Medtronic RSINT22518W Instructions for Use

Resolute Integrity™ Zotarolimus-Eluting Coronary Stent System Over the Wire Delivery System
INSTRUCTIONS FOR USE
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Table of Contents
1 RESOLUTE INTEGRITY™ ZOTAROLIMUS ELUTING CORONARY STENT SYSTEM ..................... 1
1.1 DEV ICE COMPONE NT DESCRIPTION .......................................................................................... 2
1.2 DRUG COMPONENT DESCRIPTION ............................................................................................ 3
1.2.1 Zotarolimus ................................................................................................................... 3
1.2.2 Polymer System Description ............................................................................................ 3
1.2.3 Product Matrix and Zotarolimus Content ............................................................................ 4
2 INDICATIONS ......................................................................................................................... 5
3 CONTRAINDICATIONS............................................................................................................ 5
4 WARNINGS ............................................................................................................................ 5
5 PRECAUTIONS....................................................................................................................... 5
5.1 PRE- AND POST-PROCEDURE ANTIPLATELET REGIMEN.................................................................. 6
5.1.1 Oral Antiplatelet Therapy ................................................................................................. 6
5.2 USE OF MULTIPLE STENTS ..................................................................................................... 7
5.3 USE IN CONJUNCTION WITH OTHER PROCEDURES........................................................................ 7
5.4 BRACHYTHERAPY ................................................................................................................. 7
5.5 USE IN SPECIAL POPULATIONS ................................................................................................ 7
5.5.1 Pregnancy..................................................................................................................... 7
5.5.2 Lactation ....................................................................................................................... 8
5.5.3 Gender ......................................................................................................................... 8
5.5.4 Ethnicity ........................................................................................................................ 8
5.5.5 Pediatric Use ................................................................................................................. 8
5.5.6 Geriatric Use ................................................................................................................. 8
5.5.7 Lesion/Vessel Characteristics........................................................................................... 8
5.6 DRUG INTERACTIONS ............................................................................................................ 8
5.7 MAGNETI C RESONANCE IMAGING (MRI)..................................................................................... 9
5.8 STENT HANDLI NG PRECAUTIONS .............................................................................................. 9
5.9 STENT PLACEMENT PRECAUTIONS ......................................................................................... 10
5.10 STENT/SYSTEM REMOVAL PRECAUTIONS ................................................................................. 10
5.11 POST-P ROCEDURE ............................................................................................................. 11
6 DRUG INFORMATION ........................................................................................................... 11
6.1 MECHA NISMS OF ACTION ..................................................................................................... 11
6.2 METABOLISM..................................................................................................................... 11
6.3 PHARMACOKINETICS OF THE RESOLUTE STE N T ......................................................................... 11
6.4 PHARMACOKINETICS FOLLOWING MUL T I -DOSE INTRAVENOUS ADMINISTRATION OF ZOTAROLIMUS .......... 12
6.5 MUTAGENESIS, CARCINOGENICITY AND REPRODUCTIVE TOXICOLOGY ............................................. 13
6.5.1 Mutagenesis ................................................................................................................ 13
6.5.2 Carcinogenicity ............................................................................................................ 13
6.5.3 Reproductive Toxicology ............................................................................................... 13
6.6 PREGNANCY ..................................................................................................................... 13
6.7 LACTATION ....................................................................................................................... 14
7 OVERVIEW OF CLINICAL TRIALS.......................................................................................... 14
8 ADVERSE EVENTS ............................................................................................................... 19
8.1 OBSERVED ADVERSE EVENTS ............................................................................................... 19
8.2 POTENTIAL ADVERSE EVENTS ............................................................................................... 21
8.2.1 Potential Adverse Events Related to Zotarolimus .............................................................. 21
8.2.2 Potential Adverse Events Related to BioLinx polymer ........................................................ 21
8.2.3 Potential Risks Associated with Percutaneo us Coronary Diagnostic and Treatment Procedures21
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9
CLINICAL STUDIES .............................................................................................................. 22
9.1 RESULTS OF THE RESOLUTE US TRIAL ................................................................................. 22
9.2 RESULTS OF THE RESOLUTE AC CLINICAL TRIAL..................................................................... 49
9.3 RESULTS OF THE RESOLUTE INTERNATIONAL STUDY ................................................................ 55
9.4 RESULTS OF THE RESOLUTE FIM CLINICAL TRIAL.................................................................... 57
9.5 RESULTS OF THE RESOLUTE JAPAN CLINICAL TRIAL................................................................. 62
9.6 RESULTS OF THE RESOLUTE INTEGRITY US POST MARKET STUDY ........................................... 67
9.7 SUBJECTS WITH DIABETES MELLITUS IN THE RESOLUTE POOLED ANALYSIS...................................... 71
9.7.1 Subjects with Diabetes Mellitus in the RESOLUTE 38 mm Length Stent Sub-study ................ 74
9.8 SUBJECTS WITH CHRONIC TOTAL OCCLUSION ........................................................................... 75
9.9 POOLED RESULTS OF THE GLOBAL RESOLUTE CLINICAL TRIAL PROGRAM (RESOLUTE FIM,
RESOLUTE US, RES O LU TE AC, RES OL UTE INT, RES O LU TE JAPAN) .................................... 79
9.9.1 Gender Analysis f rom the RESOLUTE Pooled On-label Dataset.......................................... 82
9.9.2 Subset Analyses from the Resolute Pooled Dataset........................................................... 86
10 PATIENT SELECTION AND TREATMENT ............................................................................... 88
11 PATIENT COUNSELING INFORMATION ................................................................................. 89
12 HOW SUPPLIED ................................................................................................................... 89
13 DIRECTIONS FOR USE ......................................................................................................... 89
13.1 ACCESS TO PACKAGE HOLDING STE R I LE STE NT DELIVERY SYS TEM ............................................... 89
13.2 INSPECTION PRIOR TO USE................................................................................................... 89
13.3 MATERIALS REQUIRE D......................................................................................................... 90
13.4 PREPARATION PRE CAUTION .................................................................................................. 90
13.4.1 Guidewire Lumen Flush................................................................................................. 90
13.4.2 Delivery System Preparation .......................................................................................... 90
13.5 DELIVERY PROCEDURE........................................................................................................ 91
13.6 DEPLOYMENT PROCEDURE ................................................................................................... 91
13.7 REMOVAL PROCEDURES ...................................................................................................... 92
13.8 IN-VITRO INFORMATION: ....................................................................................................... 92
13.9 FURTHER DILATATION OF STE N TE D SEGMENT ........................................................................... 92
14 REUSE PRECAUTION STATEMENT ....................................................................................... 93
DISCLAIMER OF WARRANTY ........................................................................................................... 94
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THE COMPONENTS OF THE RESOLUTE INTEGRITY ZOTAROLIMUS-ELUTING CORONARY STENT SYSTEM ARE STERILE.

1 RESOLUTE INTEGRITY™ ZOTAROLIMUS ELUTING CORONARY STENT SYSTEM

The Med tronic Resolute Integrity™ Zotarolimus-Eluting Coronary Stent System (Resolute Integrity System) is a device/drug combination product comprised of the following device components: the Integrity coronary stent and MicroTrac™ delivery systems and a drug component (a formulation of zotarolimus in a polymer coating). The characteristics of the Resolute Integrity System are described in Table 1-1.
Table 1-1: Device Component Description and Nominal Dimensions
Resolute Integrity Zotarolimus-Eluting Coronary Stent System
Component
Small Vessel Medium/Large Vessel
Available Stent Diameters (mm): 2.25, 2.5, 2.75 3.0, 3.5, 4.0
Available Stent Lengths Unexpanded (mm):
Stent Material & Geometry:
Drug Component: A coating of polymers loaded with zotarolimus in a formulation applied to the entire surface
Delivery System Working Length: 140 cm
Delivery System Luer Adapter Ports: Two-arm luer (side arm for access to balloon inflation/deflation lumen. Straight arm is
Stent Delivery Balloon:
8, 12, 14, 18, 22, 26, 30 9, 12, 15, 18, 22, 26, 30, 34, 38
A cobalt-based alloy conforming to ASTM F562 and ISO 5832-6:1997 with 1.0 mm length elements, 7.5 alternating crowns and
0.0035” strut thickness; the stent utilizes a single helix fusion pattern. The coronary stent is formed from a single wire bent into a continuous sinusoid pattern and then laser fused back onto itself. The stents are provided in multiple lengths and diameters.
of the stent at a dose of approximately 1.6 μg/m m drug content of 380 μg on the largest st ent (4.0 mm x 38 m m).
continuous with shaft inner lumen). Designed for guidewire less than or equal to 0.36 mm (0.014 inch).
Single-layer Pebax balloon, wrapped over an inner member tubing with 2 radiopaque marker bands to locate the stent edges.
Over the Wire Delivery System
A cobalt-based alloy conforming to ASTM F562 and ISO 5832-6:1997 with 0.9 mm length elements, 9.5 alternating crowns and 0.0035” strut thickness; utilizes a helical u-joint fusion pattern. The coronary stent is formed from a single wire bent into a continuous sinusoid pattern and then laser fused back onto itself. The stents are provided in multiple lengths and diameters.
2
which results in a maximum nominal
Balloon Inflation Pressure: Nominal Pressure: 9 ATM (912 kPa)
Rated Burst Pressure: 16 ATM (1621 kPa) for 2.25 - 3.5 mm diameters 15 ATM (1520 kPa) for 4.0 mm diameter
Minimum Guide Catheter Inner Diameter:
Catheter Shaft Outer Diameter: Proximal OD: 3.4 F (1.1 mm, 0.044 inch)
5 F (1.42 mm, 0.056 inch)
Distal Section OD: 2.7 F (0.91 mm, 0. 036 inch)
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1.1 Device Component Description

The Med tronic Resolute Integrity Zotarolimus-Eluting Coronary Stent System (Resolute Integrity System) consists of a balloon-expandable intracoronary drug-eluting stent pre-mounted on the MicroTrac Over the Wire (OTW) stent delivery system. The Resolute Integrity stent is manufactured f rom a cobalt alloy and is formed from a single wire bent into a continuous sinusoid pattern and then laser f used back onto itself. The stents are available in multiple lengths and diameters. The delivery system has two radiopaque markers to aid in the placement of the stent during fluoroscopy and is co mpatible with 0.014 inch (0.36 mm) guidewires. The MicroTrac OTW delivery system (Figure 1-1) has an ef f ective length of 140 cm.
Figure 1-1: MicroTrac OTW Delivery System (with Stent)
The stent is crimped on various size delivery catheter balloons, which are sized from 2.25 to 4.0 mm. The Resolute Integrity available stent sizes are listed in Table 1-2.
Table 1-2: Resolute Integrity Stent Sizes
Diameter
(mm)
2.25
2.5
2.75
3.0 ---
3.5 --- 9 9 --- 9 9 9 9 9 9 9
4.0 --- 9 9 --- 9 9 9 9 9 9 9
Note: “---“ indicates sizes not offered; “9” indicates s izes off ered.
8 9 12 14 15 18 22 26 30 34 38
9
9
9
9 9
---
9 9
---
9 9
---
9 9
Stent Length (mm)
9 9 9 9
---
9 9 9 9
---
9 9 9 9
---
9 9 9 9 9 9 9
---
--- ---
--- ---
--- ---
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1.2 Drug Component Description

The drug coating of the Resolute Integrity System consists of the drug zotarolimus (the active ingredient) and BioLinx
®
polymer system (the inactive ingredient).

1.2.1 Zotarolimus

The active pharmaceutical ingredient utilized in the Resolute Integrity System is zotarolimus. It is a tetrazole-containing macrocyclic immunosuppressant.
The Chemical name of zotarolimus is:
[3S-3R*[S*(1R*,3S*,4R*)],6S*,7E,9S*,10S*,12S*,14R*,15E,17E,19E,21R*, 23R*, 26S*,27S*,34aR*]]­9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[2-[3-methoxy-4­(1H-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy­3H-pyrid o[2,1-c] [1,4] oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.
The chemical structure of zotarolimus is shown in Figure 1-2:
NN
N
N
MeO
N
O
Figure 1-2: 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
and its molecular weight is 966.2.
Zotarolimus does not have any ionizable group(s) in the physiological pH range; therefore, its solubility is exp ected to be unaltered in this range.

1.2.2 Polymer System Description

The Resolute Integrity stent is comprised of a bare metal stent with a Parylene C primer coat and a co ating 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 1-3:
OO OH
O
O
MeO
OHO
OMe
O
C10 Polymer C19 Polymer PVP Polymer
Figure 1-3: Chemical Structure of the BioLinx Polymer Subunits
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1.2.3 Product Matrix and Zotarolimus Content

(μg)
Table 1-3: Resolute Integrity Zotarolimus-Eluting Coronary Stent System Product
Matrix and Nominal Zotarolimus Doses
Product Number
OTW
RSINT22508W 2.25 8 59
RSINT25008W 2.5 8 59
RSINT27508W 2.75 8 59
RSINT30009W 3.0 9 90
RSINT35009W 3.5 9 90
RSINT40009W 4.0 9 90
RSINT22512W 2.25 12 85
RSINT25012W 2.5 12 85
RSINT27512W 2.75 12 85
RSINT30012W 3.0 12 120
RSINT35012W 3.5 12 120
RSINT40012W 4.0 12 120
RSINT22514W 2.25 14 102
RSINT25014W 2.5 14 102
RSINT27514W 2.75 14 102
RSINT30015W 3.0 15 150
RSINT35015W 3.5 15 150
RSINT40015W 4.0 15 150
RSINT22518W 2.25 18 128
RSINT25018W 2.5 18 128
RSINT27518W 2.75 18 128
RSINT30018W 3.0 18 180
RSINT35018W 3.5 18 180
RSINT40018W 4.0 18 180
RSINT22522W 2.25 22 153
RSINT25022W 2.5 22 153
RSINT27522W 2.75 22 153
RSINT30022W 3.0 22 220
RSINT35022W 3.5 22 220
RSINT40022W 4.0 22 220
RSINT22526W 2.25 26 188
RSINT25026W 2.5 26 188
RSINT27526W 2.75 26 188
RSINT30026W 3.0 26 260
RSINT35026W 3.5 26 260
RSINT40026W 4.0 26 260
RSINT22530W 2.25 30 213
RSINT25030W 2.5 30 213
RSINT27530W 2.75 30 213
Nominal Expanded
Stent ID (mm)
Nominal Unexpanded
Stent Length (mm)
Nominal Zotarolimus
Content
4
Table 1-3: Resolute Integrity Zotarolimus-Eluting Coronary Stent System Product
(μg)
Matrix and Nominal Zotarolimus Doses
Product Number
OTW
RSINT30030W 3.0 30 300
RSINT35030W 3.5 30 300
RSINT40030W 4.0 30 300
RSINT30034W 3.0 34 340
RSINT35034W 3.5 34 340
RSINT40034W 4.0 34 340
RSINT30038W 3.0 38 380
RSINT35038W 3.5 38 380
RSINT40038W 4.0 38 380

2 INDICATIONS

The Resolute Integrity Zotarolimus-Eluting Coronary Stent System is indicated for improving coronary luminal diameters in patients, including those with diabetes mellitus, with symptomatic ischemic heart disease due to de nov o lesions of length 35 mm in native coronary arteries with reference vessel diameters of 2.25 to 4.2 mm. In addition, the Resolute Integrity Zotarolimus-Eluting Coronary Stent System is indicated for treating de novo chronic total occlusions.

3 CONTRAINDICATIONS

The Resolute Integrity System is contraindicated for use in:
Patients with known hypersensitivity or allergies to aspirin, heparin, bivalirudin, clopidogrel, prasug rel, ticagrelor, ticlopidine, drugs such as zotarolimus, tacrolimus, sirolimus, everolimus, or similar drugs or any other analogue or derivative.
Patients with a known hypersensitivity to the cobalt-based alloy (cobalt, nickel, chromium, and molybdenum).
Patients with a known hypersensitivity to the BioLinx polymer or its individual components (see details in Section 1.2.2 – Polymer System Description).
Coronary artery stenting is contraindicated for use in:
Patients in whom anti-platelet and/or anticoagulation therapy is contraindicated.
Patients who are judged to have a lesion that prevents complete inflation of an angioplasty balloon
or proper placement of the stent or stent delivery system.

4 WARNINGS

Please ensure that the inner package has not been opened or d amaged as this would indicate the sterile barrier has b een breached.
The use of this product carries the same risks associated with coronary artery stent implantation procedures which include subacute and late vessel thrombosis, vascular complications, and/or bleeding events.
This p ro d uct should not be used in patients who are not likely to comply with the recommended antiplatelet therapy.

5 PRECAUTIONS

Only p hysicians who have received adequate training should perform implantation of the stent.
Subsequent stent restenosis or occlusion may require repeat catheter-based treatments (including
ballo on d ilatation) of the arterial segment containing the stent. The lo ng-term outcome following repeat catheter-based treatments of previously implanted stents is not well characterized.
The risks and benefits of stent implantation should be assessed for patients with a history of severe reactio n to contrast agents.
Nominal Expanded
Stent ID (mm)
Nominal Unexpanded
Stent Length (mm)
Nominal Zotarolimus
Content
5
Do not expose or wipe the product with organic solvents such as alcohol.
When drug eluting stents (DES) are used outside the specified Indications for Use, patient
outcomes may differ fro m the results observed in the RESOLUTE pivotal clinical trials.
Comp ared to use within the specified Indications for Use, the use of DES in patients and lesions outside of the labeled indications, including more tortuous anatomy, may have an increased risk of adverse events, including stent thrombosis, stent embolization, MI, or death.
Care should be taken to control the position of the guide catheter tip during stent delivery, deployment, and balloon withdrawal. Before withdrawing the stent delivery system, visually confirm co mplete balloon deflation by fluoroscopy to avoid guiding catheter movement into the vessel and sub sequent arterial damage.
Stent thrombosis is a low-frequency event that is frequently associated with myocardial infarction (MI) o r d eath. Data from the RESOLUTE clinical trials have been prospectively evaluated and adjudicated using the d efinition developed by the Academic Research Consortium (ARC) (see
Section 9.9 – Pooled Results of the Global RESOLUTE Clinical Trial Program (RESOLUTE FIM, RESOLUTE US, RESOLUTE AC, RESOLUTE International, RESOLUTE Japan) for more
inf ormation).

5.1 Pre- and Post-Procedure Antiplatelet Regimen

In the Med tronic RESOLUTE US Clinical Trial, RESOLUTE AC Clinical Trial, RESOLUTE International Study, RESOLUTE First-In-Man (FIM) Clinical Trial and RESOLUTE Japan Clinical Trial, the protocol sp ecified administration of clopidogrel or ticlopidine prior to the p rocedure and for a p eriod of at least 6 months post-procedure and up to 12 months in patients who were not at high risk of bleeding. Aspirin was administered prior to the procedure concomitantly with clopidogrel or ticlopidine and then continued indef initely to reduce the risk of thrombosis. In the Medtronic RESOLUTE US Primary Enrollment Group, 95.9%, 93.8% and 46.6% of the patients remained on dual antiplatelet therapy at 6 months, 12 months and 60 months, respectively. In the RESOLUTE AC Clinical Trial, 93.1%, 84.2% and 11.0% of the p atients remained on dual antiplatelet therapy at 6 months, 12 months and 60 months, respectively. In the RESOLUTE International Study, 95.9%, 91.1% and 34.6% of the patients remained on dual antiplatelet therapy at 6 months, 12 months and 36 months, respectively. In the RESOLUTE FIM Clinical Trial, 79.1%, 58.1% and 39.4% of the patients remained on dual antiplatelet therapy at 6 months, 12 mo nths and 60 months,
respectively. In the RESOLUTE Japan Clinical Trial, 99.0%, 94.9% and 62.5% of the patients remained on dual antiplatelet therapy at 6 months, 12 months and 60 months, resp ectively. In the RESOLUTE 38 mm Length Group, 92.8%, 91.4% and 61.5% of the patients remained o n d ual antiplatelet therapy at 6 months, 12 months and 60 months, respectively. See
Section
9 - CLINICAL STUDIES, for more information.

5.1.1 Oral Antiplatelet Therapy

Dual antiplatelet therapy (DAPT) using a combination treatment of aspirin with a P2YP12 platelet inhibitor af ter percutaneous coronary intervention (PCI), reduces the risk of stent thrombosis and ischemic cardiac events, b ut may increase 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 p o st-procedural antiplatelet recommendations.
1
Per 2016 ACC/AHA guidelines,
a daily aspirin dose of 81 mg is recommended indefinitely after PCI. A P2Y12 platelet inhibitor should be g iven daily for at least 6 months in stable ischemic heart disease patients and f o r at least 12 months in patients with acute coronary syndrome (ACS).
In p ivo tal trials of current generation DES, subjects were prescribed DAPT for at least 6 months post­procedure, and most patients who were not at high risk of bleeding used DAPT for at least 12 months.
Consistent with the 2016 ACC/AHA guidelines,
1
and the DAPT Study,2 longer duration of DAPT may be
co nsidered in patients who have tolerated DAPT without a bleeding complication and who are not at high
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
6
bleeding risk. In patients who are at a hig h risk of bleeding or who develop significant bleeding during DAPT treatment, these guidelines suggest that a sho rter DAPT d uration may be reasonable. However, def initive evidence supporting the safety of short DAPT duration has not been established in p rospective clinical studies.
Decisions about duration of DAPT are best made on an ind ividual basis and should integrate clinical judgment, assessment of ischemic and bleeding risks, and p atient preference.
Premature discontinuation or interruption of prescribed antiplatelet medication could result in an increased risk of stent thrombosis, MI or death.
Prio r to PCI, if premature discontinuation of antiplatelet therapy is anticipated, physicians should caref ully evaluate with the patient whether a DES and its associated recommended DAPT regimen is the ap p ropriate PCI choice.
Following PCI, if elective noncardiac surgery requiring suspension of antiplatelet therapy is co nsidered, 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 d iscretion of the patient’s treating physician(s), the antiplatelet therapy should be restarted as so o n as possible.

5.2 Use of Multiple Stents

The lo ng -term effects of zotarolimus are currently unknown. The extent of the patient’s exposure to zotarolimus drug and the stent and polymer coating is directly related to the number of stents and total stent length implanted.
When multip le stents are required, stent materials should be of similar composition. Placing multiple stents of different materials in contact with each other may increase potential for corrosion. To avoid the possibility of dissimilar metal corrosion, do not implant stents of different materials in tandem where overlap or contact is possible.
Potential interactions of the Resolute Integrity 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 withd rawn f rom the patient before removing any additional equipment.

5.3 Use in Conjunction with Other Procedures

The saf ety and effectiveness of using mechanical atherectomy devices (directional atherectomy catheters, rotational atherectomy catheters) or laser angioplasty catheters in conjunction with Resolute Integrity stent implantation have not been established.

5.4 Brachytherapy

The saf ety and effectiveness of the Resolute Integrity stent in target lesions treated patients with prior brachytherapy, or the use of brachytherapy to treat in-stent restenosis of a Resolute Integrity stent, have not b een established.

5.5 Use in Special Populations

Information on use of the Resolute Integrity stent in certain special patient populations is derived from clinical studies of the Resolute stent system, which uses the same drug (zotarolimus) – see Section 7 OVERVIEW OF CLINICAL TRIALS for a d escription of the other features of the Resolute stent system co mpared to the Resolute Integrity stent system.

5.5.1 Pregnancy

Pregnancy Category C. See Section 6.6 Pregnancy under Drug Information. There are no well- co ntrolled studies in p regnant women or men intending to father children. The Resolute Integrity stent
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.
7
sho uld be used during pregnancy only if the potential benefit outweighs the potential risk to the embryo or fetus. Effective contraception should be initiated before implanting a Resolute Integrity stent and for 1 year af ter implantation.

5.5.2 Lactation

It is not kno wn whether zotarolimus is excreted in human milk. The pharmacokinetic and safety profiles of zotarolimus in infants are not known. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from zotarolimus, a decision should be made whether to discontinue nursing or to implant a Resolute Integrity stent, taking into account the imp o rtance of the stent to the mother. See Section 6.7 – Lactation under Drug Information.

5.5.3 Gender

Clinical studies of the Resolute stent did not suggest any significant differences in safety and ef f ectiveness for male and female patients. See Section 9.9.1 – Gender Analysis from the
RESOLUTE Pooled On-label Dataset.

5.5.4 Ethnicity

Clinical studies of the Resolute stent did not include sufficient numbers of patients to assess for dif ferences in safety and effectiveness due to ethnicity.
5.5.5
The saf ety and effectiveness of the Resolute Integrity stent in patients below the age of 18 years have not b een established.

5.5.6 Geriatric Use

Clinical studies of the Resolute stent did not have an upper age limit. Among the 1242 patients treated with the Resolute stent in the Resolute US Main Study that included 2.25 - 3.5 mm stents, 617 patients were ag e 65 o r o lder and 88 patients were age 80 or older. A post hoc analysis of patients treated with the Resolute stent showed no significant differences between subjects under age 65 vs. age 65 and older in the 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.

Pediatric Use

5.5.7 Lesion/Vessel Characteristics

The saf ety and effectiveness of the Resolute Integrity stent have not been established in the cerebral, caro tid , or peripheral vasculature or in the f ollowing coronary disease patient populations:
Patients with coronary artery reference vessel diameters <2.25 mm or >4.2 mm.
Patients with coronary artery lesions longer than 35 mm or requiring more than one Resolute
Integrity stent.
Patients with evidence of an acute MI within 72 hours of intended stent implantation.
Patients with vessel thrombus at the lesion site.
Patients with lesions located in a saphenous vein graft, in the left main coronary artery, ostial
lesions, or bifurcation lesions.
Patients with diffuse disease or poor flow distal to identified lesions.
Patients with tortuous vessels in the region of the target vessel or proximal to the lesion.
Patients with in-stent restenosis.
Patients with moderate or severe lesion calcification at the target lesion.
Patients with 3 vessel disease.
Patients with a left ventricular ejection fraction of <30%.
Patients with a serum creatinine of >2.5 mg/dl.
Patients with longer than 24 months of follow-up.

5.6 Drug Interactions

The ef f ect of potential drug interactions on the safety or effectiveness of the Resolute Integrity stent has not b een investigated. While no specific clinical data are available, drugs, like sirolimus, that act through the same b inding protein (FKBP12) may interfere with the efficacy of zotarolimus. Zotarolimus is metabolized by CYP3A4, a human cytochrome P450 enzyme. When administered concomitantly with
8
200 mg keto conazole bid, a strong inhibitor of CYP3A4, zotarolimus produces less than a 2-fold increase in AUC
with no ef fect on C
0-i nf
max
drug interactions when deciding to place a Resolute Integrity stent in a patient who is taking drugs that are kno wn 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.
Formal drug interaction studies have not been conducted with the Resolute Integrity stent.

5.7 Magnetic Resonance Imaging (MRI)

Non-clinical testing has demonstrated the Resolute Integrity stent up to a total length of 120 mm is MR Conditional. It can be scanned safely under the following conditions:
Static magnetic field of 1.5 and 3 Tesla.
Spatial gradient field of 1000 G/cm or less
Maximum whole body averaged specific absorption rate (SAR) of 2.0 W/kg or less under normal
operating mode only, for 15 minutes of scanning.
1.5 T
Based on non-clinical testing and modeling, a 38 mm Resolute Integrity stent was calculated to produce an in-vivo temperature rise of less than 2.35°C, and overlapped stents with a maximum length of 120 mm were calculated to produce an in-vivo temperature rise of less than 3.87°C at a maximum whole body averaged specific absorption rate (SAR) of 2.0 W/kg for 15 minutes of MR scanning per sequence in a 64 MHz whole body transmit coil, which corresponds to a static field of 1.5 Tesla. These calculations do not take into consideration the cooling effects of p erfusion and blood flow. The maximum whole body averaged specific absorption rate (SAR) was derived by calculation.
. Therefore, consideration should be given to the potential for
3 T
Based on non-clinical testing and modeling, a 38 mm Resolute Integrity stent was calculated to produce an in-vivo temperature rise of less than 3.29°C and overlapped stents with a maximum length of 120 mm were calculated to produce an in-vivo temperature rise of less than 3.95°C at a maximum whole body averaged specific absorption rate (SAR) of 2.0 W/kg for 15 minutes of MR scanning per sequence in a 3 T GE SIGNA HDx with software version 14\LX\MR release 14.0.M5A.0828.b. These calculations do not take into consideration the cooling effects of perfusion and blood flow. The maximum whole body averag ed specific absorption rate (SAR) was derived by calculation.
1.5 T and 3 T
The Resolute Integrity stent should not move or migrate when exposed to MR scanning immediately post-implantation. MRI at 3 Tesla and 1.5 Tesla may be performed immediately following the imp lantation of the stent. Non-clinical testing at field strength greater than 3 Tesla has not been performed to evaluate stent migration and heating. MR image quality may be compromised if the area of interest is in the same area or relatively close to the position of the d evice. Therefore, it may be necessary to optimize MR imaging parameters for the presence of the stent. The image artifact extends approximately 1 cm from the device, both inside and outside the device lumen when scanned in non­clinical testing using the spin echo and g radient echo sequences specified in ASTM F2119-01; the device lumen was always observed during scanning. This testing was completed using a GE SIGNA HDx with software version 14\LX\MR release 14.0.M5A.0828.b.

5.8 Stent Handling Precautions

Fo r sing le use only. The Reso lute Integrity System is provided sterile. Do not resterilize or reuse this
product. Note the “Use By” date on the product label. Do not use if package or product has been opened or damaged.
Only the contents of the pouch should be considered sterile. The outside surface of the pouch is not
sterile.
Do not remove the contents of the pouch until the device will be used immediately.
Do not remove the stent from the delivery balloon; removal may damage the stent and polymer
co ating and /or lead to stent embolization. The Reso lute Integrity System is intended to perform as a system. The stent is not designed to be crimped onto another delivery device.
9
Special care must be taken not to handle or in any way disrupt the stent on the balloon. This is most
imp o rtant while removing the catheter from the packaging, placing it over the guidewire, and advancing it through the rotating hemostatic valve and guide catheter hub.
Do not try to straighten a kinked shaft or hypotube. Straightening a kinked metal shaft may result in
breakag e of the shaft.
Stent manip ulation (e.g., rolling the mounted stent with your fingers) may cause coating damage,
co ntamination or dislodgement of the stent from the delivery system balloon.
The Resolute Integrity System must not be exposed to any direct handling or contact with liquids
prior to preparation and delivery as the coating may be susceptible to damage or premature drug elution.
Use only the ap propriate balloon inflation media. Do not use air or any gaseous medium to inflate
the b alloon as this may cause uneven expansion and difficulty in deployment of the stent.
The Resolute Integrity stent delivery system should not be used in conjunction with any other stents
or for post-dilatation.

5.9 Stent Placement Precautions

The vessel must be pre-dilated with an appropriately sized balloon. Refer to the pre-dilatation
ballo on sizing described in Section 13.5 – Delivery Procedure. Failure to do so may increase the risk o f placement difficulty and procedural complications.
Do not prepare or pre-inflate the balloon prior to stent deployment other than as directed. Use the
ballo on p urging technique described in Section 13 – DIRECTIONS FOR USE.
Guide catheters used must have lumen sizes that are suitable to accommodate the stent delivery
system (see Device Component Description in Table 1-1).
Af ter preparation of the stent delivery system, do not induce negative pressure on the delivery
catheter prior to placement of the stent across the lesion. This may cause premature dislodgment of the stent f rom the balloon or delivery difficulties.
Ballo o n pressures should be monitored during inflation. Do not exceed rated burst pressure as
indicated on the p roduct label. Use of pressures higher than those specified on the product label may result in a ruptured balloon with possible intimal damage and dissection.
In small or diffusely diseased vessels, the use of hig h balloon inflation pressures may over-expand
the vessel distal to the stent and could result in vessel dissection.
Implanting a stent may lead to a dissection of the vessel distal and/or proximal to the stented portion
and may cause acute closure of the vessel requiring additional intervention (e.g., CABG, further dilatation, placement of additional stents, or o ther intervention).
Do not expand the stent if it is not properly positioned in the vessel (see Section 5.10
PRECAUTI ONS-Stent/ System Removal Precautions).
Placement of the stent has the potential to compromise side branch patency.
Do not attempt to pull an unexpanded stent back through the guide catheter, as dislodgement of the
stent f rom the balloon may occur. Remove as a single unit per instructions in Section 5.10 PRECAUTI ONS -Stent/System Removal Precautions.
Under-expansion of the stent may result in stent movement. Care must be taken to properly size
the stent to ensure that the stent is in full contact with the arterial wall upon deflation of the balloon.
Stent retrieval methods (e.g., use of additional wires, snares and/or forceps) may result in additional
trauma to the coronary vasculature and/or the vascular access site. Complications may include bleeding, hematoma, or pseudoaneurysm.
Ensure f ull coverage of the entire lesion/dissection site so that there are no gaps between stents.
Administration of appropriate anticoagulant, antiplatelet and coronary vasodilator therapy is critical
to successful stent implantation.

5.10 Stent/System Removal Precautions

If removal of a stent system is required prior to deployment, ensure that the guide catheter is coaxially positioned relative to the stent delivery system and cautiously withdraw the stent delivery system into the g uide catheter. Should unusual resistance be felt at any time when withdrawing the stent towards the g uide 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:
10
Do not retract the stent delivery system into the guide catheter. Maintain guidewire p lacement
acro ss the lesion and carefully pull back the stent delivery system until the p roximal balloon marker of the stent delivery system is aligned with the d istal tip of the guide catheter.
The system should be pulled back into the descending aorta toward the arterial sheath. As the distal
end of the guide catheter enters into the arterial sheath, the catheter will straighten, allowing safe withd rawal 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 f ollow 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.

5.11 Post-Procedure

Care must be exercised when crossing a newly d eployed stent with an intravascular ultrasound
(IVUS) catheter, an optical coherence tomography (OCT) catheter, a coronary guidewire or a ballo on catheter to avoid disrupting the stent placement, apposition, geometry, and/or coating.
Post-dilatation: All efforts should be made to assure that the stent is not under dilated. If the
deployed stent is not fully apposed to the vessel wall, the stent may be expanded further with a larger diameter balloon that is slightly shorter (about 2 mm) than the stent. The post-dilatation can be done using a low-profile, high pressure, non-compliant balloon catheter. The balloon should not extend outside of the stented region. Do not use the stent delivery balloon for post-dilatation.
If p atient requires MR imaging, refer to Section 5.7 – Magnetic Resonance Imaging (MRI), above.
Antiplatelet therapy should be administered post-procedure (see Precautions – Section 5.1 Pre-
and Post-Procedure Antiplatelet Regimen). Patients who require early discontinuation of antiplatelet therapy (e.g., secondary to active bleeding), should be monitored carefully for cardiac events. At the discretion of the patient's treating physician, antiplatelet therapy should be restarted as soon as possible.

6 DRUG INFORMATION

6.1 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 p rotein phosphorylation events associated with translation of mRNA and cell cycle control.

6.2 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
values (3 μM and above) are many fold higher than the systemic concentrations
50
exp ected 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.

6.3 Pharmacokinetics of the Resolute Stent

The pharmacokinetics information for the Resolute Integrity stent system is derived from a study co nd ucted on the Resolute stent system. The Resolute Integrity stent system is similar to the Resolute stent system with regards to the stent design, the stent coating technology (dosing and drug to polymer ratio), and delivery system design and materials. Given these similarities and supportive bench and animal study information, the pharmacokinetics information from the RESOLUTE FIM PK Sub-study, as described b elow, is applicable to the Resolute Integrity stent system.
The pharmacokinetics (PK) of zotarolimus delivered from the Resolute Stent has been determined in patients with coronary artery disease after stent implantation in the Medtronic RESOLUTE FIM Cl i ni cal Trial. The d o se of zotarolimus was calculated per stent unit surface area and the key pharm aco ki netic parameters d etermined from these patients are provided in Table 6-1.
11
Table 6-1: Zotarolimus Pharmacokinetics in the Medtronic RESOLUTE FIM Clinical Trial PK
Sub-study Patients after Im plantation of Resolute Zotarolimus-Eluting Coronary Stents
PK
Parameter Units
Group I
(128 μg)
N = 1†
Group IIa
(180 μg)
N = 11
Group IIIa
(240 μg)
N = 7
Cmax (ng/mL) 0.129 0.210 ± 0.062 0.300 ± 0.075 0.346 ± 0.133
Tmax (h) 1.00 0.9 ± 0.7 0.9 ± 0.5 0.8 ± 0.5
AUC0-last
AUC0-inf$
(ngh/mL)
(ngh/mL)
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
‡,#
t½
(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
C
max
T
Time to C
max
AUC
0-last
AUC from time 0 to infinity (AUC
AUC
0-inf
t½ Harmonic mean half-life CL/F Mean apparent clearance Vdȕ/F Apparent volume of distribution $ Not a true sample
Area under the blood concentration-time curve (AUC) from time 0 to time of last measurable
concentration
No SD was reported when N = 1
max
Harmonic mean ± pseudo-standard deviation
). # Not a true estimate of the elimination half-life as the
0-inf
drug release from the stent was not complete during the course of the pharmacokinetic sampling
The results in Table 6-1 show that the pharmacokinetics of zotarolimus were linear in the primary dose­proportionality evaluation (including dose groups with N > 1), 180, 240 and 300 μg, following the imp lantation of the Resolute Stents as illustrated by dose proportional increases in maximum blood co ncentration (C measurable concentration (AUC clearance (CL/F) and harmonic mean half-life (t
), area under the blood concentration-time curve (AUC) from time 0 to time of last
max
) and AUC from time 0 to infinity(AUC
0-l ast
) for the primary dose groups ranged from 4.80 to 5.23
1/2
). The mean apparent
0-i nf
L/h and 167.4 to 208.3 h, respectively. The mean time to reach peak systemic concentration (T ranged from 0.8 to 0.9 h after stent implantation.
Group IVa
(300 μg)
N = 3
max
)
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.

6.4 Pharmacokinetics following Multi-dose Intravenous Administration of Zotarolimus

Zotarolimus pharmacokinetic activity has been determined following intravenous administration in healthy subjects. Table 6-2 provides a summary of the p harmacokinetic analysis.
12
Table 6-2: Pharmacokinetic Parameters (Mean ± Standard Deviation) in Patients
Following Multi-dose Intravenous Administration of Zotarolimus
200 μg QD
PK
Parameters Units
Cmax (ng/mL)
Tmax (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
AUC0-24
t1/2$ (h)
CLb (L/h)
Notes
¥
N = 16;
$ Harmonic mean ± pseudo-standard deviation
b
Clearance data is calculated using compartmental methods.
All other data presented in Table 6-2 is calculated using non-compartmental methods.
(ngh/mL)
N = 15
Day 1 Day 14 Day 1 Day 14 Day 1 Day 14
11.41±
¥
1.38
34.19 ±
¥
4.39
4.2 ± 0.6 4.2 ± 0.6 4.0 ± 0.9 4.0 ± 0.9 4.6 ± 0.4 4.6 ± 0.4
11.93 ±
1.25
47.70 ±
6.68
32.9 ± 6.8
68.43 ± 15.41
400 μg QD
N = 16
21.99 ± 3.79 23. 31± 3.15 37.72 ± 7.00 41.79 ± 6.68
100.47 ±
18.02
37.6 ± 4.5
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.

6.5 Mutagenesis, Carcinogenicity and Reproductive Toxicology

6.5.1 Mutagenesis

Zotarolimus was not genotoxic in the in v itro bacterial reverse mutation assay, the human peripheral lymphocyte chromosomal aberration assay, or the in vivo mouse micronucleus assay.
800 μg QD
N = 16
123.48 ± 13.34 174.43 ± 19.88
36.0 ± 4.7

6.5.2 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.

6.5.3 Reproductive Toxicology

No effect on fertility or early embryonic development in female rats was observed following the IV administration of zotarolimus at dosages up to 100 μg/kg/day (approximately 19 times the cumulative blood exposure provided by Resolute stents coated with 300 μg zotarolimus).
For male rats, there was no effect on the fertility rate at IV dosages up to 30 μg/kg/day (approximately 21 times the cumulative blood exposure provided by Resolute stents coated with 300 μg zotarolimus). Reduced sperm counts and motility, and failure in sperm release were observed in male rats following the IV ad ministration 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.

6.6 Pregnancy

Pregnancy Category C: There are no well-controlled studies in pregnant women, lactating women, or men intending to father children for this product.
Administration of zotarolimus to pregnant female rats in a developmental toxicity study at an intravenous dosage of 60 μg/kg/day resulted in embryolethality. Fetal ossification delays were also observed at this dosage, but no major fetal malformations or minor fetal anomalies were observed in this study. A 60 μg/kg/day dose in rats results in approximately 47 times the maximum blood level and about 11 times the cumulative blood exposure in patients receiving Resolute Integrity stents coated with 300 μg zotarolimus total dose.
13
No embryo-fetal effects were observed in pregnant rabbits administered zotarolimus in a developmental to xicity study at intravenous dosages up to 100 μg/kg/day. This dose in rabbits results in approximately 215 times the maximum blood level and about 37 times the cumulative blood exposure in patients receiving Resolute Integrity stents coated with 300 μg zotarolimus total dose.
Ef fective contraception should be initiated before implanting a Resolute Integrity stent and continued for one year p o st-stent implantation. The Resolute Integrity stent should be used in pregnant women only if potential benefits justify potential risks.

6.7 Lactation

It is not kno wn whether zotarolimus is excreted in human milk. The potential adverse reactions in nursing inf ants 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 p o tential 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.

7 OVERVIEW OF CLINICAL TRIALS

Clinical Trials in support of Pre-market Approval:
The princip al safety and effectiveness information for the Resolute Integrity stent system is derived from a series o f clinical trials conducted on the Resolute stent system. The Resolute stent system consists of a co b alt alloy bare metal stent, the zotarolimus and BioLinx stent coating, and the Sprint delivery system. The Resolute Integrity stent mounted on the MicroTrac delivery system is similar to the Resolute stent mounted on the Sprint delivery system with regard to the stent design, the stent coating technology (drug concentration and drug to polymer ratio), and delivery system design and materials. The Resolute Integrity stent is manufactured from a single wire whereas the Resolute stent is formed f rom laser fused elements. The Resolute Integrity stent is mounted on the MicroTrac delivery system, which differs fro m the Sprint delivery system with regard to the catheter manufacturing, shaft and tip design, and stent crimping process. Given the similarities between the Resolute stent system and the Resolute Integrity stent system, and supportive bench and animal study information, the findings from the RESOLUTE clinical studies, as described below, are applicable to the Resolute Integrity stent system.
The princip al 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 f ive studies have evaluated the performance of the Resolute stent in improving co ro nary 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 R-US and the RESOLUTE Asia study (R-Asia) (For 38 mm Length Group data see Tab le 7-1).
The RESOLUTE United States (RESOLUTE US) Clinical Trial is a prospective, multi-center, non­randomized trial that evaluated the safety and effectiveness of the Resolute stent for treatment of de novo lesions in native coronary artery(ies) with reference vessel diameters (RVD) ranging from 2.25 to
4.2 mm. The RESOLUTE US Clinical Trial is the pivotal trial of the overall Global RESOLUTE Clinical Trial Program. The RESOLUTE US Trial included the following:
The 2.25 to 3.5 mm Main Study: The primary endpoint was Target Lesion Failure (TLF) at 12
The 2.25 mm cohort analysis, in which the cohort was derived from subjects treated with the
The 2.25 to 3.5 mm Angio/IVUS Sub-study: The primary endpoint was in-stent late lumen loss
Table 7-1. The Resolute 38 mm Length Group was derived from subjects enrolled in the
months post-procedure, defined as Cardiac Death, Target Vessel Myocardial Infarction (MI) or clinically-driven Target Lesion Revascularization (TLR).
2.25 mm Resolute stent in the 2.25 to 3.5 mm Main Study and the 2.25 to 3.5 mm Angio/IVUS sub -study. The primary endpoint was TLF at 12 months post-procedure.
(LL) at 8 months post-procedure as measured by quantitative coronary angiography (QCA).
14
The 4.0 mm stent Sub-study: The primary endpoint was in-segment late LL at 8 months post- procedure as measured by QCA.
The total study population of the primary enrollment group (consisting of all subjects enrolled in the four studies listed above) consisted of 1402 subjects at 116 investigational sites in the United States. Post-procedure, subjects were to receive aspirin indefinitely and clopidogrel/ticlopidine for a minimum of 6 months and up to 12 months in subjects who were not at a high risk of bleeding.
The 38 mm Length Group: In addition to the primary enrollment group, the 38 mm Length Group is made up of 38 mm subjects from RESOLUTE US 38 mm Length Sub-study pooled with subjects from the RESOLUTE Asia (R-Asia) 38 mm cohort (see description of the R-Asia study below).
The primary endpoint was Target Lesion Failure (TLF) at 12 mo nths post-procedure, defined as Cardiac Death, Target Vessel Myocardial Infarction (MI) or clinically-driven Target Lesion Revascularization (TLR).
The RESOLUTE All-Comers (RESOLUTE AC) Clinical Trial is a prospective, multi-center, two-arm randomized, non-inferiority trial that compared the Resolute stent to a control DES (the Xience V
®
stent). The eligibility criteria reflected an ‘all-comers’ patient population. A total of 2292 subjects were enrolled at 17 clinical research sites from 11 countries in Western Europe (Switzerland, Belgium, Netherland s, Denmark, France, Germany, Italy, Spain, United Kingdom, Israel, and Poland). The primary endpoint was TLF defined as the composite of Cardiac Death, MI (not clearly attributable to a non-target vessel), or clinically indicated TLR within 12 months post-implantation. Post-procedure, sub jects were to receive aspirin indefinitely and clopidogrel/ticlopidine for a minimum of 6 months and up to 12 months in subjects who were not at a high risk of b leeding.
The RESOLUTE International (RESOLUTE Int) study is a prospective, multi-center, non-randomized, single-arm o bservational study with all enrolled subjects treated according to routine practices at participating hospitals. A total of 2349 subjects were enrolled at 88 clinical research sites from 17 co untries distributed over Europe, Asia, Africa and South America. The primary objective of this study was to evaluate the safety and clinical performance of the Resolute stent in an ‘all-comers’ patient population. The primary endpoint was the composite of Cardiac Death and MI (not clearly attributable to a non-target vessel) at 12 mo nths post-implantation. Post-procedure, subjects were to receive aspirin indef initely and clopidogrel/ticlopidine for a minimum of 6 months and up to 12 months in subjects who were no t at a high risk of b leeding.
The RESOLUTE FIM Clinical Trial is the first-in-human study evaluating the Resolute stent. RESOLUTE FIM is a non-randomized, prospective, multi-center, single-arm trial. The purpose of the trial was to assess the initial safety of the Resolute stent. A total of 139 subjects were enrolled at 12 investigative sites in Australia and New Zealand. The primary endpoint was in-stent late lumen loss (LL) at nine months post-implantation measured by QCA. Post-procedure, subjects were to receive aspirin indef initely and clopidogrel/ticlopidine for a minimum of 6 months. This trial had a subset of subjects undergoing pharmacokinetic (PK) assessments (see Section
6.3 for the Pharmacokinetics of the
Resolute Stent).
The RESOLUTE Jap an Clinical Trial is a prospective, multi-center, non-randomized, single-arm trial. A to tal o f 100 subjects were enrolled at 14 investigational sites in Japan. The primary endpoint was in­stent late lumen loss (LL) at 8 months post-procedure as measured by QCA. Post-procedure, subjects were to receive aspirin indefinitely and clopidogrel/ticlopidine for a minimum of 6 months and up to 12 months in subjects who were not at a high risk of bleeding.
The RESOLUTE Asia (R Asia) study is a prospective, multi-center, non-randomized study. The primary objective of this study was to document the safety and effectiveness of the Endeavor Resolute Zotarolimus-Eluting Coronary Stent System in a patient population with long lesion(s). The Primary endpoint for the 38 mm cohort was target lesion failure (TLF) at 12 months post-procedure, defined as co mposite of cardiac death, target vessel myocardial infarction (Q wave and non-Q wave) or clinically­driven target lesion revascularization (TLR) by percutaneous or surgical methods. The RESOLUTE Asia trial was designed to be included in the p ooled dataset for the RESOLUTE 38 mm Length Group (38 mm subjects from RESOLUTE US and RESOLUTE Asia). A total of 109 subjects were enrolled in the 38 mm cohort across 17 clinical research sites from six (6) co untries throughout Asia.
15
All the RESOLUTE clinical trials utilized an independent Clinical Events Committee (CEC) for adjudication of the clinical events. The definitions of clinical events were consistent across the clinical trials, and the event adjudication process was harmonized to ensure consistency and comparability of the d ata. All clinical trials had oversight by a Data and Safety Monitoring Board (DSMB). All trials had data monitored for verification and accuracy. Independent Angiographic Core Labs were utilized for angiographic and IVUS endpoints.
Post-market Approval Study:
The RESOLUTE INTEGRITY US Post Market Study is a prospective, multi-center evaluation of the procedural and clinical outcomes of subjects that are treated with the commercially available Medtronic Resolute Integ rity Zotarolimus-Eluting Coronary Stent System. The objective of this study is to assess the saf ety and efficacy of the Resolute Integrity stent for the treatment of de novo lesions in native co ro nary 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 leng th, 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. The primary endpoint for this study is composite rate of cardiac death and target vessel myocardial infarction (MI) at 12 months.
Table 7-1 summarizes the clinical trial designs for the Global RESOLUTE Clinical Trial Program and Post-market Approval Study.
16
j
p
p
)
g
5
tr eated or les ion length
separate target vessels
US (XL Sub-study)
RES OLUTE INTE GRI TY
P rospect ive
M ulti- cente r
Non- randomized
P ost approval
4
Pos t-mar ket A pprova l Study
(PEG)
RES OLUTE INTE GRI TY U S
P rospect ive
M ulti- cente r
Non- randomized
P ost approval
38 mm Cohort
RESOLUTE Asia
P rospect ive
M ulti- cente r
Non- randomized
tar get lesions located in
Single t arget les ion or t wo
XL:
vessels
lesions locat ed in separate t arget
PEG:
Single target lesion or two target
in separat e tar get v essels
Single or two de novo lesions locat ed
Lesion(s) length 35 mm
Target vessel with RVD between 3.0 to
Target lesion  mm
Target lesion  mm
4.0 mm
Tar get ves sel wit h RVD bet ween
between 2. 25 to 4.2 mm .
Target vessel with RVD
2.25 t o 4.2 mm.
of up t o two lesions
second lesion RVD (2.25 to 4.2 mm), if
Pat ients m ay have r eceived t reatment
St ent Lengt h:
34-38 mm
St ent diam eter:
3.0 – 4. 0 mm
St ent lengt h:
St ent diam eter:
2.25 – 4. 0 mm
et vessels.
the lesions were located in separate
tar
St ent diam eter:
3.0 – 4. 0 mm
Resolute Integrity stent on the
8 – 30 mm
Resolute Integrity stent on the Rapid
St ent Lengt h: 38 m m
Resolut e Stent on t he Rapid Exc hange
Aspirin indefinitely and
clopidogr el/ tic lopidine f or 
mont hs in all subject s, up to 12
Aspir in indefinitely and
Aspir in indefinitely and
mont hs if t olerated
tolerated
clopidogr el/ tic lopidine f or  months
in all subject s, up t o 12 months if
clopidogr el/ tic lopidine, fo r  mont hs in all
subject s, up to 12 m onths if tolerat ed
Rapid Exc hange Micr oTr ac
Deliver y S yst em
Exc hange Micr oTr ac Delivery Sys tem
Sprint Delivery System
RESOLUTE Japan
Prospective
M ulti- cente r
Non- randomized
Single-arm
His torical c ontrolled t rial
3
RES OLUTE FIM
Prospective
Mult i-cent er
Non-random ized
Single-arm
Hist oric al cont rolled tr ial
PK Assessment
Table 7-1: Clinical Trial Comparisons
2
RESOLUTE Int
Pros pective
Mult i-cent er
1
Pr e-ma rk et Appr oval Studi es; Gl obal R ES OLUTE C lini cal Tri al P rogra m
Pros pect ive
Mult i-cent er
ulation o
ect
Tot al: 2349 T otal: 139 T otal: 100 Total: 109 Total: 230 Tot al: 56
Non-random ized
Single-arm
Obs ervat ional st udy
Real World sub
Tot al: 2292
(1: 1 Resolute v s. Xience V)
Randomiz ed
T wo-ar m, non-infer iorit y t rial
Real World subject populat ion
(Resolut e: 1140, Xience V: 1152)
located in s eparat e coronary
art eries
Lesion(s) length ≤27 mm
between 2. 5 to 3.5 mm
Target vessel with RVD
Single or two de novo lesions
8 – 30 mm
St ent lengt h:
St ent diam eter:
2.5 – 3. 5 mm
Resolute Stent on the Rapid
Exc hange Sprint Delivery Sys tem
Aspir in indefinitely and
mont hs if t olerated
clopidogr el/ tic lopidine f or 
mont hs in all subject s, up to 12
17
and 3.5 m m
Single de novo lesion
Lesion length f rom 14 to 27 m m
Target vessel with RVD between 2.5
2.25 t o 4.0 mm
lesion length
lesion(s)/ vessel(s) treated or
No limit ation t o number of
Tar get ves sel wit h RVD bet ween
between 2. 25 to 4.0 mm .
lesion length
lesion(s) / v essel(s ) t reat ed or
No limit ation t o number of
Target vessel with RVD
8 – 30 mm
St ent lengt h:
St ent diam eter:
2.5 – 3. 5 mm
St ent lengt h:
St ent diam eter:
2.25 – 4. 0 mm
St ent lengt h:
St ent diam eter:
2.25 – 4. 0 mm
Resolut e Stent on t he Rapid Exc hange
8 – 38 mm
Resolute Stent on the Rapid
8 – 30 mm
Resolute Stent on the Rapid
Aspir in indefinitely and
Aspir in indefinitely and
Aspir in indefinitely and
clopidogr el/t iclopidine  mont hs
tolerated
clopidogr el/ tic lopidine f or  months
in all subject s, up t o 12 months if
clopidogr el/ tic lopidine f or 
mont hs in all subject s, up to 12
mont hs if t olerated
AV100 Deliv ery S yst em
Exc hange Sprint Delivery Sys tem
Exc hange Sprint Delivery Sys tem
subject s wit h 114 fr om
subject s
Angio/IVUS sub-study -
100 subject s
subject s 2. 25–3.5 m m
Tot al: 1516
-1242 subjects
- 2.25 m m Cohort- 150
- 4.0 mm Sub-study -60
- 38 mm Sub-s tudy 114
Numb er of
Subj ects
Enrolled
- 2.25–3. 5 mm Main S tudy
RESOLUTE US* RESOLUTE AC
Prospective
Mult i-cent er
Non-random ized
Hist oric al cont rolled tr ial*
Study Type
RESO LUTE US and 109
population was 223
study Total patient
subject s) ( 38 mm Sub-
from RESOLUTE Asia
located in s eparat e target
vessels
Single or two de novo lesions
Lesion(s) length 27 mm for the
Prim ary E nrollment Gr oup, ≤35
Lesion
between 2. 25 to 4.2 mm
Gr oup
mm f or the 38-m m Lengt h
Target vessel with RVD
Criteria
Enrollm ent G roup, 38 mm for the 38
St ent lengt h:
St ent diam eter:
2.25 – 4. 0 mm
8 – 30 mm f or the Primary
mm Lengt h Group
Resolute Stent on the Rapid
Exc hange Sprint Delivery Sys tem
Aspir in indefinitely and
clopidogr el/ tic lopidine f or 
mont hs in all subject s, up to 12
mont hs if t olerated
(Resolute)
Stent Sizes
Product Used
Post-
procedure
Ant ip latel et
Therapy
5
US (XL Sub-study)
RES OLUTE INTE GRI TY
4
Pos t-mar ket A pprova l Study
(PEG)
(Cont act) 2-3 year s (Cont act)
30 days ( Contac t); 6 months
(Cont act); 12 m onths (Clinic Visit
with 12-lead ECG ) and 2 years :
36-month follow-up is
complete
RES OLUTE INTE GRI TY U S
12-lead ECG ) and 2 years: (Cont act )
30 days ( Contac t); 6 months
(Cont act); 12 m onths (Clinic Visit with
24-month follow-up is
complete
38 mm Cohort
RESOLUTE Asia
30 days, 6, 9 (Clinical Visit ), 12, 18 months
then annually at 2 - 5 years
RESOLUTE Japan
telephone
6, 9 and 18 m onths and 2-5 years :
30 days and 12 m onths : c linical
8 mont hs: angiographic/ IV US
3
RES OLUTE FIM
subject subset ): clinical and
angiographic/ IVUS
30 days : c linical
Table 7-1: Clinical Trial Comparisons
2
6 mont hs and 1-5 y ears: telephone
4 (30 subject subset) and 9 mont hs (100
60-month follow-up is complete
complete.
18
60-month follow-up complete. 60-month follow-up is
RESOLUTE Int
30 days, 6 months, 1-3 year s: clinical
or telephone
1
Pr e-ma rk et Appr oval Studi es; Gl obal R ES OLUTE C lini cal Tri al P rogra m
13 mont hs (455 s ubject s ubset ):
and 9 mont hs: clinical; 6, 12 and 18
angiographic
mont hs, 2-5 years : t elephone
4.0 m m Sub- st udy: 8 months:
6 mont hs and 2-5 y ears:
clinical and angiographic; 6, 12 and
telephone
18 mont hs, 2-5 years : t elephone
2.25 - 3.5 m m Angio/ IVUS Sub-
Follow-up
38 mm Lengt h Sub-st udy : 30 days
(R-US ) and 9 mont hs clinical visit s
telephone
angiographic/ IV US 6, 12 and 18 m onths , 2-5 y ears:
st udy: 8 months: c linical and
30 days and 12 m onths : c linical
RESOLUTE US* RESOLUTE AC
2.25- 3.5 m m Main S tudy : 30 days
(pref erred) , or patient cont act 30
36-month follow-up is
complete.
60-month follow-up is
complete.
then annually at 2, 3, 4, 5 years
days ( R-As ia): 6, 12, 18 months
60-month follow-up is
complete.
551 subjects qual ified for
18-month follow-up.
Length Sub-study, and the 4.0 mm Sub-study have historical control designs. The 2.25 mm Subset outcomes were compared to a performanc e goal.
The term ‘Int’ refers to International.
The term ‘AC’ ref ers to All-comers.
Status
* The R ESOLUTE US trial is compos ed of four studies. The 2.5 - 3.5 mm s ubset of t he Main St udy, the 2. 25 – 3.5 mm Angio/ IVUS Sub-st udy, the 38 mm
The term ‘FIM’ refers to First-In-Man. 4 The term ‘PEG’ refers to Primary Enrollment Group. 5 The term ‘XL’ refers to Ex tended Length.
1
2
3
9

8 ADVERSE EVENTS

(

8.1 Observed Adverse Events

Observed adverse event experience with the Resolute stent is derived from the following five clinical trials: the RESOLUTE US, RESOLUTE AC, RESOLUTE Int, RESOLUTE FIM and RESOLUTE Japan. In ad d ition, the adverse event experience from the Resolute Integrity US Primary Enrollment Group (PEG) Po st-market Approval Study and the Extended Length (XL) Sub-study have been included.
See Section 9 CLINICAL STUDIES for a more complete description of the trial designs and results.
The Glo b al RESOLUTE Clinical Trial Program has evaluated the performance of the Resolute stent in sub jects, 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 saf ety and efficacy of the Resolute Integrity stent for the treatment of de novo lesions in native coronary arteries. Principal adverse events are shown in Table 8-1 below.
Table 8-1: Principal Adverse Events from Post-Procedure Through Latest Available Follow-up
38 mm Length Sub-
study
R-US N = 114
R-Asia N = 109
Resol ute
(N = 223)
0.0% ( 0/223) 0.0% (0/ 230) 0. 0% (0/ 56)
Resol ute
(N = 1402)
1
RESOLUTE AC RESOLUTE Int RESOLUTE FIM RESOLUTE Japan
Resol ute
(N = 1140)
0.8% ( 9/1132) 0.4% (5/ 1142) 0. 5% (12/ 2337) 0. 0% (0/ 139) 0. 0% (0/100) 0.9% (2/222) 0.0% ( 0/226) 1. 8% (1/56)
3.5% ( 40/1132) 3. 8% (43/1142) 2. 5% (59/ 2337) 5. 8% (8/ 139) 4. 0% (4/100) 2.7% (6/222) 2.2% ( 5/226) 3. 6% (2/56)
1.9% ( 21/1132) 2. 2% (25/1142) 1. 2% (27/ 2337) 0. 0% (0/139) 1. 0% (1/100) 1.4% (3/222) 2.2% ( 5/226) 0. 0% (0/56)
Xi ence V
(N = 1152)
3.6% ( 42/1152)
Resol ute
(N = 2349)
2.2% ( 51/2349) 4. 3% (6/139) 2.0% (2/100) 3. 1% (7/223) 1. 7% (4/ 230) 1.8% ( 1/56)
Resol ute (N = 139)
Resol ute (N = 100)
RESOLUTE US
In-Hospital
TLF2 1. 3% (18/ 1402) 3. 7% (42/ 1140) 4.5% ( 52/1152) 2. 6% (61/2349) 4. 3% (6/ 139) 2.0% ( 2/100) 3. 6% (8/ 223) 1.7% (4/230) 1.8% (1/ 56)
3
TVF
MACE4 1.3% ( 18/1402) 3.8% (43/ 1140) 4. 9% (56/ 1152) 2. 7% (63/2349) 4.3% ( 6/139) 2. 0% (2/ 100) 3.6% ( 8/223) 1.7% (4/ 230) 1. 8% (1/ 56) Tot al Death 0.0% (0/ 1402) 0.1% ( 1/1140) 0.8% (9/ 1152) 0.3% (7/ 2349) 0. 0% (0/ 139) 0. 0% (0/100) 0. 4% (1/223) 0.0% ( 0/230) 0. 0% (0/56)
Cardiac Death 0.0% ( 0/1402) 0.1% (1/ 1140) 0.6% (7/ 1152) 0. 3% (6/ 2349) 0.0% ( 0/139) 0. 0% (0/ 100) 0.4% ( 1/223) 0.0% (0/ 230) 0. 0% (0/56)
Non-Cardiac Death
5
TVMI
Q wave MI 0.1% ( 1/1402) 0.3% (3/1140) 0.4% ( 5/1152) 0.3% (8/ 2349) 0.0% (0/ 139) 0.0% ( 0/100) 0. 4% (1/ 223) 0. 0% (0/230) 0.0% ( 0/56)
Non-Q Wave M I 1.1% (15/1402) 2.8% ( 32/1140) 3. 2% (37/1152) 1. 8% (43/ 2349) 4. 3% (6/ 139) 2. 0% (2/100) 2.7% (6/223) 1.7% ( 4/230) 1. 8% (1/56) Cardiac Death or T VMI6 1.1% ( 16/1402) 3.2% (36/ 1140) 4. 0% (46/ 1152) 2. 4% (56/2349) 4.3% ( 6/139) 2. 0% (2/ 100) 3.6% (( 8/223) 1.7% ( 4/230) 1. 8% (1/56)
Clinically Driv en TVR7 0. 1% (2/ 1402) 0.9% ( 10/1140) 0. 9% (10/1152) 0. 4% 10/2349) 0.0% (0/139) 0. 0% (0/100) 0.0% ( 0/223) 0.4% (1/230) 0. 0% (0/56)
TLR8 0.1% ( 2/1402) 0.7% (8/1140) 0.7% ( 8/1152) 0. 4% (10/2349) 0. 0% (0/139) 0.0% ( 0/100) 0. 0% (0/ 223) 0.4% (1/230) 0.0% ( 0/56)
Non-TL TVR 0. 0% (0/ 1402) 0. 4% (4/ 1140) 0. 2% (2/ 1152) 0.0% ( 1/2349) 0.0% ( 0/139) 0. 0% (0/ 100)
ARC Def/Prob ST9 0.0% (0/1402) 0. 6% (7/ 1140) 0. 3% (4/1152) 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 Day
MACE 1. 4% (20/1399) 4.4% ( 50/1133) 5. 2% (60/1146) 3. 3% (78/ 2345) 4.3% (6/139) 3. 0% (3/100) 4.5% ( 10/223) 3. 0% (7/230) 3. 6% (2/ 56)
12 Months
TLF 4.7% ( 65/1390) 8.1% (92/ 1132) 8. 5% (97/ 1142) 7.1% (165/2337) 7. 2% (10/139) 4.0% ( 4/100) 5. 4% (12/ 222) 4.9% ( 11/226) 7.1% (4/56)
TV F 6. 2% (86/ 1390) 8.9% (101/1132) 9.7% (111/ 1142) 7. 7% (180/ 2337) 7.2% (10/139) 5.0% (5/ 100) 6. 8% (15/ 222) 7.1% ( 16/226) 7.1% (4/56)
MACE 5.5% (77/ 1390) 8. 6% (97/1132) 9. 8% (112/ 1142) 8.3% (193/ 2337) 8.6% ( 12/139) 5.0% (5/ 100) 6.3% (14/222) 5. 8% (13/226) 8. 9% (5/56) Tot al Death 1. 4% (19/ 1390) 1.6% ( 18/1132) 2.7% (31/ 1142) 2. 4% (57/ 2337) 2. 2% (3/139) 1. 0% (1/100) 0.9% (2/222) 1.8% ( 4/226) 1. 8% (1/56)
Cardiac Deat h 0. 7% (10/ 1390) 1.3% (15/1132) 1.7% ( 19/1142) 1. 5% (34/2337) 0. 7% (1/ 139) 0.0% ( 0/100) 0. 9% (2/ 222) 1.3% (3/226) 1.8% (1/56)
Non-Cardiac Death 0.6% ( 9/1390) 0.3% (3/1132) 1.1% ( 12/1142) 1. 0% (23/2337) 1. 4% (2/ 139) 1.0% ( 1/100) 0. 0% (0/ 222) 0.4% (1/226) 0.0% (0/56)
TV MI 1.3% ( 18/1390) 4.2% (48/ 1132) 4. 2% (48/ 1142) 3. 0% (71/2337) 5.8% ( 8/139) 4. 0% (4/ 100) 3.6% ( 8/222) 2.2% (5/ 226) 5. 4% (3/ 56)
Q wave MI
Non-Q Wave M I
Cardiac Deat h or TVM I 2. 0% (28/ 1390) 5. 3% (60/ 1132) 5.5% ( 63/1142) 4. 2% (99/2337) 6. 5% (9/ 139) 4.0% ( 4/100) 4. 5% (10/222) 3. 5% (8/ 226) 7. 1% (4/ 56)
Clinically Driven TV R 4.6% ( 64/1390) 4. 9% (55/1132) 4. 8% (55/ 1142) 4.2% (99/2337) 0.7% ( 1/139) 1. 0% (1/ 100) 2.7% ( 6/222) 4. 4% (10/226) 1. 8% (1/56)
TLR 2.9% (40/ 1390) 3. 9% (44/ 1132) 3.4% (39/1142) 3.5% ( 81/2337) 0. 7% (1/139) 0.0% (0/100) 1. 4% (3/222) 2. 2% (5/ 226) 1.8% ( 1/56)
Non-T L TV R 2.2% (30/ 1390)
ARC Def/ Prob ST
Latest Follow-up 60 Months 60 Months 36 Months 60 Months 60 Months 60 Months 24 Mon ths 36 Mo nth s
TLF 12. 3% (164/1329) 17.0% (191/ 1123) 16.2% ( 183/1133) 11.4% (261/2284) 11.0% (15/ 136) 6. 1% (6/98) 13.8% ( 30/217) 9.1% (20/ 219) 10.7% (6/ 56)
TV F 17. 5% (233/1329) 20.0% ( 225/1123) 19. 1% (216/ 1133) 12. 9% (294/ 2284) 13. 2% (18/ 136) 10.2% ( 10/98) 17. 1% (37/217) 12.3% ( 27/219) 12.5% (7/ 56)
MACE 18.0% (239/1329) 21.9% (246/ 1123) 21.6% (245/ 1133) 14. 4% (329/2284) 16. 2% (22/ 136) 14.3% (14/98) 17.5% ( 38/217) 11.0% (24/ 219) 17.9% (10/ 56)
Tot al Death 9. 6% (127/1329) 11.0% ( 123/1123) 10. 8% (122/ 1133) 6. 1% (139/ 2284) 6.6% ( 9/136) 7. 1% (7/ 98) 6.5% (14/ 217) 2. 7% (6/ 219) 3. 6% (2/ 56)
TV MI 3.2% ( 43/1329) 5.7% (64/ 1123) 5. 7% (65/ 1133) 3. 9% (89/2284) 6.6% ( 9/136) 4. 1% (4/98) 6.0% (13/ 217) 4. 1% (9/ 219) 5.4% (3/56)
9
Cardiac Deat h 4. 1% (55/ 1329) 6.5% (73/1123) 5.7% ( 65/1133) 3. 6% (82/2284) 1. 5% (2/ 136) 1.0% (1/ 98) 4.1% ( 9/217) 1. 8% (4/219) 1. 8% (1/ 56)
Non-Cardiac Death 5.4% ( 72/1329) 4.5% (50/ 1123) 5. 0% (57/ 1133) 2. 5% (57/2284) 5.1% ( 7/136) 6. 1% (6/98) 2.3% (5/ 217) 0.9% (2/219) 1.8% (1/ 56)
Q wav e MI 0.4% ( 5/1329) 1. 3% (15/ 1123) 0.8% (9/1133) 0.9% ( 20/2284) 0. 0% (0/136) 0.0% ( 0/98) 0.9% (2/217) 0.9% ( 2/219) 1. 8% (1/56)
Non-Q Wave MI 2.9% (38/1329) 4.6% ( 52/1123) 4. 9% (56/1133) 3. 0% (69/ 2284) 6.6% (9/136) 4. 1% (4/98) 5.1% ( 11/217) 3. 2% (7/219) 3.6% (2/56)
1.3% ( 18/1402) 3.8% (43/ 1140) 4. 7% (54/ 1152) 2. 6% (61/2349) 4.3% ( 6/139) 2. 0% (2/ 100) 3.6% ( 8/223) 1.7% (4/ 230) 1. 8% (1/ 56)
0.0% ( 0/1402) 0.0% (0/1140) 0.2% ( 2/1152) 0.0% (1/ 2349) 0.0% (0/ 139) 0.0% ( 0/100) 0. 0% (0/ 223) 0.0% (0/230) 0.0% ( 0/56)
1.1% ( 16/1402) 3.1% (35/ 1140)
0.1% ( 2/1390)
1.2% ( 16/1390)
0.1% ( 2/1390) 1. 6% (18/ 1132) 0.7% (8/1142) 0.9% ( 20/2337) 0. 0% (0/139) 0. 0% (0/ 100) 0. 9% (2/222) 0. 9% (2/ 226) 1.8% (1/56)
RESOLUTE INTEGRITY US
Resolute Integrity
(PEG)
(N= 230)
RESOLUTE
INTEGRITY US (XL
Sub-study)
N=56)
1
0
Table 8-1: Principal Adverse Events from Post-Procedure Through Latest Available Follow-up
(
38 mm Length Sub-
RESOLUTE US
Cardiac Death or T VMI
Clinically Driv en TVR
TLR
Non-TL TVR
ARC Def/Prob ST
1
Resol ute
(N = 1402)
6.7% ( 89/1329) 11. 5% (129/1123) 10.6% (120/ 1133) 7. 0% (161/2284) 8.1% (11/ 136) 5. 1% (5/98) 8.8% ( 19/217) 5.9% (13/ 219) 7.1% (4/ 56)
12.5% ( 166/1329) 11.4% (128/ 1123) 10. 9% (123/1133) 7. 4% (168/2284) 5.1% (7/136) 5. 1% (5/98) 9.7% ( 21/217) 8.2% (18/ 219) 7.1% (4/56)
6.5% ( 86/1329) 7.8% (88/ 1123) 7. 1% (81/ 1133) 5.7% (130/2284) 2.9% ( 4/136) 1.0% (1/98) 6. 0% (13/217) 5. 0% (11/ 219) 5.4% (3/56)
8.1% ( 107/1329) 6.1% (68/ 1123) 6. 1% (69/ 1133) 2. 6% (59/2284) 2.2% ( 3/136) 4. 1% (4/98) 3. 7% (8/217) 4. 1% (9/219) 5.4% (3/56)
0.5% ( 7/1329) 2. 4% (27/ 1123) 1.7% ( 19/1133) 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 AC RESOLUTE Int RESOLUTE FIM RESOLUTE Japan
Resol ute
(N = 1140)
Xi ence V
(N = 1152)
Resol ute
(N = 2349)
Resol ute (N = 139)
Resol ute (N = 100)
study
R-US N = 114
R-Asia N = 109
Resol ute
(N = 223)
RESOLUTE INTEGRITY US
Resolute Integrity
(PEG)
(N= 230)
Notes
N = The t otal number of subject s enrolled. 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 ). 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).
1
Primary Enrollment Group consisted of 1402 subjects, including 1242 subjects in the 2.25 - 3.5 mm Main Study, 100 subjec ts in the 2.25 - 3.5 m m
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
2
Target Lesion Failure (TLF) is defined as any Cardiac Death, Clinically Driven Target Lesion Revascularization by PCI or CABG or Target Vessel MI.
3
Target Vessel Failure (TVF) is defined as any Cardiac Death, Clinically Driven Target Vessel Revascularization by PCI or CABG or Target Vessel MI.
4
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).
5
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 c onsistent with my ocardial ischem ia 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 ; 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-PC I) that did not fulf ill the criteria f or Q-wav e MI are included in N on-Q Wav e MI cat egory. 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.]
6
Cardiac death/TVMI is defined as Cardiac Death or Myocardial Infarction not clearly att ributable to a non-target vessel.
7
Target Vessel Revascularization (TVR) is defined as any clinically-driven repeat intervention of the target vessel by PCI or CABG.
8
Target Lesion Revascularization (TLR) is defined as a clinically-driven repeat intervention of the target lesion by PCI or CABG
9
See Table 9-4 for the definition of the ARC defined Stent Thrombosis.
RESOLUTE
INTEGRITY US (XL
Sub-study)
N=56)
2

8.2 Potential Adverse Events

8.2.1 Potential Adverse Events Related to Zotarolimus

Patients’ exposure to zotarolimus is directly related to the total amount of stent length implanted. The actual sid e 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:
Anemia
Diarrhea
Dry Skin
Headache
Hematuria
Infection
Injectio n site reaction
Pain (abdominal, arthralgia, injection site)
Rash

8.2.2 Potential Adverse Events Related to BioLinx polymer

Although the type of risks of the BioLinx polymer coating are expected to be no different than 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:
Allergic reaction
Fo cal inflammation at the site of stent implantation
Resteno sis of the stented artery

8.2.3 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:
Abrupt vessel closure
Access site pain, hematoma or hemorrhage
Allerg ic reaction (to contrast, antiplatelet therapy, stent material, or drug and polymer
co ating)
Aneurysm, pseudoaneurysm, or arteriovenous fistula (AVF)
Arrhythmias, including ventricular fibrillation
Balloon rupture
Bleeding
Cardiac tamponade
Coronary artery occlusion, perforation, rupture, or dissection
Coro nary artery spasm
Death
Embolism (air, tissue, d evice, or thrombus)
Emergency surgery: peripheral vascular or coronary bypass
Failure to deliver the stent
Hemorrhage requiring transfusion
Hypotension / hypertension
Inco mplete stent apposition
Infection or fever
Myocardial infarction (MI)
Pericarditis
Peripheral ischemia / peripheral nerve injury
Renal Failure
21
2
Resteno sis of the stented artery
Shock / pulmonary edema
Stable o r Unstable angina
Stent deformation, collapse, or fracture
Stent migration or embolization
Stent misplacement
Stroke / transient ischemic attack
Thrombosis (acute, subacute or late)

9 CLINICAL STUDI ES

9.1 Results of the RESOLUTE US Trial

Primary Objective: To assess the safety and effectiveness of the Resolute Zotarolimus-Eluting
Coronary Stent System (Resolute stent) for the treatment of de novo lesions in native coronary arteries with a ref erence vessel diameter (RVD) of 2.25 to 4.2 mm.
Design: This is a prospective, multi-center, non-randomized controlled trial that evaluated the safety and ef fectiveness of the Resolute stent for treatment of de novo lesions in native coronary artery(ies) with ref erence vessel diameters (RVD) ranging from 2.25 to 4.2 mm. The study population included sub jects from 116 sites in the United States with clinical evidence of ischemic heart disease due to stenotic lesions with either one target lesion or two target lesions located in separate arteries, RVD between 2.25 and 4.2 mm, lesions with stenosis  but <100%, lesion length  mm  for the 38 mm Leng th Group), and TIMI f low 2.
The RESOLUTE US trial consists of the following:
The 2.25 mm to 3.5 mm Main Study
The 2.25 mm cohort analysis
The 2.25 mm to 3.5 mm Angio/IVUS Sub-study
The 4.0 mm stent Sub-study
The 38 mm Length Group
3
Fig ure 9-1 provides a chart of the subject study designation of the primary enrollment group. The primary enrollment group consists of the subjects in all of these studies and includes 1402 subjects.
Subject enrollment criteria common to all four studies listed above included: age >18 years old; clinical evidence of ischemic heart disease, stable or unstable angina, silent ischemia, and/or a positive f unctional study; and no evidence of an acute MI within 72 hours of the procedure.
Follow-up was completed at 30 days, 6, 9 and 12 months and will be performed at 18 months, 2, 3, 4 and 5 years. All subjects enrolled in the 2.25 mm – 3.5 mm Angio/IVUS Sub-study were consented to angiographic and IVUS follow-up at 8 months post-procedure. All subjects enrolled in the 4.0 mm Sub­study were consented to angiographic follow-up at 8 months post-procedure. 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 subjects who were not at a hig h risk of bleeding.
The 12-mo nth and 5-year follow-up rates for the primary enrollment group were 97.3% (1364/1402) and
92.2% (1293/1402) respectively.
Strengths of this analysis include the collection and presentation of both short and long term outcomes demonstrating safety and effectiveness in the intended population. A limitation was that the patient and lesion characteristics excluded many complex subjects.
3
The 38 mm data was analyzed separately from the R-US Primary Enrollment Group.
2
3
Figure 9-1: Study Designation of RESOLUTE US Clinical Trial
2
4
2.5 mm – 3.5 mm Subset of the Main Study
(
Demographics and clinical characteristics: There were 1112 sub jects (1001 single lesion subjects and 111 dual vessel subjects). The mean ag e of all subjects was 63.9 years with 69.2% (770/1112) being males, 20.3% (222/1095) had a prior history of MI, 32.2% (358/1112) had a prior history of PCI, and 7.6% (85/1112) had previous CABG surgery. 33.6% (374/1112) were diabetics, with 9.5% (106/1112) being insulin dependent diabetics. Past medical history of subjects indicated 87.9% (978/1112) had hyperlipidemia, 83.5% (928/1112) had hypertension, and 21.6% (240/1112) were current smokers. The mean RVD by QCA was 2.63 ± 0.42 mm, the lesion length was 13.06 ± 5.84 mm, and the average percentage diameter stenosis was 70.68 ± 11.56%. 75.8% of lesions (921/1215) were characterized as ACC/AHA type B2/C.
Primary Endpoint: The primary endpoint in the 2.5 mm - 3.5 mm Subset of the Main Study was Target Lesion Failure (TLF) at 12 months post-procedure. TLF was defined as the Cardiac Death, Target Vessel Myocardial Infarction (MI), or clinically-driven Target Lesion Revascularization (TLR).
Control Group and Statistical Analysis Plan: The primary analysis was a non-inferiority comparison of the 12-month TLF rate between the single lesion subset of the Resolute stent arm and a historical co ntrol group consisting of single lesion subjects treated with Endeavor stents who were part of the clinical follow-up cohort with diameters between 2.5 mm and 3.5 mm pooled from the following studies: ENDEAVOR II, ENDEAVOR II Continued Access, ENDEAVOR IV, and ENDEAVOR US PK.
Results: The Resolute stent single lesion cohort of the 2.5 mm – 3.5 mm subset of the Main Study met the p rimary 12-month TLF non-inferiority endpoint with the Resolute stent demonstrating a rate of 3.6% (36/994) in comparison to the Endeavor stent historical control rate of 6.5% (70/1076), P
<0.001.
inferiority
These analyses are based on the intent-to-treat population. The results are presented in the following tables:
Table 9-1: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main Study - Primary Endpoint Analysis)
Table 9-2: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main Study - Principal Safety and
Ef fectiveness - Single Lesion Outcome versus Historical Control (Endeavor)
Table 9-3: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main Study - Principal Safety and Ef fectiveness - Combined Single Lesion and Dual Lesion - Treated Subjects
Table 9-4: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main Study - ARC Defined Definite/Probable Stent Thrombosis Through 60 Months
Table 9-5: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main Study Clinical Results – Single versus Dual Lesion Subjects
Table 9-1: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main Study - Primary Endpoint
Analysis
2.5 mm - 3.5 mm Subset of the Main Study
12-month TLF- Single Lesion Subjects
Notes
N = The t otal number of subject s enrolled. TLF = Target lesion failure Subjects are only counted once for each time period. The numbers are % (Count/Number of Eligible Subjects) or least squares mean ± standard error. The primary endpoint analysis for the 2.5 mm – 3.5 mm subset of the Main Study only includes subjects with a single lesion. 12-month timeframe includes follow-up window (360 days ± 30 days ).
1
The CI and P-values are adjusted to propensity score, based on lesion length, baseline RVD, age, sex, diabetes, history of MI and w ors t
Canadian Cardiovascular Society Angina Class as the independent variables.
2
One sided p-value by non-inferiority test using asymptotic test statistic with non-inferiority margin of 3.3%, to be compared at a 0.05
significance level.
Resolute
(N = 1001)
3.6% (36/994) 6.5% (70/1076) -2.9% -1.4% <0.001
Historical Control
Endeavor
N = 1092)
Difference: Resolute
–Historical Control
Upper
One-sided
95% CI1
non-
Non-inferiority
P-value
1,2
2
5
Table 9-2: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main
(
Study - Principal Safety and Effectiveness - Single Lesion Outcome
versus Historical Control
Single Lesion 2.5 mm - 3.5
Outcomes at 12 Months
COMPOSITE SAFETY AND EFFECTIVENESS
TLF 3.6% (36/994) 6.5% (70/1076)
TVF 5.0% (50/994) 8.3% (89/1076)
MACE 4.3% (43/994) 7.0% (75/1076)
EFFECTIVENESS
Clinically Driven TVR 3.7% (37/994) 6.0% (65/1076)
TLR 2.1% (21/994) 4.0% (43/1076)
TLR, PCI 1.8% (18/994) 3.7% (40/1076)
TLR, CABG 0.3% (3/994) 0.5% (5/1076)
Non-TL TVR 1.8% (18/994) 2.5% (27/1076)
Non-TL TVR, PCI 1.5% (15/994) 2.1% (23/1076)
Non-TL TVR, CABG 0.3% (3/994) 0.5% (5/1076)
SAFETY
Total Death 1.0% (10/994) 1.3% (14/1076)
Cardiac Death 0.5% (5/994) 0.8% (9/1076)
Non-Cardiac Death 0.5% (5/994) 0.5% (5/1076)
Cardiac Death or TVMI 1.7% (17/994) 3.2% (34/1076)
TVMI 1.2% (12/994) 2.4% (26/1076)
Q wave MI 0.2% (2/994) 0.3% (3/1076)
Non-Q wave MI 1.0% (10/994) 2.1% (23/1076)
Stent Thrombosis ARC defined
Definite/Probable 0.0% (0/994) 0.7% (7/1076)
Definite 0.0% (0/994) 0.5% (5/1076)
Probable 0.0% (0/994) 0.2% (2/1076)
ACUTE SUCCESS
Procedure Success 98.7% (982/995) 97.6% (1060/1086)
Notes
N = The t otal number of subject s enrolled. 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360 days ± 30 days ). Procedure success is defined as attainment of <50 % residual stenosis of the target lesion and no in-hospital MACE. See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
mm Subset of Main study
Endeavor)
(N = 1001 subjects)
Single Lesion
Historical Control (Endeavor)
(N = 1092 subjects)
2
6
Table 9-3: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main Study - Principal Safety and
Effectiveness - Combined Single Lesion and Dual Lesion – Treated Subjects Through 60
Months
2.5 mm – 3.5 mm subset of the Main Study (N = 1112) Outcomes at 12 Months Outcomes at 60 Month s
COMPOSITE SAFETY AND EFFECTIVENESS
TLF 3.8% (42/1105)
TVF 5.2% (58/1105)
MACE 4.6% (51/1105)
EFFECTIVENESS
Clinically Driven TVR
TLR
TLR, PCI
TLR, CABG
Non-TL TVR
Non-TL TVR, PCI
Non-TL TVR, CABG
3.9% (43/1105) 11.4% (120/1051)
2.3% (25/1105) 5.7% (60/1051)
2.0% (22/1105) 5.0% (53/1051)
0.3% (3/1105) 0.7% (7/1051)
1.9% (21/1105) 7.3% (77/1051)
1.5% (17/1105) 6.4% (67/1051)
0.4% (4/1105) 1.0% (10/1051)
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
1.0% (11/1105) 8.8% (92/1051)
0.5% (5/1105) 3.4% (36/1051)
0.5% (6/1105) 5.3% (56/1051)
Cardiac Death or TVMI 1.7% (19/1105)
TVMI
Q wave MI
Non-Q wave MI
Stent Thrombosis ARC defined
1.3% (14/1105) 3.2% (34/1051)
0.2% (2/1105) 0.4% (4/1051)
1.1% (12/1105) 2.9% (30/1051)
Definite/Probable 0.0% (0/1105)
Definite 0.0% (0/1105)
Probable 0.0% (0/1105)
Notes
N = The t otal number of subject s enrolled. 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days ). See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
10.9% (115/1051)
16.1% (169/1051)
16.7% (175/1051)
6.0% (63/1051)
0.5% (5/1051)
0.3% (3/1051)
0.2% (2/1051)
2
7
g
(
Table 9-4: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main Study - ARC
Defined Definite/Probable Stent Thrombosis Throu
Stent Thrombosis
Acute (0 - 1 day)
Subacute (2 - 30 days)
Late (31 – 360 days)
Very Late (361 - 1800 days)
Notes
N = The t otal number of subject s enrolled. Subjects are only counted once for each time period. Numbers are % (Count/Number of Eligible Subjects).
60-month timeframe includes follow-up window (1800 days ±30 days). To be included in the calculation of stent thrombosis (ST) rate for a given interval, a patient either had to have a stent thrombosis during the interval (e.g. 31-360 days inclusive) or had to be stent thrombosis-free during the interval with last follow-up on or after the first day of the given interv al (e.g. 31 days ). 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 aft er intracoronary stent ing in the f ollowing cases :
Any unex plained death within the firs t 30 days f ollowing s tent implant ation. 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 absenc e of any other obv ious cause.
2.5 mm - 3.5 mm subset of the Main Study N = 1112)
0.5% (5/1051)
0.0% (0/1051)
0.0% (0/1051)
0.0% (0/1051)
0.5% (5/1051)
h 60 Months
2
8
j
Table 9-5: RESOLUTE US 2.5 mm - 3.5 mm Subset of the Main Study Clinical Results – Single versus
Dual Lesion Sub
Single Lesion 2.5 mm -3.5 mm Subset of Main study
COMPOSITE SAFETY AND EFFECTIVENESS
TLF
TVF
MACE
(N=1001 subjects)
Outcomes at 12 Months Outcomes at 60 Months
3.6% (36/994)
5.0% (50/994)
4.3% (43/994)
EFFECTIVENESS
Clinically Driven TVR
TLR
TLR, PCI
TLR, CABG
Non-TL TVR
Non-TL TVR, PCI
Non-TL TVR, CABG
3.7% (37/994)
2.1% (21/994)
1.8% (18/994)
0.3% (3/994)
1.8% (18/994)
1.5% (15/994)
0.3% (3/994)
Dual Lesion* 2.5 mm - 3.5
mm Subset of Main study
(N=111 subjects)
5.4% (6/111)
7.2% (8/111)
7.2% (8/111)
5.4% (6/111)
3.6% (4/111)
3.6% (4/111)
0.0% (0/111)
2.7% (3/111)
1.8% (2/111)
0.9% (1/111)
ects
Single Lesion 2.5-3.5 mm
Subset of Main study
(N = 1001 subjects)
10.3% (98/947) 16.3% (17/104)
15.7% (149/947) 19.2% (20/104)
16.3% (154/947) 20.2% (21/104)
11.2% (106/947) 13.5% (14/104)
5.3% (50/947) 9.6% (10/104)
4.5% (43/947) 9.6% (10/104)
0.7% (7/947) 0.0% (0/104)
7.4% (70/947) 6.7% (7/104)
6.7% (63/947) 3.8% (4/104)
0.7% (7/947) 2.9% (3/104)
Dual Lesion* 2.5-3.5 mm
Subset of Main study
(N = 111 sub jects)
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
Cardiac Death or TVMI
TVMI
Q wave MI
Non-Q wave MI
Sten t Thromb osis ARC defined
1.0% (10/994)
0.5% (5/994)
0.5% (5/994)
1.7% (17/994)
1.2% (12/994)
0.2% (2/994)
1.0% (10/994)
0.9% (1/111)
0.0% (0/111)
0.9% (1/111)
1.8% (2/111)
1.8% (2/111)
0.0% (0/111)
1.8% (2/111)
Definite/Probable 0.0% (0/994) 0.0% (0/111)
Definite 0.0% (0/994) 0.0% (0/111)
Probable 0.0% (0/994) 0.0% (0/111)
8.8% (83/947) 7.7% (8/104)
3.3% (31/947) 4.8% (5/104)
5.5% (52/947) 2.9% (3/104)
5.9% (56/947) 6.7% (7/104)
3.3% (31/947) 2.9% (3/104)
0.4% (4/947) 0.0% (0/104)
2.9% (27/947) 2.9% (3/104)
0.5% (5/947) 0.0% (0/104)
0.3% (3/947) 0.0% (0/104)
0.2% (2/947) 0.0% (0/104))
ACUTE SUCCESS
Procedure Success 98.7% (982/995) 98.2% (108/110)
Notes
* Included in the 111 subject dual lesion subset are 95 subjects with 1 t reated lesion within 2 different v essels, 13 subjects with 2 treated lesions within a single vessel, 1 subject with 3 treated lesions within a single vessel, and 2 subject s with 1 t reated les ion within a single v essel plus 2 treated les ions within a different single vessel. N = The total num ber of s ubjects enrolled. 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 8-1- Principal Adverse Events . Procedure success is defined as attainment of <50 % residual stenosis of the target lesion and no in-hospital MACE. 12-month timeframe includes follow-up window (360 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
2
9
2.25 mm Cohort Demographics and clinical characteristics: There were 150 sub jects. The mean ag e of all subjects
was 66.3 years with 64.7% (97/150) being males. 34.0% (49/144) had a prior history of MI, 42.0% (63/150) had a prio r history of PCI, and 15.3% (23/150) had previous CABG surgery. 41.3% (62/150) were d iabetics, with 10.7% (16/150) being insulin dependent diabetics. Past medical history of subjects indicated 90.0% (135/150) had hyperlipidemia, 90.7% (136/150) had hypertension, and 12.7% (19/150) were current smokers. The mean RVD by QCA was 2.15 ± 0.40 mm, the lesion length was 12.40 ± 6.03 mm and the average percentage diameter stenosis was 72.21 ± 10.45%. 67.9% of lesions (133/196) were characterized as ACC/AHA type B2/C.
Primary Endpoint: The primary endpoint in the 2.25 mm Cohort was Target Lesion Failure (TLF) at 12 months post-procedure, defined as the Cardiac Death, Target Vessel Myocardial Inf arction (MI), or clinically-driven Target Lesion Revascularization (TLR).
Control Group and Statistical Analysis Plan: The primary endpoint of 12-month TLF was compared to a p erf ormance goal that was derived from a logistic regression of TLF rates in subjects treated with Endeavor or Driver stents pooled from the following studies: ENDEAVOR II, ENDEAVOR III, and ENDEAVOR IV. The performance goal was set at 20%, which was 55% above the expected TLF rate f o r a drug-eluting stent and preserved 50% of the benefit of a drug-eluting stent vs. a bare metal stent.
Results: The Resolute stent 2.25 mm Cohort met the 12-month TLF rate primary endpoint performance goal of 20%, with a rate o f 4.8% (7/147) and an upper one-sided 95% CI of 8.8%. (P-value <0.001).
These analyses are based on the intent-to-treat population. The results are presented in the following tables:
Table 9-6: RESOLUTE US 2.25 mm Cohort - Primary Endpoint Analysis
Table 9-7: RESOLUTE US 2.25 mm Cohort - Principal Safety and Effectiveness
Table 9-8: RESOLUTE US 2.25 mm Cohort - ARC Defined Definite/Probable Stent Thrombosis
Through 60 Mo nths
2
0
(
Table 9-6: RESOLUTE US 2.25 mm Cohort - Primary Endpoint Analysis
2.25 mm Cohort
Resolute
N = 150)
Performance Goal
Upper One-sided
95% CI1
12-month TLF 4.8% (7/147) 20% 8.8% <0.001
Notes
N = The t otal number of subject s enrolled. Subjects are only counted once for each time period. The numbers are % (Count/Number of Eligible Subjects) or least squares mean ± standard error. The primary endpoint analysis utilized a randomly selected lesion from subjects who had treatment of dual 2.25 mm lesions. 12-month timeframe includes follow-up window (360 days ± 30 days).
1
One-sided confidence interval using normal approximation.
2
One sided p-value test using asymptotic test statistic, to be compared at a 0.05 significance level.
P-value2
3
(
(
Table 9-7: RESOLUTE US 2.25 mm Cohort – Principal Safety and Effectiveness
Outcomes at 12 Months
2.25 mm Cohort N = 150)
2.25 mm Cohort N = 150)
COMPOSITE SAFETY AND EFFECTIVENESS 12 Months 60 Months
TLF
TVF
MACE
5.4% (8/147) 18.5% (27/146)
8.2% (12/147) 27.4% (40/146)
6.8% (10/147) 23.3% (34/146)
EFFECTIVENESS
Clinically Driven TVR
TLR
TLR, PCI
TLR, CABG
Non-TL TVR
Non-TL TVR, PCI
Non-TL TVR, CABG 0.0% (0/147)
6.8% (10/147) 19.9% (29/146)
4.1% (6/147)
4.1% (6/147)
0.0% (0/147)
2.7% (4/147) 13.7% (20/146)
2.7% (4/147)
8.2% (12/146)
8.2% (12/146)
0.0% (0/146)
11.6% (17/146)
2.1% (3/146)
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
Cardiac Death or TVMI
TVMI 0.7% (1/147)
Q wave MI 0.0% (0/147)
Non-Q wave MI 0.7% (1/147)
Stent Thrombosis ARC defined
Definite/Probable 1.4% (2/147)
Definite 0.7% (1/147)
Probable 0.7% (1/147)
2.7% (4/147) 15.1% (22/146)
1.4% (2/147) 10.3% (15/146)
1.4% (2/147) 4.8% (7/146)
2.0% (3/147) 12.3% (18/146)
3.4% (5/146)
0.7% (1/146)
2.7% (4/146)
1.4% (2/146)
0.7% (1/146)
0.7% (1/146)
Notes
N = The t otal number of subject s enrolled. 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
31
2
p
Table 9-8: RESOLUTE US 2.25 mm Cohort - ARC Defined
Definite/Probable Stent Thrombosis Through 60 Months
Stent Thrombosis
Acute (0 - 1 day)
Subacute (2 - 30 days)
Late (31– 360 days)
Very Late (361 – 1800 days)
Notes
N = The t otal number of subject s 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 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis.
To be included in the calculation of stent thrombosis (ST) rate for a given interval, a patient either had to have a st ent thrombosis during the interval (e.g. 31-360 days inclusive) or had to be stent thrombosis-free during the interval with last follow-u
on or after the first day of the given interval (e.g. 31 days).
2.25 mm Cohort (N = 150)
1.4% (2/146)
0.0% (0/146)
0.7% (1/146)
0.7% (1/146)
0.0% (0/146)
2.25 - 3.5 mm Angio/IVUS Sub-study
Demographics and clinical characteristics: There were 100 subjects. The mean ag e of all subjects
was 64.9 years with 62.0% (62/100) being males. 22.0% (22/100) had a prior history of MI, 29.0% (29/100) had a prio r history of PCI, and 35.0% (11/100) had previous CABG surgery. 35.0% (35/100) were d iabetics, with 9.0% (9/100) being insulin dependent diabetics. Past medical history of subjects indicated 86.0% (86/100) had hyperlipidemia, 84.0% (84/100) had hypertension, and 20.0% (20/100) were current smokers. The mean RVD by QCA was 2.48 ± 0.38 mm, the lesion length was 14.04 ± 5.87 mm and the average percentage diameter stenosis was 70.75 ± 11.57%. 76.0% of lesions (79/104) were characterized as ACC/AHA type B2/C.
Primary Endpoint: The primary endpoint in the 2.25 mm to 3.5 mm Angio/IVUS Sub-study was in-stent late lumen loss (LL) at 8 months post-procedure as measured by quantitative coronary angiography (QCA).
Control group and Statistical Analysis Plan: The primary analysis was a non-inferiority comparison of the 8-month in-stent late LL in the Resolute stent compared to a historical control population of sub jects treated with an Endeavor stent in the ENDEAVOR II trial. The non-inferiority margin was set at
0.16 mm.
Results: The 2.25 mm – 3.5 mm Angio/IVUS Sub-study met the primary non-inferiority endpoint with an 8-month in-stent late LL of 0.39 ± 0.06 mm for the Resolute stent compared to the 8-month in-stent late LL histo rical control of 0.61 ± 0.03 mm for the Endeavor stent P
non-i nferi ori ty
<0.001.
These analyses are based on the intent-to-treat population. The results are presented in the following tables:
Table 9-9: RESOLUTE US 2.25-3.5 mm Angio/IVUS Sub-study - Primary Endpoint Analysis
Table 9-10: RESOLUTE US 2.25-3.5 mm Angio/IVUS Sub-study - Principal Safety and
Ef fectiveness
Table 9-11: RESOLUTE US 2.25-3.5 mm Angio/IVUS Sub-study - ARC Defined Definite/Probable Stent Thrombosis through 60 Months
Table 9-12: RESOLUTE US 2.25-3.5 mm Angio/IVUS Sub-study - Angiographic and IVUS Results
3
3
Table 9-9: RESOLUTE US 2.25 - 3.5 mm Angio/IVUS Sub-study - Primary Endpoint Analysis
(
g
2.25-3.5 mm Angio/IVUS Sub-study
8-month In-Stent Late Lumen
Loss (mm)
Resolute
(N = 100, M =104)
0.39 ± 0.06 (90) 0.61 ± 0.03 (264) -0.22 -0.11 <0.001
Historical Control
Endeavor
N = 264, M = 264)
Difference: Resolute -
Historical Control
Upper One-sided
95% CI1
Notes
N = The t otal number of subject s enrolled. M = The t otal number of lesions at baseline. Subjects are only counted once for each time period. The numbers are least squares mean ± standard error (number of evaluable lesions). The primary endpoint analysis utilized a randomly selected lesion from subjects who had treatment of dual lesions.
1
The CI and P-values are 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.
2
One sided p-value by non-inferiority test using asymptotic test statistic with non-inferiority margin of 0.16 mm, to be compared at a 0.05 si
nificance level.
Non-inferiority
P value
1,2
3
4
(
(
Table 9-10: RESOLUTE US 2.25-3.5 mm Angio/IVUS Sub-study - Principal Safety and
Effectiveness
Sub-study
N = 100)
2.25-3.5 mm Angio/IVUS
2.25 mm - 3.5 mm
Angio/IVUS Sub-study
N = 100)
COMPOSITE SAFETY AND EFFECTIVENESS 12 Months 60 Months
TLF
TVF
MACE
12.1% (12/99) 18.6% (18/97)
13.1% (13/99) 20.6% (20/97)
13.1% (13/99) 21.6% (21/97)
EFFECTIVENESS
Clinically Driven TVR
TLR
TLR, PCI
TLR, CABG
Non-TL TVR
Non-TL TVR, PCI
10.1% (10/99)
8.1% (8/99)
7.1% (7/99) 3.1% (3/97)
1.0% (1/99)
4.0% (4/99) 8.2% (8/97)
4.0% (4/99) 7.2% (7/97)
Non-TL TVR, CABG 0.0% (0/99)
16.5% (16/97)
12.4% (12/97)
11.3% (11/97)
2.1% (2/97)
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
Cardiac Death or TVMI
TVMI
Q wave MI 0.0% (0/99)
Non-Q wave MI 1.0% (1/99)
Stent Thrombosis ARC defined
Definite/Probable 0.0% (0/99)
Definite 0.0% (0/99)
Probable 0.0% (0/99)
4.0% (4/99) 10.3% (10/97)
3.0% (3/99) 6.2% (6/97)
1.0% (1/99) 4.1% (4/97)
4.0% (4/99)
1.0% (1/99)
7.2% (7/97)
2.1% (2/97)
0.0% (0/97)
2.1% (2/97)
0.0% (0/97)
0.0% (0/97)
0.0% (0/97)
Notes
N = The t otal number of subject s enrolled. 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
3
5
(
p
Table 9-11: RESOLUTE US 2.25-3.5 mm Angio/IVUS Sub-study - ARC Defined
Definite/Probable Stent Thrombosis Through 60 Months.
Stent Thrombosis
Acute (0 - 1 day)
Subacute (2 - 30 days)
Late (31 – 360 days)
Very Late (361 - 1800 days)
Notes
N = The t otal number of subject s 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 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis.
To be included in the calculation of stent thrombosis (ST) rate for a given interval, a patient either had to have a st ent thrombosis during the interval (e.g. 31-360 days inclusive) or had to be stent thrombosis-free during the interval with last follow-u
on or after the first day of the given interval (e.g. 31 days).
2.25-3.5 mm Angio/IVUS Sub-study N = 100)
0.0% (0/97)
0.0% (0/97)
0.0% (0/97)
0.0% (0/97)
0.0% (0/97)
3
6
(
Table 9-12: RESOLUTE US 2.25-3.5 mm Angio/IVUS Sub-study -
Angiographic and IVUS Results
2.25-3.5 mm Angio/IVUS Sub-study
Outcomes at 8 Months
ANGIOGRAPHIC RESULTS
MLD (mm), In-stent
Post-Procedure 2.44 ± 0.39 (104)
8-Month 2.06 ± 0.66 (93)
MLD (mm), In-segment
Post-Procedure 2.06 ± 0.39 (104)
8-Month 1.80 ± 0.58 (93)
% DS, In-stent
Post-Procedure 4.07 ± 10.12 (104)
8-Month 16.40 ± 23.55 (93)
% DS, In-segment
Post-Procedure 19.41 ± 8.22 (104)
8-Month 26.86 ± 19.65 (93)
Late Loss (mm)
In-stent 0.36 ± 0.52 (93)
In-segment 0.24 ± 0.43 (93)
Binary Restenosis
In-stent 10.8% (10/93)
In-segment 11.8% (11/93)
IVUS RESULTS
Neointimal Volume (mm3) 7.29 ± 9.30 (63)
% Volume Obstruction 5. 34 ± 5.97 (63)
Incomplete Apposition
Persistent 16.7% (10/60)
Late Acquired 1.7% (1/60)
Notes
N = The t otal number of subject s enrolled. M = The t otal number of lesions at baseline. Numbers are % (Count/Number of Evaluable Lesions) or Mean ± SD (Num ber of Evaluable Lesions). Subjects are only counted once for each time period.
N = 100, M = 104)
3
7
4.0 mm Sub-study
Demographics and Clinical Characteristics: There were 60 subjects. The mean age of all subjects
was 63.7 years with 66.7% (40/60) being males. 20.0% (12/60) had a prior history of MI, 25.0% (15/60) had a prior history of PCI and 10.0% (6/60) had previous CABG surgery. 36.7% (22/60) were diabetics, with 10.0% (6/60) being insulin dependent diabetics. Past medical history of subjects indicated 80.0% (48/60) had hyperlipidemia, 85.0% (51/60) had hypertension, and 23.3% (14/60) were current smokers. The mean RVD by QCA was 3.25 ± 0.48 mm, the lesion length was 12.83 ± 5.97 mm and the average percentage diameter stenosis was 67.70 ± 13.09%. 79.1% of lesions (57/72) were characterized as ACC/AHA type B2/C.
Primary Endpoint: The primary endpoint in the 4.0 mm Sub-study was in-segment late LL at 8 months post-procedure as measured by QCA.
Control group and Statistical Analysis Plan: The primary analysis was a superiority comparison of the 8-month in-segment late LL in the Resolute stent compared to a historical control population of sub jects treated with a Driver bare metal stent of diameters 3.5 mm or 4.0 mm in the Medtronic S8 Driver stent registry (6-month late LL) and the ENDEAVOR II trial (8-month late LL).
Results: The 4.0 mm Resolute stent met the primary superiority endpoint with an 8-month in-segment late LL of 0.11 ± 0.09 mm, compared with the historical Driver stent control in-segment late LL of 0.66 ±
0.05 mm, P
super iority
<0.001.
These analyses are based on the intent-to-treat population. The results are presented in the following tables:
Table 9-13: RESOLUTE US 4.0 mm Sub-study - Primary Endpoint Analyses
Table 9-14: RESOLUTE US 4.0 mm Sub-study – Principal Safety and Effectiveness
Table 9-15: RESOLUTE US 4.0 mm Sub-study - ARC Defined Definite/Probable Stent Thrombosis
through 60 Months
Table 9-16: RESOLUTE US 4.0 mm Sub-study - Angiographic Results
3
8
Table 9-13: RESOLUTE US 4.0 mm Sub-study - Primary Endpoint Analyses
Upper
One-sided
95% CI1
4.0 mm Sub-study
8-month In-Segment Late Lumen Loss (mm)
Resolute
(N = 60, M = 72)
0.11 ± 0.09 (50) 0.66 ± 0.05 (150) -0.56 -0.38 <0.001
Historical Control Driver
(N = 150, M = 150)
Difference: Resolute -
Historical Control
Notes
N = The t otal number of subject s enrolled. M = The t otal number of lesions at baseline. Subjects are only counted once for each time period. The numbers are least squares mean ± standard error (number of evaluable lesions). The primary endpoint analysis utilized a randomly selected lesion from subjects who had treatment of dual 4.0 mm lesions
1
The CI and P-values are 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.
2
One sided p-value by superiority test using asymptotic test statistic, to be c ompared at a 0.05 signific ance level.
Superiority
1,2
P-value
3
9
Table 9-14: RESOLUTE US 4.0 mm Sub-study – Principal Safety and Effectiveness
(
(
4.0 mm Sub-Study N = 60)
COMPOSITE SAFETY AND EFFECT IVENESS 12 Months 60 Months
TLF 6.8% (4/59)
TVF 6.8% (4/59)
MACE 8.5% (5/59)
EFFECTIVENESS
Clinically Driven TVR 3.4% (2/59)
TLR 3.4% (2/59)
TLR, PCI 3.4% (2/59)
TLR, CABG 0.0% (0/59)
Non-TL TVR 1.7% (1/59)
Non-TL TVR, PCI 1.7% (1/59)
Non-TL TVR, CABG 0.0% (0/59)
SAFETY
Total Death 1.7% (1/59)
Cardiac Death 0.0% (0/59)
Non-Cardiac Death 1.7% (1/59)
Cardiac Death or TVMI 3.4% (2/59)
TVMI 3.4% (2/59)
Q wave MI 0.0% (0/59)
Non-Q wave MI 3.4% (2/59)
Stent Thrombosis ARC defined
Definite/Probable 0.0% (0/59)
Definite 0.0% (0/59)
Probable 0.0% (0/59)
Notes
N = The t otal number of subject s enrolled. 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
4.0 mm Sub-Study N = 60)
12.7% (7/55)
14.5% (8/55)
23.6% (13/55)
9.1% (5/55)
7.3% (4/55)
7.3% (4/55)
0.0% (0/55)
7.3% (4/55)
5.5% (3/55)
1.8% (1/55)
10.9% (6/55)
0.0% (0/55)
10.9% (6/55)
5.5% (3/55)
5.5% (3/55)
0.0% (0/55)
5.5% (3/55)
0.0% (0/55)
0.0% (0/55)
0.0% (0/55)
3
0
g
Table 9-15: RESOLUTE US 4.0 mm Sub-study - ARC Defined
Definite/Probable Stent Thrombosis Through 60 Months
Stent Thrombosis
Acute (0 - 1 day)
Subacute (2 - 30 days)
Late (31 – 360 days)
Very Late (361 - 1800 days)
Notes
N = The t otal number of subject s 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 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis. To be included in the calculation of stent thrombosis (ST) rate for a given interval, a patient either had to have a stent thrombosis during the interval (e.g. 31-360 days inclusive) or had to be stent thrombosis-free during the interval with last follow-up on or after the first day of the
iven interval (e.g. 31 days).
4.0 mm Sub-study (N = 60)
0.0% (0/55)
0.0% (0/55)
0.0% (0/55)
0.0% (0/55)
0.0% (0/55)
4
Table 9-16: RESOLUTE US 4.0 mm Sub-study Angiographic Results
(
j
4.0 mm Sub-study
Outcomes at 8 Months
ANGIOGRAPHIC RESULTS
MLD (mm), In-stent
Post-Procedure 3.12 ± 0.38 (72)
8-Month 2.94 ± 0.65 (60)
MLD (mm), In-segment
Post-Procedure 2.75 ± 0.45 (72)
8-Month 2. 60 ± 0.60 (60)
% DS, In-stent
Post-Procedure 4.54 ± 9.36 (72)
8-Month 9.37 ± 19.48 (60)
% DS, In-segment
Post-Procedure 16.62 ± 8.27 (72)
8-Month 20.22 ± 14.79 (60)
Late Loss (mm)
In-stent 0. 19 ± 0.56 (60)
In-segment 0.14 ± 0.43 (60)
Binary Restenosis
In-stent 6.7% (4/60)
In-segment 6.7% (4/60)
Notes
N = The t otal number of subject s enrolled. M = The t otal number of lesions at baseline. Numbers are % (Count/Number of Evaluable Lesions) or Mean ± SD (Num ber of Evaluable Lesions). Sub
ects are only counted once for each time period.
N = 60, M = 72)
41
2
RESOLUTE US – Primary Enrollment Group - Gender Analysis
Table 9-17 shows the baseline demographic and clinical characteristics stratified by gender for subjects
in the pooled RESOLUTE US analysis, 445/1402 (31.7%) subjects were female and 957/1402 (68.3%) were male. Consistent with other DES clinical studies, female patients were older, had a higher rate of diabetes and hypertension and had smaller reference vessel diameters (RVD).
Table 9-17: RESOLUTE US Baseline Demographic and Lesion Characteristics
Male vs. Female
Male
Patient Characteristics
Age (Years)
History of smoking/tobacco use
Prior PCI
Hyperlipidemia
Diabetes Mellitus
Insulin Dependent
Hypertension
Prior MI
Prior CABG
Ejection fraction - Qualitative
<30%
30-40%
>40%
Lesion Class
A
B1
B2
C
Moderate/Severe Calcification
Pre procedure RVD
Pre procedure MLD
Pre procedure Diameter Stenosis
Lesion Length
(N = 957)
63.14±10.48 (957) 66.23±10.76 (445) <.001
67.0% (641/957) 52.8% (235/445) <.001
34.2% (327/957) 29.4% (131/445) 0.087
88.5% (847/957) 86.1% (383/445) 0.221
31.3% (300/957) 40.9% (182/445) <.001
7.2% (69/957) 14.8% (66/445) <.001
82.2% (787/957) 88.3% (393/445) 0.004
24.6% (232/943) 15.1% (66/436) <.001
10.6% (101/957) 5.2% (23/445) <.001
0.12% (1/823) 0.26% (1/386)
6.68% (55/823) 3.37% (13/386)
93.20% (767/823) 96.37% (372/386)
5.55% (60/1082) 7.64% (37/484)
17.10% (185/1082) 22.11% (107/484)
30.87% (334/1082) 27.48% (133/484)
46.49% (503/1082) 42.77% (207/484)
26.0% (281/1082) 28.9% (140/484) 0.241
2.62±0.48 (1082) 2.53±0.44 (484) <.001
0.75±0.35 (1082) 0.79±0.34 (484) 0.058
71.43±11.57 (1082) 68.98±11.24 (484) <.001
13.27±5.89 (1082) 12.60±5.83 (484) 0.036
Female
(N = 445)
p-value
0.028
0.022
The 12-mo nth rate o f TLF was 4.5% in males and 5.0% in f emales (Table 9-18). This post hoc analysis sho ws a generally similar treatment effect between genders for the primary endpoint of 12-month TLF. These data suggest that the safety and effectiveness of the Resolute stent can be generalized to males and f emales.
4
3
Table 9-18: RESOLUTE US Primary Enrollment Group - Clinical Endpoints by
Gender – Principal Safety and Effectiveness to 60 Months
Male
(N = 957)
Female
(N = 445)
Safety Measures to 12 Months COMPOSITE SAFETY AND EFFECTIVENESS
TLF 4.5% (43/952) 5.0% (22/438) TVF 5.7% (54/952) 7.3% (32/438) MACE 5.6% (53/952) 5.5% (24/438) EFFECTIVENESS Clinically Driven TVR 4.4% (42/952) 5.0% (22/438) Clinically Driven TLR 3.0% (29/952) 2.5% (11/438) SAFETY Death 1.4% (13/952) 1.4% (6/438) Cardiac Death 0.6% (6/952) 0.9% (4/438) Non-Cardiac Death 0.7% (7/952) 0.5% (2/438) TVMI (Extended Historical Definition) 1.1% (10/952) 1.8% (8/438) Cardiac Death or Target Vessel MI (TVMI) 1.7% (16/952) 2.7% (12/438) Stent Thrombosis ARC defined Definite/Probable 0.2% (2/952) 0.0% (0/438) Definite 0.1% (1/952) 0.0% (0/438) Probable 0.1% (1/952) 0.0% (0/438)
Safety Measures to 60 Months COMPOSITE SAFETY AND EFF ECTIVEN ESS
TLF TVF MACE
12.4% (113/909) 12.1% (51/420)
17.5% (159/909) 17.6% (74/420)
18.0% (164/909) 17.9% (75/420)
EFFECTIVENESS Clinically Driven TVR Clinically Driven TLR
12.7% (115/909) 12.1% (51/420)
6.9% (63/909) 5.5% (23/420)
SAFETY Death Cardiac Death Non-Cardiac Death TVMI (Extended Historical Definition) Cardiac Death or Target Vessel MI (TVMI)
9.4% (85/909) 10.0% (42/420)
4.0% (36/909) 4.5% (19/420)
5.4% (49/909) 5.5% (23/420)
2.8% (25/909) 4.3% (18/420)
6.2% (56/909) 7.9% (33/420)
Stent Thrombosis ARC defined Definite/Probable Definite Probable
0.6% (5/909) 0.5% (2/420)
0.2% (2/909) 0.5% (2/420)
0.3% (3/909) 0.0% (0/420)
Notes
N = The t otal number of subject s enrolled. 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days ). See Table 9-4 for the definition of the ARC defined Stent Thrombosis
See Section 9.9.1 Gender Analysis from the RESOLUTE Pooled On-label Dataset for the co mprehensive gender analysis.
4
4
RESOLUTE 38 mm Length Group
(
The 38 mm Length Group was designed to demonstrate the safety and effectiveness of the Resolute 38 mm stent and consisted of subjects with ischemic heart disease due to a stenotic lesion in a de novo native coronary artery with a reference vessel diameter between 3.0 mm and 4.2 mm and a lesion length 35 mm amenab le to p ercutaneous treatment with a 38 mm Resolute stent. The 38 mm Length Group was made up of 38 mm subjects pooled from the RESOLUTE US and RESOLUTE ASIA studies. 223 sub jects were enrolled at 47 sites with 114 subjects at 29 sites in the US and 109 subjects at 17 sites in Asia (Bangladesh, India, Hong Kong, Malaysia, Singapore and Thailand).
Demographics and clinical characteristics: There were 223 subjects. The mean age of all subjects was 60.9 years with 78.9% (176/223) being males. 32.4% (70/216) had a prior history of MI, 27.4% (61/223) had a prio r history of PCI and 7.2% (16/223) had previous CABG surgery. 37.7% (84/223) were d iabetics, with 10.3% (23/223) being insulin dependent diabetics. Past medical history of subjects indicated 58.7% (131/223) had hyperlipidemia, 74.9% (167/223) had hypertension, and 18.8% (42/223) were current smokers. The mean RVD by QCA was 2.78±0.42 mm, the lesion length was 25.22±8.83 mm and the average percentage diameter stenosis was 71.33±11.61%. 91.2% of lesions (240/263) were characterized as ACC/AHA type B2/C.
Primary Endpoint: The primary endpoint of the 38 mm Length Group was Target Lesion Failure (TLF) at 12 months post-procedure, defined as Cardiac Death, Target Vessel Myocardial Infarction (MI), or clinically driven Target Lesion Revascularization (TLR).
Control Group and Statistical Analysis Plan: The primary endpoint of 12-month TLF was compared to a p erf ormance goal that was derived from a logistic regression of TLF rates in subjects treated with Endeavor or Driver stents pooled from the Endeavor stent clinical program: ENDEAVOR I, ENDEAVOR II, ENDEAVOR II CA, END EAV OR III, END EAVOR IV and ENDEAVOR PK. The p erformance goal was set at 19%, which was 48% above the expected TLF rate for a d rug-eluting stent and preserved 51% of the b enef it of a drug-eluting stent vs. a bare metal stent.
Results: The 38 mm Leng th Group 12-month TLF rate was 4.5% (10/223) with an upper one-sided 95% Cl of 7.5%, which met the performance goal of 19%, (P-value <0.001). The 12-month and 60-month f o llow-up rates were 99.1% (221/223) and 93.7% (209/223), respectively.
These analyses are based on the intent-to-treat population. The results are presented in the following tables:
Table 9-19: 38 mm Length Group – Primary Endpoint Analyses
Table 9-20: 38 mm Length Group - Principal Safety and Effectiveness Through 60 Months
Table 9-21: 38 mm Length Group – ARC Defined/Probable Stent Thrombosis Through 60 Months
Table 9-22: Pooled Resolute Analysis including the 38 mm Length Group
Table 9-19: 38 mm Length Group – Primary Endpoint Analyses
38 mm Length Group
12-month TLF
Notes
N = The t otal number of subject s enrolled. Subjects are only counted once for each time period. The numbers are % (Count/Number of Eligible Subjects). The primary endpoint analysis utilized a randomly selected lesion from subjects who had treatment of dual 38 mm lesions. 12-month timeframe includes follow-up window (360 days ± 30 days ).
1
One-sided confidence interval using normal approximation.
2
One-sided p-value test using asymptotic test statistic, to be compared at a 0.05 signific ance level
Resolute
N=223)
4.5% (10/223) 19.00% 7.5% <0.001
Performance
Goal
Upper One-Sided
95% CI1
P-value2
4
5
Table 9-20: 38 mm Length Group - Principal Safety and Effectiveness
COMPOSITE SAFETY AND EFFECTIVENESSS
TLF TVF MACE
EFFECTIVENESS
Clinically-driven TVR TLR TLR, PCI TLR, CABG Non-TL TVR Non-TL TVR, PCI Non-TL TVR, CABG SAFETY Total Death Cardiac Death Non-Cardiac Death Cardiac Death or TVMI TVMI Q wave MI Non-Q wave MI
38 mm Length Group
(N = 223)
R-US Sub-study
(N = 114)
Outcomes at 12 Months Outcomes at 12 Months Outcomes at 12 Months Outcomes at 60 Months
5.4% (12/222) 7.1% (8/113) 3.7% (4/109) 13.8% (30/217)
6.8% (15/222) 9.7% (11/113) 3.7% (4/109) 17.1% (37/217)
6.3% (14/222) 8.8% (10/113) 3.7% (4/109) 17.5% (38/217)
2.7% (6/222) 4.4% (5/113) 0.9% (1/109)
1.4% (3/222) 1.8% (2/113) 0.9% (1/109)
1.4% (3/222) 1.8% (2/113) 0.9% (1/109)
0.0% (0/222) 0.0% (0/113) 0.0% (0/109)
1.4% (3/222) 2.7% (3/113) 0.0% (0/109)
1.4% (3/222) 2.7% (3/113) 0.0% (0/109)
0.0% (0/222) 0.0% (0/113) 0.0% (0/109)
0.9% (2/222) 1.8% (2/113) 0.0% (0/109)
0.9% (2/222) 1.8% (2/113) 0.0% (0/109)
0.0% (0/222) 0.0% (0/113) 0.0% (0/109)
4.5% (10/222) 5.3% (6/113) 3.7% (4/109)
3.6% (8/222) 3.5% (4/113) 3.7% (4/109)
0.9% (2/222) 0.9% (1/113) 0.9% (1/109)
2.7% (6/222) 2.7% (3/113) 2.8% (3/109)
R-Asia Cohort
(N = 109)
38 mm Length Group
(N = 223)
9.7% (21/217)
6.0% (13/217)
5.5% (12/217)
0.5% (1/217)
3.7% (8/217)
3.2% (7/217)
0.5% (1/217)
6.5% (14/217)
4.1% (9/217)
2.3% (5/217)
8.8% (19/217)
6.0% (13/217)
0.9% (2/217)
5.1% (11/217)
Side Branch Occlusion † 5.4% (12/222) 7.1% (8/113) 3.7% (4/109) 5.5% (12/217)
Stent Thrombosis ARC Defined
Definite/Probable Definite Probable
Notes
0.9% (2/222) 0.9% (1/113) 0.9% (1/109)
0.5% (1/222) 0.0% (0/113) 0.9% (1/109)
0.5% (1/222) 0.9% (1/113)
0.0% (0/109)
1.4% (3/217)
0.5% (1/217)
0.9% (2/217)
N = The t otal number of subject s enrolled. 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days).
5 subjects with side branch occlusion had a TVMI.
See Table 9-4 for the definition of the ARC defined Stent Thrombosis.
4
6
y)
)
)
g
Table 9-21: 38 mm Length Group – ARC Defined/Probable
Stent Thrombosis Through 60 Months
Stent Thrombosis Acute (0-1 da Subacute (2-30 days Late (31-360 days Very Late (361 - 1800 days)
(N = 223)
1.4% (3/217)
0.0% (0/217)
0.9% (2/217)
0.0% (0/217)
0.5% (1/217)
Notes
N = The t otal number of subject s enrolled. Subjects are only counted once for each time period. Numbers are % (Count/Number of Eligible Subjects).
38 mm Length Group
12-month timeframe includes follow-up window (360 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis.
To be included in the calculation of stent thrombosis (ST) rate for a given interval, a patient either had to have a stent thrombosis during the interval (e.g. 31-360 days inclusive) or had to be stent thrombosis-free during the interval with last follow-up on or after the first day of
iven interval (e.g. 31 days).
the
Table 9-22 shows the Pooled Resolute Analysis including the 38 mm Length Groups. The safety and ef f icacy data from the 38 mm Length Group and five (5) Resolute studies; Resolute FIM, Resolute US (PEG), Resolute International, Resolute All-Comers and Resolute Japan are presented to 60 Months.
Table 9-22: Pooled Resolute Analysis including the 38 mm Length Groups -
Through 60 Months
Poole d Resolute analysis with the 38mm Le ngth Group
Safety Measures to 12 Months COMPOSITE SAFE TY AND EFFE CTIVENESS
TLF 6.5% (348/5321) TVF 7.5% (397/5321) MACE 7.5% (398/5321) EFFECTIVENESS Clinically Driven TVR 4.2% (226/5321) Clinically Driven TLR 3.2% (169/5321) SAFETY Death 1.9% (100/5321) Cardiac Death 1.2% (62/5321) Non-Cardiac Death 0.7% (38/5321) TVMI (Extended Historical Definition) 3.0% (157/5321) Cardiac Death or Target Vessel MI (TVMI) 3.9% (210/5321) Stent Thrombosis ARC de fine d Definite/Probable 0.8% (42/5321) Definite 0.6% (30/5321) Probable 0.3% (14/5321)
Safety Measures to 36 Months COMPOSITE SAFE TY AND EFFE CTIVENESS
TLF 10.7% (562/5234) TVF 13.0% (681/5234) MACE 13.5% (708/5234) EFFECTIVENESS Clinically Driven TVR 7.9% (413/5234) Clinically Driven TLR 5.3% (276/5234)
(N=5353)
4
7
Table 9-22: Pooled Resolute Analysis including the 38 mm Length Groups -
(
(
(
Through 60 Months
Poole d Resolute analysis with the 38mm Le ngth Group
SAFETY
Death 5.4% (284/5234) Cardiac Death 3.1% (161/5234) Non-Cardiac Death 2.4% (123/5234) TVMI (Extended Historical Definition) 3.8% (200/5234) Cardiac Death or Target Vessel MI (TVMI) 6.5% (339/5234) Stent Thrombosis ARC de fine d Definite/Probable 1.1% Definite 0.7% (38/5234) Probable 0.4% (20/5234)
Safety Measures to 60 Months* COMPOSITE SAFE TY AND EFFE CTIVENESS
TLF 14.0% (406/2905) TVF 18.0% (523/2905) MACE 19.2% (559/2905) EFFECTIVENESS Clinically Driven TVR 11 .3 % (327/2905) Clinically Driven TLR 6.6% (192/2905) SAFETY Death 9.6% (280/2905) Cardiac Death 4.8% (140/2905) Non-Cardiac Death 4.8% (140/2905) TVMI (Extended Historical Definition) 4.6% (133/2905) Cardiac Death or Target Vessel MI (TVMI) 8.7% Stent Thrombosis ARC de fine d Definite/Probable 1.3% Definite 0.8% (23/2905) Probable 0.5% (15/2905)
Notes
N = The t otal number of subject s enrolled. 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 Procedure Through Latest Available Follow-up- Principal Adverse Events. 12-month timeframe 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 three years and is not included in this analysis.
See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
(N=5353)
56/5234)
253/2905)
37/2905)
Table 8-1: Principal Adverse Events from Post-
4
8
Table 9-23 shows the baseline demographic and clinical characteristics stratified by gender for sub jects in the 38 mm Length Group analysis, 47/223 (21.1%) subjects were female and 176/223 (78.9%) were male. Consistent with other DES clinical studies, female patients were older, and there was no o ther significant difference in baseline demographic and clinical characteristics observed between gender groups.
Table 9-23: RESOLUTE 38 mm Length Group - Baseline Demographic and Lesion
Characteristics Male vs. Female
Male
Patient Characteristics
Age (Years) 60.1±10.7 64.0±10.2 0.028
History of smoking/tobacco use 20.5% (36/176) 12.8% (6/47) 0.469
Prior PCI 25.0% (44/176) 36.2% (17/47) 0.142
Hyperlipidemia 56.3% (99/176) 68.1% (32/47) 0.182
Diabetes Mellitus 36.4% (64/176) 42.6% (20/47) 0.499
Insulin Dependent 9.1% (16/176) 14.9% (7/47) 0.280
Hypertension 72.2% (127/176) 85.1% (40/47) 0.088
Prior MI 32.4% (55/170) 32.6% (15/46) 1.000
Prior CABG 7.4% (13/176) 6.4% (3/47) 1.000
Ejection fraction - Qualitative 0.389
<30% 0.0% (0/144) 0.0% (0/40)
30-40% 4.2% (6/144) 7.5% (3/40)
>40% 95.8% (138/144) 92.5% (37/40)
Lesion Class 0.634
A 1.9% (4/209) 0.0% (0/54)
B1 8.1% (17/209) 3.7% (2/54)
B2 9.6% (20/209) 9.3% (5/54)
C 80.4% (168/209) 87.0% (47/54)
Moderate/Severe Calcification 32.5% (68/209) 44.4% (24/54) 0.111
Pre procedure RVD (mm) 2.79±0.44 2.75±0.37 0.504
Pre procedure MLD (mm) 0.80±0.36 0.80±0.36 0.912
Pre procedure Diameter Stenosis (%) 71.42±11.49 70.98±12.15 0.805
Lesion Length (mm) 25.16±8.45 25.48±10.27 0.808
(N = 176)
Female (N = 47) p-value
The 12-mo nth rate o f TLF was 4.0% in males and 10.9% in f emales (Table 9-24). Although event rates were numerically higher in women, the number of women in the study was small. Further, the RESOLUTE 38 mm Leng th study was not designed or powered to study the safety or effectiveness of the 38 mm Resolute stent in gender-specific subgroups, so these post hoc analyses are considered hyp o thesis-generating.
4
9
Table 9-24: RESOLUTE 38 mm Length Group - 12-Month Clinical Endpoints by
Gender – Principal Safety and Effectiveness
Male (N = 176) Female (N = 47)
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
Sten t Thromb osis ARC defined
Definite/Probable
Definite
Probable
Notes
N = The t otal number of subject s enrolled. 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 8-1: Principal Adverse Events from Post-
Procedure Through Latest Available Follow-up- Principal Adverse Events. 12-month timeframe includes follow-up window (360 days ± 30 days ). See Table 9-4 for the definition of the ARC defined Stent Throm bosis.
4.0% (7/176) 10.9% (5/46)
5.1% (9/176) 13.0% (6/46)
5.1% (9/176) 10.9% (5/46)
1.7% (3/176) 6.5% (3/46)
0.6% (1/176) 4.3% (2/46)
0.6% (1/176) 2.2% (1/46)
0.6% (1/176) 2.2% (1/46)
0.0% (0/176) 0.0% (0/46)
2.8% (5/176) 6.5% (3/46)
3.4% (6/176) 8.7% (4/46)
0.6% (1/176) 2.2% (1/46)
0.0% (0/176) 2.2% (1/46)
0.6% (1/176) 0.0% (0/46)

9.2 Results of the RESOLUTE AC Clinical Trial

Primary Objective: To compare the Resolute Zotarolimus-Eluting Coronary Stent System (Resolute
stent) with the Abbott XIENCE V Everolimus-Eluting Coronary Stent System (Xience V stent) in a “real world” patient population with respect to Target Lesion Failure, composite of Cardiac Death, MI- not clearly attributable to a non-target vessel, clinically indicated TLR at 12 months.
The data from the RESOLUTE AC trial were used to support the PMA approval of the Resolute Integrity stent. In particular, the on-label data from the RESOLUTE AC population were pooled with other on-
label RESOLUTE program data to demonstrate the long-term safety of the Resolute stent
. See Section
8.1 – Observed Adverse Events.
Design: This is a prospective, multi-center, randomized, two-arm non-inferiority trial that compared the
Resolute stent to the Abbott Xience V stent. A total of 2292 subjects were enrolled at 17 clinical research sites from 11 countries in Western Europe. Patients were eligible if they had at least one co ro nary lesion with a diameter stenosis >50%, in a vessel with a reference diameter between 2.25 mm and 4.0 mm. No restriction was placed on the total number of treated lesions, treated vessels, lesion length or number of stents implanted. The study was designed to enroll patients with symptomatic
4
0
co ro nary disease including chronic stable angina, silent ischemia, and acute coronary ischemic syndromes. Subjects were stratified as being non-complex or complex (based on clinical features and co ro nary anatomy), with complex subjects having one or more of the following patient or lesion characteristics: Bifurcation, bypass graft, in stent restenosis, AMI <72 hours, LVEF <30%, unprotected lef t main, >2 vessels stented, renal insufficiency or failure (serum creatinine >2.5 mg/dl), lesion leng th >27 mm, >1 lesion per vessel, lesion with thrombus or total occlusion (pre procedure TIMI = 0).
Follow-up was performed at 30 days, 6, 9, 12 and 24 mo nths and will be performed annually out to 5 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 o f bleeding.
Demographics and clinical characteristics: Refer to Table 9-25: R-AC – Baseline Characteristics.
Table 9-25: R-AC - Baseline Characteristics
Baseline Characteristics
Mean Age (years) 64.4 64.2
Male Enrollment 76.67% (873/1140) 77.2% (889/1152)
Hx of prior PCI 31.8% (363/1140) 32.1% (370/1152)
Hx of prior MI 28.8% (323/1122) 30.4% (341/1120)
Hx of Diabetes 23.5% (268/1140) 23.4% (270/1152)
Multi-vessel disease
Type B2/C lesions
Syntax Score
Complex*
* Complex was defined as having one or more of the following patient or lesion characteristics: Bif urcation, bypass graft, in stent restenosis, AMI <72 hr, LVEF <30%, unprotected left m ain, >2 v essels s tented, 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).
The remaining baseline clinical features were well-matched between both arms.
Resolute
(N = 1140 subjects;
M = 1661 lesions)
58.4% (666/1140) 59.2% (682/1152)
77.5% (1268/1636) 74.7% (1251/1673)
14.8 ± 9.3 14.6 ± 9.2
67% (764/1140) 65.6% (756/1152)
Xience V
(N = 1152 subjects;
M = 1705 lesions)
Clinical Results: A summary of the results is presented in the following tables:
Table 9-26: R-AC Princip al Safety and Effectiveness (All subjects)
Table 9-27: R-AC Princip al Safety and Effectiveness (Complex cohort)
Table 9-28: R-AC Princip al Safety and Effectiveness (Non-Complex cohort)
Table 9-29: R-AC ARC Defined Definite/Probable Stent Thrombosis through 60 Mo nths (Complex
and Non-Complex)
The 12mo nth and 5-year follow-up rates for the RESOLUTE All Comers study were 99.5% (2280/2292) and 98.8% (2265/2292) respectively. Strengths of this analysis include the collection and presentation of both short and long term outcomes demonstrating safety and effectiveness in a randomized study in an all comer population. A limitation was that this trial was not sized to determine the rate of low frequency events with a pre-specified precision.
The published RESOLUTE All-Comers trial results are available in Serruys PW, Silber S, Garg S, et al. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med 2010; 363: 136-46.
5
COMPOSITE SAFETY AND
(
(
(
(
EFFECTIVENESS
TLF
Table 9-26: R-AC Principal Safety and Effectiveness (All subjects)
All subjects
12 Months
Resolute N = 1140)
Xience V N = 1152)
Resolute
N = 1140)
8.1% (92/1132) 8.5% (97/1142) 17.0% (191/1123) 16.2% (183/1133)
60 Months
Xience V
N = 1152)
TVF
MACE
EFFECTIVENESS
Clinically Driven TVR
TLR
TLR, PCI
TLR, CABG
Non-TL TVR
Non-TL TVR, PCI
Non-TL TVR, CABG
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
Cardiac Death or TVMI
TVMI
Q wave MI
8.9% (101/1132) 9.7% (111/1142) 20.0% (225/1123) 19.1% (216/1133)
8.6% (97/1132) 9.8% (112/1142) 21.9% (246/1123) 21.6% (245/1133)
4.9% (55/1132) 4.8% (55/1142) 11.4% (128/1123) 10.9% (123/1133)
3.9% (44/1132) 3.4% (39/1142) 7.8% (88/1123) 7.1% (81/1133)
3.4% (38/1132) 2.7% (31/1142) 6.9% (77/1123) 6.0% (68/1133)
0.5% (6/1132) 0.8% (9/1142) 1.4% (16/1123) 1.4% (16/1133)
1.9% (21/1132) 2.2% (25/1142) 6.1% (68/1123) 6.1% (69/1133)
1.5% (17/1132) 1.9% (22/1142) 5.2% (58/1123) 5.2% (59/1133)
0.4% (4/1132) 0.4% (4/1142) 0.9% (10/1123) 1.0% (11/1133)
1.6% (18/1132) 2.7% (31/1142) 11.0% (123/1123) 10.8% (122/1133)
1.3% (15/1132) 1.7% (19/1142) 6.5% (73/1123) 5.7% (65/1133)
0.3% (3/1132) 1.1% ( 12/1142) 4.5% (50/1123) 5.0% (57/1133)
5.3% (60/1132) 5.5% (63/1142) 11.5% (129/1123) 10.6% (120/1133)
4.2% (48/1132) 4.2% (48/1142) 5.7% (64/1123) 5.7% (65/1133)
0.8% (9/1132) 0.4% (5/1142) 1.3% (15/1123) 0.8% (9/1133)
Non-Q wave MI
Sten t Thromb osis ARC defined
Definite/Probable 1.6% (18/1132) 0.7% (8/1142) 2.4% (27/1123) 1.7% (19/1133)
Definite 1.1% (13/1132) 0.3% (3/1142)
Probable 0.5% (6/1132) 0.4% (5/1142) 0.9% (10/1123) 0.9% (10/1133) Notes
N = The t otal number of subject s 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360± 30 days ) 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
3.5% (40/1132) 3.8% (43/1142) 4.6% (52/1123) 4.9% (56/1133)
1.6% (18/1123) 0.8% (9/1133)
51
2
Table 9-27: R-AC Principal Safety and Effectiveness (Complex cohort)
Complex cohort
12 Months
60 Months
COMPOSITE SAFETY AND EFFECTIVENESS
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)
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
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)
Sten t Thromb osis 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 t otal number of subject s 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360± 30 days ) 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis. Complex was defined as having one or more of the following patient or lesion characteristics: Bifurcation, bypass graf t, in st ent restenos is, AMI <72 hr., LVEF <30%, unprot ected 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).
Resolute
(N = 764)
4.2% (32/760) 4.7% (35/750) 5.9% (44/751) 6.0% (45/745)
Xience V (N = 756)
Resolute
(N = 764)
Xience V (N = 756)
5
3
(
(
(
(
Table 9-28: R-AC Principal Safety and Effectiveness (Non-Complex Cohort)
Non-Complex cohort
COMPOSITE SAFETY AND EFFECTIVENESS
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)
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
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)
Sten t Thromb osis 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 t otal number of subject s 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 8-1- Principal Adverse Events . 12-month timeframe includes follow-up window (360± 30 days ) 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis. Complex was defined as having one or more of the following patient or lesion characteristics: Bifurcation, bypass graf t, in st ent restenos is, AMI <72 hr., LVEF <30%, unprot ected 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).
Resolute
N = 376)
4.3% (16/372) 3.3% (13/392) 5.4% (20/372) 5.2% (20/388)
12 Months
Xience V
N = 396)
Resolute
N = 376)
60 Months
Xience V
N = 396)
5
4
(
(
(
(
(
(
g
Table 9-29: 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 Through 1-Year
Cumulative Stent Thrombosis Through 5-Years
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 t otal number of subject s 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).
See Table 9-4 for the definition of the ARC defined Stent Thrombosis. Complex was defined as having one or more of the following patient or lesion characteristics: Bifurcation, bypass graf t, in st ent restenosis, AMI <72 hr., LVEF <30%, unprotected left main, >2 vessels stented, renal insuffic iency or failure (s erum c reatinine >2.5 m
/dl), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or total occlusion (pre procedure TIMI = 0).
Resolute
N = 1140)
1.6% (18/1132) 0.7% (8/1142) 1.3% (5/372) 0.3% (1/392) 1.7%(13/760) 0.9%(7/750)
2.4% (27/1123) 1.7% (19/1133) 2.2% (8/372) 1.0% (4/388)
Xience V N = 1152)
Resolute
N = 376)
Xience V
N = 396)
Resolute
N = 764)
2.5%
(19/751)
Xience V
N = 756)
2.0% (15/745)
5
5

9.3 Results of the RESOLUTE International Study

Primary Objective: To evaluate the safety and overall clinical performance of the Resolute
Zotarolimus-Eluting Coronary Stent System (the Resolute stent) in an ‘all-comers’ p atient population requiring stent implantation.
Design: This is a prospective, multi-center, non-randomized observational study. A total of 2349 sub jects were enrolled at 88 clinical research sites from 17 countries in Europe, Asia, Africa and South America, where the Resolute stent is commercially available. This study was designed to treat all enrolled subjects according to routine hospital practice. No restriction was placed on the total number of treated lesions, treated vessels, lesion length or number of stents implanted. The study enrolled patients with symptomatic coronary disease (including chronic stable angina, silent ischemia, and acute co ro nary ischemic syndromes). Enrolled subjects were permitted to have complex clinical or anatomic f eatures as described in Section 9.2 - Results of the RESOLUTE AC Clinical Trial.
Follow-up was performed at 30 days, 6 and 12 months and will be performed 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 subjects who were not at a high risk of b leeding.
Demographics and clinical characteristics: The baseline demographics and clinical characteristics sho w a mean age of 63.5 years with a male enrollment of 77.8% (1828/2349). Of the subjects enrolled in this study, 29.6% (696/2349) of subjects had a prior percutaneous coronary revascularization and
8.4% (197/2349) had previous CABG surgery. In total, 30.5% (716/2349) of the subjects had a history of diabetes mellitus with 9.0% (211/2349) being insulin dependent. Past medical history of subjects indicated 63.9% (1501/2349) had hyperlipidemia, 68.0% (1598/2349) had hypertension, and 24.2% (569/2349) were current smokers. The mean RVD was 2.94 ± 0.46 mm, the lesion length was 18.75 ±
10.77 mm and the average p ercentage diameter stenosis was 84.50 ± 12.12 %. The ACC/AHA lesion classification was reported by sites as type B2/C for 57.1% (1798/3147) of the lesions.
Results: These analyses are b ased on the intent-to-treat population. The 12-month and 3-year f ollow­up rates f or the RESOLUTE International study were 97.7% (2295/2349) and 96.7% (2271/2349) respectively.
Strengths of this analysis include the collection and presentation of both short and long term out comes demonstrating safety and effectiveness in an all comer population. A limitation was that this trial was not sized to determine the rate of low frequency events with a pre-specified precision.
The results are presented in the following tables:
Table 9-30: RESOLUTE International - Principal Safety and Effectiveness
Table 9-31: RESOLUTE International - ARC Defined Definite/Probable Stent Thrombosis Through
36 Months
5
6
(
(
Table 9-30: RESOLUTE International - Principal Safety and Effectiveness
COMPOSITE SAFETY AND EFFECTIVENESS
TLF 7.1% (165/2337) 11.4% (261/2284)
TVF 7.7% (180/2337) 12.9% (294/2284)
MACE 8.3% (193/2337) 14.4% (329/2284)
EFFECTIVENESS
Clinically Driven TVR 4.2% (99/2337) 7.4% (168/2284)
TLR 3.5% (81/2337) 5.7% (130/ 2284)
TLR, PCI 3.1% (72/2337) 5.2% (118/2284)
TLR, CABG 0.4% (10/2337) 0.6% (14/2284)
Non-TL TVR 1.2% (27/2337) 2.6% (59/2284)
Non-TL TVR, PCI 1.2% (27/2337) 2.5% (56/2284)
Non-TL TVR, CABG 0.0% (0/2337) 0.2% (4/ 2284)
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
Cardiac Death or MI 4.2% (99/2337) 7.0% (161/2284)
TVMI
Q wave MI
Non-Q wave MI
Stent Thrombosis ARC defined
Definite/Probable 0.9% (20/2337) 1.1% (26/2284)
Definite 0.6% (15/2337) 0.8% (19/2284)
Probable
Notes
N = The t otal number of subject s enrolled. 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 ). 36-month timeframe includes follow-up window (1080 days ± 30 days ) The definitions of the outcomes are presented as table notes to Table 8-1- Principal Adverse Events . See Table 9-4 for the definition of the ARC defined Stent Throm bosis.
N = 2349)
12 Month s 36 Mo nths
2.4% (57/2337)
1.5% (34/2337)
1.0% (23/2337)
3.0% (71/2337)
0.5% (12/2337)
2.5% (59/2337)
0.3% (6/2337) 0.4% (8/2284)
N = 2349)
6.1% (139/2284)
3.6% (82/2284)
2.5% (57/2284)
3.9% (89/2284)
0.9% (20/2284)
3.0% (69/2284)
5
7
(
Table 9-31: RESOLUTE International - ARC Defined
Definite/Probable Stent Thrombosis Through 36 Months
Stent Thrombosis 1.1% (26/2284)
Acute (0 - 1 day) 0.1% (3/2284)
Subacute (2 - 30 days) 0.6% (14/2284)
Late (31 – 360 days) 0.1% (3/2284)
Very Late (361 – 1080 days) 0.3% (6/2284) Notes
N = The t otal number of subject s 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) See Table 9-4 for the definition of the ARC defined Stent Thrombosis

9.4 Results of the RESOLUTE FIM Clinical Trial

Primary Objective: To evaluate the safety, effectiveness, and pharmacokinetics (PK) of the Resolute
Zotarolimus-Eluting Coronary Stent (Resolute stent) for the treatment of single de novo lesions in native co ro nary arteries with a reference vessel diameter (RVD) between 2.5 mm and 3.5 mm in diameter.
Resolute
N = 2349)
Design: The RESOLUTE FIM Clinical Trial, the f irst-in-human study for the Resolute stent, is a non­randomized, prospective, multi-center, single-arm trial. A total of 139 subjects were enrolled at 12 investigative sites in Australia and New Zealand who presented with symptomatic ischemic heart disease due to a de novo stenotic lesion contained within a native coronary artery with a reference vessel diameter between 2.5 mm and 3.5 mm and a lesion length between 14 mm and 27 mm amenable to percutaneous treatment with a single stent.
Follow-up was performed at 30 days, 4, 9, 12 months and annually at 2, 3 and 4 years. Follow-up will be performed at 5 years. Thirty subjects were consented to have an angiographic and IVUS follow-up at 4 months post-procedure while an additional 100 subjects were consented to have the same type of f o llow-up at 9 months post-procedure. Following the index procedure, subjects were to b e treated with asp irin ind efinitely and clopidogrel/ticlopidine for a minimum of 6 months.
Primary Endpoint: The primary endpoint was in-stent late lumen loss (LL) at 9 months post-procedure as measured by QCA.
Control Group and Statistical Analysis Plan: The primary analysis was a non-inferiority comparison of the 9-month in-stent late LL in the Resolute stent compared to a historical control population of sub jects treated with an Endeavor stent in the ENDEAVOR II trial. The non-inferiority margin was set at
0.16 mm.
Demographics and clinical characteristics: The mean ag e was 60.7 years, with 76.3% (106/139) men, 17.3% (24/139) diabetics, 18.7% (26/139) with a history of prior percutaneous coronary revascularization, 46.4% (64/138) with a history of prior MI and 2.9% (4/139) with a history of prior CABG. Past medical history of subjects indicated 94.2% (131/139) had hyperlipidemia and 66.9% (93/139) had hypertension. The mean RVD was 2.81 ± 0.40 mm, the lesion length was 15.61 ± 6.13 mm and the average percentage diameter stenosis was 70.30 ± 11.37%. The ACC/AHA lesion classification was reported by sites as type B2/C for 81.4% (114/140) of the lesions.
Results: The Resolute stent met the primary non-inferiority endpoint with a 9-month in-stent late LL of
0.22 ± 0.27 mm, compared with the historical Endeavor stent control 8-month in-stent late LL of 0.62 ±0.45 mm, p
non-i nferi ori ty
<0.001. The 12-month and 5-year follow-up rates were 99.3% (138/139) and
97.1% (135/139) respectively.
5
8
Strengths of this analysis include the collection and presentation of both short and long term outcomes
(
demonstrating safety and effectiveness in the intended population. A limitation was that it was a single arm feasibility study.
These analyses are based on the intent-to-treat population. PK results are presented in Section 6.3 for the Pharmacokinetics of the Resolute Stent. The results are presented in the following tables:
Table 9-32: RESOLUTE FIM - Primary Endpoint Analysis
Table 9-33: RESOLUTE FIM - Principal Safety and Effectiveness
Table 9-34: RESOLUTE FIM - ARC Def ined Definite/Probable Stent Thrombosis through 60 Months
Table 9-35: RESOLUTE FIM - Angiographic and IVUS Results
Table 9-32: RESOLUTE FIM - Primary Endpoint Result
Primary Endpoint1
9-month In-stent Late Lumen Loss (mm)
Notes
N is the total number of subjects enrolled. M is the total number of lesions at baseline. Numbers are Mean ± SD (number of evaluable lesions). Subjects are only counted once for each time period.
1
Angiographic Follow-Up for RESOLUTE was at 9 Months and for Endeavor stent from the ENDEAVOR II trial was at 8 Months .
2
Confidence interval calculated using normal approximation.
3
One sided p-value by non-inferiority test using t test with non-inferiority margin of 0.16 mm, to be compared at a 0.05 significance level.
RESOLUTE
(N = 139, M = 140)
0.22 ± 0.27 (96) 0.62 ± 0.45 (256) -0.39 [-0.49, -0.30] <0.001
ENDEAVOR II
Endeavor
N = 256, M = 256)
Difference
[95% CI]2
Non-Inferiority
P-value3
5
9
(
(
Table 9-33: RESOLUTE FIM - Principal Safety and Effectiveness
Outcomes at
9 Months
N = 139)
COMPOSITE SAFETY AND EFFECTIVENESS
TVF 6.5% (9/139) 7.2% (10/139) 13.2% (18/136)
MACE 7.2% (10/139) 8.6% (12/139) 16.2% (22/136)
EFFECTIVENESS
Clinically Driven TVR 0.0% (0/139) 0.7% (1/139) 5.1% (7/136)
TLR 0.0% (0/139) 0.7% (1/139) 2.9% (4/136)
TLR, PCI 0.0% (0/139) 0.7% (1/139) 2.2% (3/136)
TLR, CABG 0.0% (0/139) 0.0% (0/139) 0.7% (1/136)
Non-TL TVR 0.0% (0/139) 0.0% (0/139) 2.2% (3/136)
Non-TL TVR, PCI 0.0% (0/139) 0.0% (0/139) 2.2% (3/136)
Non-TL TVR, CABG 0.0% (0/139) 0.0% (0/139) 0.0% (0/136)
SAFETY
Total Death 1.4% (2/139) 2.2% (3/139)
Cardiac Death 0.7% (1/139) 0. 7% (1/139)
Non-Cardiac Death
0.7% (1/139)
Outcomes at
12 Months
(N = 139)
1.4% (2/139)
Outcomes at
60 Months
N = 139)
6.6% (9/136)
1.5% (2/136)
5.1% (7/136)
Cardiac Death or MI 6.5% (9/139) 6.5% (9/139) 8.1%(11/136)
MI
Q wave MI
Non-Q wave MI
Sten t Thromb osis ARC defined
5.8% (8/139)
0.0% (0/139)
5.8% (8/139)
5.8% (8/139)
0.0% (0/139)
5.8% (8/139)
Definite/Probable 0.0% (0/139) 0.0% (0/139)
Definite 0.0% (0/139) 0.0% (0/139)
Probable 0.0% (0/139) 0.0% (0/139)
6.6% (9/136)
0.0% (0/136)
6.6% (9/136)
0.0% (0/136)
0.0% (0/136)
0.0% (0/136)
Notes
N = The t otal number of subject s enrolled. Numbers are % (Count/Number of Eligible Subjects). Subjects are only counted once for each time period. 9-month timeframe includes follow-up window (270 days ± 14 days ). 12-month timeframe includes follow-up window (360 days ± 30 days ). 60-month timeframe includes follow-up window (1800 days ± 30 days ). The definitions of the outcomes are presented as table notes to Table 8-1- Principal Adverse Events . See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
5
0
(
Table 9-34: RESOLUTE FIM - ARC Defined
Definite/Probable Stent Thrombosis through 60
Months
Resolute
Stent Thrombosis 0.0% (0/136)
Acute (0 - 1 day) 0.0% (0/136)
Subacute (2 - 30 days) 0.0% (0/136)
Late (31 – 360 days) 0.0% (0/136)
Very late (361 - 1800 days) 0.0% (0/136)
Notes
N = The t otal number of subject s enrolled. 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 ). 60-month time frame includes follow-up window (1800 days ± 30 days ). See Table 9-4 for the definition of the ARC defined Stent Thrombosis
N = 139)
6
Table 9-35: RESOLUTE FIM - Angiographic and IVUS Results
Outcomes at 4 Months
ANGIOGRAPHIC RESULTS
MLD (mm), In-stent
Post-Procedure 2.76 ± 0. 39 (140) 2. 76±0.39 (140)
Follow Up 2.68±0.39 (30) 2.51±0.48 (96)
MLD (mm), In-segment
Post-Procedure 2.36 ± 0. 43 (140) 2. 36±0.43 (140)
Follow Up 2.38±0.40 (30) 2.21±0.45 (96)
% DS, In-stent
Post-Procedure 3.36±8.54 (140) 3.36±8.54 (140)
Follow Up 7.18±7.86 (30) 10.13±12.63 (96)
% DS, In-segment
Post-Procedure 17.80±8.24 (140) 17.80±8.24 (140)
Follow Up 17.74±7.57 (30) 21.08±10.62 (96)
Late Loss (mm)
In-stent 0.12±0.26 (30) 0.22±0.27 (96)
In-segment 0.05±0.20 (30) 0.12±0.27 (96)
Binary Restenosis
(N = 30, M = 30)
Outcomes at 9 Months
(N = 100, M = 101)
In-stent 0.0% (0/30) 1.0% (1/96)
In-segment 0.0% (0/30) 2.1% (2/96)
IVUS RESULTS
Neointimal Volume (mm3) 3.72±4.21 (24) 6.55±7.83 (88)
% Volume Obstruction 2.23±2.43 (24) 3.73±4.05 (88)
Incomplete Apposition
Persistent 6.7% (2/30) 17.0% (15/88)
Late Acquired 3.3% (1/30) 6.8% (6/88)
Notes
139 subjects with 140 lesions underwent angiographic follow-up at baseline. N = The t otal number of subject s enrolled. M = The t otal number of lesions at baseline. Numbers are % (Count/Number of Evaluable Lesions) or Mean ± SD (Num ber of Evaluable Lesions). Subjects are only counted once for each time period.
61
2

9.5 Results of the RESOLUTE Japan Clinical Trial

Primary Objective: To verify the safety and effectiveness of the Resolute Zotarolimus-Eluting Coronary
Stent (Resolute stent) in a Japanese population for the treatment of de novo lesions in native coronary arteries with a ref erence vessel diameter of 2.5 mm to 3.5 mm and lesion lengths  mm.
Design: This is a non-randomized, prospective, multi-center, single-arm trial. A total of 100 subjects were enro lled at 14 investigational sites in Japan.
Follow-up was performed at 30 days, 6, 9, and 12 months and will be performed annually out to 5 years. All subjects were scheduled to have angiographic and IVUS follow-up at 8 months post-procedure. 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 subjects who were not at a high risk of b leeding.
Primary Endpoint: The primary endpoint was in-stent late LL at 8 months post-procedure measured by QCA.
Control group and Statistical Analysis Plan: The primary analysis was a non-inferiority comparison of the 8-month in-stent late LL in the Resolute stent compared to a historical control population of sub jects treated with a Taxus stent in the ENDEAVOR IV trial. The non-inferiority margin was set at
0.20 mm. If the non-inferiority endpoint was met, a sup eriority test would be p erformed.
Demographics and clinical characteristics: Baseline demographics and clinical characteristics sho wed a mean age of 67.7 years with 77.0% (77/100) of subjects being males. Of the subjects enrolled , 45.0% (45/100) had diabetes mellitus, 22.0% (22/100) were current smokers, 25.0% (25/100) had prior MI, 42.0% (42/100) had p rior PCI, 81.0% (81/100) had hypertension, and 78.0% (78/100) reported hyperlipidemia. Baseline lesion characteristics include 42.6% (46/108) LAD lesions, a mean lesion leng th of 15.52 ± 5.37 mm, 52.8% (57/108) ACC/AHA type B2/C lesions and 18.5% (20/108) lesions involving a b ifurcation. The mean RVD was 2.85 ± 0.44 mm and the percentage diameter stenosis was 69.17 ± 7.80%.
Results: The Resolute stent in-stent late LL at 8 months was 0.13 ± 0.22 mm, which met the primary non-inf eriority endpoint (and demonstrated superiority) compared with the historical Taxus stent 8­month in-stent late LL of 0.42 ± 0.50 mm. The 12-month and 5-year follow-up rates were 100% (100/100) and 96% (96/100) respectively.
Strengths of this analysis include the collection and presentation of both short and long term out comes demonstrating safety and effectiveness in the intended population. A limitation was that the patient and lesion characteristics excluded many complex subjects.
These analyses are based on the intent-to-treat population. The results are presented in the following tables:
Table 9-36: RESOLUTE Jap an - Primary Endpoint Analysis Table 9-37: RESOLUTE Japan - Principal Safety and Effectiveness Table 9-38: RESOLUTE Jap an - ARC Defined Definite/Probable Stent Thrombosis through 60 Months Table 9-39: RESOLUTE Jap an - Angiographic and IVUS Results
6
3
Table 9-36: RESOLUTE Japan - Primary Endpoint Result
Primary Endpoint
8-month In-stent Late Lumen Loss (mm)
Resolute
(N = 100, M = 108)
0.13 ± 0.22 (99) 0.42 ± 0.5 (135) -0.29 [-0.41 , -0.16]
ENDEAVOR IV Taxus
(N = 164, M = 164)
Difference
95%CI1
Non- Inferiority
P-value2
<0.001 <0.001
Notes
N = The t otal number of subject s enrolled. M = The num ber of les ions at baseline. Numbers are Mean ± SD (Number of Evaluable Lesions). Subjects are only counted once for each time period. Confidence interval and p values are adjusted using propensity score method.
1
Confidence interval calculated using normal approximation.
2
One-sided p-value by non-inferiority test using asymptotic test statistic with non-inferiority margin of 0.20 mm to be compared at a 0.05
significance level.
3
Two-sided p-value by superiority test using asymptotic test statistic, to be c ompared at a 0.05 significance level.
Superiority
P-value3
6
4
Table 9-37: RESOLUTE Japan - Principal Safety and Effectiveness
(N = 100) (N = 100)
COMPOSITE SAFETY AND EFFECTIVENESS 12 Months
TLF
TVF
MACE
EFFECTIVENESS
Clinically Driven TVR
TLR
TLR, PCI
TLR, CABG
Non-TL TVR
Non-TL TVR, PCI
Non-TL TVR, CABG
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
Cardiac Death or MI 4.0% (4/100) 5.1% (5/98)
TVMI
Q wave MI
Non-Q wave MI
Stent Thrombosis ARC defined
Definite/Probable
Definite
Probable
Notes
N = The t otal number of subject s enrolled.
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 ).
60-month timeframe includes follow-up window (1800 days ± 30 days)
The definitions of the outcomes are presented as table notes to Table 8-1- Principal Adverse Events .
See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
4.0% (4/100)
5.0% (5/100)
5.0% (5/100)
1.0% (1/100)
0.0% (0/100)
0.0% (0/100)
0.0% (0/100)
1.0% (1/100)
1.0% (1/100)
0.0% (0/100)
1.0% (1/100)
0.0% (0/100)
1.0% (1/100)
4.0% (4/100)
0.0% (0/100)
4.0% (4/100)
0.0% (0/100)
0.0% (0/100)
0.0% (0/100)
60 Months
6.1% (6/98)
10.2% (10/98)
14.3% (14/98)
5.1% (5/98)
1.0% (1/98)
1.0% (1/98)
0.0% (0/98)
4.1% (4/98)
3.1% (3/98)
1.0% (1/98)
7.1% (7/98)
1.0% (1/98)
6.1% (6/98)
4.1% (4/98)
0.0% (0/98)
4.1% (4/98)
0.0% (0/98)
0.0% (0/98)
0.0% (0/98)
6
5
(
Table 9-38: RESOLUTE Japan - ARC Defined Definite/Probable
Stent Thrombosis through 60 Months
Resolute
Stent Thrombosis
Acute (0 - 1 day)
Subacute (2 - 30 days) 0.0% (0/98)
Late (31 – 360 days) 0.0% (0/98)
Very late (361 - 1800 days) 0.0% (0/98)
Notes
N = The t otal number of subject s enrolled. 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 ). 60-month timeframe includes follow-up window (1800 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
N = 100)
0.0% (0/98)
0.0% (0/98)
6
6
(
(
(
(
(
(
(
(
(
(
(
(99)
(99)
Table 9-39: RESOLUTE Japan - Angiographic and IVUS
Results
Outcomes at 8 Months
ANGIOGRAPHIC RESULTS
MLD (mm), In-stent
Post-Procedure
8-Month
MLD (mm), In-segment
Post-Procedure
8-Month
% DS, In-stent
Post-Procedure
8-Month
% DS, In-segment
Post-Procedure
8-Month
Late Loss (mm)
In-stent
In-segment
Binary Restenosis
In-stent
In-segment
IVUS RESULTS
Neointimal Volume (mm3)
% Volume Obstruction
Incomplete Apposition
Persistent
Late Acquired
Notes
N = The t otal number of subject s enrolled. M = The num ber of les ions at baseline. Numbers are % (Count/Number of Evaluable Lesions) or Mean ± SD (Number of Evaluable Lesions). Subjects are only counted once for each time period.
N = 100, M = 108)
2.79 ± 0.40
2.66 ± 0.46
2.45 ± 0.43
2.35 ± 0.47
3.28 ± 7.19
6.52 ± 9.20
15.23 ± 7.39
17.71 ± 8.72
0.12 ± 0.22
0.10 ± 0.25
0.0% (0/107)
0.0% (0/107)
3.19 ± 4.53
2.33 ± 3.51
7.8% (8/103)
4.9% (5/103)
2.9% (3/103)
108)
107)
108)
107)
108)
107)
108)
107)
107)
107)
6
7

9.6 Results of the RESOLUTE INTEGRITY US Post Market Study

The RESOLUTE INTEGRITY US Post Market Study is a post approval study of the Medtronic Resolute Integrity Zotarolimus-Eluting Coronary Stent System in the Treatment of De Novo Lesions in Native Coronary Arteries with a Ref erence Vessel Diameter of 2.25 mm to 4.2 mm.
Primary Objective: The objective of this study is to assess the safety and efficacy of the Resolute Integrity stent f or 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 p atients, 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 o r 38 mm) ref erred to as the Extended Length (XL) Sub-study.
Design: The RESOLUTE INTEGRITY US Post Market Study is a prospective, multi-center evaluation of the procedural and clinical outcomes of subjects that are treated with the commercially available Medtronic Resolute Integrity Zotarolimus-Eluting Coronary Stent System.
This stud y enrolled 286 patients with de novo lesions in native coronary arteries who met the eligibility criteria and signed the informed consent form to participate in this study of which 230 patients were part of the PEG and 56 patients in the XL Sub-study.
For the PEG, centers were allowed to enroll a maximum of 40 subjects per center until study enrollment has been co mpleted, whichever came first. For the XL Sub study, centers were allowed to enroll a maximum of 16 sub jects per center until study enrollment was completed, whichever comes first.
The expected time of participation in the studies for each subject is two years for the PEG and three years for the XL Sub -study.
Patient f ollow up occurs at: 30 days ± 5 days (Contact); 6 months ± 14 days (Contact); 12 months ± 30 days (Clinic Visit with 12-lead ECG); 24 months ± 30 days (Contact). The XL Sub-study has additional visits at 2-3 years ± 30 days (Contact).
Primary Endpoint: The primary endpoint for this study was composite rate of cardiac death and target vessel myocardial infarction (MI) at 12 months.
Control Group and Statistical Analysis Plan: The primary analysis sample was based on intent-to-treat (ITT): For this study, all subjects who sign the written informed consent and are enrolled in the study will be co unted in the ITT set, which will b e the primary analysis set.
Demographics and Clinical Characteristics for the RESOLUTE Integrity-US PEG: Baseline demographics and clinical characteristics showed a mean age of 64.4 years with 69.6% (160/230) of subjects being males. Of the subjects enrolled, 42.2% (97/230) had diabetes mellitus, 18.3% (42/230) were current smokers, 24.4% (55/225) had prio r MI, 35.7% (82/230) had prior PCI, 86.5% (199/230) had hypertension, and 82.6% (190/230) reported hyperlipidemia. Baseline lesion characteristics include 40.9% (94/230) LAD lesions, a mean lesion length of 13.03 ± 5.76 mm, 82.9% (200/241) ACC/AHA type B2/C lesions and 36.5% (88/241) lesions involving a bif urcation. The mean RVD was 2.60 ± 0.45 mm and the p ercentage diameter stenosis was 66.84 ± 10.37%.
Results for the RESOLUTE Integrity-US PEG: These analyses are based on the intent-to-treat population.
The results specifically for the RI-US PEG are presented in the following tables:
Table 9-40 RESOLUTE Integrity US (PEG) - Primary Endpoint Analysis Table 9-41: RESOLUTE Integ rity US (PEG) - Principal Safety and Effectiveness Table 9-42: RESOLUTE Integrity US (PEG) - ARC Defined Definite/Probable Stent Thrombosis through 24 Months
Table 9-40:RESOLUTE Integrity US (PEG) - Primary Endpoint Analysis
Primary Endpoint - Cardiac Death/TVMI at 12-month- ITT set 3.5% (8/226) [1.5%, 6.9%]
1
The two-sided 95% CI is calculated by binomial (exact) distribution.
Resolute Integrity US (PEG)
(N=230)
95% Confidence
Interval1
6
8
Table 9-41: RESOLUTE Integrity US (PEG) - Principal Safety and
Effectiveness
RESOLUTE INTEGRITY US (PEG)
(N=230 Patients) (N=251 Lesions)
(m/n)1
Clinical Outcomes
Outcomes at
12 Months
Outcomes at
24 Months
Target Lesion Failure (TLF) 4.9% (11/226) 9.1% (20/219)
Target Vessel Failure (TVF) 7.1% (16/226) 12.3% (27/219)
MACE 5.8% (13/226) 11.0% (24/219)
Cardiac Death or Target Vessel MI (TVMI) 3.5% (8/226) 5.9% (13/219)
Death 1.8% (4/226) 2.7% (6/219)
Cardiac Death 1.3% (3/226) 1.8% (4/219)
Non-Cardiac Death 0.4% (1/226) 0.9% (2/219)
TVMI (Extended historical definition) 2.2% (5/226) 4.1% (9/219)
Clinically Driven TLR 2.2% (5/226) 5.0% (11/219)
Clinically Driven TVR 4.4% (10/226) 8.2% (18/219)
Stent Thrombosis (ARC) Definite/Probable 0.9% (2/220) 1.8% (4/219)
Early Thrombosis (30 days) 0.9% (2/226) 0.9% (2/219)
Late Thrombosis (31-360 days) 0.0% (0/226) 0.0% (0/219)
Very Late Thrombosis (361-720 days) N/A 0.9% (2/219)
Effectiveness Measures
Lesion Success (Definition 1)2 100.0% (245/245)
Lesion Success (Definition 2)3 99.2% (243/245)
Device Success (Definition 1)4 100.0% (245/245)
Device Success (Definition 2)5 99.2% (243/245)
Procedure Success (Definition 1)6 98.2% (223/227)
Procedure Success (Definition 2)7 97.4% (221/227)
Device Specific Procedure Success (Definition 1)8 98.2% (223/227)
Device Specific Procedure Success (Definition 2)9 97.4% (221/227)
1
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 k nown values, and percentage (%) was calculated as 100 × (m /n)
2
The attainment of <50% residual stenosis of the target lesion us ing any perc utaneous met hod.
3
The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI flow 3 after the procedure, using any percutaneous method.
4
The attainment of <50% residual stenosis of the target lesion us ing only t he assigned device.
5
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.
6
The attainment of <50% residual stenosis of the target lesion and no in-hospital MACE.
7
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 occ urrence of MAC E during the hospital stay.
8
The attainment of <50% residual stenosis of the target lesion us ing only t he assigned device and no in-hospital MACE.
9
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, and no in-hospital MACE.
6
9
Table 9-42: RESOLUTE Integrity US (PEG) - ARC Defined
(
Definite/Probable Stent Thrombosis through 24 Months
Resolute Integrity
Stent Thrombosis 1.8% (4/219)
Acute (0 - 1 day) 0.0% (0/219)
Subacute (2 - 30 days) 0.9% (2/219)
Late (31 – 360 days) 0.0% (0/219)
Very Late (361-720 days) 0.9% (2/219) Notes
N = The t otal number of subject s 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 ). 24-month time frame includes follow-up window (720 days ± 30 days). See Table 9-4 for the definition of the ARC defined Stent Thrombosis
N = 230)
The 12-mo nth and 24-month follow-up rates for the RESOLUTE Integrity US Post Market Study PEG were
94.3% (217/230) and 94.8% (218/230) respectively.
Strengths of this analysis include the collection and presentation of both short and long term outcomes demonstrating safety and effectiveness in the intended population. A limitation was that the patient and lesion characteristics excluded many complex subjects.
Results for the RESOLUTE Integrity US XL Sub-study: These analyses are based on the intent-to-treat population.
The results specifically for the RESOLUTE Integrity US XL Sub-study are presented in the following tables:
Table 9-43: RESOLUTE Integrity US (XL Sub-study) - Primary Endpoint Analysis Table 9-44: RESOLUTE Integ rity US (XL Sub-study) - Principal Safety and Effectiveness Table 9-45: RESOLUTE Integrity US (XL Sub-study) - ARC Defined Definite/Probable Stent Thrombosis through 36 Months
Table 9-43: RESOLUTE Integrity US (XL Sub-study) - Primary Endpoint Analysis
Resolute Integrity US (XL
Primary Endpoint - Cardiac Death/TVMI at 12-month- ITT set 7.1% (4/56) [2.0%, 17.3%]
1
The two-sided 95% CI is calculated by binomial (exact) distribution.
Sub-study)
(N=56)
95% Confidence
Interval1
Table 9-44: RESOLUTE Integrity US (XL Sub-study) - Principal Safety and Effectiveness
RESOLUTE INTEGRITY US (XL Sub-study)
Clinical Outcomes
Target Lesion Failure (TLF) 7.1% (4/56) 10.7% (6/56)
Target Vessel Failure (TVF) 7.1% (4/56) 12.5% (7/56)
MACE 8.9% (5/56) 17.9% (10/56)
Cardiac Death or Target Vessel MI (TVMI) 7.1% (4/56) 7.1% (4/56)
Outcomes at
12 Months
(N=56 Patients)
(N=69 Lesions) (m/n)1
Outcomes at
36 Months
6
0
Table 9-44: RESOLUTE Integrity US (XL Sub-study) - Principal Safety and Effectiveness
RESOLUTE INTEGRITY US (XL Sub-study)
(N=56 Patients)
(N=69 Lesions) (m/n)1
Clinical Outcomes
Outcomes at
12 Months
Outcomes at
36 Months
Death 1.8% (1/56) 3.6% (2/56)
Cardiac Death 1.8% (1/56) 1.8% (1/56)
Non-Cardiac Death 0.0% (0/56) 1.8% (1/56)
TVMI (Extended historical definition) 5.4% (3/56) 5.4% (3/56)
Clinically Driven TLR
Clinically Driven TVR
Stent Thrombosis (ARC) Definite/Probable
1.8% (1/56) 5.4% (3/56)
1.8% (1/56) 7.1% (4/56)
1.8% (1/56) 1.8% (1/56)
Early Thrombosis (30 days) 1.8% (1/56) 1.8% (1/56)
Late Thrombosis (31-360 days)
0.0% (0/56) 0.0% (0/56)
Very Late Thrombosis (361-1080 days) N/A 0.0% (0/56)
Effectiveness Measures
Lesion Success (Definition 1)2 100.0% (69/69)
Lesion Success (Definition 2)3
98.6% (68/69)
Device Success (Definition 1)4 97.1% (67/69)
Device Success (Definition 2)5
95.7% (66/69)
Procedure Success (Definition 1)6 98.2% (55/56)
Procedure Success (Definition 2)7
96.4% (54/56)
Device Specific Procedure Success (Definition 1)8 94.6% (53/56)
Device Specific Procedure Success (Definition 2)9
1
Numera tor (m) is the numbe r of p atien ts (or lesio ns) with th e specific cla ssificatio n, denominator (n) is the number of patients (or lesions) in
the study group with known values, and percentage (%) was calculated as 100 × (m/n)
2
The attainment of <50% residual stenosis of the target lesion using any percutaneous method.
3
The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI flow 3 after the procedure, using any
percutaneous method.
4
The attainment of <50% residual stenosis of the target lesion using only the assigned device.
5
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.
6
The attainment of <50% residual stenosis of the target lesion and no in-hospital MACE.
7
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
The attainment of <50% residual stenosis of the target lesion using only the assigned device and no in-hospital MACE.
9
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, and no in-hospital MACE.
92.9% (52/56)
7
Table 9-45: RESOLUTE Integrity US (XL Sub-study) - ARC
(
Defined Definite/Probable Stent Thrombosis through 36 Months
Resolute Integrity
Stent Thrombosis 1.8% (1/56)
Acute (0 - 1 day) 0.0% (0/56)
Subacute (2 - 30 days) 1.8% (1/56)
Late (31 – 360 days) 0.0% (0/56)
Very Late (361-1080 days) 0.0% (0/56) Notes
N = The t otal number of subject s enrolled. Numbers are % (Count/Number of Eligible Subjects). Subjects are only counted once for each time period. 36-month time frame includes follow-up window (1080 days ± 30 days). See Table 9 4 for the definition of the ARC defined Stent Thrombosis
N = 56)
The 12-mo nth f ollow-up rate for the RESOLUTE Integrity US Post Market Study XL Sub-study was 96.4% (54/56).
Strengths of this analysis include the collection and presentation of both short and long term outcomes demonstrating safety and effectiveness in the intended population. A limitation was that the patient and lesion characteristics excluded many complex subjects.

9.7 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 card iovascular morbidity and mortality.
4, 5
A Global Statistical Analysis Plan (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 sub jects with diabetes mellitus.
Primary Objective: To assess the safety and effectiveness of the Resolute Zotarolimus-Eluting 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 pre­def ined general and angiographic inclusion and exclusion criteria. Analysis populations consisted of co nsecutively enrolled eligible diabetic subjects in the trials noted below.
The f ollowing global RESOLUTE clinical trials contributed subjects to the diabetes mellitus cohort:
RESOLUTE FIM
RESOLUTE All-Comers
RESOLUTE International
RESOLUTE United States
RESOLUTE Japan
In total, there were 878 subjects included in the RESOLUTE DM cohort. RESOLUTE US provided the highest p ercentage 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).
4
American Heart Association. Heart Disease and Stroke Statistics - 2008 Update. www.americanheart.org/statistics [Online public ation]. Ac cessed
12 November 2008, 2008.
5
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.
71
2
Subjects from the 38 mm Length sub-study are not included in this Resolute Pooled Analysis of
(
p
Subjects with Diabetes Mellitus. Additional information is provided in Section 9.7.1 for the Resolute US 38 mm Leng th Group for subjects with Diabetes Mellitus.
Design: The Resolute stent performance for treatment of lesions in patients with DM was compared with a p erformance 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.
Inclusio n of study subjects in this analysis were required to have DM defined by either a history of DM or use o f 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 leng th per vessel >27 mm, >2 lesions per vessel, unprotected left main lesions, bifurcation lesions, total occlusions, bypass grafts, acute MI within 72 hours of the index procedure, thrombus­co ntaining 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 p erformance goal to demonstrate the saf ety 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 meta­analysis). 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 post­PCI card iac b iomarker 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 f o r unstable angina.
Primary Endpoint: The primary endpoint was Target Vessel Failure (TVF) at 12 months following the intervention. The TVF co mposite 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 b ound 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:
Table 9-46: RESOLUTE Diabetes Mellitus Cohort - Primary Endpoint Analysis
Table 9-47: 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
Table 9-48: RESOLUTE Diabetes Mellitus Cohort - ARC Defined Definite/Probable Stent
Thrombo sis Events through 12 Months
Table 9-46: Resolute Diabetes Mellitus Cohort - Primary Endpoint Analysis
Primary Endpoint
12-month TVF 7.84% (68/867) 9.51% 14.5% <0.001
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
rimary endpoint analysis utilized a randomly selected lesion from subjects who had treatment of dual lesions.
RESOLUTE DM
N = 878)
Upper Bound of
95%CI
1
Performance
Goal
P-value
2
7
3
12-month timeframe includes follow-up window (360 days ± 30 days).
1
One-sided confidence interval using exact method.
2
One-sided p-value using exact test statistic to be compared at a 0.05 significance level.
Table 9-47: 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
EFFECTIVENESS
Clinically Driven TVR 5.1% (44/867) 6.5% (16/246) 4.5% (28/621) 3.1% (57/1867)
TLR
TLR, CABG 0.2% (2/867)
TLR, PCI 3.1% (27/867) 4.5% (11/246) 2.6% (16/621) 1.7% (32/1867)
Non-TL TVR
Non-TL TVR, CABG 0.1% (1/867)
Non-TL TVR, PCI 2.1% (18/867) 1.6% (4/246) 2.3% (14/621) 1.1% (20/1867)
SAFETY
Total Death 2.8% (24/867) 4.1% (10/246) 2.3% (14/621) 1.0% (19/1867)
All DM Subjects
(N = 878)
7.5% (65/867) 11.8% (29/246) 5.8% (36/621) 5.7% (106/1867)
3.3% (29/867)
2.2% (19/867)
IDDM
(N = 250)
5.3% (13/246) 2.6% (16/621)
0.8% (2/246) 0.0% (0/621)
1.6% (4/246) 2.4% (15/621)
0.0% (0/246) 0.2% (1/621)
Non IDDM
(N = 628)
Non DM
(N = 1903)
2.0% (38/1867)
0.3% (6/1867)
1.3% (24/1867)
0.2% (4/1867)
Cardiac Death 2.0% (17/867) 2.8% (7/246) 1.6% (10/621) 0.4% (8/1867)
Non-Cardiac Death
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
Notes
N = The t otal number of subject s. 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 8-1- Principal Adverse Events . See Table 9-4 for the definition of the ARC defined Stent Thrombosis.
0.8% (7/867) 1.2% (3/246) 0.6% (4/621) 0.6% (11/1867)
0.3% (3/867)
0.3% (3/867) 0.8% (2/246) 0.2% (1/621) 0.3% (6/1867)
0.1% (1/867) 0.4% (1/246) 0.0% (0/621) 0.1% (2/1867)
0.8% (2/246) 0.2% (1/621)
3.3% (8/246) 0.8% (5/621)
0.3% (5/1867)
2.5% (46/1867)
7
4
Table 9-48: RESOLUTE Diabetes Mellitus Cohort - ARC
(
(
(
Defined Definite/Probable Stent Thrombosis Events through
12 Months
Resolute
(N = 878)
Stent Thrombosis 0.3% (3/867)
Acute (0 – 1 day) 0.1% (1/867)
Subacute (2 - 30 days) 0.1% (1/867)
Late (31 – 360 days) 0.1% (1/867)
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. See Table 9-4 for the definition of the ARC defined Stent Thrombosis .

9.7.1 Subjects with Diabetes Mellitus in the RESOLUTE 38 mm Length Stent Sub-study

Additional information is provided in Table 9-49 for the RESOLUTE US 38 mm Length Group in sub jects with Diabetes Mellitus.
Table 9-49: RESOLUTE 38 mm Length Group: All 38 mm Subjects, Insulin-Dependent DM
Subjects (IDDM), Non-Insulin Dependent DM Subjects (Non-IDDM), and Non-DM Subjects –
Principal Safety and Effectiveness through 12 Months
COMP OS ITE
All Diabetic 38 mm
Length Group Subje cts
(N = 8 4 Patie nts )
38 mm Length Group
IDDM
(N = 2 3 Patie nts )
38 mm Length Group –
Non-IDDM
(N = 6 1 Patie nts )
38 mm Length Group –
(N = 139 Patients)
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-d riven TVR 3.6% (3/84) 0.0 % (0/2 3) 4.9% (3/61) 2 .2% (3 /138)
TLR 2.4% (2/84) 0.0%
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) 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)
0/23) 3.3%
0.0% (0/84) 0.0% (0/23) 0.0% (0/61) 1.4% (2/138)
0.0% (0/84) 0.0% (0/23) 0.0% (0/61) 0.0% (0/138)
2/61) 0.7%
Non-DM
1/138)
7
5

9.8 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 sub-study 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 pre­sp ecified 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 o cclusions
Population: The population consisted of p rospectively enrolled subjects undergoing attempted percutaneous CTO revascularization and treated with the Resolute ZES.
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 sub jects undergoing attempted CTO. The assessment of use of Resolute ZES stents in CTO revascularization was based on prospectively enrolled CTO patients compared to a pre-specified performance goal.
An estimated MACE rate was derived based on a weighted average of the reported rates for drug­eluting stents from the PRISON II
6
and EXPERT CTO7 studies. Due to the difference in the definition of myocardial infarction (MI) 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 (MI) 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 hyp ertension, 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 Endpoint: 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 sub g roup 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 9-50, Table 9-51, and Table 9-52
Table 9-50: Primary Endpoint Analysis – MACE at 12 Months (ITT and PP)
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
Performance
Goal
6
Suttorp MJ, Laarman GJ, Rahel BM, et al. Primary Stenting of Totally Occluded N ative Coronary Arteries II (PRI SON 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.
7
Kandzari DE, Kini AS, Karmpaliotis D, et al. Safety and Effectiveness of Everolimus-Eluting Stents in Chronic Total Coronary Oc clusion
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.
7
6
Table 9-51: 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) 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 Def/Prob/Poss) 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 – 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 Def/Prob/Poss) 1.7% (3/181)
Stent Thrombosis ARC Definite/Probable 0.6% (1/181)
%(m/n)
7
7
Table 9-51: Principal Safety and Effectiveness Results
RESOLUTE CTO cohort
(N=183 Subjects)
Safety and Effectiveness Measures
Stent Thrombosis ARC Possible 1.1% (2/181)
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 – 1year) 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
2
Successful guidewire crossing with placement in distal true lumen of CTO t arget lesion
1
2
%(m/n)
92.3% (169/183)
96.2% (175/182)
Table 9-52: 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 p atients from the Global RESOLUTE Clinical Program.
The f ollowing Global RESOLUTE Clinical Trials contributed subjects to the CTO cohort:
RESOLUTE International
The RESOLUTE International Study (R-Int) was a prospective, multi-center, non-randomized, single-arm, observational study of the Resolute stent in a real world subject population. A total 2349 sub jects were enrolled into the study. Subjects were followed for 3 years post-procedure. A to tal o f 186 subjects from the R-Int study were included in the RESOLUTE Pooled CTO analysis.
RESOLUTE China Randomized Controlled Trial
The RESOLUTE China Randomized Controlled Trial (R-China RCT) was a prospective, multi­center, rando mized, open-label study designed to assess the non-inferiority of the Resolute stent co mpared to the Taxus Liberte 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 sub jects from the R-China RCT study were included in the RESOLUTE Pooled CTO analysis.
RESOLUTE China Registry
The RESOLUTE China Registry (R-China Registry) was a prospective, multi-center, non­randomized, single-arm, observational study of the Resolute stent in a real-world p atient 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.
7
8
Design: The Reso lute stent performance for the treatment of CTO lesions was analyzed from data co llected 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 to tal, 358 sub jects 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 d iabetes.
Global RESOLUTE Clinical Program results are presented in the following table:
Table 9-53: 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) 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 day s) 0.9% (3/347) Significant Bleeding Complications5 1.2% (4/347) Stroke 1.7% (6/347)
(N=527 Lesions) %(m/n)9
7
9
Table 9-53: RESOLUTE Pooled CTO Analysis Safety and Effectiveness Results
RESOLUTE Pooled CTO
(N=358 Patients)
Safety and Effectiveness Endpoints
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 (clinically driven/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) revasc ularization.
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 s cenarios: Bleedings t hat led to an interruption of anti-platelet medic ation Bleedings t hat require t ransfusion Int racerebral bleedings Bleedings t hat resulted in subst antial hemodynam ic compromise requiring treatm ent
6.The attainment of <50% residual s tenosis of the target lesion using any percutaneous method.
7.The attainment of <50% residual s tenosis of the target lesion using only the assigned device.
8.The attainment of <50% residual s tenosis of the target lesion and no in-hospit al MAC E.
9.Numerator (m) is the number of patients (or lesions) with the specific classific ation, denominat or (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

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

In o rder to better estimate the incidence of low-frequency events or o utcomes, a subject-level pooled analysis was conducted. Table 9-54 below provides the total number of subjects included in the analyses.
Table 9-54: Subjects Included in the Analyses by Clinical Study
All Subjects On-label
RESOLUTE FIM 139 139
RESOLUTE All-Comers – Resolute 1140 376
RESOLUTE International 2349 763
RESOLUTE US 1402 1402
RESOLUTE Japan 100 100
Pooled Resolute Dataset 5130 2780
Subjects from the 38 mm Length sub-study were not included in the RESOLUTE pooled analys is presented here.
The on-label subgroup includes all enrolled subjects except those that had a total o cclusion, target lesions involving a b ifurcation lesion, target lesions involving a Saphenous Vein Graft lesion (SVG), an In-Stent Restenosis (ISR) target lesion, a subject having an Acute Myocardial Inf arction (AMI) ( hrs), sub jects 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 ackno wledged that the results of retrospective pooled analyses have limitations. Definitive pro of of the p resence or absence of any dif f erences between sub -groups requires prospectively powered assessments in clinical trials. The results are presented in the following tables:
7
0
Table 9-55 : Resolute Pooled Analysis - Principal Safety and Effectiveness
(
(
Table 9-56 : Resolute Pooled Analysis - ARC Defined Definite/Probable Stent Thrombosis through 60 Months
Table 9-55: 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
6.6% (336/5098) 5.4% (150/2759)
7.5% (382/5098) 6.6% (181/2759)
7.5% (384/5098) 6.3% (174/2759)
EFFECTIVENESS
Clinically Driven TVR
Clinically Driven TLR 3.3% (166/5098) 2.5% (69/2759)
4.3% (220/5098) 3.7% (103/2759)
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
TVMI
Cardiac Death or TVMI
Stent Thrombosis
1.9% (98/5098) 1.6% (44/2759)
1.2% (60/5098) 0.9% (26/2759)
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 5.3% (267/5012) 4.4% (119/2709)
7.9% (397/5012) 7.5% (204/2709)
On-label N = 2780)
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
TVMI
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)
8
Table 9-55: Resolute Pooled Analysis - Principal Safety and
(
(
Effectiveness through 60 Months
All Subjects
N = 5130)
Cardiac Death or TVMI
Sten t Thromb osis
6.5% (324/5012) 5.4% (145/2709)
On-label N = 2780)
ARC defined
Definite/Probable
Definite
Probable
Outcomes at 60 Months*
COMPOSITE SAFETY AND EFFECTIVENESS
TLF
TVF
MACE
EFFECTIVENESS
Clinically Driven TVR
Clinically Driven TLR 6.7% (179/2688) 5.8% (112/1937)
SAFETY
Total Death
Cardiac Death
Non-Cardiac Death
TVMI
Cardiac Death or TVMI
Sten t Thromb osis
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)
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)
ARC defined
Definite/Probable
Definite
Probable
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 t otal number of subject s 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 ± 30days ). 60-month timeframe includes follow-up window (1800 days ± 30days )
Note: R-Int. follow-up ends at three years and is not included in this analysis.
* The definitions of the outcomes are presented as table notes to Table 8-1 - Principal Adverse Ev ents. See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
81
2
Table 9-56: Resolute Pooled Analysis - ARC Defined Definite/Probable
(
(
Age(y
(
(
(
(
(
(
(
Stent Thrombosis Through 60 Months
Stent Thrombosis
Early (0 - 30 days)
Late (31 - 360 days)
Very Late (361 - 1800 days)*
Notes
N = The t otal number of subject s 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 three years and is not included in this analysis.
See Table 9-4 for the definition of the ARC defined Stent Thrombosis .
All Subjects*
N = 2781)
1.3% (34/2688) 0.8% (15/1937)
0.5% (13/2688) 0.2% (3/1937)
0.3% (8/2688) 0.2% (4/1937)
0.5% (14/2688) 0.4% (8/1937)
On-label*
N = 2017)

9.9.1 Gender Analysis from the RESOLUTE Pooled On-label Dataset

In the United States, an estimated 17,600,000 adults age 20 and older (9.1% of men and 7.0% of women) suffer from coronary artery disease (CAD).
8
However, it is estimated that only 36% of annual PCIs are p erf ormed in women. In PCI clinical trials, women represent only 25-35% of the enrolled populations, and there are relatively little gender-specific data. The disproportionate enrollment distribution in clinical studies may be partly attributable to gender differences in presenting symptoms and patho physiology,
9
which may lead to under-diagnosis and under-referral of female patients with CAD. Once d iagnosed and treated, poorer revascularization outcomes have been reported in women (co mpared with men) due to smaller coronary arteries and increased prevalence of baseline co morbidities including advanced age, diabetes, hypertension, and peripheral vascular disease.
Subjects from the 38 mm Length sub-study were not included in the RESOLUTE pooled analysis.
Table 9-53 describes the baseline and demographic characteristics by gender for subjects in the pooled on-label analysis. 784/2780 (28.2%) subjects were female and 1996/2780 (71.8%) were male. Female patients at baseline were older, had higher rates of diabetes and hypertension, and had smaller reference vessel diameters (RVD).
Table 9-57: Baseline Characteristics of Male vs. Female for Pooled On-Label Resolute Patients
Patient Characteristics
ears) 62.9±10.5 History of Smoking/Tobacco use 64.1% (1280/1996) 45.5% (357/784) <.001 Prior PCI 32.4% (646/1996) 28.1% Hyperlipidemia 78.6% (1568/1996) 80.9% (634/784) 0.194 Diabetes Mellitus 29.2% Insulin Dependent 7.0% (140/1996) 13.9% (109/784) <.001 Histo ry of Hypertension 75.1% Prior MI 28.1% (556/1977) 18.3% (141/772) <.001
Mal e
N = 1996
1996) 67.1±10.6
582/1996) 37.6%
1499/1996) 84.3%
Fema le
N = 784
784) <.001
220/784) 0.029
295/784) <.001
661/784) <.001
p-value
8
Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart Disease and St roke St atistic s—2010 Update. A Report From the American Heart As sociation.
Circulation. 2010;121(7):e46-e215.
9
Shaw LJ, Bairey Merz CN, Pepine CJ, et al. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) St udy: Part I :
gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic st rategies. J Am Coll Cardiol. 2006; 47(3):S4-S20.
8
3
Table 9-57: Baseline Characteristics of Male vs. Female for Pooled On-Label Resolute Patients
Patient Characteristics
Prior CABG 9.4% (187/1996) 5.7% (45/784) 0.002 Ejection Fraction (%) 0.059 <30% 0.1% (1/1463) 0.2% (1/593) 30 - 40% 6.9% (101/1463) 4.6% (27/593) >40% 93.0% (1361/1463) 95.3% (565/593) Lesion Class ACC/AHA 0.133 A 7.8% (172/2219) 9.5% (81/857) B1 25.8% (573/2219) 27.5% (236/857) B2 32.0% (710/2219) 29.8% (255/857) C 34.4% (764/2219) 33.3% (285/857) Moderate/Severe Calcification 39.1% (867/2216) 39.2% (335/855) 1.000 Pre procedure RVD (mm) 2.7 ± 0.5 (2201) 2.6±0.5 (855) <.001 Pre procedure MLD (mm) 0.7 ± 0.4 (2212) 0.8±0.4 (856) 0.025 Pre procedure Diameter Stenosis (%) 73.0±13.8 (2212) 70.5±13.5 (856) <.001 Lesion Length (mm) 13 .8±5 .8 (2201) 12.9±5.7 (855) <.001
Mal e
N = 1996
Fema le
N = 784
p-value
The pooled Resolute stent on-label use data were evaluated retrospectively for gender-based clinical outcomes. Table 9-54shows a post-hoc analysis of the principal safety and effectiveness outcomes through 12 months in subjects treated with Resolute stents for o n-label indications stratified by gender. In g eneral, event rates were low for both gender groups. The event rates were numerically higher in women (except for non-cardiac death) at 12 months; although after 60 months are evenly distributed among the two groups. These results suggest that the safety and effectiveness profile of the Resolute stent is generalizable to both males and females.
8
4
Table 9-58: Resolute Pooled On-Label Gender (Male vs. Female) – Principal Safety
and Effectiveness Through 60 Months
Sa fe ty Outc om es (to 12 Months) COMPOSITE SAFE TY AND EFFE CTIVENESS
TLF 4.9% (97/1983) 6.8% (53/776) TVF 5.8% (115/1983) 8.5% (66/776) MACE 6.0% (118/1983) 7.2% (56/776) EFFECTIVENESS Clinically Driven TVR 3.3% (66/1983) 4.8% (37/776) Clinically Driven TLR 2.3 % (46/1983) 3.0% (23/776) SAFETY Death 1.5% (30/1983) 1.8% (14/776) Cardiac Death 0.8% (15/1983) 1.4% (11/776) Non-Cardiac Death 0.8% (15/1983) 0.4% (3/776) TVMI (Extended Historical Definition) 2.1% (41/1983) 3.2% (25/776) Cardiac Death or Target Vessel MI (TVMI) 2.8% (55/1983) 4.5% (35/776) Stent Thrombosis ARC de fine d Definite/Probable 0.3% (5/1983) 0.5% (4/776) Definite 0.2% (4/1983) 0.3% (2/776) Probable 0.1% (1/1983) 0.3% (2/776)
Outcomes to 3 6 Months COMPOSITE SAFE TY AND EFFE CTIVENESS
TLF 8.8% (172/1949) 10.1% (77/760) TVF 11.4% (222/1949) 13.4% (102/760) MACE 11.8% (230/1949) 12.5% (95/760) EFFECTIVENESS Clinically Driven TVR 7.3% (142/1949) 8.2% (62/760) Clinically Driven TLR 4.4 % (86/1949) 4.3% (33/760) SAFETY Death 5.0% (98/1949) 4.9% (37/760) Cardiac Death 2.5% (48/1949) 2.9% (22/760) Non-Cardiac Death 2.6% (50/1949) 2.0% (15/760) TVMI (Extended Historical Definition) 2.6% (51/1949) 4.3% (33/760) Cardiac Death or Target Vessel MI (TVMI) 4.8% (94/1949) 6.7% (51/760) Stent Thrombosis ARC de fine d Definite/Probable 0.4% (7/1949) 0.8% (6/760) Definite 0.3% (5/1949) 0.3% (2/760) Probable 0.1% (2/1949) 0.5% (4/760)
Outcomes to 6 0 Months* COMPOSITE SAFE TY AND EFFE CTIVENESS
TLF 12.4% (169/1363) 12.2% (70/574) TVF 16.6% (226/1363) 16.4% (94/574) MACE 18.3% (249/1363) 17.9% (103/574) EFFECTIVENESS Clinically Driven TVR 10 .6 % (144/1363) 10.6% (61/574) Clinically Driven TLR 5.9 % (80/1363) 5.6% (32/574) SAFETY Death 9.8% (133/1363) 9.6% (55/574) Cardiac Death 4.3% (58/1363) 4.4% (25/574) Non-Cardiac Death 5.5% (75/1363) 5.2% (30/574) TVMI (Extended Historical Definition) 3.6% (49/1363) 4.7% (27/574) Cardiac Death or Target Vessel MI (TVMI) 7.3% (99/1363) 8.0% (46/574)
Mal e
(N = 1996)
Fema le
(N = 784)
8
5
Table 9-58: Resolute Pooled On-Label Gender (Male vs. Female) – Principal Safety
(
(
and Effectiveness Through 60 Months
Stent Thrombosis ARC de fine d
Definite/Probable 0.7% (9/1363) 1.0% (6/574) Definite 0.4% (6/1363) 0.5% (3/574) Probable 0.2% (3/1363) 0.5% (3/574)
Notes
N = The t otal number of subject s enrolled. 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 8-1- Principal Adv erse Ev ents. 12-month timeframe 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 three years and is not included in this analysis. See Table 9-4 for the definition of the AR C defined Stent Thrombosis Subjects from the 38 mm Length sub-study were not included in the RESOLUTE pooled analysis.
Mal e
N = 1996)
Fema le N = 784)
The RESOLUTE clinical trials were not designed or powered to study the safety or effectiveness of the Resolute Integrity stent in gender-specific subgroups, so these post hoc analyses are considered hyp o thesis-generating.
8
6

9.9.2 Subset Analyses from the Resolute Pooled Dataset

(
(
(
(
(
(
(
(
(
(
(
(
(
In o rder to provide the totality of data on the Resolute stent, the clinical outcomes in key patient and lesion subsets are provided. The RESOLUTE All-Comers Clinical Trial and the RESOLUTE International Study enrolled an ‘all-comers’ patient population representing an expanded use of the Resolute stent beyond those enrolled in the pivotal RESOLUTE US trial. In the RESOLUTE All-Comers and RESOLUTE International studies, 33% of enrolled subjects who fit the on-label criteria, whereas the remaining 67% had complex subject/lesion characteristics. Clinical outcomes at 12 months in key patient subsets from the pooled Resolute trials are provided in the tables below (Table 9-59 , Table 9-60 , Table 9-61 ).
It is ackno wledged that the results of such retrospective pooled analyses have limitations. Definitive proof of the p resence or absence of any differences between subsets requires prospectively powered assessments in clinical trials.
Table 9-59: Resolute Pooled Analysis - Subset Outcomes Through 12 Months
On-label Single
COMPOSITE SAFETY AND EFFECTIVENESS
TLF 5.3% (128/2428) 7.0% (177/2515)
TVF 6.4% (155/2428) 8.0% (202/2515)
MACE 6.1% (147/2428) 8.4% (211/2515)
EFFECTIVENESS
Clinically Driven TVR 3.6% (88/2428) 4.3% (108/2515)
TLR 2.4% (58/2428) 3.1% (79/2515)
SAFETY
Total Death 1.6% (39/2428)
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) 1.8% (9/495)
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) 1.4% (7/495)
TVMI
Cardiac Death or TVMI 3.2% (77/2428) 4.5% (113/2515)
Stent Thrombosis ARC defined
Lesion
N = 2466)
2.3% (57/2428) 2.9% (74/2515)
Age
 yrs
N = 2547)
3.1% (78/2515) 1.9% (70/3780) 2.1% (26/1264) 1.7% (62/3577) 1.7% (32/1928) 3.2% (16/495)
Male
(N = 3843)
6.3%
239/3780)
7.1%
270/3780)
7.3%
277/3780)
4.3%
162/3780)
3.3%
124/3780)
2.8%
105/3780)
3.6%
137/3780)
Female
(N = 1287)
7.4% (94/1264) 6.7% (239/3577) 7.3% (141/1928) 7.9% (39/495)
8.6%
109/1264)
8.0%
101/1264)
4.4% (55/1264) 4.4% (157/3577) 5.0% (96/1928) 5.7% (28/495)
3.1% (39/1264) 3.3% (118/3577) 3.7% (71/1928) 5.1% (25/495)
3.6% (45/1264) 3.2% (115/3577) 3.5% (67/1928) 1.8% (9/495)
4.9% (62/1264) 4.0% (144/3577) 4.4% (84/1928) 3.4% (17/495)
B2/C Lesions
(N = 3636)
7.6% (272/3577) 8.5% (164/1928) 8.5% (42/495)
7.6% (271/3577) 8.1% (157/1928) 9.3% (46/495)
RVD
 mm
N = 1956)
Lesion Length
 mm
N = 509)
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)
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)
0.5% (12/2515) 0.6% (24/3780) 0.4% (5/1264) 0.7% (25/3577) 0.5% (10/1928) 0.6% (3/495)
8
7
(
(
(
(
Table 9-60: Resolute Pooled Analysis – Subset Outcomes Through 12 Months
COMPOSITE SAFETY AND EFFECTIVENESS
TLF 7.8% (137/1758) 7.8% (49/632) 17.2% (11/64) 8.2% (62/756)
TVF
MACE 8.8% (155/1758) 9.3% (59/632) 17.2% (11/64) 9.0% (68/756)
EFFECTIVENESS
Clinically Driven TVR 5.1% (89/1758) 5.4% (34/632) 10.9% (7/64) 5.0% (38/756)
TLR 4.1% (72/1758) 4.4% (28/632) 7.8% (5/64) 4.4% (33/756)
SAFETY
Total Death 2.0% (36/1758) 3.0% (19/632) 3.1% (2/64)
Cardiac Death
Non-Cardiac Death 0.8% (14/1758) 1.6% (10/632) 0.0% (0/64)
TVMI
Cardiac Death or TVMI 4.5% (79/1758) 4.4% (28/632) 9.4% (6/64) 4.5% (34/756)
Stent Thrombosis ARC defined
Multiple Stents
(N = 1788)
8.6% (152/1758) 8.7% (55/632) 17.2% (11/64) 8.9% (67/756)
1.3% (22/1758) 1.4% (9/632) 3.1% (2/64)
3.5% (62/1758) 3.3% (21/632) 7.8% (5/64)
Overlapping
Stents
N = 644)
Saphenous
Vein Graft
N = 64)
Multi-Vessel
Stenting
N = 770)
1.9% (14/756)
1.3% (10/756)
0.5% (4/756)
3.3% (25/756)
BMS In-Stent
Restenosis
N = 199)
11.1% (22/198)
12.1% (24/198)
12.1% (24/198)
9.1% (18/198)
8.1% (16/198)
3.0% (6/198)
2.0% (4/198)
1.0% (2/198)
3.0% (6/198)
4.0% (8/198)
Definite/Probable 1.1% (20/1758) 1.1% (7/632) 1.6% (1/64) 1.2% (9/756)
Definite
Probable 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) 1.5% (3/198)
2.5% (5/198)
1.0% (2/198)
8
8
(
(
(
Table 9-61: Resolute Pooled Analysis – Subset Outcomes Through 12 Months
Bifurcation
(N = 702)
COMPOSITE SAFETY
AND
EFFECTIVENESS
TLF
TVF 11.4% (79/690) 6.6% (33/497) 16.1% (9/56) 12.8% (17/133) 8.1% (64/788)
MACE 11.3% (78/690) 6.6% (33/497) 17.9% (10/56) 16.5% (22/133) 8.2% (65/788)
EFFECTIVENESS
Clinically Driven TVR 6.1% (42/690) 4.2% (21/497) 7.1% (4/56) 4.5% (6/133) 5.6% (44/788)
TLR 4.8% (33/690) 3.6% (18/497) 7.1% (4/56) 3.0% (4/133) 4.7% (37/788)
SAFETY
Total Death 2.3% (16/690) 1.2% (6/497) 7.1% (4/56) 10.5% (14/133) 2.2% (17/788)
Cardiac Death 1.6% (11/690) 1.0% (5/497) 5.4% (3/56) 6.8% (9/133) 1.5% (12/788)
Non-Cardiac Death
TVMI 5.9% (41/690) 2.4% (12/497) 7.1% (4/56) 5.3% (7/133) 2.4% (19/788)
Cardiac Death or TVMI 7.1% (49/690) 3.4% (17/497) 10.7% (6/56) 9.8% (13/133) 3.8% (30/788)
Stent Thrombosis
ARC defined
Definite/Probable 2.0% (14/690)
Definite 1.6% (11/690)
Probable
Notes
N = The t otal number of subject s 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 ). The definitions of the outcomes are presented as table notes to Table 8-1 - Principal Adverse Ev ents. See Table 9-4 for the definition of the ARC defined Stent Thrombosis
1
Total Occlusion is defined as pre procedure TIMI = 0.
2
Renal Insufficiency is defined as serum creatinine >2.5 mg/dl.
Subjects from the 38 mm Length sub-study were not included in the RESOLUTE pooled analysis
10.3% (71/690) 6.2% (31/497) 16.1% (9/56) 12.0% (16/133) 7.5% (59/788)
0.7% (5/690) 0.2% (1/497) 1.8% (1/56) 3.8% (5/133) 0.6% (5/788)
0.6% (4/690)
Total
Occlusion1
N = 505)
2.0% (10/497)
1.0% (5/497)
1.0% (5/497)

10 PATIENT SELECTION AND TREATMENT

See also Section 5.5 Use in Special Population. The risks and benefits described above should be caref ully considered for each patient before use of the Resolute Integrity stent system. Factors to be utilized for patient selection should include an assessment of the risk of prolonged anti-thrombotic therapy. In the clinical studies reviewed to support the approval of the Resolute Integrity stent system, sub jects were prescribed DAPT f or at least 6 months post-procedure, and most patients who were not at a high risk o f bleeding used DAPT f or at least 12 months.
Unprotected
Left Main
N = 57)
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)
Renal
Insufficiency2
N = 135)
AMI <72 hours
(N = 799)
Post-Resolute Integrity stent implantation, aspirin should be continued indefinitely, and a P2Y12 platelet inhib ito r should b e given for at least 6 months in stable ischemic heart disease patients and for at least 12 months in patients with acute coronary syndrome (ACS). A longer duration of DAPT may be co nsidered in patients who have tolerated DAPT without a bleeding complication and who are not at a high bleed ing risk. In patients who are at a high risk of bleeding, or who develop significant bleeding during DAPT treatment, a shorter DAPT duration may be reasonable (see Section
5.1 - Pre- and Post-
Procedure Antiplatelet Regimen). However, definitive evidence supporting the safety of short DAPT
8
9
duration has not been established in prospective clinical studies. The safety and effectiveness of the Resolute Integrity stent have not been evaluated in patients at high bleeding risk.

11 PATIENT COUNSELING INFORMATION

Physicians should consider the following in counseling the patient about this product:
Discuss the risks associated with stent placement
Discuss the risks associated with a zotarolimus-eluting stent implant
Discuss the risk/benefit issues for the p articular patient
Discuss alteration to current lifestyle immediately following the procedure and over the long term
Discuss the risks of early discontinuation of the antiplatelet therapy
The f ollowing 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 imp lant procedure:
A Patient Guid e which includes information on the Resolute Integrity Zotarolimus-Eluting Coronary Stent System, coronary artery disease, and the stent implantation procedure.
A Stent Patient Implant Card that includes patient information, stent implant inf ormat ion and MRI guidelines. All patients should be instructed to keep this card in their pos se ssi o n a t al l t ime s f or procedure/stent identification.

12 HOW SUPPLIED

STERILE: This product is sterilized with ethylene oxide (EO) and is nonpyrogenic. Do not use if the
package is opened or damaged. Do not resterilize. If the product or p ackage is opened or damaged, return to Medtronic Returned Goods. Contact your local Medtronic representative for return information.
CONTENTS: Package contains one (1) Resolute Integrity Zotarolimus-Eluting Coronary Stent mounted on an Over the Wire (OTW) stent delivery system.
STORAGE: Store in the original container. Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59­86ºF). Use by the “Use By” date noted on the package.
DISPOSAL INSTRUCTIONS: After use, dispose of the product and packaging in accordance with hosp ital, administrative and/ or lo cal government policy.

13 DI RECTIONS FOR USE

13.1 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 d isrupt 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, e.g., rolling the mounted stent, may cause dislodgement of the stent from the delivery balloon.

13.2 Inspection Prior to Use

Bef ore 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 proximal and distal marker bands) on the balloon.
8
0
p
[
p
q
p
y sy
y
y sy
y
g

13.3 Materials Required

Quantity Material
N/A Guide catheter [5 F (1.42 mm, 0.056 inch) inner diameter] 2-3 20 cc syringe 1,000 u /500 cc He
arinized normal saline 1 Guidewire 1 Rotating hemostatic valve N/A Contrast medium diluted 1:1 with he 1 Inflation device 1 Stopcock (3-way minimum) 1 Tor
ue device
N/A Appropriate anticoagulation and antiplatelet drugs

13.4 Preparation Precaution

DO NOT use the product if the protective sheath is not present or the stent is damaged/displaced.
AVOID manipulation of the stent during flushing of the guidewire lumen, a s t his m ay disrupt t he
placement of the stent on the balloon.
DO NOT app ly positive pressure to the balloon during the delivery system preparation.

13.4.1 Guidewire Lumen Flush

 inch (0.36 mm) outer diameter]
arinized normal saline
Flush the stent system guidewire lumen with heparinized normal saline until the fluid exits the distal tip.

13.4.2 Delivery System Preparation

Step Action
1. Pre
2. Remo ve the stent deliver
are the guide catheter and guidewire according to the manufacturer’s instructions.
stem from the package.
3. Remo ve the protective sheath covering from the stent/balloon. Removing the protective sheath
will also remove the st
lette.
4. Inspect the stent to assure it has not been damaged or displaced from its original position on
the b alloon. Verify that the stent is positioned between the p roximal and distal balloon markers. Verif y that there is no visible damage to the stent or the balloon. Note: Should there be movement of or damage to the stent, do not use.
5. Flush the Stent Delivery System guidewire lumen with heparinized normal saline in the routine
manner.
6. Fill a 20 cc syringe with 5 cc of contrast/heparinized normal saline mixture (1:1).
7. Attach to the deliver
8. Slowl
release the pressure to allow negative pressure to draw mixture into the balloon lumen.
stem and apply negative pressure for 20 - 30 seconds.
9. Detach the syringe and leave a meniscus of mixture on the hub of the b alloon lumen.
10. Prepare the inflation device in the standard manner and purge to remove all air f rom the
syring e and tubing.
11 Attach the inflation device to the catheter, directly ensuring no b ubbles remain at the
co nnection. 12 Leave o n ambient pressure (neutral position). Note: Do not apply negative pressure on the inflation device after balloon preparation and prior to deliverin
the s tent.
9

13.5 Delivery Procedure

prop
y
p
g
Step Action
1. Prepare the vascular access site according to standard practice.
2. Pre-dilate the lesion with a PTCA catheter. Pre-dilatation must be performed using a balloon
with the f ollowing three characteristics:
A diameter at least 0.5 mm smaller than the treatment stent.
A length equal to or shorter than the lesion length to be dilated.
A length shorter than the stent to be implanted.
3. Maintain neutral pressure on the inflation device. Open the rotating hemostatic valve as widely
as p o ssible.
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 Resolute Integrity System into the
co ro nary artery. Carefully advance the Resolute Integrity System into the hub of the guide
catheter.
5. Advance the stent delivery system over the g uidewire to the target lesion under direct
f luoroscopic visualization. Use the radiopaque balloon markers to position the stent across the
lesion; perform angiography to confirm the p osition of the stent. If the position of the stent is not
optimal, it should be carefully repositioned or removed (see Precautions – Section 5.10
Stent/System Removal Precautions). Expansion of the stent should not be undertaken if the
stent is not
6. Suf ficiently tighten the rotating hemostatic valve. The stent is now ready to be deployed.
Note: Sho uld unusual resistan ce be felt at any time during eith er les ion acc ess o r remo val of the sten t deli very 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 –Section 5.10 Stent/System Removal Precautions for specific stent delivery system removal instructions. In the event the stent is not deployed, contact
our local Medtronic representative for return information and avoid handling sten t with bare hands.
erly positioned in the target lesion segment of the vessel.

13.6 Deployment Procedure

Step Action
1. Prior to stent expansion, utilize high-resolution fluoroscopy to verify the stent has not been
damaged or shifted during positioning.
2. Maintain inflation
3. Do not exceed Rated Burst Pressure (RBP). The RBP is 16atm for the 2.25 mm – 3.5
mm stent diameters and 15atm for the 4.0 mm stent diameter. The Resolute Integrity
stents should not be expanded to a diameter beyond the maximum labeled diameter
listed on the label. Do not dilate the 2.25 mm - 2.75 mm stents to greater than 3.50 mm.
Do not dilate the 3.0 m m - 4.0 m m stents to
4. Fluoroscopic visualization during stent expansion should be used in order to properly judge
the o p timum stent diameter as compared to the proximal and distal native coronary artery
diameters (reference vessel diameters). Optimal stent expansion and proper apposition
requires that the stent be in full contact with the arterial wall.
ressure for 15 - 30 seconds for full expansion of the stent.
reater than 4.75 mm.
91
2
g
y sy

13.7 Removal Procedures

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
def lation. Deflation of the b alloon should be confirmed by absence of contrast within the
balloon.
2. Op en the hemo static valve to allow removal of the delivery system.
3. Maintain the position of the guide catheter and guidewire. Very slowly, withdraw the balloon
f rom the stent, maintaining negative pressure, allowing movement of the myocardium to
ently dislodge the balloon from the stent.
4. Af ter removal of the deliver
5. Repeat angiography and visually assess the vessel and the stent for proper expansion.

13.8 In-vitro Information:

Table 13-1: Inflation Pressure Recommendations
stem, tighten the hemostatic valve.
Pressure
ATM kPa 2.25 2.5 2.75 3.0 3.5 4.0
6 608 2.20 2.45 2.70 2.90 3.30 3.75
7 709 2.20 2.45 2.70 2.95 3.35 3.80
8 811 2.25 2.50 2.75 3.00 3.40 3.90
9 912 Nominal 2.30 2.55 2.80 3.05 3.50 3.95
10 1013 2.30 2.60 2.85 3.10 3.55 4.05
11 1115 2.35 2.60 2.90 3.15 3.60 4.10
12 1216 2.40 2.65 2.95 3.20 3.65 4.15
13 1317 2.40 2.70 3.00 3.20 3.70 4.20
14 1419 2.45 2.70 3.05 3.25 3.75 4.25
15 1520 RBP for 4.0 m m 2.50 2.75 3.10 3.30 3. 80 4.30
16 1621 RBP* 2.55 2.80 3.15 3.35 3.85 4.35
17 1723 2.60 2.80 3.20 3.40 3.90 4.40 18 1824 2.60 2.85 3.25 3.45 3.95 4.45
19 1925 2.90 3.30 3.50 4.00 4.50
20 2027 2.95 3.40 3.55 4.05 *Do not exceed the rated burst pressure (RBP). The RBP for 4.0 mm diam eter is 15 ATM . ** The shaded cells at pressures 19 ATM and 20 ATM signif y that 99% of the balloons did not pas s at the lis ted pressure beyond RBP with 95% confidence.
Nominal and Rated
Burst Pressure*
Stent Nominal Inner Diameter (mm)**

13.9 Further Dilatation of Stented Segment

The stent delivery balloon may not be used for post-dilatation. Post-dilatation may be performed at
the p hysician’s discretion with appropriately sized (length and diameter) balloons to ensure that the stent is in f ull contact with the vessel wall. To achieve this, a balloon to artery ratio of 1.0 to 1.1:1.0 sho uld 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).
9
3
Precaution: Do not dilate the stent beyond the following limits:
Nominal Stent Diameter Dilatation Limits
2.25 mm 3.50 mm
2.50 mm 3.50 mm
2.75 mm 3.50 mm
3.00 mm 4.75 mm
3.50 mm 4.75 mm
4.00 mm 4.75 mm
All ef forts should be taken to assure 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 ballo on 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 sho uld be recrossed carefully with a prolapsed guidewire to avoid dislodging or displacing the stent. The ballo on should be centered within the stent and should not extend outside of the stented region. The
Resolute Integrity stents should not be expanded to a diameter beyond the maximum labeled diameter listed on the label. Do not dilate the 2.25 mm - 2.75 mm stents to greater than 3.50 mm. Do not dilate the 3.0 mm - 4.0 mm stents to greater than 4.75 mm.

14 REUSE PRECAUTION STATEMENT

For single use only.
Do not Resterilize or Reuse.
9
4

DISCLAIMER OF WARRANTY

THE WARNINGS CONTAINED IN THE PROD UCT LABELING PROVIDE MORE D ETA ILE D INFORMATION AND ARE CONSIDERED AN INTEGRAL PART OF THIS DISCLAIMER OF WARRANTY. ALTHOUGH THE MEDTRONIC RESOLUTE INTEGRITY ZOTAROLIMUS­ELUTING CORONARY STENT SYSTEM, HEREAFTER REFERRED TO AS “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 WARRANTIE S , B OTH 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 PROD UCT, 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, co ntravene 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.
9
MANUFACTURER: MEDTRONIC, INC.
710 Medtronic Parkway Minneap o lis, MN 55432 U.S.A. Tel: (+1-763) 514-4000 Fax: (+1-763) 514-4879
www.medtronic.com
U.S. CUSTOMER SERVICE / PRODUCT INQUIRIES
Tel: (+1-888) 283-7868 Fax: (+1-888) 838-3103
*M724129B001* Rev AA
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