← Product Code NIQ · P110019

# Xience Skypoint Everolimus Eluting Coronary Stent System (P110019)

_Abbott Vascular · NIQ · Nov 1, 2011 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P110019

## Device Facts

- **Applicant:** Abbott Vascular
- **Product Code:** NIQ
- **Decision Date:** Nov 1, 2011
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic

## Intended Use

The XIENCE PRIME stent system is indicated for improving coronary luminal diameter in patients with symptomatic heart disease due to de novo native coronary artery lesions (length ≤ 32 mm) with reference vessel diameters of ≥ 2.25 mm to ≤ 4.25 mm.

## Device Story

The XIENCE PRIME is a drug-eluting coronary stent system consisting of a cobalt-chromium (CoCr) alloy stent coated with everolimus embedded in a non-erodible polymer (PBMA and PVDF-HFP). It is delivered via a balloon-expandable rapid exchange (RX) catheter system. Used by interventional cardiologists in a cardiac catheterization lab, the device is deployed in native coronary arteries to improve luminal diameter. The stent provides mechanical scaffolding while the everolimus inhibits neointimal growth via mTOR pathway inhibition. The physician uses fluoroscopic guidance to position the stent; balloon inflation expands the stent against the lesion. The device benefits patients by reducing restenosis compared to bare metal stents. The system is compatible with 5F guiding catheters and is MR conditional.

## Clinical Evidence

Prospective, non-randomized, open-label, multicenter SPIRIT PRIME trial (N=505). Primary endpoint: Target Lesion Failure (TLF) at 1 year. Core Size Registry (N=401) TLF rate was 6.5% (ARC-defined) vs 9.2% PG (p=0.0338). Long Lesion Registry (N=104) TLF rate was 12.5% (ARC-defined) vs 19.2% PG (p=0.0484). Both registries met primary endpoints. Safety data included stent thrombosis rates (0.5% Core Size, 0.0% Long Lesion at 1 year).

## Technological Characteristics

Stent: L-605 Cobalt Chromium alloy. Coating: Everolimus (100 μg/cm²) in non-erodible PBMA/PVDF-HFP polymer. Delivery system: Rapid Exchange (RX) balloon-expandable catheter, 143 cm working length, 5F guiding catheter compatibility. Sterilization: Ethylene Oxide (EO). MR Conditional (1.5T/3T).

## Regulatory Identification

Stent, coronary, drug-eluting -- a metal scaffold with a drug coating placed via a delivery catheter into the coronary artery or saphenous vein graft to maintain the lumen.  The drug coating is intended to inhibit restenosis.

## Predicate Devices

- XIENCE V Everolimus Eluting Coronary Stent System ([P070015](/device/P070015.md))
- Multi-Link Vision Coronary Stent System ([P020047](/device/P020047.md))
- Voyager NC Coronary Dilatation Catheter ([P810046](/device/P810046.md)/S226)

## Reference Devices

- Multi-Link 8 ([P020047](/device/P020047.md)/S017)
- Multi-Link Mini Vision ([P020047](/device/P020047.md)/S003)
- Multi-Link Tetra

## Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA
(SSED)

I. GENERAL INFORMATION

Device Generic Name: Drug Eluting Coronary Stent System (NIQ)
Device Trade Name: XIENCE PRIME™ Everolimus Eluting Coronary Stent System
XIENCE PRIME™ LL Everolimus Eluting Coronary Stent System
Applicant's Name and Address: Abbott Vascular
3200 Lakeside Drive
Santa Clara, CA 95054
Date of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P110019
Date of FDA Notice of Approval: November 1, 2011
Expedited: Not Applicable

II. INDICATIONS FOR USE

The XIENCE PRIME stent system is indicated for improving coronary luminal diameter in patients with symptomatic heart disease due to de novo native coronary artery lesions (length ≤ 32 mm) with reference vessel diameters of ≥ 2.25 mm to ≤ 4.25 mm.

III. CONTRAINDICATIONS

The XIENCE PRIME stent system is contraindicated for use in patients:

- Who cannot receive anti-platelet and/or anti-coagulant therapy
- With lesions that prevent complete angioplasty balloon inflation or proper placement of the stent or stent delivery system
- With hypersensitivity or contraindication to everolimus or structurally-related compounds, cobalt, chromium, nickel, tungsten, acrylic, and fluoropolymers

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the XIENCE PRIME and XIENCE PRIME LL Everolimus Eluting Coronary Stent System labeling.

# V. DEVICE DESCRIPTION

The XIENCE PRIME family of stent systems includes:

- The XIENCE PRIME Everolimus Eluting Coronary Stent System (stent diameters 2.25, 2.5, 2.75, 3.0, 3.5, 4.0 mm, stent lengths 8, 12, 15, 18, 23 mm)
- XIENCE PRIME LL Everolimus Eluting Coronary Stent System (stent diameters 2.25¹, 2.5, 2.75, 3.0, 3.5, 4.0 mm, stent lengths 28, 33, 38 mm) Everolimus Eluting Coronary Stent Systems

Hereafter the XIENCE PRIME family of stent systems is referred to as the XIENCE PRIME stent or XIENCE PRIME stent system. The XIENCE PRIME stent systems are device/drug combination products consisting of a drug-coated stent and a balloon expandable delivery system. The stent is coated with a formulation containing everolimus, the active ingredient, embedded in a non-erodible polymer, which is identical to the XIENCE V® Everolimus Eluting Coronary Stent System (XIENCE V EECSS) approved in P070015.

The device component consists of medical grade L-605 cobalt chromium (CoCr) drug-coated stent mounted onto the XIENCE PRIME stent delivery system. The device component characteristics are summarized in Table 1.

¹ The 2.25 mm stent diameter for XIENCE PRIME LL is only available in the 28 mm stent length.

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Table 1 XIENCE PRIME and XIENCE PRIME LL Product Description

|   | XIENCE PRIME EECSS |   |   | XIENCE PRIME LL EECSS  |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|  Available Stent Lengths (mm) | 8, 12, 15, 18, 23 |   |   | 28, 33, 38  |   |   |
|  Available Stent Diameters (mm) | 2.25, 2.5, 2.75, 3.0, 3.5, 4.0 |   |   | 2.25*, 2.75, 3.0, 3.5, 4.0  |   |   |
|  Stent Material | A medical grade L-605 Cobalt Chromium (CoCr) alloy  |   |   |   |   |   |
|  Drug Component |  | Stent Design | Diameters (mm) | Stent Length (mm) | Surface Area (cm²) | Target Drug Amount (μg)  |
|   |   |  Small | 2.25, 2.5, 2.75, 3.0 | 8 | 0.3972 | 40  |
|   |   |  Small | 2.25, 2.5, 2.75, 3.0 | 12 | 0.6048 | 60  |
|   |   |  Small | 2.25, 2.5, 2.75, 3.0 | 15 | 0.7431 | 74  |
|   |   |  Small | 2.25, 2.5, 2.75, 3.0 | 18 | 0.8815 | 88  |
|   |   |  Small | 2.25, 2.5, 2.75, 3.0 | 23 | 1.0891 | 109  |
|   |   |  Small | 2.25, 2.5, 2.75, 3.0 | 28 | 1.3658 | 137  |
|   |   |  Small | 2.5, 2.75, 3.0 | 33 | 1.5734 | 157  |
|   |   |  Small | 2.5, 2.75, 3.0 | 38 | 1.8501 | 185  |
|   |   |  Medium | 3.5, 4.0 | 8 | 0.4979 | 50  |
|   |   |  Medium | 3.5, 4.0 | 12 | 0.7466 | 75  |
|   |   |  Medium | 3.5, 4.0 | 15 | 0.9124 | 91  |
|   |   |  Medium | 3.5, 4.0 | 18 | 1.1612 | 116  |
|   |   |  Medium | 3.5, 4.0 | 23 | 1.4099 | 141  |
|   |   |  Medium | 3.5, 4.0 | 28 | 1.7415 | 174  |
|   |   |  Medium | 3.5, 4.0 | 33 | 1.9903 | 199  |
|   |   |  Medium | 3.5, 4.0 | 38 | 2.3219 | 232  |
|  Delivery System Working Length | 143 cm  |   |   |   |   |   |
|  Delivery System Design | Single access port to inflation lumen; guide wire exit notch is located 25.5 cm from tip; designed for guide wires ≤ 0.014".  |   |   |   |   |   |
|  Stent Delivery System Balloon | A compliant, tapered balloon, with two radiopaque markers located on the catheter shaft to indicate balloon positioning and expanded stent length  |   |   |   |   |   |
|  Balloon Inflation Pressure |  | Rated Burst Pressure (RBP): 18 atm (1824 kPa)  |   |   |   |   |
|   |   |  Stent Diameter (mm) |   | In Vitro Stent Nominal Pressure (atm)  |   |   |
|   |   |  2.25 |   | 8  |   |   |
|   |   |  2.5 |   | 8  |   |   |
|   |   |  2.75 |   | 8  |   |   |
|   |   |  3.0 |   | 10  |   |   |
|   |   |  3.5 |   | 10  |   |   |
|   |   |  4.0 |   | 10  |   |   |
|  Guiding Catheter Inner Diameter | ≥ 5F (0.056")  |   |   |   |   |   |
|  Catheter Shaft Outer Diameter | Distal: 0.034" (0.86 mm)
Proximal: 0.031" (0.79 mm)  |   |   |   |   |   |

* The 2.25 mm diameter stent for XIENCE PRIME LL is only available in the 28 mm stent length.

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# A. Device Component Description

The XIENCE PRIME stent system consists of the coated Cobalt Chromium (CoCr) alloy stent mounted on a delivery system. The XIENCE PRIME stent uses the identical stent and balloon materials, and the identical drug coating formulation and drug dose density (100ug/cm²) as the XIENCE V Everolimus Eluting Coronary Stent System (P070015 and supplements). The XIENCE PRIME stent design is similar to that of the XIENCE V stent with regard to the Multi-Link Vision Coronary Stent System (P020047 and supplements) stent design in strut thickness and similar metal to artery ratios that, when expanded, allows for similar drug dosing to the vessel. The XIENCE PRIME stent design has been slightly modified from that of the XIENCE V stent design in order to accommodate design improvements while not affecting the overall structural integrity of the design. These modifications include longer cell length and a modified proximal end ring.

The XIENCE PRIME stent delivery system utilizes the same principle of operations as other Abbott Vascular Rapid Exchange (RX) stent systems and dilatation catheters. The XIENCE PRIME stent delivery system materials are similar to those used in the XIENCE V EECSS and the Voyager NC Coronary Dilatation Catheter (DCD) (P810046/S226).

# B. Drug Component Description

Identical to the XIENCE V stent, the XIENCE PRIME and XIENCE PRIME LL Everolimus Eluting Coronary Stents (XIENCE PRIME stent) are coated with everolimus (active ingredient), embedded in a non-erodible polymer (inactive ingredient).

# B1. Everolimus

Everolimus is the active pharmaceutical ingredient in the XIENCE PRIME stent. It is a novel semi-synthetic macrolide immunosuppressant, synthesized by chemical modification of rapamycin (INN: sirolimus). The everolimus chemical name is 40-O-(2-hydroxyethyl)-rapamycin and the chemical structure is shown in Figure 1 below.

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![img-0.jpeg](img-0.jpeg)
Figure 1 Chemical Structure of Everolimus

## B2. Inactive Ingredients

The XIENCE PRIME stent contains inactive ingredients, including poly n-butyl methacrylate (PBMA), a polymer that adheres to the stent and drug coating, and PVDF-HFP, which is comprised of vinylidene fluoride and hexafluoropropylene monomers as the drug matrix layer containing everolimus. PBMA is a homopolymer with a molecular weight (Mw) of 264,000 to 376,000 dalton. PVDF-HFP is a non-erodible semi-crystalline random copolymer with a molecular weight (Mw) of 254,000 to 293,000 dalton. The drug matrix copolymer is mixed with everolimus (83%/17% w/w polymer/everolimus ratio) and applied to the entire PBMA-coated stent surface. The drug load is $100\ \mu\mathrm{g}/\mathrm{cm}^2$. No topcoat layer is used. The polymer chemical structures are shown in Figure 2a and 2b below.

![img-1.jpeg](img-1.jpeg)
Figure 2a Chemical Structure of Poly (n-butyl methacrylate) (PBMA)

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![img-2.jpeg](img-2.jpeg)

Figure 2b Formula for Vinylidene Fluoride and Hexafluoropropylene Copolymer (PVDF-HFP)

The product matrix, including nominal dosages of everolimus in each XIENCE PRIME stent is described in Table 2. The nominal everolimus content is based on stent design and length.

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Table 2
XIENCE PRIME and XIENCE PRIME LL EECSS Product Matrix and Everolimus Content

|  XIENCE PRIME™
US and Japan Commercial Part # | Nominal Expanded Stent Diameter (mm) | Nominal Unexpanded Stent Length (mm) | Nominal Everolimus Content (μg)  |
| --- | --- | --- | --- |
|  1011730-08 | 2.25 | 8 | 40  |
|  1011730-12 | 2.25 | 12 | 60  |
|  1011730-15 | 2.25 | 15 | 74  |
|  1011730-18 | 2.25 | 18 | 88  |
|  1011730-23 | 2.25 | 23 | 109  |
|  1011730-28 | 2.25 | 28 | 137  |
|  1011731-08 | 2.5 | 8 | 40  |
|  1011731-12 | 2.5 | 12 | 60  |
|  1011731-15 | 2.5 | 15 | 74  |
|  1011731-18 | 2.5 | 18 | 88  |
|  1011731-23 | 2.5 | 23 | 109  |
|  1011731-28 | 2.5 | 28 | 137  |
|  1011731-33 | 2.5 | 33 | 157  |
|  1011731-38 | 2.5 | 38 | 185  |
|  1011732-08 | 2.75 | 8 | 40  |
|  1011732-12 | 2.75 | 12 | 60  |
|  1011732-15 | 2.75 | 15 | 74  |
|  1011732-18 | 2.75 | 18 | 88  |
|  1011732-23 | 2.75 | 23 | 109  |
|  1011732-28 | 2.75 | 28 | 137  |
|  1011732-33 | 2.75 | 33 | 157  |
|  1011732-38 | 2.75 | 38 | 185  |
|  1011733-08 | 3.0 | 8 | 40  |
|  1011733-12 | 3.0 | 12 | 60  |
|  1011733-15 | 3.0 | 15 | 74  |
|  1011733-18 | 3.0 | 18 | 88  |
|  1011733-23 | 3.0 | 23 | 109  |
|  1011733-28 | 3.0 | 28 | 137  |
|  1011733-33 | 3.0 | 33 | 157  |
|  1011733-38 | 3.0 | 38 | 185  |

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Table 2
XIENCE PRIME and XIENCE PRIME LL EECSS Product Matrix and Everolimus Content (cont'd)

|  XIENCE PRIME™
US and Japan Commercial Part # | Nominal Expanded Stent Diameter (mm) | Nominal Unexpanded Stent Length (mm) | Nominal Everolimus Content (μg)  |
| --- | --- | --- | --- |
|  1011734-08 | 3.5 | 8 | 50  |
|  1011734-12 | 3.5 | 12 | 75  |
|  1011734-15 | 3.5 | 15 | 91  |
|  1011734-18 | 3.5 | 18 | 116  |
|  1011734-23 | 3.5 | 23 | 141  |
|  1011734-28 | 3.5 | 28 | 174  |
|  1011734-33 | 3.5 | 33 | 199  |
|  1011734-38 | 3.5 | 38 | 232  |
|  1011735-08 | 4.0 | 8 | 50  |
|  1011735-12 | 4.0 | 12 | 75  |
|  1011735-15 | 4.0 | 15 | 91  |
|  1011735-18 | 4.0 | 18 | 116  |
|  1011735-23 | 4.0 | 23 | 141  |
|  1011735-28 | 4.0 | 28 | 174  |
|  1011735-33 | 4.0 | 33 | 199  |
|  1011735-38 | 4.0 | 38 | 232  |

## C. Mechanism of Action

The mechanism by which the XIENCE PRIME stent inhibits neointimal growth as seen in preclinical and clinical studies has not been established. At the cellular level, everolimus inhibits growth factor-stimulated cell proliferation. At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12 (FK 506 Binding Protein). This complex binds to and interferes with FRAP (FKBP-12 Rapamycin Associated Protein), also known as mTOR (mammalian Target Of Rapamycin), leading to inhibition of cell metabolism, growth and proliferation by arresting the cell cycle at the late G1 stage.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the treatment of patients with coronary artery disease including exercise, diet, drug therapy, percutaneous coronary interventions (i.e., balloon angioplasty, atherectomy, bare metal stents, coated stents, and other drug-eluting stents), and coronary artery bypass grafting (CABG) surgery. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

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# VII. MARKETING HISTORY

The XIENCE PRIME and XIENCE PRIME LL Everolimus Eluting Coronary Stent System is commercially available in the following countries:

|  Afghanistan | France | Luxembourg | Serbia  |
| --- | --- | --- | --- |
|  Albania | French Polynesia | Macedonia | Singapore  |
|  Algeria | French Guyana | Malaysia | Slovakia  |
|  Aruba | Georgia | Malta | Slovenia  |
|  Australia | Germany | Martinique | South Korea  |
|  Austria | Greece | Mauritius | Spain  |
|  Bahamas | Guadeloupe | Morocco | Sri Lanka  |
|  Bahrain | Guatemala | Myanmar | Suriname  |
|  Bangladesh | Guyana | Netherlands | Sweden  |
|  Barbados | Honduras | New Caledonia | Switzerland  |
|  Belgium | Hong Kong | New Zealand | Syria  |
|  Belize | Hungary | Nicaragua | Thailand  |
|  Bermuda | Iceland | Niederl. Antill. | Trinidad and Tobago  |
|  Bolivia | India | Nigeria | Tunisia  |
|  Brazil | Indonesia | Norway | Turkey  |
|  British Virgin Islands | Iran | Oman | Uganda  |
|  Brunei | Iraq | Pakistan | Ukraine  |
|  Bulgaria | Ireland | Panama | United Arab Emirates.  |
|  Cambodia | Israel | Paraguay | United Kingdom  |
|  Cayman Islands | Italy | Philippines | Uruguay  |
|  Chile | Jamaica | Poland | Vietnam  |
|  Colombia | Jordan | Portugal | Zimbabwe  |
|  Cyprus | Kenya | Qatar |   |
|  Czech Republic | Kosovo | Rep. of Armenia |   |
|  Denmark | Kuwait | Rep. of Yemen |   |
|  Dominican Republic | Latvia | Réunion |   |
|  Egypt | Lebanon | Romania |   |
|  El Salvador | Libya | Russian Federation |   |
|  Estonia | Liechtenstein | San Marino |   |
|  Finland | Lithuania | Saudi Arabia |   |

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The XIENCE PRIME and XIENCE PRIME LL EECSS have not been withdrawn from marketing in any country for any reason.

As of September 30, 2011, 472,860 XIENCE PRIME™ and XIENCE PRIME™ LL Everolimus Eluting Coronary Stent Systems have been distributed outside of the United States.

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the XIENCE PRIME and XIENCE PRIME LL Everolimus Eluting Coronary Stent System.

Adverse events (in alphabetical order) which may be associated with percutaneous coronary and treatment procedures, where coronary stents are used in native coronary arteries include, but are not limited to:

- Abrupt closure
- Access site pain, hematoma, or hemorrhage
- Acute myocardial infarction
- Allergic reaction or hypersensitivity to contrast agent or cobalt, chromium, nickel, tungsten, acrylic, and fluoropolymers; and drug reactions to antiplatelet drugs or contrast agent
- Aneurysm
- Arterial perforation and injury to the coronary artery
- Arterial rupture
- Arteriovenous fistula
- Arrhythmias, atrial and ventricular
- Bleeding complications, which may require transfusion
- Cardiac tamponade
- Coronary artery spasm
- Coronary or stent embolism
- Coronary or stent thrombosis
- Death
- Dissection of the coronary artery
- Distal emboli (air, tissue or thrombotic)
- Emergent or non-emergent coronary artery bypass graft surgery
- Fever
- Hypotension and/or hypertension
- Infection and pain at insertion site
- Injury to the coronary artery
- Ischemia (myocardial)
- Myocardial infarction (MI)
- Nausea and vomiting
- Palpitations

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- Peripheral ischemia (due to vascular injury)
- Pseudoaneurysm
- Renal failure
- Restenosis of the stented segment of the artery
- Shock/pulmonary edema
- Stroke/cerebrovascular accident (CVA)
- Total occlusion of coronary artery
- Unstable or stable angina pectoris
- Vascular complications, including at the entry site, which may require vessel repair
- Vessel dissection

Everolimus is approved in the United States under the name of Zortress by Novartis Pharmaceuticals for the prophylaxis of organ rejection in adult kidney transplant recipients at low-moderate immunologic risk, at the dose of 1.5 mg/day when taken by mouth. Outside the United States, Zortress is sold under the brand name Certican in more than 70 countries. Everolimus is also approved in the United States under the name of Afinitor for the treatment of patients with advanced renal cell carcinoma (cancer) after failure of treatment with sunitinib or sorafenib, at doses of 5 to 20 mg/day when taken by mouth. The amount of drug that circulates in the bloodstream following implantation of a XIENCE PRIME stent is several folds lower than that obtained with oral doses (1.5 mg to 20 mg/day).

The following list includes the known risks of everolimus at the oral doses listed above:

- Abdominal pain
- Acne
- Anemia
- Anorexia
- Asthenia
- Coagulopathy
- Cough
- Diarrhea
- Dyspnea
- Dysgeusia
- Dry skin
- Edema peripheral
- Epistaxis
- Fatigue
- Headache
- Hemolysis
- Hypercholesterolemia
- Hyperglycemia
- Hyperlipidemia
- Hypertension
- Hypertriglyceridemia
- Hypogonadism male

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- Infections: wound infection, urinary tract infection, pneumonia, pyelonephritis, sepsis and other viral, bacterial, and fungal infections
- Increased serum creatinine
- Leukopenia or lymphopenia
- Pruritus
- Pyrexia
- Liver function test abnormality
- Lung and breathing problems
- Lymphocele
- Mucosal inflammation
- Myalgia
- Nausea
- Non-infectious pneumonitis
- Pain in extremity
- Rash
- Renal tubular necrosis
- Stomatitis
- Surgical wound complication
- Thrombocytopenia
- Venous thromboembolism
- Vomiting

There may be other potential adverse events that are unforeseen at this time.

For the specific adverse events that occurred in the clinical studies, please see Section X below.

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# IX. SUMMARY OF PRECLINICAL STUDIES

A series of non-clinical laboratory studies related to the XIENCE PRIME and XIENCE PRIME LL product were performed. Studies included those performed on the bare metal stent system (Multi-Link family — ML8, VISION and MINI VISION), the combination product XIENCE V or the finished combination product (XIENCE PRIME and XIENCE PRIME LL Stent Systems). Leveraging data from testing performed on the Multi-Link family is appropriate because the stent materials and manufacturing process are identical to the XIENCE PRIME for testing where it is appropriate to test bare metal stents.

## A. Laboratory Studies

### A1. Biocompatibility Studies

A series of GLP biocompatibility tests were conducted to demonstrate the components of the XIENCE PRIME and XIENCE PRIME LL Everolimus Eluting Coronary Stent System are non-toxic.

All biocompatibility testing was conducted in accordance with one or more of the following general regulations and guidance documents:

- Guidance for Industry and FDA Staff - Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems (April 18, 2010)
- Good Laboratory Practices Regulations (21 CFR § 58)
- ISO 10993, Biological Evaluation of Medical Devices
- USP <85> Bacterial Endotoxin Test
- USP <87/88> Biological Reactivity Tests
- USP <161> Transfusion and Infusion Assemblies and Similar Medical Devices

Table 3 describes the biocompatibility testing.

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Table 3 Biocompatibility Test Summary

|  Test Name | Description of Test | Test Article and Results  |
| --- | --- | --- |
|  Cytotoxicity | ISO 10993-5 USP: Cytotoxicity ISO Elution Test (MEM Extract) | • Composite sample of XIENCE PRIME stent and delivery system: Pass (non-cytotoxic)
• XIENCE V stent: Pass (non-cytotoxic below toxicity threshold of everolimus)
• Polymer-only coated stent: Pass (non-cytotoxic)  |
|  Sensitization | ISO 10993-10: Maximization Test for Delayed Hypersensitivity (ISO) | • Composite sample of XIENCE PRIME stent and delivery system: Pass (non-sensitizing)
• XIENCE V stent: Pass (non-sensitizing below toxicity threshold of everolimus)
• Polymer-only coated stent: Pass (non-sensitizing)  |
|  Intracutaneous Reactivity | ISO 10993-10 USP: Intracutaneous (Intradermal) Reactivity Test (ISO) | • Composite sample of XIENCE PRIME stent and delivery system: Pass (non-irritating)
• XIENCE V stent: Pass (non-irritating below toxicity threshold of everolimus)
• Polymer-only coated stent: Pass (non-irritating)  |
|  Systemic Toxicity | ISO 10993-11 USP: ISO Acute Systemic Toxicity | • Composite sample of XIENCE PRIME stent and delivery system: Pass (non-toxic)  |
|   |  USP <88>: Systemic Injection Test (Mouse Injection) | • Polymer-only coated stent: Pass (non-toxic)  |
|  Hemocompatibility/Hemolysis* | ISO 10993-4: Hemolysis Test – Extraction Method | Composite sample of XIENCE PRIME stent and delivery system: Pass (non-hemolytic)  |
|   |  ISO 10993-4: Hemolysis, Direct Contact (Rabbit Red Blood Cells) | • XIENCE V stent: Pass (non-hemolytic)  |
|   |  ISO 10993-4: Hemolysis, Indirect Contact (Rabbit Red Blood Cells) | • XIENCE V stent: Pass (non-hemolytic)  |
|  Complement Activation | ISO 10993-4: Complement Activation Test (C3a and SC5b-9) | XIENCE PRIME stent: Pass
XIENCE PRIME delivery system: Pass  |
|  Pyrogenicity | ISO 10993-11 USP: LAL Bacterial Endotoxins Test for Medical Devices – Chromogenic Method | Composite sample of XIENCE PRIME stent and delivery system: Pass (non-pyrogenic)  |
|   |  ISO 10993-11: Systemic Toxicity (Material Mediated Rabbit) | Composite sample of XIENCE PRIME stent and delivery system: Pass (non-pyrogenic)  |
|  Implantation | ISO 10993-6: 90-day (Rabbit, Intramuscular) | • 2.6X XIENCE V stent: Pass  |
|   | Sub-chronic Toxicity (fulfilled through 90-day implant) |   |
|   | USP <88> 7-day (Rabbit, Intramuscular) | • Polymer-only coated stent: Pass  |
|  Genotoxicity | ISO 10993-3: Bacterial | (2.6X XIENCE V stent: Pass (non-  |

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|   | Reverse Mutation Assay (Ames test) | mutagenic)  |
| --- | --- | --- |
|   | ISO 10993-3: In Vitro Chromosomal Aberration (Chinese Hamster Ovary cells) | • 2.6X XIENCE V stent: Pass (non-mutagenic)  |
|   | ISO 10993-3: Clastogenicity in Mammalian Cells (CHO/HGPRT forward mutation) | (2.6X XIENCE V stent: Pass (non-mutagenic)  |
|  ? | ISO 10993-3: Mammalian Erythrocyte Micronucleus Test | • 2.6X XIENCE V stent: Pass (non-mutagenic)  |
|  Reproductive Toxicity (Teratology) | ISO 10993-3: Reproductive and Developmental Toxicity | • XIENCE V stent: Pass (non-teratogenic)  |
|  Carcinogenicity | ISO 10993-3: Carcinogenicity | (XIENCE V stent: Pass (non-carcinogenic)  |

## A2. In Vitro Engineering Testing

In vitro engineering testing, in accordance with FDA “Guidance for and FDA Staff- Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems,” April 2010, was conducted on the XIENCE PRIME Stent except where the testing could be leveraged from the MULTI-LINK VISION, MULTI-LINK MINI VISION, or MULTI-LINK 8 stents, approved in P020047, P020047/S003, and P020047/017 respectively, or the XIENCE V stent, approved in P070017. Supplementary in vitro engineering tests were also performed on the XIENCE PRIME delivery systems containing the XIENCE PRIME stent mounted on a delivery catheter. This testing is summarized in Table 4. "Pass" denotes that the test results met product specifications and/or the recommendations in the above-referenced guidance document.

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Table 4 In Vitro Engineering Studies

|  Test | Test Description | Results  |
| --- | --- | --- |
|  Material Characterization Testing  |   |   |
|  Material Analysis | Evaluations were conducted on the stent tubing provided by the material supplier prior to any processing to confirm chemical analysis, grain size, and inclusion content per relevant ASTM standards (F90, A751, E1086, F1479, E1019, E112, F138, F2527, E45). In addition, SEM analysis was conducted on bare metal stents to identify and analyze trace contaminants which may be present on the stent. | PASS  |
|  Material Properties: Tensile Strength and Elongation | Tensile strength and elongation testing was performed on the stent tubing prior to any processing. The tensile strength and elongation met acceptance criteria. | PASS  |
|  Corrosion Testing | Initial pitting corrosion testing conducted on the MULTI-LINK VISION stents (P020047) is leveraged to support the approval of the XIENCE PRIME Stent System. In addition, corrosion testing was conducted on MULTI-LINK 8 stents (P020047/S017) following 400 million cycles (ten year equivalent) of radial fatigue in an overlapped 15 mm static bend. The corrosion testing was conducted according to ASTM F2129 “Standard Test Method for Conducting Cyclic Potentiodynamic Measurements to Determine the Corrosion Susceptibility of Small Implant Devices” to demonstrate that the finished stents exhibit acceptable corrosion resistance. All MULTI-LINK VISION and MULTI-LINK 8 stents tested exceeded the minimum acceptance criteria for rest potential and breakdown potential and therefore exhibited acceptable pitting corrosion resistance.
Both bare metal and polymer-only coated XIENCE V stents were tested according to ASTM F2129 to demonstrate that the finished stents exhibit acceptable corrosion resistance.
Since the XIENCE PRIME stent is similar in design to the MULTI-LINK VISION and XIENCE V stents, identical to the MULTI-LINK 8 stent, and has the identical material and manufacturing processes as all three stents, the corrosion test results can be leveraged in support of the XIENCE PRIME Stent System. | PASS  |
|  Fretting Corrosion | XIENCE PRIME stents were evaluated following 400 million cycles (10 year equivalent) of radial fatigue testing in an overlapped 15mm static bend to determine the potential for fretting corrosion. The results met all acceptance criteria and indicated that the stents possess a high resistance to fretting corrosion. | PASS  |
|  Galvanic Corrosion | Testing was conducted on marketed stainless steel (MULTI-LINK TETRA) and CoCr (MULTI-LINK VISION) overlapped in a passive manner, and overlapped in an active manner (with disruption of the oxide layer) to determine the potential for galvanic corrosion. The results met the acceptance criteria and indicated a high resistance to galvanic corrosion. | PASS  |
|  Stent Dimensional and Functional Attributes  |   |   |
|  Stent Dimensional Inspection | Measurements were taken of the bare metal stent strut width, thickness, and length. All stents met product specifications. | PASS  |
|  Stent Percent Surface Area | Determines the metal-to-artery ratio of the nominal XIENCE PRIME stent using a theoretical calculation that divides the total vessel contact metal surface area of the stent by the theoretical surface area of the vessel at the desired diameter. Metal to artery percentage ratios were calculated for each stent diameter, with the highest surface to artery ratio (17%) occurring at the smallest stent diameter (2.25 mm). | PASS  |

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Table 4 In Vitro Engineering Studies

|  Test | Test Description | Results  |
| --- | --- | --- |
|  Stent Uniformity of Expansion Test | Determines the uniformity of expansion along the stent length. XIENCE PRIME units were inflated to either nominal or post-dilated inner diameters, deflated, and diameter measurements were taken at various points along the stent length. Measurements were averaged and all XIENCE PRIME stents met product specifications. | PASS  |
|  Stent Percent Length Change (Foreshortening) Test | Determines the difference in stent length pre-and post-expansion to either nominal or post-dilated inner diameters. All stents met product specifications. | PASS  |
|  Stent Percent Recoil Test | Quantifies the amount of recoil of the stent after balloon expansion. The system was inflated to either nominal or post-dilated diameters and measurements were taken of the stent diameter at various locations along the stent length. The system was then deflated and the same measurements taken. The percent recoil is calculated by subtracting the average stent inner diameter (ID) without the balloon from the average stent ID with the balloon, dividing by the average stent ID with the balloon and multiplying by 100. All XIENCE PRIME stents met product specifications. | PASS  |
|  Radial Stiffness | Radial stiffness was evaluated on the XIENCE PRIME stent for information only. | For characterization only  |
|  Stent Radial (Hoop) Strength Test | Testing was conducted to determine the radial strength of the stent under compression force. Stents were expanded to either nominal or post-dilated diameters, placed in an Instron tester, and subjected to incrementally increasing compression forces. The pressure at which deformation is no longer completely reversible was recorded. All XIENCE PRIME stents met product specifications. | PASS  |
|  Finite Element Analysis (FEA) | An in-depth analysis of the stent was conducted to ensure that the implant conditions to which the stent will be subjected would not result in failure due to fatigue. The FEA evaluated the structural integrity of the stent when subjected to the expected loading conditions generated in coronary arteries. The analysis took into account manufacturing, delivery, implantation and clinical loading over the implant life, and predicted that fatigue failures of the XIENCE PRIME stent will not likely occur. | PASS  |
|  Accelerated Structural Fatigue | Testing was conducted to demonstrate structural durability of the XIENCE PRIME stent under expected in vivo cyclic loading conditions for an equivalent of 10 years (~400 million cycles) in an overlapped configuration on a static bend with a radius of 15 mm.
The stents were expanded to the largest intended diameter, and were dynamically cycled in a simulated vessel for 400 million cycles. Following cycling, stents were visually inspected under 40X magnification. No signs of strut cracking or breaking were detected. | PASS  |

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Table 4 In Vitro Engineering Studies

|  Test | Test Description | Results  |
| --- | --- | --- |
|  Magnetic Resonance Imaging (MRI) | Nonclinical testing has demonstrated that the XIENCE PRIME stent, in single and in overlapped configurations up to 71 mm in length, is MR Conditional. It can be scanned safely under the following conditions:

• Static magnetic field of 1.5 or 3 Tesla
• Spatial gradient field of 2500 Gauss/cm or less
• Maximum whole-body-averaged specific absorption rate (SAR) of 2.0 W/kg (normal operating mode) for up to 15 minutes of scanning for each sequence

The XIENCE PRIME stent should not migrate in this MRI environment. Nonclinical testing at field strengths greater than 3 Tesla has not been performed to evaluate stent migration or heating. MRI at 1.5 or 3 Tesla may be performed immediately following the implantation of the XIENCE PRIME stent.

Stent heating was derived by using the measured nonclinical, in vitro temperature rises in a GE Excite 3 Tesla scanner and in a GE 1.5 Tesla coil in combination with the local specific absorption rates (SARs) in a digitized human heart model. The maximum whole body averaged SAR was determined by validated calculation. At overlapped lengths of up to 71 mm, the XIENCE PRIME stent produced a nonclinical maximum local temperature rise of 3.3°C at a maximum whole body averaged SAR of 2.0 W/kg (normal operating mode) for 15 minutes. These calculations do not take into consideration the cooling effects of blood flow.

The effects of MRI on overlapped stents greater than 71 mm in length or stents with fractured struts are unknown.

As demonstrated in nonclinical testing, an image artifact can be present when scanning the XIENCE PRIME stent. MR image quality may be compromised if the area of interest is in the exact same area, or relatively close to, the position of the XIENCE PRIME stent. Therefore, it may be necessary to optimize the MR imaging parameters for the presence of XIENCE PRIME stent.

It is suggested that patients register the conditions under which the implant can safely be scanned with the MedicAlert Foundation (www.medicalert.org) or an equivalent organization | PASS  |

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Table 4 In Vitro Engineering Studies

|  Test | Test Description | Results  |
| --- | --- | --- |
|  Radiopacity | Confirms that the XIENCE PRIME stent is adequately visible under fluoroscopic imaging equipment. Testing indicated that visibility of the XIENCE PRIME stent is comparable to that of the MULTI-LINK VISION and MULTILINK MINI VISION under fluoroscopy. | PASS  |
|  Delivery System Dimensional and Functional Attributes  |   |   |
|  Catheter Dimensional Measurements | The following characteristics were tested to conform to the applicable specifications: Tip Length, Tip Seal Length, Tip Unsealed Length, Proximal Unsealed Balloon Shaft, Total Catheter Length & Distal Catheter Length, Guide Wire Lumen Dimensions (Tip Inner Diameter (ID) & Distal Shaft Junction Notch ID), Stent Placement, Balloon Shoulder to Marker Alignment, Balloon Working Length, Proximal Shaft Marker Locations (Femoral Marker & Brachial Marker), Delivery System Outer Diameters (Distal Shaft OD, Mid Shaft OD, Proximal Shaft OD, Tip Entry OD, Guide Wire Notch OD). All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Delivery, Deployment, and Retraction | Design validations demonstrate that the XIENCE PRIME Stent System meets the user needs. | PASS  |
|  Balloon Rated Burst Pressure | Statistically demonstrates with 95% confidence, at least 99.9% of the XIENCE PRIME Stent Systems will not rupture below the rated burst pressure (RBP) and to demonstrate that at a 95% confidence level, at least 99% of the XIENCE PRIME Stent Systems will not rupture below the maximum labeled compliance (MLC) pressure. All XIENCE PRIME Stent Systems met product specifications and confidence/reliability limits. | PASS  |
|  Unconstrained Balloon Fatigue | Statistically demonstrates with 95% confidence, at least 90% of the XIENCE PRIME Stent Systems will sustain 10 repeated inflations to the rated burst pressure inside the stent. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Stent Diameter vs. Balloon Pressure (Compliance) | Determines how the diameter of a deployed balloon varies with applied balloon pressures. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Soft Tip Tensile | Determines the tensile strength of the soft tip. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Distal Delivery System Tensile | Determines the tensile strength of the distal portion of the delivery system. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Proximal Adaptation Tensile Strength | Determines the tensile strength of the proximal adaptation of the delivery system. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Delivery System Crossing Profile – Crimped Stent Outer Diameter | Determines the crimped stent outer diameter. Measurements were taken at various locations along the length of the stent and averaged to calculate the mean outer diameter. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Delivery System Balloon Inflation/Deflation Times | Determines the amount of time required to inflate or deflate the delivery catheter balloon. Inflation times were tested for information only. All XIENCE PRIME Stent Systems met product specifications for deflation times. | PASS  |
|  Stent Dislodgement | Determines the amount of force required to displace a stent in both distal and proximal direction from its original, crimped position on the delivery system balloon after a pre-conditioning step where the system is tracked through a tortuous artery model. All XIENCE PRIME Stent Systems met product specifications. | PASS  |

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Table 4 In Vitro Engineering Studies

|  Test | Test Description | Results  |
| --- | --- | --- |
|  Delivery System Guiding Catheter Pullback | Statistically demonstrates that with 95% confidence, at least 99% of the XIENCE PRIME Stent Systems can be successfully retracted back into a 5F guiding catheter after tracking through a simulated tortuous model prior to the deployment of the stent. All XIENCE PRIME Stent Systems met product specifications and confidence/reliability limits. | PASS  |
|  Delivery System Preparation | Evaluates the ease of preparing the XIENCE PRIME Stent System using the aspiration method. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Delivery System Inner Member Collapse | Verifies that irreversible collapse of the inner member does not occur at or below 325 psi. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Delivery System Shaft Pressure (Proximal Adaption Pressure Integrity & Catheter Body Pressure Integrity). | Determines the pressure integrity of the catheter shaft proximal to the delivery system balloon. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Delivery System Coating Friction (Hydrophilic) | Determines the coefficient of frictions along the hydrophilic coated portion of the XIENCE PRIME catheter using an aorta lined fixture. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Delivery System Coating Dry Adhesion (Hydrophilic) | Determines the percent adhesion of the hydrophilic coating to the XIENCE PRIME catheter. The percent coating adhesion is determined by subtracting the percent coating removed from 100. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Catheter Kink and Flexibility Test | Determines the radius of curvature at which the delivery system kinks. All XIENCE PRIME Stent Systems met product specifications. | PASS  |
|  Catheter Torque Test - Turns to Failure | Determines the minimum number of rotations to break joints and/or materials or to lose functional integrity of the delivery system. All XIENCE PRIME Stent Systems met product specifications. | PASS  |

## A3. Coating Characterization Testing

The coating Characterization testing conducted on the XIENCE PRIME stent is summarized in Table 5.

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Table 5 Coating Characterization Testing

|  Test | Test Description | Results  |
| --- | --- | --- |
|  Stent Coating Durability  |   |   |
|  Coating Physical Structure and Chemical Properties | Characterizes various aspects of the coated stent including:
• the coating thickness along the length of the stent and the drug density and its distribution in the stent coating,
• the cross section of the coated stent struts,
• the content uniformity along the length of the stent,
• adhesion of the coating to the delivery system balloon, and
• physical microstructure. | PASS  |
|  Coating Adhesion | Evaluates adhesion properties between the coating and the metal stent with shear stress analysis using a Nano-Scratch Tester | PASS  |
|  Coating Surface Integrity | Determines the stent coating surface integrity of the XIENCE PRIME stent after tracking through a tortuosity fixture, expansion, and post-dilated to RBP. Defect quantities and sizes were recorded. The compromised coating area was calculated as a percentage of entire coated stent surface. All stents met product specifications. | PASS  |
|  Coating Integrity after Balloon Rupture | Evaluates the stent coating surface integrity of the XIENCE PRIME stent after balloon rupture within the stent. The stents were compared to control stents expanded to nominal diameter. | PASS  |
|  Accelerated Coating Fatigue | Testing was conducted to demonstrate coating durability of the XIENCE PRIME stent under expected in vivo cyclic loading conditions for an equivalent of 10 years (~400 million cycles) in an overlapped configuration on a static bend with a radius of 15 mm.

The stents were deployed and post-dilated to the largest intended diameter. The drug was eluted from the coating. The stents were evaluated under SEM and then loaded into tubing and the fatigue tester. The stents were dynamically cycled within simulated vessel conditions for 400 million cycles. The stents were removed and visually inspected under SEM for changes to coating morphology in the documented anomalies that were captured prior to fatigue testing. All XIENCE PRIME stents met product specifications and confidence/reliability limits. | PASS  |
|  Particulate Matter: Regulatory Tracking Method (Particulates: Stents on a bend) | Determines the particulate matter after navigating simulated, challenging vasculature followed by deployment in a 15 mm radius bend. The XIENCE PRIME system was tracked through a simulated tortuous artery model and the stent was deployed unconstrained to RBP inside simulated vasculature. Water was drawn through the vasculature and the particle quantities and sizes were counted and recorded. All stents met product specifications. | PASS  |
|  Particulate Matter: Beaker Method (Over Expansion) | Determines the particulate matter generated during deployment and over expansion of the XIENCE PRIME stent in a beaker of water. The distal end (balloon and stent) was inserted into glassware filled with clean water. The stents were deployed and post-dilated to the maximum stent diameter. After agitation, aliquots of the water were withdrawn and the particle quantities and sizes were counted and recorded. All stents met product specifications. | PASS  |

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|  Test | Test Description | Results  |
| --- | --- | --- |
|  Particulate Matter: Tracking on a Bend Method (Overlap Configuration) | Determines the particulate matter after navigating simulated, challenging vasculature followed by deployment of two stents in an overlapped configuration. The XIENCE PRIME system was tracked through tortuous artery model and the stent was deployed constrained to RBP on a bend of the tortuous path. A second stent was then deployed, overlapping the first. Water was drawn through the vasculature and the particle quantities and sizes were counted and recorded. All stents met product specifications. | PASS  |
|  Embolic Fatigue (Overlap Configuration) | Investigates the embolic particle size and count from the XIENCE PRIME stent during an accelerated radial fatigue test. The test was performed under an accelerated pulsatile pressure loading with physiologic displacements for an equivalent of 10 years (~400 million cycles). The stents were tested on a static bend with a radius of 15 mm in an overlapped configuration by overlapping two stents of the same size with an overlapped length of 4 mm. Particle quantities and sizes were recorded from each pair of stents through the testing duration. | PASS  |

## A4. Chemistry, Manufacturing &amp; Controls (CMC) Testing

Where applicable, International Conference on Harmonization (ICH) Guidelines were followed for the testing routinely performed on the XIENCE PRIME stent as part of CMC. This testing is summarized in Table 6. Information to support the stability of the XIENCE V stent is summarized separately in Section IX.A5 Stability/Shelf Life.

Table 6: XIENCE PRIME Stent Release Testing

|  Test | Test Description  |
| --- | --- |
|  Appearance | A visual inspection is conducted to verify that the XIENCE PRIME meets product appearance specifications.  |
|  Identity | Assays are conducted to verify the identity of the drug substance, everolimus, on the XIENCE PRIME stent using two different methods  |
|  Total Content | Assay is conducted to quantitatively verify that the total amount of drug on the XIENCE PRIME stent met specification for finished good release.  |
|  Content Uniformity | Multiple stents are tested to verify that the uniformity of the drug content between individual stents was within specifications established for finished good release.  |
|  Degradation Products | Assays are conducted to quantitatively verify the amount and type of degradation products on the XIENCE PRIME stent.  |
|  USP <85> Bacterial Endotoxins Test | The amount of bacterial endotoxins is verified to be within the specification limits established for finished good release.  |
|  Sterility Biological Indicator | Release of each lot of XIENCE PRIME stents is based on verification that the individual lot complied with validated sterilization cycle parameters and satisfies the requirement for labeling the finished goods as sterile.  |
|  Drug Release | The in vitro drug release profile of the drug substance, everolimus, is measured on the XIENCE PRIME stent. The product meets specifications established for finished good release.  |
|  Residual Solvents | The amount of residual solvent is verified to be within the specification limits established for finished good release.  |
|  Particulate | Particulate levels are verified to meet product specifications.  |

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# A5. Stability/Shelf Life

A formal stability study was conducted to establish a shelf life / expiration date for the XIENCE PRIME Stent System. Testing included appearance, total content, drug release, degradation products, oxygen content, molecular weight and polydispersity, bubble leak test (packaging integrity), endotoxin (pyrogen), particulates, and butylated hydroxytoluene (BHT) content. Testing to establish container closure integrity was conducted to ensure sterility was maintained during the shelf life of the product. Functional testing of the stent system was conducted on aged product. The data generated to-date support a shelf life of 9 months.

# A6. Sterilization

The XIENCE PRIME Stent System is sterilized using ethylene oxide (EO) sterilization. The cycle is validated per the ISO 11135-1: 2007 Medical Devices – Validation and Routine Control of Ethylene Oxide Sterilization. Results obtained from the sterilization studies show that the product satisfies a minimum Sterility Assurance Level (SAL) of $10^{-6}$. In addition, the amount of bacterial endotoxins was verified to be within the specification limits.

# B. In Vivo Animal Studies

## B1. In Vivo Pharmacokinetics

One in vivo PK study was carried out in an animal model to evaluate the PK profile of the drug from the XIENCE PRIME stent system and to assess the bioequivalence between the XIENCE PRIME stent system and the XIENCE V Stent System by comparing their drug release profiles through biostatistic analysis.

A summary of the performed PK study to support product safety is included in Table 4.

## B2. Drug Interactions

Formal drug interaction studies have not been conducted with the XIENCE PRIME stent. Everolimus is extensively metabolized by cytochrome P450 3A4 (CYP3A) isozyme in the gut wall and liver and is a substrate for the countertransporter Pglycoprotein. Therefore, absorption and subsequent elimination of everolimus may be influenced by drugs that affect these pathways. Coadministration of strong CYP3A inhibitors (such as ketoconazole, itraconazole, ritonavir) and inducers (such as rifampicin, rifabutin) should be avoided. Coadministration of moderate CYP3A inhibitors (such as erythromycin, fluconazole, calcium channel blockers) and inducers (such as carbamazepine, phenobarbital, phenytoin) should be accompanied by everolimus therapeutic drug monitoring. The pharmacokinetic interaction between orally administered everolimus and concomitantly administered drugs is described in the XIENCE PRIME stent system Instructions for Use.

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# B3. Animal Safety Studies

Detailed arterial histopathology and histomorphometry are not obtainable through human clinical trials, so a series of animal studies were conducted to evaluate safety, efficacy (proof of concept dosing), and overall product performance.

The two *in vivo* safety studies, conducted in the porcine coronary model at 28 and 180 days, demonstrate the safety of the XIENCE PRIME stent system and an overall comparability to the XIENCE V Stent System. The 28 and 180 day time points were selected as key time points to evaluate drug effect and vascular healing following stent implantation.

Summaries of the major animal studies performed to support product safety are included in Table 7.

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Table 7 GLP Animal Studies for the XIENCE PRIME Stent System Findings

|  Study # | Stent Design | Animal Model (n) | # of Stents | Follow-up Duration | Endpoints  |
| --- | --- | --- | --- | --- | --- |
|  R0061003
KBP | Test Article:
XIENCE PRIME
(3.0 x 12 mm, 100 μg/cm²)
Control:
• XIENCE V (3.0 x 12 mm, 100 μg/cm²)
• MULTI-LINK VISION (3.0 x 12 mm)
GLP: Yes | Farm Swine (12)
(LAD, LCX, RCA)
1 stent/vessel;
2 or 3 stents/animal | Test: 12
(XIENCE PRIME =12)
Control: 23
(XIENCE V = 11, MULTI-LINK VISION =12) | 28 days | • Chronic vascular response
• Quantitative Coronary Angiography
• Histological & histomorphometric evaluations.
• Evaluation of degree of endothelialization by SEM  |
|  R0061002
KBP | Test Article:
XIENCE PRIME
(3.0 x 12 mm, 100 μg/cm²)
Controls:
• XIENCE V (3.0 x 12 mm, 100 μg/cm²)
• MULTI-LINK VISION (3.0 x 12 mm)
GLP: yes | Yucatan Swine (12)
(LAD, LCX, RCA)
1 stent/vessel;
3 stents/animal | Test: 12
(XIENCE PRIME = 12.
Control: 24
(XIENCE V = 12, MULTI-LINK VISION = 12) | 180 days | • Quantitative Coronary Angiography
• Histological & histomorphometric evaluations
• Evaluation of degree of endothelialization by SEM
• Chronic vascular response  |
|  R0061106
MJL | Test Article:
XIENCE PRIME
(3.0 x 12 mm, 100 μg/cm²)
GLP: yes | Yucatan Swine (8)
Farm Swine (16)
(LAD, LCX, RCA)
1 stent/vessel
2 or 3 stents/animal | Test: 69
XIENCE PRIME | 0.125, 1, 3, 7, 14, 28, 60, 90, 120, 180, 240, 300 days | • In vivo pharmacokinetics
• Bioequivalence between XIENCE V and XIENCE PRIME  |

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# X. SUMMARY OF CLINICAL STUDIES

The XIENCE PRIME Stent System safety and effectiveness is derived from the SPIRIT PRIME clinical trial that was conducted under IDE #G090068. The SPIRIT PRIME clinical trial was designed to demonstrate the safety and effectiveness of the XIENCE PRIME family of stent systems in improving coronary luminal diameter in subjects with symptomatic heart disease due to a maximum of two *de novo* native coronary artery lesions, each in a different epicardial vessel. This global trial consists of two separate arms, the Core Size Registry and the Long Lesion Registry. One-year results are presented here and yearly follow-up for clinical parameters through 5 years is ongoing. Given the substantial similarities between the XIENCE PRIME and XIENCE V stent systems, clinical trials previously conducted on the XIENCE V stent are also relevant and included in the Instructions For Use (IFU). For additional details on the SPIRIT family of trials, see the SSED for P070015 (http://www.accessdata.fda.gov/cdrh_docs/pdf7/P070015b.pdf).

## A. Study Design

The SPIRIT PRIME clinical trial is a prospective, nonrandomized, open-label, multicenter study consisting of two separate arms, the Core Size Registry (stent diameters 2.25, 2.5, 3.0, 3.5, 4.0 mm with stent lengths 8, 18, and $28^{11}$ mm) and the Long Lesion Registry (stent diameters, 2.5, 3.0, 3.5, 4.0 mm with stent lengths 33 and 38 mm) in 505 subjects at up to 75 global sites. For clinical trial design purposes, the 28 mm length stent is included in the Core Size Registry because the historical data on XIENCE V used to develop the comparative performance goal includes stent lengths up to 28 mm. The Long Lesion Registry only includes subjects with at least one 33 and 38 mm length stents as there were limited data on these stent lengths from which to develop a comparative performance goal.

Each subject was to receive treatment in up to two *de novo* native coronary lesions, each lesion in a different epicardial vessel. Subjects in the Core Size Registry were allowed to have: one target lesion treated with the core size XIENCE PRIME stent systems (stent diameters $2.25 - 4.0\mathrm{mm}$ with stent lengths 8, 18, $28\mathrm{mm}$) or two target lesions in separate epicardial vessels, treated with two core size XIENCE PRIME stent systems (stent diameters $2.25 - 4.0\mathrm{mm}$ with stent lengths 8, 18, $28\mathrm{mm}$).

Subjects in the Long Lesion Registry were allowed to have: one target lesion treated with the XIENCE PRIME stent system (stent diameters $2.5 - 4.0\mathrm{mm}$ with stent lengths 33 or $38\mathrm{mm}$) or two target lesions in separate epicardial vessels, treated with two XIENCE PRIME stent system (stent diameters $2.5 - 4.0\mathrm{mm}$ with stent lengths 33 or $38\mathrm{mm}$) or one XIENCE PRIME stent system (stent diameters $2.5 - 4.0\mathrm{mm}$ with stent lengths 33 or $38\mathrm{mm}$) and one XIENCE PRIME stent system (stent diameters $2.25 - 4.0\mathrm{mm}$ with stent lengths 8, 18, $28\mathrm{mm}$). All subjects in the Long Lesion Registry were required to be treated with at least one XIENCE

i The 28 mm length stent was studied in the XIENCE PRIME Core Size Registry. The results of the Core Size Registry are presented in Table 10.

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PRIME stent of 33 or 38 mm in length. For both the Core Size Registry and Long Lesion Registry, planned overlap was not allowed, however overlap was allowed in case of bailout stenting.

The primary endpoint is target lesion failure (TLF) at one year, a composite endpoint of cardiac death, target vessel myocardial infarction (TV-MI), and clinically indicated target lesion revascularization (CI-TLR). The primary endpoint rates of TLF at 1 year (per protocol and per ARC definitions) were compared to a set of pre-specified performance goals (PGs) for both Core Size Registry and Long Lesion Registry as shown below.

The PG for the Core Size Registry was developed utilizing historical data from the SPIRIT III trial, while the PG for the Long Lesion Registry was developed based on a regression analysis conducted on the historical data from the pooled SPIRIT II and III trials. Although the SPIRIT PRIME trial defined TLF based on the ARC definition of MI, the historical SPIRIT II and III trials used to develop the initial PG were based on the per protocol definition of MI. In order to provide a comparison of outcomes using the same definitions for both the treatment arms and PGs, two subsequent analyses, with PGs developed using the same definitions (per protocol and per ARC), were developed and are presented in rows 2 and 3 of the table below.

Table 8 Analyses of the Primary Endpoint

|  TLF
Primary Endpoint | Core Size Registry*
Performance Goal | Long Lesion Registry**
Performance Goal  |
| --- | --- | --- |
|  TLF
Cardiac Death,
ARC-Defined TV-MI, CI-TLR | 9.2%^{1} | 19.2%^{1}  |
|  TLF
Cardiac death,
Protocol-Defined TV-MI, CI-TLR | 9.2%^{1} | 19.2%^{1}  |
|  TLF
Cardiac death,
ARC-Defined TV-MI, CI-TLR | 15.3%^{2} | 26.0%^{2}  |

1 Performance goal developed based on per protocol-defined MI.
2 Performance goal developed based on per ARC-defined MI.
* The Core Size Registry includes 2.25 - 4.0 mm stent diameters, 8, 18, 28 mm lengths
** The Long Lesion Registry includes 2.5 - 4.0 mm stent diameters, 33 and 38 mm stent lengths

The primary analysis of the SPIRIT PRIME data was performed on the Full Analysis Set (FAS) population which was defined as the subjects who received the XIENCE PRIME stent. The Intent to Treat (ITT) population was defined as the subjects enrolled into the study, regardless of the treatment actually received; this population excludes de-registered subjects.

The clinical trial design for SPIRIT PRIME is summarized in Table 9.

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Table 9 SPIRIT PRIME Clinical Trial Design

|   | SPIRIT PRIME  |
| --- | --- |
|  Study Type/Design | • Prospective
• Two-arm
• Open-label
• Multi-center
• Registry  |
|  Number of Subjects Enrolled | Total 529
Core Size Registry 419
Long Lesion Registry 110  |
|  Treatment | Maximum of two de novo coronary lesions, each in a different epicardial vessel.  |
|  Lesion Size | XIENCE PRIME, Core Size
RVD: ≥2.25 mm and ≤4.25 mm
Lesion Length: ≤22 mm

XIENCE PRIME, Long Lesion
RVD: ≥2.5 mm and ≤4.25 mm
Lesion Length: >22 mm and ≤32 mm  |
|  Stent Sizes | Core Size Registry
Stent diameter: 2.25, 2.5, 3.0, 3.5, and 4.0mm
Stent Lengths: 8, 18, and 28 mm

Long Lesion Registry
Stent diameter: 2.5, 3.0, 3.5, and 4.0 mm
Stent Length: 33 and 38 mm  |
|  Post-procedure Antiplatelet Therapy | Clopidogrel 12 months minimum (or ticlopidine per site standard), aspirin indefinitely  |
|  Primary Endpoint | Target lesion failure (TLF) defined as the composite rate of cardiac death, target vessel myocardial infarction (TV-MI) and clinically indicated target lesion revascularization (CI-TLR) at 1year.  |
|  Co-Primary Endpoint | None  |
|  Major Secondary Endpoint | None  |
|  Clinical Follow-up | 30 days, 180 days, 1-5 years  |
|  Angiographic Follow-up | None  |
|  IVUS Follow-up | None  |
|  PK Study | None  |
|  Status | One year reported  |

1. Clinical Inclusion/Exclusion Criteria

Enrollment in the SPIRIT PRIME clinical trial was limited to subjects who met the eligibility criteria and who provided a signed informed consent form prior to enrollment. Subjects had to be at least 18 years old, with evidence of myocardial ischemia based on the presence of angina, silent ischemia, a positive functional study or reversible ECG changes consistent with ischemia. Female subjects with childbearing potential had to have a negative pregnancy test within 7 days of the index procedure.

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# Angiographic Inclusion Criteria

- One or two *de novo* target lesions each in a different epicardial vessel.
- If there are two target lesions, both lesions must satisfy the angiographic eligibility criteria for that registry.
- Multiple focal *de novo* lesions in a target vessel that can be covered by a single stent are allowed.
- The target lesion(s) must be located in a major artery or branch with a visually estimated diameter stenosis of ≥ 50% and &lt; 100% with a TIMI flow of ≥ 1.
- Target lesion(s) must be located in a native coronary artery with vessel diameter by visual estimation of:
- ≥ 2.25 mm and ≤ 4.25 mm for treatment by the core size XIENCE PRIME stent
- 2.5 mm and ≤ 4.25 mm for treatment by the XIENCE PRIME LL stent
- Target lesion(s) must be located in a native coronary artery with length by visual estimation of:
- ≤ 22 mm for treatment by the core size XIENCE PRIME stent
- &gt;22 mm and ≤ 32 mm for treatment by the XIENCE PRIME LL stent

# Angiographic Exclusion Criteria

All angiographic exclusion criteria are based on visual estimation.

- Target lesion located within an arterial or saphenous vein graft or distal to a diseased (vessel irregularity per angiogram and &gt; 20% stenosed lesion) arterial or saphenous vein graft.
- Target lesion involving a bifurcation with a side branch ≥ 2 mm in diameter and/or ostial lesion &gt; 40% stenosed or side branch requiring protection guide wire, or side branch requiring predilatation.
- Target lesion with total occlusion (TIMI flow 0), prior to crossing with wire.
- Another lesion requiring revascularization is located in the same epicardial vessel of the target lesion.
- Restenotic target lesion.
- Aorto-ostial target lesion (within 3 mm of the aorta junction).
- Target lesion is in a left main location.
- Target lesion located within 2 mm of the origin of the LAD or LCX.
- Extreme angulation (≥ 90°) or excessive tortuosity (≥ two 45° angles) proximal to or within the target lesion.
- Heavy calcification proximal to or within the target lesion.
- Target vessel contains thrombus as indicated in the angiographic images.
- Target lesion has a high probability that a procedure other than pre-dilatation and stenting will be required at the time of index procedure for treatment of the target vessel (e.g. atherectomy, cutting balloon).
- Target vessel was previously treated with any type of PCI (e.g. balloon angioplasty, stent, cutting balloon, atherectomy) &lt; 9 months prior to index procedure.

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- Non-target vessel was previously treated with any type of PCI &lt; 90 days prior to the index procedure.
- Additional clinically significant lesion(s) (e.g. %DS ≥ 50%) in a target vessel or side branch for which PCI may be required &lt; 90 days after the index procedure.

## 2. Follow-up Schedule

All subjects will be followed up to five years. All subjects were required to have a hospital or office follow-up visit at 30 days and 1 year. There was the option for an office or telephone follow-up visits at 180 days and 2-5 years.

## 3. Stent Thrombosis Definitions

Stent Thrombosis (ST) was defined in the protocol as clinical presentation of acute coronary syndrome with angiographic appearance of thrombus within or adjacent to a previously treated target lesion. In the absence of angiography, any unexplained death, or acute MI (ST segment elevation or new Q-wave in the distribution of the target lesion within 30 days. Stent thrombosis was categorized as acute (≤ 1 day), subacute (&gt; 1 day ≤ 30 days) and late (&gt; 30 days).

### Stent thrombosis was defined by ARC criteria as:

- Definite (angiographic confirmation with at least one of the following: acute onset of ischemic symptoms at rest, new ischemic changes suggestive of acute ischemia, typical rise and fall of cardiac biomarkers, or non-occlusive or occlusive thrombus)
- Probable (any unexplained death within the first 30 days or, irrespective of the time after the index procedure, any MI related to documented acute ischemia in the territory of the stent without angiographic confirmation), and
- Possible (any unexplained death from 30 days to end of trial follow-up).

### Timing:

- Acute ST: 0 to 24 hours post stent implantation
- Subacute ST: &gt; 24 hours - 30 days post stent implantation
- Late ST: 30 days to 1 year post stent implantation
- Very late ST: &gt; 1 year post stent implantation

### Level of probability:

- Definite ST - considered to have occurred by either angiographic or pathologic confirmation.
- Probable ST - considered to have occurred after intracoronary stenting in the following cases:
1. Any unexplained death within the first 30 days.

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2. Irrespective of the time after the index procedure, any MI which is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of ST and in the absence of any other obvious cause.

- Possible ST - considered to have occurred with any unexplained death following 30 days after the intracoronary stenting until the end of trial follow-up.⁴¹

## 4. Clinical Endpoints

The SPIRIT PRIME clinical trial primary endpoint was TLF at 1 year, defined as the composite of:

1. Cardiac death
2. Target Vessel Myocardial Infarction (TV-MI)
3. Clinically-indicated Target Lesion Revascularization (TLR).

Other key secondary endpoints to examine the safety and efficacy included the following:

- Acute Success: (combined clinical and angiographic)
- Clinical Device Success (Lesion basis)
- Clinical Procedural Success (Subject basis)
- Procedure time (from insertion to withdrawal of guide catheter)
- Clinical Endpoint in hospital and at each clinical follow-up time point (30 days, 180 days, 1,2,3,4 and 5 years):

- All Death (Cardiac, Vascular, Non-cardiovascular)
- TV-MI - Q-wave and non Q-wave (defined as MI not clearly attributable to a non-target vessel)
- Non-target vessel MI (Q-wave, Non Q-wave)
- CI-TLR
- Clinically indicated Target Vessel Revascularization (TVR = TLR and non-TLR in TV)
- All TLR (CI and non-CI)
- All TVR (CI and non-CI)
- All Coronary Revascularization (TVR and non-TVR)
- Cardiac Death/All MI
- Cardiac Death/All MI/CI-TLR
- All Death/All MI/All Coronary Revascularization
- Stent Thrombosis (per protocol and per ARC)

⁴¹ All data presented as definite + probable only.

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## B. Accountability of Subjects

**SPIRIT PRIME Core Size Registry**: The Core Size Registry analysis population had a total of 419 subjects. The ITT population consisted of 415 subjects, as four subjects were de-registered. The FAS population (only subjects receiving a XIENCE PRIME stent with stent diameters 2.25 - 4.0 and stent lengths 8, 18, 28 mm) consisted of 413 subjects. Only subjects with available cardiac enzyme data in window (between 8 hours post-procedure and hospital discharge) were included in the main data analysis of the primary and secondary endpoints in the FAS and ITT, resulting in a population of 401. The 401 subjects in the FAS population received a total of 484 XIENCE PRIME stent with stent diameters 2.25 - 4.0 and stent lengths 8, 18, 28 mm. Of the 401 subjects 88.3% (354/401) of these subjects were single target lesion subjects and 11.7% (47/401) were dual target lesion subjects.

**SPIRIT PRIME Long Lesion Registry**: The Long Lesion Registry analysis population had a total of 110 subjects. The ITT population consisted of 110 subjects and the FAS population (only subjects receiving at least one XIENCE PRIME stent with stent diameters 2.5 - 4.0 mm and stent lengths 33 and 38 mm) consisted of 107 subjects. Only subjects with available cardiac enzyme data in window (between 8 hours post-procedure and hospital discharge) were included in the main data analysis of the primary and secondary endpoints in the FAS and ITT, resulting in an ITT population of 106 and a FAS population of 104. The 104 subjects in the FAS population received a total of 105 XIENCE PRIME stent with stent diameters 2.5 - 4.0 mm and stent lengths 33 and 38 mm and 46 XIENCE PRIME stent with stent diameters 2.25 - 4.0 and stent lengths 8, 18, 28 mm. Of the 104 subjects, 80.8% (84/104) were single target lesion subjects and 19.2% (20/104) were dual target lesion subjects.

## C. Study Population Demographics and Baseline Parameters

**SPIRIT PRIME Core Size Registry**: In the Core Size Registry, the mean age was 62.70 ± 10.23 years, 70.3% (282/401) were male, 29.7% (119/401) were female and 92.3% (346/375) were white. The average body mass index (BMI) was 30.86 ± 5.83 kg/m² and 50.3% (192/382) of subjects were obese, with a BMI ≥ 30. Regarding medical risk factors in the Core Size Registry, 19.2% (77/401) were tobacco users, 76.6% (307/401) were hypertensive requiring medication, and 80.3% (322/401) were hypercholesterolemic requiring medication. There were 11.1% (44/397) of subjects having had a prior cardiac intervention on the target vessel and 23.0% (91/395) had a prior MI. In addition, there were 45.6% (183/401) of subjects with stable angina and 24.9% (100/401) of subjects with unstable angina. Furthermore, the Core Size Registry consisted of 34.9% (140/401) diabetics, 29.9% (120/401) diabetics requiring medication and 3.5% (14/401) diabetics requiring diet and exercise only.

**SPIRIT PRIME Long Lesion Registry**: In the Long Lesion Registry, the mean age was 63.46 ± 9.44 years, 62.5% (65/104) were male, 37.5% (39/104) were female and 91.7% (88/96) were white. The average body mass index (BMI) was 30.67 ± 5.84 kg/m², and 49.5% (50/101) of subjects were obese, with a BMI ≥ 30. Regarding medical risk factors in

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the Long Lesion Registry, 26.9% (28/104) were tobacco users, 75.0% (78/104) were hypertensive requiring medication, and 80.8% (84/104) were hypercholesterolemic requiring medication. There were 11.8% (12/102) of subjects having had a prior cardiac intervention on the target vessel and 22.5% (23/102) had a prior MI. In addition, there were 49.0% (51/104) of subjects with stable angina and 23.1% (24/104) of subjects with unstable angina. Furthermore, the Long Lesion Registry consisted of 35.6% (37/104) diabetics, 31.7% (33/104) diabetics requiring medication and 1.9% (2/104) diabetics requiring diet and exercise only.

## D. Safety and Effectiveness Results

The results are presented in Table 10 (Primary endpoint), Table 11 (Core Size Registry Clinical Results), and Table 12 (Long Lesion Registry Clinical Results). The primary endpoints and the components are presented in Figure 3 and Figure 4 for the Core Size Registry and in Figure 5 and Figure 6 for the Long Lesion Registry. These analyses are based on the Full Analysis Set (FAS). The FAS population is defined as subjects who have received at least one XIENCE PRIME stent including bailout. SPIRIT PRIME Core Size and Long Lesion Registries met all pre-specified PGs with statistical significance. The observed TLF rate at one year was 4.5% (18/399) (per protocol defined MI) and 6.5% (26/399) (per ARC defined MI) in the Core Size Registry, and 7.7% (8/104) (per protocol defined MI) and 12.5% (13/104) (per ARC defined MI) in the Long Lesion Registry respectively.

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Table 10 SPIRIT PRIME Primary Endpoint Results

|  Core Size Registry* | XIENCE PRIME (N=401) | Performance Goal | P-Value  |
| --- | --- | --- | --- |
|  1 Year TLF
Cardiac Death,
ARC-Defined TV-MI, CI-TLR | 6.5% (26/399) | 9.2%§ | 0.0338  |
|  1 Year TLF
Cardiac Death,
Protocol-Defined TV-MI, CI-TLR | 4.5% (18/399) | 9.2%§ | 0.0003  |
|  1 Year TLF
Cardiac Death,
ARC-Defined TV-MI, CI-TLR | 6.5% (26/399) | 15.3%# | < 0.0001  |
|  Long Lesion Registry** | XIENCE PRIME (N=104) | Performance Goal | P-Value  |
|  1 Year TLF
Cardiac Death,
ARC-Defined TV-MI, CI-TLR | 12.5% (13/104) | 19.2%§ | 0.0484  |
|  1 Year TLF
Cardiac Death,
Protocol-Defined TV-MI, CI-TLR) | 7.7% (8/104) | 19.2%§ | 0.0009  |
|  1 Year TLF
Cardiac Death,
ARC-Defined TV-MI, CI-TLR | 12.5% (13/104) | 26.0%# | 0.0006  |

Notes:
- N is the total number of subjects.
- Population for SPIRIT PRIME consists of those subjects who were treated with at least one PRIME stent and had cardiac enzyme data between 8 hour post index procedure and hospital discharge.
- TLF includes cardiac death, target vessel MI and clinically indicated TLR.
- Time Frame includes follow-up window (365 + 28 days).
1 One-sided p-value against pre-specified performed goals, to be compared at a 0.05 significance level.
§ Performance Goal developed based on per-protocol definition MI.
# Performance Goal developed based on per-ARC definition MI.
* The Core Size Registry includes 2.25 - 4.0 mm stent diameters, 8, 18, 28 mm lengths
** The Long Lesion Registry includes 2.5 - 4.0 mm stent diameters, 33 and 38 mm stent lengths

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Table 11 SPIRIT PRIME Core Size Registry Clinical Results*

|   | OUTCOMES AT 1 YEAR
Core Size Registry
(N=401)  |
| --- | --- |
|  COMPOSITE EFFECTIVENESS & SAFETY |   |
|  TLF (per protocol) | 4.5% (18/399)  |
|  TLF (per ARC) | 6.5% (26/399)  |
|  EFFECTIVENESS |   |
|  CI-TLR | 2.5% (10/399)  |
|  CI-TLR, CABG | 0.3% (1/399)  |
|  CI-TLR, PCI | 2.5% (10/399)  |
|  CI-TVR | 4.5% (18/399)  |
|  SAFETY |   |
|  All Death | 0.8% (3/399)  |
|  Cardiac Death | 0.3% (1/399)  |
|  Non-Cardiac Death | 0.5% (2/399)  |
|  Target Vessel MI (per protocol) | 1.8% (7/399)  |
|  Target Vessel QMI (per protocol) | 0.3% (1/399)  |
|  Target Vessel NQMI (per protocol) | 1.5% (6/399)  |
|  All MI (per protocol) | 1.8% (7/399)  |
|  QMI (per protocol) | 0.3% (1/399)  |
|  NQMI (per protocol) | 1.5% (6/399)  |
|  Target Vessel MI (per ARC) | 4.0% (16/399)  |
|  Target Vessel QMI (per ARC) | 0.3% (1/399)  |
|  Target Vessel NQMI (per ARC) | 3.8% (15/399)  |
|  All MI (per ARC) | 4.5% (18/399)  |
|  QMI (per ARC) | 0.3% (1/399)  |
|  NQMI (per ARC) | 4.3% (17/399)  |
|  Cardiac Death or All protocol MI | 2.0% (8/399)  |
|  Cardiac Death or All ARC MI | 4.8% (19/399)  |
|  ARC Definite + Probable Stent Thrombosis |   |
|  Cumulative through 1 year | 0.5% (2/399)  |
|  Acute/Subacute (0 – 30 days) | 0.5% (2/401)  |
|  Late (31 days – 1 year) | 0.0% (0/399)  |

Notes:
- TLF is defined as a hierarchical composite of cardiac death, Target Vessel MI, and clinically-indicated TLR.
- Population for SPIRIT PRIME Core Size Registry consists of those subjects who were treated with at least one PRIME stent and had cardiac enzyme data between 8 hour post index procedure and hospital discharge.
- ARC: Academic Research Consortium
* The Core Size Registry includes 2.25 - 4.0 mm stent diameters, 8, 18, 28 mm lengths

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![img-3.jpeg](img-3.jpeg)

![img-4.jpeg](img-4.jpeg)

![img-5.jpeg](img-5.jpeg)
Figure 3 Core Size Registry Primary endpoint-TLF at 1 year per protocol (A) and its components of cardiac death (B), TV-MI per protocol (C) and CI-TLR (D)

![img-6.jpeg](img-6.jpeg)

![img-7.jpeg](img-7.jpeg)

![img-8.jpeg](img-8.jpeg)

![img-9.jpeg](img-9.jpeg)
Figure 4 Core Size Registry-Primary endpoint-TLF at 1 year per ARC (A) and its components of cardiac death (B), TV-MI per protocol (C) and CI-TLR (D)

![img-10.jpeg](img-10.jpeg)

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Table 12 SPIRIT PRIME Long Lesion Registry Clinical Results*

|  OUTCOMES AT 1 YEAR
Long Lesion Registry
(N=104)  |   |
| --- | --- |
|  COMPOSITE EFFECTIVENESS & SAFETY |   |
|  TLF (per protocol) | 7.7% (8/104)  |
|  TLF (per ARC) | 12.5% (13/104)  |
|  EFFECTIVENESS |   |
|  CI-TLR | 2.9% (3/104)  |
|  CI-TLR, CABG | 0.0% (0/104)  |
|  CI-TLR, PCI | 2.9% (3/104)  |
|  CI-TVR | 4.8% (5/104)  |
|  SAFETY |   |
|  All Death | 1.0% (1/104)  |
|  Cardiac Death | 0.0% (0/104)  |
|  Non-Cardiac Death | 1.0% (1/104)  |
|  Target Vessel MI (per protocol) | 4.8% (5/104)  |
|  Target Vessel QMI (per protocol) | 1.9% (2/104)  |
|  Target Vessel NQMI (per protocol) | 2.9% (3/104)  |
|  All MI (per protocol) | 4.8% (5/104)  |
|  QMI (per protocol) | 1.9% (2/104)  |
|  NQMI (per protocol) | 2.9% (3/104)  |
|  Target Vessel MI (per ARC) | 10.6% (11/104)  |
|  Target Vessel QMI (per ARC) | 1.9% (2/104)  |
|  Target Vessel NQMI (per ARC) | -8.7% (9/104)  |
|  All MI (per ARC) | 10.6% (11/104)  |
|  QMI (per ARC) | 1.9% (2/104)  |
|  Cardiac Death or All protocol MI | 4.8% (5/104)  |
|  Cardiac Death or All ARC MI | 10.6% (11/104)  |
|  ARC Definite + Probable Stent Thrombosis |   |
|  Cumulative through 1 year | 0.0% (0/104)  |
|  Acute/Subacute (0 – 30 days) | 0.0% (0/104)  |
|  Late (31 days – 1 year) | 0.0% (0/104)  |

Notes:
- TLF is defined as a hierarchical composite of cardiac death, Target Vessel MI, and clinically-indicated TLR.
- Population for SPIRIT PRIME Core Size Registry consists of those subjects who were treated with at least one PRIME stent and had cardiac enzyme data between 8 hour post index procedure and hospital discharge.
- ARC: Academic Research Consortium
* The Long Lesion Registry includes 2.5 - 4.0 mm stent diameters, 33 and 38 mm stent lengths

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![img-11.jpeg](img-11.jpeg)

![img-12.jpeg](img-12.jpeg)

![img-13.jpeg](img-13.jpeg)
Figure 5 Long Lesion Registry Primary endpoint-TLF at 1 year per protocol (A) and its components of cardiac death (B), TV-MI per protocol (C) and CI-TLR (D)

![img-14.jpeg](img-14.jpeg)

![img-15.jpeg](img-15.jpeg)

![img-16.jpeg](img-16.jpeg)

![img-17.jpeg](img-17.jpeg)
Figure 6 Long Lesion Registry Primary endpoint-TLF at 1 year per ARC (A) and its components of cardiac death (B), TV-MI per protocol (C) and CI-TLR (D)

![img-18.jpeg](img-18.jpeg)

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Geriatric Use: The XIENCE PRIME clinical trial did not have an upper age limit. Among the 401 patients in the SPIRIT PRIME Core Size Registry, 167 were older than age 65 and 234 were age 65 or younger. Among the 104 patients in the SPIRIT PRIME Long Lesion Registry, 48 patients were older than age 65 and 56 were age 65 or younger. A post hoc analysis showed no clinically significant differences in clinical endpoints between patients older than age 65 compared to those age 65 years or younger.

## XI. Gender-Based Analysis

Abbott Vascular performed a post hoc evaluation of the SPIRIT PRIME clinical trial for possible sex-based differences in baseline characteristics and clinical outcomes, as well as for any interaction between treatment and sex/gender. The SPIRIT PRIME trial was not designed or powered to study safety or effectiveness differences between sexes, so these analyses are considered exploratory without definitive conclusions.

In the Core Size Registry, 119/401 (29.7%) subjects were female and 282/401 (70.3%) were male. In the Long Lesion Registry, 39/104 (37.5%) subjects were female and 65/104 (62.5%) were male. In comparison, the prevalence of coronary artery disease (CAD) is estimated at 9.2 million in males and 8.4 million in females for adults age 20 and older the United States (i.e., the CAD population is estimated to be 52.2% males and 47.7% females). The disproportionate enrollment distribution in this trial may be partly attributable to gender differences in symptoms and pathophysiology, which may lead to under-diagnosis and under-referral of female patients with CAD. The gender proportions enrolled in this trial are similar to other drug-eluting stent trials.¹,²

Table 13 presents the baseline demographics, risk factors, and angiographic characteristics by gender for subjects in the Core Size Registry. As is consistent with previous literature, female patients at baseline were numerically older and had a higher BMI. Additionally, more females than males had hypertension requiring medication and diabetes mellitus. Table 14 presents the baseline demographics, risk factors, and angiographic characteristics by gender for subjects in the Long Lesion Registry

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Table 13 Demographics, Risk Factors, and Baseline Angiographic Characteristics for SPIRIT PRIME Core Size Registry Subjects *

|  Subject/Lesion Characteristics | Male
(N=282)
(M=315) | Female
(N=119)
(M=132) | Total
(N=401)
(M=447) | P-Value  |
| --- | --- | --- | --- | --- |
|  Baseline Demographics, Mean ± SD (n)  |   |   |   |   |
|  Age (year) | 61.63 ± 10.37 (282) | 65.23 ± 9.47 (119) | 62.70 ± 10.23 (401) | 0.0009^{1}  |
|  Baseline Risk Factors, % (No./total)  |   |   |   |   |
|  All Diabetes | 31.9% (90/282) | 42.0% (50/119) | 34.9% (140/401) | 0.0663^{2}  |
|  Diabetes Treated with Insulin | 7.4% (21/282) | 14.3% (17/119) | 9.5% (38/401) | 0.0400^{2}  |
|  Current Tobacco Use | 19.1% (54/282) | 19.3% (23/119) | 19.2% (77/401) | 1.0000^{2}  |
|  Hypertension Requiring Medication | 73.4% (207/282) |…

---

**Source:** [https://fda.innolitics.com/device/P110019](https://fda.innolitics.com/device/P110019)

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