Medtronic RONYX20018UX Instructions for Use
Resolute Onyx™
Zotarolimus-Eluting Coronary Stent System
Rapid Exchange and Over-the-Wire Delivery Systems
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 Resolute Onyx™ Zotarolimus-Eluting Coronary Stent System.......................................... 4
2.1 Device component description ........................................................................................ 6
2.2 Drug component description ........................................................................................... 7
2.2.1 Zotarolimus..................................................................................................................... 7
2.2.2 Polymer system description ........................................................................................... 8
2.2.3 Product matrix and zotarolimus content ......................................................................... 8
3 Indications .............................................................................................................................. 10
4 Contraindications .................................................................................................................. 10
5 Warnings ................................................................................................................................ 10
6 Precautions ............................................................................................................................ 10
6.1 Pre- and post-procedure antiplatelet regimen ............................................................. 11
6.1.1 Oral antiplatelet therapy ............................................................................................... 11
6.2 Use of multiple stents ..................................................................................................... 12
6.3 Use in conjunction with other procedures ................................................................... 13
6.4 Brachytherapy ................................................................................................................. 13
6.5 Use in special populations ............................................................................................. 13
6.5.1 Pregnancy .................................................................................................................... 13
6.5.2 Lactation ....................................................................................................................... 13
6.5.3 Gender ......................................................................................................................... 13
6.5.4 Ethnicity ........................................................................................................................ 13
6.5.5 Pediatric use ................................................................................................................ 13
6.5.6 Geriatric use ................................................................................................................. 14
6.5.7 Lesion/vessel characteristics ....................................................................................... 14
6.6 Drug interactions ............................................................................................................ 14
6.7 Magnetic resonance imaging (MRI) safety information .............................................. 14
6.8 Stent handling precautions ............................................................................................ 15
6.9 Stent placement precautions ......................................................................................... 15
6.10 Stent/system removal precautions ............................................................................... 16
6.11 Post-procedure ................................................................................................................ 16
7 Drug information ................................................................................................................... 17
7.1 Mechanisms of action .................................................................................................... 17
7.2 Metabolism ...................................................................................................................... 17
7.3 Pharmacokinetics of the Resolute OnyxTM stent ......................................................... 17
7.4 Pharmacokinetics following multi-dose intravenous administration of zotarolimus
.......................................................................................................................................... 18
7.5 Mutagenesis, carcinogenicity and reproductive toxicology ...................................... 19
7.5.1 Mutagenesis ................................................................................................................. 19
7.5.2 Carcinogenicity ............................................................................................................. 19
7.5.3 Reproductive toxicology ............................................................................................... 19
7.6 Pregnancy ........................................................................................................................ 19
7.7 Lactation .......................................................................................................................... 19
8 Overview of clinical trials ..................................................................................................... 20
i
8.1
The RESOLUTE ONYX Clinical Program ...................................................................... 20
8.2 Supportive RESOLUTE and RESOLUTE INTEGRITY data: ........................................ 21
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
9.2.3 Potential risks associated with percutaneous coronary diagnostic and treatment
procedures ................................................................................................................... 35
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 ......................... 45
10.4 Subjects with diabetes mellitus in the RESOLUTE 38 mm length group .................. 48
10.5 Subjects receiving short-term DAPT ............................................................................ 49
10.5.1 Onyx ONE Clear Primary Analysis .............................................................................. 49
10.5.2 The Onyx ONE Global RCT ......................................................................................... 53
10.6 Subjects with chronic total occlusion .......................................................................... 53
10.7 Pooled results of the Global RESOLUTE Clinical Trial Program (RESOLUTE FIM,
RESOLUTE US, RESOLUTE AC, RESOLUTE Int, RESOLUTE Japan) ....................... 58
TM*
polymer............................................... 34
11 Patient selection and treatment ........................................................................................... 65
12 Patient counseling information ............................................................................................ 65
13 How supplied ......................................................................................................................... 65
14 Directions for use .................................................................................................................. 65
14.1 Access to package holding sterile stent delivery system .......................................... 65
14.2 Inspection before use ..................................................................................................... 66
14.3 Materials required ........................................................................................................... 66
14.4 Preparation precaution ................................................................................................... 66
14.4.1 Guidewire lumen flush .................................................................................................. 66
14.4.2 Delivery system preparation......................................................................................... 66
14.5 Delivery procedure.......................................................................................................... 67
14.6 Deployment procedure ................................................................................................... 67
14.7 Removal procedure......................................................................................................... 68
14.8
14.9 Further dilatation of stented segment .......................................................................... 69
14.10 Instructions for simultaneous use of 2 devices in guide catheter (kissing balloon
15 Reuse precaution statement ................................................................................................ 70
In-vitro
technique) ........................................................................................................................ 69
information: ........................................................................................................ 68
ii
The components of the Resolute Onyx™ zotarolimus-eluting coronary stent system are
sterile.
© 2021. Medtronic. All rights reserved. Medtronic and Medtronic with logo are trademarks of
Medtronic, Inc. All other brands are trademarks of their respective owners.
3
1 Symbol glossary
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 damaged or opened.
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.
Clause 5.1.5
ISO 15223-1,
Clause 5.1.1
ISO 15223-1,
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.
2 Resolute Onyx™ Zotarolimus-Eluting Coronary Stent System
The Medtronic Resolute Onyx™ zotarolimus-eluting coronary stent system (Resolute Onyx™
system) is a device/drug combination product that consists of the following device
components: the Resolute Onyx™ coronary stent and delivery system and a drug component
(a formulation of zotarolimus in a polymer coating). The characteristics of the Resolute
Onyx™ system are described in Table 2-1.
Table 2-1: Device component description and nominal dimensions
Resolute Onyx™ zotarolimus-eluting coronary stent system
rapid exchange and over-the-wire delivery systems
Component
Stent design 1
(small vessel)
Available stent diameters (mm) 2.0, 2.25, 2.5 2.75, 3.0 3.5, 4.0 (RX only) – 4.5, 5.0
Stent design 2
(medium
vessel)
Stent design 3
(large vessel)
Stent design 4
(extra large vessel)
4
Table 2-1: Device component description and nominal dimensions
Resolute Onyx™ zotarolimus-eluting coronary stent system
rapid exchange and over-the-wire delivery systems
Component
Available stent lengths (mm)
Stent material and geometry
Drug component
Delivery systems effective (working)
length
RX
Delivery system luer adapter
ports
OTW
Stent design 1
(small vessel)
8, 12, 15, 18, 22, 26,
30, 34*, 38*
*34, 38 mm lengths not
available in 2.0 mm
A continuous sinusoid pattern stent manufactured from a composite metal material, consisting
of a cobalt-based 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).
Y-connector with side arm for access to balloon inflation/deflation lumen. Straight arm is
continuous with shaft inner lumen designed for guidewire less than or equal to 0.014 inch
(0.36 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
Stent design 4
(extra large vessel)
(RX only) – 12, 15, 18,
22, 26, 30
Stent delivery balloon
Balloon inflation pressure
Minimum guide catheter inner
diameter
Catheter shaft outer
diameter
Single-layer Pebax balloon, 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), RX only: 4.5-5.0 mm = 16 ATM
(1621kPa)
≥5 F (1.42 mm, 0.056 in)
Proximal shaft OD: 2.1 F (0.69 mm)
RX
Distal shaft OD 2.0 – 4.0 mm: 2.7 F (0.91 mm)
Distal shaft OD 4.5 and 5.0 mm: 3.2 F (1.07 mm)
Proximal shaft OD: 3.4 F (1.12 mm)
OTW
Distal shaft OD: 2.7 F (0.91 mm)
5
2.1 Device component description
The Medtronic Resolute Onyx™ zotarolimus-eluting coronary stent system (Resolute Onyx™
system) consists of a balloon-expandable, intracoronary, drug-eluting stent (DES)
premounted on a rapid exchange (RX) or an over-the-wire (OTW) stent delivery system. The
Resolute Onyx™ 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 Resolute Onyx™ RX delivery
system (Figure 2-1) and the Resolute Onyx™ OTW delivery system (Figure 2-2) have an
effective length of 140 cm.
Diameter
(mm)
2.0
2.25
2.5
2.75
Figure 2-1: Resolute Onyx™ rapid exchange (RX) delivery system (with stent)
Illustration is not to scale
Figure 2-2: Resolute Onyx™ over-the-wire (OTW) delivery system (with stent)
Illustration is not to scale
The stent is crimped on various sizes of delivery catheter balloons, which range from 2.0 mm
to 5.0 mm. The Resolute Onyx™ available stent sizes are listed in Table 2-2.
Table 2-2: Resolute Onyx™ stent sizes
Stent length (mm)
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
- -
6
Table 2-2: Resolute Onyx™ stent sizes
Diameter
(mm)
3.0
3.5
4.0
4.5 - 9* 9* 9* 9* 9* 9* - -
5.0 - 9* 9* 9* 9* 9* 9* - -
“-” Denotes stent length is not available
“*” Not available for OTW
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
Stent length (mm)
2.2 Drug component description
The drug coating of the Resolute Onyx™ system 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 Resolute Onyx™ system is zotarolimus. It
is a tetrazole-containing 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 2-3:
NN
N
N
MeO
OO OH
N
O
O
O
MeO
OHO
OMe
O
Figure 2-3: 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
and its molecular weight is 966.2.
Zotarolimus does not have any ionizable group(s) in the physiological pH range; therefore, its
solubility is expected to be unaltered in this range.
7
2.2.2 Polymer system description
The Resolute Onyx™ 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
TM
BioLinx
(polyvinyl pyrrolidone). The structural formula of the BioLinx
is a blend of the Medtronic proprietary components C10 and C19, and PVP
TM
polymer subunits are shown in
TM
polymer system.
Figure 2-4:
Figure 2-4: Chemical structure of the BioLinx
TM
polymer subunits
2.2.3 Product matrix and zotarolimus content
Table 2-3: Resolute Onyx™ zotarolimus-eluting coronary stent system product matrix and
nominal zotarolimus doses
Product number
RX
RONYX20008UX RONYX20008W 2.0 8 51
RONYX22508UX RONYX22508W 2.25 8 51
RONYX25008UX RONYX25008W 2.5 8 51
RONYX27508UX RONYX27508W 2.75 8 67
RONYX30008UX RONYX30008W 3.0 8 67
RONYX35008UX RONYX35008W 3.5 8 77
RONYX40008UX RONYX40008W 4.0 8 77
RONYX20012UX RONYX20012W 2.0 12 70
RONYX22512UX RONYX22512W 2.25 12 70
RONYX25012UX RONYX25012W 2.5 12 70
RONYX27512UX RONYX27512W 2.75 12 94
RONYX30012UX RONYX30012W 3.0 12 94
RONYX35012UX RONYX35012W 3.5 12 108
RONYX40012UX RONYX40012W 4.0 12 108
RONYX45012UX - 4.5 12 132
RONYX50012UX - 5.0 12 132
RONYX20015UX RONYX20015W 2.0 15 85
RONYX22515UX RONYX22515W 2.25 15 85
RONYX25015UX RONYX25015W 2.5 15 85
RONYX27515UX RONYX27515W 2.75 15 117
RONYX30015UX RONYX30015W 3.0 15 117
RONYX35015UX RONYX35015W 3.5 15 132
Product number
OTW
Nominal expanded
stent ID (mm)
Nominal unexpanded
stent length (mm)
Nominal zotarolimus
content (μg)
8
Table 2-3: Resolute Onyx™ zotarolimus-eluting coronary stent system product matrix and
nominal zotarolimus doses
Product number
RX
RONYX40015UX RONYX40015W 4.0 15 132
RONYX45015UX - 4.5 15 158
RONYX50015UX - 5.0 15 158
RONYX20018UX RONYX20018W 2.0 18 104
RONYX22518UX RONYX22518W 2.25 18 104
RONYX25018UX RONYX25018W 2.5 18 104
RONYX27518UX RONYX27518W 2.75 18 140
RONYX30018UX RONYX30018W 3.0 18 140
RONYX35018UX RONYX35018W 3.5 18 156
RONYX40018UX RONYX40018W 4.0 18 156
RONYX45018UX - 4.5 18 188
RONYX50018UX - 5.0 18 188
RONYX20022UX RONYX20022W 2.0 22 127
RONYX22522UX RONYX22522W 2.25 22 127
RONYX25022UX RONYX25022W 2.5 22 127
RONYX27522UX RONYX27522W 2.75 22 171
RONYX30022UX RONYX30022W 3.0 22 171
RONYX35022UX RONYX35022W 3.5 22 186
RONYX40022UX RONYX40022W 4.0 22 186
RONYX45022UX - 4.5 22 227
RONYX50022UX - 5.0 22 227
RONYX20026UX RONYX20026W 2.0 26 146
RONYX22526UX RONYX22526W 2.25 26 146
RONYX25026UX RONYX25026W 2.5 26 146
RONYX27526UX RONYX27526W 2.75 26 198
RONYX30026UX RONYX30026W 3.0 26 198
RONYX35026UX RONYX35026W 3.5 26 221
RONYX40026UX RONYX40026W 4.0 26 221
RONYX45026UX - 4.5 26 265
RONYX50026UX - 5.0 26 265
RONYX20030UX RONYX20030W 2.0 30 168
RONYX22530UX RONYX22530W 2.25 30 168
RONYX25030UX RONYX25030W 2.5 30 168
RONYX27530UX RONYX27530W 2.75 30 225
RONYX30030UX RONYX30030W 3.0 30 225
RONYX35030UX RONYX35030W 3.5 30 252
RONYX40030UX RONYX40030W 4.0 30 252
RONYX45030UX - 4.5 30 304
RONYX50030UX - 5.0 30 304
RONYX22534UX RONYX22534W 2.25 34 187
Product number
OTW
Nominal expanded
stent ID (mm)
Nominal unexpanded
stent length (mm)
Nominal zotarolimus
content (μg)
9
Table 2-3: Resolute Onyx™ zotarolimus-eluting coronary stent system product matrix and
nominal zotarolimus doses
Product number
RX
RONYX25034UX RONYX25034W 2.5 34 187
RONYX27534UX RONYX27534W 2.75 34 257
RONYX30034UX RONYX30034W 3.0 34 257
RONYX35034UX RONYX35034W 3.5 34 282
RONYX40034UX RONYX40034W 4.0 34 282
RONYX22538UX RONYX22538W 2.25 38 206
RONYX25038UX RONYX25038W 2.5 38 206
RONYX27538UX RONYX27538W 2.75 38 284
RONYX30038UX RONYX30038W 3.0 38 284
RONYX35038UX RONYX35038W 3.5 38 317
RONYX40038UX RONYX40038W 4.0 38 317
Product number
OTW
Nominal expanded
stent ID (mm)
Nominal unexpanded
stent length (mm)
Nominal zotarolimus
content (μg)
3 Indications
The Resolute Onyx™ 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 Resolute
Onyx™ zotarolimus-eluting coronary stent system is indicated for treating de novo
chronic total
occlusions.
4 Contraindications
The Resolute Onyx™ system is contraindicated for use in:
• 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.
• Patients with a known hypersensitivity to the cobalt-based alloy (cobalt, nickel, chromium,
and molybdenum) or platinum-iridium alloy.
• 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:
• Patients in whom antiplatelet and/or anticoagulation therapy is contraindicated.
• 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
• Ensure that the inner package has not been opened or damaged as this would indicate
that the sterile barrier has been breached.
• 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.
• This product should not be used in patients who are not likely to comply with the
recommended antiplatelet therapy.
6 Precautions
• Only physicians who have received adequate training should perform implantation of the
stent.
10
• 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.
• The risks and benefits of stent implantation should be assessed for patients with a history
of severe reaction to contrast agents.
• Do not expose or wipe the product with organic solvents such as alcohol.
• 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.
• 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.
• 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
for more information).
10.7 – Pooled results of the Global RESOLUTE Clinical Trial Program
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.
• 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.
• 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.
Per 2016 ACC/AHA guidelines,
after PCI. A P2Y12 platelet inhibitor should be given daily for at least 6 months in stable
1
a daily aspirin dose of 81 mg is recommended indefinitely
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
11
ischemic heart disease patients and for at least 12 months in patients with acute coronary
syndrome (ACS).
2
Consistent with the DAPT Study,
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)
. Additionally, evidence from a dedicated study of
Resolute Onyx in HBR patients and those who are unable to tolerate long term DAPT after
4
PCI has been published
.
Based on the Onyx ONE Clear Analysis, Resolute Onyx 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
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 Resolute Onyx™ 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
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.
12
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 Resolute Onyx™
not been established.
6.4 Brachytherapy
The safety and effectiveness of the Resolute Onyx™ stent in target lesions treated with prior
brachytherapy, or the use of brachytherapy to treat in-stent restenosis of a Resolute Onyx™
stent, have not been established.
6.5 Use in special populations
Information on use of the Resolute Onyx™ 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 Resolute Onyx™ 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 Resolute Onyx™ stent and for 1 year
after implantation.
See Section 7.6 – Pregnancy under Drug information.
stent have
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
Resolute Onyx™ stent, taking into account the importance of the stent to the mother.
See Section 7.7 – Lactation under Drug information.
6.5.3 Gender
TM
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
TM
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 Resolute Onyx™ stent in patients below the age of 18
years have not been established.
13
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 Resolute Onyx™ stent have not been established in the
cerebral, carotid, or peripheral vasculature or in the following coronary disease patient
populations:
• Patients with coronary artery reference vessel diameters < 2.0 mm or > 5.0 mm.
• Patients with evidence of an acute ST-elevation MI within 72 hours of intended stent
implantation.
• Patients with vessel thrombus at the lesion site.
• Patients with lesions located in a saphenous vein graft, in the left main coronary
artery, ostial lesions, or bifurcation lesions.
• Patients with diffuse disease or poor flow distal to identified lesions.
• Patients with 3 vessel disease.
6.6 Drug interactions
The effect of potential drug interactions on the safety or effectiveness of the Resolute Onyx™
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
Therefore, 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
max
.
Formal drug interaction studies have not been conducted with the Resolute Onyx™ stent.
6.7 Magnetic resonance imaging (MRI) safety information
Non-clinical testing has demonstrated that the Resolute Onyx™ stent is MR Conditional for
single and overlapping lengths up to 120 mm. A patient with this device can be safely
scanned in an MR system meeting the following conditions:
• Static magnetic field of 1.5 and 3 Tesla only
• Maximum spatial gradient magnetic field of 3000 gauss/cm (30 T/m) or less
• Maximum MR system reported, whole body averaged specific absorption rate (SAR) of
2.0 W/kg (Normal Operating Mode)
Under the scan conditions defined above, the Resolute Onyx™ stent is expected to produce
a maximum temperature rise of 4.3°C after 15 minutes of continuous scanning.
In non-clinical testing, the image artifact caused by the device extended approximately 10
mm from the Resolute Onyx™ stent when imaged with a spin echo pulse sequence and a 3
Tesla MRI system. The artifact does obscure the device lumen.
14
6.8 Stent handling precautions
• For single use only. The Resolute Onyx™ 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.
• Only the contents of the pouch should be considered sterile. The outside surface of the
pouch is not sterile.
• Do not remove the contents of the pouch until the device will be used immediately.
• Do not remove the stent from the delivery balloon; removal may damage the stent and
polymer coating and/or lead to stent embolization. The Resolute Onyx™ system is
intended to perform as a system. The stent is not designed to be crimped onto another
delivery device.
• 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.
• Do not try to straighten a kinked shaft or hypotube. Straightening a kinked metal shaft
may result in breakage of the shaft.
• 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.
• The Resolute Onyx™ 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.
• 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.
• The Resolute Onyx™ stent delivery systems should not be used in conjunction with any
other stents or for post-dilatation.
6.9 Stent placement precautions
• 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.
• Do not prepare or pre-inflate the balloon before stent deployment other than as directed.
Use the balloon purging technique described in Section 14 –
• Guide catheters used must have lumen sizes that are suitable to accommodate the stent
delivery system (see Device component description in Table 2-1).
• 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.
• 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.
• 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.
• 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).
• Do not expand the stent if it is not properly positioned in the vessel (see Section
Precautions–Stent/system removal precautions).
• Placement of the stent has the potential to compromise side branch patency.
Directions for use.
6 -
15
• 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.
• 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.
• 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.
• Ensure full coverage of the entire lesion/dissection site so that there are no gaps between
stents.
• 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:
• 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.
• 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
• 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.
• 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.
• If patient requires MR imaging, refer to Section 6.7 – Magnetic resonance imaging
(MRI) safety information above.
• 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.
16
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 Resolute Onyx
The pharmacokinetics information for the Resolute Onyx™ stent system is derived from a
study conducted on the Resolute stent system. The Resolute Onyx™ stent system is similar
to the Resolute stent 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
Resolute Onyx™ stent system.
TM
stent
values (3 μM and above) are many
50
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
$
(ng•h/mL)
(ng•h/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
Maximum observed blood concentration a Primary dose groups
C
max
T
Time to C
max
AUC
0-last
Area under the blood concentration-time curve
† 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
). #
0-inf
Group IIa
(180 μg)
N = 11
Group IIIa
(240 μg)
N = 7
‡ Harmonic mean ± pseudo-standard deviation
Group IVa
(300 μg)
N = 3
17
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
(128 μg)
N = 1†
t½ Harmonic mean half-life
CL/F Mean apparent clearance
Vd
/F Apparent volume of distribution $ Not a true sample
ȕ
Group IIa
(180 μg)
N = 11
Group IIIa
(240 μg)
N = 7
Group IVa
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
(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 pharmacokinetic activity has been determined following intravenous
administration in healthy subjects. Table 7-2 provides a summary of the pharmacokinetic
analysis.
Table 7-2: Pharmacokinetic parameters (mean ± standard deviation) in patients following
multi-dose intravenous administration of zotarolimus
200 μg QD
PK
parameters Units
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
(ng•h/mL)
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.
34.19 ± 4.39¥ 47.70 ± 6.68 68.43 ± 15.41
4.2 ± 0.6 4.2 ± 0.6 4.0 ± 0.9 4.0 ± 0.9 4.6 ± 0.4 4.6 ± 0.4
N = 15
Day 1 Day 14 Day 1 Day 14 Day 1 Day 14
All other data presented in Table 7-2 is calculated using non-compartmental methods.
400 μg QD
N= 16
100.47 ±
18.02
123.48 ±
13.34
800 μg QD
N=16
174.43 ±
19.88
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
18
subjects. No clinically significant abnormalities in physical examinations, vital signs, or
laboratory measurements were observed during the study.
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).
For male rats, there was no effect on the fertility rate at IV dosages up to 30 μg/kg/day
(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.
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
Resolute Onyx™ 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 Resolute Onyx™ stents coated with 300 μg
zotarolimus total dose.
Effective contraception should be initiated before implanting a Resolute Onyx™ stent and
continued for one year post-stent implantation. The Resolute Onyx™ 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.
19
8 Overview of clinical trials
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
Lesion
criteria
Stent sizes
(Resolute
Onyx™)
Product
used
RESOLUTE ONYX™
Core (2.25 mm – 4.0
mm) Clinical Study
Prospective
Multi-center
Non-randomized
Historical controlled
trial
United States
75 101
Single or two de
novo lesions located
in separate target
vessels
Lesion(s) length ≤35
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
RESOLUTE ONYX 2.0
mm Clinical Study
Prospective
Multi-center
Non-randomized
Compared to a
performance goal
United States and
Japan
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 ≤27
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
RESOLUTE ONYX™
Post-Approval Study
Primary Cohort
Prospective
Multi-center
Non-randomized
Compared to a
performance goal
United States and
Europe
416
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 ≤35
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
RESOLUTE ONYX™
Post-Approval Study
XLV Cohort
Prospective
Multi-center
Non-randomized
Descriptively
evaluate the TLF
rate
United States and
Europe
101
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 ≤35
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
RESOLUTE ONYX™
Post-Approval Study
Bifurcation Cohort
Prospective
Multi-center
Non-randomized
Compared to a
performance goal
United States and
Europe
205
Single de novo
bifurcated lesion
amenable to
treatment with a 2.0
to 5.0 mm stent with
provisional stenting
technique
Lesion(s) length ≤35
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
20
Table 8-1: The RESOLUTE ONYX Clinical Program
Postprocedure
antiplatelet
therapy
Follow-up
Status
RESOLUTE ONYX™
Core (2.25 mm – 4.0
mm) Clinical Study
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
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
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
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
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 Resolute Onyx™ stent
system.
XLV Cohort
RESOLUTE ONYX™
Post-Approval Study
Bifurcation Cohort
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
TM
stent,
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 (RAC), 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
TM
Resolute Integrity
safety and efficacy of the Resolute Integrity
zotarolimus-eluting coronary stent system was designed to assess the
TM
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.
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