← Product Code [NIM](/productcode/NIM) · P140026S016

# ENROUTE Transcarotid Stent System (P140026S016)

_Boston Scientific Corporation · NIM · Apr 28, 2022 · Cardiovascular · APPR_

**Canonical URL:** https://fda-staging.innolitics.com/device/P140026S016

## Device Facts

- **Applicant:** Boston Scientific Corporation
- **Product Code:** [NIM](/productcode/NIM.md)
- **Decision Date:** Apr 28, 2022
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic, Real-World Evidence

## Real-World Evidence

| Submission | Device | Sponsor | RWD Sources | RWE Use Summary | Key Tags |
| --- | --- | --- | --- | --- | --- |
| P140026S016 · Apr 28, 2022 | ENROUTE Transcarotid Stent System | Boston Scientific Corporation | Society for Vascular Surgery Vascular Quality Initiative (SVS VQI) Carotid Artery Stenting (CAS) registry; Society for Vascular Surgery Vascular Quality Initiative (SVS VQI) Carotid Endarterectomy (CEA) registry | The sponsor utilized propensity score matched analysis of retrospective registry data to demonstrate that TCAR using the ENROUTE Stent is non-inferior to CEA in standard surgical risk patients. | Propensity score matching; Registry data; SVS VQI; Standard surgical risk; Non-inferiority analysis |

### Clinical Evidence

| Study Design | Population | Comparator | Key Endpoints |
| --- | --- | --- | --- |
| SVS VQI Propensity Score Matched Analysis; Retrospective propensity score matched cohort study; Follow-up/Duration: 30 days and 1 year; Study Period: August 8, 2016 through September 2, 2020 | Patients at standard risk for adverse events from carotid endarterectomy (CEA) requiring carotid revascularization; Sample Size: 5,066 TCAR patients matched to 15,198 CEA patients (3:1 ratio); Number of Sites: 565 centers (SVS VQI participating sites) | Carotid Endarterectomy (CEA) | Composite of death/stroke/myocardial infarction through 30 days and ipsilateral stroke from day 31 through day 365 |

## Indications for Use

The ENROUTE® Transcarotid Stent System used in conjunction with the ENROUTE Transcarotid Neuroprotection System (NPS) is indicated for the treatment of patients at high and standard risk for adverse events from carotid endarterectomy who require carotid revascularization and meet the criteria outlined below: High Risk: With neurological symptoms: ≥ 50% stenosis of the common or internal carotid artery by ultrasound or angiogram; Without neurological symptoms: ≥ 80% stenosis of the common or internal carotid artery by ultrasound or angiogram; Reference vessel diameter: Must be within 4.0 mm – 9.0 mm at the target lesion; Carotid bifurcation location: Minimum 5 cm above the clavicle to allow for placement of the ENROUTE Transcarotid NPS. Standard Risk: With neurological symptoms: ≥ 70% stenosis of the common or internal carotid artery by ultrasound or ≥ 50% stenosis of the common or internal carotid artery by angiogram; Without neurological symptoms: ≥ 70% stenosis of the common or internal carotid artery by ultrasound or ≥ 60% stenosis of the common or internal carotid artery by angiogram.

## Device Story

Self-expanding nitinol stent preloaded on sheathed delivery system; used with ENROUTE Transcarotid Neuroprotection System (NPS) for transcarotid artery revascularization (TCAR). Delivery system features inner shaft with radiopaque markers, Tuohy Borst valve, and guidewire lumen for .014" guidewire. Stent deployed via sheath retraction; forms open lattice to maintain vessel patency. Used in clinic/OR by vascular specialists. Provides mechanical support to carotid artery; NPS provides flow reversal to capture embolic debris during procedure. Benefits include reduced risk of cranial nerve injury compared to CEA; non-inferiority to CEA in major adverse event rates (death/stroke/MI).

## Clinical Evidence

Real-world evidence (RWE) study using SVS VQI registry data. Propensity score matched analysis (3:1 CEA to TCAR). Primary endpoint: composite of death/stroke/MI through 30 days and ipsilateral stroke from 31-365 days. Results: TCAR non-inferior to CEA (difference 0.14%, upper 95% CI 0.81%, margin 5%). In-hospital cranial nerve injury lower for TCAR (0.30% vs 2.68%).

## Technological Characteristics

Nitinol self-expanding stent; stainless steel delivery system components (wire, hypotube, coil). Dimensions: 5-10mm diameter, 20-40mm length. Delivery system crossing profile 5F-6F. Radiopaque markers for visualization. Standalone device used with NPS. Sterilization method not specified.

## Regulatory Identification

Stent, Carotid -- a metal scaffold placed via a delivery catheter into the carotid artery to maintain the lumen

## Predicate Devices

- ENROUTE Transcarotid Stent System ([P140026](/device/P140026.md))

## Reference Devices

- ROADSTER study ([K143072](/device/K143072.md))
- ACT-1 (Rosenfield et al., 2016)
- CREST study (Brott et al., 2010)

## Submission Summary (Full Text)

> This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com.
>
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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Carotid Stent

Device Trade Name: ENROUTE® Transcarotid Stent System

Device Procode: NIM

Applicant's Name and Address: Silk Road Medical, Inc.
1213 Innsbruck Drive
Sunnyvale, CA 94089

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P140026/S016

Date of FDA Notice of Approval: April 28, 2022

The original PMA (P140026) for the ENROUTE® Transcarotid Stent System was approved on May 18, 2015 and is indicated for use in conjunction with the ENROUTE Transcarotid Neuroprotection System (NPS) for the treatment of patients at high risk for adverse events from carotid endarterectomy who require carotid revascularization and meet the criteria outlined below.

1. Patients with neurological symptoms and ≥ 50% stenosis of the common or internal carotid artery by ultrasound or angiogram OR patients without neurological symptoms and ≥ 80% stenosis of the common or internal carotid artery by ultrasound or angiogram, AND
2. Patients must have a vessel diameter of 4-9mm at the target lesion, AND
3. Carotid bifurcation is located at minimum 5 cm above the clavicle to allow for placement of the ENROUTE Transcarotid NPS.

The SSED to support the indication is available on the CDRH website and is incorporated by reference here. The current supplement was submitted to expand the indication for the ENROUTE® Transcarotid Stent System to include patients at standard risk for adverse events from carotid endarterectomy.

## II. INDICATIONS FOR USE

The ENROUTE® Transcarotid Stent System used in conjunction with the ENROUTE Transcarotid Neuroprotection System (NPS) is indicated for the treatment of patients at high and standard risk for adverse events from carotid endarterectomy who require carotid revascularization and meet the criteria outlined below:

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|   | **High Risk** | **Standard Risk**  |
| --- | --- | --- |
|  With neurological symptoms | ≥ 50% stenosis of the common or internal carotid artery by ultrasound or angiogram | ≥ 70% stenosis of the common or internal carotid artery by ultrasound or ≥ 50% stenosis of the common or internal carotid artery by angiogram  |
|  Without neurological symptoms | ≥ 80% stenosis of the common or internal carotid artery by ultrasound or angiogram | ≥ 70% stenosis of the common or internal carotid artery by ultrasound or ≥ 60% stenosis of the common or internal carotid artery by angiogram  |
|  Reference vessel diameter | Must be within 4.0 mm – 9.0 mm at the target lesion  |   |
|  Carotid bifurcation location | Minimum 5 cm above the clavicle to allow for placement of the ENROUTE Transcarotid NPS  |   |

### III. CONTRAINDICATIONS

Use of the ENROUTE® Transcarotid Stent System is contraindicated in the following patients:

1. Patients in whom antiplatelet and/or anticoagulation therapy is contraindicated.
2. Patients in whom the ENROUTE® Transcarotid NPS is unable to be placed.
3. Patients with uncorrected bleeding disorders.
4. Patients with known allergies to nitinol.
5. Lesions in the ostium of the common carotid artery.

### IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the ENROUTE® Transcarotid Stent System labeling.

### V. DEVICE DESCRIPTION

The SRM ENROUTE® Transcarotid Stent System for standard surgical risk patients is identical to that approved under P140026 for high surgical risk patients.

The SRM ENROUTE® Transcarotid Stent System consists of a nitinol self-expanding stent preloaded on a .065 inch (1.65 mm) or .078 inch (1.98 mm) sheathed delivery system. The delivery system consists mainly of an inner shaft and an outer sheath with radiopaque markers, and a Tuohy Borst valve. The distal inner shaft consists of a support member and

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wire lumen. The proximal portion of the support member is comprised of a hub connected to a stainless steel wire and hypotube and distally of a stainless steel coil. The wire lumen originates distally in a catheter tip and terminates proximally at a guidewire exit port located mid-shaft and designed to accept a .014" (0.36 mm) guidewire. The outer sheath has a proximal shaft and distal outer sheath with a nominal working length of 57 cm. The self-expanding stent is constrained within the space between the inner shaft and the distal outer sheath, located between distal and proximal stent markers on the inner shaft. The stent expands to its unconstrained diameter when released from the deployment catheter into the vessel. Upon deployment, the stent forms an open lattice and pushes outward on the luminal surface, helping to maintain the patency of the vessel. Due to the self-expanding behavior of nitinol, the stents are indicated for placement into vessels that are 1-2 mm smaller in diameter than the unconstrained diameter of the stent. Device depictions and components are provided in Figure 1.

Figure 1: ENROUTE® Transcarotid Stent System

![img-0.jpeg](img-0.jpeg)

|  Item | Description  |
| --- | --- |
|  1 | Tuohy Borst valve  |
|  2 | Hypotube  |
|  3 | Coil  |
|  4 | Catheter inner shaft tip  |
|  5 | Inner shaft hub  |
|  6A | Proximal shaft  |
|  6B | Distal outer sheath  |
|  7 | Outer shaft Luer hub  |
|  8 | Pod housing crimped stent  |
|  9 | Tuohy Borst Y-connection  |
|  10 | Proximal inner shaft marker (stop) marks trailing end of stent  |
|  11 | Outer sheath radiopaque marker  |
|  12 | Proximal valve end  |
|  13 | Distal inner shaft stent marker  |
|  14 | Coil sleeve  |
|  15 | Wire lumen  |
|  16 | Guidewire exit port  |

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Table 1 lists the stent configurations. Due to the self-expanding behavior of nitinol, the stents are indicated for placement into vessels that are 1-2mm smaller in diameter than the unconstrained diameter of the stent.

**Table 1: Silk Road ENROUTE® Transcarotid Stent System Catalog Numbers**

|  Catalog Number | Unconstrained Stent Dimensions Diameter x Length (mm) | Crossing Profile  |
| --- | --- | --- |
|  SR-0520-CS | 5 x 20 | 5F (.078", 1.98mm)  |
|  SR-0530-CS | 5 x 30 | 5F (.078", 1.98mm)  |
|  SR-0540-CS | 5 x 40 | 5F (.078", 1.98mm)  |
|  SR-0620-CS | 6 x 20 | 5F (.078", 1.98mm)  |
|  SR-0630-CS | 6 x 30 | 5F (.078", 1.98mm)  |
|  SR-0640-CS | 6 x 40 | 5F (.078", 1.98mm)  |
|  SR-0720-CS | 7 x 20 | 5F (.078", 1.98mm)  |
|  SR-0730-CS | 7 x 30 | 5F (.078", 1.98mm)  |
|  SR-0740-CS | 7 x 40 | 5F (.078", 1.98mm)  |
|  SR-0820-CS | 8 x 20 | 5F (.078", 1.98mm)  |
|  SR-0830-CS | 8 x 30 | 5F (.078", 1.98mm)  |
|  SR-0840-CS | 8 x 40 | 5F (.078", 1.98mm)  |
|  SR-0920-CS | 9 x 20 | 6F (.087", 2.21mm)  |
|  SR-0930-CS | 9 x 30 | 6F (.087", 2.21mm)  |
|  SR-0940-CS | 9 x 40 | 6F (.087", 2.21mm)  |
|  SR-1020-CS | 10 x 20 | 6F (.087", 2.21mm)  |
|  SR-1030-CS | 10 x 30 | 6F (.087", 2.21mm)  |
|  SR-1040-CS | 10 x 40 | 6F (.087", 2.21mm)  |

## **VI. ALTERNATIVE PRACTICES AND PROCEDURES**

Alternatives to stenting for the correction of carotid artery disease include surgery, medical therapy, or a combination of both. The primary treatment used to prevent stroke in patients with significant carotid artery disease is surgery (endarterectomy) to remove plaque from the affected artery. Medical therapy includes use of antiplatelet and/or anticoagulant medicine, as well as antihypertensive and antilipidemic drugs as indicated. Antiplatelet drugs include aspirin, Plavix® (clopidogrel), or Ticlid® (ticlopidine). Anticoagulants include Coumadin® (warfarin). Medical therapy can also include modification of lifestyle risk factors for stroke, such as cigarette smoking and alcohol use. 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 ENROUTE® Transcarotid Stent System has been commercially available in the United States since June 2015. As of December 2021, 57,895 stents have been distributed within the United States. The ENROUTE® Transcarotid Stent System (initially marketed as the KOBI Transcervical Carotid Stent System in Europe) has been on the market in the following countries since August 2013:

- United Kingdom
- Belgium
- France
- Germany

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- Hungary
- Spain
- The Netherlands
- Switzerland

As of December 2021, 536 stents have been distributed outside the United States (OUS). The ENROUTE® Transcarotid Stent System that is marketed OUS does not include risk stratification of patients in the labeling (i.e. patient risk status is not defined in the labeling).

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

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

- Air embolism
- Allergic/anaphylactoid reaction
- Aneurysm
- Angina/coronary ischemia
- Arrhythmia (including bradycardia, possibly requiring need for a temporary or permanent pacemaker)
- Arterial dissection
- Arterial occlusion/restenosis of the treated vessel
- Arterial occlusion/thrombus, at puncture site
- Arterial occlusion/thrombus, remote from puncture site
- Arteriovenous fistula
- Bacteremia or septicemia
- Cerebral edema
- Death
- Embolization, arterial
- Embolization, stent
- Emergent repeat hospital intervention
- Fever
- Gastrointestinal disorders
- GI bleeding from anticoagulation/antiplatelet medication
- Hallucination
- Hematoma bleed, access site
- Hematoma bleed, remote site
- Hemorrhage
- Hyperperfusion syndrome
- Hypotension/hypertension
- Hypomagnesaemia
- Hypophosphatemia
- Infection
- Intimal injury/dissection
- Ischemia/infarction of tissue/organ
- Local infection and pain at insertion site

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- Malposition (failure to deliver the stent to the intended site)
- Myocardial infarction
- Nausea
- Oxygen saturation decrease
- Pain
- Pseudoaneurysm
- Renal failure
- Respiratory infection
- Restenosis of the vessel (> 50% obstruction)
- Rhinorrhea
- Seizure
- Severe unilateral headache
- Stent migration
- Stent thrombosis
- Stroke
- Transient ischemic attack
- Transient intolerance to reverse flow
- Urinary tract infection
- Vasospasm
- Venous occlusion/thrombosis, at puncture site
- Venous occlusion/thrombosis, remote from puncture site
- Vessel rupture, dissection, perforation
- Vomiting
- Wheezing

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

### IX. SUMMARY OF NONCLINICAL STUDIES

Because the ENROUTE® Transcarotid Stent System for standard surgical risk patients is identical to the ENROUTE® Transcarotid Stent System approved for high surgical risk patients, non-clinical and pre-clinical testing was leveraged from the P140026 approval for high surgical risk subjects. Please reference the P140026 SSED for additional detail on the preclinical testing that supported the approval.

### X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant utilized real-world data (RWD) housed within the Society for Vascular Surgery Vascular Quality Initiative (SVS VQI) to conduct analyses presented to support the standard risk approval. The analyses establish real-world evidence (RWE) to provide reasonable assurance of the safety and effectiveness of the ENROUTE® Transcarotid Stent System in standard surgical risk patients during transcarotid artery revascularization (TCAR) procedures. Reasonable assurance of safety and effectiveness was demonstrated through an analysis of patient-level data from the carotid artery stenting (CAS) and carotid endarterectomy (CEA) registries of the SVS VQI.

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The TCAR Surveillance Project (TSP) was initiated in 2016 by the Society for Vascular Surgery Vascular Quality Initiative (SVS VQI) to obtain more data about real-world outcomes of TCAR in patients deemed high surgical risk for CEA as performed by centers participating in the SVS VQI. As of January 2021, 565 centers have contributed almost 28,000 TCAR cases to the CAS registry.

#### **A. Study Design**

Patients deemed to be at standard risk for adverse events from CEA were analyzed in a propensity score matched analysis to provide RWE. Outcomes include major adverse events (death/stroke/myocardial infarction) through 30 days and ipsilateral stroke from 31 days through 365 days. The outcomes are presented as a composite endpoint. Propensity score matching and data analyses were conducted on behalf of the sponsor by a third party that is unaffiliated with the sponsor.

All standard risk CEA and TCAR patients that underwent the procedure from August 8, 2016 through September 2, 2020 that were entered into the SVS VQI CAS and CEA registries were considered for inclusion. The analysis was conducted with data through September 2, 2020.

##### **1. Clinical Inclusion and Exclusion Criteria**

Patients included in this analysis were consecutively entered into the SVS VQI. TCAR patients were treated with the ENROUTE® Transcarotid Stent System (ENROUTE Stent) in conjunction with the ENROUTE® Transcarotid Neuroprotection System (ENROUTE NPS). Only patients deemed to be at standard risk for adverse events from CEA were included.

In the TSP, the following patients are considered high surgical risk (HSR):

##### *Anatomic High-Risk Inclusion Criteria:*

- Contralateral carotid artery occlusion
- Tandem stenoses in the internal carotid artery >70% diameter reducing
- High cervical carotid artery stenosis above the C2 vertebra
- Restenosis after prior ipsilateral carotid endarterectomy
- Hostile neck including but not limited to prior neck irradiation, prior radical neck dissection, stoma presence or cervical spine immobility

##### *Clinical High-Risk Inclusion Criteria:*

- Patient is ≥ 75 years of age
- Patient has ≥ 2-vessel coronary artery disease and history of angina
- Patient has a history of unstable angina or Canadian Cardiovascular Society (CCS) angina class 3 or 4
- Patient has congestive heart failure (CHF) - New York Heart Association (NYHA) Functional Class III or IV

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- Patient has known severe left ventricular dysfunction with left ventricular ejection fraction (LVEF) <30%
- Patient has had a myocardial infarction < 6 weeks prior to procedure
- Patient has severe pulmonary disease (COPD) with either forced expiratory volume (FEV1) <50% predicted or chronic oxygen therapy or resting partial pressure of oxygen (PO2) of <= 60 mmHg (on room air) or is on home oxygen
- Patient has permanent contralateral laryngeal nerve injury
- Patient has chronic renal insufficiency (serum creatinine > 2.5 mg/dL) or is on dialysis
- Patient has need for open heart or other major operation within 30 days of carotid treatment

Hence, patients that present without any of these HSR anatomic or clinical features would be considered standard surgical risk (SSR) except for age ≥75 years. While CMS considers age ≥75 years to be a high-risk criterion, the sponsor has altered the age threshold for patients included in this analysis to patients age <80 years. This aligns with other standard risk trials such as ACT-1 (Ref. 1) which excluded patients <80 years and the CREST study (Ref. 2) which had no upper age limit. In the FDA analysis from the CREST study, octogenarians accounted for only 10.2% of enrollment in the transfemoral carotid artery stenting (TFCAS) arm (Ref. 3). In the lead-in phase of CREST (Ref. 4), the incidence of death or stroke within 30 days in octogenarians was 12.12%. This was significantly higher than the incidence of death or stroke within 30 days in non-octogenarians (3.23%; p<0.0001) and is the reason for establishing the threshold in this analysis at <80 years.

Patients excluded from these analyses are as follows:

- Tandem, traumatic or dissection lesions
- More than one stented lesion
- CEA with concomitant procedures
- TCAR patients treated with another manufacturer's stent

## 2. Follow-up Schedule

Patients deemed to be at standard risk for adverse events from CEA were analyzed in a propensity score matched analysis. Outcomes include Major Adverse Events (MAE; death/stroke/myocardial infarction) through 30 days and ipsilateral stroke from 31 days through 365 days.

## 3. Clinical Endpoints

The composite primary endpoint to establish reasonable assurance of the safety and effectiveness of the subject device is death/stroke/myocardial infarction through 30 days and ipsilateral stroke from day 31 through day 365.

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The objective of the analysis is to determine if TCAR is non-inferior to CEA based on the primary endpoint definition. The null hypothesis and alternative hypothesis are presented below.

Ho: $\pi_{\text{TCAR}} - \pi_{\text{CEA}} \geq$ non-inferiority margin (%)

Ha: $\pi_{\text{TCAR}} - \pi_{\text{CEA}} <$ non-inferiority margin (%)

Where $\pi_{\text{TCAR}}$ represents the percentage of TCAR patients who experience the composite primary endpoint, $\pi_{\text{CEA}}$ represents the percentage of CEA patients who experience the composite primary endpoint, and non-inferiority margin (%) refers to the pre-specified non-inferiority margin.

A non-inferiority margin of 5% was chosen.

The cumulative incidence of the endpoint was estimated among the matched population using Kaplan Meier methods. Statistical inference was performed using the bootstrap method.

Other procedural and outcome measures were also assessed including the following:

*Secondary Endpoints*

- Outcomes by Gender
- Outcomes by Age (<65 and ≥65)
- Cranial Nerve Injury, in-hospital

*Observational Endpoints*

- Outcomes by Race
- Outcomes by Ethnicity
- Stroke, in-hospital
- Death, in-hospital
- Myocardial Infarction (MI), in-hospital
- Stroke/Death/MI, in-hospital
- Access Site Complication
- Hematoma/bleeding
- Postoperative stenosis/occlusion
- Pseudoaneurysm
- Return to Operating Room

**B. Accountability of PMA Cohort**

All CEA and TCAR patients that underwent the procedure from August 8, 2016 through September 2, 2020 who were entered into the SVS VQI CAS and CEA registries were considered for inclusion. A total of 44,743 CEA patients and 5,066 TCAR patients over the aforementioned period were available for the analyses. After matching CEA and TCAR patients in a 3:1 ratio, 15,198 CEA patients and 5,066 TCAR patients who received the ENROUTE stent were available for the analyses.

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This includes 2,988 CEA patients with 1-year follow-up and 996 TCAR patients treated with the ENROUTE stent with 1-year follow-up that were analyzed.

### C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for standard surgical risk carotid artery stenting study performed in the US.

#### Demographics and Baseline Characteristics (All Matched Patients)

Table 2 provides a tabulation of the baseline demographics for all matched CEA and TCAR patients. Three CEA patients were matched to each TCAR patient (3:1 nearest neighbor, no caliper). There were no TCAR patients treated with the ENROUTE Stent that were excluded from matching. Key demographic parameters were similar between the matched cohorts: symptom status, age, gender, congestive heart failure, COPD, dialysis, smoking, hypertension, kidney function, coronary artery disease and percent stenosis. TCAR patients had a slightly higher mean body mass index based on the arithmetic mean, and a slightly higher incidence of mild coronary artery disease, but neither was considered clinically significant. The median BMI differed by 0.5 (kg/m$^{2}$) between TCAR and CEA. The incidence of severe stenosis (>70%) was 91.3% and 90.2% for the CEA and TCAR cohorts, respectively.

**Table 2: Demographics and Baseline Characteristics after Matching (All Patients)**

|   | Total | Treatment Modality |   | Std Diff (%)  |
| --- | --- | --- | --- | --- |
|   |  n = 20264 | CEA n = 15198 | TCAR n = 5066  |   |
|  Presenting Symptom Status |  |  |  | 1.5  |
|  Stroke | 6187 (30.5%) | 4619 (30.4%) | 1568 (31.0%) |   |
|  Cortical TIA | 2435 (12.0%) | 1823 (12.0%) | 612 (12.1%) |   |
|  Retinal TIA | 838 (4.1%) | 630 (4.1%) | 208 (4.1%) |   |
|  Unknown Stroke Severity | 1516 (7.5%) | 1135 (7.5%) | 381 (7.5%) |   |
|  Asymptomatic | 9288 (45.8%) | 6991 (46.0%) | 2297 (45.3%) |   |
|  Age |  |  |  | 3.1  |
|  Mean ± SD | 70.22 ± 6.72 | 70.17 ± 6.66 | 70.38 ± 6.88 |   |
|  Median (IQR) | 72.00 (66.00, 76.00) | 71.00 (66.00, 75.00) | 72.00 (66.00, 76.00) |   |
|  Age ≥65 | 16360 (80.7%) | 12285 (80.8%) | 4075 (80.4%) | 1.0  |
|  Male | 12943 (63.9%) | 9684 (63.7%) | 3259 (64.3%) | 1.3  |
|  Caucasian | 18211 (89.9%) | 13670 (89.9%) | 4541 (89.6%) | 1.0  |
|  Race |  |  |  | 1.7  |
|  American Indian or Alaskan Native | 95 (0.5%) | 70 (0.5%) | 25 (0.5%) |   |
|  Asian | 160 (0.8%) | 122 (0.8%) | 38 (0.8%) |   |
|  Black or African American | 1149 (5.7%) | 854 (5.6%) | 295 (5.8%) |   |
|   | 17 (0.1%) | 12 (0.1%) | 5 (0.1%) |   |
|  Native Hawaiian or other Pacific Islander | 18211 (89.9%) | 13670 (89.9%) | 4541 (89.6%) |   |
|  White | 41 (0.2%) | 29 (0.2%) | 12 (0.2%) |   |
|  More than 1 race | 591 (2.9%) | 441 (2.9%) | 150 (3.0%) |   |
|  Unknown / Other |  |  |  |   |
|  Body Mass Index |  |  |  | 5.6  |
|  Mean ± SD | 28.79 ± 8.14 | 28.68 ± 7.95 | 29.14 ± 8.68 |   |
|  Median (IQR) | 28.25 (25.01, 32.04) | 28.17 (24.98, 31.93) | 28.44 (25.09, 32.42) |   |
|  Hispanic or Latino | 944 (4.7%) | 712 (4.7%) | 232 (4.6%) | 0.5  |
|  None vs mild CAD (i.e., without unstable angina or MI within 6 months) | 9020 (44.5%) | 6657 (43.8%) | 2363 (46.6%) | 5.7  |
|  None vs. Asymptomatic/Mild CHF | 2277 (11.2%) | 1683 (11.1%) | 594 (11.7%) | 2.0  |
|  None vs mild COPD (i.e., not on home oxygen) | 4377 (21.6%) | 3273 (21.5%) | 1104 (21.8%) | 0.6  |

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|   | Total | Treatment Modality |   | Std Diff (%)  |
| --- | --- | --- | --- | --- |
|   |  n = 20264 | CEA n = 15198 | TCAR n = 5066  |   |
|  Dialysis | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |   |
|  ASA Class |  |  |  | 1.7  |
|  1 | 112 (0.6%) | 84 (0.6%) | 28 (0.6%) |   |
|  2 | 748 (3.7%) | 562 (3.7%) | 186 (3.7%) |   |
|  3 | 14631 (72.2%) | 10999 (72.4%) | 3632 (71.7%) |   |
|  4 or 5 | 4773 (23.6%) | 3553 (23.4%) | 1220 (24.1%) |   |
|  Smoking |  |  |  | 0.9  |
|  None | 5220 (25.8%) | 3904 (25.7%) | 1316 (26.0%) |   |
|  Prior | 10130 (50.0%) | 7615 (50.1%) | 2515 (49.6%) |   |
|  Current | 4914 (24.2%) | 3679 (24.2%) | 1235 (24.4%) |   |
|  Hypertension | 18184 (89.7%) | 13635 (89.7%) | 4549 (89.8%) | 0.3  |
|  Diabetes |  |  |  | 1.5  |
|  None | 12177 (60.1%) | 9158 (60.3%) | 3019 (59.6%) |   |
|  Diet | 993 (4.9%) | 738 (4.9%) | 255 (5.0%) |   |
|  Non-Insulin | 4098 (20.2%) | 3068 (20.2%) | 1030 (20.3%) |   |
|  Insulin/medication dependent | 2996 (14.8%) | 2234 (14.7%) | 762 (15.0%) |   |
|  Prior CABG | 3991 (19.7%) | 3012 (19.8%) | 979 (19.3%) | 1.2  |
|  Prior PCI | 5097 (25.2%) | 3827 (25.2%) | 1270 (25.1%) | 0.3  |
|  Creatinine mg/dl |  |  |  | 1.5  |
|  Mean ± SD | 1.03 ± 0.32 | 1.03 ± 0.32 | 1.04 ± 0.32 |   |
|  Median (IQR) | 0.98 (0.80, 1.20) | 0.98 (0.80, 1.20) | 0.99 (0.80, 1.20) |   |
|  GFR |  |  |  | 1.9  |
|  Mean ± SD | 75.29 ± 18.60 | 75.38 ± 18.64 | 75.03 ± 18.48 |   |
|  Median (IQR) | 79.44 (61.76, 88.92) | 79.65 (61.91, 89.03) | 78.64 (61.56, 88.48) |   |
|  GFR<60 | 4614 (22.8%) | 3448 (22.7%) | 1166 (23.0%) | 0.8  |
|  Pre-admission Living Status |  |  |  | 0.4  |
|  Home | 20018 (98.8%) | 15014 (98.8%) | 5004 (98.8%) |   |
|  Nursing home | 220 (1.1%) | 164 (1.1%) | 56 (1.1%) |   |
|  Homeless | 26 (0.1%) | 20 (0.1%) | 6 (0.1%) |   |
|  Percent Lesion Stenosis |  |  |  | 4.0  |
|  > 50% | 1257 (6.2%) | 907 (6.0%) | 350 (6.9%) |   |
|  > 60% | 560 (2.8%) | 417 (2.7%) | 143 (2.8%) |   |
|  > 70% | 2610 (12.9%) | 1949 (12.8%) | 661 (13.0%) |   |
|  > 80% | 15837 (78.2%) | 11925 (78.5%) | 3912 (77.2%) |   |

### Procedure Information (All Matched Patients)

Table 3 provides a tabulation of the procedure information for all matched CEA and TCAR patients by treatment modality. The use of general anesthesia was higher in the CEA cohort. The use of pre-operative P2Y12 antagonists was higher in the TCAR patients which is expected in accordance with multi-society, treatment guidelines following CAS procedures. Mean procedure times were longer for CEA than TCAR (117.30 min vs 72.50 min respectively). The use of dual antiplatelet therapy was higher in the TCAR cohort, which is expected in accordance with multi-society, treatment guidelines following CAS procedures.

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**Table 3: Procedure Information after Matching (All Patients)**

|   | Total | Treatment modality |   | Std Diff (%)  |
| --- | --- | --- | --- | --- |
|   |  n = 20264 | CEA n = 15198 | TCAR n = 5066  |   |
|  Lesion Laterality |  |  |  | 0.4  |
|  Right | 10468 (51.7%) | 7843 (51.6%) | 2625 (51.8%) |   |
|  Left | 9796 (48.3%) | 7355 (48.4%) | 2441 (48.2%) |   |
|  Lesion Length (mm) |  |  |  |   |
|  Mean ± SD | 25.46 ± 11.51 | Not Reported | 25.46 ± 11.51 | N/A  |
|  Median (IQR) | 25.00 (18.00, 30.00) |   | 25.00 (18.00, 30.00)  |   |
|  Missing |  |   | 605  |   |
|  General Anesthesia Use | 18387 (90.7%) | 14203 (93.5%) | 4184 (82.6%) | 33.9  |
|  Pre-op P2Y12 Antagonist |  |  |  | 117.6  |
|  None | 9305 (45.9%) | 8716 (57.3%) | 589 (11.6%) |   |
|  Clopidogrel | 10010 (49.4%) | 5737 (37.7%) | 4273 (84.3%) |   |
|  Prasugrel | 99 (0.5%) | 56 (0.4%) | 43 (0.8%) |   |
|  Ticagrelor | 1 (0.0%) | 1 (0.0%) | 0 (0.0%) |   |
|  Other P2Y12 Inhibitor | 238 (1.2%) | 116 (0.8%) | 122 (2.4%) |   |
|  No. for Medical Reason | 34 (0.2%) | 28 (0.2%) | 6 (0.1%) |   |
|  Non-compliant | 542 (2.7%) | 517 (3.4%) | 25 (0.5%) |   |
|  Aggrenox | 32 (0.2%) | 27 (0.2%) | 5 (0.1%) |   |
|  Missing | 3 (0.0%) | 0 (0.0%) | 3 (0.1%) |   |
|  Pre-op Statin | 18190 (89.8%) | 13627 (89.7%) | 4563 (90.1%) | 1.4  |
|  Pre-op ASA | 18406 (90.8%) | 13803 (90.8%) | 4603 (90.9%) | 0.1  |
|  Medication Loading |  |  |  |   |
|  None | 2957 (59.0%) | Not Applicable | 2957 (59.0%) | N/A  |
|  ASA or P2Y12 antagonist | 846 (16.9%) |   | 846 (16.9%)  |   |
|  Statin | 138 (2.8%) |   | 138 (2.8%)  |   |
|  Both | 1072 (21.4%) |   | 1072 (21.4%)  |   |
|  Missing |  |  | 53 |   |
|  Pre-op Chronic Anticoagulant | 2319 (11.4%) | 1722 (11.3%) | 597 (11.8%) | 1.4  |
|  Prophylactic Anti-bradyarrhythmic | 2669 (53.1%) | Not Applicable | 2669 (53.1%) | N/A  |
|  Missing |  |   | 39  |   |
|  Pre-dilatation | 965 (19.1%) | Not Applicable | 965 (19.1%) | N/A  |
|  Missing |  |   | 13  |   |
|  Number of stents placed |  |  |  |   |
|  1 | 4783 (94.4%) | Not Applicable | 4783 (94.4%) | N/A  |
|  2 | 283 (5.6%) |   | 283 (5.6%)  |   |
|  Missing |  |   |   |   |
|  Contrast Volume (mL) |  |  |  |   |
|  Mean ± SD | 31.20 ± 22.19 | Not Applicable | 31.20 ± 22.19 | N/A  |
|  Median (IQR) | 25.00 (18.00, 40.00) |   | 25.00 (18.00, 40.00)  |   |
|  Missing |  |   | 155  |   |
|  Total Procedure Time |  |  |  | 57.2  |
|  Mean ± SD | 106.13 ± 66.49 | 117.30 ± 44.43 | 72.50 ± 101.40 |   |
|  Median (IQR) | 98.00 (73.00, 129.00) | 110.00 (87.00, 139.00) | 65.00 (52.00, 84.00) |   |
|  Missing | 58 | 29 | 29 |   |

#### Demographics and Baseline Characteristics (Patients with 1-Year Follow-Up)

Table 4 provides a tabulation of the baseline demographics for matched CEA and TCAR patients with 1-year follow-up. For the composite endpoint analysis, there were 2,988 CEA patients and 996 TCAR patients with 1-year follow-up. Key demographic parameters were similar between the matched cohorts: symptom status, age, gender, congestive heart failure, COPD, smoking, hypertension, dialysis, kidney function, coronary artery disease and percent stenosis. Body mass index and the

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incidence of mild coronary artery disease were similar in patients with 1-year follow-up. The incidence of severe stenosis (>70%) was 91.5% and 91.1% for the CEA and TCAR cohorts respectively. There were differences in the procedural variables that are likely due to variations in the treatment modalities.

**Table 4: Demographics and Baseline Characteristics after Matching (Patients with 1-Year Follow-Up)**

|   | Total | Treatment Modality |   | Std Diff (%)  |
| --- | --- | --- | --- | --- |
|   |  n = 3984 | CEA n = 2988 | TCAR n = 996  |   |
|  Presenting Symptom Status |  |  |  | 2.6  |
|  Stroke | 1211 (30.4%) | 904 (30.3%) | 307 (30.8%) |   |
|  Cortical TIA | 479 (12.0%) | 360 (12.0%) | 119 (11.9%) |   |
|  Retinal TIA | 159 (4.0%) | 117 (3.9%) | 42 (4.2%) |   |
|  Unknown Stroke Severity | 205 (5.1%) | 152 (5.1%) | 53 (5.3%) |   |
|  Asymptomatic | 1930 (48.4%) | 1455 (48.7%) | 475 (47.7%) |   |
|  Age |  |  |  | 1.0  |
|  Mean ± SD | 70.69 ± 6.46 | 70.70 ± 6.37 | 70.64 ± 6.72 |   |
|  Median (IQR) | 72.00 (67.00, 76.00) | 72.00 (67.00, 76.00) | 72.00 (66.00, 76.00) |   |
|  Age ≥65 | 3307 (83.0%) | 2491 (83.4%) | 816 (81.9%) | 3.8  |
|  Male | 2629 (66.0%) | 1971 (66.0%) | 658 (66.1%) | 0.2  |
|  Caucasian | 3564 (89.5%) | 2673 (89.5%) | 891 (89.5%) | 0.0  |
|  Race |  |  |  | 3.6  |
|  American Indian or Alaskan Native | 26 (0.7%) | 18 (0.6%) | 8 (0.8%) |   |
|  Asian | 38 (1.0%) | 28 (0.9%) | 10 (1.0%) |   |
|  Black or African American | 201 (5.0%) | 151 (5.1%) | 50 (5.0%) |   |
|   | 7 (0.2%) | 5 (0.2%) | 2 (0.2%) |   |
|  Native Hawaiian or other Pacific Islander | 3564 (89.5%) | 2673 (89.5%) | 891 (89.5%) |   |
|  White | 17 (0.4%) | 12 (0.4%) | 5 (0.5%) |   |
|  More than 1 race | 131 (3.3%) | 101 (3.4%) | 30 (3.0%) |   |
|  Unknown / Other |  |  |  |   |
|  Body Mass Index |  |  |  | 0.3  |
|  Mean ± SD | 29.01 ± 7.46 | 29.02 ± 5.89 | 28.99 ± 10.88 |   |
|  Median (IQR) | 28.41 (25.31, 32.26) | 28.37 (25.28, 32.19) | 28.73 (25.41, 32.60) |   |
|  Hispanic or Latino | 183 (4.6%) | 136 (4.6%) | 47 (4.7%) | 0.8  |
|  None vs mild CAD (i.e., without unstable angina or MI within 6 months) | 1793 (45.0%) | 1341 (44.9%) | 452 (45.4%) | 1.0  |
|  None vs. Asymptomatic/Mild CHF | 503 (12.6%) | 377 (12.6%) | 126 (12.7%) | 0.1  |
|  None vs mild COPD (i.e., not on home oxygen) | 917 (23.0%) | 685 (22.9%) | 232 (23.3%) | 0.9  |
|  Dialysis | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | N/A  |
|  ASA Class |  |  |  | 1.8  |
|  1 | 14 (0.4%) | 10 (0.3%) | 4 (0.4%) |   |
|  2 | 160 (4.0%) | 118 (3.9%) | 42 (4.2%) |   |
|  3 | 2710 (68.0%) | 2033 (68.0%) | 677 (68.0%) |   |
|  4 or 5 | 1100 (27.6%) | 827 (27.7%) | 273 (27.4%) |   |

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|   | Total | Treatment Modality |   | Std Diff (%)  |
| --- | --- | --- | --- | --- |
|   |  n = 3984 | CEA n = 2988 | TCAR n = 996  |   |
|  Smoking |  |  |  | 2.3  |
|  None | 922 (23.1%) | 694 (23.2%) | 228 (22.9%) |   |
|  Prior | 2111 (53.0%) | 1575 (52.7%) | 536 (53.8%) |   |
|  Current | 951 (23.9%) | 719 (24.1%) | 232 (23.3%) |   |
|  Hypertension | 3611 (90.6%) | 2711 (90.7%) | 900 (90.4%) | 1.3  |
|  Diabetes |  |  |  | 2.1  |
|  None | 2360 (59.2%) | 1776 (59.4%) | 584 (58.6%) |   |
|  Diet | 160 (4.0%) | 118 (3.9%) | 42 (4.2%) |   |
|  Non Insulin | 842 (21.1%) | 631 (21.1%) | 211 (21.2%) |   |
|  Insulin/medication dependent | 622 (15.6%) | 463 (15.5%) | 159 (16.0%) |   |
|  Prior CABG | 794 (19.9%) | 591 (19.8%) | 203 (20.4%) | 1.5  |
|  Prior PCI | 1021 (25.6%) | 769 (25.7%) | 252 (25.3%) | 1.0  |
|  Creatinine mg/dl |  |  |  | 1.7  |
|  Mean ± SD | 1.04 ± 0.32 | 1.04 ± 0.33 | 1.04 ± 0.31 |   |
|  Median (IQR) | 0.99 (0.81, 1.20) | 0.99 (0.81, 1.20) | 0.99 (0.81, 1.20) |   |
|  GFR |  |  |  | 1.6  |
|  Mean ± SD | 74.41 ± 18.46 | 74.34 ± 18.53 | 74.63 ± 18.27 |   |
|  Median (IQR) | 78.12 (60.50, 88.07) | 78.10 (60.50, 88.07) | 78.20 (60.54, 88.18) |   |
|  GFR<60 | 964 (24.2%) | 728 (24.4%) | 236 (23.7%) | 1.6  |
|  Pre-admission Living Status |  |  |  | 2.0  |
|  Home | 3938 (98.8%) | 2955 (98.9%) | 983 (98.7%) |   |
|  Nursing home | 43 (1.1%) | 31 (1.0%) | 12 (1.2%) |   |
|  Homeless | 3 (0.1%) | 2 (0.1%) | 1 (0.1%) |   |
|  Dual antiplatelet therapy | 1744 (43.8%) | 947 (31.7%) | 797 (80.0%) | 111.4  |
|  Percent Lesion Stenosis |  |  |  | 2.8  |
|  > 50% | 220 (5.5%) | 163 (5.5%) | 57 (5.7%) |   |
|  > 60% | 121 (3.0%) | 90 (3.0%) | 31 (3.1%) |   |
|  > 70% | 434 (10.9%) | 320 (10.7%) | 114 (11.4%) |   |
|  > 80% | 3209 (80.5%) | 2415 (80.8%) | 794 (79.7%) |   |

### Procedure Information (Patients with 1-Year Follow-Up)

Table 5 provides a tabulation of the procedure information for matched CEA and TCAR patients with 1-year follow-up by treatment modality. The use of general anesthesia was higher in the CEA cohort. The use of pre-operative P2Y12 antagonists was higher in the TCAR patients which is expected in accordance with multi-society, treatment guidelines following CAS procedures. Mean procedure times were longer for CEA than TCAR (118.56 min vs 74.18 min respectively). The use of dual antiplatelet therapy was higher in the TCAR cohort which is expected in accordance with multi-society, treatment guidelines following CAS procedures.

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**Table 5: Procedure Information after Matching (Patients with 1-Year Follow-Up)**

|   | Total | Treatment Modality |   | Std Diff (%)  |
| --- | --- | --- | --- | --- |
|   |  n = 3984 | CEA n = 2988 | TCAR n = 996  |   |
|  Lesion Laterality |  |  |  | 0.3  |
|  Right | 1984 (49.8%) | 1489 (49.8%) | 495 (49.7%) |   |
|  Left | 2000 (50.2%) | 1499 (50.2%) | 501 (50.3%) |   |
|  Lesion Length (mm) |  |  |  |   |
|  Mean ± SD | 24.96 ± 12.03 | Not Reported | 24.96 ± 12.03 | N/A  |
|  Median (IQR) | 22.00 (17.00, 30.00) |   | 22.00 (17.00, 30.00)  |   |
|  Missing | 3094 |   | 106  |   |
|  General Anesthesia Use | 3623 (90.9%) | 2803 (93.8%) | 820 (82.3%) | 36.0  |
|  Pre-op P2Y12 Antagonist |  |  |  | 123.3  |
|  None | 1901 (47.7%) | 1779 (59.5%) | 122 (12.2%) |   |
|  Clopidogrel | 1885 (47.3%) | 1048 (35.1%) | 837 (84.0%) |   |
|  Prasugrel | 20 (0.5%) | 7 (0.2%) | 13 (1.3%) |   |
|  Ticagrelor | 32 (0.8%) | 20 (0.7%) | 12 (1.2%) |   |
|  Other P2Y12 Inhibitor | 8 (0.2%) | 4 (0.1%) | 4 (0.4%) |   |
|  No, for Medical Reason | 131 (3.3%) | 124 (4.1%) | 7 (0.7%) |   |
|  Non-compliant | 6 (0.2%) | 6 (0.2%) | 0 (0.0%) |   |
|  Aggrenox | 1 (0.0%) | 0 (0.0%) | 1 (0.1%) |   |
|  Pre-op Statin | 3513 (88.2%) | 2629 (88.0%) | 884 (88.8%) | 2.4  |
|  Pre-op ASA | 3583 (89.9%) | 2682 (89.8%) | 901 (90.5%) | 2.4  |
|  Medication Loading |  |  |  |   |
|  None | 608 (61.7%) | Not Applicable | 608 (61.7%) | N/A  |
|  ASA or P2Y12 antagonist | 169 (17.1%) |   | 169 (17.1%)  |   |
|  Statin | 33 (3.3%) |   | 33 (3.3%)  |   |
|  Both | 176 (17.8%) |   | 176 (17.8%)  |   |
|  Missing |  |   | 10  |   |
|  Pre-op Chronic Anticoagulant | 561 (14.1%) | 424 (14.2%) | 137 (13.8%) | 1.3  |
|  Prophylactic Anti-bradyarrhythmic Missing | 469 (47.4%) | Not Applicable | 469 (47.4%) 6 | N/A  |
|  Pre-dilatation Missing | 163 (16.4%) | Not Applicable | 163 (16.4%) 2 | N/A  |
|  Number of stents placed |  |  |  |   |
|  1 | 949 (95.3%) | Not Applicable | 949 (95.3%) | N/A  |
|  2 | 47 (4.7%) |   | 47 (4.7%)  |   |
|  Missing |  |   | 0  |   |
|  contrast |  |  |  |   |
|  Mean ± SD | 36.19 ± 23.22 | Not Applicable | 36.19 ± 23.22 | N/A  |
|  Median (IQR) | 30.00 (20.00, 45.00) |   | 30.00 (20.00, 45.00)  |   |
|  Missing |  |   | 35  |   |
|  Total Procedure Time |  |  |  | 118.8  |
|  Mean ± SD | 107.51 ± 45.65 | 118.56 ± 45.08 | 74.18 ± 27.58 |   |
|  Median (IQR) | 100.00 (75.00, 130.00) | 111.00 (88.00, 140.00) | 69.50 (55.00, 88.00) |   |
|  Missing | 7 | 1 | 6 |   |
|  Post-dilation (Stent 1) Missing | 574 (57.9%) | Not Applicable | 574 (57.9%) 4 | N/A  |

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|   | Total | Treatment Modality |   | Std Diff (%)  |
| --- | --- | --- | --- | --- |
|   |  n = 3984 | CEA n = 2988 | TCAR n = 996  |   |
|  Post-dilation (Stent 2) Missing | 25 (54.3%) | Not Applicable | 25 (54.3%) 950 | N/A  |
|  Percent Lesion Stenosis |  |  |  | 2.8  |
|  > 50% | 220 (5.5%) | 163 (5.5%) | 57 (5.7%) |   |
|  > 60% | 121 (3.0%) | 90 (3.0%) | 31 (3.1%) |   |
|  > 70% | 434 (10.9%) | 320 (10.7%) | 114 (11.4%) |   |
|  > 80% | 3209 (80.5%) | 2415 (80.8%) | 794 (79.7%) |   |

### D. Safety and Effectiveness Results

#### 1. Composite Endpoint Analysis

There were two analysis populations generated to compare the propensity score matched results between CEA and TCAR to evaluate the safety and effectiveness profile of the ENROUTE® Transcarotid Stent System (ENROUTE Stent) relative to CEA; all matched patients and patients with 1-year follow-up.

#### Results Based on All Matched Patients

All TCAR patients were treated with the ENROUTE Stent used in conjunction with the ENROUTE Transcarotid Neuroprotection System (ENROUTE NPS). The CEA and TCAR cohorts were propensity score matched (3:1 nearest neighbor, no caliper). There were no TCAR patients excluded from the matching (i.e., all standard surgical risk TCAR patients who received the ENROUTE stent from the SVS VQI were included in the analysis). The primary endpoint is a composite of death/stroke/myocardial infarction through 30 days and ipsilateral stroke from day 31 to day 365 (365 days minus 45 days).

The estimates generated for comparison of the individual outcomes between CEA and TCAR were derived using a right-censored approach for patients who did not experience the event of interest. The Kaplan-Meier (K-M) approach provides adjusted estimates based on the number of patients that remain at risk of experiencing the event. This risk-based approach is appropriate when dealing with longitudinal data where the duration of follow-up varies across patients and clinical sites. From the K-M analysis, the estimate of the rate at a specific time can be determined.

The first analysis population includes all TCAR patients (n=5,066) and three (3) matched CEA patients for every TCAR patient (n=15,198). Outcomes using Kaplan-Meier estimates are presented in Table 6 and Figure 2.

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**Table 6: Endpoint Analysis (All Matched Patients)**

|  Outcome | K-M Estimate for TCAR | K-M Estimate for CEA | Bootstrap 95% Confidence interval (TCAR-CEA)  |
| --- | --- | --- | --- |
|  **30 Day Death/Stroke/MI* + 1yr Ipsilateral stroke** | 2.93% | 2.62% | -0.38%, 1.08%  |
|  30 Day Stroke | 1.40% | 1.12% |   |
|  30 Day Death | 0.34% | 0.38% |   |
|  30 Day Death/Stroke | 1.62% | 1.42% |   |
|  30 Day Death/Stroke/MI* | 2.00% | 2.01% |   |
|  1yr Ipsilateral Stroke | 1.40% | 1.08% |   |

*MI is reported in-hospital as the CEA registry of the SVS VQI does not track MI past discharge whereas the CAS registry does.

There were no differences in the composite endpoint or components of the composite endpoint between the CEA and TCAR cohorts. To establish non-inferiority relative to the pre-specified non-inferiority margin of 5%, the upper bound of the 2-sided 95% confidence interval of the difference (TCAR minus CEA) for the composite endpoint was calculated. The results presented in Figure 2 are drawn directly from Table 6 and demonstrates that the upper bound of the confidence interval of the difference for the composite endpoint is firmly below the 5% non-inferiority margin. The observed difference in the composite endpoint between the TCAR and CEA cohorts was 0.14% with an upper 95% confidence limit of 0.81% (within the pre-specified non-inferiority margin of 5%). Based on these results, TCAR using the ENROUTE Stent in conjunction the ENROUTE NPS is non-inferior to CEA in the standard surgical risk patient population.

**Figure 2 Graphical Representation of the Non-Inferiority Analysis (All Matched Patients)**

(Difference in the Event Rates [TCAR minus CEA] from the Kaplan-Meier Estimates with the 95% Confidence Interval)

![img-1.jpeg](img-1.jpeg)

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Figure 3 shows the Kaplan-Meier estimate of the freedom from the composite endpoint event for all matched patients.

Figure 3 Freedom from Composite Endpoint Event Through 1 Year (All Matched Patients)

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

# Patients with 1-Year Follow-Up

The second analysis population includes TCAR patients with 1-year follow-up (n=996) and three (3) matched CEA patients with 1-year follow-up for every TCAR patient (n=2,988).

Table 7: Endpoint Analysis (Matched Patients with 1-Year Follow-Up)

|  Outcome | K-M Estimate for TCAR | K-M Estimate for CEA | Bootstrap 95% Confidence interval (TCAR-CEA)  |
| --- | --- | --- | --- |
|  30 Day Death*/Stroke/MI** + 1yr Ipsilateral Stroke | 2.31% | 2.18% | -0.95%, 1.15%  |

*By definition, the 1-year follow-up cohort had to survive ≥320 days to be included in this analysis because a patient is only included in the 1-year cohort exclusive of a 30-day periprocedural death.
** MI is reported as in-hospital. The CEA registry of the SVS VQI does not track MI past discharge whereas the CAS registry does.

There was no difference in the 1-year endpoint between the CEA and TCAR cohorts. To establish non-inferiority relative to the pre-specified non-inferiority margin of 5%, the upper bound of the 2-sided 95% confidence interval of the difference (TCAR minus CEA) for the composite endpoint was calculated. Supplemented by an analysis of the 1-year component of the composite endpoint in CEA and TCAR patients with

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1-year follow-up, TCAR using the ENROUTE Stent in conjunction the ENROUTE NPS is non-inferior to CEA in the standard surgical risk patient population.

## 2. Other Endpoint Analyses

### *Procedural Outcomes*

Table 8 presents other outcome and procedural measures from all matched TCAR and CEA patients. Certain procedural variables that are captured in the CAS registry of the SVS VQI are not captured in the CEA registry. Conversely, certain procedural variables that are captured in the CEA registry of the SVS VQI are not captured in the CAS registry. Those variables are presented as “Not Reported.”

**Table 8: Other Outcomes and Procedural Measures (All Matched Patients)**

|   | Total | Treatment Modality |   | TCAR-CEA, difference  |
| --- | --- | --- | --- | --- |
|   |  n = 20264 | CEA n = 15198 | TCAR n = 5066  |   |
|  Stroke, in-hospital | 226 (1.12%) | 158 (1.04%) | 68 (1.34%) | -0.30%  |
|  Death, in-hospital | 27 (0.13%) | 18 (0.12%) | 9 (0.18%) | -0.06%  |
|  Myocardial Infarction (MI), in-hospital | 127 (0.63%) | 102 (0.67%) | 25 (0.49%) | 0.18%  |
|  Stroke/Death/MI, in-hospital | 353 (1.74%) | 260 (1.71%) | 93 (1.84%) | -0.13%  |
|  Cranial Nerve Injury, in-hospital | 423 (2.09%) | 408 (2.68%) | 15 (0.30%) | 2.39%  |
|  Access Site Complication |  |  |  |   |
|  No | 4915 (97.06%) | Not Reported | 4915 (97.06%) | N/A  |
|  Yes | 149 (2.94%) |   | 149 (2.94%)  |   |
|  Missing |  |   | 2  |   |
|  Hematoma/bleeding |  |  |  |   |
|  None | 4930 (97.35%) | Not Reported | 4930 (97.35%) | N/A  |
|  Medical Treatment | 84 (1.66%) |   | 84 (1.66%)  |   |
|  Interventional Treatment | 6 (0.12%) |   | 6 (0.12%)  |   |
|  Surgical Treatment | 44 (0.87%) |   | 44 (0.87%)  |   |
|  Missing |  |  | 2 |   |
|  Postoperative stenosis/occlusion |  |  |  |   |
|  None | 5058 (99.88%) | Not Reported | 5058 (99.88%) | N/A  |
|  Medical Treatment | 2 (0.04%) |   | 2 (0.04%)  |   |
|  Interventional Treatment | 1 (0.02%) |   | 1 (0.02%)  |   |
|  Surgical Treatment | 3 (0.06%) |   | 3 (0.06%)  |   |
|  Missing |  |  | 2 |   |
|  Pseudoaneurysm |  |  |  |   |
|  No | 5062 (99.96%) | Not Reported | 5062 (99.96%) | N/A  |
|  Moderate, thrombin injection | 2 (0.04%) |   | 2 (0.04%)  |   |
|  Missing |  |   | 2  |   |
|  Return to Operating Room |  |  |  |   |
|  No | 14916 (98.16%) | 14916 (98.16%) | Not Reported | N/A  |
|  Yes, bleeding | 161 (1.06%) | 161 (1.06%)  |   |   |
|  Yes, neurologic | 37 (0.24%) | 37 (0.24%)  |   |   |
|  Yes, both | 3 (0.02%) | 3 (0.02%)  |   |   |
|  bleeding/neurologic | 7 (0.05%) | 7 (0.05%)  |   |   |
|  Yes, other CEA incision | 71 (0.47%) | 71 (0.47%)  |   |   |
|  Yes, other | 5069 | 3 |  |   |
|  Missing |  |  |  |   |

As shown in Table 8, the incidence of in-hospital stroke, in-hospital death or in-hospital MI were similar for CEA and TCAR. The incidence of the in-hospital composite of stroke/death/MI was similar for CEA and TCAR. TCAR had a lower

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incidence of in-hospital cranial nerve injury than CEA (0.30% vs 2.68% respectively).

The incidence of access site complications for TCAR was 2.94%. There was no equivalent variable for CEA in the SVS VQI. The ROADSTER study supported approval of the high surgical risk indication approved in P140026. For reference, the incidence of access site complications requiring intervention in the ROADSTER study was 2.3% (K143072). The incidence of hematoma/bleeding for TCAR was 2.70%; the incidence of those requiring interventional or surgical treatment was 0.99%. There was no equivalent variable for CEA in the SVS VQI. For reference, the incidence of wound hematoma requiring intervention in the ROADSTER study was 2.3%. The incidence of postoperative stenosis/occlusion for TCAR was 0.12%; the incidence of those requiring interventional or surgical treatment was 0.08%. There was no equivalent variable for CEA. For reference, the incidence of stenosis/occlusion in the ROADSTER study was 1.0%. The incidence of pseudoaneurysm for TCAR was 0.04%; both incidents were treated with thrombin injection. There was no equivalent variable for CEA in the SVS VQI. For reference, there were no reports of pseudoaneurysm in the ROADSTER study. For CEA, the incidence of a return to the operating room was 1.84% (bleeding/neurologic/incision/other). There was no equivalent variable for TCAR in the SVS VQI. These events are similar to those in the ROADSTER study and are expected of this device type.

# *Supplemental Analysis (all subjects eligible for 1-year follow-up)*

At the request of FDA, the sponsor conducted a supplemental analysis on all patients that were 1-year follow-up eligible. This combined all patients with documented 1-year follow-up who had their procedure on or before September 2, 2019 (one year prior to database lock), plus all patients without documented 1-year follow-up who had their procedure on or before September 2, 2019 (one year prior to database lock). The following table shows the number of TCAR patients in this population that were subsequently matched to CEA patients 3:1.

**Table 9: TCAR Patients Included in Supplemental Analysis**

|   | Patients with Documented 1-Year Follow-Up* | Patients without Documented 1-Year Follow-Up | Total Number of TCAR Patients Available for Matching  |
| --- | --- | --- | --- |
|  TCAR Patients | 983* | 1979* | 2962*  |

*Had their procedure on or before Sept 2, 2019 (one year prior to database lock), thus 1-year follow-up eligible.

After matching, 2,962 TCAR patients were matched to 8,886 CEA patients. Table 10 shows the post-matching data for the TCAR and CEA cohorts in the supplemental analysis population.

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**Table 10: All CEA and TCAR Patients in Supplemental Analysis Population After Matching**

|   | Total | Modality |   | Std Diff (%)  |
| --- | --- | --- | --- | --- |
|   |  n = 11848 | CEA n = 8886 | TCAR n = 2962  |   |
|  Symptomatic Status |  |  |  | 1.0  |
|  1 Stroke | 3572 (30.1%) | 2678 (30.1%) | 894 (30.2%) |   |
|  2 Cortical TIA | 1486 (12.5%) | 1121 (12.6%) | 365 (12.3%) |   |
|  3 Retinal TIA | 459 (3.9%) | 343 (3.9%) | 116 (3.9%) |   |
|  4 Unknown severity | 903 (7.6%) | 674 (7.6%) | 229 (7.7%) |   |
|  5 Asymptomatic | 5428 (45.8%) | 4070 (45.8%) | 1358 (45.8%) |   |
|  Age |  |  |  | 1.0  |
|  Mean ± SD | 70.39 ± 6.61 | 70.38 ± 6.51 | 70.44 ± 6.87 |   |
|  Median (IQR) | 72.00 (66.00, 76.00) | 72.00 (66.00, 76.00) | 72.00 (66.00, 76.00) |   |
|  Age>=65 | 9634 (81.3%) | 7240 (81.5%) | 2394 (80.8%) | 1.7  |
|  Male | 7687 (64.9%) | 5777 (65.0%) | 1910 (64.5%) | 1.1  |
|  Caucasian | 10630 (89.7%) | 7986 (89.9%) | 2644 (89.3%) | 2.0  |
|  Race |  |  |  | 3.4  |
|  1 American Indian or Alaskan Native | 65 (0.5%) | 44 (0.5%) | 21 (0.7%) |   |
|  2 Asian | 93 (0.8%) | 71 (0.8%) | 22 (0.7%) |   |
|  3 Black or African American | 683 (5.8%) | 508 (5.7%) | 175 (5.9%) |   |
|  4 Native Hawaiian or other Pacific Islander | 17 (0.1%) | 13 (0.1%) | 4 (0.1%) |   |
|  5 White | 10630 (89.7%) | 7986 (89.9%) | 2644 (89.3%) |   |
|  6 More than 1 race | 28 (0.2%) | 20 (0.2%) | 8 (0.3%) |   |
|  7 Unknown / Other | 332 (2.8%) | 244 (2.7%) | 88 (3.0%) |   |
|  Body Mass Index |  |  |  | 4.5  |
|  Mean ± SD | 28.78 ± 10.05 | 28.67 ± 10.01 | 29.13 ± 10.16 |   |
|  Median (IQR) | 28.33 (25.00, 32.13) | 28.28 (24.98, 32.04) | 28.52 (25.05, 32.34) |   |
|  Hispanic or Latino | 527 (4.4%) | 385 (4.3%) | 142 (4.8%) | 2.2  |
|  Any CAD | 5444 (45.9%) | 4071 (45.8%) | 1373 (46.4%) | 1.1  |
|  Prior CHF | 1427 (12.0%) | 1065 (12.0%) | 362 (12.2%) | 0.7  |
|  COPD | 2591 (21.9%) | 1936 (21.8%) | 655 (22.1%) | 0.8  |
|  Dialysis | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |   |
|  ASA Class |  |  |  | 1.2  |
|  1 | 83 (0.7%) | 61 (0.7%) | 22 (0.7%) |   |
|  2 | 524 (4.4%) | 391 (4.4%) | 133 (4.5%) |   |
|  3 | 8374 (70.7%) | 6291 (70.8%) | 2083 (70.3%) |   |
|  4 | 2867 (24.2%) | 2143 (24.1%) | 724 (24.4%) |   |
|  Smoking |  |  |  | 0.7  |
|  0 None | 2985 (25.2%) | 2236 (25.2%) | 749 (25.3%) |   |
|  1 Prior | 5895 (49.8%) | 4417 (49.7%) | 1478 (49.9%) |   |
|  2 Current | 2968 (25.1%) | 2233 (25.1%) | 735 (24.8%) |   |
|  Hypertension | 10743 (90.7%) | 8064 (90.7%) | 2679 (90.4%) | 1.0  |

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|   | Total | Modality |   | Std Diff (%)  |
| --- | --- | --- | --- | --- |
|   |  n = 11848 | CEA n = 8886 | TCAR n = 2962  |   |
|  Diabetes |  |  |  | 1.7  |
|  0 None | 7071 (59.7%) | 5318 (59.8%) | 1753 (59.2%) |   |
|  1 Diet | 490 (4.1%) | 363 (4.1%) | 127 (4.3%) |   |
|  2 Non Insulin | 2438 (20.6%) | 1828 (20.6%) | 610 (20.6%) |   |
|  3 Insulin | 1849 (15.6%) | 1377 (15.5%) | 472 (15.9%) |   |
|  Prior CABG | 2232 (18.8%) | 1678 (18.9%) | 554 (18.7%) | 0.5  |
|  Prior PCI | 2962 (25.0%) | 2225 (25.0%) | 737 (24.9%) | 0.4  |
|  Creatinine mg/dl |  |  |  | 1.0  |
|  Mean ± SD | 1.04 ± 0.32 | 1.04 ± 0.32 | 1.04 ± 0.31 |   |
|  Median (IQR) | 0.99 (0.81, 1.20) | 0.99 (0.81, 1.20) | 1.00 (0.81, 1.20) |   |
|  Glomerular filtration rate (GFR) |  |  |  | 1.4  |
|  Mean ± SD | 74.97 ± 18.33 | 75.03 ± 18.36 | 74.77 ± 18.24 |   |
|  Median (IQR) | 78.54 (61.69, 88.43) | 78.71 (61.76, 88.62) | 78.18 (61.13, 88.00) |   |
|  GFR<60 | 2703 (22.8%) | 2017 (22.7%) | 686 (23.2%) | 1.1  |
|  General Anesthesia | 10729 (90.6%) | 8314 (93.6%) | 2415 (81.5%) | 37.1  |
|  Pre-op P2Y12 Antagonist |  |  |  | 117.5  |
|  0 None | 5521 (46.6%) | 5157 (58.0%) | 364 (12.3%) |   |
|  1 Clopidogrel | 5754 (48.6%) | 3264 (36.7%) | 2490 (84.1%) |   |
|  2 Prasugrel | 61 (0.5%) | 36 (0.4%) | 25 (0.8%) |   |
|  4 Ticagrelor | 121 (1.0%) | 68 (0.8%) | 53 (1.8%) |   |
|  5 Other P2Y12 Inhibitor | 16 (0.1%) | 10 (0.1%) | 6 (0.2%) |   |
|  6 No. for Medical Reason | 350 (3.0%) | 333 (3.7%) | 17 (0.6%) |   |
|  7 Non-compliant | 22 (0.2%) | 18 (0.2%) | 4 (0.1%) |   |
|  9 | 3 (0.0%) | 0 (0.0%) | 3 (0.1%) |   |
|  Pre-op Statin | 10710 (90.4%) | 8034 (90.4%) | 2676 (90.3%) | 0.2  |
|  Pre-op ASA | 10659 (90.0%) | 7993 (90.0%) | 2666 (90.0%) | 0.2  |
|  Pre-op Anticoagulation | 1448 (12.2%) | 1086 (12.2%) | 362 (12.2%) | 0.0  |
|  Total Procedure Time |  |  |  | 120.0  |
|  Mean ± SD | 105.77 ± 44.94 | 116.89 ± 43.66 | 72.21 ± 29.39 |   |
|  Median (IQR) | 98.00 (74.00, 129.00) | 110.00 (87.00, 138.00) | 66.00 (53.00, 85.50) |   |
|  Missing | 41 | 19 | 22 |   |
|  Pre-admission Living Status |  |  |  | 1.3  |
|  1 Home | 11709 (98.8%) | 8785 (98.9%) | 2924 (98.7%) |   |
|  2 Nursing home | 128 (1.1%) | 93 (1.0%) | 35 (1.2%) |   |
|  3 Homeless | 11 (0.1%) | 8 (0.1%) | 3 (0.1%) |   |
|  DAPT | 5374 (45.4%) | 3016 (33.9%) | 2358 (79.6%) | 103.9  |
|  % Stenosis |  |  |  | 2.9  |
|  2 > 50% | 756 (6.4%) | 553 (6.2%) | 203 (6.9%) |   |
|  3 > 60% | 390 (3.3%) | 298 (3.4%) | 92 (3.1%) |   |
|  4 > 70% | 1443 (12.2%) | 1078 (12.1%) | 365 (12.3%) |   |
|  5 > 80% | 9259 (78.1%) | 6957 (78.3%) | 2302 (77.7%) |   |

After matching, the baseline covariates are well balanced between the TCAR and CEA cohorts. TCAR patients had a higher mean Body Mass Index. For procedural

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variables after matching, TCAR patients were still more likely to be treated under local anesthesia as well as being more likely to be treated with pre-operative P2Y12 antagonists. The use of pre-operative P2Y12 antagonists is expected in accordance with multi-society, treatment guidelines following CAS procedures. Mean total procedure time for TCAR was lower than CEA.

Table 11 shows the primary endpoint results in the supplemental analysis population (composite of D/S/MI at 30 days plus 1-year ipsilateral stroke) as well as the components of the composite endpoint.

Table 11: Primary Endpoint Results for All Matched Patients in the Supplemental Analysis Population

|  Outcome | KM Estimate for TCAR N=2962 | KM Estimate for CEA N=8886 | Bootstrap 95% Confidence interval (TCAR minus CEA)  |
| --- | --- | --- | --- |
|  30 Day Stroke | 1.55% | 1.13% |   |
|  30 Day Death | 0.34% | 0.41% |   |
|  30 Day Death/Stroke | 1.79% | 1.45% |   |
|  30 Day Death/Stroke/MI* | 2.20% | 2.05% |   |
|  Primary Endpoint: 30 Day Death/Stroke/MI* and 1-Year Ipsilateral Stroke | 2.96% | 2.56% | -0.43%, 1.24%  |

*MI is reported as in-hospital. The CEA registry of the SVS VQI does not track MI past discharge whereas the CAS registry does.

There were no statistically significant differences in the composite endpoint or the components of the composite endpoint between the TCAR and CEA cohorts. To establish non-inferiority relative to the pre-specified non-inferiority margin of 5%, the upper bound of the 2-sided 95% confidence interval of the difference (TCAR minus CEA) for the composite endpoint was calculated. The observed difference in the composite endpoint between the TCAR and CEA cohorts was 0.4% with an upper 95% confidence limit of 1.24% (within the pre-specified non-inferiority margin of 5%). Based on these results, TCAR using the ENROUTE Stent in conjunction the ENROUTE NPS is non-inferior to CEA in standard surgical risk patients included in the supplemental analysis population.

The following figure shows the Kaplan-Meier estimate of the freedom from the composite endpoint event (time-to-event) for all matched patients in the supplementary analysis population.

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**Figure 4: Product-Limit Survival Estimates for the Supplemental Analysis Population**

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

### 3. Subgroup Analyses

The following subgroups were evaluated for potential association with outcomes:

- Age <65 vs ≥65
- Gender (male vs female)
- Caucasian vs non-Caucasian
- Hispanic vs non-Hispanic

To evaluate the individual subgroups, a test for interaction between the proportion of patients who met the primary endpoint was calculated for each individual subgroup factor. Given that a pre-specified threshold for determining significant interaction was not pre-determined, probability values were calculated. This demonstrated that there was no interaction for gender, race or ethnicity.

The age of the patient (<65 vs. ≥65) had an interaction term <0.1 and was investigated further. The hazard ratio by age group revealed that the upper limit of the 2-sided 95% confidence interval was 2.76 for patients <65 years of age and 1.27 for patients ≥65 years of age. While the outcomes by age stratification showed some interaction, the upper bounds were below the pre-specified non-inferiority margin of 5%.

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# 4. Pediatric Extrapolation

In this premarket application, existing clinical data was 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 1 investigator. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data.

# XI. 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 Systems Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

# XII. CONCLUSIONS DRAWN FROM CLINICAL STUDIES

# A. Effectiveness Conclusions

The results from analyses using patient-level data from the SVS VQI demonstrate reasonable assurance of effectiveness for the ENROUTE® Transcarotid Stent System for use in standard surgical risk subjects with carotid artery disease. Effectiveness of the device was analyzed by evaluating the composite primary endpoint of death, stroke and myocardial infarction through 30 days and one-year ipsilateral stroke. These analyses demonstrated that TCAR with the ENROUTE® Transcarotid Stent System used in conjunction with ENROUTE Neuroprotection System is non-inferior to carotid endarterectomy by 5% when used to treat patients at standard risk for complications from CEA.

# B. Safety Conclusions

The risks of the device are based on data collected in a clinical study conducted to support PMA approval as described above including procedural information for both procedures. These data show that the TCAR procedure with the ENROUTE® Transcarotid Stent System is non-inferior to CEA relative to the primary endpoint (death/stroke/myocardial infarction through 30 days plus ipsilateral stroke from day 31 through day 365). Furthermore, the Kaplan-Meier estimates (time-to-event analysis) were similar for TCAR and CEA for the primary endpoint. These analyses provide reasonable assurance of the safety and effectiveness of the TCAR procedure with the ENROUTE® Transcarotid Stent System in the standard surgical risk population.

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For other observational clinical outcomes, the incidence of in-hospital stroke, in-hospital death and in-hospital MI were similar for CEA and TCAR. The incidence of the composite of stroke/death/MI in-hospital was similar for CEA and TCAR. TCAR had a lower incidence of in-hospital cranial nerve injury (a well characterized surgical complication) compared to CEA (0.30% vs 2.68% respectively).

The incidence of access site complications for TCAR (both procedure and device related) was 2.94%. This is comparable to the incidence of access site complications in prior clinical studies of TCAR. The incidence of hematoma/bleeding for TCAR was 2.70%; the incidence of those requiring interventional or surgical treatment (defined as serious) was 0.99%. Serious events of this nature are treated and resolved prior to hospital discharge. The incidence of serious wound hematomas requiring intervention in this clinical study was lower than in prior studies of TCAR.

The incidence of postoperative stenosis/occlusion for TCAR was 0.12%; the incidence of those requiring interventional or surgical treatment (defined as serious) was 0.08%. These are device-related complications and are well characterized in CAS. Post-operative stenosis or occlusion can manifest during the initial hospitalization or after discharge. The incidence of postoperative stenosis/occlusion in this clinical study was lower than in prior clinical studies of TCAR.

The incidence of pseudoaneurysm requiring intervention (defined as serious) for TCAR was 0.04%. Such events can manifest during the initial hospitalization or after discharge. These events can be either device or procedure related. The incidence in this clinical study is comparable to prior clinical studies of TCAR.

### C. Benefit-Risk Conclusions

Reasonable assurance of the safety and effectiveness of TCAR with the ENROUTE® Transcarotid Stent System in standard surgical risk patients has been demonstrated through a non-inferiority analysis with a pre-specified non-inferiority margin compared to CEA in standard surgical risk patients. Low rates of major adverse clinical events (death, stroke and myocardial infarction) which are events that can occur during any carotid artery interventional modality were seen for both TCAR and CEA. As a prophylactic procedure largely targeted to prevent the occurrence or recurrence of neurological events related to carotid artery stenosis, the chosen endpoints are clinically meaningful and have been used in multiple clinical trials of carotid interventions. The incidence of serious and non-serious device and procedure related adverse events is low and is comparable to similar FDA-approved devices and prior studies of TCAR. Therefore, the benefits of TCAR with the ENROUTE® Transcarotid Stent System in standard surgical risk patients outweigh the associated device or procedural risks.

The probable benefits and risks of the device are based on clinical data collected from the SVS VQI and also leveraged from the non-clinical testing and clinical study conducted to support the original PMA approval. The ENROUTE® Transcarotid Stent

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System used in conjunction with the ENROUTE® Transcarotid Neuroprotection System offers similar benefits compared to carotid endarterectomy. The benefits and risks of the ENROUTE® Transcarotid Stent System are similar to those for carotid endarterectomy with a reduction of the risk of cranial nerve injury.

Since complication rates in carotid stenting procedures are known to correlate with the experience of the operator, the sponsor plans to mitigate these risks through physician training.

#### 1. Patient Perspective

This submission either did not include specific information on patient perspectives or the information did not serve as part of the basis of the decision to approve or deny the PMA for this device.

In conclusion, given the available information above, the data support that for the treatment of patients at standard risk for adverse events from carotid endarterectomy who require carotid revascularization, the probable benefits of the ENROUTE® Transcarotid Stent System used in conjunction with the ENROUTE® Transcarotid Neuroprotection System (NPS) outweigh the probable risks.

### **D. Overall Conclusions**

The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use. Two analyses demonstrated that TCAR is statistically non-inferior to CEA when performed using the ENROUTE® Transcarotid Stent System in conjunction with the ENROUTE® Transcarotid Neuroprotection System to treat standard surgical risk subjects with disease in the internal carotid artery. Both periprocedural and one-year outcomes have established the safety and effectiveness of the ENROUTE® Transcarotid Stent System for this supplemental pre-market approval application.

### **XIII. CDRH DECISION**

CDRH issued an approval order on April 28, 2022. The final conditions of approval cited in the approval order are described below.

The sponsor agreed to conduct a study as follows:

The ROADSTER 3 Study is an open label, single arm, multi-center post-approval study to evaluate real world usage of the ENROUTE® TSS and the ENROUTE Transcarotid NPS for the treatment of patients at standard risk for adverse events from carotid endarterectomy who require carotid revascularization and who are eligible for treatment with these devices. A maximum of 400 patients will be enrolled in up to 60 sites in the United States and up to 5 sites in the European Union according to the protocol (SRM–2022–01) provided via email dated March 2, 2022. Patients will be followed at 30 days (±7 days), 6 months/180 days (±30 days), and 1 year/365 days (±45 days).

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The primary endpoint is the hierarchical composite of Major Adverse Events (MAEs) defined as any death, stroke, or myocardial infarction (MI) within 30 days of the index procedure and ipsilateral stroke within 31 days to 365 days of the index procedure.

Key secondary endpoints are:

- Incidence of cranial nerve injury within 30 days of the index procedure
- Stroke within 30 days of the index procedure
- Death within 30 days of the index procedure
- MI within 30 days of the index procedure
- Stroke/Death/MI within 30 days of the index procedure
- Ipsilateral stroke at 1 year

Additional secondary endpoints are:

- Persistent cranial nerve injury at 6 months and 1 year
- Rate of cardiac death within 30 days of the index procedure
- Rate of neurological death within 30 days of the index procedure
- Rate of hierarchical ipsilateral stroke, death, and MI within 30 days of the index procedure
- Cardiac death at 1 year of patients who experienced an MI within 30 days of the index procedure
- Access site complications (arterial/venous)
- Hematoma/bleeding complications (arterial/venous access site)
- Rate of stent thrombosis or occlusion within 30 days of the index procedure
- Rate of dissection within 30 days of the index procedure (during index procedure or a reintervention procedure)

The applicant's manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

# XIV. 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.

# XV. REFERENCES

1. Rosenfield, et al. Randomized Trial of Stent versus Surgery for Asymptomatic Carotid Stenosis. N Engl J Med. 2016 Mar 17;374(11):1011-20.
2. Brott, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010 Jul 1;363(1):11-23.
3. https://www.accessdata.fda.gov/cdrh_docs/pdf/P040012S034B.pdf

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4. Hobson RW 2nd, et al. Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase. *J Vasc Surg*. 2004 Dec;40(6):1106-11.

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**Source:** [https://fda-staging.innolitics.com/device/P140026S016](https://fda-staging.innolitics.com/device/P140026S016)

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