Zilver Vena Venous Self-Expanding Stent

P200023 · Cook Ireland, Ltd. · QAN · Oct 9, 2020 · Cardiovascular

Device Facts

• Record ID: P200023
• Device Name: Zilver Vena Venous Self-Expanding Stent
• Applicant: Cook Ireland, Ltd.
• Product Code: QAN · Cardiovascular
• Decision Date: Oct 9, 2020
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The Zilver Vena Venous Self-Expanding Stent is indicated for improving luminal diameter in the iliofemoral veins for the treatment of symptomatic iliofemoral venous outflow obstruction.

Device Story

Self-expanding nitinol stent preloaded on 7 Fr delivery system; used to treat iliofemoral venous outflow obstruction. Physician deploys stent via 'pin & pull' technique under fluoroscopic guidance (gold radiopaque markers). Stent exerts outward radial force to establish vessel patency. Used in clinical/hospital settings. Output is a stented venous segment; helps restore blood flow, reduce symptoms (pain/edema), and improve quality of life. Clinical decision-making informed by venography and clinical assessment (VCSS, VDS, CEAP).

Clinical Evidence

Prospective, multicenter, single-arm VIVO study (N=243). Primary safety: 30-day freedom from MAEs (96.7%, p<0.0001 vs 87% goal). Primary effectiveness: 12-month primary quantitative patency (89.9%, p<0.0001 vs 76% goal). Secondary endpoints: significant improvement in VCSS at 1 and 12 months (p<0.0001), sustained through 3 years. Supportive data from VIVO-EU study (N=35).

Technological Characteristics

Self-expanding nitinol (nickel-titanium alloy) stent; gold radiopaque markers. Diameters 10-16mm; lengths 40-140mm. 7 Fr delivery system (80/120cm). Sterilized via ethylene oxide (ISO 11135). Materials conform to ASTM F2063. MRI safe/compatible.

Indications for Use

Indicated for patients with symptomatic iliofemoral venous outflow obstruction requiring improvement in luminal diameter. Contraindicated in patients with lesions preventing complete balloon dilatation or proper stent placement, and patients unable to receive intraprocedural anti-coagulation therapy.

Regulatory Classification

Identification

A metal scaffold placed via a delivery catheter in the iliac vein to maintain the lumen

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Stent, Iliac Vein
Device Trade Name: Zilver® Vena™ Venous Self-Expanding Stent
Device Procode: QAN
Applicant’s Name and Address: Cook Ireland, Ltd.
O’Halloran Road
National Technology Park
Limerick, Ireland
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P200023
Date of FDA Notice of Approval: October 9, 2020

II. INDICATIONS FOR USE

The Zilver Vena Venous Self-Expanding Stent is indicated for improving luminal diameter in the iliofemoral veins for the treatment of symptomatic iliofemoral venous outflow obstruction.

III. CONTRAINDICATIONS

The Zilver Vena Venous Self-Expanding Stent System is contraindicated for use in:
- Patients who are judged to have a lesion that prevents complete inflation of a balloon dilatation catheter or proper placement of the stent or the stent delivery system.
- Patients who cannot receive intraprocedural anti-coagulation therapy.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Zilver Vena Venous Self-Expanding Stent labeling (Instructions for Use).

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# V. DEVICE DESCRIPTION

The Zilver Vena Venous Self-Expanding Stent (the Zilver Vena Venous Stent) is a self-expanding nitinol (nickel titanium alloy) stent preloaded onto a delivery system. To facilitate fluoroscopic visualization of the stent, four radiopaque gold markers are positioned on each end of the stent (Figure 1). Post-deployment, the stent is designed to impart an outward radial force upon the inner lumen of the vessel, thereby establishing patency of the stented region. The Zilver Vena Venous Stent is available in diameters of $10\mathrm{mm}$ , $12\mathrm{mm}$ , $14\mathrm{mm}$ , and $16\mathrm{mm}$ (based on inner diameter) and lengths of $40\mathrm{mm}$ , $60\mathrm{mm}$ , $100\mathrm{mm}$ , and $140\mathrm{mm}$ (Table 1).

Figure 1. Schematic Drawing of the Zilver Vena Venous Stent

The Zilver Vena Venous Stent is preloaded within a 7 Fr (2.3 mm) delivery system (Figure 2). The delivery system is available in 80 cm and 120 cm lengths and is compatible with a 0.035" wire guide. The delivery system is used to deliver the stent to the appropriate anatomical location. When in position, the stent is deployed by retracting the handle while holding the metal cannula stationary (i.e., the "pin &amp; pull" technique).

Figure 2. Schematic Drawing of the Zilver Vena Venous Stent and Delivery System

a. Handle
b. Hub
c. Safety Lock
d. Delivery System: Outer Sheath
e. Tip of Delivery System Inner Catheter
f. Side-arm Flushing Port
g. Metal Cannula
h. Radiopaque Marker on the Delivery System
i. Gold Radiopaque Markers

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Table 1. Zilver Vena Venous Stent and Delivery System Size Matrix

| 2.3 mm (7 French) Delivery System | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Stent Length (mm) | | 40 | | 60 | | 100 | | 140 | |
| Delivery System (cm) | | 80 | 120 | 80 | 120 | 80 | 120 | 80 | 120 |
| Stent Inner Diameter (mm) | 10 | X | X | X | X | X | X | X | X |
| | 12 | X | X | X | X | X | X | X | X |
| | 14 | NA | NA | X | X | X | X | X | X |
| | 16 | NA | NA | X | X | X | X | X | X |

VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several alternatives used in the treatment and management of patients with symptomatic iliofemoral venous outflow obstruction. The current standard of care includes:

- Noninvasive treatment (exercise, leg elevation, compression therapy, and/or drug therapy such as oral anticoagulation, including Vitamin K antagonists or direct oral anticoagulants);
- Minimally invasive treatment (thrombectomy and/or thrombolysis, balloon angioplasty, and/or stent placement); and
- Surgical treatment (endophlebectomy or bypass).

Each alternative has its own advantages and disadvantages. The physician should fully discuss these alternatives with the patient to select the method that best meets expectations and lifestyle.

VII. MARKETING HISTORY

The Zilver Vena Venous Stent has been commercially available outside the United States since October 2010. It was first marketed in the European Union and has been commercialized in the Middle East/Africa, Asia, and South America (Table 2).

The device has never been withdrawn from any market for any reason related to safety or effectiveness.

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Table 2. Commercial Availability of the Zilver Vena Venous Stent

| Region | Countries | | |
| --- | --- | --- | --- |
| Europe, Middle East, and Africa | • Belarus | • Jordan | • Serbia |
| | • Bulgaria | • Kuwait | • Slovakia |
| | • Croatia | • Latvia | • Spain |
| | • Egypt | • Lebanon | • Turkey |
| | • France | • Palestine | • Ukraine |
| | • Iran | • Poland | • United Arab Emirates |
| | • Israel | • Russia | |
| | • Italy | • Saudi Arabia | |
| Asia | • China | • India | • Singapore |
| | • Hong Kong | • Malaysia | • Thailand |
| South America | • Argentina | • Colombia | • Mexico |
| | • Brazil | • Costa Rica | • Peru |
| | • Chile | • Ecuador | • Uruguay |
| Other | • Australia | • Canada | • New Zealand |

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

Below is a list of the potential adverse effects (e.g., complications) that may be associated with the use of the device:

- Abdominal or back pain
- Abrupt stent closure
- Allergic reaction to anticoagulant and/or antithrombotic therapy or contrast medium
- Allergic reaction to nitinol (nickel-titanium)
- Amputation
- Aneurysm
- Arrhythmia
- Arteriovenous fistula
- Bleeding associated with anticoagulation
- Death
- Embolism
- Fever
- Hematoma/hemorrhage at access site
- Hypersensitivity reactions
- Hypertension
- Hypotension, nausea, or symptoms of a vasovagal response
- Infection/abscess formation at access site
- Intimal injury/dissection
- Myocardial infarction (MI)
- Pseudoaneurysm formation
- Pulmonary embolism

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- Renal failure
- Restenosis, occlusion, or thrombosis of the stented vein
- Septicemia/bacteremia
- Stent malapposition
- Stent migration or embolization
- Stent strut fracture
- Stroke
- Tissue necrosis
- Vasospasm
- Vessel perforation/rupture
- Worsened pain

For the specific adverse events that occurred in the clinical study, please see Section X, D. Safety and Effectiveness Results below.

## IX. SUMMARY OF NONCLINICAL STUDIES

### A. Biocompatibility Testing

A thorough panel of biocompatibility testing was performed on the Zilver Vena Venous Stent and delivery system in accordance with ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing, the FDA Guidance for Industry and Food and Drug Administration Staff, Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process (June 16, 2016), and 21 CFR 58 Good Laboratory Practice (GLP) requirements. Specifically, the Zilver Vena Venous Stent was assessed by tests considered appropriate for devices categorized as a permanent blood-contacting implant (i.e., &gt;30 days), and the Zilver Vena Venous Stent delivery system was assessed by tests considered appropriate for devices categorized as an externally communicating device in contact with circulating blood for a limited period (i.e., ≤24 hours).

Tables 3 and 4 summarize the test results for the Zilver Vena Venous Stent and delivery system, respectively.

Table 3. Summary of Biocompatibility Testing for the Zilver Vena Venous Stent

| Test Name | Purpose of Testing | Test Results |
| --- | --- | --- |
| Cytotoxicity (ISO MEM elution method) | Determine the potential for the test article to cause cytotoxicity | Pass; the test article showed no evidence of causing cell lysis or toxicity |

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| Test Name | Purpose of Testing | Test Results |
| --- | --- | --- |
| Sensitization (ISO guinea pig maximization sensitization study) | Investigate the potential for delayed dermal contact sensitization | Pass; the test article extract showed no evidence of causing delayed dermal contact sensitization in the guinea pig and is not considered a sensitizer |
| Irritation or intracutaneous reactivity (ISO intracutaneous study) | Determine if the test article causes local dermal irritation following intracutaneous injection in rabbits | Pass; no evidence of significant irritation over the 72-hour test period from the test article extracts injected intracutaneously into rabbits compared to the control extracts |
| Acute systemic toxicity (ISO systemic toxicity study) | Determine if the test article causes local dermal irritation following injection in mice | Pass; no mortality or evidence of systemic toxicity over the 72-hour test period from the test article extracts injected into mice |
| Material-mediated pyrogenicity (USP material-mediated pyrogenicity study) | Determine if the test article induces a pyrogenic response following intravenous injection in rabbits | Pass; the test article extract was considered nonpyrogenic. The rise in temperature during the 3-hour observation period after extract injection in rabbits was within acceptable USP limits |
| Subacute/subchronic toxicity (subchronic intravenous toxicity study) | Determine if the test article causes systemic toxicity | Pass; no evidence of systemic toxicity from the test article extracts injected intravenously into rats |
| Implantation (ISO muscle implantation study – 2 weeks) | Determine if the test article causes a local tissue response after 2 weeks implantation into muscle tissue of rabbits | Pass; microscopically, the test article was classified as a nonirritant compared to the negative control article |
| Implantation (muscle implantation with systemic toxicity study – 4 weeks) | Determine if the test article causes a local tissue response after 4 weeks implantation into muscle tissue of rabbits | Pass; microscopically, the test article was classified as a nonirritant compared to the negative control article |
| Implantation (muscle implantation with systemic toxicity study – 13 weeks) | Determine if the test article causes a local tissue response after 13 weeks implantation into muscle tissue of rabbits | Pass; microscopically, the test article was classified as a nonirritant compared to the negative control article |
| Hemocompatibility (hemolysis study) | Determine if the test article causes hemolysis | Pass; both the test article in direct contact with blood and the test article extract were nonhemolytic |
| Hemocompatibility (in vivo thromboresistance study) | Determine if the placement of the test article would cause thrombosis during simulated clinical use | Thrombogenicity evaluated as part of the in vivo animal studies (Section B) showed no evidences of thromboses in vessels implanted with Zilver Vena Venous Stents |
| Hemocompatibility (plasma recalcification time study) | Determine if the test article causes a change in degree of inhibition or promotion of clotting time | Pass; the test article extract had no significant effect on recalcification time compared to the negative control |
| Hemocompatibility (C3a complement activation assay) | Evaluate the test article’s potential to activate the C3a complement system | Pass; the test article extract was considered a nonactivator of the complement system |

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Table 4. Summary of Biocompatibility Testing for the Zilver Vena Venous Stent Delivery System

| Test Name | Purpose of Testing | Test Results |
| --- | --- | --- |
| Cytotoxicity (ISO elution method) | Determine the potential for the test article to cause cytotoxicity | Pass; the test article showed no evidence of causing cell lysis or toxicity |
| Sensitization (ISO guinea pig maximization sensitization study) | Investigate the potential for delayed dermal contact sensitization | Pass; the test article extract showed no evidence of causing delayed dermal contact sensitization in the guinea pig and is not considered a sensitizer |
| Irritation or intracutaneous reactivity (ISO intracutaneous study) | Determine if the test article causes local dermal irritation following intracutaneous injection in rabbits | Pass; no evidence of significant irritation over the 72-hour test period from the test article extracts injected intracutaneously into rabbits compared to the control extracts |
| Acute systemic toxicity (ISO acute systemic toxicity study) | Determine if the test article causes local dermal irritation following injection in mice | Pass; no mortality or evidence of systemic toxicity over the 72-hour test period from the test article extracts injected into mice |
| Material-mediated pyrogenicity (USP material-mediated pyrogenicity study) | Determine if the test article induces a pyrogenic response following intravenous injection in rabbits | Pass; the test article extract was considered nonpyrogenic. The rise in temperature during the 3-hour observation period after extract injection in rabbits was within acceptable USP limits |
| Hemocompatibility (Hemolysis) | Determine if the test article causes hemolysis | Pass; both the test article in direct contact with blood and the test article extract were nonhemolytic |
| Hemocompatibility (SC5b-9 complement activation assay study) | Evaluate the test article's potential to activate the SC5b-9 complement system | Pass; the test article extract was considered a nonactivator of the complement system |

Chemical characterization of the Zilver Vena Venous Stent was used to address the endpoints of carcinogenicity and genotoxicity. Chemical characterization was conducted in accordance with the FDA Guidance for Industry and Food and Drug Administration Staff, Use of International Standard ISO 10993-1, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (June 16, 2016), ISO 10993-18 (2005), Biological evaluation of medical devices - Part 18: Chemical characterization of materials, and ISO 10993-17 (2002), Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances.

Chemical characterization testing included:

- Exhaustive extraction: water/hexane/ethanol

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- Inductively coupled plasma (ICP)/mass spectroscopy (MS): water
- Ion chromatography (IC): water
- Gas chromatography (GC)/mass spectroscopy (MS): water/hexane/ethanol
- Fourier transform infrared spectroscopy (FTIR): water/hexane/ethanol
- Ultra performance liquid chromatography-mass spectrometry (UPLC-MS): water/hexane/ethanol

The results for all tests were acceptable.

The biocompatibility test results demonstrate that both the stent and delivery system are biocompatible and nonpyrogenic, indicating that the Zilver Vena Venous Stent is safe and acceptable for clinical use.

## B. Animal Studies

The safety and biological response specific to the Zilver Vena Venous Stent was assessed in sheep. Specifically, four animal studies (26 stents assessed in 20 animals) were completed in accordance with 21 CFR 58 (Good Laboratory Practice) as summarized in Table 5.

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Table 5. Summary of Animal Testing for the Zilver Vena Venous Stent

| Study Objective | Device Size (mm) and Samples (N) | Implant Duration; Number of Animals | Results |
| --- | --- | --- | --- |
| Evaluate acute performance characteristics of the stent and delivery system (deliverability and deployability) | 14 x 140 (N=4) | Procedural; 4 animals | All stents and delivery systems were tracked, the stents were deployed, and the delivery systems were withdrawn without difficulty or incident, with no evidence of vessel injury or damage and no evidence of stent fracture. All devices achieved a rating of adequate (i.e., acceptable for clinical use) or better for each performance characteristic. |
| Evaluate acute performance characteristics and the 1-month safety of and biological response to the stent | 14 x 140 (N=8) | 1 month; 5 animals | • All stents were deployed and the delivery systems withdrawn without difficulty or incident, with no evidence of vessel injury or damage and no evidence of stent fracture.
• At 1-month follow-up, angiography and histomorphometry indicated that the stents were patent. Histopathology revealed complete endothelialization, with minimal injury and minimal to mild inflammation. |
| Evaluate acute performance characteristics and the 3-month safety of and biological response to the stent | 14 x 140 (N=8) | 3 months; 7 animals | • All stents were deployed and the delivery systems withdrawn without difficulty or incident, with no evidence of vessel injury or damage and no evidence of stent fracture. All achieved a rating of adequate or better for each performance characteristic.
• At 3-month follow-up, angiography showed the stented vessels to be patent with no evidence of vessel damage or injury (i.e., no evidence of thrombus deposition, dissection, aneurysm, contrast extravasation, spasm, or filling defects). Histomorphometry confirmed stent patency at follow-up. High-resolution radiography revealed no strut fractures at follow-up. Histopathology revealed that all vessels were healed with minimal injury and inflammation and 100% endothelialization. |
| Evaluate acute performance characteristics and the 1-month safety of and biological response to the stent | 10 x 140 (N=6) | 1 month; 4 animals | • All stents were deployed and the delivery systems withdrawn without difficulty or incident, with no evidence of vessel injury or damage and no evidence of stent fracture.
• At 1-month follow-up, angiography and histomorphometry indicated that stents remained patent. Histopathology revealed nearly complete endothelialization, with minimal injury and minimal to mild inflammation. |

The animal studies demonstrate that the delivery systems were tracked, the stents deployed, and the delivery systems withdrawn without difficulty or incident and that the stents did not cause any abnormal localized tissue responses. Moreover, the results showed no safety problems associated with the stents. Therefore, the animal testing

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results for the Zilver Vena Venous Stent support a reasonable assurance of device safety and effectiveness.

## C. Non-clinical Bench Testing

Comprehensive non-clinical bench testing was conducted as part of the design verification and validation to support the safety and effectiveness of the Zilver Vena Venous Stent and delivery system. The test plan was developed in accordance with appropriate guidance documents and international standards, including FDA’s Guidance for Industry and Staff, Non-clinical tests and recommended labeling for intravascular stents and associated delivery systems (2005, 2010, supplemented in 2015), and ISO 25539-2 (2012), Cardiovascular implants – Endovascular devices – Part 2: Vascular Stents. The test results are presented in Table 6. The test results verified that the Zilver Vena Venous Stent and delivery system met their product performance and design specifications and would perform as intended under anticipated clinical conditions. Table 6 indicates which tests were performed on both nonaged and aged (1-year and 3-year timepoints) devices in order to support the product shelf life.

Table 6. Summary of Non-clinical Bench Testing for the Zilver Vena Venous Stent and Delivery System

| Test | Purpose | Specification/ Acceptance Criterion | Results |
| --- | --- | --- | --- |
| Material Characterization | | | |
| Material composition | To verify the chemical composition of the stent implant | Material composition must comply with ASTM F2063, Wrought Nickel-Titanium Shape Memory Alloy for Medical Devices and Surgical Implants | The stent materials conform to material standards |
| Shape memory and superelasticity of intravascular stents | To verify the transition temperature of the nitinol implant | Stent comprises nitinol conforming to ASTM F2063; the austenite finish temperature of the electropolished stent is 25 °C ± 5 °C | The stent materials conform to applicable material standards |
| Stent corrosion resistance | To verify the stent’s ability to resist corrosion (pitting) | The mean breakdown potential must be > 600 mV_{SCE} and the minimum breakdown potential must be > 300 mV_{SCE}
Visual inspection completed for characterization purposes only | Pass |
| Fretting corrosion | To verify the stent’s ability to resist fretting corrosion after fatigue analysis | | Pass |

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| Test | Purpose | Specification/ Acceptance Criterion | Results |
| --- | --- | --- | --- |
| Stent Dimensional and Functional Attributes | | | |
| Dimensional verificationa | To evaluate the final stent dimension and ensure design specifications were met | The stent recovers to its specified, unconstrained diameter and expanded stent length | Pass |
| Percent surface area | To calculate the percent surface area of the expanded stent | N/A | Stented vessel covered surface areas were determined for 10 mm, 12 mm, 14 mm, and 16 mm devices using computer aided techniques |
| Foreshorteninga | To determine the percent length change of the stent from its compressed to deployed state | N/A, report for characterization purposes | Assessed |
| Stent integritya | To evaluate the integrity of the stent after deployment | No strut fractures allowed; no cracks visible on the stent surface greater than 10 μm when viewed at magnification 56X | Pass |
| Radial outward forcea | To evaluate the outward radial force exerted by the stent | The radial force (normalized per unit length) shall be between 0.063 N/mm and 4.97 N/mm | Pass |
| Mechanical properties | Stent comprise nitinol conforming to ASTM F2063 | | |
| Stress/strain analysis (finite element analysis; FEA) | The stress and strain during loading and deployment, as well as in nonoverlapped distensible vein radial loading, axial loading, bending loading, May-Thurner loading and overlapped bending loading and May-Thurner loading, were characterized | | |
| Fatigue analysis | To evaluate fatigue resistance under various loading conditions, including bending | Analyses must result in a fatigue safety factor > 1.0 | Pass |
| Accelerated durability (fatigue testing) | To evaluate the durability of the stent under various loading conditions, including bending loading for 10 years of simulated use | The devices tested must withstand the loading conditions with no fracture | Pass |

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| Test | Purpose | Specification/ Acceptance Criterion | Results |
| --- | --- | --- | --- |
| MRI safety and compatibility | To evaluate the MRI safety and compatibility of the stent | The displacement force deflection angle shall be ≤ 45°; the magnetically induced torque shall be ≤ the worst-case torque due to the earth's gravity; the RF heating of the stent during an MRI procedure 15 minutes in duration must have a CEM43 value of < 10 minutesImage artifact was for characterization only | Pass; results met the established acceptance criteriaAssessed |
| Radiopacity | To evaluate the ability of the implant to be viewed under fluoroscopy | The stent gold rivets shall be visible using fluoroscopy | Pass |
| Crush resistance | To establish the crush resistance of the stent by examining the geometry following local compressive loading and compressive loading between parallel plates | The stent shall recover to its specified unconstrained diameter when released from a compressed state and will vary minimally over its length | Pass |
| Kink resistance | To evaluate the overall flexibility and kink resistance of the stent after deployment | No kink at radius of ≥ 19 mm | Pass |
| Delivery System Dimensional and Functional Attributes | | | |
| Dimensional verificationa | To verify the delivery system meets dimensional criteria pre- and post-deployment | The maximum sheath outer diameter, delivery system length, and distance from the marker band distal edge to the Flexor distal edge will all be within design specifications | Pass |
| Delivery, deployment, and retractiona | To confirm the delivery system meets it prespecified acceptance criteria with respect to its delivery, deployment, and retraction under simulated use conditions | 100% of delivery systems are able to be flushed, access the intended delivery location, and are able to be withdrawn100% of deployments are successful in the mock vessel | Pass |
| Deployment forcea | Determine the force to deploy the stent is within the user's ability to deliver the device accurately | The force to deploy the stent must be within the user's capability (i.e., ≤ 32N) | Pass |
| Deployment accuracya | To assess the accuracy of deploying the stent at the target location. | The stent shall be deployed ± 4.0 mm from the intended deployment location. | Pass |

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| Test | Purpose | Specification/ Acceptance Criterion | Results |
| --- | --- | --- | --- |
| Catheter bond strength and tip pull testa | To establish the bond strength of delivery system joints and verify that the strength of the bond joints is adequate for the intended use | The tensile and compressive strength of delivery system bonds will meet design requirements | Pass |
| Flexibility and kink testa | To evaluate the overall flexibility and kink resistance of the delivery system | Pre- and post-deployment, the delivery system does not kink at a radius of ≥ 19 mm | Pass |

a Testing was performed on devices that had undergone aging conditions to support shelf life.

The testing detailed in Table 6 verified that the Zilver Vena Venous Stent and delivery system met the product performance and design specifications and would perform as intended under anticipated clinical conditions.

## D. Sterilization, Packaging, and Shelf Life Testing

The Zilver Vena Venous Stent is sterilized by a validated ethylene oxide (EO) sterilization process to achieve a minimum sterility assurance level (SAL) of 10⁻⁶. The methods used to validate the sterilization cycle are in accordance with ISO 11135 (2014), Sterilization of healthcare products – Ethylene oxide: Requirements for development, validation and routine control of a sterilization process for medical devices.

Product and package stability testing of the Zilver Vena Venous Stent was performed and validated to support the device’s shelf life. Packaging testing included visual assessment, bubble leak testing, and seal strength testing at baseline and aged conditions. Non-clinical functional testing of the device after aging was performed as indicated in Table 6. Together, the data support a 3-year shelf life for the Zilver Vena Venous Stent.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish reasonable assurance of safety and effectiveness of the Zilver Vena Venous Stent for the treatment of patients with symptomatic iliofemoral venous outflow obstruction in the United States and Taiwan under an Investigational Device Exemption (IDE #G110228). Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

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# A. Study Design

The Evaluation of the Zilver Vena Venous Stent in the Treatment of Symptomatic Iliofemoral Venous Outflow Obstruction (VIVO) Clinical Study was a prospective, global, multicenter, nonrandomized, single-arm clinical study intended to assess the safety and effectiveness of the Zilver Vena Venous Stent for the treatment of patients with symptomatic iliofemoral venous outflow obstruction. Patients with symptomatic venous outflow obstruction in one iliofemoral venous segment were eligible for enrollment. A total of 243 patients were treated with Zilver Vena Venous Stents between 13 December 2013 and 31 October 2016. The database for this PMA reflects data locked on 10 April 2020 and the data include 243 patients. Study patients were enrolled at 30 investigational sites, including 29 sites in the United States and 1 site in Taiwan.

The study protocol prespecified enrollment by disease status, i.e., acute (initial onset of symptoms within 30 days of the procedure) or chronic (initial onset of symptoms greater than 30 days prior to the procedure). The study population was prespecified to include 30% patients (73 patients) with acute disease and 70% patients (170 patients) with chronic disease.

The study was overseen by an independent Data Safety Monitoring Board (DSMB) in accordance with an established DSMB charter. An independent Clinical Events Committee (CEC) adjudicated predefined clinical events reported during the study in accordance with the CEC charter. An independent core laboratory provided uniformly defined imaging analysis.

## 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the VIVO clinical study was limited to patients who met the following inclusion criteria:

1) symptomatic venous outflow obstruction in one iliofemoral venous segment (i.e., one limb) per patient, demonstrated by:
- CEAP “C” ≥ 3, or
- VCSS pain score ≥ 2; and

2) planned stenting of the study lesion with only the Zilver Vena Venous Stent.

Patients were not permitted to enroll in the VIVO Clinical Study if they met any of the following exclusion criteria:

### General Exclusion Criteria:

1) &lt; 18 years of age;
2) unwilling to provide informed consent;
3) unwilling or unable to comply with all study related follow-up procedures;
4) pregnant or planning to become pregnant in the next 12 months;

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5) simultaneous participation in another investigational drug or device study (the patient must have completed the follow-up phase for the primary endpoint of any previous study at least 30 days prior to enrollment in this study);
6) history of bleeding diathesis, uncorrectable hypercoagulopathy (i.e., hypercoagulopathy that cannot be adequately managed/controlled with medication), or refusal of blood transfusions;
7) history of intracranial hemorrhage;
8) a medical condition or disorder (e.g., cancer) that may limit life expectancy to less than 12 months or that may cause non-compliance with the Clinical Investigation Plan;
9) known hypersensitivity or contraindication to antiplatelet and/or anticoagulant therapy, nitinol, or contrast medium which cannot be adequately premedicated;
10) surgical or interventional procedures of the target limb (except thrombolysis and/or thrombectomy in preparation for the procedure or vena cava filter placement prior to stent implantation in patients at high risk for pulmonary embolism) within 30 days prior to the study procedure, or planned surgical or interventional procedures of the target limb any time after the study procedure;
11) surgical or interventional procedures for other medical conditions (i.e., not associated with the target limb) within 30 days prior to the study procedure, or planned surgical or interventional procedures within 30 days after the study procedure;
12) complications of an arterial or venous access site in the legs within 30 days prior to the study procedure;
13) untreated systemic or local infection, or infection treated for less than 10 days prior to the study procedure;
14) lesions with intended treatment lengths extending into the inferior vena cava or below the level of the lesser trochanter;
15) significant obstruction (i.e., &gt; 20%) or occlusion of the inflow or outflow tract (i.e., ipsilateral tibial, popliteal, and femoral veins and inferior vena cava); if thrombus is treated prior to stenting the study lesion, treatment (thrombolysis or thrombectomy) must result in &lt; 20% residual stenosis/obstruction;
16) lesion with malignant obstruction;
17) presence of symptomatic pulmonary embolism within 30 days prior to the study procedure;
18) previous stenting of the target vessel;
19) lesion located within or beyond a bypass graft; and
20) total venous occlusion that cannot be dilated to allow passage of the introducer system or wire guide.

Venographic Exclusion Criterion:

1) iliofemoral venous segment unsuitable for treatment with the available sizes of study devices.

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# 2. Follow-up Schedule

All patients underwent evaluation (clinical assessment and imaging evaluation) prior to the study procedure. Patient follow-up was scheduled at pre-discharge through 36 months. Follow-up included venography at 12 months, and ultrasound and X-ray at 6, 12, 24, and 36 months. In addition, clinical assessments occurred at 1, 6, 12, 24, and 36 months. Telephone contact was scheduled at 3 months. Table 7 provides the data collection schedule through the 36-month visit.

Clinical assessments included medical history and documentation of the symptom(s) indicative of venous outflow obstruction, using Venous Clinical Severity Score (VCSS), Venous Disability Score (VDS), Clinical Etiological Anatomical Pathophysiological (CEAP) "C" Classification, and Chronic Venous Insufficiency Quality of Life Questionnaire (CIVIQ), and assessment of adverse events and medications. Adverse events and complications were recorded at all visits.

The key timepoints are shown below in the tables summarizing safety and effectiveness.

Table 7. Data Collection Schedule for the VIVO Clinical Study

| Data Collection | Pre-Procedure | Procedure | Post-Procedure | 1 Month | 3 Months | 6 Months | 12 Months | 24 Months | 36 Months |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical assessment^{a} | X | | | X | | X | X | X | X |
| Venography | | X | | | | | X | | |
| X-ray | | | X | | | X | X | X | X |
| Duplex ultrasound | | | X | | | X | X | X | X |
| Telephone contact | | | | | X | | | | |

a Clinical assessment included, VCSS, VDS, CEAP “C” classification, and CIVIQ score.

# 3. Clinical Endpoints

## Primary Safety Endpoint

The primary safety endpoint was 30-day freedom from major adverse events (MAEs). MAEs were defined as procedural bleeding requiring transfusion, procedure- or device-related death, clinically driven target lesion reintervention, clinical migration, new symptomatic pulmonary embolism, or procedure-related perforation requiring open surgical repair or flow-limiting dissection of the target vessel. Clinically driven reinterventions were reinterventions performed in a patient with recurrent symptoms of venous outflow obstruction of the target lesion and with venography showing a treated venous segment minimum lumen diameter (MLD) ≤ 50% of the immediate post-procedure stented MLD. Clinical

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migration was defined as proximal or distal movement of the stent requiring surgical or endovascular intervention. Bleeding events occurring prior to study enrollment, and related to procedures such as thrombolysis or thrombectomy, were not considered procedural bleeding events.

The analysis requires that a single performance goal of 87% be met. The performance goal was a weighted average of 85% (computed based on safety data for patients with acute disease, defined as initial symptom onset within 30 days of the procedure) and 88% (computed based on safety data for patients with chronic disease, defined as initial symptom onset greater than 30 days prior to the procedure), with the weight prespecified as 30% acute patients and 70% chronic patients. The weighted averages were based on published clinical literature and included a 10% margin. The study device was considered to have met the safety endpoint if the one-sided p-value from hypothesis testing (H₀: πₛ ≤ 87%; Hₐ: πₛ &gt; 87%) using exact binomial test was less than 0.025.

## Primary Effectiveness Endpoint

The primary effectiveness endpoint was primary quantitative patency at 12 months. Primary quantitative patency was defined as a treated venous segment (including the region within ± 1 cm proximal and/or distal of the treated venous segment) that retained (uninterrupted; intervention-free) an MLD &gt; 50% of the immediate post-procedure stented MLD as demonstrated by venography as determined by the core laboratory. The statistical analysis plan pre-specified that missing data be addressed using multiple imputation with best-available data, case deletion, or other analyses (i.e. tipping point). The analysis plan specified assessment of patients with reinterventions within the treated venous segment as follows in relation to the primary effectiveness endpoint: failures were patients presenting with an MLD ≤ 50% of the immediate post-procedure stented MLD at reintervention occurring ≤ 410 days post-procedure, successes were patients presenting with an MLD &gt; 50% of the immediate post-procedure stented MLD at reintervention occurring ≥ 320 days, and missing were patients presenting with an MLD &gt; 50% of the immediate post-procedure stented MLD at reintervention &lt; 320 days.

The analysis required that a single performance goal of 76% be met; the performance goal was derived based on 12-month patency data available in published literature and included a 10% margin. The study device was considered to have met the effectiveness endpoint if the one-sided p-value from hypothesis testing (H₀: πₑ ≤ 76% Hₐ: πₑ &gt; 76%) using exact binomial test was less than 0.025.

## Secondary Endpoint

The secondary endpoint was the change in VCSS from baseline to 1 month and 12 months. The study device was considered to have met the secondary endpoint if p-values from hypothesis testing (H₀: S_diff = 0 Hₐ: S_diff ≠ 0) using paired t-test

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are less than 0.05. The p-values at 1 month and 12 months were adjusted for multiplicity using the Holm procedure at a family-wise type I error rate of 0.05.

Additional measures without prespecified hypothesis testing were collected through 3 years and included the following:

- Technical success, defined as successful delivery and deployment of the Zilver Vena Venous Stent in the intended location
- Procedural success, defined as improved flow through the target vessel demonstrated by diminished flow through collateral veins and/or reduced filling defect in the target vessel and no MAEs before discharge
- Adverse events
- Type, rate, and interval of clinically driven reintervention within the treated venous segment following treatment
- Type, rate, and interval of reintervention within the treated venous segment following treatment
- Rates of primary quantitative patency, assisted primary quantitative patency, and secondary quantitative patency
- Rate of patency by ultrasound
- Rate of clinical patency, defined as lack of occlusion of the treated venous segment determined by evidence of blood flow proximal and distal to the study lesion assessed via ultrasound and/or venography and no worsening of pain or edema from baseline (according to VCSS) as related to the target lesion
- Rate of modified clinical patency, defined as lack of occlusion of the treated venous segment determined by evidence of blood flow proximal and distal to the study lesion as assessed via ultrasound and/or venography and no worsening of pain or edema from baseline (according to VCSS) as related to the target lesion in two or more consecutive visits
- Device integrity (X-ray assessment for stent fracture)
- Device migration (X-ray assessment for migration)
- Change in VCSS from baseline
- Change in VDS from baseline
- Change in CEAP clinical classification (i.e., "C" classification) from baseline
- Change in CIVIQ score from baseline

## B. Patient Accountability in the VIVO Clinical Study

Overall, 243 patients were enrolled in the VIVO Clinical Study. The number of patients available for analysis at each time point is shown in Figure 3.

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Figure 3. Subject Accountability for the VIVO Clinical Study
a 351 consented patients - 108 screen failures = 243 enrolled patients
b 243 enrolled patients - 2 discontinued patients - 3 missed visits = 238 patients with completed 30-day follow-up
c 243 enrolled patients - 3 discontinued patients - 14 missed visits = 226 patients with completed 3-month telephone follow-up
d 243 enrolled patients - 7 discontinued patients - 13 missed visits = 223 patients with completed 6-month follow-up
e 243 enrolled patients - 15 discontinued patients - 17 missed visits = 211 patients with completed 12-month follow-up

# C. Study Population Demographics and Baseline Parameters

The demographics of the VIVO Clinical Study population are typical for an iliofemoral venous stent study performed in the United States. The mean age of enrolled patients was $53.0 \pm 15.3$ years (range: 18-89 years). The majority of patients were female ( $70.0\%$ ; 170/243) and white ( $81.5\%$ ; 198/243). More than half of the study patients had past or current DVT ( $67.5\%$ ; 164/243).

Table 8 provides a summary of the demographics and baseline characteristics for patients in the VIVO Clinical Study. Table 9 provides a summary of the VIVO patients' medical history and comorbid conditions at baseline.

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Table 8. Demographics and Baseline Patient Characteristics for the VIVO Clinical Study

| Demographic | Percent Patients (number/total number) or Mean ± SD (N, range) |
| --- | --- |
| Gender | |
| Male | 30.0% (73/243) |
| Female | 70.0% (170/243) |
| Age (years) | |
| All patients | 53.0 ± 15.3 (243, 18-89) |
| Male | 57.1 ± 13.2 (73, 23-82) |
| Female | 51.2 ± 15.8 (170, 18-89) |
| Ethnicity | |
| White | 81.5% (198/243) |
| Black or African American | 11.9% (29/243) |
| Asian | 3.3% (8/243) |
| Hispanic or Latino | 2.9% (7/243) |
| First Nations/White | 0.4% (1/243) |
| Height (in) | 66.4 ± 4.2 (243, 54-79) |
| Weight (lbs) | 197.0 ± 57.5 (243, 99.0-415.8) |
| Body mass index (BMI) | 31.3 ± 8.5 (243, 17.5-64.8) |

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Table 9. Medical History and Comorbid Conditions for the VIVO Clinical Study

| Condition | Percent Patients (number/total number) |
| --- | --- |
| Recent trauma (within 30 days) | 1.2% (3/243) |
| Recent immobilization (within 30 days) | 2.1% (5/243) |
| Cardiovascular | |
| Coronary artery disease | 7.4% (18/243) |
| Previous myocardial infarction (MI) | 4.1% (10/243) |
| Congestive heart failure | 3.7% (9/243) |
| Vascular | |
| Bleeding diathesis/coagulopathy | 7.0% (17/243) |
| Clotting disorder (family history) | 7.9% (19/242) |
| Hypertension | 43.2% (105/243) |
| Peripheral arterial disease | 3.3% (8/243) |
| Presence of reflux (venous) | 18.1% (44/243) |
| Existing tissue loss related to venous disease: | 4.5% (11/243) |
| Gangrene | 0% (0/11) |
| Stasis ulcers | 100% (11/11) |
| Amputation | 0% (0/11) |
| Past or current deep vein thrombosis (DVT): | 67.5% (164/243) |
| Past DVT | 27.4% (45/164) |
| Current and past DVT | 15.9% (26/164) |
| Current DVT | 56.7% (93/164) |
| Current DVT status: | |
| Acute (within 30 days) | 49.6% (59/119) |
| Acute DVT on Chronic DVT/post-thrombotic syndrome | 14.3% (17/119) |
| Chronic DVT/post-thrombotic syndrome | 36.1% (43/119) |
| DVT (family history) | 9.9% (24/242) |
| Pulmonary | |
| Chronic obstructive pulmonary disease (COPD) | 5.8% (14/243) |
| Pulmonary embolism (PE): | 14.8% (36/243) |
| Past PE | 91.7% (33/36) |
| Current PE (within 30 days) | 8.3% (3/36) |
| Renal | |
| Chronic renal failure | 2.5% (6/243) |
| Endocrine | |
| Diabetes: | 13.6% (33/243) |
| Type I | 9.1% (3/33) |
| Type II | 90.9% (30/33) |
| Hypercholesterolemia | 31.7% (77/243) |
| Hypothyroidism | 11.1% (27/243) |
| Gastrointestinal | |
| Gastrointestinal bleeding | 1.2% (3/243) |

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| Condition | Percent Patients (number/total number) |
| --- | --- |
| Neoplasms | |
| History of cancer: | 16.9% (41/243) |
| Current cancer | 7.3% (3/41) |
| Chemotherapy in the last 12 months | 2.4% (1/41) |
| Undergone radiation treatment to the pelvis | 14.6% (6/41) |
| Neurologic | |
| Stroke | 2.5% (6/243) |
| Transient ischemic attack (TIA) | 2.5% (6/243) |
| History of intracranial hemorrhage | 0% (0/243) |
| Smoking status | |
| Never | 62.1% (151/243) |
| Past | 24.7% (60/243) |
| Current | 13.2% (32/243) |
| Hormone-based contraceptives (females only) | 11.8% (20/170) |
| Hormone replacement therapy | 8.2% (20/243) |
| IVC filter present prior to study procedure | 13.6% (33/243) |

Baseline venous clinical assessments, lesion characteristics, and venographic measurements (Tables 10 and 11) were also as expected for this patient population. Most patients had a VCSS of 2 or greater (75.7%; 184/243); similarly, most patients had a CEAP “C” classification of 3 or greater (95.5%; 232/243). Study lesions were predominately located in the left leg (86.0%; 209/243) and most commonly affected the common iliac vein (CIV; 88.1%; 214/243) and the external iliac vein (EIV; 51.9%; 126/243). By core laboratory assessment, prior to stent placement, the mean lesion length was 98.6 mm ± 69.8 mm and the mean MLD was 6.0 mm ± 5.3 mm. Among lesions, 23.3% (52/233) were characterized as total occlusions pre-procedure.

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Table 10. Baseline Venous Clinical Assessments for the VIVO Clinical Study

| Assessment | Mean ± SD (N, range) or Percent Patients (number/total number) |
| --- | --- |
| VCSS | 8.0 ± 4.2 (243, 1-24) |
| VDS | |
| 0 | 5.3% (13/243) |
| 1 | 28.0% (68/243) |
| 2 | 41.6% (101/243) |
| 3 | 25.1% (61/243) |
| CEAP “C” classification | |
| C0 | 0.4% (1/243) |
| C1 | 0.8% (2/243) |
| C2 | 3.3% (8/243) |
| C3 | 66.7% (162/243) |
| C4a | 16.9% (41/243) |
| C4b | 3.7% (9/243) |
| C5 | 2.9% (7/243) |
| C6 | 5.3% (13/243) |
| CIVIQ score | 44.6 ± 23.5 (236, 1.3-98.8) |

Table 11. Core Laboratory-Reported Baseline Lesion Characteristics and Venographic Measurements for the VIVO Clinical Study

| Characteristic | Percent Patients (number/total number) or Mean ± SD (N, range) |
| --- | --- |
| Study lesion side | |
| Left | 86.0% (209/243) |
| Right | 14.0% (34/243) |
| Study lesion locationa | |
| Common iliac vein (CIV) | 88.1% (214/243) |
| External iliac vein (EIV) | 51.9% (126/243) |
| Common femoral vein (CFV) | 22.6% (55/243) |
| Femoral vein (FV) | 2.1% (5/243) |
| Presence of collateral vessels | 59.1% (143/242) |
| Presence of filling defect | 50.4% (122/242) |
| Presence of thrombus | 40.0% (96/240) |
| Lesion extending into the inferior vena cava | 2.9% (7/243) |
| Lesion extending below the level of the lesser trochanter | 4.6% (11/238) |
| Lesion length (mm) | 98.6 ± 69.8 (232, 3.5-319) |
| MLD (mm) | 6.0 ± 5.3 (233, 0-22.9) |
| Total occlusion (i.e., MLD of 0 mm) | 22.3% (52/233) |

a Lesions may involve more than one location; therefore, the total number of lesion locations is more than the total number of patients enrolled.

Details associated with the Zilver Vena Venous Stent implant procedure are summarized in Table 12. Stent placement occurred primarily via an ipsilateral popliteal vein (64.8%;

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151/233) or ipsilateral femoral vein (30.0%; 70/233) approach. Procedures infrequently occurred via contralateral access (7.4%; 18/243); when used, contralateral access was often in combination with ipsilateral access (44.4%; 8/18). Pre-stent dilatation (64.6%; 157/243) and post-stent dilatation (96.7%; 235/243) was performed in most implant procedures. In total, 365 Zilver Vena Venous Stents were placed in 243 patients; most patients were implanted with one stent (57.2%; 139/243) or two stents (35.4%; 86/243).

Table 12. Procedure Characteristics for the VIVO Clinical Study

| Characteristic | Percent Patients (number/total number) |
| --- | --- |
| Access Site^{a} | |
| Ipsilateral Access sites | 95.9% (233/243) |
| Popliteal vein | 64.8% (151/233) |
| Femoral vein | 30.0% (70/233) |
| Tibial vein | 2.1% (5/233) |
| Jugular vein | 0.4% (1/233) |
| “Other” vein | 5.6% (13/233) |
| Contralateral Access site | 7.4% (18/243) |
| Femoral vein | 50.0% (9/18) |
| Jugular vein | 44.4% (8/18) |
| Popliteal vein | 5.6% (1/18) |
| Pre-stent dilatation | 64.6% (157/243) |
| Post-stent dilatation | 96.7% (235/243) |
| Number of Zilver Vena Venous Stents placed per patient | |
| 1 | 57.2% (139/243) |
| 2 | 35.4% (86/243) |
| 3 | 7.4% (18/243) |

a Access site(s) may involve more than one location; therefore, the total number of access site(s) may be more than the number of patients enrolled. “Other” access vein sites included great saphenous vein, collateral vein off the femoral vein, small saphenous vein, and lesser saphenous vein.

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of the primary safety endpoint was based on a composite endpoint of 30-day freedom from MAEs (defined as procedural bleeding requiring transfusion, procedure- or device-related death, clinically driven target lesion reintervention, clinical migration, new symptomatic pulmonary embolism, or procedure-related perforation requiring open surgical repair or flow-limiting dissection of the target vessel).

Safety data through 30 days post-procedure were available for 240 of the 243 VIVO Clinical Study patients. The 3 patients with missing data included 2 patients who exited the study before 30 days without experiencing a MAE and

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1 patient who was excluded from the analysis due to a technical failure (specifically, the stent was placed in an unintended vein).

The 30-day freedom from MAE rate for the analyzable population was 96.7% (232/240; Table 13), and the lower limit of the two-sided 95% confidence interval (CI) was 93.5%, which is greater than the performance goal of 87% (p &lt; 0.0001). In summary, the null hypothesis for the 30-day primary safety hypothesis was rejected, supporting the safety of the Zilver Vena Venous Stent.

Table 13. VIVO Clinical Study Primary Safety Endpoint (Analyzable Population)

| 30-day Freedom from MAE Rate (%; number/total number) | 95% Exact CI | Performance Goal | P-value |
| --- | --- | --- | --- |
| 96.7% (232/240) | 93.5%-98.6% | 87% | <0.0001 |

In total, 8 patients experienced a MAE through 30 days; MAEs reported through 30 days included clinically-driven target lesion reintervention (n=7) and new symptomatic pulmonary embolism (n=1). Table 14 summarizes these events, as well as all MAEs reported through 3 years. In total, 26 MAEs have been reported through 3 years. Clinically driven target lesion reinterventions accounted for the majority (n=16) of MAEs. The clinical migration reported was a stent migration to a patient's heart that required surgical removal; the CEC adjudicated this as technique-related (the stent was undersized). Although the stent migration was not identified until the 6-month imaging (x-ray and ultrasound), the migration was considered to have occurred on the day of the procedure. After an unsuccessful endovascular attempt to remove the migrated stent, the stent was removed from the pulmonary artery through sternotomy. The patient was reported to have developed atrial flutter 23 days after undergoing open surgery to remove the migrated stent.

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Table 14. MAEs Reported Through 3 Years in the VIVO Clinical Study

| Major Adverse Event (MAE) | Number of MAEs | | | | Total |
| --- | --- | --- | --- | --- | --- |
| | 0-30 Days | 31-365 Days | 366-730 Days | >730 Days | |
| Clinically driven target lesion reintervention | 7 | 3 | 5 | 1 | 16 |
| New symptomatic pulmonary embolism | 1 | 1 | 1 | 6 | 9 |
| Clinical migration | 0 | 1 | 0 | 0 | 1 |
| Procedure- or device-related death | 0 | 0 | 0 | 0 | 0 |
| Procedural bleeding requiring transfusion | 0 | 0 | 0 | 0 | 0 |
| Procedure-related perforation requiring open surgical repair | 0 | 0 | 0 | 0 | 0 |
| Flow-limiting dissection of the target vessel | 0 | 0 | 0 | 0 | 0 |
| Total | 8 | 5 | 6 | 7 | 26 |

Note: bleeding events occurring prior to study enrollment, and related to procedures such as thrombolysis or thrombectomy, are not considered procedural bleeding events.

## Adverse events that occurred in the VIVO Clinical Study

All adverse events reported in the VIVO Clinical Study through 3 years are summarized in Table 15. There were no unanticipated adverse device effects observed during the study. There were 5 patient deaths through 3 years; 3 of these deaths were related to cancer, 1 death was due to sepsis, and 1 death was due to suicide. The CEC adjudicated all mortalities as not related to the study device or procedure.

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Table 15. All Adverse Events Reported Through 3 Years in the VIVO Clinical Study

| Event Type | Percent Patients (number /total number) | | | | Total Number of Events |
| --- | --- | --- | --- | --- | --- |
| | 0-30 Days | 31-365 Days | 366-730 Days | >730 Days | |
| Access site/incision events | 0.8% (2/243) | 0.4% (1/241) | 0% (0/220) | 0% (0/207) | 3 |
| Infection requiring intervention | 0.4% (1/243) | 0% (0/241) | 0% (0/220) | 0% (0/207) | 1 |
| Hematoma requiring intervention | 0.4% (1/243) | 0.4% (1/241) | 0% (0/220) | 0% (0/207) | 2 |
| Abscess formation requiring intervention | 0% (0/243) | 0% (0/241) | 0% (0/220) | 0% (0/207) | 0 |
| Bleeding requiring transfusion | 0% (0/243) | 0% (0/241) | 0% (0/220) | 0% (0/207) | 0 |
| Cardiovascular | 1.2% (3/243) | 2.9% (7/241) | 1.8% (4/220) | 1.9% (4/207) | 19 |
| Cardiac arrhythmia requiring intervention | 0.4% (1/243) | 0.4% (1/241) | 0.5% (1/220) | 0.5% (1/207) | 4 |
| Chest pain | 0.8% (2/243) | 2.1% (5/241) | 1.4% (3/220) | 1.4% (3/207) | 13 |
| Myocardial infarction (MI) | 0% (0/243) | 0.8% (2/241) | 0% (0/220) | 0% (0/207) | 2 |
| Cerebrovascular/neurologic | 0% (0/243) | 0.4% (1/241) | 0% (0/220) | 0.5% (1/207) | 2 |
| Stroke | 0% (0/243) | 0.4% (1/241) | 0% (0/220) | 0.5% (1/207) | 2 |
| Pulmonary | 1.6% (4/243) | 2.1% (5/241) | 2.3% (5/220) | 4.3% (9/207) | 24 |
| Pulmonary embolism (PE) | 0.4% (1/243) | 0.4% (1/241) | 0.5% (1/220) | 2.9% (6/207) | 9 |
| Shortness of breath | 1.6% (4/243) | 1.7% (4/241) | 1.8% (4/220) | 1.4% (3/207) | 15 |
| Renal | 0% (0/243) | 0.4% (1/241) | 0.5% (1/220) | 0% (0/207) | 2 |
| Renal failure requiring intervention | 0% (0/243) | 0.4% (1/241) | 0.5% (1/220) | 0% (0/207) | 2 |
| Vascular | 5.3% (13/243) | 8.3% (20/241) | 8.6% (19/220) | 2.9% (6/207) | 72 |
| Arteriovenous fistula | 0% (0/243) | 0% (0/241) | 0% (0/220) | 0% (0/207) | 0 |
| Embolism | 0% (0/243) | 0% (0/241) | 0.5% (1/220) | 0% (0/207) | 3 |
| Hypertension requiring intervention | 0% (0/243) | 0.4% (1/241) | 0.5% (1/220) | 0% (0/207) | 3 |
| Hypotension requiring intervention | 0% (0/243) | 0% (0/241) | 0% (0/220) | 0.5% (1/207) | 1 |
| Occlusion | 4.9% (12/243) | 4.1% (10/241) | 3.6% (8/220) | 1.0% (2/207) | 34 |
| Pseudoaneurysm | 0% (0/243) | 0.4% (1/241) | 0.5% (1/220) | 0% (0/207) | 2 |
| Restenosis | 0% (0/243) | 2.9% (7/241) | 2.7% (6/220) | 1.0% (2/207) | 17 |
| Stasis ulcer of the study leg | 0% (0/243) | 2.1% (5/241) | 0.5% (1/220) | 1.0% (2/207) | 9 |
| Tissue necrosis of the study leg | 0% (0/243) | 0% (0/241) | 0% (0/220) | 0% (0/207) | 0 |
| Vascular injury | 0.4% (1/243) | 0% (0/241) | 0.9% (2/220) | 0% (0/207) | 3 |

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| Event Type | Percent Patients (number /total number) | | | | Total Number of Events |
| --- | --- | --- | --- | --- | --- |
| | 0-30 Days | 31-365 Days | 366-730 Days | >730 Days | |
| Miscellaneous | 31.7% (77/243) | 49.8% (120/241) | 40.9% (90/220) | 39.1% (81/207) | 674 |
| Bleeding associated with anticoagulant/antiplatelet therapy | 8.2% (20/243) | 5.4% (13/241) | 2.7% (6/220) | 1.9% (4/207) | 47 |
| Fever requiring treatment | 0.4% (1/243) | 0% (0/241) | 0.5% (1/220) | 0.5% (1/207) | 3 |
| Hypersensitivity/allergic reaction | 3.7% (9/243) | 0% (0/241) | 0% (0/220) | 0% (0/207) | 9 |
| Nausea requiring treatment | 0.8% (2/243) | 0% (0/241) | 0% (0/220) | 0.5% (1/207) | 3 |
| Septicemia/bacteremia | 0% (0/243) | 0.8% (2/241) | 1.8% (4/220) | 0.5% (1/207) | 9 |
| Worsened pain of study leg | 1.6% (4/243) | 3.3% (8/241) | 2.7% (6/220) | 1.9% (4/207) | 23 |
| Abdominal pain | 0.4% (1/243) | 2.1% (5/241) | 0.9% (2/220) | 1.9% (4/207) | 13 |
| Back pain | 2.5% (6/243) | 2.5% (6/241) | 0.5% (1/220) | 1.0% (2/207) | 15 |
| Other | 18.9% (46/243) | 43.6% (105/241) | 39.1% (86/220) | 35.7% (74/207) | 552 |

Note: Values in bold indicate total numbers of patients and events under each event type.

## 2. Effectiveness Results

The primary effectiveness endpoint was primary quantitative patency at 12 months. Primary quantitative patency was defined as a treated venous segment (including the region within ± 1 cm proximal and/or distal of the treated venous segment) that retained (uninterrupted; intervention-free) an MLD &gt; 50% of the immediate post-procedure stented MLD as demonstrated by venography as determined by the core laboratory.

Among the 243 enrolled patients, 189 patients had venographic primary patency outcome data available and therefore make-up the analyzable population. The venographic results consisted of core laboratory assessed venogram results for 181 patients and site assessed venogram results for 8 patients, as per the analysis plan. Among the 189 analyzable patients, 19 patients had a loss of primary quantitative patency. Importantly, no patient experienced a surgical bypass of the treated segment or amputation of the extremity determined to result from venous outflow occlusion. For the 54 patients with a missing primary effectiveness outcome, the outcome was imputed by random sampling from the Bernoulli distribution based on outcomes for the 189 analyzable patients without covariate adjustment. The imputation was performed 20 times.

Table 16 presents the results of the intent-to-treat (ITT) analysis with multiple imputations for 12-month primary quantitative patency. The analysis was based on 189 patients with observed outcomes and 54 patients with imputed outcomes. The 12-month primary quantitative patency rate was 89.9%, and the lower limit of the two-sided 95% CI was 85.1%, which is greater than the performance goal of 76% (p &lt; 0.0001).

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Table 16. VIVO Clinical Study Primary Effectiveness Endpoint (ITT Population)

| 12-Month Quantitative Patency (%) | 95% CI | Performance Goal | P-value |
| --- | --- | --- | --- |
| 89.9% | 85.1%-93.4% | 76% | <0.0001 |

Similar results were obtained for patients with venographic primary patency outcome data, or the analyzable population (N=189 patients; 181 patients with core lab assessed venogram results and 8 with site assessed venogram results). As presented in Table 17, the 12-month primary quantitative patency rate for the analyzable population was 89.9% (170/189), and the lower limit of the two-sided 95% CI was 84.7%, which is greater than the performance goal of 76% (p &lt; 0.0001).

Table 17. VIVO Clinical Study Primary Effectiveness Endpoint (Analyzable Population)

| 12-month Quantitative Patency (%; number/total number) | 95% Exact CI | Performance Goal | P-value |
| --- | --- | --- | --- |
| 89.9% (170/189) | 84.7% - 93.8% | 76% | <0.0001 |

In summary, the null hypothesis for the 12-month primary effectiveness endpoint was rejected, supporting the effectiveness of the Zilver Vena Venous Stent.

3. Secondary Endpoint

The secondary hypothesis was the change in VCSS from baseline to 1 month and 12 months. The secondary endpoint hypotheses for 1 month and 12 months were tested by a paired t-test with p-values adjusted for multiple comparisons using the Holm’s procedure to control for a family-wise Type I error rate of 0.05, with 95% CIs also reported.

The results for the change in VCSS from baseline to 1 month, 12 months, 2 years, and 3 years are provided in Table 18. Compared to baseline, the mean change (note: negative change is improvement) in VCSS was -3.0 (95% CI: -3.5 to -2.6) at 1 month (p &lt; 0.0001) and -4.2 (95% CI: -4.7 to -3.7) at 12 months (p &lt; 0.0001). Therefore, the null hypothesis is rejected at both 1 month and 12 months.

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Table 18. VIVO Clinical Study Secondary Endpoint (Change in VCSS from Baseline)

| VCSS Assessment Time Point | VCSS Mean ± SD (N, range) | VCSS Change from Baseline Mean (N, 95% CI) | P-value^{a} | Accept/Reject Null Hypothesis |
| --- | --- | --- | --- | --- |
| Baseline | 8.0 ± 4.2 (243, 1-24) | NA | NA | NA |
| 1 month | 5.0 ± 4.0 (233, 0-23) | -3.0 (233, -3.5 to -2.6) | <0.0001 | Reject |
| 12 months | 3.8 ± 4.0 (202, 0-27) | -4.2 (202, -4.7 to -3.7) | <0.0001 | Reject |
| 2 years | 3.7 ± 3.5 (190, 0-20) | -4.2 (190, -4.8 to -3.7) | NA | NA |
| 3 years | 3.7 ± 3.6 (173, 0-21) | -4.1 (173, -4.6 to -3.5) | NA | NA |

a p-values for 1 month and 12 months were adjusted for multiplicity using Holm’s procedure.

These data demonstrate significantly improved VCSS score at 1 month, with continued or maintained improvement through 12 months following stent placement. The improvement in VCSS was sustained through 2 years and 3 years post-treatment, supporting device effectiveness and demonstrating clinical benefit for patients receiving the Zilver Vena Venous Stent.

## 4. Additional Measures

This section presents the additional measures that were assessed for the VIVO Clinical Study. The additional measures included many device-related effectiveness measures and clinical benefit measures, including technical success, procedural success, device integrity, device migration, rate of freedom from clinically driven reintervention, rate of freedom from reintervention, rate of primary quantitative patency, rate of patency by ultrasound, rate of assisted primary quantitative patency, rate of secondary quantitative patency, rate of clinical patency, rate of modified clinical patency, and change in VCSS, VDS, CEAP “C” classification, and CIVIQ score from baseline. Additional measures were not hypothesis driven; descriptive statistics are presented.

Procedural success measures included technical success (ability to deliver and deploy the study stent in the intended location) and procedural success (improved flow through the target vessel demonstrated by diminished flow through collateral vein and/or reduced filling defect in the target vessel and no MAE before discharge). Technical success was assessed for all study stents and was reported based on site assessment. The rate of technical success was 97.3% (355/365 stents). Procedural success was assessed for all patients with evidence of collateral veins or filling defect in the target vessel at the time of the procedure, and any patient with a MAE before discharge was considered a failure. Procedure success included core laboratory assessment of procedure imaging. The rate of procedural success was 96.7% (175/181 patients).

Table 19 summarizes the Kaplan Meier estimates for freedom from stent fracture and stent migration through 3 years. The core laboratory reported no stent fractures through 3 years and 1 stent migration through 3 years. The stent

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migration was the clinical migration of the study stent to the patient's heart, as described above in the Safety Results.

Table 19. VIVO Clinical Study Device Measures (Kaplan-Meier estimate ± SD) through 3 years

| X-Ray Assessment Time Point | Freedom from Stent Fracture Kaplan Meier Estimate ± SD | Freedom from Stent Migration Kaplan Meier Estimate ± SD |
| --- | --- | --- |
| 0 days | 100% | 100% |
| 12 months | 100% | 99.7% ± 0.3% |
| 2 years | 100% | 99.7% ± 0.3% |
| 3 years | 100% | 99.7% ± 0.3% |

Table 20 reports the results for 12-month quantitative patency outcome measures. These results demonstrate the effectiveness of the Zilver Vena Venous Stent in establishing and maintaining patency through 12 months. Table 21 reports the results for reintervention and patency outcome measures through 3 years.

Table 20. VIVO Clinical Study Quantitative Patency Measures (binary rates and Kaplan-Meier estimate ± SD) through 410 days

| Measure | Binary Rate Outcomes | Kaplan-Meier Estimate Outcomes (n=243) |
| --- | --- | --- |
| 12-month rates of primary quantitative patency | | |
| Overall study population | 89.9% (170/189) | 89.8% ± 3.5% |
| Population classified as acute | 86.3% (44/51) | 88.7% ± 5.2% |
| Population classified as chronic | 91.3% (126/138) | 90.4% ± 4.0% |
| Population with past or current DVT at enrollment | 85.3% (110/129) | 85.0% ± 5.3% |
| Population with no past or current DVT at enrollment | 100% (60/60) | 100% |
| 12-month assisted primary quantitative patency | 91.4% (170/186) | 90.0% ± 3.5% |
| 12-month secondary quantitative patency | 98.9% (185/187) | 98.9% ± 0.7% |

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Table 21. VIVO Clinical Study Reintervention and Patency Measures (binary rates and Kaplan-Meier estimate ± SD) through 3 years

| Measure | Binary Rate Outcomes | Kaplan-Meier Estimate Outcomes (n=243) |
| --- | --- | --- |
| 12-month Outcomes (through 410 days) | | |
| 12-month rate of freedom from clinically driven reinterventiona | 94.8% (201/212) | 95.3% ± 1.5% |
| 12-month rate of freedom from reinterventionb | 85.8% (188/219) | 86.7% ± 2.3% |
| 12-month patency by ultrasound | 91.2% (187/205) | 92.0% ± 2.0% |
| 12-month clinical patency | 79.4% (166/209) | 80.7% ± 2.8% |
| 12-month modified clinical patency | 87.5% (182/208) | 88.3% ± 2.3% |
| 2-year Outcomes (through 730 days) | | |
| 2-year rate of freedom from clinically driven reinterventiona | 92.0% (173/188) | 93.2% ± 1.8% |
| 2-year rate of freedom from reinterventionb | 81.9% (172/210) | 83.4% ± 2.5% |
| 2-year patency by ultrasound | 88.5% (161/182) | 90.3% ± 2.2% |
| 2-year clinical patency | 72.7% (133/183) | 76.8% ± 3.0% |
| 2-year modified clinical patency | 82.4% (145/176) | 85.6% ± 2.6% |
| 3-year Outcomes (through 1,095 days) | | |
| 3-year rate of freedom from clinically driven reinterventiona | 90.2% (147/163) | 92.6% ± 2.0% |
| 3-year rate of freedom from reinterventionb | 78.9% (146/185) | 82.9% ± 2.6% |
| 3-year patency by ultrasound | 85.9% (128/149) | 90.3% ± 2.2% |
| 3-year clinical patency | 66.7% (108/162) | 74.4% ± 3.3% |
| 3-year modified clinical patency | 75.8% (116/153) | 81.5% ± 3.6% |

aClinically driven reinterventions were reinterventions performed in patients with recurrent symptoms of venous outflow obstruction of the target lesion and with venography showing a treated venous segment (including the region within $\pm 1$ cm proximal and/or distal to the treated venous segment) minimum lumen diameter $(\mathrm{MLD}) \leq 50\%$ of the immediate post-procedure stented MLD. Most commonly, the clinical symptom in these patients was edema or pain.
bReinterventions were any endovascular or surgical intervention performed in a treated venous segment (including the region within $\pm 1$ cm proximal and/or distal to the treated venous segment). Reinterventions were those treatments in the treated venous segment when the MLD was $&gt;50\%$ of the immediate post-procedure stented MLD or treatments reported outside the treated venous segment, in the presence or absence of clinical symptoms.

Table 22 presents the change in the clinical scores of VDS, CEAP “C”, and CIVIQ through 3 years. The data demonstrate that stent placement resulted in clinical improvement, as demonstrated by improved clinical scores following stent placement, which were maintained through 3 years. Specifically, the number of patients with a VDS of 2 or 3 or a CEAP “C3” classification decreased dramatically from pre-procedure to 1 month, with continued or maintained improvement through 3 years. Likewise, an improvement in the CIVIQ score was observed at 1 month, with continued or maintained improvement through 3 years following stent placement.

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Table 22. VIVO Clinical Study Clinical Outcome Measures

| Clinical Measure | Time Point | | | | |
| --- | --- | --- | --- | --- | --- |
| | Pre-procedure | 1 Month | 12 Months | 2 Years | 3 Years |
| VDS (percent patients [number/total number]) | | | | | |
| 0 | 5.3% (13/243) | 40.8% (95/233) | 55.0% (111/202) | 53.2% (101/190) | 57.2% (99/173) |
| 1 | 28.0% (68/243) | 34.3% (80/233) | 27.7% (56/202) | 31.6% (60/190) | 28.3% (49/173) |
| 2 | 41.6% (101/243) | 21.5% (50/233) | 14.4% (29/202) | 13.7% (26/190) | 11.6% (20/173) |
| 3 | 25.1% (61/243) | 3.4% (8/233) | 3.0% (6/202) | 1.6% (3/190) | 2.9% (5/173) |
| CEAP “C” Classification (percent patients [number/total number]) | | | | | |
| C0 | 0.4% (1/243) | 25.3% (59/233) | 36.1% (73/202) | 30.0% (57/190) | 27.7% (48/173) |
| C1 | 0.8% (2/243) | 9.0% (21/233) | 14.9% (30/202) | 11.6% (22/190) | 12.7% (22/173) |
| C2 | 3.3% (8/243) | 7.3% (17/233) | 9.9% (20/202) | 11.6% (22/190) | 12.1% (21/173) |
| C3 | 66.7% (162/243) | 34.3% (80/233) | 20.8% (42/202) | 29.5% (56/190) | 30.6% (53/173) |
| C4a | 16.9% (41/243) | 13.7% (32/233) | 13.4% (27/202) | 10.5% (20/190) | 10.4% (18/173) |
| C4b | 3.7% (9/243) | 4.3% (10/233) | 1.5% (3/202) | 2.1% (4/190) | 1.7% (3/173) |
| C5 | 2.9% (7/243) | 3.4% (8/233) | 1.5% (3/202) | 2.6% (5/190) | 2.3% (4/173) |
| C6 | 5.3% (13/243) | 2.6% (6/233) | 2.0% (4/202) | 2.1% (4/190) | 2.3% (4/173) |
| CIVIQ Score (mean [N; 95%CI]) | | | | | |
| Mean change from baseline | NA | -20.5
(209; -23.6 to -17.3) | -22.6
(168; -26.2 to -19.0) | -22.1
(155; -26.0 to -18.2) | -20.8
(131; -24.8 to -16.8) |

N/A = not applicable.

In summary, the Zilver Vena Venous Stent was associated with high technical and procedural success rates, a low rate of migration, and no fractures. Finally, the low reintervention rates, favorable patency rates, and improvements in venous clinical symptoms (as measured by VDS, CEAP “C” classification, and CIVIQ score) demonstrate the clinical benefit of the Zilver Vena Venous Stent.

## 5. Subgroup Analyses

Although the study was not powered for this purpose, patient characteristics were evaluated for their potential contribution to the treatment effect and overall event rates. Analyses to evaluate impacts on the primary and secondary endpoints of the evaluable patients were conducted for predefined characteristics such as age, sex, presence of thrombotic disease, presence of occlusive disease, presence of thrombophilia, venous disease status (acute or chronic), and DVT status. No significant impact on the endpoint was found for any of the aforementioned covariates; specifically, no differences were noted based on age or gender. As expected, patients with less severe disease tended to perform slightly better than patients with more severe venous disease (DVT, longer lesion length, etc.). However, given the robust study results of the overall study data, interpretation of most results was limited due to the small sample size of the subgroups.

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## 6. Pediatric Extrapolation

In this premarket application, existing clinical data were not leveraged to support approval of a pediatric patient population.

## E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 36 principal investigators, of whom none were full-time or part-time employees of the sponsor and 5 had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c), and (f) and described below:

- Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0
- Significant payment of other sorts: 5
- Proprietary interest in the product tested held by the investigator: 0
- Significant equity interest held by investigator in sponsor of covered study: 0

The applicant has adequately disclosed the financial interest/arrangements with clinical investigators. Statistical analyses were conducted by FDA to determine whether the financial interests/arrangements had any impact on the clinical study outcome. The information provided does not raise any questions about the reliability of the data.

## XI. Summary of Supplemental Clinical Information

The VIVO-EU Clinical Study was a prospective, nonrandomized, multicenter study in Europe that enrolled patients with symptomatic obstruction in up to two iliofemoral venous segments. The study was designed to assess the performance of the Zilver Vena Venous Stent in the treatment of patients with symptomatic iliofemoral venous outflow obstruction.

A total of 35 patients were enrolled at five European sites. The study entry criteria were similar to the VIVO Clinical Study with the exception that there was no limitation associated with significant obstruction or occlusion of the inflow or outflow tract, and inclusion of bilateral limbs with obstruction and malignant obstruction was allowed. Patient follow-up included clinical assessments at 1, 6, and 12 months and noninvasive ultrasound at 6 and 12 months. Study assessments included: 1) procedural success; 2) MAEs; 3) qualitative patency at 6 and 12 months post-procedure; 4) clinical symptoms of venous insufficiency at 1, 3, 6, 9, and 12

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months post-procedure; and 5) reintervention within the treated venous segment. An independent core laboratory was used for image analysis. Study follow-up is complete.

Patient demographics and medical history were comparable to the VIVO Clinical Study; specifically, the mean age was 45.1 ± 15.5 years, most patients were female (77.1%; 27/35) and white/Caucasian (68.6%; 24/35), and more than half of the study population had acute or chronic DVT (62.9%; 22/35). Lesions were predominantly left-sided (94.1%; 32/35) and most commonly affected the common iliac vein (94.1%; 32/35) and external iliac vein (38.2%; 13/35). The mean lesion length was 89.3 mm ± 58.6 mm based on core laboratory assessment. In total, 45 Zilver Vena Venous Stents were implanted to treat study patients' iliofemoral venous lesions.

MAEs were defined as procedural bleeding requiring transfusion, procedure- or device-related death, clinically driven target lesion reintervention for occlusion, stent migration requiring an intervention, procedure- or device-related symptomatic pulmonary embolism, or procedure-related uncorrectable perforation or flow-limiting dissection of the target vessel. In total, three MAEs were reported in the study, including two clinically driven reinterventions for occlusion and one procedure- or device-related symptomatic pulmonary embolism.

Freedom from occlusion (lack of occlusion of the treated venous segment by evidence of blood flow proximal, within, and distal to the study lesion) was determined by Kaplan-Meier estimate. The 6-month and 12-month rate of freedom from occlusion was 88.2%.

Qualitative patency (defined as a lack of occlusion of the treated venous segment determined by evidence of blood flow both proximal and distal to the study lesion assessed via ultrasound and/or venography and no worsening of pain or edema symptoms from baseline [according to VCSS]) was similarly determined by Kaplan-Meier estimate. The 6-month rate of qualitative patency was 88.2% and the 12-month rate of qualitative patency was 85.2%.

In total, seven reinterventions were reported in five patients; reinterventions occurred between 4 and 392 days after stent placement. Clinical measures included VCSS, VDS, CEAP "C" classification, and CIVIQ score. Stent placement resulted in clinical improvement, as demonstrated by improvement in each respective clinical score following stent placement, which was maintained through 12 months.

In conclusion, the results from the VIVO-EU Clinical Study provide supportive evidence confirming the safety and effectiveness of the Zilver Vena Venous Stent for the treatment of patients with symptomatic iliofemoral venous outflow obstruction.

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# XII. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(3) 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

## A. Effectiveness Conclusions

The non-clinical engineering testing conducted on the stent and delivery system demonstrates that the performance characteristics of the device met the product specifications. The test results obtained from sterilization testing demonstrate that the product can be adequately sterilized and is acceptable for clinical use. The shelf life testing has established acceptable performance for a labeled shelf life up to 3 years.

The VIVO Clinical Study was a prospective, global, multi center, nonrandomized, single-arm clinical study intended to evaluate the Zilver Vena Venous Stent for the treatment of patients with symptomatic iliofemoral venous outflow obstruction. The primary effectiveness endpoint was primary quantitative patency at 12 months and was defined as a treated venous segment that retained (uninterrupted; intervention-free) an MLD &gt; 50% of the immediate post-procedure stented MLD as demonstrated by venography as determined by the core laboratory.

The 12-month primary quantitative patency rate for the intent-to-treat population was 89.9% with a 95% CI of 85.1%-93.4% and met the performa…