Medtronic RSINT22514UX Instructions for Use
Resolute Integrity™ Zotarolimus-Eluting Coronary Stent System
Rapid Exchange Delivery System
INSTRUCTIONS FOR USE
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co untries . All o ther trademarks are the p ro perty of th eir r espec tive o wners.
End eavor, Medtronic, Resolute Integrity
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Table of Contents
1 RESOLUTE INTEGRITY™ ZOTAROLIMUS-ELUTING CORONARY STENT SYSTEM ..................... 1
1.1 DEV ICE COMPONENT 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-P ROCEDURE 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 Lactatio n ....................................................................................................................... 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 ............................................................................................................ 9
5.7 MAGNETIC RESONA NCE IMAGING (MRI)..................................................................................... 9
5.8 STENT HANDLING 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 EVE NTS ............................................................................................... 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 Percutaneous Coronary Diagnostic and Treatment Procedures21
i
9
CLINICAL STUDIES .............................................................................................................. 22
9.1 RESULTS OF THE RESOLUTE US TRIAL ................................................................................. 22
9.2 RESULTS OF THE RESOLUTE ALL COMERS (AC) CLINICAL TRIAL ................................................. 49
9.3 RESULTS OF THE RESOLUTE INTERNATI ONAL 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 OL UTE AC, RES OL UTE INT, RES OLUTE JAPAN) .................................... 79
9.9.1 Gender Analysis from the RESOLUTE Pooled On-label Dataset.......................................... 83
9.9.2 Subset Analyses from the Resolute Pooled Dataset........................................................... 87
10 PATIENT SELECTION AND TREATMENT ............................................................................... 90
11 PATIENT COUNSELING INFORMATION ................................................................................. 90
12 HOW SUPPLIED ................................................................................................................... 90
13 DIRECTIONS FOR USE ......................................................................................................... 90
13.1 ACCESS TO PACKAGE HOL DING STE RI L E STE N T DELIVERY SYSTE M ............................................... 90
13.2 INSPECTION PRIOR TO USE................................................................................................... 91
13.3 MATERIALS REQUIRED......................................................................................................... 91
13.4 PREPARATION PRECAUTION .................................................................................................. 91
13.4.1 Guidewire Lumen Flush................................................................................................. 91
13.4.2 Delivery System Preparation .......................................................................................... 91
13.5 DELIVERY PROCEDURE........................................................................................................ 92
13.6 DEPLOYMENT PRO CEDURE ................................................................................................... 92
13.7 REMOVAL PROCEDURES ...................................................................................................... 92
13.8 IN-VITRO INFORMATION: ....................................................................................................... 93
13.9 FURTHER DILATATION OF STE NT E D SEGMENT ........................................................................... 93
14 REUSE PRECAUTION S TATEMENT ....................................................................................... 93
DISCLAIMER OF WARRANTY ........................................................................................................... 94
ii
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 z otarolimus in a formulat ion applied to t he entire s urface of t he
Delivery System Working Length: 140 c m
Delivery System Luer Adapter Port s: Single access port to the inflation lumen. A guidewire exit port is loc ated approximat ely 25 cm from
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 s tent utiliz es a single helix
fusion pattern. The coronary stent is formed f rom
a single wire bent into a continuous sinusoid
pattern and then laser fused back ont o itself. The
stents are provided in multiple lengths and
diameters.
stent at a dose of approximat ely 1.6 μg/ mm
380 μg on the largest stent (4.0 x 38 mm).
the tip. 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.
Rapid Exchange 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 ujoint 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 diam eters.
2
which results in a maximum nominal drug content of
Balloon Inflation Pressure: Nominal Inflation Pressure: 9 ATM (912 kPa)
Rated Burst Pressure: 16 ATM (1621 kPa) f or 2.25-3.5mm diameters
15 ATM (1520 kPa) for 4.0 mm diameter
Minimum Guide Catheter Inner
Diameter:
Catheter Shaft Outer Diamet er: Proximal OD: 2.1 F (0.69 m m, 0.027 inc h)
≥ 5 F (1.42 mm, 0.056 inch)
Distal Section OD: 2.7 F (0.91 mm, 0.036 inch)
1
1.1 Device Component Description
The Med tronic Resolute Integrity Zotarolimus-Eluting Coronary Stent System (Resolute Integ rity
System) consists of a balloon-expandable intracoronary drug-eluting stent pre-mounted on the
MicroTrac Rapid Exchange (RX) 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 fused back onto itself. The stents are available in multiple lengths and diameters. The d elivery
system has two radiopaque markers to aid in the placement of the stent during fluoroscopy and is
co mpatible with 0.014-inch (0.36mm) guidewires. The MicroTrac RX delivery system (Figure 1-1) has an
ef f ective length of 140 cm.
Figure 1-1: MicroTrac RX 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 9 --- 9 9 --- 9 9 9 9 --- ---
2.5 9 --- 9 9 --- 9 9 9 9 --- ---
2.75 9 --- 9 9 --- 9 9 9 9 --- ---
3.0 ---
3.5 ---
4.0 ---
Note: “---“ indicat es sizes not offered; “9” indicates sizes offered.
8 9 12 14 15 18 22 26 30 34 38
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 9 9
---
2
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 b e 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
3
(μg)
1.2.3 Product Matrix and Zotarolimus Content
Table 1-3: Resolute Integrity Zotarolimus-Eluting Coronary Stent System
Product Matrix and Nominal Zotarolimus Doses
Product Number
RX
RSINT22508UX 2.25 8 59
RSINT25008UX 2.5 8 59
RSINT27508UX 2.75 8 59
RSINT30009UX 3.0 9 90
RSINT35009UX 3.5 9 90
RSINT40009UX 4.0 9 90
RSINT22512UX 2.25 12 85
RSINT25012UX 2.5 12 85
RSINT27512UX 2.75 12 85
RSINT30012UX 3.0 12 120
RSINT35012UX 3.5 12 120
RSINT40012UX 4.0 12 120
RSINT22514UX 2.25 14 102
RSINT25014UX 2.5 14 102
RSINT27514UX 2.75 14 102
RSINT30015UX 3.0 15 150
RSINT35015UX 3.5 15 150
RSINT40015UX 4.0 15 150
RSINT22518UX 2.25 18 128
RSINT25018UX 2.5 18 128
RSINT27518UX 2.75 18 128
RSINT30018UX 3.0 18 180
RSINT35018UX 3.5 18 180
RSINT40018UX 4.0 18 180
RSINT22522UX 2.25 22 153
RSINT25022UX 2.5 22 153
RSINT27522UX 2.75 22 153
RSINT30022UX 3.0 22 220
RSINT35022UX 3.5 22 220
RSINT40022UX 4.0 22 220
RSINT22526UX 2.25 26 188
RSINT25026UX 2.5 26 188
RSINT27526UX 2.75 26 188
RSINT30026UX 3.0 26 260
RSINT35026UX 3.5 26 260
RSINT40026UX 4.0 26 260
RSINT22530UX 2.25 30 213
RSINT25030UX 2.5 30 213
RSINT27530UX 2.75 30 213
Nominal Expanded
Stent ID (mm)
Nominal Unexpanded
Stent Length (mm)
Nominal Zotarolimus
Content
4
(μg)
Table 1-3: Resolute Integrity Zotarolimus-Eluting Coronary Stent System
Product Matrix and Nominal Zotarolimus Doses
Product Number
RX
RSINT30030UX 3.0 30 300
RSINT35030UX 3.5 30 300
RSINT40030UX 4.0 30 300
RSINT30034UX 3.0 34 340
RSINT35034UX 3.5 34 340
RSINT40034UX 4.0 34 340
RSINT30038UX 3.0 38 380
RSINT35038UX 3.5 38 380
RSINT40038UX 4.0 38 380
2 INDICATIONS
The Resolute Integrity Zotarolimus-Eluting Coronary Stent System is indicated for improving coronary
luminal diameters in p atients, including those with diabetes mellitus, with symptomatic ischemic heart
disease d ue to de novo lesions of length 35 mm in native coronary arteries with reference vessel
diameters of 2.25 mm to 4.2 mm. In addition, the Resolute Integrity Zotarolimus-Eluting Coronary Stent
System is indicated for treatment of de novo chronic total occlusions.
3 CONTRAINDICATI ONS
The Resolute Integrity System is contraindicated for use in:
• Patients with known hypersensitivity or allergies to aspirin, heparin, bivalirudin, clopidogrel,
prasugrel, ticagrelor, ticlopidine, drugs such as zotarolimus, tacrolimus, sirolimus, everolimus, or
similar drugs or any other analogue or derivative.
• Patients with a known hypersensitivity to the cobalt-based alloy (cobalt, nickel, chromium, and
molybdenum).
• 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 who m 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 prop er placement of the stent or stent delivery system.
Nominal Expanded
Stent ID (mm)
Nominal Unexpanded
Stent Length (mm)
Nominal Zotarolimus
Content
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 o f 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 product should not be used in p atients who are no t likely to comply with the recommended
antiplatelet therapy.
5 PRECAUTIONS
• Only physicians 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 long-term outcome following
repeat catheter-based treatments of previously implanted stents is not well characterized.
• The risks and benefits of stent implantation should be assessed for patients with a history of severe
reaction to contrast agents.
• Do not expose or wipe the product with organic solvents such as alcohol.
• When d rug eluting stents (DES) are used outside the specified Indications for Use, patient
outcomes may differ from the results observed in the RESOLUTE pivotal clinical trials.
5
• Compared 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 p rospectively 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 Medtronic 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 procedure and for a period 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 o ptimal 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 ost-procedural antiplatelet recommendations.
1
Per 2016 ACC/AHA guidelines,
a daily aspirin dose of 81 mg is recommended indefinitely after PCI. A
P2Y12 platelet inhibitor should be given daily for at least 6 months in stable ischemic heart disease
patients and for at least 12 months in patients with acute coronary syndrome (ACS).
In p ivo tal trials of current generation DES, subjects were prescribed DAPT f or 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 bleed ing 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 shorter DAPT duration may be reasonable.
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. F or full text, please refer to the following website:
http://content.onlinejacc.org/article.aspx?doi=10.1016/j.jacc.2016.03.513
2
Mauri L, et al. Twelve or 30 Months of Dual Antiplatelet Therapy After Drug-Eluting Stents. N Engl J Med. 2014;371:2155–66.
6
However, definitive evidence supporting the safety of short DAPT duration has not been established in
prospective clinical studies.
Decisions about duration of DAPT are best made on an individual basis and should integrate clinical
judgment, assessment of ischemic and bleeding risks, and patient 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 propriate PCI choice.
Following PCI, if elective non-cardiac surgery requiring suspension of antiplatelet therapy is considered,
the risks and benefits of the procedure should be weighed against the possible risk associated with
interruptio n 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 d issimilar 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 o r 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 safety 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 safety and effectiveness of the Resolute Integrity stent in target lesions treated with prior
brachytherapy, or the use of brachytherapy to treat in-stent restenosis of a Resolute Integrity stent, have
not been 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 description 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 und er Drug Information. There are no well-
co ntrolled studies in p regnant women or men intending to father children. The Resolute Integrity stent
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.
7
5.5.2 Lactation
It is not known whether zotarolimus is excreted in human milk. The pharmacokinetic and safety profiles
of zotarolimus in infants are not known. Because many drugs are excreted in human milk and because
of the potential for adverse reactions in nursing infants from zotarolimus, a decision should be made
whether to discontinue nursing or to implant a Resolute 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 Pediatric Use
The safety and effectiveness of the Resolute Integrity stent in patients below the age of 18 years have
not been established.
5.5.6 Geriatric Use
Clinical studies of the Resolute stent did not have an up per age limit. Among the 1242 p atients 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 older 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.
5.5.7 Lesion/Vessel Characteristics
The safety 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.
8
5.6 Drug Interactions
The ef fect of potential drug interactions on the safety or effectiveness of the Resolute Integrity stent has
not been 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
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
drug interactions when deciding to place a Resolute Integ rity stent in a patient who is taking d rugs that
are known substrates or inhibitors of the cytochrome P450 isoenzyme CYP3A4. Systemic exposure of
zotarolimus should also be taken into consideration if the patient is treated concomitantly with systemic
immunosuppressive therapy.
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 b ody 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 pro duce 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 perfusion and b lood flow. The maximum
whole body averaged specific absorption rate (SAR) was derived by calculation.
. Therefore, consideration should be given to the potential for
max
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 pro duce 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 device. Theref ore, 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 gradient 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
• For single use only. The Resolute Integrity System is provided sterile. Do not resterilize or reuse
this p roduct. 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.
9
• 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 Resolute Integrity System is intended to perform as a
system. The stent is not designed to be crimped onto another delivery device.
• Special care must be taken not to handle or in any way disrupt the stent on the balloon. This is most
imp o rtant while removing the catheter from the packaging, placing it over the g uidewire, and
advancing it through the rotating hemostatic valve and guide catheter hub.
• Do not try to straighten a kinked shaft or hypotube. Straightening a kinked metal shaft may result in
breakage of the shaft.
• Stent 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 Integ rity 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 d amage or premature drug
elution.
• Use only the appropriate 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 Integ rity 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.
• Balloon pressures should be monitored during inflation. Do not exceed rated b urst pressure as
indicated on the product label. Use of pressures higher than those specified on the product label
may result in a ruptured balloon with possible intimal damage and dissection.
• In small or diffusely diseased vessels, the use of high balloon inflation pressures may over-expand
the vessel distal to the stent and could result in vessel dissection.
• Imp lanting 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 other intervention).
• Do not expand the stent if it is not properly positioned in the vessel (see Section 5.10 -
PRECAUTIONS–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 from the balloon may occur. Remove as a single unit per instructions in Section 5.10 PRECAUTIONS –Stent/System Removal Precautions.
• Under-expansion of the stent may result in stent movement. Care must be taken to properly size
the stent to ensure that the stent is in full contact with the arterial wall upon deflation of the balloon.
• Stent retrieval methods (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 full coverage of the entire lesion/dissection site so that there are no g aps 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
10
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:
• Do not retract the stent delivery system into the guide catheter. Maintain guidewire placement across
the lesion and caref ully pull back the stent delivery system until the proximal balloon marker of the
stent delivery system is aligned with the distal tip of the guide catheter.
• The system should be pulled back into the descending aorta toward the arterial sheath. As the distal
end of the guide catheter enters into the arterial sheath, the catheter will straighten, allowing safe
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 p ost-dilatation can
be done using a low-profile, high pressure, non-compliant balloon catheter. The b alloon should not
extend outside of the stented region. Do not use the stent delivery balloon for post-dilatation.
• If patient requires MR imaging, refer to Section 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 protein 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 ab o ve) 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 Reso lute 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.
11
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 Clinical
Trial. The d o se of zotarolimus was calculated per stent unit surface area and the key pharmacokinetic
parameters determined from these patients are provided in Table 6-1.
Table 6-1: Zotarolimus Pharmacokinetics in the Medtronic RESOLUTE FIM Clinical Trial PK
Sub-study Patients after Implantation 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
Group IVa
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 (ng•h/mL) 15.08 16.04 ± 4.74 35. 89 ± 12.79 31. 19 ± 17.69
AUC0-inf$ (ng•h/mL) 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
C
Maximum observed blood concentration a Primary dose groups
max
T
Time to C
max
AUC
0-last
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
AUC from time 0 to infinity (AUC
† No SD was reported when N = 1
max
‡ Harmonic mean ± pseudo-standard deviation
). #
0-inf
Not a true estimate of the elimination half-life as the drug
release from the stent was not complete during the
course of the pharmacokinetic sampling
The results in Table 6-1 show that the p harmacokinetics of zotarolimus were linear in the primary doseproportionality evaluation (including dose groups with N > 1), 180, 240 and 300 μg, following the
implantation of the Resolute stents as illustrated by dose proportional increases in maximum blood
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.
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.
(300 μg)
N = 3
max
)
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 pharmacokinetic analysis.
12
g
Table 6-2: Pharmacokinetic Parameters (Mean ± Standard Deviation) in Patients Following Multi-
dose Intravenous Administration of Zotarolimus
200 μg QD
PK
Parameters
Cmax (ng/mL) 11.41± 1.38¥ 11.93 ± 1.25 21.99 ± 3.79 23.31± 3.15 37.72 ± 7.00 41.79 ± 6.68
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) 32.9 ± 6.8 37.6 ± 4.5 36.0 ± 4.7
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 usin
Units
(ng•h/mL)
34.19 ± 4.39¥ 47.70 ± 6.68 68.43 ± 15.41 100.47 ± 18.02 123.48 ± 13.34 174.43 ± 19.88
4.2 ± 0.6 4.2 ± 0.6 4.0 ± 0.9 4.0 ± 0.9 4.6 ± 0.4 4.6 ± 0.4
N = 15
Day 1 Day 14 Day 1 Day 14 Day 1 Day 14
non-compartmental methods.
400 μg QD
N= 16
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 vitro bacterial reverse mutation assay, the human peripheral
lymphocyte chromosomal aberration assay, or the in vivo mouse micronucleus assay.
800 μg QD
N=16
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 f emale 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 (ap proximately 21
times the cumulative b lood exp osure provided by Resolute stents co ated with 300 μg zotarolimus).
Reduced sperm counts and motility, and failure in sperm release were observed in male rats following the
IV administration of zotaro limus f or 28 d ays at d o sages of >30 μg/kg/day. Testicular germ cell
degeneration and histological lesions were observed in rats f ollowing 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
13
the cumulative blood exposure in patients receiving Resolute Integrity stents coated with 300 μg
zotarolimus total dose.
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 ab out 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 ost-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 known whether zotarolimus is excreted in human milk. The potential adverse reactions in
nursing inf ants from zotarolimus have not been determined. The p harmacokinetic and safety profiles of
zotarolimus in infants are not known. Because many drugs are excreted in human milk and because of
the p otential 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 principal 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 Reso lute Integrity stent is mounted on the MicroTrac delivery system,
which differs from 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 Integ rity 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 principal safety and effectiveness information for the Resolute stent was derived from the Global
RESOLUTE Clinical Trial Program, which consists of the following clinical trials – the RESOLUTE
United States Clinical Trial(R-US), the RESOLUTE All-Comers Clinical Trial(R-AC), the RESOLUTE
International Study(R-Int), the RESOLUTE First-in-Man(FIM) Clinical Trial, and the RESOLUTE Japan
Clinical Trial(R-J). These f ive studies have evaluated the performance of the Resolute stent in improving
co ronary luminal diameters in patients, including those with diabetes mellitus, with symptomatic
ischemic heart disease due to de novo lesions of length 35 mm in native coronary arteries with
reference vessel diameters of 2.25 mm to 4.2 mm. Key elements of these studies are summarized
below and in
Table 7-1. The Resolute 38 mm Length Group was derived from subjects enrolled in the
R-US and the RESOLUTE Asia study (R-Asia) (For 38 mm Length Group data see Table 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 mm
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 mm to 3.5 mm Main Study: The primary endpoint was Target Lesion Failure (TLF) at
12 months p ost-procedure, defined as Cardiac Death, Target Vessel Myocardial Infarction (MI),
or clinically-driven Target Lesion Revascularization (TLR).
• The 2.25 mm co hort analysis, in which the cohort was derived from subjects treated with the
2.25 mm Resolute stent in the 2.25 mm 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.
14
• The 2.25 mm to 3.5 mm Angio/IVUS Sub-study: The primary endpoint was in-stent late lumen
loss (LL) at 8 months post-procedure as measured by quantitative coronary angiography (QCA).
• 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 hig h 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
sub jects 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 months 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 ind efinitely 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 International (RESOLUTE Int) study is a prospective, multi-center, non-randomized,
single-arm observational 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 months 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 bleeding.
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 Pharmacokinetic of the
Resolute Stent).
The RESOLUTE Jap an Clinical Trial is a prospective, multi-center, non-randomized, single-arm trial. A
to tal of 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 a
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 pooled 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) countries 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 ronary arteries with a reference vessel diameter (RVD) of 2.25 mm to 4.2 mm in two groups of
patients, specifically those patients receiving stents mm in length, referred to as the Primary
Enrollment Group (PEG) and those patients who receive extended length stents (34 mm or 38 mm)
referred to as the Extended Length (XL) Sub-study. The primary endpoint for this study is composite
rate of cardiac death and target vessel myocardial infarction (MI) at 12 mo nths.
Table 7-1 summarizes the clinical trial designs for the Global RESOLUTE Clinical Trial Program and
Post-market Approval Study.
.
16
(
)
(
y)
j
p
p
)
y
y
5
XL Sub-stud
mm treated or
or two target l esions
US
RESOLUTE INTEGRITY
Prospectiv e
Multi-center
Non-randomi zed
4
PEG
Post-market Approval Study
RESOLUTE
INTEGRITY US
38 mm Cohort
RESOLUTE Asia
RES OLUTE Japan
3
Post approval
Post approval
Prospectiv e
Multi-center
Non-randomi zed
Prospectiv e
Multi-center
Non-randomi zed
Prospectiv e
Multi-center
Non-randomi zed
Single-arm
Historical control led tri al
located i n separate
. Single target lesion
or two target l esions located i n separate
Single target lesion
separate target vessels
lesions located in
Single or two de novo
separate coronary
lesions located in
Single or two de novo
lesi on length
target vessels
Target lesion
Target lesion
mm
Target vessel with
Target ves sel wi th RVD
between 2.25 to 4.2 mm.
Target ves sel wi th RVD
mm
Target vessel with RVD
between 2.25 to 4.2
up to two lesions
4.0 mm
received treatment of
RVD between 3.0 to
Patients may have
between 2.5 to 3.5 mm
separate target
lesions were located in
second l esion RVD
(2.25 to 4.2 mm), if the
XL:
target vessels
PEG:
mm
Lesion(s) length ≤35
arteries
Lesion(s) length ≤27 mm
34-38 mm
Stent Length:
Stent diameter:
3.0 – 4.0 mm
8 – 30 mm
Stent length:
Stent diameter:
2.25 – 4.0 mm
vessels.
Stent Length: 38 mm
Stent diameter:
3.0 – 4.0 mm
8 – 30 mm
Stent length:
Stent diameter:
2.5 – 3.5 mm
stem
MicroTrac Delivery
Resolute Integrity stent
on the Rapid Exchange
S
stem
Resolute Integrity stent
on the Rapid Exchange
MicroTrac Deliv ery
S
Resolute s tent on the
Rapid Exc hange Sprint
Deli very Sy stem
Resolute s tent on the Rapid
Exc hange Sprint Delivery
System
Aspi rin indefinitel y and
Aspi rin indefinitel y and
Aspi rin indefinitel y and
Aspi rin indefinitel y and
clopi dogrel/ticlopi dine for
clopi dogrel/ticlopi dine
clopi dogrel/ticlopi dine, for
clopi dogrel/ticlopi dine for
tolerated
up to 12 months if
months in al l subj ec ts,
months if tol erated
subjec ts, up to 12
for months in all
tolerated
up to 12 months if
months in al l subj ec ts,
months in al l subjects, up to
12 months if tol erated
Prospectiv e
Multi-center
Non-randomi zed
Single-arm
Historical control led tri al
PK Assessment
Non-randomi zed
ulation
o
ec t
Total: 2349 Total: 139 Total: 100 Total: 109 Total:230 Total: 56
Single-arm
Observational study
Real World sub
RES OLUTE FIM
2
Prospectiv e
Multi-center
RESOLUTE Int
1
between 2.5 and 3.5 mm
Single de nov o lesion
Lesion l ength from 14 to 27 mm
Target ves sel wi th RVD
lesi on length
lesi on(s)/ vessel(s) treated or
between 2.25 to 4.0 mm
No limitation to number of
Target ves sel wi th RVD
8 – 30 mm
Stent length:
Stent diameter:
2.5 – 3.5 mm
Stent length:
Stent diameter:
2.25 – 4.0 mm
Resolute s tent on the Rapid
Exc hange AV100 Delivery System
Aspi rin indefinitel y and
clopi dogrel/ticlopi dine months
8 – 38 mm
Resolute s tent on the Rapid
Exc hange Sprint Delivery S ystem
Aspi rin indefinitel y and
months if tol erated
months in al l subjects, up to 12
clopi dogrel/ticlopi dine for
17
Table 7-1: Clinical Trial Comparisons
Total: 2292
vess el(s) treated or lesion length
2.25 to 4.0 mm
No limitation to number of lesion(s)/
Target vess el with RVD between
located i n separate target
Single or two de novo les ions
Group
vessels
Lesion(s) length ≤27 mm fo r the
Primary Enrollment Group, ≤35
between 2.25 to 4.2 mm
mm for the 38 mm Length
Target ves sel wi th RVD
8 – 30 mm
Stent length:
Stent diameter:
2.25 – 4.0 mm
Stent length:
Stent diameter:
2.25 – 4.0 mm
Resolute s tent on the Rapid Ex change
Sprint Deliv ery System
38 mm Length Group
Enrollment Group, 38 mm for the
8 – 30 mm for the Primary
Resolute s tent on the Rapid
Exc hange Sprint Delivery S ystem
Aspi rin indefinitel y and
Aspi rin indefinitel y and
tolerated
all s ubjects, up to 12 months if
clopi dogrel/ticlopi dine for mo nths in
months if tol erated
months in al l subjects, up to 12
clopi dogrel/ticlopi dine for
- 2.25 mm Cohort -150
(Resolute: 1140, Xience V : 1152)
subjec ts
sub-study - 100 subjects
subjec ts
- 2.25–3.5 mm Angio/IVUS
- 4.0 mm Sub-study - 60
subjec ts (38 mm Sub-study
total patient population was
223 with 114 from
RESOLUTE US and 109
from RESOLUTE Asia
- 38 mm Sub-study -114
(1:1 Resolute vs. Xience V)
P rospectiv e
Mul ti-center
Randomi zed
Two-arm, non-i nferiority trial
Real World subject population
1242 subjec ts
Prospectiv e
Multi-center
Non-randomi zed
Historical control led tri al *
Total: 1516
- 2.25–3.5 mm Main Study -
Pr e-ma rke t Appr oval Studie s; Globa l RE SOLUTE Clinic al Tr ial Progra m
RESOLUTE US* RESOLUTE AC
Study Type
Number of
Subj ects
Enrolled
Lesion Criteria
Stent Sizes
(Res olute)
Pr oduct Us ed
Post-
proc edure
Antiplatelet
Therapy
(
)
(
y)
p
g
5
XL Sub-stud
US
RESOLUTE INTEGRITY
4
PEG
Post-market Approval Study
RESOLUTE
INTEGRITY US
38 mm Cohort
RESOLUTE Asia
RES OLUTE Japan
3
years: (Contact) 2-3
years (Contact)
12-lead ECG) and 2
months (Clinic Visit with
30 days (Contact); 6
months (Contact); 12
months (Clinic Visit with
years: (Contact)
30 days (Contact); 6
months (Contact); 12
12-lead ECG) and 2
annually at 2 - 5 years
30 days, 6, 9 (Clinical
Vis it), 12, 18 months then
30 days and 12 months:
clinical
8 months:
angiographic/IVUS
6, 9 and 18 months and 2-5
years: telephone
36-month follow-up is
complete
24-month follow-up is
complete
60-month follow-up is
complete
complete
18
cli nical and angi ographic/IVUS
months (100 subject subset):
30 days: c linical
4 (30 subject s ubs et) and 9
6 months and 1-5 years: telephone
RES OLUTE FIM
2
30 days, 6 months, 1-3 years:
cli nical or telephone
RESOLUTE Int
1
Table 7-1: Clinical Trial Comparisons
angiographic
6 months and 2-5 years: telephone
30 days and 12 months: clinical
13 months (455 subject subset):
60-month follow-up is compl ete 36-month follow-up is compl ete 60-month follow-up complete 60-month follow-up is
th.
and 18 months, 2-5 years :
telephone
angiographic/ IVUS;6, 12 and 18
2.25 mm - 3.5 mm Angio/IVUS
Follow -up
and 18 months, 2-5 years :
telephone
days and 9 months: clinical; 6, 12
cli nical and angiographi c; 6, 12
4.0 mm Sub-study: 8 months:
2.25 mm - 3.5 mm Main Study: 30
Pr e-ma rke t Appr oval Studie s; Globa l RE SOLUTE Clinic al Tr ial Progra m
RESOLUTE US* RESOLUTE AC
then annually at 2, 3, 4, 5 years
days (R-Asia), 6, 12, 18 months
38 mm Length Sub-study: 30 days
(R-US) and 9 months clinical v isits
(preferred) or patient contac t 30
60-month follow-up is compl ete.
551 subjec ts qualified for 18-month
follow-u
Status
The term ‘AC’ refers t o All-Comers. 2 The term ‘Int’ refers to Internat ional. 3 The term ‘FIM’ refers t o First-I n-Man. 4 The term ‘PEG’ refers to Primary Enrollment Group. 5 The term ‘XL’ refers t o Extended Len
* The RESOLUTE US trial is compos ed of four studies. The 2. 5 mm - 3.5 mm s ubset of t he Main St udy, the 2.25 mm – 3.5 mm Angio/ IVUS Sub-study, the 38 mm
Length Sub-study, and the 4.0mm Sub-st udy have hist orical control des igns. The 2.25 mm Subset outcomes were compared t o a performance goal.
1
months, 2-5 years: telephone
Sub-study: 8 months: clini cal and
(
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 dition, the adverse event experience from the Resolute Integrity US Primary Enrollment Group
(PEG) Post-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)
Resol ute
(N = 2349)
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
6
TVMI
Clinically Driv en TV R7 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 Days
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
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 Death or
TVMI
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 Months 36 Months
TLF
TVF
MACE
Total Death
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)
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) 3.6% ( 42/1152) 2.2% ( 51/2349) 4.3% (6/139) 2. 0% (2/ 100) 3. 1% (7/223) 1.7% (4/ 230) 1.8% (1/56)
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)
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)
0.1% ( 2/1390)
1.2% ( 16/1390)
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)
9
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)
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)
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)
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)
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)
RESOLUTE INTEGRITY US
Resolute Integrity
(PEG)
(N= 230)
RESOLUTE
INTEGRITY US (XL
Sub-study)
N=56)
19
(
Table 8-1: Principal Adverse Events from Post-Procedure Through Latest Available Follow-
up
RESOLUTE US
Non-Cardiac
Death
TVMI
Q wave MI
Non-Q Wave M I
Cardiac Death or
TVMI
Clinically Driv en TV R
TLR
Non-TL TVR
ARC Def/Prob ST
Notes
1
Resol ute
(N = 1402)
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)
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)
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)
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)
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)
Sub-study
R-US N = 114
R-Asia N = 109
Resol ute
(N = 223)
RESOLUTE INTEGRITY US
Resolute Integrity
(PEG)
(N= 230)
38 mm Length
N = The t otal number of subject s enrolled.
The numbers are % (Count/Number of Eligible Subjects).
Subjects are only counted once for eac h 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 w indow (360 day s ± 30 days).
24-month timeframe includes follow-up w indow (720 day s ±30 day s).
36-month timeframe includes follow-up window (1080 days ± 30 day s).
60-month timeframe includes follow-up window (1800 days ± 30 day s).
1
Primary Enrollment Group consis ted of 1402 subjects , including 1242 subjects in the 2.25 mm - 3.5 m m
Main Study, 100 subjects in the 2.25 mm - 3. 5 mm Angio/I VUS Sub-study and 60 subjects in the 4. 0
mm Sub-study. The Primary Enrollment Group does not include t he 38 mm Length Sub-s tudy.
2
Target Lesion Failure (TLF) is defined as any Cardiac D eath, Clinic ally Driven T arget Les ion
Revascularization by PCI or CABG or T arget Vessel M I.
3
Target Vessel Failure (TVF) is defined as any Cardiac Deat h, Clinically Driven Target Vessel
Revascularization by PCI or CABG or T arget Vessel M I.
4
Major adverse cardiac events (MACE) is defined as com posite of deat h, MI (Q wave and non-Q w ave),
emergent bypass surgery , or clinically driven t arget lesion revas cularization (repeat PTC A or CABG).
5
TVMI is composed of both Q wave and non-Q wav e MI whic h are not clearly at tributable to a non-target
vessel.
Q wave MI defined when any occurrence of chest pain or ot her acut e sympt oms cons istent w ith
myocardial ischemia and new pathological Q waves in two or m ore cont iguous ECG leads as
determined by an ECG core laboratory or independent review of the CEC, in the absence of tim ely
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 clinic al 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 institut ion’s upper limit of normal) in the absenc e of new
pathological Q waves.
[Note: Periprocedural MIs (events <48 hours post-PCI) that did not fulfill the crit eria for Q-w ave MI are
included in Non-Q Wave MI category . Periprocedural MI s did not require clinic al sy mptoms 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 C ardiac D eath or M yocardial Inf arction not c learly attribut able to a
non-target vessel.
7
Target Vessel Revascularization (T VR) is defined as any c linically-driven repeat interv ention of the target
vessel by PCI or C ABG.
8
Target Lesion Revascularization (TLR ) is defined as a clinically -driven repeat intervention of the t arget
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)
20
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:
•
Anemi a
• Diarrh ea
• Dry Skin
• Headache
• Hematuria
• Infection
• Injection site reaction
• Pain (abdomin al, arth ralgia, in jectio n 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 p otential for these risks are currently unknown as the coating has limited
previous use in humans. These risks may include but are no t limited to the following:
• Allergic reaction
• Focal inflammation at the site of stent implantation
• Restenosi s of the sten ted ar tery
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
• All ergic reac tion (to contrast, an tiplatel et therapy, s tent material , or d rug and po lymer co atin g)
• Aneurysm, ps eudo aneurys m, or ar terio venous fi stula (AVF)
• Arrhythmias, including ventricular fibrillation
• Balloon rupture
• Bleed ing
• Cardiac tamponade
• Co ronary artery o ccl usion, p erfo ration, rupture, o r dis secti on
• Coronary artery spasm
• Death
• Emboli sm (air, ti ssue, dev ice, o r thro mbus)
• Emerg ency s urger y: peripheral vas cular or coronary bypass
• Fai lure to d eliver the sten t
• Hemorrhage requiring transfusion
• Hyp o ten sion / h y perten sion
• Incomplete stent apposition
• In fectio n or fever
• Myo card ial in farction (MI)
• Pericarditis
• Peri ph eral isc hemia / peripheral nerv e injury
• Renal Failure
• Restenosi s of the sten ted ar tery
21
• Shock / pulmonary edema
• Stable o r Unstabl e ang ina
• Stent deformation, collapse, or fracture
• Sten t migration or embo lizati on
• Stent misplacement
• Stroke / transi ent ischemic attack
• Th ro mbosi s (ac ute, subacute or late)
9 CLINICAL STUDIES
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 mm to 4.2 mm.
Design: This is a p rospective, multi-center, non-randomized controlled trial that evaluated the safety
and effectiveness 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 mm 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 mm and 4.2 mm, lesions with stenosis but <100%, lesion length mm for
the 38 mm Length Group), and TIMI flow 2.
The RESOLUTE US trial consists of the following:
• The 2.25 mm to 3.5 mm Main Study,
• The 2.25 mm co hort analysis,
• The 2.25 mm to 3.5 mm Angio/IVUS Sub-study,
• The 4.0 mm stent Sub-study.
• The 38 mm Leng th 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 high 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 lo ng 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.
22
Figure 9-1: Study Designation of RESOLUTE US Clinical Trial
23
(
2.5 mm – 3.5 mm Subset of the Main Study
Demographics and clinical characteristics: There were 1112 subjects (1001 single lesion subjects
and 111 dual vessel subjects). The mean age 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 p rior history of PCI,
and 7.6% (85/1112) had p revious 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 p rimary 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 Targ et 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
non-
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 Mo nths
• 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 s quares mean ± standard error.
The primary endpoint analysis for the 2.5 – 3.5 mm subs et of the M ain Study only includes subject s with a s ingle lesion.
12-month timeframe includes follow-up w indow (360 day s ± 30 days).
1
The CI and P-values are adjusted to propensity score, based on lesion length, bas eline RVD , age, sex, diabet es, hist ory of MI and worst
Canadian Cardiovascular Society Angina Class as t he independent variables.
2
One-sided p-value by non-inferiority test using asym ptotic t est st atistic wit h non-inferiority m argin of 3.3%, t o 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-inferiority
P-value
1,2
24
Table 9-2: RESOLUTE US 2.5-3.5 mm Subset of the Main Study - Principal Safety and
Effectiveness - Single Lesion Outcome versus Historical Control (Endeavor)
Single Lesion 2.5-3.5 mm
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)
Subset of Main study
(N=1001 subjects)
Single Lesion
Historical Control (Endeavor)
(N=1092 subjects)
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 eac h time period.
The definitions of the outcomes are presented as table not es to Table 8-1- Princ ipal Adverse Events.
12-month timeframe includes follow-up w indow (360 day s ± 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 T hrombosis.
25
Table 9-3: RESOLUTE US 2.5-3.5 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 Months
COMPOSITE SAFETY AND EFFECTIVENESS
TLF 3.8% (42/1105)
TVF 5.2% (58/1105)
MACE 4.6% (51/1105)
10.9% (115/1051)
16.1% (169/1051)
16.7% (175/1051)
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
Cardiac Death or TVMI 1.7% (19/1105)
TVMI
Q wave MI
Non-Q wave MI
Stent Thrombosis
ARC defined
Definite/Probable 0.0% (0/1105)
Definite 0.0% (0/1105)
Probable 0.0% (0/1105)
1.0% (11/1105) 8.8% (92/1051)
0.5% (5/1105) 3.4% (36/1051)
0.5% (6/1105) 5.3% (56/1051)
6.0% (63/1051)
1.3% (14/1105) 3.2% (34/1051)
0.2% (2/1105) 0.4% (4/1051)
1.1% (12/1105) 2.9% (30/1051)
0.5% (5/1051)
0.3% (3/1051)
0.2% (2/1051)
Notes
N = The t otal number of subject s enrolled.
Numbers are % (Count/Number of Eligible Subjects).
Subjects are only counted once for eac h time period.
The definitions of the outcomes are presented as table notes t o Table 8-1- Principal Adverse Events.
12-month timeframe includes follow-up w indow (360 day s ± 30 days).
60-month timeframe includes follow-up window (1800 days ± 30 day s).
See Table 9-4 for the definition of the ARC defined Stent Thrombos is.
26
(
p
Table 9-4: RESOLUTE US 2.5-3.5 mm Subset of the Main Study - ARC
Defined Definite/Probable Stent Thrombosis Through 60 Months
Stent Thrombosis
Acute (0 - 1 day)
Subacute (2 - 30 day s)
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 eac h time period.
Numbers are % (Count/Number of Eligible Subjects).
60-month timeframe includes follow-up window (1800 days ± 30 day s).
To be included in the calculation of stent t hrombosis (ST ) rate for a given int erval, a patient either had to have
a stent thrombosis during the interval (e. g. 31-360 day s inclusiv e) or had to be s tent throm bosis-free during t he
interval with last follow-up on or af ter the first day of the given interval (e. g. 31 day s).
Academic Research Consort ium (ARC) s tent throm bosis is def ined as f ollows.
1. Definite ST is c onsidered to have occurred after int racoronary st enting by either angiographic or
pathologic confirmation of st ent thrombos is.
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 relat ed to doc umented acute isc hemia in t he territory of the
im
lanted stent without angiographic confirmation of ST and in the abs ence of any other obvious 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)
27
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