Onyx Frontier™
Zotarolimus-Eluting Coronary Stent System
Rapid Exchange Delivery System
Instructions for Use
Caution: Federal (USA) law restricts this device to sale by or on the order of a physician.
TABLE OF CONTENTS
1 Symbol glossary ...................................................................................................................... 4
2 Onyx Frontier Zotarolimus-Eluting Coronary Stent System ............................................... 4
2.1 Device component description ........................................................................................ 5
2.2 Drug component description ........................................................................................... 6
2.2.1 Zotarolimus..................................................................................................................... 6
2.2.2 Polymer system description ........................................................................................... 7
2.2.3 Product matrix and zotarolimus content ......................................................................... 7
3 Indications ................................................................................................................................ 9
4 Contraindications .................................................................................................................... 9
5 Warnings ................................................................................................................................ 10
6 Precautions ............................................................................................................................ 10
6.1 Pre- and post-procedure antiplatelet regimen ............................................................. 10
6.1.1 Oral antiplatelet therapy ............................................................................................... 11
6.2 Use of multiple stents ..................................................................................................... 12
6.3 Use in conjunction with other procedures ................................................................... 12
6.4 Brachytherapy ................................................................................................................. 12
6.5 Use in special populations ............................................................................................. 12
6.5.1 Pregnancy .................................................................................................................... 12
6.5.2 Lactation ....................................................................................................................... 12
6.5.3 Gender ......................................................................................................................... 13
6.5.4 Ethnicity ........................................................................................................................ 13
6.5.5 Pediatric use................................................................................................................. 13
6.5.6 Geriatric use ................................................................................................................. 13
6.5.7 Lesion/vessel characteristics ....................................................................................... 13
6.6 Drug interactions ............................................................................................................ 13
6.7 Magnetic resonance imaging (MRI) safety information .............................................. 14
6.8 Stent handling precautions ............................................................................................ 14
6.9 Stent placement precautions ......................................................................................... 15
6.10 Stent/system removal precautions ............................................................................... 15
6.11 Post-procedure ................................................................................................................ 16
7 Drug information ................................................................................................................... 16
7.1 Mechanisms of action .................................................................................................... 16
7.2 Metabolism ...................................................................................................................... 16
7.3 Pharmacokinetics of the stent ....................................................................................... 16
7.4 Pharmacokinetics following multi-dose intravenous administration of zotarolimus
.......................................................................................................................................... 17
7.5 Mutagenesis, carcinogenicity, and reproductive toxicology ..................................... 18
7.5.1 Mutagenesis ................................................................................................................. 18
7.5.2 Carcinogenicity ............................................................................................................. 18
7.5.3 Reproductive toxicology ............................................................................................... 18
7.6 Pregnancy ........................................................................................................................ 18
7.7 Lactation .......................................................................................................................... 19
8 Overview of clinical trials ..................................................................................................... 19
i
The RESOLUTE ONYX Clinical Program ...................................................................... 19
8.1
8.2 Supportive RESOLUTE and RESOLUTE INTEGRITY data: ........................................ 20
9 Clinical outcomes .................................................................................................................. 26
9.1 Clinical outcomes for RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study and
RESOLUTE ONYX 2.0 mm Clinical Study ..................................................................... 26
9.2 Potential adverse events ................................................................................................ 34
9.2.1 Potential adverse events related to zotarolimus .......................................................... 34
9.2.2 Potential adverse events related to BioLinx polymer ................................................... 34
9.2.3 Potential risks associated with percutaneous coronary diagnostic and treatment
procedures ................................................................................................................... 34
10 Clinical studies ...................................................................................................................... 35
10.1 Results of the RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study .............. 35
10.2 Results of the RESOLUTE ONYX 2.0 mm Clinical Study ............................................ 40
10.3 Subjects with diabetes mellitus in the RESOLUTE pooled analysis ......................... 44
10.4 Subjects with diabetes mellitus in the RESOLUTE 38 mm length group .................. 47
10.5 Subjects receiving short-term DAPT ............................................................................ 48
10.5.1 Onyx ONE Clear Primary Analysis .............................................................................. 48
10.5.2 The Onyx ONE Global RCT ......................................................................................... 52
10.6 Subjects with chronic total occlusion .......................................................................... 52
10.7 Pooled results of the Global RESOLUTE Clinical Trial Program (RESOLUTE FIM,
RESOLUTE US, RESOLUTE AC, RESOLUTE Int, RESOLUTE Japan) ....................... 57
11 Patient selection and treatment ........................................................................................... 64
12 Patient counseling information ............................................................................................ 64
13 How supplied ......................................................................................................................... 64
14 Directions for use .................................................................................................................. 64
14.1 Access to package holding sterile stent delivery system .......................................... 64
14.2 Inspection before use ..................................................................................................... 65
14.3 Materials required ........................................................................................................... 65
14.4 Preparation precaution ................................................................................................... 65
14.4.1 Guidewire lumen flush .................................................................................................. 65
14.4.2 Delivery system preparation ......................................................................................... 65
14.5 Delivery procedure.......................................................................................................... 66
14.6 Deployment procedure ................................................................................................... 66
14.7 Removal procedure......................................................................................................... 67
14.8
14.9 Further dilatation of stented segment .......................................................................... 67
14.10 Instructions for simultaneous use of 2 devices in guide catheter (kissing balloon
15 Reuse precaution statement ................................................................................................ 68
In-vitro
technique) ........................................................................................................................ 68
information: ........................................................................................................ 67
ii
The components of the Onyx Frontier zotarolimus-eluting coronary stent system are sterile.
Medtronic, Medtronic with rising man logo, and Medtronic logo are trademarks of Medtronic. Thirdparty trademarks (“TM*”) belong to their respective owners. The following list includes trademarks or
registered trademarks of a Medtronic entity in the United States and/or in other countries.
Biolinx™, Endeavor™, Euphora™, Onyx Frontier™, Resolute™, Resolute Integrity™, Resolute
Onyx™, Sprinter Legend™
3
1 Symbol glossary
g
Explanation of symbols that may appear on package labeling
Refer to the device labeling to see which symbols apply to this product.
Standard title:
ISO 15223-1:2016 Cor 2017: Medical Devices — Symbols to be used with medical device
labels, labeling and information to be supplied.
Symbol Reference Symbol title Explanatory text
ISO 15223-1,
Clause 5.4.3
ISO 15223-1,
Clause 5.2.8
Consult instructions for use
Do not use if package is
damaged
Indicates the need for the user to
consult the instructions for use.
Indicates a medical device that
should not be used if the package
has been dama
Indicates a medical device that is
ISO 15223-1,
Clause 5.4.2
Do not reuse
intended for one use, or for use on
a single patient during a single
procedure.
ISO 15223-1,
Clause 5.1.5
ISO 15223-1,
Clause 5.1.1
ISO 15223-1,
Clause 5.1.6
ISO 15223-1,
Clause 5.2.3
ISO 15223-1,
Clause 5.1.4
ISO 15223-1,
Clause 5.1.3
Lot number
Manufacturer
Catalog number
Sterilized using ethylene
oxide
Use-by date
Date of manufacture
Indicates the manufacturer’s batch
code so that the batch or lot can
be identified.
Indicates the medical device
manufacturer.
Indicates the manufacturer's
catalogue number so that the
medical device can be identified.
Indicates a medical device that
has been sterilized using ethylene
oxide.
Indicates the date after which the
medical device is not to be used.
Indicates the date when the
medical device was manufactured.
ed or opened.
2 Onyx Frontier Zotarolimus-Eluting Coronary Stent System
The Medtronic Onyx Frontier zotarolimus-eluting coronary stent system (Onyx Frontier
system) is a device/drug combination product that consists of the following device
components: the Resolute Onyx coronary stent, a rapid exchange (RX) delivery system and a
drug component (a formulation of zotarolimus in a polymer coating). The characteristics of
the Onyx Frontier system are described in Table 2-1.
Table 2-1: Device component description and nominal dimensions
Onyx Frontier zotarolimus-eluting coronary stent system
Component
Available stent
diameters (mm)
Available stent lengths
(mm)
Stent design 1
(small vessel)
2.0, 2.25, 2.5 2.75, 3.0 3.5, 4.0 4.5, 5.0
8, 12, 15, 18, 22, 26,
30, 34*, 38*
*34, 38 mm lengths not available in
2.0 mm
Stent design 2
(medium vessel)
8, 12, 15, 18, 22, 26, 30,
34, 38
Stent design 3
(large vessel)
8, 12, 15, 18, 22, 26,
30, 34, 38
4
Stent design 4
(extra-large vessel)
12, 15, 18, 22, 26, 30
Table 2-1: Device component description and nominal dimensions
Onyx Frontier zotarolimus-eluting coronary stent system
Component
Delivery System Onyx Frontier Onyx Frontier Onyx Frontier Resolute Onyx RX
Stent design 1
(small vessel)
Stent design 2
(medium vessel)
Stent design 3
(large vessel)
Stent design 4
(extra-large vessel)
Stent material and
geometry
Drug component
Delivery systems
effective (working)
length
Delivery system luer
adapter ports
Stent delivery balloon
Balloon inflation
pressure
Minimum guide
catheter inner
diameter
Catheter shaft outer
diameter
A continuous sinusoid pattern stent manufactured from a composite metal material, consisting of a cobaltbased alloy shell conforming to ASTM F562 and a platinum-iridium alloy core conforming to ASTM B684.
A coating of polymers loaded with zotarolimus in a formulation applied to the entire surface of the stent at a
dose of approximately 1.6 μg/mm2 which results in a maximum nominal drug content of 317 μg on the stent
with the largest surface area (4.0 x 38 mm).
140 cm
Single access port to the inflation lumen. A guidewire exit port is located approximately 25 cm from the tip.
Designed for guidewire less than or equal to 0.014 inch (0.36 mm).
Dual-layer Pebax™* balloon (stent designs 1, 2, and 3) or single-layer Pebax™* balloon (stent design 4),
wrapped over an inner member tubing with 2 radiopaque marker bands to locate the stent edges.
Nominal inflation pressure: 12 ATM (1216 kPa)
Rated burst pressure: 2.0-4.0 mm = 18 ATM (1824 kPa), 4.5-5.0 mm = 16 ATM (1621kPa)
t5 F (1.42 mm, 0.056 in)
Proximal shaft OD: 2.1 F (0.69 mm)
Distal shaft OD 2.0 – 4.0 mm: 2.8 F (0.92 mm)
Distal shaft OD 4.5 and 5.0 mm: 3.2 F (1.07 mm)
2.1 Device component description
The Onyx Frontier system consists of a balloon-expandable, intracoronary, drug-eluting stent
(DES) premounted on a rapid exchange (RX) stent delivery system. The stent is
manufactured from a composite material of cobalt alloy and platinum-iridium alloy and is
formed from a single wire bent into a continuous sinusoid pattern and then laser fused back
onto itself. The stents are available in multiple lengths and diameters. The delivery system
has 2 radiopaque markers to aid in the placement of the stent during fluoroscopy and is
compatible with 0.014 inch (0.36 mm) guidewires and 1.42 mm (5 Fr / 0.056 in) minimum
inner diameter guide catheters. The RX delivery system (Figure 2-1) has an effective length
of 140 cm.
5
Figure 2-1: Rapid exchange (RX) delivery system (with stent)
The stent is crimped on various sizes of delivery catheter balloons, which range from 2.0 mm
to 5.0 mm. The available stent sizes are listed in Table 2-2.
Diameter
(mm)
2.0
2.25
2.5
2.75
3.0
3.5
4.0
4.5 -
5.0 -
“-” Denotes stent length is not available
8 12 15 18 22 26 30 34 38
9 9 9 9 9 9 9
9 9 9 9 9 9 9 9 9
9 9 9 9 9 9 9 9 9
9 9 9 9 9 9 9 9 9
9 9 9 9 9 9 9 9 9
9 9 9 9 9 9 9 9 9
9 9 9 9 9 9 9 9 9
9 9 9 9 9 9
9 9 9 9 9 9
Illustration is not to scale
Table 2-2: Stent sizes
Stent length (mm)
- -
- -
- -
2.2 Drug component description
The drug coating of the stent consists of the drug zotarolimus (the active ingredient) and the
BioLinx polymer system (the inactive ingredient).
2.2.1 Zotarolimus
The active pharmaceutical ingredient utilized in the stent is zotarolimus. It is a tetrazolecontaining macrocyclic immunosuppressant.
The chemical name of zotarolimus is:
[3S-[3R*[S*(1R*,3S*,4R*)],6S*,7E,9S*,10S*,12S*,14R*,15E,17E,19E,21R*, 23R*,
26S*,27S*,34aR*]]-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27dihydroxy-3-[2-[3-methoxy-4-(1H-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c] [1,4] oxaazacyclohentriacontine1,5,11,28,29(4H,6H,31H)-pentone.
The chemical structure of zotarolimus is shown in Figure 2-2:
6
NN
N
N
MeO
OO OH
N
O
O
O
MeO
OHO
Figure 2-2: Zotarolimus chemical structure
Zotarolimus has extremely low water solubility and is a lipophilic compound that is freely
soluble in propylene glycol, acetone, toluene, acetonitrile, ethanol, benzyl alcohol and DMSO.
The molecular formula of zotarolimus is C
52H79N5O12
Zotarolimus does not have any ionizable group(s) in the physiological pH range; therefore, its
solubility is expected to be unaltered in this range.
2.2.2 Polymer system description
The stent consists of a bare metal stent with a Parylene C primer coat and a coating that
consists of a blend of the drug zotarolimus and the BioLinx polymer system. BioLinx is a
blend of the Medtronic proprietary components C10 and C19, and PVP (polyvinyl
pyrrolidone). The structural formula of the BioLinx polymer subunits are shown in Figure 2-3:
OMe
O
and its molecular weight is 966.2.
Figure 2-3: Chemical structure of the BioLinx polymer subunits
2.2.3 Product matrix and zotarolimus content
Table 2-3: Product matrix and nominal zotarolimus doses
Product number
ONYXNG20008UX 2.0 8 51
ONYXNG22508UX 2.25 8 51
ONYXNG25008UX 2.5 8 51
ONYXNG27508UX 2.75 8 67
ONYXNG30008UX 3.0 8 67
Nominal expanded
stent ID (mm)
Nominal unexpanded
stent length (mm)
Nominal zotarolimus
content (μg)
7
Table 2-3: Product matrix and nominal zotarolimus doses
Product number
ONYXNG35008UX 3.5 8 77
ONYXNG40008UX 4.0 8 77
ONYXNG20012UX 2.0 12 70
ONYXNG22512UX 2.25 12 70
ONYXNG25012UX 2.5 12 70
ONYXNG27512UX 2.75 12 94
ONYXNG30012UX 3.0 12 94
ONYXNG35012UX 3.5 12 108
ONYXNG40012UX 4.0 12 108
ONYXNG45012UX 4.5 12 132
ONYXNG50012UX 5.0 12 132
ONYXNG20015UX 2.0 15 85
ONYXNG22515UX 2.25 15 85
ONYXNG25015UX 2.5 15 85
ONYXNG27515UX 2.75 15 117
ONYXNG30015UX 3.0 15 117
ONYXNG35015UX 3.5 15 132
ONYXNG40015UX 4.0 15 132
ONYXNG45015UX 4.5 15 158
ONYXNG50015UX 5.0 15 158
ONYXNG20018UX 2.0 18 104
ONYXNG22518UX 2.25 18 104
ONYXNG25018UX 2.5 18 104
ONYXNG27518UX 2.75 18 140
ONYXNG30018UX 3.0 18 140
ONYXNG35018UX 3.5 18 156
ONYXNG40018UX 4.0 18 156
ONYXNG45018UX 4.5 18 188
ONYXNG50018UX 5.0 18 188
ONYXNG20022UX 2.0 22 127
ONYXNG22522UX 2.25 22 127
ONYXNG25022UX 2.5 22 127
ONYXNG27522UX 2.75 22 171
ONYXNG30022UX 3.0 22 171
ONYXNG35022UX 3.5 22 186
ONYXNG40022UX 4.0 22 186
ONYXNG45022UX 4.5 22 227
ONYXNG50022UX 5.0 22 227
ONYXNG20026UX 2.0 26 146
ONYXNG22526UX 2.25 26 146
Nominal expanded
stent ID (mm)
Nominal unexpanded
stent length (mm)
Nominal zotarolimus
content (μg)
8
Table 2-3: Product matrix and nominal zotarolimus doses
Product number
ONYXNG25026UX 2.5 26 146
ONYXNG27526UX 2.75 26 198
ONYXNG30026UX 3.0 26 198
ONYXNG35026UX 3.5 26 221
ONYXNG40026UX 4.0 26 221
ONYXNG45026UX 4.5 26 265
ONYXNG50026UX 5.0 26 265
ONYXNG20030UX 2.0 30 168
ONYXNG22530UX 2.25 30 168
ONYXNG25030UX 2.5 30 168
ONYXNG27530UX 2.75 30 225
ONYXNG30030UX 3.0 30 225
ONYXNG35030UX 3.5 30 252
ONYXNG40030UX 4.0 30 252
ONYXNG45030UX 4.5 30 304
ONYXNG50030UX 5.0 30 304
ONYXNG22534UX 2.25 34 187
ONYXNG25034UX 2.5 34 187
ONYXNG27534UX 2.75 34 257
ONYXNG30034UX 3.0 34 257
ONYXNG35034UX 3.5 34 282
ONYXNG40034UX 4.0 34 282
ONYXNG22538UX 2.25 38 206
ONYXNG25038UX 2.5 38 206
ONYXNG27538UX 2.75 38 284
ONYXNG30038UX 3.0 38 284
ONYXNG35038UX 3.5 38 317
ONYXNG40038UX 4.0 38 317
Nominal expanded
stent ID (mm)
Nominal unexpanded
stent length (mm)
Nominal zotarolimus
content (μg)
3 Indications
The Onyx Frontier zotarolimus-eluting coronary stent system is indicated for improving coronary
luminal diameters in patients, including those with diabetes mellitus or high bleeding risk, with
symptomatic ischemic heart disease due to de novo lesions of length 35 mm in native coronary
arteries with reference vessel diameters of 2.0 mm to 5.0 mm. In addition, the Onyx Frontier
zotarolimus-eluting coronary stent system is indicated for treating de novo
chronic total
occlusions.
4 Contraindications
The Onyx Frontier system is contraindicated for use in:
x Patients with known hypersensitivity or allergies to aspirin, heparin, bivalirudin,
clopidogrel, prasugrel, ticagrelor, ticlopidine, drugs such as zotarolimus, tacrolimus,
sirolimus, everolimus, or similar drugs or any other analogue or derivative.
9
x Patients with a known hypersensitivity to the cobalt-based alloy (cobalt, nickel, chromium,
and molybdenum) or platinum-iridium alloy.
x Patients with a known hypersensitivity to the BioLinx polymer or its individual components
(see details in Section 2.2.2 – Polymer system description).
Coronary artery stenting is contraindicated for use in:
x Patients in whom antiplatelet and/or anticoagulation therapy is contraindicated.
x Patients who are judged to have a lesion that prevents complete inflation of an
angioplasty balloon or proper placement of the stent or stent delivery system.
5 Warnings
x Ensure that the inner package has not been opened or damaged as this would indicate
that the sterile barrier has been breached.
x The use of this product carries the same risks associated with coronary artery stent
implantation procedures, which include subacute and late vessel thrombosis, vascular
complications, and bleeding events.
x This product should not be used in patients who are not likely to comply with the
recommended antiplatelet therapy.
6 Precautions
x Only physicians who have received adequate training should perform implantation of the
stent.
x Subsequent stent restenosis or occlusion may require repeat catheter-based treatments
(including balloon dilatation) of the arterial segment containing the stent. The long-term
outcome following repeat catheter-based treatments of previously implanted stents is not
well characterized.
x Th
e risks and benefits of stent implantation should be assessed for patients with a history
of severe reaction to contrast agents.
x Do not expose or wipe the product with organic solvents such as alcohol.
x The use of a DES outside of the labeled indications, including use in patients with more
tortuous anatomy, may have an increased risk of adverse events, including stent
thrombosis, stent embolization, myocardial infarction (MI), or death.
x Care should be taken to control the position of the guide catheter tip during stent delivery,
stent deployment, and balloon withdrawal. Before withdrawing the stent delivery system,
confirm complete balloon deflation using fluoroscopy to avoid arterial damage caused by
guiding catheter movement into the vessel.
x Stent thrombosis is a low-frequency event that is frequently associated with MI or death.
Data from the RESOLUTE clinical trials have been prospectively evaluated and
adjudicated using the definition developed by the Academic Research Consortium (ARC)
(see Section 10.7 – Pooled results of the Global RESOLUTE Clinical Trial Program
for more information).
6.1 Pre- and post-procedure antiplatelet regimen
In the Medtronic RESOLUTE ONYX Core (2.25 mm-4.0 mm) Clinical Study and RESOLUTE
ONYX 2.0 mm Clinical Study, the protocols specified administration of clopidogrel or
ticlopidine (or any approved P2Y12 platelet inhibitor), including dosages before the
procedure, and for a period of at least 6 months post-procedure. Aspirin was administered
before the procedure concomitantly with a P2Y12 platelet inhibitor and then continued postprocedure to reduce the risk of thrombosis.
10
x In the Medtronic RESOLUTE ONYX Core (2.25 mm-4.0 mm) Clinical Study, 93.3%,
93.2%, 89.2%, and 52.2% of the subjects remained on dual antiplatelet therapy at 6
months, 8 months, 12 months, and 36 months, respectively.
x In the Medtronic RESOLUTE ONYX 2.0 mm Clinical Study, 91.1%, 87.1%, and 51%
of the subjects remained on dual antiplatelet therapy at 6 months, 12 months, and 36
months, respectively.
6.1.1 Oral antiplatelet therapy
Dual antiplatelet therapy (DAPT) using a combination treatment of aspirin with a P2Y12
platelet inhibitor after percutaneous coronary intervention (PCI), reduces the risk of stent
thrombosis and ischemic cardiac events, but increases the risk of bleeding complications.
The optimal duration of DAPT (specifically a P2Y12 platelet inhibitor in addition to aspirin)
following DES implantation is unknown, and DES thrombosis may still occur despite
continued therapy. It is very important that the patient is compliant with the post-procedural
antiplatelet recommendations.
1
Per 2016 ACC/AHA guidelines,
a daily aspirin dose of 81 mg is recommended indefinitely
after PCI. A P2Y12 platelet inhibitor should be given daily for at least 6 months in stable
ischemic heart disease patients and for at least 12 months in patients with acute coronary
syndrome (ACS).
Consistent with the DAPT Study,
2
and the 2016 ACC/AHA guidelines, longer duration of
DAPT may be considered in patients at higher ischemic risk with lower bleeding risk.
The Academic Research Consortium (ARC) proposed a standardized definition for identifying
3
patients at high bleeding risk (HBR)
Resolute Onyx in HBR patients and those who are unable to tolerate long term DAPT after
PCI has been published
4
.
. Additionally, evidence from a dedicated study of
Based on the Onyx ONE Clear Analysis, the Resolute Onyx stent is safe and effective in
patients at high risk of bleeding treated with one month of DAPT. The patients evaluated in
the Onyx ONE Clear Analysis met the pre-defined criteria for high bleeding risk and were
those whom in the opinion of their physician, the potential benefit of 1-Month DAPT
outweighed the potential risk. In addition to at least one HBR risk factor, enrollment included
48.6% ACS patients (unstable angina 22.8%, Non-STEMI 21.7% and STEMI 4.2%). (see
Section 10.5.1 - Onyx ONE Clear Primary Analysis).
Decisions about duration of DAPT are best made on an individual basis and should integrate
clinical judgment, assessment of the benefit/risk ratio, and patient preference.
Premature discontinuation or interruption of prescribed antiplatelet medication could result in
a higher risk of stent thrombosis, MI, or death. Before PCI, if premature discontinuation of
antiplatelet therapy is anticipated, physicians should carefully evaluate with the patient
1 Levine GN, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With
Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on
Clinical Practice Guidelines. J Am Coll Cardiol. 2016; doi:10.1016/j.jacc.2016.03.513. For full text, please refer to the
following website: http://content.onlinejacc.org/article.aspx?doi=10.1016/j.jacc.2016.03.513
2 Mauri L, et al. Twelve or 30 Months of Dual Antiplatelet Therapy After Drug-Eluting Stents. N Engl J Med. 2014;
371:2155–66.
3 Urban P, Mehran R, Colleran R, et al. Defining High Bleeding Risk in Patients Undergoing Percutaneous Coronary
Intervention. Circulation 2019;140:240-6
4 Windecker S, Latib A, Kedhi E, et al. Polymer-based or Polymer-free Stents in Patients at High Bleeding Risk. The New
England Journal of Medicine 2020:10.1056/NEJMoa1910021.
11
whether a DES and its associated recommended DAPT regimen is the appropriate PCI
choice.
Following PCI, if elective noncardiac surgery requiring suspension of antiplatelet therapy is
considered, the risks and benefits of the procedure should be weighed against the possible
risk associated with interruption of antiplatelet therapy.
Patients who require premature DAPT discontinuation should be carefully monitored for
cardiac events. At the discretion of the patient’s treating physician(s), the antiplatelet therapy
should be restarted as soon as possible.
6.2 Use of multiple stents
The long-term effects of zotarolimus are currently unknown. The extent of the patient’s
exposure to the zotarolimus drug and the stent and polymer coating is directly related to the
number of stents and total stent length implanted.
When multiple stents are required, stent materials should be of similar composition. Placing
multiple stents of different materials in contact with each other may increase potential for
corrosion. To avoid the possibility of dissimilar metal corrosion, do not implant stents of
different materials in tandem where overlap or contact is possible.
Potential interactions of the stent with other drug-eluting or coated stents have not been
evaluated and should be avoided whenever possible.
When using two wires, care should be taken when introducing, torquing, and removing one or
both guidewires to avoid entanglement. In this situation, it is recommended that one
guidewire be completely withdrawn from the patient before removing any additional
equipment.
6.3 Use in conjunction with other procedures
The safety and effectiveness of using atherectomy devices with the stent
established.
6.4 Brachytherapy
The safety and effectiveness of the stent in target lesions treated with prior brachytherapy, or
the use of brachytherapy to treat in-stent restenosis of the stent, have not been established.
6.5 Use in special populations
Information on use of the stent in certain special patient populations is derived from clinical
studies of the Resolute stent system, which uses the same drug (zotarolimus) – See Section
8 – Overview of clinical trials
6.5.1 Pregnancy
Pregnancy Category C. There are no well-controlled studies in pregnant women or men
intending to father children. The stent should be used during pregnancy only if the potential
benefit outweighs the potential risk to the embryo or fetus. Effective contraception should be
initiated before implanting a stent and for 1 year after implantation.
Pregnancy under Drug information.
have not been
See Section 7.6 –
6.5.2 Lactation
It is not known whether zotarolimus is excreted in human milk. The pharmacokinetic and
safety profiles of zotarolimus in infants are not known. Because many drugs are excreted in
human milk and because of the potential for adverse reactions in nursing infants from
zotarolimus, a decision should be made whether to discontinue nursing or to implant a stent,
taking into account the importance of the stent to the mother. See Section 7.7 – Lactation
under Drug information.
12
6.5.3 Gender
Clinical studies of the Resolute stent did not suggest any significant differences in safety and
effectiveness for male and female patients.
6.5.4 Ethnicity
Clinical studies of the Resolute stent did not include sufficient numbers of patients to assess
for differences in safety and effectiveness due to ethnicity.
6.5.5 Pediatric use
The safety and effectiveness of the stent in patients below the age of 18 years have not been
established.
6.5.6 Geriatric use
The RESOLUTE ONYX Core (2.25 mm-4.0 mm) Clinical Study,
mm Clinical Study, and the RESOLUTE clinical studies did not have an upper age limit.
Among the 1,242 patients treated with the Resolute stent in the RESOLUTE US Main Study,
which included 2.25 mm to 3.5 mm stents, 617 patients were age 65 or older and 88 patients
were age 80 or older. A post hoc analysis of patients treated with the Resolute stent showed
no significant differences in rates of cardiac death, target vessel MI, target lesion
revascularization, ARC definite or probable stent thrombosis, or target lesion failure at 12
months. The rate of all-cause death at 12 months was 0.3% in patients under age 65 vs.
1.8% in patients age 65 or older.
6.5.7 Lesion/vessel characteristics
The safety and effectiveness of the stent have not been established in the cerebral, carotid,
or peripheral vasculature or in the following coronary disease patient populations:
x Patients with coronary artery reference vessel diameters < 2.0 mm or > 5.0 mm.
x Patients with evidence of an acute ST-elevation MI within 72 hours of intended stent
implantation.
x Patients with vessel thrombus at the lesion site.
x Patients with lesions located in a saphenous vein graft, in the left main coronary
artery, ostial lesions, or bifurcation lesions.
x Patients with diffuse disease or poor flow distal to identified lesions.
x Patients with 3 vessel disease.
6.6 Drug interactions
The effect of potential drug interactions on the safety or effectiveness of the stent has not
been investigated. While no specific clinical data are available, drugs like sirolimus that act
through the same binding protein (FKBP12) may interfere with the efficacy of zotarolimus.
Zotarolimus is metabolized by CYP3A4, a human cytochrome P450 enzyme. When
administered concomitantly with 200 mg ketoconazole bid, a strong inhibitor of CYP3A4,
zotarolimus produces less than a 2-fold increase in AUC
consideration should be given to the potential for drug interactions when deciding to place a
Resolute Onyx stent in a patient who is taking drugs that are known substrates or inhibitors of
the cytochrome P450 isoenzyme CYP3A4. Systemic exposure of zotarolimus should also be
taken into consideration if the patient is treated concomitantly with systemic
immunosuppressive therapy.
the RESOLUTE ONYX 2.0
with no effect on C
0-inf
. Therefore,
max
Formal drug interaction studies have not been conducted with the stent.
13
6.7 Magnetic resonance imaging (MRI) safety information
MR Conditional
MRI Safety Information
Non-clinical testing has demonstrated that the Onyx Frontier stent is MR Conditional for
single and overlapping lengths up to 120 mm. A person with the Onyx Frontier implant may
be safely scanned under the following conditions. Failure to follow these conditions may
result in injury.
Device name
Static magnetic field strength [B0] Static magnetic field of 1.5 and 3 Tesla only
Maximum spatial field gradient Maximum spatial gradient magnetic field of 3000 gauss/cm
RF excitation Circulatory polarized (CP)
RF transmit coil type There are no Transmit Coil restrictions
Operating mode Normal operating mode
Maximum whole-body SAR [W/kg] Maximum MR system reported, whole body averaged
Scan duration 15 continuous minutes of scan duration with 11 minutes
MR image artifact In non-clinical testing, the image artifact caused by the
6.8 Stent handling precautions
x For single use only. The Onyx Frontier system is provided sterile. Do not resterilize or
reuse this product. Note the use-by date on the product label. Do not use the product if
the package or product has been opened or damaged.
x Only the contents of the pouch should be considered sterile. The outside surface of the
pouch is not sterile.
x Do not remove the contents of the pouch until the device will be used immediately.
x Do not remove the stent from the delivery balloon; removal may damage the stent and
polymer coating and/or lead to stent embolization. The Onyx Frontier system is intended
to perform as a system. The stent is not designed to be crimped onto another delivery
device.
x Special care must be taken not to handle or in any way disrupt the stent on the balloon.
This is most important while removing the catheter from the packaging, placing it over the
guidewire, and advancing it through the rotating hemostatic valve and guide catheter hub.
x Do not try to straighten a kinked shaft or hypotube. Straightening a kinked metal shaft
may result in breakage of the shaft.
x Stent manipulation (for example, rolling the mounted stent with your fingers) may cause
coating damage, contamination, or dislodgement of the stent from the delivery system
balloon.
x The Onyx Frontier system must not be exposed to any direct handling or contact with
liquids before preparation and delivery as the coating may be susceptible to damage or
premature drug elution.
x Use only the appropriate balloon inflation media. Do not use air or any gaseous medium
to inflate the balloon as this may cause uneven expansion and difficulty in deployment of
the stent.
Onyx Frontier
(30 T/m) or less
specific absorption rate (SAR) of 2.0 W/kg (Normal
Operating Mode)
wait time before more scanning
device extended approximately 10 mm from the Onyx
Frontier stent when imaged with a spin echo pulse
sequence and a 3 Tesla MRI system. The artifact can
obscure the device lumen. Some manipulation of scan
parameters may be needed to compensate for the artifact.
14
x The stent delivery systems should not be used in conjunction with any other stents or for
post-dilatation.
6.9 Stent placement precautions
x The vessel must be pre-dilated with an appropriately sized balloon. Refer to the pre-
dilatation balloon sizing described in Section 14.5 – Delivery procedure. Failure to do
so may increase the risk of placement difficulty and procedural complications.
x Do not prepare or pre-inflate the balloon before stent deployment other than as directed.
Use the balloon purging technique described in Section 14 – Directions for use.
x Guide catheters used must have lumen sizes that are suitable to accommodate the stent
delivery system (see Device component description in Table 2-1).
x After preparation of the stent delivery system, do not induce negative pressure on the
delivery catheter before placement of the stent across the lesion. This may cause
premature dislodgment of the stent from the balloon or delivery difficulties.
x Balloon pressures should be monitored during inflation. Do not exceed rated burst
pressure as indicated on the product label. Use of pressures higher than those specified
on the product label may result in a ruptured balloon with possible intimal damage and
dissection.
x In small or diffusely diseased vessels, the use of high balloon inflation pressures may
over-expand the vessel distal to the stent and could result in vessel dissection.
x Implanting a stent may lead to a dissection of the vessel distal and/or proximal to the
stented portion and may cause acute closure of the vessel requiring additional
intervention (for example, CABG, further dilatation, placement of additional stents, or
other intervention).
x Do not expand the stent if it is not properly positioned in the vessel (see Section 6 -
Precautions–Stent/system removal precautions).
x Placement of the stent has the potential to compromise side branch patency.
x Do not attempt to pull an unexpanded stent back through the guide catheter, as
dislodgement of the stent from the balloon may occur. Remove as a single unit per the
instructions in Section 6 - Precautions –Stent/system removal precautions.
x Under-expansion of the stent may result in stent movement. Care must be taken to
properly size the stent to ensure that the stent is in full contact with the arterial wall upon
deflation of the balloon.
x Stent retrieval methods (for example, use of additional wires, snares and/or forceps) may
result in additional trauma to the coronary vasculature and/or the vascular access site.
Complications may include bleeding, hematoma, or pseudoaneurysm.
x Ensure full coverage of the entire lesion/dissection site so that there are no gaps between
stents.
x Administration of appropriate anticoagulant, antiplatelet, and coronary vasodilator therapy
is critical to successful stent implantation.
6.10 Stent/system removal precautions
If removal of a stent system is required before deployment, ensure that the guide catheter is
coaxially positioned relative to the stent delivery system and cautiously withdraw the stent
delivery system into the guide catheter. Should unusual resistance be felt at any time when
withdrawing the stent towards the guide catheter, the stent delivery system and the guide
catheter should be removed as a single unit. This must be done under direct visualization
with fluoroscopy.
When removing the stent delivery system and guide catheter as a single unit:
x Do not retract the stent delivery system into the guide catheter. Maintain guidewire
placement across the lesion and carefully pull back the stent delivery system until the
proximal balloon marker of the stent delivery system is aligned with the distal tip of the
guide catheter.
15
x The system should be pulled back into the descending aorta toward the arterial sheath. As
the distal end of the guide catheter enters into the arterial sheath, the catheter will
straighten, allowing safe withdrawal of the stent delivery system into the guide catheter and
the subsequent removal of the stent delivery system and the guide catheter from the
arterial sheath.
Failure to follow these steps and/or applying excessive force to the stent delivery system can
potentially result in loss or damage to the stent and/or stent delivery system components
such as the balloon.
6.11 Post-procedure
x Care must be exercised when crossing a newly deployed stent with an intravascular
ultrasound (IVUS) catheter, an optical coherence tomography (OCT) catheter, a coronary
guidewire, or a balloon catheter to avoid disrupting the stent placement, apposition,
geometry, and coating.
x Post-dilatation: All efforts should be made to ensure that the stent is not under-dilated. If
the deployed stent is not fully apposed to the vessel wall, the stent may be expanded
further with a larger diameter balloon that is slightly shorter (about 2 mm) than the stent.
The post-dilatation can be done using a low-profile, high-pressure, non-compliant balloon
catheter. The balloon should not extend outside of the stented region. Do not use the
stent delivery balloon for post-dilatation.
x If patient requires MR imaging, refer to Section 6.7 – Magnetic resonance imaging
(MRI) safety information above.
x Antiplatelet therapy should be administered post-procedure (see Precautions – Section
6.1 - Pre- and post-procedure antiplatelet regimen). Patients who require early
discontinuation of antiplatelet therapy (for example, secondary to active bleeding), should
be monitored carefully for cardiac events. At the discretion of the patient's treating
physician, the antiplatelet therapy should be restarted as soon as possible.
7 Drug information
7.1 Mechanisms of action
The suggested mechanism of action of zotarolimus is to bind to FKBP12, leading to the
formation of a trimeric complex with the protein kinase mTOR (mammalian target of
rapamycin), inhibiting its activity. Inhibition of mTOR results in the inhibition of protein
phosphorylation events associated with translation of mRNA and cell cycle control.
7.2 Metabolism
Zotarolimus undergoes oxidative metabolism in the liver to form the demethyl and
hydroxylated metabolites of the parent drug. Further metabolism can lead to the formation of
hydroxyl-demethyl and dihydroxyl-demethyl metabolites. Enzymes of the CYP3A family are
the major catalysts of oxidative metabolism of zotarolimus. Zotarolimus is a competitive
inhibitor of CYP3A-dependent activities, however the IC
fold higher than the systemic concentrations expected following implantation of a drug-eluting
stent. The anticipated zotarolimus blood levels in stented patients are expected to be less
than 0.004 μM, suggesting that clinically significant drug-drug interactions are unlikely.
7.3 Pharmacokinetics of the stent
The pharmacokinetics information for the Onyx Frontier system is derived from a study
conducted on the Resolute system. The Onyx Frontier system is similar to the Resolute
system with regards to the stent design, the stent coating technology (dosing and drug to
polymer ratio), and delivery system design and materials. Given these similarities and
supportive bench and animal study information, the pharmacokinetics information from the
RESOLUTE FIM PK Sub-study, as described below, is applicable to the Onyx Frontier
system.
values (3 μM and above) are many
50
16
The pharmacokinetics (PK) of zotarolimus delivered from the Resolute stent have been
determined in patients with coronary artery disease after stent implantation in the Medtronic
RESOLUTE FIM Clinical Trial. The dose of zotarolimus was calculated per stent unit surface
area and the key pharmacokinetic parameters determined from these patients are provided in
Table 7-1.
Table 7-1: Zotarolimus pharmacokinetics in the Medtronic RESOLUTE FIM clinical trial PK
Sub-study patients after implantation of Resolute zotarolimus-eluting coronary stents
Group I
PK
parameter Units
C
(ng/mL) 0.129 0.210 ± 0.062 0.300 ± 0.075 0.346 ± 0.133
max
T
(h) 1.00 0.9 ± 0.7 0.9 ± 0.5 0.8 ± 0.5
max
AUC
AUC
0-last
0-inf
$
(ngxh/mL)
(ngxh/mL)
(128 μg)
N = 1†
15.08 16.04 ± 4.74 35.89 ± 12.79 31.19 ± 17.69
41.89 39.09 ± 11.77 52.41 ± 12.57 80.12 ± 51.00
ȕ$ (1/h) 0.003 0.004 ± 0.001 0.004 ± 0.001 0.003 ± 0.002
‡,#
t
(h) 263.4 195.5 ± 74.4 167.4 ± 29.7 208.3 ± 144.4
½
CL/F$ (L/h) 3.06 5.23 ± 2.55 4.80 ± 1.11 5.14 ± 3.55
Vdȕ/F$ (L) 1161.2 1449.3 ± 221.6 1181.2 ± 336.4 1658.6 ± 494.8
Notes
C
Maximum observed blood concentration a Primary dose groups
max
Time to C
T
max
Area under the blood concentration-time curve
AUC
0-last
† No SD was reported when N = 1
max
(AUC) from time 0 to time of last measurable
concentration
AUC from time 0 to infinity (AUC
AUC
0-inf
t
Harmonic mean half-life
½
). #
0-inf
CL/F Mean apparent clearance
/F Apparent volume of distribution $ Not a true sample
Vd
ȕ
Group IIa
(180 μg)
N = 11
Group IIIa
(240 μg)
N = 7
‡ Harmonic mean ± pseudo-standard deviation
Not a true estimate of the elimination half-life as the drug
release from the stent was not complete during the
course of the pharmacokinetic sampling
Group IVa
(300 μg)
N = 3
The results in Table 7-1 show that the pharmacokinetics of zotarolimus were linear in the
primary dose-proportionality evaluation (including dose groups with N > 1), 180, 240, and 300
μg, following the implantation of the Resolute stents as illustrated by dose proportional
increases in maximum blood concentration (C
curve (AUC) from time 0 to time of last measurable concentration (AUC
time 0 to infinity(AUC
) for the primary dose groups ranged from 4.80 to 5.23 L/h and 167.4 to 208.3 h,
(t
1/2
). The mean apparent clearance (CL/F) and harmonic mean half-life
0-inf
respectively. The mean time to reach peak systemic concentration (T
), area under the blood concentration-time
max
) and AUC from
0-last
) ranged from 0.8 to
max
0.9 h after stent implantation.
The data demonstrate dose proportionality and linearity similar to that seen with increasing
zotarolimus doses from the Endeavor stent and intravenous administration. Based on
available zotarolimus pharmacokinetic data, systemic safety margins of 78-fold have been
established for the Resolute stent at 380 μg due to the extended elution of zotarolimus from
the BioLinx polymer.
7.4 Pharmacokinetics following multi-dose intravenous administration of zotarolimus
Zotarolimus p
harmacokinetic activity has been determined following intravenous
administration in healthy subjects. Table 7-2 provides a summary of the pharmacokinetic
analysis.
17
Table 7-2: Pharmacokinetic parameters (mean ± standard deviation) in patients following
multi-dose intravenous administration of zotarolimus
200 μg QD
PK
Units
(ngxh/mL)
34.19 ± 4.39¥ 47.70 ± 6.68 68.43 ± 15.41
4.2 r 0.6 4.2 r 0.6 4.0 r 0.9 4.0 r 0.9 4.6 r 0.4 4.6 r 0.4
parameters
C
(ng/mL) 11.41± 1.38¥ 11.93 ± 1.25 21.99 ± 3.79 23.31± 3.15 37.72 ± 7.00 41.79 ± 6.68
max
T
(h) 1.05 ± 0.04¥ 1.03 ± 0.04 1.00 ± 0.14 1.05 ± 0.04 1.03 ± 0.04 1.03 ± 0.05
max
AUC
0-24
$
t
(h) 32.9 ± 6.8 37.6 ± 4.5 36.0 ± 4.7
1/2
CLb (L/h)
Notes
¥
N = 16
$ Harmonic mean ± pseudo-standard deviation
b
Clearance data is calculated using compartmental methods.
All other data presented in Table 7-2 is calculated using non-compartmental methods.
N = 15
Day 1 Day 14 Day 1 Day 14 Day 1 Day 14
400 μg QD
N = 16
100.47 ±
18.02
800 μg QD
N = 16
123.48 ±
13.34
When administered intravenously for 14 consecutive days, zotarolimus showed dose
proportionality. Renal excretion is not a major route of elimination for zotarolimus as
approximately 0.1% of the dose was excreted as unchanged drug in the urine per day. In
multiple doses of 200, 400, and 800 μg, zotarolimus was generally well tolerated by the
subjects. No clinically significant abnormalities in physical examinations, vital signs, or
laboratory measurements were observed during the study.
174.43 ±
19.88
7.5 Mutagenesis, carcinogenicity, and reproductive toxicology
7.5.1 Mutagenesis
Zotarolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the human
peripheral lymphocyte chromosomal aberration assay, or the in vivo mouse micronucleus
assay.
7.5.2 Carcinogenicity
No long-term studies in animals have been performed to evaluate the carcinogenic potential
of zotarolimus. The carcinogenic potential of the Resolute stent is expected to be minimal
based on the types and quantities of materials present.
7.5.3 Reproductive toxicology
No effect on fertility or early embryonic development in female rats was observed following the
IV administration of zotarolimus at dosages up to 100 μg/kg/day (approximately 19 times the
cumulative blood exposure provided by Resolute stents coated with 300 μg zotarolimus).
ale rats, there was no effect on the fertility rate at IV dosages up to 30 μg/kg/day
For m
(approximately 21 times the cumulative blood exposure provided by Resolute stents coated
with 300 μg zotarolimus). Reduced sperm counts and motility, and failure in sperm release
were observed in male rats following the IV administration of zotarolimus for 28 days at
dosages of >30 μg/kg/day. Testicular germ cell degeneration and histological lesions were
observed in rats following IV dosages of 30 μg/kg/day and above.
7.6 Pregnancy
Pregnancy Category C: There are no well-controlled studies in pregnant women, lactating
women, or men intending to father children for this product.
18
Administration of zotarolimus to pregnant female rats in a developmental toxicity study at an
intravenous dosage of 60 μg/kg/day resulted in embryolethality. Fetal ossification delays were
also observed at this dosage, but no major fetal malformations or minor fetal anomalies were
observed in this study. A 60 μg/kg/day dose in rats results in approximately 47 times the
maximum blood level and about 11 times the cumulative blood exposure in patients receiving
stents coated with 300 μg zotarolimus total dose.
No embryo-fetal effects were observed in pregnant rabbits administered zotarolimus in a
developmental toxicity study at intravenous dosages up to 100 μg/kg/day. This dose in
rabbits results in approximately 215 times the maximum blood level and about 37 times the
cumulative blood exposure in patients receiving stents coated with 300 μg zotarolimus total
dose.
Effective contraception should be initiated before implanting a stent and continued for one
year post-stent implantation. The stent should be used in pregnant women only if potential
benefits justify potential risks.
7.7 Lactation
It is not known whether zotarolimus is excreted in human milk. The potential adverse
reactions in nursing infants from zotarolimus have not been determined. The pharmacokinetic
and safety profiles of zotarolimus in infants are not known. Because many drugs are excreted
in human milk and because of the potential for adverse reactions in nursing infants from
zotarolimus, a decision should be made whether to discontinue nursing or to implant the
stent, taking into account the importance of the stent to the mother.
verview of clinical trials
8 O
8.1 The RESOLUTE ONYX Clinical Program
The RESOLUTE ONYX Clinical Program currently includes the RESOLUTE ONYX Core
(2.25 mm – 4.0 mm) Clinical Study, conducted in the United States (US), the RESOLUTE
ONYX 2.0 mm Clinical Study conducted in the US and Japan, and the RESOLUTE ONYX
Post-Approval Study (PAS) – which consists of the Primary Cohort, the XLV Cohort, and the
Bifurcation Cohort.
Table 8-1 summarizes the clinical trial designs for the RESOLUTE ONYX Core (2.25 mm –
4.0 mm) Clinical Study, the RESOLUTE ONYX 2.0 mm Clinical Study, and the RESOLUTE
ONYX PAS.
Table 8-1: The RESOLUTE ONYX Clinical Program
Study type
Study site
location
Number of
subjects
enrolled
RESOLUTE ONYX
Core (2.25 mm – 4.0
mm) Clinical Study
Prospective
Multi-center
Non-randomized
Historical controlled
trial
United States
75 101
RESOLUTE ONYX 2.0
mm Clinical Study
Prospective
Multi-center
Non-randomized
Compared to a
performance goal
United States and
Japan
Prospective
Multi-center
Non-randomized
Compared to a
United States and
Europe
416
RESOLUTE ONYX
Post-Approval Study
Primary Cohort
performance goal
RESOLUTE ONYX
Post-Approval Study
XLV Cohort
Prospective
Multi-center
Non-randomized
Descriptively
evaluate the TLF
rate
United States and
Europe
101
RESOLUTE ONYX
Post-Approval Study
Bifurcation Cohort
Prospective
Multi-center
Non-randomized
Compared to a
performance goal
United States and
Europe
205
19
Table 8-1: The RESOLUTE ONYX Clinical Program
Lesion
criteria
Stent sizes
(Resolute
Onyx)
Product
used
Postprocedure
antiplatelet
therapy
Follow-up
Status
RESOLUTE ONYX
Core (2.25 mm – 4.0
mm) Clinical Study
Single or two de
novo lesions located
in separate target
vessels
Lesion(s) length d35
mm
Target vessel with
RVD between 2.25
to 4.2 mm
Stent diameter:
2.25 to 4.0 mm
Stent length:
8 to 38 mm
Resolute Onyx stent
on a rapid exchange
(RX) stent delivery
system
Aspirin indefinitely and
market approved
thienopyridine
(clopidogrel, prasugrel,
ticagrelor, ticlopidine,
etc.) for a minimum of
6 months in all
subjects, and up to 12
months in subjects
who are not at high
risk of bleeding
30 days, 6 months, 1
to 3 years: clinical or
contact
8 months: clinical and
angiographic, IVUS
(subset)
8 months: clinical and
angiographic follow-up
is complete
RESOLUTE ONYX 2.0
mm Clinical Study
Single or two de
novo lesions located
in separate target
vessels with at least
one of the target
lesions amenable to
treatment with a 2.0
mm study stent
Lesion(s) length d27
mm
Target vessel with
RVD between 2.0 to
2.25 mm
Stent diameter:
2.0 mm
Stent length:
8 to 30 mm
Resolute Onyx stent
on a rapid exchange
(RX) stent delivery
system
Aspirin indefinitely and
market approved
thienopyridine
(clopidogrel, prasugrel,
ticagrelor, ticlopidine,
etc.) for a minimum of
6 months in all
subjects, and up to 12
months in subjects
who are not at high
risk of bleeding
30 days, 6 months, 1
to 3 years: clinical or
contact
13 months: clinical and
angiographic, IVUS
(subset)
13 months: clinical and
angiographic follow-up
is complete
RESOLUTE ONYX
Post-Approval Study
Primary Cohort
Lesions located in
separate target
vessels with at least
one of the target
lesions amenable to
treatment with a 2.0
to 4.0 mm stent
Lesion(s) length d35
mm
Stent diameter:
2.0 to 4.0 mm
Stent length:
8 to 38 mm
Resolute Onyx stent
on a rapid exchange
(RX) or over-the-wire
(OTW) stent delivery
system
Antiplatelet medication
should be
administered
according to hospital
routine and in line with
the applicable
guidelines on
percutaneous coronary
interventions and the
Instructions for Use of
the device.
30 days, 6 months, 1
year, 2 years, 3 years:
clinical or contact
12 months: clinical
follow-up is complete
RESOLUTE ONYX
Post-Approval Study
XLV Cohort
Lesions located in
separate target
vessels with at least
one of the target
lesions amenable to
treatment with a 4.5
or 5.0 mm stent
Lesion(s) length d35
mm
Stent diameter:
4.5 to 5.0 mm
Stent length:
12 to 30 mm
Resolute Onyx stent
on a rapid exchange
(RX) or over-the-wire
(OTW) stent delivery
system
Antiplatelet medication
should be
administered
according to hospital
routine and in line with
the applicable
guidelines on
percutaneous coronary
interventions and the
Instructions for Use of
the device.
30 days, 6 months, 1
year, 2 years, 3 years:
clinical or contact
Enrollment complete,
in follow-up
RESOLUTE ONYX
Post-Approval Study
Bifurcation Cohort
Single de novo
bifurcated lesion
amenable to
treatment with a 2.0
to 5.0 mm stent with
provisional stenting
technique
Lesion(s) length d35
mm
Stent diameter:
2.0 to 5.0 mm
Stent length:
8 to 38 mm
Resolute Onyx stent
on a rapid exchange
(RX) or over-the-wire
(OTW) stent delivery
system
Antiplatelet medication
should be
administered
according to hospital
routine and in line with
the applicable
guidelines on
percutaneous coronary
interventions and the
Instructions for Use of
the device.
30 days, 6 months, 1
year, 2 years, 3 years:
clinical or contact
Enrollment complete,
in follow-up
8.2 Supportive RESOLUTE and RESOLUTE INTEGRITY data:
The Resolute Onyx stent is an iterative design update to the Resolute Integrity stent, utilizing
the same continuous sinusoid manufacturing technology with slight modifications
incorporated to provide a lower crossing profile and thus improved deliverability over
predicate products. Given the similarities between the Resolute stent system and the
Resolute Onyx stent system, and supportive bench and animal study information, the findings
from the RESOLUTE clinical studies are applicable to the Onyx Frontier stent system.
The principal safety and effectiveness information for the Resolute stent was derived from the
Global RESOLUTE Clinical Trial Program, which consists of the following clinical trials – the
RESOLUTE United States Clinical Trial (R-US), the RESOLUTE All-Comers Clinical Trial (R-
20
AC), the RESOLUTE International Study (R-Int), the RESOLUTE First-in-Man (FIM) Clinical
Trial, and the RESOLUTE Japan Clinical Trial (R-J). These 5 studies have evaluated the
performance of the Resolute stent in improving coronary luminal diameters in patients,
including those with diabetes mellitus, with symptomatic ischemic heart disease due to de
novo lesions of length 35 mm in native coronary arteries with reference vessel diameters of
2.25 mm to 4.2 mm. Key elements of these studies are summarized below and in Table 8-2.
The Resolute 38 mm Length Group was derived from subjects enrolled in the R-US and the
RESOLUTE Asia study (R-Asia) (for 38 mm Length Group data see Table 8-2). In addition,
the RESOLUTE INTEGRITY US Post Market Study, a prospective, multi-center evaluation of
the procedural and clinical outcomes of subjects who were treated with the Medtronic
Resolute Integrity zotarolimus-eluting coronary stent system was designed to assess the
safety and efficacy of the Resolute Integrity stent for the treatment of de novo lesions in
native coronary arteries with a reference vessel diameter (RVD) of 2.25 mm to 4.2 mm in two
groups of patients, specifically those patients receiving stents mm in length, referred to
as the Primary Enrollment Group (PEG) and those patients who receive extended length
stents (34 mm or 38 mm) referred to as the Extended Length (XL) Sub-study.
Table 8-2 summarizes the clinical trial designs for the Global RESOLUTE Clinical Trial
Program and RESOLUTE INTEGRITY US Post-Market Study.
21
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