Conditions: Coronary Artery Lesions
Keywords: Coronary Artery Lesions XIENCE Dual Antiplatelet Therapy (DAPT) Reduced DAPT Risk of bleeding Drug-eluting stents
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2047
Healthy volunteers: no

Brief summary:
XIENCE 90 study is a prospective, single arm, multi-center, open label trial to evaluate the safety of 3-month dual antiplatelet therapy (DAPT) in subjects at high risk of bleeding (HBR) undergoing percutaneous coronary intervention (PCI) with the approved XIENCE family of coronary drug-eluting stents.

The XIENCE family stent systems include commercially approved XIENCE Xpedition Everolimus Eluting Coronary Stent System (EECSS), XIENCE Alpine EECSS, XIENCE PRO\^X EECSS \[rebrand of the XIENCE Xpedition Stent System and is only available outside of the United States (OUS)\], XIENCE PRO\^A EECSS (rebrand of the XIENCE Alpine Stent System and is only available OUS) and XIENCE Sierra EECSS of coronary drug-eluting stents.

Detailed description:
A. Primary Objective:

To show non-inferiority of the primary endpoint of all death or all MI (modified ARC) from 3 to 12 months following XIENCE implantation in HBR subjects treated with 3-month DAPT compared to a historical control after propensity score adjustment.

B. Secondary Objective:

* To show superiority of the major secondary endpoint of major bleeding (Bleeding Academic Research Consortium \[BARC\] type 2-5) from 3 to 12 months following XIENCE implantation in HBR subjects treated with 3-month DAPT compared to a historical control after propensity score adjustment.
* To evaluate stent thrombosis (ARC definite/probable) from 3 to 12 months following XIENCE implantation in HBR subjects treated with 3-month DAPT against a performance goal (PG).

All registered subjects will be followed at 3, 6 and 12 months post index procedure.

The data collected from this study will be compared with the historical control of non-complex HBR subjects treated with standard DAPT duration of up to 12 months from the XIENCE V USA study, which is a US post-approval study to evaluate the safety of XIENCE V EECSS in "all-comer" population under real-world setting.

Arms:
arm 1: Subjects will receive XIENCE family stents and if a subject was DAPT compliant and event free, then took 3 month DAPT, following with aspirin mono-therapy until 12 month

Interventions: intervention 1: XIENCE intervention 2: DAPT
Intervention descriptions: intervention 1: Subjects who received XIENCE family stent systems will be included. intervention 2: 3-month clear subjects who receive 3-month DAPT without interruption of either aspirin and/or P2Y12 receptor inhibitor for \> 7 consecutive days.

Subject who are "3-month clear" will discontinue P2Y12 inhibitor after 3-month visit, but continue taking aspirin through 12-month follow-up. Subjects who are not eligible for early P2Y12 inhibitor discontinuation will be treated per site standard of care.

Protocol document:
Prot_000.pdf: 
Abbott Vascular 
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PROTOCOL #16-308-Redacted 
XIENCE 90 Study 
 
Version Number 
Version 3.0 
Date 
May 25, 2018 
Principal Investigator 
 
Roxana Mehran, MD,  
Professor of Medicine,  
Director, Interventional Cardiovascular Research and Clinical 
Trials at the Zena and Michael A. Weiner Cardiovascular Institute 
at Mount Sinai 
School of Medicine 
New York, NY 
Planned Number of Sites 
and Region(s) 
Approximately 100 sites globally 
Abbott Vascular Medical 
Expert 
Charles A Simonton, MD  
Chief Medical Officer 
Trial Type 
Prospective, single arm, multi-center, open label trial  
Sponsor /Data Monitoring 
 
Abbott Cardiovascular Systems, Inc., 
A subsidiary of Abbott Vascular, Inc. 
3200 Lakeside Drive 
Santa Clara, CA  95054 
Trial Monitor 
Novella Clinical LLC 
1700 Perimeter Parkway           
 Morrisville, NC 27560  
Electronic Data Capture 
Software 
Medidata RAVE 
Clinical Events Committee 
Cardiovascular Research Foundation 
1700 Broadway, 9th Floor 
New York, NY 10019 
Data Safety Monitoring 
Board 
Axio Research 
2601 4th Avenue, Suite 200 
Seattle, WA 98121 
Protocol Author 
Lijuan Jenny Wang, PhD 
 
 
 


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COMPLIANCE STATEMENT:  
This trial will be conducted in accordance with this Protocol, the Declaration of Helsinki, 
applicable Good Clinical Practices and regulations (e.g., US 21 CFR Part 50, 21 CFR Part 56, 
21 CFR Part 812, 45 CFR Part 46 and OUS ISO14155) and the appropriate local 
legislation(s). The most stringent requirements, guidelines, or regulations must always be 
followed. The conduct of the trial will be approved by the appropriate Institutional Review 
Board (IRB)/Ethics Committee (EC) of the respective investigational site and by the 
applicable regulatory authorities (e.g., FDA, PMDA, MHRA, etc.). 
 
 
 


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PROTOCOL SUMMARY 
Trial Name and 
Number 
XIENCE 90 Study: #16-308-Redacted 
 
Title 
XIENCE 90 Study 
Trial Device 
The commercially approved XIENCE family of coronary drug-
eluting stents1 manufactured by Abbott Vascular, Inc., including: 
• XIENCE Xpedition (stent diameter 2.5, 2.75, 3.0, 3.25, 3.5 
and 4.0 mm, stent length 8, 12, 15, 18, 23 and 28 mm), 
XIENCE Xpedition SV (stent diameter 2.25 mm, stent length 
8, 12, 15, 18, 23, 28 mm) and XIENCE Xpedition LL 
Everolimus Eluting Coronary Stent System (stent diameter 
2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm, stent length 33 and 38 
mm). 
• XIENCE Alpine Everolimus Eluting Coronary Stent System: 
stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent 
length 8, 12, 15, 18, 23, 28, 33, and 38 mm. Stent lengths 33 
mm and 38 mm are not available for 2.25 mm diameter stent. 
• XIENCE PROX Everolimus Eluting Coronary Stent System 
(OUS only)2: stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 
4.0 mm; stent length 8, 12, 15, 18, 23, 28, 33, and 38 mm. 
Stent lengths 33 mm and 38 mm are not available for 2.25 
mm diameter stent. 
• XIENCE PROA Everolimus Eluting Coronary Stent System 
(OUS only)3: stent diameter 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 
and 4.0 mm; stent length 8, 12, 15, 18, 23, 28, 33, and 38 mm. 
Stent lengths 33 mm and 38 mm are not available for 2.25 
mm diameter stent.  
• XIENCE Sierra Everolimus Eluting Coronary Stent System: 
stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent 
length 8, 12, 15, 18, 23, 28, 33, and 38 mm. 
The above XIENCE family stent system will hereinafter be called 
“XIENCE” in this study.   
 
 
 
 
 
1 The commercially approved XIENCE stent will be used in geographies where it is commercially available  
2 XIENCE PROX is a rebrand of the XIENCE Xpedition Stent System and is only available outside of the 
United States. 
3 XIENCE PROA is a rebrand of the XIENCE Alpine Stent System and is only available outside of the United 
States. 


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Objective 
The objective of this trial is to evaluate safety of 3-month dual 
antiplatelet therapy (DAPT) in subjects at high risk of bleeding 
(HBR) undergoing percutaneous coronary intervention (PCI) with 
XIENCE.  
 
Primary Objective: to show non-inferiority of the primary endpoint 
of all death or all MI (modified ARC) from 3 to 12 months following 
XIENCE implantation in HBR subjects treated with 3-month DAPT 
compared to a historical control after propensity score adjustment.  
Secondary Objective:  
• To show superiority of the major secondary endpoint of major 
bleeding (Bleeding Academic Research Consortium [BARC] 
type 2-5) from 3 to 12 months following XIENCE implantation 
in HBR subjects treated with 3-month DAPT compared to a 
historical control after propensity score adjustment.  
• To evaluate stent thrombosis (ARC definite/probable) from 3 to 
12 months following XIENCE implantation in HBR subjects 
treated with 3-month DAPT against a performance goal (PG). 
Targeted Number 
of Subjects  
Approximately 2,000 subjects from approximately 100 sites 
globally, with at least 50% of subjects in the United States. Subject 
registration is capped at 300 per site.  
Clinical Trial 
Design 
A prospective, single arm, multi-center, open label, non-randomized 
trial to evaluate the safety of 3-month DAPT in HBR subjects 
undergoing PCI with XIENCE.  
Primary Endpoint The primary endpoint is a composite rate of all death or all 
myocardial infarction (modified 4Academic Research Consortium 
[ARC]) from 3 to 12 months. 
Major Secondary 
Endpoints  
• Major bleeding rate (BARC type 2-5) from 3 to 12 months. 
• Stent thrombosis (ARC definite/probable) from 3 to 12 months 
Secondary 
Endpoints 
The following endpoints will be assessed from 3 to 12 months: 
• All death, cardiac death, vascular death, non-cardiovascular death 
 
 
 
 
 
4 Patients present any of the following clinical or imaging evidence of ischemia (symptoms of ischemia;  ECG 
changes  indicative of new ischemia -  [new ST-T changes or new LBBB],  development of pathological Q 
waves;  or  imaging evidence of a new loss of  viable myocardium or a new regional wall  motion abnormality), 
AND confirmed with elevated cardiac biomarkers  per ARC criteria  (periprocedural MI: CK-MB > 3x URL or 
Troponin > 3x URL within 48 hours after PCI; CK-MB > 5x URL or Troponin > 5x URL within 72 hours after 
CABG; Assessment of CK-MB is preferred over troponin for the diagnosis of periprocedural MI, if possible. 
For spontaneous MI: CK-MB > URL or Troponin > URL) (Circulation 2007; 116: 2344-2351)  


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• All myocardial infarction (MI) and MI attributed to target vessel 
(TV-MI, modified ARC) 
• Composite of cardiac death or MI (modified ARC) 
• All stroke, ischemic stroke and hemorrhagic stroke  
• Clinically-indicated target lesion revascularization (CI-TLR)  
• Clinically-indicated target vessel revascularization (CI-TVR)  
• Target lesion failure (TLF, composite of cardiac death, TV-MI 
and CI-TLR)  
• Target vessel failure (TVF, composite of cardiac death, TV-MI 
and CI-TVR)  
• Major bleeding defined by the Bleeding Academic Research 
Consortium (BARC) type 3-5  
Point of 
Registration  
Subject registration will occur after the index procedure but prior to 
discharge and up to 3 days post index procedure, upon confirmation 
of the following:  
• Signed informed consent has been obtained;  
• Subject has met all the inclusion and none of the exclusion 
criteria (including both general and angiographic criteria). 
Planned staged procedures are allowed (recommend to be performed 
within 30 days). The site may consent the subject after the initial 
procedure. Subject registration will occur once the last staged 
procedure is performed and the last staged procedure is considered 
as the index procedure.  
Subject Follow-
Up 
Subjects registered in the trial will receive the following clinical 
follow-up: 
• 3 months (90 ± 7 days): office visit (Note: A formal office visit is 
required at 3-month follow-up to ensure a thorough clinical 
evaluation. A telephone contact is an option only for subjects 
who would otherwise be lost to follow-up due to being unable to 
complete an office visit, but a formal follow-up visit is still 
preferred at 3 months.) 
• 6 months (180 ± 14 days): office visit/ telephone contact (office 
visit is strongly recommended whenever possible) 
• 12 months (365 ± 28 days): office visit/ telephone contact (office 
visit is strongly recommended whenever possible)  
Primary Analysis 
Sample Size 
Justification 
To evaluate the safety of the 3-month DAPT, non-inferiority (NI) 
will be tested comparing 3-month DAPT to XIENCE V USA 
historical control for the primary endpoint of all death or all 
myocardial infarction (modified ARC) from 3- to 12-month follow-
up in a “3-month clear” population (defined as subjects who are free 


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from myocardial infarction [modified ARC], repeat coronary 
revascularization, stroke, or stent thrombosis [ARC 
definite/probable] within 3 months (prior to 3-month visit but at least 
90 days) after stenting AND have been compliant with 3-month 
DAPT without interruption of either aspirin and/or P2Y12 receptor 
inhibitor for > 7 consecutive days).  
This analysis will be stratified by propensity score with the following 
assumptions: 
 
• True event rate for the primary endpoint is assumed to be 
approximately 6.1% for both arms 
• One-sided alpha = 0.025 
• Attrition rate of 15% due to using “3-month clear” population for 
the XIENCE 90 3-month DAPT arm  
• Sample size: ~2,000 for the XIENCE 90 3-month DAPT arm and 
~1,150 for the XIENCE V USA control arm  
• Non-inferiority margin = 2.8% 
• Approximately 87% power  
Major Secondary 
Analysis  
Given the success of the primary analysis for the primary endpoint, 
the following major secondary analyses will be performed:  
• Superiority test for major bleeding rate (BARC type 2-5) from 3- 
to 12-month follow-up will be tested between XIENCE 90 and 
the XIENCE V USA historical control stratified by propensity 
scores. 
 
• Stent thrombosis (ARC definite/probable) from 3- to 12-month 
follow-up of XIENCE 90 will be evaluated against a pre-
specified PG.  
 
Details of the above major secondary analyses could be found in the 
Statistical Analysis Plan (SAP). 
Antiplatelet 
Medication  
Antiplatelet Medication Loading Dose: 
• Subjects must receive a loading dose of aspirin AND a P2Y12 
inhibitor (Clopidogrel, Prasugrel or Ticagrelor). The dosages of 
aspirin and P2Y12 inhibitor shall be determined by physician per 
standard of care and label indication for loading dose usage. The 
choice of P2Y12 inhibitor is per site standard of care, but 
clopidogrel is strongly recommended for HBR subjects.  Per 
physician’s discretion, a loading dose of P2Y12 inhibitor may be 
omitted if the subject was on chronic usage for ≥ 7 days.   


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Antiplatelet Medication Post-Procedure Daily Dose: 
• All subjects must receive ≥75 to ≤100 mg of aspirin daily 
throughout the study. All subjects must maintain a minimum of 
75 mg of clopidogrel daily or 5 or 10 mg of prasugrel daily (10 
mg preferred in most subjects*) or 90 mg twice daily of 
ticagrelor for at least 3 months following the procedure.  
­ The choice of P2Y12 inhibitor is per site standard of care, 
but clopidogrel is strongly recommended for HBR 
subjects. 
­ For subjects taking chronic anticoagulants, dual therapy 
(oral anticoagulant and a P2Y12 inhibitor, clopidogrel 
preferred) may be considered for the first 3 months after 
index procedure per investigator’s discretion.  
• At 3-month follow up, subject will be assessed for their 
eligibility of P2Y12 inhibitor discontinuation. Eligible subjects 
will discontinue P2Y12 inhibitor and receive ≥75 to ≤100 mg of 
aspirin daily through 1-year follow-up during the study if they 
are “3-month clear”, defined as subjects who are free from 
myocardial infarction (modified ARC), repeat coronary 
revascularization, stroke, or stent thrombosis (ARC 
definite/probable) within 3 months (prior to 3-month visit but at 
least 90 days) after stenting AND have been compliant with 3-
month dual antiplatelet therapy (DAPT) without interruption of 
either aspirin and/or P2Y12 receptor inhibitor for > 7 consecutive 
days.  
­ Peri-procedural MI (occurred within 48 hours post index 
procedure) without any clinical symptoms will not be 
considered exclusionary event for the definition of “3-
month clear”.  
­ Dual therapy (oral anticoagulant and a P2Y12 inhibitor, 
clopidogrel is preferred) within the first 3 months post 
index procedure for subjects who are on chronic 
anticoagulants is acceptable for the definition of “3-
month clear”.  
• Subjects who are not “3-month clear” are NOT eligible for 
P2Y12 inhibitor discontinuation at 3-month. These subjects will 
be treated per the investigator's discretion and will continue to be 
followed up through 12 months. 
*For prasugrel subjects < 60 kg in weight or ≥ 75 years of age, a 
maintenance dose of 5 mg per day for 12 months is allowable.  


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Cardiac 
Biomarker 
Collection 
Cardiac biomarker CK, CK-MB and/or troponin collection shall be 
done per site’s standard of care. CK and CK-MB are preferred. If 
CK and CK-MB are not available, troponin should be collected.  
Key Inclusion 
Criteria 
General Inclusion Criteria 
1. Subject is considered at high risk for bleeding (HBR), defined as 
meeting one or more of the following criteria at the time of 
registration and in the opinion of the referring physician, the risk 
of major bleeding with > 3-month DAPT outweighs the benefit: 
a) ≥ 75 years of age.  
b) Clinical indication for chronic (at least 6 months) or 
lifelong anticoagulation therapy. 
c) History of major bleeding which required medical 
attention within 12 months of the index procedure. 
d) History of stroke (ischemic or hemorrhagic).  
e) Renal insufficiency (creatinine ≥ 2.0 mg/dl) or failure 
(dialysis dependent). 
f) Systemic conditions associated with an increased 
bleeding risk (e.g. hematological disorders, including a 
history of or current thrombocytopenia defined as a 
platelet count <100,000/mm3, or any known coagulation 
disorder associated with increased bleeding risk). 
g) Anemia with hemoglobin < 11g/dl. 
2. Subject must be at least 18 years of age.  
3. Subject or a legally authorized representative must provide 
written informed consent as approved by the Institutional Review 
Board (IRB)/Ethics Committee (EC) of the respective clinical 
site prior to any study related procedure.  
4. Subject is willing to comply with all protocol requirements, 
including agreement to stop taking P2Y12 inhibitor at 3 months, 
if eligible per protocol. 
5. Subject must agree not to participate in any other clinical trial for 
a period of one year following the index procedure. 
 
Angiographic Inclusion Criteria  
1. Up to three target lesions with a maximum of two target lesions 
per epicardial vessel. Note: 
• The definition of epicardial vessels means left anterior 
descending coronary artery (LAD), left circumflex coronary 
artery (LCX) and right coronary artery (RCA) and their 
branches. For example, the patient must not have >2 lesions 


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requiring treatment within both the LAD and a diagonal 
branch in total. 
• If there are two target lesions within the same epicardial 
vessel, the two target lesions must be at least 15 mm apart per 
visual estimation; otherwise this is considered as a single 
target lesion.  
2. Target lesion ≤ 32 mm in length by visual estimation. 
3. Target lesion must be located in a native coronary artery with 
visually estimated reference vessel diameter between 2.25 mm 
and 4.25 mm.  
4. Exclusive use of XIENCE family of stent systems during the 
index procedure. 
5. Target lesion has been treated successfully, which is defined as 
achievement of a final in-stent residual diameter stenosis of 
<20% with final TIMI-3 flow assessed by online quantitative 
angiography or visual estimation, with no residual dissection 
NHLBI grade ≥ type B, and no transient or sustained 
angiographic complications (e.g., distal embolization, side branch 
closure), no chest pain lasting > 5 minutes, and no ST segment 
elevation > 0.5 mm or depression lasting > 5 minutes. 
Key Exclusion 
Criteria 
General Exclusion Criteria 
1. Subject with an indication for the index procedure of acute ST-
segment elevation MI (STEMI).  
2. Subject has a known hypersensitivity or contraindication to 
aspirin, heparin/bivalirudin, P2Y12 inhibitors 
(clopidogrel/prasugrel/ticagrelor), everolimus, cobalt, 
chromium, nickel, tungsten, acrylic and fluoro polymers or 
contrast sensitivity that cannot be adequately pre-medicated. 
3. Subject with implantation of another drug-eluting stent (other 
than XIENCE) within 9 months prior to index procedure. 
4. Subject has a known left ventricular ejection fraction (LVEF) 
<30%. 
5. Subject judged by physician as inappropriate for discontinuation 
from P2Y12 inhibitor use at 3 months, due to another condition 
requiring chronic P2Y12 inhibitor use. 
6. Subject with planned surgery or procedure necessitating 
discontinuation of P2Y12 inhibitor within 3 months following 
index procedure. 
7. Subject with a current medical condition with a life expectancy 
of less than 12 months. 


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8. Subject intends to participate in an investigational drug or 
device trial within 12 months following the index procedure. 
9. Pregnant or nursing subjects and those who plan pregnancy in 
the period up to 1 year following index procedure. Female 
subjects of child-bearing potential must have a negative 
pregnancy test done within 7 days prior to the index procedure 
per site standard test.  
Note: Female patients of childbearing potential should be 
instructed to use safe contraception (e.g., intrauterine devices, 
hormonal contraceptives: contraceptive pills, implants, 
transdermal patches, hormonal vaginal devices, injections with 
prolonged release.) It is accepted, in certain cases, to include 
subjects having a sterilised regular partner or subjects using a 
double barrier contraceptive method. However, this should be 
explicitly justified in special circumstances arising from the 
study design, product characteristics and/or study population 
10. Subject is part of a vulnerable population, defined as subject 
whose willingness to volunteer in a clinical investigation could 
be unduly influenced by the expectation, whether justified or 
not, of benefits associated with participation or of retaliatory 
response from senior members of a hierarchy in case of refusal 
to participate.  Examples of populations which may contain 
vulnerable subjects include: individuals with lack of or loss of 
autonomy due to immaturity or through mental disability, 
persons in nursing homes, children, impoverished persons, 
subjects in emergency situations, ethnic minority groups, 
homeless persons, nomads, refugees, and those incapable of 
giving informed consent. Other vulnerable subjects include, for 
example, members of a group with a hierarchical structure such 
as university students, subordinate hospital and laboratory 
personnel, employees of the sponsor, members of the armed 
forces, and persons kept in detention. 
11. Subject is currently participating in another clinical trial that has 
not yet completed its primary endpoint. 
  
Angiographic Exclusion Criteria  
1. Target lesion is in a left main location.  
2. Target lesion is located within an arterial or saphenous vein 
graft. 
3. Target lesion is restenotic from a previous stent implantation. 
4. Target lesion is a total occluded lesion (TIMI flow 0). 


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5. Target lesion contains thrombus as indicated in the angiographic 
images (per SYNTAX score thrombus definition). 
6. Target lesion is implanted with overlapping stents, whether 
planned or for bailout. 
 
Note: If there is more than one target lesion, all target lesions must 
satisfy the angiographic eligibility criteria. Non-target lesion (i.e., 
lesions that do not meet the angiographic criteria listed above) 
treatments are not allowed during the index procedure. 
Primary Analysis 
Population 
The primary analysis population is “3-month clear” population, 
defined as subjects who are free from myocardial infarction 
(modified ARC), repeat coronary revascularization, stroke, or stent 
thrombosis (ARC definite/probable) within 3 months (prior to 3-
month visit but at least 90 days) after stenting AND have been 
compliant with 3-month DAPT without interruption of either aspirin 
and/or P2Y12 receptor inhibitor for > 7 consecutive days.  
 
 


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1.0 
INTRODUCTION 
1.1 
Trial Design 
XIENCE 90 study is a prospective, single arm, multi-center, open label trial to evaluate the 
safety of 3-month dual antiplatelet therapy (DAPT) in subjects at high risk of bleeding (HBR) 
undergoing percutaneous coronary intervention (PCI) with the approved XIENCE family of 
coronary drug-eluting stents. 
The XIENCE family stent systems include commercially approved5 XIENCE Xpedition 
Everolimus Eluting Coronary Stent System (EECSS), XIENCE Alpine EECSS, XIENCE 
PROX EECSS (OUS only)6, XIENCE PROA EECSS (OUS only)7, and XIENCE Sierra 
EECSS, which are all manufactured by Abbott Vascular, Inc., Santa Clara, USA.  The above 
XIENCE family stent systems will hereinafter be called “XIENCE” in this study.  
Approximately 2,000 subjects from approximately 100 sites globally will be registered in this 
study, with at least 50% of subjects in the United States (US). Study population consists of 
non-complex HBR subjects with up to three native coronary artery lesions (a maximum of 
two lesions per epicardial vessel) with reference vessel diameter between 2.25 mm and 4.25 
mm. Eligibility of P2Y12 receptor inhibitor discontinuation will be assessed at 3-month 
follow-up. Subjects who are free from myocardial infarction (modified ARC), repeat 
coronary revascularization, stroke, or stent thrombosis (ARC definite/probable) within 3 
months (prior to 3-month visit but at least 90 days) after stenting AND have been compliant 
with 3-month DAPT without interruption of either aspirin and/or P2Y12 receptor inhibitor for 
> 7 consecutive days are considered as “3-month clear”, and will discontinue P2Y12 receptor 
inhibitor and continued with aspirin monotherapy after 3-month follow-up.   
All registered subjects will be followed at 3, 6 and 12 months post index procedure.  
The data collected from the XIENCE 90 study will be compared with the historical control of 
non-complex HBR subjects treated with standard DAPT duration of up to 12 months from the 
XIENCE V USA study, which is a US post-approval study to evaluate the safety of XIENCE 
V EECSS in “all-comer” population under real-world setting.   
1.2 
Trial Objective 
Primary Objective: to show non-inferiority of the primary endpoint of all death or all MI 
(modified ARC) from 3 to 12 months following XIENCE implantation in HBR subjects 
treated with 3-month DAPT compared to a historical control after propensity score 
adjustment.  
Secondary Objective:  
• To show superiority of the major secondary endpoint of major bleeding (Bleeding 
Academic Research Consortium [BARC] type 2-5) from 3 to 12 months following 
 
 
 
 
 
5 The commercially approved XIENCE stent will be used in geographies where it is commercially available 
6 XIENCE PROX is a rebrand of the XIENCE Xpedition Stent System and is only available outside of the 
United States. 
7 XIENCE PROA is a rebrand of the XIENCE Alpine Stent System and is only available outside of the United 
States. 


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XIENCE implantation in HBR subjects treated with 3-month DAPT compared to a 
historical control after propensity score adjustment.  
• 
To evaluate stent thrombosis (ARC definite/probable) from 3 to 12 months following 
XIENCE implantation in HBR subjects treated with 3-month DAPT against a 
performance goal (PG). 
2.0 
BACKGROUND INFORMATION 
2.1 
Background and Rationale 
Although drug-eluting stents (DES) have been shown to effectively reduce restenosis 
compared with bare-metal stents (BMS), there was a concern that DES might lead to an 
increased risk of stent thrombosis based on data from first-generation DES1-4.  This increased 
risk has been attributed, in part, to polymer hypersensitivity reactions, delayed arterial 
healing, endothelial dysfunction, and late acquired stent malapposition.  Stent thrombosis 
generally will manifest in serious clinical outcomes of MI and/or death. As a result of this 
concern, the previous 2011 ACCF/AHA/SCAI guidelines recommend a prolonged duration 
of DAPT, a continuation of at least 1 year of DAPT following DES implantation as compared 
to a minimum of 1 month of DAPT following BMS implantation for patients without acute 
coronary syndrome (ACS)5.  However, these recommendations were based primarily on 
observational data with the first generation DES. Compared with first-generation DES, 
currently used second-generation DES have a lower risk of stent thrombosis. Data from five 
RCTs 6-10of primarily low-risk patients (non-ACS) treated with DES comparing shorter-
duration (3 to 6 months) DAPT with 12 months of DAPT, as well as several meta-analyses 
and data review11-16, did not find an increased risk of stent thrombosis with shorter duration 
of DAPT. Therefore, the most recently published 2016 ACC/AHA guideline updated their 
recommendations to decrease the minimum DAPT duration from 12 months to 6 months after 
DES implantation in patients with stable ischemic heart disease (SIHD)17. 
Long-term DAPT is known to increase the risk of bleeding. Multiple studies have 
demonstrated the relationship between bleeding and an increased risk for short- and long-
term mortality18,19, with major bleeding being identified as an independent predictor of 
mortality with a weight similar to or event greater than MI20. This was confirmed in a recent 
meta-analysis by Palmerini with 12 trials comprising > 34,000 patients randomized to 
different duration strategies of DAPT21. In this meta-analysis (including patient level data of 
11,473 patients from 6 of those 12 RCT trials), bleeding was an independent predictor of 
mortality occurring within 1 year of the bleeding episode (hazard ratio: 6.93; 95% CI: 4.53 to 
10.60; p < 0.0001). More importantly, shorter DAPT was associated with lower rates of all-
cause mortality compared with longer DAPT, which was driven by lower rates of bleeding-
related deaths with shorter DAPT duration. This important finding may underlie the potential 
mortality benefit with shorter DAPT, which is especially relevant for patients who are at high 
risk of bleeding (HBR). 
HBR patients represent approximately 15% or more of patients undergoing PCI22,23.  This 
patient population is of a significant size but is usually excluded from traditional DES 
approval trials.   The traditional standard treatment for HBR patients who undergo 
percutaneous coronary intervention (PCI) is often stenting with BMS followed by 1 month of 
DAPT. While this strategy aims to minimize the risk of bleeding in such patients, the use of 
BMS poses a higher risk of restenosis and re-intervention. Therefore, stenting with DES 
followed by a shortened course of DAPT may represent a more favourable treatment option 
providing that the potential risk of stent thrombosis can be addressed.  With advances in stent 
technology, second-generation DES is equipped with novel stent materials and designs, 


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polymers, and anti-proliferative agents, which may modify the propensity of DES for 
ischemic events.  It is possible that the same level of safety may be maintained for second-
generation DES even if combined with a significantly shortened course of DAPT. In fact, the 
European ESC/EACTS guidelines have recommended 3 months of DAPT with second-
generation DES for HBR patients undergoing PCI24.  Consistent with the European guideline, 
the updated 2016 ACC/AHA guideline also provided a class IIb recommendation of 3-month 
DAPT in SIHD patients with high risk of bleeding following DES implantation17.  
The second generation everolimus-eluting stent (EES) has been the subject of extensive 
clinical studies across multiple geographies. A consistently low late and very late stent 
thrombosis rate has been demonstrated with EES from randomized controlled studies 25-30 as 
well as real-world registry studies 31,32. The XIENCE family of stents has consistently been 
shown to have the best safety profile among coronary stents, including second-generation 
DES.   
To investigate whether there are any major differences in the risk of stent thrombosis between 
first- and second-generation DES, or between DES and BMS, Palmerini et al. conducted a 
comprehensive network meta-analysis involving 50,844 patients from 49 RCTs implanted 
with DES or BMS33.  This meta-analysis demonstrated that XIENCE V had the lowest rate of 
stent thrombosis within 2 years of implantation compared with other stents.  Not only was 
XIENCE V associated with significantly lower 1-year rate of definite stent thrombosis than 
the other first- and second-generation DES, including Cypher, Taxus, Endeavor, and 
Resolute, XIENCE V was also associated with significantly lower rates of definite stent 
thrombosis than BMS at both 1 year (odds ratio [OR]: 0.23, 95% confidence interval [CI]: 
0.13-0.41) and 2 years (OR: 0.35, 95% CI: 0.17-0 .69), a result not duplicated by other DES.  
The reduction in stent thrombosis with XIENCE V compared with BMS was apparent both 
early (0-30 days) and late (31 days-1 year), suggesting the reduction was not caused by the 
difference in DAPT durations between XIENCE V and BMS as the reduction was already 
evident as early as 30 days when all patients should be treated with DAPT regardless of 
device types.    
Another recent large meta-analysis involving 106,427 patients from 126 RCTs was conducted 
to compare the safety and efficacy of these biodegradable polymer DES (BP-DES) with those 
of durable polymer DES and BMS34.  Among all the stents compared, XIENCE V was the 
safest with a lower risk of clinical events when compared to DES, including BP-DES and 
other first and second generation DES. Even when compared to BMS, XIENCE V was still 
associated with significant reductions in the rates of definite stent thrombosis (rate ratio: 0.35, 
95% CI: 0.21 to 0.53), MI (rate ratio: 0.65, 95% CI: 0.55 to 0.75), and death (rate ratio: 0.72, 
95% CI: 0.58 to 0.90).   
Even in the setting of elevated risk for thrombosis such as acute coronary syndrome, 
XIENCE V still demonstrated a favourable safety outcome as reported in the 
EXAMINATION trial, which was an all-comer trial randomizing 1,504 subjects with ST-
segment elevation myocardial infarction (STEMI) in a 1: 1 ratio to XIENCE V or BMS 
(Vision).  This study demonstrated that XIENCE V was associated with reduced rates of stent 
thrombosis compared with BMS at 1 year and 2 years, with the rates becoming comparable 
between the two groups at 3, 4, and 5 years with similar DAPT usage at 5-year follow-up 
35,36.  It suggests that the risk of stent thrombosis with XIENCE V, if not lower, is at least 
comparable to that of BMS even in this high risk STEMI population. 
The excellent safety profile of XIENCE in terms of stent thrombosis is likely attributed to the 
unique combination of its thin struts (81 µm), the thromboresistant nature of the 
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proliferative agent, everolimus. Autopsy studies in humans have suggested that incomplete 
endothelialization of strut surface is a pathologic substrate for late stent thrombosis38,39.  In a 
pre-clinical study conducted in rabbit iliac arteries, areas between struts showed most 
complete coverage (90.4%) for EES compared with other stents at 14 days40.  The rapid strut 
coverage by endothelium with XIENCE V was confirmed in humans in an optical coherence 
tomography (OCT) cohort of the MECHANISM-Elective study41, which showed 93.6% strut 
coverage at 1 month (N=49) and 98% strut coverage at 3 months (N=46) in subjects with 
stable coronary artery disease receiving XIENCE V.   
The XIENCE family of stents is unique from other currently marketed stents in featuring a 
fluorinated co-polymer coating [poly (vinylidene fluoride-co-hexafluoropropylene)] (PVDF-
HFP). This polymer coating not only serves as the vehicle for the controlled elution of 
everolimus, but just as importantly the fluorinated co-polymer offers a non-thrombogenic 
surface through a mechanism known as fluoropassivation42. Pre-clinical models comparing 
inflammation and platelet adhesion among XIENCE V, BMS and Resolute showed that 
XIENCE V had a lower propensity for inflammation and platelet adhesion43,44.  In a series of 
ex vivo studies using porcine arterio-venous shunt model to assess and compare the 
thrombogenicity of XIENCE to different stent platforms, XIENCE showed a significant 
reduction in acute thrombus formation (measured as platelet adhesion) in comparison to BMS 
as well as new generation of bioresorbable polymer-coated stent (Synergy) and polymer-free 
stent (BioFreedom)8. The high degree of stent coverage within 1 and 3 months of implant, 
together with the results of ex vivo studies which consistently showed low thrombogenic 
potential of XIENCE through the unique properties of its fluorinated co-polymer coating, 
provides further evidence to support the safety of shorter DAPT with XIENCE.   
Short-term DAPT has been recently studied in HBR patients. The ZEUS study is a 
randomized, single-blind trial evaluating Endeavor DES vs. BMS combined with a tailored 
course of DAPT for treating subjects who were considered uncertain DES candidates, 
including HBR patients, patients at high risk for thrombosis, and patients at low risk for 
restenosis45.  A total of 1,606 subjects were randomized in a 1:1 ratio to either Endeavor or 
thin-strut BMS (strut thickness < 100 µm).  DAPT duration was prescribed based on patient 
characteristics, rather than stent characteristics, and a personalized regimen of 1-month 
DAPT was allowed.  The primary endpoint of the study was MACE (death, MI, or target 
vessel revascularization [TVR]) at 1 year.  In this study, approximately half of the enrolled 
subjects were HBR patients (51.6%), who were qualified for 1-month DAPT. In the pre-
specified HBR subgroup analysis from ZEUS trial, MACE occurred in 22.6% of the 
Endeavor group and 29% of the BMS group with a hazard ratio 0.75 (p=0.033)46.  The 
definite or probable ST was also significantly reduced in the Endeavor group (2.6% vs. 6.2%, 
p=0.016). 
The LEADERS FREE study is a randomized, double-blind trial evaluating BioFreedom 
combined with 1 month of DAPT for treating HBR patients undergoing PCI as compared to 
BMS47.  A total of 2,466 HBR patients were randomized in a 1:1 ratio to BioFreedom or a 
very similar BMS (Gazelle). All patients received 1 month of DAPT and were to be followed 
at 1, 2, and 4 months, and 1 and 2 years.  The primary safety endpoint, tested for both non-
inferiority and superiority, was a composite of cardiac death, MI, or stent thrombosis 
 
 
 
 
 
8 Data on file with Abbott Vascular 


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(definite/probable).  The primary efficacy endpoint was clinically driven target lesion 
revascularization (CD-TLR).  At 1 year, the rate of the composite of cardiac death, MI, or 
stent thrombosis was significantly lowered in the BioFreedom group than in the BMS group 
(9.4% (112/1221) vs. 12.9% (154/1211); P < 0.001 for noninferiority and P=0.005 for 
superiority).  The 1-year rate of CD-TLR was also significantly lower in the BioFreedom 
group than in the BMS group (5.1% (59/1221) vs. 9.8% (113/1211), P <0.001).  There was 
also a significant reduction in the 1-year rate of MI with BioFreedom compared with BMS 
(6.1% vs. 8.9%, p = 0.01), whereas no differences in the 1-year rates of stent thrombosis were 
observed between the two groups (2.0% vs. 2.2%, p = 0.75). 
Results from both ZEUS and LEADER FREE suggest that DES can be as safe or even safer 
choice for HBR patients than BMS with short duration of DAPT. The confirmed safety of 
Endeavor and BioFreedom with short-term DAPT for HBR patients in the ZEUS and 
LEADERS FREE studies are of particular relevance to the safety of the proposed study of 
XIENCE.  XIENCE V has consistently been shown to have a better safety profile than 
Endeavor based on results from several meta-analyses33,34.  Pre-clinical studies of 
endothelialization also demonstrate that XIENCE V had a faster rate of strut coverage 
following stent implantation than Endeavor 40, and was equivalent to BioFreedom48.  
Additionally, XIENCE showed a significant reduction in platelet adherence compared to 
BioFreedom stents in ex vivo studies9. Taken together, these clinical data of Endeavor and 
BioFreedom indirectly support the safety to evaluate short-term DAPT with XIENCE.  
There is also clinical data exclusively evaluating short DAPT duration with XIENCE.  
STOPDAPT trial is a prospective multi-center, single-arm study evaluating 3-month DAPT 
duration after XIENCE implantation in 1,525 patients49 . Using the XIENCE group in the 
RESET trial as a historical comparison group, where nearly 90% of patients were on DAPT 
at 1 year, the cumulative incidence of the primary endpoint (a composite of cardiovascular 
death, myocardial infarction, stroke, definite stent thrombosis and TIMI major/minor 
bleeding) at 1 year tended to be lower in the STOPDAPT than in the RESET (2.8% vs. 4.0%, 
p = 0.06). The difference is driven by the significantly lower rate of the composite major 
secondary endpoint of cardiovascular death, myocardial infarction, stroke and definite stent 
thrombosis rate (2.1% vs. 3.2%, p = 0.045) while the TIMI major/minor bleeding rates were 
similar between the two groups (1.0% vs. 1.3%, p = 0.4). The cumulative incidence of 
definite/probable stent thrombosis was also lower in the STOPDAPT (0% vs. 0.3%, p = 
0.03). The STOPDAPT trial data support the safety of short-term DAPT following XIENCE 
V implantation.   
To assess the relationship between stent thrombosis and DAPT usage, a patient-level pooled 
analysis was conducted on a total of 11,219 patients who had complete DAPT usage data 
through the 2-year follow-up period from seven Abbott Vascular-sponsored XIENCE V trials 
(including three pre-approval trials: SPIRIT II, III, IV, and four post-approval single-arm 
registry studies: XIENCE V USA, XIENCE V India, SPIRIT V and SPIRIT Women)50 .  
DAPT requirement varied among these studies.  For the three randomized pre-approval trials, 
at least 6 months of DAPT was required in the protocol.  In the four single-arm registry 
studies, DAPT usage was recommended as per standard of care. The large sample size in this 
pooled analysis allows for a more robust evaluation of stent thrombosis and its association 
 
 
 
 
 
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with DAPT interruption/discontinuation for patients implanted with XIENCE V.  In this 
pooled analysis, the overall rate of definite/probable stent thrombosis at 2 years was 0.75%, 
with 0.36% for early stent thrombosis (within 1 month), 0.29% for late stent thrombosis (1-12 
months) and 0.11% for very late stent thrombosis (after 1 year).  The risk of stent thrombosis 
with permanent DAPT discontinuation after 3 months was low, with similar ST rate through 
2 years compared to those without permanent DAPT discontinuation (0.78% vs. 0.83%, 
respectively).  By propensity and DAPT usage adjusted multivariable analysis, permanent 
DAPT discontinuation in any interval after 90 days was not associated with the occurrence of 
ST.     
The optimal duration of DAPT remains a dilemma for clinicians with the current clinical 
practice. The possible benefits of extended DAPT therapy to prevent late stent thrombosis 
and the progression of atherosclerotic disease need to be weighed against the increased risk of 
bleeding in an individual patient based on stent type. The optimal duration of DAPT is of 
particular interest to HBR patients, in whom it is believed that the benefit of reduced bleeding 
with shorter DAPT outweighs the potential risk of thrombosis and ischemic events. There is 
clearly an unmet medical need to be addressed for this patient population. XIENCE has 
consistently been shown to have the best safety profile among the coronary stents, even when 
compared to BMS and biodegradable polymer DES. The benefit/risk ratio of a shorter 
duration of DAPT following XIENCE implantation in this population has not been 
thoroughly evaluated. Therefore, the XIENCE 90 study is designed to prospectively evaluate 
the safety of XIENCE followed with 3-month DAPT in HBR patients. 
2.2 
Summary of Investigational Device 
2.2.1 Name of the Investigational Device 
• XIENCE Xpedition®, XIENCE Xpedition® Small Vessel (SV) and XIENCE 
Xpedition® LL Everolimus Eluting Coronary Stent System (XIENCE Xpedition Stent 
System; P110019 / S025, approved on December 21, 2012) 
• XIENCE Alpine® Everolimus Eluting Coronary Stent System (XIENCE Alpine Stent 
System; P110019 / S070; approved on September 3, 2014) 
• XIENCE PROX Everolimus Eluting Coronary Stent System10 
• XIENCE PROA Everolimus Eluting Coronary Stent System11 
• XIENCE Sierra Everolimus Eluting Coronary Stent System (XIENCE Sierra Stent 
System; P110019 / S094; approved on May 22, 2018) 
All the above trial devices (hereinafter be called as “XIENCE” in the study) are manufactured 
by Abbott Vascular. The XIENCE Xpedition, XIENCE Alpine, and XIENCE Sierra EECSS 
have been approved by the Food and Drug Administration (FDA) and are currently in 
commercial use in the United States. These stent systems, the XIENCE PROX EECSS and the 
XIENCE PROA EECSS have also received Conformité Européene (CE) mark and are 
currently in commercial use in different European countries. Please refer to the Instructions 
for Use (IFU) for details of each stent system. 
 
 
 
 
 
10 XIENCE PROX is a rebrand of the XIENCE Xpedition Stent System and is only available outside of the U.S. 
11 XIENCE PROA is a rebrand of the XIENCE Alpine Stent System and is only available outside of the U.S. 


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2.2.2 Intended Indication for Use 
The following is the proposed Intended Use/Indications for Use for the XIENCE Xpedition, 
XIENCE Alpine and XIENCE Sierra stent system in US as a result of the XIENCE 90 trial: 
“The XIENCE [Xpedition/Alpine/Sierra] stent system is indicated for improving coronary 
artery luminal diameter in patients, including those at high risk for bleeding and those with 
diabetes mellitus, with symptomatic heart disease due to de novo native coronary artery 
lesions (length ≤ 32 mm) with reference vessel diameters of ≥ 2.25 mm to ≤ 4.25 mm. In 
addition, the XIENCE [Xpedition/Alpine/Sierra] stent system is indicated for treating de novo 
chronic total coronary occlusions.” 
2.2.3 Description of the Investigational Device 
A full description of XIENCE Xpedition, XIENCE Alpine, XIENCE PROX, XIENCE PROA 
and XIENCE Sierra stent can be found in the individual stent IFU.  
3.0 
CLINICAL TRIAL/INVESTIGATION FLOW AND FOLLOW-UP 
SCHEDULE 
3.1 
Number of Subjects to be Registered 
Approximately 2,000 subjects from approximately 100 sites globally will be registered in this 
study, with at least 50% of subjects in the US. Subject registration is capped at 300 per site. 
3.2 
Overall Flow of the Trial and Follow-up Schedule 
The clinical investigation flow is shown in Appendix V. Subjects who satisfy eligibility 
criteria become registered in the study. Subjects have follow-up visits at 3, 6 and 12 months. 
Assessment of eligibility of DAPT discontinuation will occur at 3-month follow-up. 
3.3 
Measures Taken to Avoid and Minimize Bias 
All the clinical endpoint events will be adjudicated by the Clinical Events Committee (CEC). 
The CEC is an independent adjudication body comprised of qualified physicians who are not 
participants in the trial. The CEC will review and adjudicate events as defined in the CEC 
charter and according to definitions provided in this protocol.  
3.4 
Early Termination of the Clinical Trial 
No formal statistical rule for early termination of the trial is defined.  
The Sponsor reserves the right to discontinue the clinical trial/investigation at any stage or 
reduce the follow up period with suitable written notice to the investigator. Possible reason(s) 
may include, but are not limited to: 
• Unanticipated adverse device effect (e.g., UADE) occurs and it presents an 
unreasonable risk to the participating subjects. 
• Any oversight committee (e.g., Steering/Executive Committee, Data Safety 
Monitoring Board [DSMB]) makes a recommendation to stop or terminate the trial 
(such as higher frequency of anticipated adverse device effects). 
• Further product development is cancelled. 
Should the clinical trial be discontinued by the Sponsor, subjects will be followed up as per 
routine hospital practice with device related AEs being reported to the Sponsor as per 
vigilance/commercial reporting requirements. 


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Should this occur, the investigator shall return all clinical trial/investigation materials to the 
Sponsor, and provide a written statement as to why the premature termination has taken place 
to the IRB/EC (if applicable). All applicable Clinical Investigation documents shall be 
subject to the same retention policy as detailed in Section 12 Data Handling and Record 
Keeping.  
4.0 
ENDPOINTS 
4.1 
Primary Endpoint  
The primary endpoint is a composite rate of all death or all myocardial infarction (MI, 
modified ARC) from 3 to 12 months.  This composite endpoint was chosen because death 
and MI are important safety endpoints to evaluate short-term DAPT after PCI.  
4.2 
Major Secondary Endpoint(s) 
• Major bleeding rate (BARC type 2-5) from 3 to 12 months 
• Stent thrombosis (ARC definite/probable) from 3 to 12 months 
4.3 
Other Secondary Endpoint(s) 
The following endpoints will be assessed from 3 to 12 months: 
• All death, cardiac death, vascular death, non-cardiovascular death  
• All MI (modified ARC) and MI attributed to target vessel (TV-MI, modified ARC) 
• Composite of cardiac death or MI (modified ARC) 
• All stroke, ischemic stroke and hemorrhagic stroke  
• Clinically-indicated target lesion revascularization (CI-TLR)  
• Clinically-indicated target vessel revascularization (CI-TVR)  
• Target lesion failure (TLF, composite of cardiac death, TV-MI and CI-TLR)  
• Target vessel failure (TVF, composite of cardiac death, TV-MI and CI-TVR) 
• Major bleeding defined by the Bleeding Academic Research Consortium (BARC) type 3-
5   
5.0 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 
Subject Population 
This trial will register male and female HBR subjects from the general interventional 
cardiology population who satisfy the inclusion and exclusion criteria. Approximately 2,000 
subjects will be registered. Subjects must meet all clinical and angiographic eligibility criteria 
and provide written informed consent prior to conducting any trial-specific procedures not 
considered standard of care.  
5.1.1 Medicare Population 
This trial will register male and female HBR subjects including those age 65 years old and 
older, i.e., Medicare age.  The study results are expected to be generalizable to the Medicare 
population. It is not expected that the results will be any different for Medicare patients than 
for non-Medicare patients.  


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5.2 
Subject Screening and Informed Consent  
5.2.1 Subject Screening 
Subjects admitted for a percutaneous coronary artery revascularization procedure must be 
screened for clinical trial eligibility by a member of the clinical trial team (physician and/or 
research coordinator) previously trained to the clinical trial protocol and if applicable will be 
entered into a site specific screening log.  
Subjects meeting the general inclusion and exclusion criteria will be asked to sign an 
informed consent. Pre-procedure (or baseline) imaging will be used for the final assessment 
of subject eligibility (details are described in Section 5.3). Subjects who do not satisfy the 
angiographic inclusion and exclusion criteria are considered screen failures and will not be 
registered and proceed further in the trial. These subjects will be entered into the screening 
log. Also, the reason for screen failure as well as supporting data will be entered into the log. 
Patient data will be collected following registration into the trial/investigation. 
5.2.2 Informed Consent 
The Investigator or designee, who has been trained on the Protocol, will explain the nature 
and scope of the trial, potential risks and benefits of participation, and answer questions for 
the subjects. All subjects (or legally authorized subjects’ representatives if applicable) must 
sign and date (and time, as per applicable local standards) the Institutional Review Board 
(IRB)/Ethics Committee (EC) approved informed consent (ICF) prior to any clinical 
trial/investigation-specific procedures. All efforts should be made to consent a subject prior 
to index procedure. However, it is acceptable for the subject to provide consent prior to 
hospital discharge and up to 3 days after the index procedure, only if the site confirms that the 
protocol required DAPT regimen is site’s standard of care.  If staged procedures are needed 
for a subject, the site may consent the subject after the initial procedure. 
Obtaining the consent and provisioning of a copy to the subject, along with the date and time 
must be documented in the subject’s medical records. The ICF must be signed by the 
investigator or designate (if allowed per country specific regulations). In addition, the signed 
informed consent must be kept in the subject’s medical records/research chart and a copy 
must be given to the subject or the legally authorized representative. 
In addition, an authorization for use and disclosure of the subject’s protected health 
information, in accordance with the Health Insurance Portability and Accountability Act 
(HIPAA), must be obtained from the subject or their legally authorized representative (US 
only). 
For Live cases at congresses the patients need to sign a specific Live Case ICF, approved by 
the IRB/EC. The investigator must notify Abbott Vascular prior to performing a Live Case.  
FDA approval is also required for a live case conducted in US. 
5.3 
Eligibility Criteria 
5.3.1   General Eligibility Criteria 
Assessment for general eligibility criteria is based on medical records of the site and 
interview with a candidate subject. If some of the clinical and laboratory tests are not 
included in site standard tests, they must be done but after written informed consent is 
obtained. Subjects must meet ALL of the inclusion criteria to be considered for the clinical 
evaluation. If ANY of the exclusion criteria are met, the subject is excluded from the clinical 
evaluation and cannot be registered.   


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5.3.1.1 
General Inclusion Criteria 
1. 
Subject is considered at high risk for bleeding (HBR), defined as meeting one or more of 
the following criteria at the time of registration and in the opinion of the referring 
physician, the risk of major bleeding with > 3-month DAPT outweighs the benefit: 
a) ≥ 75 years of age.  
b) Clinical indication for chronic (at least 6 months) or lifelong anticoagulation 
therapy. 
c) History of major bleeding which required medical attention within 12 months of 
the index procedure. 
d) History of stroke (ischemic or hemorrhagic).  
e) Renal insufficiency (creatinine ≥ 2.0 mg/dl) or failure (dialysis dependent). 
f) Systemic conditions associated with an increased bleeding risk (e.g. hematological 
disorders, including a history of or current thrombocytopenia defined as a platelet 
count <100,000/mm3, or any known coagulation disorder associated with 
increased bleeding risk). 
g) Anemia with hemoglobin < 11g/dl. 
2. Subject must be at least 18 years of age.  
3. Subject or a legally authorized representative must provide written informed consent as 
approved by the Institutional Review Board (IRB)/Ethics Committee (EC) of the 
respective clinical site prior to any study related procedure. 
4. Subject is willing to comply with all protocol requirements, including agreement to stop 
taking P2Y12 inhibitor at 3 months, if eligible per protocol. 
5. Subject must agree not to participate in any other clinical trial for a period of one year 
following the index procedure. 
5.3.1.2 
General Exclusion Criteria 
1. Subject with an indication for the index procedure of acute ST-segment elevation MI 
(STEMI).  
2. Subject has a known hypersensitivity or contraindication to aspirin, heparin/bivalirudin, 
P2Y12 inhibitors (clopidogrel/prasugrel/ticagrelor), everolimus, cobalt, chromium, 
nickel, tungsten, acrylic and fluoro polymers or contrast sensitivity that cannot be 
adequately pre-medicated. 
3. Subject with implantation of another drug-eluting stent (other than XIENCE) within 9 
months prior to index procedure. 
4. Subject has a known left ventricular ejection fraction (LVEF) <30%. 
5. Subject judged by physician as inappropriate for discontinuation from P2Y12 inhibitor 
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6. Subject with planned surgery or procedure necessitating discontinuation of P2Y12 
inhibitor within 3 months following index procedure. 
7. Subject with a current medical condition with a life expectancy of less than 12 months 
8. Subject intends to participate in an investigational drug or device trial within 12 months 
following the index procedure. 
9. Pregnant or nursing subjects and those who plan pregnancy in the period up to 1 year 
following index procedure. Female subjects of child-bearing potential must have a 
negative pregnancy test done within 7 days prior to the index procedure per site standard 
test.  
Note: Female patients of childbearing potential should be instructed to use safe 
contraception (e.g., intrauterine devices, hormonal contraceptives: contraceptive pills, 
implants, transdermal patches, hormonal vaginal devices, injections with prolonged 
release.) It is accepted, in certain cases, to include subjects having a sterilised regular 
partner or subjects using a double barrier contraceptive method. However, this should be 
explicitly justified in special circumstances arising from the study design, product 
characteristics and/or study population. 
10. Subject is part of a vulnerable population, defined as subject whose willingness to 
volunteer in a clinical investigation could be unduly influenced by the expectation, 
whether justified or not, of benefits associated with participation or of retaliatory response 
from senior members of a hierarchy in case of refusal to participate.  Examples of 
populations which may contain vulnerable subjects include: individuals with lack of or 
loss of autonomy due to immaturity or through mental disability, persons in nursing 
homes, children, impoverished persons, subjects in emergency situations, ethnic minority 
groups, homeless persons, nomads, refugees, and those incapable of giving informed 
consent. Other vulnerable subjects include, for example, members of a group with a 
hierarchical structure such as university students, subordinate hospital and laboratory 
personnel, employees of the sponsor, members of the armed forces, and persons kept in 
detention. 
11. Subject is currently participating in another clinical trial that has not yet completed its 
primary endpoint. 
5.3.2 Angiographic Eligibility Criteria 
All angiographic eligibility criteria are based on visual assessment. 
5.3.2.1 
Angiographic Inclusion Criteria 
1. Up to three target lesions with a maximum of two target lesions per epicardial vessel. 
Note: 
• The definition of epicardial vessels means left anterior descending coronary artery 
(LAD), left circumflex coronary artery (LCX) and right coronary artery (RCA) and 
their branches. For example, the patient must not have >2 lesions requiring treatment 
within both the LAD and a diagonal branch in total. 


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• If there are two target lesions within the same epicardial vessel, the two target lesions 
must be at least 15 mm apart per visual estimation; otherwise this is considered as a 
single target lesion. 
2. Target lesion ≤ 32 mm in length by visual estimation. 
3. Target lesion must be located in a native coronary artery with visually estimated reference 
vessel diameter between 2.25 mm and 4.25 mm.  
4. Exclusive use of XIENCE family of stent systems during the index procedure. 
5. Target lesion has been treated successfully, which is defined as achievement of a final in-
stent residual diameter stenosis of <20% with final TIMI-3 flow assessed by online 
quantitative angiography or visual estimation, with no residual dissection NHLBI grade ≥ 
type B, and no transient or sustained angiographic complications (e.g., distal 
embolization, side branch closure), no chest pain lasting > 5 minutes, and no ST segment 
elevation > 0.5 mm or depression lasting > 5 minutes. 
5.3.2.2 
Angiographic Exclusion Criteria  
1. Target lesion is in a left main location.  
2. Target lesion is located within an arterial or saphenous vein graft. 
3. Target lesion is restenotic from a previous stent implantation.  
4. Target lesion is a total occluded lesion (TIMI flow 0). 
5. Target lesion contains thrombus as indicated in the angiographic images (per SYNTAX 
score thrombus definition).  
6. Target lesion is implanted with overlapping stents, whether planned or for bailout. 
Note: If there is more than one target lesion, all target lesions must satisfy the angiographic 
eligibility criteria. Non-target lesion (i.e., lesions that do not meet the angiographic criteria 
listed above) treatments are not allowed during the index procedure. 
5.4 
Subject Registration  
Subject registration will occur after the index procedure but prior to discharge and up to 3 
days post index procedure, upon confirmation of the following:  
• Signed informed consent has been obtained;  
• Subject has met all the inclusion and none of the exclusion criteria (including both 
general and angiographic criteria). 
Planned staged procedures are allowed (recommend to be performed within 30 days). The 
site may consent the subject after the initial procedure. Subject registration will occur once 
the last staged procedure is performed, and the last staged procedure is considered as the 
index procedure. 
5.5 
Subject Discontinuation 
All registered subjects will be considered to have completed the study upon study completion 
of the 12-month follow-up.  


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Each registered subject shall remain in the trial until completion of the required follow-up 
period; however, a subject’s participation in any clinical trial is voluntary and the subject has 
the right to withdraw at any time without penalty or loss of benefit. Conceivable reasons for 
discontinuation may include, but not be limited to, the following: 
• Subject death 
• Subject voluntary withdrawal  
• Subject withdrawal by physician as clinically-indicated 
• Subject lost-to follow-up as described below  
• Subject’s follow-up is terminated according to Section 3.4 Early termination of the 
Clinical Trial 
The Sponsor must be notified of the reason(s) for subject discontinuation. The site will record 
this information on the eCRF and source documents and provide this information to the 
Sponsor. Investigators must also report this to their respective IRB/EC as defined by their 
institution’s procedure(s).  
No additional follow–up will be required or data recorded from subjects once withdrawn 
from the trial, except for the status (deceased/alive). 
However, if a subject withdraws from the study due to problems related to the investigational 
device safety or performance, the investigator shall ask for the subject's permission to follow 
his/her status/condition outside of the clinical investigation. 
Lost-to-Follow-up:   
If the subject misses two consecutive scheduled follow up time points and the attempts at 
contacting the subject detailed below are unsuccessful, then the subject is considered lost-to 
follow-up. Site personnel shall make all reasonable efforts to locate and communicate with 
the subject (and document these efforts in the source documents), including the following, at 
each contact time point: 
• A minimum of 2 telephone calls on different days over the specified follow-up windows to 
contact the subject should be recorded in the source documentation, including date, time 
and initials of site personnel trying to make contact. 
• If these attempts are unsuccessful, a letter (certified if applicable) should be sent to the 
subject. 
• If a subject misses one or more non-consecutive follow-up contact time points it will be 
considered a missed visit. The subject may then return for subsequent visits. If the subject 
misses two consecutive time points and the above-mentioned attempts at communicating 
with the subject are unsuccessful, the subject will be considered lost-to-follow-up.  
Note: Telephone contact with General Practitioner, non-study cardiologist or relative without 
presence of subject or indirect documentation obtained via discharge letters will not be 
considered as subject contact. 
Missed Visits: 
• If a subject misses one or more non-consecutive follow-up contact time points, the visit 
will be considered a missed visit and subject is not lost-to-follow-up.   


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• If subject responds via written communication (including email correspondence), 
providing the protocol required data, these data will be collected in the case report form 
and the visit will not be considered a missed visit.   
5.6 
Total Expected Duration of the Clinical Investigation 
The total expected duration of the clinical investigation is approximately 30 months. 
5.7 
Expected Duration of Each Subject’s Participation 
The expected duration of each subject’s participation in this clinical investigation is 
approximately 12 months. 
5.8 
Number of Subjects Required to be Included in the Clinical Investigation 
Approximately 2,000 subjects are required to be included in the clinical investigation. 
5.9 
Estimated Time Needed to Register this Number  
The estimated time needed to register 2,000 subjects is approximately 18 months. 
5.10 
Trial Completion 
A Trial Completion eCRF must be completed when: 
• the subject is considered lost to follow-up per the above definition or  
• the subject withdraws from the Clinical Trial or 
• the investigator withdraws the subject from the Clinical Trial or 
• the subject has died or 
• upon Clinical Trial completion or 
• sponsor termination of trial. 
Sponsor must be notified of the reason for subject discontinuation. The site will provide this 
information on the eCRF. Investigators must also report this to their EC/IRB as defined by 
their institution’s procedure. Subjects will not be replaced. 
6.0 
TREATMENT AND EVALUATION  
6.1 
Baseline and Pre-procedure 
6.1.1 Laboratory Assessments  
Baseline 12-lead electrocardiogram (ECG) and laboratory assessments (such as blood counts, 
chemistry panel and lipid panel, cardiac enzymes, etc.) should be obtained per site’s standard 
of care. Baseline laboratory results related to inclusion/exclusion criteria should be available 
and reviewed prior to the index procedure for screening. 
6.1.2 Clinical Assessments 
Subject demographics (age, gender, race), height, weight, family history of coronary artery 
disease (CAD), smoking status, cardiac history (myocardial infarction, diabetes mellitus, 
hypertension, hypercholesterolemia, and previous PCI/CABG information), subject’s current 
cardiac status (presentation of CAD and multivessel disease) and indication of high bleeding 
risk (per criteria specified in Section 5.3.1.1) will be obtained and recorded in electronic case 
report form (eCRF).   
6.1.3 Pre-procedure Antiplatelet Medication 
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• Subjects must receive a loading dose of aspirin AND a P2Y12 inhibitor (Clopidogrel, 
Prasugrel or Ticagrelor). The dosages of aspirin and P2Y12 inhibitor shall be 
determined by physician per standard of care and label indication for loading dose 
usage. The choice of P2Y12 inhibitor is per site standard of care, but clopidogrel is 
strongly recommended for HBR subjects.  Per physician’s discretion, a loading dose 
of P2Y12 inhibitor may be omitted if the subject was on chronic usage for ≥ 7 days.  
The details of the antiplatelet loading dose, including type of drug, dosage, date and time, 
will be recorded in eCRF.  
6.2 
Index Procedure 
Only XIENCE stent can be used for target lesion(s). Stent implantation procedure should be 
performed according to the instruction for use (IFU) of the XIENCE family stent used. If 
XIENCE stent is delivered beyond the guide catheter but not implanted, the subject should 
not be registered in the study. If other DES was implanted, the subject should not be 
registered in the study.  
In this study, a maximum of three target lesions may be treated with a maximum of two target 
lesions per epicardial vessel. Non-target lesion (i.e., lesions that do not meet the angiographic 
eligibility criteria) treatments are not allowed during the index procedure.  
Planned staged procedures are allowed (recommend to be performed within 30 days). The 
site may consent the subject after the initial procedure. Subject registration will occur once 
the last staged procedure is performed and the last staged procedure is considered as the 
index procedure. Post-procedure DAPT duration will be measured from the last staged 
procedure.  Any planned stenting procedure must be done prior to subject registration. The 
subject must not have any additional stenting procedure planned after the index procedure.    
Subjects may receive appropriate anticoagulation and other therapy according to standard 
hospital practice.  
Overlapping stents are not allowed in the study, whether planned or for bailout. Subjects who 
received overlapping stents should not be registered in this study.  
Lesion characteristics (lesion location, % diameter stenosis, TIMI flow, RVD, lesion length, 
thrombus presence, bifurcation or not, lesion complexity), device (device name, size, number 
of device implanted, bailout usage, overlapping stent) and procedural information (procedure 
time, access site, procedural anticoagulant and anti-thrombotic medications, any procedure 
complications) will be collected and recorded in eCRF.  
6.3 
Post–procedure  
6.3.1 Post-procedure Laboratory and Clinical Tests 
Post-procedure ECG and cardiac enzymes are not mandatory in the study, and shall be 
performed per site’s standard care. CK and CK-MB are preferred. If CK and CK-MB are not 
available, troponin should be collected. 
6.3.2 Antiplatelet Medications during Follow-up  
• All subjects must receive ≥75 to ≤100 mg of aspirin daily throughout the study. All 
subjects must maintain a minimum of 75 mg of clopidogrel daily or 5 or 10 mg of 
prasugrel daily (10 mg preferred in most subjects*) or 90 mg twice daily of ticagrelor for 
at least 3 months following the procedure.  
­ The choice of P2Y12 inhibitor is per site standard of care, but clopidogrel is 
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­ For subjects taking chronic anticoagulants, dual therapy (oral anticoagulant and a 
P2Y12 inhibitor, clopidogrel preferred) may be considered for the first 3 months 
after index procedure per investigator’s discretion. 
• At 3-month follow up, subject will be assessed for their eligibility of P2Y12 inhibitor 
discontinuation. Eligible subjects will discontinue P2Y12 inhibitor and receive ≥75 to 
≤100 mg of aspirin daily through 1-year follow-up during the study if they are “3-month 
clear”, defined as subjects who are free from myocardial infarction (modified ARC), 
repeat coronary revascularization, stroke, or stent thrombosis (ARC definite/probable) 
within 3 months (prior to 3-month visit but at least 90 days) after stenting AND have been 
compliant with 3-month dual antiplatelet therapy (DAPT) without interruption of either 
aspirin and/or P2Y12 receptor inhibitor for > 7 consecutive days.  
­ Peri-procedural MI (occurred within 48 hours post index procedure) without any 
clinical symptoms will not be considered exclusionary event for the definition of 
“3-month clear”. 
­ Dual therapy (oral anticoagulant and a P2Y12 inhibitor, clopidogrel preferred) 
within the first 3 months post index procedure for subjects who are on chronic 
anticoagulants is acceptable for the definition of “3-month clear”. 
• Subjects who are not “3-month clear” are NOT eligible for P2Y12 inhibitor 
discontinuation at 3-month. These subjects will be treated per the investigator's discretion 
and will continue to be followed up through 12 months. 
*For prasugrel subjects < 60 kg in weight or ≥ 75 years of age, a maintenance dose of 5 mg 
per day for 12 months is allowable.   
The use of the above antiplatelet medications, including the start and stop date, any changes, 
as well as the reason to stop, will be documented in the eCRF. 
6.3.3 Other Chronic Concomitant Medications 
Administration of concomitant medications other than any approved P2Y12 inhibitors and 
aspirin are not required in this protocol. Subjects may receive other medications as needed 
per physician’s discretion.  
6.4 
Clinical Follow-up for All Subjects 
Subjects registered in the trial will receive the following clinical follow-up: 
• 3 months (90 ± 7 days): office visit (Note: A formal office visit is required at 3-month 
follow-up to ensure a thorough clinical evaluation. A telephone contact is an option 
only for subjects who would otherwise be lost to follow-up due to being unable to 
complete an office visit, but a formal follow-up visit is still preferred at 3 months.) 
• 6 months (180 ± 14 days): office visit/ telephone contact (office visit is strongly 
recommended whenever possible) 
• 12 months (365 ± 28 days): office visit/ telephone contact (office visit is strongly 
recommended whenever possible) 
 
Clinical follow-up visits should be conducted by the investigator or study personnel who 
have been trained to the protocol. At 3-month follow-up visit, the investigator or designee 


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will assess whether the subject is “3-month clear” and eligible for P2Y12 inhibitor 
discontinuation per criteria defined in Section 6.3.2.  
All registered subjects will be followed up through 12 months, regardless of eligibility to 
discontinue P2Y12 inhibitor. 
The following information will be collected at each of the time points: 
• Any adverse events  
• Use and compliance of protocol required antiplatelet medication 
• Details of any subsequent coronary interventions (e.g., repeat PCI or CABG) 
Note that information obtained through indirect contacts with a subject’s healthcare provider 
or immediate family member will NOT be considered as a study visit. 
6.5 
Additional Follow-up Visits for All Subjects  
Additional subject visits, such as unscheduled visits, may occur as clinically warranted. The 
following information will be collected and recorded in eCRF:  
• Any adverse events  
• Use and compliance of protocol required antiplatelet medication 
• Details of any subsequent coronary interventions (e.g., repeat PCI or CABG) 
If an unscheduled visit is conducted due to a suspected ischemic cardiac event, cardiac 
enzymes and ECG may be performed per site’s standard care. CK and CK-MB are preferred. 
If CK and CK-MB are not available, troponin should be collected. 
All efforts must be made to obtain follow-up information on subjects who have undergone 
procedures or have been treated for adverse events in a non-trial-related hospital(s). 
7.0 
ADVERSE EVENTS 
To comply with worldwide standards and guidelines on clinical trial adverse event reporting, 
AV has developed uniform and worldwide applicable standard definitions and reporting 
timelines to be used and adhered to by the investigators. 
7.1 
Definition  
7.1.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. 
Note 1: This definition includes events related to the investigational medical device or the 
comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
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7.1.2 Serious Adverse Event 
If the AE meets any of the criteria below, it is regarded as a serious adverse event (SAE).  
a) Led to a death, 
b) Led to a serious deterioration in health that either: 
1) Resulted in a life-threatening illness or injury, or 
2) Resulted in a permanent impairment of a body structure or a body function, or 
3) Required in-patient hospitalization or prolongation of existing hospitalization, or 
4) Resulted in medical or surgical intervention to prevent life threatening illness or 
injury or permanent impairment to a body structure or a body function. 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
d) An important medical event that may not result in death, be life-threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical 
judgment, may jeopardize the subject and/or may require intervention to prevent one of the 
outcomes listed in this definition. 
Note 1: This includes device deficiencies that might have led to a serious adverse event if a) 
suitable action had not been taken or b) intervention had not been made or c) if circumstances 
had been less fortunate. These are handled under the SAE reporting system. 
Note 2: A planned hospitalization for pre-existing condition, or a procedure required by the 
Clinical Investigation Plan, without a serious deterioration in health, is not considered to be a 
serious adverse event. 
7.1.3 Device Deficiency/Device Malfunction 
Device deficiency (DD) is defined as an inadequacy of a medical device related to its 
identity, quality, durability, reliability, safety or performance, such as malfunction, misuse or 
use error and inadequate labeling. This includes the failure of the device to meet its 
performance specifications or otherwise perform as intended. Note: Performance 
specifications include all claims made in the labeling of the device. 
A device malfunction (DM) is the failure of a device to meet its performance specifications 
or otherwise perform as intended, when used in accordance with the instructions for use or 
the study protocol. 
7.2 
Device Relationship 
Determination of whether there is a reasonable possibility that an investigational product or 
device caused or contributed to an AE is to be determined by the Investigator and recorded 
on the appropriate eCRF form. Determination should be based on assessment of temporal 
relationships, evidence of alternative etiology, medical/biologic plausibility, and patient 
condition (pre-existing condition). 
7.2.1 Unanticipated (Serious) Adverse Device Effect  
Unanticipated (serious) adverse device effect [U(S)ADE] refers to any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan 
or application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects. 


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7.3 
Adverse Event Reporting 
7.3.1 Adverse Event Reporting 
For all registered subjects, AE reporting starts when the guiding catheter enters the subject’s 
vasculature. All AEs will be collected through 12-month follow-up visit.   
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be 
recorded on the AE eCRF page.  
Non-cardiac related abnormal laboratory values will not be considered AEs unless:  
1) the investigator determined that the value is clinically significant,  
2) the abnormal lab value required intervention, or  
3) the abnormal lab value required subject termination from the study. 
The Investigator will monitor the occurrence of AEs for each subject during the course of the 
clinical trial and report as required by this protocol in Section 7 per AE and SAE definitions. 
AEs need to be collected as of the time point of guiding catheter enters the subject’s 
vasculature on the appropriate AE eCRF form. Additional information with regards to an 
adverse event should be updated within the appropriate case report form.  
A fax form will be made available to allow the investigator to report SAEs in the event the 
entry cannot be made in the EDC. This does not replace the EDC reporting system. All 
information must still be entered in the EDC system as soon as feasible.  
The investigator should report all SAEs to the Sponsor as soon as possible but no later than 
outlined below.  
Study site 
Reporting timelines 
All Study Sites 
SAEs must be reported no later than 3 calendar days from the day the 
study personnel became aware of the event or as per the investigative 
site’s local requirements, if the requirement is more stringent than 
those outlined. 
The date the site staff became aware that the event met the criteria of a serious adverse event 
must be recorded in the source document.  
Serious adverse events that occurred in the user or persons other than the study subject should 
not be entered in the EDC system, however need to be reported via the SAE Notification 
Form.   
The Investigator will further report the SAE to the local IRB/EC according to the institution’s 
IRB/EC reporting requirements.    
7.3.2 Unanticipated Serious Adverse Device Effect Reporting to Sponsor and IRB 
Abbott Vascular requires the Investigator to report any USADE to the sponsor within 3 
calendar days of the investigator’s knowledge of the event, unless local requirements are 
more stringent, and to the IRB/EC per IRB/EC requirements.  
7.3.3 Device Deficiency/Device Malfunction Reporting  
 
All device deficiencies/malfunctions should be reported within the EDC System on the 
appropriate eCRF form. A fax form will be made available to allow the investigator to report 
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does not replace the EDC reporting system. All information must still be entered in the EDC 
system as soon as feasible.  
In case a device deficiency/malfunction occurred before the patient ID has been assigned, the 
device deficiency should be reported to the Sponsor via the fax form. 
The investigator should report all DDs/DMs to the Sponsor as soon as possible but no later 
than outlined below:  
Study sites 
Reporting timelines 
All Study Sites 
DDs/DMs must be reported no later than 3 calendar days from the 
day the study personnel became aware of the event or as per the 
investigative site’s local requirements, if the requirement is more 
stringent than those outlined. 
The device, if not implanted or not remaining in the subject, should be returned to Abbott 
Vascular.   
Device deficiencies/malfunctions should be reported to the IRB/EC per the investigative 
site’s local requirements.  
 
If there is a device deficiency/malfunction related to other AV products, please contact the 
Product Performance Group (PPG) by e-mail: qahotline@av.abbott.com or contact AV Sales 
person to complete a Product Experience Form (PER Form). 
7.3.4 Adverse Event Reporting to Country Regulatory Authorities by the Sponsor  
The Sponsor or designee will report the SAEs and DDs/product experiences (PEs) to the 
country regulatory authority, per local requirements.  
7.4 
Safety Monitoring by Data Safety Monitoring Board (DSMB) 
The DSMB will serve in an advisory role to Abbott Vascular to ensure safety by reviewing 
cumulative data from the clinical trial at prescribed intervals for the purpose of safeguarding 
the interests of trial participants.  
The DSMB may consider a recommendation for modifications or termination of the trial 
based on any perceived safety concerns regardless of statistical significance. The 
recommendations of the DSMB are not binding, and all final decisions related to trial 
modifications rest with Abbott Vascular. 
8.0 
ADJUDICATION OF EVENTS 
The Clinical Events Committee (CEC) is comprised of qualified physicians who are not 
investigators in the trial. The CEC will review and adjudicate pre-specified events reported 
by trial investigators or identified by the Clinical Safety personnel/designate for the trial as 
documented in CEC Manual of Operations (MOPs).  
9.0 
STATISTICAL ANALYSIS  
9.1 
Statistical Overview  
The XIENCE 90 trial is powered based on primary endpoint of all death or all myocardial 
infarction [modified ARC] (Death/MI) from 3- to 12-month follow-up.  
Primary endpoint analysis for 3-month DAPT 


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The primary endpoint of Death/MI between 3-month and 12-month follow-up will be 
evaluated based on the “3-month clear” population (as defined in section 9.2). The hypothesis 
test is designed for non-inferiority of 3-month DAPT from XIENCE 90 compared to standard 
DAPT duration up to 12 months from XIENCE V USA historical control for the primary 
endpoint with one-sided alpha of 0.025 after propensity score stratification. The null (H0) and 
alternative (HA) hypothesis are of the following form: 
                        H0: Death/MI3m-DAPT  -  Death/MIXience V USA   ≥ δ 
HA: Death/MI3m-DAPT  -  Death/MIXience V USA  < δ 
A stratified statistical method through propensity score will be performed to test non-
inferiority (NI) of 3-month DAPT to XIENCE V USA historical control. 
The trial success is defined as passing the non-inferiority test on the primary endpoint 
Death/MI for the “3-month clear” population.  
Major secondary endpoint analyses for 3-month DAPT  
If the hypothesis testing for the primary endpoint is successful, the following major 
secondary analyses will be performed. 
A superiority test for the major secondary endpoint of BARC type 2-5 bleeding. Stratified 
propensity score method will be applied for the analysis of the major secondary endpoint as 
well. This test will be based on one-sided alpha of 0.025. The null (H0) and alternative (HA) 
hypotheses are of the following form: 
                  H0: B3m-DAPT –BXience V USA  ≥ 0 
HA: B3m-DAPT –BXience V USA  < 0 
B3m-DAPT and BXience V USA are major bleeding rates (BARC type 2-5) between 3-month and 12-
month follow-up for XIENCE 90 and XIENCE V USA historical control, respectively.  
Major secondary endpoint of stent thrombosis (ARC definite/probable) from 3 to 12 months 
of XIENCE 90 will be evaluated against a pre-specified performance goal (PG). 
Other secondary clinical endpoints will be descriptively analyzed.   
9.2 
Analysis Populations  
The primary analysis population is “3-month clear” population, defined as subjects who are 
free from myocardial infarction (modified ARC), repeat coronary revascularization, stroke, or 
stent thrombosis (ARC definite/probable) within 3 months (prior to 3-month visit but at least 
90 days) after stenting AND have been compliant with 3-month dual antiplatelet therapy 
(DAPT) without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 
consecutive days. 
9.3 
Sample Size Calculations and Assumptions  
9.3.1 Primary Endpoint  
To evaluate the safety of the 3-month DAPT, the non-inferiority test will be performed on the 
primary endpoint of Death/MI between 3-month and 12-month follow-up for XIENCE 90 
against XIENCE V USA historical control after propensity score stratification with the 
following assumptions: 
True event rate for the primary endpoint is assumed to be 6.1% for both arms    
Non-inferiority margin: 2.8%  
Attrition rate of 15% due to using “3-month clear” population for the XIENCE 90 3-month 
DAPT arm  
One-sided alpha = 0.025 
Sample size in the control arm: ~1,150 
Approximately 87% power 
Sample size of 2,000 subjects in XIENCE 90 will be required for this test.  
The sample size calculations were performed using NCSS PASS 11 (Hintze, J., 2011, NCSS, 
LLC. Kaysville, Utah). 


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9.3.2 Major Secondary Endpoint  
Given the success of the primary analysis for the primary endpoint, the following major 
secondary analyses will be performed: 
Superiority test for the major bleeding rate (BARC type 2-5) from 3- to 12-month follow-up 
will be tested between XIENCE 90 and the XIENCE V USA historical control stratified by 
propensity scores. 
Stent thrombosis (ARC definite/probable) from 3- to 12-month follow-up of XIENCE 90 will 
be evaluated against a pre-specified performance goal (PG).  
Details of the above major secondary analyses could be found in the Statistical Analysis Plan 
(SAP). 
 
9.4 
Statistical Analyses  
A stratified statistical method through propensity score will be used to test non-inferiority of 
3-month DAPT in XIENCE 90 to XIENCE V USA historical control for the primary 
endpoint of death/MI at a 0.025 significant level.  
Major secondary analyses will be performed only if the primary hypothesis testing is 
successful. 
Analyses of other secondary endpoints and additional endpoints will be descriptive in nature. 
For binary variables such as TLR, TVR, counts, percentages and 95% confidence intervals 
will be calculated, and p-values may be presented for hypothesis generating purposes. 
Pearson’s Chi-squared test of Fisher’s exact test will be performed when appropriate. 
For continuous variables such as age, means, standard deviation, and 95% confidence 
intervals for the mean will be calculated and p-values may be presented for hypothesis 
generating purposes. For time-to-event variables, such as time to Death/MI, survival curves 
will be constructed using Kaplan-Meier estimates, and log rank test results will be displayed. 
Unless specified, analyses will be performed with pooled data across all study sites. 
For further details, refer to the Statistical Analysis Plan (SAP). 
9.4.1 Primary Endpoint Analysis  
A non-inferiority test will be performed on the primary endpoint of Death/MI between 3-
month and 12-month follow up for the “3-month clear” population of XIENCE 90 3-month 
DAPT arm and the XIENCE V USA historical control stratified by propensity scores. 
Details of the analyses for the powered primary endpoint can be found in the Statistical 
Analysis Plan (SAP). 
9.4.2 Major Secondary Endpoint Analysis 
• Superiority will be tested for the major secondary endpoint of major bleeding (BARC 
type 2-5) between 3-month and 12-month follow up for the “3-month clear” 
population of XIENCE 90 3-month DAPT arm and the XIENCE V USA historical 
control stratified by propensity scores.   
• Stent thrombosis (ARC definite/probable) from 3 to 12 months for the “3-month 
clear” population of XIENCE 90 will be evaluated against a pre-specified 
performance goal (PG).  
9.4.3 Secondary Endpoint Analyses  
Other secondary and additional clinical endpoints will be descriptively analyzed.  


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9.4.4 Subgroup Analysis 
Analyses will be performed for subgroups such as gender (male versus female), diabetes 
(diabetes versus non-diabetes), ethnicity (white versus non-white), age (age ≥ median versus 
< median), clinical presentation (ACS NSTEMI, ACS unstable angina, non-ACS), and the 
subgroup of US elderly patient with age ≥ 65 years old.  
9.4.5 Procedures for Accounting for Missing, Unused or Spurious Data 
The primary and secondary endpoint analyses will be evaluated after propensity score 
stratification. To handle missing data, multiple imputation method will be performed to 
compute propensity scores from these datasets. For further details, refer to the SAP. 
All other analyses will be based on available data with missing data excluded. Any unused or 
spurious data will be noted as appropriate in the final report.   
9.5  
Deviations from the Original Statistical Plan 
Any major changes to the statistical plan will be documented in an amendment to the 
statistical plan. Less significant changes to the planned analyses will be documented in the 
final report. 
10.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution will permit direct access to source data/documents in order for 
clinical investigation-related monitoring, audits, IRB/EC review and regulatory inspections to 
be performed. 
Subjects providing informed consent are agreeing to allow Sponsor and/or its designee access 
and copying rights to pertinent information in their medical records concerning their 
participation in this clinical investigation. The investigator will obtain, as part of the informed 
consent, permission for clinical investigation monitors or regulatory authorities to review, in 
confidence, any records identifying the subjects in this clinical investigation. This 
information may be shared with regulatory agencies; however, Sponsor undertakes not to 
otherwise release the subject's personal and private information.  
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Selection of Clinical Sites and Investigators 
Sponsor will select investigators qualified by training and experience, to participate in the 
investigation of the Clinical Investigation device. Sites will be selected based upon review of 
a recent site assessment, if applicable, and the qualifications of the Primary Investigator or 
multidisciplinary team at the site.  
11.2  Protocol Amendments  
Approved protocol amendments will be provided to the Investigators by the Sponsor prior to 
implementing the amendment. The Primary Investigator is responsible for notifying the IRB 
or equivalent committee of the protocol amendment (administrative changes) or obtaining 
IRB’s approval of the protocol amendment (changes in subject care or safety), according to 
the instructions provided by the Sponsor with the protocol amendment.   
Acknowledgement/approval by the IRB/EC of the protocol amendment must be documented 
in writing prior to implementation of the protocol amendment. Copies of this documentation 
must also be provided to the Sponsor. 


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11.3 
Training 
 
11.3.1 Site Training  
All Investigators/trial personnel are required to attend Sponsor training sessions, which may 
be conducted at an Investigator's meeting, a site initiation visit or other appropriate training 
sessions. Over-the-phone or self-training may take place as required. Training of 
Investigators/trial personnel will include, but is not limited to, the Protocol requirements, 
electronic case report form completion and trial personnel responsibilities. All 
Investigators/trial personnel that are trained must sign a training log (or an equivalent) upon 
completion of the training. Prior to signing the training log, Investigator/trial personnel must 
not perform any trial-related activities that are not considered standard of care at the site.  
11.3.2 Training of Sponsor’s Monitors 
 
Sponsor and/or designated monitors will be trained to the Protocol and case report forms. 
Documentation of this training will be according to written procedures. 
11.4 
Monitoring 
 
Sponsor and/or designee will monitor the study over its duration according to the pre-
specified monitoring plan which will include the planned extent of source data verification.  
The Sponsor should be contacted for additional information on the person(s) responsible for 
monitoring activities. 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the 
following criteria are met:  
• The investigator understands and accepts the obligation to conduct the research study 
according to the Protocol and applicable regulations, and has signed the Investigator 
Agreement or the Clinical Study Agreement.  
• The Investigator and his/her staff have sufficient time and facilities to conduct the study 
and that they have access to an adequate number of appropriate subjects to conduct the 
study.  
• Source documentation (including original medical records) must be available to 
substantiate proper informed consent procedures, adherence to Protocol procedures, 
adequate reporting and follow-up of adverse events, accuracy of data collected on case 
report forms, and device information.  
The Investigator/site will permit access to such records. A monitoring visit sign-in log will be 
maintained at the site. The Investigator will agree to dedicate an adequate amount of time to 
the monitoring process. The Investigator and/or research coordinator will be available for 
monitoring visits. It is expected that the Investigator will provide the study monitor with a 
suitable working environment for review of study-related documents. 
11.5 
Deviations from the Protocol 
The Investigator will not deviate from the Protocol for any reason without prior written 
approval from Sponsor except in cases of medical emergencies, when the deviation is 
necessary to protect the rights, safety and well-being of the subject or eliminate an apparent 
immediate hazard to the subject. In that event, the Investigator will notify Sponsor 
immediately by phone or in writing. All deviations must be reported to the Sponsor. In 
subject-specific deviations from the Protocol, a Protocol deviation case report form will be 
completed. The occurrence of Protocol deviations will be monitored by the Sponsor for 
evaluation of investigator compliance to the Protocol and regulatory requirements and dealt 


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with according to written procedures. Investigators will inform their IRB/EC or equivalent 
committee of all Protocol deviations in accordance with their specific IRB/EC or equivalent 
committee reporting policies and procedures.  
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor 
or company representative will attempt to secure compliance by one or more of the following 
(and not limited to):  
• Visiting the investigator and/or delegate 
• Telephoning the investigator and/or delegate 
• Corresponding with the investigator and/or delegate 
Repeated non-compliance with the signed agreement, the Protocol or any other conditions of 
the study may result in further escalation in accordance with the Sponsor’s written procedures 
including securing compliance or, at its sole discretion; Sponsor may terminate the 
investigator's participation in the study.  
The following categories of protocol deviations will be considered as major: 
• Informed Consent deviation 
• Eligibility deviation 
• Serious adverse event reporting deviation 
• Treatment/procedure compliance deviation  
 
The following categories of protocol deviations will be considered as minor: 
• Data outside time window 
• Missed visit 
11.6 
Quality Assurance Audits  
A Sponsor representative or designee may request access to all clinical investigation records, 
including source documentation, for inspection and duplication during a Quality Assurance 
audit. In the event that an investigator is contacted by a Regulatory Agency in relation to this 
clinical investigation, the Investigator will notify Sponsor immediately. The Investigator and 
Research Coordinator must be available to respond to reasonable requests and audit queries 
made during the audit process. The Investigator must provide Sponsor with copies of all 
correspondence that may affect the review of the current clinical investigation (e.g., Form 
FDA 483, Inspectional Observations, Warning Letters, Inspection Reports, etc.). Sponsor 
may provide any needed assistance in responding to regulatory audits.  
11.7 
Committees  
11.7.1 Steering Committee 
The Steering Committee is assigned by the Sponsor and comprises the Principal Investigator 
as specified on the cover page of this Protocol, the Trial Chairman (if applicable) and 
four/five dedicated members from the trial sites. The Sponsor will be represented by at least 
one person each from the Clinical Science and Clinical Program Management groups. The 
Chairman of the core laboratories and other sponsor’s personnel may also participate in the 
Committee meetings if appropriate. Meeting minutes from this committee will be filed with 
the Sponsor. 
 
The Steering Committee is responsible for overseeing the scientific and operational aspects of 
the trial. This committee will meet regularly to monitor patient registration or randomization, 
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and act upon recommendations of the Data and Safety Monitoring Board, to review 
operational issues that may arise and warrant a Protocol amendment or other corrective action 
and to determine policy regarding any publications arising from data generated from the 
performance of the trial. 
11.7.2  Data Safety Monitoring Board (DSMB) 
 
The Data Safety Monitoring Board (DSMB) is an independent multidisciplinary group that is 
restricted to individuals free of apparent significant conflicts of interest. The source of these 
conflicts may be financial, scientific, or regulatory in nature. The DSMB is typically 
composed of at least two physicians with relevant interventional experience (e.g., vascular 
surgeon, interventional radiologist, interventional cardiologist) and a biostatistician and is 
responsible for making recommendations regarding endpoint analyses and any potentially 
significant patient safety-related observations. The composition of the DSMB, frequency of 
the DSMB sessions and the statistical monitoring guidelines are described in detail in the 
DSMB charter. DSMB meeting minutes and recommendations are forwarded to Abbott 
Vascular.    
In addition to an Abbott Vascular/designee safety monitor reviewing adverse events at 
regular intervals, a monthly listing of Adverse Events will be sent to the DSMB Chair or 
designee for review. If a safety signal is identified during this review, then the DSMB chair 
will call for an ad hoc full DSMB meeting. 
11.7.3 Clinical Events Committee (CEC) 
 
The Clinical Events Committee (CEC) is an independent adjudication body comprised of 
qualified physicians who are not participants in the trial. The CEC will review and adjudicate 
events as defined in the CEC charter and according to definitions provided in this Protocol 
Appendix II.      
12.0 
DATA HANDLING AND RECORD KEEPING  
Data Management will include documentation of the systems and procedures used in data 
collection for the duration of the trial.  
All CRF data collection will be performed through a secure web portal and all authorized 
personnel with access to the Electronic Data Capture (EDC) system must use an electronic 
signature access method to enter, review or correct data. Passwords and electronic signatures 
will be strictly confidential.   
All CRF data will be downloaded from the EDC system and reformatted into a data structure 
acceptable to Abbott Vascular. The data will be subjected to consistency and validation 
checks within the EDC system and will be subject to supplemental validation following 
download.   
At the conclusion of the trial, completed CRF images with the date-and-time stamped 
electronic audit trail indicating the user, the data entered, and any reason for change (if 
applicable) will be archived for each investigational site and a backup copy archived with 
Abbott Vascular.  
For the clinical trial/investigation duration, the Investigator will maintain complete and 
accurate documentation including, but not limited to, medical records, clinical 
trial/investigation progress records, laboratory reports, electronic case report forms, signed 
ICFs, device accountability records, correspondence with the IRB and clinical 
trial/investigation monitor/Sponsor, adverse event reports, and information regarding subject 
discontinuation or completion of the clinical trial/investigation. 


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12.1 
Source Documentation 
 
Regulations and GCP require that the Investigator maintain information in the subject’s 
original medical records that corroborates data collected on the case report forms. In order to 
comply with these regulatory requirements/GCP, the following information should be 
included in the subject record at a minimum and if applicable to the investigation: 
• Medical history/physical condition of the subject before involvement in the trial 
sufficient to verify Protocol entry criteria 
• Dated and signed notes on the day of entry into the trial referencing the Sponsor, 
Protocol number, subject ID number and a statement that informed consent was 
obtained 
• Dated and signed notes from each subject visit (for specific results of procedures and 
exams) 
• Adverse events reported and their resolution including supporting documents such as 
discharge summaries, catheterization laboratory reports, ECGs, and lab results 
including documentation of site awareness of SAEs and of investigator device 
relationship assessment of SAEs. 
• Any laboratory reports and 12-lead ECGs (if performed), reviewed and annotated for 
clinical significance of out of range results.  
• Notes regarding Protocol-required and prescription medications taken during the trial 
(including start and stop dates) 
• Subject’s condition upon completion of or withdrawal from the trial 
• 
Any other data required to substantiate data entered into the CRF 
12.2 
Electronic Case Report Form Completion  
Primary data collection based on source-documented hospital and/or clinic chart reviews will 
be performed clearly and accurately by site personnel trained on the protocol and eCRF 
completion. eCRF data will be collected for all subjects that are registered into the trial.  
12.3 
Record Retention 
 
The Sponsor will archive and retain all documents pertaining to the trial as per the applicable 
regulatory record retention requirements. The Investigator must obtain permission from 
Sponsor in writing before destroying or transferring control of any clinical trial/investigation 
records. 
13.0 
ETHICAL CONSIDERATION 
 
13.1 
Institutional Review Board/Medical Ethics Committee Review  
Institutional Review Board (IRB)/ Ethics Committee (EC) approval for the Protocol and 
ICF/other written information provided to the patient will be obtained by the Primary 
Investigator at each investigational site prior to participation in this clinical trial/investigation. 
The approval letter must be received prior to the start of this clinical trial/investigation and a 
copy must be provided to the Sponsor. No changes will be made to the Protocol or ICF or 
other written information provided to the patient without appropriate approvals, including 
IRB/EC, the Sponsor, and/or the regulatory agencies.  
Until the clinical trial/investigation is completed, the Investigator will advise his/her IRB/EC 
of the progress of this clinical trial/investigation, per IRB/EC requirements. Written approval 


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must be obtained from the IRB/EC yearly to continue the clinical trial/investigation, or 
according to each institution’s IRB/EC requirements (US studies only). Further, any 
amendments to the Protocol as well as associated ICF changes will be submitted to the 
IRB/EC and written approval obtained prior to implementation, according to each 
institution’s IRB/EC requirements. 
No investigative procedures other than those defined in this Protocol will be undertaken on 
the registered subjects without the written agreement of the IRB/EC and the Sponsor. 
14.0 
PUBLICATION POLICY  
The data and results from the trial are the sole property of the Sponsor. The Sponsor shall 
have the right to access and use all data and results generated during the clinical trial. The 
Sponsor will submit trial results for publication, regardless of trial outcome, following the 
conclusion or termination of the trial.  The Investigators will not use the Clinical 
trial/investigation-related data without the written consent of the Sponsor for any other 
purpose than for Clinical trial/investigation completion or for generation of publication 
material, as referenced in the Clinical trial/investigation Site Agreement. The publication 
and/or presentation of results from a single clinical trial/investigation site are not allowed 
until publication and/or presentation of the multi-center results. The Sponsor acknowledges 
that the trial’s Principal Investigator intends to publish a multi-center publication regarding 
the clinical trial/investigation results. The Sponsor must receive any proposed publication 
and/or presentation materials at least 60 days prior to the proposed date of the presentation or 
the initial submission of the proposed publication in order for the materials to be reviewed by 
the Sponsor in compliance with the Sponsor’s publication policy set forth in the Clinical 
trial/investigation Site Agreement. 
The Sponsor will be responsible for determining whether to register the Clinical Investigation 
on www.clinicaltrials.gov or any other clinical investigations, in accordance with the 
International Committee of Medical Journal Editors guidelines, or any other applicable 
guidelines. In the event Sponsor determines that the Trial should be registered, Sponsor shall 
be responsible for any such registration and results posting as required by ClinicalTrials.gov. 
Institution and/or Principal Investigator(s) shall not take any action to register the Trial. 
15.0 
RISK ANALYSIS 
 
The optimal duration of DAPT remains a dilemma for clinicians with the current clinical 
practice, and is of particular interest to HBR patients which represent approximately 15% or 
more of patients undergoing PCI22,23. The default management of care for HBR patients who 
undergo PCI is often stenting with BMS followed by 1 month of DAPT. The European 
ESC/EACTS guidelines have recommended 3 months of DAPT with second-generation DES 
for HBR patients undergoing PCI24.  Consistent with the European guideline, the updated 
2016 ACC/AHA guideline also provided a class IIb recommendation of 3-month DAPT in 
SIHD patients with high risk of bleeding following DES implantation17. Studies with some 
DES (Endeavor, BioFreedom) have demonstrated safety of short-term DAPT for HBR 
patients45,47. 
 
XIENCE has consistently been shown to have the best safety profile among the coronary 
stents, even when compared to BMS, in both clinical trials and commercial data analysis. 
However, the benefit/risk ratio of a shorter duration of DAPT following XIENCE 
implantation in the HBR population has not been thoroughly evaluated. There is clearly an 
unmet medical need to be addressed for the HBR patient population as the possible benefits 
of extended DAPT therapy to prevent late stent thrombosis and the progression of 


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atherosclerotic disease need to be weighed against the increased risk of bleeding in an 
individual patient. Therefore, the XIENCE 90 study is designed to prospectively evaluate the 
safety of XIENCE followed with 3-month DAPT in HBR patients. 
15.1 
Anticipated Clinical Benefits 
The excellent safety profile of XIENCE family of stents has been well demonstrated. Stent 
implantation and the following medical treatment are the same for subjects registered in this 
study as if they are not participating in this clinical study, except for DAPT duration. Short-
term DAPT may decrease the risk of bleeding in HBR subjects. Participation of this study 
contributes to defining the optimum duration of DAPT in HBR subjects treated with 
XIENCE. 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects  
Observed and potential adverse events occurring with the XIENCE family of stents are listed 
in the IFUs. The incidence of these adverse events is comparable to other PCI devices. There 
may be risks related to the device that are unknown at present. 
Please refer to the drug labelling (most recent versions available at www.fda.gov – drugs - 
drugs@fda and www.ema.europa.eu – find medicine – human medicines), and published 
guidelines on PCI and DAPT use17,24 for information on bleeding and other risks associated 
with DAPT use. 
Short-term DAPT use may decrease the risk of bleeding in HBR subjects, but may increase 
the risk of late stent thrombosis and progression of atherosclerotic disease.  
15.3 
Residual Risks Associated with the Investigational Device, as Identified in the 
Risk Analysis Report 
The XIENCE Risk Assessment Report12 utilizes the Failure Modes and Effects Analysis 
(FMEA) tool to systematically identify potential hazards associated with the process, design, 
components, and use of the XIENCE product family. Based upon preclinical, clinical, bench 
data, and commercial post-production data, all residual risks are appropriate and acceptable. 
The benefit of treatment from the XIENCE outweighs the potential risks to the patient. 
Comprehensive analysis of product level clinical data, including clinical trial, post-marketing, 
and literature data, confirms that any undesirable risks identified are outweighed by the 
clinical benefits of the device13 . 
15.4 
Risks Associated with Participation in Clinical Investigation 
All procedures required by the protocol are routine standard of care. There are no additional 
risks to the subjects, except that short-term DAPT may increase the risk of stent thrombosis 
and ischemic events. 
15.5 
Possible Interactions with Protocol Required Concomitant Medications 
Other than DAPT, the study protocol does not require concomitant medications. 
 
 
 
 
 
12 RAM1070000 XIENCE Xpedition/XIENCE PROx EECSS RAM; RAM 1100000 XIENCE Alpine/XIENCE 
PROA EECSS RAM; RAM 1500000 XIENCE Sierra EECSS RAM 
13 RPT2098376 Rev G XIENCE EECSS Clinical Evaluation Report 


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15.6 
Steps that will be Taken to Control or Mitigate the Risks 
In-depth recommendations, special precautions and instructions regarding patient selection, 
vessel sizing, device handling, device placement and system removal are included in the IFU. 
It is also stated in the IFU that the devices can only be used by physicians who have received 
appropriate training on how to use the device. This statement is interpreted to mean that the 
physician users are expected to be aware of the known and foreseeable safety risks associated 
with the use of the devices including the surgical and/or non-surgical treatment of these 
conditions. 
Risks associated with the use of the device during this clinical study are minimized through 
device design, investigator selection and training, pre-specified patient eligibility 
requirements, study monitoring to ensure adherence to the protocol, clinical follow-up by 
investigator or designee at pre-specified time points and the use of a DSMB.  
All adverse events and device deficiencies observed in this study will be reported to Abbott 
Vascular, will be monitored internally for safety surveillance purposes, and will be reported 
to the regulatory authorities, as applicable (Refer to section 7.3 of this protocol ). 
Abbott Vascular updates the risk assessment reports and conducts comprehensive analysis of 
product level clinical data on a regular basis. 
The XIENCE family of stents has not been tested in pregnant women. Effects on the 
developing fetus and excretion of everolimus in breast milk have not been studied. Pregnant 
or nursing subjects and those who plan pregnancy in the period up to 1 year following index 
procedure are excluded from participation in the clinical study. Female subjects of child-
bearing potential must have a pregnancy test done within 7 days prior to the index procedure 
with negative results known to confirm eligibility prior to registration.  
15.7 
Risk to Benefit Rationale  
The XIENCE family of stent has consistently been shown to have the best safety profile 
among the coronary stents, in both clinical trials and commercial data analysis. The optimal 
duration of DAPT remains a dilemma for clinicians with the current clinical practice, and is 
of particular interest to HBR patients which represent approximately 15% or more of patients 
undergoing PCI. The XIENCE 90 study is designed to prospectively evaluate the safety of 
XIENCE followed with 3-month DAPT in HBR patients. Reduced DAPT treatment duration 
may decrease the risk of bleeding, but may increase the risk of late stent thrombosis and 
progression of atherosclerotic disease, although studies with other DES have demonstrated 
safety of short-term DAPT for HBR patients. Other than a reduction in the duration of DAPT, 
all procedures required by the protocol are routine standard of care and conducted according 
to the current IFU. 


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APPENDIX I: 
ABBREVIATIONS AND ACRONYMS 
 
Acronym or Abbreviation 
Complete Phrase or Definition 
%DS 
percent diameter stenosis 
ACS 
Acute Coronary Syndrome 
AE 
adverse event 
AMI 
acute myocardial infarction 
ARC 
Academic Research Consortium  
BARC 
Bleeding Academic Research Consortium 
BMS 
Bare metal stents 
CABG 
coronary artery bypass graft 
CAD 
coronary artery disease 
CASS 
Coronary Artery Surgery Study 
CCS 
Canadian Cardiovascular Society (Canada) 
CEC 
Clinical Events Committee 
CVA 
Cerebrovascular Accident 
CI 
clinically-indicated 
CI 
confidence interval 
CK 
creatine kinase 
CK-MB 
creatine kinase myocardial-band isoenzyme 
CoCr-EES 
cobalt chromium everolimus-eluting stent 
CVA 
cerebrovascular accident (or stroke) 
DAPT 
dual antiplatelet therapy 
DD 
device deficiency 
DES 
Drug-eluting stent 
DM 
device malfunction 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee (EU) 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EECS 
everolimus eluting coronary stent  
EECSS 
everolimus eluting coronary stent system   
FDA 
Food and Drug Administration 
FMEA 
Failure Modes and Effects Analysis  
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
HBR 
High bleeding risk 
ICF 
Informed Consent Form  


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Acronym or Abbreviation 
Complete Phrase or Definition 
IDE 
Investigational Device Exemption 
IFU 
Instructions for Use 
IRB 
Institutional Review Board (US and Japan) 
KM 
Kaplan-Meier 
LAD 
left anterior descending coronary artery 
LCX 
left circumflex coronary artery 
LMCA 
left main coronary artery 
LVEF 
left ventricular ejection fraction 
MACCE 
major adverse cerebral and cardiovascular event 
MEC 
Medical Ethics Committee (EU) 
MOP 
Manual of Operations 
µg 
microgram 
mg 
milligram 
MI 
myocardial infarction 
mL 
milliliter 
MLD 
mean lumen diameter 
mm 
millimeter 
N 
sample size; also N 
NSTEMI 
non ST-segment elevation MI 
NQMI 
non-Q wave myocardial infarction 
OCT 
optical coherence tomography 
OR 
odds ratio 
OUS 
Outside of United States 
PE 
product experience 
PCI 
percutaneous coronary intervention 
PG 
performance goal 
PTCA 
percutaneous transluminal coronary angioplasty 
QCA 
quantitative coronary angiography 
RCA 
right coronary artery 
RCT 
randomized clinical trial  
RVD 
reference vessel diameter 
RX 
Rapid Exchange 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SIHD 
stable ischemic heart disease 
ST 
stent thrombosis 
STEMI 
ST-segment elevation myocardial infarction 
TIA 
transient ischemic attack 
TIMI 
thrombolysis in myocardial infarction 


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Acronym or Abbreviation 
Complete Phrase or Definition 
TLR 
target lesion revascularization 
TLF 
target lesion failure 
TVF 
target vessel failure 
TVR 
target vessel revascularization 
UADE 
unanticipated adverse device effect 
ULN 
upper limit of normal 
US 
United States 
USADE 
unanticipated serious adverse device effect 


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APPENDIX II: 
DEFINITIONS 
 
CLINICAL ENDPOINT DEFINITIONS 
 
DEATH (Per ARC Circulation 2007; 115: 2344-2351) 
All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. 
Specifically, any unexpected death even in patients with coexisting potentially fatal non-
cardiac disease (e.g. cancer, infection) should be classified as cardiac.  
 
Cardiac death:  
Any death due to proximate cardiac cause (e.g. MI, low-output failure, fatal arrhythmia), 
unwitnessed death and death of unknown cause, all procedure related deaths including those 
related to concomitant treatment. 
 
Vascular death: 
Death due to non-coronary vascular causes such as cerebrovascular disease, pulmonary 
embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular cause. 
   
Non-cardiovascular death: 
Any death not covered by the above definitions such as death caused by infection, malignancy, 
sepsis, pulmonary causes, accident, suicide or trauma. 
 
MYOCARDIAL INFARCTION (MI) 
 
MI Definition (Modified ARC) 
 
Patients present any of the following clinical or imaging evidence of ischemia: 
• Clinical symptoms of ischemia;  
• ECG changes indicative of new ischemia - new ST-T changes or new left bundle branch 
block (LBBB), development of pathological Q waves*;  
• Imaging evidence of a new loss of viable myocardium or a new regional wall motion 
abnormality)  
 
AND confirmed with elevated cardiac biomarkers** per ARC criteria (Circulation 2007; 115: 
2344-2351): 
• Periprocedural MI: 
• Within 48h after PCI: CK-MB >3 x URL or Troponin > 3 x URL with baseline value 
< URL 
• Within 72h after CABG: CK-MB >5 x URL or Troponin > 5 x URL with baseline 
value < URL 
• Spontaneous MI (> 48h following PCI, > 72h following CABG): CK-MB > URL or 
Troponin > URL with baseline value < URL 
 
* Pathologic Q waves may be defined according to the Global Task Force, Minnesota code, or Novacode  
**The assessment of CK-MB is preferred over the assessment of troponin for the diagnosis of peri-procedural MI, if possible. 
Baseline biomarker value requiring before study procedure and presumes a typical rise and fall.  
 
Electrocardiographic Classification 
 
• Based on Q-Wave 
o Q-wave MI [QMI] 


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 Development of new pathological Q waves in 2 or more contiguous 
leads with or without post- procedure CK or CK-MB levels elevated 
above normal. 
 
o Non Q-wave MI [NQMI] 
 All MIs not classified as Q waves. 
 
• Relation to the Target Vessel 
All infarcts that cannot be clearly attributed to a vessel other than the target vessel 
will be considered related to the target vessel. 
 
WHO MI Definition 
 Myocardial infarctions will also be adjudicated based on the following definition:  
 Q wave MI: Development of new, pathological Q wave on the ECG  
 
 Non-Q wave MI: Elevation of CK levels to ≥ two times the upper limit of normal (ULN) 
with elevated CK-MB in the absence of new pathological Q waves 
  
 
STENT THROMBOSIS (Per ARC Circulation 2007; 115: 2344-2351) 
 
Timing:  
Acute stent thrombosis*:  
 
0 - 24 hours post stent implantation  
Subacute stent thrombosis*:   
>24 hours . 30 days post stent implantation  
Late stent thrombosis†:  
 
30 days - 1 year post stent implantation  
Very late stent thrombosis†:   
>1 year post stent implantation  
 
*  
Acute/subacute can also be replaced by early stent thrombosis. Early stent thrombosis 
(0 - 30 days) - this definition is currently used in the community.  
† 
Including “primary” as well as “secondary” late stent thrombosis; “secondary” late 
stent thrombosis is a stent thrombosis after a target segment revascularization.  
 
Categories (Definite, Probable, and Possible): 
 
Definite stent thrombosis 
Definite stent thrombosis is considered to have occurred by either angiographic or 
pathologic confirmation. 
 
 
Angiographic confirmation of stent thrombosis* 
The presence of a thrombus† that originates in the stent or in the segment 5 mm 
proximal or distal to the stent and presence of at least 1 of the following criteria 
within a 48-hour time window:  
• Acute onset of ischemic symptoms at rest  
• New ischemic ECG changes that suggest acute ischemia  
• Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous 
MI)  
• Non-occlusive thrombosis 
o Thrombus Intracoronary thrombus is defined as a (spheric, ovoid, or 
irregular) non-calcified filling defect or lucency surrounded by contrast 
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projections, or persistence of contrast material within the lumen, or a 
visible embolization of intraluminal material downstream.  
• Occlusive thrombus  
o TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most 
adjacent proximal side branch or main branch (if originates from the 
side branch).  
 
Pathological confirmation of stent thrombosis  
Evidence of recent thrombus within the stent determined at autopsy or via 
examination of tissue retrieved following thrombectomy.  
 
    * 
The incidental angiographic documentation of stent occlusion in the absence 
of clinical signs or symptoms is not considered a confirmed stent thrombosis 
(silent occlusion). 
 
    † 
Intracoronary thrombus. 
 
Probable stent thrombosis 
Clinical definition of probable stent thrombosis is considered to have occurred after 
intracoronary stenting in the following cases: 
• Any unexplained death within the first 30 days‡  
• Irrespective of the time after the index procedure, any MI that is related to 
documented acute ischemia in the territory of the implanted stent without 
angiographic confirmation of stent thrombosis and in the absence of any other 
obvious cause  
 
    ‡ 
For studies with ST-elevation MI population, one may consider the exclusion 
of unexplained death within 30 days as evidence of probable stent thrombosis. 
 
Possible stent thrombosis 
Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death from 30 days after intracoronary stenting until end of trial follow-up. 
 
STROKE 
 
An acute symptomatic episode of neurological dysfunction attributed to a vascular cause 
lasting more than 24 hours or lasting 24 hours or less with a brain imaging study or autopsy 
showing new infarction. 
• Ischemic Stroke: An acute symptomatic episode of focal cerebral, spinal, or retinal 
dysfunction caused by an infarction of central nervous system tissue. 
• Hemorrhagic Stroke: An acute symptomatic episode of focal or global cerebral or 
spinal dysfunction caused by a non-traumatic intraparenchymal, intraventricular, or 
subarachnoid hemorrhage. 
• Undetermined Stroke: A stroke with insufficient information to allow categorization 
as ischemic or hemorrhagic. 
 
Note: an event that last < 24 hours may be adjudicated as a stroke if the following treatments 
were used: 
• Pharmacologic, i.e., thrombolytic drug administration, or 
Non-pharmacologic, i.e., neurointerventional procedure (e.g., intracranial angioplasty) 
 


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BLEEDING (Per BARC, Circulation 2011; 123: 2736-2747) 
Bleeding will also be adjudicated per Bleeding Academic Research Consortium (BARC) 
definitions: 
• Type 0: no bleeding 
• Type 1: bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a healthcare 
professional; may include episodes leading to self-discontinuation of medical therapy 
by the patient without consulting a healthcare professional 
• Type 2: any overt, actionable sign of hemorrhage (eg, more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) that 
does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following 
criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, 
(2) leading to hospitalization or increased level of care, or (3) prompting evaluation 
• Type 3 
o Type 3a 
 Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL* (provided 
hemoglobin drop is related to bleed) 
 Any transfusion with overt bleeding 
o Type 3b 
 Overt bleeding plus hemoglobin drop ≥ 5 g/dL*(provided hemoglobin 
drop is related to bleed) 
 Cardiac tamponade 
 Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid) 
 Bleeding requiring intravenous vasoactive agents 
o Type 3c 
 Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal) 
 Subcategories confirmed by autopsy or imaging or lumbar puncture 
 Intraocular bleed compromising vision 
• Type 4: CABG-related bleeding 
o Perioperative intracranial bleeding within 48 h 
o Reoperation after closure of sternotomy for the purpose of controlling 
bleeding 
o Transfusion of ≥ 5 U whole blood or packed red blood cells within a 48-h 
period† 
o Chest tube output ≥ 2L within a 24-h period 
• Type 5: fatal bleeding 
o Type 5a 
 Probable fatal bleeding; no autopsy or imaging confirmation but 
clinically suspicious 
o Type 5b 
 Definite fatal bleeding; overt bleeding or autopsy or imaging 
confirmation 


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CABG indicates coronary artery bypass graft. Platelet transfusions should be recorded 
and reported but are not included in these definitions until further information is obtained 
about the relationship to outcomes. If a CABG-related bleed is not adjudicated as at least 
a type 3 severity event, it will be classified as not a bleeding event. If a bleeding event 
occurs with a clear temporal relationship to CABG (i.e., within a 48-h time frame) but 
does not meet type 4 severity criteria, it will be classified as not a bleeding event. 
* Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dL 
hemoglobin). 
† Cell saver products are not counted. 
 
 
REVASCULARIZATION (Per ARC Circulation 2007; 115: 2344-2351) 
 
Target Lesion Revascularization (TLR)  
TLR is defined as any repeat percutaneous intervention of the target lesion or bypass surgery 
of the target vessel performed for restenosis or other complication of the target lesion. All 
TLR should be classified prospectively as clinically indicated [CI] or not clinically indicated 
by the investigator prior to repeat angiography. The target lesion is defined as the treated 
segment from 5 mm proximal to the stent and to 5 mm distal to the stent. 
Target Vessel Revascularization (TVR) 
TVR is defined as any repeat percutaneous intervention or surgical bypass of any segment of 
the target vessel. The target vessel is defined as the entire major coronary vessel proximal and 
distal to the target lesion which includes upstream and downstream branches and the target 
lesion itself  
Non Target Lesion Revascularization (Non-TLR) 
Any revascularization in the target vessel for a lesion other than the target lesion is 
considered a non-TLR. 
Non Target Vessel Revascularization (Non-TVR) 
Revascularization of the vessel identified and treated as the non-target vessel at the time of 
the index procedure.  
Clinically Indicated [CI] Revascularization (TLR/TVR) 
A revascularization is considered clinically indicated if angiography at follow-up shows a 
percent diameter stenosis ≥ 50% and if one of the following occurs:  
• A positive history of recurrent angina pectoris, presumably related to the target vessel;  
• Objective signs of ischemia at rest (ECG changes) or during exercise test (or 
equivalent), presumably related to the target vessel;  
• Abnormal results of any invasive functional diagnostic test (e.g., Doppler flow 
velocity reserve, fractional flow reserve);  
• A TLR/TVR with a diameter stenosis ≥70% in the absence of the above mentioned 
ischemic signs or symptoms. 
 
TARGET LESION FAILURE (TLF) 
TLF is defined as a composite of all cardiac death, myocardial infarction attributed to target 
vessel or clinically-indicated TLR. 
 


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TARGET VESSEL FAILURE (TVF) 
TVF is defined as a composite of cardiac death, MI attributed to target vessel, clinically-
indicated TLR, or clinically-indicated TVR, non-TLR. 


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OTHER DEFINTIONS (in alphabetic order) 
 
ACC/AHA Classification Scheme of Coronary Lesions: Lesion-Specific Characteristics 
Type A Lesions (High Success, >85%; Low Risk) 
• 
Discrete (< 10 mm length) 
• 
Little or no calcification 
• 
Concentric 
• 
Less than totally occlusive 
• 
Readily accessible 
• 
Not ostial in location 
• 
Non-angulated segment, < 45° 
• 
No major branch involvement 
• 
Smooth contour 
• 
Absence of thrombus 
Type B Lesions* (Moderate Success, 60-85%; Moderate risk) 
• 
Tubular (10-20 mm length) 
• 
Moderate-to-heavy calcification 
• 
Eccentric 
• 
Total occlusions < 3 mo old 
• 
Moderate tortuosity of proximal segment 
• 
Ostial in location 
• 
Moderately angulated segment, > 45°, < 90° 
• 
Bifurcation lesions requiring double guide 
wires 
• 
Irregular contour 
• 
Some thrombus present 
* Type B1 lesions: One adverse characteristic 
* Type B2 lesions: ≥ two adverse characteristics 
Type C Lesions (Low Success, <60%; High Risk) 
• 
Diffuse (> 2 cm length) 
• 
Total occlusions > 3 mo old 
• 
Excessive tortuosity of proximal segment 
• 
Inability to protect major side branches 
• 
Extremely angulated segments > 90° 
• 
Degenerated vein grafts with friable lesions 
 
ACUTE CORONARY SYNDROME (ACS) 
ACS is defined as ischemic symptoms occurring at rest and lasting 10 minutes or more and 
occurring within 72 hours before index procedure AND either ST-segment deviation of 1 mm 
or more or elevated levels of a cardiac biomarker of necrosis (CK-MB or troponin T or I 
greater than the upper limit of normal.).  
 
DE NOVO LESION 
A native coronary artery lesion not previously treated. 
 
DISSECTION  
National Heart, Lung, and Blood Institute [NHLBI] Dissection Classification System: 
A. Minor radiolucencies within the lumen during contrast injection with no persistence 
after dye clearance. 
B. Parallel tracts or double lumen separated by a radiolucent area during contrast 
injection with no persistence after dye clearance. 
C. Extraluminal cap with persistence of contrast after dye clearance from the lumen. 
D. Spiral luminal filling defects. 
E. New persistent filling defects. 
F. Non-A-E types that lead to impaired flow or total occlusion. 
Note: Type E and F dissections may represent thrombus. 
 
MAJOR EPICARDIAL VESSELS 
• Left anterior descending artery [LAD] with septal and diagonal branches; 


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• Left circumflex artery [LCX] with obtuse marginal and/or ramus intermedius 
branches; 
• Right coronary artery [RCA] and any of its branches. 
 
MINIMUM LUMEN DIAMETER (MLD) 
The average of 2 orthogonal views (when possible) of the narrowest point within the area of 
assessment, assessed by visual estimation or online QCA by the investigator. 
 
PERCENT DIAMETER STENOSIS (% DS) 
The value calculated by the following: 
100 * (1 – minimum lumen diameter / reference vessel diameter)  
using the mean values from 2 orthogonal views (when possible) assessed by visual estimation or 
online QCA by the investigator. 
 
PRINCIPAL INVESTIGATOR 
A physician-specialist, related to the study, who is responsible for the overall conduct of the 
trial at all sites and compliance with protocol/CIP and relevant.  
 
PRIMARY INVESTIGATOR 
A physician responsible for conducting the clinical trial at each investigational site. 
 
PROCEDURE START DATE AND TIME 
Procedure start date and time is recorded as the date and time the first guiding catheter was 
inserted into the subject. 
 
PROCEDURE END DATE AND TIME 
Procedure end date and time is recorded as the time the last guiding catheter was removed 
from the subject. 
 
REFERENCE VESSEL DIAMETER (RVD) 
An approximation of the treated lesion vessel diameter. The reference vessel diameter is visually 
estimated during angiography or online QCA by the investigator. 
 
STAGED PROCEDURE  
A staged procedure is defined as the planned treatment of baseline lesions during one or more 
cardiac catheterization procedures following the initial procedure. Revascularization of the 
baseline lesions treated at the initial procedure is not considered a staged procedure. 
 
TARGET LESION  
The target lesion is defined as the lesion that has met the angiographic inclusion and 
exclusion criteria, and is implanted with XIENCE stent during the index procedure. 
 
TARGET VESSEL 
The entire epicardial vessel in which the target lesion is located, which includes upstream and 
downstream branches and the target lesion itself. 
 
THROMBUS (PER SYNTAX SCORE DEFINITION) 
Spheric, ovoid or irregular intraluminal filling defect or lucency surrounded on three sides by 
contrast medium seen just distal or within the coronary stenosis in multiple projections or a 
visible embolization of intraluminal material downstream. 


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TIMI (THROMBOSIS IN MYOCARDIAL INFARCTION) FLOW GRADES  
0. No contrast flow through the stenosis. 
 
 
1. A small amount of contrast flows through the stenosis but fails to fully opacify the 
artery beyond. 
2. Contrast material flows through the stenosis to opacify the terminal artery segment. 
However, contrast enters the terminal segment perceptibly more slowly than more 
proximal segments. Alternatively, contrast material clears from a segment distal to a 
stenosis noticeably more slowly than from a comparable segment not preceded by a 
significant stenosis. 
3. Anterograde flow into the terminal coronary artery segment through a stenosis is as 
prompt as anterograde flow into a comparable segment proximal to the stenosis. 
Contrast material clears as rapidly from the distal segment as from an uninvolved, 
more proximal segment. 


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APPENDIX III: 
CONTACT INFORMATION 
A list of investigational site co-ordinates can be obtained upon request from the Clinical 
Project Manager for the study. 


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APPENDIX IV: 
SCHEDULE OF EVENTS 
 
PROCEDURE/TEST 
Baseline  
Pre-Procedure 
(within 24 hours) 
Procedure 
Post-Procedure 
3-month (±  7d) 
Office visit2 
6-month (±  14d) 
 Office visit or 
phone contact 3 
12-month (±  28d) 
Office visit or 
phone contact3 
Unscheduled visits 
Subject Medical/Clinical History (Age, Sex, 
Risk Factors, Cardiac Status, Cardiac 
History) 
 
 
 
 
 
  
 
 
Subject Informed Consent (Must be obtained 
prior to any study related testing or 
procedures) 
 
 
 
 
 
 
 
 
General Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
Angiographic Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
Coronary Angiogram 
 
 
 
 
 
 
 
 
Study Stent and Procedure Information 
 
 
 
 
 
 
 
 
Antiplatelet Medications Loading Dose 
 
 
 
 
 
 
 
 
P2Y12 Inhibitor Discontinuation Eligibility 
Assessment 
 
 
 
 
 
 
 
 
Post-procedure Antiplatelet Medications1  
 
 
 
 
 
 
 
 
Adverse Events  
 
 
 
 
 
 
 
 
1Subject who are “3-month clear” will discontinue P2Y12 inhibitor after 3-month visit, but continue taking aspirin through 12-month 
follow-up. Subjects who are not eligible for early P2Y12 inhibitor discontinuation will be treated per site standard of care.  
2Office visit is required for 3-month follow-up. A formal office visit is required at 3-month follow-up to ensure a thorough clinical 
evaluation. A telephone contact is an option only for subjects who would otherwise be lost to follow-up due to being unable to complete an 
office visit, but a formal follow-up visit is still preferred at 3 months. 
3Office visit is strongly recommended whenever possible. 
 
 


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APPENDIX V: 
CLINICAL INVESTIGATION FLOW 
 
 
1Consenting after the index procedure but prior to hospital discharge (or up to 3 days after the index procedure) is acceptable, only if the site 
confirms that the protocol required DAPT regimen is site’s standard of care. If staged procedures are needed for a subject, the site may 
consent the subject after the initial procedure. 
2Office visit is required for 3-month follow-up. A formal office visit is required at 3-month follow-up to ensure a thorough clinical 
evaluation. A telephone contact is an option only for subjects who would otherwise be lost to follow-up due to being unable to complete an 
office visit, but a formal follow-up visit is still preferred at 3 months. 
3 “3-month clear” is defined as subjects who are free from myocardial infarction (modified ARC), repeat coronary revascularization, stroke, 
or stent thrombosis (ARC definite/probable) within 3 months (prior to 3-month visit but at least 90 days) after stenting AND have been 
compliant with 3-month dual antiplatelet therapy (DAPT) without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 
consecutive days. 
4Office visit is strongly recommended whenever possible. 
   
Yes 
3-month clear3? 
No 
Yes 
Yes 
Yes 
Informed consent signed1 
Angiographic 
inclusion/exclusion met  
3-month (90±7 days) 
Office visit2.  
6-month (180±14 days) 
Office visit or telephone contact4 
12-month (365±28 days) 
Office visit or telephone contact4 
Screen failure, do 
not register 
No 
Subject registered in the trial 
No 
Discontinue 
P2Y12 inhibitor 
Continue DAPT 
per standard care 
Subject was screened and met general 
inclusion/exclusion criteria 


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APPENDIX VI: 
MONITORING PLAN 
A copy of the Monitoring Plan can be obtained upon request from the Clinical Project 
Manager for the study. 


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APPENDIX VII: 
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course of dual antiplatelet therapy. Am Heart J. May 2013;165(5):704-709. 


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Shinke T, Itoh T, Ishida M, et al. Early vascular responses to everolimus-eluting 
cobalt-chromium stent for the treatment of stable coronary artery disease: The results 
of MECHANISM-Elective 1 and 3 months OCT follow-up cohort. ESC; 2016. 
42. 
Szott LM, Irvin CA, Trollsas M, Hossainy S, Ratner BD. Blood compatibility 
assessment of polymers used in drug eluting stent coatings. Biointerphases. Jun 15 
2016;11(2):029806. 
43. 
Van Dyck CJ, Hoymans VY, Bult H, et al. Resolute and Xience V polymer-based 
drug-eluting stents compared in an atherosclerotic rabbit double injury model. 
Catheterization and cardiovascular interventions : official journal of the Society for 
Cardiac Angiography & Interventions. Jun 1 2013;81(7):E259-268. 
44. 
Kolandaivelu K, Swaminathan R, Gibson WJ, et al. Stent thrombogenicity early in 
high-risk interventional settings is driven by stent design and deployment and 
protected by polymer-drug coatings. Circulation. Apr 5 2011;123(13):1400-1409. 
45. 
Valgimigli M, Patialiakas A, Thury A, et al. Zotarolimus-eluting versus bare-metal 
stents in uncertain drug-eluting stent candidates. Journal of the American College of 
Cardiology. Mar 3 2015;65(8):805-815. 
46. 
Ariotti S, Adamo M, Costa F, et al. Is Bare-Metal Stent Implantation Still Justifiable 
in High Bleeding Risk Patients Undergoing Percutaneous Coronary Intervention?: A 
Pre-Specified Analysis From the ZEUS Trial. JACC. Cardiovascular interventions. 
Mar 14 2016;9(5):426-436. 
47. 
Urban P, Meredith IT, Abizaid A, et al. Polymer-free Drug-Coated Coronary Stents in 
Patients at High Bleeding Risk. N Engl J Med. Nov 19 2015;373(21):2038-2047. 
48. 
Yazdani S, Su S, Schulze J, Kolodgie F, Virmani R. Endothelialization of polymers-
free drug coated stents. EuroIntervention. 2011;7(Supplement M). 
49. 
Natsuaki M, Morimoto T, Yamamoto E, et al. One-year outcome of a prospective trial 
stopping dual antiplatelet therapy at 3 months after everolimus-eluting cobalt-
chromium stent implantation: ShortT and OPtimal duration of Dual AntiPlatelet 
Therapy after everolimus-eluting cobalt-chromium stent (STOPDAPT) trial. 
Cardiovasc Interv Ther. Oct 30 2015. 
50. 
Genereux P, Rutledge DR, Palmerini T, et al. Stent Thrombosis and Dual Antiplatelet 
Therapy Interruption With Everolimus-Eluting Stents: Insights From the Xience V 
Coronary Stent System Trials. Circulation. Cardiovascular interventions. May 
2015;8(5). 
 


Abbott Vascular 
Version 3.0 
XIENCE 90 Protocol #16-308-Redacted 
 
May 25, 2018 
 
 
 
 APPENDIX VIII: 
SUMMARY OF CHANGES 
 
VERSION 
# 
DATE OF 
RELEASE 
REASON FOR AMENDMENT 
1.0 
12 MAY 2017 
N/A, ORIGINAL VERSION 
2.0 
17 JANUARY 2018 
TO ADDRESS FDA FEEDBACK 
3.0 
25 MAY 2018 
TO ADD XIENCE SIERRA AND XIENCE PROA IN THIS 
STUDY 
 
 
 
 
 
 
 
  

SAP_001.pdf: 
 
Protocol 16-308: XIENCE 90 
Version 7.0 
September 04, 2020 
Page 1 of 28 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
 
 
 
 
 
 
 
 
 
 
PROTOCOL #16-308 
 
 
XIENCE 90 Study 
 
Statistical Analysis Plan 
 
 
Version 7.0 
 September 04, 2020 
 
 
 
 
 
 
 
Yan Zheng 
Jin Wang 
 
 
 
Confidential and Proprietary 
 
Nothing herein is to be disclosed without the expressed written consent of 
Abbott Vascular
TABLE OF CONTENTS 


 
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1. SYNOPSIS OF STUDY DESIGN AND PROCEDURES ....................................................................... 4 
1.1 
Purpose of the Statistical Analysis Plan ...................................................................................... 4 
1.2 
Study Objectives .......................................................................................................................... 4 
1.3 
Study Design ............................................................................................................................... 4 
1.3.1 Selection of Control .................................................................................................................... 5 
1.3.2  
Primary Endpoint .................................................................................................................... 6 
1.3.3  
Secondary Endpoint(s) ............................................................................................................ 6 
1.3.3.1 
  Major Secondary Endpoint(s) ....................................................................................... 6 
1.3.3.2 
  Other Secondary Endpoint(s) ....................................................................................... 6 
1.4 
Analysis Populations ................................................................................................................... 7 
Primary Analysis Population ................................................................................................................ 7 
1.5  
Sample Size Calculations ............................................................................................................ 7 
1.5.1  
Primary Endpoint .................................................................................................................... 7 
1.5.2 
 Major Secondary Endpoint..................................................................................................... 8 
1.5.2.1 Major Secondary Endpoint #1: Bleeding rate (BARC type 2-5) from 3- to 12-month 
follow-up .......................................................................................................................................... 8 
1.5.2.2 Major Secondary Endpoint #2: Stent Thrombosis (ARC definite/probable) from 3- to 12-
month follow-up .............................................................................................................................. 8 
1.6 
Study Success .............................................................................................................................. 9 
2. ANALYSIS CONSIDERATIONS ......................................................................................................... 10 
2.1  
Statistical Methods .................................................................................................................... 10 
2.1.1 
 Descriptive Statistics for Continuous Variables ................................................................... 10 
2.1.2  
Descriptive Statistics for Categorical Variables .................................................................... 12 
2.1.3 Propensity Score ........................................................................................................................ 14 
2.1.3-1 Propensity Score Variable List .......................................................................................... 15 
2.1.4  
Hypothesis Testing ................................................................................................................ 16 
I. 
Major Secondary Endpoint #1: Bleeding rate (BARC type 2-5) from 3- to 12-month follow-
up 
18 
II. 
Major Secondary Endpoint #2: Stent Thrombosis (ARC definite/probable) from 3- to 12-
month follow-up ............................................................................................................................ 18 
2.1.5 
 Survival Analyses ................................................................................................................. 19 
2.2  
Endpoint Analyses ..................................................................................................................... 19 
2.2.1 Primary Endpoint Analysis ....................................................................................................... 19 
2.2.2 Major Secondary Endpoint Analysis ......................................................................................... 19 
2.2.3 Secondary Endpoint Analyses ................................................................................................... 20 
2.3  
Subgroups for Analysis ............................................................................................................. 20 
2.3.1  
Sex ......................................................................................................................................... 20 
2.3.2 
 Diabetes ................................................................................................................................ 20 
2.3.3 
Covid-19 pandemic impact ................................................................................................... 20 
2.3.4 
Other Subgroups .................................................................................................................... 20 
2.4  
Analysis Window ...................................................................................................................... 21 
2.5  
Handling of Missing Data.......................................................................................................... 21 
2.6  
 Poolability Issue ....................................................................................................................... 21 
2.6.1 Multiple Geography Effect ........................................................................................................ 21 
2.6.2 Multiple Center Effect ............................................................................................................... 21 
2.7  
Adjustments for Covariates ....................................................................................................... 22 
2.8  
Multiplicity Issues ..................................................................................................................... 22 
2.9 
Sensitivity Analysis ................................................................................................................... 23 


 
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2.10  
Documentation and Other Considerations ................................................................................. 24 
3. ACRONYMS AND ABBREVIATIONS ............................................................................................... 25 
4. REFERENCES ....................................................................................................................................... 26 
5. APPENDICES ........................................................................................................................................ 27 
 
 
 


 
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1. SYNOPSIS OF STUDY DESIGN AND PROCEDURES 
 
1.1 
Purpose of the Statistical Analysis Plan 
This statistical analysis plan (SAP) is intended to provide a detailed and comprehensive 
description of the planned methodology and analysis to be used for Protocol 16-308 the XIENCE 
90 clinical study. This plan is based on the Version 3.0, May 25, 2018 study protocol.  
 
1.2 
Study Objectives 
 
Primary Objective: to show non-inferiority of the primary endpoint of all death or all MI 
(modified ARC) from 3 to 12 months following XIENCE implantation in HBR subjects treated 
with 3-month DAPT compared to a historical control after propensity score adjustment.  
Secondary Objective:  
• To show superiority of the major secondary endpoint of major bleeding (Bleeding 
Academic Research Consortium [BARC] type 2-5) from 3 to 12 months following 
XIENCE implantation in HBR subjects treated with 3-month DAPT compared to a 
historical control after propensity score adjustment.  
• To evaluate stent thrombosis (ARC definite/probable) from 3 to 12 months following 
XIENCE implantation in HBR subjects treated with 3-month DAPT against a 
performance goal (PG). 
1.3 
Study Design 
XIENCE 90 study is a prospective, single arm, multi-center, open label trial to evaluate the 
safety of 3-month dual antiplatelet therapy (DAPT) in subjects at high risk of bleeding (HBR) 
undergoing percutaneous coronary intervention (PCI) with the approved XIENCE family of 
coronary drug-eluting stents. 
The XIENCE family stent systems include commercially approveda XIENCE Xpedition 
Everolimus Eluting Coronary Stent System (EECSS), XIENCE Alpine EECSS or XIENCE 
PROX EECSS (OUS only)b, XIENCE PROA EECSS (OUS only)c, and XIENCE Sierra EECSS, 
 
 
 
a The commercially approved XIENCE stent will be used in geographies where it is commercially available 
b XIENCE PROX is a rebrand of the XIENCE Xpedition Stent System and is only available outside of the United 
States. 
c XIENCE PROA is a rebrand of the XIENCE Alpine Stent System and is only available outside of the United States. 
 


 
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which are all manufactured by Abbott Vascular, Inc, Santa Clara, USA.  The above XIENCE 
family stent systems will hereinafter be called “XIENCE” in this study.  
Approximately 2,000 subjects from approximately 100 sites globally will be registered in this 
study, with at least 50% of subjects in the United States (US). Study population consists of non-
complex HBR subjects with up to three native coronary artery lesions (a maximum of two 
lesions per epicardial vessel) with reference vessel diameter between 2.25 mm and 4.25 mm. 
Eligibility of P2Y12 receptor inhibitor discontinuation will be assessed at 3-month follow-up. 
Subjects who are free from myocardial infarction (modified ARC), repeat coronary 
revascularization, stroke, or stent thrombosis (ARC definite/probable) within 3 months (prior to 
3-month visit but at least 90 days) after stenting AND have been compliant with 3-month DAPT 
without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 consecutive days 
are considered as “3-month clear”, and will discontinue P2Y12 receptor inhibitor and continued 
with aspirin monotherapy after 3-month follow-up.   
All registered subjects will be followed at 3, 6 and 12 months post index procedure.  
The data collected from the XIENCE 90 study will be compared with the historical control of 
non-complex HBR subjects treated with standard DAPT duration of up to 12 months from the 
XIENCE V USA study, which is a US post-approval study to evaluate the safety of XIENCE V 
EECSS in “all-comer” population under real-world setting. 
1.3.1 Selection of Control 
The XIENCE V USA historical HBR control for 3-month DAPT study is derived based on the 
following criteria: 
Definition of non-complex HBR from XIENCE V USA 
• HBR inclusion criteria (any one of the below HBR criteria):  
o Age ≥ 75 years  
o History of major bleeding  
o History of stroke 
o Receiving or scheduled to receive chronic anticoagulation therapy 
o Renal insufficiency (creatinine > 2mg/dl) 
o Anemia (Hb < 11g/dl or transfusion) 
o Thrombocytopenia (platelet count < 100.000/mm3) 
• Exclusion criteria for non-complex: 
o STEMI 
o LVEF < 30% 
o Patients with more than 3 lesions treated during index procedure 
o Patients with more than 2 vessels treated during index procedure 


 
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o At least one lesion with RVD < 2.25 mm or > 4.25 mm (visual estimation) 
o At least one lesion located in left main 
o At least one lesion located in graft 
o At least one in-stent restenosis lesion 
o At least one lesion containing thrombus 
o At least one target lesion having TIMI flow 0 
o At least one target lesion with length > 32 mm by visual estimation. 
 
The above selection criteria for the XIENCE V USA historical control aligns with the key 
inclusion/exclusion criteria of the XIENCE 90 Study. 
For primary analysis, the XIENCE V USA non-complex HBR control subjects must be also 3-
month clear, following the same logic as defined for the primary analysis population (refer to 
Section 1.4). 
1.3.2  Primary Endpoint 
The primary endpoint is a composite rate of all death or all myocardial infarction (Academic 
Research Consortium [ARC]) from 3 months to 12 months.   
1.3.3  Secondary Endpoint(s) 
1.3.3.1   Major Secondary Endpoint(s)  
• Major bleeding rate (BARC type 2-5) from 3 to 12 months. 
• Stent thrombosis (ARC definite/probable) from 3 to 12 months 
1.3.3.2   Other Secondary Endpoint(s) 
The following endpoints will be assessed from 3 to 12 months: 
• All death, cardiac death, vascular death, non-cardiovascular death 
• All MI (modified ARC) and MI attributed to target vessel (TV-MI, modified ARC) 
• Composite of cardiac death or MI (modified ARC) 
• All stroke, ischemic stroke and hemorrhagic stroke  
• Clinically-indicated target lesion revascularization (CI-TLR)  
• Clinically-indicated target vessel revascularization (CI-TVR)  
• Target lesion failure (TLF, composite of cardiac death, TV-MI and CI-TLR)  
• Target vessel failure (TVF, composite of cardiac death, TV-MI and CI-TVR) 
• Major bleeding defined by the Bleeding Academic Research Consortium (BARC) type 3-
5   
 


 
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1.4 
Analysis Populations 
Primary Analysis Population 
The primary analysis population includes “3-month clear” population, defined as subjects who 
are free from myocardial infarction (modified ARC), repeat coronary revascularization, stroke, 
or stent thrombosis (ARC definite/probable) within 3 months (prior to 3-month visit but at least 
90 days) after stenting AND have been compliant with 3-month dual antiplatelet therapy 
(DAPT)without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 consecutive 
days. 
Exceptions include the following: 
• Peri-procedural MI (occurred within 48 hours post index procedure) without any clinical 
symptoms will not be considered exclusionary event for the definition of “3-month 
clear”. 
• Dual therapy (oral anticoagulant and a P2Y12 inhibitor, clopidogrel preferred) for 
subjects who are on chronic anticoagulants is acceptable for the definition of “3-month 
clear”. 
 
 
1.5  
Sample Size Calculations 
1.5.1  Primary Endpoint 
The primary endpoint of Death/MI from 3-month to 12-month follow-up will be evaluated based 
on the “3-month clear” population (as defined in section 1.4). The hypothesis test is designed for 
non-inferiority of 3-month DAPT from XIENCE 90 compared to standard DAPT duration up to 
12 months from XIENCE V USA historical control for the primary endpoint after propensity 
score stratification.  
This analysis will be stratified by propensity score with the following assumptions: 
• True event rate for the primary endpoint is assumed to be 6.1% for both arms    
• Non-inferiority margin: 2.8% (approximately 46% of the assumed true event rate) 
• Attrition rate of 15% due to “3-month clear” population and lost to follow-up for XIENCE 
90  
• One-sided alpha = 0.025 
• Sample size in the control arm (3-month clear): ~1,150 
• Approximately 87% power. 
A total sample size of 2,000 subjects in the XIENCE 90 study will be required for this test.  
The sample size calculations were performed using NCSS PASS 11 (Hintze, J., 2011, NCSS, 
LLC. Kaysville, Utah). 


 
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1.5.2  Major Secondary Endpoint 
Given the success of the primary analysis for the primary endpoint, the following major 
secondary analyses will be performed in the following sequence: 
I. Superiority test for the major bleeding rate (BARC type 2-5) from 3- to 12-month 
follow-up will be tested for 3-month DAPT from XIENCE 90 as compared to 
standard DAPT duration up to 12 months from XIENCE V USA historical control 
stratified by propensity scores. 
II. Stent thrombosis (ARC definite/probable) from 3- to 12-month follow-up of XIENCE 
90 will be evaluated against a pre-specified performance goal (PG).  
1.5.2.1 Major Secondary Endpoint #1: Bleeding rate (BARC type 2-5) from 3- to 12-month 
follow-up 
 
The major bleeding rate (BARC type 2-5) from 3- to 12-month follow-up will be tested for 
superiority of 3-month DAPT from XIENCE 90 as compared to standard DAPT duration up to 
12 months from XIENCE V USA historical control in the “3-month clear” population. This 
analysis will be stratified by propensity score with the following assumptions: 
• True event rate is assumed to be 6.0% for XIENCE V USA historical control 
• One-sided alpha = 0.025 
• 15% attrition rate due to “3-month clear” population and lost to follow-up for XIENCE 
90 
Under the assumptions above, the study has approximately 95% power to detect ~50% reduction 
in bleeding rate for XIENCE 90 study as compared to XIENCE V USA historical control. 
 
1.5.2.2 Major Secondary Endpoint #2: Stent Thrombosis (ARC definite/probable) from 3- 
to 12-month follow-up 
The powered endpoint of stent thrombosis (ARC definite/probable) from 3- to 12-month follow-
up will be evaluated against a pre-specified clinical performance goal (PG) for XIENCE 90. The 
analysis will be performed in the primary analysis population. The power calculation is based on 
the following assumptions: 
• The true 3-12 month stent thrombosis rate is assumed to be 0.5%  
• PG is 1.2%  
• One-sided alpha= 0.025  
• 15%  attrition rate due to “3-month clear” population and lost to follow-up for XIENCE 


 
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90 
A total sample size of 2,000 subjects will provide approximately 85% power using the exact test. 
 
1.6 
Study Success 
The trial success is defined as passing the non-inferiority test on the primary endpoint of 
Death/MI for the “3-month clear” population. Detail of the test is specified in section 2.1.4. 


 
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2. ANALYSIS CONSIDERATIONS 
 
2.1  
Statistical Methods  
Baseline demographic, clinical, angiographic, procedural, and device data, and clinical results 
will be summarized using descriptive summary statistics. 
2.1.1  Descriptive Statistics for Continuous Variables 
For continuous variables (e.g., age, percent diameter stenosis and lesion length), results will be 
summarized with the numbers of observations, means, and standard deviations and where 
specified in the table mockups, with quartiles, minimums, maximums, and two-sided 95% 
confidence intervals for the means as per the table mockups. Differences between two 
comparison groups of interest, where specified, will be summarized with the differences of the 
two means, and two-sided 95% confidence intervals for the difference between the means. These 
calculations will be done under the assumption that the data for the two arms are independent 
and approximately normal in distribution. The confidence interval for the difference of two 
means will be calculated under the assumption of unequal variances. If the asymptotic 
assumptions fail, then nonparametric summary statistics (medians, 25th and 75th percentiles) may 
be displayed as an alternative.  
Formulas for calculation of the confidence intervals for the continuous variables are given 
below: 
1. 100(1- α)% Confidence Interval For A Single Mean5 
 
n
s
t
x
2
α
±
 
 
where:  
 
freedom
 
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 1
for 
 
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 t
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2. 100(1-α)% Confidence Interval For The Difference of Two Means Under The Assumption 
Of Equal Variances Between The Two Groups5 
(
)






+
±
−
2
1
2
2
2
1
1
1
n
n
s
t
x
x
p
α
 
 


 
Protocol 16-308: XIENCE 90 
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where:  
 
freedom
 
of
 
degrees
 2
for 
 
statistic
-
 t
alpha/2
 
the
2 
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3. 100(1-α) % Confidence Interval for the Difference of Two Means under the Assumption of 
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(
)
SED
t
x
x
2
2
1
α
±
−
  
 
With the degrees of freedom for the approximate t statistic is determined by 
Satterthwaite’s formula2 as follows: 
 
(
)
1
1
2
2
2
1
2
1
2
2
1
−
+
−
+
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where:  
 
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Protocol 16-308: XIENCE 90 
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2
2
2
2
n
s
w =
 
 
 
2.1.2  Descriptive Statistics for Categorical Variables 
For categorical variables such as gender, Death/MI and TLF, results   will be summarized with 
subject counts and percentages/rates, and where specified in the table mockups, with exact two-
sided 95% Clopper-Pearson6 confidence intervals. Differences between two comparison groups 
of interest, when specified, will be summarized with the difference in percentages and the 
Newcombe5 score two-sided 95% confidence interval for the difference of two percentages.  
For efficacy and safety endpoint(s), relative risks (i.e., the ratio of rates), confidence interval for 
the relative risks, the difference in rates and the confidence interval for difference in rates (using 
previously-described formulas), and p-values may also be presented for hypothesis generating 
purposes. The p-values will be based on either Pearson’s Chi-square test or Fisher’s exact test by 
checking the expected frequency for each cell in the 2x2 contingency table against Cochran’s 
rule8, i.e., if the expected frequencies for all cells are ≥ 5, then Pearson’s Chi-square test will be 
used, otherwise Fisher’s exact test will be used. 
For the determination of binary event rates at all time points (6 months and 12 months), the 
denominators are defined as below based on the type of events. 
• Death/MI/Revascularization (DMR) event  
Subjects will be included in the analysis if they either had the DMR event by the analysis 
time point or they did not have the DMR event but had follow-up visit through that time 
point. In other words, subjects will be included in a given analysis if it can be determined 
whether or not the subject would have had the DMR event by the time point. 
• Stent Thrombosis, Bleeding and stroke 
Subjects will be included in the analysis if they either had the specific event (for example, 
for analysis on ST, only ST is considered) by the analysis time point or they did not have 
the event but had follow-up visit for that time point. In other words, subjects will be 
included in a given analysis if it can be determined whether or not the subject would have 
had the specific event by the time point. 
 
Formulas for calculating confidence intervals for the categorical variables are given below.  
1. 100(1-α) % Exact Clopper-Pearson Confidence Interval for A Single Proportion6 


 
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)
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a. 100(1-α) % Wilson Score Confidence Interval for A Single Proportion5 
 
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2
/2
2
/2
2
/
2
/2
α
α
α
α
+
+
−
+
+
=
 
where: 
 
 
on
distributi
 
normal
 
standard
 
 the
of
 
percentile
/2)th 
-
100(1
events"
" 
of
number 
size
 
sample
/
ˆ
2
/
α
α
=
=
=
=
Z
x
n
n
x
p
 
 
b. 100(1-α) % Newcombe Score Confidence Interval for the Difference of Two 
Proportions4 


 
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Lower Confidence Limit = (
)
2
2
2
1
1
1
2
/
2
1
/
)
1(
/
)
1(
ˆ
ˆ
n
U
U
n
L
L
Z
p
p
−
+
−
−
−
α
 
 
Upper Confidence Limit = (
)
2
2
2
1
1
1
2
/
2
1
/)
1(
/)
1(
ˆ
ˆ
n
L
L
n
U
U
Z
p
p
−
+
−
+
−
α
 
 
where:  
 
on
distributi
 
normal
 
standard
 
 the
of
 
percentile
/2)th 
-
100(1
for 
 
limits
 
confidence
 
Score
on 
upper Wils
 
and
lower 
 
 the
are
 
 
and
 
for 
 
limits
 
confidence
 
Score
on 
upper Wils
 
and
lower 
 
 the
are
 
 
and
 
2 
group
for 
 
proportion
 
sample
ˆ
1 
group
for 
 
proportion
 
sample
ˆ
2
/
2
2
2
1
1
1
2
1
α
α
=
=
=
Z
p
U
L
p
U
L
p
p
 
2.1.3 Propensity Score 
Given that subjects in the two comparison groups (XIENCE 90 vs XIENCE V USA) are not 
randomized and thus may not have balanced baseline characteristics, the non-inferiority and 
superiority tests for 3-12 month period will be carried out through   stratified analysis in the “3-
month clear” population. The stratification will be performed through propensity scores (PS). For 
each individual a propensity score (i.e., predicted probability between 0 and 1) for group 
(XIENCE 90) membership will be calculated using logistics regression, with “group” as the 
outcome and baseline variables including demographic, lesion characteristics, and risk factors as 
the predictors. Subjects will be categorized into 5 groups based on the calculated propensity 
scores and their quintiles. Non-inferiority and superiority will then be carried out for the rate of 
the endpoint using the method described in sections below stratified by the propensity quintiles.  
 
The propensity score modeling and design will be performed by an independent statistician who 
has no access to any outcome data of both the XIENCE 90 study and the XV USA historical 
control for the integrity and interpretability of study results. The independent statistician will be 
blinded and have no access to clinical outcome and any follow-up information to avoid 
introducing bias into the analysis. The independent statistician will be requested to perform PS 
building at interims (such as enrollment of 500 or 1000 subjects) and enrollment completion to 
assess the extent of PS overlapping. The independent statistician can inform Abbott Vascular 
about the distribution of patients for the two comparison groups within each PS quintile, while 
the individual PS will be blinded to Abbott Vascular.  Relevant PS building information will be 
provided to FDA prior to the final analysis. 
 
Adequacy of propensity stratification will be performed by first assessing the distribution of 
treatment groups in each quintile. If there is inadequate representation of one treatment group in 
the highest or lowest quintile (less than ten patients for a given treatment group), then quartile 


 
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subgrouping may be attempted. If that does not succeed (still less than ten patients in a given 
quartile for at least one treatment group as in Li et al1.), an alternative approach may also be 
employed when inadequate representation is observed in each propensity score quintile. 
Specifically, control patients in the highest or lowest quintile may be excluded (depending on the 
quintile that contains mostly control patients), and the propensity score calculation will be 
repeated and the adequacy of propensity stratification will be reassessed.  No experimental 
patients will be excluded.  
 
Once the subgrouping is finalized, comparing treatments on the mean values of the baseline 
characteristics adjusting for propensity subgroup will be carried out as in D’Agostino et al2.  If 
the propensity stratification is adequate, this will result in non-significant p-values (p>0.05) for 
almost all baseline characteristics.  
 
Per the recent publication by Yue et al28 on two-stage study designs involving propensity score 
adjustment, the propensity score calculation results will subsequently be sent to the FDA for 
review and approval prior to performing the primary endpoint and major secondary endpoint 
analyses. In the event that the groups’ baseline characteristics are too different to use, a 
propensity score adjustment and a performance goal approach may need to be used instead, the 
performance goal will be established upon agreement with the FDA prior to performing the 
primary endpoint and major secondary endpoint analyses. 
 
2.1.3-1 Propensity Score Variable List 
Based on prior clinical experience and clinical research, below is the list of variables that are 
considered to be related to assignments modeling building: 
• Gender  
• Age  
• Creatinine 
• Chronic anticoagulant  
• History of stroke  
• History of major bleeding  
• Platelet  
• Hb 
• BMI 
• Hypertension  
• Dyslipidemia  
• Prior PCI  
• Prior CABG  


 
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• Prior MI  
• Multivessel disease  
• Clinical Presentation (ACS (NSTEMI, ACS unstable angina) vs. non-ACS) 
• Diabetes  
• ACC/AHA lesion complexity  
• Total lesion length per patient 
• RVD  
• Diameter stenosis%  
• Bifurcation  
• Number of lesions treated 
• Number of vessel treated 
• Number of stents per patient 
• Total stent length per patient 
• Discharge P2Y12  
• Paris bleeding score 
• PRECISE DAPT score 
The list is subject to change upon the quality of the data after the completion of the trial 
enrollment. 
2.1.4  Hypothesis Testing 
Primary endpoint analysis for 3-month DAPT 
The XIENCE 90 study is powered based on primary endpoint of Death/MI between 3-month and 
12-month follow-up. Death/MI is defined as the composite endpoint of all death or all 
myocardial infarction (Academic Research Consortium [ARC]). This primary endpoint will be 
evaluated between XIENCE 90 and XIENCE V USA historical control stratified by propensity 
score quintiles in the primary analysis population. The null (H0) and alternative (HA) hypothesis 
are of the following form: 
                        H0: Death/MI3m-DAPT -  Death/MIXIENCE V USA   ≥ δ 
HA: Death/MI3m-DAPT -  Death/MIXIENCE V USA  < δ 
Where δ is the non-inferiority margin. The test will be carried out with a one-sided significance 
level of 0.025 and a non-inferiority margin  (δ) of 2.8%.  
 
The stratified Farrington-Manning method will be performed to test non-inferiority (NI) of 3-
month DAPT from XIENCE 90 compared to standard DAPT duration up to 12 months from 


 
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XIENCE V USA historical control. Details for stratified Farrington-Manning method   can be 
found below.  
 
For stratum i, let Nit and pit be the number of subjects and the observed proportion for the test 
arm, Nic and pic be the number of subjects and the observed proportion for active control arm, 
and δ be the non-inferiority margin, and pimt  and  pimc be the Maximum Likelihood estimates 
under the null hypothesis (Farrington and Manning, 19903), then test statistic 
𝑍𝑍𝑤𝑤=
෌wi(𝛿𝛿𝚤𝚤෡−𝛿𝛿)
𝑖𝑖
ට∑𝑤𝑤𝑖𝑖
2𝑉𝑉(𝛿𝛿𝚤𝚤෡)
𝑖𝑖
 
 
follows an approximate normal distribution, where 
 
ic
imc
imc
it
imt
imt
i
i
ic
it
ic
it
i
ic
it
i
N
p
p
N
p
p
V
N
N
N
N
w
p
p
)
1(
)
1(
)
ˆ
(
)
(
)
(
ˆ
−
+
−
=
+
+
=
−
=
∑
δ
δ
 
       Pimt and Pimc are calculated as follows:  
     ri = Nit/Nic 
 
  a1 =  - ( 1+ ri +pic+ ri *pit- δ *( ri +2) ) 
        a2 = δ **2 - δ *(2*pic+ ri +1) + pic + ri *pit 
 
  a3 = pic* δ *(1- δ) 
   u = a1**3/(3+3* ri)**3 - a1*a2/(6*(1+ ri)**2) + a3/(2+2* ri) 
 
  v = sign(u)*sqrt( a1**2/((3+3* ri)**2)-a2/(3+3* ri) ) 
       w = 1/3*( arcos(-1) + arcos(u/v**3) ) 
 
  pimc = 2*v*cos(w) - a1/(3+3* ri) 
        pimt = pimc + δ 
 
   
 
Major secondary endpoints analyses for 3-month DAPT  
If the hypothesis testing for the primary endpoint is successful, the hypotheses testing for the 
major secondary endpoint #1 will be performed followed by the hypotheses test for the major 
secondary endpoint #2.   


 
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I. Major Secondary Endpoint #1: Bleeding rate (BARC type 2-5) from 3- to 12-month 
follow-up 
The superiority test for the major secondary endpoint #1 will be performed stratified by 
propensity score quintiles in the primary analysis population. This test will be based on one-
sided alpha of 0.025. The null (H0) and alternative (HA) hypotheses are of the following form: 
                  H0: B3m-DAPT–BXIENCE V USA  ≥ 0 
HA: B3m-DAPT –BXIENCE V USA  < 0 
B3m-DAPT and BXIENCE V USA  are bleeding rates (BARC type 2-5) between 3-month and 12-month 
follow-up for the 3-month DAPT arm and XIENCE V USA historical control, respectively.  
The stratified Farrington and Manning method will be performed where the non-inferiority 
margin is set at 0 and the weight scheme for the stratified analysis will be the same as above. 
 
II. Major Secondary Endpoint #2: Stent Thrombosis (ARC definite/probable) from 3- to 
12-month follow-up 
The exact test will be performed for major secondary endpoint #2 in the primary analysis 
population. The null and alternative hypotheses will be of the following form: 
H0:  ST3m-DAPT ≥  PG 
HA:  ST3m-DAPT < PG 
ST3m-DAPT is the stent thrombosis rate (ARC definite/probable) from 3- to 12-month follow-up. 
 
Exact Test Statistic for Test against Performance Goal for Binary Endpoint: 
Let p0 be the performance goal and N the number of subjects, the test statistic r will be the 
number of observed events for the 3-month DAPT arm, r is assumed to follow the binomial 
distribution with parameters N and p0, and the p-value is calculated as:  
 
p = ∑
=












r
k
k
N
0
 p0k (1- p0) N-k 
Where k = 0, 1, 2, ····· r and 






k
N  represents the number of combinations of taking k objects out 
of N. 
The null hypothesis will be rejected (i.e., successfully passing the PG) if the p-value is calculated 
to be less than 0.025. 


 
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This test will be performed if the superiority of major secondary endpoint #1 is established. 
2.1.5  Survival Analyses 
Survival analysis may be conducted to analyze time-to-event variables. Subjects without events 
will be censored at their last known event-free time point. Survival curves will be constructed 
using Kaplan-Meier estimates.  
Summary tables for the endpoints will include failure rates (Kaplan-Meier estimates). For the 
primary analysis report, all available data will be used. 
 
2.2  
Endpoint Analyses  
 
2.2.1 Primary Endpoint Analysis 
Primary Analysis:  
A non-inferiority test will be performed on the primary endpoint for the primary analysis 
population of the XIENCE 90 study and the XIENCE V USA historical control stratified by 
propensity score quintiles as described in section 2.1.4.  
To ensure all subjects to be included in this analysis, multiple imputations will be performed in 
calculating the propensity scores. 
Secondary Analysis (as a sensitivity analysis):  
In addition to the primary analysis stratified by propensity score quintile, a non-inferiority test 
will be performed on the primary endpoint stratified by propensity score quartile, with the same 
methodology as described above.  
 
2.2.2 Major Secondary Endpoint Analysis 
The stratified Farrington and Manning method will be used for the stratified superiority test of 
major secondary endpoint #1 between 3-month and 12-month follow up for the primary analysis 
population of XIENCE 90 and XIENCE V USA historical control.  The stratification is 
performed by propensity score quintiles. 
To ensure all subjects to be included in this analysis, multiple imputations will be performed in 
calculating the propensity scores. 
The exact test will be used for stent thrombosis between 3-month and 12-month follow-up 
against a PG for the primary analysis population as described in section 2.1.4. This test will be 
performed if the superiority of major secondary endpoint #1 is established. 


 
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2.2.3 Secondary Endpoint Analyses 
Other secondary clinical endpoints will be descriptively analyzed for both the primary analysis 
population and all registered subjects without propensity stratification.   
 
2.3  
Subgroups for Analysis 
All of the following subgroup analyses are intended for the primary analysis population. The 
comparison between the XIENCE 90 study and the XIENCE V USA historical control will 
analyzed descriptively within each quintile for the primary and major secondary endpoints in a 
specific subgroup. The above quintiles are based on the overall PS, not PS built within each 
subgroup, as baseline characteristics of subjects are likely to be comparable in each quintile of 
the overall PS. 
 
2.3.1  Sex 
Sex-specific subgroup analyses will be performed on primary analysis population for the primary 
endpoint and the major secondary endpoints stratified by the overall PS.  
2.3.2  Diabetes 
Diabetic subgroup analysis will be performed on primary analysis population for the primary and 
major secondary endpoints stratified by the overall PS.  Analyses will be performed within the 
following subgroups: 
• All diabetes mellitus, defined as any diabetics with or without medical treatment 
• Non diabetes mellitus.  
2.3.3 Covid-19 pandemic impact 
In order to assess the COVID-19 impact on the primary endpoint and major secondary endpoints, 
a descriptive subgroup comparison will be performed on the primary analysis population 
between subjects whose primary endpoint follow-up overlaps with the pandemic outbreak (such 
as March 01, 2020 and after) and those whose primary endpoint follow-up is prior to the 
pandemic outbreak.   
 
2.3.4 Other Subgroups 
The following subgroups will be evaluated for the primary analysis population for the primary 
and major secondary endpoints stratified by the overall PS. Analyses will be performed within 
the following subgroups: 


 
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• Ethnicity (white versus non-white) 
• Age (age ≥ median vs < median) 
• Age ≥ 65 years old (US elderly patient) 
• Clinical presentation (ACS NSTEMI, ACS unstable angina, non-ACS) 
2.4  
Analysis Window 
 
• 6 months  
• 12 months  
 
2.5  
Handling of Missing Data 
 
The primary and major secondary endpoint analyses will be evaluated after propensity score 
stratification. To handle missing data in propensity score building, multiple imputation method 
will be performed for baseline characteristics to compute propensity scores from these datasets.  
All other analyses will be based on available data with missing data excluded. Any unused or 
spurious data will be noted as appropriate in the final report.   
 
2.6  
 Poolability Issue 
 
2.6.1 Multiple Geography Effect 
Analysis will be performed by pooling data between geographies (US and OUS). XIENCE 90 
study will enroll 2,000 subjects from approximately 100 sites globally, with at least 50% of 
subjects in the United States (US). 
 
To evaluate the geography effect on the primary endpoint, Fisher’s exact test will be tested for 
geography effect in the XIENCE 90 study against an alpha level of 0.05. 
 
If the p-value is < 0.05, Abbott Vascular will examine subject demographics, baseline clinical, 
and angiographic characteristics for possible correlations and confounding factors.  
 
 
2.6.2 Multiple Center Effect 
Analysis will be performed by pooling data across study sites. 
The XIENCE 90 study will have 100 sites globally, with at least 50% of subjects in the United 
States. Subject registration is capped at 300 per site. This cap per site will prevent the scenario 


 
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where the results from a few sites dominate the overall study result. For the analysis of center 
effect, data from smaller sites may be combined for the analysis. Smaller sites are defined as 
sites with fewer than 20 subjects per site. 
The pooling of the smaller sites will be based on the following rules: 
• Sort all smaller sites based on the number of subjects per site in an ascending order. If 
there are ties, sort further by site number. 
• Starting from the smallest site in this list, combine sites by going up the list until the 
combined group size first reaches 20 or larger. At this point, a super site is identified. 
• Repeat the above grouping process from the next smallest site above the newly formed 
super site. 
• The grouping process ends when all smaller sites have been accounted for. 
 
This way, the sizes of the super sites (which are a result of grouping smaller sites) will range 
between 20 and up to 38 (19+19). Abbott Vascular believes this represents a reasonable range of 
sample sizes which will provide meaningful estimates of within-sites variations and in the 
meantime will not alter between-sites variation. 
To evaluate the multiple center effect on the primary endpoint, Fisher’s exact test will be 
performed for 3-month DAPT cohort against an alpha level of 0.05. 
 
If the p-value is < 0.05, Abbott Vascular will examine subject demographics, baseline clinical, 
and angiographic characteristics for possible correlations and confounding factors.  
 
If the p-value is statistically marginal, yet the endpoint outcomes among sites are considered to 
be clinically significantly different, Abbott Vascular will examine subject demographics, 
baseline clinical, and angiographic characteristics for possible correlations and confounding 
factors.  
 
2.7  
Adjustments for Covariates 
 
Unless otherwise specified, no adjustments for covariates will be made for any of the variables in 
the analyses.  
 
2.8  
Multiplicity Issues 
 
No multiplicity adjustment is necessary because the tests in this analysis plan are sequential. 


 
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2.9 
Sensitivity Analysis 
The primary and major secondary endpoints between 3-month and 12-month follow-up will be 
analyzed descriptively for the 3-month clear population removing the patients who do not have 
antiplatelet medication compliance after 3 months. 
  
For the 3-month DAPT arm, antiplatelet medication non-compliance beyond 3-month follow-up 
for 3-month clear population is defined as patients who resume P2Y12 inhibitor for more than 7 
consecutive days, and/or interrupt aspirin for more than 7 consecutive days between 3-month and 
12-month follow up.  
 
In order to assess the COVID-19 impact on the primary and major secondary endpoints between 
3-month and 12-month follow-up, additional sensitivity analyses will be carried out descriptively 
for the endpoint on the 3-month clear population: 
• Removing the events that have been adjudicated by CEC to be related to COVID-19 at 
the event level. 
• Removing the events that have been adjudicated by CEC to be related or possibly related 
to COVID-19 at the event level. 
• Removing the subjects with the event that has been adjudicated by CEC to be related to 
COVID-19 at the subject level. 
• Removing the subjects with the event that has been adjudicated by CEC to be related or 
possibly related to COVID-19 at the subject level.  
 
In order to evaluate the impact of the stratification weight on the primary endpoint analysis 
result, an additional sensitivity analysis will be performed using the statistical optimal weight [30] 
as below in stratified Farrington Manning method to replace ѡi in Section 2.1.4, and Rubin’s 
combination rule [29]  for analysis consolidation: 
 
∑
+
+
=
−
−
i
ic
it
ic
it
ic
it
ic
it
i
N
N
N
N
N
N
N
N
w
1
1
)
(
)
(
 
In addition, a sensitivity analysis will be performed for the primary endpoint analysis to evaluate 
the impact of the missing outcome.  The analysis will be carried out based on the primary 
analysis population, and by imputing the missing outcomes for each imputed baseline PS dataset, 
and Rubin’s combination rule [29] will be used to consolidate the final analysis for the 10 
duplicates of the imputed dataset. Refer to Appendix A for more details.  


 
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2.10  Documentation and Other Considerations 
 
All analyses will be performed using SAS for Windows, version 9.1 or higher.  
 
 


 
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3. ACRONYMS AND ABBREVIATIONS  
 
Acronym or Abbreviation 
Complete Phrase or Definition 
ACS 
Acute Coronary Syndrome 
AMI 
Acute Myocardial Infarction 
ARC 
Academic Research Consortium  
BARC 
Bleeding Academic Research Consortium 
BMI 
Body Mass Index 
CABG 
Coronary artery bypass grafting 
CTO 
Chronic Total Occlusion 
DAPT 
Dual Antiplatelet Therapy 
DMR 
Death/MI/Revascularization 
EECSS 
Everolimus Eluting Coronary Stent System 
Hb 
Hemoglobin 
HBR 
High Bleeding Risk 
LVEF 
Left Ventricular Ejection Fraction 
MI 
Myocardial Infarction 
NSTEMI 
non ST-segment elevation MI 
PCI 
Percutaneous Coronary Syndrome 
PS 
Propensity Score 
RVD 
Reference Vessel Diameter 
SAP 
Statistical Analysis Plan 
ST 
Stent Thrombosis 
STEMI 
ST-segment elevation myocardial infarction 
TLF 
Target Lesion Failure 
TLR 
Target Lesion Revascularization 
TVR 
Target Vessel Revascularization 
US 
United State 


 
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4. REFERENCES 
 
1. Li, H., Mukhi, V., Lu, N., Xu, Y.L. and Yue, L.Q., 2016. A Note on Good Practice of 
Objective Propensity Score Design for Premarket Nonrandomized Medical Device 
Studies with an Example. Statistics in Biopharmaceutical Research, 8(3), pp.282-286. 
2. D’Agostino, R.B., 1998. Tutorial in biostatistics: propensity score methods for bias 
reduction in the comparison of a treatment to a non-randomized control group. Stat 
Med, 17(19), pp.2265-2281. 
3. Farrington, C. P., Manning, G., Test Statistics and Sample Size Formulae for 
Comparative Binomial Trials with Null Hypothesis of Non-Zero Risk Difference or 
Non-Unity Relative Risk. Statistics in Medicine, 1990, 9, 1447-1454. 
4. Hintze J. NCSS and PASS. Number Cruncher Statistical Systems. Kaysville, Utah. 
2005. 
5. SAS/STAT® 9.2 User’s Guide, Second Edition, SAS Institute Inc., Cary, NC, 2009. 
6. Clopper C. J., Pearson E. S., The Use of the Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Biometrika, 1934, 26, 404-413. 
7. Newcombe, R. G., Interval estimation for the difference between independent 
proportions: comparison of eleven methods, Statistics in Medicine, 1998, 17, 873-890. 
8. Cochran, W. G., Some Methods for Strengthening the Common χ2 Test. Biometrics, 
1954, 10, 417-451. 
9. Wilson, E. B., Probable inference, the law of succession, and statistical inference, 
Journal of the American Statistical Association, 1927, 22, 209-212. 
10. Draft Guidance for Industry and Food and Drug Administration Staff: Evaluation of Sex 
Differences in Medical Device Clinical Studies, December 19, 2011, CDRH 
11. Gail, M., Simon, R., Testing for Qualitative Interactions between Treatment Effects and 
Patient Subsets, Biometrics, 1985, 41, 361-372. 
12. Dmitrienko, A. et. al., Analysis of Clinical Trials Using SAS: A Practical Guide, SAS 
Institute, Cary, NC, 2005. 
13. Fleming TR& Harrington DP 1991. Counting Processes and Survival Analysis. New 
York: Wiley.  
14. Miller R & Halpern J 1982. Regression with censored data. Biometrika 69, 521-31. 
15. Allison PD. Survival Analysis Using the SAS system: A Practical Guide, Cary, NC: 
SAS Institute Inc., 1995.  
16. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am 
Stat Assoc 1958; 53:457-481.  
17. Therneau TM, Grambsch PM. Modeling survival data: extending the Cox model. New 
York: Springer-Verlag; 2000.  
18. Allison PD. Multiple Imputation for Missing Data. Sociological Methods & Research, 
Feb 2000; Vol. 28 No. 3:301-309.  


 
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19. Barnes SA, Lindborg SR, Seaman JW. Multiple Imputation Techniques in Small Sample 
Clinical Trials. Stat Med 2006 Jan 30; 25(2):233-45. 
20. Clopper CJ, Pearson E. The Use of the Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika 1934; 26:404-413. 
21. Lavori PW, Dawson R, Shera D. A Multiple Imputation Strategy for Clinical Trials with 
Truncation of Patient Date. Statistics in Medicine 1995; 14:1913-1925. 
22. Li X, Mehrotra DV, Barnard J. Analysis of Incomplete Longitudinal Binary Data Using 
Multiple Imputations. Stat Med. 2006 Jun 30; 25(12):2107-24. 
23. Lavori PW, Dawson R, Shera D. A multiple imputation strategy for clinical trials with 
truncation of patient data. Stat Med. 1995; 14:1913–1925.  
24. Little RJA. Rubin D B. Statistical Analysis with Missing Data. New York: John Wiley 
&Sons; 1987. 
25. Rubin DB. Inference and missing data. Biometrika. 1976; 63:581-592. 
26. Little RJA, Schenker N. Handbook of Statistical Methodology-Missing Data. New 
York: Plenum Press; 1995.  
27. D’Agostino, R. B., Jr., Rubin, D. B. (2000). Estimating and using propensity scores with 
partially missing data. Journal of the American Statistical Association 95:749–759 
28. Yue, L.Q., Lu, N. and Xu, Y., 2014. Designing premarket observational comparative 
studies using existing data as controls: challenges and opportunities. Journal of 
biopharmaceutical statistics, 24(5), pp.994-1010. 
29. Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley: New York, 1987. 
30. Nelson Lu, Yunling Xu, and Lilly Q. Yue (2020) Some Considerations on Design and 
Analysis Plan on a Nonrandomized Comparative Study Using Propensity Score 
Methodology for Medical Device Premarket Evaluation, Statistics in Biopharmaceutical 
Research, 12:2, 155-163, DOI: 10.1080/19466315.2019.1647873 
 
 
5. APPENDICES 
 
APPENDIX A. Statistical Methodology for Multiple Imputation   
 
For a given set of baseline characteristics, it is possible that not all subjects will have value for 
all the baseline characteristics. In certain situations such as propensity score building, it is 
preferred for all subjects to have value for baseline characteristics used for PS building otherwise 
subjects with missing value in at least one baseline characteristic will have missing PS.  
 


 
Protocol 16-308: XIENCE 90 
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In this study, multiple imputation by PROC MI[5] in SAS will be implemented with a sample 
seed = 20170204 through Markov Chain Monte Carlo (MCMC) method with 10 duplications. 
Therefore, 10 sets of PS will be generated for the study through imputation.  Rubin’s 
combination rule [29] will be used to consolidate the final analysis for the 10 duplicates of the 
imputed dataset. 
 
The sample SAS code is provided below: 
 
PROC MI DATA=InputData SIMPLE SEED=20170204 NIMPUTE=10 
OUT=OutData  MINIMUM=0 
    MAXIMUM = . 1 1 1 1 1 1 . . . 1 1 
    ROUND = 0.001 1 1 1 1 1 1 . . . 1 1 
    ; 
              MCMC CHAIN=MULTIPLE DISPLAYINIT INITIAL=EM(ITPRINT); 
              VAR VarableList; 
RUN; 
 
 
For the sensitivity analysis to be performed for the primary endpoint analysis to evaluate the 
impact of the missing outcome.  The missing outcomes will be imputed. In this study, 10 
imputed baseline PS datasets are from the independent statistician, where all baseline values are 
complete through imputation by the independent statistician. The missing outcome data are 
imputed with 1 duplicate (NIMPUTE=1) for each of 10 imputed PS datasets. The same 
imputation method as described above applies to the imputation for the outcome variable, with 
the outcome variable added to the imputation variable list. After this step, each imputed dataset 
would have both complete baseline data and outcome data.  The stratified FM method is then 
performed for each of the above imputed dataset with complete outcome and baseline data, and 
the overall analysis result is obtained through the Rubin’s combination rule.