EXPRESS LD ILIAC PREMOUNTED STENT SYSTEM
Device Facts
| Record ID | P090003 |
|---|---|
| Device Name | EXPRESS LD ILIAC PREMOUNTED STENT SYSTEM |
| Applicant | Boston Scientific Corporation |
| Product Code | NIO · Cardiovascular |
| Decision Date | Mar 5, 2010 |
| Decision | APPR |
| Device Class | Class 3 |
| Attributes | Therapeutic |
Intended Use
The Express LD Iliac Premounted Stent System is indicated for the treatment of atherosclerotic lesions found in iliac arteries up to 100 mm in length, with a reference diameter of 6 mm to 10 mm.
Device Story
The Express LD Iliac Premounted Stent System is a balloon-expandable, 316L stainless steel stent premounted on an over-the-wire balloon delivery system. Used in the clinic by physicians to treat iliac artery atherosclerotic lesions. The device is advanced over a guidewire to the target site; the balloon is inflated to expand the stent against the vessel wall, followed by potential post-dilation to optimize apposition. The stent provides mechanical scaffolding to maintain vessel patency. The delivery system features a dual-lumen shaft, radiopaque marker bands for positioning, and a hydrophilic coating for tracking. The output is a permanently implanted metal stent that restores luminal diameter, improving blood flow and reducing symptoms of peripheral artery disease.
Clinical Evidence
Prospective, multi-center, single-arm study (MELODIE) of 151 subjects. Primary endpoint: mean % loss of luminal diameter at 6 months (16.2% ± 18.4%, p=0.0061 vs 20% OPC). Secondary endpoints included binary restenosis (5.6% at 6 months), target lesion patency (97.2% at 12 months, 94.1% at 24 months), and Major Adverse Events (10.2% at 24 months).
Technological Characteristics
Stent: 316L stainless steel, laser-cut sinusoidal bands. Delivery system: Over-the-wire balloon catheter, dual-lumen, hydrophilic coating, radiopaque marker bands. Sterilization: Ethylene oxide (SAL 10^-6). MRI compatibility: 3.0 Tesla. Complies with ASTM F138-00 (material), ASTM F2129-01 (corrosion), and ISO 10993 (biocompatibility).
Indications for Use
Indicated for patients ≥ 18 years old with chronic symptomatic (Fontaine class IIa, IIb, and III) atherosclerotic disease in iliac arteries (de novo or restenotic). Contraindicated in patients with persistent acute intraluminal thrombus, uncorrected bleeding disorders, known allergies to stainless steel/nickel, lesions within/adjacent to aneurysms, excessive vessel tortuosity, or perforated vessels.
Regulatory Classification
Identification
Stent, Iliac -- a metal scaffold placed via a delivery catheter into the iliac artery to maintain the lumen
Reference Devices
- Palmaz balloon-expandable stent
Related Devices
- P110028 — ABSOLUTE PRO VASCULAR SELF-EXPANDING STENT SYSTEM · Abbott Vascular, Inc. · Feb 22, 2012
- P110043 — OMNILINK ELITE PERIPHERAL BALLOON-EXPANDABLE STENT SYSTEM · Abbott Vascular-Cardiac Therapies · Jul 31, 2012
- P030045 — INTRASTENT DOUBLESTRUT STENT · Medtronic Vascular, Inc. · Jun 8, 2004
- P110011 — ASSURANT COBALT ILIAC BALLOON-EXPANDABLE STENT SYSTEM · Medtronic, Ireland · Oct 26, 2011
- P160024 — LIFESTREAM BALLOON EXPANDABLE VASCULAR COVERED STENT · Bard Peripheral Vascular, Inc. · Apr 24, 2017
Submission Summary (Full Text)
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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)
I. GENERAL INFORMATION
Device Generic Name: Stent, Iliac (NIO)
Device Trade Name: Express® LD Iliac Premounted Stent System
Applicant's Name and Address: Boston Scientific Corporation
One Boston Scientific Place
Natick, MA 01760-1537
USA
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P090003
Date of FDA Notice of Approval: March 05, 2010
Expedited: Not Applicable
II. INDICATIONS FOR USE
The Express LD Iliac Premounted Stent System is indicated for the treatment of atherosclerotic lesions found in iliac arteries up to 100 mm in length, with a reference diameter of 6 mm to 10 mm.
III. CONTRAINDICATIONS
Generally, contraindications for Percutaneous Transluminal Angioplasty (PTA) are also contraindications for stent placement. Contraindications associated with the use of the Express LD Iliac Premounted Stent System include:
- Patients who exhibit persistent acute intraluminal thrombus at the treatment site, following thrombolytic therapy
- Patients with uncorrected bleeding disorders or patients who cannot receive anticoagulation or antiplatelet aggregation therapy
- Persons with known allergies to stainless steel or its components (for example nickel)
- A lesion that is within or adjacent to the proximal or distal segments of an aneurysm
- Patients who experience the complication of arterial perforation or a fusiform or sacciform aneurysm during the procedure, preceding possible stent implantation
- Patients with excessive vessel tortuosity
- Patients with perforated vessels evidenced by extravasation of contrast media
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# IV. WARNINGS AND PRECAUTIONS
The warnings and precautions can be found in the Express LD Iliac Premounted Stent System labeling.
# V. DEVICE DESCRIPTION
The Express® LD Iliac Premounted Stent System consists of a balloon expandable stent premounted on an over-the-wire balloon delivery system. The device is designed for use in patients with atherosclerotic disease of the iliac arteries.
The Express LD Iliac stent is delivered by advancing the device over a guide wire, through the peripheral vasculature to the iliac artery. Once in place, the stent is subsequently expanded with the balloon on the stent delivery system. Following stent deployment, the delivery balloon may be inflated with additional pressure to optimize the stent luminal diameter and strut apposition to the vessel wall.
The proposed product matrix for this PMA is provided in Table 1 below. Each stent size is available on both a 75 cm and a 135 cm length delivery system. The Express LD stent models are separated into Small Vessel and Large Vessel configurations according to vessel diameter to be treated.
Table 1: Express LD Iliac Device Matrix
| Balloon Length (mm) | Stent Length (mm) | Balloon/Stent Diameter (mm) | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | | 6 | 7 | 8 | 9 | 10 |
| 20 | 17 | H74938046620750^{1} | H74938046720750^{1} | H74938046820750^{1} | | |
| | | H74938047620130^{2} | H74938047720130^{2} | H74938047820130^{2} | | |
| 30 | 27 | H74938046630750^{1} | H74938046730750^{1} | H74938046830750^{1} | | |
| | | H74938047630130^{2} | H74938047730130^{2} | H74938047830130^{2} | | |
| | 25 | | | | H74938046920750^{1} | H74938046102070^{1} |
| | | | | | H74938047920130^{2} | H74938047120130^{2} |
| 40 | 37 | H74938046640750^{1} | H74938046740750^{1} | H74938046840750^{1} | H74938046940750^{1} | H74938046104070^{1} |
| | | H74938047640130^{2} | H74938047740130^{2} | H74938047840130^{2} | H74938047940130^{2} | H74938047140130^{2} |
| 60 | 57 | H74938046660750^{1} | H74938046760750^{1} | H74938046860750^{1} | H74938046960750^{1} | H74938046106070^{1} |
| | | H74938047660130^{2} | H74938047760130^{2} | H74938047860130^{2} | H74938047960130^{2} | H74938047160130^{2} |
| | | Small Vessel (SV) Stent Models | | | Large Vessel (LV) Stent Models | |
1 75 cm Length Delivery System
2 135 cm Length Delivery System
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# Stent Description
The Express LD stent is a balloon expandable device fabricated from 316L stainless steel tubing. The stent is formed by laser cutting a geometric pattern from the tube. The geometric pattern consists of large and small sinusoidal bands interconnected by longitudinally oriented struts (see Figure 1). The stent is radiopaque under fluoroscopy.
Figure 1: Photograph of Expanded Express® LD Iliac Stent
# Stent Delivery System Description
The Express LD stent delivery system (SDS) is an over-the-wire balloon catheter with a dual lumen shaft and a Y-connector hub with luer lock fittings. One lumen is used to pass the catheter over 0.035" guidewires. The second lumen communicates with the balloon and is used to inflate and deflate the balloon during the procedure. The stent is centered on the balloon between two radiopaque marker bands to aid in positioning the system during the procedure. A hydrophilic coating is applied to the catheter shaft proximal to the balloon to enhance device tracking performance. The tip of the catheter is gradually tapered to facilitate advancement of the catheter through the stenosis. A drawing of the Express LD stent delivery system is shown in Figure 2.
Figure 2: Express LD Stent Delivery System
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# VI. ALTERNATIVE PRACTICES AND PROCEDURES
There are several other alternatives for the treatment of peripheral artery disease: exercise, diet, drug therapy, percutaneous interventions, including percutaneous transluminal angioplasty (PTA) and placement of other marketed stents, and surgical bypass. 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.
# VII. MARKETING HISTORY
The Express LD Premounted Stent System has been commercially available as a biliary stent in the United States since October 2002. The Express LD Premounted Stent System has been available as a peripheral vascular stent since July 2002 in the following countries:
| Argentina | France | Luxemburg | Serbia/Montenegro |
| --- | --- | --- | --- |
| Austria | Germany | Macedonia | Singapore |
| Bahrain | Greece | Malaysia | Slovakia |
| Belgium | Hong Kong | Malta | Slovenia |
| Brazil | Hungary | Mexico | South Africa |
| Bulgaria | Iceland | Moldova | Spain |
| Colombia | India | Morocco | Sweden |
| Chile | Indonesia | Netherlands | Switzerland |
| China | Ireland | Norway | Taiwan |
| Costa Rica | Israel | New Zealand | Thailand |
| Croatia | Italy | Pakistan | Trinidad |
| Czech Rep. | Jordan | Panama | Turkey |
| Cyprus | Korea | Peru | Ukraine |
| Denmark | Kuwait | Philippines | United Kingdom |
| Dominican Republic | Latvia | Poland | Uruguay |
| Egypt | Lebanon | Portugal | Venezuela |
| El Salvador | Libya | Qatar | Vietnam |
| Estonia | Liechtenstein | Romania | Virgin Islands |
| Finland | Lithuania | Saudi Arabia | Yemen |
As of December 2008, approximately 204,000 units have been sold in the United States and approximately 112,000 units have been sold outside of the United States.
The Express LD Premounted Stent System has not been withdrawn from marketing in any country for any reason.
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# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
Based on literature, and the clinical and commercial history, the potential adverse events (e.g. complications) that may be associated with the implantation of stents in the iliac artery may include, but are not limited to:
- Abscess
- Aneurysm
- Arrhythmias
- AV fistula
- Bleeding / Hemorrhage
- Death
- Drug reaction, allergic reaction (including to antiplatelet agent, contrast medium, stent materials, or other)
- Embolization of device, air, plaque, thrombus, tissue, or other
- Emergency surgery to correct vascular complications
- Extremity ischemia / amputation
- Hematoma
- Hypotension or Hypertension
- Myocardial infarction
- Pseudoaneurysm formation
- Renal insufficiency or renal failure
- Restenosis of the stented artery
- Sepsis / Infection
- Stent migration
- Stent thrombosis
- Stroke, TIA, or other cerebrovascular accidents
- Vessel injury, including perforation, trauma, rupture, and dissection
- Vessel occlusion
For the specific adverse events that occurred in the clinical studies, please see Section X below.
# IX. SUMMARY OF PRECLINICAL STUDIES
Following is a summary of the preclinical studies performed with the Express LD Premounted Stent System. Testing included: biocompatibility testing, in vitro (physical) device testing, sterility testing, shelf-life testing, packaging testing and animal studies.
## A. Laboratory Studies
### Biocompatibility Testing
A series of biocompatibility tests and USP Physiochemical tests were conducted to demonstrate that the components of the Express LD device are non-toxic. Tests were conducted on ethylene oxide (EO) sterilized bare metal stents and stent delivery systems. In all of these test systems, the materials were non-reactive and produced no greater response than the negative control employed in each test system.
All biocompatibility testing was conducted in accordance with:
- FDA Guidance for Industry and Staff: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, January 13, 2005
- ISO 10993-1:2003, Biological Evaluation of Medical Devices: Evaluation and Testing
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The tests summarized in Table 2 have been conducted in support of the Express LD stent component as recommended for a permanent implant device contacting circulating blood.
Table 2: Stent Biocompatibility Testing Summary
| Test Performed | Test Description | Results |
| --- | --- | --- |
| Cytotoxicity | MEM Elution (ISO 10993-5) | Pass (non-cytotoxic) |
| Hemocompatibility | Hemolysis Direct Contact (ISO 10993-4) | Pass (non-hemolytic) |
| Genotoxicity | Bacterial Mutagenicity Test - Ames Assay (ISO 10993-3) | Pass (non-mutagenic) |
| | In Vitro Mouse Lymphoma (ISO 10993-3) | Pass (non-mutagenic) |
| Implantation | 180-Day Porcine Direct Implantation Study including Thrombogenicity (ISO 10993-6) | Pass (no thrombosis) |
| | 14-Day Rabbit Intramuscular Study (ISO 10993-6) | Pass (non-toxic) |
| | 30-Day Rabbit Intramuscular Study (ISO 10993-6) | Pass (non-toxic) |
| | 14-Day Mouse Repeat Dose Intravenous Toxicity (Subacute) (ISO 10993-11) | Pass (non-toxic) |
| | 90-Day Rat Chronic Toxicity Study following Subcutaneous Implantation (ISO 10993-6 and ISO 10993-11) | Pass. (No evidence of systemic toxicity. Non-irritant.) |
| Metal Extracts | Saline Leaching of Solid Samples by ICP OES | Cr, Ni and Pt are non-detectable. Fe at 0.016 μg/mL |
The tests summarized in Table 3 have been performed in support of the Express LD Premounted Stent System as recommended for a limited exposure, externally communicating, circulating blood contact device. With the exception of the Direct Contact Hemolysis testing, all tests were performed on the stent delivery system with the stent loaded.
Table 3: Delivery System Biocompatibility Testing Summary
| Test Performed | Test Description | Results |
| --- | --- | --- |
| Cytotoxicity | MEM Elution (ISO 10993-5) | Pass (non-cytotoxic) |
| Sensitization | Sensitization (Kligman Maximization) (ISO 10993-10) | Pass (non-sensitizing) |
| Intracutaneous Reactivity | Irritation (ISO 10993-10) | Pass (non-irritant) |
| Acute Systemic Toxicity | Systemic Toxicity (Acute) (ISO 10993-11) | Pass (non-toxic) |
| Pyrogenicity | Systemic Toxicity: Materials Mediated Rabbit Pyrogen (ISO 10993-11) | Pass (non-pyrogenic) |
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| Test Performed | Test Description | Results |
| --- | --- | --- |
| Hemocompatibility | ASTM Hemolysis Assay – Extract Method (ISO 10993-4) | Pass (non-hemolytic) |
| | Partial Thromboplastin Time (ISO 10993-4) | Pass (Results comparable to negative control) |
| | In Vitro Hemocompatibility Assay (ISO 10993-4) | Results comparable to Negative Control.
WBC: 85%
RBC: 87%
Hemoglobin: 87%
Hematocrit: 87%
Platelet: 93% |
| | Hemolysis Direct Contact (SDS only) (ISO 10993-4) | Pass (non-hemolytic) |
| Complement Activation | C3a and SC5b-9 Complement Activation Assay (ISO 10993-4) | Pass (negative for assay) |
| Volatile/Metal Extracts | USP Physicochemical Extracts | Pass |
| FTIR | NA | N/A – testing conducted for information purposes only. |
| Latex Detection | ASTM D6499-03 ELISA Inhibition Assay for Antigenic Protein (Natural Rubber Latex) | Below detection |
## In Vitro (Physical) Testing
A brief summary of the in vitro (physical) testing and analytical modeling performed is provided in Table 4. The table includes the device component tested, name of the test, the functional requirement of the test, and a summary of test results.
Table 4: Summary of In vitro (Physical) Testing Performed
| In vitro Test | Significance / Relevance Functional Requirement | Summary of Tests / Results |
| --- | --- | --- |
| Stent Material | | |
| Material Composition Analysis | Suitability of material for implant | Chemical composition of 316L Stainless steel tubing meets chemical composition requirements of ASTM F138-00. |
| Ultimate Tensile Strength and Percent Elongation | Stent integrity during deployment and implant life | Percent elongation and tensile strength were measured for all tubing diameters. Percent elongation and tensile strength were within specification for all samples tested. |
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| In vitro Test | Significance / Relevance Functional Requirement | Summary of Tests / Results |
| --- | --- | --- |
| Corrosion Resistance | Suitability of material for implant | All stents tested met requirements for corrosion resistance per ASTM F2129-01. |
| Stent | | |
| Dimensional Verification: Strut Width, Wall Thickness, Stent Length | Stent integrity and suitability of device for implant | Dimensional requirements for strut width, wall thickness and stent length are routinely measured during in-process testing. |
| Stent Expansion Uniformity | Uniformity of expansion following deployment | All stents, expanded to nominal diameter, met the specification. |
| Metal to Lumen Ratio | Metal to lumen contact for expanded stent | The metal to lumen ratio for each stent length and each labeled stent diameter met the requirement for metal to lumen surface contact. |
| Foreshortening | Deployed and expanded stent length | Percent of stent shortening when expanded to labeled diameter met requirements for stent length. |
| Recoil for Balloon Expandable Stents | Recoil following deployment | Stent diameter measurements with fully expanded delivery system and after delivery system removal met requirements set for recoil. |
| Stent Integrity / Stent Over-expansion | Integrity and suitability of material for implant when over-expanded | All stents tested were examined and exhibited no structural damage after over expansion. |
| Compression Resistance / Hoop Strength | Characterization of radial stiffness | Stent demonstrated acceptable compression resistance / hoop strength for all samples tested. |
| Stent Radial Stiffness and Radial Strength | Characterization of radial stiffness | Stent demonstrated acceptable radial stiffness when subjected to external radial loads. |
| Stress and Fatigue Analysis / Finite Element Analysis (FEA) | Structural integrity after stent fatigue | Results indicate a safe fatigue design in that the modeled stress of implant conditions will not result in failure of stent due to fatigue. |
| Accelerated Durability Testing / Pulsatile Fatigue | Failure modes detection over simulated 10-year use | No evidence of fatigue induced surface defects were observed in stents with 10-year simulated use. |
| Flex Fatigue | Cyclic loading forces during flexure | No stent fractures were seen in stents after flexing. |
| Magnetic Resonance Imaging (MRI) Safety and Compatibility | MRI compatibility | RF induced heating assessment – maximum temperature rise in testing would not impose a safety risk to the patient.
Displacement Force – determined to be less than would be induced by gravitational forces.
Magnetically induced torque – no torque interaction was demonstrated at 3.0 Tesla. |
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| In vitro Test | Significance / Relevance Functional Requirement | Summary of Tests / Results |
| --- | --- | --- |
| Radiopacity | Stent visibility using angiographic or radiographic imaging | Radiopacity of stents was demonstrated to be clinically acceptable. |
| Stent Conformability | Ability of the stent to bend to a particular curvature | All stents met the conformability specification of torque required to bend the stent. |
| Kink Resistance | Ability of the stent to reach a small radius of curvature without kinking | The results of the kink resistance test were considered acceptable for all curvatures tested. |
| Stent Delivery System | | |
| System Flexibility | Ability to access target vessel | System met the flexibility/tracking specification. |
| Sheath Insertion | Ability to insert and withdraw the delivery system through the recommended size introducer sheath | Delivery systems were inserted and withdrawn through introducer sheaths with forces below the specified maximum allowed removal forces. |
| Balloon Rated Burst Pressure | Ability to meet the labeled burst specifications | All catheter models tested; burst pressure data provided in product labeling. |
| Multiple Inflation (Constrained and Unconstrained) | Balloon is capable of inflation within stent multiple times | All balloon models tested met required number of inflate/deflate cycles while positioned within a stent. |
| Stent Diameter to Balloon Pressure (Compliance Chart) | Delivery system balloon compliance | Values for balloon compliance included in product labeling. |
| Stent Deployment Accuracy | To confirm that stent deploys accurately and safely | All stents deployed at pressures below the maximum allowable deployment pressure with stents being deployed accurately in position relative to the delivery catheter marketbands. |
| Stent Inner Diameter | Stent to reach labeled diameter at nominal balloon pressure. | Balloon expansion to nominal pressures resulted in stents expanding to labeled diameter. |
| Proximal Balloon Bond Strength | Tensile strength of balloon bond | All bonds tested exceeded requirements of tensile strength. |
| Crossing Profile | Ability to access target vessel | All stent systems measured below maximum allowable profile specifications. |
| Balloon Inflation and Deflation Time | Inflate and deflate rate for each delivery system model | All models tested inflated to rated burst pressure (RBP) and deflated at rates below the specification. |
| Stent Securement Post Conditioning | Force required to displace stent from delivery system | All stent models remained in place on the delivery systems at forces greater than the specified minimum force specified for model. |
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# Sterilization Verification
The Express LD Premounted Stent System is sterilized using an ethylene oxide sterilization process. Validation of the sterilization process was based on ISO 11135:1994, “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 $10^{-6}$.
# Product Shelf Life Verification
Performance testing was conducted following accelerated aging to simulate 2 years of aging to demonstrate that the device performs within product specification for the labeled shelf life of 2 years.
# Packaging Verification
Packaging verification testing was performed to demonstrate that the design of the device packaging will withstand the hazards of the distribution environment and that the sterility of the device will be maintained throughout the labeled shelf life of the product per ASTM F-88 (package peel strength) and ASTM F-1929 (packaging seal integrity).
# B. Animal Studies
The Express LD stent has been evaluated in a preclinical animal study conducted to evaluate the 30-day and 180-day vascular response to the stent, and to assess the safety of the stent via clinical, physiologic, and gross tissue observations in a healthy porcine model under Good Laboratory Practices (GLP) per 21 CFR Part 58. Additionally, the animal study evaluated the acute performance of the Express LD Premounted Stent System in a healthy porcine model. A summary of the study is provided in Table 5.
Table 5: GLP Study to Assess the Safety and Vascular Response of Express LD Stents in Iliac Arteries of Domestic Swine
| Study Objectives | Number of Animals / Time points / Devices Tested | Relevant Findings |
| --- | --- | --- |
| Establish safety of Express LD stents.
Determine mortality, morphology, morphometry parameters, device handling characteristics | • 10 animals
• 30 and 180 days
• 12 devices (6, 7, 8/37 mm) | • No device-related mortality (0/9, 0%)
• Percent stenosis low at 30 days, further decreased at 180 days
• Luminal thrombi <5% at 30 days, absent at 180 days
• Vessels were widely patent at 30 and 180 days
• >90% endothelialization at 180 days
• Inflammation grades were none to mild at 30 days, increased at 180 days but not severe
• Acceptable acute device performance for all parameters |
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This animal study demonstrated that the Express LD stent can be delivered as specified in the labeling and does not cause any adverse tissue, downstream iliac or systemic responses when placed in non-injured arteries of domestic swine.
## X. SUMMARY OF PRIMARY CLINICAL STUDY
The applicant performed a clinical study in Europe (the Netherlands, Belgium, the Czech Republic and Poland) and Canada to establish a reasonable assurance of safety and effectiveness of iliac stenting with the Express LD Stent System for the treatment of atherosclerotic lesions found in iliac arteries. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.
## A. Study Design
Subjects were treated between January 7, 2004 and February 4, 2005. The database for this PMA reflected data collected through February 15, 2007 and included 151 subjects. One additional subject was enrolled and received a study stent but was de-registered due to lack of a signed written informed consent form. There were 10 investigational sites.
The study was a prospective, multi-center, single-arm clinical study designed to assess safety and effectiveness of the Express LD stent at 6 months as compared to an objective performance criterion (OPC) representative of the Palmaz® balloon-expandable stent as reported in the literature.
Subjects were enrolled after they had signed the written informed consent form, their eligibility had been established and a guide wire was successfully passed through the target lesion(s). The study was considered complete with regard to the primary endpoint after all enrolled subjects had completed the 6-month follow-up. The study was fully completed after enrolled subjects had completed the 24-month follow-up. All major adverse events, including target lesion revascularization, were adjudicated by an independent clinical events committee.
Subject demographics, clinical history, risk factors, pre- and post-procedure lesion characteristics, procedural characteristics, and outcome variables were summarized using descriptive statistics for continuous variables (mean, standard deviation, n, minimum and maximum) and frequency tables or proportions for discrete variables.
The primary objective of this study was to demonstrate that the mean % loss of luminal diameter at six months was lower than the pre-specified, literature-derived objective performance criterion (OPC) plus delta (15% + 5% = 20%) representative of the Palmaz® balloon-expandable stent. Secondary and tertiary endpoints were summarized using survival analysis for time-to-event endpoints, descriptive statistics for continuous variables and frequency tables or proportions for discrete variables. Analyses were based on subject, limb and/or lesion depending on the variables.
A core laboratory (Bio-Imaging B.V., Leiden, the Netherlands) was employed to review angiographic data (QVA). An independent, multidisciplinary Clinical Events Committee was utilized to categorize agreed upon clinical events according to study endpoints.
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# 1. Clinical Inclusion and Exclusion Criteria
Enrollment in the MELODIE study was limited to patients who met the following inclusion criteria:
- Patient ≥ 18 years old
- Patient signed an informed consent form
- Patient with chronic symptomatic (Fontaine class IIa, IIb, and III) atherosclerotic disease in the iliac arteries
- Atherosclerotic de novo or restenotic lesions in the common and/or external iliac artery
- Baseline percent diameter stenosis of ≥ 50% at the target lesion
- Reference Vessel Diameter ≥ 5 mm and ≤ 10 mm
- Patient has at least one sufficient ipsilateral infrapopliteal run-off vessel
- Length of diseased segment(s) ≤ 10 cm and can be treated with a maximum of two overlapping Express LD Iliac stents
Patients were not permitted to enroll in the MELODIE study if they met any of the following exclusion criteria:
- Patients with chronic symptomatic atherosclerotic disease classified as Fontaine class I or IV
- Patients with acute leg ischemia
- Pregnant subjects
- Patients with uncorrected bleeding disorders (platelet count < 150,000/mm³, or platelet count > 450,000/mm³) or subjects who could not receive anticoagulant or antiplatelet aggregation therapy (e.g. subjects with active peptic ulcer or gastrointestinal bleeding)
- Patients with a known allergy to stainless steel.
- Patients with known anaphylactoid or other non-anaphylactic allergic reactions to contrast agents that could not be adequately pre-medicated prior to the index procedure
- Patients with a life expectancy of less than 24 months due to other medical comorbid condition(s) that could limit the subject’s ability to take part in the study, the subject’s compliance with follow-up requirements or could impact on the scientific integrity of the study
- Patients currently participating in other investigational drug or device studies that had not completed the primary endpoint or that clinically interfered with the endpoints of this study
- Patients who had already participated in this study
- Patients with prior or planned bypass surgery at the target vessel(s)
- Patients with prior stent placement in the target vessel(s)
- Patients with any previous coronary intervention within 30 days of enrollment in this study, or planned coronary intervention within 30 days after enrollment into this study
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# Angiographic Exclusion Criteria:
- Patients in whom the origin of the profunda femoris and superficial femoral artery was occluded in the limb supplied by the iliac artery to be treated without planned surgical repair
- Patients with heavily calcified and excessive tortuous lesions as determined by angiography at the target site(s)
- Patients with target lesion(s) within or adjacent to the proximal or distal segment of an aneurysm
- Patients with persistent, acute intraluminal thrombus of the proposed target lesion(s) site post thrombolytic therapy
- Patients with perforated vessels evidenced by extravasation of contrast media.
- Patients with multiple lesions in the target vessel(s)
# 2. Follow-up Schedule
All subjects were scheduled to return for follow-up examinations at 30 days and 6 months post-index procedure, with additional follow-up at 12 months and 24 months post-index procedure.
The schedule of observations and assessments that took place during the study is presented in Table 6 below.
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Table 6: Study Events Schedule
| | Before implantation stent | Post-Procedure | Hospital Discharge | 30 Days (30±14 days) | 6 months (180±30 days) | 1 year (365±60 days) | 2 years (730±60 days) |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Screening | | | | | | | |
| Written Informed Consent | • | | | | | | |
| Demographics and Medical History | • | | | | | | |
| Pregnancy test in females of child-bearing potential | • | | | | • | • | • |
| Platelet count | • | | | | | | |
| Eligibility check | • | | | | | | |
| Fontaine classification | • | | | | | | |
| Baseline angiography | • | | | | | | |
| ABI | • | | | | | | |
| | | | | | | | |
| Angiography | | • | | | • | | |
| CTA | | | | | | • | • |
| ABI | | | • | • | • | • | • |
| Fontaine classification | | | | • | • | • | • |
| TLR | | | • | • | • | • | • |
| Safety Assessments | | | | | | | |
| Adverse and Serious Adverse (Device) Events | | • | • | • | • | • (Only SA(D)Es) | |
| Major Adverse Events | | • | • | • | • | • | • |
| Other assessments | | | | | | | |
| Antiplatelet therapy
Anticoagulant therapy | • | • | • | • | • | • | • |
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# 3. Clinical Endpoints
With regards to safety, Adverse (Device) Events (AEs) were collected throughout the study with a pre-specified subset of events reviewed and adjudicated by an independent Clinical Events Committee.
With regards to effectiveness, the primary endpoint was angiographic mean percent loss of luminal diameter at 6 months post-procedure defined as ((Post-procedure MLD – Follow-up MLD)/Post-procedure MLD) x100 which was compared against an objective performance criterion (OPC) representative of the Palmaz® balloon-expandable stent as reported in the literature.
With regard to success/failure criteria, the objective of the study was to demonstrate non-inferiority of treatment with the Express LD stent compared to an OPC representative of treatment with the Palmaz® stent. The primary efficacy endpoint was the mean percent loss of luminal diameter at 6 months post-procedure as determined by angiography (% Late Loss). The % Late Loss was 16.2%. This value was compared to the OPC of 15% plus a non-inferiority margin (delta) of 5%. The study was deemed successful as a statistically significant primary hypothesis test result (p=0.0061) led to rejection of the null hypothesis of inferiority and a conclusion of non-inferiority.
# B. Accountability of PMA Cohort
At the time of database lock, of 151 subjects enrolled in the PMA study, 92% (138/150) of subjects were available for analysis at the completion of the 6 month follow-up, which was the final visit evaluated for safety and effectiveness as the basis for the PMA submission. One hundred, twenty-three subjects (123) completed follow-up through the two year follow-up visit. Table 7 details the follow-up compliance throughout the entire study.
Table 7: Subject Disposition - Clinical Follow-up Compliance
| | Total |
| --- | --- |
| All Subjects Enrolled | 151 |
| All Treated Subjects | 151 |
| No 30-Day Clinical Follow-up | 4 |
| Prematurely Discontinued | 0 |
| Died | 0 |
| Device or Procedure Related Death | 0 |
| Withdrew Consent | 0 |
| Lost to Follow-up | 0 |
| Adverse Event | 0 |
| Other | 0 |
| Missed 30-Day Visit | 4 |
| 30-Day Clinical Follow-Up Compliance | 97.4% (147/151) |
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| | Total |
| --- | --- |
| No 6-Month Clinical Follow-up | 13 |
| Prematurely Discontinued | 4 |
| Died | 1 |
| Device or Procedure Related Death | 0 |
| Withdrew Consent | 1 |
| Lost to Follow-up | 2 |
| Adverse Event | 0 |
| Other | 0 |
| Missed 6-Month Visit | 9 |
| 6-Month Clinical Follow-Up Compliance | 92.0% (138/150) |
| 6-Month Angiographic Follow-Up (Subject) | 122 |
| 6-Month Angiographic Follow-Up (Lesion) | 130 |
| No 12-Month Clinical Follow-up | 18 |
| Prematurely Discontinued | 15 |
| Died | 3 |
| Device or Procedure Related Death | 0 |
| Withdrew Consent | 6 |
| Lost to Follow-up | 6 |
| Adverse Event | 0 |
| Other | 0 |
| Missed 12-Month Visit | 3 |
| 12-Month Clinical Follow-Up Compliance | 89.9% (133/148) |
| 12-Month CTA Follow-up (Subject) | 123 |
| 12-Month CTA Follow-up (Lesion) | 132 |
| No 24-Month Clinical Follow-up | 28 |
| Prematurely Discontinued | 26 |
| Died | 9 |
| Device or Procedure Related Death | 0 |
| Withdrew Consent | 8 |
| Lost to Follow-up | 8 |
| Adverse Event | 0 |
| Other | 1 |
| Missed 24-Month Visit | 2 |
| 24-Month Clinical Follow-Up Compliance | 86.6% (123/142) |
| 24-Month CTA Follow-up (Subject) | 119 |
| 24-Month CTA Follow-up (Lesion) | 127 |
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C. Study Population Demographics and Baseline Parameters
The patient population in the MELODIE study is representative of the US population with PVD that is eligible to receive an iliac stent. The differences seen between the various iliac stenting study populations reported in the literature compared to MELODIE are minimal and do not affect the clinical interpretation of the study results. Baseline demographics and lesion characteristics of the MELODIE subjects are summarized in Table 8 through Table 10 below.
Table 8: Baseline Demographic Characteristics
| Characteristic | (N =151 subjects) | [95% CI] |
| --- | --- | --- |
| Demographics | | |
| Male | 74.8% (113/151) | [67.1%, 81.5%] |
| Female | 25.2% (38/151) | [18.5%, 32.9%] |
| Age (yr) | 60.1±8.4 (151)
(43.0, 84.5) | [58.8, 61.5] |
| Risk factors | | |
| Known Smoking, Ever | 87.4% (132/151) | [81.0%, 92.3%] |
| current | 62.1% (82/132) | [53.3%, 70.4%] |
| previous | 37.9% (50/132) | [29.6%, 46.7%] |
| Known Medically Treated Diabetes | 12.6% (19/151) | [7.7%, 19.0%] |
| Insulin Requiring | 6.0% (9/151) | [2.8%, 11.0%] |
| Non-insulin Requiring | 6.6% (10/151) | [3.2%, 11.8%] |
| Hypertension | 60.3% (91/151) | [52.0%, 68.1%] |
| Hyperlipidemia | 54.4% (80/147) | [46.0%, 62.6%] |
| Comorbidities | | |
| History of Myocardial Infarction | 22.0% (33/150) | [15.7%, 29.5%] |
| Angina Pectoris | 14.7% (22/150) | [9.4%, 21.4%] |
| Stroke or Transient Ischemic Attack | 7.3% (11/151) | [3.7%, 12.7%] |
| Renal Disease | 1.3% (2/151) | [0.2%, 4.7%] |
| Chronic Obstructive Pulmonary Disease | 8.7% (13/150) | [4.7%, 14.4%] |
| Previous treatment of atherosclerotic lesions in the iliac artery | 10.7% (16/149) | [6.3%, 16.9%] |
| Previous vascular surgical intervention in legs | 13.9% (21/151) | [8.8%, 20.5%] |
| Other Disease | 28.5% (43/151) | [21.4%, 36.4%] |
Table 9: Baseline Clinical Characteristics
| Characteristic | (N = 151 subjects) | [95% CI] |
| --- | --- | --- |
| Platelet count (x10³) | 234.0±59.4 (143)
(115.0, 420.0) | [224.3, 243.8] |
| Claudication | | |
| >1000 meters | 1.3% (2/150) | [0.2%, 4.7%] |
| 200 – 1000 meters | 15.3% (23/150) | [10.0%, 22.1%] |
| < 200 meters | 83.3% (125/150) | [76.4%, 88.9%] |
| Tissue Loss | | |
| Right leg | 0.0% (0/145) | [0.0%, 2.5%] |
| Left leg | 0.0% (0/145) | [0.0%, 2.5%] |
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Table 10: Baseline Lesion Characteristics Determined by QVA
| Characteristic | (N = 163 lesions) | [95% CI] |
| --- | --- | --- |
| Target Lesion Location | | |
| Right Common Iliac Artery | 22.1% (36/163) | [16.0%, 29.2%] |
| Right Common Iliac Artery Extending Into External | 3.1% (5/163) | [1.0%, 7.0%] |
| Right External Iliac Artery | 19.0% (31/163) | [13.3%, 25.9%] |
| Left Common Iliac Artery | 19.0% (31/163) | [13.3%, 25.9%] |
| Left Common Iliac Artery Extending Into External | 3.7% (6/163) | [1.4%, 7.8%] |
| Left External Iliac Artery | 33.1% (54/163) | [26.0%, 40.9%] |
| Minimum Lumen Diameter (MLD, mm) | 3.3±1.4 (99)
(0.0, 8.2) | [3.0, 3.5] |
| Reference Vessel Diameter (RVD, mm) | 7.9±1.6 (99)
(5.0, 13.3) | [7.5, 8.2] |
| Mean Lumen Diameter (mm) | 6.9±1.4 (99)
(4.0, 11.9) | [6.7, 7.2] |
| Percent Diameter Stenosis (%DS) | 62.9±19.3 (116)
(30.2, 100.0) | [59.4, 66.4] |
| Target Lesion Length (mm) | 32.0±21.7 (99)
(3.9, 99.1) | [27.7, 36.3] |
D. Safety and Effectiveness Results
1. Safety Results
The analysis of safety was based on all subjects enrolled in the MELODIE study. Table 11 and Table 12 provide the observed adverse event experience reported in the MELODIE Clinical Study.
Table 11: Major Adverse Events (CEC Adjudicated), All Treated Subjects (N=151)
| Events | (N=151 Subjects) | | [95% CI] |
| --- | --- | --- | --- |
| | # of Events | Subjects with Events | |
| Procedure through Hospital Discharge | | | |
| MAE | 1 | 0.7% (1/151) | [0.0%, 3.6%] |
| Device/Procedure Related Death | 0 | 0.0% (0/151) | [0.0%, 2.4%] |
| TLR | 1 | 0.7% (1/151) | [0.0%, 3.6%] |
| Distal Embolization | 0 | 0.0% (0/151) | [0.0%, 2.4%] |
| Procedure through 30 Days | | | |
| MAE | 1 | 0.7% (1/151) | [0.0%, 3.6%] |
| Device/Procedure Related Death | 0 | 0.0% (0/151) | [0.0%, 2.4%] |
| TLR | 1 | 0.7% (1/151) | [0.0%, 3.6%] |
| Distal Embolization | 0 | 0.0% (0/151) | [0.0%, 2.4%] |
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| Events | (N=151 Subjects) | | [95% CI] |
| --- | --- | --- | --- |
| | # of Events | Subjects with Events | |
| Procedure through 6 Months | | | |
| MAE | 10 | 6.3% (9/144) | [2.9%, 11.5%] |
| Device/Procedure Related Death | 0 | 0.0% (0/144) | [0.0%, 2.5%] |
| TLR | 10 | 6.3% (9/144) | [2.9%, 11.5%] |
| Distal Embolization | 0 | 0.0% (0/144) | [0.0%, 2.5%] |
| Procedure through 12 Months | | | |
| MAE | 13 | 8.9% (12/135) | [4.7%, 15.0%] |
| Device/Procedure Related Death | 0 | 0.0% (0/135) | [0.0%, 2.7%] |
| TLR | 13 | 8.9% (12/135) | [4.7%, 15.0%] |
| Distal Embolization | 0 | 0.0% (0/135) | [0.0%, 2.7%] |
| Procedure through 24 Months | | | |
| MAE | 17 | 10.2% (13/127) | [5.6%, 16.9%] |
| Device/Procedure Related Death | 0 | 0.0% (0/127) | [0.0%, 2.9%] |
| TLR | 17 | 10.2% (13/127) | [5.6%, 16.9%] |
| Distal Embolization | 0 | 0.0% (0/127) | [0.0%, 2.9%] |
| Procedure through End of Study | | | |
| MAE | 17 | 10.2% (13/127) | [5.6%, 16.9%] |
| Device/Procedure Related Death | 0 | 0.0% (0/127) | [0.0%, 2.9%] |
| TLR | 17 | 10.2% (13/127) | [5.6%, 16.9%] |
| Distal Embolization | 0 | 0.0% (0/127) | [0.0%, 2.9%] |
For each event type, rates are based on the number of subjects with at least one event.
"Events" numbers are total episodes of each type of event among all subjects.
"Subjects with Event" numbers are counts of subjects who experienced one or more episodes of the event.
"Events" numbers for "Any MAE" are the sum of the individual MAE component totals.
"Subjects with Event" numbers for "Any MAE" may be less than the sum of the individual "Subjects with Event" totals since a subject could have experienced multiple events of different types.
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Table 12: Principal Safety Results; All Treated Subjects (N=151)
| Safety Measures | (N=151 subjects)
(N=163 lesions)
(N=159 limbs) | [95% CI] |
| --- | --- | --- |
| Lesion Based | | |
| Target Lesion Revascularization | | |
| In-Hospital | 0.6% (1/163) | [0.0%, 3.4%] |
| 30 Days | 0.6% (1/163) | [0.0%, 3.4%] |
| 6 Months | 6.5% (10/154) | [3.2%, 11.6%] |
| 12 Months | 9.0% (13/145) | [4.9%, 14.8%] |
| 24 Months | 10.3% (14/136) | [5.7%, 16.7%] |
| End of Study | 10.3% (14/136) | [5.7%, 16.7%] |
| Subject Based | | |
| In-Hospital Major Adverse Events (MAE) | 0.7% (1/151) | [0.0%, 3.6%] |
| Device/Procedure Related Death | 0.0% (0/151) | [0.0%, 2.4%] |
| TLR | 0.7% (1/151) | [0.0%, 3.6%] |
| Distal Embolization | 0.0% (0/151) | [0.0%, 2.4%] |
| Major Adverse Events (MAE) through 30 Days | 0.7% (1/151) | [0.0%, 3.6%] |
| Device/Procedure Related Death | 0.0% (0/151) | [0.0%, 2.4%] |
| TLR | 0.7% (1/151) | [0.0%, 3.6%] |
| Distal Embolization | 0.0% (0/151) | [0.0%, 2.4%] |
| Major Adverse Events (MAE) through 6 Months | 6.3% (9/144) | [2.9%, 11.5%] |
| Device/Procedure Related Death | 0.0% (0/144) | [0.0%, 2.5%] |
| TLR | 6.3% (9/144) | [2.9%, 11.5%] |
| Distal Embolization | 0.0% (0/144) | [0.0%, 2.5%] |
| Major Adverse Events (MAE) through 12 Months | 8.9% (12/135) | [4.7%, 15.0%] |
| Device/Procedure Related Death | 0.0% (0/135) | [0.0%, 2.7%] |
| TLR | 8.9% (12/135) | [4.7%, 15.0%] |
| Distal Embolization | 0.0% (0/135) | [0.0%, 2.7%] |
| Major Adverse Events (MAE) between 24 Months | 10.2% (13/127) | [5.6%, 16.9%] |
| Device/Procedure Related Death | 0.0% (0/127) | [0.0%, 2.9%] |
| TLR | 10.2% (13/127) | [5.6%, 16.9%] |
| Distal Embolization | 0.0% (0/127) | [0.0%, 2.9%] |
| Major Adverse Events (MAE) through End of Study | 10.2% (13/127) | [5.6%, 16.9%] |
| Device/Procedure Related Death | 0.0% (0/127) | [0.0%, 2.9%] |
| TLR | 10.2% (13/127) | [5.6%, 16.9%] |
| Distal Embolization | 0.0% (0/127) | [0.0%, 2.9%] |
| Non-MAE Death | | |
| Through 210 days | 1.4% (2/144) | [0.2%, 4.9%] |
| Through 365 days | 2.2% (3/137) | [0.5%, 6.3%] |
| Through 730 days | 5.3% (7/131) | [2.2%, 10.7%] |
| Through End of Study | 6.9% (9/131) | [3.2%, 12.6%] |
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# 2. Effectiveness Results
Primary, secondary, and tertiary safety and effectiveness results and major adverse event rates are summarized in Table 13, Table 14, Table 15, and Figure 3.
Table 13: Principal Effectiveness and Safety Results, All Treated Subjects (N=151)
| Effectiveness and Safety Measures | (N=151 subjects)
(N=163 lesions)
(N=159 limbs) | [95% CI] |
| --- | --- | --- |
| *Effectiveness Measures* | | |
| Lesion Based | | |
| Angiographic Mean Percent Loss of Lumen Diameter at 6 Months | 16.2±18.4 (112)
(-18.5, 100.0) | [12.8, 19.6] |
| Angiographic Binary Restenosis at 6 Months | 5.6% (7/124) | [2.3%, 11.3%] |
| Angiographic Percent Diameter Stenosis at 6 Months | 24.3±16.0 (124)
(-9.5, 100.0) | [21.5, 27.1] |
| CTA Target Lesion Patency at 12 Months | 97.2% (103/106) | [92.0%, 99.4%] |
| CTA Target Lesion Patency at 24 Months | 94.1% (95/101) | [87.5%, 97.8%] |
| Technical Success | 98.0% (147/150) | [94.3%, 99.6%] |
| *Subject Based* | | |
| Procedural Success | 97.1% (136/140) | [92.8%, 99.2%] |
| Clinical Success | | |
| 30 Days | 88.2% (127/144) | [81.8%, 93.0%] |
| 6 Months | 83.1% (108/130) | [75.5%, 89.1%] |
| 12 Months | 82.5% (99/120) | [74.5%, 88.8%] |
| 24 Months | 78.8% (89/113) | [70.1%, 85.9%] |
| *Limb Based* | | |
| Hemodynamic Success | | |
| In-Hospital | 75.3% (116/154) | [67.7%, 81.9%] |
| 30 Days | 79.3% (119/150) | [72.0%, 85.5%] |
| 6 Months | 71.2% (94/132) | [62.7%, 78.8%] |
| 12 Months | 60.2% (71/118) | [50.7%, 69.1%] |
| 24 Months | 57.9% (66/114) | [48.3%, 67.1%] |
| *Safety Measures* | | |
| Lesion Based | | |
| Target Lesion Revascularization | | |
| In-Hospital | 0.6% (1/163) | [0.0%, 3.4%] |
| 30 Days | 0.6% (1/163) | [0.0%, 3.4%] |
| 6 Months | 6.5% (10/154) | [3.2%, 11.6%] |
| 12 Months | 9.0% (13/145) | [4.9%, 14.8%] |
| 24 Months | 10.3% (14/136) | [5.7%, 16.7%] |
| End of Study | 10.3% (14/136) | [5.7%, 16.7%] |
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| Effectiveness and Safety Measures | (N=151 subjects)
(N=163 lesions)
(N=159 limbs) | [95% CI] |
| --- | --- | --- |
| Subject Based | | |
| In-Hospital Major Adverse Events (MAE) | 0.7% (1/151) | [0.0%, 3.6%] |
| Device/Procedure Related Death | 0.0% (0/151) | [0.0%, 2.4%] |
| TLR | 0.7% (1/151) | [0.0%, 3.6%] |
| Distal Embolization | 0.0% (0/151) | [0.0%, 2.4%] |
| Major Adverse Events (MAE) through 30 Days | 0.7% (1/151) | [0.0%, 3.6%] |
| Device/Procedure Related Death | 0.0% (0/151) | [0.0%, 2.4%] |
| TLR | 0.7% (1/151) | [0.0%, 3.6%] |
| Distal Embolization | 0.0% (0/151) | [0.0%, 2.4%] |
| Major Adverse Events (MAE) through 6 Months | 6.3% (9/144) | [2.9%, 11.5%] |
| Device/Procedure Related Death | 0.0% (0/144) | [0.0%, 2.5%] |
| TLR | 6.3% (9/144) | [2.9%, 11.5%] |
| Distal Embolization | 0.0% (0/144) | [0.0%, 2.5%] |
| Major Adverse Events (MAE) through 12 Months | 8.9% (12/135) | [4.7%, 15.0%] |
| Device/Procedure Related Death | 0.0% (0/135) | [0.0%, 2.7%] |
| TLR | 8.9% (12/135) | [4.7%, 15.0%] |
| Distal Embolization | 0.0% (0/135) | [0.0%, 2.7%] |
| Major Adverse Events (MAE) between 24 Months | 10.2% (13/127) | [5.6%, 16.9%] |
| Device/Procedure Related Death | 0.0% (0/127) | [0.0%, 2.9%] |
| TLR | 10.2% (13/127) | [5.6%, 16.9%] |
| Distal Embolization | 0.0% (0/127) | [0.0%, 2.9%] |
| Major Adverse Events (MAE) through End of Study | 10.2% (13/127) | [5.6%, 16.9%] |
| Device/Procedure Related Death | 0.0% (0/127) | [0.0%, 2.9%] |
| TLR | 10.2% (13/127) | [5.6%, 16.9%] |
| Distal Embolization | 0.0% (0/127) | [0.0%, 2.9%] |
| Non-MAE Death | | |
| Through 210 days | 1.4% (2/144) | [0.2%, 4.9%] |
| Through 365 days | 2.2% (3/137) | [0.5%, 6.3%] |
| Through 730 days | 5.3% (7/131) | [2.2%, 10.7%] |
| Through End of Study | 6.9% (9/131) | [3.2%, 12.6%] |
* All measurements taken after a confirmed TLR are excluded from this table.
"Technical Success" defined as successful delivery and deployment of the study stent to the target lesion with ≤ 30% residual stenosis as determined by angiography.
"Procedural Success" defined as Technical Success without the occurrence of Major Adverse Events during the procedure and immediately post-procedure until discharge.
"Clinical Success" defined as an improvement of the Fontaine classification by at least one class compared to the pre-procedure classification.
"Hemodynamic Success" defined as improved ankle brachial index (ABI) by ≥ 0.1 above pre-procedure value and not deteriorated by > 0.15 from the maximum post-procedure value.
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Table 14: Primary Endpoint: Angiographic Mean % Loss of Luminal Diameter, All Treated Lesions (N=163) in All Treated Subjects (N=151)
| | (N=112 paired lesions) | Literature OPC | Delta | p-value |
| --- | --- | --- | --- | --- |
| Angiographic Mean % Loss of Luminal Diameter | 16.21±18.42 | 15.0±16.0 | 5.0 | 0.0061 |
* All measurements taken after a confirmed TLR are excluded from this table.
Table 15: Summary of Secondary and Tertiary Endpoints, All Treated Subjects (N=151)
| Effectiveness and Safety Measures | (N=151 subjects) (N=163 lesions) (N=159 limbs) | [95% CI] |
| --- | --- | --- |
| **Effectiveness Measures** | | |
| Lesion Based | | |
| Angiographic Binary Restenosis at 6 Months | 5.6% (7/124) | [2.3%, 11.3%] |
| Angiographic Percent Diameter Stenosis at 6 Months | 24.3±16.0 (124) (-9.5, 100.0) | [21.5, 27.1] |
| CTA Target Lesion Patency at 12 Months | 97.2% (103/106) | [92.0%, 99.4%] |
| CTA Target Lesion Patency at 24 Months | 94.1% (95/101) | [87.5%, 97.8%] |
| Technical Success | 98.0% (147/150) | [94.3%, 99.6%] |
| Subject Based | | |
| Procedural Success | 97.1% (136/140) | [92.8%, 99.2%] |
| Clinical Success | | |
| 30 Days | 88.2% (127/144) | [81.8%, 93.0%] |
| 6 Months | 83.1% (108/130) | [75.5%, 89.1%] |
| 12 Months | 82.5% (99/120) | [74.5%, 88.8%] |
| 24 Months | 78.8% (89/113) | [70.1%, 85.9%] |
| Limb Based | | |
| Hemodynamic Success | | |
| In-Hospital | 75.3% (116/154) | [67.7%, 81.9%] |
| 30 Days | 79.3% (119/150) | [72.0%, 85.5%] |
| 6 Months | 71.2% (94/132) | [62.7%, 78.8%] |
| 12 Months | 60.2% (71/118) | [50.7%, 69.1%] |
| 24 Months | 57.9% (66/114) | [48.3%, 67.1%] |
| **Safety Measures** | | |
| Lesion Based | | |
| Target Lesion Revascularization | | |
| In-Hospital | 0.6% (1/163) | [0.0%, 3.4%] |
| 30 Days | 0.6% (1/163) | [0.0%, 3.4%] |
| 6 Months | 6.5% (10/154) | [3.2%, 11.6%] |
| 12 Months | 9.0% (13/145) | [4.9%, 14.8%] |
| 24 Months | 10.3% (14/136) | [5.7%, 16.7%] |
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| Subject Based | | |
| --- | --- | --- |
| Major Adverse Events (MAE) | | |
| In-Hospital | 0.7% (1/151) | [0.0%, 3.6%] |
| 30 Days | 0.7% (1/151) | [0.0%, 3.6%] |
| 6 Months | 6.3% (9/144) | [2.9%, 11.5%] |
| 12 Months | 8.9% (12/135) | [4.7%, 15.0%] |
| 24 Months | 10.2% (13/127) | [5.6%, 16.9%] |
All measurements taken after a confirmed TLR are excluded from this table.
The Kaplan-Meier curve for all pivotal subjects is presented in Figure 3. As can be seen, major adverse events occur with acceptable rates throughout the study.
Figure 3: Freedom from Major Adverse Events (CEC Adjudicated) to End of Study, Event-Free Survival $\pm 1.96$ SE, All Enrolled Subjects (N=151)
| (N = 151 Subjects) | 0 | 30 | 60 | 90 | 180 | 210 | 365 | 730 | End of Study |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Entered | 151 | 150 | 149 | 145 | 144 | 141 | 129 | 123 | 71 |
| Censored | 0 | 1 | 4 | 1 | 1 | 6 | 3 | 51 | 71 |
| At Risk | 151 | 149.5 | 147 | 144.5 | 143.5 | 138 | 127.5 | 97.5 | 35.5 |
| Events | 1 | 0 | 0 | 0 | 2 | 6 | 3 | 1 | 0 |
| Events/Month | 30.0 | 0.0 | 0.0 | 0.0 | 0.7 | 6.0 | 0.6 | 0.1 | 0.0 |
| Event Free | 99.3% | 99.3% | 99.3% | 99.3% | 98.0% | 93.7% | 91.5% | 90.7% | -- |
| Std Error | 0.7% | 0.7% | 0.7% | 0.7% | 1.2% | 2.0% | 2.3% | 2.4% | -- |
Intervals are inclusive, e.g., interval 180 is defined as 91-180 days, inclusive.
Entered: # subjects eligible at the start of the interval.
Censored: # subjects censored during the interval.
At risk is # entered – half of # censored in the time interval.
Events: # subjects with events in the interval.
Survival rate estimates are from the Kaplan-Meier method, reported at each interval’s end.
The standard error was calculated using Greenwood’s formula.
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# XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION
## A. Retrospective Performance Goal
To assess further the safety and effectiveness of the Express LD stent in the treatment of stenosed or occlusive atherosclerotic iliac artery disease, a composite safety and effectiveness performance goal was developed from contemporary literature, and retrospectively applied to the MELODIE data.
The endpoint for this retrospective performance goal is a composite of the following safety and effectiveness endpoints:
- procedure/device-related death to 30 days
- in-hospital MI
- TLR through 12 months (365 days)
- amputation of the target limb through 12 months (365 days)
Based on a review of the literature, the expected rate for this endpoint at 12 months was estimated to be 10%. Using a delta of 9%, the performance goal for this endpoint was 19%.
The observed rate of this endpoint in the MELODIE study was 11.1% with a one-sided 95% upper confidence limit of 16.7% (see Table 16). This is lower than the performance goal of 19%, further supporting the safety and effectiveness of iliac stenting with the Express LD stent.
Table 16: Analysis of 12-month Composite Safety and Effectiveness Endpoint for the MELODIE study, All Treated Subjects (N=151)
| Endpoint | (N = 151. Subjects) | One-sided 95% upper CI to test the performance goal* |
| --- | --- | --- |
| 12-Month MAE | 11.1% (15/135) | 16.7% |
| Procedure/device-related death to 30 days | 0.0% (0/135) | |
| In-hospital MI | 0.7% (1/135) | |
| TLR to 12 months | 8.9% (12/135) | |
| Amputation to 12 months | 2.2% (3/135) | |
* The hypotheses for testing the performance goal of 19% are: H₀: π≥19% and H₁: π<19%, where π is the rate of 12-month MAE for the MELODIE study. To conclude the Express LD stent is significantly less than the performance goal, the one-sided 95% upper confidence interval under H₀ from the MELODIE study must be less than 19%.
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# B. Overlapping Stent Analysis
An analysis was completed comparing outcomes in subjects with overlapping stents to those subjects without overlapping stents. Twenty-seven subjects in the MELODIE study had overlapping stents placed. Table 17 shows the number of subjects that had overlapping stents by overlap configuration.
Table 17: Quantity of Overlapping Stent Configurations
| Stent Size | 27 mm | 37 mm | 57 mm |
| --- | --- | --- | --- |
| 25 mm | 0 | 1 | 0 |
| 27 mm | 1 | 2 | 1 |
| 37 mm | | 8 | 7 |
| 57 mm | | | 7 |
Table 18 displays outcomes in MELODIE subjects treated with overlapping stents compared to those without overlapping stents. In general, outcomes in patients treated with overlapping stents are similar to outcomes in patients not treated with overlapping stents. Technical, procedural and hemodynamic success endpoints were very similar between the two groups. There were no device or procedure related deaths and no instances of distal embolization in either group. Any conclusions drawn from Table 18 must be interpreted with caution as the MELODIE study was not designed or powered to compare outcomes in patients with and without overlapping stents. It is generally known that there is a trend for more MAEs, particularly TVR, in patients with overlapped stents and longer lesions in the peripheral arteries, just as is seen in the coronary arteries.
Table 18: Principal Effectiveness and Safety Results, Patients with overlapping stents versus patients with no overlapping stents
| | Subjects with overlapping stents | | Subjects with no overlapping stents | |
| --- | --- | --- | --- | --- |
| Effectiveness and Safety Measures | (N=27 subjects)
(N=34 lesions)
(N=32 limbs) | [95% CI] | (N=124 subjects)
(N=129 lesions)
(N=127 limbs) | [95% CI] |
| Effectiveness Measures | | | | |
| Lesion Based | | | | |
| Angiographic Mean Percent Loss of Lumen Diameter at 6 Months | 18.3±22.4 (26)
(-18.5, 100.0) | [9.7, 26.9] | 15.6±17.1 (86)
(-18.3, 100.0) | [12.0, 19.2] |
| Angiographic Binary Restenosis at 6 Months | 11.1% (3/27) | [2.4%, 29.2%] | 4.1% (4/97) | [1.1%, 10.2%] |
| Angiographic Percent Diameter Stenosis at 6 Months | 28.2±19.3 (27)
(8.8, 100.0) | [20.9, 35.5] | 23.2±14.8 (97)
(-9.5, 100.0) | [20.2, 26.1] |
| CTA Target Lesion Patency at 12 Months | 90.9% (20/22) | [70.8%, 98.9%] | 98.8% (83/84) | [93.5%, 100.0%] |
| CTA Target Lesion Patency at 24 Months | 90.5% (19/21) | [69.6%, 98.8%] | 95.0% (76/80) | [87.7%, 98.6%] |
| Technical Success | 96.9% (31/32) | [83.8%, 99.9%] | 98.3% (116/118) | [94.0%, 99.8%] |
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| | Subjects with overlapping stents | | Subjects with no overlapping stents | |
| --- | --- | --- | --- | --- |
| Effectiveness and Safety Measures | (N=27 subjects)
(N=34 lesions)
(N=32 limbs) | [95% CI] | (N=124 subjects)
(N=129 lesions)
(N=127 limbs) | [95% CI] |
| **Subject Based** | | | | |
| Procedural Success | 96.2% (25/26) | [80.4%, 99.9%] | 97.4% (111/114) | [92.5%, 99.5%] |
| Clinical Success | | | | |
| 30 Days | 92.0% (23/25) | [74.0%, 99.0%] | 87.4% (104/119) | [80.1%, 92.8%] |
| 6 Months | 91.3% (21/23) | [72.0%, 98.9%] | 81.3% (87/107) | [72.6%, 88.2%] |
| 12 Months | 90.5% (19/21) | [69.6%, 98.8%] | 80.8% (80/99) | [71.7%, 88.0%] |
| 24 Months | 95.0% (19/20) | [75.1%, 99.9%] | 75.3% (70/93) | [65.2%, 83.6%] |
| **Limb Based** | | | | |
| Hemodynamic Success | | | | |
| In-Hospital | 81.3% (26/32) | [63.6%, 92.8%] | 73.8% (90/122) | [65.0%, 81.3%] |
| 30 Days | 80.6% (25/31) | [62.5%, 92.5%] | 79.0% (94/119) | [70.6%, 85.9%] |
| 6 Months | 89.3% (25/28) | [71.8%, 97.7%] | 66.3% (69/104) | [56.4%, 75.3%] |
| 12 Months | 73.9% (17/23) | [51.6%, 89.8%] | 56.8% (54/95) | [46.3%, 67.0%] |
| 24 Months | 69.6% (16/23) | [47.1%, 86.8%] | 54.9% (50/91) | [44.2%, 65.4%] |
| **Safety Measures** | | | | |
| **Lesion Based** | | | | |
| Target Lesion Revascularization | | | | |
| In-Hospital | 0.0% (0/34) | [0.0%, 10.3%] | 0.8% (1/129) | [0.0%, 4.2%] |
| 30 Days | 0.0% (0/34) | [0.0%, 10.3%] | 0.8% (1/129) | [0.0%, 4.2%] |
| 6 Months | 12.9% (4/31) | [3.6%, 29.8%] | 4.9% (6/123) | [1.8%, 10.3%] |
| 12 Months | 16.1% (5/31) | [5.5%, 33.7%] | 7.0% (8/114) | [3.1%, 13.4%] |
| 24 Months | 16.7% (5/30) | [5.6%, 34.7%] | 8.5% (9/106) | [4.0%, 15.5%] |
| End of Study | 16.7% (5/30) | [5.6%, 34.7%] | 8.5% (9/106) | [4.0%, 15.5%] |
| **Subject Based** | | | | |
| In-Hospital Major Adverse Events (MAE) | 0.0% (0/27) | [0.0%, 12.8%] | 0.8% (1/124) | [0.0%, 4.4%] |
| Device/Procedure Related Death | 0.0% (0/27) | [0.0%, 12.8%] | 0.0% (0/124) | [0.0%, 2.9%] |
| TLR | 0.0% (0/27) | [0.0%, 12.8%] | 0.8% (1/124) | [0.0%, 4.4%] |
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| | Subjects with overlapping stents | | Subjects with no overlapping stents | |
| --- | --- | --- | --- | --- |
| Effectiveness and Safety Measures | (N=27 subjects) (N=34 lesions) (N=32 limbs) | [95% CI] | (N=124 subjects) (N=129 lesions) (N=127 limbs) | [95% CI] |
| Distal Embolization | 0.0% (0/27) | [0.0%, 12.8%] | 0.0% (0/124) | [0.0%, 2.9%] |
| Major Adverse Events (MAE) through 30 Days | 0.0% (0/27) | [0.0%, 12.8%] | 0.8% (1/124) | [0.0%, 4.4%] |
| Device/Procedure Related Death | 0.0% (0/27) | [0.0%, 12.8%] | 0.0% (0/124) | [0.0%, 2.9%] |
| TLR | 0.0% (0/27) | [0.0%, 12.8%] | 0.8% (1/124) | [0.0%, 4.4%] |
| Distal Embolization | 0.0% (0/27) | [0.0%, 12.8%] | 0.0% (0/124) | [0.0%, 2.9%] |
| Major Adverse Events (MAE) through 6 Months | 12.0% (3/25) | [2.5%, 31.2%] | 5.0% (6/119) | [1.9%, 10.7%] |
| Device/Procedure Related Death | 0.0% (0/25) | [0.0%, 13.7%] | 0.0% (0/119) | [0.0%, 3.1%] |
| TLR | 12.0% (3/25) | [2.5%, 31.2%] | 5.0% (6/119) | [1.9%, 10.7%] |
| Distal Embolization | 0.0% (0/25) | [0.0%, 13.7%] | 0.0% (0/119) | [0.0%, 3.1%] |
| Major Adverse Events (MAE) through 12 Months | 16.0% (4/25) | [4.5%, 36.1%] | 7.3% (8/110) | [3.2%, 13.8%] |
| Device/Procedure Related Death | 0.0% (0/25) | [0.0%, 13.7%] | 0.0% (0/110) | [0.0%, 3.3%] |
| TLR | 16.0% (4/25) | [4.5%, 36.1%] | 7.3% (8/110) | [3.2%, 13.8%] |
| Distal Embolization | 0.0% (0/25) | [0.0%, 13.7%] | 0.0% (0/110) | [0.0%, 3.3%] |
| Major Adverse Events (MAE) between 24 Months | 16.7% (4/24) | [4.7%, 37.4%] | 8.7% (9/103) | [4.1%, 15.9%] |
| Device/Procedure Related Death | 0.0% (0/24) | [0.0%, 14.2%] | 0.0% (0/103) | [0.0%, 3.5%] |
| TLR | 16.7% (4/24) | [4.7%, 37.4%] | 8.7% (9/103) | [4.1%, 15.9%] |
| Distal Embolization | 0.0% (0/24) | [0.0%, 14.2%] | 0.0% (0/103) | [0.0%, 3.5%] |
| Major Adverse Events (MAE) through End of Study | 16.7% (4/24) | [4.7%, 37.4%] | 8.7% (9/103) | [4.1%, 15.9%] |
| Device/Procedure Related Death | 0.0% (0/24) | [0.0%, 14.2%] | 0.0% (0/103) | [0.0%, 3.5%] |
| TLR | 16.7% (4/24) | [4.7%, 37.4%] | 8.7% (9/103) | [4.1%, 15.9%] |
| Distal Embolization | 0.0% (0/24) | [0.0%, 14.2%] | 0.0% (0/103) | [0.0%, 3.5%] |
| Non-MAE Death | | | | |
| Through 210 days | 0.0% (0/25) | [0.0%, 13.7%] | 1.7% (2/119) | [0.2%, 5.9%] |
| Through 365 days | 0.0% (0/25) | [0.0%, 13.7%] | 2.7% (3/112) | [0.6%, 7.6%] |
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| | Subjects with overlapping stents | | Subjects with no overlapping stents | |
| --- | --- | --- | --- | --- |
| Effectiveness and Safety Measures | (N=27 subjects) (N=34 lesions) (N=32 limbs) | [95% CI] | (N=124 subjects) (N=129 lesions) (N=127 limbs) | [95% CI] |
| Through 730 days | 4.2% (1/24) | [0.1%, 21.1%] | 5.6% (6/107) | [2.1%, 11.8%] |
| Through End of Study | 4.2% (1/24) | [0.1%, 21.1%] | 7.5% (8/107) | [3.3%, 14.2%] |
* All measurements taken after a confirmed TLR are excluded from this table.
## XII. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Circulatory System Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.
## XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
The data in this application support the reasonable assurance of safety and effectiveness of the Express LD Iliac Premounted Stent System when used in accordance with the indications for use.
Non-clinical studies, including biocompatibility testing, in vitro testing, sterilization testing, shelf life testing, packaging testing, and animal studies demonstrate that the stent will perform as intended. Specifically, the biocompatibility and in vivo animal testing that were conducted demonstrated that the acute and chronic in vivo performance characteristics of the product provide reasonable assurance of safety and are acceptable for clinical use. The in vitro engineering testing conducted on the stent and delivery system(s) demonstrated that the performance characteristics met the product specifications. The test results obtained from the sterilization testing demonstrated that the product can be adequately sterilized and is acceptable for clinical use. The shelf-life testing demonstrated that the product can be labeled with a shelf life of 2 years.
The MELODIE study demonstrated that the Express LD stent is safe and effective in the treatment of stenosed or occlusive atherosclerotic iliac artery disease. Specifically, the primary efficacy endpoint was met. At six months post-implantation, the angiographic mean percent loss of luminal diameter for the Express LD stent was $16.2\% \pm 18.4\%$ with an upper $95\%$ confidence bound of $18.7\%$, which was lower than the OPC plus delta value of $20.0\%$ (15% plus 5% delta) representative of the Palmaz® balloon-expandable stent ($p = 0.0061$). Angiographic binary restenosis at 6 months was $5.6\%$. Computer tomographic angiography (CTA) performed at the 12-month and 24-month follow-up visits demonstrated maintained target lesion patency ($\% \mathrm{DS} < 50\%$) of $97.2\%$ and $94.1\%$, respectively. Clinical and hemodynamic effectiveness were also demonstrated. Eighty-eight percent of MELODIE subjects improved by at least one Fontaine class 30 days after the procedure, with improvement maintained through the 24-month conclusion of the study for $79\%$ of subjects. The percent of subjects with Fontaine Stage IIb symptoms or
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worse improved from 84.1% pre-procedure to 16.8% at 24 months (p<0.0001). Ankle-brachial index improved from 0.68 at baseline to 0.87 at 24 months (p <0.0001). The MELODIE study demonstrated an acceptable safety profile for Express LD Iliac Premounted Stent System. The incidence of MAE at 24 months was low (10.2%), consisting only of TLR. There was no distal embolization or device/procedure-related death. Of the nine deaths occurring in the 24-month study period, three were from cardiovascular causes, five were from cancer, and one from respiratory insufficiency.
Outcomes in patients treated with overlapping stents are similar to outcomes in patients not treated with overlapping stents. Technical, procedural and hemodynamic success endpoints were similar between the two groups. There were no device or procedure related deaths and no instances of distal embolization in either group.
Additionally, retrospective assessment of the MELODIE data using a contemporary literature-derived composite performance goal further supports the safety and effectiveness of the Express LD stent in the treatment of stenosed or occlusive atherosclerotic iliac artery disease. The 12-month composite safety and effectiveness rate in the MELODIE study was 11.1% with a one-sided 95% upper confidence limit of 16.7%, as compared to the performance goal of 19%.
## XIV. CDRH DECISION
CDRH issued an approval order on March 05, 2010.
The applicant’s manufacturing facilities were inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).
## XV. APPROVAL SPECIFICATIONS
Directions for use: See device labeling.
Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.
Post-approval Requirements and Restrictions: See approval order.
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