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ONLINE APPENDIX
Inclusion and Exclusion Criteria
Inclusion Criteria
1. Patient  18 years old.
2. Eligible for percutaneous coronary intervention (PCI).
3. Patient understood the nature of the procedure and provided written informed
consent prior to the catheterization procedure.
4. Patient was willing to comply with specified follow-up evaluation and could be
contacted by telephone.
5. Acceptable candidate for coronary artery bypass graft (CABG) surgery.
6. Stable angina pectoris (Canadian Cardiovascular Society (CCS) I, II, III, IV) or
unstable angina pectoris (Braunwald Class I, II, III, B-C) or a positive
functional ischemia study (e.g., ETT, SPECT, Stress echocardiography or
Cardiac CT).
7. Male or non-pregnant female patient (Note: females of child bearing potential
had a negative pregnancy test prior to enrollment in the study).
Angiographic Inclusion Criteria
1. Patient indicated for elective stenting of a single stenotic lesion in a native
coronary artery.
2. Reference vessel  2.5 mm and  4.0 mm in diameter by visual estimate.
3. Target lesion  24 mm in length by visual estimate (the intention was to cover
the whole lesion with one stent of adequate length).
4. Protected left main lesion with >50% stenosis.
5. Target lesion stenosis  70% and < 100% by visual estimate.
6. Target lesion stenosis <70% who meet physiological criteria for
revascularization (i.e. positive FFR).
Exclusion Criteria: Patients were excluded from the study if any of the following
conditions were present:
1. Currently enrolled in another investigational device or drug trial that had not
completed the primary endpoint or that clinically interfered with the current
study endpoints.
2. Previously enrolled in another stent trial within the prior 2 years.
3. ANY planned elective surgery or percutaneous intervention within the
subsequent 3 months.
4. A previous coronary interventional procedure of any kind within 30 days prior
to the procedure.
5. The patient required staged procedure of either the target or any non-target
vessel within 9 months post-procedure.
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6. The target lesion required treatment with a device other than PTCA prior to
stent placement (such as, but not limited to, directional coronary atherectomy,
excimer laser, rotational atherectomy, etc.).
7. Previous drug eluting stent (DES) deployment anywhere in the target vessel.
8. Any previous stent placement within 15 mm (proximal or distal) of the target
lesion.
9. Co-morbid condition(s) that could limit the patient’s ability to participate in the
trial or to comply with follow-up requirements, or impact the scientific integrity
of the trial.
10. Concurrent medical condition with a life expectancy of less than 12 months.
11. Documented left ventricular ejection fraction (LVEF) < 30% within 12 months
prior to enrollment.
* Protocol version 13 May 2013, and 11 Oct 2013 stated “Documented left
ventricular ejection fraction (LVEF) <30% at most recent evaluation.”
12. Patients with diagnosis of MI within 72 hours (i.e. CK-MB must be returned to
normal prior to enrollment) or suspected acute MI at time of enrollment.
13. Previous brachytherapy in the target vessel.
14. History of cerebrovascular accident or transient ischemic attack in the last 6
months.
15. Leukopenia (leukocytes < 3.5  109 / liter).
16. Neutropenia (Absolute Neutrophil Count < 1000/mm3)  3 days prior to
enrollment.
17. Thrombocytopenia (platelets  100,000/mm3) pre-procedure.
18. Active peptic ulcer or active GI bleeding.
19. History of bleeding diathesis or coagulopathy or inability to accept blood
transfusions.
20. Known hypersensitivity or contraindication to aspirin, heparin or bivalirudin,
clopidogrel or ticlopidine, cobalt, nickel, L-605 Cobalt chromium alloy or
sensitivity to contrast media, which cannot be adequately pre-medicated.
21. Serum creatinine level > 2.0 mg/dL within 7 days prior to index procedure.
22. Patients unable to tolerate dual anti-platelets therapy (DAPT) for one month
post procedure.
Angiographic Exclusion Criteria
1. Unprotected left main coronary artery disease (obstruction greater than 50%
in the left main coronary artery that is not protected by at least one nonobstructed bypass graft to the LAD or Circumflex artery or a branch
thereof).
2. Target vessel with any lesions with greater than 50% diameter stenosis
outside of a range of 5 mm proximal and distal to the target lesion based on
visual estimate or on-line QCA.
* Protocol version 13 May 2013 and 11 Oct 2013 stated “Target vessel with
any lesions with greater than 60% diameter stenosis outside of a range of
5mm proximal and distal to the target lesion based on visual estimate or online QCA.”
3. Target lesion (or vessel) exhibiting an intraluminal thrombus (occupying
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4.
5.
6.
7.
8.
9.
> 50% of the true lumen diameter) at any time.
Lesion location that is aorto-ostial or within 5 mm of the origin of the left
anterior descending (LAD) or left circumflex (LCX).
Target lesion with side branches > 2.0 mm in diameter.
Target vessel is excessively tortuous (two bends > 90˚ to reach the target
lesion).
Target lesion was severely calcified.
TIMI flow 0 or 1.
Target lesion was in a bypass graft.
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PzF SHIELD Study Organization
Principal Investigator
Donald Cutlip MD, Beth Israel Deaconess Medical Center,
Boston, MA
Co-Principal Investigator
Sigmund Silber MD, Heart Center at the Isar, Munich
Germany
Site Monitoring
CeloNova BioSciences Inc, San Antonio, TX: Diana
Sanchez-Garcia (Manager); Medpass International, Paris
France; Medpace, Cincinnati, OH
Data Management
DSG Inc, Malvern, PA Sara Olafsen (Project Manager)
Clinical Events Committee and
Harvard Clinical Research Institute, Boston MA,
Data Monitoring Committee
Coordination
ECG Core Laboratory
Nadine Grella (Project Manager)
Harvard Clinical Research Institute, Boston MA
Nadine Grella (Project Manager)
Angiographic Core Laboratory
Beth Israel Deaconess Medical Center, Boston MA,
Jeffrey Popma MD, Alexandra Popma Almonacid MD
Optical Coherence Tomography Stanford University Medical Center, Stanford CA, Peter
Laboratory
Fitzgerald, MD
Sponsor
CeloNova BioSciences, Inc, San Antonio, TX: Mark
Barakat, MD (Sr. Director, Medical Affairs) and Jane Hart
(Sr. Director, Clinical Affairs)
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Study Definitions according to Clinical Events Committee Charter
ABRUPT CLOSURE
Abrupt Closure. Defined as the occurrence of new (during the index procedure) severely
reduced flow (TIMI grade 0-1) within the target vessel that persisted and required rescue by
stenting or other treatment, or resulted in myocardial infarction or death. Abrupt closure
requires proven association with a mechanical dissection of the treatment site or
instrumented vessel, coronary thrombus, or severe spasm. Abrupt closure does not connote
“no reflow” (due to microvascular flow limitation), in which the epicardial artery is patent
but had reduced flow. Abrupt closure also does not connote transient closure with reduced
flow in which the index treatment application does reverse the closure.
Subabrupt Closure. Defined as abrupt closure that occurred after the index procedure is
completed (and the patient left the catheterization laboratory) and before the 30-day followup evaluation.
Threatened Abrupt Closure. Defined as a grade B dissection and ≥ 50% diameter stenosis or
any dissection of grade C or higher.
ACUTE SUCCESS1
Device Success: Attainment of < 30% final residual stenosis of the target lesion using only
the COBRA PzFTM Coronary Stent System.
Lesion Success: Attainment of < 30% residual stenosis of the target lesion using any
percutaneous method.
Procedure Success: Attainment of < 30% residual stenosis of the target lesion and no inhospital MACE.
ADVERSE EFFECT
An adverse event which was or may have been caused by a device.
ADVERSE EVENT
An adverse event is any undesirable medical occurrence in a clinical study patient, whether
it is considered to be related to the device or not, that includes a clinical sign, symptom, or
condition and/or an observation of a near incident.
ANTICIPATED ADVERSE EVENT
Any undesirable experience (sign, symptom, illness, abnormal laboratory value, or other
medical event) occurring to a patient, whether or not considered related to the
investigational product(s) or drug regimen prescribed as part of the clinical protocol,
predefined in the clinical protocol and/or IFU, that is identified or worsens during a clinical
1 All analyses to determine acute success measures were conducted utilizing in-stent residual stenosis values. When
in-stent % residual stenosis was not available, in-lesion % residual stenosis was used to complete the analysis.
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study.
BLEEDING COMPLICATION
Defined as a procedure-related hemorrhagic event that requires a transfusion and/or
surgical intervention. These complications may include a hematoma requiring treatment
(at access site > 5 cm), or retroperitoneal bleeding.
Reported as major or minor as defined below:
Major: Requires the transfusion of 2 or more units of blood and/or surgical repair.
Minor: Requires the transfusion of less than 2 units of blood.
BRAUNWALD CLASSIFICATION OF UNSTABLE ANGINA
Severity:
Class 1: New onset of severe or accelerated angina. Patients with new onset (< 2 months
in duration) exertional angina pectoris that is severe or frequent (> 3 episodes/day) or
patients with chronic stable angina who develop accelerated angina (that is, angina
distinctly more frequent, severe, longer in duration, or precipitated by distinctly less
exertion than previously) but who have not experienced pain at rest during the preceding
2 months.
Class 2: Angina at rest, subacute. Patients with one or more episodes of angina at rest
during the preceding month but not within the preceding 48 hours.
Class 3: Angina at rest, acute. Patients with one or more episodes of angina at rest
within the preceding 48 hours.
Clinical circumstances in which unstable angina occurs:
Class A: Secondary unstable angina. Patients in whom unstable angina develops
secondary to a clearly identified condition extrinsic to the coronary vascular bed that has
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intensified myocardial ischemia. Such conditions reduce myocardial oxygen supply or
increase myocardial oxygen demand and include anaemia, fever, infection, hypotension,
uncontrolled hypertension, tachyarhythmia, unusual emotional stress, thyrotoxicosis,
and hypoxemia secondary to respiratory failure.
Class B: Primary unstable angina. Patients who develop unstable angina pectoris in the
absence of an extracardiac condition that have intensified ischemia, as in class A.
Class C: Postinfarction unstable angina. Patients who develop unstable angina within
the first 2 weeks after a documented acute myocardial infarction.
CABG
Coronary Artery Bypass Graft
CANADIAN CARDIOVASCULAR SOCIETY CLASSIFICATION (CCSC) OF ANGINA
Class I
Ordinary physical activity does not cause angina, such as walking and climbing
stairs. Angina with strenuous or rapid or prolonged exertion at work or
recreation.
Class II Slight limitation of ordinary activity. Angina upon walking or climbing stairs
rapidly, walking uphill, walking or stair climbing after meals, or in cold, or in
wind, or under emotional stress, or only during the first hours after awakening.
Angina if walking more than two blocks on the level and climbing more than one
flight of ordinary stairs at a normal pace and in normal conditions.
Class III Marked limitations of ordinary physical activity. Walking one to two blocks on
the level and climbing one flight of stairs in normal conditions and at a normal
pace.
Class IV Inability to carry on any physical activity without discomfort. Angina syndrome
may be present at rest.
CLINICALLY DRIVEN TARGET LESION REVASCULARIZATION (TLR)
Revascularization at the target site associated with positive functional ischemia study or
ischemic symptoms AND an angiographic minimal lumen diameter stenosis ≥ 50% by
QCA, or revascularization of a target site with diameter stenosis ≥ 70% by QCA without
either angina or a positive functional study.
CLINICALLY DRIVEN TARGET VESSEL REVASCULARIZATION (TVR)
Revascularization of a lesion within the target vessel in the presence of (1) a positive functional
study for ischemia, or (2) ischemic EKG changes at rest in a distribution consistent with the
target vessel and an angiographic diameter stenosis of >50% or (3) angiographic diameter
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stenosis of >70% in the absence of ischemic symptoms or a positive functional study.
CEREBROVASCULAR ACCIDENT (CVA) (see Stroke)
The occurrence of cerebral infarction (ischemic stroke) and intracerebral hemorrhage and
subarachnoid hemorrhage (hemorrhagic stroke).
de novo LESION
Defined as a native coronary artery lesion not previously treated.
DEATH
Divided into 2 categories:
Cardiac death is defined as death due to any of the following:






Acute myocardial infarction.
Cardiac perforation/pericardial tamponade.
Arrhythmia or conduction abnormality.
Cerebrovascular accident within 30 days of the procedure or cerebrovascular
accident suspected of being related to the procedure.
Death due to complication of a cardiac procedure including bleeding, vascular
repair, transfusion reaction, or bypass surgery.
Any death in which a cardiac cause cannot be excluded.
Non-cardiac death is defined as a death not due to cardiac causes (as defined above).
DEVICE RELATED ADVERSE EVENT
A device related adverse event is defined as any adverse event for which a causal
relationship between the device and the event is at least a reasonable possibility, i.e., the
relationship cannot be excluded.
Device Failure: A device has failed if it is used in accordance with the IFU, but does not
perform according to IFU and negatively impacts the treatment.
Device Malfunction: A device malfunction is an unexpected change to the device that is
contradictory to the IFU and may or may not affect device performance.
Near Incident: Malfunction or deterioration in the characteristics and/or performance of the
device which might have led to death or serious deterioration in health; incident occurred
and is such that if it occurred again, it might lead to death or serious deterioration in health.
Device Misuse: A misused device (one that is used by the Investigator in a manner that is
contradictory to the IFU) will not be considered a malfunction.
DIABETES MELLITUS (DM)
History of diabetes mellitus. The condition will be further categorized as treated by diet,
oral hypoglycemic medications or insulin.
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DISSECTION, NHLBI (National Heart, Lung, and Blood Institute) CLASSIFICATION
Grade A Small radiolucent area within the lumen of the vessel disappearing with the
passage of the contrast material.
Grade B Appearance of contrast medium parallel to the lumen of the vessel disappearing
within a few cardiac cycles.
Grade C Dissection protruding outside the lumen of the vessel persisting after passage of
the contrast material.
Grade D Spiral shaped filling defect with or without delayed run-off of the contrast
material in the antegrade flow.
Grade E Persistent luminal filling defect with delayed run-off of the contrast material in
the distal lumen.
Grade F Filling defect accompanied by total coronary occlusion.
DISTAL EMBOLIZATION
Defined as a new abrupt cut off or filling defect distal to the treated lesion.
EMERGENT BYPASS SURGERY
Defined as coronary bypass surgery performed on an urgent or emergent basis for severe
vessel dissection or closure, or treatment failure resulting in new ischemia.
IN-SEGMENT MEASUREMENT
Defined as the measurements either within the stented segment or within 5 mm proximal
and distal to the stent edges.
IN-STENT MEASUREMENT
Defined as the measurements within the boundaries of the stent.
LESION CLASS (American College of Cardiology/American Heart Association Class)
Type A Lesions: Minimally complex, discrete (length <10 mm), concentric, readily
accessible, non-angulated segment (<45°), smooth contour, little or no calcification, less
than totally occlusive, not ostial in location, no major side branch involvement, and an
absence of thrombus.
Type B Lesions: Moderately complex, tubular (length 10 to 20 mm), eccentric, moderate
tortuosity of proximal segment, moderately angulated segment (>45°, <90°), irregular
contour, moderate or heavy calcification, total occlusions <3 months old, ostial in location,
bifurcation lesions requiring double guidewires, and some thrombus present.
Type C Lesions: Severely complex, diffuse (length >20 mm), excessive tortuosity of
proximal segment, extremely angulated segments >90°, total occlusions >3 months old
and/or bridging collaterals, inability to protect major side branches, and degenerated vein
grafts with friable lesions.
MAJOR ADVERSE CARDIAC EVENTS (MACE)
Defined as cardiac death, myocardial infarction (MI), emergent bypass surgery, or clinically
driven target lesion revascularization (TLR) (PCI or CABG).
MINIMAL LUMINAL DIAMETER (MLD)
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The average of two orthogonal views (when possible) of the narrowest point within the area
of assessment – in lesion, in stent or in segment. MLD is visually estimated during
angiography by the Investigator; it is measured during QCA by the Angiographic Core
Laboratory.
MYOCARDIAL INFARCTION
All myocardial infarction data will be reported per protocol definitions and according to the
Academic Research Consortium (ARC) definitions.
Definition:
Defined as either a Q wave MI (QWMI) or Non-Q wave MI (NQWMI)
QWMI is defined as development of new, pathological Q waves in 2 or more
contiguous leads (as assessed by the Clinical Events Committee) with post-procedure
CK-MB levels elevated above normal.
NQWMI is defined as any elevation of post-procedure CK-MB to 3 times site normal
in the absence of pathological Q waves will be classified as a non- Q-wave MI.
MYOCARDIAL INFARCTION (continued)
Academic Research Consortium (ARC) DEFINITION.
Classification
Biomarker Criteria†
Additional Criteria
Peri-procedural PCI
Troponin >3 times URL or
Baseline value <URL
CKMB >3 times URL
Peri-Procedural CABG
Troponin >5 times URL or
Baseline value <URL
CKMB >5 times URL
AND
Any of the following:
 New pathologic Q
waves‡ or LBBB
 New native or graft
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vessel occlusion
 Imaging evidence of
loss of viable
myocardium
Spontaneous
Troponin >URL or
CKMB >URL
Sudden Death
Death before biomarkers
Symptoms suggestive of
obtained or before expected
ischemia AND
to be elevated
Any of the following:
 New ST elevation or
LBBB
 Documented thrombus
by angiography or
autopsy
Reinfarction
Stable or decreasing values on
If biomarkers increasing
2 samples AND 20% increase
or peak not reached then
3-6 hours after second sample
insufficient data to
diagnose recurrent MI.
† Baseline biomarker value required before study procedure and presumes a typical rise and
fall
‡Pathologic Q waves may be defined according to the Global Task Force, Minnesota code, or
Novacode
URL = upper reference limit, defined as 99th percentile of normal reference range
LBBB = left bundle branch block
ST = stent thrombosis
PCI = percutaneous coronary intervention
CABG = coronary artery bypass graft
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NON-CLINICALLY DRIVEN REPEAT TARGET LESION REVASCULARIZATIONS
Defined as those in which the patient undergoes a non-emergent revascularization for a
diameter stenosis <50% (by QCA). Non-emergent repeat target lesion revascularization for
a diameter stenosis <70% (by QCA) in patients without either a positive functional study or
angina were also considered non-clinically driven.
NO REFLOW
Defined as a sustained or transient reduction in antegrade flow that is not associated with an
obstructive lesion at the treatment site.
PERCENT DIAMETER STENOSIS
The value calculated as 100 x (RVD – MLD)/RVD using the mean values from two
orthogonal views (when possible) by QCA.
PERFORATION
Perforations will be classified as follows:
Angiographic perforation: perforation detected by the clinical site or the core laboratory at
any point during the procedure.
Clinical perforation: perforation requiring additional treatment (including efforts to seal the
perforation or pericardial drainage), or resulting in significant pericardial effusion, abrupt
closure, myocardial infarction, or death.
Pericardial hemorrhage/tamponade: perforation resulting in cardiac tamponade.
PERCUTANEOUS CORONARY INTERVENTION (PCI)
Refers to all interventional cardiology methods for treatment of coronary artery disease.
PERSISTING DISSECTION
Dissection at follow-up that was present post-procedure.
RESTENOTIC LESION
Defined as a lesion in a vessel segment that has undergone prior percutaneous treatment
with or without a stent placement.
REFERENCE VESSEL DIAMETER (RVD)
Defined as the average of normal segments within 10 mm proximal and distal to the target
lesion from 2 orthogonal views using QCA.
SERIOUS ADVERSE EVENT
A study-related adverse event that is fatal, life-threatening, requires inpatient hospitalization
or prolongation of existing hospitalization, requires intervention to prevent permanent
impairment/damage, results in persistent or significant disability or results in a congenital
anomaly/birth defect.
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STENT THROMBOSIS [ARC DEFINITION].
Stent Thrombosis should be reported as a cumulative value at the different time points and
with the different separate time points. Time 0 is defined as the time point after the guiding
catheter has been removed and the patient has left the Cathlab.
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
1. Confirmed/definite:
(is considered either angiographic confirmed or pathologic confirmed).
Angiographic confirmed stent thrombosis [The incidental angiographic
documentation of stent occlusion in the absence of clinical syndromes is not considered
a confirmed stent thrombosis (silent thrombosis)] is considered to have occurred if :
1. Thrombolysis In Myocardial Infarction (TIMI) flow is:
a. TIMI flow grade 0 with occlusion originating in the stent or in the segment
5mm proximal or distal to the stent region in the presence of a thrombus(*).
b. TIMI flow grade 1, 2, or 3 originating in the stent or in the segment 5mm
proximal or distal to the stent region in the presence of a thrombus(*).
AND at least one of the following criteria, up to 48 hours, has been fulfilled:
2. New onset of ischemic symptoms at rest (typical chest pain with duration > 20
minutes)
3. New ischemic ECG changes suggestive of acute ischemia
4. Typical rise and fall in cardiac biomarkers (> 2x ULN of CK).
5. Non-occlusive thrombus:
Intracoronary thrombus is defined as a (spheric, ovoid or irregular) non-calcified
filling defect or lucency surrounded by contrast material (on three sides or within
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a coronary stenosis) seen in multiple projections, or persistence of contrast
material within the lumen, or a visible embolization of intraluminal material
downstream.
6. Occlusive thrombus:
A TIMI 0 or TIMI 1 intra-stent or proximal to a stent up to the most adjacent
proximal side branch or main branch (if originating 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.
2. Probable:
Clinical definition of probable stent thrombosis is considered to have occurred in the
following cases:
1. Any unexplained death within the first 30 days.
2. Irrespective of the time after the index procedure any myocardial
infarction (MI) in the absence of any obvious cause which is related to
documented acute ischemia in the territory of the implanted stent
without angiographic confirmation of stent thrombosis.
STROKE
Defined as sudden onset of vertigo, numbness, dysphasia, weakness, visual field defects,
dysarthria or other focal neurological deficits due to vascular lesions of the brain such as
hemorrhage, embolism, thrombosis, or rupturing aneurysm, that persists >24 hours.
TARGET LESION
The lesion intended to be treated with the treatment device.
TARGET LESION REVASCULARIZATION (TLR)
TLR is defined as any percutaneous intervention of the target lesion or bypass surgery of the
target vessel performed for restenosis or other complication of the target lesion. All TLRs
should be classified prospectively as clinically indicated* or not clinically indicated by the
investigator prior to repeat angiography. An independent angiographic core laboratory
should verify that the severity of percent diameter stenosis meets requirements for clinical
indication and will overrule in cases where investigator reports are not in agreement. The
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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 FAILURE (TVF)
Defined as cardiac death, target vessel myocardial infarction (MI) [Q wave or non-Q wave],
or clinically driven target vessel revascularization (TVR) by percutaneous or surgical
methods.
TARGET VESSEL REVASCULARIZATION (TVR)
TVR is defined as any 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.
TARGET VESSEL REVASCULARIZATION, NON TARGET LESION
REVASCULARIZATION (TVR NON-TLR)
Defined as any clinically-driven (as defined for TLR) repeat percutaneous intervention or
bypass surgery of the target vessel outside of the target lesion.
THROMBOLYSIS IN MYOCARDIAL INFARCTION (TIMI) CLASSIFICATION
TIMI 0
No perfusion.
TIMI 1
Penetration with minimal perfusion. Contrast fails to opacify the entire bed
distal to the stenosis for the duration of the cine run.
TIMI 2
Partial perfusion. Contrast opacifies the entire coronary bed distal to the
stenosis. However, the rate of entry and/or clearance is slower in the coronary
bed distal to the obstruction than in comparable areas not perfused by the dilated
vessel.
TIMI 3
Complete perfusion. Filling and clearance of contrast equally rapid in the
coronary bed distal to stenosis as in other coronary beds.
TRANSIENT ISCHEMIC ATTACK (TIA)
Defined as sudden onset of vertigo, numbness, dysphasia, weakness, visual field defects,
dysarthria or other focal neurological deficits due to vascular lesions of the brain such as
hemorrhage, embolism, thrombosis, or rupturing aneurysm, that persists <24 hours.
UNANTICIPATED ADVERSE DEVICE EFFECT (UADE)
An UADE is defined as any adverse effect on health or safety or any life-threatening
problem or death that is caused by or associated with an investigational device. The effect
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must have not been previously identified in nature, severity or degree of incidence in the
clinical protocol, Investigator’s Brochure or Instructions for Use. Other serious problems
associated with the device that affects the rights or welfare of study patients may also be
considered UADEs.
VASCULAR COMPLICATIONS
Vascular complications may include the following:
1. Pseudoaneurysm
2. Arteriovenous fistula (AVF)
3. Peripheral ischemia/nerve injury
4. Vascular event requiring transfusion or surgical repair
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PERFORMANCE GOAL AND SAMPLE SIZE JUSTIFICATION
Performance Goal for TVF Primary Endpoint
The performance goal (PG) was derived from a meta-analysis of coronary stent trials that
included at least one arm with bare metal stents. (See Table) This analysis yielded a TVF rate at
270 days of 13.62%. However, since absolute equivalence to a constant cannot be proved
statistically, this non-randomized, single-arm study will assess if the COBRA PzF™ stent
primary endpoint rate falls below 19.62%.
Justification of Performance Goal
For this study a PG is necessary since absolute equivalence to a constant cannot be proved
statistically. Specifically, this study allows the primary endpoint rate to be 6% (absolutely)
higher than the rate derived from the meta-analysis. It is based on an absolute delta that
represents a 44% increase over the 13.62% obtained from the meta-analysis, which was deemed
acceptable by the United States Food and Drug Administration during protocol development.
Details of Meta-Analysis and Performance Goal Determination
We performed a systematic search of the PubMed/MEDLINE literature database of articles
published in order to establish a target vessel failure rate at 9 months following PCI. The
following terms were used to query: bare metal stent, target vessel failure, DES control arm,
stent, TVF, and stenting. This search strategy was supplemented with a manual search of
secondary sources, including references cited in the primary articles. Subsequently, we limited
the results to include only those studies with 9 months or longer clinical follow-up data based on
the TVF rate (cardiac death, MI, or TVR). The 5 studies meeting these criteria with associated 9month TVF rates are shown in Table. Since COBRA PzF SHIELD specified completing clinical
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follow-up for TVF prior to planned angiographic follow-up, the TVF rates in the meta-analysis
were adjusted downward to account for angiographic follow-up bias in TVF rates.
No. of
Patients
Study
Treatment Group
TAXUS IV
EXPRESS
652
ENDEAVOR
II
Driver
591
PIONIR
Presillion/Presillion
plus
278
DRIVER S8
Driver
298
NIRVANA
NIR
418
Adjusted TVF Rate
assuming No
Mandated
Angiographic
Follow-up (95% CI)
0.117
(0.092, 0.142)
0.119
(0.094, 0.146)
0.093
(0.059;0.128)
0.079
(0.048, 0.110)
0.109
(0.079, 0.139)
The TVF rate at 270 days post-procedure derived from the meta-analysis assuming no mandated
angiographic follow-up is 10.62% (95% CI 9.35%, 11.90%). Notably, MI rates in these studies
were based on the historical modified WHO definition of total CK >2 times ULN. Since
COBRA PzF SHIELD defined MI according CKMB >3 times normal, the MI rate was adjusted
upward by 3% based on prior studies comparing these definitions. The meta-analysis rate for
TVF was determined thus as 13.62%.
Statistical Hypothesis and Sample Size Justification
The null hypothesis for this study states that the COBRA PzF stent and delivery system will have
a primary endpoint rate greater than or equal to 19.62%. The alternative hypothesis states that the
COBRA PzF stent and delivery system will have a primary endpoint rate less than 19.62%.
Specifically:
Ho:  COBRA PzF ≥19.62%
HA: 
COBRA PzF
<19.62%
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where 
COBRA PzF
is the true primary endpoint rate for the COBRA PzF stent and delivery system
and the 19.62% is the meta-analytically derived PG for the primary endpoint rate. Rejection of
the null hypothesis will signify that the PG has been met, and that the COBRA PzF stent and
delivery system’s primary endpoint rate is less than 19.62%.
The primary hypothesis test will be carried out by comparing the upper bound of the one-sided
95% confidence interval (CI) of the 270-day TVF rate to 19.62%, the PG. If this upper bound is
less than 19.62%, then it is considered that the COBRA PzF stent and delivery system meets the
PG. The necessary sample size for testing the primary hypothesis was estimated with PASS
software using exact hypothesis testing based on the exact distribution with the following
assumptions:

Type I error (α) = 0.05 (one-sided)

Statistical power (1 – β) = 85%

PG = 19.62%


COBRA PzF
= 13.62%
An evaluable sample size of 281 provides 85% power to reject the above null hypothesis in favor
of the alternative. Thus, 296 patients were to be enrolled to account for loss to follow-up, which
was expected to be approximately 5%. With evaluable sample size of 281 patients and observed
rate of 9-month TVF ≤14.9% (critical value to reject Ho) the performance goal of 19.62% will be
met.
Performance Goal and Hypothesis Testing for Secondary Endpoint Late Lumen Loss
In-stent late loss (LL) is a powered secondary endpoint for this trial. The hypothesis for this
endpoint is to be tested only if alternative hypothesis of 270- day TVF endpoint is accepted. The
available literature expected in-stent late loss for BMS at 9 months is 0.9±0.6 mm. The goal of
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the secondary analysis will be to assess the comparability of the observed 9-month in-stent LL
for the COBRA PzF stent and delivery system to the expected LL. However, since absolute
equivalence to a constant cannot be proven, this non-randomized, single-arm study will assess if
the COBRA PzF stent and delivery system late loss was below 1.1 mm. Specifically, this study
assessed the ability of the COBRA PzF stent and delivery system to meet this PG, which allows
the primary endpoint rate to be 0.2 mm (absolutely) higher than the expected late loss for BMS.
The null hypothesis for this study states that the COBRA PzF stent and delivery system will have
in-stent LL at 9 months greater than or equal to 1.1 mm. The alternative hypothesis states that the
COBRA PzF stent and delivery system will have LL less than 1.1 mm.
Specifically:
Ho: µCOBRA PzF ≥1.1mm
HA: µCOBRA PzF <1.1mm
where µCOBRA PzF ™ is the true in-stent LL for the COBRA PzF stent and delivery system and
the 1.1 mm is PG for the in-stent LL. Rejection of the null hypothesis will signify that the PG
has been met, and that the COBRA PzF stent and delivery system’s in-stent LL is less than
1.1 mm.
The hypothesis test was carried out by comparing the upper bound of the one-sided 97.5% CI of
the 270-day in-stent LL to 1.1 mm, the PG. If this upper bound is less than 1.1 mm, then it is
considered that the COBRA PzF stent and delivery system meets the PG. The necessary sample
size for testing the secondary hypothesis was estimated with PASS software using the following
assumptions:

Type I error (α) = 0.025 (one-sided)

Angiographic cohort evaluable sample size of 90 patients
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
PG = 1.1mm

µCOBRA PzF = 0.9mm

One-sample t-test, corresponding to the testing algorithm described previously
An evaluable sample size of 90 provides 87.6% power to reject the above null hypothesis in
favor of the alternative.
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PzF SHIELD Participating Study Sites and Principal Investigators
Beth Israel Deaconess Medical Center
Donald Cutlip
Boston, MA
Aurora Health Care, Inc.
Suhail Allaqaband
Milwaukee, WI
St Joseph's Hospital Cardiac Catheterization
Ronald Caputo
Associates
Liverpool, NY
Mt Sinai Medical Center
Nirat Beohar
Miami Beach, FL
Baylor Research Institute – The Heart Group
David Brown
Plano, TX
Northwell Health
Kirk Garratt / Rajiv Jauhar
New York, NY
Deborah Heart and Lung Center
Jon George / Vincent Varghese
Brown Nills, NJ
Southern Oregon Cardiology, LLC
Mark Huth
Medford, OR
Aspirus Heart & Vascular Institute
German Larrain
Wausau, WI
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Bakersfield Memorial Hospital – Golden
Tommy Lee
Empire Cardiology
Bakersfield, CA
Texas Plaza Medical Center of Fort Worth
Amir Malik
Fort Worth, TX
Covenant Medical Center
Scott Martin
Saginaw MI
Oklahoma Foundation for Cardiovascular
Thomas McGarry
Research
Oklahoma City, OK
Virginia Cardiovascular Specialists
Charles Phillips
Richmond, VA
Houston Methodist Hospital
Alpesh Shah
Houston, TX
Baylor Heart and Vascular/CCT
Robert Stoler
Dallas, TX
Heart Center of Indiana – St. Vincent
Michael Ball
Medical Group, Inc.
Price, R. Jeffrey
Indianapolis, IN
Rossi, Joseph
Taylor, Charles
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Tyler Cardiovascular Consultants
Thaddeus Tolleson
Tyler, TX
York Hospital
William Nicholson
York, PA
Mt Sinai Medical Center
Srinivas Kesanakurthy
New York, NY
Caprock Cardiac Center Research Institute
Mohammad Shoukfeh
Lubbock, TX
Emory University Hospital Midtown
Aloke Finn / Chandanreddy
Devireddy
Atlanta, GA
Waco Cardiology Consultants – Providence
Charles Shoultz
Health Center
Waco, TX
Vanderbilt University Medical Center
Mark Robbins
Nashville, TN
San Antonio Endovascular & Heart Institute
Radoslaw Kiesz
San Antonio, TX
Louisiana Heart Hospital
Pramod Menon
Lacombe, LA
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Kantonsspital St. Gallen
Daniel Weilenmann
Kardiologie
St. Gallen Switzerland
CardioVasculaeres Centrum
Horst Sievert
Frankfurt/M. Germany
Latvian Centre of Cardiology
Andrejs Erglis
Riga, Latvia
Klinicki Centar Srbija
Goran Stankovic
Belgrade Serbia
Clinique St. Hilaire
Jacques Berland
Rouen France
Centre Hospitalier Francois Mitterrand de
Nicolas Delarche
Pau
Pau France
Hopital Henri Duffault
Jean Lou Hirsch
Avignon France
Clinique Axium
Luc Maillard
Aix-en-Provence France
Clinique du Diaconat Fonderie
John Shayne
Mulhouse France
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Hospital de la Santa Creu Sant Pau
Antonio Serra
Barcelona Spain
Hospital Clinico San Carlos
Antonio Fernandez-Ortiz
Madrid Spain
Hopital Albert Schweitzer
Jean-Pierre Monassier
Colmar France
Kardiologische Praxis und Praxisklinik
Sigmund Silber
Munich Germany
S26
Supplemental Results Table 1. Event rates and 95% confidence intervals (CI) for comparison
within 4 pre-specified sub-groups. P values represent comparison of individual subgroups.
TVF
Subgroup
N
N (%)
95% CI
Males
208
23 (11.4)
(7.4-16.6)
Females
88
10 (11.8)
(5.8-20.6)
Yes
99
6 (6.3)
(2.3 -13.1)
No
195
26 (13.8)
(9.2-19.5)
Yes
115
15 (13.2)
(7.6 – 20.8)
No
181
18 (10.4)
(6.3 – 15.9)
U.S. Site
166
17 (10.6)
(6.3 – 16.4)
Non U.S. Site
130
16 (12.7)
(7.4 – 19.8)
Gender
0.99
Diabetes
Angiographic
Follow-up
P Value
0.07
Geography
U.S. = United States; TVF = Target vessel failure.
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0.57
0.58
Supplemental Results Table 2. Mean late lumen loss and 95% confidence intervals (CI) for
comparison within 4 pre-specified sub-groups. P values represent comparison of individual
subgroups. Results for routine angiographic follow-up subset.
Late Loss
Subgroup
N
Mean ± SD
95% CI
Males
80
0.84 ± 0.52
0.73-0.96
Females
33
0.83 ± 0.37
0.71-0.96
Yes
33
0.81 ± 0.39
0.67-0.95
No
79
0.85 ± 0.52
0.74-0.97
U.S. Site
34
0.88 ± 0.52
0.70-1.06
Non U.S. Site
79
0.82 ± 0.47
0.72-0.93
Gender
P Value
0.89
Diabetes
0.66
Geography
0.57
U.S. = United States
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