Study of Access Site for Enhancing PCI in STEMI for Seniors (SAFE STEMI for Seniors)
Phase: NA
Conditions: Myocardial Infarction
Sponsor: David Kong, M.D.

 
Duke Clinical Research Institute 
 
This document is a confidential communication of the Duke Clinical Research Institute 
(DCRI). Acceptance of the document constitutes agreement by the recipient that the 
contents will not be disclosed to any unauthorized personnel, without the prior written 
authorization of the DCRI. In the event of actual or suspected breach of this agreement, 
the DCRI will be promptly notified. 
PROTOCOL 
 
Study of Access Site for Enhancing PCI in STEMI for Seniors 
 (SAFE-STEMI for Seniors) 
 
Phase: U.S. Investigational Device Exemption # G160113 
Date: June 15, 2017 
Version: 1.2.1 
Protocol Number: MDEpiNet-001 
NCT02939976 
Principal Investigator:  
 
 
Study Chair: 
 
 
David F. Kong, MD 
Sunil V. Rao, MD (Co-Investigator) 
Duke University Medical Center 
Durham NC 27705  USA 
 
Mitchell W. Krucoff, MD 
Duke University Medical Center 
Durham NC 27705  USA 
 
 
Sponsor: 
David F. Kong, MD 
Duke Clinical Research Institute 
2400 Pratt Street 
Durham, NC 27705  USA  
 
Partners: 
 
Medtronic Vascular, Inc. 
3576 Unocal Place 
Santa Rosa, CA 95403  USA 
 
Philips Volcano Corporation 
3721 Valley Centre Drive, Suite 500 
San Diego, CA 92130  USA 
 
Terumo Medical Corporation 
265 Davidson Avenue 
Somerset, NJ 08873  USA 
 

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PROTOCOL APPROVAL PAGE 
 
Study Title:  
Study of Access Site for Enhancing PCI in STEMI for Seniors  
(SAFE-STEMI for Seniors) 
 
Version:  
 
1.2.1 
Date of Issue: 
June 15, 2017 
 
 
I have read and approve this protocol and agree on its content. 
 
 
 
 
 
 
David F. Kong, MD 
Sponsor: 
Duke Clinical Research Institute 
 
Date 

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PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version Number/Amendment 
Approval Date 
Final protocol: Version 1.0 
May 25, 2016 
Revised protocol: Version 1.1 
July 29, 2016 
Revised protocol:  Version 1.2.1 
June 15, 2017 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS  
Protocol Title 
Study of Access Site for Enhancing PCI in STEMI for  Seniors 
(SAFE PCI in STEMI for Seniors) 
Main Criteria for Inclusion 
Patients > 65 years old with chest pain < 12 hours and ST-
elevation myocardial infarction or LBBB on ECG with intent to 
perform primary percutaneous coronary intervention (PCI) via 
right or left radial arterial access. 
Study Objectives 
To simultaneously address four potential advances in STEMI 
care for patients at least 65 years old. 
1. To examine the effectiveness of zotarolimus-eluting 
stents for radial Primary PCI in STEMI  
2. To evaluate the safety and benefit of iFR-guided 
complete revascularization vs. infarct artery only 
revascularization in Primary PCI of patients with multi-
vessel CAD 
3. To obtain data on the real world application of radial 
access for Primary PCI in the public health focus on an 
elderly population. 
4. To evaluate the safety of the Terumo Glidesheath 
Slender and TR Band on an elderly population. 
Study Design 
Multicenter, randomized, open-label, unblinded, active and 
historical-controlled trial in which approximately 875 seniors 
undergoing urgent PCI from approximately 70 centers will be 
enrolled.  All consented subjects will undergo attempted radial 
arterial access.  
For DES (Drug Eluting Stent) eligible patients without 
randomization exclusion criteria and with multi-vessel disease 
will be randomized by site in a ratio of 1:1 to IRA-only 
revascularization or iFR-guided complete revascularization.  
After randomization, subjects with stable TIMI-3 flow 
established in the IRA using the protocol specified treatment 
will proceed with the randomized procedure.  Subjects in whom 
IRA reperfusion with TIMI-3 flow is not achieved will be treated 
according to clinical best practice standard of care independent 
of randomized procedure assignment and will not be 
considered protocol violations.  These patients will be followed 
identically to all study patients. 
After stent implantation, subjects will be contacted for follow-up 
at 30 days by the enrolling site and at 1 year by the DCRI Call 
Center. 

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Primary endpoint results will be reported after all subjects have 
completed the 1 year (12 months) of clinical follow-up. 
Treatment Regimen 
STEMI patients eligible for radial access: 
DES Eligible with single vessel CAD will receive DES to IRA 
DES Eligible with Multi-vessel CAD will randomize by site in a 
ratio of 1:1 to IRA-only revascularization or iFR-guided 
complete revascularization.  
Duration of Subject Study 
Participation 
Patients will be seen by sites for their standard of care follow-
up visit approximately 30 days after their procedure. Patients 
will be contacted by the DCRI Call Center at 1 Year to collect 
data for the primary endpoint analysis. Medicare Claims data 
will be collected at 18 months post-procedure after the final 
patient is enrolled. 
Number of Patients 
A total of approximately 875 patients > 65 years old   
Number of Sites 
Approximately 70 centers are planned in the US and Canada. 
Endpoints 
for 
Evaluating 
Medtronic Resolute® Family 
of Stents for Primary PCI in 
STEMI  
 
Primary Endpoint:  
• 
Adjudicated 1-year infarct-related artery (IIVR) 
MACE as defined in HORIZON as cardiac death, 
index infarct -vessel MI, or ischemia-driven index 
infarct 
related 
vessel 
revascularization 
by 
percutaneous or surgical methods rate 
This endpoint has been powered to test the superiority of 
the primary endpoint rate when using the Medtronic 
Resolute® Family of Stents in STEMI versus HORIZON 
based performance goal. 
Secondary Endpoints: 
Using the Medtronic Resolute® Family of Stents in STEMI: 
Efficacy: 
• 
Adjudicated Death (all causes) at 30 days and 1 
year. 
• 
Adjudicated Cardiac death at 30 days and 1 year. 
• 
Adjudicated Nonfatal (re-)MI at 30 days and 1 year. 
• 
Adjudicated Index Infarct Related-vessel (re-)MI at 
30 days and 1 year.  

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• 
Adjudicated 
Index 
Infarct 
Related 
Lesion 
Revascizlation (IILR) (ischemia driven) at 30 days 
and 1 year.  
• 
Adjudicated IIVR (ischemia driven) at 30 days and 1 
year.  
Safety: 
• 
Adjudicated Academic Research Consortium (ARC) 
definite/probable 
stent 
thrombosis 
at 
post 
procedure, 30 days and 1 year. 
• 
Adjudicated ARC definite stent thrombosis at post 
procedure, 30 days and 1 year.  
• 
Adjudicated Stroke at post-procedure, 30 days and 
1 year. 
Device Performance Endpoints: 
• 
Site determination of Device success, defined as 
attainment of less than 20% residual stenosis of the 
infarct related lesion at the time of the index 
procedure (IILR) using only the study stent..  
• 
Site determination of Lesion success, defined as 
attainment of less than 20% residual stenosis using 
any percutaneous method at the time of the index 
procedure.  
• 
Site determination of Procedure success, defined as 
lesion success without the occurrence of in-hospital 
death, 
nonfatal 
MI, 
stroke, 
or 
emergency 
revascularization at the time of the index procedures 
 
Endpoints for Evaluating iFR 
Guided 
iFR-Guided 
Complete Revascularization 
in STEMI  
 
Primary Endpoint:  
The endpoint is Adjudicated 1-year modified CvLPRIT MACE 
defined as all-cause mortality, recurrent MI, heart failure 
(requiring hospitalization or 12 hour ER visit) or ischemia-
driven revascularization.  This endpoint has been powered 
to test the superiority of the primary endpoint rate when using 
iFR guided complete revascularization versus infarct related 
vessel only revascularization in STEMI. 
Secondary Endpoints: 

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• 
Adjudicated 
cardiovascular 
death 
at 
post-
procedure, 30 Days, and 1 Year 
• 
Individual components of the modified CvLPRIT 
MACE endpoint 
• 
Adjudicated Stroke at post-procedure, 30 Days and 
1 year. 
Device Performance Endpoints: 
Using iFR guided revascularization with Volcano based 
pressure wires Verrata®, Verrata Plus® and any subsequent 
marketed Volcano pressure wire technology 
• 
Site reported index hospitalization bleeding and 
vascular complication defined as bleeding or 
vascular complication requiring intervention 
• 
Total procedure time 
• 
Total contrast used 
• 
Occurrence of renal insufficiency (increase from 
baseline creatinine of at least 0.5 mg/dL or at least 
25%) assessed at 48-72 hours post-procedure, 30 
days. 
 
Endpoints to Evaluate the 
Terumo Slender GlideSheath 
and TR Band for radial 
access PCI in the elderly 
Primary Observational Endpoint:  
• 
Estimate the incidence rate of RAO acute and at 
30day stratified by whether or not the Terumo TR 
Band was employed (use of the TR Band is 
recommended not required) 
Secondary Observational Endpoints:  
• 
Time to Hemostasis stratified by whether the 
Terumo TR Band was employed 
• 
Incidence rate of cross over to from the initial access 
point to another stratified by whether or not Terumo 
Slender GlideSheath was employed (Use of the 
Slender 
GlideSheath 
is 
recommended 
not 
required)] 
• 
Incidence rate of Access success defined as 
successfully deploying the stent through the right or 
left radial artery stratified by whether or not Terumo 
Slender GlideSheath was employed 

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• 
Incidence of RAO acute and at 30day stratified by 
whether or not the Terumo  TR Band was employed 
in combination with Glidesheath Slender 
These are observational endpoints. 
Clinical Events Committee 
An independent Clinical Events Committee (CEC) will be 
formed to provide independent central adjudication of 
suspected endpoints through the 1 year follow-up for each 
patient. 
Data and Safety Monitoring 
Committee 
An independent DSMC will monitor the trial conduct. The 
DSMC will consist of 2 clinicians and a statistician. The 
members of this committee will not participate in the enrollment 
or treatment of patients in this trial. The guidelines for the 
DSMC operations will be reported in a separate DSMC Charter.  
Statistical Analysis  
 
Sample Size/ 
Power Considerations 
There are two powered primary endpoints this study.   
1-year infarct-related artery (IIVR) MACE: The SAFE-STEMI 
for Seniors study has been powered at 85% to meet a 
performance goal of 15% for the Medtronic Resolute® Family of 
Stents assuming 1-year infarct-related artery MACE of 10% in 
patients 65 years or older and a two-sided type I error of 0.05. 
To meet this performance goal endpoint a total of 477 DES 
patients will be required accounting for a 10% attrition rate.  
1-year modified CvLPRIT MACE: The study is also powered for 
iFR-guided multi-vessel PCI with 0ne-year CvLPRIT MACE 
endpoint, by assuming 1 year MACE rate of 22% in the IRA 
only arm and 12% in the complete revascularization arm, 
yielding the multi-vessel cohort (n=550 pts) which will provide 
at least 85% power to detect a 45% relative reduction in 1 year 
MACE, accounting for approximately 10% attrition.   
 
Given that: 
• 
The iFR-guided complete revascularization arm of 
the multi-vessel patient cohort is not used for the 1-
year MACE evaluation of Medtronic Resolute® 
Family of Stents 
• 
The single vessel patient used in the evaluation of 
the Medtronic Resolute® Family of Stents and is not 
used in the evaluation of iFR  
• 
The 
1-year 
MACE 
evaluation 
of 
Medtronic 
Resolute® Family of Stents pools the single and 
multi-vessel patients and compares the binary 
endpoint to a performance goal;  

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• 
 iFR analysis compares randomized multi-vessel 
arms using the difference in the K-M estimates 
the two primary endpoint are considered to be statistically 
independent and there is no need to adjust the type I error for 
multiple endpoints 
 
 

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TABLE OF CONTENTS 
 
Protocol Approval Page .........................................................................................2 
Protocol Version and Amendment Tracking ..........................................................3 
PROTOCOL SYNOPSIS .......................................................................................4 
TABLE OF CONTENTS ...................................................................................... 10 
LIST OF TABLES ................................................................................................ 13 
LIST OF FIGURES .............................................................................................. 13 
ABBREVIATIONS ............................................................................................... 14 
1. 
INTRODUCTION AND BACKGROUND ................................................... 16 
1.1 
Background .................................................................................... 16 
1.2 
New Generation DES in STEMI ..................................................... 17 
1.3 
Multi-vessel Intervention during Primary PCI ................................. 17 
1.4 
Radial Access for Primary PCI ....................................................... 20 
1.5 
Terumo® Glidesheath Slender and TR Band ................................ 21 
1.6 
SAFE Site Network ........................................................................ 21 
2. 
STUDY OBJECTIVES .............................................................................. 22 
3. 
STUDY DESIGN ....................................................................................... 23 
3.1 
Overview of Study .......................................................................... 23 
3.2 
Endpoints ....................................................................................... 24 
3.2.1 
Endpoints for Evaluating Medtronic Resolute® Family of 
Stents for Primary PCI in STEMI ...................................... 24 
3.2.2 
Endpoints for Evaluating iFR Guided iFR-Guided Complete 
Revascularization in STEMI ............................................. 27 
3.2.3 
Endpoints to Evaluate the Terumo Slender GlideSheath and 
TR Band for radial access PCI in the elderly .................... 28 
3.2.4 
Endpoint Adjudication ....................................................... 29 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ................................... 29 
4.1 
Inclusion Criteria ............................................................................ 29 
4.2 
Exclusion Criteria ........................................................................... 30 
4.3 
Randomization Completion ............................................................ 31 
4.4 
Withdrawal of Patients ................................................................... 31 

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5. 
STUDY PROCEDURES ........................................................................... 32 
5.1 
Screening Procedures ................................................................... 32 
5.2 
Informed Consent .......................................................................... 32 
5.3 
Enrollment ...................................................................................... 33 
5.3.1 
Stent Deployment ............................................................. 33 
5.4 
Randomization for Subjects with Multi-vessel CAD Receiving a DES
 ....................................................................................................... 33 
5.4.1 
iFR Guided Complete Revascularization .......................... 33 
5.5 
Post-procedure Follow-up .............................................................. 36 
5.6 
Use of Medicare Claims Data ........................................................ 36 
5.7 
Schedule of Events ........................................................................ 36 
6. 
CONCOMITANT MEDICATIONS/THERAPIES ........................................ 38 
6.1 
Pre-PCI Medications ...................................................................... 38 
6.1.1 
Aspirin .............................................................................. 38 
6.1.2 
Platelet Adenosine Diphosphate Receptor Antagonists ... 38 
6.1.3 
Other Medications ............................................................ 38 
6.2 
During PCI Medications ................................................................. 38 
6.3 
Post-PCI Medications .................................................................... 38 
6.3.1 
Aspirin .............................................................................. 39 
6.3.2 
Platelet Adenosine Diphosphate Receptor Antagonists ... 39 
7. 
SUBJECT SAFETY AND ADVERSE EVENTS ........................................ 40 
7.1 
Definitions ...................................................................................... 40 
7.1.1 
Adverse Event .................................................................. 40 
7.1.2 
Serious Adverse Event ..................................................... 40 
7.1.3 
Anticipated Adverse Device Effects .................................. 41 
7.1.4 
Unanticipated Adverse Device Effects ............................. 41 
7.1.5 
Device Failure and Device Malfunction ............................ 42 
7.1.6 
User Error ......................................................................... 42 
7.2 
Assessment ................................................................................... 43 
7.2.1 
Causality .......................................................................... 43 
7.3 
Reporting ....................................................................................... 44 
7.3.1 
Time Frame for Reporting ................................................ 45 
7.4 
Device Failures, Device Malfunctions, and User Error ................... 46 
7.5 
Regulatory Reporting of Unanticipated Adverse Device Effects .... 46 
8. 
STATISTICAL ANALYSIS AND DETERMINATION OF SAMPLE SIZE ... 47 
8.1 
Medtronic Resolute® Family of Stents for STEMI .......................... 47 
8.2 
IFR-Guided Multivessel PCI ........................................................... 50 
8.3 
Performance of Terumo TR Band .................................................. 53 

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8.4 
Secondary and Device Performance Endpoints ............................ 54 
8.5 
Controlling Bias .............................................................................. 54 
8.5.1 
Type I Error ...................................................................... 54 
8.5.2 
Blinding and Randomization ............................................. 54 
8.5.3 
Poolability across sites ..................................................... 54 
9. 
ESTIMATED DURATION OF THE STUDY .............................................. 55 
10. 
STUDY ETHICAL CONSIDERATIONS .................................................... 55 
10.1 Confidentiality of Patients .............................................................. 55 
11. 
ADMINISTRATIVE PROCEDURES ......................................................... 55 
11.1 DCRI Coordinating Center Responsibilities ................................... 55 
11.1.1 Investigator Training ......................................................... 55 
11.1.2 Study Monitoring .............................................................. 56 
11.2 Investigator’s Responsibilities ........................................................ 57 
11.2.1 Reporting and Recording of Study Data ........................... 57 
11.2.2 Source Documentation ..................................................... 57 
11.2.3 Records Retention ............................................................ 57 
12. 
STEERING COMMITTEE, DATA SAFETY AND MONITORING 
COMMITTEE, AND ADJUDICATION COMMITTEE ................................. 58 
12.1 Steering Committee ....................................................................... 58 
12.2 Independent Data and Safety Monitoring Committee (DSMC) ...... 58 
12.3 Independent Clinical Events Committee (CEC) ............................. 58 
13. 
POLICY FOR PUBLICATION AND PRESENTATION OF DATA ............. 60 
14. 
REFERENCES ......................................................................................... 61 
15. 
Appendices ............................................................................................... 64 
15.1 Appendix A:  National Cardiovascular Research Infrastructure 
CathPCI Registry ........................................................................... 64 
15.2 Appendix B:  Clinical Data Sources ............................................... 65 
15.3 Appendix C: Medtronic Stent IFU .................................................. 71 
15.4 Appendix D: Volcano Verrata PGW IFU ........................................ 72 
15.5 Appendix E: Volcano PremeWire Ptrstige PLUS PGW IFU ........... 73 
15.6 Appendix F: Terumo Guidesheath Slender IFU ............................. 74 
15.7 Appendix G: Terumo TR Band IFU ................................................ 75 
 

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LIST OF TABLES 
Table 1 
Schedule of Assessments ................................................................... 37 
Table 2 
Causality ............................................................................................. 43 
Table 3 
1-Year Major Adverse Cardiac and Cerebrovascular Events Rates for 
STEMI Patients Treated with DES from HORIZONS Study ................ 47 
Table 4 
Pooled 1-Year MACE Rates Across Available DES and BMS Platforms 
from Published Studies and the Bern-Rotterdam Registry .................. 48 
 
LIST OF FIGURES 
Figure 1 Study Design and Treatment Schema ................................................ 24 
Figure 2 iFR Guided Complete Revascularization Procedure Flow .................. 35 
Figure 3 Power to exclude the upper 95% confidence interval for the Medtronic 
Resolute® Family of Stents Performance Goal of 15% Using the Exact 
Binominal Method*. ............................................................................. 50 
Figure 4 Subgroup Analysis from the CvLPRIT study ....................................... 52 
Figure 5 Power Curves for Multivessel Cohort: Farrington Manning Score Test for 
Two Proportions. ................................................................................. 53 
Figure 6: Submission Timeline ............................................................................ 66 
Figure 7:  Events Ascertainment process for 1 year Clinical Report ................... 67 
Figure 8:  Event Ascertainment process for the Updated One Year Primary Endpoint 
Clinical Report (updated after CMS pull) ............................................. 68 
Figure 9: Alternative Event Ascertainment process for the Updated One Year 
Primary Endpoint Clinical Report For Volcano (updated after CMS pull)69 
 

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ABBREVIATIONS 
ACC 
American College of Cardiology 
ADE 
Adverse Device Effect 
ADP 
Adenosine Diphosphate 
AE 
Adverse Event 
AHA 
American Heart Association 
ARC 
Academic Research Consortium 
BARC 
Bleeding Academic Research Consortium 
BMS 
Bare Metal Stent 
CABG 
Coronary Artery Bypass Graft 
CAD 
Coronary Artery Disease 
CEC 
Clinical Events Classification 
CMS 
Center for Medicare and Medicaid Services 
CTO 
Chronic Total Occlusion 
CvLPRIT 
Complete versus Lesion-only Primary PCI trial 
DAPT 
Dual Anti-Platelet Therapy 
DCRI 
Duke Clinical Research Institute 
DES 
Drug Eluting Stent 
DSMC 
Data and Safety Monitoring Committee 
EC 
Ethics Committee 
ECMO 
Extra Corporeal Membrane Oxygenation 
EES 
Everolimus Eluting Stent 
FDA 
Food and Drug Administration 
FFR 
Fractional Flow Reserves 
GPIIb/IIIa 
Glycoprotein IIb/IIIa 
HF 
Heart Failure 
HORIZONS-
AMI 
Harmonizing Outcomes with Revascularization and Stents in Acute 
Myocardial Infarction  
IABP 
Intra-Aortic Balloon Pump 

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IDE 
Investigational Device Exemption 
iFR 
Instantaneous Wave Free Ratio 
IIVR 
Index Infarct Vessel Revascularization 
IILR 
Index Infarct lesion Revascularization 
INIVR 
Index Non-Infarct Vessel Revascularization 
IRA 
Infarct Related Artery 
IRB 
Institutional Review Board 
IVUS 
Intra Vascular Ultra Sound 
MACCE 
Major Adverse Cardiac and Cerebrovascular Event 
MACE 
Major Adverse Cardiac Events 
NACE 
Net Adverse Cardiac Events 
NCDR 
National Cardiovascular Data Registry 
NCRI 
National Cardiovascular Research Infrastructure 
NDI 
National Death Index 
NOAC 
Novel Oral Anti-Coagulant 
NSTEMI 
Non ST Elevation Myocardial Infarction 
PCI 
Percutaneous Coronary intervention 
PES 
Paclitaxel Eluting Stent 
RAO 
Radial Artery Occlusion 
RR 
Relative Risk 
SAE 
Serious Adverse Event 
STEMI 
ST Elevation Myocardial Infarction 
TIMI 
Thrombolysis in Myocardial Infarction risk score 
IILR 
Index Infarct Related Lesion Revascularization 
TR Band 
Trans Radial Band 
IIVR 
Index Infarct Related Vessel Revascularization 
UADE 
Unanticipated Adverse Devise Effect 
ZES 
Zotarolimus Eluting Stent 
 

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1. 
INTRODUCTION AND BACKGROUND 
1.1 
Background 
Ischemic heart disease is the leading cause of death in the United States, with ST-
segment elevation myocardial infarction (STEMI) accounting for over 300,000 cases each 
year.[1]  Multicenter registries have shown that myocardial loss, mechanical 
complications, and short-term mortality after STEMI have decreased over the past 3 
decades due to aggressive antithrombotic therapy and accelerated access to primary 
PCI.[2, 3] Although rapid primary PCI with potent anti-thrombotic therapy is standard care 
for STEMI, unmet medical challenges remain, including multi-vessel disease, recurrent 
ischemia, and repeat revascularization. These complications prolong hospitalization and 
increase the risk for additional revascularization, bleeding, re-infarction, stroke, and 
death. Multi-vessel disease and comorbidities are more frequent in elderly patients,[4] 
who epidemiologically constitute a high impact public health challenge as the most rapidly 
increasing population sector in the United States [5].  Age is not only directly related to 
worse outcomes from STEMI [2, 6, 7] but also associated with higher complication rates 
with primary PCI and anti-thrombotic therapies used to interrupt STEMI [8, 9]. 
Traditional clinical trial approaches to addressing the many factors affecting the safety 
and efficacy of primary PCI in elderly STEMI patients are confounded by logistics [7]. The 
Safe STEMI for Seniors protocol represents a national network of clinical sites linked to 
Medicare claims data for long term clinical follow up (1 year and beyond). The prospective 
randomized design encourages innovation and robust evaluation of approved state-of-
the-art technologies to support extensions to device regulatory labeling through IDE 
investigations. Collaborative models strategically partnering multiple manufacturers also 
help mitigate costs related to studying such labeling extensions, while encouraging the 
expansion of state-of-the-art devices into new markets to address previously unmet 
needs. The Safe STEMI for Seniors study is designed to simultaneously address four 
potential advances in STEMI care for patients at least 65 years old: 
1. To examine the effectiveness of zotarolimus-eluting stents for radial Primary 
PCI in STEMI  
2. To evaluate the safety and benefit of iFR-guided complete revascularization vs. 
infarct artery only revascularization in Primary PCI of patients with multi-vessel 
CAD 
3. To obtain data on the real world application of radial access for Primary PCI in 
the public health focus on an elderly population. 
4. To evaluate the safety of the Terumo Glidesheath Slender and TR Band on an 
elderly population 
 

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1.2 
New Generation DES in STEMI 
Drug eluting stents have consistently been shown to significantly reduce restenosis rates 
after primary PCI for STEMI.[10] Underpowered, short term studies and concerns about 
stent thrombosis, strongly tempered use of DES for this indication until the HORIZONS 
trial was reported[11], leading to the approval of the Taxus paclitaxel-eluting stent (PES) 
for primary PCI for STEMI. Even this study, however, was underpowered for detection of 
stent thrombosis signals. 
Multiple reports and meta-analyses have consistently shown that subsequent generation 
DES, with more biocompatible polymer delivering zotarolimus (ZES) and everolimus 
(EES) have significantly lower stent thrombosis rates than paclitaxel-eluting stents in 
elective, “all comers” and STEMI populations.[12] Clinical use of DES for primary PCI in 
STEMI has crossed equipoise (>50%) in many centers worldwide.  However, there is no 
third generation DES yet approved for this indication in the United States. 
The Medtronic Resolute® Family of Stents are highly flexible and deliverable third 
generation DES, well suited to investigation in the setting of seniors undergoing primary 
PCI for STEMI.   
1.3 
Multi-vessel Intervention during Primary PCI 
Overall approximately 30-50% of patients with STEMI also have concomitant obstructive 
coronary artery disease in other non-culprit vessels, with additional patients presenting 
with borderline lesions in the non-infarct related artery (IRA). In seniors the incidence of 
multi-vessel CAD in the STEMI setting has been reported as 55-60%. [13, 14] Functional 
dependence on the non-infarct zones of myocardium to compensate for the “stunned” 
areas of reperfusion have raised concerns when coronary flow to the non-infarct zones is 
abnormal. Other than in shock states, however, observational studies have shown 
equivocal benefit when these other lesions are intervened upon during primary PCI,[15] 
possibly related to the very stimulated platelet environment that characterizes STEMI.    
For example, a total of 505 patients from the Mid-America Heart Institute[16]  with multi-
vessel disease who presented with STEMI were subdivided in 3 groups on the basis of 
the revascularization strategy: 1) patients undergoing percutaneous coronary intervention 
(PCI) of the infarct-related artery (IRA) only; 2) patients undergoing PCI of both the IRA 
and non-IRA(s) during the initial procedure; and 3) patients undergoing PCI of the IRA 
followed by staged, in-hospital PCI of the non-IRA(s). There were no significant 
differences in procedural complications among these three (non-randomized ) groups, 
but patients undergoing multi-vessel PCI during the initial procedure had significantly 
higher in-hospital mortality (p=0.003). Outcomes were compared among these three 
groups and to 314 AMI patients with single-vessel disease who were treated during the 

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same period. In patients with multi-vessel disease, compared with PCI restricted to the 
IRA only, multi-vessel PCI was associated with higher rates of re-infarction (13.0% vs. 
2.8%, P <.001), revascularization (25% vs. 15%, P = .007), and major adverse clinical 
events (MACE) (40% vs. 28%, P = .006). This series and similar reports have led to a 
Class III recommendation (harmful; should not be performed) in the STEMI treatment 
guidelines.[1]  
This recommendation has led to the routine use of multiple revascularization procedures 
in patients with multi-vessel disease presenting with STEMI, even within the initial 
hospitalization. Although some have argued early multi-vessel PCI after acute MI carries 
additional risk, an observational analysis of 239 multi-vessel disease patients from the 
Mayo Clinic[17]  showed that multi-vessel PCI within 7 days after AMI compared with 1-
vessel PCI was not associated with an excess risk of death or of combined death, 
myocardial infarction, coronary artery bypass graft, or target vessel revascularization. The 
multi-vessel PCI group had a significantly higher prevalence of adverse prognostic 
indicators. Despite this, observed event rates were similar between the multi-vessel PCI 
and 1-vessel PCI groups. The Kaplan-Meier estimated 1-year survival was 0.91 (95% 
confidence interval [CI] 0.87 to 0.95) for the multi-vessel PCI group and 0.93 (95% CI 
0.92 to 0.95) for the 1-vessel PCI group (p = 0.43). Similarly, 1-year survival free of 
recurrent infarction and target vessel revascularization rates were similar between the 2 
groups: multi-vessel PCI 0.78 (95% CI 0.73 to 0.84) and 1-vessel PCI 0.78 (95% CI 0.75 
to 0.81). 
The PRAMI randomized trial [18] has challenged these previous assumptions.  In PRAMI 
the randomized strategy to do PCI in non-IRA lesion(s) immediately following successful 
primary PCI was associated with a significant reduction in intractable ischemia, re-MI and 
death compared with IRA-only intervention in an event-driven model that was terminated 
early for benefit by the Data and Safety Monitoring Board. Less than 2 years after the 
PRAMI study was publicly reported, the CvLPRIT study [19], in which 296 STEMI patients 
with multi-vessel CAD were randomized to complete revascularization vs. infarct artery 
only.  The primary endpoint was a composite of all-cause death, recurrent myocardial 
infarction (MI), heart failure, and ischemia-driven revascularization within 12 months.  The 
65% reduction in this endpoint at 1 year was highly significant favoring complete 
revascularization.   
Thus in the face of a large body of observational evidence suggesting that PCI in addition 
to the IRA during primary PCI may be more risk than benefit, and best practice guidelines 
long promoting those observations, two independent, contemporary randomized trials 
suggest that primary PCI with complete revascularization leads to significant clinical 
benefit. A meta-analysis [20] of 46,324 subjects in randomized and non-randomized 
studies suggests a long-term mortality benefit with complete revascularization if non-
infarct-related artery (N-IRA) PCI is performed on a staged basis as opposed to being 

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undertaken the time of the index PCI. Contemporary aggressive anti-coagulant and anti-
platelet regimens have likely improved the risk/benefit profile of non-IRA PCI immediately 
after primary intervention.  In conjunction with radial vascular access which reduces 
bleeding risk, the potential clinical and economic value of more complete 
revascularization after acute STEMI warrants definitive study.  Elderly patients, a 
population at particular risk for multi-vessel CAD and bleeding complications, represent 
current unmet needs for interventional device applications and modernize best practice 
guidelines.  The SAFE STEMI for Seniors protocol has been developed to address these 
objectives. 
One central concern about multi-vessel PCI in conjunction with STEMI intervention is the 
criteria with which to determine if non-IRA lesions are appropriate for PCI.  Although IVUS 
and OCT assessments of plaque composition in non-culprit ACS lesions have been 
associated with subsequent MACE events, [21, 22] these techniques have not been 
validated in large studies.  Most observational and randomized studies have used 
angiographic estimates of stenosis severity to determine non-IRA lesions requiring 
treatment.[15] However, there is often a disparity between angiographic and physiologic 
measurements of non-IRA lesion significance in STEMI patients.[23] In 408 STEMI 
patients with evidence of multi-vessel disease defined by presence of N-IRA lesions with 
diameter stenosis of >50 %, FFR measurements performed at the time of index procedure 
showed that in 56.5 % the FFR was negative (<0.8).[24]  FFR measurements have been 
shown to be reliable and reproducible for non-culprit lesions in acute myocardial 
infarction. [25]The need for adenosine with FFR creates a safety concern in the STEMI 
setting, particularly in patients with high-grade AV block, concomitant pulmonary disease, 
hypotension, or bradycardia.[23] iFR in elective settings provides physiologic lesion 
assessment with outcome correlations without the need for provocative chemical 
infusion.[26]  Thus, iFR guided non-IRA lesion assessment provides an objective 
physiologic lesion/vessel specific measurement that may be safe and logistically feasible 
for use in STEMI settings.[27]  
The use of iFR in this protocol is intended to objectively avoid treating lesions that are not 
appropriate for revascularization. In the PRIMULTI trial[28], of 314 patients with 
angiographically significant lesions (50% or greater angiographic diameter stenosis) 
assigned to complete FFR-guided revascularization, 97 (31%) subjects had FFR values 
that were greater than the FFR discrimination threshold of 0.80, and these individuals 
received no further PCI. Likewise, in the COMPARE ACUTE study[24] the FFR 
assessment was negative in 56.5% of non-IRA with 50% or greater angiographic diameter 
stenosis. The use of iFR, rather than FFR, is intended to reduce the risk of physiologic 
assessment attributable to the vasodilators required for FFR. The risk attributable to 
revascularization of non-IRA vessels, even “obviously significant” ones, remains in 
equipoise. Retrospective registry data have indicated that non-IRA vessels should not be 

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treated during an initial admission, but the PRAMI and CvLPRIT trials suggest otherwise. 
Consequently, these subjects are expected to undergo randomization in SAFE-PCI in 
STEMI for Seniors. 
 
1.4 
Radial Access for Primary PCI 
The most common complication of primary PCI for STEMI is bleeding in the setting of 
combined antithrombotic therapy and femoral arteriotomy.  Studies have consistently 
shown that STEMI patients experience a higher rate of hemorrhagic complications 
compared with NSTEMI patients.  Moreover, bleeding in this population is associated with 
an increased risk of short- and long-term morbidity and mortality.  
Approximately half of the bleeding complications that occur among patients undergoing 
primary PCI occur at the femoral vascular access site.  Since age is a strong predictor of 
bleeding, seniors are at particularly high risk for bleeding and bleeding-related morbidity. 
Radial access, compared with femoral access, is associated with a 60-70% reduction in 
bleeding complications, primarily driven by a reduction in access site bleeding.  Three 
independent randomized studies conducted largely outside the United States have 
reported reductions in 30-day MACE and mortality rates with trans-radial compared with 
trans-femoral primary PCI.  The RIVAL study[29] reported a pre-specified STEMI 
subgroup analysis from the larger ACS cohort comparing radial and femoral approach 
that, in the overall analysis, showed no advantage of radial access for ACS, but clinical 
benefit for the STEMI patients treated from the radial approach.  RIFLE STEACS was a 
randomized trial conducted at 4 centers in Italy, randomizing STEMI patients to radial vs. 
femoral access and reporting clinical benefits, including a significant mortality reduction, 
in the radial group.[30]  Most recently the MATRIX study[31], a multicenter European trial 
conducted in over 7000 patients with acute coronary syndrome (including STEMI) 
demonstrated a significant reduction in net adverse clinical events (NACE) defined as 
MACE plus BARC 3 or greater bleeding and a reduction in 30-day mortality, although the 
mortality reduction was not seen in STEMI patients per se.  
Whether these results are generalizable to the US where the use of radial approach is 
less common is unclear.  Furthermore, seniors may have more upper extremity 
atherosclerotic disease and tortuosity, and in STEMI patients a central concern would be 
whether radial access would delay reperfusion times sufficiently to offset benefits of 
bleeding reduction. With rapidly expanding use of radial approach in the USA, and these 
reports generating interest and expanding use of radial techniques for primary PCI more 
data on procedure techniques, antithrombotic medications, catheter choice, and 
outcomes is essential to understanding the features of successful trans-radial primary 
PCI programs and their impact on the public health in the United States. 

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1.5 
Terumo® Glidesheath Slender and TR Band 
Similar to trans-femoral catheterization, sheath size is an important predictor of access 
site-related complications after trans-radial catheterization with larger sheaths 
independently associated with increased pain as well as increased major and minor 
complications. In a randomized trial of 5 French (Fr) versus 6 Fr trans-radial PCI, 
procedural success was achieved in 95.4% of 5 Fr and 92.9% of 6 Fr patients, while 1.1% 
of 5 Fr and 5.9% of 6 Fr patients (p = 0.05) suffered a loss of radial pulse due to radial 
occlusion. The Terumo® Glidesheath Slender is a dedicated thin walled, hydrophilic radial 
sheath that combines an inner diameter compatible with a 6 Fr guiding catheter with an 
outer diameter close to current 5 Fr sheaths. Conceptual advantages of the Glidesheath 
Slender include smaller arteriotomies (especially important in women with small radial 
arteries) and the flexibility to perform diagnostic (5 Fr) and interventional procedures (6 
Fr) without upsizing to a larger sheath. In a feasibility study of 114 patients at a single 
center undergoing trans-radial catheterization with the Glidesheath Slender, procedural 
success was 99.1%. Complications included 6 minor hematomas (no major vascular 
complications), a 4.4% rate of symptomatic radial spasm, and 1 case of radial artery 
occlusion (RAO; 0.88%). At present, the generalizability of these results to elderly patients 
undergoing primary trans-radial PCI for STEMI is not known.  
In addition to sheath-to-artery ratio, achieving patent hemostasis after trans-radial 
catheterization is among the most important factors in reducing RAO. The Terumo® TR 
Band is a radial artery compression device consisting of dual balloons within a transparent 
wrist band. As air is introduced into the dual balloons, compression of the radial artery 
occurs, achieving patent hemostasis. Advantages of the TR Band include ease of use, 
the ability to precisely titrate the amount of air (compression) within the band, and the 
ability to continuously observe the access site. 
1.6 
SAFE Site Network  
The SAFE site network includes experienced radial operators who have demonstrated 
willingness and ability to randomize subjects for clinical investigations, such as the SAFE 
PCI for Women study, with more than 1,800 women randomized at 60 US sites.  
In addition, the SAFE network of sites are experienced with workflow utilizing timely 
hospital-based NCDR data entry, including NCDR data checks and data quality 
processes, for NCRI clinical trial application.  This workflow in the SAFE PCI for Women 
study utilized programming from the NCRI to auto populate a Part-11 compliant Oracle 
database, providing historical descriptors, concomitant medications, PCI procedural 
details and MACE events for the index hospitalization without duplicative case report form 

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data entry work for the site coordinators.  This structure also seamlessly supports Part 11 
compliance in conjunction with the conduct of IDE studies. 
An upgrade of the NCDR CathPCI Registry database from v4.0 to v5.0 is currently 
scheduled for 2018. The data definitions for SAFE STEMI for Seniors will be harmonized 
with CathPCI v5.0 to permit future auto-population of index hospitalization data from the 
CathPCI Registry when interfaces become available. Until that time, all data will initially 
be entered directly into the part 11 compliant database by site personnel. This approach 
allows the study to approach non-SAFE sites in the United States as well as Canadian 
sites to participate in SAFE STEMI for Seniors.      
Finally, with the focus of SAFE PCI in STEMI for Seniors, long term follow up at and 
beyond 18 months can be efficiently incorporated by linking directly to Medicare claims 
data (for US sites) which will provide long term follow up for death, MI, stroke, 
hospitalizations and repeat revascularizations data for the study database. This method 
has been proven to provide more complete information, with fewer subjects lost to follow-
up, and at a reduced effort for sites and local site IRBs. 
 
See Appendix A, Section 15.1.  
2. 
STUDY OBJECTIVES 
The SAFE STEMI for Seniors study is designed: 
1. To examine the effectiveness of zotarolimus-eluting stents for radial Primary 
PCI in STEMI  
2. To evaluate the safety and benefit of iFR-guided complete revascularization 
vs. infarct artery only revascularization in Primary PCI of patients with multi-
vessel CAD 
3. To obtain data on the real world application of radial access for Primary PCI 
in the public health focus on an elderly population. 
4. To evaluate the safety of the Terumo Glidesheath Slender and TR Band on 
an elderly population.  
These objectives are accomplished by the evaluation of the primary and secondary 
endpoints. 

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3. 
STUDY DESIGN 
3.1 
Overview of Study 
This is a prospective, multi-center, unblinded, randomized clinical trial in primary PCI 
subjects 65 years and older. All subjects will have radial arterial access attempted as 
principal access for primary PCI. Prior to vascular access all patients will be selected as 
DES patients by the study investigator based on clinical assessment regarding potential 
for interruption or non-compliance with DAPT (Dual Anti-Platelet Therapy) over a 1-year 
period.  By protocol, DES patients will be treated with a Medtronic Resolute® Family of 
Stents.  
The intended population is subjects undergoing primary PCI for STEMI, who are 
considered eligible for a drug-eluting stent. Subjects with multivessel disease are enrolled 
and receive the Medtronic Resolute® Family of Stents to the IRA regardless of their 
randomization assignment. The design seeks to reflect the general population of seniors 
presenting with STEMI. 
DES subjects in whom multi-vessel disease is identified with absence of shock or 
prohibitive angiographic anatomy (unprotected left main disease, CTO to large 
distributions, etc.) will be randomized by site in a ratio of 1:1 to complete revascularization 
(guided by iFR using Volcano based pressure wires Verrata®, Verrata Plus® and any 
subsequent marketed Volcano pressure wire technology) or infarct artery-only 
revascularization strategies.  Only those randomized subjects that have a stable TIMI 3 
in the IRA using the protocol specified treatment will complete the randomized procedure.  
Subjects in whom IRA reperfusion with TIMI 3 flow is not achieved will be treated 
according to clinical best practice standard of care independent of randomized procedure 
assignment and will not be considered protocol violations.  These patients will be followed 
identically to all study patients 
During the index hospitalization, no study assessments that are not part of standard of 
care will be performed.  After hospital discharge, subjects will be seen for follow-up at 
their standard of care visit approximately ~ 30 days (+/- 7 days) post-procedure. Subjects 
will be contacted by the DCRI Call Center at 1 year for data needed for the primary 
analysis of the study. Additionally, Claims data follow up will be collected at 18 months 
post-procedure after the final patient is enrolled. 
Primary endpoint results will be reported after all enrolled and/or randomized subjects 
have completed a minimum of 12 months of clinical follow-up. 

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The numbers in Figure 1 are estimates, although we will not enroll more than 875total.  
The enrollment cap is controlled at 875 DES subjects regardless of the number of single-
vessel or multi-vessel CAD patients. 
Figure 1 
Study Design and Treatment Schema 
 
 
 
For additional detail regarding data sources reference 15.2 Appendix B. 
3.2 
Endpoints 
3.2.1 Endpoints for Evaluating Medtronic Resolute® Family of Stents for Primary 
PCI in STEMI 
 
3.2.1.1 Primary Endpoint 
Adjudicated 1-year infarct-related artery MACE as defined in HORIZON as cardiac death, 
index infarct P1-MI or ischemia-driven index infarct related vessel revascularization (IIVR) 

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by percutaneous or surgical methods.  P1-MI is defined according to the HORIZON 
protocol: 
(A) MI diagnosis before angiography, or, in medically treated patients.  
Patients with unstable angina (without NSTEMI):  
i. 
Any elevation of troponin or CPK-MB (or CPK) greater than the 
upper limits of normal (ULN). 
Patients with NSTEMI:  
(1) If the peak troponin or CPK-MB (or CPK) has not yet been 
reached: Recurrent chest pain lasting ≥30 minutes, or new 
electrocardiographic changes consistent with MI and the next 
troponin or CPK-MB (or CPK) level measured approximately 8 to 12 
hours after the event be elevated by at least 50% above the previous 
level.  
(2) If the elevated troponin or CPK-MB (or CPK) levels are falling or 
have returned to normal: A new elevation of troponin or CPK-MB (or 
CPK) >ULN if the troponin or CPK-MB (or CPK) level has returned 
to <ULN, or a rise by >50% above the previous nadir level if the 
troponin or CPK-MB (or CPK) level has not returned to <ULN. 
(B) MI diagnosis after PCI: 
If the elevated CPK-MB (or CPK) levels are falling or are normal:  
(1) any CPK-MB (or CPK) ≥3 × ULN within 24 hours after PCI that is 
also increased at least 50% over the most recent pre-PCI levels, or 
new, significant (≥0.04 second) Q waves in ≥2 contiguous 
electrocardiographic leads with CPK-MB (or CPK) >ULN. 
Patients with NSTEMI: If the peak CPK-MB (or CPK) has not yet been reached before 
PCI:  
(1) Recurrent chest pain ≥30 minutes, or new electrocardiographic 
changes consistent with a second MI and the next CPK-MB (or CPK) 
level measured approximately 8 to 12 hours after the event is 
elevated by at least 50% above the previous level; or new, significant 
(≥0.04 second) Q waves in ≥2 contiguous electrocardiographic 
leads. 

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(C) MI diagnosis after CABG. Any CPK-MB (or CPK) ≥10 × ULN within 24 hours 
of CABG and increased at least 50% over the most recent pre-CABG levels, or 
any CPK-MB (or CPK) ≥5 × ULN within 24 hours of CABG and increased at least 
50% over the most recent pre-CABG levels and new, significant (≥0.04 second) Q 
waves in ≥2 contiguous electrocardiographic leads. 
(D) Q-wave versus non–Q-wave MI. Once the enzymatic criteria for MI are met, a 
Q-wave MI will be diagnosed if new pathologic Q-waves develop in ≥2 
electrocardiographic contiguous leads as adjudicated by the Clinical Events 
Committee. An MI not meeting this definition will be considered a non–Q-wave MI. 
 
This endpoint has been powered to test the superiority of the primary endpoint rate 
when using the Medtronic Resolute® Family of Stents in STEMI versus HORIZON 
performance goal. 
3.2.1.2 Secondary Endpoints 
Using the Medtronic Resolute® Family of Stents in STEMI: 
Efficacy: 
• Adjudicated Death (all causes) at 30 days and 1 year. 
• Adjudicated Cardiac death at 30 days and 1 year. 
• Adjudicated Nonfatal (re-)P1-MI (see section definition in 3.2.1.1) at 30 days 
and 1 year. 
• Adjudicated Index Infarct Related-vessel (re-)P1-MI at 30 days and 1 year.  
• Adjudicated Index Infarct Related Lesion Revascularization (IILR) (ischemia 
driven) at 30 days and 1 year.  
• Adjudicated IIVR (ischemia driven) at 30 days and 1 year.  
Safety: 
• Adjudicated Academic Research Consortium (ARC) definite/probable stent 
thrombosis at post procedure, 30 days and 1 year. 
• Adjudicated ARC definite stent thrombosis at post procedure, 30 days and 
1 year  
• Adjudicated Stroke at post-procedure, 30 days and1 year. 

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3.2.1.3 Device Performance Endpoints 
• Site determination of Device success, defined as attainment of less than 
20% residual stenosis of the infarct related lesion at the time of the index 
procedure (IILR) using only the study stent. 
• Site determination of Lesion success, defined as attainment of less than 
20% residual stenosis using any percutaneous method at the time of the 
index procedure.  
• Site determination of Procedure success, defined as lesion success without 
the occurrence of in-hospital death, nonfatal MI, stroke, or emergency 
Endpoints 
for 
Evaluating 
iFR 
Guided 
iFR-Guided 
Complete 
Revascularization in STEMI  
 
3.2.2 Endpoints 
for 
Evaluating 
iFR 
Guided 
iFR-Guided 
Complete 
Revascularization in STEMI 
3.2.2.1 Primary Endpoint 
The endpoint is Adjudicated 1-year modified CvLPRIT MACE defined as all-cause 
mortality, recurrent MI, heart failure (requiring hospitalization or 12 hour ER visit) 
or ischemia-driven revascularization. The definition of P2-MI is a modified MI 
definition from CvLPRIT, and is based on the Third Universal definitions for 
myocardial infarction:  
 
Myocardial (re)infarction will require a hospital admission, or be diagnosed in 
hospital, with one or more of the following: 
 
• Type 1 – Spontaneous re-MI: Recurrent angina symptoms or new ECG 
changes occurring before PCI or < 48 hours from PCI that is compatible 
with re-MI associated  with an elevation of CK-MB, troponin, or total CK 
beyond ULN and 20% or more above the previous value. 
• Type 4a – CK-MB or total CK > 3 times the ULN within 48 hours following 
PCI, if the pre-PCI CK-MB or total CK level is higher than the ULN, there 
also needs to be: 
 
o Either the demonstration of a falling CK-MB or total CK level prior to 
the onset of the suspected event,  
o Or a subsequent peak of the cardiac biomarker of at least 20% above 
the previous value obtained prior to the onset of the suspected event. 
o With either an appropriate clinical presentation or new ischemic ECG 
changes (ST-segment depression or ST-segment elevation or 
development of new pathological Q waves /LBBB). 

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• Type 4b – Myocardial infarction associated with stent thrombosis as 
documented by angiography or at autopsy AND fulfilling the criteria of 
spontaneous MI (Type 1) 
 
This endpoint has been powered to test the superiority of the primary endpoint rate 
when using iFR guided complete revascularization versus infarct related vessel 
only revascularization in STEMI. 
3.2.2.2 Secondary Endpoints 
• Adjudicated All-cause death at post procedure, 30 days and 1 year. 
• Adjudicated Cardiac death at post procedure, 30 days and 1 year. 
• Adjudicated (re-)P2-MI (see definition in section 3.2.2)  at post procedure, 30 
days and 1 year. 
• Heart failure (requiring hospitalization or 12 hour ER visit) post procedure, 30 days 
and 1 year. 
• Ischemia-driven revascularization for index infarct related (IIVR) or any 
treated index non-infarct related vessels (INIVR). 
• Adjudicated Stroke at post-procedure, 30 Days and 1 year 
3.2.2.3 Device Performance Endpoints 
Using iFR guided revascularization with Volcano based pressure wires Verrata®, 
Verrata Plus® and any subsequent marketed Volcano pressure wire technology 
• Site reported index hospitalization bleeding and vascular complication 
defined as bleeding or vascular complication requiring intervention 
• Total procedure time 
• Total contrast used 
• Occurrence of renal insufficiency (increase from baseline creatinine of at least 
0.5 mg/dL or at least 25%) assessed at 48-72 hours post-procedure, 30 days. 
3.2.3 Endpoints to Evaluate the Terumo Slender GlideSheath and TR Band for 
radial access PCI in the elderly 
3.2.3.1 Primary Observational Endpoint 
Estimate of the incidence rate of RAO acute and at 30day stratified by whether or 
not the Terumo TR Band was employed (use of the TR Band is recommended not 
required) 

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3.2.3.2 Secondary Observational Endpoints 
• Time to Hemostasis stratified by whether the Terumo TR Band was employed 
• 
Incidence rate of cross over to from the initial access point to another stratified 
by whether or not Terumo Slender GlideSheath was employed (Use of the 
Slender GlideSheath is recommended not required)] 
• 
Incidence rate of Access success defined as successfully deploying the stent 
through the right or left radial artery stratified by whether or not Terumo 
Slender GlideSheath was employed 
• Incidence of RAO acute and at 30 day stratified by whether or not the Terumo  
TR Band was employed in combination with Glidesheath Slender 
3.2.4 Endpoint Adjudication 
The DCRI Clinical Events Committee will adjudicate the following protocol-specified 
endpoint events through 1 year as defined in the CEC Charter (see Section 12.3):  
• Death  
•  MI  
• Heart Failure  
• Revascularizations 
• Stroke 
• Stent thrombosis 
Events occurring beyond 1 year will not be adjudicated. 
 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
A total of approximately 875 STEMI patients > 65 years of age who are eligible for radial 
access will be enrolled. Approximately 550 STEMI patients with multi-vessel CAD will be 
randomized to IRA vs. complete revascularization PCI.  
4.1 
Inclusion Criteria 
To be eligible for enrollment in this trial, subjects must meet all of the following criteria: 

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1. Have the capacity to understand and sign an informed consent or have a Legally 
Authorized Representative that can understand and sign an informed consent prior 
to initial arteriotomy access.  
2. Age > 65 years of age at the time of signing the informed consent and/or 
randomization. 
3. Significant ST-elevation myocardial infarction or left bundle branch block (LBBB) 
on ECG with chest pain < 12 hours.  
4. Accessible right or left radial artery conduit for PCI. 
5. Physician intent to perform trans-radial PCI. 
6. Willing to be contacted at 1 year by the DCRI Call Center 
Study Randomization Inclusion Criteria 
To be eligible for randomization in the ‘IRA only vs. Complete Revascularization’ phase 
of this trial, subjects must meet all of the above criteria and all of the following criteria 
subsequent to arterial access: 
 
1.  Subject eligible for DES implantation. 
2. Angiographic multi-vessel CAD determined by local visual estimation.  
4.2 
Exclusion Criteria 
If a subject meets any of the following criteria, he or she may not be consented for 
enrollment in the SAFE STEMI for Seniors study: 
1. Patient that have known medical conditions that would prevent or interrupt the 
recommended post procedure DES treatment regimen.  
2. Patients that have known medical conditions that would prevent catheterization 
through the radial artery.  
3. Patients that have known medical conditions that increase patient's risk above 
standard when using IFR.  
4. Patients with a known history of Coronary Artery Bypass Grafting (CABG). 
5. Has had a cerebrovascular accident or transient ischemic neurological attack 
within the past 6 months. 
6. Known history of substance abuse (alcohol, cocaine, heroin, etc.) that may cause 
noncompliance with the protocol 
7. Any condition associated with a life expectancy of less than 1 year. 

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8. Participation in another clinical study using an investigational agent or device 
within the past 3 months. 
Study Randomization Exclusion Criteria 
If a subject who has been consented into the SAFE STEMI study develops or is found to 
have any of the following, they will not be eligible for randomization to an iFR guided 
complete revascularization vs. IRA-only primary PCI and will be excluded from the study. 
1. Shock requiring pressors or mechanical circulatory assist support (IABP, 
Impella, ECMO, etc.)Significant chronic renal disease (eGFR < 30) and/or on 
dialysis 
2. Other angiographic exclusions: 
• Single vessel CAD 
• Unprotected left main coronary artery disease 
• One or more major coronary distributions with CTO or indeterminate IRA 
3. Clinical circumstances, which, in the judgment of the operator, preclude 
randomization. 
4.3 
Randomization Completion 
To be eligible to complete randomized procedures, stable TIMI 3 must be established in 
the IRA using the protocol specified treatment.   
Subjects in whom IRA reperfusion with TIMI-3 flow is not achieved will be treated 
according to clinical best practice standard of care independent of randomized procedure 
assignment and will not be considered protocol violations.  These patients will be followed 
identically to all study patients. 
4.4 
Withdrawal of Patients 
Patients may voluntarily withdraw for any reason without penalty or loss of benefits to 
which they are entitled. Patients may be withdrawn because of the appearance of a new 
health condition suspected to require care, refusal to continue treatment, or at the 
Investigator’s discretion if it is in the patient’s best interest according to the Investigator’s 
clinical judgment.  
If a patient withdraws from the study at any time either at his or her request or at the 
Investigator’s discretion, the reason(s) for withdrawal must be recorded on the relevant 
page of the patient’s electronic Case Report Form (eCRF). Patients who withdraw from 
the study prematurely should undergo all end-of-study assessments, if possible. Study 
site personnel should make every effort to prevent losing patients to follow-up.  

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Any adverse experiences that are ongoing at the time of discontinuation / withdrawal 
should be reported and followed up in accordance with the safety requirements. Any 
adverse experiences that are ongoing at the time of discontinuation/withdrawal should be 
reported and followed up in accordance with the safety requirements outlined in Section 
7.3. 
 
5. 
STUDY PROCEDURES 
This study will be conducted in accordance with current U.S. Food and Drug 
Administration (FDA) regulations and guidelines, International Council on Harmonization 
(ICH) guidelines, and all other applicable laws and regulations. 
Medical questions regarding subject eligibility, procedures, or patient care should be 
directed to the study Principal Investigator who can be reached as follows:  
Dr. David F. Kong at 919-668-8946 during U.S. business hours, or 919-684-8111 after 
U.S. business hours. 
5.1 
Screening Procedures 
Potentially eligible subjects will be screened upon presentation with ischemic symptoms 
of acute myocardial infarction of duration < 12 hours.  
After a diagnosis of STEMI is made and primary radial PCI is planned, the patient will be 
screened to determine eligibility for SAFE STEMI for Seniors. Study personnel will assess 
each subject against study inclusion and exclusion criterion, and the investigator will 
determine the subject’s eligibility for participation.  
5.2 
Informed Consent 
Each site will submit the study protocol, ICF, and other study documents to their ethics 
committee (EC)/institutional review board (IRB) for approval. A copy of the signed and 
dated EC/IRB approval for each enrolling center will be stored at the Data Coordinating 
Center. Any amendments to the protocol, other than minor administrative changes, must 
be approved by the site’s EC/IRB before the changes are implemented at the site. 
The informed consent process will be documented in the subject’s medical record or 
comparable source document. 
Consent will be obtained from the subject or their legally authorized representative prior 
to arterial access and, if the subject is consenting, prior to the administration of any 
medications that might affect patient cognition. 

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5.3 
Enrollment  
Once a subject has met all inclusion / exclusion criteria and provided informed consent, 
the subject will be considered to be enrolled in the study.  Operators are encouraged to 
appropriately identify candidates for DES, consistent with study objectives.  
Subjects who are DES eligible and have unequivocal 1-vessel disease by angiography 
will receive their stent via IRA. 
5.3.1 Stent Deployment 
In a manner comparable to Horizons-AMI[11] and current clinical practice, direct stenting 
will be permitted in SAFE-PCI in STEMI for Seniors at the discretion of the physician. Pre-
dilation is encouraged if needed to demonstrate eligibility for DES implantation.    
5.4 
Randomization for Subjects with Multi-vessel CAD Receiving a DES  
Subjects with investigator determined angiographic stenosis with a > 50% diameter 
reduction in a non-infarct artery will be randomized prior to the primary PCI procedure  
once clinical and angiographic criteria are met (excluding shock, left main, major 
distribution CTOs, etc.) Subjects will be randomized by site in a ratio of 1:1 to an iFR-
guided complete revascularization strategy or an IRA-only strategy.   
The investigator may determine that some subjects need a staged approach for 
revascularization. As long as the additional procedure(s) are planned and performed 
within the index hospitalization, they are considered part of the index intervention. Use of 
the Medtronic Resolute® Family of Stents is strongly encouraged for all index 
interventions in the complete revascularization arm, regardless of staging. 
5.4.1 iFR Guided Complete Revascularization 
In the iFR guided arm, all stenoses with a > 50% diameter reduction via angiographic 
determination and reference vessel diameter ≥2.25 mm in the non-infarct artery will be 
evaluated with iFR.  
Stenoses with iFR measurement < 0.90 will be re-vascularized using a stent from the 
Medtronic Resolute® Family of Stents.  
Stenoses with iFR measurement >= 0.90 will be managed medically. 
The iFR cut point of 0.9 is based upon the recognition that an iFR cut-point of 0.89 to 0.90 
matches best with an FFR ischemic cut-point of 0.80, with a c-index of 0.87.[32-34]  Also, 
similarly to what has been observed with FFR, an iFR value of >0.90 increases the 
negative predictive value of iFR to 95% to exclude ischemic stenoses (FFR ≤ 0.75). 

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In the event that the iFR measurement is not evaluable (due to ECG artifacts, pressure 
artifacts, or transducer drift), revascularization will be performed if the investigator-
determined angiographic stenosis is >= 70% diameter reduction. Medical management 
will be performed if the angiographic stenosis is < 70% reduction.  
The recommended schema for obtaining iFR is provided below. The dose of intracoronary 
nitroglycerin is left to the discretion of the investigator; 50-300 mcg is the recommended 
range. If clinical circumstances dictate, the pullback to verify normalization may be 
performed after PCI of the vessel is complete. 

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Figure 2 
iFR Guided Complete Revascularization Procedure Flow 
. 
 

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5.5 
Post-procedure Follow-up 
Subjects will be followed clinically with device related serious adverse events collected 
per Safety Section 7.0. Subjects will be seen for their standard post-procedure visit (30 
days post-procedure). Additional follow up will be completed by the DCRI Call Center for 
a minimum of 12 months. Patients will be asked to report current medications, 
hospitalizations and general health assessments.   
5.6 
Use of Medicare Claims Data  
For US patients, Medicare claims data will be obtained and study patients identified. 
Relevant data will be collected for subjects at 18 months post-procedure after the final 
patient is enrolled. 
5.7 
Schedule of Events 
The schedule of study assessments and procedures is provided in Table 1: 
 

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Table 1 
Schedule of Assessments 
 
Screening and 
Pre-
randomization 
Enrollment and 
Randomization/ 
Implantation 
Post-procedure 
30 (± 7) Days 
1 Year DCRI Call 
Center (± 30 
Days) 
18 Month Last 
Patient Post-
Procedure CMS 
(± 60 Days) 
Follow-up  
Inclusion/exclusion criteria - 
enrollment 
X 
 
 
 
 
 
Informed consent and Patient 
Contact Form details 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Physical assessment, vital 
signs (standard of care) 
Xa, b 
 
 
X 
 
 
Concomitant medications 
Xa 
 
 
X 
X 
 
Diagnostic angiogram 
X 
 
 
 
 
 
Assess eligibility for 
randomization to IRA only vs. 
complete revascularization  
X 
X 
 
 
 
 
Implant Stent in IRA 
 
X 
 
 
 
 
iFR assessment 
 
X 
 
 
 
 
Full revascularization, depending 
on randomization arm 
 
X 
 
 
 
 
Collection of device 
performance measures  
 
Xc 
Xc 
Xc 
 
 
Collection of investigational 
device related serious 
adverse events 
 
Xd 
Xd 
Xd 
 
 
Event data collection for 
instances of specified 
cardiovascular endpoint 
events 
 
Xe 
Xe 
Xe 
Xe 
Xe 
a Within 7 days or immediately before randomization. 
b If not done within the previous 7 days. 
c OIfstandard of care is to do the Reverse Bardeau by pulse oximetry tests, the test performed before discharge and at 
30 days will be collected 
d All serious adverse events related to the Medtronic Resolute® Family of Stents, Volcano based pressure wires 
Verrata®, Verrata Plus® and any subsequent marketed Volcano pressure wire technology. Specified cardiovascular 
endpoint events data collection will be reported on the eCRF endpoint pages only. 
e See section 3.2  

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6. 
CONCOMITANT MEDICATIONS/THERAPIES 
6.1 
Pre-PCI Medications 
6.1.1 Aspirin 
Preloading with at least 81 mg aspirin is mandatory. For subjects receiving chronic aspirin 
therapy, the loading dose of between 81 and 325 mg aspirin, according to regional 
standard of care, should be given.  
6.1.2 Platelet Adenosine Diphosphate Receptor Antagonists 
Procedural antiplatelet treatment with an adenosine diphosphate (ADP) receptor 
antagonist or a glycoprotein IIb/IIIa receptor antagonist is mandatory.  
The choice of either clopidogrel, prasugrel, cangrelor, ticagrelor, or other approved 
thienopyridines, or the choice of GPIIb/IIIa agents, is left to the discretion of the 
investigator.  
6.1.3 Other Medications 
The use of other medications (e.g., beta-blockers, angiotensin-converting enzyme 
inhibitors) before PCI is left to the discretion of the treating physicians. Best medical 
practice is recommended. 
As additionally noted in the ACC/NCDR PCI Guidelines, lipid management is strongly 
recommended. 
6.2 
During PCI Medications 
During the procedure, subjects will receive appropriate anticoagulation medications 
according to standard hospital practice. The use of any approved anticoagulant agent at 
the discretion of the investigator is acceptable. 
The use of glycoprotein GPIIb/IIIa receptor inhibitors is allowed at the discretion of the 
investigator. 
6.3 
Post-PCI Medications 
It is very important that the subject is compliant with the post procedural antiplatelet 
recommendations. Premature discontinuation of prescribed antiplatelet medications 
could result in a higher risk of thrombosis, MI or death. 

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DAPT  should not be discontinued within the first year after DES implantation, according 
to recommended standard of care, unless absolutely necessary due to major bleeding, 
major trauma, or major surgery (e.g., intracranial surgery) necessitating discontinuation 
of antiplatelet therapy. 
6.3.1 Aspirin 
Dosing with aspirin will be at least 81 mg daily after PCI while in the hospital and after 
discharge, according to regional standard of care. Dosing should then continue with at 
least 81 mg per day indefinitely. Daily aspirin should be given through the 1 year follow-
up. Aspirin should not be discontinued for CABG or other reasons unless absolutely 
necessary. 
6.3.2 Platelet Adenosine Diphosphate Receptor Antagonists 
All subjects must receive chronic daily DAPT according to regional standard of care, with 
the choice of agent left to the discretion of the investigator. 
DAPT should not be discontinued within the first year after DES implantation, according 
to recommended standard of care, unless absolutely necessary due to major bleeding, 
major trauma, or major surgery (e.g., intracranial surgery) necessitating discontinuation 
of antiplatelet therapy. Major surgeries can safely be performed while the subject is on 
DAPT. If a subject on DAPT requires surgery, strong consideration should be given to 
performing the surgery without antiplatelet agent discontinuation. 
Investigators may continue DAPT for longer than 12 months at their discretion, as 
suggested by current ACC/AHA clinical guidelines [35]. 

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7. 
SUBJECT SAFETY AND ADVERSE EVENTS 
The SAFE-STEMI for Seniors study will be overseen by DCRI Safety Surveillance who 
will provide real time site reported Medtronic Resolute® Family of Stents, Volcano based 
pressure wires Verrata®, Verrata Plus® and any subsequent marketed Volcano pressure 
wire technology related serious adverse event collection, evaluation, and expedited 
regulatory reporting from informed consent to the 30 day visit. A DCRI Safety Medical 
Monitor will be responsible for evaluating site reported UADEs to confirm protocol-specific 
serious reporting criteria, causality assessment, and expectedness compared to product 
labels. Details of this process can be found in the study-specific Safety Management Plan. 
7.1 
Definitions 
7.1.1 Adverse Event 
An AE is defined as any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users, or 
other persons, related to the Medtronic Resolute® Family of Stents, Volcano based 
pressure wires Verrata®, Verrata Plus® and any subsequent marketed Volcano pressure 
wire technology.  
Any pre-existing condition known to the investigator will not, in general, be reportable as 
an AE, unless the investigator believes that the participation of the subject in this study 
contributed to the progression of that condition. 
When an AE has, by its nature, a prolonged course, the event will be considered a single 
event and not multiple events; for example, if a subject develops end-stage renal failure 
requiring regular dialysis, the event is considered end-stage renal failure, not multiple 
single renal events. 
7.1.2 Serious Adverse Event 
Any AE that:  
• Led to death 
• Led to a serious deterioration in the health of the subject that resulted in 
o Life-threatening illness or injury or 
o Permanent impairment of a body structure or a body function or 
o In-patient hospitalization or prolongation of existing hospitalization.  
o Medical or surgical intervention to prevent permanent impairment of a 
body structure or a body function 

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o Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect  
o The following hospitalizations are not considered AEs/SAEs: 
 Visit to the emergency room or other hospital department for less 
than 24 hours that does not result in admission (unless considered 
"important medical event" or “event life threatening”). 
 Elective surgery, planned before signing consent. 
 Admissions per protocol for a planned medical/surgical procedure. 
 Routine health assessment requiring admission for baseline/trending 
of health status (e.g., routine colonoscopy). 
 Medical/surgical admission for purpose other than remedying ill 
health state and planned before entry into the study. Appropriate 
documentation is required in these cases. 
 Admission encountered for another life circumstance that carries no 
bearing on health status and requires no medical/surgical 
intervention (e.g., lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative). 
7.1.3 Anticipated Adverse Device Effects 
A serious adverse device effect (ADE) that by its nature, incidence, severity or outcome 
has been previously identified as noted in the device’s IFU/IB.  
7.1.4 Unanticipated Adverse Device Effects 
Per United States Code of Federal Regulations (CFR) Title 21, Part 812.3, an 
unanticipated ADE (UADE) is 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. 
Unanticipated ADEs will include events meeting either A or B as stated below: 
A. Events meeting ALL of the following criteria: 
• Not included in the list of anticipated events (see IFU) 
• Possibly, probably, or definitely related to the Medtronic Resolute® Family 
of Stents, Volcano based pressure wires Verrata®, Verrata Plus® and any 
subsequent marketed Volcano pressure wire technology 

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• Serious (meets any of the following criteria): 
o Life-threatening illness or injury 
o Results in permanent impairment of a body structure or a body 
structure 
o Necessitates medical or surgical intervention to prevent permanent 
impairment of a body function or a body structure 
o Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect 
o Led to death 
 
(Permanent means irreversible impairment or damage to a body 
structure or function, excluding trivial impairment or damage.) 
B. Any other unanticipated serious problem associated with the Medtronic Resolute® 
Family of Stents, Volcano based pressure wires Verrata®, Verrata Plus® and any 
subsequent marketed Volcano pressure wire technology that relates to the rights, 
safety, or welfare of subjects. 
7.1.5 Device Failure and Device Malfunction 
A device has failed or malfunctioned if it is used in accordance with the IFU but does not 
perform according to the IFU and negatively impacts the treatment. Device failures 
include: 
• Inability to position at desired location 
• Inability to activate/deploy device 
• Incorrect activation/deployment of device 
Because all devices used in this study are marketed and being used from hospital supply, 
any device failures or malfunctions will be reported to the device manufacturer and FDA 
per local policy. 
7.1.6 User Error 
A device is used by the investigator in a manner that is an act, or omission of an act, that 
results in a different medical device response than intended by the manufacturer or 
expected by the user. The term "user error" refers to an error made by the person using 
the device, for example an error of use of the device outside of the IFU/IB.  If user error 
leads to a UADE, it will be reported and captured as a UADE.  

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7.2 
Assessment  
7.2.1 Causality  
Table 2 
Causality  
RELATIONSHIP  
CAUSALITY 
DEFINITION 
REPORTING 
Not 
related to 
investigational 
device  
Unrelated 
An event for which an 
alternative 
explanation 
(e.g., concomitant drug or 
concomitant 
disease) 
is 
conclusively 
identified 
and/or the relationship in 
time suggests that a causal 
relationship 
is 
highly 
unlikely 
No AE/SAEs that are 
not 
related 
to 
the 
investigational 
device 
will be reported. 
 
Specified 
cardiovascular endpoint 
events collection will be 
reported on the eCRF 
endpoint pages only 
 

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Related 
to 
investigational 
device  
Possible   
Probable  
Definite 
An event that might be due 
to the use of the study 
device. 
An 
alternative 
explanation 
(e.g., 
concomitant 
drug 
or 
concomitant 
disease) 
is 
inconclusive. 
The 
relationship 
in 
time 
is 
reasonable; therefore the 
causal relationship cannot 
be excluded. 
All SAEs related to the 
investigational 
device, 
except events listed as 
protocol-specific 
endpoints 
occurring 
from informed consent 
to the 30 day visit will be 
reported in the eCRF as 
soon as possible.  
Specified 
cardiovascular endpoint 
events collection will be 
reported on the eCRF 
endpoint pages only.  
 
 
7.3 
Reporting 
If required, the site investigator or their delegate is responsible for notifying the site 
director of a reported SAE within the expected time frame. The investigator or qualified 
designee will enter the required information about the Medtronic Resolute® Family of 
Stents, Volcano based pressure wires Verrata®, Verrata Plus® and any subsequent 
marketed Volcano pressure wire technologytechnology related SAE into the SAE page of 
the eCRF, which will be distributed to the appropriate manufacturer contact.  
It is understood that complete information about a potential Medtronic Resolute® Family 
of Stents, Volcano based pressure wires Verrata®, Verrata Plus® and any subsequent 
marketed Volcano pressure wire technology related SAEs potential UADE may not be 
known at the time the initial report is submitted. The investigator must assess the 
relationship of the event to the investigational device (including the rationale for the 
assessment) and should make every attempt to obtain as much information as possible 
concerning the event. Additional information pertaining to a device related SAE should be 
reported in the eCRF as it becomes available.  
Protocol-specified endpoints (Section 3.2), which include anticipated Medtronic 
Resolute® Family of Stents, Volcano based pressure wires Verrata®, Verrata Plus® and 
any subsequent marketed Volcano pressure wire technology related serious adverse 
events, will be reported on the eCRF endpoint page. 

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Safety data, which includes events reported on the Medtronic Resolute® Family of Stents, 
Volcano based pressure wires Verrata®, Verrata Plus® and any subsequent marketed 
Volcano pressure wire technology related serious adverse events and protocol specified 
endpoint page, will be periodically reviewed by the Data Safety and Monitoring Committee 
to monitor subjects’ safety from informed consent to the 30 day visit. Study leadership will 
be monitoring any aggregate events that are occurring at an unexpected rate for this study 
population. Risks will be continually assessed to determine if a protocol or ICF revision is 
warranted.   
Any safety reporting on devices other than Medtronic Resolute® Family of Stents, Volcano 
based pressure wires Verrata®, Verrata Plus® and any subsequent marketed Volcano 
pressure wire technology will be the responsibility of the site per local site policy. 
 
7.3.1 Time Frame for Reporting 
7.3.1.1 Device Related Serious Adverse Events 
Except events listed as protocol-specific endpoints (Section 3.2), Medtronic Resolute® 
Family of Stents, Volcano based pressure wires Verrata®, Verrata Plus® and any 
subsequent marketed Volcano pressure wire technology device-related SAEs that occur 
after informed consent through the first 30 day visit will be reported by the site on the 
device related SAEs page of the eCRF as soon as possible.   
If the eCRF reporting capability is not available for more than 24 hours, the Medtronic 
Resolute® Family of Stents, Volcano based pressure wires Verrata®, Verrata Plus® and 
any subsequent marketed Volcano pressure wire technology device related SAE should 
be reported on the paper back-up SAE form and faxed or e-mailed to DCRI Safety 
Surveillance. If eCRF, e-mail, and FAX are not available, the event should be reported by 
telephone (see contact information below). If the report is initially given by e-mail, FAX, 
or telephone, then the required information about the SAE will be entered into the 
appropriate module of the eCRF immediately after the eCRF system is available by the 
site. 
SAE FACSIMILE TRANSMISSION: 
Duke Clinical Research Institute (DCRI) Safety Surveillance 
Fax: +1-919-668-7138; toll-free within the U.S.: 1-866-668-7138 
SAE e-mail: DCRISafetySurveillance@dm.duke.edu  
SAE telephone: +1-919-668-8624 or toll-free within U.S.: 1-866-668-7799 

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7.4 
Device Failures, Device Malfunctions, and User Error 
In the case of a device failure or malfunction related to the investigation, the manufacturer 
should be notified and the device returned to the manufacturing company, if possible. 
Since these are approved devices, device failures, malfunctions, and user errors will be 
reported to the appropriate company and FDA per local site policy.  
7.5 
 Regulatory Reporting of Unanticipated Adverse Device Effects 
There are situations that may necessitate rapid communication of the occurrence of 
events to the regulatory authorities. The DCRI Safety Medical Monitor will determine if a 
device-related event meets “unanticipated” criteria (i.e., is not identified in the IFU/IB or 
literature) for the Medtronic Resolute® Family of Stents, Volcano based pressure wires 
Verrata®, Verrata Plus® and any subsequent marketed Volcano pressure wire technology. 
Unanticipated ADEs will be reported by the sponsor to the FDA, all reviewing IRBs/ECs, 
and all participating investigators within 10 working days of when the sponsor determines 
that the UADE meets the criteria for reporting (per FDA guidance) or within accordance 
of country regulations.  
Investigators are responsible for: 
• Reporting investigation medical device UADEs to their reviewing IRB/EC within 10 
working days of notification from sponsor. 
• Any regulatory, IRB or manufacturer reporting requirements for the other devices 
used in this study 
The sponsor will notify the FDA and site investigators of any adverse events that are 
occurring at an unexpected rate and which meets the criteria for a UADE. 

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8. 
STATISTICAL ANALYSIS AND DETERMINATION OF SAMPLE SIZE 
This is a prospective, multi-center, randomized clinical trial designed to assess the safety 
and effectiveness of the Medtronic Resolute® Family of Stents in elderly subjects with 
STEMI undergoing primary PCI, and the efficacy of an iFR-guided complete 
revascularization strategy for complete revascularization in elderly STEMI subjects. The 
full details of the statistical design and analysis will be included in a Statistical Analysis 
Plan (SAP) which will be finalized prior to database lock. 
8.1 
Medtronic Resolute® Family of Stents for STEMI 
For the primary Medtronic Resolute® Family of Stents efficacy endpoint, this study uses 
a performance goal derived from historical controls. Event rates from the Bern-Rotterdam 
registry, COMPARE-AMI, Diaz de La Lera, EXAMINATION, HAAMU-STEMT, 
HORIZONS-AMI, KOMER, MISSION, PASEO, PASSION, PROSIT, Resolute AC, 
SESAMI, STRATEGY, TYPHOON, and ZEST-AMI were pooled to derive MACE 
estimates for BMS, Cypher, Taxus, Resolute Integrity, and Xience platforms (Table). 
To adjust these rates for an elderly population, 1-year major adverse cardiac and 
cerebrovascular events (MACCE) rates for STEMI patients treated with DES from 
HORIZONS study are shown in Table 3 below: 
 
 
Table 3 
1-Year Major Adverse Cardiac and Cerebrovascular Events Rates for 
STEMI Patients Treated with DES from HORIZONS Study 
Endpoint 
Group 
DES 
BMS 
MACCE 
Overall 
8.0% 
7.9% 
 
Age >65 
13.4% 
17.7% 
 
Age <65 
5.0% 
2.8% 
 
 
 
 
Death or ReMI 
Overall 
6.7% 
6.9% 

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Endpoint 
Group 
DES 
BMS 
 
Age >65 
8.5% 
11.4% 
 
Age <65 
5.7% 
4.6% 
 
 
 
 
 
Pooled 1-year MACE rates across available DES and BMS platforms from published 
studies and the Bern-Rotterdam Registry are included in  
 
Table 4 below: 
 
 
Table 4 
Pooled 1-Year MACE Rates Across Available DES and BMS Platforms 
from Published Studies and the Bern-Rotterdam Registry 
Stent 
Events 
Sample 
Event Rate 
Binomial 95% CI 
BMS  
238 
2788 
8.54 
(7.53,  9.65) 
 
 
 
 
 
Cypher  
146 
2179 
6.70 
(5.70,  7.85) 
Endeavor  
24 
311 
7.72 
(5.09,11.44) 
Resolute* 
17 
284 
5.99 
(3.52,  9.41) 
Taxus 
452 
4679 
9.66 
(8.84,10.55) 
Xience  
204 
2120 
9.62 
(8.42,10.98) 

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Taking an upper bound for pooled DES of 9.39%, based on Horizons AMI study[11] we 
estimated a relative risk of 1.67 for MACE in patients at least 65 years old (assuming the 
age distribution in previous DES trials is similar to Horizons). The RR of 1.67 was 
estimated from HORIZONS AMI study which among subjects older than 65 years had a 
1-yr adjudicated MACE rate of 13.4% (109/814). The study had an overall 8% MACE rate 
at 1-year, thus 1.67 was estimated at 0.134/0.08). Thus we set the performance goal for 
the intended population at 15.68%. 
If we assume a Medtronic Resolute®  Family of Stents MACE rate of 6% in an unselected 
population, the expected Medtronic Resolute® Family of Stents rate in a population age 
≥65 might be 10%, if the same relative risk applies to Integrity as applies to other DES. 
Thus for the hypothesis: 
H0: 𝑃𝑃1 ≥0.15 𝑣𝑣𝑣𝑣.    H𝑎𝑎:  𝑃𝑃1 < 0.15 
                                 
Where 𝑃𝑃1 is the proportion of MACE in the Medtronic Resolute® Family of Stents  arm. 
The null hypothesis (H0) will be rejected when the upper two-sided 95% confidence 
interval (CI) excludes 0.15. 
 
Based on these assumptions, the study has about 85% power to meet the performance 
goal with upper two-sided 95% confidence using the exact binomial method[36] would be 
achieved with a total sample size of 429 analyzable DES patients (Figure 3).  Assuming 
an attrition rate of 10%, this will lead to an enrollment goal of 477 DES patients overall. 
  
All DES 
843 
9573 
8.81 
(8.25,  9.39) 

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Figure 3 
Power to exclude the upper 95% confidence interval for the Medtronic 
Resolute® Family of Stents Performance Goal of 15% Using the Exact 
Binominal Method*. 
 
*Sample Sizes were generated using SAS Version 9.4 TS Level 12 procedure PROC POWER with using the onesamplefreq 
statement with the option test=exact  
If site operators designate 875 seniors enrolled into SAFE-PCI for STEMI as DES 
candidates, we expect about 37% (n=325) to have single-vessel disease, and from the 
multi-vessel disease subjects (n=550), 275 would be randomized to IRA-only 
revascularization.  Thus, the available cohort for this indication could reach a total of 600 
Medtronic Resolute® Family of Stents DES exposures, all treated with IRA-only approach 
as used in the HORIZONS study.  
 
8.2 
IFR-Guided Multivessel PCI 
The study is also powered for iFR-guided multi-vessel PCI with one-year modified 
CvLPRIT MACE endpoint, by assuming 1 year modified CvLPRIT MACE rate of 22% in 
the IRA only arm [19] and 12% (roughly 45% reduction) in the complete revascularization 
429
300
350
400
450
500
550
600
Total Sample Size
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Power
0.85
Exact Test for Binomial Proportion
0.11
0.1
0.09
Proportion

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arm, yielding the multi-vessel cohort (n=550 pts) which will provide at least 85% power to 
detect 45% reduction in 1 year modified CvLPRIT MACE and accounts for 10% lost-to-
follow up.   
The difference in the Kaplan-Meier(KM) estimate at 1 year [37] will be utilized as the 
primary analytic tool for assessing outcome differences between the 2 randomized arms.  
The difference and the 95% CI of the difference of the KM estimates between the IRA 
only and the complete revascularization arms of difference at 1 year will be calculated 
using the product limit method and the greenwood variance.  Thus, the following two-
sided alternative hypothesis will be tested using the intent-to-treat (ITT) cohort: 
H0: 𝑆𝑆(1𝑌𝑌𝐼𝐼𝐼𝐼𝐼𝐼 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜) −𝑆𝑆(1𝑌𝑌𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅) = 0 
 𝑣𝑣𝑣𝑣.     H𝐴𝐴 𝑆𝑆(1𝑌𝑌𝐼𝐼𝐼𝐼𝐼𝐼 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜) −𝑆𝑆(1𝑌𝑌𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅) ≠0 
For the time-to-event (MACE) analysis above will be performed according to the 
principle of "intention-to-treat", subjects who did not experience an event, their efficacy 
measure will be censored on the last visit (or last contact date). For those with an event, 
their efficacy measure (in days) will be measured as the time from randomization to the 
first occurrence of any of the CvLPRIT MACE components.  
We will examine the data for consistency and robustness of the findings across clinically 
important subgroups such as sex and geographical regions. 
If this performance goal is met, and if the iFR complete revascularization endpoint was 
also met, additional labeling for Multi-vessel STEMI revascularization would be 
supported. 
Figure 4 is a subgroup analysis from the CvLPRIT study [19] (presented at ESC 2014) 
which suggests that the relative risk reduction of complete revascularization in subjects 
65 years of age and older is 0.37 (95% CI; 0.18, 0.79). 
. 

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Figure 4 
Subgroup Analysis from the CvLPRIT study 
 
If there is no censoring and all events occur at one-time point, Greenwood’s estimate is 
the same as the SD for a proportion based on the binomial distribution.  Therefore, to 
estimate the sample size, a conservative method would be to determine the sample size 
for the difference between two proportions and adjusting the sample size up for LTFU.  
Figure 5 shows the power curves for the multi-vessel cohort using the Farrington Manning 
method for the difference between two rates.  The power curves show that iFR-guided 
multi-vessel PCI with one-year CvLPRIT MACE endpoint, by assuming 1 year MACE rate 
of 22% in the IRA only arm[19] and 12% (roughly 45% reduction) in the complete 
revascularization arm, the power is 85% for 500 patients.  Assuming a 10% LTFU, the 
total sample size is 550 patients.  The sample size calculation was also confirmed using 
simulations.  The details about the simulations will be in the statistical analysis plan.  
 

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Figure 5 
Power Curves for Multivessel Cohort: Farrington Manning Score Test 
for Two Proportions. 
 
*Sample Sizes were generated using SAS Version 9.4 TS Level 12 procedure PROC POWER with using the twosamplefreq 
statement with the option test=FM  
 
In addition, Cox proportional hazards model[37] will be utilized as to determine the hazard 
ratio (HR) and the 95% CI of the complete revascularization to IRA only treatment arms 
for descriptive purposes only.   
 
8.3 
Performance of Terumo TR Band 
The incidence rate of RAO acute and at 30day stratified by whether or not the Terumo 
TR Band was employed is an observational endpoint.  No formal hypothesis testing will 
be performed.  Therefore, there is no need to control for Type I or Type II error for this 
endpoint. 
500
300
400
500
600
700
Total Sample Size
0.55
0.60
0.65
0.70
0.75
0.80
0.85
0.90
0.95
1.00
Power
0.85
Farrington-Manning Score Test for Two Proportions
0.12 0.23
0.12 0.22
0.12 0.21
Proportions

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8.4 
Secondary and Device Performance Endpoints 
All secondary endpoints and device performance endpoints will be presently descriptively 
with no formal hypothesis testing. 
8.5 
Controlling Bias 
8.5.1 Type I Error 
The cohort that will be used to evaluate the 1-Year MACE endpoint for Medtronic 
Resolute® Family of Stents includes the single vessel patients  and the multi-vessel 
patients randomized to index infarct vessel only revascularization (IIVR).  The cohort that 
will be used to evaluate the IFR endpoint of 1-Year CvLprit MACE includes the multi-
vessel patients than have been randomized to IIVR or complete revascularization. Even 
though these two analyses share the IIVR patients, for the one year MACE endpoint, the 
IIVR patients are pooled together with the single vessel patients and the result will be 
compared a performance goal; whereas the IFR endpoint of 1-Year CvLprit MACE is 
looking at the different between the IIVR and the complete revascularization patients.  
Success in the 1 Year MACE endpoint would not predict success in the 1 Year Cvlprit 
MACE endpoint.  Therefore, the two endpoints are considered to be statistically 
independent and there is no need for any adjustment in type I error. 
All secondary endpoint analyses will be reported after all subjects have completed a 
minimum of 12 months of follow-up. 
8.5.2 Blinding and Randomization 
For both primary endpoints, given the nature of the treatment and the trial design, neither 
patient nor sites can be blinded.  However, the primary and secondary endpoints will be 
adjudicated by an independent Clinical Events Committee (see section12.3) and the 
safety will be evaluated on an ongoing basis by an independent Data Safety Monitoring 
Board (see section 12.2) to reduce bias in endpoint assessment. 
 
8.5.3 Poolability across sites 
The site poolability will be assessed by testing whether there is a site by treatment 
interaction effect for both primary endpoints using the methods described in the statistical 
analysis plan.  If there is a strong (p <0.05) interaction effect, the data will be investigated 
as to the source of the interaction effect and the analysis will be adjusted as described in 
the statistical analysis plan.  

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9. 
ESTIMATED DURATION OF THE STUDY 
It is estimated that the study involvement for all sites will extend approximately four 
months after the last entered subject’s procedure.  
US Medicare fee-for-service subjects will have their data reviewed at 18 months post-
procedure after the final patient is enrolled using the CMS database. Data will be analyzed 
to check if any endpoints have occurred. At Year 1, since data will be obtained both from 
the call center and CMS, a comparison of the quality and completeness of each method 
can be performed. 
10. 
STUDY ETHICAL CONSIDERATIONS 
10.1 
Confidentiality of Patients 
Patient confidentiality will be maintained throughout the clinical study in a way that 
ensures the information can always be tracked back to the source data. For this purpose, 
a unique patient identification code will be used that allows identification of all data 
reported for each study patient. 
Patient information collected in this study will comply with the standards for protection of 
privacy of individually identifiable health information as promulgated in the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). All records will be kept 
confidential, and the patient’s name will not be released at any time.  Patient records will 
not be released to anyone other than sponsor or its designees, and responsible regulatory 
authorities, when requested.  For endpoint ascertainment, the patient has agreed that 
their social security number and/or Medicare identifier will be used for endpoint 
ascertainment using the CMS and/or NDI database.  In all cases, caution will be exercised 
to assure the data are treated confidentially and that the patient’s privacy is guaranteed.   
11. 
ADMINISTRATIVE PROCEDURES 
11.1 
DCRI Coordinating Center Responsibilities 
11.1.1 Investigator Training 
All Investigators and their study personnel will receive training regarding the study 
procedures. This training will take place prior to enrollment of the first patient at each 
study center.  

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11.1.2 Study Monitoring 
The study will be monitored by sponsor or its designee according to the Clinical Monitoring 
Plan (CMP) will be developed using a risk-based monitoring approach.  This will focus on 
the following quality guiding principles for this trial. 
 
 
• For cause site visits will be scheduled based on the sites’ risk-based performance 
metrics that are based on the guiding principles for the patient data collected through 
30 days.  The key risk indicators and performance metrics will be provided in the CMP. 
 
 
Questions around eCRF completion or study procedures should be directed to the site’s 
Clinical Research Associate (CRA).   

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11.2 
Investigator’s Responsibilities 
11.2.1 Reporting and Recording of Study Data 
It is the Investigator’s responsibility to ensure the accuracy, completeness, and timeliness 
of the data reported on the patient’s eCRF. Source documentation supporting the eCRF 
data should indicate the patient’s participation in the study and should document the dates 
and details of study procedures and patient’s clinical status from informed consent though 
the 1 year DCRI call center contact. 
11.2.2 Source Documentation 
The Investigator must maintain adequate and accurate source documents upon which 
case reports for each patient are based. They are to be separate and distinct from eCRFs. 
These records should include detailed notes on: 
− The medical history prior to participation in the study 
− The basic identifying information, such as demographics, that link the patient’s 
source documents with the eCRF 
− The results of all diagnostic tests performed, diagnoses made, therapy provided, 
and any other data on the condition of the patient 
− The patient’s exposure to study treatment 
− The patient’s exposure to any concomitant therapy (including date and quantity 
dispensed) 
− All relevant observations and data on the condition of the patient throughout the 
study 
− The oral and written communication with the patient regarding the study treatment 
(including the risks and benefits of the study) 
− The date of informed consent must be recorded in the source documentation. 
11.2.3 Records Retention 
The Investigator must inform, and receive approval from, the Sponsor prior to the 
destruction of any documents, if documents are to be transferred to a different facility, or 
transferred to a different owner. 

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The Investigator shall maintain the records required for this investigation for a period of 2 
years after the later of the two date: 
• The date on which the investigation is terminated or completed, or 
• The date that the records are no longer required for purposes of supporting a 
premarket approval application or a notice of completion of a product development 
protocol. 
 
12. 
STEERING COMMITTEE, DATA SAFETY AND MONITORING COMMITTEE, 
AND ADJUDICATION COMMITTEE 
12.1 
Steering Committee 
The Steering Committee for this study will supervise the conduct, administration, and 
course of the clinical trial. They will provide scientific and clinical oversight and will meet 
periodically to monitor subject enrollment and overall study progress. This committee will 
also be responsible for reviewing the final results, determining the methods of 
presentation and publication, and selection of secondary projects and publications.     
12.2 
Independent Data and Safety Monitoring Committee (DSMC) 
An independent DSMC will monitor the trial conduct. The DSMC will consist of 2 clinicians 
and a statistician. The members of this committee will not participate in the enrollment or 
treatment of patients in this trial. The guidelines for the DSMC operations will be reported 
in a separate DSMC Charter.  
The DSMC will review safety data at predefined times established prior to the start of 
enrollment. The DSMC is responsible for making recommendations regarding any safety 
or compliance issues throughout the course of the clinical trial and may recommend to 
the Steering Committee to modify or stop the clinical trial. However, all final decisions 
regarding trial modifications rest with the Steering Committee. 
All analyses required for the DSMC assessment of feasibility and efficacy will be 
performed and/or supported by statisticians at the DCRI. Full details of the composition 
and the operation of the DSMC and how the analyses are to be performed will be detailed 
in a separate DSMC Charter and associated Statistical Analysis Plan. 
12.3 
Independent Clinical Events Committee (CEC) 
An Independent Clinical Events Committee (CEC) will provide independent central 
adjudication of death, cardiac death, P1-MI (for definition, see section 3.2.1), index infarct 

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related vessel P2-MI (for definition, see section 3.2.1), IIVR and INIVR. IILR (ischemia 
driven) revascularizations, stroke, heart failure and stent thrombosis (ARC Definition). 
The guidelines for the adjudication process will be reported in a separate document, the 
CEC Charter. The members of this Committee will not participate in the enrollment or 
treatment of patients in this trial, nor will they participate in the DSMC or the steering or 
executive committee. 

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13. 
POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
The sponsor will encourage the scientific publication of data from clinical research trials. 
However, Investigators may not present or publish partial or complete study results 
individually. The Principal Investigators and the Partners may propose appropriate 
scientific manuscripts or abstracts from the study data. Any manuscript or abstract 
proposed by the Investigators must be reviewed and approved in writing by the SAFE 
STEMI for Seniors Steering Committee before submission for publication. Names of all 
investigators enrolling in the study will be included in the manuscript. 

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14. 
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O'Gara, P.T., et al., 2013 ACCF/AHA Guideline for the Management of ST-
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Mozaffarian, D., et al., Heart Disease and Stroke Statistics—2016 Update: A 
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3. 
Yeh, R.W., et al., Population trends in the incidence and outcomes of acute 
myocardial infarction. N Engl J Med, 2010. 362(23): p. 2155-65. 
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Johnman, C., et al., Percutaneous Coronary Intervention in the Elderly: Changes 
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Newell, M.C., et al., Impact of age on treatment and outcomes in ST-elevation 
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Alexander, K.P., et al., Acute Coronary Care in the Elderly, Part II: ST-Segment–
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Gharacholou, S.M., et al., Age and outcomes in ST-segment elevation myocardial 
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Stone, G.W., et al., Paclitaxel-Eluting Stents versus Bare-Metal Stents in Acute 
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Lim, H.S., et al., Survival of Elderly Patients Undergoing Percutaneous Coronary 
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Leal, M.F., et al., Acute myocardial infarction in elderly patients: comparative 
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15. 
Banning, A.S. and A.H. Gershlick, Management of Multivessel Coronary Disease 
in ST-segment Elevation Myocardial Infarction. Curr Cardiol Rep, 2015. 17(9): p. 
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with multivessel disease and acute myocardial infarction. Am Heart J, 2004. 
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coronary revascularization after acute myocardial infarction. Am J Cardiol, 2005. 
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infarction. N Engl J Med, 2013. 369(12): p. 1115-23. 
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revascularization in patients undergoing primary percutaneous coronary 
intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll 
Cardiol, 2015. 65(10): p. 963-72. 
20. 
Bainey, K.R., et al., Complete vs culprit-only revascularization for patients with 
multivessel disease undergoing primary percutaneous coronary intervention for 
ST-segment elevation myocardial infarction: a systematic review and meta-
analysis. Am Heart J, 2014. 167(1): p. 1-14 e2. 
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Stone, G.W., et al., A prospective natural-history study of coronary atherosclerosis. 
N Engl J Med, 2011. 364: p. 226-35. 
22. 
Kato, K., et al., Nonculprit plaques in patients with acute coronary syndromes have 
more vulnerable features compared with those with non-acute coronary 
syndromes: a 3-vessel optical coherence tomography study. Circ Cardiovasc 
Imaging, 2012. 5(4): p. 433-40. 
23. 
Sulimov, D.S., M. Abdel-Wahab, and G. Richardt, Fractional Flow Reserve in 
Acute Myocardial Infarction: A Guide for Non-Culprit Lesions? Cardiology and 
Therapy, 2015. 4(1): p. 39-46. 
24. 
Smits, P.C., et al., TCT-328 FFR-guided complete revascularization during primary 
PCI: Preliminary data from the COMPARE ACUTE trial. Journal of the American 
College of Cardiology, 2014. 64(11, Supplement): p. B95. 
25. 
Ntalianis, A., et al., Fractional flow reserve for the assessment of nonculprit 
coronary artery stenoses in patients with acute myocardial infarction. J Am Coll 
Cardiol Intv, 2010. 3(12): p. 1274-1281. 
26. 
Sen, S., et al., Development and Validation of a New Adenosine-Independent 
Index of Stenosis Severity From Coronary Wave–Intensity Analysis: Results of the 
ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) Study. Journal 
of the American College of Cardiology, 2012. 59(15): p. 1392-1402. 
27. 
Di Mario, C. and G. Rosser, Open questions for non-infarct-related arteries in 
STEMI. The Lancet, 2015. 386(9994): p. 630-632. 
28. 
Engstrøm, T., et al., Complete revascularisation versus treatment of the culprit 
lesion only in patients with ST-segment elevation myocardial infarction and 
multivessel disease (DANAMI-3 -- PRIMULTI): an open-label, randomised 
controlled trial. The Lancet, 2015. 386(9994): p. 665-671. 

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29. 
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acute coronary syndromes with or without ST-segment elevation. J Am Coll 
Cardiol, 2012. 60(24): p. 2490-9. 
30. 
Romagnoli, E., et al., Radial Versus Femoral Randomized Investigation in ST-
Segment Elevation Acute Coronary SyndromeThe RIFLE-STEACS (Radial Versus 
Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) 
Study. Journal of the American College of Cardiology, 2012. 60(24): p. 2481-2489. 
31. 
Valgimigli, M., et al., Radial versus femoral access in patients with acute coronary 
syndromes undergoing invasive management: a randomised multicentre trial. 
Lancet, 2015. 385(9986): p. 2465-76. 
32. 
Park, J.J., et al., Clinical validation of the resting pressure parameters in the 
assessment of functionally significant coronary stenosis; results of an 
independent, blinded comparison with fractional flow reserve. Int J Cardiol, 2013. 
168(4): p. 4070-5. 
33. 
Petraco, R., et al., Real-time use of instantaneous wave-free ratio: results of the 
ADVISE in-practice: an international, multicenter evaluation of instantaneous 
wave-free ratio in clinical practice. Am Heart J, 2014. 168(5): p. 739-48. 
34. 
Petraco, R., et al., Classification performance of instantaneous wave-free ratio 
(iFR) and fractional flow reserve in a clinical population of intermediate coronary 
stenoses: results of the ADVISE registry. EuroIntervention, 2013. 9(1): p. 91-101. 
35. 
Levine, G.N., et al., 2016 ACC/AHA Guideline Focused Update on Duration of Dual 
Antiplatelet Therapy in Patients With Coronary Artery DiseaseA Report of the 
American College of Cardiology/American Heart Association Task Force on 
Clinical Practice Guidelines. Journal of the American College of Cardiology, 2016. 
36. 
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Illustrated in the Case of the Binomial,” Biometrika, 26, 404–413.  
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Censored: A Randomized Trial of Treatments For B Non-Hodgkin Lymphoma, 
Statistics in Medicine, 1993 12: p. 1353-1364  
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Royal Statistical Society, 1972. Series B 34(2): p. 187-220. 
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40. 
Baklanov, D.V., et al., The prevalence and outcomes of transradial percutaneous 
coronary intervention for ST-segment elevation myocardial infarction: analysis 
from the National Cardiovascular Data Registry (2007 to 2011). J Am Coll Cardiol, 
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15. 
APPENDICES 
15.1 
Appendix A:  National Cardiovascular Research Infrastructure CathPCI 
Registry 
The SAFE-PCI in STEMI for Seniors trial is a large trial that could potentially leverage the 
NIH-funded National Cardiovascular Research Infrastructure (NCRI).  The NCRI is a 
research platform that utilizes the ongoing American College of Cardiology-National 
Cardiovascular Data Registry (ACC-NCDR)  CathPCI registry as the data collection 
platform.  The  CathPCI registry is the largest ongoing registry of PCI in the world and 
includes over 1500 US sites and over 5 million patient records.  The Duke Clinical 
Research Institute (DCRI), in collaboration with the American College of Cardiology 
Foundation (ACCF), will develop a software interface through which data collected as part 
of the new  CathPCI v5.0 Registry “auto populates” a clinical trial case report form.  This 
significantly reduces workload at the site, and can produce cost savings up to 30% of 
overall trial costs.  In addition, access to the  CathPCI Registry allows for “evidence-
based” site identification to enhance patient recruitment.  
This construct was impressively successful in its first implementation in the SAFE PCI for 
Women study, reported as the featured late breaking clinical trial at TCT 2013, and is 
proposed to drive efficiencies, reduce timelines and reduce cost for the SAFE STEMI for 
Seniors study in support of both its IDE and public health missions.  A unique feature of 
this construct to be executed in SAFE STEMI for Seniors will be the electronic linkage of 
the NCRI-NCDR data accrual network to Medicare claims data for US sites, yielding long 
term (1 year and beyond) follow up of death, MI, stroke, re-hospitalization and repeat 
revascularization.  
An upgrade of the NCDR CathPCI Registry database from v4.0 to v5.0 is currently 
scheduled for 2018.  The data definitions for SAFE STEMI for Seniors will be harmonized 
with CathPCI v5.0 to permit future auto-population of index hospitalization data from the 
CathPCI Registry when interfaces become available.  Until that time, all data will initially 
be entered directly into the part 11 compliant database by site personnel. 
This approach allows the study to approach non-SAFE sites in the United States as well 
as Canadian sites to participate in SAFE STEMI for Seniors. 
 
 

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15.2 
Appendix B:  Clinical Data Sources 
The submission timeline is illustrated in figure 1 below.  This figure shows the first 
submission of the 1-year primary endpoint clinical report within 6 months of the last 
patient’s 1-year follow-up.  The figure also shows an updated 1-Year primary endpoint 
clinical report that includes events out to 18 months ascertained using the CMS database 
that will be submitted within 6 months after the CMS data pull.   
The event ascertainment process for first submission of the 1-year primary endpoint 
clinical report is outlined in figure 2.  The task in green in each column in figure 2 is the 
process start and the task in red is the process end.  There is approximately a 3 – 6 month 
lag between when UB-04 claim form is submitted and the information from that form is 
included in the CMS database.  Therefore, 6 months after the last patient reaches his/her 
1 year follow-up, data will be pulled from the CMS database for the all patients in the ITT 
population starting from the date of the first patient’s index procedure up to the latest CMS 
update.  For patients that were lost-follow-up before their 1-year follow-up, the CMS data 
will be used to ascertain whether a primary endpoint event occurred between the date of 
last contact and the 1-year follow-up date.  The ascertainment process is outlined in the 
30-Day and 1-Year column of figure 3.  For all patients, the CMS data will be used to 
ascertain primary endpoint events between 1-year and 18 months according to the 
process outlined in the 18-month column in figure 3.  The task in green in each of the 
column of figure 3 is the process start and the task in red is the process end.  The 1-year 
primary endpoint report event tables will updated with the primary endpoint event 
information ascertained through the CMS database for the patients that were lost to 
follow-up before their 1-year follow-up date.  In addition, a table will be added to the1 year 
primary endpoint report with the events ascertained from CMS between 1-year and 18 
months each patients of follow-up.  In addition a Kaplan-Meier Curve with a landmarked 
start at 1 year out up to the time where 75% of the patients have reached an endpoint or 
are censored (~2.5 years).  Figure 5 shows the expected distribution of patient follow-up 
at the time of the CMS pull.  The bars in figure 5 show the percent and number of patients 
whose maximum follow-up fall within the interval on the x-axis.  The line shows the 
percent and number of the cumulative follow-up for the patients that have at least the 
follow-up specified in the interval.   The updated 1-year primary endpoint report will be 
submitted within 6 months after the CMS data pull.  Using our current enrollment 
projection, 80% (N=697) of the patients will have at least 18 months of follow-up and 92% 
will have at least 15 months of follow-up(N=802). 
However, for the Volcano primary endpoint, if the blinded assessment of the pooled event 
rates indicates the rates are lower than expected, the first submission of the 1-year 
primary endpoint clinical report will only include the Medtronic primary endpoint and 
Terumo observational endpoint analyses.  The updated 1-year primary endpoint clinical 

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report submitted 6 months after the CMS data pull will include the Volcano primary 
endpoint using the event ascertainment process outlined in figure 4.  In this process 
(figure 4) CMS will be used to ascertain and adjudicate any primary endpoint events that 
happen in the first year of follow-up for all patients as opposed to figure 3 which only uses 
CMS to ascertain events for patients that were LTFU.  This will assure that all possible 
adjudicated primary endpoint events between index procedure and 1-year follow-up that 
have been identified using the CMS database will be included in the analysis.  The 
updated 1-year primary endpoint clinical report using the event ascertainment process 
outlined in figure 4 will be submitted within 6 months after the CMS pull. 
 
Figure 6: Submission Timeline  
 
 
 
 
Year 2
Clinical Report w/ 
1Y Primary 
Endpoint results 
CMS Data Pull
Clinical Report w/ updated 
1Y and new 18M data using 
CMS Event ascertainment
Year 1
Enrollment 
Begins
3 Year
Year 4
Enrollment Ends
Last Patient 1Y 
follow-up
Year 5

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Figure 7:  Events Ascertainment process for 1 year Clinical Report 
 

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Figure 8:  Event Ascertainment process for the Updated One Year Primary Endpoint Clinical Report (updated after CMS 
pull) 
 

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Figure 9: Alternative Event Ascertainment process for the Updated One Year Primary Endpoint Clinical Report For 
Volcano (updated after CMS pull) 

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Figure 10: Distribution of patient follow-up at the time of the CMS data pull 
 

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15.3 
Appendix C: Medtronic Stent IFU 
 
 

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15.4 
Appendix D: Volcano Verrata PGW IFU 
 
 

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15.5 
Appendix E: Volcano PremeWire Ptrstige PLUS PGW IFU 
 
 

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15.6 
Appendix F: Terumo Guidesheath Slender IFU 
 
 

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15.7 
Appendix G: Terumo TR Band IFU