SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)
I. GENERAL INFORMATION
Device Generic Name: Drug-Eluting Coronary Stent System
Device Trade Name: Svelte SLENDER Sirolimus-Eluting Coronary
Stent Integrated Delivery System (SLENDER
IDS
®
)
Svelte DIRECT Sirolimus-Eluting Coronary Stent
Rapid Exchange Delivery System (DIRECT RX
®
)
Device Procode: NIQ
Applicant’s Name and Address: Svelte Medical Systems, Inc.
675 Central Avenue, Suite 2
New Providence, New Jersey 07974
USA
Date(s) of Panel Recommendation: None
Premarket Approval
Application (PMA) Number: P210014
Date of FDA Notice of Approval: December 13, 2021
II. INDICATIONS FOR USE
The Svelte SLENDER Sirolimus-Eluting Coronary Stent Integrated Delivery System
(Svelte SLENDER IDS) is indicated for improving coronary artery luminal diameter in
patients with symptomatic heart disease due to atherosclerotic lesions 24 mm in length
in native coronary arteries with 2.25 mm to 4.00 mm reference vessel diameters,
using direct stenting or pre-dilatation interventional techniques.
The Svelte DIRECT Sirolimus-Eluting Coronary Stent Rapid Exchange Delivery System
(Svelte DIRECT RX) is indicated for improving coronary artery luminal diameter in
patients with symptomatic heart disease due to atherosclerotic lesions 34 mm in length
in native coronary arteries with 2.25 mm to 4.00 mm reference vessel diameters,
using direct stenting or pre-dilatation interventional techniques.
III. CONTRAINDICATIONS
The Svelte SLENDER IDS and the Svelte DIRECT RX (collectively, Svelte DES) are
contraindicated for use in patients:
x Unable to receive anti-platelet and/or anti-coagulant therapy.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 1 of 55
x With known hypersensitivity to sirolimus, PEA III Ac Bz, cobalt, chromium,
nickel, tungsten or contrast media.
x Judged to have lesions preventing complete inflation of an angioplasty balloon or
proper placement of a coronary stent or delivery system, including chronic total
occlusions.
IV. WARNINGS AND PRECAUTIONS
The warnings and precautions can be found in the Svelte DES labeling.
V. DEVICE DESCRIPTION
The Svelte DES is a combination product consisting of (1) a cobalt chromium (CoCr)
alloy stent coated with a bioresorbable polymeric drug carrier containing the anti-
proliferative drug sirolimus and (2) the delivery system, either fixed-wire (SLENDER
IDS) or rapid exchange (DIRECT RX).
The characteristics of the Svelte DES are described in Table 1.
Table 1. Svelte DES Product Characteristics
Characteristic
Svelte DES Svelte DES
SLENDER IDS DIRECT RX
Stent Pattern
3-cell (2.25, 2.50, 2.75, 3.00 mm diameter)
4
-
cell (3.5
0
, 4.0
0
mm diameter)
Stent
Lengths (mm)
8, 13, 18, 23, 28
8, 13, 18, 23, 28, 33, 38
Stent
Diameters (mm)
2.25, 2.50, 2.75, 3.00, 3.50, 4.00
Stent Strut Thickness (mm) 2.25 – 3.00 mm diameters: 0.081 mm
3.50
–
4.00 mm diameters:
0.084 mm
Stent Material
A medical grade L605 CoCr alloy
Drug Component A conformal (all surfaces of the stent) coating of a
bioresorbable
polymer
loaded with 213
g/cm
2
of sirolimus
Delivery System Working
Length
145 cm 139 cm
Delivery System Design
0.014” fixed-wire catheter Rapid exchange with a single
with integrated torquer and access port to inflation lumen.
single access port to inflation Designed for guide wires
lumen
0.014
”
Stent Delivery System
Balloon
Compliant balloon with two radiopaque markers to designate
the stent placement on the balloon
Guiding Catheter
Compatibility
5 F (min. guide catheter ID of 0.056”/1.42 mm)
Balloon Inflation Pressure
Nominal: 12 atm (1216 kPa)
Rated Burst Pressure: 18
atm
(1824
kPa)
Catheter Shaft Outer
Diameter
Distal: 0.029 in
(2.2 F, 0.73 mm)
Proximal:
0.025 in
Distal: 0.035 in
(2.7 F, 0.89 mm)
Proximal:
0.026 in
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 2 of 55
Characteristic
Svelte DES
SLENDER IDS
Svelte DES
DIRECT RX
(
1.9
F
,
0.63
mm)
(
2.0
F
,
0.67
mm)
A. Device Component Description
The Svelte DES stent is made of CoCr. The stent has two designs that are differentiated
by the number of cells and the number of links. The 3-cell design with three links around
the circumference is used for 2.25-3.00 mm diameter stents and the 4-cell design with
four links around the circumference is used for 3.50-4.00 mm diameter stents. Each stent
length configuration has end units that make up the end columns and repeating inner units
that make up the internal columns. In order to create various stent lengths, the number of
repeating inner columns is varied. Figure 1 illustrates a 3-cell (top) and 4-cell (bottom)
Svelte DES stent.
Figure 1: 3-Cell (top) and 4-Cell (bottom) Stent Configurations
The stent is crimped onto the balloon of one of the two available delivery systems:
SLENDER IDS or DIRECT RX.
SLENDER IDS is a novel fixed-wire delivery system consisting of a shapeable,
radiopaque wire tip, low-compliant delivery balloon and proximal shaft. SLENDER IDS
contains two proximal shaft markers (90 cm and 100 cm) indicating the position of
SLENDER IDS relative to the end of a brachial or femoral catheter. An integrated
torquing device located on the proximal end of the catheter shaft facilitates navigation.
The Slender IDS has a very low profile and integrated design that is particularly suited
for use with a direct PCI strategy. Figure 2 provides a pictorial representation of the
SLENDER IDS.
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Figure 2: SLENDER IDS Delivery System
DIRECT RX is a rapid exchange delivery system with a low-compliant delivery balloon.
Figure 3 provides a pictorial representation of the DIRECT RX.
Figure 3: DIRECT RX Delivery System
B. Drug Component Description
The Svelte DES stent is conformally coated with a bioresorbable drug coating. The drug
matrix is composed of sirolimus (the active ingredient) and bioresorbable polyesteramide
(PEA; inactive ingredient).
1. Sirolimus
Sirolimus (also known as rapamycin) is the active pharmaceutical ingredient in the
Svelte family of stents. The sirolimus chemical name is:
[3S[3R*[S*(1R*,3S*,4S*)),6S*,7E,9S*,10S*,12S*,14R*,15E,17E,19E,21R*,23R*,2
6S*,27S*,34aR*]]-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-
9,27-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethyl]-10,21-
dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]
oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.
The molecular structure of sirolimus is C
51
H
79
NO
13
and its molecular weight is
914.19 Da. The chemical structure is provided in Figure 4.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 4 of 55
Figure 4: Chemical Structure of Sirolimus
The Svelte DES product matrix and nominal total loaded dose of sirolimus per
nominal stent length/diameter is shown in Table 2.
Table 2. Svelte DES Product Matrix and Drug Content
Stent
Design
Stent Diameters
(mm)
Stent Length
(mm)
Sirolimus Dose
(μg/stent)
SLENDER IDS DIRECT RX
3-cell
2.25
2.50
2.75
3.00
8 58 58
13 87 87
18 126 126
23 156 156
28 195 195
33 224
38 263
4-cell
3.50
4.00
8 79 79
13 119 119
18 173 173
23 213 213
28 266 266
33 306
38 360
2. Inactive Ingredient: polyesteramide (PEA)
The bioresorbable PEA carrier is a synthetic amorphous elastomeric random
copolymer consisting of amino acid units (L-leucine and L-lysine benzyl ester)
separated by hydrocarbon diacid (decanedioic acid) and diol (1,6-hexanediol and
1,4-dianhydrosorbitol) spacers. The structural formula of the PEA carrier is shown in
Figure 5.
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Figure 5: Chemical Structure of PEA Carrier
3. Mechanism of Action of Sirolimus
Sirolimus inhibits T-lymphocyte activation, smooth muscle and endothelial cell
proliferation in response to cytokine and growth factor stimulation. In cells, sirolimus
binds to the immunophilin, FK Binding Protein-12 (FKBP-12). The sirolimus-FKBP-
12 complex binds to and inhibits the activation of the mammalian Target of
Rapamycin (mTOR), leading to inhibition of cell cycle progression from the G
1
to S
phase.
The sirolimus drug coated on the Svelte DES has an ancillary function as an anti-
proliferative and anti-restenotic agent due to its ability to interrupt smooth muscle cell
migration and proliferation.
VI. ALTERNATIVE PRACTICES AND PROCEDURES
There are several other alternatives for the correction of coronary artery disease. These
may include exercise, diet, smoking cessation, drug therapy, percutaneous coronary
interventions (such as angioplasty and placement of other coronary stents), and coronary
artery bypass graft surgery (CABG). Each alternative has its own advantages and
disadvantages. A patient should fully discuss these alternatives with his/her physician to
select the method that best meets expectations and lifestyle.
VII. MARKETING HISTORY
The Svelte DES have been market released (CE Mark certified) outside the United States
since 2016 and have been in commercial use in the Netherlands, Belgium, Czech
Republic and United Kingdom. No Svelte devices have been withdrawn from distribution
in any country for any reason related to product safety or effectiveness.
VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
Adverse events (in alphabetical order) that may be associated with the use of a stent in
native coronary arteries include but are not limited to:
x Access site complications (incl. arteriovenous fistula, hematoma, infection, nerve
injury, pain, peripheral ischemia, phlebitis, pseudoaneurysm)
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 6 of 55
x Acute myocardial infarction
x Acute pulmonary edema
x Allergic reaction or hypersensitivity to contrast media, antiplatelets, anticoagulants,
L-605 cobalt chromium alloy, PEA, sirolimus or sirolimus derivatives
x Aneurysm formation
x Angina pectoris (stable or unstable)
x Atrial fibrillation
x Bradycardia
x Bleeding complications that may require transfusions or surgical repair
x Cardiac arrhythmias, including ventricular fibrillation and ventricular tachycardia
x Cardiac perforation
x Cardiac tamponade
x Cardiogenic shock
x Congestive heart failure
x Coronary artery complications (incl. abrupt closure, dissection, embolism, injury,
perforation, plaque rupture/shift, restenosis, rupture, spasm, thrombosis, total
occlusion)
x Death
x Delayed endothelialization
x Distal emboli
x Endocarditis
x Emergency cardiac surgery
x Fever or pyrogenic reactions
x Hypotension/hypertension
x Infections
x Myocardial ischemia
x Nausea and vomiting
x Palpitations
x Perforation of the heart or great vessels
x Pericardial effusion
x Respiratory insufficiency or failure
x Renal failure
x Retroperitoneal hematoma
x Stent collapse
x Stent dislodgement from the delivery system
x
Stent embolization
x Stent thrombosis or occlusion
x Stroke/cerebrovascular accident/transient ischemic attack
x Vasovagal reaction
x Vasospasm
x Volume overload
Potential adverse events related to the oral administration of sirolimus include, but are not
limited to:
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 7 of 55
x Abnormal liver function tests
x Anemia
x Arthralgia
x Diarrhea
x Hypercholesterolemia
x Hypersensitivity (including anaphylactic/anaphylactoid type reactions)
x Hypertriglyceridemia
x Hypokalemia
x Infections
x Interstitial lung disease
x Leukopenia
x Lymphoma and other malignancies
x Thrombocytopenia
There may be other potential adverse events that are unforeseen at this time.
For the specific adverse events that occurred in clinical studies, please see Section X
below.
IX. SUMMARY OF NONCLINICAL STUDIES
A series of non-clinical laboratory studies and pharmacokinetic studies related to the
product were performed. Studies included those performed on the bare metal stent alone,
the coated stent alone, the polymer-only coated stent alone, the delivery systems, and the
finished combination product.
A. Laboratory Studies
1. In Vitro Engineering Testing
In vitro engineering testing was conducted on test samples representative of the
Svelte DES in accordance with the following FDA guidance documents:
x FDA Guidance Document issued on April 18, 2010, Non-Clinical
Engineering Tests and Recommended Labelling for Intravascular Stents and
Associated Delivery Systems
x FDA Guidance Document issued on August 18, 2015, Select Updates for
Non-Clinical Engineering Tests and Recommended Labeling for Intravascular
Stents and Associated Delivery Systems
x FDA Guidance Document issued on May 20, 2021, Testing and Labeling
Medical Devices for Safety in the Magnetic Resonance (MR) Environment
Specific in vitro engineering tests were performed on the representative uncoated,
bare metal version of the Svelte DES and the delivery systems.
Table 3 summarizes this testing. “Pass” denotes that the test results met product
specifications and/or the recommendations in the above referenced guidance
documents.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 8 of 55
Table 3. Summary of Engineering Testing
Test Purpose Acceptance Criteria Results
Material Characterization
Material Composition
To identify and list The stent is fabricated from L605
all components and CoCr alloy tubing, to which ASTM
their respective F90 applies.
materials used in
the construction of The incoming raw materials conform
the stent and to specifications.
delivery
systems.
Pass
Stent Mechanical
Properties
To test the The stent tubing tensile, yield
mechanical strength, and elongation must meet
properties for the specification.
stent tubing.
Pass
Stent Corrosion
Resistance
To determine the Per ASTM F2129
stent resistance to
fretting, pitting, and
crevice
corrosion.
Pass
Stent Dimensional and Functional Attributes
Dimensional
Verification
(Unexpanded Stent
Dimensions
)
To inspect and Stent dimensions must meet
measure the stent specifications.
dimensions.
Pass
Dimensional
Verification
(Uniformity of Stent
Expansion)
To measure the The uniformity of stent expansion
diameter of the must meet specifications.
expanded stent per
ASTM F2081.
Pass
Percent Surface Area
To determine the
surface coverage of
the stent in the
vessel.
Percent contact surface area must be
6-15%.
The percent surface area of the stent
must
me
e
t
specification
s
.
Pass
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 9 of 55
Test Purpose Acceptance Criteria Results
Foreshortening To ensure the
foreshortening of
the stent falls
within acceptable
limits.
Maximum
Dia. Length
Foreshortening %
IDS RX
2.25
8 – 13
20% 20%
–
mm
2.75
18 – 28
12% 12%
mm
mm
8* – 13
20%* 20%*
3.00
mm
mm
18 – 28
12% 12%
mm
8 – 13
20% 20%
3.50
mm
mm
18 – 28
12% 12%
mm
8* – 13
20%* 20%*
4.00
mm
mm
18 – 28
15% 15%
mm
*Stent sizes 3.00x8 and 4.00x8mm
did not meet the acceptance criteria,
with reported maximum
foreshortenings of up to 21.2% and
27.4%, respectively. This was
deemed acceptable based on robust
scientific and clinical rationales.
Accurate foreshortening percentages
are
in the product labeling.
Pass
Recoil
To measure the
elastic recoil of
stent from its
expanded diameter
while still on the
delivery balloon to
its relaxed diameter
after deflating the
balloon per
ASTM
F2079.
Stent recoil 8% at nominal pressure
and rated burst pressure
Pass
Stent Integrity
To examine the
deployed stent for
defect
s
.
Stent will have no significant surface
defects such as cracks or scratches
when examined
under microscope
.
Pass
Radial Stiffness and To characterize the Radial Stiffness: Characterization
Radial Strength
ability of the stent
to resist collapse
under external
loads.
only
Radial Strength: Diameter decreases
to 15% of starting diameter at
5
psi
Pass
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 10 of 55
Test Purpose Acceptance Criteria Results
Stress/Strain and To identify the Goodman and Maximum Equivalent
Fatigue Analysis critical locations of Strain Damage (MESD) analysis
stress or strain on must demonstrate acceptable safety Pass
the stent using factors (>1).
FEA.
Accelerated To determine the Per ASTM F2477. No stent fractures
Durability long-term integrity that would adversely affect stent
of the stent under performance after 400 million cycles
cyclical loading (10 year equivalent) Pass
conditions in an
overlapping and
bent configuration.
Magnetic Resonance To determine the See product labeling for safe MRI
Imaging (MRI) Safety effect of MR on the use conditions
and Compatibility position and
temperature of the
stent, and to Pass
determine the
extent of image
artifact during
MRI.
Radiopacity To determine stent Stent is visible under fluoroscopy.
visibility using
angiographic
Pass
imaging to assure
proper stent
placement.
Delivery System Dimensional and Functional Attributes
Dimensional To inspect and The stent delivery systems must
Verification measure the meet dimensional specifications
dimensional (e.g., length, inner and outer
Pass
properties of the diameter, and crossing profile).
stent delivery
systems.
Delivery, To evaluate the The stent delivery systems can
Deployment, and performance of the safely and reliably deliver the stent
Retraction stent delivery to the intended location according to
systems to safely the instructions for use, without Pass
and reliably deliver damage to the stent.
the stent to the
intended lo
cation.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 11 of 55
Test Purpose Acceptance Criteria Results
Balloon Rated Burst
Pressure
To determine the
rated burst pressure
(RBP) of the
balloon with the
mounted stent.
RBP 18 atm
The RBP label claim is the pressure
at which 99.9% of the balloons can
survive with 95% confidence.
Pass
Balloon Fatigue
To determine the
ability of the
balloon to withstand
repeated inflation/
deflation cyc
les.
The balloon catheter must
demonstrate that 90% of the
balloons will survive 10 inflations to
RBP, with 95% confidence and
maintain pressure
per specification
.
Pass
Balloon Compliance
(Stent Diameter vs.
Balloon Pressure)
To determine the
relationship between
the stent diameter
and the balloon
inflation pressure.
To generate a compliance chart in
the labeling that relates stent
diameter to balloon pressure. Pass
Balloon Inflation and
Deflation Time
To determine the
amount of time
required to inflate or
deflate the balloon
delivery systems.
Inflation Time: Characterization of
time to inflate the balloon to targeted
label RBP.
Deflation Time:
IDS: Upper STI of Deflation Time
20 seconds from RBP
RX: Upper STI of Deflation Time
30
seconds from RBP
Pass
Catheter Bond
Strength and Tip Pull
Test
To determine the
bond strengths of
the delivery systems
and their tips
Catheter bond strengths must meet
specifications.
Pass
Flexibility and Kink
Test
To demonstrate the
smallest radius that
the delivery systems
can conform to prior
to kinking.
The stent delivery systems will not
kink or exhibit a diameter reduction
affecting the performance while
traversing vessels with a bend radius
of 0.50 in (12.7 mm)
.
Pass
Catheter Torque To demonstrate that IDS & RX: Withstand 15 full
Strength
the delivery systems
can withstand
torsional forces that
are typical of
clinical use.
rotations without failure.
IDS Only: Hold pressure to targeted
label RBP for 30 seconds after 3 full
rotations
.
Pass
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 12 of 55
Test
Coating Integrity
Purpose
To demonstrate
minimal degradation
of the coating on the
stent delivery
systems during
acute clinical
performance.
Acceptance Criteria
Characterization only
Results
Pass
Stent Securement
To measure the
force that will
dislodge the stent
prior to deployment.
Stent dislodgement by forward
motion and reverse motion: Lower
STI 0.5N
Pass
2. Coating Characterization Testing
The coating characterization testing conducted on the Svelte DES is summarized in
Table 4.
Table 4. Coating Characterization Testing
Test Purpose Acceptance Criteria Results
Acute Particulate
Evaluation – Baseline
unconstrained expansion
to RBP
To measure the
particulate matter
generated by the stent
during unconstrained
expansion to RBP
without tracking.
Characterization only Pass
Acute Particulate
Evaluation – Simulated
use
To measure the
particulate matter
generated during
simulated use of the
delivery system through
an in vitro model to
maximum dilatation limit
in an overlapping
configuration in a mock
vessel with 15mm bend
radius.
Characterization only Pass
Acute Coating Integrity
To assess the drug
coating integrity of the
stent as manufactured
(e.g. prior to tracking and
expansion).
Characterization only Pass
Acute Coating Durability
To assess the durability
of the coating when
subjected to simulated
clinical use conditions.
Characterization only Pass
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 13 of 55
Test
Chronic Coating
Integrity, including
Particulate Evaluation
Coating Thickness and
Uniformity
Purpose
Particulate evaluation and
coating integrity
assessment of stents in
bent overlapped
configuration after
exposure to pulsatile
stresses and strains.
To measure the coating
thickness along the length
of the expanded stent post
deployment to RBP for
both the abluminal and
luminal stent surfaces.
To analyze the coating
uniformity along the
length and circumference
of the stent via assaying
individual stent segments
for sirolimus.
Acceptance Criteria
Characterization only
Characterization only
Results
Pass
Pass
Coating Characterization To measure the coating
– Adhesion of the coating adhesion (delamination
to the stent substrate
strength) of the expanded
stent post deployment to
RBP
.
Characterization only Pass
3. Chemistry, Manufacturing & Controls (CMC) Release Testing
Each batch of finished devices undergoes testing prior to release and distribution.
Where applicable, the test methods follow International Conference on
Harmonization (ICH) guidelines. This testing is summarized in Table 5.
Table 5. CMC Release Testing
Test
Purpose
Drug Identity
To verify the identity of the drug substance in the
finished stent.
Drug Content
To verify that the total amount of the drug on the
stent
is within the specifications established for the
finished product.
Content Uniformity
To verify the uniformity of the drug content
between individual stents is within the
specifications established for the finished stent.
Related Substances
Testing is conducted to verify that the amount of
impurities are within the specifications established
for the finished product.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 14 of 55
Test
Purpose
To verify that the in vitro release of the drug
Drug Release substance is within the specifications established
for the finished product.
Testing is conducted to verify that the amount of
BHT Content BHT is within the specifications established for
the finished product.
To verify that particle counts are below acceptable
Particulate Matter
levels for the finished product.
Testing is conducted to verify that the molecular
weight of the polymer in the drug coating is within
Molecular Weight
the specifications established for the finished
produc
t.
Bacterial Endotoxins
To verify that endotoxin levels are within
specifications established for the finished product.
Sterility To verify the sterility of the finished product.
4. Stability and Shelf Life
Stability/shelf-life studies were conducted to establish a shelf life for the Svelte DES.
The stability testing included a combination of real time and accelerated aging
stability studies for drug properties, particulate matter, packaging integrity and
sterility, polymer coating properties, and relevant engineering attributes of the stent
and delivery system. The data generated supports a product shelf life of 2 years.
5. Packaging and Sterilization
Packaging verification testing was performed to demonstrate that the design of the
Svelte DES packaging can withstand the hazards of the distribution environment and
that the sterility of the product is maintained throughout the labeled shelf life. The
Svelte DES are sterilized with ethylene oxide (EtO) gas to a sterility assurance level
(SAL) of 1x10
-6
. The quantity of bacterial endotoxins was verified to be within the
specification limits. The sterilization processes are in compliance with EN ISO
11135:2014.
6. Biocompatibility
A series of Good Laboratory Practice (GLP) biocompatibility tests and USP
Physicochemical tests were conducted to demonstrate that the components of the
Svelte DES are non-toxic and biocompatible. Tests were conducted on final, ethylene
oxide sterilized coated stents, polymer only coated stents, uncoated stents, stent
delivery systems and the insertion tool accessory device. These test articles were
processed in the same manner as the finished Svelte DES. The results of the
biocompatibility studies indicated that the Svelte DES was biologically safe and
acceptable for clinical use:
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All biocompatibility testing was conducted in accordance with one or more of the
following general regulations, standards and guidance documents:
x Good Laboratory Practices Regulations (21 CFR § 58)
x ISO 10993-1:2018, Biological evaluation of medical devices – Part 1:
Evaluation and testing within a risk management process
x AAMI / ANSI / ISO 10993-1:2009, Biological evaluation of medical devices
– Part 1: Evaluation and testing within a risk management process
x FDA Use of International Standard ISO 10993-1, “Biological evaluation of
medical devices – Part 1: Evaluation and testing within a risk management
process”, Guidance for Industry and Food and Drug Administration Staff,
June 16, 2016
x USP "Physicochemical Test – Containers Plastics" <661>
Table 6 provides a summary of the biocompatibility testing conducted to support the
Svelte DES.
Table 6. Summary of Biocompatibility Testing
Test Name Test Description Test Article
Chemical
Characterization
ISO 10993-18: Chemical Characterization
of Materials
Extraction of Chemical Compounds
x Coated (drug and
polymer blend) stent
Cytotoxicity
ISO 10993-5: In vitro Cytotoxicity
(L929 MEM Elution)
x Coated (drug and
polymer blend) stent
x Polymer only coated
stent
x Uncoated stent
x IDS Delivery System
x RX Delivery System
x
Insertion Tool
Result
Extractables/
leachables not of
toxicological
concern for
applicable
endpoints
Pass
(non-cytotoxic)
ISO 10993-5: In vitro Cytotoxicity
(Neutral Red Uptake)
x Coated (drug and
polymer blend) stent
x Polymer only coated
stent
Sensitization
ISO 10993-10: Sensitization Kligman
Maximization
(Guinea Pig)
x Coated (drug and
polymer blend) stent
x Uncoated stent
x IDS Delivery System
x
RX Delivery System
Pass
(non-sensitizer)
Intracutaneous
Reactivity
ISO 10993-10: Intracutaneous Injection
(Rabbit)
x Coated (drug and
polymer blend) stent
x Uncoated stent
x IDS Delivery System
x
RX Delivery System
Pass
(non-irritant)
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 16 of 55
Test Name Test Description Test Article Result
Pyrogenicity
ISO 10993-11: Material Mediated
Pyrogenicity
(Rabbit)
x Coated (drug and
polymer blend) stent
x Uncoated stent
x IDS Delivery System
x
RX Delivery System
Pass
(non-pyrogenic)
Systemic Toxicity
(Acute)
ISO 10993-11: Systemic Injection
(Mouse)
x Coated (drug and
polymer blend) stent
x Uncoated stent
x IDS Delivery System
x
RX Delivery System
Pass
(non-toxic)
Systemic Toxicity
(Subchronic)
ISO 10993-6 and ISO 10993-11: 90 Day
Subcutaneous Implantation
(Rabbit)
x Coated (drug and
polymer blend) stent
Pass
(non-toxic)
ISO 10993-6 and ISO 10993-11: 90 Day
Intramuscular Implantation
(Rat)
x Uncoated stent
Systemic Toxicity
(Chronic)
ISO 10993-6 and ISO 10993-11: 26 Week
Subcutaneous Implantation
(Rat)
x Coated (drug and
polymer blend) stent
Pass
(non-toxic)
Implantation
ISO 10993-6: 7 Day Intramuscular
(Rabbit)
x Coated (drug and
polymer blend) stent
Pass
(non-toxic,
non-irritant)
ISO 10993-6: 4 Week Intramuscular
(Rabbit)
Hemocompatibility
ISO 10993-4: Thrombogenicity
(Dog)
x Coated (drug and
polymer blend) stent
x Uncoated stent
x
IDS Delivery System
Pass
(non-
thrombogenic)
ISO 10993-4: Thrombogenicity
(Swine)
x RX Delivery System
ASTM F756: In vitro Hemolysis
(Rabbit Blood - Direct & Indirect Contact)
x Coated (drug and
polymer blend) stent
x Uncoated stent
x IDS Delivery System
x
RX Delivery System
Pass
(non-hemolytic)
ISO 10993-4: In vitro Hemocompatibility
(Human Blood - Direct Contact)
x Coated (drug and
polymer blend) stent
x
Uncoated stent
Pass
(no effect on
hematology)
ISO 10993-4: In vitro Hemocompatibility
(Human Blood - Indirect Contact)
x Coated (drug and
polymer blend) stent
ISO 10993-4: In vitro UPTT
(Human Plasma - Direct Contact)
x Coated (drug and
polymer blend) stent
x
Uncoated stent
Pass
(no effect on
clotting time)
ISO 10993-4: In vitro Complement
Activation-C3a and SC5b-9
(Human Plasma - Direct Contact)
x Coated (drug and
polymer blend) stent
x Uncoated stent
x IDS Delivery System
x
RX Delivery System
Pass
(no activation of
complement)
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 17 of 55
Test Name Test Description Test Article Result
Genotoxicity
ISO 10993-3: Salmonella Typhimurium and
Escherichia Coli Reverse Mutation Assay
(Ames)
x Polymer only coated
stent
x Uncoated stent
x IDS Delivery System
x
RX Delivery System
Pass
(non-mutagenic)
ISO 10993-3: Mouse Lymphoma Forward
Mutagenesis Assay
x Polymer only coated
stent
x
Uncoated stent
Pass
(non-mutagenic)
ISO 10993-3: Mouse Peripheral Blood
Micronucleus Study
x Polymer only coated
stent
Pass
(non-mutagenic)
ISO 10993-3: Rodent Bone Marrow
Micronucleus Study
x Uncoated stent
Pass
(non
-
mutagenic)
Chemical Characterization:
Extractable/Leachable Chemical
Compounds and Toxicological Risk
Assessment
x Coated (drug and
polymer blend) stent
Pass based on
toxicological risk
assessment
Carcinogenicity
Reproductive
Toxicity
Degradation
Chemical Characterization: In vitro Polymer
Intermediate Degradation Products and
Toxicological Risk Assessment
x Coated (drug and
polymer blend) stent
Pass based on
toxicological risk
assessment
Physiochemical
USP 39/ NF 34 Supplement 2, <661.2> -
Absorbance
x Insertion Tool
Pass
USP 39/ NF 34 Supplement 2, <661.2> -
Alkalinity or Acidity
Pass
USP 39/ NF 34 Supplement 2, <661.2> -
Total Organic Carbon
Pass
Genotoxicity, carcinogenicity and reproductive toxicity testing on the finished drug
and polymer coated Svelte DES were not conducted based on a chemical
characterization and toxicological assessment along with the negative results of
genotoxicity testing of the uncoated and polymer only coated stents, which showed
no toxicological concern for these endpoints.
A toxicological risk assessment was conducted on the degradants from the PEA in the
stent coating and was found to be acceptable.
Based on the known molecular structures and properties and in vitro analytical and
stability testing results, there is no evidence to suggest that any chemical interactions
occur between the PEA carrier and the sirolimus drug under the established
processing and storage conditions that would lead to the formation of covalent bonds
or that would alter the structure of the drug in any way to form a new intermediate or
molecular entity.
B. Animal Studies
A series of animal studies were conducted to evaluate safety, efficacy, and overall
product performance.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 18 of 55
To assess the safety, acute performance and certain biocompatibility endpoints of the
Svelte DES, SLENDER IDS and DIRECT RX delivery systems, animal studies were
conducted to evaluate the inflammation, neointimal proliferation, endothelialization,
necrosis, thrombogenicity, embolism, pharmacokinetics, polymer degradation kinetics,
device deliverability and radiopacity. The animal studies also included high dose and
overlapping DES evaluations. Quantitative angiography, gross evaluation, quantitative
histomorphometry and histopathology were performed for stents implanted in the
coronary arteries as well as downstream myocardial assessments. All Svelte stents that
were successfully implanted remained structurally intact for the duration of implantation.
All animal studies were performed using healthy pigs in accordance with the Good
Laboratory Practice (GLP) for Non-clinical Laboratory Studies requirements outlined in
21 CFR Part 58, unless otherwise noted below. The results of these studies support the
safety and biocompatibility of the Svelte DES. A summary of the major animal studies
performed to support product safety are shown in Table 7 below.
Table 7. Summary of Major Supportive Animal Studies
Study Type
Test Article
Size
Treatment
PEA/API ratio
Dosage/stent
Dose Density
Type:
Number of
Animals
Number
of Stents
Evaluation
Time Points
Testing Objectives
Major Endpoints
Chronic Tissue
Response Safety
Study
(GLP)
Svelte DES-IDS
3.00x18mm
single &
overlapped
70/30
API: 126g
213 g/cm
2
Yucatan
miniswine:
69
Test: 88
Controls
BMS: 34
XIENCE
DES: 60
3, 30, 90,
180 and 390
days
High Dose Tissue
Response Safety
Study
(GLP)
Svelte HD-DES
3.00x18mm
100% overlapped
70/30
API: 278g
469 g/cm
2
2.2x coating
Yucatan
miniswine:
12
Test: 48
Control
BMS: 24
30 and 90
days
Yucatan
miniswine:
15
Test: 45
30, 60, 90,
120, 180,
270, 360
days
Angiographic analysis
Stent PEA carrier
content at explant
0, 1, 5, 15,
30, 60 mins
2, 4, 6, 8,
24 hrs
2, 3, 4, 8,
12, 14
days
Drug concentration -
blood
Acute performance
(preparation, delivery,
deployment,
thrombogenicity)
Angiographic analysis
Clinical Pathology
Radiography
Histopathology
Morphometric analysis
SEM analysis
Myocardial assessment
Angiographic analysis
Clinical Pathology
Radiography
Histopathology
Morphometric analysis
Myocardial assessment
Pharmacokinetic,
Carrier Degradation
Kinetics Study
Svelte DES-IDS
3.00x18mm
single
70/30
API: 124g
213 g/cm
2
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 19 of 55
Study Type
Pharmacokinetic
Study
Chronic Carrier
Only Tissue
Response Safety
Feasibility Study
RX
Acute Performance
and
Thrombogenicity
Assessment Study
(GLP)
IDS
Acute Performance
Assessment Study
(non
-
GLP)
Test Article
Size
Treatment
PEA/API ratio
Dosage/stent
Dose Density
Svelte DES-IDS
3.00x18mm
single
70/30
API: 124g
213
g/cm
2
Svelte DES-IDS
3.00x18mm
70/30
single
API: 124g
213 g/cm
2
Svelte DES-RX
2.50x18mm
3.00x18mm
single
70/30
API: 126g
213 g/cm
2
Svelte BMS-IDS
2.50x13mm
Single
Type:
Number of
Animals
Yorkshire
swine:
6
Yucatan
miniswine:
27
Yorkshire
swine:
3
Yucatan
swine:
1
Number
of Stents
Test: 36
Test: 24
Controls
PEAS: 20
BMS: 26
XIENCE:
8
Test: 10
Test: 4
Evaluation
Time Points
1, 3, 8, 14,
30 and 60
days
30, 90 and
390 days
0 and 3 days
0 days
Testing Objectives
Major Endpoints
Angiographic analysis
Stent drug content at
explant
Drug concentration -
arterial tissue at explant
Acute performance
(preparation, delivery,
deployment,
thrombogenicity)
Angiographic analysis
Clinical Pathology
Radiography
Histopathology
Morphometric analysis
SEM analysis
Myocardial assessment
Acute performance
(preparation, delivery,
deployment,
thrombogenicity)
Angiographic analysis
Clinical Pathology
Histopathology
Histomorphology
Myocardial assessment
Non-cardiac organ
assessment
Acute performance
(preparation, delivery)
IDS
Acute Performance
Assessment Study
(GLP)
Svelte BMS-IDS
4.00x28mm
Single
Yorkshire
swine:
3
Test:
BMS: 5
IDS: 8
Control
Vision
Stent: 5
SDS: 8
0 days
Acute performance
(preparation, delivery,
deployment,
thrombogenicity)
Angiographic analysis
Heart necropsy
C. Additional Studies
1. In Vivo Pharmacokinetics
A prospective, open, non-randomized human pharmacokinetic (PK) study was
conducted in the United States. A total of eight patients with symptomatic ischemic
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 20 of 55
heart disease were consented and treated from December 2018 through April 2019.
At least 38% (3 patients) received a sufficiently large stent so that the total implanted
stent dose was >1.7 times the sirolimus dose of the workhorse Svelte DES
(3.0x18mm). Blood samples were drawn to evaluate the systemic PK parameters of
sirolimus release from the implanted Svelte DES.
For each patient, peripheral blood samples were collected at 10 and 30 minutes, at 1,
2, 4, 6, 12, 24, 48, and 72 hours, and at 7, 14, and 30 days post-stent implantation
with continued follow-up for 2 years. Whole blood concentration of sirolimus was
determined using a validated high performance liquid chromatography mass
spectrometry (HPLC-MS) method. PK parameters were calculated and summarized in
Table 8. Terms and definitions of PK parameters are shown in Table 9.
Table 8. Individual and Mean PK Parameters for Sirolimus
Table 9. Terms and Definitions of PK Parameters
Term Definition
AUC
inf
Area under the curve to infinite time (AUC
0-inf
)
AUC
last
Area under the curve to the last measured concentration (AUC
0-t
)
CL/F Clearance of drug
C
max
Peak drug concentration
T
half
Drug elimination half-life
T
max
Time to peak drug concentration
Vz/F Volume of drug distribution
z Apparent terminal first-order elimination rate constant
Results obtained from the PK study:
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 21 of 55
x Stent nominal sirolimus dose ranged from 119 to 360 g/stent (DES implants
from 3.50x13mm to 4.00x38mm).
x Whole blood C
max
values increased with increasing dose and ranged from
0.436 to 1.56 ng/mL.
x AUC
last
and AUC
inf
values ranged from 68.0 to 409 hr*ng/mL and 94.9 to
528 hr*ng/mL, respectively.
x The drug elimination half-life of sirolimus ranged from 191 to 419 hrs across
all dose levels.
x The systemic clearance of sirolimus ranged from 6.96 to 15.9 L/hr/kg across
all dose levels.
x A dose-proportional linear trend was observed for C
max
, AUC
last
, and AUC
inf
over a 3-fold range of both total stent sirolimus dose and normalized patient
dose.
X. SUMMARY OF PRIMARY CLINICAL STUDY
The applicant performed a clinical study, OPTIMIZE, to establish a reasonable assurance
of safety and effectiveness of the Svelte DES for improving coronary artery luminal
diameter in patients with symptomatic heart disease due to atherosclerotic lesions 24
mm in length in native coronary arteries with 2.25 mm to 4.00 mm reference vessel
diameters, using direct stenting or pre-dilatation interventional techniques in the United
States, Japan and the Netherlands under IDE # G160227. Data from this clinical study
were the basis for the PMA approval decision. Data from the previous DIRECT I-III
studies conducted outside of the US were provided as supplemental, non-primary clinical
data; these studies are described in Section XI. A summary of the pivotal OPTIMIZE
study is presented below.
A. Study Design
Patients were treated between January 2, 2018 and June 4, 2019. The database for this
PMA reflected data collected through June 25, 2020 and included 1639 patients. There
were 74 investigational sites.
The study was a prospective, single-blind, randomized (1:1), active-control, multi-center
clinical study to compare the safety and effectiveness of the Svelte DES to coronary
drug-eluting stents (DES) (Abbott Vascular XIENCE or Boston Scientific Promus). The
control treatments were legally marketed alternatives with similar indications for use.
Patients were randomized 1:1 to the Svelte DES (SLENDER IDS or DIRECT RX at
investigator discretion), or the XIENCE DES or Promus DES (control DES pooled
group).
For each treatment group, the number and percentage of patients with 12-month TLF
were summarized. The risk difference and the two-sided 95% confidence interval of the
risk difference between two treatment groups were calculated based on the Farrington-
Manning test. The null hypothesis was also tested using the Farrington-Manning test, as
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 22 of 55
was an assessment of the poolability of the Control DES (XIENCE or Promus DES) to
confirm consistency of results.
OPTIMIZE utilized an independent angiographic core laboratory and independent
clinical events committee (CEC) to evaluate and adjudicate study primary and secondary
endpoint data. The core laboratories and CEC were composed of experts in their field.
1. Clinical Inclusion and Exclusion Criteria
Enrollment in the OPTIMIZE study was limited to patients who met the following
inclusion criteria:
General Inclusion Criteria:
1. Subject is Ӌ 18 years old;
2. Subject understands the study requirements, the treatment procedures and
provides written informed consent before any study-specific tests or procedures
are performed;
3. Subject is an eligible candidate for PCI;
4. Subject has symptomatic coronary artery disease with objective evidence of
ischemia or silent ischemia;
5. Subject has clinical symptoms or ECG changes consistent with non-ST elevation
MI (NSTEMI), is clinically and hemodynamically stable and has cardiac enzymes
documented to be decreasing prior to the study procedure (CK-MB is preferred,
but if troponin is assessed, enzymes decreasing, stable or elevated up to 20% over
the prior assessment are acceptable);
6. Subject is an acceptable candidate for CABG;
7. Subject agrees to comply with specified follow-up evaluations.
Angiographic Inclusion Criteria (visual estimate):
1. Subject has ӊ3 de novo target lesions in ӊ2 native coronary artery vessels, with ӊ2
lesions in a single vessel, each meeting the angiographic criteria and none of the
exclusion criteria.
2. Target lesion(s) must be located in a native coronary artery with RVD Ӌ2.25 mm
and ӊ4.00 mm;
3. Target lesion(s) length must be ӊ34 mm in length (the intention should be to cover
the whole lesion with one stent of adequate length);
4. Target lesion(s) must have visually estimated stenosis Ӌ50% and <100% with
Thrombolysis in Myocardial Infarction (TIMI) flow >1. For lesions with visually
estimated stenosis Ӌ50% and ӊ70%, additional confirmation by ACC/AHA
guideline compliant physiologic assessment is required;
5. Coronary anatomy is likely to allow delivery of a study device(s) to the target
lesion(s).
Patients were not permitted to enroll in the OPTIMIZE study if they met any of the
following exclusion criteria:
General Exclusion Criteria:
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 23 of 55
1. Subject has clinical symptoms or electrocardiogram (ECG) changes consistent
with acute ST elevation MI (STEMI). Subject may be included if primary PCI for
STEMI was successfully completed and subject is clinically and
hemodynamically stable with cardiac enzymes documented to be decreasing Ӌ72
hours prior to the study procedure;
2. Subject has cardiogenic shock, hemodynamic instability requiring inotropic or
mechanical circulatory support, intractable ventricular arrhythmia, or ongoing
intractable angina;
3. Subject has received an organ transplant or is on a waiting list for an organ
transplant;
4. Subject is receiving or scheduled to receive chemotherapy 30 days before or after
the index procedure;
5. Subject requires a planned PCI (including staged procedures), CABG or surgical
or catheter-based valvular intervention within 12 months of the index procedure;
6. Subject was previously treated at any time with intravascular brachytherapy;
7. Subject has a known allergy to contrast (that cannot be adequately premedicated)
and/or the study stent systems or protocol-required concomitant medications (e.g.,
platinum, platinum-chromium alloy, stainless steel, sirolimus, everolimus or
structurally related compounds, polymer or individual components, all P2Y12
inhibitors or aspirin);
8. Subject has one of the following (as assessed prior to the index procedure):
a. Other serious medical illness (e.g., cancer, congestive heart failure) with
estimated life expectancy of <24 months;
b. Current problems with substance abuse (e.g., alcohol, cocaine, heroin, etc.);
c. Planned procedure that may cause non-compliance with the protocol or
confound data interpretation;
9. Subject is receiving chronic (Ӌ72 hours) anticoagulation therapy (e.g., heparin,
coumadin) for indications other than acute coronary syndrome (ACS);
10. Subject has a platelet count <100,000 cells/mm
3
or >700,000 cells/mm
3
;
11. Subject has a white blood cell (WBC) count <3,000 cells/mm
3
;
12. Subject has documented significant liver disease, including laboratory evidence of
hepatitis;
13. Subject is on dialysis or has a baseline serum creatinine level >2.0 mg/dL (177
mol/L);
14. Subject has a history of bleeding diathesis or coagulopathy or will refuse blood
transfusions;
15. Subject has a history of cerebrovascular accident (CVA) or transient ischemic
attack (TIA) within the past 6 months;
16. Subject has an active peptic ulcer or active gastrointestinal (GI) bleeding;
17. Subject has severe symptomatic heart failure (i.e., NYHA class IV);
18. Subject intends to participate in another investigational drug or device clinical
study within 12 months after the index procedure;
19. Subject has a known intention to procreate within 12 months after the index
procedure (a woman of child-bearing potential who is sexually active must agree
to use a reliable method of contraception from the time of screening through 12
months after the index procedure);
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 24 of 55
20. Subject is pregnant or nursing (subject must have a negative pregnancy test within
14 days prior to the index procedure if a woman of child-bearing potential);
21. Subject is participating in another investigational drug or device clinical study;
22. Planned use of cutting balloon or atherectomy (rotational, orbital, laser or other)
or any other form of treatment of the target lesion(s) during the index procedure
other than plain balloon angioplasty and the randomized stent.
Angiographic Exclusion Criteria (visual estimate):
1. Subject has a planned treatment of >3 lesions;
2. Subject has a planned treatment of >2 major epicardial vessels;
3. Subject has a planned treatment of a single lesion with >1 stent;
4. Subject has 2 target lesions in the same vessel that are separated by <15 mm;
5. Subject’s target lesion(s) is located in the left main coronary artery;
6. Subject’s target lesion(s) is located within 3 mm of the origin of the left anterior
descending (LAD) coronary artery or left circumflex (LCX) coronary artery;
7. Subject’s target lesion(s) is located within a saphenous vein graft (SVG) or an
arterial graft;
8. The subject’s target lesion(s) will be accessed via SVG or arterial graft;
9. Subject has a target lesion(s) with TIMI flow 0 (total occlusion) or TIMI flow 1
prior to guide wire crossing;
10. Subject’s target lesion(s) involves a complex bifurcation (e.g., bifurcation lesion
requiring treatment with more than one stent);
11. Subject’s target lesion is located within 10 mm of a previously implanted stent or
involves in-stent restenosis;
12. Subject has unprotected left main coronary artery disease (>50% diameter
stenosis);
13. Subject has been treated with any type of PCI (i.e., balloon angioplasty, stent,
cutting balloon, or atherectomy) within 24 hours of the index procedure
14. Subject has thrombus or possible thrombus present in the target vessel.
2. Follow-up Schedule
All patients were scheduled to return for follow-up examinations at 12 months post-
procedure. Telephone assessments were scheduled for 1 month, 6 months, 2 years,
and annually through 5 years. Due to the COVID-19 global pandemic, some 12-
month assessments were conducted via telephone. The first 150 patients enrolled
were assigned to receive angiographic evaluation at the index procedure and at 12-
month follow up. The first 60 patients were also assigned to have IVUS performed at
the index procedure and 12-month follow up.
Preoperatively, patients received physical examinations, angina status was recorded,
routine laboratory tests including cardiac enzyme assessments were conducted, and
12-lead electrocardiograms were performed. Postoperatively, prior to discharge,
patients received another physical examination, angina status was recorded, cardiac
enzymes were drawn (4 – 2 hours post-procedure and again 12 – 20 hours post-
procedure or at discharge), another ECG was performed, and all adverse events were
recorded. At follow-up visits and calls, angina assessment, cardiovascular and other
important medication intake, and any adverse events were recorded.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 25 of 55
The key timepoints are shown below in the tables summarizing safety and
effectiveness.
3. Clinical Endpoints
The primary endpoint was a composite of outcomes related to both safety and
effectiveness: target lesion failure (TLF) at 12 months, defined as cardiac death,
target vessel myocardial infarction (TVMI) (Q-wave or non-Q-wave; MI defined
below), or clinically-indicated target lesion revascularization (TLR).
With regards to safety, secondary clinical outcomes evaluated at all study timepoints
included the following:
x Death (all cause)
x Cardiac death
x TVMI
x Stent thrombosis according to Academic Research Consortium (ARC) criteria
With regards to effectiveness, the primary endpoint of the angiographic substudy was
12-month in-stent late lumen loss (LLL). Post-procedural secondary endpoints
included the following:
x Device Success: Attainment of <30% final residual stenosis of the target lesion
using only the randomized stent;
x Lesion Success: Attainment of <30% final residual stenosis of the target lesion
using any stent, with or without other interventional devices;
x Procedure Success: Lesion success and no in-hospital major adverse cardiac
events (MACE);
x Direct Stent Strategy Success: Attainment of <30% final residual stenosis of
the target lesion without pre-dilatation if the operator had originally chosen to
proceed using a direct stent approach.
Clinical effectiveness endpoints included clinically-driven TLR and clinically-driven
target vessel revascularization (TVR) at all study timepoints.
With regards to success/failure criteria, non-inferiority testing of the primary endpoint
was planned. Assuming a 12-month TLF rate of 6.5% and an absolute non-inferiority
margin of 3.58% with a one-sided alpha of 0.025, a total of 1,548 patients had 80%
power to demonstrate non-inferiority of TLF at 12 months follow up. To account for
loss to follow-up (expected to be approximately 5%), a total of 1,630 patients were
required to be randomized. The assumption of the 12-month TLF rate of 6.5% was
based on the rate of 12-month TLF observed for Promus in the EVOLVE II study,
which used the same patient selection criteria.
The non-inferiority null and alternative hypotheses were:
x H
0
: π
SV
– π
C
Ӌ 0.0358
x H
1
: π
SV
– π
C
< 0.0358
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 26 of 55
where π
SV
and π
C
are the true 12-month TLF rate for Svelte DES and the combined
control group of XIENCE or Promus DES, respectively, and 0.0358 is the non-
inferiority margin. The one-sided significance level was 0.025. For each treatment
group (Svelte DES vs. combined control DES), the number and percentage of patients
with 12-month TLF were presented, as was the risk difference and the two-sided 95%
confidence interval of the risk difference, calculated using the Farrington-Manning
test. The primary endpoint was evaluated on an intent-to-treat (ITT) basis.
The angiographic substudy’s non-inferiority null and alternative hypotheses were:
x H
0
: μ
SV
- μ
C
0.20
x H
1
: μ
SV
- μ
C
< 0.20
where
SV
and
C
were the true mean 12-month in-stent LLL for Svelte DES and the
control DES, respectively, and 0.20 was the non-inferiority margin. The one-sided
significance level was 0.05. For each treatment group (Svelte DES vs. control DES),
descriptive statistics (sample size, mean, median, standard deviation, minimum and
maximum) of in-stent 12-month in-stent LLL were presented, as was the difference
between means and the one-sided 95% confidence interval of the difference between
means. The null hypothesis was tested using a two-sample t-test.
Protocol Definition of MI: All MI was assumed target vessel (a component of the
primary endpoint) unless objective evidence presented otherwise. The protocol
definition of MI was identical to that used in the EVOLVE II study, which was itself
a modification of the first Academic Research Consortium (ARC) definition (2006)
and the 2007 Global Task Force Universal definition of peri-procedural MI [1] [2] [3].
The OPTIMIZE MI definition was as follows:
Spontaneous MI: Detection of rise and/or fall of cardiac biomarkers (CK-MB or
troponin) with at least one value above the 99
th
percentile of the upper reference limit
(URL) together with evidence of myocardial ischemia with at least one of the
following:
1. Symptoms of ischemia;
2. ECG changes indicative of new ischemia (new ST-T changes or new left
bundle branch block [LBBB]);
3. Development of pathological Q waves in the ECG;
4. Imaging evidence of new loss of viable myocardium or new regional wall
motion abnormality.
Percutaneous Coronary Intervention-Related MI: Peri-procedural PCI MI was defined
by any of the following criteria. Symptoms of cardiac ischemia were not required.
1. Biomarker elevations within 48 hours of PCI:
x CK-MB > 3X URL or
x CK-MB not measured and CK > 2X URL or
x Neither CK-MB nor CK measured and troponin > 3X URL
AND
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 27 of 55
No evidence that cardiac biomarkers were elevated prior to the procedure OR
both of the following must have been true:
x 50% increase in cardiac biomarker result
x Evidence that cardiac biomarker values were decreasing (e.g., two samples
3-hours apart) prior to the suspected MI
2. New pathological Q waves
3. Autopsy evidence of acute MI
B. Accountability of PMA Cohort
At the time of database lock, of 1639 patients enrolled in the PMA study, 95.3% (1563)
are available for analysis at the completion of the study, the 12-month post-index
procedure visit. The disposition of the patients is summarized in Table 10.
Table 10. Patient Disposition
Patient Disposi
tion
Svelte DES Control DES Total
Signed Informed Consent
Screen Failures
Number of Patients Randomized (ITT Population)
Deaths Prior to 12-Month Visit
Withdrew Consent/Lost to Follow-up/Other
Missed 12-Month Visit
Completed 12 Month Visit
N/A
N/A
827
0.7%
(6/827)
1.7%
(14/827)
2.2%
(18/827)
95.4%
(789/827)
N/A
N/A
812
1.1%
(9/812)
1.8%
(15/812)
1.7%
(14/812)
95.3%
(774/812)
6184
4542
1639
0.9%
(15/1639)
1.8%
(29/1639)
1.9%
(32/1639)
95.4%
(1563/1639)
Primary Endpoint Evaluable Patients
96.2%
(796/827)
96.0%
(780/812)
96.2%
(1576/1639)
The intention-to-treat (ITT) population consisted of all 1639 patients randomized in the
study. Patients exiting the study early for reasons marked as “other” include those where
the investigative site discontinued intent-to-treat follow-up in error due to not receiving a
study stent, being randomized in error and no study procedure occurring. "Primary-
Endpoint Evaluable Patients" are defined as patients 1) experiencing a TLF event within
12 months of the study procedure, or 2) completing clinical follow-up 330 days after
the study procedure.
C. Study Population Demographics and Baseline Parameters
The demographics of the study population are relatively typical for a coronary stent study
performed in the US. Table 11 presents demographics for the OPTIMIZE study ITT
population. The mean age of the study patients was 65.4 years and 28.25% were female.
Patients were predominantly white (81.9%) and overweight (mean body mass index
(BMI) 29.4 kg/m
2
).
Table 11. OPTIMIZE Study Baseline Demographics
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 28 of 55
Patient Characteristics
Svelte DES
(N=827 Patients)
XIENCE/Promus DES
(N=812 Patients)
Age (years)
Mean±SD (N)
Range (min, max)
Sex
Male
Female
Race
American Indian or Alaska Native
Asian
Black or African American
Native Hawaiian or Pacific Islander
White
Other
Ethnicity
Hispanic or Latino
BMI (kg/m
2
)
65.09±10.02 (827)
(25.00,89.00)
72.67% (601/827)
27.33% (226/827)
0.24% (2/827)
10.88% (90/827)
3.87% (32/827)
0.24% (2/827)
81.38% (673/827)
0.85% (7/827)
2.78% (23/827)
29.08±5.69 (826)
65.79±10.33 (812)
(36.00,90.00)
70.81% (575/812)
29.19% (237/812)
0.25% (2/812)
10.96% (89/812)
3.33% (27/812)
0.00% (0/812)
82.39% (669/812)
0.62% (5/812)
2.83% (23/812)
29.20±5.92 (811)
Error! Not a valid bookmark self-reference. shows the baseline clinical characteristics
and medical history of the ITT population. Groups were evenly matched, with the
majority of patients reporting prior or current smoking, hypertension and hyperlipidemia.
Approximately 30% of patients were diabetic, consistent with previously reported and
recent prospective studies.
Table 12: Baseline Clinical Characteristics
Parameter
Svelte DES
(N=827 Patients)
XIENCE/Promus DES
(N=812 Patients)
Smoking Status
Never Smoked
Previous Smoker
Current Smoker
History of MI
Previous Revascularization
Previous PCI
Previous CABG
History of Stroke
History of Transient Ischemic Attack
Congestive Heart Failure
Diabetes
Insulin-Dependent
Non Insulin-Dependent
Hypertension
Hypercholesterolemia
Hyperlipidemia
Chronic Obstructive Pulmonary Disease
Kidney Disease w/dialysis
Kidney Disease w/o dialysis
Renal Insufficiency
Peripheral Artery Disease
Arrhythmia
Atrial Fibrillation/Flutter
History of Cancer
36.28% (300/827)
47.52% (393/827)
16.20% (134/827)
31.44% (260/827)
36.88% (305/827)
93.77% (286/305)
11.80% (36/305)
3.51% (29/827)
3.99% (33/827)
6.89% (57/827)
28.54% (236/827)
30.51% (72/236)
69.49% (164/236)
74.49% (616/827)
33.25% (275/827)
54.90% (454/827)
9.67% (80/827)
0.12% (1/827)
10.76% (89/827)
0.48% (4/827)
5.68% (47/827)
11.97% (99/827)
3.39% (28/827)
14.15% (117/827)
38.67% (314/812)
44.09% (358/812)
17.24% (140/812)
32.76% (266/812)
34.48% (280/812)
93.93% (263/280)
11.07% (31/280)
5.30% (43/812)
4.31% (35/812)
5.91% (48/812)
30.67% (249/812)
27.31% (68/249)
72.69% (181/249)
74.63% (606/812)
35.84% (291/812)
54.06% (439/812)
10.71% (87/812)
0.00% (0/812)
11.95% (97/812)
0.37% (3/812)
6.90% (56/812)
13.67% (111/812)
3.20% (26/812)
15.02% (122/812)
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 29 of 55
Baseline ischemic status was similar between the treatment and control groups with no
significant differences in distribution of ischemic symptoms as presented in Table 13.
Table 13. Ischemic Status at Baseline
Ischemic Status
Svelte DES
(N=827 Patients)
XIENCE/Promus DES
(N=812 Patients)
Angina Status
Asymptomatic/Free of Symptoms
Silent Ischemia
Stable Angina
Unstable Angina
CCS classification
I
II
III
IV
Braunwald classification
IA
IIA
IIIA
IB
IIB
IIIB
IC
IIC
IIIC
21.31% (176/826)
3.63% (30/826)
49.52% (409/826)
25.54% (211/826)
18.09% (74/409)
45.23% (185/409)
31.78% (130/409)
4.89% (20/409)
8.70% (18/207)
5.31% (11/207)
8.70% (18/207)
19.81% (41/207)
21.74% (45/207)
28.02% (58/207)
2.42% (5/207)
1.93% (4/207)
3.38% (7/207)
20.57% (167/812)
4.56% (37/812)
49.88% (405/812)
25.00% (203/812)
18.77% (76/405)
47.16% (191/405)
30.37% (123/405)
3.70% (15/405)
4.95% (10/202)
2.97% (6/202)
7.92% (16/202)
21.78% (44/202)
20.30% (41/202)
32.67% (66/202)
3.47% (7/202)
3.96% (8/202)
1.98% (4/202)
Key Baseline Lesion Characteristics:
Table 14 presents baseline lesion characteristics as interpreted by an independent core
lab using quantitative coronary analysis (QCA). In OPTIMIZE patients, mean reference
vessel diameter was 2.78 ± 0.50 mm, mean lesion length was 14.57 ± 7.28 mm, and mean
percent diameter stenosis was 83%. The target lesion location distribution is generally
reflective of patients presenting for PCI with 44% in the LAD, 27% in the LCX, and 28%
in the RCA. Approximately 74% of lesions were classified as complex (B2/C).
Table 14. Baseline Lesion Characteristics
Baseline Lesion Characteristics
Svelte DES
(N=827 Patients
N=1018 Lesions)
XIENCE/Promus DES
(N=812 Patients
N=970 Lesions)
Number of Target Lesions (Mean±SD (n))
Vessel Location
LAD
LCX
RCA
LM
Lesion Location
Proximal
Mid
Distal
Ostial
ACC/AHA Lesion Class
A
B1
B2
C
1.27 ± 0.52 (822)
42.93% (437/1018)
27.31% (278/1018)
29.57% (301/1018)
0.20% (2/1018)
37.43% (381/1018)
36.54% (372/1018)
22.00% (224/1018)
4.03% (41/1018)
5.70% (58/1018)
18.96% (193/1018)
32.22% (328/1018)
43.12% (439/1018)
1.22 ± 0.45 (809)
45.82% (444/969)
26.52% (257/969)
27.66% (268/969)
0.00% (0/969)
39.32% (381/969)
35.50% (344/969)
19.71% (191/969)
5.47% (53/969)
5.88% (57/969)
22.08% (214/969)
31.06% (301/969)
40.97% (397/969)
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 30 of 55
Baseline Lesion Characteristics
Svelte DES
(N=827 Patients
N=1018 Lesions)
XIENCE/Promus DES
(N=812 Patients
N=970 Lesions)
Calcification
None/Mild
Moderate
Severe
Bifurcation
Lesion Length (mm)
Mean±SD (N)
Reference Vessel Diameter (mm)
Mean±SD (N)
Minimal Lumen Diameter (mm)
Mean±SD (N)
65.13% (663/1018)
24.66% (251/1018)
10.22% (104/1018)
22.79% (232/1018)
14.88±7.04 (1018)
2.78±0.51 (1018)
1.00±0.41 (1018)
63.26% (613/969)
25.90% (251/969)
10.84% (105/969)
22.39% (217/969)
14.25±7.52 (969)
2.77±0.50 (969)
1.00±0.40 (969)
D. Safety and Effectiveness Results
The primary endpoint was a composite that combined measures of both safety and
effectiveness.
Primary Endpoint: The primary endpoint was not met (Table 15). Non-inferiority of
the primary endpoint of target lesion failure (TLF; cardiac death, target vessel MI, or
clinically-driven TLR) 12 months following Svelte DES implantation compared to the
Control DES group was not demonstrated.
The 12-month TLF rate was 10.30% in the Svelte DES group compared to 9.49% in the
Control DES group. The difference in rates was 0.81% with a two-sided 95% confidence
interval (CI) of -2.15% to 3.78%. Because the upper bound of this CI is higher than the
pre-specified non-inferiority delta of 3.58%, non-inferiority of the Svelte DES to the
Control DES with regard to 12-month TLF was not met.
Table 15. Analysis of Primary Endpoint and Components at 12-Months
Svelte DES
(N=827 Patients)
XIENCE/Promus DES
(N=812 Patients)
All Patients
(N=1639 Patients)
Difference
[95% Confidence Interval]
1
Non-Inferiority
P-Value
1
TLF
Cardiac Death
Protocol-defined TVMI
Clinically-driven TLR
10.30% (82/796)
0.25% (2/791)
9.43% (75/795)
1.52% (12/789)
9.49% (74/780)
0.26% (2/777)
8.22% (64/779)
1.93% (15/777)
9.90% (156/1576)
0.26% (4/1568)
8.83% (139/1574)
1.72% (27/1566)
0.81% [-2.15%,3.78%]
-0.00% [-1.35%,1.34%]
1.22% [-1.60%,4.04%]
-0.41% [-2.06%,1.24%]
0.034
1
Two-sided 95% confidence interval and non-inferiority p-value for ߨ
ௌ
െߨ
ͲǤͲ͵ͷͺ were calculated from Farrington-Manning test where ߨ
ௌ
and ߨ
are the true
12-month TLF rates for Svelte DES and the combined control group of XIENCE and Promus DESs, respectively.
Cumulative incidence curves for TLF (Kaplan-Meier) from index procedure to 12 months
are presented in Figure 6 below.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 31 of 55
Figure 6: Cumulative Incidence of TLF to 12 Months (Kaplan-Meier)
Examination of Primary Endpoint: The primary endpoint was not met. Additional
information is presented below to examine the factors that may have influenced this
outcome.
Poolability of the Control DES data:
The two stents comprising the control group (XIENCE and Promus) are considered to
have similar performance characteristics and were assumed to be interchangeable during
the design of the OPTIMIZE study. To test this assumption, the consistency of results of
the primary endpoint across the two control stents was assessed using a prespecified
analysis of the primary endpoint separately for Svelte DES vs. each of the control DES.
When comparing Svelte DES patients with XIENCE DES patients only, the rate of 12-
month TLF was 6.57% in the XIENCE DES group (N=563). The difference in rates was
3.79% with two-sided 95% CI of 0.82% to 6.75%. When comparing Svelte DES patients
with Promus DES patients only (N=190), the rate of 12-month TLF was 17.89% in the
Promus DES group and the difference in rates was -7.54% with two-sided 95% CI of
12.33% to 2.75%. Additional prespecified consistency analyses using a logistic
regression model and Cox proportional hazards regression model identified the type of
control DES to be a statistically significant predictor of 12-month TLF, indicating the
primary endpoint rates were not homogenous between the two control DES groups. As
discussed below, this unexpected difference between the control stents is explained by an
imbalance in the biomarkers used to adjudicate TVMI and does not reflect a true
difference in performance.
Potential Role of Biomarkers
While cardiac death and TLR were similar and at the low end of the expected range
across randomized treatment groups, rates of TVMI were higher than the expected rate of
5% (9.4% Svelte DES vs 8.2% control DES), with 90% of all TVMI occurring peri-
procedurally. TVMI varied widely by biomarker used for detection but was similar across
treatment groups, although the Promus DES group unexpectedly displayed far higher
rates of TVMI than the XIENCE DES group (16.9% vs 5.3%). Per protocol definition,
TVMI was preferentially assessed using CK-MB, then total CK, with troponin allowed
when CK-MB or total CK was not available. Because troponin is known to be a more
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 32 of 55
sensitive marker, the percentage of patients evaluated using each biomarker was assessed
as follows:
x CK-MB was used in 837 patients (53%); 25 (3.0%) met criteria for MI
(>3X ULN);
x Total CK was used in 331 patients (21%); 3 (0.9%) met criteria for MI
(>2X ULN);
x Troponin I was used in 335 patients (21%); 104 (31%) met criteria for MI
(>3X ULN);
x Troponin T was used in 63 patients (4%); 6 (9.5%) met criteria for MI
(>3X ULN).
Troponin I or troponin T was used to diagnose TVMI in 25% of all study patients; this
group contributed 80% of all protocol-defined TVMI observed. The rates of MI in
EVOLVE II were used to set the expected MI rates for OPTIMIZE. However, although
both studies preferentially assessed MI using CK-MB, troponin use in OPTIMIZE was
far higher – 25% vs 1% – reflecting the increased use of troponin in clinical practice
since the EVOLVE II study was conducted.
The incidence of TVMI within the control DES group varied by DES (XIENCE, 5.3% vs.
Promus, 17.2%). Retrospective analysis revealed that this difference was driven by
biomarker type used to identify MI. Specifically, a high enrolling study site only used
troponin assays and Promus DES as the control device and had a 12-month protocol-
defined TVMI rate of 44.9% (40.9% Svelte DES vs. 48.9% control DES [Promus]) for
the study. This one site resulted in the diagnosis of 22 of the 59 peri-procedural MIs in
the control DES group and is also responsible for the statistical heterogeneity observed
between the two control stents.
Post-hoc Exploratory Analyses: Unexpectedly high rates of TVMI in both treatment
groups appeared driven by the increased use of troponin compared to EVOLVE II,
coupled with a low threshold MI study definition, effectively underpowering the study.
Rates of TLF in both treatment groups exceeded the estimates used to power the study
and the analysis for non-inferiority did not reach the required pre-specified level of
statistical significance (p=0.025). The fixed non-inferiority margin (NIM) of 3.58% that
was chosen based on the TLF estimate of 6.5% resulted in loss of statistical power. For
this reason, the applicant conducted additional post-hoc analyses to assess non-inferiority
of the Svelte DES to the control DES. Please note that these statistics should be
interpreted with caution as these analyses were not pre-specified. They are presented here
to add additional context to the approval decision.
Relative Risk Analysis
The OPTIMIZE study statistical analysis plan specified an absolute/fixed non-inferiority
margin of 3.58%. Because TLF rates in both arms were higher than estimated, many
more patients would have needed to be enrolled in the study for adequate statistical
power to demonstrate non-inferiority. To examine whether using a relative margin would
have changed the study outcome, a relative risk (RR) assessment was conducted. This
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 33 of 55
analysis compared the maximum RR estimate established during study design (TLF
estimate + NIM/TLF estimate [(6.5+3.58)/6.5=1.55]) with that observed in the
OPTIMIZE study (RR=1.09, 95% CI [0.81-1.46]). Had the OPTIMIZE study been
designed with a relative margin, non-inferiority of the Svelte DES compared with the
control DES for 12-month TLF would have been demonstrated (P
NI
=0.009).
Increased Troponin Assumption Analysis
When the OPTIMIZE study was designed, the assumed TLF rate was based on data
where CK-MB or total CK was used to assess 99% of patients; however, during the
actual trial 25% of patients were assessed using the more sensitive troponin marker. To
examine whether an assumed TLF rate based on contemporary biomarker use would have
changed the study outcome, a new assumed literature-derived TVMI rate was estimated
based on diagnostic assessment using CK-MB or total CK in 75% and troponin in 25% of
study patients. MI diagnosis based on CK-MB >3X ULN was therefore estimated at 4-
7% and MI diagnosis based on troponin >3X ULN was estimated at 15-20%. In this
analysis, the assumed TLF rate was 10.5% (95% CI 8.75%-12.25%) with an updated
absolute NIM of 4.37% chosen to maintain 80% statistical power. This analysis
demonstrated that had the OPTIMIZE success criteria accounted for increased troponin
use, non-inferiority of the Svelte DES compared with the control DES for 12-month TLF
would have been demonstrated (P
NI
=0.010).
Alternative MI Definitions Analyses
The MI definition used in the OPTIMIZE study was relatively sensitive compared to
other contemporary definitions. To examine whether alternative definitions of MI would
have changed the study outcome, analyses for non-inferiority of 12-month TLF using the
SCAI and 4
th
Universal definitions of MI, which take into account and accommodate
troponin levels used in the assessment of peri-procedural MI, were performed. An
independent CEC separately adjudicated all biomarker values through 12 months under
the SCAI and 4
th
Universal definitions of MI.
Applying the SCAI definition of MI, 12-month TLF was 3.66% and 3.33% for the Svelte
DES and Control DES groups, respectively. Applying the 4
th
Universal definition of MI,
12-month TLF was 4.04% and 2.95% for the Svelte DES and Control DES groups,
respectively. Assuming the CEC was able to make accurate post-hoc adjudications, if the
OPTIMIZE trial had used either the SCAI or 4
th
Universal definitions of MI, non-
inferiority of the Svelte DES compared with the Control DES would have been
demonstrated.
All post-hoc analyses are summarized in Table 16.
Table 16. Post-hoc Assessments of Non-Inferiority of 12-Month TLF
OPTIMIZE Study Endpoint
Analysis
TLF: MI per protocol definition
Svelte DES
(N=827
Patient
s)
10.30%
(82/796)
Control DES
(N=812
Patient
s)
9.49% (74/780)
Non
-
Inferiority
Absolute Margin
3.58%
Difference or Relative Risk
[95% Confidence Interval]
1
0.81%
[
-
2.15%, 3.78%]
Non-
Inferiority
P value
1
0.034
1) TLF: Protocol-defined MI
with relative NIM
10.30%
(82/796)
9.49% (74/780)
Relative Margin
1.55
%
1.09%
[0.81
%
, 1.46
%
]
0.009
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 34 of 55
2)
3)
TLF: Protocol-defined MI
with troponin-adjusted
absolute NIM
TLF: MI per SCAI
definition
10.30%
(82/796)
3.66%
(29/793)
9.49% (74/780)
3.33% (26/780)
Absolute Margin
4.37%
Absolute Margin
3.58
%
0.81%
[-2.17%, 3.79%]
0.32%
[
-
1.
64
%, 2.2
9
%]
0.010
<0.001
4)
TLF: MI per 4
th
Universal
definition
4.04%
(32/793)
2.95% (23/779)
Absolute Margin
3.58%
1.08%
[
-
0.
85
%,
3.01
%]
0.006
1
Two-sided 95% confidence interval and non-inferiority p-value were calculated from Farrington-Manning test.
1. Safety Results
The analysis of safety was based on the ITT cohort of 1639 patients available for the
12-month evaluation. Key safety outcomes are presented in Table 17. Adverse events
are reported in Tables 18 and 19.
Safety endpoint rates were very similar across treatment groups. ARC
definite/probable stent thrombosis was very low, occurring in 3 patients in both
treatment groups. The only endpoint that numerically favored the control group was
TVMI; this difference is relatively slight.
Table 17. Summary of Safety Endpoints
Svelte DES XIENCE/Promus DES
Event
(n=827)
(n=812)
IN-HOSPITAL EVENTS
Death
0.00% (0/822) 0.00% (0/809)
Target Vessel MI
7.91% (65/822) 7.42% (60/809)
12-MONTH EVENTS
Death
0.75% (6/795)
1.15% (9/783)
Cardiac death
0.25% (2/791)
0.26% (2/777)
Non-cardiac death
0.50% (4/793)
0.90% (7/781)
Target Vessel MI
9.43% (75/795)
8.22% (64/779)
STENT THROMBOSIS (ARC DEFINITE/PROBABLE)
Any, all timepoints
0.38% (3/791) 0.39% (3/776)
Acute (24 hours)
0.12% (1/822) 0.12% (1/809)
Subacute (>24 hours, 30 days)
0.12% (1/819)
0.12% (1/808)
Late (> 30 days, 1 year)
0.13% (1/790)
0.13% (1/777)
Adverse effects that occurred in the PMA clinical study:
Adverse events that occurred in the OPTIMIZE study are presented below in Table
18 and Table 19. Adverse events were reported by sites using MedDRA preferred
terms. Only categories of adverse events occurring at a rate of 1% in either
treatment group are reported. No CEC-adjudicated unanticipated adverse device
effects were reported during the course of the study.
There were a total of 1331 adverse events reported in 536 patients in the Svelte DES
group, compared to a total of 1318 adverse events reported in 520 patients in the
control DES group through 12 months of follow up. The frequency and nature of
adverse events observed in the OPTIMIZE trial were similar to those observed for
other drug-eluting stents approved in the US.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 35 of 55
Table 18. All Adverse Events Occurring in >1% of Patients
Svelte DES XIENCE/Promus DES
System Organ Class/Preferred Term
(N=827 Patients) (N=812 Patients)
Any Adverse Event to 360 Days 64.81% (536/827) 64.04% (520/812)
Blood and lymphatic system disorders 0.60% (5/827) 2.09% (17/812)
Anaemia 0.48% (4/827) 1.35% (11/812)
Cardiac disorders 31.20% (258/827) 29.93% (243/812)
Angina pectoris 6.65% (55/827) 8.87% (72/812)
Angina unstable 3.26% (27/827) 2.83% (23/812)
Arrhythmia 5.08% (42/827) 2.46% (20/812)
Chest pain 4.59% (38/827) 3.94% (32/812)
Coronary artery dissection 7.74% (64/827) 5.79% (47/812)
Coronary artery restenosis 0.73% (6/827) 1.23% (10/812)
Dizziness 3.14% (26/827) 3.20% (26/812)
Myocardial infarction 2.06% (17/827) 2.96% (24/812)
Endocrine disorders 0.97% (8/827) 2.09% (17/812)
Diabetes mellitus 0.60% (5/827) 1.35% (11/812)
Eye disorders 1.69% (14/827) 1.23% (10/812)
Gastrointestinal disorders 8.71% (72/827) 8.62% (70/812)
Abdominal pain 1.93% (16/827) 1.60% (13/812)
Diarrhoea 0.73% (6/827) 1.85% (15/812)
Gastrointestinal haemorrhage 1.09% (9/827) 0.99% (8/812)
Nausea 0.97% (8/827) 1.35% (11/812)
General disorders and administration site
12.33% (102/827) 15.27% (124/812)
conditions
Administration site haematoma 2.18% (18/827) 4.56% (37/812)
Administration site pain 0.36% (3/827) 1.11% (9/812)
Adverse drug reaction 1.93% (16/827) 1.85% (15/812)
Chest pain 1.81% (15/827) 2.22% (18/812)
Fatigue 2.42% (20/827) 2.34% (19/812)
Oedema peripheral 1.57% (13/827) 1.85% (15/812)
Hepatobiliary disorders 1.45% (12/827) 0.62% (5/812)
Infections and infestations 4.47% (37/827) 3.82% (31/812)
Upper respiratory tract infection 1.33% (11/827) 0.49% (4/812)
Injury, poisoning and procedural complications 5.68% (47/827) 6.28% (51/812)
Plaque shift 1.21% (10/827) 1.23% (10/812)
Investigations 4.35% (36/827) 4.56% (37/812)
Myocardial necrosis marker increased 1.93% (16/827) 2.09% (17/812)
Metabolism and nutrition disorders 0.85% (7/827) 1.97% (16/812)
Musculoskeletal and connective tissue disorders 10.88% (90/827) 9.73% (79/812)
Arthralgia 1.33% (11/827) 1.72% (14/812)
Back pain 1.57% (13/827) 1.23% (10/812)
Myalgia 2.66% (22/827) 1.72% (14/812)
Pain in extremity 2.30% (19/827) 1.72% (14/812)
Neoplasms benign, malignant and unspecified 0.73% (6/827) 1.48% (12/812)
(incl cysts and polyps)
Nervous system disorders 8.34% (69/827) 5.67% (46/812)
Cerebrovascular accident 1.09% (9/827) 0.62% (5/812)
Headache 1.69% (14/827) 1.23% (10/812)
Syncope 1.81% (15/827) 0.74% (6/812)
Psychiatric disorders 1.09% (9/827) 1.48% (12/812)
Renal and urinary disorders 4.72% (39/827) 4.68% (38/812)
Urinary tract infection 1.33% (11/827) 1.35% (11/812)
Reproductive system and breast disorders 0.97% (8/827) 1.11% (9/812)
Respiratory, thoracic and mediastinal disorders 14.75% (122/827) 14.66% (119/812)
Dyspnoea 5.20% (43/827) 6.28% (51/812)
Epistaxis 1.93% (16/827) 1.11% (9/812)
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 36 of 55
System Organ Class/Preferred Term
Svelte DES
(N=827 Patients)
XIENCE/Promus DES
(N=812 Patients)
Non-cardiac chest pain
Skin and subcutaneous tissue disorders
Contusion
Skin infection
Surgical and medical procedures
Vascular disorders
Hypertension
Hypotension
4.72% (39/827)
8.10% (67/827)
1.33% (11/827)
3.51% (29/827)
1.45% (12/827)
8.95% (74/827)
1.93% (16/827)
1.69% (14/827)
4.43% (36/812)
7.39% (60/812)
1.60% (13/812)
2.83% (23/812)
2.46% (20/812)
8.00% (65/812)
1.72% (14/812)
1.97% (16/812)
A summary of serious adverse events is presented below in Table XX. A serious
adverse event either resulted in death, was life-threatening, required inpatient
hospitalization or caused prolongation of existing hospitalization, resulted in
persistent or significant disability/incapacity, or required intervention to prevent
permanent impairment or damage. Serious adverse events were reported using
MedDRA preferred terms. Only serious adverse events occurring at a rate of 1% in
either treatment group are reported.
There were a total of 319 serious adverse events reported in 207 patients in the Svelte
DES group, compared to a total of 313 serious adverse events reported in 196 patients
in the control DES group. Of these, 60 events were reported as related or possibly
related to the Svelte device or index procedure, while 55 events were reported as
related or possibly related to the control device or index procedure.
Table 19. All Serious Adverse Events Occurring in >1% of Patients
System Organ Class/Preferred Term
Svelte DES
(N=827 Patients)
XIENCE/Promus DES
(N=812 Patients)
Any Serious Adverse Event
Cardiac disorders
Angina pectoris
Angina unstable
Arrhythmia
Coronary artery dissection
Myocardial infarction
Gastrointestinal disorders
General disorders and administration site conditions
Injury, poisoning and procedural complications
Musculoskeletal and connective tissue disorders
Nervous system disorders
Renal and urinary disorders
Respiratory, thoracic and mediastinal disorders
Non-cardiac chest pain
Vascular disorders
25.03% (207/827)
11.73% (97/827)
1.45% (12/827)
1.81% (15/827)
2.30% (19/827)
1.09% (9/827)
1.69% (14/827)
2.42% (20/827)
1.21% (10/827)
1.09% (9/827)
1.45% (12/827)
3.02% (25/827)
1.33% (11/827)
2.90% (24/827)
1.09% (9/827)
3.26% (27/827)
24.14% (196/812)
12.56% (102/812)
2.71% (22/812)
2.59% (21/812)
0.74% (6/812)
0.49% (4/812)
1.85% (15/812)
2.34% (19/812)
1.85% (15/812)
1.11% (9/812)
1.48% (12/812)
1.60% (13/812)
1.23% (10/812)
2.96% (24/812)
1.23% (10/812)
1.85% (15/812)
2. Effectiveness Results
The analysis of effectiveness was based on the ITT cohort of 1639 evaluable patients
at the 12-month time point. Key effectiveness outcomes are presented in Table 20.
Device success was analyzed per lesion and defined as attainment of <30% final
residual stenosis of the target lesion using only the randomized stent. Lesion success
was also analyzed per lesion and defined as attainment of <30% final residual
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 37 of 55
stenosis of the target lesion using any stent, with or without other interventional
devices. Procedure success was analyzed per patient and defined as lesion success
and no in-hospital MACE. Acute success rates, TLR, and TVR were very similar in
both study groups.
Table 20. Summary of Effectiveness Endpoints
Svelte DES XIENCE/Promus DES
(n=827 Patients
(n=812 Patients
Event
N=1044 Lesions
)
N=990 Lesions
)
ACUTE SUCCESS
Device Success
95.40% (995/1043) 95.24% (941/988)
Lesion Success
99.33% (1036/1043) 99.09% (979/988)
Procedural Success
91.35% (750/821) 91.57% (739/807)
IN-HOSPITAL EVENTS
Clinically-indicated TLR
0.36% (3/822) 0.37% (3/809)
Clinically-indicated TVR
0.36% (3/822) 0.49% (4/809)
12-MONTH EVENTS
Clinically-indicated TLR
1.52% (12/789)
1.93% (15/777)
Clinically-indicated TVR
3.67% (29/790)
3.47% (27/778)
Angiographic and IVUS Substudy: According to the protocol, the first 150 patients
were to be included in the angiographic sub-study and undergo additional
angiographic evaluation at 12 months, with the first 60 additionally undergoing IVUS
at baseline and 12 months. However, the sub-study was not fully enrolled, with a total
of 132 ITT patients (69 Svelte DES and 63 control DES). Of these, a total of 65
patients (33 Svelte DES and 32 control DES) made up the IVUS cohort. Baseline
characteristics were similar between treatment groups with the exception of diabetes,
which was more frequent in the Svelte DES group compared with the Control DES
group (11.6% vs. 1.6%). Analysis of the angiographic primary endpoint of 12-month
in-stent LLL was carried out on all angiographic sub-study patients with available
angiograms at both the index procedure and at 12 months.
Angiographic sub-study results are presented below in Table 21. The primary
endpoint of the sub-study was met. Per ITT analysis, at 12 months, in-stent LLL of
the Svelte DES was noninferior to the control DES (all control patients in the
angiographic cohort received XIENCE). The upper one-sided 95% CI of 0.19 mm
was lower than the delta for non-inferiority (0.20 mm).
While most outcomes were similar between treatment groups, a trend in favor of the
control DES was noted for in-segment late loss and both in-stent and in-segment
binary restenosis. Review of the data showed that the greater prevalence of diabetic
patients in the Svelte group likely accounted for these outcome differences. All other
angiographic and IVUS measurements were similar between groups with the
exception of incomplete stent apposition assessed by IVUS post-procedure (14.3%
and 40.7%) and at 12 months (0.0% and 15.4%) in the Svelte DES and control DES
groups, respectively.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 38 of 55
Table 21. Angiographic and IVUS Sub-Study Endpoints
Angiographic Endpoints
Svelte DES
(n=69 Patients
N=88 Lesions
)
XIENCE DES
(n=63 Patients
N=74 Lesions
)
Difference
[Upper One-sided 95% CI]
Substudy Primary Endpoint
In
-
stent Late Lumen Loss
In-Segment Late Loss
In-Stent Minimal Lumen Diameter
In-Segment Minimum Lumen Diameter
In-Stent Percent Diameter Stenosis
In-Segment Percent Diameter Stenosis
In-Stent Binary Restenosis
In-Segment Binary Restenosis
0.29 ± 0.33 mm
0.27 ± 0.39 mm
2.45 ± 0.59 mm
2.37 ± 0.61 mm
13.62 ± 14.04%
17.14 ± 12.12%
4.11% (3/73)
5.48% (4/73)
0.21 ± 0.41 mm
0.15 ± 0.47 mm
2.47 ± 0.56 mm
2.39 ± 0.53 mm
12.58 ± 14.71%
15.37 ± 13.35%
1.59% (1/63)
1.59% (1/63)
0.08 mm [0.19 mm]
0.11 mm [0.26 mm]
-0.02 mm [0.18]
-0.03 mm [0.17]
1.03% [5.89%]
1.70% [6.39%]
2.52% [8.02%]
3.89% [9.96%]
IVUS Endpoints
Svelte DES
(n=33 Patients
N=37 Lesions)
XIENCE DES
(n=32 Patients
N=33 Lesions)
Difference
[95% CI]
Mean Plaque Burden (% Area)
Procedure
12 Months
In-Stent Obstruction Volume (%)
Procedure
12 Months
Incomplete Stent Apposition
Procedure
12 Months
Resolved
Persistent
Late Acquired
49.37 ± 7.71 (28)
57.07 ± 6.98 (29)
15.28 ± 11.66 (28)
18.93 ± 20.21 (25)
14.29% (4/28)
0.00% (0/29)
18.18% (4/22)
0.00% (0/22)
0.00% (0/22)
49.35 ± 5.83 (27)
56.97 ± 5.88 (26)
20.15 ± 16.79 (27)
22.15 ± 14.77 (24)
40.74% (11/27)
15.38% (4/26)
34.78% (8/23)
8.70% (2/23)
8.70% (2/23)
0.01 [-3.59, 3.62]
0.10 [-3.30, 3.50]
-4.87 [-12.53, 2.80]
-3.22 [-13.10, 6.67]
-26.46% [-49.07%, -3.84%]
-15.38% [-29.25%, -1.52%]
-16.60% [-41.87%, 8.67%]
-8.70% [-20.21%, 2.82%]
-8.70% [-20.21%, 2.82%]
3. Subgroup Analyses
The following pre-operative characteristics were evaluated for potential association
with outcomes:
Sex/Gender
To assess for heterogeneity of treatment effect, the OPTIMIZE clinical protocol
prespecified analyzing the primary clinical endpoint by sex. The results are presented
in Table 22 below.
Table 22. TLF at 12 Months in Male and Female ITT Patients
Sex
Svelte DES
(N=827
Patient
s)
XIENCE/PROMUS
DES (N=812
Patient
s)
Difference
[95%
Confidence Interval]
Male
9.62% (56/582)
8.50% (47/553)
1.12%
[
-
2.2%,
4.46%]
Female
12.15% (26/214)
11.89% (27/227)
0.26% [
-
5.82%, 6.33%]
Although not prespecified, secondary endpoint outcomes for male and female patients
from OPTIMIZE are also available (Table 23).
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 39 of 55
Table 23. OPTIMIZE Secondary Endpoints by Sex/Gender
Svelte DES
(N = 827 Patients)
Male Female
(N = 601 Patients) (N = 226 Patients)
XIENCE/Promus DES
(N = 812 Patients)
Male Female
(N = 575 Patients) (N = 237 Patients)
All death
Cardiac death
Target Vessel Q-Wave or non-Q-wave MI
Clinically-driven TLR
Clinically-driven TVR
Stent Thrombosis (ARC definition)
1.03% (6/582) 0.00% (0/213)
0.35% (2/578) 0.00% (0/213)
8.78% (51/581) 11.21% (24/214)
1.56% (9/576) 1.41% (3/213)
3.47% (20/576) 4.21% (9/214)
0.35% (2/578) 0.47% (1/213)
1.26% (7/554) 0.87% (2/229)
0.36% (2/550) 0.00% (0/227)
7.61% (42/552) 9.69% (22/227)
1.45% (8/550) 3.08% (7/227)
3.09% (17/551) 4.41% (10/227)
0.55% (3/550) 0.44% (1/227)
The overall conclusions of the trial regarding the safety and effectiveness of the
Svelte DES can be generalized to males and females.
Age
To assess for heterogeneity of treatment effect, the OPTIMIZE clinical protocol
prespecified analyzing the primary clinical endpoint by age (75 years and >75
years). The results are presented in Table 24 below.
Table 24. TLF at 12 Months in ITT Patients ≤75 and >75 Years Old
Age Svelte DES
(N=827
Patient
s)
XIENCE/PROMUS DES
(N=812
Patient
s)
Difference
[95%
Confidence Interval]
75 years
10.13% (69/681)
10.17% (65/639)
-
0.04%
[
-
3.30
%,
3.22
%]
>75 years
11.30% (13/115)
6.38% (9/141)
4.92
% [
-
2.13
%,
11.98
%]
Although not prespecified, secondary endpoint outcomes by age from OPTIMIZE are
also available (Table 25).
Table 25. OPTIMIZE Secondary Endpoints by Age
Svelte DES
(N = 827 Patients)
Age ≤ 75 Age > 75
(N = 707 Patients) (N = 120 Patients)
XIENCE/Promus DES
(N = 812 Patients)
Age ≤ 75 Age > 75
(N = 707 Patients) (N = 120 Patients)
All death
Cardiac death
Target Vessel Q-Wave or non-Q-wave MI
Clinically-driven TLR
Clinically-driven TVR
Stent Thrombosis (ARC definition)
0.44% (3/679) 2.59% (3/116)
0.29% (2/678) 0.00% (0/113)
9.26% (63/680) 10.43% (12/115)
1.48% (10/676) 1.77% (2/113)
3.69% (25/677) 3.54% (4/113)
0.29% (2/678) 0.88% (1/113)
1.09% (7/641) 1.41% (2/142)
0.31% (2/637) 0.00% (0/140)
8.62% (55/638) 6.38% (9/141)
2.35% (15/637) 0.00% (0/140)
3.92% (25/638) 1.43% (2/140)
0.63% (4/637) 0.00% (0/140)
Race and Ethnicity
Although not prespecified, outcomes by race and ethnicity for the OPTIMIZE study
are presented in Table 26. Of the 1,571 patients completing 12-month follow-up,
1,292 (82.2%) identified as white and 1548 (98.5%) did not identify as Hispanic or
Latino. The available race and ethnicity information is too limited to comment on any
potential associations.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 40 of 55
Table 26. Primary and Secondary Endpoints by Race and Ethnicity
Svelte DES
(N = 827 Patients)
XIENCE/Promus DES
(N = 812 Patients)
Primary &
Secondary
Endpoints
White
(N = 671
Patients)
American
Indian or
Alaska
Native
(N = 2
Patients)
Asian
(N = 90
Patients)
Black or
African
American
(N = 32
Patients)
Hispanic
or
Latino
(N = 23
Patients)
Native
Hawaiian
or
Pacific
Islander
(N = 2
Patients)
White
(N = 665
Patients)
American
Indian or
Alaska
Native
(N = 2
Patients)
Asian
(N = 89
Patients)
Black or
African
American
(N = 27
Patients)
Hispanic
or
Latino
(N = 23
Patients)
Native
Hawaiian
or Pacific
Islander
(N = 0
Patients)
TLF
Cardiac
Death
Target Vessel
Q-Wave or
non-Q-wave
MI
Clinically-
driven TLR
All Death
Clinically-
driven TVR
10.65% 0.00% 8.99% 3.45% 20.00%
(69/648) (0/1) (8/89) (1/29) (4/20)
0.16% 0.00% 0.00% 3.45% 0.00%
(1/645) (0/1) (0/88) (1/29) (0/19)
9.89% 0.00% 6.74% 3.45% 20.00%
(64/647) (0/1) (6/89) (1/29) (4/20)
1.40% 0.00% 2.27% 0.00% 5.26%
(9/644) (0/1) (2/88) (0/28) (1/19)
0.77% 0.00% 0.00% 3.45% 0.00%
(5/649) (0/1) (0/88) (1/29) (0/19)
3.72% 0.00% 2.27% 7.14% 5.26%
(24/645) (0/1) (2/88) (2/28) (1/19)
0.00% 9.59% 0.00% 3.37% 32.00% 9.09%
0.00%(0/0)
(0/2) (61/636) (0/2) (3/89) (8/25) (2/22)
0.00% 0.00% 0.00% 0.00% 8.00% 0.00% 0.00%(0/0)
(0/2) (0/633) (0/2) (0/89) (2/25) (0/22)
0.00% 8.49% 0.00% 3.37% 25.00% 4.55%
0.00%(0/0)
(0/2) (54/636) (0/2) (3/89) (6/24) (1/22)
0.00% 1.74% 0.00% 0.00% 12.50% 4.55% 0.00%(0/0)
(0/2) (11/634) (0/2) (0/89) (3/24) (1/22)
0.00% 1.10% 0.00% 0.00% 8.00% 0.00% 0.00%
(0/2) (7/639) (0/2) (0/89) (2/25) (0/22) (0/0)
0.00% 2.99% 0.00% 3.37% 12.50% 9.09%
0.00%(0/0)
(0/2) (19/635) (0/2) (3/89) (3/24) (2/22)
Stent 0.46% 0.00% 0.00% 0.00% 0.00% 0.00% 0.32% 0.00% 0.00% 8.00% 0.00% 0.00%(0/0)
Thrombosis
(ARC
definition)
(3/646) (0/1) (0/88) (0/28) (0/19) (0/2) (2/633) (0/2) (0/89) (2/25) (0/22)
Diabetic Patients
To assess for heterogeneity of treatment effect, the OPTIMIZE clinical protocol
prespecified analyzing the primary clinical endpoint by diabetes status. The results
are presented in Table 27 below. Outcomes were similar across treatment groups.
Table 27. TLF Through 12 Months With and Without Diabetes
Svelte DES XIENCE/Promus DES Difference
Subgroup
(N=827 Patients) (N=812 Patients) [95% Confidence Interval]
Diabetes 10.81% (24/222) 10.97% (26/237) -0.16% [-5.86%,5.54%]
Non-Diabetes 10.10% (58/574) 8.84% (48/543) 1.26% [-2.17%,4.70%]
Small vs. Large Vessels
To assess for heterogeneity of treatment effect, the OPTIMIZE clinical protocol
prespecified analyzing the primary clinical endpoint by vessel size. Patients with at
least one target lesion with RVD the median RVD were placed in the small vessel
subgroup. The results are presented in Table 28 below. Outcomes were similar across
treatment groups.
Table 28. TLF Through 12 Months in Small vs. Large Vessels, ITT Population
Svelte DES XIENCE/Promus DES Difference
Subgroup
(N=827 Patients) (N=812 Patients) [95% Confidence Interval]
Vessel Diameter
Small Vessels 9.88% (42/425) 9.71% (40/412) 0.17% [-3.85%,4.20%]
Large Vessels 10.78% (40/371) 9.24% (34/368) 1.54% [-2.78%,5.87%]
Lesion Length
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 41 of 55
To assess for heterogeneity of treatment effect, the OPTIMIZE clinical protocol
prespecified analyzing the primary clinical endpoint by lesion length. Patients with at
least one target lesion with lesion length the median lesion length were placed in
the long lesion subgroup. The results are presented in Table 29 below. Outcomes
were similar across treatment groups.
Table 29. TLF Through 12 Months in Short vs Long Lesions, ITT Population
Svelte DES XIENCE/Promus DES Difference
Subgroup
(N=827 Patients) (N=812 Patients) [95% Confidence Interval]
Lesion Length
Short Lesions 6.91% (23/333) 6.81% (25/367) 0.09% [-3.66%,3.84%]
Long Lesions 12.74% (59/463) 11.86% (49/413) 0.88% [-3.47%,5.23%]
Delivery Approaches
To assess for heterogeneity of treatment effect, the OPTIMIZE clinical protocol
prespecified analyzing the primary clinical endpoint by radial vs femoral access. The
results are presented in Table 30 below. Outcomes were similar across treatment
groups.
Table 30. TLF Through 12 Months in Short vs Long Lesions, ITT Population
Svelte DES XIENCE/Promus DES Difference
Subgroup
(N=827 Patients) (N=812 Patients) [95% Confidence Interval]
Access Site
Radial 9.31% (59/634) 9.25% (57/616) 0.05% [-3.16%,3.27%]
Femoral 14.19% (22/155) 10.32% (16/155) 3.87% [-3.42%,11.16%]
Direct Stenting and Pre-Dilatation Strategies
The OPTIMIZE study additionally evaluated the procedural and clinical effectiveness
of the Svelte DES and Control DES using direct stenting (DS) and pre-dilatation
strategies. Investigators declared their intended treatment strategy based on vessel and
lesion characteristics on the diagnostic angiogram prior to patient randomization. DS
was limited by protocol to 30% of total enrollment. At Japanese sites, investigators
did not use DS strategies in patients randomized to the Control DES group because
this was considered an off label use. A DS treatment strategy was attempted in 30%
(491/1,639) of study patients. Of these, 32.4% (159/491) were treated using the
SLENDER IDS, 22.2% (109/491) were treated using the DIRECT RX, and 45.4%
(223/491) were treated using a control DES. A total of 207 Svelte DES were
delivered using the SLENDER IDS, of which 94.7% (196/207) were used with a DS
strategy. A total of 888 Svelte DES were delivered using the DIRECT RX, of which
15.0% (133/888) were used with a DS strategy.
Patient demographics and baseline clinical characteristics were similar across
treatment strategy groups with the exception of hypercholesterolemia (higher in the
DS group) and hyperlipidemia and atrial fibrillation (higher in the pre-dilatation
group).
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 42 of 55
Pre-procedural lesion characteristics including lesion classification, TIMI flow, lesion
length, calcification, reference vessel diameter, minimal lumen diameter and %
percent diameter stenosis favored the direct stenting group. Table 31 summarizes pre-
procedural lesion characteristics as assessed by an independent core lab:
Table 31. Pre-Procedure Lesion Characteristics
Measure
Direct Stenting
(n=491 Patients,
n=562 Lesions)
Pre-dilatation
(n=1,148 Patients,
n=1,426 Lesions)
Difference
[95% Confidence Interval]
Vessel Location
LAD
LCX
RCA
LM
Lesion Location
Proximal
Mid
Distal
Ostial
ACC/AHA Lesion Class
A
B1
B2
C
Pre-Procedure TIMI Flow
0
1
2
3
Lesion Length (mm)
Mean±SD (N)
Eccentric
Bend (degrees)
Mean±SD (N)
Thrombus
Tortuosity
None
Moderate
Severe
Calcification
None/Mild
Moderate
Severe
Reference Vessel Diameter (mm)
Mean±SD (N)
Minimal Lumen Diameter (mm)
Mean±SD (N)
Percent Diameter Stenosis (%)
Mean±SD (N)
47.86% (269/562)
26.16% (147/562)
25.98% (146/562)
0.00% (0/562)
37.01% (208/562)
38.26% (215/562)
19.75% (111/562)
4.98% (28/562)
7.83% (44/562)
23.49% (132/562)
31.32% (176/562)
37.37% (210/562)
0.00% (0/562)
0.00% (0/562)
7.47% (42/562)
92.53% (520/562)
13.47±6.27 (562)
31.32% (176/562)
26.52±25.23 (562)
0.36% (2/562)
79.18% (445/562)
16.37% (92/562)
4.45% (25/562)
70.82% (398/562)
23.31% (131/562)
5.87% (33/562)
2.82±0.48 (562)
1.08±0.38 (562)
61.61±12.46 (562)
42.95% (612/1425)
27.23% (388/1425)
29.68% (423/1425)
0.14% (2/1425)
38.88% (554/1425)
35.16% (501/1425)
21.33% (304/1425)
4.63% (66/1425)
4.98% (71/1425)
19.30% (275/1425)
31.79% (453/1425)
43.93% (626/1425)
0.63% (9/1422)
1.27% (18/1422)
11.81% (168/1422)
86.29% (1227/1422)
15.01±7.60 (1425)
30.25% (431/1425)
27.42±26.57 (1425)
0.42% (6/1425)
75.86% (1081/1425)
17.26% (246/1425)
6.88% (98/1425)
61.61% (878/1425)
26.04% (371/1425)
12.35% (176/1425)
2.76±0.51 (1425)
0.97±0.41 (1425)
64.69±13.10 (1425)
4.92% [0.05%,9.78%]
-1.07% [-5.38%,3.23%]
-3.71% [-8.04%,0.63%]
-0.14% [-0.33%,0.05%]
-1.87% [-6.59%,2.86%]
3.10% [-1.62%,7.82%]
-1.58% [-5.50%,2.34%]
0.35% [-1.75%,2.45%]
2.85% [0.35%,5.34%]
4.19% [0.13%,8.25%]
-0.47% [-5.01%,4.06%]
-6.56% [-11.32%, -1.81%]
-0.63% [-1.05%, -0.22%]
-1.27% [-1.85%, -0.68%]
-4.34% [-7.09%, -1.59%]
6.24% [3.42%,9.05%]
-1.55 [-2.20, -0.89]
1.07% [-3.44%,5.59%]
-0.90 [-3.41,1.60]
-0.07% [-0.66%,0.53%]
3.32% [-0.70%,7.35%]
-0.89% [-4.53%,2.74%]
-2.43% [-4.58%, -0.28%]
9.20% [4.68%,13.73%]
-2.73% [-6.90%,1.45%]
-6.48% [-9.07%, -3.89%]
0.06 [0.02,0.11]
0.10 [0.06,0.14]
-3.08 [-4.31, -1.84]
Results
Lesion and device success were similar across treatment strategy groups. Procedure
success favored the DS group due to lower rates of protocol-defined TVMI in the DS
group (in-hospital MACE is a component of procedure success) as seen in Table 32.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 43 of 55
Table 32. Acute Success - ITT Population
Secondary Endpoints
Direct Stenting
(N = 491 Patients
N = 573 Lesions)
Pre-dilatation
(N = 1148 Patients
N = 1461 Lesions)
Difference
[95% Confidence Interval]
Lesion Success
Device Success
Procedure Success
Direct Stent Strategy Success
99.48% (570/573)
95.99% (550/573)
96.95% (476/491)
93.89% (538/573)
99.11% (1445/1458)
95.06% (1386/1458)
89.09% (1013/1137)
0.00% (0/0)
0.37% [-0.39%,1.13%]
0.92% [-1.03%,2.88%]
7.85% [5.48%,10.22%]
--
While cardiac death and clinically-driven TLR were similar across treatment strategy
groups, an approximate 3-fold increase in protocol-defined TVMI was observed in
the pre-dilatation group as seen in Table 33. Post-hoc analysis revealed this was a
consequence of certain sites exclusively using both predilation strategies and high
sensitivity cardiac biomarkers.
Table 33. TLF at 12 Months By Treatment Strategy
Subgroup
Direct Stenting
(n=491 Patients)
Pre-dilatation
(n=1,148 Patients)
Difference
[95% Confidence Interval]
1
TLF
Cardiac Death
Protocol-defined TVMI
Clinically-driven TLR
4.19% (20/477)
0.00% (0/476)
3.56% (17/477)
1.47% (7/476)
12.37% (136/1,099)
0.37% (4/1,092)
11.12% (122/1,097)
1.83% (20/1,090)
-8.18% [-11.67%,-4.70%]
-0.37% [-2.12%,1.38%]
-7.56% [-10.91%, -4.21%]
-0.36% [-2.44%,1.71%]
To examine potential differences between the Svelte DES and Control DES, 12-
month TLF and component outcomes in DS and pre-dilatation subgroups were
prespecified in the OPTIMIZE protocol and assessed as seen in Table 34. TLF
Through 12 Months in DS vs Pre-dilatation, ITT Population
Table 34. TLF Through 12 Months in DS vs Pre-dilatation, ITT Population
Procedural Svelte DES XIENCE/Promus DES Difference
Strategy (N=827 Patients) (N=812 Patients) [95% Confidence Interval]
Direct Stenting 3.42% (9/263) 5.14% (11/214) -1.72% [-5.40%,1.97%]
Pre-Dilatation 13.70% (73/533) 11.13% (63/566) 2.57% [-1.34%,6.47%]
To validate the performance of both Svelte delivery system models, outcomes when
using the SLENDER IDS and DIRECT RX delivery systems using a DS strategy are
presented in Table 35.
Table 35. Clinical Outcomes Using DS Strategy by Svelte Delivery System
Clinical Outcome
SLENDER IDS
N=159 Patients
(187 Lesions)
DIRECT RX
N=109 Patients
(135
Lesions)
Lesion Success
Device Success
Procedure Success
Direct Stent Strategy Success
TLF
Cardiac Death
Target Vessel MI
Clinically
-
indicated TLR
Stent Thrombosis
98.93% (185/187)
98.40% (184/187)
96.86% (154/159)
91.98% (172/187)
4.46% (7/157)
0.00% (0/157)
3.82% (6/157)
2.55% (4/157)
0.00% (0/157)
100% (135/135)
91.85% (124/135)
98.17% (107/109)
94.07% (127/135)
1.89%
(2/106)
0.00% (0/105)
1.89% (2/106)
0.00% (0/105)
0.00% (0/105)
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 44 of 55
4. Poolability Analyses
As OPTIMIZE combined patients from Europe, Japan, and the US, the study protocol
prespecified that a poolability analysis was conducted to determine if data from these
regions were sufficiently homogenous to combine. For the primary endpoint, a
logistic regression with treatment, region (US vs. outside the US, or OUS) and their
interaction as covariates was employed. Statistical significance (0.15 level) of the
interaction term indicates the observed effects are not homogeneous between the
regions and may potentially negate poolability of the regions for the primary analysis
or require assessment of the endpoint rate adjusting for region variability.
Consistency of the treatment effect across regions (US vs. OUS) was established with
a p-value for interaction of region and treatment of 0.883, indicating the interaction
was non-significant as shown in Table 36:
Table 36. Heterogeneity Analysis across Regions: TLF at 12 Months
Svelte DES XIENCE/Promus DES Difference P-Value for
Region
(N=827 Patients) (N=812 Patients) [95% Confidence Interval] interaction
Region 0.883
US 15.28% (68/445) 13.90% (61/439) 1.39% [-3.27%,6.04%]
OUS 3.99% (14/351) 3.81% (13/341) 0.18% [-2.71%,3.06%]
While the poolability analysis demonstrated that outcomes in the US and OUS were
sufficiently homogenous to combine, TLF rates were notably higher in the US compared
to OUS. To further examine this issue, baseline patient characteristics were compared
between US and OUS patients. As expected, there were a greater concentration of
Japanese patients in the OUS group. The US group had a higher mean BMI (30.95 ±
6.11) compared to the OUS group (26.74 ± 4.32), and the OUS group had greater
smoking habits. Differences in medical history largely favored the OUS group, which had
higher rates of diabetes, hypertension, hyperlipidemia, congestive heart failure, chronic
obstructive pulmonary dysfunction, kidney disease, and arrhythmia.
The major difference in outcomes between the US and OUS groups was in peri-
procedural MI, which was experienced by 11.8% of US patients (110/933) and only 2.1%
(15/706) of OUS patients. Cardiac enzyme biomarker differences again appear to have
driven this difference in outcomes, as
US investigative sites utilized troponin I or T in
388/933 patients (41.6%), and OUS sites utilized troponin I or T in 167/706 patients (24.9%).
Additionally, the ULN used by each site varied, with OUS sites tending to use higher ULNs
for troponin assays than US sites.
5. Pediatric Extrapolation
In this premarket application, existing clinical data was not leveraged to support
approval of a pediatric patient population.
E. Financial Disclosure
The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires
applicants who submit a marketing application to include certain information concerning
the compensation to, and financial interests and arrangement of, any clinical investigator
conducting clinical studies covered by the regulation. The pivotal clinical study included
473 investigators of which none were full-time or part-time employees of the sponsor and
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 45 of 55
19 had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c)
and (f) and described below:
x Compensation to the investigator for conducting the study where the value
could be influenced by the outcome of the study: 0
x Significant payment of other sorts: 19
x Proprietary interest in the product tested held by the investigator: 0
x Significant equity interest held by investigator in sponsor of covered study: 0
The applicant has adequately disclosed the financial interest/arrangements with clinical
investigators. Statistical analyses were conducted by FDA to determine whether the
financial interests/arrangements had any impact on the clinical study outcome. The
information provided does not raise any questions about the reliability of the data.
XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION
OPTIMIZE was the pivotal trial used to support this PMA. Three additional clinical
studies have been conducted outside of the US on the Svelte DES – DIRECT I (first-in-
human study), DIRECT II (randomized, controlled trial), and DIRECT III (post-market
study). These studies provide additional assurance of device safety and effectiveness and
are summarized below.
A. DIRECT I (First-In-Human Feasibility Study)
Device: The device used in this study was an earlier generation version of the fixed-wire
system (SLENDER IDS); the stent had a slightly different geometric design (with the
same strut thickness) and the delivery system had a different wire tip configuration. The
drug coating was the same as the current coating.
Primary Objective: The objective of the DIRECT I study was to assess the safety and
clinical performance of the Svelte Drug Eluting Stent-on-a-Wire Coronary Stent System
in patients with single de novo coronary artery lesions.
Design: DIRECT I was a prospective, single-arm study. Patients were followed for five
years.
Patients enrolled were 18 years in age with stable or unstable angina pectoris, silent
ischemia or clinical evidence of MI undergoing planned percutaneous intervention in a
single de novo native coronary lesion. Angiographic inclusion criteria included a
reference vessel diameter 2.50 and 3.5 mm with lesion length of 20 mm by visual
estimation.
A total of 30 patients in 4 centers in New Zealand were treated with the earlier generation
Svelte DES between 2011 and 2012.
Demographics: Average age was 61±11 years. Eighty percent of patients were male and
17% had diabetes; 57% had experienced a prior myocardial infarction.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 46 of 55
Baseline lesion characteristics: Mean RVD was 2.7±0.5 mm. Percent diameter stenosis
was 81.7±11.6%. Fifty percent of the 30 lesions were type B2/C according to the
American College of Cardiology/American Heart Association classification scheme,
including 1 true bifurcation lesion. Direct stenting was performed in 77% of patients.
Results:
Safety
By 12 months, one of the 29 patients available for follow up had a non-target vessel MI
(3
rd
Universal Definition was used for this study). There were zero deaths or stent
thrombosis events in the 29 patients through five years of follow up.
There were a total of five device or procedure-related (possible, probable, or definite)
serious adverse events (SAEs). None of these events were considered unexpected in the
context of the trial. These events are listed in Table 37.
Table 37. DIRECT I Device or Procedure Related Serious Adverse Events
SAE Description
Relationship to
Study Device
Relationship to
Study Procedure
Procedural dissection
–
Grade A
Vessel trauma
–
Grade B dissection
Proximal edge dissection on deploying study stent
In Stent Restenosis
Chest Pain
Possible
Possible
Possible
Definite
Possible
Definite
Definite
Definite
No
No
Effectiveness
Device, lesion and procedure success rates were 97%, 100%, and 100%, respectively.
Two patients required additional devices to attain an acceptable angiographic result.
There was one device deficiency reported in which the stent could not be deployed. Post-
procedure in-stent diameter stenosis was 10.9 ± 6.37%. All but one patient had
deployment of the stent with <20% residual stenosis.
At six months, mean in-stent LLL was 0.22+0.27 mm and mean in-segment LLL was
0.14+0.27 mm. One patient developed binary restenosis. Percent diameter in-stent
restenosis was 18+10%. No acquired or persistent stent malapposition was observed at 6
months. Two patients underwent angiographically-driven revascularization at 6 months;
one at the target lesion and one proximal to the study stent. No patients experienced
clinically-driven TLR through five years.
B. DIRECT II
Device: Same as DIRECT I (earlier generation SLENDER IDS).
Primary Objective: To establish non-inferiority of 6-month in-stent LLL with the Svelte
IDS compared with a commercially available DES.
Design: DIRECT II was a prospective, multicenter, randomized trial. Patients were
randomized at a 2:1 ratio, Svelte DES: Medtronic Resolute Integrity DES. All patients
were followed for five years.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 47 of 55
Patients enrolled were eligible for PCI with a target lesion stenosis 50% and <100% by
visual estimate. Up to 2 coronary lesions located in different major epicardial vessels
could be treated though only one lesion, designated as the target lesion, could be treated
with the study device. Non-target lesions had to be successfully treated with non-study
stent(s) prior to treatment of the target lesion. Patients with recent myocardial infarction
(within 72-hours) or left ventricular ejection fraction ӊ30% were excluded.
A total of 159 patients from 18 centers in seven European countries were randomized in
2013, with 108 patients assigned to the Svelte DES and 51 to the control DES.
Demographics: Average age of Svelte DES patients was 62.7 ± 9.9; control DES patient
average age was 64.2 ± 12.4. Most patients were male (75.9% of Svelte DES and 66.7%
of control DES). Diabetes was present in 16.8% of Svelte DES and 21.6% of control DES
patients. Patients were well-matched in most baseline demographics, with the exception
of the number of current or past smokers (30.8% Svelte DES, 19.6% control DES).
Baseline lesion characteristics: Mean reference vessel diameter was very similar
between groups (2.68 ± 0.47 mm Svelte DES, 2.74 ± 0.53 mm control DES). Percent
diameter stenosis was also very similar (58.8 ± 11.9% Svelte DES, 60.2 ± 11.3% control
DES). There was a trend toward inclusion of more lesions with moderate to heavy
calcification in the Svelte DES group (21.7%) than the control DES group (9.8%). Direct
stenting was attempted in 91% of procedures.
Results
Safety
There were no deaths at 12 months in either group. TVMI rates were 1.9% (2/108) in the
Svelte DES group and 7.8% (4/51) in the control DES group. MI was defined using the
3
rd
Universal Definition, and all MIs observed in the study were attributed to the target
vessel. No stent thrombosis was observed in either group at 12 months. Svelte DES safety
endpoint rates remained low through 5 years of follow up. Table 38 summarizes safety
outcomes for the 5 years of follow up.
Table 38. DIRECT II Safety Outcomes Through 5 Years
Svelte DES Control DES
Outcome
(n=108)
(n=51)
Death
1 Year
0.0% (0/108)
0.0% (0/51)
2 Years
0.9% (1/108)
0.0% (0/51)
5 Years
4.6% (5/108)
5.9% (3/51)
Cardiac Death
1 Year
0.0% (0/108)
0.0% (0/51)
2 Years
0.0% (0/108)
0.0% (0/51)
5 Years
0.0% (0/108)
2.0% (1/51)
TVMI
1 Year
1.9% (2/108)
7.8% (4/51)
2 Years
1.9% (2/108)
7.8% (4/51)
5 Years
3.7% (4/108)
11.8% (6/51)
ARC Stent Thrombosis
(Definite/Probable)
1 Year
0.0% (0/108)
0.0% (0/51)
2 Years
0.0% (0/108)
0.0% (0/51)
5 Years
0.0% (0/108)
2.0% (1/51)
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 48 of 55
There were a total of 22 SAEs in 17% (18/108) of patients in the Svelte DES group and 8
SAEs in 14% (7/51) of patients in the control DES group. These events are summarized
in Table 39.
Table 39. DIRECT II Serious Adverse Events
SAE
Svelte DES
(N=108)
Control DES
(N=51)
Angina, stable
Arrhythmia
Hyperthyroidism
Gastrointestinal bleeding
Nausea
Local infection
Depression
Fainting/syncope/vasovagal reaction
Bronchitis
Other respiratory
Arthralgia
Arthritis
Back pain
Renal failure/insufficiency
Atypical chest pain
Fever/pyrexia
Chest pain without cardiac
enzyme elevation
Endometrial carcinoma
Black
-
out after drinking wine
Carotid stenosis
Silent ischemia
Claudication
(Re)stenosis
2
1
1
1
1
0
1
1
1
1
1
0
1
0
1
1
1
1
1
1
1
2
0
0
1
0
0
0
2
0
1
0
0
0
1
0
1
1
0
0
0
0
0
0
0
1
Effectiveness
Non-inferiority of the Svelte DES to the control DES was established with 6 -month in-
stent late lumen loss of 0.09 ± 0.31 mm (Svelte DES) and 0.13 ± 0.271 mm (control
DES), for a mean difference of -0.05 mm (95% CI [-0.16, 0.07], p for non-inferiority
<0.0001).
Device failure was 1.9% and 0% in the Svelte DES and control DES groups, respectively,
with 37% of operators being first-time users of the Svelte DES. Lesion and procedural
success rates between groups were similar (lesion success: 96.3% vs 100; procedural
success: 94.4% vs 94.1% for Svelte DES and control DES, respectively).
Significant differences in post-procedural angiographic findings, including smaller acute
gain, post-procedural MLD, and % diameter stenosis presented in the Svelte DES group
compared with the control DES group. Smaller post-procedure acute gain and MLD for
the Svelte DES group was attributed to differences in compliance between the Svelte
DES and control DES delivery system balloons. The instructions for use for the device
were subsequently revised to clarify that a higher deployment pressure is needed to
achieve the same stent diameter as less compliant balloons.
At 6-month follow-up, differences in MLD and % diameter stenosis remained; however,
there were no significant differences observed with in-stent LLL or binary restenosis.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 49 of 55
Six-month OCT results were available in 22 Svelte DES patients. Neointimal hyperplasia
area was 0.89 ± 0.33 mm
2
and neointimal hyperplasia volume obstruction was 11.3%.
Malapposed struts were detected in 0.7 ± 1.9% of struts. Average strut coverage was 94.2
± 9.0%.
At 12 months, clinically-indicated TLR was 1.9% (2/108) in the Svelte DES group and
2.0% (1/51) in the control DES group. Clinically-indicated TVR was 3.7% (4/108) and
3.9% (2/51) in the Svelte DES and control DES groups, respectively. Table 40
summarizes revascularization rates through 5 years of follow up.
Table 40. DIRECT II Clinically-Driven Revascularization Through 5 Years
Revascularization Svelte DES Control DES
Rates
(n=108)
(n=51)
Clinically
-
driven TLR
1 Year
1.9
% (
2
/108)
2
.0% (
1
/51)
2 Years
1
.9% (
2
/108)
2
.0% (
1
/51)
5 Years
5
.6% (
6
/108)
2.0
% (
1
/51)
Clinically
-
driven TVR
1 Year
3.7
% (
4
/108)
3.9
% (
2
/51)
2
Years
3.7
% (
4
/108)
3.9
% (
2
/51)
5 Years
8.3
% (
9
/108)
5.9
% (
3
/51)
C. DIRECT III
Device: Primarily SLENDER IDS with a small cohort treated with DIRECT RX.
Primary Objective: To evaluate the feasibility of a systematic direct stenting strategy
with SLENDER IDS in a commercial setting in an all-comers, real-world population.
Design: The DIRECT III study was a prospective, multicenter, single-arm, post-market
observational study conducted after CE Mark certification in Europe. Patients were
treated with Svelte DES and followed up for one year.
Patients enrolled were intended to be treated with PCI and implantation of the Svelte
DES as part of their standard treatment. Exclusion criteria were minimal and reflected an
all-comers population.
A total of 529 lesions in 449 patients were treated with 555 Svelte DES (528 SLENDER
IDS and 27 DIRECT RX systems) in 2016-2018. Eleven additional consented patients
were treated with another or no DES at the operator’s discretion. Patients were treated at
10 sites, nine in the Netherlands and one in the UK.
Demographics: Average age was 64.8 ± 11.0 years. 68.2% of patients were male, and
19.7% had type 2 diabetes. At baseline, 13.3% had no angina, 42.8% had stable angina,
and 40.2% had unstable angina.
Baseline lesion characteristics: The mean reference vessel diameter was 3.02 ± 0.42
mm and mean lesion length was 16.3 ± 7.13 mm. Approximately one third of lesions
were moderately or severely calcified.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 50 of 55
Results: The observational study primary endpoint was TLF at 12 months post-
procedure, defined as cardiac death, TVMI, or clinically-indicated TLR by percutaneous
or surgical methods. TLF was 3.3% (15/448) at 12 months in the ITT population and
3.2% (14/437) in the modified ITT population (only patients receiving a Svelte DES).
The MI definition was the same as that used for OPTIMIZE.
At 12 months, cardiac death was 1.1%, TVMI was 0.9% and TLR was 1.4%. All events
assumed worst case scenario (any death not confirmed as non-cardiac, all MIs and any
revascularization not confirmed as non-target were counted in TLF). No stent thrombosis
was reported in any patient enrolled in the study.
XII. PANEL MEETING RECOMMENDATION AND FDA’S POST-PANEL ACTION
In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe
Medical Devices Act of 1990, this PMA was not referred to the Circulatory Systems
Devices Panel, an FDA advisory committee, for review and recommendation because the
information in the PMA substantially duplicates information previously reviewed by this
panel.
XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
The principal safety and effectiveness information for the Svelte Sirolimus-Eluting
Coronary Stent Systems is derived from preclinical studies and from the OPTIMIZE
clinical trial.
Preclinical testing performed during the design and development of the Svelte DES
confirmed the product design characteristics, specifications and intended use.
The in vitro engineering testing conducted on the stent and delivery systems demonstrate
the performance characteristics met the product specifications. The biocompatibility
evaluation and in vivo animal studies demonstrated the acute and chronic in vivo
performance characteristics of the Svelte DES are safe and acceptable for clinical use.
The sterilization testing demonstrated that the product can be adequately sterilized and is
acceptable for clinical use. The shelf-life testing has established acceptable performance
for the labeled shelf life of two years.
A. Effectiveness Conclusions
The results from the OPTIMIZE trial as designed could not statistically demonstrate that
the rate of target lesion failure (a composite endpoint including both safety and
effectiveness outcomes) at 12 months in the Svelte DES group was non-inferior to the
control XIENCE/Promus DES group (10.3% vs 9.5%). However, no clinically significant
differences in performance across study groups were observed in any study endpoint.
Unexpectedly high rates of TVMI in both groups in combination with a low-threshold MI
definition caused the study to be statistically underpowered. High rates of TVMI were
specifically seen at sites using troponin as the peri-procedural MI biomarker. Post hoc
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 51 of 55
analyses demonstrated that had the OPTIMIZE trial been designed with a relative rather
than an absolute noninferiority margin, or with taking into account increased clinical use
of troponin to assess MI, or used a different widely accepted PPMI definition (SCAI or
4
th
Universal Definition), non-inferiority would have been demonstrated.
Other measures of effectiveness were generally in line with expectations for a current
generation DES. Clinically-driven TLR was 1.52% at 12 months, compared to 1.93% for
the control. Clinically-driven TVR at 12 months was 3.67% vs 3.47%. Revascularization
rates remained very similar in both groups after two years. When examining acute
success of the stenting procedure, overall measures were also acceptable. Lesion, device,
and procedure success rates were high and equivalent in both study groups.
The direct stenting strategy attempted in 268 Svelte DES patients was successful in
92.86% of lesions. Imbalances in lesion types selected for direct stenting make outcome
comparisons to pre-dilatation strategies difficult, but the OPTIMIZE trial demonstrated
that both the SLENDER IDS and DIRECT RX systems can be used successfully for
direct stenting when the operator believes such a strategy to be appropriate.
The totality of the available effectiveness data, including that from the previous DIRECT
I-III studies, support the conclusion that the Svelte DES is effective for its intended use.
B. Safety Conclusions
The risks of the Svelte DES are based on non-clinical laboratory and animal studies, as
well as data collected in a clinical study conducted to support PMA approval as described
above.
No safety signals of concern were identified from a review of serious adverse events and
CEC-adjudicated events. Device or procedure-related serious adverse events were of
similar type and frequency to those previously reported for other US-approved coronary
stents. No CEC-adjudicated unanticipated device-related adverse events occurred during
the OPTIMIZE study.
The TLF composite endpoint of the OPTIMIZE trial included two safety outcomes, rates
of cardiac death and TVMI at 12 months. The rate of cardiac death was low and
numerically equivalent to the control DES group (0.3%). The rate of TVMI was high in
both groups (9.4% Svelte DES vs 8.2% control DES), with 90% of all TVMI occurring
peri-procedurally. However, the clinical relevance of peri-procedural elevated troponin in
the absence of other clinical findings is currently not known. In OPTIMIZE, 87.5% of
patients with protocol-defined elevated troponins were discharged without delay post-
procedure. A post-hoc analysis requested by FDA did not reveal any clear differences in
death, cardiac death, spontaneous MI, or heart failure between OPTIMIZE patients that
were assessed with peri-procedural MI and those that were not. The post-hoc analysis
conducted by the applicant that re-adjudicated MI events using the SCAI and 4
th
Univeral
definitions found TVMI rates that were much lower in both groups and more similar to
expectations.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 52 of 55
In addition, the 12-month rate of stent thrombosis according to the ARC definition was
very low and similar in both groups (0.38% in Svelte DES vs 0.51% for the control DES
group).
Long-term evaluations out to 5 years are ongoing and require additional data collection
and analysis. Available data from the DIRECT I-III studies support long--term safety of
the Svelte DES. Additionally, 2 year data from OPTIMIZE were available in summary
form at the end of the review period; while not the basis for the approval decision, these
data provided additional assurance of safety.
C. Benefit-Risk Determination
The probable benefits of the device are based on data collected in the OPTIMIZE clinical
study conducted to support PMA approval as described above.
The probable benefits of the Svelte DES are the same as other contemporary DES.
Patients treated with the Svelte DES had immediate increases to their coronary luminal
diameter that persisted through one year, as demonstrated in the angiographic substudy.
The sirolimus coating on the stent prevents restenosis, as evidenced by low clinically-
driven target lesion revascularization rates at one year.
The probable risks of the device are also based on data collected in the OPTIMIZE
clinical study conducted to support PMA approval as described above. There were no
increased device-related risks compared to the control DES group. OPTIMIZE also did
not find any procedure-related risks associated with the use of the Svelte DES that would
not be expected with any other coronary stent system. Please refer to Section VIII:
Potential Adverse Effects of the Device on Health.
Additional factors to be considered in determining probable risks and benefits for the
Svelte DES include:
While there was no evidence of increased risk associated with use of the Svelte DES, the
lack of trial statistical power to demonstrate statistical noninferiority leads to some
remaining uncertainty. Factors mitigating this uncertainty include other supportive data
from the DIRECT I-III studies, a history of safe use in countries outside the US, and a
post-approval study that will be conducted to ascertain a more precise TVMI rate
associated with the use of the Svelte DES.
Another factor to be considered is the availability of alternative treatments. Coronary
artery disease can be accompanied by symptomatic chest pain or silent ischemia that
affects patients’ quality of life. Coronary artery disease is treatable, but if left untreated,
the condition can progress to further stenosis within the arteries, increased symptoms, and
the need for revascularization. Available treatments for coronary artery disease include
medical therapy, PCI, and coronary artery bypass graft surgery. When treatment for
coronary artery disease beyond medications and lifestyle changes is warranted, patients
often choose stent deployment over surgical revascularization due to shorter recovery
times and the less invasive nature of PCI. The risks associated with use of drug eluting
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 53 of 55
stents are already well established, and in comparison to medical therapy, PCI has been
shown to reduce the incidence of angina and increase quality of life.
There are several other coronary DES with similar indications available in the US. When
comparing the relative risk ratios of other contemporary coronary DES pivotal trials that
have supported approval, the Svelte DES relative risk of 1.09 [95% CI [0.81-1.46]) is
similar, and the clinical outcomes in OPTIMIZE (apart from TVMI, as discussed) were
all acceptable.
1. Patient Perspective
This submission did not include specific information on patient perspectives for this
device.
In conclusion, given the available information above, the data support that for improving
coronary luminal diameter in patients with symptomatic heart disease due to
atherosclerotic lesions in native coronary arteries with a reference vessel diameter of 2.25
mm to 4.0 mm and a lesion length of 34 mm, the probable benefits outweigh the
probable risks.
D. Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness
of this device when used in accordance with the indications for use. Although the
OPTIMIZE study did not meet its primary endpoint, the totality of the available data
supports the approval decision. Residual uncertainty regarding the true rate of TVMI will
be addressed in a post approval study as outlined in the conditions of approval below.
XIV. CDRH DECISION
CDRH issued an approval order on December 13, 2021. The final clinical conditions of
approval cited in the approval order are described below.
1. OPEQ Lead PMA Post-Approval Study – Continued Follow-Up of OPTIMIZE Clinical
Study. The Office of Product Evaluation and Quality (OPEQ) will have the lead for this
clinical study, which was initiated prior to device approval. The OPTIMIZE Clinical
Study (G160227/S004) is a single-blind, randomized, active-control, multi-center clinical
study which enrolled 1,645 subjects. The OPTIMIZE Clinical Study was designed to
compare the safety and efficacy of the Svelte Sirolimus-Eluting Coronary Stent
Integrated Delivery System (Svelte DES-IDS) and Svelte Sirolimus-Eluting Coronary
Stent Rapid Exchange Delivery System (Svelte DES-RX) to the commercially available
Abbott Vascular XIENCE or Boston Scientific Promus Drug-Eluting Coronary Stents
(control DES) through 5 years post-index procedure. The primary endpoint is target
lesion failure (TLF) at 12 months post-procedure, defined as cardiac death, target vessel
myocardial infarction (TVMI, including Q wave and non-Q wave) or clinically-driven
target lesion revascularization (TLR) by percutaneous or surgical methods. You must
collect and report clinical outcomes to FDA through 5 years post-procedure on patients
enrolled in the OPTIMIZE Clinical Study.
PMA P210014: FDA Summary of Safety and Effectiveness Data Page 54 of 55
2. OPEQ Lead PMA Post-Approval Study – Svelte Post-Approval Study. The Office of
Product Evaluation and Quality (OPEQ) will have the lead for this clinical study, which
has not been initiated. The Svelte PAS is a prospective, multicenter, non-randomized
study intended to monitor and evaluate the safety and efficacy outcomes of the
Svelte DES post-PMA approval of the SLENDER IDS and DIRECT RX systems in a
real world setting. The study will enroll approximately 500 subjects with coronary artery
disease (CAD) at up to 50 clinical sites, with at least one-half of clinical sites and study
subjects from the United States. The primary endpoint for all study subjects enrolled in
the Svelte PAS is percentage of subjects with target lesion failure (TLF) at 12 months
post-procedure, defined as cardiac death, non-fatal target vessel myocardial infarction
(TVMI, including Q wave and nonQ wave) or clinically-driven target lesion
revascularization (TLR) by percutaneous or surgical methods. All subjects will require
pre-procedure enrollment to ensure pre- and post-procedural cardiac biomarkers are
collected. A central core lab will be used in the assessment of cardiac biomarkers.
Follow-up contacts post-procedure will be made for clinical assessment at 30 days and 1,
2 and 3 years. There are additionally several secondary endpoints. The final protocol was
revised and emailed on November 24, 2021. You must collect and report clinical
outcomes to FDA through at least 3 years post-procedure on patients enrolled in the
Svelte PAS.
The applicant’s manufacturing facilities have been inspected and found to be in
compliance with the device Quality System (QS) regulation (21 CFR 820).
XV. APPROVAL SPECIFICATIONS
Directions for use: See device labeling.
Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings,
Precautions, and Adverse Events in the device labeling.
Post-approval Requirements and Restrictions: See approval order.
XVI. REFERENCES
[1] S. Mendis, K. Thygesen and K. Kuulasmaa, et al., and Writing group on behalf of
the participating experts of the WHO consultation for revision of WHO definition of
myocardial infarction. "World Health Organization definition of myocardial
infarction: 2008–09 revision." International Journal of Epidemiology, 40: 139-146,
2011.
[2] K. Thygesen, J. Alpert and H. White, Joint ESC/ACCF/AHA/WHF Task Force for
the Redefinition of Myocardial Infarction. "Universal definition of myocardial
infarction." Circulation, 116: 2634-2653, 2007.
[3] P. Vranckx, et al. "Myocardial infarction adjudication in contemporary all-comer
stent trials: balancing sensitivity and specificity - Addendum to the historical MI
definitions used in stent studies." EuroIntervention, 5: 871-874, 2010.
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