• Hyperglycemia (may include new onset of diabetes) 
• Hyperlipidemia 
• Hyperkalemia 
• Hypertension 
• Hypokalemia 
• Hypomagnesemia 
• Hypophosphatemia 
• Increased serum creatinine 

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• Infections and serious infections: bacterial, viral, fungal, and protozoal infections (may 
include herpes virus infection, polyoma virus infection which may be associated with BK 
virus associated nephropathy, and/or other opportunistic infections) 
• Insomnia 
• Interaction with strong inhibitors and inducers of CY3PA4 
• Leukopenia 
• Lymphoma and other malignancies (including skin cancer) 
• Male infertility (azospermia and/or oligospermia) 
• Mucosal inflammation (including oral ulceration and oral mucositis) 
• Nausea 
• Neutropenia 
• Non-infectious pneumonitis 
• Pain: extremity, incision site and procedural, and back 
• Proteinuria 
• Pruritus 
• Pyrexia 
• Rash 
• Stomatitis 
• Thrombocytopenia 
• Thrombotic microangiopathy (TMA)/Thrombotic thrombocytopenic purpura (TTP)/ 
Hemolytic uremic syndrome (HUS) 
• Tremor 
• Urinary tract infection 
• Upper respiratory tract infection 
• Vomiting 
 
 
Live vaccines should be avoided and close contact with those that have had live vaccines should 
be avoided. Fetal harm can occur when administered to a pregnant woman. There may be other 
potential adverse events that are unforeseen at this time. 
 
Exposure to drug and polymer on the XIENCE stent is directly related to the number and lengths 
of the stents implanted. The use of multiple XIENCE stents will result in receiving larger 
amounts of drug and polymer. It should be noted that a kidney or heart transplant patient or a 
patient with advanced renal cell carcinoma usually receives a daily dose of the drug everolimus 
by mouth that is several times higher than the maximum dose of the drug contained on one 
XIENCE stent. 
 
Everolimus, when given by mouth daily to organ transplant patients or renal cell carcinoma 
patients, may interact with other drugs or substances. Patient should notify the physician about 
any medications they might be taking. 
 
The XIENCE Xpedition stent system is similar to XIENCE PRIME with a new stent delivery 
system optimized for acute performance. The XIENCE PRIME and XIENCE Xpedition stent 
systems are similar to the clinically proven XIENCE V EECSS.  XIENCE PRO (for OUS use 
only) is just rebranding of XIENCE V EECSS and XIENCE PRIME LL EECSS. The XIENCE 
V EECSS has been shown to be safe and effective in four clinical trials, SPIRIT FIRST, SPIRIT 

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II, SPIRIT III and SPIRIT IV.  The SPIRIT PRIME clinical trial is Abbott Vascular’s pivotal US 
trial evaluating the XIENCE PRIME stent system. The SPRIIT PRIME trial has met all pre- 
specified performance goals with statistical significance for its primary endpoint of target lesion 
failure at 1 year. Long-term risks and benefits associated with the XIENCE PRIME stent system 
are currently unknown. 
 
15.1.3. Drug Interactions with Everolimus 
 
Everolimus is extensively metabolized by the cytochrome P4503A4 (CYP3A4) in the gut wall 
and liver and is a substrate for the counter transporter P-glycoprotein. Therefore, absorption and 
subsequent elimination of everolimus may be influenced by drugs that also affect this pathway. 
Everolimus has also been shown to reduce the clearance of some prescription medications when it 
was administered orally along with cyclosporine (CsA). Formal drug interaction studies have not 
been performed with the XIENCE stent because of limited systemic exposure to everolimus eluted 
from the XIENCE stent. However, due consideration should be given to the potential for both 
systemic and local drug interactions in the vessel wall when deciding to place the XIENCE stent 
in a subject taking a drug with known interaction with everolimus. 
Everolimus, when prescribed as an oral medication, may interact with the drugs/foods87, 88 listed 
below. Medications that are strong inhibitors of CYP3A4 might reduce everolimus metabolism 
in vivo. Hence, co-administration of strong inhibitors of CYP3A4 may increase the blood 
concentrations of everolimus while co-administration of inducers of CYP3A4 may decrease the 
blood concentrations of everolimus. 
 
•  CYP3A4 isozyme inhibitors (ketoconazole, itraconazole, voriconazole, ritonavir, 
erythromycin, clarithromycin, fluconazole, calcium channel blockers (verapamil and 
diltiazem), aprepitant atazanavir, nefazodone, amprenavir, indinavir, nelfinavir, 
delavirdine, fosamprenavir, saquinavir and telithromycin) 
• Inducers of CYP3A4 isozyme (rifampin, rifabutin, carbamazepine, phenobarbital, 
phenytoin, dexamethasone) 
• Antibiotics (ciprofloxacin, ofloxacin) 
• Glucocorticoids 
• HMG CoA reductase inhibitors (simvastatin, lovastatin) 
• Digoxin 
• Cisapride (theoretical potential interaction) 
• Sildenafil (Viagra®) (theoretical potential interaction) 
• Antihistaminics (terfenadine, astemizole) 
• Grapefruit / grapefruit juice 
 
15.1.4. Associated Risks of XIENCE Polymer 
 
The safety and biocompatibility of acrylic and fluoro deposited polymer coatings have been 
demonstrated based upon XIENCE PRIME stent system biocompatibility testing per ISO 10993- 
1 and the long term use of these polymers in medical implants. These polymers are the same as 
those of the FDA approved XIENCE V EECS. However, the long-term outcome of the XIENCE 
PRIME/XIENCE Xpedition stent system polymer as a permanent implant is presently unknown. 
 

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15.1.5. Genotoxicity, Carcinogenicity and Reproductive Toxicity of XIENCE 
 
The carcinogenicity, genotoxicity, and reproductive toxicity of the XIENCE PRIME and XIENCE 
Xpedition stent have not been evaluated; however, long term carcinogenicity and teratology 
studies were performed with the XIENCE V EECS, a similar everolimus eluting 
subcutaneously in transgenic mice. Based on the results of this study, the XIENCE V EECS does 
not appear to be carcinogenic when implanted in transgenic mice for 26 weeks. In the 
reproductive toxicity studies, XIENCE V EECS was implanted in rats and showed no effect on 
their fertility or reproductive capability. Additionally, there were no teratogenic effects in the 
offspring in this study89. 
 
15.1.5.1. 
Pregnancy/Fertility 
 
There are no adequate studies in pregnant women or men intending to father children regarding 
the safety of everolimus or the XIENCE stent.  Everolimus when administered at oral doses of 
0.1 mg/kg and above showed effects on pre- and post-natal rat development limited to slight 
body weight changes and fetal survival without any specific toxic potential.87 
 
Therefore, pregnant subjects and those planning pregnancy up to one year following the index 
procedure are excluded from this study. Women of child bearing age must have a recent negative 
pregnancy test prior to randomization. If a female subject does get pregnant, the risks to the fetus 
are unknown. Effective contraception must be used before implanting a XIENCE stent system. 
The method of contraception is a personal choice but needs to be made with respect to the 
subject’s  values  with  adequate  medical  information on  the  effectiveness and  safety  of  the 
method. Except for surgical removal of the uterus and ovaries or total abstinence, all methods of 
birth control have a failure rate. Intrauterine devices (IUD), hormonal contraceptives (birth 
control pills, injections or implants), tubal ligation or partner’s vasectomy and barrier 
contraceptives (condoms, diaphragms, and cervical caps) are available means of birth control. 
The primary care provider or a gynecologist should be consulted concerning the best birth 
control method for the subject given his/her medical history and lifestyle choices. 
 
15.1.5.2. 
Lactation 
 
It is unknown whether everolimus is distributed in human milk. Everolimus pharmacokinetic and 
safety profiles have not been determined in infants. Consequently, mothers should be advised of 
potential serious adverse reactions to everolimus in nursing infants. Prior to XIENCE stent 
system implantation, a decision should be made regarding whether to discontinue nursing or 
conduct an alternate percutaneous coronary intervention procedure. 
 
15.2. Potential Risks – CABG 
 
The potential benefits, risks and complications of CABG have been extensively studied and 
documented over the last five decades. 
 
In contemporary surgical practice overall hospital mortality for CABG is approximately 2% (1% 
for elective subjects).  For example in the whole cohort of 113,000 subjects undergoing CABG in 
the United Kingdom in the four year period 2005 to 2008, including those who were urgent, the 

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overall mortality was 1.8% (1.1% in the 78,000 elective subjects).90 
 
Complications of CABG are: 
 
 
• 
Death, stroke, shock, prolonged healing of the surgical incision on the chest due to separation 
 
of the sides of the wound, sternal surgical infection, in-advertent injury to the aorta and/or its 
branches, emergency or non-emergency need for reoperation or angioplasty may occur in < 
2% of the patients. 
 
• 
Excessive bleeding, heart attack, kidney failure, a state of subnormal or depressed amount of 
 
blood being pumped by the heart (low cardiac output syndrome) requiring intravenous 
 
medicine support and/or mechanical assistance from an intra-aortic balloon pump, 
 
development of blood clots, abnormal blood pressure, fluid development in the lungs 
 
(pulmonary edema), may occur in 2% to 5% of the patients. 
 
• 
Chest pain, respiratory failure, need for mechanical support for breathing, rapid or slow heart 
 
beat, post-op impaired neurocongnitive functioning, fever, nausea may occur in 5-10% of the 
 
patients. 
 
The rates of surgical and procedural risks for patients being treated for LM disease or Left Main 
Equivalent disease may be higher than the experience worldwide with cardiac catheterization and 
interventional procedures. 
 
15.3. Major Adverse Event Rates in Left Main Studies 
 
Long term adverse event data for PCI in the LM population has not been extensively studied or 
reported and is therefore not provided in the risk analysis section. Recent literature on major 
cardiac event rates in left main procedures1,2,3,4,5,6,7,8 is limited and emerging. In trials conducted 
in patients with LM disease treated with either PCI or CABG, the following range of major 
adverse event rates were observed: death (2.0% at one year to 11.2% at 5 years), myocardial 
infarction (1.0% at one year to 15.7% at 5 years), stroke (0.1% at one year to 5.9% at 5 years) and  
revascularization (3.4% at one year to 19.7% at 5 years). 
 
15.4. Gender/ Race Specific Prevalence 
 
Coronary artery disease (CAD) continues to be the leading cause of morbidity and mortality 
among women in the United States and throughout the world.91,92   The prevalence of coronary 
artery disease in United States is estimated at 17.6 million for both sexes of which 8.5 million are  
 
reported to be in females.93   The age-adjusted death rate resulting from coronary artery disease 
(CAD) in females, which accounts for about half of all cardiovascular disease (CVD) deaths in 
women, was 95.7 per 100, 000 females in 2007 which was a third of what was observed in 
1980.94, 95   Despite a decline in the overall cardiovascular deaths in females, recently CAD rates 
in US women 35 to 54 years age appear to be increasing, likely associated with obesity.96 
 
Limited race specific data available has shown African-American women to have higher coronary 
heart disease mortality risk in comparison to white women since the 1940s97 attributed mainly to 
substantially lower rate of awareness of heart disease and stroke that has been documented among 
black versus white women. 98 , 99 In contrast, Hispanics have the lowest percentage of 
cardiovascular deaths (21.7%) compared with non-Hispanics (26.3%) despite their lower 

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socioeconomic status, and inadequate access to healthcare in United States (known as 
‘Hispanic Paradox’).100, 101, 102 
 
1 Serruys, P. TCT 2011. 4 year outcomes of the Syntax trial in a subset of patients with left main disease. 
2 Salvatella N., Morice MC., Darremont O., et al. (2011). Unprotected left main stenting with a second generation 
drug eluting stent: 1 year outcomes for the LEMAX Pilot study. Eurointervention. 7(6):689-96. 
3 Carrie D., Eltchanionoff H., Lefevre T., et al. (2011). Early and long term results of unprotected left main coronary 
artery stenosis with paclitaxel eluting stents: the FRIEND registry. Eurointervention. 7(6):680-88. 
4 Seung KB, Park DW, Kim YK et al. (2008). Stents versus coronary artery bypass grafting for left main coronary 
artery disease. NEJM. 358:1781-92. 
5 Park SJ, Kim YK, Park DW, et al. (2011). Randomized Trial of stents versus bypass surgery for left main coronary 
artery disease. NEJM. 364:1718-27. 
6 Park SJ. PRECOMBAT Trial. ACC 2011. 
7 Park DK., Kim YK, Yun SC, et al. (2010). Long term outcomes after stenting versus coronary artery bypass 
grafting for unprotected left main coronary artery disease. 10 year results of bare metal stents and 5 year results of 
drug eluting stents from the ASAM-MAIN registry. JACC; 56(17):1366-75. 
8  Capodanno, D, Stone GW, Morice MC, et al. (2011). Percutaneous coronary intervention versus coronary artery 
bypass graft surgery in left main coronary artery disease. JACC; 58(14):1426-32. 

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In the EXCEL clinical trial, the intended patient population is a group with unprotected left main 
coronary artery (ULMCA) disease.  Literature for Left Main (LM) disease with respect to gender 
shows a lower prevalence in women than men particularly in the definite angina group.  In the 
CASS study, it was observed that in men 50 years or older, 50% had three-vessel or left main 
disease whereas in women left main disease or three-vessel disease occurred in over 40% of 
women older than 60 years of age.103 
 
15.4.1. Gender-specific and Race-specific Diagnosis and Treatment Patterns 
 
It is well documented in literature that men and women present with CAD differently in terms of 
epidemiology, pathophysiology, clinical  presentation, diagnosis and  management. 104 , 105 , 106 , 
107,108, 109 
 
In general, women are less likely to be referred for functional testing of ischemia and that a 
lower rate of diagnostic angiograms and interventional procedures are performed compared with 
men.110  A study that used referral to cardiac catheterization as an indication of perceived patient 
risk observed that approximately 42% women underwent cardiac catheterization compared to 
approximately 50% men.111 
 
Although men and women share most classic risk factors, the significance and the relative 
weighting of these factors are different for the two genders.  In women, menopause is associated 
with a worsening of CAD risk profile.112  The clinical presentation of CAD and the interpretation 
of noninvasive diagnostic testing is less reliable in women (atypical symptoms) compared with 
men, especially in the age group below 55 years when the prevalence of coronary artery disease is 
still relatively low.113  Thus, women in this age group are significantly less likely than men to 
have ECGs suggestive of myocardial ischemia.114  Additionally, women presenting with chest 
pain are less likely to undergo diagnostic testing and are less likely to have a positive exercise 
test or imaging study.115  In general, women usually experience a delay in the clinical diagnosis, 
which may easily translate into increased procedural morbidity and mortality.  Additionally, 
disparities have been found in the administration and performance of both noninvasive testing 
and cardiac catheterization.  Four times as many men as women receive device therapy for 
sudden cardiac arrest prevention.99,100 
 
Gender/race specific data on diagnosis and treatment patterns in the intended population is not 
available in literature. 
 
15.4.2. Proportions of Women Included in Past Trials 
 
Limited gender specific data is available on key trials related to Left Main disease and CABG 
trials.  However, Table 15-1 summarizes the proportions of women included in the past trials 
(both AV sponsored and non-AV sponsored clinical trials). 
 
 
 
 
 
 
 
 

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Table 15-1       Proportions of Women Included in Past Trials 
Study No. 
Trial Name 
Total number 
of patients 
Men (%) 
Women (%) 
Abbott PCI (DES) Trials 
1 
SPIRIT II 
300 
219 (73%) 
81 (27%) 
2 
SPIRIT III 
1002 
687 (68.6%) 
314 (31.4%) 
3 
SPIRIT IV 
3687 
2499 (67.8%) 
1188 (32.2%) 
4 
SPIRIT PRIME 
(CSR+LLR) 
525 
361 (68.8%) 
164 (31.2%) 
5 
XV USA 
5054 
3478 (68.8%) 
1576 (31.2%) 
Non-Abbott DES and CABG Trials 
6 
Pooled data from RAVEL, SIRIUS, 
E-SIRIUS, C-SIRIUS116 
1748 
1251 (71.6%) 
497 (28.4%) 
7 
ENDEAVOR clinical trial program117 
2132 
1524 (71.5%) 
608 (28.5%) 
8 
TAXUS Women118 
810 
642 (79.3%) 
168 (20.7%) 
9 
CABG (Effect of gender on post- 
operative outcomes)119 
1743 
1220 (70%) 
523 (30%) 
10 
CABG (Gender differences in clinical 
and angiographic outcomes)120 
954 
766 (80%) 
188 (20%) 
Trials for Target Indication (Left Main Disease) 
11 
SYNTAX Trial121 
1800 
1398 (77.6%) 
402 (22.4%) 
12 
Left Main DES122 
1452 
1048 (72.2%) 
404 (27.8%) 
 
Typically in a drug eluting stent trial, 20-33% women participated which is comparable to the 
proportion of women participated in CABG, SYNTAX, and Left Main DES trials. 
 
Within Abbott sponsored trials, the participation of African American men ranged from 
approximately 3-6% compared to 4-10% women of the same race; percentage of Hispanic men 
ranged from 1.4-3.2% compared to women (0.9-3.2%) whereas white men represented 89-95% 
of the male population compared to white women representing 85-88% of the female population. 
 
15.4.3. Clinically Significant Gender Differences in Outcomes Related to 
 
Safety or Effectiveness 
 
The recognition of gender disparities in the epidemiology, diagnosis and treatment of 
cardiovascular disease are well-established.  However, there is limited literature regarding the 
influence of gender on treatment patterns and outcomes of coronary revascularization.  Due to a 
higher baseline risk profile and more complex angiographic characteristics, women tend to have 
worse clinical outcomes compared to men.123, 124, 125 
 
Several studies indicate that women are less likely than men to undergo diagnostic 
catheterization.126,127, 128  However, in recent drug eluting trials as discussed below, it is indicated 
that women who underwent stent based PCI procedures or CABG procedures irrespective of the 
type of DES including the left main disease, had similar clinical outcomes as observed in men. 
 
Despite less favorable baseline clinical and angiographic features in women compared with men, 
the angiographic and clinical benefits are independent of gender using different drug eluting  
stents.116,117,129, 130, 131   Similar observations have been reported for men and women undergoing  
by-pass surgery after accounting for differences in the risk variables.119,120,121    Of particular 

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interest is the observation by the Investigators of SYNTAX trial where despite gender related 
differences in baseline co-morbidities, the outcomes between CABG and PCI at 12 months were 
similar for men and women in the most challenging group of patients with three vessel and/or 
left main disease.122 
 
 
15.5. Risk Management Procedures 
 
Subjects will be monitored closely throughout the trial duration. Subjects will be evaluated 
clinically at pre-determined timepoints to assess their clinical status. 
 
An independent DSMB will monitor safety of the subjects throughout the trial. 
 
15.5.1. Post PCI 
 
As part of the dual antiplatelet strategy, aspirin ≥75 mg per day indefinitely is mandatory post 
procedure.  Additionally chronic daily ADP antagonist therapy is mandated following PCI with 
choices including either: 
 
• clopidogrel 75 mg per day, or 150 mg per day for 7-30 days then reduced to 75 mg per day, 
unless subject is hyporesponsive to clopidogrel, or 
•   prasugrel 5 or 10 mg per day, or 
• ticagrelor per labeling and recommended guidelines if approved by the local regulatory 
authorities during the treatment period of this protocol. 
 
In subjects who received a ULMCA DES, a daily ADP antagonist must be given for at least one 
year, and is recommended for the duration of the trial in the absence of major bleeding 
complications or other major complications. ADP antagonists must not be discontinued within 
the first year after DES implantation unless absolutely necessary for major bleeding 
complications, major trauma, major surgery necessitating discontinuation of antiplatelet therapy 
(e.g. intracranial surgery), etc.  If an ADP antagonist must be discontinued, a GP IIb/IIIa bridging 
strategy up until the time of surgery may be considered, followed by re-loading of the ADP 
antagonist as soon as possible post surgery. 
 
15.5.2. Post CABG 
 
Aspirin must be used daily for the duration of the trial.  Subjects who are treated with CABG 
should receive the following medications as per the local institution standard of care unless 
medically contraindicated: beta blocker and statins.  If there is left ventricular dysfunction, an 
ACE inhibitor should also be prescribed. 
 
Section 22 outlines the recommended care of post-CABG subjects. 
 
15.5.3. Gender-specific 
 
Abbott Vascular plans to encourage investigators participating in this trial to randomize women  
that meet inclusion/exclusion criteria of this study.  Site staff will be trained by way of the 
investigator training material to encourage randomization of women in the EXCEL trial.  It is 

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pertinent to note that the study inclusion or exclusion criteria are open to both genders except the 
exclusion criteria where pregnant women or women who are planning to be pregnant within one 
year of the study after randomization are excluded from this study. This exclusion is because the 
effects of the XIENCE Drug Eluting Stents have not been studied in pregnant females in the past 
and any potential iatrogenic effects of the drug/device on the pregnant female and the fetus 
remain unknown. 
 
In an effort to better understand any potential gender differences from this trial, the gender 
subgroup has been prespecified in the EXCEL protocol (Section 9.1 Gender-specific subgroup 
analysis, Section 17.5 QoL subgroup analyses and Section 21.2 Pre-specified subgroups). These 
analyses will be descriptive and hypothesis generating and may provide further insights in 
understanding any potential gender differences. 
 
Abbott Vascular believes that the proportion of women randomized in the EXCEL clinical trial 
will reflect the proportion of women reaching the catheterization laboratory.  Moreover, the data 
obtained from the prespecified gender subgroup analysis in the EXCEL trial will provide robust 
descriptive data in terms of diagnosis, treatment, and clinical outcomes in men and women. 
 
15.6. Potential Benefits 
 
15.6.1. Potential benefits of stenting. 
 
The XIENCE PRIME and XIENCE Xpedition stent systems are very similar to the approved 
XIENCE V EECSS. The XIENCE V EECSS has been evaluated in the SPIRIT FIRST, SPIRIT 
II, SPIRIT III and SPIRIT IV trials and demonstrated safety and efficacy. 
 
Additionally, the SPIRIT PRIME study, a prospective, two-arm, open-label, multi-center registry 
using the XIENCE PRIME Stent system (XIENCE PRIME and XIENCE PRIME LL EECSS) in 
500 subjects is being conducted at up to 75 global sites. Overall, the long-term effects and 
potential benefits of XIENCE PRIME stent system are not yet known. 
 
Drug eluting stents have been associated with a reduction in the need for repeat revascularization 
without an increase in the risk of death or myocardial infarction for subjects with ULMCA 
stenosis compared to bare metal stent.89  In another study by Tamburino et al, in a large population 
of subjects with acute coronary syndrome and ULMCA disease, DES were more effective than 
BMS in reducing myocardial infarction and target lesion revascularization.132 The LEMANS 
Registry has shown good long term outcome with implantation of DES for ULMCA coronary 
artery disease. DES stenting of ULMCA decreased the risk of long-term MACCE with improved 
survival in subjects with distal ULMCA disease.133 The ISAR-Left Main randomized clinical trial 
has shown that implantation with either paclitaxel or sirolimus eluting stents in ULMCA lesions 
is safe and effective with comparable clinical and angiographic outcomes. Additionally, for both 
stent types, definite stent thrombosis rates at two years were low and comparable with no new 
events beyond 30 days post index procedure.23 
 
These studies not only demonstrate the safety and effectiveness of drug eluting stents in the 
treatment of ULMCA disease but also indicate the absence of signal suggesting an increased  
safety risk with DES stenting of the ULMCA.25, 134 
 

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15.6.2. Potential benefits of CABG. 
 
Indications for CABG can either be classified as symptomatic, prognostic or a combination. 
Traditional prognostic indications for CABG include subjects with significant left main stem 
stenosis and those with two or three vessel coronary artery disease particularly involving the 
proximal left anterior descending coronary artery and thus far CABG procedure has been the 
standard of care for the treatment of left main disease.  CABG may also be indicated in subjects 
who remain symptomatic with angina and/or breathlessness despite optimal medical therapy 
even in the absence of a prognostic indication.  Numerous studies have demonstrated that 
improvement in symptoms correlates well with significant improvements in quality of life.90 
 
 

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16. 
APPENDIX A: DEFINITIONS, ABBREVIATIONS, AND ACRONYMS 
 
16.1. Primary and Major Secondary Endpoint Definitions 
 
16.1.1. Definition of Death 
 
The cause of death will be adjudicated as being due to cardiovascular causes, non cardiovascular 
causes, or undetermined causes. 
• Cardiovascular Death includes sudden cardiac death, death due to acute myocardial 
infarction, death due to heart failure or cardiogenic shock, death due to stroke, death due to 
other cardiovascular causes, and death due to bleeding as follows: 
 
◦ 
Sudden Cardiac Death refers to death that occurs unexpectedly and includes the  
 following deaths: 
    Witnessed and instantaneous without new or worsening symptoms 
    Witnessed within 60 minutes of the onset of new or worsening cardiac symptoms 
 Witnessed and attributed to an identified arrhythmia (e.g., captured on an 
electrocardiographic (ECG) recording or witnessed on a monitor by either a medic or 
paramedic) 
    Subjects unsuccessfully resuscitated from cardiac arrest 
 Subjects successfully resuscitated from cardiac arrest but who die without identification 
of a non-cardiac etiology (Post-Cardiac Arrest Syndrome) 
 Unwitnessed death or other causes of death (information regarding the subject’s 
clinical status preceding death should be provided, if available) 
 
◦ 
Death due to Acute Myocardial Infarction refers to an acute myocardial infarction 
 
(MI) leading inexorably to death, generally within 30 days.  Death due to known sequelae 
 
of MI including mechanical complications, arrhythmia, and/or pump failure, as well as 
 
death resulting from a procedure to treat myocardial ischemia or to treat a complication 
 
resulting from myocardial infarction should be considered death due to acute MI.  The 
 
acute myocardial infarction should be verified either by the diagnostic criteria outlined 
 
for acute myocardial infarction or by autopsy findings showing recent myocardial 
 
infarction or recent coronary thrombus, and there should be no conclusive evidence of 
 
another cause of death. 
 
If death occurs before biochemical confirmation of myocardial necrosis can be obtained, 
adjudication should be based on clinical presentation and ECG evidence. 
 
Death due to a myocardial infarction that occurs as a direct consequence of a 
cardiovascular investigation, procedure, or operation should be classified as death due to 
other cardiovascular cause. 
 
◦ 
Death due to Heart Failure or Cardiogenic Shock refers to death occurring in the 
 
context of clinically worsening symptoms and/or signs of heart failure without evidence 
 
of another cause of death. 

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Death due to heart failure or cardiogenic shock should include sudden death occurring 
during an admission for worsening heart failure as well as death from progressive heart 
failure or cardiogenic shock following implantation of a mechanical assist device. 
 
New or worsening signs and/or symptoms of congestive heart failure (CHF) include any 
of the following: 
 New or increasing symptoms and/or signs of heart failure requiring the initiation of, 
or an increase in, treatment directed at heart failure or occurring in a subject already 
receiving maximal therapy for heart failure 
 Heart failure symptoms or signs requiring continuous intravenous therapy or chronic 
oxygen administration for hypoxia due to pulmonary edema 
    Confinement to bed predominantly due to heart failure symptoms 
 Pulmonary edema sufficient to cause tachypnea and distress not occurring in the 
context of an acute myocardial infarction, worsening renal function, or as the 
consequence of an arrhythmia occurring in the absence of worsening heart failure 
 Cardiogenic shock not occurring in the context of an acute myocardial infarction or as 
the consequence of an arrhythmia occurring in the absence of worsening heart failure. 
Cardiogenic shock is defined as systolic blood pressure (SBP) <90 mm Hg for greater 
than 1 hour, not responsive to fluid resuscitation and/or heart rate correction, and felt 
to  be  secondary to  cardiac  dysfunction and  associated with  at  least  one  of  the 
following signs of hypoperfusion: 
•    Cool, clammy skin or 
•    Oliguria (urine output < 30 mL/hour) or 
•    Altered sensorium or 
•    Cardiac index < 2.2 L/min/m2 
 
Cardiogenic shock can also be defined if SBP < 90 mm Hg and increases to ≥ 90 mm 
Hg in less than 1 hour with positive inotropic or vasopressor agents alone and/or with 
mechanical support. 
 
Note: Heart failure may have a number of underlying causes, including acute or 
chronic ischemia, structural heart disease (e.g. hypertrophic cardiomyopathy), and 
valvular heart disease.  Where treatments are likely to have specific effects, and it is 
likely possible to distinguish between the various causes, then it may be reasonable to 
separate out the relevant treatment effects.  In other cases, the aggregation implied by 
the definition above may be more appropriate. 
◦ 
Death due to Stroke (Cerebrovascular Event:  intracranial hemorrhage or non- 
hemorrhagic stroke) refers to a cerebrovascular event or a complication of a 
cerebrovascular event that leads inexorably to death, generally within 30 days after the 
suspected event.  These deaths may be based on clinical signs and symptoms as well as 
neuroimaging and/or autopsy.  There should be no conclusive evidence of another cause 
of death. 
◦ 
Death due to Other Cardiovascular Causes refers to death due to a cardiovascular 
cause not included in the above categories (e.g. dysrhythmia, pulmonary embolism,  
 
 

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cardiovascular  intervention,  aortic  aneurysm  rupture,  or  peripheral  arterial  disease). 
Mortal complications of cardiac surgery or PCI, even if “non-cardiovascular” in nature, 
should be classified as cardiovascular deaths. 
◦ 
Death Due to Bleeding refers to fatal bleeding or bleeding which contributes to death, 
with categories being mutually exclusive. 
 Fatal Bleeding: death in which a bleeding event directly leads to death within 7 days. 
Examples of fatal bleeding include an intracranial hemorrhage that leads to herniation 
of the brain and death within 24 hours, or a massive gastrointestinal hemorrhage that 
results in shock, hemodynamic collapse, and death.  If a bleeding event is considered 
fatal, then the cause of death should be either intracranial or non-intracranial bleeding. 
 Bleeding Contributes to Death:  death in which a bleeding event is part of a causal 
chain of medical events that ultimately leads to death within 30 days of the bleed, but 
bleeding  is  not  directly  and/or  immediately related  to  the  subject’s  death.    An 
example of bleeding that contributes to death is a large retroperitoneal bleed that 
leads to surgical evacuation and subsequent development of an abscess in the area of 
bleeding that leads to sepsis, multiorgan failure, and death 10 days after the onset of 
bleeding. If bleeding contributes to death (but the bleeding is not categorized as 
“fatal”), then the cause of death should be recorded as something other than 
intracranial/non-intracranial bleeding. 
 
• Non-Cardiovascular Death is defined as any death not covered by cardiac death or vascular 
death. Categories include but are not limited to: 
◦ 
Pulmonary causes 
◦ 
Renal causes 
◦ 
Gastrointestinal causes 
◦ 
Infection (includes sepsis) 
◦ 
Non-infectious (e.g., systemic inflammatory response syndrome (SIRS)) 
◦ 
Malignancy (i.e., new malignancy, worsening of prior malignancy) 
◦ 
Accidental/Trauma 
◦ 
Suicide 
◦ 
Non-cardiovascular system organ failure (e.g., hepatic failure) 
◦ 
Non-cardiovascular surgery 
◦ 
Other non-cardiovascular 
 
• Undetermined cause of death refers to a death not attributable to one of the above 
categories of cardiovascular death or to a non-cardiovascular cause. For this trial all deaths 
with undetermined causes will be included in the cardiovascular category. 
 
16.1.2.        Definition of Myocardial Infarction 
 
Different criteria for spontaneous and peri-procedural MI will be utilized. 
•   Spontaneous MI (occurring >72 hours after any PCI or CABG) 
 
Detection of rise and/or fall of cardiac biomarkers (CK-MB or troponin) with at least one value  
 

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above the upper reference limit (URL)* together with evidence of myocardial ischemia with at 
least one of the following: 
 
◦ 
ECG changes indicative of new ischemia [ST-segment elevation or depression as defined 
below, in the absence of other causes of ST-segment changes such as left ventricular 
hypertrophy (LVH) or bundle branch block (BBB)] or 
◦    Development of pathological Q waves (≥0.04 seconds in duration and ≥1 mm in depth) 
in ≥2 contiguous precordial leads or ≥2 adjacent limb leads) of the ECG, or 
◦ 
Angiographically documented graft or native coronary artery occlusion or new severe 
stenosis with thrombosis and/or diminished epicardial flow, or 
◦ 
Imaging  evidence  of  new  loss  of  viable  myocardium or  new  regional  wall  motion 
abnormality 
 
*If the upper reference limit (URL) from the respective laboratory performing the assay 
is not available, then the URL for myocardial necrosis from the laboratory should be 
used.  If the URL or the URL for myocardial necrosis is not available, the MI decision 
limit for the particular laboratory should be used as the URL.  Reference limits from the 
laboratory performing the assay are preferred over the manufacturer’s listed reference 
limits in an assay’s instructions for use. 
    ST elevation 
 
New ST elevation at the J point in two anatomically contiguous leads with the cut-off 
points: ≥0.2 mV in men (>0.25 mV in men <40 years) or ≥0.15 mV in women in 
leads V2-V3 and/or ≥0.1 mV in other leads 
    ST depression 
 
New horizontal or down-sloping ST depression ≥0.05 mV in two contiguous leads. 
The above ECG criteria illustrate patterns consistent with myocardial ischemia 
• 
Procedure-Related Myocardial Infarction (occurring within 72 hours of either PCI or 
CABG) 
 
In the present study it is essential to have an identical definition for MI after both PCI and 
CABG to eliminate ascertainment bias.  Furthermore, given that MI represents one 
component of the primary composite endpoint of death, stroke or MI, and that death and 
stroke are devastating complications, only prognostically important MI that has clearly been 
associated with subsequent mortality will be included in the primary endpoint. In this regard, 
small levels of cardiac enzyme elevation after PCI reflect the underlying degree of 
atherosclerosis 135 and seem to have little or no prognostic significance, 136 , 137 Large-scale 
studies in the stent era have shown that peak post-PCI levels of ≥8x the upper limits of 
normal ULN or ≥10x ULN are required before an association with subsequent mortality 
emerges,138 although some studies have suggested that a CPK-MB of CPK-MB ≥5x ULN 
may be prognostically important.137,139, 140 Myocardial infarction may be difficult to diagnosis 
in the peri-surgical period given an obligate release of cardiac enzymes from all CABG 
procedures, although post CABG CPK-MB levels of ≥5 fold or ≥10 fold increased have been 
shown to be prognostically related to subsequent mortality. 141 , 142 , 143 , 144 Moreover, cardiac 
troponin elevations after PCI are of uncertain prognostic importance, in contrast to  
 

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spontaneous troponin elevations in subjects with myonecrosis unrelated to revascularization 
procedures (spontaneous MI), for which numerous studies have shown to be strongly 
predictive of subsequent mortality.140, 145,146, 147, 148, 149, 150 Thus, in the present study only CK-
MB elevations will be used for determination of peri-procedural MI, whereas troponin or 
CK-MB elevations may be used to diagnose spontaneous MI. 
 
CK-MB levels will be drawn at baseline and at 12±2 hrs and at 24±2 hrs post procedure (or 
at discharge if this occurs before 24±2 hrs), and more frequently for signs or cardiac 
symptoms of clinical or hemodynamic instability.  12-lead EKGs will be recorded at baseline, 
within 24 hours after the procedure (at the same time as the CK-MB draw if possible) and at 
discharge. 
 
The baseline CK-MB must be normal for subject enrolment in this study. A post procedure 
MI will be defined as the occurrence within 72 hours after either PCI or CABG of either: 
◦    CK-MB above 10 x URL (*determined on a single measurement), OR 
◦    CK-MB above 5 x URL (*determined on a single measurement), PLUS 
 new pathological Q waves in at least 2 contiguous leads or new persistent non-rate 
related LBBB, or 
 angiographically documented graft or native coronary artery occlusion or new severe 
stenosis with thrombosis and/or diminished epicardial flow, or 
 imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality 
 
Symptoms of cardiac ischemia (which are of course difficult to assess in the post CABG 
patient either because of intubation or incisional pain) are not required for the diagnosis of 
peri-procedural MI. 
 
For each MI identified by the CEC, the type of MI will also be described as: 
◦    ST-Elevation MI (STEMI) 
 Also categorize as: 
• Q-wave** 
• Non-Q-wave 
• Unknown (no ECG or ECG not interpretable) 
◦    Non-ST-Elevation MI (NSTEMI) 
 Also categorize as: 
• Q-wave** 
• Non-Q-wave 
• Unknown (no ECG or ECG not interpretable) 
◦    Unknown (no ECG or ECG not interpretable) 
 
**  Development  of  new  (i.e.,  not  present  on  the  subject’s  ECG  before  allocation) 
pathological Q-waves (≥0.04 seconds in duration and ≥1 mm in depth) in ≥2 contiguous 
precordial leads or ≥2 adjacent limb leads. 
 

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16.1.3. Definition of Stroke 
 
Stroke is defined as the rapid onset of a new persistent neurologic 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).  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. 
 
All patients to be randomized into the Excel RCT will have a modified Rankin Scale (mRS) 
assessment conducted by mRS trained personnel at baseline and each visit and telephone 
interview. Additionally, the site research coordinator will evaluate each subject at 30 days, 6 
months, 1, 2, 3, 4 and 5 Y follow-up time points and at the primary endpoint follow-up time 
point (either at annual follow-up or at subject contact for primary endpoint AE check) using a 
Transient Ischemic Attack (TIA)/Stroke Questionnaire and mRS Disability Questions (Appendix 
J).  This questionnaire is a National Institute of Health Stroke Scale (NIHSS) validated 
questionnaire used in the CREST clinical trial. The mRS disability questions are adapted from a 
structured interview developed for stroke patients1. If a subject’s response to this questionnaire 
indicates a  possible stroke or  a  change in  the  mRS, then a  vascular neurologist or  stroke 
specialist or a mRS certified personnel will confirm the  mRS scale, determine whether a stroke 
has occurred and determine the stroke severity using the NIHSS TIA/Stroke questionnaire. 
 
If a new stroke is diagnosed at the site, the investigators at the site will prepare a short narrative 
that describes the findings that support the diagnosis.  All stroke events will be adjudicated by 
the Clinical Events Committee (CEC).  Furthermore, if there is an increase in the mRS by one or 
more points noted at any visit, then an evaluation will be carried out to determine if a stroke or 
other outcome event has occurred. Post procedure, if a patient is diagnosed and adjudicated with a  
stroke  event  by  the  Clinical  Events  Committee  (CEC),  a  disability  assessment  will  be 
performed at least 90 days±2 weeks after the diagnosis of stroke using the mRS assessment 
instrument. 
 
Any certification or mRS training for the personnel should be based on the structured interview 
version as in Appendix J ( Modified Rankin Disability Questionnaire). 
 
A.  For the diagnosis of stroke, the following four criteria should be fulfilled: 
 
1.   Rapid onset* of a focal/global neurological deficit with at least one of the following: 
• Change in level of consciousness 
• Hemiplegia 
• Hemiparesis 
• Numbness or sensory loss affecting one side of the body 
• Dysphasia/Aphasia 
• Hemianopia (loss of half of the field of vision of one or both eyes) 
 
1 Wilson JTL, Hareendran A, Grant M, Baird  T, Shultz UGR, Muir KW, and Bone I.  “Improving the Assessment 
 of Outcomes in Stroke:  Use of a Structured Interview to Assign Grades  on the Modified Rankin Scale.” 
 Stroke. 2002; 33; 2243-46. 
 
 

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• Amaurosis fugax (transient complete/partial loss of vision of one eye) 
• Other new neurological sign(s)/symptom(s) consistent with stroke 
 
*If the mode of onset is uncertain, a diagnosis of stroke may be appropriate provided 
that there is no plausible non-stroke cause for the clinical presentation 
 
2. Duration of a focal/global neurological deficit ≥24 hours or<24 hours if any of the 
following conditions exist: 
i. 
at least one of the following therapeutic interventions: 
a.   Pharmacologic (i.e., thrombolytic drug administration) 
b.   Non-pharmacologic (i.e., neurointerventional procedure such as 
intracranial angioplasty) 
ii. 
Available brain imaging clearly documents a new hemorrhage or infarct 
iii. 
The neurological deficit results in death 
 
3.   No other readily identifiable non-stroke cause for the clinical presentation (e.g., brain 
tumor, trauma, infection, hypoglycemia, other metabolic abnormality, peripheral 
lesion, or drug side effect). Patients with non-focal global encephalopathy will not be 
reported as a stroke without unequivocal evidence based upon neuroimaging studies. 
 
4.   Confirmation of the diagnosis by a neurology or neurosurgical specialist and at least 
one of the following: 
a.   Brain imaging procedure (at least one of the following): 
i. 
CT scan 
ii. 
MRI scan 
iii. 
Cerebral vessel angiography 
b.   Lumbar puncture (i.e. spinal fluid analysis diagnostic of intracranial hemorrhage) 
 
B.  If the acute focal signs represent a worsening of a previous deficit, these signs must have 
either 
1. Persisted for more than one week, or 
2. Persisted for more than 24 hours and were accompanied by an appropriate new CT 
or MRI finding 
 
C.  Strokes may be sub-classified as follows: 
1. Ischemic (Non-hemorrhagic):  a stroke caused by an arterial obstruction due to 
either a thrombotic (e.g., large vessel disease/atherosclerotic or small vessel 
disease/lacunar) or embolic etiology. 
2. Hemorrhagic: a stroke due to a hemorrhage in the brain as documented by 
neuroimaging or autopsy.  This category will include strokes due to primary 
intracerebral hemorrhage (intraparenchymal or intraventricular), ischemic strokes 
with hemorrhagic transformation (i.e., no evidence of hemorrhage on an initial 
imaging study but appearance on a subsequent scan), subdural hematoma,* and 
primary subarachnoid hemorrhage. 
 
*All subdural hematomas that develop during the clinical trial should be recorded 
and classified as either traumatic versus nontraumatic. 
3. Unknown:   the stroke type could not be determined by imaging or other means 
(e.g., lumbar puncture, neurosurgery, or autopsy) or no imaging was performed. 
 
 

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D. Stroke Disability 
All strokes with stroke disability of Modified Rankin Scale (mRS) ≥1 will be  
 
included in the primary endpoint. All diagnosed strokes (even with mRS 0) 
will also be tabulated. Stroke disability will be classified using an adaptation of the 
modified Rankin Scale as follows, the assessment of which will be based on 
the Modified Rankin Disability Questionnaire (Appendix J.) 
 
Scale 
Disability 
0 
No stroke symptoms at all. (May have other complaints) 
1 
No significant disability; symptoms present but no physical or other limitations. 
2 
Slight  disability; 
limitations in participation in usual social roles, but 
independent for activities of daily living (ADL) 
3 
some need for assistance but able to walk without assistance 
4 
Moderately severe disability; need for assistance with some basic ADL, but not 
requiring constant care 
5 
Severe disability; requiring constant nursing care and attention. 
Stroke: Modified Rankin score ≥1 and increase by ≥1 from baseline 
 
E.  Transient Ischemic Attack (as compared to stroke) is defined as: 
 
• New focal neurologic deficit with rapid symptom resolution, usually 1-2 hours, 
always within 24 hours 
 
• Neuroimaging without tissue injury 
 
16.1.4. Definition of Coronary Revascularization Procedures 
 
A coronary revascularization procedure may be either a coronary artery bypass graft (CABG) 
surgery or a percutaneous coronary intervention (PCI) (for example, angioplasty, stenting), 
regardless of procedural success. 
 
Coronary revascularization procedures may be further classified as follows: 
 
• 
Urgent:  an urgent procedure is one that is performed within 48 hours of upon diagnosis of 
 
the subject’s status due to urgency of the medical condition, but is not otherwise considered 
 
emergent 
• 
Emergent: an emergent procedure is one that is performed as soon as possible (usually 
within 6 hours) 
•    Elective: an elective procedure is one that is scheduled and is not urgent or emergent 
 
Procedural Success may be defined as follows: 
• 
CABG:  the successful placement of at least one conduit with either a proximal and distal 
anastomosis or a distal anastomosis only 
 

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• 
PCI:  successful balloon inflation with or without stenting and the achievement of a residual 
stenosis <50% of the left anterior descending coronary artery and/or the left circumflex 
artery.  The balloon inflation and/or stenting could have been preceded by adjunctive device use  
(e.g., Angiojet, rotational atherectomy etc.) 
 
Target  Lesion:  A  lesion  revascularized  in  the  index  procedure  (or  during  a  planned  or 
provisional staged procedure).  The LM target lesion extends from the left main stem ostium to 
the end of the 5 mm proximal segments of the left anterior descending and left circumflex 
arteries as well as the ramus intermedius if the latter vessel has a vessel diameter of ≥2 mm. 
 
Target Vessel:  The target vessel is defined as the entire major coronary vessel proximal and 
distal to the target lesion including upstream and downstream branches and the target lesion 
itself.  The left main and any vessel originating from the left main coronary artery or its major 
branches is, by definition, considered a target vessel for the purposes of this trial (unless either 
the LAD or LCX are occluded at baseline and no attempt was made to revascularize these 
territories by either PCI or CABG). 
 
Target Vessel-Non-Target Lesion:  The target vessel but non-target lesion consists of a lesion in 
the epicardial vessel/branch/graft that contains the target lesion; however, this lesion is outside of 
the target lesion by at least 5 mm distal or proximal to the target lesion determined by quantitative 
coronary angiography (QCA) 
 
Non-Target Vessel:  For the purposes of this trial, the only possible non-target vessel would be 
the right coronary artery and its major branches that were not treated by either PCI or CABG at 
the index procedure (unless either the LAD or LCX are occluded at baseline and no attempt was 
made to revascularize these territories by either PCI or CABG). 
 
Target Vessel Revascularization (TVR):   Target vessel revascularization is any repeat 
percutaneous intervention of the target vessel or bypass surgery of the target vessel 
 
Target Lesion Revascularization (TLR):   Target lesion revascularization is defined as any 
repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel 
 
All revascularization events will be adjudicated as either ischemia-driven or non ischemia- 
driven 
 
Ischemia-Driven Target Lesion (or Vessel) Revascularization:  A target lesion (vessel) 
revascularization will be considered ischemia-driven if the target lesion diameter stenosis is 
≥50% by QCA (analysis segment measurement, involving the lesion itself and 5 mm of proximal 
and/or distal margin) and any of the following criteria for ischemia are met: 
•    A positive functional study corresponding to the area served by the target lesion; or 
•    Ischemic ECG changes at rest in a distribution consistent with the target vessel; or 
•    Typical ischemic symptoms referable to the target lesion; or 
 
• IVUS of the target lesion with a minimal lumen area (MLA) of ≤4mm2for non left main 
 
lesions or ≤6mm2for left main lesions. If the lesions are de novo (i.e. not restenotic), the 
 
plaque burden must also be ≥60%; or 
•    FFR of the target lesion ≤0.80 
 
 
 
 

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Note: 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. 
 
Ischemia-Driven Non-Target Vessel Revascularization:  A non target vessel revascularization 
will be considered ischemia-driven if any lesion the non target vessel has a diameter stenosis 
≥ 50% by QCA with any of the above criteria for ischemia met. 
 
Unplanned revascularization for ischemia: Any repeat revascularization of either a target 
vessel or non-target vessel with any of the above criteria for ischemia met. 
 
16.2.       Other Definitions 
 
Adverse Device Effect 
 
Represents a possibly, probably or definitely device-related Adverse Event. 
 
Adverse Event 
 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. 
 
Bleeding Complication 
 
Bleeding will be classified by the TIMI hemorrhage classification. 
 
Severity 
Major 
• 
Intracranial hemorrhage –OR– 
• 
A ≥5 g/dL decrease in the hemoglobin concentration –OR– 
• 
A ≥15% absolute decrease in the hematocrit 
Minor 
• 
Observed blood loss: 
o 
A ≥3 g/dL decrease in the hemoglobin concentration –OR– 
o 
A ≥10% absolute decrease in the hematocrit 
• 
No observed blood loss: 
o 
o 
A ≥4 g/dL decrease in the hemoglobin concentration –OR– 
A ≥12% absolute decrease in the hematocrit 
Minimal 
• 
Any clinically overt sign of hemorrhage (including imaging) that is associated 
with a <3 g/dL decrease in hemoglobin concentration or <9% decrease in the 
  
hematocrit  
 
 
All TIMI definitions take into account blood transfusions, so that hemoglobin and hematocrit values 
are adjusted by 1 g/dl or 3%, respectively, for each unit of blood transfused. Therefore, the true change 
in hemoglobin or hematocrit if there has been an intervening transfusion between two blood 
measurements is calculated as follows: 
 
•    Δ Hemoglobin = [baseline Hgb – post-transfusion Hgb] + [number of transfused units]; 
 
•    Δ Hematocrit = [baseline Hct – post-transfusion Hct] + [number of transfused units X 3]. 
 
 

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Bleeding Academic Research Consortium (BARC) Definition for Bleeding1 
 
 
Type 0: no bleeding 
 
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional; may include 
episodes leading to self-discontinuation of medical therapy by the patient without consulting a 
healthcare professional 
 
Type 2: any overt, actionable sign of hemorrhage (eg, more bleeding than would be expected for a 
clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for 
type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, 
medical intervention by a healthcare professional, (2) leading to hospitalization or increased 
level of care, or (3) prompting evaluation 
 
Type 3 
 
Type 3a 
• 
Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL* (provided hemoglobin drop is related to 
 
bleed) 
• 
Any transfusion with overt bleeding 
 
Type 3b 
• 
Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is related to bleed) 
• 
Cardiac tamponade 
• 
Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) 
• 
Bleeding requiring intravenous vasoactive agents 
 
Type 3c 
• 
Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does 
   include intraspinal) 
• 
Subcategories confirmed by autopsy or imaging or lumbar puncture 
• 
Intraocular bleed compromising vision 
 
Type 4: CABG-related bleeding 
• 
Perioperative intracranial bleeding within 48 h 
• 
Reoperation after closure of sternotomy for the purpose of controlling bleeding 
• 
Transfusion of ≥ 5 U whole blood or packed red blood cells within a 48-h period† 
• 
Chest tube output ≥ 2L within a 24-h period 
 
 
1 Mehran R, Rao SV, Bhatt DL, et al. Stnadardized Bleeding Definitions for Cardiovascular Clinical Trials: A 
Consensus Report From the Bleeding Academic Research Consortium.Circulation.2011.123:2736-2747. 

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Type 5: fatal bleeding 
 
Type 5a 
 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious 
 
Type 5b 
 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 
Note: CABG indicates coronary artery bypass graft. Platelet transfusions should be recorded and reported but are not 
included in these definitions until further information is obtained about the relationship to outcomes. If a CABG- 
related bleed is not adjudicated as at least a type 3 severity event, it will be classified as not a bleeding event. If a 
bleeding event occurs with a clear temporal relationship to CABG (ie, within a 48-h time frame) but does not meet 
type 4 severity criteria, it will be classified as not a bleeding event. 
 
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood =1 g/dL hemoglobin). 
†Cell saver products are not counted. 
 
Chronic Concomitant Medications 
 
Medication that: 
 
• has been prescribed or is an over the counter (OTC) medication that has been taken or 
will continue to be taken regularly for at least a period of 6 months, or 
 
• is required to be taken indefinitely by the subject, or 
 
• has been prescribed or is an OTC medication that has been taken multiple times (each 
time for at least 6 months) 
 
Complete Revascularization 
 
See Section 19, Appendix D for the definitions of complete anatomic and ischemic 
revascularization. 
 
Major Adverse Event (assessed in-hospital and 30 days only) 
 
Composite of death, myocardial infarction, stroke, transfusion of ≥ 2 units of blood, major 
arrhythmia, unplanned coronary revascularization for ischemia, any unplanned surgery or 
radiologic procedure, renal failure, sternal wound dehiscence, infection requiring antibiotics 
for treatment, intubation for >48 hours, or post-pericardiotomy syndrome. 
 
Major Arrhythmia 
 
Ventricular tachycardia or fibrillation requiring cardioversion or countershock; atrial 
fibrillation lasting >24 hours; bradycardia or conduction system disease requiring a permanent 
pacemaker. 
 
Myocardial Infarction from Universal Definition 
The analysis of RCT data will include the incidence of MI using the Universal Definition151 for 
each treatment group evaluated descriptively as a secondary endpoint. 

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The term myocardial infarction should be used when there is evidence of myocardial necrosis in a 
clinical setting consistent with myocardial ischemia. Under these conditions any one of the 
following criteria meets the diagnosis for myocardial infarction: 
 
• Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one 
value above the upper reference limit together with evidence of myocardial ischemia with 
at least one of the following: 
 
•    Symptoms of ischaemia; 
 
• ECG changes indicative of new ischemia (new ST-T changes or new left bundle branch 
block); 
 
•    Development of pathological Q waves in the ECG; 
 
• Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality. 
 
• Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST  
 
 
elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography 
and/or at autopsy, but death occurring before blood samples could be obtained, or at a 
time before the appearance of cardiac biomarkers in the blood. 
 
• For percutaneous coronary interventions (PCI) in patients with normal baseline troponin 
values, elevations of cardiac biomarkers above the URL are indicative of peri-procedural 
myocardial necrosis. By convention, increases of biomarkers greater than 3 X URL have 
been designated as defining PCI-related myocardial infarction. A subtype related to a 
documented stent thrombosis is recognized. 
 
• For coronary artery bypass grafting (CABG) in patients with normal baseline troponin 
values, elevations of cardiac biomarkers above the URL are indicative of peri-procedural 
myocardial necrosis. By convention, increases of biomarkers greater than 5 X URL plus 
either new pathological Q waves or new LBBB, or angiographically documented new 
graft or native coronary artery occlusion, or imaging evidence of new loss of viable 
myocardium have been designated as defining CABG-related myocardial infarction. 
 
• Pathological findings of an acute myocardial infarction. 
 
Renal Failure 
 
Serum creatinine increase by ≥1 mg/dL from baseline or need for dialysis. 
 
Serious Adverse Event 
 
If the adverse event meets any of the criteria below, it is regarded as a serious adverse event 
(SAE). 
 
• a) Led to a death, 
 
b) Led to a serious deterioration in health that either: 
     1) Resulted in a life-threatening illness or injury, or 

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   2) Resulted in a permanent impairment of a body structure or a body function, or 
   3) Required in-patient hospitalization or prolongation of existing hospitalization, or 
     
4) Resulted in medical or surgical intervention to prevent life threatening illness or injury or                       
 
permanent impairment to a body structure or a body function. 
 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
d) An important medical event that may not result in death, be life-threatening, or require 
 
hospitalization but may be considered serious when, based upon appropriate medical 
 
judgment, may jeopardize the patient or subject and/or may require intervention to prevent 
 
one of the outcomes listed in this definition. 
 
Stent Thrombosis 
 
For this trial, stent thrombosis will be defined as the occurrence of definite or probable 
stent thrombosis according to the ARC criteria. 
 
1.   Stent Thrombosis: Timing 
 
 
Type 
Timing 
Acute stent thrombosis* 
0 to 24 hours after stent implantation 
Subacute stent thrombosis 
>24 hours to 30 days after stent implantation 
Late stent thrombosis† 
>30 days to 1 year after stent implantation 
Very late stent thrombosis† 
>1 year after stent implantation 
Stent thrombosis will be reported as a cumulative value over time and at the various individual timepoints specified 
above.  Time 0 is defined as the timepoint after the guiding catheter has been removed and the subject has left the 
catheterization laboratory. 
*Acute or subacute can also be replaced by the term early stent thrombosis.  Early stent thrombosis (0 to 30 days) 
will be used in the remainder of this document. 
†Includes primary as well as secondary late stent thrombosis; secondary late stent thrombosis is a stent thrombosis 
after a target lesion revascularization. 
 
 
2.   ARC Definitions of Definite, Probable, and Possible Stent Thrombosis 
 
• Definite Stent Thrombosis 
 
Definite stent thrombosis is considered to have occurred by either angiographic or 
pathological confirmation: 
a.   Angiographic confirmation of stent thrombosis† 
 
The presence of a thrombus‡ that originates in the stent or in the segment 5 mm 
proximal or distal to the stent and presence of at least 1 of the following 
criteria within a 48-hour time window: 
1.   Acute onset of ischemic symptoms at rest 
2.   New ischemic ECG changes that suggest acute ischemia 
 
 

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3. Typical rise and fall in cardiac biomarkers (refer to definition of 
spontaneous MI:  Troponin or CK-MB > 99th percentile of URL) 
4.   Nonocclusive thrombus 
a.  Intracoronary thrombus is defined as a (spheric, ovoid, or 
irregular) noncalcified filling defect or lucency surrounded by 
contrast material (on 3 sides or within a coronary stenosis) seen in 
multiple projections, or persistence of contrast material within the 
lumen, or a visible embolization of intraluminal material downstream 
5.   Occlusive thrombus 
a.   TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most 
adjacent proximal side branch or main branch (if originates from the 
side branch) 
b.   Pathological confirmation of stent thrombosis 
 
Evidence of recent thrombus within the stent determined at autopsy or via 
examination of tissue retrieved following thrombectomy 
 
•    Probable Stent Thrombosis 
 
Clinical  definition  of  probable  stent  thrombosis  is  considered  to  have  occurred  after 
intracoronary stenting in the following cases: 
a.   Any unexplained death within the first 30 days 
b.   Irrespective of the time after the index procedure, any MI that is related to documented acute 
ischemia in the territory of the implanted stent without angiographic confirmation of stent 
thrombosis and in the absence of any other obvious cause 
 
•    Possible Stent Thrombosis 
 
Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death from 30 days after intracoronary stenting until end of trial follow-up. 
 
†The incidental angiographic documentation of stent occlusion in the absence of clinical signs or 
symptoms is not considered a confirmed stent thrombosis (silent occlusion) 
 
‡Intracoronary thrombus 
 
Symptomatic Graft Stenosis or Occlusion 
 
Ischemic symptoms in the presence of ≥50% diameter stenosis in a coronary bypass graft. 
 
Unplanned Revascularization, Surgery, or Radiologic Procedure 
 
Vascular access complications, sternal refixation or other complications requiring the subject to 
return to the cath lab or surgical rooms. 
 
Disability After Stroke 
 
In case of an event of stroke disability at 90-days±2 weeks will be an overall measurement of 
severity of stroke as assessed by mRS scale as defined in Section 16.1.3. 
Left Main Equivalent Disease 
Left main Medina classification 0, 1, 1 bifurcation disease (diameter stenosis of both the true 
ostial LAD and LCX [within 5 mm of the left main distal bifurcation]) ≥50%, in the absence of 
significant angiographic stenosis in the left main coronary artery, may also be randomized if one 

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of the two following conditions are present: 
◦ 
Both the ostial LAD and ostial LCX stenoses are ≥70% stenotic by visual estimation, or 
◦ 
If one or both of the ostial LAD and ostial LCX stenoses are ≥50% and <70% stenotic by 
visual estimation, then this lesion(s) is demonstrated to be significant either by 
 a) non-invasive evidence of ischemia in its myocardial distribution; and/or 
 b) FFR ≤0.80; and/or 
 c) IVUS MLA ≤4.0mm2 (FFR is preferred). 
 
Note: If both the ostial LAD and ostial LCX stenoses are ≥50% and <70% stenotic by visual 
estimation, then both lesions must be significant by these criteria for the patient to be eligible for 
randomization. 
 

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16.3  Abbreviations and Acronyms 
 
Acronym 
Definition 
ACEF 
Age, creatinine and left ventricle ejection fraction. 
ACS 
Acute coronary syndrome 
ADP 
Adenosine diphosphate (as in ADP antagonist) 
AE 
Adverse event 
ARC 
Academic Research Consortium 
Atm 
BARC 
Atmospheres (measurement of pressure) 
Bleeding Academic Research Consortium 
BNP 
Brain natriuretic peptide 
CABG 
Coronary artery bypass graft 
CASS 
Coronary Artery Surgery Study (a trial that has contributed a standard map 
of coronary artery system) 
CEC 
Clinical Events Committee 
CK-MB 
Creatine kinase – muscle brain 
CRF/eCRF 
Case report form / electronic case report form 
CRO 
Contract research organization -or- Clinical research organization 
hsCRP 
High sensitivity C-reactive protein 
CTO 
Chronic total occlusion 
CSA 
Cross-sectional area 
DES 
Drug eluting stent 
DS 
Diameter stenosis (%) 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee  
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EECS / EECSS 
Everolimus eluting coronary stent / everolimus eluting coronary stent system 
EOC 
Executive Operations Committee 
EU 
Europe 
FDA 
Food and Drug Administration 
FFR 
Fractional flow reserve 
GPIIb/IIIa 
Glycoprotein IIb/IIIa 
HgbA1c 
Glycated or glycosylated hemoglobin (average blood glucose concentration 
over prolonged periods of time) 
HR 
Hazard ratio 
IRB 
Institutional Review Board 
ITA 
Internal thoracic artery 
ITT 
Intent-to-treat 

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Acronym 
Definition 
IVRS 
Interactive voice response system 
IVUS 
Intravascular ultrasound 
LAD 
Left anterior descending artery 
LCX 
Left circumflex artery 
LM 
Left main (coronary artery) 
LVEF 
Left ventricular ejection fraction 
MACE 
Major Adverse Cardiac Event 
MACCE 
Major Adverse Cardiac and Cerebrovascular Events 
MI 
Myocardial infarction 
MLA 
Minimum lumen area 
MRI 
Magnetic resonance imaging 
mRS 
Modified Rankin Scale 
OUS 
Outside the U.S. 
PCI 
Percutaneous coronary intervention 
PES 
Paclitaxel eluting stent 
QALY 
Quality adjusted year of life 
QoL 
Quality of life 
RCA 
Right coronary artery 
RCT 
RHI 
Randomized clinical trial 
Regular Human Insulin 
SAE 
Serious adverse event 
SAQ                  
Seattle Angina Questionnaire 
SOP                     
Standard operating procedure 
ST                           Stent thrombosis 
STS 
Society of Thoracic Surgeons 
TEE 
Transesophageal echocardiogram 
TIA 
Transient ischemic attack 
TIMI 
Thrombolysis In Myocardial Infarction (a trial that has contributed 
definitions for bleeding as well as coronary artery blood flow) 
TLF 
Target lesion failure 
TLR 
Target lesion revascularization  
TVR 
Target vessel revascularization 
UADE 
Unanticipated adverse device effect 
U.S. 
United States 
ULMCA 
Unprotected left main coronary artery 
ULN 
Upper limit of normal 

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17. 
APPENDIX B: QUALITY OF LIFE AND U.S. HEALTH ECONOMICS 
SUB-STUDIES 
 
As described in the main clinical protocol, the EXCEL trial will randomize approximately 1900 
selected subjects with unprotected left main disease to the XIENCE DES vs. CABG and follow 
them for up to 10 years; the primary endpoint of the trial is death, MI, or stroke at a median 
follow-up of 3-years. Given the large sample size and extended follow-up duration, EXCEL will 
provide an ideal setting in which to definitively examine the relative costs, quality of life 
benefits, and cost-effectiveness of PCI for this important subject population. In this proposal, the 
specific goals of the proposed health economic and quality of life studies are outlined as well as 
the general analytic plans. 
 
The proposed analyses will be directed in about 1800 subjects by David J. Cohen, M.D., M.Sc. 
in conjunction with the Health Economics and Technology Assessment (HETA) Group of Saint 
Luke’s Mid America Heart Institute.  Of note, since cost-effectiveness is dependent on the 
perspective of the analysis, the health economic analyses described in this proposal will be 
performed specifically from the U.S. perspective. If additional perspectives from other countries 
are desired, it should be possible to collaborate with local health economists to extend these 
methods to these additional countries. 
 
17.1. Study Objectives 
 
17.1.1. Cost Studies 
 
• To compare long-term medical care costs for subjects with unprotected left main 
coronary disease treated with either PCI (using the XIENCE drug-eluting stent) or CABG 
from the perspective of the U.S. healthcare system 
 
• To identify factors in addition to treatment assignment that are associated with variations 
in long-term medical care costs in subjects undergoing revascularization for unprotected 
left main coronary disease. 
 
17.1.2. Quality of Life Studies 
 
• To compare health-related quality of life between alternative strategies of percutaneous 
or surgical coronary revascularization, according to the design of the EXCEL trial. 
 
• To identify factors, in addition to treatment assignment, those are associated with 
variations in quality of life for subjects with left main coronary disease. 
 
17.1.3. Cost-effectiveness Studies 
 
• Within the context of the EXCEL trial, to evaluate the relative cost-effectiveness of PCI 
with drug-eluting stents and CABG, measured as cost per quality-adjusted year of life 
gained, over a 3 to 5-year time horizon. 

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• 
To evaluate the relative cost-effectiveness of PCI with drug-eluting stents vs. CABG in terms 
of additional endpoints including cost per life-year gained, cost per death, MI, or stroke avoided, 
and cost per repeat revascularization procedure avoided. 
 
17.2. Subject Population 
 
The population for the quality of life and cost-effectiveness sub-studies will consist of 1800 
subjects.  The primary analyses will be conducted on an intention-to-treat (ITT) basis.  In 
particular, any subjects who die prior to receiving their initial revascularization procedure will be 
retained in the ITT analyses and considered as part of their randomization group.  Secondary 
analyses will be performed based on the per-protocol population (i.e., sub-study subjects who 
receive their assigned treatment) and a treatment-received population (sub-study subjects based on 
the initial revascularization procedure performed). 
 
17.3. Quality of Life Assessment 
 
Health-related quality of life will be measured using an instrument incorporating both disease- 
specific and generic health status measures appropriate for the assessment of subjects with 
coronary artery disease.  Each of the individual health status measures described below has been 
selecting from an existing instrument that has undergone extensive reliability and validity testing 
and is appropriate for the subject population being studied in the EXCEL trial. 
 
17.3.1. Disease-specific measures 
 
The goal of the disease-specific measures is to detect differences in health-related quality of life 
related directly to the two revascularization strategies under consideration.  Thus, the primary 
focus of the disease-specific measures will be to detect differences in symptoms or in quality of 
life directly attributable to coronary artery disease and its principal complications. 
 
Cardiovascular-specific quality of life will be measured using the Seattle Angina Questionnaire 
(SAQ)77 along with the London School of Hygiene Dyspnea Questionnaire.79    The SAQ is a 19-
item questionnaire that measures five domains of CAD-related health status: angina frequency, 
physical limitations, disease perception/QoL, angina stability, and treatment satisfaction.  Scores 
range from 0 to 100 with higher scores indicating fewer symptoms and thus better health status.  
The SAQ has undergone extensive reliability and validity testing77, 78and has been shown to 
correlate with long-term survival and ACS hospitalization among subjects with chronic 
CAD.152The London School of Hygiene Dyspnea Questionnaire was originally adapted from the 
Rose Angina Questionnaire and assesses the individual’s level of dyspnea with common 
activities.79   Previous research has demonstrated that this scale measures an important component 
of HRQoL in subjects with chronic coronary disease that is independent of traditional angina 
scales.80   In addition to their established validity and reliability in subjects with coronary artery 
disease, these instruments are easily administered either by written questionnaire or direct 
interview. 

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17.3.2. Generic quality of life measures 
 
The principal generic quality of life measure for this study will be the Medical Outcomes Study 
12-item Short Form Health Status questionnaire (SF-12).82The SF-12 is derived from the larger 
Medical Outcomes Study Short-Form 36 (SF-36), a 36 item questionnaire that has undergone 
extensive consistency, reliability, and validity testing and has been used to assess quality of life 
outcomes in more than 250 clinical trials.153, 154 The SF-12 produces two summary scales that 
assess both physical and mental/emotional health; these summary scores  have been shown to 
correlate well with those obtained from the longer, more time consuming SF-36.82   In addition to 
limiting subject burden, a specific advantage of the SF-12 for the purposes of this study is that 
the summary scales are scored such that the U.S. population mean is 50 and the population 
standard deviation is 10, thus providing highly interpretable data relative to other populations 
and health states. 
 
17.3.3. Mental Health/Depression 
 
In both anecdotal experience and uncontrolled observations, depression has been reported to be a 
relatively common and debilitating late-term complication of CABG.  Therefore, in addition to 
the mental health index provided by the SF-12, a more detailed assessment of depression using 
the PHQ-8 will be performed. This 8-item module derived from the larger Patient Health 
Questionnaire has been shown to be a highly valid and reliable measure of depression.  Scores 
range from 0 to 24 with levels ≥5 generally considered to represent mild depression and levels 
≥10 representing moderate depression. 155  It differs from the original PHQ-9 only in the 
elimination of the suicidality question, which may be considered to be inappropriate for many 
clinical trial population.81  Similar to the SAQ and SF-12, culturally valid translations are 
available in multiple languages including virtually all of the countries that are expected to 
contribute subjects to the EXCEL trial. 
 
17.3.4. Utility measurement 
 
For the purposes of cost-effectiveness analysis, quality of life must also be measured in terms of 
“utility”, a global rating (on a 0-1 scale) that reflects an individual’s preference for his or her 
current health state relative to perfect health.29   Although in the past, it had been customary to 
measure utility directly from trial participants using time-tradeoff techniques,156, 157 there is an 
emerging consensus that cost-effectiveness analyses designed to inform societal resource 
allocation use community-based (rather than subject-based) preferences.158 
 
There are a number of potential techniques for measurement of subject-specific, population- 
based utility weights within the EXCEL trial.  These include the Health Utilities Index (HUI),159 
the Quality of Well-Being Scale (QWB), 160 the EuroQol (EQ-5D),83  and recently published 
algorithms that allow mapping of the SF-36 or SF-12 to health state utilities.161, 162   Although 
each of these approaches has intrinsic advantages (and disadvantages), the preferred utility 
instrument for the EXCEL trial is the EQ-5D.  The EQ-5D is a multiattribute health status 
classification system with an empirically-derived preference based scoring system based on 
analysis of time trade-off utilities for selected health states among 2997 randomly-selected 
members of the adult population of the U.K. 163 Recently, analogous preference-weights have 
been developed for U.S. population utilities.84 

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Although the EQ-5D was not specifically developed for use in subjects with coronary artery 
disease, it offers several specific advantages for this trial.  First, it is based on a health state 
classification system that includes five specific domains of health: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression.  By incorporating many of the domains that 
are likely to be affected by coronary artery disease and its complications, such as pain, physical 
limitations, and role limitations, the EQ-5D should capture important differences in health within 
the study population.  Second, the EQ-5D may be administered by either a five item written 
questionnaire or telephone interview and thus should add little burden to the overall data 
collection task.  By comparison, both the HUI and the QWB questionnaires are substantially 
longer and, in previous experience, are often too burdensome for chronically-ill subjects. Finally, 
considerable practical experience with the EQ-5D exists as it has been used successfully as the 
principal utility measure in the Benestent II Trial (n=823)164 and the PAMI Stent trial 
(n=900),165 and most recently in the SYNTAX trial. 
 
17.3.5. Economic Data Collection 
 
The following data elements will be obtained from the EXCEL trial database for use in this sub- 
study: 
 
• Measures of global medical resource utilization for each hospitalization including length of 
stay and number of ICU days. 
 
• Cardiac catheterization laboratory resource utilization for the index procedure as well as any 
subsequent catheterizations or PCI procedures required during the follow-up period. Data 
collected will include total procedure duration; numbers of angioplasty balloons, stents 
(bare and drug-eluting), guidewires, ultrasound catheters, and guiding catheters used; 
adjunctive medications used including glycoprotein IIb/IIIa antagonists and direct thrombin 
inhibitors; and the amount and type of contrast dye required.  These data will provide a 
direct measure of resource utilization for the two strategies, and will be used to examine the 
true costs of initial PCI based on standard, “bottom-up” accounting measures.85,166 
 
• Measures of global resource utilization for each initial and follow-up hospitalization for 
treatment of cardiovascular disease, its direct complications, and potential complications of 
treatment.  For each hospital admission, these data will include total length of stay, number 
of ICU days, principal diagnosis, and major procedures performed during the 
hospitalization 
(e.g., 
coronary 
revascularization, pacemaker 
or 
ICD 
implantation, 
peripheralvascular   surgery).  Hospital admissions unrelated to treatment of cardiovascular 
disease or potential complications of its treatment will be identified by an independent review 
committee, blinded to initial treatment assignment and excluded from the economic analysis, 
since any differences in these events are unlikely to be related to the assigned treatment 
strategy.  Thus, their inclusion in the economic analysis would only increase the variance of 
the cost estimates and reduce statistical power. 
 
• Detailed listing of outpatient medications for treatment of cardiovascular disease at each 
follow-up subject contact. 
 
• Subject estimates (by  self-report) of  utilization of  outpatient cardiovascular services 
including diagnostic testing (e.g., ETT, nuclear stress testing, echocardiography, cardiac 

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CT); outpatient procedures (e.g., diagnostic catheterization, cardioversion); and physician 
visits. 
 
• Number and duration of admissions to rehabilitation hospitals, nursing homes, and other 
chronic care facilities. 
 
17.4. Cost Measurement 
 
17.4.1. Procedural Costs 
 
Catheterization laboratory and bypass costs will be calculated for each subject using standard, 
“bottom-up” cost accounting methods using the most current unit costs available at the time of 
each analysis.85   For example, if the 1-year analysis is performed in 2013, every effort will be 
made to obtain updated unit costs for 2013.  Similarly, if the 5-year analysis is performed in 
2015, unit costs for that year will be used as the basis for the cost analysis.  The rationale for 
using updated costs is that the goal of the cost-effectiveness analysis is to inform ongoing policy 
development and not merely to describe historically-relevant costs. 
 
For major disposable items (including angioplasty balloons, bare metal and drug-eluting stents, 
guidewires, and guiding catheters), costs will be based on a survey of U.S. hospital and 
catheterization laboratory administrators as to the acquisition costs for the item at the time of the 
analysis.  Drug costs for procedural anticoagulants including glycoprotein 2b/3a antagonists, 
direct thrombin inhibitors, and thrombolytic agents will be determined in a similar fashion. 
Updated cost data for the final calculations and analysis will ensure that the cost estimates are 
accurate at the time of publication.  The cost of other disposables, depreciation, and overhead for 
catheterization laboratory maintenance, and non-physician personnel will be estimated based on 
the average cost per procedure at 3-5 geographically diverse U.S. medical centers during the 
same time frame and adjusted for measured procedure duration.  Similar methods will be applied to 
estimate the procedural cost of CABG. 
 
17.4.2. Non-procedural Hospitalization Costs 
 
The non-procedural costs of hospitalizations will be estimated in two ways.  The primary method 
will utilize an event-based approach to estimating costs; the secondary approach will utilize a 
resource-based approach.  The advantage of the event-based approach to hospitalization costs is 
that it does not rely on an assumption of comparability of length of stay between U.S. and non- 
U.S. subjects.  Rather, nationally-representative data will be used to estimate the cost of an 
uncomplicated hospital admission and also the relationship between specific procedural 
complications and hospital costs.  This approach is identical to one that has recently been 
employed for calculation of costs in the SYNTAX trial.  Details of this estimation process are 
outlined below. 
 
The event-based approach relies on the Medicare Provider and Review (MedPAR) database. 
The MedPAR file is an administrative database maintained by the Centers for Medicare and 
Medicaid Services containing all claims submitted by hospitals for services provided to Medicare 
beneficiaries.  For each hospitalization, the MedPAR record includes information on age, sex, 
race, date of admission, date of discharge; the principal diagnosis code (ICD-9-CM), eight 
secondary ICD-9-CM diagnosis codes, six ICD-9-CM procedure codes, discharge status, total 

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charges, total reimbursement, and the hospital’s Medicare provider number. 
 
Estimating costs consists of three steps.  In the first step, the MedPAR database will be used to 
model the relationship between the total index hospitalization costs and the costs associated with 
various complications occurring after the procedure of interest but during the index 
hospitalization.  Estimates of the costs of these complications will be obtained via a regression 
using a model with structure: 
 
TC i  = A + X i β + Zi δ + u i 
 
where TCi  is the total cost of the index hospitalization for subject i, Xi  is a set of indicator 
variables for subject i denoting whether particular complications occurred, β is an associated 
parameter vector representing the estimated costs of the complications, Zi is a set of individual 
baseline subject characteristics (e.g., age, sex, etc.), δ is an associated parameter vector 
representing the incremental cost of the characteristics, A represents the sum of procedural costs 
and any other costs for an uncomplicated hospitalization, and ui is a residual.  This model will be 
estimated separately for each procedure type. 
 
The second step will be to obtain an estimate of the mean cost of uncomplicated hospitalizations. 
Letting UHC be uncomplicated hospitalization costs (excluding procedural costs), and PC be 
procedural costs, for each subject is defined as: 
 
      Wi = UHCi + PCi, 
 
which would imply 
 
 
W = UHC + PC. 
 
Since the regression in step 1 does not specify a separate intercept for each subject, it is 
reasonable to think of A as an average across all subjects, i.e., that Â is an estimate of  W .  Then a 
straightforward way to estimate mean uncomplicated hospital costs (UHC ) is to subtract an 
estimate of mean procedure costs ( PC ) from the estimate of A, i.e., 
 
      ^  
 
 
^ 
    ^   
      UHC = A− PC 
 
Mean procedure costs for use in this step will be obtained from the REPLACE-2 trial (14) or a 
comparable multicenter registry or trial that reflects contemporary PCI practice in a broad, 
relatively unselected subject population. 
 
The third step is to combine the previously obtained parameter values to produce an estimate of 
U.S.-relevant costs based on the data from the EXCEL trial. First, an estimate of subject-specific 
variable costs (Qi) will be obtained by the estimates of β and δ (as previously derived from the 
MedPAR analyses) to the EXCEL subject data, i.e., 
 
^ 
^ 
^
 
 
Qi  = X i β+ Zi δ , 
                 ^                ^ 
where β and δ are the estimates of β and δ, respectively.  An estimate of non-procedural costs 
          
 
         ^ 
( NPC i ) is then obtained for each subject i by adding subject specific variable costs to the 
average cost of an uncomplicated subject 

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^ 
      ^      
^ 
NPCi  = UHC+ Qi . 
 
We will then calculate total hospital cost by adding the resource-based procedure costs to the 
estimated non-procedural costs, i.e. 
 
^ 
^ 
^ 
TC i  = NPC i + PC i  . 
 
Finally, in order to preserve subject variability in the cost data, residuals drawn from the step (1) 
regression will be added to the expected values.  The approach outlined above will be used to 
calculate the cost of each index hospitalization as well as any subsequent hospitalizations during 
which a coronary revascularization procedure is performed. 
 
For all other cardiovascular hospitalizations, data on principal and secondary diagnoses and any 
major procedures performed will be used to assign a DRG to the hospitalization.  This mapping 
procedure will be performed in a blinded fashion by the MAHI HETA group working in 
conjunction with a trained Medicare coder.  For each subsequent hospitalization, costs will be 
assigned based on the average cost for the relevant DRG based on MedPAR data.   As noted 
previously, prior to performing the economic analysis, all rehospitalizations will be reviewed by 
an independent review committee (blinded to treatment group) to determine those 
hospitalizations that are unrelated to cardiovascular disease or its direct complications that will 
be excluded from the analysis. 
 
As a sensitivity analysis, a more direct, resource-based approach to estimating non-procedural 
hospital costs will be considered.  For this approach, either the MEDPAR database or a large, 
single-center database (e.g., Mid America Heart Institute) will be used to develop a regression 
model for non-procedural hospital costs based on subject characteristics, length of stay (LOS) 
elements (ICU, non-ICU), as well as specific procedures and in-hospital complications.   The 
regression coefficients from the associated models will then be used to estimate non-procedural 
hospitalization  costs  based  on  the  observed  resource  utilization  data  from  the  EXCEL 
population.   All other costs (e.g., procedural costs, cardiovascular hospitalizations without 
revascularization procedures) will be calculated in the identical fashion to the “event-based” 
approach described previously. 
 
17.4.3. Other costs 
 
For all hospitalizations associated with coronary revascularization procedures, physician costs 
will be estimated on the basis of standard procedural codes and the Medicare Fee Schedule.  For 
all other hospitalizations, physician costs will be estimated as a percentage of hospital costs 
according to DRG and corresponding Medicare physician cost to hospital cost ratio.167, 168   Costs 
for outpatient medical care resource utilization (office visits, ER visits, non-protocol diagnostic 
tests) will be applied according to the Medicare Fee Schedule, and skilled nursing facility and 
rehabilitation stays will be estimated using Medicare reimbursement rates.  Medication costs will 
be estimated based on an average per subject per month cost for each medication class.  The 
mean cost for each class of medication will be based on an analysis of managed care pharmacy 
claims for subjects with coronary artery disease.  
 

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17.5. Analytic Plan 
 
17.5.1. Quality of Life Endpoints 
 
Since quality of life is a multidimensional construct for which different subjects may have different 
individual preferences, no specific scale will be considered as the “primary” QoL endpoint of the 
EXCEL trial. Rather, the goal of the study will be to describe any differences in the various quality of 
life scales over the time-frame of the trial.  To limit any “false positive” results due to the large 
number of scales and timepoints evaluated, all QoL analyses will be performed using a p-value of 
<0.01 as an indicator of statistical significance. 
 
For each of the quality of life measures in this study, data analysis will proceed in two stages. First, a 
simple descriptive and comparative analyses of cross-sectional data by intention-to-treat will be 
performed.  For these cross-sectional analyses, comparisons will be performed at each follow-up 
timepoint using analysis of covariance to adjust for any baseline differences, including baseline 
score, between the treatment groups.  Second, in order to account for missing data, longitudinal 
random coefficient growth curve models will be used to examine the effect of CABG versus PCI 
over time on each health status/QoL outcome.  These models readily accommodate linear and 
nonlinear changes over time, as well as missing data patterns commonly seen in longitudinal 
studies.  These analyses will incorporate all available QoL scores including those for subjects 
who die, withdraw from the study, or are lost to follow-up.  Variables included in the longitudinal 
models for each outcome will include treatment (according to intention to treat), follow-up time 
(using linear, quadratic, and cubic terms), and interactions between treatment and each time 
term. In addition, these analyses will adjust for any baseline sociodemographic and clinical 
factors that differ between the two groups. 
 
A particular challenge in the analysis of quality of life data relates to the problem of missing data 
(due to death, incapacity, subject refusal, or loss to follow-up).   The proposed analytic strategy 
assumes that measurements are missing at random, however it is possible that subjects with impaired 
quality of life may be less likely to complete the interview. The sensitivity of the results to a variety of 
alternative assumptions regarding the relationship between quality of life and the likelihood of 
completing the QoL questionnaires will be examined.  Potential approaches will include imputing 
missing values with the natural “worst case” score for each of the quality of life endpoints and 
application of multiple imputation techniques.169 
 

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17.5.2. Exploratory Analyses:  Impact of Events on Quality-Adjusted Life 
 
Expectancy 
 
One of the secondary goals of this study is to better understand the relative impact of outcome 
events on overall subject health.  For these analyses, the longitudinal growth curve models to 
estimate quality of life over time for the two treatment groups will be used. Similar to the 
approach described above, these analyses will incorporate all available QoL scores including 
those for subjects who die, withdraw from the study, or are lost to follow-up. Variables included 
in the longitudinal models for each outcome will include treatment (according to intention to 
treat), follow-up time (using linear, quadratic, and cubic terms), and interactions between 
treatment and each time term.   In addition, a broad range of baseline sociodemographic and 
clinical characteristics will be included. Finally, these models will include terms for each 
outcome variable of interest including myocardial infarction, stroke, and the occurrence of one or 
more repeat revascularization procedures (as time-dependent covariates).  The interpretation of 
these analyses will be focused on the beta coefficients, which will indicate the independent impact 
of each outcome event on the various health status domains (including utility weights) for subjects 
undergoing revascularization for left main disease. 
 
17.5.3. Cost and Resource Use Comparisons 
 
The primary endpoints for the cost analysis will be total cardiovascular-related health care costs at 
3 years.  Because of concerns that extreme cost outliers may be driven by unobserved factors 
unrelated to the study, all cost data will be censored at the upper 99th percentile to limit the 
impact of any such high-cost outliers. 
 
Health economic decisions regarding the efficient allocation of scarce resources involve 
consideration of the total costs of treating all subjects with a specific disease with the particular 
treatment in question.  In such settings it is the arithmetic mean, which is the per-person cost of 
implementing the treatment or intervention that is the most relevant measure for summarizing 
and comparing cost.170   Characteristics of cost distributions can complicate the task of the data 
analyst needing to carry out a formal comparison of mean costs, however.  The distribution of 
cost data tends to be skewed, with a large proportion of costs at the lower end of the distribution 
and a long right tail.  As the appropriateness of many statistical tests and models relies on an 
approximately normal underlying distribution of the data, many common tests, such as the two- 
sample t test for the comparison of means, may not be appropriate. 
 
Statistical inference for all cost endpoints will therefore be performed by means of the non- 
parametric bootstrapping.171   Use of this approach avoids making any parametric assumptions 
regarding the  sampling distribution of  a  statistic by  deriving an  empirical estimate of  the 
sampling distribution by drawing a large number of samples with replacement form the original 
data.  The statistic of interest is then calculated for each of the samples, and the bootstrap 
replicates of the original sample yield an empirical estimate of the sampling distribution.  The 
bootstrap approach has been advocated as a preferred method for testing hypotheses, particularly 
with relatively modest sample sizes, because it can be more accurate than tests based on 
asymptotic approximations.  For each comparison, an expected difference for the two treatment 
groups and an associated 95% confidence interval based on bootstrap resampling will be 

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calculated. 
 
17.5.4. Cost-Effectiveness Analyses 
 
Cost effectiveness will be expressed in terms of the incremental cost-effectiveness ratio, 
comparing the more effective treatment (Treatment A) to the less effective treatment (Treatment 
B).  The cost-effectiveness ratio is calculated as: 
 
Mean Cost (Treatment A) – Mean Cost (Treatment B) 
Effectiveness (A) – Effectiveness (B) 
where effectiveness is measured either in terms of quality-adjusted life years, life-years, or in 
terms of the proportion of subjects experiencing a major adverse event (death, MI, stroke +/- 
repeat revascularization).  For the purposes of these analyses, all costs will be expressed in 
constant dollars and both future costs and quality-adjusted life years will be discounted at 
3%/year, consistent with current guidelines. 172  For each analysis, a cost-effectiveness 
acceptability curve to relate any specific cost-effectiveness threshold to the probability of 
treatment A being cost-effective at that threshold will be constructed. 
 
17.5.5. Lifetime Cost-Effectiveness 
 
If there are important differences in irreversible clinical outcomes between the PCI and CABG 
groups, a life-time cost-effectiveness analysis will be performed in addition to the within-trial 
analysis described above.  For this analysis, the data from the in-trial analysis to project life- 
expectancy and quality-adjusted life expectancy for each surviving subject will be used, 
contingent on the observed clinical outcomes during the trial. If there are differences in survival, 
the remaining life-expectancy for the two treatment groups will be estimated by relating the 
observed annual follow-up mortality to the mortality that would have been predicted based on a 
comparable age- and gender-matched U.S. population.173   Quality-adjusted life expectancy will 
be calculated by assuming that each subjects’ health status remains unchanged beyond the last 
observation in the trial. 
 
On the other hand, if there are differences in other non-fatal outcomes but not survival, a state- 
transition (Markov) model will be developed to project lifetime costs, survival, and quality- 
adjusted life expectancy for each treatment group.174   The model will be developed based on the 
observed within-trial data and calibrated to match the 3-year outcomes (in terms of aggregate 
costs and quality-adjusted life-expectancy) for the two treatment groups.  Under this approach, 
standard one-way, multi-way, and probabilistic sensitivity analyses will also be performed to 
explore the impact of plausible variations in the assumptions on the incremental cost- 
effectiveness ratios. 
 
17.5.6. Evaluation of Heterogeneity by Country 
 
Given that the primary cost-effectiveness analysis will be based on approximately 1800 patients of 
EXCEL trial population, a series of heterogeneity tests will be performed to identify whether it is 
appropriate to generalize these results to the U.S. as a whole or whether an analysis based 
specifically on U.S. subjects is more appropriate.175Although heterogeneity in terms of costs and 

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clinical outcomes can be evaluated through standard statistical techniques and interaction tests, 
heterogeneity in cost-effectiveness results will be evaluated using a net benefit regression 
approach through the use of country by treatment group interaction terms. 176 Because of the 
inherently low power of these tests, clinical outcomes, resource use, and cost and cost- 
effectiveness results will be stratified by country as well, in an effort to identify countries with 
markedly outlying clinical, economic or cost-effectiveness outcomes.  If important heterogeneity is 
detected, results for a particular country may need to be based on the individual country data or 
on pooled data with other countries with comparable outcomes and resource use. 
 
17.5.7. Subgroup Analyses 
 
In addition to each of the main analyses specified above, each of the cost and cost-effectiveness 
analyses will be performed on several pre-specified subgroups of interest.  These subgroups will 
include diabetic vs. non-diabetic subjects, type of left main disease (ostium/shaft vs. distal 
bifurcation), terciles of angiographic complexity (by SYNTAX score), 7 age subgroups (<65, 65-
75, >75), gender, and U.S. vs. non-U.S. subjects.  Additional subgroup analyses for the cost and 
cost-effectiveness calculations will be performed for any subject subgroups identified as 
clinically-relevant based on the main clinical outcomes as well. 
 
17.6. Approach to Unanticipated Protocol Modifications 
 
Finally, it  is  important to  note that in  contrast to  traditional statistical analyses which are 
designed to test a specific hypothesis, cost-effectiveness analyses are inherently descriptive.  As a 
result, it may be the case that the analysis plan above may be modified as a result of unanticipated 
data sources or results from the clinical trial.  Such modifications will be at the discretion of 
the MAHI HETA group and will be reviewed by the Executive Committee of the EXCEL trial. 
 
17.7. Independence of Research 
 
Increasing scientific scrutiny of cost-effective analysis has led to the recent development of 
generally-accepted guidelines for the conduct of industry-sponsored cost-effectiveness 
research.177Such guidelines are necessary to ensure the independence of the investigators and 
thus to establish the scientific validity and credibility of the research.  Publication of results will 
be normally governed by Publication Policy mentioned elsewhere in this document and as 
approved by the EOC. 
 
 

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18.    APPENDIX C: IVUS SUBSTUDY 
 
The IVUS substudy will explore whether procedural use of IVUS improves outcomes of left 
main stenting, as well as determine the IVUS parameters that most strongly correlate with left 
main stent thrombosis or restenosis. Although in this regard a randomized trial would be ideal, 
the current protocol is already sufficiently complex such that adding another level of 
randomization is not practical. Moreover, although assessment of minimal luminal area by IVUS is 
relatively simple, not all sites are expert in the use of IVUS guidance for complex left main 
stenoses. Therefore, the potential utility of IVUS guidance in improving the acute and late results 
of left main stenting with the XIENCE stent will be determined from a multivariable and 
propensity adjusted non randomized analysis of the outcomes based on IVUS usage. All left 
main lesions in which IVUS was used will undergo rigorous core laboratory evaluation. The 
principal events to be analyzed according to IVUS use will be procedural success and 
complications, MACE, TLR and stent thrombosis, both on a subject level (all lesions) and 
adjudicated to those adverse events arising from the left main lesion. 
 
 
 
Analyses to be performed: 
 
• PCI outcomes according to  IVUS  use  on  a  subject  level.  The  outcomes of  subjects 
undergoing PCI will be compared according to the frequency of left main IVUS use for 
procedural guidance. The results will be adjusted by differences in baseline clinical and 
angiographic characteristics between the subjects and lesions in the 2 groups (IVUS used vs. 
not used for procedural guidance), including the use of a propensity score for IVUS 
guidance. In addition, propensity analysis will be used to create 2 matched groups with 
100% vs. 0% left main IVUS guidance for comparison of procedural and late outcomes. 
 
• PCI outcomes according to IVUS use on a site level. The outcomes in the upper 50% of 
sites according to left main IVUS guidance will be compared to the lower 50% of sites 
according to left main IVUS guidance. The results will be adjusted by differences in baseline 
clinical and angiographic characteristics between the subjects and lesions in the 2 groups, 
including the use of a propensity score for IVUS guidance. Results will also be examined 
according to tertiles of IVUS use frequency on a site level. 
 
• IVUS predictors of clinical events. Among subjects undergoing left main IVUS guided 
intervention, the univariate and multivariable IVUS predictors of TLR, stent thrombosis and 
MACE will be determined, and the incremental value of IVUS variables in predicting adverse 
outcomes will be analyzed. The primary hypotheses will be that MACE will be inversely 
predicted by minimal stent area (MSA). Radiofrequency IVUS parameters will also be 
collected for analysis of relationship of pre-stent and post–stent plaque morphology to 
subsequent MACE. 

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19.   APPENDIX D: OPTIMAL REVASCULARIZATION DEFINITIONS 
 
Numerous prior studies have attempted to determine the differences in the extent of 
revascularization between CABG and PCI, and whether complete vs. incomplete revascularization 
is prognostically important with either modality.  The results of these studies have been 
extremely inconsistent, with limitations including: 1) different definitions for complete 
revascularization used for PCI and CABG; 2) different definitions for complete revascularization 
used between studies; 3) definitions created and applied post hoc; 4) use of operator 
assessment to determine the extent of revascularization, rather than independent committee; 5) 
sample size and follow-up duration limitations; 6) analysis of varying subgroups; 7) lack of 
distinction between the extent of anatomic and ischemic revascularization. 
 
EXCEL is a large-scale, multicenter, prospective trial in which subjects with coronary artery 
disease will undergo surgical or percutaneous revascularization and be followed for a minimum of 
5 years.  EXCEL will employ comprehensive angiographic core laboratory analysis and an 
independent clinical events committee to adjudicate events.  This affords an opportunity to pre- 
specify criteria and methodology for analysis of the impact of the extent of anatomic and 
ischemic revascularization in subjects undergoing PCI and CABG. 
 
19.1. Principles: 
 
1)  The same criteria for complete revascularization should apply for PCI and CABG 
 
2)  The importance of the extent of anatomic vs. ischemic revascularization should be 
 
differentiated (which is prognostically more useful, and how much overlap there is between 
 
the two) 
 
3)  The extent of revascularization will be determined by independent committees and core 
 
laboratories (i.e. not the treating physician) using pre-specified definitions and methodology 
 
4)  The significance of complete vs. incomplete revascularization will be assessed in each study 
 
for the primary and major secondary endpoint, as well as for death, repeat revascularization 
 
and QoL in all subjects, and in subsets of subjects with a) normal vs. depressed LVEF; b) 
 
CTOs vs. no CTOs; c) diabetics vs. non diabetics; d) LAD vs. non LAD disease and/or 
 
complete revascularization (includes left main disease in subjects without significant LAD 
 
disease) 
 
5)  The implications of revascularization of non ischemic vessels (deleterious effect) will be 
 
determined by analysis of subjects with complete ischemic vs. “potentially excessive” 
 
revascularization 
 
6)  Revascularization will be defined as complete (all significant lesions revascularized as 
 
determined by the core laboratory), vs. incomplete. Incomplete revascularization will be 
 
further subdivided into 1 vs. 2 or more non revascularized territories, and to LAD vs. non 
 
LAD non revascularized territories.  The implications of incomplete revascularization will 
 
also be defined according to the non revascularized myocardial jeopardy score. 

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19.2. Anatomic revascularization: 
 
1)  Complete anatomic revascularization requires revascularization of all vessels ≥2.0 mm 
reference vessel diameter with a DS ≥60% (both as measured by core angiographic 
laboratory analysis). 
 
 
- While this will be the pre-specified criteria for anatomically significant lesions, sensitivity 
analysis will be performed using different criteria (e.g. ≥2.5 mm vessels, DS ≥70%, etc.) 
 
2)  From the baseline angiogram, the angiographic core lab will identify and designate 
those lesions and vessels requiring revascularization in all subjects according to this definition, 
prior to knowledge of the extent of actual revascularization. 
 
 
Contrast dye used in angiography may cause allergy, bradycardia, hypotension, renal 
dysfunction, decreased contractility, heart failure and fluid overload. Such risks are reported 
in <5% of the patients.  Patients will be given intravenous fluids to protect from such risks 
from the contrast dye. 
 
3)  Following PCI, the angiographic core lab will determine the extent of revascularization  (after 
all planned (i.e. staged) procedures) 
 
 
- Only vessels with TIMI 2 or 3 flow post procedure with a core laboratory DS <50% will be 
considered successfully revascularized. 
 
4)  Following CABG, the angiographic core lab will determine the extent of revascularization  (by 
review of the operative note, which will need to be routinely collected), or if there is a repeat 
angiogram during the index hospitalization. 
 
 
- It is acknowledged that there will be some grafted vessels which are incorrectly identified 
in the operative note, and some grafts that will close immediately post op that will not be 
detected by this methodology.  However, routine post operative angiography is not standard of 
care, and is not recommended as a substudy as it could affect clinical event rates. 
 
19.3. Ischemic revascularization: 
 
1)   Complete ischemic revascularization requires revascularization of all vessels containing 
lesions with a core laboratory diameter stenosis of ≥50% with any of the following: 
 
a) noninvasive evidence of ischemia in that territory regardless of vessel size. If by 
angiographic core laboratory analysis there is more than one lesion with diameter 
stenosis ≥50% or more than one vessel containing lesions with diameter stenosis 
≥50% in the ischemic territory, complete revascularization requires treatment of all 
such lesions and vessels with reference vessel diameter ≥2.0 mm; OR 
 
b) lesions in vessels with reference vessel diameter ≥2.0 mm with either IVUS 
MLA ≤4 mm2 + plaque burden ≥60%, and/or FF≤0.80; OR 
 
c) an angiographic core lab DS ≥70% with ≥2.0 mm reference vessel diameter, 
unless FFR and/or IVUS criteria above are negative, or the vessel subtends  non-
viable myocardium as demonstrated by either perfusion imaging or akinesis  
 

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(Note: this is a practical definition – some cases of hibernating myocardium may be 
missed). 
 
- For assessment of the completeness of ischemic revascularization, physiologic 
significance “trumps” anatomic severity. e.g. If the angiographic diameter 
stenosis is >70% but the FFR is >0.80, that lesion does not require treatment for 
ischemic revascularization to be considered complete. 
 
3)  The angiographic core lab will determine the extent of revascularization in both groups by 
review of baseline functional tests, angiograms, cath reports (for IVUS and FFR results) and 
op notes (note – source documents need to be collected) 
 
 

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20.   APPENDIX E: IVUS AND FFR RECOMMENDATIONS 
 
20.1. Pre-Revascularization Assessment of Intermediate ULMCA Lesions 
 
20.1.1. Prior to Randomization 
 
If the ULMCA lesion is intermediate (≥50% and <70% by angiographic visual estimate) without a  
markedly positive noninvasive test (see Section 6.5.1 – inclusion criteria): either IVUS (strongly 
recommended) or FFR (alternatively) must be performed for the subject to qualify for 
randomization. 
 
20.1.2. IVUS Criteria 
 
IVUS criteria to defer revascularization of the ULMCA and not randomize subjects into the 
study is a ULMCA minimum lumen area (MLA) >6.0 mm2.178   Conversely, if the MLA is ≤6.0 
mm2, the ULMCA lesion may be considered to be hemodynamically significant and subject may 
be randomized.  In order to determine the true MLA in the ULMCA, it may be necessary to 
image back to the aorto-ostial junction from both the LAD and LCX; the smaller of the two 
MLAs is the more accurate and should be used for decision-making.  Practically, however, this is 
only necessary if the first pullback shows an MLA >6.0 mm2.  Examples of false positive and 
false angiograms appear in the figures below. 
 
False Positive Angiogram 
 
 
 
 
 
 
 
 
 
 
 
MLA=10.5mm2 
 
0 
1.0 
4.0m 

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False Negative Angiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MLA=4.6mm2 
 
0 
2.0 
5.0mm 
 
 
 
 
 
20.1.3. FFR Criteria 
 
Deferral of borderline left main lesions with a negative FFR has been demonstrated to be safe.179 
In the present study, the FFR criteria used to defer revascularization of the ULMCA and not 
randomize subjects into the study is an FFR >0.80.180,181 This is most useful if there are no other 
lesions in both the LAD and LCX (otherwise there may be false positive and false negative FFR 
measurements in the ULMCA).  The pressure wire transducer should be positioned just distal to 
the ULMCA lesion and proximal to any secondary lesions, as long as there is a major branch 
after the left main which appears angiographically nearly normal for adequate runoff (e.g. the 
LAD or a large diagonal). 
 
Note: See figure below.  If there is also a tight stenosis in the proximal LAD distal to the 
ULMCA bifurcation lesion, and the FFR transducer is placed between these lesions, FFR may be 
false negative (>0.80); if the transducer is placed distal to a second hemodynamically significant 
lesion, the FFR may be false positive (≤0.80); therefore, IVUS evaluation is strongly preferred in 
most scenarios except to assess an isolated borderline left main stenosis. 

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Possible False Negative 
 
Possible False Positive 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LAD 
 
 
LCX 
 
 
 
 
 
 
 
 
 
 
For subjects who meet all eligibility criteria for randomization, except that either the 
interventional cardiologist or cardiac surgeon on the local Heart Team (or both) believe that the 
ULMCA diameter stenosis is visually assessed to be ≥50% - <70% stenotic without clear 
noninvasive evidence demonstrating hemodynamic significance of the ULMCA lesion (see 
Section 6.5.1 – inclusion criteria), consent for the randomized trial can be obtained pre- 
catheterization.  Cardiac catheterization is then performed, with either IVUS (strongly 
recommended) or alternatively FFR assessment of the ULMCA.  Randomization can be 
performed on the cath lab table if IVUS or FFR then demonstrates a significant left main lesion.  
If the subject randomizes to PCI, intervention may be directly performed.  If the subject 
randomizes to CABG, the procedure is terminated and CABG performed as soon as logistically 
appropriate.  Alternatively, if the subject with an intermediate lesion was not consented pre-cath, 
the subject must be removed from the table, sedation allowed to completely reverse, the protocol 
explained, consent obtained, and randomization and revascularization performed during a separate 
procedure. 
 
If IVUS or FFR evaluation was not done before randomization, and if the subject was randomized 
to PCI, and if at the time of the planned ULMCA intervention the ULMCA lesion was found to 
be intermediate (<70% by angiographic visual estimate, without a positive nuclear or 
echocardiographic noninvasive study demonstrating ischemia which cannot be attributed to  
 

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other lesions) prior to PCI (see Section 6.5.1 – inclusion criteria), either IVUS (strongly 
recommended) or FFR (alternatively) must be performed to verify the significance of the lesion 
before randomization.  Refer to section 20.1.2 for IVUS criteria and Section 20.1.3 for FFR 
criteria. If the ULMCA lesion is deemed insignificant, the left main lesion should in most cases 
not be treated (unless, for example, treatment of an ostial LAD or ostial LCX lesion necessitates 
LM treatment, or the lesion is irregular or otherwise disrupted), and PCI of other lesions should 
be performed as clinically indicated.  The subject will remain in the PCI arm by intention to treat. 
 
 
 
 
LMCA lesion ≥50% DS (visually assessed; all other randomization criteria met) 
 
 
Angio DS≥70% 
 
 
Randomization 
 
Strongly positive 
noninvasive test 
 
No IVUS (FFR) 
Evaluation 
Angio DS<70% 
 
 
 
IVUS (FFR) 
Evaluation 
 
CABG 
PCI 
 
 
IVUS (FFR) Non- 
Guided 
 
 
MLA 
 
 
 
 
IVUS (FFR) 
Guided 
 
 
 
 
 
 
 
 
MLA 
 
 
MLA 
≤6.0mm2 
 
 
Randomization 
 
 
MLA 
>6.0mm2 
 
 
Deferred LMCA 
Treatment 
 
 
 
PCI 
≤6.0mm2 
>6.0mm2 
 
 
Deferred LMCA 
PCI 
CABG 
PCI 
Borderline Lesion 
Registry (first 100 
subjects) 

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20.2. IVUS for PCI Guidance of ULMCA PCI 
 
The use of IVUS to guide ULMCA intervention is strongly recommended as a recent publication 
describing the results of a large non randomized but adjusted registry182 suggests that 3-year 
mortality may be improved with IVUS-guided DES implantation of the ULMCA. 
 
In subjects in whom IVUS is used to guide PCI, it is strongly recommended that both the LAD 
and LCX be imaged prior to intervention back to the aorto-ostial junction to assist with stent size 
and length selection. If it is unexpectedly discovered that the ULMCA lesion is not significant 
(MLA >6.0 mm2 in both pullback directions), the left main lesion should not be treated, and PCI of 
other lesions performed as clinically indicated. If ULMCA disease extends into the ostial/proximal 
LAD (as it does in the majority of subjects), it is recommended that stent length be selected so as 
to end the stent in a segment of LAD with a plaque burden <50%. While there are no IVUS 
criteria for selecting a one-stent (cross-over) vs. a two-stent strategy, in general a LCX ostium 
lumen area >4.0 mm2 or a plaque burden ≤60% in a short segment of disease may indicate that a 
one-stent (cross-over) strategy will be adequate. 
 
Iterative IVUS and post-dilation should be performed until the ULMCA minimum stent area is 
>8.5mm2 and the ostial/proximal LAD minimum stent area is at least >5.5mm2 and preferably 
matched to the distal reference vessel diameter if larger. Observational data in non-LMCA 
lesions has shown that in general the larger the minimal stent area the lower the likelihood of 
restenosis and stent thrombosis183, 184, 185 and thus post-dilation with non compliant balloons sized 
up to 0.25-0.5mm less than the IVUS determined true vessel diameter (average media-media 
dimension) to safely achieve the largest maximal luminal dimension is recommended. It is 
strongly recommended that IVUS is also performed post-LMCA stenting from at least one 
epicardial coronary artery, usually the LAD, with pullback into the aorta (disengaging the guide to 
ensure the ostium is not missed). If a 1-stent technique is used (most commonly from the 
ULMCA into the LAD, “crossing over” the LCX), it is desirable but not mandatory that the 
ostial LCX also be imaged post-intervention if possible. If a 2-stent technique is used, IVUS 
pullback across the LAD and LCX is strongly recommended if the IVUS catheter passes easily 
into the LCX. LCX or side branch imaging should not be pursued aggressively to avoid IVUS- 
related (or pressure wire-related) complications. If the IVUS catheter or pressure wire can be 
safely positioned into the LCX, then, in general, an LCX ostium lumen area >4.0mm2 (single 
stent strategy) or >5.5mm2 (two stent strategy) or an FFR >0.80 (single stent strategy) indicates 
that no further intervention is necessary. 
 
Severe dissections present by IVUS (residual true lumen within the dissection flap ≤8.5mm2 in 
the ULMCA either proximal or distal to the stent or ≤5.5mm2 in the proximal LAD or LCX 
distal to the stent) should in general receive an additional stent. Malapposition with stent area 
≤8.5mm2 in the ULMCA or ≤5.5mm2 in the proximal LAD or LCX should in general be treated 
by additional post-dilatation with larger balloons. 
 
 
 
 

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20.3. IVUS and FFR for Guidance of Non-ULMCA Lesion PCI 
 
20.3.1. Pre-intervention non-ULMCA lesion assessment 
 
To avoid unnecessary interventions with subsequent peri-procedural and late myocardial 
infarctions and repeat revascularization procedures139  PCI of non ischemia producing lesions 
should in general not be performed. Whereas IVUS is strongly recommended (preferable to FFR) to 
assess intermediate ULMCA stenoses, it is just as strongly recommended that FFR be performed 
(preferable to IVUS) in all intermediate non-LMCA lesions (those with an angiographic diameter 
stenosis <70% by visual estimate), unless there is a positive nuclear or echocardiographic 
noninvasive study with ischemia clearly present in the distribution of that lesion. In the setting 
of serial stenoses, stenting should only be performed if the FFR beyond all narrowings is 
≤0.80138. Under maximum intravenous hyperemia (140 µg/kg/min IV adenosine for at least 3 
minutes, or until peak hyperemia is observed), the pressure sensor is pulled back by hand slowly 
under fluoroscopic guidance, and the pressure curves are recorded.  If the FFR is 0.81 or 0.82, 
increasing the intravenous adenosine to 280 µg/kg/min for at least 3 minutes, or until peak 
hyperemia is observed may demonstrate that the lesion is hemodynamically significant (FFR 
decreases to ≤0.80), warranting treatment. The investigator should first stent the stenosis that 
appears most significant or is responsible for the largest pressure gradient during pullback of the 
pressure sensor. After stenting the first lesion, FFR is measured again and any residual narrowing 
causing an FFR ≤0.80 is stented. (Note: for all FFR procedures, intravenous adenosine is required 
as opposed to intracoronary adenosine to ensure optimal coronary vasodilatation, and because 
intravenous adenosine provides prolonged hyperemia allowing adequate time to perform pullback 
of the pressure wire and localize pressure gradients.) 
 
For sites that do not use FFR, it is strongly recommended that pre-interventional IVUS is used in 
all intermediate lesions (those with a visually estimated angiographic stenosis of <70% (unless 
there is a positive nuclear or echocardiographic noninvasive study with ischemia clearly present in 
the distribution of that lesion). A significant lesion by IVUS criteria that should be stented has  
both a minimal luminal area (MLA) of ≤4 mm2and a plaque burden of >60%. In the absence of 
extenuating circumstances (e.g. plaque rupture, etc.), lesions that do not have both of these 
criteria should not undergo PCI. 
 
20.3.2. IVUS guidance of non-ULMCA stenting 
 
If IVUS is used to guide treatment of ULMCA lesions, it is recommended that IVUS also be 
used to guide treatment of important non-LMCA lesions in the LAD, LCX, and RCA 
circulations. XIENCE stent size and length should be selected and optimized to achieve a 
minimum stent area >5.5mm2 in non ULMCA lesions (with post-dilation with non compliant 
balloons sized up to 0.25-0.5mm less than the IVUS determined true vessel diameter (average 
media-to-media dimension), and to end the stents in arterial segments with a plaque burden 
<50%.  Severe dissections present by IVUS (residual true lumen within the dissection flap 
≤5.5mm2 either proximal or distal to the stent) should in general receive an additional stent. 
Malapposition with stent area ≤5.5mm2 should in general be treated by additional post-dilatation 
with larger balloons. 
 

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20.4. Follow-up 
 
Since the site of restenosis after distal ULMCA bifurcation intervention is typically the ostium of 
the LCX, and since many presumed ostial LCX restenoses are angiographic artifacts (i.e. appear 
angiographically severe, but in fact are not hemodynamically significant),68 it is strongly 
recommended that FFR be performed before treating any presumed restenotic lesions in the 
ostial LCX location (regardless of angiographic severity, unless totally occluded) unless there is 
unequivocal lateral wall ischemia by nuclear or echocardiographic noninvasive testing. If the 
FFR is >0.80, the ostial LCX lesion should not be treated and, thus, TLR (and possible procedural 
complications) avoided.  For sites that do not use FFR, it is strongly recommended that pre-
interventional IVUS of the ostial LCX be performed instead with an MLA >4.0mm2 used as 
the criteria to defer intervention and avoid TLR.186  Similarly, prior to performing a repeat 
intervention elsewhere in the coronary tree, if the visually assessed angiographic diameter stenosis 
is <70%, ischemia should be documented according to either a positive nuclear or 
echocardiographic noninvasive test in the distribution of the recurrent lesion, or an FFR ≤0.80, or 
IVUS with a MLA ≤4.0 mm2. 
 
20.5. Technical Considerations 
 
IVUS should be performed using motorized transducer pullback at 0.5  mm/sec using 
only sheath-based, rotating, mechanical transducers.  The pullback should start at least 1 cm distal 
to the lesion or stent, and conclude at least 1 cm proximal to the lesion or stent. 
 
FFR should be performed using intravenous adenosine infusion (140 µg/kg/min) for at least 
3 minutes or until maximal hyperemia is achieved.  Occasionally doses as high as 280 µg/kg/min 
will lead to a positive FFR when a lower dose did not.  To avoid turbulence, the pressure 
transducer should be placed 2-3 cm beyond the lesion to be assessed. 

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21. 
APPENDIX F:  PROPOSED ANALYSES FOR SECONDARY 
PUBLICATIONS 
 
The following endpoints and analysis will be considered for publication.  Analysis will be 
performed on available data with no additional data collected specifically for these analyses. 
 
21.1. Other Endpoints 
 
• Utility of the SYNTAX score, ACEF score, clinical SYNTAX score, and novel 
predictive instruments 
 
• Multivariable predictors of the primary and major secondary endpoints and their 
components in all subjects and in the PCI and CABG arms individually 
 
• Weighted Composite Endpoint 
 
• Competing Risk Analysis 
 
 
PCI arm: 
 
• Frequency and impact of IVUS and/or FFR guidance 
 
• Frequency and impact of involvement of the distal left main vs. left main ostial/body 
lesions 
 
• Frequency and impact of different treatment strategies for the distal left main bifurcation 
 
• Frequency and impact of lesion preparation 
 
• Frequency and impact of chronic total occlusions and bifurcation lesions 
 
CABG arm: 
 
• Frequency and impact of on vs. off pump CABG 
 
• Frequency and impact of single vs. bilateral ITA vs. multiple arterial graft use 
 
• Frequency and impact of endoscopic versus open saphenous vein harvest technique 
 
• Frequency and impact of epi-aortic ultrasound and/or TEE 
 
• Impact of prophylactic and management strategies for atrial fibrillation 
 
• Value of carotid screening 
 
21.2. Pre-specified subgroups 
 
Subgroup analysis will be considered exploratory and hypothesis-generating only.  Details of the 
subgroup analysis will be provided in the SAP.  The following subgroups are of particular 
interest: 
 
• Diabetics, women, elderly, poor left ventricular function, chronic kidney disease (CKD), 

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# of diseased vessels, distal bifurcation involvement, chronic total occlusion (CTO), 
geographic location 
 
• SYNTAX score, clinical SYNTAX score, ACEF score 

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22.   APPENDIX G: OPTIMAL MEDICAL THERAPIES 
 
Optimal medical therapy (secondary prevention plus angina therapy) in the EXCEL trial will be 
intensive and evidence-based, and will be applied equally to both treatment groups.  Every 
subject should undergo individual risk assessment followed by aggressive risk factor reduction 
with tailored lifestyle intervention and pharmacological therapy to control risk factors, prevent 
future cardiovascular events, and manage symptoms (angina).187, 188, 189 These recommendations 
should be given in writing to all subjects, with a plan in place prior to discharge for close follow- 
up care to optimize long-term medical therapy. Table 22-1 illustrates the risk factor goals which 
are recommended. 
 
Table 22-1       Risk Factor Modification Goals 
Risk Factor 
Goal 
Smoking 
Cessation 
Total Dietary Fat / Saturated Fat 
<30% calories / <7% calories 
Dietary Cholesterol 
<200 mg/day 
Sodium 
<2,400 mg/day 
Fish 
≥2 servings per week 
Physical Activity 
≥30 minutes of moderate intensity, ≥5 times/week 
Body Weight by Body Mass Index (kg/m2) 
Initial BMI 
Weight Loss Goal 
25-27.5 kg/m2 
BMI < 25 kg/m2 
>27.5 kg/m2 
10% relative weight loss 
Blood Pressure 
<130/80 mm/Hg 
LDL cholesterol (primary goal) 
<70 mg/dL (<1.8 mmol/L) 
Non-HDL cholesterol (secondary goal) 
<100 mg/dL (<2.6 mmol/L) if TG >150 (≥1.69 mmol/L) 
Triglycerides (secondary goal) 
<150 mg/dL (<1.7 mmol/L) 
HDL cholesterol (secondary goal) 
>40   mg/dL   (>1.0   mmol/L)   for   men;   >50   mg/dL 
(>1.3 mmol/L) for women 
Diabetes 
HbA1c<7.0% 
Influenza Vaccination 
All subjects annually 
 
Table 22-2 
Waist Circumference Thresholds for Abdominal Obesity 
Ethnicity 
Waist Circumference Threshold 
European descent 
Men 
Women 
>102 cm (40 in) 
>88 cm (35 in) 
Asian or ethnic Central & South American 
Men 
Women 
>90 cm (35 in) 
>80 cm (32 in) 
Mediterranean or sub-Saharan African 
Men 
Women 
>94 cm (37 in) 
>80 cm (32 in) 

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22.1. General Recommendations and Goals 
 
22.1.1. Smoking 
All subjects who are smokers should enter a smoking cessation program (or practice-based 
counseling with nurse coordinators) with a focus upon quitting, avoiding relapses, and 
minimizing exposure to secondhand smoke.187, 188, 189 
 
22.1.2. Dietary and Weight Goals 
 
In subjects with an initial BMI of between 25-27.5 (kg/m2) the goal should be a BMI of less than 
25 kg/m2.  If BMI is greater than 27.5, the goal is 10% relative weight loss. 
 
Table 22-2 lists waist circumference thresholds for abdominal obesity.  Although these are not in 
themselves therapeutic targets, they are a useful screening tool for abdominal obesity as one of 
the components of the metabolic syndrome. 
 
An ideal diet should comprise less than 30% of calories as total fat and less than 7% of calories 
as saturated fat.  Dietary cholesterol should be limited to less than 200 mg per day, sodium less 
than 2400 mg per day, and at least 2 servings of fish per week are recommended. 
 
22.1.3. Physical Activity 
 
Physical activity goals are 30-60 minutes of moderate intensity exercise five or more times per 
week.  Based upon evidence of contemporary cardiac rehabilitation programs and taking into 
account that subjects in the EXCEL trial will have undergone coronary revascularization there 
should be little concern in regard to ischemic risk from exercise training.  An exercise prescription 
based upon the guidelines from the American Association of Cardiovascular Pulmonary 
Rehabilitation and the American College of Sports Medicine may be prescribed. Specifics are 
frequency of five or more times per week, an intensity based upon a resting heart rate plus 20 
beats per minute, a Borg rating of perceived exertion (RPE) of 11-13 (“fairly light to somewhat 
hard”), or below the subject’s angina-ischemia threshold.  The duration should be 30-60 minutes 
and the modes include walking, treadmill, cycling, elliptical, rowing, stair climbing, or other.190, 
191 
 
22.1.4. Influenza Vaccination 
 
Influenza vaccination should be encouraged on an annual basis for all subjects. 
 
22.1.5. Diabetes 
 
The goals for diabetes management are to maintain fasting blood glucose levels between 80 to 
125 mg/dL (4.44 – 7.49 mmol/L) and hemoglobin A1c levels of less than 7% in accordance with 
published recommendations.192, 193, 194   More stringent goals, i.e., a hemoglobin A1c level of less 
than 6%, can be considered in individual subjects. All subjects with hemoglobin A1c  levels of 
greater than 7% should be referred to a diabetes clinic or a physician with expertise in the 
management of diabetes.  Management will be in accordance with published guidelines and 
recommendations.

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22.1.6. Lipid Goals 
 
Aggressive lipid-lowering therapy is advocated with the primary goal being LDL cholesterol of 
less than 70 mg/dL (less than 1.8 mmol/L).188, 189,195, 196 Secondary goals including increasing the 
levels of HDL cholesterol to greater than 40 mg/dL (greater than 1.0 mmol/L) for men and 
greater than 50 mg/dL (greater than 1.3 mmol/L) for women.  Other secondary goals include 
maintaining triglyceride levels below 150 mg/dL (less than 1.7 mmol/L), non-HDL cholesterol 
below 100 mg/dL (<2.6 mmol/L), and total cholesterol/HDL cholesterol ratio of less than 4.0. 
Fasting lipid profiles should be analyzed at baseline, 6 weeks after starting therapy, 6 months, 
and then annually throughout the trial but are not a protocol requirement. 
 
22.1.7. Hypertension 
 
The goal is a blood pressure of less than 130/80 mmHg.  All subjects with hypertension 
will receive lifestyle counseling focused on sodium restriction, weight loss, and exercise. 
Medications will be prescribed if necessary. 
 
22.2. Pharmacologic Therapy 
 
Table 22-3 lists the recommended drugs to be used for each condition and the indications for 
therapy (Subject to modification, pending finalization and subsequent changes to ACC/AHA and 
ESC clinical practice guidelines for stable and unstable ischemic heart disease).  Goals of 
therapy are to achieve the desired level of risk factors and to control symptoms according to the 
subject’s individual tolerance of medications, so as to maintain an acceptable quality of life. 
 
Table 22-3       Pharmacologic Therapy Indications 
Medication Class 
Indication 
Aspirin 
See Sections 7.6.2 and 7.7.3. 
Thienopyridine 
See Sections 7.6.2 and 7.6.3 
ACE inhibitor 
Hypertension, diabetes, left ventricular systolic dysfunction, 
chronic kidney disease 
Angiotensin receptor blocker 
Individuals with hypertension, diabetes, left ventricular 
systolic dysfunction, chronic kidney disease who are 
intolerant of ACE inhibitors 
Beta-blocker 
All post-MI subjects unless contraindicated1, all others2 
Thiazide diuretic 
Hypertension, as indicated 
Calcium antagonist 
Hypertension, angina/ischemia 
Long-acting nitrate 
Angina/ischemia 
Late inward Na+ current inhibitor: ranolazine 
Angina/ischemia 
Other anti-anginal agents: ivabradine, 
trimetazadine, nicorandil 
Angina/ischemia 
Statin 
All subjects 
 
 

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Medication Class 
Indication 
Niacin: extended-release niacin 
LDL >70 mg/dL (1.8 mmol/L), non-HDL >100 mg/dL (2.6 
mmol/L) if TG >150 mg/dL (1.7 mmol/L) on statin; HDL < 
40 mg/dL (1.0 mmol/L) in men, HDL < 50 mg/dL (1.3 
mmol/L in women 
Cholesterol absorption inhibitor: ezetimibe 
LDL >70 mg/dL (1.8 mmol/L) on maximally-tolerated dose 
of statin 
Bile acid sequestrant 
LDL >70 mg/dL (1.8 mmol/L) on maximally-tolerated dose 
of statin 
Fibrate 
TG >10 mg/dL (1.7 mmol/L) on statin (not recommended for 
low HDL when TG < 150 mg/dL (1.69 mmol/L) 
Omega-3 fatty acids 
All subjects receive 1 gm/d; 2-4 gm/d to lower non-HDL 
<100 mg/dL (2.6 mmol/L) 
ACE=angiotensin converting enzyme; HDL=high density lipoprotein cholesterol; LDL=low density lipoprotein cholesterol; 
LVEF=left ventricular ejection fraction; MI=myocardial infarction; TG=triglycerides 
1Class IA recommendation according to ACC/AHA guidelines 
2Class IB recommendation according to ACC/AHA guidelines 
 
22.2.1. Antiplatelet Therapy 
 
See Section 7.6.2 and Section 7.6.3 for specific recommendations for antiplatelet therapy after 
PCI and CABG, respectively. 
 
22.2.2. Treatment of Hypertension 
 
The overall goal of therapy for hypertension is to provide maximal protection against 
cardiovascular consequences with minimal side effects.  There remains, however, some 
uncertainty with regard to which drug should be used and in what order. 
 
Since all subjects in this trial have symptomatic coronary artery disease, initial therapy should be 
an angiotensin converting enzyme inhibitor (ACE-I) or a beta-blocker.  If the goal blood 
pressure is not reached, the next step is the addition of a diuretic or a calcium-channel 
blocker.  All subjects should be on a beta blocker and an ACE-I prior to the addition of other 
agents.  If there are contraindications to use, side effects, or blood pressure is not controlled, 
subjects should be referred to the principal investigator for further consultation.  An ACE-I or 
angiotensin receptor blocker (ARB) should be administered to all subjects with diabetes, left 
ventricular systolic dysfunction, and/or chronic kidney disease. 
 
22.2.3. Lipid Lowering Therapy 
 
After the procedure, all subjects should be started on a high dose “statin” based on LDL level 
according to the recommended regimens included in Table 22-4. 
 
Table 22-4    Lipid Lowering Recommendations 
Medication 
Baseline LDL 70-100 mg/dL 
Baseline LDL ≥ 100 mg/dL 
Atorvastatin (Lipitor) 
40 mg 
80 mg 
Rosuvastatin (Crestor) 
20 mg 
40 mg 
 
 
If lipid goals are not reached after the maximum tolerated dose of a statin, then the preferred 

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option is to add Niacin ER 500 mg daily for 4 weeks to be titrated over a period of 4 weeks for 
each increase in dosage up to a maximum of 2000 mg daily.  Other options if the triglycerides 
are less than or equal to 200 mg/dL (2.3 mmol/L) are to add a bile acid sequestrant such as  
colesevelam 6 tablets daily or 3 tablets twice per day with a meal and liquid or ezetimibe 10 mg  
daily.  If triglycerides are greater than or equal to 200 mg/dL (greater than 2.3 mmol/L) add 
either Tricor (fenofibrate) 145 mg per day or fish oils up to a dose of 4 gm daily.  If subject still 
does not reach lipid goals, the principal investigator should be consulted. 
 
22.2.4. Anti-anginal Therapy 
 
All subjects should receive sublingual nitroglycerin for pain relief and prophylaxis. The choice 
between beta blockers and calcium channel blockers for first line anti-anginal therapy is not clear 
cut but in general, beta-blockers are advised as initial therapy, particularly in subjects with 
hypertension, left ventricular systolic dysfunction, and/or a history of myocardial infarction. 
Absolute contraindications to beta-blockers are severe resting sinus bradycardia, pre-existing 
second degree AV block, sick sinus node syndrome, asthma of at least moderate severity, or 
decompensated (class IV) heart failure.   Most diabetics and subjects with chronic obstructive 
pulmonary disease but without frank bronchospasm will tolerate beta blockers although close 
monitoring is recommended. 
 
Subsequent steps include the addition of drugs not already utilized, e.g., the addition of a calcium 
channel-blocker, long-acting nitrate, or ranolazine in subjects already on a beta-blocker. 
Conversely, the addition of a beta-blocker to subjects who are already on a calcium-channel 
blocker should be considered. 
 
New anti-anginal agents such as Trimetazidine (approved for use in Europe) and Ivabradine 
(approved for use in Europe) may be tried in selected subjects. 
 
22.2.5. Vitamin Supplementation 
 
Vitamin supplementation with vitamin E, folic acid, vitamin B6, and vitamin B12 are not 
recommended.  Although the evidence for vitamin D deficiency as a risk factor for CAD is 
growing, evidence for vitamin D supplementation as effective secondary prevention is lacking. 
Vitamin D supplementation is therefore not currently recommended, but may be considered if 
new evidence emerges during the course of the trial as appropriate, depending on results from 
two large ongoing trials. 

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23. 
APPENDIX H: ANGIOGRAPHIC CORE LABORATORY  
 
INSTRUCTIONS 
 
Angiographic core laboratory is at Cardiovascular Research Foundation, New York, NY, 
USA. Instruction to the sites 
• DICOM CD-R should be acquired at 15-30 frames/second for baseline and post 
procedural angiograms.  Please specify the frame rate on the Technician’s Worksheet 
 
• Use ≥ 6 Fr diagnostic or guiding catheters, and provide the size of the catheter on the log. 
 
• Use 50-200 mcg IC nitroglycerin and record on the Technician's Worksheet at baseline, 
during, and after the coronary intervention. 
 
• Please provide a full baseline diagnostic angiogram with at least 3 different views of 
every major epicardial vessel. 
 
• The left main bifurcation must be imaged in at least 3 orthogonal views to minimize 
vessel overlap and or foreshortening, making every effort to display the left main lesion 
in its most severe and least foreshortened view. 
 
• For subjects undergoing CABG, please provide detailed operative report to core 
laboratory for determination of complete revascularization. 
 
• For subjects undergoing PCI, please provide 2 matched orthogonal views of the lesion at 
baseline, and after final intervention. 
 
• Please film as much detail of the intervention as possible (pre and post stent placement, 
complications etc). 
 
• Please film all stent deployments so that an accurate assessment can be made for the areas 
of stent overlap/gap. 
 
• Please ensure that at least 5 cardiac cycles are captured on film for each coronary vessel 
imaged to ensure optimal TIMI flow assessment at baseline and final intervention. 
 
• Left ventriculography should be performed in the 30 degree RAO view ensuring that at 
least 2 consecutive sinus beats are available for analysis. 
 
• Labels are provided and must include your site ID, the subject ID, the procedure date, and 
the event. 
 
Shipping Instruction for Procedural and Event Angiograms 
 
• Original Technician's Worksheet (please keep a photocopy of the Technician's Worksheet 
at the Clinical Site). 
 
• Cardiac catheterization and procedure report 
 
• Procedural Film 
 
• All unscheduled event films should be sent to the Angiographic Core Laboratory. 

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Ship Films and Reports to: 
Katharine Lymberis 
Attn: EXCEL TRIAL Angiographic 
Core Laboratory Cardiovascular 
Research Foundation 
111 East 59th Street, 12th Floor 
New York, NY 10022 
Phone:  (212)851-9193 
Fax: 
(212)851-9330 
Email: 
klymberis@crf.org 

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24.  APPENDIX I: EXCEL Insulin Protocol for Glycemic Control  
Note: Do not use for diabetic ketoacidosis (DKA). 
This protocol is only for patients who are NPO (nothing by mouth) or are receiving continuous 
enteral or parenteral nutrition.  It is not appropriate for those taking scheduled meals or tube 
feeding boluses or Type I diabetics. 
 
Goal Blood Glucose 
 
Goal blood glucose is 110-150 mg/dL.  In addition, the goal blood glucose at 6:00 a.m. on 
POD #1 and #2 is <200 mg/dL. 
•   At the time of ICU admission: 
◦ 
If blood glucose is ≥140 mg/dL and the patient is not receiving insulin infusion, then 
initiate infusion at 0.05 units/kg/hr. 
◦ 
If blood glucose is 110-150 mg/dL and the patient is receiving insulin infusion, then 
reduce the infusion by 50%, unless the rate has already been reduced by 50% in operating 
room. 
•   If blood glucose is <200 mg/dL on day of surgery, POD (post-operative day) #1 or #2, follow 
Insulin Infusion Adjustment Protocol found in Table A. 
 
Table A            Insulin Infusion Adjustment 
***DO NOT ADJUST INSULIN RATE EVERY HOUR. ONLY MAKE ADJUSTMENTS TO THE 
INSULIN RATE EVERY TWO HOURS.*** 
 
Blood Glucose 
(mg/dL) 
If blood glucose 
DECREASES ≥30 mg/dL 
since last level 
If blood glucose is 
STABLE 
(change in blood glucose is 
<30 mg/dL since last level) 
If blood glucose 
INCREASES ≥30 mg/dL 
since last level 
≤70 
Stop insulin infusion 
See Hypoglycemia Protocol 
Stop insulin infusion 
See Hypoglycemia Protocol 
-- 
71-79 
Stop insulin infusion 
See Hypoglycemia Protocol 
Stop insulin infusion 
-- 
80-109 
Stop insulin infusion 
Decrease rate by 50% 
-- 
110-150 
Decrease rate by 50% 
Continue current rate 
Increase rate by 25% 
151-170 
Decrease rate by 50% 
Increase rate by 25% 
Increase rate by 50% 
171-200 
Decrease rate by 25% 
Increase rate by 25% 
Bolus 2 units 
Increase rate by 25% 
201-250 
Continue current rate 
Bolus 2 units 
Increase rate by 25% 
Bolus 4 units 
Increase rate by 25% 
251-300 
Continue current rate 
Bolus 4 units 
Increase rate by 50% 
Bolus 6 units 
Increase rate by 50% 
301-350 
Continue current rate 
Bolus 6 units 
Increase rate by 50% 
Bolus 8 units 
Increase rate by 50% 
351-400 
Continue current rate 
Bolus 8 units 
Increase rate by 50% 
Bolus 10 units 
Increase rate by 50% 
>400 
Notify medical staff 
Notify medical staff 
Notify medical staff 

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Note: If insulin rate is ≥30 units/hr or if blood glucose is not being controlled using the protocol, notify the medical 
staff.  If the protocol requires RHI rates to be <0.5 cc/hr, hold infusion and recheck blood glucose level in one hour. 
• If blood glucose is ≥200 mg/dL on day of surgery, POD #1 or #2: 
◦ 
Bolus with 4 units regular insulin IV and either change rate to 0.05 unit/kg/hr or increase 
rate by 25%, whichever is greater. 
◦ 
If diabetic or on epinephrine, bolus 6 units regular insulin IV and either change rate to 0.1 
unit/kg/hr or increase rate by 50%, whichever is greater. 
◦ 
Note: Patients who require insulin rates greater than 20 units per hour must have blood 
glucose monitoring every 1 hour. If blood glucose is <180 mg/dL and has decreased by 
more than 100 mg/dL from the previous reading done one hour earlier, call the medical 
staff to inquire whether regular insulin dose reduction per protocol is sufficient. 
◦ 
Note: If patient is on epinephrine and blood glucose is >300mg/dL and lactate is >10 
mmol/L and blood glucose is not decreasing, call the medical staff to consider changing 
from epinephrine to dobutamine. 
◦ 
Note: Expect a rapid decrease in insulin needs after stopping epinephrine. 
• Caution: Treating hyperkalemia with insulin and glucose may be associated with poor 
glycemic control.  Inform the medical staff if pretreatment blood glucose is ≥180 mg/dL or if 
two post-treatment blood glucoses are outside the goal range of 110-150 mg/dL. 
• Measure blood glucose every hour in the following circumstances: 
◦ 
If blood glucose is ≥200 mg/dL.  If so, continue monitoring and treating every hour until 
blood glucose is <170 mg/dL for two consecutive hours then measure blood glucose 
every 2 hours. 
◦ 
If blood glucose is <200 mg/dL and the blood glucose has increased or decreased by ≥50 
mg/dL from the previous measurement. 
◦ 
If insulin infusion rate is >20 units/hr. 
◦ 
As required under Section “Hypoglycemia Protocol”. 
 
Insulin Continuous Infusion 
 
Do NOT use for diabetic ketoacidosis (DKA). 
• Regular insulin 100 units/100 ml in 0.9% normal saline; concentration 1 unit/ml 
• If patient is not on insulin infusion and blood glucose is 150-170 mg/dL, repeat blood 
glucose measurement after 2 hours. 
• If blood glucose is 150-170 mg/dLl for 2 consecutive measurements: 
◦ 
Bolus dose: 0.05 units/kg (maximum bolus is 5 units) 
◦ 
Then initiate continuous infusion with initial rate of 0.05 units/kg/hr (maximum initial 
rate is 5 units/hr). 
 
• If blood glucose >170 mg/dL, do not repeat the measurement after 2 hours.  Instead, give 
bolus and start infusion immediately as above. 
• See Table A for adjustment of insulin rate. 

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Blood Glucose Monitoring 
 
Monitor blood glucose every 2 hours (exceptions noted in Section Hypoglycemia Protocol and 
Section Goal Blood Glucose) 
 
Sampling site and lab analysis should remain consistent.  Arterial sampling is preferred method 
for obtaining blood glucose measurements. 
 
Verify blood glucose results using an alternate method (e.g. fingerstick) for: 
•   Variations in blood glucose lab results >100mg/dL on consecutive blood draws 
•   Suspicion of false lab results or contaminated specimen 
•   Blood glucose results reading “I” or “Lo” on the accu- check meter 
 
Hypoglycemia Protocol 
 
• If blood glucose ≤ 70 mg/dL − stop insulin infusion, give 25-50 mL of 50% dextrose 
solution, notify medical staff, obtain BG level every 30 minutes until blood glucose is >80 
mg/dL for three consecutive levels, and then check blood glucose every 2 hours. 
• If blood glucose DECREASES ≥30 mg/dL since last level and blood glucose is 71-79 
mg/dL – stop infusion, obtain blood glucose level every 30 minutes until blood glucose level 
is >80 mg/dL for three consecutive levels, then check blood glucose level every 2 hours. 
• If enteral nutrition or total parenteral nutrition is stopped, decrease insulin infusion rate 
by 50% and monitor blood glucose levels every 1 hour until blood glucose >80 mg/dl for 
three consecutive levels, then check blood glucose every 2 hours. 
 
Resuming Insulin Infusion: 
•   Restart insulin infusion when first blood glucose value is ≥ 150 mg/dL.  Do not bolus. 
Restart insulin infusion at half the previous rate. 
Obtain blood glucose in 1 hour and 
reevaluate. 
 
Important Notes 
 
Insulin sensitivity will usually improve over time in the critically ill patient.  Because of this, the 
need for insulin may decrease throughout the ICU stay. 
 
Insulin requirements will usually increase when starting glucocorticoid therapy.  Large 
fluctuations in blood glucose may occur, requiring more frequent blood glucose measurements. 
 
Prior to discharge from the ICU, patients should be evaluated for transition to the standardized 
subcutaneous insulin order set. 
 
Subcutaneous insulin (combination of intermediate/long acting plus sliding scale/prandial insulin) 
is appropriate for ICU patients taking meals or receiving boluses of tube feeding. 
 
Patients who develop hypoglycemia while receiving subcutaneous insulin (combination of 
intermediate/long acting 
plus sliding 
scale/prandial 
insulin) 
may require 
a different 
hypoglycemia protocol to account for the prolonged effect of insulin. 

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Calculation of Insulin Infusion 
 
Use current weight when starting the insulin infusion for the first time. 
• 
If DECREASING RATE by 50% 
New rate = Current rate X 0.5 
• 
If DECREASING RATE by 25% 
New rate = Current rate X 0.75 
• 
If INCREASING RATE by 50% 
New rate = Current rate X 1.5 

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25.  
APPENDIX J:  Transient Ischemic Attack (TIA)/Stroke Questionnaire 
 
A. Transient Ischemic Attack (TIA)/Stroke Questionnaire 
 
 
Site #   
  
  
Pt #   
   
  
 
 
Follow-up 
 
 
 
(Questionnaire for Verifying Stroke-Free Status) 
 
 
 
Exam Time Interval 
30 Days 
6 Month 
1 Year 
2 Year 
3 Year 
4 Year 
5 Year 
 
 
Other  
 
 
 
 
Instructions: This form is to be used during the EXCEL follow-up contacts either in clinic 
visits or telephone. Remind respondent of date of last contact. 
 
 
 
Date and time of form completion:       /           /                     (mm/dd/yyyy) 
 
 
         :          (Hr/min (24 hr. format)) 
 
 
1. Since the last routine EXCEL contact by phone or 
YES 
NO 
Don’t know/Not sure 
clinic, have you been told by a physician 
that you have had a stroke? 
 
2. Since the last routine EXCEL contact by phone or 
in the clinic, have you been told by a physician that 
you had a TIA, mini-stroke, or transient ischemic attack? 
YES 
NO 
Don’t know/Not sure 
3. Since the last routine EXCEL contact by phone or 
in the clinic, have you had sudden painless weakness 
on one side of your body? 
YES 
NO Don’t Know/ Not sure 
4. Since the last routine EXCEL contact by phone or 
YES 
NO Don’t Know/ Not sure 

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in the clinic, have you had sudden numbness or a 
dead feeling on one side of your body? 
 
 
5. Since the last routine EXCEL contact by phone or 
YES 
NO 
Don’t Know/ Not sure 
in the clinic, have you had sudden painless loss of 
vision in one or both eyes? 
 
 
6. Since the last routine EXCELcontact by phone or 
YES 
NO 
 Don’t Know/ Not sure 
in the clinic, have you suddenly lost one half 
of your vision? 
 
 
7. Since the last routine EXCEL contact by phone or 
YES 
NO 
Don’t Know/ Not sure 
in the clinic, have you suddenly lost the ability 
to understand what people were saying? 
 
 
 
8. Since the last routine EXCEL contact by phone or 
YES 
NO 
Don’t Know/ Not sure 
in the clinic, have you suddenly lost the ability 
to express yourself verbally or in writing? 
 
 
 
 
 
 
 
If any of questions 1 – 8 are answered “YES”, follow procedures for a potential 
stroke; that is, submit the Major Event Form, Neurological Event Form, NIHSS 
TIA/Stroke Questionnaire, etc. 

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B.Modified Rankin Disability Questionnaire 
 
 
A.  Rankin 5-Severe disability; requiring constant nursing care and attention. 
Question: Does the person require constant care?  <  YES   <   NO  
B.  Rankin 4-Moderately severe disability; need for assistance with some basic ADL, but 
not requiring constant care. 
 
Question: Is assistance essential for eating, using the toilet, daily hygiene, or walking? 
 <  YES   <   NO 
 
C.  Rankin 3-some need for assistance but able to walk without assistance. 
 
 
Question: Is assistance essential for preparing a simple meal, doing household chores, 
looking after money, shopping, or traveling locally?  <  YES   <   NO 
 
D.  Rankin  2-Slight  disability;  limitations  in  participation  in  usual  social  roles,  but 
independent for ADL. 
 
Questions: Has there been a change in the person’s ability to work or look after others? 
<  YES   <   NO 
 
Question: Has there been a change in the person’s ability to participate in previous social 
and leisure activities? <  YES < NO < 
 
Question:  Has the person had problems with relationships or become isolated? <   YES 
< NO  
 
 
E.  Rankin  1-No  significant  disability;  symptoms  present  but  no  physical  or  other 
limitations. 
 
Question: Does the person have symptoms that do not interfere with the ability to carry 
out all usual activities ?  <  YES  < NO  
 
 
F.   Rankin 0-No symptoms at all. 
 
 
Score Rankin 0 if answers to all questions A-E are “No”. 

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26. APPENDIX K: REFERENCES 
 
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41 
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