Medtronic ONYXNG20012UX Technical Manual

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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

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

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™

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 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

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.

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

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:

MeO

OO OH

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

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)

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)

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.

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.

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.

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,

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

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

. 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.

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.

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.

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.

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.

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

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

parameter Units

(ng/mL) 0.129 0.210 ± 0.062 0.300 ± 0.075 0.346 ± 0.133

max

(h) 1.00 0.9 ± 0.7 0.9 ± 0.5 0.8 ± 0.5

max

AUC

0-last

0-inf

(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

‡,#

(h) 263.4 195.5 ± 74.4 167.4 ± 29.7 208.3 ± 144.4

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

max

Time to C

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

Harmonic mean half-life

). #

0-inf

CL/F Mean apparent clearance

/F Apparent volume of distribution $ Not a true sample

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,

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.

Table 7-2: Pharmacokinetic parameters (mean ± standard deviation) in patients following

multi-dose intravenous administration of zotarolimus

200 μg QD

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

(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

(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

(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

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.

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

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

 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

 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

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

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

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

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

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

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-

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.

Sub-study)

RESOLUTE

INTEGRITY US (XL

 Prospective

 Multi-center

 Non-randomized

 Post approval

Study

(PEG)

RESOLUTE

RESOLUTE INTEGRITY US Post-Market

INTEGRITY US

 Prospective

 Multi-center

38 mm Cohort

RESOLUTE Asia

 Prospective

 Multi-center

 Non-randomized

 Post approval

 Non-randomized

 Prospective

 Multi-center

 Non-randomized

RESOLUTE Japan

controlled trial

 Single-arm

 Historical

 Prospective

 Multi-center

 Non-randomized

RESOLUTE FIM

 Non-randomized

 Prospective

 Multi-center

RESOLUTE Int

Table 8-2: RESOLUTE and RESOLUTE INTEGRITY clinical trials overview

Global RESOLUTE Clinical Trial Program

 Randomized

 Prospective

 Multi-center

controlled trial

 Single-arm

 Historical

study

 Observational

 Single-arm

)

TM*

Xience V

(1:1 Resolute vs.

 Two-arm, non-

 PK Assessment

Total: 2349 Total: 139 Total: 100 Total: 109 Total:230 Total: 56

population

 Real World subject

: 1152)

TM*

Total: 2292

inferiority trial

 Real World subject

(Resolute: 1140,

population

Xience V

population was

223 with 114 from

RESOLUTE US

mm Sub-study

Study - 1242

subjects

150 subjects

Angio/IVUS sub-

study - 100

subjects

 Multi-center

controlled trial*

 Non-randomized

 Historical

Total: 1516

- 2.25–3.5 mm Main

- 2.25 mm Cohort -

- 2.25–3.5 mm

- 60 subjects

- 4.0 mm Sub-study

- 38 mm Sub-study -

114 subjects (38

total patient

and 109 from

RESOLUTE Asia)

RESOLUTE US* RESOLUTE AC

Study type  Prospective

Number of

subjects

enrolled

Sub-study)

RESOLUTE

INTEGRITY US (XL

lesions located in

separate target

or two target

 Single target lesion

vessels

XL:

mm treated or

 Target lesion 

RVD between 2.25

 Target vessel with

to 4.2 mm

Stent diameter:

3.0 – 4.0 mm

Stent length:

34-38 mm

Resolute Integrity

stent on the rapid

exchange MicroTrac

delivery system

Aspirin indefinitely

and

clopidogrel/ticlopidine for  months in all

subjects, up to 12

months if tolerated

lesion length

Study

(PEG)

RESOLUTE

RESOLUTE INTEGRITY US Post-Market

INTEGRITY US

lesions located in

separate target

or two target

 Single target lesion

vessels

PEG:

 Target lesion 

RVD between 2.25

 Target vessel with

to 4.2 mm

Stent diameter:

2.25 – 4.0 mm

Stent length:

8 – 30 mm

Resolute Integrity

stent on the rapid

exchange MicroTrac

delivery system

Aspirin indefinitely

and

clopidogrel/ticlopidine

for  months in all

subjects, up to 12

months if tolerated

38 mm Cohort

RESOLUTE Asia

RESOLUTE Japan

 Single or two de

novo lesions

RVD between 3.0

target vessels

located in separate

d35 mm

 Lesion(s) length

coronary arteries

d27 mm

 Lesion(s) length

 Target vessel with

RVD between 2.5

 Target vessel with

to 4.0 mm

 Patients may have

to 3.5 mm

received treatment

of up to two lesions second lesion RVD

the lesions were

located in separate

(2.25 to 4.2 mm) if

target vessels.

Stent diameter:

3.0 – 4.0 mm

Stent diameter:

2.5 – 3.5 mm

Stent length:

Stent length: 38 mm

8 – 30 mm

Resolute stent on the

rapid exchange sprint

delivery system

Aspirin indefinitely

and

clopidogrel/ticlopidine for  months in all

subjects, up to 12

months if tolerated

delivery system

Aspirin indefinitely

and

clopidogrel/ticlopidine

for  months in all

subjects, up to 12

months if tolerated

RVD between 2.5

lesion

 Single de novo

RESOLUTE FIM

number of

 No limitation to

RESOLUTE Int

 Lesion length from

lesion(s)/ vessel(s)

14 to 27 mm

treated or lesion

 Target vessel with

length

 Target vessel with

and 3.5 mm

RVD between 2.25

to 4.0 mm

Stent length:

Stent diameter:

8 – 30 mm

2.5 – 3.5 mm

2.25 – 4.0 mm

Stent length:

8 – 38 mm

Resolute stent on the

rapid exchange

rapid exchange sprint

AV100 delivery

system

Aspirin indefinitely

and

clopidogrel/ticlopidine  months

delivery system

Aspirin indefinitely

and

clopidogrel/ticlopidine

for  months in all

subjects, up to 12

months if tolerated

Table 8-2: RESOLUTE and RESOLUTE INTEGRITY clinical trials overview

Global RESOLUTE Clinical Trial Program

length

RVD between 2.25

 No limitation to

number of

lesion(s)/ vessel(s)

treated or lesion

 Target vessel with

to 4.0 mm

Stent diameter:

2.25 – 4.0 mm

Stent length:

8 – 30 mm

Resolute stent on the

rapid exchange sprint

delivery system

Aspirin indefinitely

and

clopidogrel/ticlopidine for  months in all

subjects, up to 12

months if tolerated

RVD between 2.25

 Single or two de

Group, d35 mm for

the 38 mm Length

target vessels

d27 mm for the

novo lesions

located in separate

 Lesion(s) length

Primary Enrollment

Group

 Target vessel with

to 4.2 mm

Stent diameter:

2.25 – 4.0 mm

Stent length:

8 – 30 mm for the

Primary Enrollment

Group, 38 mm for the

38 mm Length Group

Resolute stent on the

rapid exchange sprint

delivery system

Aspirin indefinitely

and

clopidogrel/ticlopidine

for  months in all

subjects, up to 12

months if tolerated

RESOLUTE US* RESOLUTE AC

Lesion

criteria

Stent sizes

(Resolute)

Product

used

Post-

procedure

antiplatelet therapy

Sub-study)

RESOLUTE

INTEGRITY US (XL

30 days (contact); 6

months (contact); 12

with 12-lead ECG)

and 2 years:

(contact) 3 years

months (clinic visit

(contact)

36-month follow-up is

complete

Study

(PEG)

RESOLUTE

RESOLUTE INTEGRITY US Post-Market

INTEGRITY US

30 days (contact); 6

months (contact); 12

38 mm Cohort

RESOLUTE Asia

30 days, 6, 9 (clinical

visit), 12, 18 months

30 days and 12

months: clinical

RESOLUTE Japan

months (clinic visit

then annually at 2 - 5

with 12-lead ECG)

and 2 years:

(contact)

years

8 months:

angiographic/IVUS

6, 9 and 18 months

and 2-5 years:

telephone

24-month follow-up is

complete

60-month follow-up is

complete

60-month follow-up is

complete

and 9 months (100

subject subset):

clinical and

angiographic/IVUS

6 months and 1-5

30 days: clinical

4 (30 subject subset)

RESOLUTE FIM

30 days, 6 months, 1-

3 years: clinical or

RESOLUTE Int

telephone

years: telephone

60-month follow-up

complete

36-month follow-up is

complete

Table 8-2: RESOLUTE and RESOLUTE INTEGRITY clinical trials overview

Global RESOLUTE Clinical Trial Program

30 days and 12

months: clinical

13 months (455

subject subset):

angiographic

6 months and 2-5

years: telephone

and 9 months:

Main Study: 30 days

clinical; 6, 12 and 18

months, 2-5 years:

telephone

4.0 mm Sub-study: 8

and 18 months, 2-5

months: clinical and

angiographic; 6, 12

years: telephone

2.25 mm - 3.5 mm

clinical and

angiographic/

IVUS;6, 12 and 18

months, 2-5 years:

Angio/IVUS Sub-

study: 8 months:

telephone

US) and 9 months

38 mm Length Sub-

study: 30 days (R-

clinical visits

(preferred) or patient

Asia), 6, 12, 18

contact 30 days (R-

RESOLUTE US* RESOLUTE AC

Follow-up 2.25 mm - 3.5 mm

60-month follow-up is

complete

at 2, 3, 4, 5 years

months then annually

complete.

551 subjects qualified

for 18-month follow-

Status 60-month follow-up is

Sub-study)

RESOLUTE

INTEGRITY US (XL

Study

(PEG)

RESOLUTE

RESOLUTE INTEGRITY US Post-Market

INTEGRITY US

38 mm Cohort

RESOLUTE Asia

RESOLUTE Japan

RESOLUTE FIM

RESOLUTE Int

Table 8-2: RESOLUTE and RESOLUTE INTEGRITY clinical trials overview

Global RESOLUTE Clinical Trial Program

RESOLUTE US* RESOLUTE AC

The term ‘AC’ refers to All-Comers.

* The RESOLUTE US trial is composed of 4 studies. The 2.5 mm - 3.5 mm subset of the Main Study, the 2.25 mm – 3.5 mm Angio/IVUS Sub-study, the 38 mm Length Sub-study, and the 4.0mm

The term ‘Int’ refers to International. 3 The term ‘FIM’ refers to First-In-Man.

Sub-study have historical control designs. The 2.25 mm Subset outcomes were compared to a performance goal.

)

9 Clinical outcomes

9.1 Clinical outcomes for RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study and RESOLUTE ONYX 2.0 mm Clinical Study

Table 9-1: Resolute Onyx clinical outcomes

RESOLUTE ONYX 2.0 mm

Clinical Study

(N=101 subjects N=104 lesions)

%(m/n)1

Safety and effectiveness measures

RESOLUTE ONYX Core (2.25 mm - 4.0 mm)

Clinical Study

(N=75 subjects N=85 lesions) %(m/n)1

In-hospital

Target lesion failure (TLF

Target vessel failure (TVF)3

MACE4 Cardiac death or target vessel MI (TVMI)5

Death or TVMI

Death

Cardiac death

Non-cardiac death

TVMI (extended historical definition)6

Clinically-driven TLR7

Clinically-driven TVR8

Stent thrombosis (ARC) definite/probable9

4.0% (3/75)

2.7% (2/75)

0.0% (0/75)

2.7% (2/75)

1.3% (1/75)

30 days

MACE

4.0% (3/75)

Follow-up (12-months)

Target lesion failure (TLF

Target vessel failure (TVF

MACE4

9.3% (7/75) 5.0% (5/101)

14.7% (11/75) 5.0% (5/101)

13.3% (10/75) 5.0% (5/101)

2.0% (2/101)

0.0% (0/101)

2.0% (2/101)

0.0% (0/101)

2.0% (2/101)

Cardiac death or target vessel MI (TVMI)5 4.0% (3/75) 3.0% (3/101)

Death or TVMI 6.7% (5/75) 3.0% (3/101)

Death 2.7% (2/75) 0.0% (0/101)

Cardiac death 0.0% (0/75) 0.0% (0/101)

Non-cardiac death 2.7% (2/75) 0.0% (0/101)

TVMI (extended historical definition) 6 4.0% (3/75) 3.0% (3/101)

Clinically-driven TLR7 5.3% (4/75) 2.0% (2/101)

Clinically-driven TVR8 10.7% (8/75) 2.0% (2/101)

Stent thrombosis (ARC) definite/probable9 1.3% (1/75) 0.0% (0/101)

Early thrombosis (30 days) 1.3% (1/75) 0.0% (0/100)

Late thrombosis (31-360 days) 0.0% (0/75) 0.0% (0/101)

Latest follow-up (36-months)

Target lesion failure (TLF

14.7% (11/75) 13.9% (14/101)

)

Table 9-1: Resolute Onyx clinical outcomes

RESOLUTE ONYX Core (2.25 mm - 4.0 mm)

Safety and effectiveness measures

(N=75 subjects N=85 lesions) %(m/n)1

Target vessel failure (TVF

MACE4 Cardiac death or target vessel MI (TVMI)5 9.3% (7/75) 5.9% (6/101)

Death or TVMI 14.7% (11/75) 6.9% (7/101)

Death 8.0% (6/75) 3.0% (3/101)

Cardiac death 2.7% (2/75) 2.0% (2/101)

Non-cardiac death 5.3% (4/75) 1.0% (1/101)

TVMI (extended historical definition) 6 8.0% (6/75) 4.0% (4/101)

Clinically-driven TLR7 8.0% (6/75) 7.9% (8/101)

Clinically-driven TVR8 13.3% (10/75) 10.9% (11/101)

Stent thrombosis (ARC) definite/probable9 1.3% (1/75) 0.0% (0/101)

Early thrombosis (30 days) 1.3% (1/75) 0.0% (0/101)

Late thrombosis (31-360 days) 0.0% (0/75) 0.0% (0/101)

Very late thrombosis (>360 days) 0.0% (0/75) 0.0% (0/101)

Clinical Study

18.7% (14/75) 14.9% (15/101)

21.3% (16/75) 14.9% (15/101)

RESOLUTE ONYX 2.0 mm

Clinical Study

(N=101 subjects N=104 lesions)

%(m/n)1

Table 9-1: Resolute Onyx clinical outcomes

RESOLUTE ONYX 2.0 mm

Clinical Study

(N=101 subjects N=104 lesions)

%(m/n)1

Safety and effectiveness measures

Notes

N = The total number of subjects enrolled.

RESOLUTE ONYX Core (2.25 mm - 4.0 mm)

Clinical Study

(N=75 subjects N=85 lesions) %(m/n)1

The numbers are % (count/number of eligible subjects). Subjects are only counted once for each time period. NA = Not applicable; variable and/or time point not calculated In-hospital is defined as hospitalization less than or equal to the discharge date 12-month timeframe includes follow-up window (360 days ± 30 days). 36-month timeframe includes follow-up window (1080 days ± 30 days).

Target lesion failure (TLF) is defined as any cardiac death, clinically-driven target lesion revascularization by PCI or CABG or target vess

MI.

Target vessel failure (TVF) is defined as any cardiac death, clinically-driven target vessel revascularization by PCI or CABG or target

vessel MI.

Major adverse cardiac events (MACE) is defined as composite of death, MI (Q wave and non-Q wave), emergent bypass surgery, or clinically-driven target lesion revascularization (repeat PTCA or CABG).

Cardiac death/TVMI is defined as cardiac death or myocardial infarction not clearly attributable to a non-target vessel.

TVMI is composed of both Q wave and non-Q wave MI which are not clearly attributable to a non-target vessel.

Q wave MI defined when any occurrence of chest pain or other acute symptoms consistent with myocardial ischemia and new pathological Q waves in two or more contiguous ECG leads as determined by an ECG core laboratory or independent review of the CEC, in the absence of timely cardiac enzyme data, or new pathologic Q waves in two or more contiguous ECG leads as determined by an ECG core laboratory or independent review of the CEC and elevation of cardiac enzymes. In the absence of ECG data the CEC may adjudicate Q wave MI based on the clinical scenario and appropriate cardiac enzyme data. Non-Q Wave MI is defined as elevated CK  2X the upper laboratory normal with the presence of elevated CK-MB (any amount above the institution’s upper limit of normal) in the absence of new pathological Q waves. [Note: Periprocedural MIs (events <48 hours post-PCI) that did not fulfill the criteria for Q-wave MI are included in Non-Q Wave MI category. Periprocedural MIs did not require clinical symptoms or ECG evidence of myocardial ischemia, and in the absence of CK measurements, were based on an elevated CKMB > 3 X the upper laboratory normal, an elevated troponin > 3 X the upper laboratory normal, or CEC adjudication of the clinical scenario.]

Target lesion revascularization (TLR) is defined as a clinically-driven repeat intervention of the target lesion by PCI or CABG

Target vessel revascularization (TVR) is defined as any clinically-driven repeat intervention of the target vessel by PCI or CABG.

Academic Research Consortium (ARC) stent thrombosis is defined as follows.

1. Definite ST is considered to have occurred after intracoronary stenting by either angiographic or pathologic confirmation of stent thrombosis.

2. Probable ST is considered to have occurred after intracoronary stenting in the following cases: Any unexplained death within the first 30 days following stent implantation. Irrespective of the time after the index procedure, any MI which is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of ST and in the absence of any other obvious cause

See Section 10 - Clinical studies for a more complete description of the trial designs and results

The Global RESOLUTE Clinical Trial Program has evaluated the performance of the Resolute stent in subjects, including those with diabetes mellitus, with symptomatic ischemic heart disease in de novo lesions of native coronary arteries. The RESOLUTE INTEGRITY US Post-Market Approval Study assessed the safety and efficacy of the Resolute Integrity stent for the treatment of de novo lesions in native coronary arteries. Clinical outcomes are shown in Table 9-2 below.

Table 9-2: Clinical outcomes from post-procedure through latest available follow-up

38 mm Length

RESOLUTE

Resolute

(N = 1402)

RESOLUTE AC RESOLUTE Int

Resolute

(N = 1140)

Xience

TM*

(N = 1152)

Resolute

(N = 2349)

In-hospital

TLF 1.3% (18/1402)

TVF

1.3% (18/1402)

MACE 1.3% (18/1402)

Total Death 0.0% (0/1402)

Cardiac death

Non-cardiac death

TVMI

0.0% (0/1402)

1.1% (16/1402)

Q wave MI 0.1% (1/1402)

Non-Q wave

MI Cardiac death

or TVMI Clinically-driven

TVR

1.1% (15/1402)

1.1% (16/1402)

0.1% (2/1402)

TLR 0.1% (2/1402)

Non-TL TVR 0.0% (0/1402)

ARC Def/Prob ST

0.0% (0/1402)

3.7%

(42/1140)

3.8%

(43/1140)

3.8%

(43/1140)

0.1%

(1/1140)

0.1%

(1/1140)

0.0%

(0/1140)

3.1%

(35/1140)

0.3%

(3/1140)

2.8%

(32/1140)

3.2%

(36/1140)

0.9%

(10/1140)

0.7%

(8/1140)

0.4%

(4/1140)

0.6%

(7/1140)

(52/1152)

(54/1152)

(56/1152)

(9/1152)

(7/1152)

(2/1152)

(42/1152)

(5/1152)

(37/1152)

(46/1152)

(10/1152)

(8/1152)

(2/1152)

(4/1152)

4.5%

4.7%

4.9%

0.8%

0.6%

0.2%

3.6%

0.4%

3.2%

4.0%

0.9%

0.7%

0.2%

0.3%

2.6% (61/2349) 4.3% (6/139) 2.0% (2/100) 3.6% (8/223) 1.7% (4/230) 1.8% (1/56)

2.7% (63/2349) 4.3% (6/139) 2.0% (2/100) 3.6% (8/223) 1.7% (4/230) 1.8% (1/56)

0.3% (7/2349) 0.0% (0/139) 0.0% (0/100) 0.4% (1/223) 0.0% (0/230) 0.0% (0/56)

0.3% (6/2349) 0.0% (0/139) 0.0% (0/100) 0.4% (1/223) 0.0% (0/230) 0.0% (0/56)

0.0% (1/2349) 0.0% (0/139) 0.0% (0/100) 0.0% (0/223) 0.0% (0/230) 0.0% (0/56)

2.2% (51/2349) 4.3% (6/139) 2.0% (2/100) 3.1% (7/223) 1.7% (4/230) 1.8% (1/56)

0.3% (8/2349) 0.0% (0/139) 0.0% (0/100) 0.4% (1/223) 0.0% (0/230) 0.0% (0/56)

1.8% (43/2349) 4.3% (6/139) 2.0% (2/100) 2.7% (6/223) 1.7% (4/230) 1.8% (1/56)

2.4% (56/2349) 4.3% (6/139) 2.0% (2/100) 3.6% ((8/223) 1.7% (4/230) 1.8% (1/56)

0.4% 10/2349) 0.0% (0/139) 0.0% (0/100) 0.0% (0/223) 0.4% (1/230) 0.0% (0/56)

0.4% (10/2349) 0.0% (0/139) 0.0% (0/100) 0.0% (0/223) 0.4% (1/230) 0.0% (0/56)

0.0% (1/2349) 0.0% (0/139) 0.0% (0/100) 0.0% (0/223) 0.0% (0/230) 0.0% (0/56)

0.4% (9/2349) 0.0% (0/139) 0.0% (0/100) 0.4% (1/223) 0.0% (0/230) 1.8% (1/56)

30 days

MACE

1.4%

(20/1399)

4.4%

(50/1133)

5.2%

(60/1146)

3.3%

(78/2345)

12 months

TLF 4.7% (65/1390)

TVF 6.2% (86/1390)

MACE 5.5% (77/1390)

Total death 1.4% (19/1390)

Cardiac death

Non-cardiac death

0.7% (10/1390)

0.6% (9/1390)

8.1%

(92/1132)

8.9%

(101/1132)

8.6%

(97/1132)

1.6%

(18/1132)

1.3%

(15/1132)

0.3%

(3/1132)

8.5%

(97/1142)

9.7%

(111/1142)

9.8%

(112/1142)

2.7%

(31/1142)

1.7%

(19/1142)

1.1%

(12/1142)

7.1%

(165/2337)

7.7%

(180/2337)

8.3%

(193/2337)

2.4% (57/2337) 2.2% (3/139) 1.0% (1/100) 0.9% (2/222) 1.8% (4/226) 1.8% (1/56)

1.5% (34/2337) 0.7% (1/139) 0.0% (0/100) 0.9% (2/222) 1.3% (3/226) 1.8% (1/56)

1.0% (23/2337) 1.4% (2/139) 1.0% (1/100) 0.0% (0/222) 0.4% (1/226) 0.0% (0/56)

RESOLUTE

FIM

RESOLUTE

Japan

Sub-study

R-US N = 114

RESOLUTE INTEGRITY US

R-Asia N = 109

RESOLUTE

Resolute (N = 139)

Resolute (N = 100)

Resolute (N = 223)

Resolute

Integrity (PEG)

(N=230)

INTEGRITY

US (XL

Sub-study)

(N=56)

4.3% (6/139) 3.0% (3/100)

4.5%

(10/223)

3.0% (7/230) 3.6% (2/56)

7.2% (10/139) 4.0% (4/100) 5.4% (12/222) 4.9% (11/226) 7.1% (4/56)

7.2% (10/139) 5.0% (5/100) 6.8% (15/222) 7.1% (16/226) 7.1% (4/56)

8.6% (12/139) 5.0% (5/100) 6.3% (14/222) 5.8% (13/226) 8.9% (5/56)

Table 9-2: Clinical outcomes from post-procedure through latest available follow-up

TVMI 1.3% (18/1390)

Q wave MI

Non-Q wave

MI Cardiac death

or TVMI Clinically-driven

TVR

TLR 2.9% (40/1390)

Non-TL TVR 2.2% (30/1390)

ARC Def/Prob ST

Latest followup

TLF

TVF

MACE

Total death

Cardiac death

Non-cardiac death

TVMI

Q wave MI

Non-Q wave

Cardiac death or TVMI

Clinically-driven TVR

TLR 6.5% (86/1329)

RESOLUTE

Resolute

(N = 1402)

RESOLUTE AC RESOLUTE Int

Resolute

(N = 1140)

4.2%

(48/1132)

0.1% (2/1390)

1.2% (16/1390)

2.0% (28/1390)

4.6% (64/1390)

0.8%

(9/1132)

3.5%

(40/1132)

5.3%

(60/1132)

4.9%

(55/1132)

3.9%

(44/1132)

1.9%

(21/1132)

0.1% (2/1390)

1.6%

(18/1132)

60 months 60 months 36 months 60 months 60 months 60 months 24 months 36 months

12.3%

(164/1329)

17.5%

(233/1329)

18.0%

(239/1329)

9.6%

(127/1329)

4.1% (55/1329)

5.4% (72/1329)

3.2% (43/1329)

0.4% (5/1329)

2.9% (38/1329)

6.7% (89/1329)

12.5%

(166/1329)

17.0%

(191/1123)

20.0%

(225/1123)

21.9%

(246/1123)

11.0%

(123/1123)

6.5%

(73/1123)

4.5%

(50/1123)

5.7%

(64/1123)

1.3%

(15/1123)

4.6%

(52/1123)

11.5%

(129/1123)

11.4%

(128/1123)

7.8%

(88/1123)

Xience

TM*

(N = 1152)

4.2%

(48/1142)

0.4%

(5/1142)

3.8%

(43/1142)

5.5%

(63/1142)

4.8%

(55/1142)

3.4%

(39/1142)

2.2%

(25/1142)

0.7%

(8/1142)

16.2%

(183/1133)

19.1%

(216/1133)

21.6%

(245/1133)

10.8%

(122/1133)

5.7%

(65/1133)

5.0%

(57/1133)

5.7%

(65/1133)

0.8%

(9/1133)

4.9%

(56/1133)

10.6%

(120/1133)

10.9%

(123/1133)

7.1%

(81/1133)

38 mm Length

RESOLUTE

FIM

RESOLUTE

Japan

Sub-study

R-US N = 114

RESOLUTE INTEGRITY US

R-Asia N = 109

RESOLUTE

Resolute

(N = 2349)

Resolute (N = 139)

Resolute (N = 100)

Resolute (N = 223)

Resolute

Integrity (PEG)

(N=230)

INTEGRITY

US (XL

Sub-study)

(N=56)

3.0% (71/2337) 5.8% (8/139) 4.0% (4/100) 3.6% (8/222) 2.2% (5/226) 5.4% (3/56)

0.5% (12/2337) 0.0% (0/139) 0.0% (0/100) 0.9% (2/222) 0.0% (0/226) 1.8% (1/56)

2.5% (59/2337) 5.8% (8/139) 4.0% (4/100) 2.7% (6/222) 2.2% (5/226) 3.6% (2/56)

4.2% (99/2337) 6.5% (9/139) 4.0% (4/100) 4.5% (10/222) 3.5% (8/226) 7.1% (4/56)

4.2% (99/2337) 0.7% (1/139) 1.0% (1/100) 2.7% (6/222) 4.4% (10/226) 1.8% (1/56)

3.5% (81/2337) 0.7% (1/139) 0.0% (0/100) 1.4% (3/222) 2.2% (5/226) 1.8% (1/56)

1.2% (27/2337) 0.0% (0/139) 1.0% (1/100) 1.4% (3/222) 2.2% (5/226) 0.0% (0/56)

0.9% (20/2337) 0.0% (0/139) 0.0% (0/100)

11.4%

(261/2284)

12.9%

(294/2284)

14.4%

(329/2284)

6.1%

(139/2284)

11.0% (15/136) 6.1% (6/98)

13.2% (18/136) 10.2% (10/98)

16.2% (22/136) 14.3% (14/98)

6.6% (9/136) 7.1% (7/98)

3.6% (82/2284) 1.5% (2/136) 1.0% (1/98)

2.5% (57/2284) 5.1% (7/136) 6.1% (6/98)

0.9% (2/222)

13.8%

(30/217)

(37/217)

(38/217)

6.5% (14/217)

4.1% (9/217))

2.3% (5/217)

17.1%

17.5%

0.9% (2/226) 1.8% (1/56)

9.1% (20/219)

12.3% (27/219)

11.0% (24/219)

10.7% (6/56)

12.5% (7/56)

17.9%

(10/56)

2.7% (6/219) 3.6% (2/56)

1.8% (4/219) 1.8% (1/56)

0.9% (2/219) 1.8% (1/56)

3.9% (89/2284) 6.6% (9/136) 4.1% (4/98) 6.0% (13/217) 4.1% (9/219) 5.4% (3/56)

0.9% (20/2284) 0.0% (0/136) 0.0% (0/98) 0.9% (2/217) 0.9% (2/219) 1.8% (1/56)

3.0% (69/2284) 6.6% (9/136) 4.1% (4/98) 5.1% (11/217) 3.2% (7/219) 3.6% (2/56)

(161/2284)

(168/2284)

(130/2284)

7.0%

7.4%

5.7%

8.1% (11/136) 5.1% (5/98) 8.8% (19/217) 5.9% (13/219) 7.1% (4/56)

5.1% (7/136) 5.1% (5/98) 9.7% (21/217) 8.2% (18/219) 7.1% (4/56)

2.9% (4/136) 1.0% (1/98) 6.0% (13/217) 5.0% (11/219) 5.4% (3/56)

Table 9-2: Clinical outcomes from post-procedure through latest available follow-up

38 mm Length

RESOLUTE

RESOLUTE AC RESOLUTE Int

RESOLUTE

FIM

RESOLUTE

Japan

Sub-study

R-US N = 114

RESOLUTE INTEGRITY US

R-Asia N = 109

RESOLUTE

Non-TL TVR

ARC Def/Prob ST

Resolute

(N = 1402)

8.1%

(107/1329)

0.5% (7/1329)

Resolute

(N = 1140)

6.1%

(68/1123)

2.4%

(27/1123)

Xience

TM*

(N = 1152)

6.1%

(69/1133)

1.7%

(19/1133)

Resolute

(N = 2349)

Resolute (N = 139)

Resolute (N = 100)

Resolute (N = 223)

2.6% (59/2284) 2.2% (3/136) 4.1% (4/98) 3.7% (8/217) 4.1% (9/219) 5.4% (3/56)

1.1% (26/2284) 0.0% (0/136) 0.0% (0/98) 1.4% (3/217) 1.8% (4/219) 1.8% (1/56)

Resolute

Integrity (PEG)

(N=230)

INTEGRITY

Sub-study)

Notes

N = The total number of subjects enrolled. The numbers are % (count/number of eligible subjects). Subjects are only counted once for each time period. The definitions of the outcomes are presented as table notes to Table 9-1. In-hospital is defined as hospitalization less than or equal to the discharge date. 12-month timeframe includes follow-up window (360 days ± 30 days). 24-month timeframe includes follow-up window (720 days ±30 days). 36-month timeframe includes follow-up window (1080 days ± 30 days). 60-month timeframe includes follow-up window (1800 days ± 30 days).

Primary Enrollment Group consisted of 1402 subjects, including 1242 subjects in the 2.25 mm - 3.5 mm Main Study, 100 subjects in the 2.25 mm - 3.5 mm

Angio/IVUS Sub-study and 60 subjects in the 4.0 mm Sub-study. The Primary Enrollment Group does not include the 38 mm Length Sub-study.

In the RESOLUTE All-Comers (R-AC) trial, a randomized trial comparing the Resolute ZES

TM*

with the Xience V

EES for treatment of patients with coronary lesions who had minimal exclusion criteria, there were similar safety and efficacy outcomes between the 2 stents. Through 5 years of follow-up, the clinical effectiveness of the Resolute ZES was sustained in the complex and non-complex cohorts as shown in Table 9-3, Table 9-4, and Table 9-5 below.

Table 9-3: R-AC Clinical outcomes (complex cohort)

Complex cohort

Composite safety and effectiveness

Resolute

(N = 764)

12 months 60 months

(N = 756)

TM*

Resolute (N = 764)

Xience V

(N = 756)

TM*

US (XL

(N=56)

TLF 8.8% (67/760) 10.0% (75/750) 18.2% (137/751) 18.4% (137/745)

TVF 9.7% (74/760) 11.3% (85/750) 22.1% (166/751) 21.3% (159/745)

MACE 9.1% (69/760) 11.7% (88/750) 22.5% (169/751) 24.6% (183/745)

Effectiveness

Clinically-driven TVR 5.5% (42/760) 5.6% (42/750) 13.4% (101/751) 11.7% (87/745)

TLR 4.3% (33/760) 4.1% (31/750) 8.9% (67/751) 8.1% (60/745)

TLR, PCI 3.9% (30/760) 3.2% (24/750) 8.1% (61/751) 6.7% (50/745)

TLR, CABG 0.4% (3/760) 1.1% (8/750) 1.2% (9/751) 1.7% (13/745)

Safety

Total death 1.4% (11/760) 3.3% (25/750) 10.4% (78/751) 13.2% (98/745)

Table 9-3: R-AC Clinical outcomes (complex cohort)

Complex cohort

Composite safety and effectiveness

Resolute

(N = 764)

Cardiac death 1.3% (10/760) 2.1% (16/750) 6.4% (48/751) 7.4% (55/745)

Non-cardiac death 0.1% (1/760) 1.2% (9/750) 4.0% (30/751) 5.8% (43/745)

Cardiac death or TVMI 5.4% (41/760) 6.4% (48/750) 11.9% (89/751) 12.2% (91/745)

TVMI

4.2% (32/760) 4.7% (35/750) 5.9% (44/751) 6.0% (45/745)

Q wave MI 0.7% (5/760) 0.5% (4/750) 1.3% (10/751) 0.9% (7/745)

Non-Q wave MI 3.7% (28/760) 4.1% (31/750) 4.8% (36/751) 5.1% (38/745)

Stent thrombosis ARC defined

Definite/probable 1.7% (13/759) 0.9% (7/749) 2.5% (19/751) 2.0% (15/745)

Definite 1.2% (9/759) 0.4% (3/749) 1.7% (13/751) 0.9% (7/745)

Probable 0.7% (5/759) 0.5% (4/749) 0.9% (7/751) 1.1% (8/745)

Notes

N = The total number of subjects enrolled. Subjects are only counted once for each time period. Numbers are % (count/number of eligible subjects). The definitions of the outcomes are presented as table notes to Table 9-1. 12-month timeframe includes follow-up window (360 ± 30 days). 60-month timeframe includes follow-up window (1800 days ± 30 days). Complex was defined as having one or more of the following patient or lesion characteristics: bifurcation, bypass graft, in stent restenosis, AMI < 72 hr., LVEF < 30%, unprotected left main, >2 vessels stented, renal insufficiency or failure (serum creatinine >2.5 mg/dl), lesion length > 27 mm, > 1 lesion per vessel, lesion with thrombus or total occlusion (pre procedure TIMI = 0).

12 months 60 months

(N = 756)

TM*

Resolute (N = 764)

Xience V

(N = 756)

TM*

Table 9-4: R-AC clinical outcomes (non-complex cohort)

Non-complex cohort

Composite safety and effectiveness

Resolute (N = 376)

12 months

Xience V

(N = 396)

TM*

Resolute (N = 376)

TLF 6.7% (25/372) 5.6% (22/392) 14.5% (54/372) 11.9% (46/388)

TVF 7.3% (27/372) 6.6% (26/392) 15.9% (59/372) 14.7% (57/388)

MACE 7.5% (28/372) 6.1% (24/392) 20.7% (77/372) 16.0% (62/388)

Effectiveness

Clinically-driven TVR 3.5% (13/372) 3.3% (13/392) 7.3% (27/372) 9.3% (36/388)

TLR 3.0% (11/372) 2.0% (8/392) 5.6% (21/372) 5.4% (21/388)

TLR, PCI 2.2% (8/372) 1.8% (7/392) 4.3% (16/372) 4.6% (18/388)

TLR, CABG 0.8% (3/372) 0.3% (1/392) 1.9% (7/372) 0.8% (3/388)

Safety

Total death 1.9% (7/372) 1.5% (6/392) 12.1% (45/372) 6.2% (24/388)

Cardiac death 1.3% (5/372) 0.8% (3/392) 6.7% (25/372) 2.6% (10/388)

60 months

Xience V

(N = 396)

TM*

Table 9-4: R-AC clinical outcomes (non-complex cohort)

Non-complex cohort

Composite safety and effectiveness

Resolute (N = 376)

12 months

Xience V

(N = 396)

TM*

Resolute (N = 376)

60 months

Xience V

(N = 396)

TM*

Non-cardiac death 0.5% (2/372) 0.8% (3/392) 5.4% (20/372) 3.6% (14/388)

Cardiac death or TVMI 5.1% (19/372) 3.8% (15/392) 10.8% (40/372) 7.5% (29/388)

TVMI

4.3% (16/372) 3.3% (13/392) 5.4% (20/372) 5.2% (20/388)

Q wave MI 1.1% (4/372) 0.3% (1/392) 1.3% (5/372) 0.5% (2/388)

Non-Q wave MI 3.2% (12/372) 3.1% (12/392) 4.3% (16/372) 4.6% (18/388)

Stent thrombosis ARC defined

Definite/probable 1.3% (5/372) 0.3%(1/392) 2.2% (8/372) 1.0% (4/388)

Definite 1.1% (4/372) 0.0%(0/392) 1.3% (5/372) 0.5% (2/388)

Probable 0.3% (1/372) 0.3%(1/392) 0.8% (3/372) 0.5% (2/388)

Notes

N = The total number of subjects enrolled. Subjects are only counted once for each time period. Numbers are % (count/number of eligible subjects). The definitions of the outcomes are presented as table notes to Table 9-1. 12-month timeframe includes follow-up window (360± 30 days). 60-month timeframe includes follow-up window (1800 days ± 30 days). Complex was defined as having one or more of the following patient or lesion characteristics: bifurcation, bypass graft, in stent restenosis, AMI < 72 hr., LVEF < 30%, unprotected left main, >2 vessels stented, renal insufficiency or failure (serum creatinine > 2.5 mg/dl), lesion length > 27 mm, > 1 lesion per vessel, lesion with thrombus or total occlusion (pre procedure TIMI = 0).

Table 9-5: R-AC ARC defined definite/probable stent thrombosis through 60 months

(all subjects, and complex and non-complex subjects)

All Subjects Non-complex Complex

Cumulative stent thrombosis

Resolute

Xience V

(N = 1140)

TM*

(N = 1152)

Resolute (N = 376)

Xience V

1.6% (18/1132) 0.7% (8/1142) 1.3% (5/372) 0.3% (1/392) 1.7% (13/760) 0.9% (7/750)

(N = 396)

TM*

Resolute (N = 764)

Xience V

(N = 756)

TM*

through 1-Year

Cumulative stent thrombosis through 5 -Years

2.4% (27/1123) 1.7% (19/1133) 2.2% (8/372) 1.0% (4/388) 2.5% (19/751) 2.0% (15/745)

Acute (0 - 1 day) 0.4% (5/1123) 0.2% (2/1133) 0.3% (1/372) 0.0% (0/388) 0.5% (4/751) 0.3% (2/745)

Subacute (2 - 30 days) 0.7% (8/1123) 0.4% (4/1133) 0.3% (1/372) 0.3% (1/388) 0.9% (7/751) 0.4% (3/745)

Late (31 – 360 days) 0.6% (7/1123) 0.2% (2/1133) 0.8% (3/372) 0.0% (0/388) 0.5% (4/751) 0.3% (2/745)

Very Late (361 – 1800 days) 0.8% (9/1123) 1.0% (11/1133) 0.8% (3/372) 0.8% (3/388) 0.8% (6/751) 1.1% (8/745)

Notes

N = The total number of subjects enrolled. Subjects are only counted once for each time period. Numbers are % (count/number of eligible subjects). 12-month timeframe includes follow-up window (360 ± 30 days) 60-month timeframe includes follow-up window (1800 days ± 30 days). Complex was defined as having one or more of the following patient or lesion characteristics: bifurcation, bypass graft, in stent restenosis, AMI < 72 hr., LVEF <30%, unprotected left main, >2 vessels stented, renal insufficiency or failure (serum creatinine > 2.5 mg/dl), lesion length > 27 mm, > 1 lesion per vessel, lesion with thrombus or total occlusion (pre procedure TIMI = 0).

9.2 Potential adverse events

9.2.1 Potential adverse events related to zotarolimus

Patients’ exposure to zotarolimus is directly related to the total amount of stent length implanted. The actual side effects/complications that may be associated with the use of zotarolimus are not fully known. The adverse events that have been associated with the intravenous injection of zotarolimus in humans include but are not limited to:

x Anemia x Diarrhea x Dry skin x Headache x Hematuria x Infection x Injection site reaction x Pain (abdominal, arthralgia, injection site) x Rash

9.2.2 Potential adverse events related to BioLinx polymer

Although the type of risks of the BioLinx

those of other stent coatings, the potential for these risks are currently unknown as the coating has limited previous use in humans. These risks may include but are not limited to the following:

polymer coating are expected to be no different than

x Allergic reaction x Focal inflammation at the site of stent implantation x Restenosis of the stented artery

9.2.3 Potential risks associated with percutaneous coronary diagnostic and treatment procedures

Other risks associated with using this device are those associated with percutaneous coronary diagnostic (including angiography and IVUS) and treatment procedures. These risks (in alphabetical order) may include but are not limited to the following:

x Abrupt vessel closure x Access site pain, hematoma, or hemorrhage x Allergic reaction (to contrast, antiplatelet therapy, stent material, or drug and polymer

coating)

x Aneurysm, pseudoaneurysm, or arteriovenous fistula (AVF) x Arrhythmias, including ventricular fibrillation x Balloon rupture x Bleeding x Cardiac tamponade x Coronary artery occlusion, perforation, rupture, or dissection x Coronary artery spasm x Death x Embolism (air, tissue, device, or thrombus) x Emergency surgery: peripheral vascular or coronary bypass x Failure to deliver the stent x Hemorrhage requiring transfusion x Hypotension or hypertension x Incomplete stent apposition x Infection or fever x Myocardial infarction (MI) x Pericarditis

x Peripheral ischemia or peripheral nerve injury x Renal failure x Restenosis of the stented artery x Shock or pulmonary edema x Stable or unstable angina x Stent deformation, collapse, or fracture x Stent migration or embolization x Stent misplacement x Stroke or transient ischemic attack x Thrombosis (acute, subacute, or late)

10 Clinical studies

10.1 Results of the RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study

Primary objective: The purpose of this study was to assess the safety and efficacy of the Resolute

Onyx zotarolimus-eluting coronary stent system for the treatment of de novo lesions in native coronary arteries with a reference vessel diameter of 2.25 mm to 4.2 mm.

Design: The Medtronic RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study is a single arm, open label, multi-center trial that enrolled 75 subjects with ischemic heart disease attributable to stenotic lesions of the native coronary arteries that are amenable to percutaneous treatment with stenting. Subjects may have received treatment of one or two lesions with stent diameters 2.25 mm -

4.0 mm, one lesion per target vessel, for a maximum of two target vessels. Only one lesion may have been treated in a single target vessel. All treatments with the study stents were to be performed during a single index procedure. All enrolled subjects had an 8 month angiogram to assess late lumen loss. The first 20 subjects were to also undergo an IVUS assessment at baseline and 8 months.

Primary endpoint: In-stent late lumen loss (LL) at 8-months post-procedure as measured by quantitative coronary angiography (QCA).

Follow-up was performed at 30 days, 6, and 8 months, and annually out to 3 years. Following the index procedure, subjects were to be treated with aspirin indefinitely and clopidogrel/ticlopidine for a minimum of 6 months and up to 12 months in those who were not at a high risk of bleeding.

Demographics: The mean age was 66 years with 73.3% (55/75) of subjects being males. Of the subjects enrolled, 32.0% (24/75) had diabetes mellitus, 16.0% (12/75) were current smokers, 23.0% (17/74) had prior MI, 40.0% (30/75) had prior PCI, 73.3% (55/75) had hypertension, and 85.3% (64/75) reported hyperlipidemia. Baseline lesion characteristics include 49.3% (37/75) of subjects with LAD lesions, a mean lesion length of 14.28 ± 6.68 mm, and 85.9% (73/85) ACC/AHA type B2/C lesions. The mean RVD was 2.57 ± 0.48 mm and the percentage diameter stenosis was 62.98 ±

10.75%.

Results: The primary end point of in-stent late lumen loss (LL) at 8-months post-procedure as

measured by quantitative coronary angiography (QCA) demonstrated not only non-inferiority (p <

0.001), but also superiority (p = 0.027), when compared to the historical control in-stent late loss value from the RESOLUTE US Angio/IVUS Sub-study.

The RESOLUTE ONYX Core (2.25 mm to 4.0 mm) Clinical Study outcomes at 8-months are consistent with the 9 month clinical outcomes of the RESOLUTE US 2.25-3.5 mm Angio/IVUS Substudy that evaluated a similar patient population (with mandated angiographic follow up at 8 months). These analyses are based on the intent-to-treat population. The results are presented in the following tables:

x Table 10-1: RESOLUTE ONYX - primary endpoint analysis x Table 10-2: RESOLUTE ONYX - clinical and Angio / IVUS outcomes x Table 10-3: RESOLUTE ONYX - ARC defined definite/probable stent thrombosis through 8

months

Table 10-1: RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study – primary endpoint

analysis (non-inferiority test with propensity score adjustment)

Historical

control

Resolute

(N=100

subjects

N=104

lesions)

Difference:

RESOLUTE

ONYX Core

- historical control1

Upper

one-

sided

95% CI2

Non-

inferiority

margin

Non-

inferiority

P value

Superiority

Primary endpoint – In-

stent late lumen loss

at 8 months

RESOLUTE ONYX Core

(N=75

subjects

N=85

lesions)

Primary analysis with available data:

P value3

– ITT set 0.24 ± 0.05

(73)

– PP set

0.24 ± 0.05 (66)

0.36 ± 0.05 (93)

0.35 ± 0.05 (89)

-0.14 -0.02 0.20 < 0.001 0.027

-0.15 -0.02 0.20 < 0.001 0.027

Secondary analysis with multiple imputation:

– ITT set 0.23 ± 0.05 0.36 ± 0.05 -0.15 -0.03 0.20 < 0.001

– PP set 0.22 ± 0.05 0.35 ± 0.05 -0.16 -0.03 0.20 < 0.001

The Resolute Onyx Core measure non-inferiority of 8-month in-stent late lumen loss compared to 8-month in-stent late lumen loss of

the historical control All target lesions are included in the analysis. The treatment differences have been adjusted with propensity score quintile.

The CI is adjusted to propensity score, based on lesion-length, baseline RVD, age, sex, diabetes, history of MI, and worst Canadian

Cardiovascular Society Angina Class as the independent variables.

Superiority test was performed after non-inferiority was demonstrated.

0.023

Table 10-2: RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study – clinical and Angio /

IVUS outcomes

RESOLUTE ONYX

Safety measures (to 180 days)

Target lesion failure (TLF)

Target vessel failure (TVF)

MACE

Cardiac death or target vessel MI (TVMI)

Death or TVMI

Death

Cardiac death

Noncardiac death

TVMI (extended historical definition)

Clinically-driven TLR

Clinically-driven TVR

Stent thrombosis (ARC) definite/probable

Safety measures (to 240 days)

(N=75 subjects N=85 lesions)

%(m/n)1

5.3% (4/75)

8.0% (6/75)

2.7% (2/75)

4.0% (3/75)

1.3% (1/75)

0.0% (0/75)

1.3% (1/75)

2.7% (2/75)

5.3% (4/75)

1.3% (1/75)

Table 10-2: RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study – clinical and Angio /

IVUS outcomes

RESOLUTE ONYX

Target lesion failure (TLF)

Target vessel failure (TVF)

MACE

Cardiac death or target vessel MI (TVMI) 2.7% (2/75)

Death or TVMI 4.0% (3/75)

Death 1.3% (1/75)

Cardiac death 0.0% (0/75)

Non-cardiac death 1.3% (1/75)

TVMI (extended historical definition) 2.7% (2/75)

Clinically-driven TLR 4.0% (3/75)

Clinically-driven TVR 9.3% (7/75)

Stent thrombosis (ARC) definite/probable 1.3% (1/75)

Early thrombosis (30 days) 1.3% (1/75)

Late thrombosis (31-240 days) 0.0% (0/75)

Safety measures (to 1080 days)

Target lesion failure (TLF)

Target vessel failure (TVF)

MACE

Cardiac death or target vessel MI (TVMI)

Death or TVMI

Death

Cardiac death

Non-cardiac death 5.3% (4/75)

TVMI (extended historical definition) 8.0% (6/75)

Clinically-driven TLR 8.0% (6/75)

Clinically-driven TVR 13.3% (10/75)

Stent thrombosis (ARC) definite/probable 1.3% (1/75)

Early thrombosis (30 days) 1.3% (1/75)

Late thrombosis (31-240 days) 0.0% (0/75)

Very Late thrombosis (>360 days) 0.0% (0/75)

Angiography (8 months)

Percent diameter stenosis (% DS)

In-stent

n 73

Mean±SD

(N=75 subjects N=85 lesions)

%(m/n)1

6.7% (5/75)

12.0% (9/75)

9.3% (7/75)

14.7% (11/75)

18.7% (14/75)

21.3% (16/75)

9.3% (7/75)

14.7% (11/75)

8.0% (6/75)

2.7% (2/75)

15.56 ± 16.75

Table 10-2: RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study – clinical and Angio /

IVUS outcomes

RESOLUTE ONYX (N=75 subjects N=85 lesions)

%(m/n)1

Median (1Q, 3Q)

Min, max

In-segment

Mean±SD

Median (1Q, 3Q)

Min, max

Minimal lumen diameter (mm)

In-stent

Mean±SD

Median (1Q, 3Q)

Min, max

In-segment

Mean±SD

Median (1Q, 3Q)

Min, max

Late luminal loss (mm)

In-stent

Mean±SD

Median (1Q, 3Q)

Min, max

In-segment

Mean±SD

Median (1Q, 3Q)

Min, max

In-stent binary angiographic restenosis (BAR) rate

In-segment binary angiographic restenosis (BAR) rate

IVUS (8 months)

14.86 (5.26, 22.24)

-21.18, 82.89

25.84 ± 14.20

22.35 (17.71, 29.75)

4.99, 82.89

2.13 ± 0.55

2.14(1.80, 2.45)

0.45, 3.69

1.88 ± 0.49

1.89 (1.58, 2.19)

0.45, 3.10

0.24 ± 0.39

0.18 (0.03, 0.37)

-0.49, 2.06

0.16 ± 0.37

0.13 (-0.03, 0.29)

-0.65, 1.88

5.5% (4/73)

8.2% (6/73)

Incomplete stent apposition

Table 10-2: RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study – clinical and Angio /

IVUS outcomes

RESOLUTE ONYX (N=75 subjects N=85 lesions)

%(m/n)1

Persistent 10.0% (2/20)

Late 0.0% (0/20)

Neointimal hyperplastic volume (mm3 )

n 17

Mean±SD (N) 9.88 ± 9.38

Median (Q1,Q3) 6.80 (2.20, 18.10)

Min, max 0.00, 27.20

Percent volume obstruction

n 17

Mean±SD (N) 6.88 ± 8.00

Median (Q1,Q3) 4.52 (1.48, 8.79)

Min, max 0.00, 31.38

Effectiveness measures

Lesion success2

Device success3

Procedure success4

Numerator (m) is the number of subjects with the specific classification, denominator (n) is the number of subjects in the study group

100.0% (85/85)

96.0% (72/75)

with known values, and percentage (%) was calculated as 100 × (m/n).

The definitions of the outcomes are presented as table notes to Table 9-1.

The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI Flow 3 after the procedure, using any

percutaneous method.

The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI Flow 3 after the procedure, using the

assigned device only.

The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI Flow 3 after the procedure, using any

percutaneous method without the occurrence of MACE during the hospital stay. 8-month timeframe includes follow-up window (240 days ± 14 days). Extended historical definition of MI is used for all the composite endpoints.

Table 10-3: RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study – ARC defined

definite/probable stent thrombosis throu

Stent thrombosis

Early thrombosis (30 days)

Late thrombosis (31-360 days)

Very late thrombosis (>360 days)

Notes

N = The total number of subjects enrolled. Numbers are % (count/number of eligible subjects). Subjects are only counted once for each time period.

h 36 months

RESOLUTE ONYX

(N=75 subjects N=85 lesions)

%(m/n)1

1.3% (1/75)

0.0% (0/75)

Table 10-3: RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study – ARC defined

definite/probable stent thrombosis throu

36-month timeframe includes follow-up window (1080 days ± 30 days). See Table 9-1 for the definition of the ARC defined stent thrombosis.

h 36 months

RESOLUTE ONYX

(N=75 subjects N=85 lesions)

%(m/n)1

10.2 Results of the RESOLUTE ONYX 2.0 mm Clinical Study

Primary objective: The purpose of this study is to assess the safety and efficacy of the Resolute

Onyx zotarolimus-eluting coronary stent system for the treatment of de novo lesions in native coronary arteries that require the use of a 2.0 mm diameter stent.

Design: The Medtronic RESOLUTE ONYX 2.0 mm Clinical Study is a single arm, open label, multicenter trial that enrolled 101 subjects in the US and Japan with ischemic heart disease attributable to stenotic lesions of the native coronary arteries that are amenable to percutaneous treatment with stenting. Subjects may have received treatment of one or two lesions with stent diameter 2.0 mm, one lesion per target vessel, for a maximum of two target vessels. Only one lesion may have been treated in a single target vessel. All treatments with the study stents were to be performed during a single index procedure. The first 20 subjects were to undergo an angiogram assessment at 13 months.

Primary endpoint: Target lesion failure (TLF) at 12-months post-procedure, defined as cardiac death, target vessel myocardial infarction (TVMI) (Q wave or non-Q wave) or target lesion revascularization by percutaneous or surgical methods.

Follow-up w

as performed at 30 days, 6, 12, and 13 months, and annually out to 3 years. Following the index procedure, subjects were to be treated with aspirin indefinitely and clopidogrel/ticlopidine for a minimum of 6 months and up to 12 months in those who were not at a high risk of bleeding.

Demographics: The mean age was 67.3 years with 70.3% (71/101) of subjects being males. Of the subjects enrolled, 46.5% (47/101) had diabetes mellitus, 11.9% (12/101) were current smokers,

35.7% (35/98) had prior MI, 59.4% (60/101) had prior PCI, 82.2% (83/101) had hypertension, and

94.1% (95/101) reported hyperlipidemia. Baseline lesion characteristics include 36.6% (37/101) of subjects with LAD lesions, a mean lesion length of 12.59 ± 6.27mm, and 65.4% (68/104) ACC/AHA type B2/C lesions. The mean RVD was 1.91 ± 0.26 mm and the percentage diameter stenosis was

65.83 ± 10.89%.

Results: The rate of TLF in the ITT primary analysis set at 12 months was 5.0% (5/100), fulfilling the pre-specified performance criterion (upper 1-sided 95% CI of 10.2%, compared with the performance goal of 19%, p < 0.001). The primary endpoint was also analyzed by gender, resulting in a TLF rate of

7.0% (5/71) in male subjects and 0.0% (0/30) in female subjects.

These analyses are based on the intent-to-treat population. The results are presented in the following

tables:

x Table 10-4: RESOLUTE ONYX 2.0 mm - primary endpoint analysis x Table 10-5: RESOLUTE ONYX 2.0 mm - clinical and angiographic outcomes x Table 10-6: RESOLUTE ONYX 2.0 mm - ARC defined definite/probable stent thrombosis

through 12 months

x Table 10-7: RESOLUTE ONYX 2.0 mm – primary endpoint analysis by gender

Table 10-4: RESOLUTE ONYX 2.0 mm Clinical Study – primary endpoint analysis

Resolute Onyx 2.0mm

Primary endpoint - TLF at 12-month

(N = 101 subjects)

Primary analysis – with analysis lesion only 2

– ITT set 5.0% (5/100) 10.2% 19%

– PP set 2.2% (2/90) 6.8% 19%

Secondary analysis – with all lesions included 3

– ITT set 5.0% (5/100) 10.2% 19%

– PP set 2.2% (2/90) 6.8% 19%

The one-sided upper 95% CI is calculated by binomial (exact) distribution

The lesions with a Resolute Onyx 2.0 mm stent are included in the analysis. For 2 or more lesions with Resolute Onyx 2.0 mm stents

per subject, the lesion is randomly selected.

All target lesions are included in the analysis.

One-side upper 95% confidence interval1 Performance goal

Table 10-5: RESOLUTE ONYX 2.0 mm Clinical Study – clinical and angiographic outcomes

RESOLUTE ONYX 2.0 mm

(N=101 subjects

N=104 lesions)

Safety and effectiveness measures

Safety measures (to 180 days)

Target lesion failure (TLF)2 4.0% (4/101)

Target vessel failure (TVF)3 4.0% (4/101)

MACE4 4.0% (4/101)

Cardiac death or target vessel MI (TVMI) 3.0% (3/101)

Death or TVMI 3.0% (3/101)

Death 0.0% (0/101)

Cardiac death 0.0% (0/101)

Non-cardiac death 0.0% (0/101)

TVMI (extended historical definition) 3.0% (3/101)

Clinically-driven TLR 1.0% (1/101)

Clinically-driven TVR 1.0% (1/101)

Stent thrombosis (ARC) definite/probable 0.0% (0/101)

Safety measures (to 360 days)

Target lesion failure (TLF)2 5.0% (5/101)

Target vessel failure (TVF)3 5.0% (5/101)

MACE4 5.0% (5/101)

Cardiac death or target vessel MI (TVMI) 3.0% (3/101)

Death or TVMI 3.0% (3/101)

Death 0.0% (0/101)

Cardiac death 0.0% (0/101)

Non-cardiac death 0.0% (0/101)

TVMI (extended historical definition) 3.0% (3/101)

Clinically-driven TLR 2.0% (2/101)

Clinically-driven TVR 2.0% (2/101)

%(m/n)1

Table 10-5: RESOLUTE ONYX 2.0 mm Clinical Study – clinical and angiographic outcomes

RESOLUTE ONYX 2.0 mm

(N=101 subjects

N=104 lesions)

Safety and effectiveness measures

Stent thrombosis (ARC) definite/probable 0.0% (0/101)

Early thrombosis (30 days) 0.0% (0/101)

Late thrombosis (31-360 days) 0.0% (0/101)

Safety measures (up to 1080 days)

Target lesion failure (TLF)2 13.9% (14/101)

Target vessel failure (TVF)3 14.9% (15/101)

MACE4 14.9% (15/101)

Cardiac death or target vessel MI (TVMI) 5.9% (6/101)

Death or TVMI 6.9% (7/101)

Death 3.0% (3/101)

Cardiac death 2.0% (2/101)

Non-cardiac death 1.0% (1/101)

TVMI (extended historical definition) 4.0% (4/101)

Clinically-driven TLR 7.9% (8/101)

Clinically-driven TVR 10.9% (11/101)

Stent thrombosis (ARC) definite/probable 0.0% (0/101)

Early thrombosis (30 days) 0.0% (0/101)

Late thrombosis (31-360 days) 0.0% (0/101)

Very late thrombosis (>360 days) 0.0% (0/101)

Angiography (13 months)

Percent diameter stenosis (% DS)

In-stent

N 25

Mean±SD 22.49 ± 26.89

Median (Q1, Q3) 15.66 (9.57, 31.72)

Min, max -26.71, 100.00

In-segment

N 25

Mean±SD 37.92 ± 21.54

Median (Q1, Q3) 31.72 (23.54, 42.50)

Min, max 14.06, 100.00

Minimal lumen diameter (mm)

In-stent

N 25

Mean±SD 1.55 ± 0.52

Median (Q1, Q3) 1.63 (1.53, 1.81)

Min, max 0.00, 2.20

In-segment

N 25

%(m/n)1

Table 10-5: RESOLUTE ONYX 2.0 mm Clinical Study – clinical and angiographic outcomes

RESOLUTE ONYX 2.0 mm

(N=101 subjects

N=104 lesions)

Safety and effectiveness measures

Mean±SD 1.25 ± 0.46

Median (Q1, Q3) 1.44 (1.09, 1.52)

Min, max 0.00, 1.77

Late luminal loss (mm)

In-stent

N 25

Mean±SD 0.26 ± 0.48

Median (Q1, Q3) 0.06 (0.00, 0.33)

Min, max -0.42, 1.58

In-segment

N 25

Mean±SD 0.25 ± 0.41

Median (Q1, Q3) 0.21 (-0.08, 0.42)

Min, max -0.39, 1.30

In-stent binary angiographic restenosis (BAR) rate 12.0% (3/25)

In-segment binary angiographic restenosis (BAR) rate 20.0% (5/25)

Effectiveness measures

Lesion success5 99.0% (103/104)

Device success6 96.2% (100/104)

Procedure success7 97.0% (98/101)

Numerator (m) is the number of subjects with the specific classification, denominator (n) is the number of subjects in the study group

with known values, and percentage (%) was calculated as 100 × (m/n).

Cardiac death, target vessel myocardial infarction (Q wave and non-Q wave) or clinically-driven target lesion revascularization (TLR) by

percutaneous or surgical methods.

Cardiac death, target vessel myocardial infarction (Q wave and non-Q wave) or clinically-driven target vessel revascularization (TVR)

by percutaneous or surgical methods.

Defined as death, myocardial infarction (Q wave and non Q-wave), emergent coronary bypass surgery, or repeat target lesion

revascularization (clinically-driven/clinically-indicated) by percutaneous or surgical methods.

The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI flow 3 after the procedure, using any

percutaneous method.

The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI flow 3 after the procedure, using the

assigned device only.

The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI flow 3 after the procedure, using any percutaneous method without the occurrence of MACE during the hospital stay. Extended historical definition of MI is used for all the composite endpoints.

%(m/n)1

Table 10-6: RESOLUTE ONYX 2.0 mm Clinical Study – ARC defined definite/probable stent

thrombosis through 12 months

Stent thrombosis 0.0% (0/101)

Early thrombosis (30 days) 0.0% (0/101)

Late thrombosis (31-360 days) 0.0% (0/101)

RESOLUTE ONYX 2.0 mm

(N=101 subjects

N=104 lesions)

%(m/n)1

Table 10-7: RESOLUTE ONYX 2.0 mm - primary endpoint analysis by gender

Male

Primary endpoint

Target lesion failure to 12 months 7.0% (5/71) 0.0% (0/30)

(N = 71 subjects)

Female

(N = 30 subjects)

10.3 Subjects with diabetes mellitus in the RESOLUTE pooled analysis

Subjects with diabetes mellitus (DM) comprise an important patient subgroup that is at increased risk for cardiovascular morbidity and mortality (GSAP) was created with a pre-specified hypothesis to evaluate the safety and effectiveness of the Resolute stent to treat stenotic lesions in diabetic subjects with coronary artery disease. This section provides an overview of this plan and the results supporting the indication of the Resolute stent to treat coronary artery disease in subjects with diabetes mellitus.

Primary objective: To assess the safety and effectiveness of the Resolute zotarolimuseluting coronary stent system (Resolute stent) for the treatment of de novo lesions in native coronary arteries in patients with DM with a reference vessel diameter (RVD) of 2.25 mm to

4.2 mm.

Population: The study population for the GSAP was selected by combining subjects with DM from the Global RESOLUTE Clinical Trial Program. The study population selected for this analysis met pre-defined general and angiographic inclusion and exclusion criteria. Analysis populations consisted of consecutively enrolled eligible diabetic subjects in the trials noted below.

5,6

. A Global Statistical Analysis Plan

The following global RESOLUTE clinical trials contributed subjects to the diabetes mellitus

cohort:

x RESOLUTE FIM

x RESOLUTE All-Comers (AC)

x RESOLUTE International (Int)

x RESOLUTE United States (US), and

x RESOLUTE Japan

American Heart Association. Heart Disease and Stroke Statistics - 2008 Update. www.americanheart.org/statistics

[Online publication]. Accessed 12 November 2008, 2008.

Fang J, Alderman MH. Impact of the increasing burden of diabetes on acute myocardial infarction in New York City:

1990-2000. Diabetes. 2006;55(3):768-773.

In total there were 878 subjects included in the RESOLUTE DM cohort. RESOLUTE US provided the highest percentage of subjects at 54.9% (482/878) while RESOLUTE Int contributed 27.6% (242/878), RESOLUTE AC 9.7% (85/878), RESOLUTE Japan 5.1% (45/878), and RESOLUTE FIM 2.7% (24/878).

Subjects from the 38 mm Length sub-study are not included in this Resolute Pooled Analysis of Subjects with Diabetes Mellitus. Additional information is provided in Section 10.4 for the Resolute US 38 mm Length Group for subjects with Diabetes Mellitus.

Design: The Resolute stent performance for treatment of lesions in patients with DM was compared with a performance goal (PG) derived from a meta-analysis of published studies of coronary DES use in DM subjects and from data from the ENDEAVOR pooled studies.

Inclusion of study subjects in this analysis were required to have DM defined by either a history of DM or use of medications to treat DM (i.e., oral hypoglycemics or insulin) at time of enrollment. The Resolute stent DM subjects and those included in the meta-analysis were also required to have clinical characteristics of an on-label population, consistent with the enrollment criteria of the RESOLUTE US Clinical Trial. That is, subjects with the following clinical or lesion characteristics were excluded: total lesion length per vessel >27mm, >2 lesions per vessel, unprotected left main lesions, bifurcation lesions, total occlusions, bypass grafts, acute MI within 72 hours of the index procedure, thrombus-containing lesions, left

ventricular ejection fraction <30%, or renal impairment (serum creatinine >2.5 mg/dl).

The Resolute DM TVF rate at 12-month follow-up was compared to a performance goal to demonstrate the safety and effectiveness of the Resolute stent in diabetic subjects. The objective of the primary endpoint analysis in the RESOLUTE DM cohort was to assess whether the true primary endpoint rate of 12-month target vessel failure (TVF) for the Resolute stent met the PG established as 14.5% (which is a 31% increase over the expected rate of 11.08% for DES use in DM subjects derived from the meta-analysis). The hypothesis for this analysis accounted for the differences in the protocols of the individual studies in the published literature, the ENDEAVOR pooled studies, and the Global RESOLUTE Clinical Trial Program. Specifically, in calculating the meta-analytic PG for DM subjects, adjustments were made to the 12-month TVF rate based on protocol-required follow-up angiography and protocol-required post-PCI cardiac biomarker measurements.

Demographics: The mean age of subjects was 65.2 years and 66.4% (583/878) were male.

28.5% (250/878) of the subjects were insulin-dependent diabetics. Of the subjects included in this analysis, 24.9% (216/867) of the subjects had a prior MI and 28.9% (254/878) were undergoing revascularization for unstable angina.

Primary endpoint: The primary endpoint was Target Vessel Failure (TVF) at 12 months following the intervention. The TVF composite endpoint includes cardiac death, MI that cannot be attributed to vessel(s) other than the target vessel, and clinically-driven target vessel revascularization (TVR).

Results: The analysis met the primary endpoint’s performance goal of 14.5%, as the TVF rate of the DM Cohort was 7.84% at 12 months with an upper bound of the 95% CI of 9.51%.

These analyses are based on the intent-to-treat population. The results are presented in the following tables:

x Table 10-8: RESOLUTE diabetes mellitus cohort - primary endpoint analysis

x Table 10-9: RESOLUTE diabetes mellitus (DM) cohort: all DM subjects, insulin-

dependent DM subjects (IDDM), non-insulin dependent DM subjects (non-IDDM), and non-DM subjects – principal safety and effectiveness

x Table 10-10: RESOLUTE diabetes mellitus cohort - ARC defined definite/probable

stent thrombosis events through 12 months

Table 10-8: RESOLUTE diabetes mellitus cohort - primary endpoint analysis

Primary endpoint

12-month TVF

RESOLUTE DM

(N = 878)

7.84% (68/867) 9.51% 14.5% < 0.001

Upper bound of

95%CI

Performance goal P-value

Notes

N is the total number of subjects. Numbers are % (count/number of eligible subjects). Subjects are only counted once for each time period. The primary endpoint analysis utilized a randomly selected lesion from subjects who had treatment of dual lesions. 12-month timeframe includes follow-up window (360 days ± 30 days).

One-sided confidence interval using exact method.

One-sided p-value using exact test statistic to be compared at a 0.05 significance level.

Table 10-9: RESOLUTE diabetes mellitus (DM) cohort: all DM subjects, insulin-dependent

DM subjects (IDDM), non-insulin dependent DM subjects (non-IDDM), and non-DM subjects

– principal safety and effectiveness through 12 months

Composite safety and effectiveness

TLF 6.6% (57/867) 10.6% (26/246) 5.0% (31/621) 4.9% (92/1867)

TVF 8.1% (70/867) 11.8% (29/246) 6.6% (41/621) 5.9% (110/1867)

MACE 7.5% (65/867) 11.8% (29/246) 5.8% (36/621) 5.7% (106/1867)

Effectiveness

Clinically-driven TVR 5.1% (44/867) 6.5% (16/246) 4.5% (28/621) 3.1% (57/1867)

TLR 3.3% (29/867) 5.3% (13/246) 2.6% (16/621) 2.0% (38/1867)

TLR, CABG

TLR, PCI 3.1% (27/867)

Non-TL TVR 2.2% (19/867) 1.6% (4/246) 2.4% (15/621) 1.3% (24/1867)

Non-TL TVR, CABG 0.1% (1/867) 0.0% (0/246) 0.2% (1/621) 0.2% (4/1867)

Non-TL TVR, PCI

Safety

Total death 2.8% (24/867) 4.1% (10/246) 2.3% (14/621) 1.0% (19/1867)

Cardiac death

Non-cardiac death 0.8% (7/867) 1.2% (3/246) 0.6% (4/621) 0.6% (11/1867)

Cardiac death or TVMI 3.6% (31/867) 6.1% (15/246) 2.6% (16/621) 3.2% (59/1867)

TVMI 1.8% (16/867) 4.1% (10/246) 1.0% (6/621) 2.7% (51/1867)

Q wave MI

Non-Q wave MI 1.5% (13/867)

Stent thrombosis ARC defined

Definite/probable

Definite 0.2% (2/867) 0.4% (1/246) 0.2% (1/621) 0.2% (4/1867)

Probable 0.1% (1/867) 0.4% (1/246) 0.0% (0/621) 0.1% (2/1867)

All DM subjects

(N = 878)

IDDM

(N = 250)

Non IDDM

(N = 628)

Non DM

(N = 1903)

0.2% (2/867)

2.1% (18/867)

0.8% (2/246) 0.0% (0/621)

4.5% (11/246) 2.6% (16/621)

1.6% (4/246) 2.3% (14/621)

0.3% (6/1867)

1.7% (32/1867)

1.1% (20/1867)

2.0% (17/867) 2.8% (7/246) 1.6% (10/621) 0.4% (8/1867)

0.3% (3/867)

0.8% (2/246) 0.2% (1/621)

3.3% (8/246) 0.8% (5/621)

0.3% (5/1867)

2.5% (46/1867)

0.3% (3/867) 0.8% (2/246) 0.2% (1/621) 0.3% (6/1867)

Table 10-9: RESOLUTE diabetes mellitus (DM) cohort: all DM subjects, insulin-dependent

DM subjects (IDDM), non-insulin dependent DM subjects (non-IDDM), and non-DM subjects

– principal safety and effectiveness through 12 months

Notes

N = The total number of subjects. Numbers are % (count/number of eligible subjects). Subjects are only counted once for each time period. 12-month timeframe includes follow-up window (360 days ± 30 days). The definitions of the outcomes are presented as table notes to Table 9-1.

All DM subjects

(N = 878)

IDDM

(N = 250)

Non IDDM

(N = 628)

Non DM

(N = 1903)

Table 10-10: RESOLUTE diabetes mellitus cohort - ARC defined definite/probable stent

thrombosis events through 12 months

Resolute

Stent thrombosis 0.3% (3/867)

Acute (0 to 1 day) 0.1% (1/867)

Subacute (2 to 30 days) 0.1% (1/867)

Late (31 to 360 days)

Notes

N is the total number of subjects. Numbers are % (count/number of eligible subjects). 12-month time frame includes follow-up window (360 days ± 30 days). Subjects are only counted once for each time period.

(N = 878)

0.1% (1/867)

10.4 Subjects with diabetes mellitus in the RESOLUTE 38 mm length group

Additional information is provided in Table 10-11 for the RESOLUTE 38 mm length group in subjects with diabetes mellitus.

Table 10-11: RESOLUTE 38 mm length group: all 38 mm subjects, insulin-dependent DM

subjects (IDDM), mon-insulin dependent DM subjects (non-IDDM), and non-DM subjects –

principal safety and effectiveness through 12 months

All diabetic 38 mm length

group subjects (N = 84

Composite safety and effectiveness

TLF 6.0% (5/84) 4.3% (1/23) 6.6% (4/61) 5.1% (7/138) TVF 7.1% (6/84) 4.3% (1/23) 8.2% (5/61) 6.5% (9/138) MACE 8.3% (7/84) 4.3% (1/23) 9.8% (6/61) 5.1% (7/138) Effectiveness Clinically-driven TVR 3.6% (3/84) 0.0% (0/23) 4.9% (3/61) 2.2% (3/138) TLR 2.4% (2/84) 0.0% (0/23) 3.3% (2/61) 0.7% (1/138) Safety Total death 1.2% (1/84) 0.0% (0/23) 1.6% (1/61) 0.7% (1/138) Cardiac death 1.2% (1/84) 0.0% (0/23) 1.6% (1/61) 0.7% (1/138) Non-cardiac death 0.0% (0/84) 0.0% (0/23) 0.0% (0/61) 0.0% (0/138)

patients)

38 mm length group

IDDM

(N = 23 patients)

38 mm length group –

non-IDDM

(N = 61 patients)

38 mm length group –

non-DM (N = 139

patients)

Table 10-11: RESOLUTE 38 mm length group: all 38 mm subjects, insulin-dependent DM

subjects (IDDM), mon-insulin dependent DM subjects (non-IDDM), and non-DM subjects –

principal safety and effectiveness through 12 months

All diabetic 38 mm length

group subjects (N = 84

Cardiac death or TVMI 3.6% (3/84) 4.3% (1/23) 3.3% (2/61) 5.1% (7/138) TVMI 2.4% (2/84) 4.3% (1/23) 1.6% (1/61) 4.3% (6/138)

Stent thrombosis ARC defined

Stent thrombosis (ARC def/prob)

Early (30 days) 0.0% (0/84) 0.0% (0/23) 0.0% (0/61) 1.4% (2/138) Late (>30 and 360 days) 0.0% (0/84) 0.0% (0/23) 0.0% (0/61) 0.0% (0/138)

patients)

0.0% (0/84) 0.0% (0/23) 0.0% (0/61) 1.4% (2/138)

38 mm length group

IDDM

(N = 23 patients)

38 mm length group –

non-IDDM

(N = 61 patients)

38 mm length group –

non-DM (N = 139

patients)

10.5 Subjects receiving short-term DAPT

The Onyx ONE Clear Primary Analysis subject population was formed by pooling data from eligible subjects enrolled into the Onyx ONE US & Japan Trial (a prospective, multi-center, single-arm trial, which enrolled subjects in the United States and Japan) with data from eligible subjects treated with Resolute Onyx only in the Onyx ONE Global RCT (a prospective, multi-center, randomized trial [See

Section 10.5.2]).

10.5.1 Onyx ONE Clear Primary Analysis

Primary Objective: To assess the safety and effectiveness of the Resolute Onyx stent with use of

one-month DAPT in subjects deemed at high risk for bleeding and/or medically unsuitable for more than one-month DAPT treatment.

Population: Subjects with an indication for percutaneous coronary intervention deemed at high risk for bleeding and/or candidates for one-month DAPT who are acceptable candidates to receive treatment with the Resolute Onyx stent.

Design: The Onyx ONE US & Japan Trial is a prospective, multi-center, post-market single-arm study which enrolled subjects undergoing attempted PCI. Subjects received DAPT through one month, before transitioning to SAPT thereafter.

Eligible subjects enrolled in the Onyx ONE US & Japan Trial (N=751) combined with eligible subjects from the Resolute Onyx arm of the Onyx ONE Global RCT (N=1018) (See Section 10.5.2) to form an Onyx As Treated population (Onyx AT).

The one-month clear population excluded subjects who interrupted or discontinued DAPT (greater than 3 cumulative days) within the first month of procedure (2.1%), those who experienced adverse events that would prohibit them from discontinuing DAPT beyond one month (3.4%), who did not intend to transition from DAPT to SAPT one month after procedure (6.2%), and who were lost to follow-up (3.1%). Peri-procedural MIs did not exclude subjects from being considered as one-month clear.

Assessment of the use of Resolute Onyx stents in HBR patients was based on analyses combining outcomes from patients compared to a pre-specified performance goal (PG). The PG was based on a clinically acceptable margin added to an expected composite event rate of cardiac death, and myocardial infarction (CD/MI) rate at 12 months, adapted from historical short DAPT studies with

high-bleeding risk patient populations (LEADERS FREE

, ZEUS

8,9

, and SENIOR10). The expected

CD/MI rate between one month and one year was estimated to be 6.8%.

The PG for the composite event rate of CD/MI at one-year post-procedure in a one-month clear population was 9.7% based on an estimated CD/MI rate of 6.8% and a one sided 0.025 significance level.

Demographics: The mean age was 74.0 ± 9.5, 67.7% (1019/1506) were male, 72.4% (1091/1506)

reported dyslipidemia, 84.0% (1265/1506) had hypertension, 9.4% (141/1498) were current smokers,

39.4% (593/1506) were diabetic 13.7% (206/1506) reported as insulin dependent], 26.3% (396/1506) had a prior MI, and 48.6% (701/1441) were classified as having acute coronary syndrome.

The mean number of high bleeding risk criteria was 1.6±0.8. The most common HBR qualifying features were age > 75 years, 59.0% (889/1506), long-term oral anticoagulation use, 41.0% (617/1506), anemia (hemoglobin level <11 g/dL) or recent transfusion, 14.4% (217/1506) and chronic kidney disease (creatinine clearance <40ml/min, 12.5% (188/1506).

Primary endpoint: The composite rate of cardiac death and myocardial infarction (CD/MI) at one year for a one-month clear population [timeframe: one month to one year].

Results: The Onyx As Treated (Onyx AT) one-month clear population was defined as the primary analysis population for the study. The CD/MI rate at one year for the Onyx ONE Clear cohort was

7.0% (104/1491) with the upper limit of 95% confidence interval of 8.4% which was lower than the prespecified performance goal of 9.7%.

The Onyx ONE Clear Primary Analysis results are presented in Table 10-12 and Table 10-13.

Post hoc analyses by gender and ACS vs non-ACS presentation for the primary endpoint are presented in Table 10-14 and Table 10-15. For gender, CD/MI rates at one year were 7.6% (77/1010) in male subjects and 5.6% (27/481) in female subjects. Patients who presented with ACS had a CD/MI rate at 1 year of 7.9% (55/694) compared with 6.0% (44/733) for patients who did not present with ACS.

Table 10-12: Primary endpoint analysis – Onyx ONE Clear

Resolute Onyx

(N = 1506

Primary Endpoint at 12 month1

Primary Analysis

– Onyx ONE Clear 7.0% (104/1491) [5.7%, 8.4%] 9.7% <0.001 Yes

Best Case Analysis3

– Onyx ONE Clear 6.9% (104/1506) [5.7%, 8.3%] 9.7% <0.001 Yes

Urban P, Meredith IT, Abizaid A, et al. Polymer-free Drug-Coated Coronary Stents in Patients at

Subjects)

Two-side 95%

Confidence

Interval2

Performance

Goal p-value

Primary

Objective Met?

(Yes or No)

High Bleeding Risk. N Engl J Med 2015;373:2038-4.

Valgimigli M, Patialiakas A, Thury A, et al. Zotarolimus-eluting versus bare-metal stents in uncertain

drug-eluting stent candidates. J Am Coll Cardiol. 2015;65:805–15.

Ariotti S, Adamo M, Costa F, et al. Is Bare-Metal Stent Implantation Still Justifiable in High Bleeding

Risk Patients Undergoing Percutaneous Coronary Intervention?: A Pre-Specified Analysis From the ZEUS Trial. JACC Cardiovasc Interv 2016;9:426-36.

Varenne O, Cook S, Sideris G, et al. Drug-eluting stents in elderly patients with coronary artery

disease (SENIOR): a randomised single-blind trial. Lancet. 2018 Jan 6;391(10115):41-50.

Table 10-12: Primary endpoint analysis – Onyx ONE Clear

Resolute Onyx

(N = 1506

Primary Endpoint at 12 month1

Worst Case Analysis4

– Onyx ONE Clear 7.9% (119/1506) [6.6%, 9.4%] 9.7% 0.009 Yes

1 The primary endpoint is a composite of cardiac death, myocardial infarction at one year post-procedure. 2 The two-sided 95% CI was calculated by binomial (exact) distribution carried out to assess statistical significance at the 0.025 level. 3 Best case analysis imputed all the missing 12-month primary endpoint status as no. 4 Worst case analysis imputed all the missing 12-month primary endpoint status as yes.

Subjects)

Two-side 95%

Confidence

Interval2

Performance

Goal p-value

Primary

Objective Met?

(Yes or No)

Table 10-13: Principal safet

Safety and effectiveness measures

Safety measures (to 180 days)

Target lesion failure (TLF)2 4.1% (61/1500)

Target vessel failure (TVF)3 4.5% (67/1500)

MACE4 6.0% (90/1500)

Cardiac death, MI, and definite/probable stent thrombosis 3.7% (56/1500)

Cardiac death or MI 3.7% (56/1500)

Cardiac death or target vessel MI (TVMI) 3.3% (50/1500)

Death or TVMI 4.9% (73/1500)

Death 2.5% (38/1500)

Cardiac death 1.0% (15/1500)

Non cardiac death 1.5% (23/1500)

TVMI (3rd UDMI) 2.5% (38/1500)

Clinically driven TLR 1.6% (24/1500)

Clinically driven TVR 2.2% (33/1500)

Stroke 0.7% (11/1500)

Stent thrombosis (ARC) definite/probable 0.4% (6/1500)

Bleeding

All BARC 7.3% (110/1500)

BARC 3-5 2.3% (34/1500)

BARC 2-5 6.5% (97/1500)

Safety measures (to 365 days)

Target lesion failure (TLF)2 8.1% (121/1491)

Target vessel failure (TVF)3 8.8% (131/1491)

MACE4 11.7% (174/1491)

Cardiac death, MI, and definite/probable stent thrombosis 7.0% (104/1491)

and effectiveness results – Onyx ONE Clear

RESOLUTE ONYX

(N=1506 subjects

N=1960 lesions)

%(m/n)1

Table 10-13: Principal safet

and effectiveness results – Onyx ONE Clear

RESOLUTE ONYX

(N=1506 subjects

N=1960 lesions)

Safety and effectiveness measures

%(m/n)1

Cardiac death or MI 7.0% (104/1491)

Cardiac death or target vessel MI (TVMI) 6.5% (97/1491)

Death or TVMI 9.7% (144/1491)

Death 6.0% (89/1491)

Cardiac death 2.6% (39/1491)

Non cardiac death 3.4% (50/1491)

TVMI (3rd UDMI) 4.4% (65/1491)

Clinically driven TLR 3.4% (50/1491)

Clinically driven TVR 4.3% (64/1491)

Stroke 1.5% (22/1491)

Stent thrombosis (ARC) definite/probable 0.7% (10/1491)

Bleeding

All BARC 13.1% (195/1491)

BARC 3-5 4.0% (60/1491)

BARC 2-5 11.7% (175/1491)

Effectiveness measures

Lesion success5 94.6% (1817/1920)

Device success6 93.3% (1790/1919)

Procedure success7 88.5% (1295/1463)

Numerator (m) is the number of Subjects with the specific classification, denominator (n) is the number of

Subjects in the study group with known values, and percentage (%) was calculated as 100 × (m/n)

Cardiac death, target vessel myocardial infarction (Q wave and non Q wave) or clinically-driven target lesion

revascularization (TLR) by percutaneous or surgical methods.

Cardiac death, target vessel myocardial infarction (Q wave and non Q wave) or clinically-driven target vessel

revascularization (TVR) by percutaneous or surgical methods.

Defined as death, myocardial infarction (Q wave and non Q-wave), emergent coronary bypass surgery, or repeat target lesion revascularization (clinically driven/clinically indicated) by percutaneous or surgical methods.

The attainment of <30% residual stenosis by QCA (or < 20% by visual assessment) AND TIMI flow 3 after the procedure using any percutaneous method.

The attainment of <30% residual stenosis by QCA (or < 20% by visual assessment) AND TIMI flow 3 after the procedure using the assigned device only.

The attainment of <30% residual stenosis by QCA (or < 20% by visual assessment) AND TIMI flow 3 after the procedure using any percutaneous method without the occurrence of MACE during the hospital. Third universal definition of MI is used for all the composite endpoints.

Table 10-14: Primary endpoint analysis by gender – Onyx ONE Clear

Primary endpoint Male subjects

Resolute Onyx

(N=1019 subjects)

% (m/n)

CD/MI at 12 months 7.6% (77/1010) 5.6% (27/481)

Female subjects

Resolute Onyx

(N=487 subjects)

% (m/n)

Table 10-15: Primary endpoint analysis ACS vs. non-ACS patients- Onyx ONE Clear

Non-ACS

(N=740 Subjects)

(N=958 Lesions)

Primary endpoint

CD/MI at 12 months 6.0% (44/733) 7.9% (55/694)

%(m/n)1

ACS

(N=701 Subjects)

(N=914 Lesions)

%(m/n)1

10.5.2 The Onyx ONE Global RCT

Study design: The Onyx ONE Global RCT

was an international, randomized, single-blind trial that compared zotarolimus-eluting stents (Resolute Onyx) with polymer-free umirolimus–coated stents in patients at high bleeding risk. After PCI, patients were treated with one-month of DAPT, followed by SAPT. A total of 1996 HBR patients were randomly assigned in a 1:1 ratio to receive Resolute Onyx stents (1003 patients) or polymer-free drug-coated stents (993 patients).

Objective: The purpose of this clinical study was to evaluate the clinical safety of the Resolute Onyx stent as compared to the polymer-free drug coated stents with use of 1 month DAPT in subjects deemed at HBR and/or medically unsuitable for more than 1 month DAPT treatment. In the

LEADERS-FREE trial, the same polymer-free drug-coated stent showed superiority in safety and effectiveness to a bare-metal stent in a similar HBR population treated with 1 month of DAPT.

Primary Endpoint: The composite rate of cardiac death, myocardial infarction, and stent thrombosis (definite/probable) at one year.

Results: At 1 year, the primary outcome was observed in 169 of 988 patients (17.1%) in the Resolute Onyx stent group and in 164 of 969 (16.9%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% confidence interval [CI],

3.5; noninferiority margin, 4.1; P = 0.01 for noninferiority). Among patients at HBR who received 1 month of DAPT after PCI, Resolute Onyx stents were noninferior to use of polymer-free drug-coated stents with regard to safety and effectiveness composite outcomes.

10.6 Subjects with chronic total occlusion

The PERSPECTIVE Study – RESOLUTE CTO cohort

The PERSPECTIVE Study included a retrospective and a prospective study arm. Both arms of this

study enrolled approximately 250 patients at a single center experienced in CTO procedures. The prospective arm essentially comprised a separate substudy designed to evaluate procedural and 1year clinical outcomes among consecutive patients undergoing attempted percutaneous Chronic Total Occlusion (CTO) revascularization. The prospective arm of the PERSPECTIVE study included a pre-specified subgroup analysis of patients treated with the Resolute family of drug-eluting stents (all were Resolute Integrity).

Primary objective: To assess the safety and effectiveness of the Resolute zotarolimus-eluting coronary stent system (Resolute ZES) for the treatment of chronic total occlusions.

Population: Th

e population consisted of prospectively enrolled subjects undergoing attempted

percutaneous CTO revascularization and treated with the Resolute ZES.

Windecker S, Latib A, Kedhi E, et al. Polymer-based or Polymer-free Stents in Patients at High

Bleeding Risk. New England Journal of Medicine 2020.

Design: The PERSPECTIVE Study

(Prospective Arm/Prespecified Resolute ZES for CTO Analysis)

was a single-center, investigator-initiated, observational study which prospectively enrolled

approximately 250 subjects undergoing attempted CTO. Assessment of use of Resolute ZES stents in CTO revascularization was based on prospectively enrolled CTO patients compared to a prespecified performance goal.

An estimated MACE rate was derived based on a weighted average of the reported rates for drug-

eluting stents from the PRISON II

and EXPERT CTO13 studies. Due to difference in the definition of myocardial infarction used in the PRISON II study, an adjustment for the MACE rate was made to approximate the MACE rate if the ARC definition of myocardial infarction had been applied. The weighted average produced an estimated MACE rate of 16.6% using the ARC definition of MI. The performance goal (PG) for the pre-specified RESOLUTE CTO Cohort analysis was 25.2% based on the estimated MACE rate of 16.6% and a one-sided 95% CI.

Demographics: In the RESOLUTE CTO Cohort of the PERSPECTIVE Study, the mean age was

63.4 ± 9.5, 79.8% (146/183) were male, 98.4% (180/183) reported dyslipidemia, 88.5% (162/183) had hypertension, 18.0% (31/172) were current smokers, 35.5% (65/183) were diabetic including 12.6% (23/182) reported as insulin-dependent, 33.3% (61/183) had a prior MI, and 80.9% (140/173) were classified as having stable angina.

Primary en

dpoint: Major Adverse Cardiac Events (MACE) at one year; a composite of death,

myocardial infarction (MI) (ARC defined), and clinically-driven target lesion revascularization (TLR).

Results: The observed MACE rate at one year for the RESOLUTE CTO Cohort was 18.2% (33/181) for the ITT population. The ITT population met the primary endpoint. The upper limit of the 95% confidence interval was 23.6% which is lower than the pre-specified performance goal (25.2%). A post hoc gender subgroup analysis of the primary endpoint resulted in MACE rates at one year of

18.8% (27/144) in male subjects and 16.2% (6/37) in female subjects.

The PERSPECTIVE Study results are presented in Table 10-16, Table 10-17, and Table 10-18:

Table 10-16: Primary endpoint analysis – MACE at 12 months (ITT)

One-side upper

RESOLUTE CTO cohort

Primary endpoint

MACE at 12 months

ITT 18.2% (33/181) 23.6% 25.2%

(N=183 Subjects)

95%

confidence interval

Table 10-17: Principal safety and effectiveness results

RESOLUTE CTO cohort

(N=183 subjects)

Safety and effectiveness measures

Safety measures (in-hospital)

TLF 15.3% (28/183) TVF 15.3% (28/183)

Suttorp MJ, Laarman GJ, Rahel BM, et al. Primary Stenting of Totally Occluded Native Coronary Arteries II (PRISON II): a

randomized comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions. Circulation 2006; 114(9); 921 – 928.

Kandzari DE, Kini AS, Karmpaliotis D, et al. Safety and Effectiveness of Everolimus-Eluting Stents in Chronic Total Coronary

Occlusion Revascularization: Results From the EXPERT CTO Multicenter Trial (Evaluation of the XIENCE Coronary Stent, Performance, and Technique in Chronic Total Occlusions). J Am Coll Cardiol Intv 2015; 8(6); 761 – 769.

%(m/n)

Performance

goal

Table 10-17: Principal safety and effectiveness results

RESOLUTE CTO cohort

(N=183 subjects)

Safety and effectiveness measures

MACE 15.3% (28/183) Cardiac death or MI 15.3% (28/183) Death or MI 15.3% (28/183) Death 1.1% (2/183) Cardiac death 1.1% (2/183) Non-cardiac death 0.0% (0/183) MI 14.8% (27/183) TLR 0.0% (0/183) TVR 0.0% (0/183)

Safety measures (to 6 Months/183 days)

TLF 17.5% (32/183) TVF 17.5% (32/183) MACE 17.5% (32/183) Cardiac death or MI 17.5% (32/183) Death or MI 17.5% (32/183) Death 2.7% (5/183) Cardiac death 2.2% (4/183) Non-cardiac death 0.5% (1/183) MI 15.8% (29/183) TLR 0.5% (1/183) TVR 0.5% (1/183) All stent thrombosis (ARC definite/probable/possible) 1.6% (3/183) Stent thrombosis ARC definite/probable 0.6% (1/183) Stent thrombosis ARC possible 1.1% (2/183) Early stent thrombosis (0 to 30 days) 0.6% (1/183) Definite 0.6% (1/183) Probable 0.0% (0/183) Possible 0.0% (0/183) Late stent thrombosis (31 days to 6 months) 1.1% (2/183) Definite 0.0% (0/183) Probable 0.0% (0/183) Possible 1.1% (2/183)

Safety measures (to 1 year/365 days)

TLF 18.2% (33/181) TVF 18.2% (33/181) MACE 18.2% (33/181) Cardiac death or MI 17.7% (32/181) Death or MI 17.7% (32/181) Death 2.8% (5/181) Cardiac death 2.2% (4/181) Non-cardiac death 0.6% (1/181) MI 16.0% (29/181) TLR 1.1% (2/181) TVR 1.1% (2/181)

All stent thrombosis (ARC definite/probable/possible) 1.7% (3/181)

Stent thrombosis ARC definite/probable 0.6% (1/181)

Stent thrombosis ARC possible 1.1% (2/181)

%(m/n)

Table 10-17: Principal safety and effectiveness results

RESOLUTE CTO cohort

(N=183 subjects)

Safety and effectiveness measures

Early stent thrombosis (0 to 30 days) 0.6% (1/181)

Definite 0.6% (1/181)

Probable 0.0% (0/181)

Possible 0.0% (0/181)

Late stent thrombosis (31 days to 1 year) 1.1% (2/181)

Definite 0.0% (0/181)

Probable 0.0% (0/181)

Possible 1.1% (2/181)

Effectiveness measures

Clinical success Technical success 1CTO procedural success as defined by achievement of <50% residual stenosis with 7,0, 2 antegrade flow

Successful guidewire crossing with placement in distal true lumen of CTO target lesion

%(m/n)

92.3% (169/183)

96.2% (175/182)

Table 10-18: RESOLUTE CTO cohort – primary endpoint analysis by gender

Male subjects

RESOLUTE CTO cohort

Primary endpoint

MACE at 12 months 18.8% (27/144) 16.2% (6/37)

(N=146 subjects)

% (m/n)

Female subjects

RESOLUTE CTO cohort

(N=37 subjects)

% (m/n)

Global RESOLUTE Clinical Program – RESOLUTE pooled CTO

Population: In order to provide additional support for the performance of the Resolute family of

stents in the treatment of CTOs, a retrospective, pooled analysis was performed which was comprised of pooled CTO patients from the Global RESOLUTE Clinical Program.

The following Global RESOLUTE Clinical Trials contributed subjects to the CTO cohort:

x RESOLUTE International

The RESOLUTE International Study (R-Int) was a prospective, multi-center, nonrandomized, single-arm, observational study of the Resolute stent in a real world subject population. A total 2349 subjects were enrolled into the study. Subjects were followed for 3 years post-procedure. A total of 186 subjects from the R-Int study were included in the RESOLUTE Pooled CTO analysis.

x RESOLUTE China Randomized Controlled Trial

The RESOLUTE China Randomized Controlled Trial (R-China RCT) was a prospective, multi-center, randomized, open-label study designed to assess the non-

inferiority of the Resolute stent compared to the TAXUS™* Liberté™* stent for in-stent late lumen loss. A total of 198 subjects were treated with the Resolute stent. Subjects were followed for 5 years post-procedure. A total of 15 subjects from the R-China RCT study were included in the RESOLUTE Pooled CTO analysis.

x RESOLUTE China Registry

The RESOLUTE China Registry (R-China Registry) was a prospective, multi-center, non-randomized, single-arm, observational study of the Resolute stent in a real-world patient population requiring stent implantation. A total of 1800 subjects were treated with the Resolute stent. Subjects were followed for 5 years post-procedure. A total of 157 subjects from the R-China Registry were included in the RESOLUTE Pooled CTO Analysis.

Design: The Resolute stent performance for the treatment of CTO lesions was analyzed from data collected in the R-Int, R-China RCT, and R-China Registry studies. The results pooled datasets from the 5-year data of R-China RCT, 4-year data of R-China Registry, and 3-year data from R-Int. In total, 358 subjects were evaluable for this CTO subset.

Demographics: The average age in the RESOLUTE Pooled CTO subset (n=358) was 60.4 ±

11.3 years and 84.4% (302/358) were male. For this population, 37.7% (133/353) experienced a prior MI, 65.1% (233/358) had hypertension, 50.3% (180/358) had hyperlipidemia and 26.5% (95/358) had diabetes.

Global RESOLUTE Clinical Program results are presented in Table 10-19:

Table 10-19: RESOLUTE pooled CTO analysis – safety and effectiveness results

RESOLUTE pooled CTO

(N=358 patients)

Safety and effectiveness endpoints

Effectiveness measures

Lesion success6 100.0% (526/526) Device success7 94.1% (496/527) Procedure success8 97.5% (348/357) 1 Year TLF1 4.5% (16/352) TVF2 4.8% (17/352) MACE3 5.7% (20/352) Composite endpoint4 12.2% (43/352) Cardiac death or TVMI 3.1% (11/352) Death or TVMI 4.0% (14/352) Death 1.7% (6/352) Cardiac death 0.9% (3/352) Non-cardiac death 0.9% (3/352) TVMI (extended historical definition) 2.3% (8/352) Clinically-driven TLR 2.0% (7/352) Clinically-driven TVR 2.3% (8/352) Stent thrombosis (ARC) definite/probable) 0.6% (2/352) Early thrombosis (30 days) 0.3% (1/352) Late thrombosis (>30 and 360 days) 0.3% (1/352) Significant bleeding complications5 1.1% (4/352) Stroke 0.9% (3/352) 3 Years TLF1 8.9% (31/347) TVF2 10.1% (35/347) MACE3 10.1% (35/347) Composite endpoint4 18.4% (64/347) Cardiac death or TVMI 6.6% (23/347) Death or TVMI 7.8% (27/347) Death 5.5% (19/347) Cardiac death 4.3% (15/347)

(N=527 lesions) %(m/n)9

Table 10-19: RESOLUTE pooled CTO analysis – safety and effectiveness results

RESOLUTE pooled CTO

(N=358 patients)

Safety and effectiveness endpoints

Non-cardiac death 1.2% (4/347) TVMI (extended historical definition) 3.2% (11/347) Clinically-driven TLR 3.2% (11/347) Clinically-driven TVR 4.3% (15/347) Stent thrombosis (ARC) definite/probable) 1.2% (4/347) Early thrombosis (30 days) 0.3% (1/347) Late thrombosis (>30 and 360 days) 0.3% (1/347) Very late thrombosis (>360 days) 0.9% (3/347) Significant bleeding complications5 1.2% (4/347) Stroke 1.7% (6/347)

1.Cardiac death, target vessel myocardial infarction (Q wave and non-Q wave), or clinically-driven target lesion revascularization (TLR) by percutaneous or surgical methods.

2.Cardiac death, target vessel myocardial infarction, or clinically-driven target vessel revascularization.

3.Death, myocardial infarction, (Q wave and non-Q-wave), emergent coronary bypass surgery, or repeat target lesion revascularization (clinicallydriven/clinically-indicated) by percutaneous or surgical methods.

4.The combined clinical outcome of (all cause) mortality, myocardial infarction (Q-wave and non-Q wave), or (any) revascularization.

5.Bleeding complication is defined as a procedure related hemorrhagic event that requires a transfusion or surgical repair. These may include a hematoma requiring treatment of retroperitoneal bleed. Significant bleeding complication is defined as the bleeding complication that has at least one of the following scenarios:

• Bleedings that led to an interruption of anti-platelet medication;

• Bleedings that require transfusion;

• Intracerebral bleedings; or

• Bleedings that resulted in substantial hemodynamic compromise requiring treatment

6.The attainment of <50% residual stenosis of the target lesion using any percutaneous method.

7.The attainment of <50% residual stenosis of the target lesion using only the assigned device.

8.The attainment of <50% residual stenosis of the target lesion and no in-hospital MACE.

9.Numerator (m) is the number of patients (or lesions) with the specific classification, denominator (n) is the number of patients (or lesions) in the study group with known values, and percentage () was calculated as 100 × (m/n) Extended historical definition of MI is used for all the composite endpoints.

(N=527 lesions) %(m/n)9

10.7 Pooled results of the Global RESOLUTE Clinical Trial Program (RESOLUTE FIM, RESOLUTE US, RESOLUTE AC, RESOLUTE Int, RESOLUTE Japan)

In order to better estimate the incidence of low-frequency events or outcomes, a subject-level pooled analysis was conducted. Table 10-20 provides the total number of subjects included in the analyses.

Table 10-20: Subjects included in the analyses by clinical study

RESOLUTE FIM 139 139

RESOLUTE All-Comers – Resolute 1140 376

RESOLUTE International 2349 763

RESOLUTE US 1402 1402

RESOLUTE Japan 100 100

Pooled Resolute Data set 5130 2780

Subjects from the 38 mm length sub-study were not included in the RESOLUTE pooled analysis presented here

All subjects On-label

The on-label subgroup includes all enrolled subjects except those that had a total occlusion, target lesions involving a bifurcation lesion, target lesions involving a saphenous vein graft lesion (SVG), an in-stent restenosis (ISR) target lesion, a subject having an acute myocardial infarction (AMI)  hrs), subjects with a demonstrated left-ventricular ejection fraction (LVEF) less than 30%, target lesions located in an unprotected left main artery, subjects with  treated vessels, subjects with a serum creatinine of >2.5 mg/dl, a lesion length >27 mm, 2 or more lesions treated per vessel, and target lesions with the presence of a thrombus.

It is acknowledged that the results of retrospective pooled analyses have limitations. Definitive proof of the presence or absence of any differences between sub-groups requires prospectively powered assessments in clinical trials. The results are presented in the following tables:

x Table 10-21: RESOLUTE pooled analysis - principal safety and effectiveness

through 60 months

x Table 10-22: RESOLUTE pooled Analysis - ARC defined definite/probable stent

thrombosis through 60 months

ble 10-23: RESOLUTE pooled analysis - subset outcomes through 12 months

x Ta x Table 10-24: RESOLUTE pooled analysis – subset outcomes through 12 months

x Table 10-25: RESOLUTE pooled analysis – subset outcomes through 12 months

Table 10-21: RESOLUTE pooled analysis - principal safety and effectiveness through 60

months

All subjects

(N = 5130)

Outcomes at 12 months

Composite safety and effectiveness

TLF

TVF

MACE

Effectiveness

Clinically-driven TVR

Clinically-driven TLR

Safety

Total death

Cardiac-death

6.6% (336/5098) 5.4% (150/2759)

7.5% (382/5098) 6.6% (181/2759)

7.5% (384/5098) 6.3% (174/2759)

4.3% (220/5098) 3.7% (103/2759)

3.3% (166/5098) 2.5% (69/2759)

1.9% (98/5098) 1.6% (44/2759)

1.2% (60/5098) 0.9% (26/2759)

On-label

(N = 2780)

Table 10-21: RESOLUTE pooled analysis - principal safety and effectiveness through 60

months

All subjects

(N = 5130)

Non-cardiac death

TVMI

Cardiac death or TVMI

Stent thrombosis

0.7% (38/5098) 0.7% (18/2759)

2.9% (149/5098) 2.4% (66/2759)

3.9% (200/5098) 3.3% (90/2759)

ARC defined

Definite/probable

Definite

Probable

0.8% (40/5098) 0.3% (9/2759)

0.6% (29/5098) 0.2% (6/2759)

0.3% (13/5098) 0.1% (3/2759)

Outcomes at 36 months

Composite safety and effectiveness

TLF

TVF

MACE

10.8% (539/5012) 9.2% (249/2709)

13.0% (652/5012) 12.0% (324/2709)

13.5% (679/5012) 12.0% (325/2709)

Effectiveness

Clinically-driven TVR

Clinically-driven TLR

7.9% (397/5012) 7.5% (204/2709)

5.3% (267/5012) 4.4% (119/2709)

Safety

Total death

Cardiac death

Non-cardiac death

TVMI

Cardiac death or TVMI

Stent thrombosis

5.5% (275/5012) 5.0% (135/2709)

3.1% (156/5012) 2.6% (70/2709)

2.4% (119/5012) 2.4% (65/2709)

3.8% (188/5012) 3.1% (84/2709)

6.5% (324/5012) 5.4% (145/2709)

ARC defined

Definite/probable

Definite

Probable

Outcomes at 60 months*

Composite safety and effectiveness

TLF

TVF

MACE

Effectiveness

Clinically-driven TVR

TLR

Safety

1.1% (54/5012) 0.5% (13/2709)

0.7% (37/5012) 0.3% (7/2709)

0.4% (19/5012) 0.2% (6/2709)

14.0% (376/2688) 12.3% (239/1937)

18.1% (486/2688) 16.5% (320/1937)

19.4% (521/2688) 18.2% (352/1937)

11.4% (306/2688) 10.6% (205/1937)

6.7% (179/2688) 5.8% (112/1937)

On-label

(N = 2780)

Table 10-21: RESOLUTE pooled analysis - principal safety and effectiveness through 60

months

All subjects

(N = 5130)

Total death

Cardiac death

Non-cardiac death

TVMI

Cardiac death or TVMI

Stent thrombosis ARC defined

Definite/probable

Definite

Probable

9.9% (266/2688) 9.7% (188/1937)

4.9% (131/2688) 4.3% (83/1937)

5.0% (135/2688) 5.4% (105/1937)

4.5% (120/2688) 3.9% (76/1937)

8.7% (234/2688) 7.5% (145/1937)

1.3% (34/2688) 0.8% (15/1937)

0.8% (22/2688) 0.5% (9/1937)

0.5% (13/2688) 0.3% (6/1937)

Notes

N = The total number of subjects enrolled. Numbers are % (count/number of eligible subjects). Subjects are only counted once for each time period. 12-month time frame includes follow-up window (360 days ± 30 days). 36-month timeframe includes follow-up window (1080 days ± 30 days). 60-month timeframe includes follow-up window (1800 days ± 30 days).

Note: R-Int. follow-up ends at 3 years and is not included in this analysis.

* The definitions of the outcomes are presented as table notes to Table 9-1.

On-label

(N = 2780)

Table 10-22: RESOLUTE pooled analysis - ARC defined definite/probable stent thrombosis

through 60 months

Stent thrombosis

Early (0 to 30 days)

1.3% (34/2688) 0.8% (15/1937)

0.5% (13/2688) 0.2% (3/1937)

Late (31 to 360 days)

Very late (361 to 1440 days)*

0.5% (14/2688) 0.4% (8/1937)

N = The total number of subjects enrolled. Numbers are % (count/number of eligible subjects). Subjects are only counted once for each time period. 12-month time frame includes follow-up window (360 days ± 30 days). 60-month timeframe includes follow-up window (1800 days ± 30 days). * Note: R-Int. follow-up ends at 3 years and is not included in this analysis.

All subjects*

(N = 2781)

0.3% (8/2688) 0.2% (4/1937)

On-label* (N = 2017)

 mm

(N = 509)

Lesion length

RVD

 mm

(N = 1956)

(N = 3636)

B2/C lesions

Female

(N = 1287)

Male

(N = 3843)

1.4% (7/495)

1.8% (9/495)

Age

 yrs.

(N = 2547)

7.0% (177/2515) 6.3% (239/3780) 7.4% (94/1264) 6.7% (239/3577) 7.3% (141/1928) 7.9% (39/495)

(N = 2466)

8.4% (211/2515) 7.3% (277/3780) 8.0% (101/1264) 7.6% (271/3577) 8.1% (157/1928) 9.3% (46/495)

8.0% (202/2515) 7.1% (270/3780) 8.6% (109/1264) 7.6% (272/3577) 8.5% (164/1928) 8.5% (42/495)

Table 10-23: RESOLUTE pooled analysis - subset outcomes through 12 months

On-label single lesion

Composite safety and

effectiveness TLF 5.3% (128/2428)

TVF 6.4% (155/2428)

MACE 6.1% (147/2428)

Effectiveness Clinically-driven TVR 3.6% (88/2428)

3.1% (79/2515) 3.3% (124/3780) 3.1% (39/1264) 3.3% (118/3577) 3.7% (71/1928) 5.1% (25/495)

4.3% (108/2515) 4.3% (162/3780) 4.4% (55/1264) 4.4% (157/3577) 5.0% (96/1928) 5.7% (28/495)

TLR 2.4% (58/2428)

Safety Total death 1.6% (39/2428)

3.1% (78/2515) 1.9% (70/3780) 2.1% (26/1264) 1.7% (62/3577) 1.7% (32/1928) 3.2% (16/495)

Cardiac death 0.9% (22/2428) 1.9% (48/2515) 1.0% (39/3780) 1.5% (19/1264) 1.0% (36/3577) 1.0% (20/1928)

Non-cardiac death 0.7% (17/2428) 1.2% (30/2515) 0.8% (31/3780) 0.6% (7/1264) 0.7% (26/3577) 0.6% (12/1928)

2.3% (57/2428) 2.9% (74/2515) 2.8% (105/3780) 3.6% (45/1264) 3.2% (115/3577) 3.5% (67/1928) 1.8% (9/495)

TVMI

4.5% (113/2515) 3.6% (137/3780) 4.9% (62/1264) 4.0% (144/3577) 4.4% (84/1928) 3.4% (17/495)

Cardiac death or TVMI 3.2% (77/2428)

Stent thrombosis ARC defined Definite/probable 0.3% (7/2428) 0.8% (19/2515) 0.8% (31/3780) 0.7% (9/1264) 0.9% (31/3577) 0.7% (14/1928) 1.0% (5/495)

Definite 0.2% (5/2428) 0.5% (12/2515) 0.6% (24/3780) 0.4% (5/1264) 0.7% (25/3577) 0.5% (10/1928) 0.6% (3/495)

Probable 0.1% (2/2428) 0.3% (8/2515) 0.2% (9/3780) 0.3% (4/1264) 0.2% (8/3577) 0.3% (6/1928) 0.4% (2/495)

(N = 199)

BMS in-stent restenosis

12.1% (24/198)

9.1% (18/198)

8.1% (16/198)

3.0% (6/198)

2.0% (4/198)

1.0% (2/198)

4.0% (8/198)

3.0% (6/198)

2.5% (5/198)

1.5% (3/198)

1.0% (2/198)

(N = 770)

Multi-vessel stenting

(N = 64)

Saphenous vein graft

(N = 644)

Overlapping stents

1.9% (14/756)

0.5% (4/756)

1.3% (10/756)

3.3% (25/756)

(N = 1788)

Multiple stents

7.8% (137/1758) 7.8% (49/632) 17.2% (11/64) 8.2% (62/756) 11.1% (22/198)

8.6% (152/1758) 8.7% (55/632) 17.2% (11/64) 8.9% (67/756)

8.8% (155/1758) 9.3% (59/632) 17.2% (11/64) 9.0% (68/756)

5.1% (89/1758) 5.4% (34/632) 10.9% (7/64) 5.0% (38/756)

4.1% (72/1758) 4.4% (28/632) 7.8% (5/64) 4.4% (33/756)

2.0% (36/1758) 3.0% (19/632) 3.1% (2/64)

1.3% (22/1758) 1.4% (9/632) 3.1% (2/64)

0.8% (14/1758) 1.6% (10/632) 0.0% (0/64)

4.5% (79/1758) 4.4% (28/632) 9.4% (6/64) 4.5% (34/756)

3.5% (62/1758) 3.3% (21/632) 7.8% (5/64)

1.1% (20/1758) 1.1% (7/632) 1.6% (1/64) 1.2% (9/756)

0.4% (7/1758) 0.6% (4/632) 1.6% (1/64) 0.7% (5/756)

0.9% (15/1758) 0.6% (4/632) 0.0% (0/64) 0.7% (5/756)

Table 10-24: RESOLUTE pooled analysis – subset outcomes through 12 months

Composite safety and effectiveness

TLF

TVF

MACE

Effectiveness

Clinically-driven TVR

TLR

Safety

Total death

Cardiac death

Non-cardiac death

TVMI

Cardiac death or TVMI

Stent thrombosis ARC defined

Definite/probable

Definite

Probable

(N = 799)

AMI <72 hours

Renal

(N = 135)

insufficiency

(N = 57)

left main

Unprotected

3.6% (2/56) 2.3% (3/133) 2.2% (17/788)

1.8% (1/56) 0.8% (1/133) 1.5% (12/788)

1.8% (1/56) 1.5% (2/133) 0.8% (6/788)

Total occlusion

(N = 505)

(N = 702)

10.3% (71/690) 6.2% (31/497) 16.1% (9/56) 12.0% (16/133) 7.5% (59/788)

11.4% (79/690) 6.6% (33/497) 16.1% (9/56) 12.8% (17/133) 8.1% (64/788)

11.3% (78/690) 6.6% (33/497) 17.9% (10/56) 16.5% (22/133) 8.2% (65/788)

6.1% (42/690) 4.2% (21/497) 7.1% (4/56) 4.5% (6/133) 5.6% (44/788)

4.8% (33/690) 3.6% (18/497) 7.1% (4/56) 3.0% (4/133) 4.7% (37/788)

2.3% (16/690) 1.2% (6/497) 7.1% (4/56) 10.5% (14/133) 2.2% (17/788)

0.7% (5/690) 0.2% (1/497) 1.8% (1/56) 3.8% (5/133) 0.6% (5/788)

1.6% (11/690) 1.0% (5/497) 5.4% (3/56) 6.8% (9/133) 1.5% (12/788)

5.9% (41/690) 2.4% (12/497) 7.1% (4/56) 5.3% (7/133) 2.4% (19/788)

7.1% (49/690) 3.4% (17/497) 10.7% (6/56) 9.8% (13/133) 3.8% (30/788)

1.0% (5/497)

2.0% (10/497)

2.0% (14/690)

1.0% (5/497)

0.6% (4/690)

1.6% (11/690)

Table 10-25: RESOLUTE pooled analysis – subset outcomes through 12 months

Bifurcation

Composite safety and

effectiveness

TLF

TVF

MACE

Effectiveness

Clinically-driven TVR

TLR

Safety

Total death

Cardiac death

Non-cardiac death

TVMI

Cardiac death or TVMI

Stent thrombosis ARC defined

Definite/probable

Definite

Probable

Numbers are % (count/number of eligible subjects).

Notes

N = The total number of subjects enrolled.

Total occlusion is defined as pre procedure TIMI = 0. 2Renal insufficiency is defined as serum creatinine >2.5 mg/dl.

The definitions of the outcomes are presented as table notes to Table 9-1.

12-month time frame includes follow-up window (360 days ± 30 days).

Subjects are only counted once for each time period.

Subjects from the 38 mm Length sub-study were not included in the RESOLUTE pooled analysis.

11 Patient selection and treatment

See also Section 6.5 - Use in special populations. The risks and benefits described above should be carefully considered for each patient before use of the Onyx Frontier system. Factors to be utilized for patient selection should include an assessment of the risk of prolonged anticoagulation. In accordance with the 2016 American College of Cardiology / American Heart Association guidelines, administration of P2Y12 platelet inhibitor is recommended pre-procedure and for at least 6 months in stable ischemic heart disease patients and for at least 12 months in patients with acute coronary syndrome (ACS). In patients at higher risk of bleeding, Resolute Onyx stent is safe and effective with one-month DAPT based on results of the Onyx ONE Clear Primary Analysis as described in 6.1.1 Oral antiplatelet therapy. Aspirin should be administered concomitantly with an approved antiplatelet medication and then continued indefinitely.

12 Patient counseling information

Physicians should consider the following in counseling the patient about this product:

x Discuss the risks associated with stent placement x Discuss the risks associated with a zotarolimus-eluting stent implant x Discuss the risks and benefits tradeoff for the patient x Discuss alteration to current lifestyle immediately following the procedure and over the long

term

x Discuss the risks of early discontinuation of the antiplatelet therapy

The following patient materials will be provided to physicians to educate their patients about the options available for treating coronary artery disease and provide contact information to the patient after their stent implant procedure:

x A Patient Guide which includes information on the Onyx Frontier zotarolimus-eluting

coronary stent system, coronary artery disease, and the stent implantation procedure.

x A Stent Patient Implant Card that includes patient information, stent implant information

and MRI guidelines. All patients should be instructed to keep this card in their possession at all times for procedure/stent identification.

13 How supplied

Sterile: This product is sterilized with ethylene oxide (EO) and is nonpyrogenic. Do not use

the product if the package is opened or damaged. Do not resterilize the product. If the product or package is opened or damaged, return the product to Medtronic Returned Goods. Contact your local Medtronic representative for return information.

Contents: The package contains one (1) Resolute Onyx zotarolimus-eluting coronary stent mounted on either an Onyx Frontier rapid exchange (RX) or Resolute Onyx RX stent delivery system.

Storage: Store the product in the original container. Store at 25ºC (77ºF); excursions permitted to 15 - 30ºC (59 - 86ºF). Use by the use-by date noted on the package.

Disposal instructions: After use, dispose of the product and packaging in accordance with hospital, administrative and local government policy.

14 Directions for use

14.1 Access to package holding sterile stent delivery system

Remove the stent delivery system from the package. Special care must be taken not to handle the stent or in any way disrupt its placement on the balloon. This is most important during catheter removal from packaging, placement over guidewire, and advancement through the rotating hemostatic valve and guiding catheter hub. Excessive manipulation, for example, rolling the mounted stent, may cause dislodgement of the stent from the delivery balloon.

(

y sy

14.2 Inspection before use

Before opening the product, carefully inspect the stent delivery system package, and check for damage to the sterile barrier. Do not use after the use-by date. If the sterile package is intact, carefully remove the system from the package and inspect it for bends, kinks, and other damage. Do not use the product if any damage to the packaging or system is noted.

A protective sheath covers the stent mounted on the balloon. After removal of the sheath, visually inspect the stent to ensure that it has not been damaged or displaced from its original position (between the proximal and distal marker bands) on the balloon.

14.3 Materials required

Quantity Material

N/A 2 to 3 20 cc s 1,000 u /500 cc Heparinized normal saline 1 Guidewire [ 0.014 in 1 Rotatin N/A Contrast medium diluted 1:1 with heparinized normal saline 1 Inflation device 1 Stopcock 1 Torque device N/A Appropriate anticoa

Guide catheter [t 5 Fr (1.42 mm, 0.056 in) inner diameter]

ringe

0.36 mm) outer diameter]

hemostatic valve

3-way minimum)

ulation and antiplatelet drugs

14.4 Preparation precaution

x Do not use product if the protective sheath is not present or the stent is damaged or

displaced.

x Avoid manipulation of the stent during flushing of the guidewire lumen, as this may disrupt

the placement of the stent on the balloon.

x Do not apply positive pressure to the balloon during the delivery system preparation.

14.4.1 Guidewire lumen flush

Flush the stent system guidewire lumen with heparinized normal saline until the fluid exits the distal tip.

14.4.2 Delivery system preparation

Step Action

1. Prepare the

uide catheter and guidewire according to the manufacturer’s instructions.

2. Remove the stent deliver

3. Remove the protective sheath covering from the stent/balloon. Removing the protective sheath will also remove the st

4. Inspect the stent to ensure that it has not been damaged or displaced from its original position on the balloon. Verify that the stent is positioned between the proximal and distal balloon markers. Verify that there is no visible damage to the stent or the balloon. Note: Should there be movement of or dama

5. Flush the stent delivery system guidewire lumen with heparinized normal saline in routine manner.

6. Fill a 20 cc s

ringe with 5 cc of contrast/heparinized normal saline mixture (1:1).

7. Attach to deliver

8. Slowly release pressure to allow negative pressure to draw the mixture into the balloon lumen.

9. Detach the s

ringe and leave a meniscus of mixture on the hub of the balloon lumen.

10. Prepare the inflation device in standard manner and purge to remove all air from the s

ringe and tubing.

stem from the package.

lette.

e to the stent, do not use.

stem and apply negative pressure for 20 to 30 seconds.

(

Step Action

11. Attach the inflation device to the catheter directly, ensuring no bubbles remain at the connection.

12. Leave on ambient pressure

Note: Do not apply negative pressure on the inflation device after balloon preparation and before deliverin

the stent.

14.5 Delivery procedure

Step Action

1. Prepare the vascular access site accordin

2. Pre-dilate the lesion with a PTCA catheter. Pre-dilatation must be performed using a balloon with the following 3 characteristics:

x A diameter at least 0.5 mm smaller than the treatment stent. x A length equal to or shorter than the lesion length to be dilated. x A len

3. Maintain neutral pressure on the inflation device. Open the rotating hemostatic valve as widely as possible. Note: If resistance is encountered, do not force passage. Resistance may indicate a problem and may result in damage to the stent if it is forced. Remove the system and examine.

4. Ensure guide catheter stability before advancing the Onyx Frontier system into the coronary artery. Carefully advance the Onyx Frontier system into the hub of the guide catheter.

5. Advance the stent delivery system over the guidewire to the target lesion under direct fluoroscopic visualization. Use the radiopaque balloon markers to position the stent across the lesion; perform angiography to confirm the position of the stent. If the position of the stent is not optimal, it should be carefully repositioned or removed (see Precautions – 6 stent/system removal precautions). Expansion of the stent should not

be undertaken if the stent is not properly positioned in the target lesion segment of the vessel.

6. Sufficiently tighten the rotating hemostatic valve. The stent is now ready to be deployed.

Note: Should unusual resistance be felt at any time during either lesion access or removal of the stent delivery system before stent implantation, do not force passage. Maintain guidewire placement across the lesion and remove the stent delivery system as a single unit. See Precautions – 6 Stent/system removal precautions for specific stent delivery system removal instructions. In the event the stent is not deployed, contact your local Medtronic representative for return information and avoid handling the stent with bare hands.

neutral position).

to standard practice.

th shorter than the stent to be implanted.

14.6 Deployment procedure

Step Action

1. Before stent expansion, utilize high-resolution fluoroscopy to verify that the stent has not

been dama

ed or shifted during positioning.

2. Maintain inflation pressure for 15 to 30 seconds for full expansion of the stent.

3. Do not exceed Rated Burst Pressure (RBP). The RBP is 18 atm for the 2.0 mm to

4.0 mm stent diameters and 16 atm for the 4.5 mm and 5.0 mm stent diameters. The stents should not be expanded to a diameter beyond the maximum diameter listed on the label. Do not dilate the 2.0, 2.25, and 2.5 mm stents to greater than 3.5 mm. Do not dilate the 2.75 and 3.0 mm stents greater than 4.0. Do not dilate the 3.5 and

4.0 mm stents to greater than 5.0 mm. Do not dilate the 4.5 mm and 5.0 mm stents to

reater than 6.0 mm.

4. Fluoroscopic visualization during stent expansion should be used to properly judge the

optimum stent diameter as compared to the proximal and distal native coronar

artery

y sy

giog

diameters (reference vessel diameters). Optimal stent expansion and proper apposition requires that the stent be in full contact with the arterial wall.

14.7 Removal procedure

Step Action

1. Deflate the balloon by pulling negative pressure on the inflation device. Allow adequate

time, at least 30 seconds, for full balloon deflation. Longer stents may require more time for deflation. Deflation of the balloon should be confirmed by absence of contrast within the balloon.

2. Open the hemostatic valve to allow removal of the deliver

3. Maintain position of the guide catheter and guidewire. Very slowly, withdraw the balloon

from the stent, maintaining negative pressure, allowing movement of the myocardium to

ently dislodge the balloon from the stent.

4. After removal of the deliver

5. Repeat an

14.8

In-vitro

information:

Table 14-1: Inflation pressure recommendations

Pressure

stem.

stem, tighten the hemostatic valve.

raphy and visually assess the vessel and the stent for proper expansion.

Stent nominal inner diameter (mm)

Nominal and

ATM kPa

7 atm 709 kPa 1.80 1.95 2.20 2.50 2.75 3.20 3.70 4.10 4.55 8 atm 811 kPa 1.85 2.05 2.25 2.55 2.80 3.30 3.75 4.20 4.65

9 atm 912 kPa 1.90 2.10 2.35 2.60 2.90 3.35 3.85 4.30 4.80 10 atm 1013 kPa 1.95 2.15 2.40 2.70 2.95 3.40 3.90 4.40 4.90 11 atm 1115 kPa 2.00 2.20 2.45 2.75 3.00 3.50 3.95 4.45 4.95

12 atm 1216 kPa Nominal 2.05 2.25 2.50 2.75 3.05 3.50 4.00 4.50 5.05

13 atm 1317 kPa 2.10 2.30 2.55 2.80 3.05 3.55 4.10 4.55 5.10 14 atm 1419 kPa 2.10 2.30 2.60 2.85 3.10 3.60 4.10 4.60 5.15 15 atm 1520 kPa 2.15 2.35 2.65 2.90 3.15 3.65 4.15 4.65 5.20

16 atm 1621 kPa 2.20 2.40 2.70 2.95 3.20 3.70 4.20 4.70 5.25 17 atm 1723 kPa 2.20 2.45 2.70 3.00 3.25 3.75 4.25 4.80 5.30 18 atm 1824 kPa RBP 2.25 2.45 2.75 3.05 3.30 3.80 4.30 4.85 5.35 19 atm 1925 kPa 2.30 2.50 2.80 3.10 3.35 3.85 4.35 20 atm 2027 kPa 2.35 2.55 2.85 3.15 3.40 3.90 4.45

21 atm 2128 kPa 2.40 2.60 2.90 3.20 3.50 4.00 4.50

rated burst

pressure

2.0 2.25 2.5 2.75 3.0 3.5 4.0

4.5

- -

5.0

14.9 Further dilatation of stented segment

The stent delivery balloon may not be used for post-dilatation. Post-dilatation may be

performed at the physician’s discretion with appropriately sized (length and diameter) balloons to ensure that the stent is in full contact with the vessel wall. To achieve this, a balloon to artery ratio of 1.0 to 1.1:1.0 should be used to leave a residual diameter stenosis of

near 0% (with a recommended maximum of no greater than 10%). Whenever possible, avoid

the use of grossly oversized balloons (balloon: artery ratio > 1.2).

Precaution: Do not dilate the stent beyond the following limits:

Table 14-2: Nominal stent diameters and dilatation limits

Nominal stent diameter Dilatation limits

2.00 mm 3.50 mm

2.25 mm 3.50 mm

2.50 mm 3.50 mm

2.75 mm 4.00 mm

3.00 mm 4.00 mm

3.50 mm 5.00 mm

4.00 mm 5.00 mm

4.50 mm 6.00 mm

5.00 mm 6.00 mm

All efforts should be taken to ensure that the stent is not under-dilated. If the deployed stent size is still inadequate with respect to vessel diameter, or if full contact with the vessel wall is not achieved, a larger balloon may be used to expand the stent further. This further expansion should be performed using a low profile, high pressure, and non-compliant balloon catheter. If this is required, the stented segment should be recrossed carefully with a prolapsed guidewire to avoid dislodging or displacing the stent. The balloon should be centered within the stent and should not extend outside of the stented region. The stents

should not be expanded to a diameter beyond the maximum diameter listed on the label. Do not dilate the 2.0 mm, 2.25 mm, and 2.5 mm stents to greater than 3.5 mm,

2.75 mm and 3.0 mm stents to greater than 4.0 mm, 3.5 mm and 4.0 mm stents to greater than 5.0 mm, and 4.5 mm and 5.0 mm stents to greater than 6.0 mm.

14.10 Instructions for simultaneous use of 2 devices in guide catheter (kissing balloon technique)

6 Fr (2 mm) compatibility: Any combination of one stent (models 2.0 mm to 4.0 mm) and one balloon catheter (Sprinter Legend RX models 1.25 mm to 3.5 mm up to 30 mm length, Euphora RX models 1.5 to 3.5 mm up to 30 mm length, or NC Euphora RX models 2.0 mm to

3.5 mm up to 27 mm length) can be used simultaneously within a 6 Fr (2 mm)/GC/MID 1.8 mm (0.070 in) guide catheter.

The technique can be performed as per the instructions listed below:

1. Insert the stent using the instructions provided (refer to Section 14.5).

2. Insert a second guidewire and a balloon catheter, track to the target site and inflate the balloon.

3. Removing the catheters: Remove one catheter and its associated guidewire completely before removing the other catheter and its associated guidewire.

15 Reuse precaution statement

For single use only.

Do not resterilize or reuse.

Disclaimer of warranty

The warnings contained in the product labeling provide more detailed information and are considered an integral part of this disclaimer of warranty. Although the product has been manufactured under carefully controlled conditions, Medtronic has no control over the conditions under which this product is used. Medtronic, therefore, disclaims all warranties, both express and implied, with respect to the product, including, but not limited to, any implied warranty of merchantability or fitness for a particular purpose. Medtronic shall not be liable to any person or entity for any medical expenses or any direct, incidental, or consequential damages caused by any use, defect, failure, or malfunction of the product, whether a claim for such damages is based upon warranty, contract, tort, or otherwise. No person has any authority to bind Medtronic to any representation or warranty with respect to the product.

The exclusions and limitations set out above are not intended to, and should not be construed so as to, contravene mandatory provisions of applicable law. If any part or term of this disclaimer of warranty is held to be illegal, unenforceable, or in conflict with applicable law by a court of competent jurisdiction, the validity of the remaining portions of this disclaimer of warranty shall not be affected, and all rights and obligations shall be construed and enforced as if this disclaimer of warranty did not contain the particular part or term held to be invalid.

Medtronic, Inc.

710 Medtronic Parkway Minneapolis, MN 55432 USA +1 763 514 4000

www.medtronic.com

US Customer Service / Product Inquiries

+1 888 283 7868

  Rev %

Medtronic ONYXNG20012UX Technical Manual

Specifications and Main Features

Frequently Asked Questions

User Manual

1 Symbol glossary

2 Onyx Frontier Zotarolimus-Eluting Coronary Stent System

2.1 Device component description

2.2 Drug component description

2.2.1 Zotarolimus

2.2.2 Polymer system description

2.2.3 Product matrix and zotarolimus content

3 Indications

4 Contraindications

5 Warnings

6 Precautions

6.1 Pre- and post-procedure antiplatelet regimen

6.1.1 Oral antiplatelet therapy

6.2 Use of multiple stents

6.3 Use in conjunction with other procedures

6.4 Brachytherapy

6.5 Use in special populations

6.5.1 Pregnancy

6.5.2 Lactation

6.5.3 Gender

6.5.4 Ethnicity

6.5.5 Pediatric use

6.5.6 Geriatric use

6.5.7 Lesion/vessel characteristics

6.6 Drug interactions

6.7 Magnetic resonance imaging (MRI) safety information

6.8 Stent handling precautions

6.9 Stent placement precautions

6.10 Stent/system removal precautions

6.11 Post-procedure

7 Drug information

7.1 Mechanisms of action

7.2 Metabolism

7.3 Pharmacokinetics of the stent

7.4 Pharmacokinetics following multi-dose intravenous administration of zotarolimus

7.5 Mutagenesis, carcinogenicity, and reproductive toxicology

7.5.1 Mutagenesis

7.5.2 Carcinogenicity

7.5.3 Reproductive toxicology

7.6 Pregnancy

7.7 Lactation

8.1 The RESOLUTE ONYX Clinical Program

8.2 Supportive RESOLUTE and RESOLUTE INTEGRITY data:

9 Clinical outcomes

9.1 Clinical outcomes for RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study and RESOLUTE ONYX 2.0 mm Clinical Study

9.2 Potential adverse events

9.2.1 Potential adverse events related to zotarolimus

9.2.2 Potential adverse events related to BioLinx polymer

9.2.3 Potential risks associated with percutaneous coronary diagnostic and treatment procedures

10 Clinical studies

10.1 Results of the RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study

10.2 Results of the RESOLUTE ONYX 2.0 mm Clinical Study

10.3 Subjects with diabetes mellitus in the RESOLUTE pooled analysis

10.4 Subjects with diabetes mellitus in the RESOLUTE 38 mm length group

10.5 Subjects receiving short-term DAPT

10.5.1 Onyx ONE Clear Primary Analysis

10.5.2 The Onyx ONE Global RCT

10.6 Subjects with chronic total occlusion

10.7 Pooled results of the Global RESOLUTE Clinical Trial Program (RESOLUTE FIM, RESOLUTE US, RESOLUTE AC, RESOLUTE Int, RESOLUTE Japan)

11 Patient selection and treatment

12 Patient counseling information

13 How supplied

14 Directions for use

14.1 Access to package holding sterile stent delivery system

14.2 Inspection before use

14.3 Materials required

14.4 Preparation precaution

14.4.1 Guidewire lumen flush

14.4.2 Delivery system preparation

14.5 Delivery procedure

14.6 Deployment procedure

14.7 Removal procedure

14.9 Further dilatation of stented segment

14.10 Instructions for simultaneous use of 2 devices in guide catheter (kissing balloon technique)

15 Reuse precaution statement