RX ACCULINK CAROTID STENT SYSTEM

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) # I. GENERAL INFORMATION Device Generic Name: Acculink Device Trade Name: RX Acculink® Carotid Stent System (RX Acculink) Applicant's Name and Address: Abbott Vascular 3200 Lakeside Drive Santa Clara, CA 95054 Date of Panel Recommendation: January 26, 2011 Premarket Approval Application (PMA) Number: P040012/S034 Date of FDA Notice of Approval: May 6, 2011 Expedited: Not applicable The original PMA (P040012) was approved on August 30, 2004 and is indicated as follows: The RX Acculink Carotid Stent System, used in conjunction with Abbott Vascular's Accunet or Emboshield family of Embolic Protection Systems (EPS), is indicated 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 \(\geq 50\%\) stenosis of the common or internal carotid artery by ultrasound or angiogram OR patients without neurological symptoms and \(\geq 80\%\) stenosis of the common or internal carotid artery by ultrasound or angiogram, AND 2. Patients must have a reference vessel diameter within the range of \(4.0\mathrm{mm}\) and \(9.0\mathrm{mm}\) at the target lesion. 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 RX Acculink Carotid Stent System to include patients at standard risk for adverse events from carotid endarterectomy. # II. INDICATIONS FOR USE The RX Acculink Carotid Stent System, used in conjunction with the Abbott Vascular embolic protection system specified below, is indicated for the treatment of patients at PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 1 6 {1} high and standard risk for adverse events from carotid endarterectomy who require carotid revascularization and meet the criteria outlined below: | | High Risk | Standard Risk | | --- | --- | --- | | Embolic Protection System | Abbott Vascular's Accunet or Emboshield Family | Abbott Vascular's Accunet only | | 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 | | ### III. CONTRAINDICATIONS The RX Acculink Carotid Stent System is contraindicated for use in: Patients in whom anti-coagulant and / or anti-platelet therapy is contraindicated. - Patients with severe vascular tortuosity or anatomy that would preclude the safe introduction of a guide catheter, sheath, embolic protection system, or stent system. Patients with known hypersensitivity to nickel-titanium. Patients with uncorrected bleeding disorders. - Lesions in the ostium of the common carotid artery. ### IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the RX Acculink Carotid Stent System labeling. ### V. DEVICE DESCRIPTION The RX Acculink Carotid Stent Systems are designed to deliver nitinol self-expanding stents, designed to maintain patency of obstructed carotid arteries, via a sheathed delivery system. The stent systems are equivalent in design to the RX Acculink Stent Systems market approved for the high surgical risk population. The RX Acculink Carotid Stent System is comprised of two main components: the stent (Acculink Carotid Stent) the delivery system (RX Acculink Stent Delivery System) PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 2 7 {2} # A. Acculink Carotid Stent The Acculink Carotid Stent is a nickel-titanium, self-expanding stent. The Acculink Carotid Stent is available in diameters of 5, 6, 7, 8, 9, and 10 mm and lengths of 20, 30, and 40 mm in a straight configuration; a tapered configuration is available in diameters from 6-8 mm and 7-10 mm, each available in lengths of 30 and 40 mm. The stent is implanted into a target vessel, which is smaller than the stent diameter, so that the stent applies a force to the vessel to keep it open. Figure 1: RX Acculink Carotid Stent Geometric Model (20mm Stent Length)  The device is available in the following sizes: Table 1: RX Acculink Carotid Stent System – Stent Diameters | Unconstrained Stent Diameter (mm) | Stent Length (mm) | Reference Vessel Diameter (mm) | | --- | --- | --- | | 5.0 | 20, 30, 40 | 3.6 – 4.5 | | 6.0 | 20, 30, 40 | 4.3 – 5.4 | | 7.0 | 20, 30, 40 | 5.0 – 6.4 | | 8.0 | 20, 30, 40 | 5.7 – 7.3 | | 9.0 | 20, 30, 40 | 6.4 – 8.2 | | 10.0 | 20, 30, 40 | 7.1 – 9.1 | Table 2: RX Acculink Carotid Stent System – Tapered Stent Diameters | Unconstrained Stent Diameter (mm) | Stent Length (mm) | ICA Reference Vessel Diameter (mm) | CCA Reference Vessel Diameter (mm) | | --- | --- | --- | --- | | 6 – 8 Taper | 30, 40 | 4.3 – 5.4 | 5.7 – 7.3 | | 7 – 10 Taper | 30, 40 | 5.0 – 6.4 | 7.1 – 9.1 | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 3 8 {3} # B. RX Acculink Stent Delivery System The Rapid Exchange (RX) Acculink Stent Delivery System, is a single-use device that uses a sheath to mechanically constrain the Acculink Carotid Stent at a small diameter for delivery to the treatment site. The system is inserted through a guide catheter or sheath, and is tracked over a 0.014" guide wire. Radiopaque markers located on the delivery system at the proximal and distal ends of the stent, aid in accurate placement of the stent in the lesion. Figure 2: RX Acculink Carotid Stent System – Delivery System Schematic  # VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the correction of carotid artery disease: - Surgery (endarterectomy) Medical therapy (use of antiplatelet and/or anticoagulant medicine, as well as antihypertensive and antilipidemic drugs as indicated) A combination of surgery and medical therapy - Modification of lifestyle risk factors for stroke, such as cigarette smoking and alcohol use, can lower the risk of stroke 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 RX Acculink Carotid Stent System is commercially available in the European Economic Area (EEA), Australia, and other countries. On August 30, 2004, the RX Acculink Carotid Stent System was approved for marketing in the United States for use in the high surgical risk population. The stent systems approved for the standard surgical risk population under this PMA Supplement are identical to those market approved for the high surgical risk population. # 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: PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 4 9 {4} - Allergic reactions to anti-platelet agents / contrast medium - Aneurysm - Angina / coronary ischemia - Arrhythmia - Arterial occlusion / thrombosis at puncture site or remote site - Arteriovenous fistula - Bacteremia or septicemia - Bleeding from anticoagulant or antiplatelet medications - Cerebral edema - Cerebral hemorrhage - Cerebral ischemia / transient ischemic attack (TIA) - Congestive heart failure (CHF) - Death - Detachment and / or implantation of a component of the system - Emboli, distal (air, tissue or thrombotic emboli) - Emergent or urgent endarterectomy surgery (CEA) - Fever - Filter thrombosis / occlusion - Groin hematoma, with or without surgical repair - Hemorrhage, with or without transfusion - Hyperperfusion syndrome - Hypotension / hypertension - Infection and pain at insertion site - Ischemia / infarction of tissue / organ - Myocardial infarction (MI) - Pain (head, neck) - Pseudoaneurysm, femoral - Renal failure / insufficiency - Restenosis of stented segment - Seizure - Severe unilateral headache - Stent / filter entanglement / damage - Stent embolization - Stent malposition - Stent migration - Stent thrombosis / occlusion - Stroke / cerebrovascular accident (CVA) - Total occlusion of carotid artery - Vessel dissection, perforation, or rupture - Vessel spasm or recoil For the specific adverse events that occurred in the clinical studies, please see Section X below. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 5 10 {5} # IX. SUMMARY OF PRECLINICAL STUDIES No new preclinical studies were submitted or required for the approval of the expanded indication proposed in this PMA supplement. Please see the original SSED for details of the non-clinical testing that was conducted to obtain approval of P040012. # X. SUMMARY OF PRIMARY CLINICAL STUDY The applicant performed a clinical study in the US and Canada under IDE # G000080 to establish a reasonable assurance of safety and effectiveness of carotid stenting using the Acculink Carotid Stent System for the treatment of patients at standard risk for adverse events from carotid endarterectomy who require carotid revascularization and meet the criteria specified in the indication. The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) was a prospective, randomized, two-arm multi-center trial, with blinded endpoint evaluation. Data from this clinical study were the basis for the PMA Supplement approval decision. A summary of the clinical study is presented below. # A. Study Design Enrollment in CREST began on December 21, 2000 and the last patient was enrolled on July 18, 2008. The database for this PMA supplement reflected data collected through March 26, 2010 and included 2502 patients. There were 116 investigational sites in the United States and Canada. Subjects were treated prospectively with either carotid endarterectomy (CEA), the current standard of care for subjects with stenosis of the internal carotid artery at standard risk of adverse events, which served as the control arm in the study, or with carotid artery stenting (CAS) using the Abbott Vascular devices. The commercially available Acculink and RX Acculink Carotid Stent Systems and Accunet and RX Accunet Embolic Protection Devices (EPDs) were used during the trial. P040012/S034 seeks approval for an expanded indication for the RX Acculink Carotid Stent System based on the CREST data. The Acculink and RX Acculink differ only with respect to their delivery systems. The Acculink system uses an over-the-wire delivery system, and the RX Acculink uses a rapid exchange delivery system. Since the devices are otherwise similar, FDA did not have concerns with using the combined Acculink and RX Acculink data to support approval of the expanded RX Acculink indication. The primary endpoint events, including death, stroke, and myocardial infarction within 30 days and ipsilateral stroke occurring between 31 and 365 days of the study procedure have historically been used to assess the safety and effectiveness of carotid stenting in symptomatic and asymptomatic patient populations. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 6 // {6} # 1. Clinical Inclusion and Exclusion Criteria Enrollment in the CREST study was limited to patients who met the inclusion criteria outlined in the table below. Patients were not permitted to enroll in the CREST study if they met any of the exclusion criteria outlined in the table below. Table 3: CREST Inclusion and Exclusion Criteria | Category | Symptomatic | Asymptomatic | | --- | --- | --- | | Age | • Subjects > 18 years old | | | Symptomatic Status | • Subject with history of TIA, amaurosis fugax, minor or non-disabling stroke within 180 days of randomization date • Subjects were excluded with: o Evolving stroke o Stroke within 7 days putting subject at risk for hemorrhagic conversion o Ischemic stroke with hemorrhagic transformation within 60 days | • Not symptomatic | | Carotid Stenosis | • Stenosis ≥ 50% defined as: o Stenosis ≥ 50% by angiography or o Stenosis ≥ 70% by ultrasound or o Stenosis ≥ 70% by MRA or CTA confirmed by radiologist (if 50-69% by ultrasound) | • Stenosis > 60% defined as: o Stenosis ≥ 60% by angiography or o Stenosis ≥ 70% by ultrasound or o Stenosis ≥ 80% by MRA or CTA confirmed by radiologist (if 50-69% by ultrasound) | | Vessel Characteristics | • Discrete lesion in ICA with or without involvement in CCA • Vessel diameter > 4.0 mm and < 9.0 mm from reference or contralateral artery • Absence of excessive vessel tortuosity that would impede delivery of devices | | | Medical Condition | Symptomatic and asymptomatic subjects were excluded with 1 or more of the following: • Knowledge of two or more proximal or major diseased coronary arteries with ≥ 70% stenosis that have not, or cannot be revascularized • Ejection fraction < 30% or New York Heart Association (NYHA) Functional Class III or higher • Unstable angina defined as rest angina with ECG changes • Currently listed for major organ transplantation or being evaluated for such • Malignancy or respiratory insufficiency limiting life expectancy to < 5 years or FEV1< 30% (predicted) • Dialysis dependent renal failure • Uncontrolled diabetes defined as fasting glucose > 400 mg/dl and ketones > +2 • Concurrent requirement for any surgery requiring general anesthesia | | | CEA (Additional eligibility for CEA arm only) | • Subject was a candidate for CEA and met all other eligibility criteria • CEA were excluded with: o Status/post radiation treatment to the neck o Status/post radical neck surgery o Surgically inaccessible lesion (i.e. lesions above C2) o Spinal immobility – inability to flex neck beyond neutral or kyphotic deformity o Symptomatic, well-delineated carotid artery dissection below carotid siphon o Ostial lesion of LCCA/RCCA below clavicle o Presence of tracheostomy stoma o Contralateral laryngeal nerve paralysis o Previous CEA, extracranial-intracranial or subclavian bypass ipsilateral to carotid stenosis | | | Neurologic | • Ability to understand and cooperate with study procedure • Symptomatic and asymptomatic subjects were excluded with: o Severe dementia o Neurologic illnesses within past 2 years which could not be distinguished from a TIA or stroke o History of major ipsilateral stroke likely to confound study endpoints • History of spontaneous intracranial hemorrhage within past 12 months | | | Cardiac | Symptomatic and asymptomatic subjects were excluded with: • Myocardial infarction within previous 30 days • Knowledge of cardiac sources of emboli • Chronic atrial fibrillation • Any episode of paroxysmal atrial fibrillation within past 6 months or history of such requiring chronic anticoagulation | | | Blood Abnormality | Symptomatic and asymptomatic subjects were excluded with: • Hgb < 10 g/dL, platelet count < 125,000/μL, uncorrected INR > 1.5, bleeding time >1 minute beyond upper limit normal, or heparin-associated thrombocytopenia • Active bleeding diathesis or coagulopathy or subject would refuse blood transfusions | | | Medications | Symptomatic and asymptomatic subjects were excluded with: • Recent GI bleed that would interfere with antiplatelet therapy | | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 7 12 {7} | Category | Symptomatic | Asymptomatic | | --- | --- | --- | | | - Known untoward reaction to anesthesia not able to be overcome by pretreatment with medications - History of intolerance or allergic reaction to any study medication including ASA, ticlopidine and clopidogrel | | | Angiography | Symptomatic and asymptomatic subjects who had angiography prior to randomization were excluded with: - Severe vascular tortuosity or anatomy precluding safe introduction of guiding catheter / sheath or stent placement - Presence of a previously placed intravascular stent or graft in the ipsilateral artery - Presence of extensive or diffuse atherosclerotic disease involving the aortic arch and proximal common carotid artery precluding safe introduction of guiding catheter / sheath - An intraluminal filling defect that was not associated with an ulcerated target lesion - Abnormal angiographic findings constituting a contraindication to CEA - Bilateral carotid stenosis if intervention was planned within the 30-day CREST peri-procedural period - Occlusion "string sign" >1 cm of the ipsilateral common or internal carotid artery | | ## 2. Follow-up Schedule A 24-hour post-procedural neurological assessment was required prior to hospital discharge in order to assure detection of early post-procedural strokes. All patients were scheduled to return for follow-up examinations at 30 days, 6 months, 12 months, 18 months and annually until study exit. Telephone contact was scheduled at 2 weeks, 3 months, and 9 months, and annually thereafter. The following table provides a summary of the required clinical and laboratory tests for both CAS and CEA subjects: PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 8 13 {8} Table 4: CREST Clinical and Laboratory Tests | Test | Pre-Procedure | Post-Procedure | Post-Discharge | | --- | --- | --- | --- | | Carotid duplex ultrasound | √^{1} | | 1, 6, 12 months, yearly thereafter | | CT scan/MRI | √^{1} | | PRN^{1} | | Neurological exam | √^{2} | √^{2} | 1 and 12 months^{2} | | NIH Stroke Scale (NIHSS) | √^{2} | √^{2} | 1, 6 and 12 months^{2,3} | | Modified Rankin Scale | √ | | 1, 6 and 12 months | | Barthel Index | √ | | 1, 6 and 12 months | | Quality of Life Scales | √ | | 2 weeks, 1 month and 1 year | | Medical History, Risk Factor Profile | √ | | 1, 3, 6, 9, 12 months and yearly thereafter | | ECG | √ | √^{3} | 1 month^{3} | | Cardiac Biomarkers (CPK, CK-MB or troponin) | √ | √^{4} | None | | Lipid Profile | √ | | 6, 12 months and yearly thereafter | | SMAC-7 | √ | | 6, 12 months and yearly thereafter | | Fasting Blood Sugar | √ | | 6, 12 months and yearly thereafter | | Cerebral Angiogram | √^{5} | | PRN | $^{1}$ Most recent pre-procedural neurological image was used for baseline (if available), and additional CT scans were performed as needed to evaluate subsequent cerebrovascular events. $^{2}$ Neurological examinations performed pre-procedure, immediately post-procedure, and at 1 and 12 month follow-up visits were performed by the independent study neurologist or neurosurgeon certified in the use of the NIHSS. This physician was not the physician who performed the study procedure. $^{3}$ In addition to post-procedure ECG, an ECG was obtained for chest pain lasting more than 15 minutes or for symptoms indicating myocardial ischemia. $^{4}$ In addition to post-procedure cardiac biomarkers (CPK, CK-MB, or troponin), cardiac biomarkers were repeated every 8 hours x 3 with pathological elevation of post-procedure biomarkers, for ECG changes or for chest pain lasting more than 15 minutes. $^{5}$ A NIHSS was assessed 3 months after the occurrence of a potential stroke occurring with 12 months of the study procedure. At the 6 month follow-up visit, the NIHSS could be administered by a health care professional on the study staff who was certified in the use of the NIHSS if the independent study neurologist/neurosurgeon was not available. Adverse events and complications were recorded at all visits. The key endpoints are shown below in the tables summarizing safety and effectiveness. ### 3. Clinical Endpoints The primary safety and effectiveness endpoint of CREST was the composite of death, stroke and myocardial infarction (DSMI) at 30 days plus stroke ipsilateral to the study artery between 31 and 365 days. Key additional analyses included the 1-year composite endpoint by strata defined by symptomatic status and octogenarian status, peri-procedural DSMI at 30 days, target lesion revascularization (TLR) at 12 months, access site complications, cranial nerve injury and the composite endpoint of DSMI at 30 days plus stroke ipsilateral to study artery after 31 days. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 9 14 {9} The study protocol design defined study success as CAS being non-inferior to CEA when measured by the primary endpoint. # • Pre-Specified Statistical Analysis Plan The null hypothesis was that the CAS arm was worse than the CEA arm by a pre-specified non-inferiority margin of 2.6% (i.e., the event rate for the CAS arm was greater than or equal to the event rate for the CEA arm plus a non-inferiority margin of 2.6%). The null hypothesis was rejected based on a non-inferiority analysis. The primary endpoint analysis was performed based on the Per-Protocol (PP) analysis population. The Intent-to-Treat (ITT) population was also evaluated. In addition, a propensity score-adjusted non-inferiority analysis was performed on the PP population. The propensity score was estimated from logistic regression using baseline characteristics and medical history data for age, gender, symptomatic status, prior CAD, CABG, diabetes, dyslipidemia, hypertension, smoking, and pre-procedure target lesion percentage diameter stenosis. Non-inferiority tests were also performed for the: - 1 year composite endpoint by strata defined by symptomatic status - Peri-procedural endpoint events - 4 year composite endpoint rate - 1 year composite endpoint for non-octogenarian subjects # • External Evaluation Groups All primary endpoint events (death, MI, and all potential strokes) were adjudicated by a Clinical Events Committee (CEC). The angiograms, carotid duplex ultrasounds, and electrocardiograms were assessed by central core laboratories. An NIH-appointed Data Safety Monitoring Board assessed the ongoing safety of CREST. # • Study Design Discussion CREST compared the safety and effectiveness of carotid artery stenting (CAS) to carotid endarterectomy (CEA) in symptomatic and asymptomatic subjects deemed to be eligible for CEA and at standard risk for complications from surgery at 1 year (death, stroke and MI at 30 days plus ipsilateral stroke between 31 and 365 days). Eligible subjects were randomly assigned in a 1:1 ratio to CAS or CEA, with stratification according to the clinical center and subject's symptomatic status. Recruitment restrictions were imposed to ensure that the proportion of symptomatic subjects was between 800 (32%) and 1700 (68%) of the total study population at the conclusion of the study. CREST evaluated strokes between 31 and 365 days as an effectiveness measure. Death, stroke and MI at 30 days were the primary safety measure. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 10 15 {10} All potential primary endpoint events were independently adjudicated by a CEC. CREST evaluated potential MI based on the assessment of prospectively collected ECG, cardiac biomarker data in addition to clinical symptoms. ### B. Accountability of PMA Cohort At the time of database lock, of the 2502 randomized subjects enrolled in the PMA study at 107 clinical sites in the United States and 9 sites in Canada, 96.0% (2365/2464) of subjects at 1 month and 90.3% (2140/2369) of subjects at 1 year post-procedure were available for analysis. Long-term follow-up is available for 82.3% (1770/2150) of subjects at 2 years, 78.9% (1179/1494) of subjects at 3 years, and 72.4% (589/813) of subjects at 4 years. The follow-up rates are balanced between the CAS and CEA arms at all scheduled follow-up intervals as indicated below in Table 5. Table 5: Summary of Follow-Up Assessment for All Randomized Subjects | | | CAS N=1262 | CEA N=1240 | Total N=2502 | | --- | --- | --- | --- | --- | | 30 Days | Subjects Followed-up | 1195 | 1170 | 2365 | | | Percent (Followed-up/Eligible^{1}) | 95.9% | 96.1% | 96.0% | | 12 Months | Subjects Followed-up | 1080 | 1060 | 2140 | | | Percent (Followed-up/Eligible) | 90.6% | 90.1% | 90.3% | | 48 Months | Subjects Followed-up | 306 | 283 | 589 | | | Percent (Followed-up/Eligible) | 73.4% | 71.5% | 72.4% | $^{1}$Patients who died or withdrew their consent prior to the visit or who had not yet reached that follow-up time point were not considered eligible. Please see Figure 3 below. Figure 3 shows subject accountability for the CAS and CEA arms at various important study intervals. Figure 3 includes subjects censored only up to 4 years, and therefore does not include subjects contributing data during the 48-month (+ 6 week) follow-up window or thereafter (who are included in Table 5). PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 11 16 {11} Figure 3: Subject Accountability in the CAS and CEA Arms (N=2502)  Notes: - The denominators for determination of number of subjects participating at each time point are CAS = 1262 and CEA = 1240. - The number of subjects who expired, withdrew, were lost to follow-up or not due for follow-up are reflective of each time interval (not cumulative). PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 12 17 {12} ### C. Study Population Demographics and Baseline Parameters The demographics of the study population are typical for a carotid artery stenting study performed in the US. Key baseline demographics and risk factors were comparable between CAS and CEA and are shown in Table 6 for all CREST randomized subjects. The calculated difference with 95% confidence intervals between the two study arms suggests that data for CREST subjects randomized to CAS and CEA were balanced in all the key demographic categories. The mean age was 69.1 years and 9.7% (243/2502) of the study population were octogenarians. Male subjects comprised 65.1% (1630/2502) of the study population which is consistent with recently published data from an observational study in which 60.9% of subjects with atherosclerotic lesions who underwent CAS were male [J Vasc Surg 51(5): 1116-1123 (2010)]. This is also consistent with the 66%-78% proportion of males enrolled in several randomized CAS and CEA clinical trials that studied similar patient populations. Baseline characteristics that occurred most frequently in greater than 10% of the CREST population were prior cardiovascular disease 43.7% (1046/2394), previous CABG 20.7% (514/2480), diabetes using oral anti-diabetic agents only 22.8% (567/2488), hypertension 85.9% (2141/2492), dyslipidemia 84.4% (2093/2481) and history of / or current smoker 65.7% (1619/2465). PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 13 18 {13} Table 6: Baseline Demographics and Medical History for All Randomized Subjects (N = 2502) | | CAS N = 1262 | CEA N = 1240 | Total N = 2502 | Difference [95% CI] | | --- | --- | --- | --- | --- | | Mean Age ± SD (N) | 68.9 ± 9.0 (1262) | 69.2 ± 8.8 (1240) | 69.1 ± 8.9 (2502) | -0.3 | | Median | 69.1 | 70.0 | 69.7 | [-1.0, 0.4] | | Range (min, max) | (39.8, 96.2) | (40.7, 91.5) | (39.8, 96.2) | | | [95% Conf. Interval] | [68.4, 69.4] | [68.7, 69.7] | [68.7, 69.4] | | | Age ≥ 80 years | 10.2% (129/1262) | 9.2% (114/1240) | 9.7% (243/2502) | 1.0% | | [95% Conf. Interval] | [8.6%, 12.0%] | [7.6%, 10.9%] | [8.6%, 10.9%] | [-1.3%, 3.3%] | | Male | 63.9% (807/1262) | 66.4% (823/1240) | 65.1% (1630/2502) | -2.4% | | [95% Conf. Interval] | [61.2%, 66.6%] | [63.7%, 69.0%] | [63.2%, 67.0%] | [-6.2%, 1.3%] | | Symptomatic | 52.9% (668/1262) | 52.7% (653/1240) | 52.8% (1321/2502) | 0.3% | | [95% Conf. Interval] | [50.1%, 55.7%] | [49.8%, 55.5%] | [50.8%, 54.8%] | [-3.6%, 4.2%] | | Prior Cardiovascular Disease | 42.4% (514/1211) | 45.0% (532/1183) | 43.7% (1046/2394) | -2.5% | | [95% Conf. Interval] | [39.6%, 45.3%] | [42.1%, 47.9%] | [41.7%, 45.7%] | [-6.5%, 1.4%] | | Aortic / Mitral Valvular Disease | 5.8% (72/1231) | 4.4% (54/1215) | 5.2% (126/2446) | 1.4% | | [95% Conf. Interval] | [4.6%, 7.3%] | [3.4%, 5.8%] | [4.3%, 6.1%] | [-0.3%, 3.2%] | | Previous CABG | 19.9% (249/1250) | 21.5% (265/1230) | 20.7% (514/2480) | -1.6% | | [95% Conf. Interval] | [17.7%, 22.2%] | [19.3%, 23.9%] | [19.1%, 22.4%] | [-4.8%, 1.6%] | | Cardiac Arrhythmia | 6.0% (75/1240) | 6.5% (79/1210) | 6.3% (154/2450) | -0.5% | | [95% Conf. Interval] | [4.8%, 7.5%] | [5.2%, 8.1%] | [5.4%, 7.3%] | [-2.4%, 1.4%] | | Presence of Left Ventricular Hypertrophy | 6.1% (69/1127) | 5.7% (63/1104) | 5.9% (132/2231) | 0.4% | | [95% Conf. Interval] | [4.8%, 7.7%] | [4.4%, 7.2%] | [5.0%, 7.0%] | [-1.5%, 2.4%] | | Diabetes Mellitus | 30.5% (384/1257) | 30.4% (375/1232) | 30.5% (759/2489) | 0.1% | | [95% Conf. Interval] | [28.0%, 33.2%] | [27.9%, 33.1%] | [28.7%, 32.3%] | [-3.5%, 3.7%] | | Hypertension | 85.8% (1080/1259) | 86.1% (1061/1233) | 85.9% (2141/2492) | -0.3% | | [95% Conf. Interval] | [83.7%, 87.7%] | [84.0%, 87.9%] | [84.5%, 87.3%] | [-3.0%, 2.5%] | | Dyslipidemia | 82.9% (1040/1254) | 85.8% (1053/1227) | 84.4% (2093/2481) | -2.9% | | [95% Conf. Interval] | [80.7%, 85.0%] | [83.7%, 87.7%] | [82.9%, 85.8%] | [-5.7%, -0.0%] | | History of / or Current Cigarette/Cigar Smoking | 65.2% (811/1244) | 66.2% (808/1221) | 65.7% (1619/2465) | -1.0% | | [95% Conf. Interval] | [62.5%, 67.8%] | [63.4%, 68.8%] | [63.8%, 67.6%] | [-4.7%, 2.8%] | | Family History of Stroke | 32.2% (339/1052) | 32.7% (339/1037) | 32.5% (678/2089) | -0.5% | | [95% Conf. Interval] | [29.4%, 35.1%] | [29.8%, 35.6%] | [30.4%, 34.5%] | [-4.5%, 3.5%] | | Prior Contralateral CEA | 4.5% (57/1257) | 5.2% (64/1230) | 4.9% (121/2487) | -0.7% | | [95% Conf. Interval] | [3.5%, 5.8%] | [4.0%, 6.6%] | [4.1%, 5.8%] | [-2.4%, 1.0%] | ### Symptomatic and Asymptomatic Subjects Of the randomized study subjects enrolled in the trial, 52.8% (1321/2502) were symptomatic subjects and 47.2% (1181/2502) were asymptomatic subjects, as shown in Table 7. The enrollment was well balanced between the symptomatic and asymptomatic subgroups. The recruitment restriction for enrollment of between 800 (32.0%) and 1700 (68.0%) symptomatic subjects was satisfied. Within each of the symptomatic and the asymptomatic subgroups, subjects were evenly randomized between the CAS and the CEA treatment arms. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 14 19 {14} Table 7: Subject Enrollment by Symptomatic Status | Analysis Population | Symptomatic Subjects | | | Asymptomatic Subjects | | | | --- | --- | --- | --- | --- | --- | --- | | | CAS | CEA | Total | CAS | CEA | Total | | PP Population (N = 2307) | 599 | 620 | 1219 (52.8%) | 532 | 556 | 1088 (47.2%) | | All Randomized Subjects (N = 2502) | 668 | 653 | 1321 (52.8%) | 594 | 587 | 1181 (47.2%) | The medical history of subjects in the CAS and the CEA arms were balanced in both the symptomatic and asymptomatic subgroups of the PP population, the primary analysis population. ### D. Safety and Effectiveness Results The Per-Protocol (PP) population was designated as the primary population for analysis of the primary endpoint and secondary endpoints. This population is composed of the subjects treated with either CAS or CEA as their randomized procedure by an approved study investigator. #### 1. Safety Results The analysis of safety was based on the CREST randomized population treated with CAS or CEA, with follow-up data available for 96.0% (2365/2464) of subjects at 1 month and 90.3% (2140/2369) of subjects at 1 year post-procedure. Safety outcomes are presented in Tables 8 through 12 and Figures 4 through 9. Kaplan-Meier survival analysis of the primary endpoint through 365 days post-procedure for the PP analysis population is presented in Figure 4. Adverse effects are reported in Tables 13 to 15. CREST has met the primary endpoint of the trial with p < 0.05 in the PP population, the primary analysis population, as shown in Table 8. The observed difference between the primary endpoint event rates for CAS and CEA arms is 0.5% with a 95% upper confidence limit of 2.26% within the pre-specified non-inferiority margin of 2.6% (p = 0.0245). The primary endpoint was also met in all other analysis groups, e.g. the Per-Protocol (Adjusted) and ITT populations. CAS is statistically non-inferior to CEA when performed using the Acculink Carotid Stent System with the Accunet Embolic Protection System to treat standard surgical risk subjects with disease in the internal carotid artery. Table 8: Summary of Non-inferiority Test Primary Endpoint Analyses | Analyses | One Year Primary Endpoint Event Rate (%) ± SE (%) (N) | | | Non-inferiority Test | | | --- | --- | --- | --- | --- | --- | | | CAS | CEA | Difference [95% CI] | Non-inferiority Test Margins | p-Value | | Per-protocol | 7.1% ± 0.77% (N = 1131) | 6.6% ± 0.73% (N = 1176) | 0.5% [-, 2.26%] | 2.6% | 0.0245 | | Per-protocol (Adjusted) | 7.2% ± 0.77% (N = 1131) | 6.5% ± 0.72% (N = 1176) | 0.7% [-, 2.41%] | 2.6% | 0.0342 | | Intent-to-treat | 7.0% ± 0.73% (N = 1259) | 6.9% ± 0.73% (N = 1237) | 0.1% [-, 1.80%] | 2.6% | 0.0077 | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 15 20 {15} Figure 4: Freedom from Primary Endpoint Events at 365 Days (PP Population)  Valid low CAS Subjects (n= 303) Method low CEA Subjects (n= 303) | Days Post Index Procedure | 0 | (0, 2] | (2, 30] | (30, 180] | (180, 365] | | --- | --- | --- | --- | --- | --- | | CAS | | | | | | | Subjects at Risk | 1131 | 1094 | 1082 | 1062 | 1031 | | Subjects Censored | 0 | 1 | 3 | 21 | 1026 | | Number of Events | 37 | 11 | 17 | 10 | 5 | | % Event Free | 96.7% | 95.8% | 94.2% | 93.4% | 92.9% | | % Standard Error | 0.5% | 0.6% | 0.7% | 0.7% | 0.8% | | CEA | | | | | | | Subjects at Risk | 1176 | 1150 | 1127 | 1110 | 1083 | | Subjects Censored | 0 | 1 | 5 | 19 | 1074 | | Number of Events | 26 | 22 | 12 | 8 | 9 | | % Event Free | 97.8% | 95.9% | 94.9% | 94.2% | 93.4% | | % Standard Error | 0.4% | 0.6% | 0.6% | 0.7% | 0.7% | | Tests Between Groups | Test | Chi-Square | DF | p-value | | | | Log-Rank | 0.268 | 1 | 0.6047 | | | | Wilcoxon | 0.304 | 1 | 0.5815 | | ## Assessment of the Primary Endpoint for Symptomatic and Asymptomatic Subjects For both symptomatic and asymptomatic subgroups, CREST has also met the endpoint with p < 0.05 in the pre-specified non-inferiority test for both the PP and ITT analysis populations as shown in Table 9. CAS is statistically non-inferior to CEA regardless of the subject symptomatic status when CAS is performed using the Acculink Carotid Stent System with the Accunet Embolic Protection System to treat standard surgical risk subjects with disease in the internal carotid artery. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 16 21 {16} Table 9: Summary of Non-inferiority Tests by Symptomatic Status | Analyses | One Year Primary Endpoint Event Rate (%) ± SE (%) (N) | | | Non-inferiority Test | | | --- | --- | --- | --- | --- | --- | | | CAS | CEA | Difference [95% CI] | Non-inferiority Test Margins (N) | p-Value | | PP -- Symptomatic | 8.7% ± 1.16% (N = 599) | 7.5% ± 1.06% (N = 620) | 1.3% [-, 3.84%] | 3.875% (N = 1219) | 0.0477 | | PP -- Asymptomatic | 5.3% ± 0.97% (N = 532) | 5.6% ± 0.98% (N = 556) | -0.3% [-, 1.95%] | 3.400% (N = 1088) | 0.0035 | | ITT -- Symptomatic | 8.5% ± 1.09% (N = 667) | 8.0% ± 1.07% (N = 652) | 0.6% [-, 3.08%] | 3.775% (N = 1319) | 0.0179 | | ITT -- Asymptomatic | 5.3% ± 0.93% (N = 592) | 5.7% ± 0.97% (N = 585) | -0.4% [-, 1.79%] | 3.200% (N = 1177) | 0.0035 | The freedom from the estimated one-year composite primary endpoint event rates are 91.3% in the CAS arm and 92.5% in the CEA arm for symptomatic subjects. The Kaplan-Meier survival curves of CAS and CEA are comparable (see Figure 5 below). PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 17 22 {17} Figure 5: CREST - SYMPTOMATIC CAS and CEA Subjects – Freedom from One-Year Composite Endpoint (PP Population)  Solid line: CAS Subjects (n=599) Dashed line: CEA Subjects (n=620) Vertical bar: 95% Confidence Limit | Days Post Index Procedure | 0 | (0, 2] | (2, 30] | (30, 180] | (180, 365] | | --- | --- | --- | --- | --- | --- | | CAS | | | | | | | Subjects at Risk | 599 | 576 | 568 | 552 | 531 | | Subjects Censored | 0 | 1 | 1 | 17 | 528 | | Number of Events | 23 | 7 | 15 | 4 | 3 | | % Event Free | 96.2% | 95.0% | 92.5% | 91.8% | 91.3% | | % Standard Error | 0.8% | 0.9% | 1.1% | 1.1% | 1.2% | | CEA | | | | | | | Subjects at Risk | 620 | 604 | 589 | 579 | 563 | | Subjects Censored | 0 | 0 | 5 | 12 | 557 | | Number of Events | 16 | 15 | 5 | 4 | 6 | | % Event Free | 97.4% | 95.0% | 94.2% | 93.5% | 92.5% | | % Standard Error | 0.6% | 0.9% | 0.9% | 1.0% | 1.1% | | Tests Between Groups | Test | Chi-Square | DF | p-value | | | | Log-Rank | 0.685 | 1 | 0.4078 | | | | Wilcoxon | 0.731 | 1 | 0.3926 | | | Note: Subjects at risk gives the number of subjects at risk of an event at the start of the interval, while subjects censored and number of events are the incremental counts of subjects censored or with events during the interval. The intervals are denoted as half-open bracket expression, where the start of interval 't' is exclusive and the end of the interval 'J' is inclusive. | | | | | | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 18 23 {18} The freedom from the estimated one-year composite primary endpoint event rates are 94.7% in the CAS arm and 94.4% in the CEA arm for asymptomatic subjects. The Kaplan-Meier survival curves of CAS and CEA are comparable (see Figure 6 below). Figure 6: CREST - ASYMPTOMATIC CAS and CEA Subjects – Freedom from One-Year Composite Endpoint (PP Population)  Solid line: CAS Subjects (n=532) Dashed line: CEA Subjects (n=556) Vertical bar: 95% Confidence Limit | Days Post Index Procedure | 0 | (0, 2] | (2, 30] | (30, 180] | (180, 365] | | --- | --- | --- | --- | --- | --- | | CAS | | | | | | | Subjects at Risk | 532 | 518 | 514 | 510 | 500 | | Subjects Censored | 0 | 0 | 2 | 4 | 498 | | Number of Events | 14 | 4 | 2 | 6 | 2 | | % Event Free | 97.4% | 96.6% | 96.2% | 95.1% | 94.7% | | % Standard Error | 0.7% | 0.8% | 0.8% | 0.9% | 1.0% | | CEA | | | | | | | Subjects at Risk | 556 | 546 | 538 | 531 | 520 | | Subjects Censored | 0 | 1 | 0 | 7 | 517 | | Number of Events | 10 | 7 | 7 | 4 | 3 | | % Event Free | 98.2% | 96.9% | 95.7% | 95.0% | 94.4% | | % Standard Error | 0.6% | 0.7% | 0.9% | 0.9% | 1.0% | | Tests Between Groups | Test | Chi-Square | DF | p-value | | | | Log-Rank | 0.049 | 1 | 0.8240 | | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 19 29 {19} | | Wilcoxon | 0.041 | 1 | 0.8390 | | | --- | --- | --- | --- | --- | --- | | Note: Subjects at risk gives the number of subjects at risk of an event at the start of the interval, while subjects censored and number of events are the incremental counts of subjects censored or with events during the interval. The intervals are denoted as half-open bracket expression, where the start of interval '[' is exclusive and the end of the interval ']' is inclusive. | | | | | | ## Assessment of DSMI at 30 days Peri-procedural death, stroke and myocardial infarction (DSMI) comprise a secondary safety endpoint. CREST has met the DSMI endpoint of the trial with p < 0.05 in the PP population, the primary analysis population, as shown in Table 10. The observed difference between the DSMI event rates for CAS and CEA arms is 0.6% for PP population with a 95% upper confidence limit of 2.20% within the pre-specified non-inferiority margin of 2.3% (p = 0.0401). The DSMI endpoint was also met in the ITT population. CAS is statistically non-inferior to CEA when performed using the Acculink Carotid Stent System with the Accunet Embolic Protection System to treat standard surgical risk subjects with disease in the internal carotid artery. Table 10: Summary of Non-inferiority Tests for Peri-procedural Events | Analyses^{1} | Peri-procedural Events Event Rate (%) ± SE (%) (N) | | | Non-inferiority Test | | | --- | --- | --- | --- | --- | --- | | | CAS | CEA | Difference [95% CI] | Non-inferiority Test Margins | p-Value | | Per-protocol | 5.8% ± 0.69% (N = 1131) | 5.1% ± 0.64% (N = 1176) | 0.6% [-, 2.20%] | 2.3% | 0.0401 | | Intent-to-treat | 5.8% ± 0.66% (N = 1259) | 5.5% ± 0.65% (N = 1237) | 0.3% [-, 1.83%] | 2.3% | 0.0155 | The components of DSMI were evaluated separately and the results show that the stroke rate, driven predominantly by minor (non-major) strokes, is significantly higher in CAS and the MI rate is significantly higher in CEA as shown in Table 11. The stroke rate in CAS is 4.1% (46/1127), compared to 1.9% (22/1175) in the CEA arm. The MI rate in CAS is 2.0% (22/1127), compared to 3.4% (40/1175) in the CEA arm. Both of these differences in rates are statistically significant. Table 11: DSMI Event Rates at 30 Days (PP Population – Non-Hierarchical Events) | Non-hierarchical Events | CAS N = 1131 | CEA N = 1176 | Total N = 2307 | Difference [95% CI] | | --- | --- | --- | --- | --- | | All Stroke [95% Conf. Interval] | 4.1% (46/1127) [3.0%, 5.4%] | 1.9% (22/1175) [1.2%, 2.8%] | 3.0% (68/2302) [2.3%, 3.7%] | 2.2% [0.8%, 3.6%] | | Minor Stroke [95% Conf. Interval] | 3.2% (36/1127) [2.2%, 4.4%] | 1.5% (18/1175) [0.9%, 2.4%] | 2.3% (54/2302) [1.8%, 3.0%] | 1.7% [0.4%, 2.9%] | | MI [95% Conf. Interval] | 2.0% (22/1127) [1.2%, 2.9%] | 3.4% (40/1175) [2.4%, 4.6%] | 2.7% (62/2302) [2.1%, 3.4%] | -1.5% [-2.8%, -0.1%] | | Death [95% Conf. Interval] | 0.5% (6/1127) [0.2%, 1.2%] | 0.3% (3/1175) [0.1%, 0.7%] | 0.4% (9/2302) [0.2%, 0.7%] | 0.3% Assumptions not met | The peri-procedural death and stroke rate of 5.9% (35/597) for CAS is within the AHA guideline of 6% death and stroke for treating symptomatic subjects. The PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 20 25 {20} peri-procedural death and stroke rate of 2.5% (13/530) for CAS for asymptomatic subjects is within the AHA guideline of 3% death and stroke for treating asymptomatic subjects. These findings suggest that CAS is acceptable with respect to peri-procedural safety when treating symptomatic and asymptomatic subjects. ## Analysis by Octogenarian Status For the non-octogenarian subgroup, the composite endpoint rates are 6.7% in the CAS arm vs. 6.2% in the CEA arm in the PP population, and are 6.5% in the CAS arm vs. 6.5% in the CEA arm in the ITT population. Both analyses reach statistical significance with a p-value < 0.05% with a non-inferiority margin of 2.6%, as seen in Table 12. Therefore, CAS is non-inferior to CEA for treating non-octogenarian subjects. Table 12: Non-inferiority Test on One-Year Composite Endpoint for Non-Octogenarian Subjects | Analyses | One Year Primary Endpoint Event Rate (%) ± SE (%) (N) | | | Non-inferiority Test | | | --- | --- | --- | --- | --- | --- | | | CAS | CEA | Difference [95% CI] | Non-inferiority Test Margins | p-Value | | Per-protocol | 6.7% ± 0.78% (N = 1025) | 6.2% ± 0.74% (N = 1073) | 0.5% [-, 2.24%] | 2.6% | 0.0238 | | Intent-to-treat | 6.5% ± 0.74% (N = 1132) | 6.5% ± 0.74% (N = 1124) | 0.0% [-, 1.75%] | 2.6% | 0.0070 | The 30-day DSMI rate is 5.5% (56/1021) in the CAS arm and 4.8% (51/1072) in the CEA arm in non-octogenarians and 8.5% (9/106) in the CAS arm and 8.7% (9/103) in the CEA arm in octogenarians. No significant difference is shown between the CAS and the CEA treatment arms for both the octogenarian and non-octogenarian subgroups. ## Access Site Complications For the 2403 subjects with at least one study procedure attempted, and based on the first attempted treatment, the rate of access site complications requiring treatment is 1.1% (13/1157) in the CAS arm and 3.5% (43/1246) in the CEA arm. There is a statistically significant difference between the rates of access site complications in the CAS and CEA arms. ## Cranial Nerve Injury Unresolved at 1 and 6 months For the 2403 subjects with at least one study procedure attempted, and based on the first attempted treatment, the data show that 5.2% (65/1246) of subjects had cranial nerve injury due to the CEA treatment. The cranial nerve injury was unresolved in 3.5% (44/1246) of CEA subjects at 1 month and in 2.0% (25/1246) of CEA subjects at 6 months post-procedure. Cranial nerve injury did not occur in subjects treated with CAS. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 21 26 {21} ## Adverse events that occurred in the PMA clinical study: Tables 13 through 15 present the adverse events reported for patients in the CREST study during the time points indicated. There were 213 deaths reported of which 112 were in the CAS arm and 101 in the CEA arm as presented in Table 16. In the CAS arm, 8 deaths occurred in the first 30 days after the procedure or randomization for those subjects without a study procedure, 4 are related to stroke, 2 are related to cardiac causes, 1 is related to bleeding and 1 is related to sepsis. In the CEA arm, 4 deaths occurred in the first 30 days and all 4 were related to stroke. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 22 27 {22} Table 13: All Reported Non-Primary Endpoint Adverse Events within 30 Days following the Study Procedure (All Randomized Subjects) | Category | Subcategory | First Attempted CAS^{1} N = 1156 | | | First Attempted CEA^{1} N = 1246 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | Access Site Complication Not Requiring Treatment | | 0.1% (1/1156) | 4.2% (49/1156) | 4.3% (50/1156) | 0.2% (2/1246) | 5.7% (71/1246) | 5.9% (73/1246) | | | Bleeding | 0.0% (0/1156) | 1.6% (18/1156) | 1.6% (18/1156) | 0.0% (0/1246) | 0.3% (4/1246) | 0.3% (4/1246) | | | Fistula/Pseudoaneurysm/Dissection | 0.0% (0/1156) | 0.3% (3/1156) | 0.3% (3/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Hematoma | 0.1% (1/1156) | 2.3% (27/1156) | 2.4% (28/1156) | 0.1% (1/1246) | 1.6% (20/1246) | 1.7% (21/1246) | | | Incision Complication | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.1% (1/1246) | 2.1% (26/1246) | 2.2% (27/1246) | | | Pain | 0.0% (0/1156) | 0.5% (6/1156) | 0.5% (6/1156) | 0.0% (0/1246) | 2.1% (26/1246) | 2.1% (26/1246) | | Access Site Complication Requiring Treatment | | 0.9% (10/1156) | 0.3% (4/1156) | 1.1% (13/1156) | 2.0% (25/1246) | 1.4% (18/1246) | 3.4% (42/1246) | | | Bleeding | 0.3% (4/1156) | 0.1% (1/1156) | 0.4% (5/1156) | 0.2% (3/1246) | 0.2% (2/1246) | 0.4% (5/1246) | | | Hematoma | 0.3% (3/1156) | 0.2% (2/1156) | 0.4% (5/1156) | 1.3% (16/1246) | 0.4% (5/1246) | 1.7% (21/1246) | | | Incision Complication | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.2% (3/1246) | 0.0% (0/1246) | 0.2% (3/1246) | | | Infection | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.1% (1/1246) | 0.5% (6/1246) | 0.6% (7/1246) | | | Occlusion | 0.2% (2/1156) | 0.1% (1/1156) | 0.3% (3/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Pain | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.1% (1/1246) | 0.3% (4/1246) | 0.4% (5/1246) | | | Pseudoaneurysm | 0.1% (1/1156) | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1246) | 0.1% (1/1246) | 0.2% (2/1246) | $^{1}$ Subjects first attempted procedure was CAS or CEA. The denominator for each treatment arm is based on the first treatment attempted so that CAS subjects crossed over to CEA after the procedure was attempted are counted in CAS. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 23 28 {23} Table 13 (continued) | Category | Subcategory | First Attempted CAS^{a} N = 1156 | | | First Attempted CEA^{a} N = 1246 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs^{a} | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | Allergic Reaction | | 0.3% (4/1156) | 0.8% (9/1156) | 1.1% (13/1156) | 0.2% (2/1246) | 0.3% (4/1246) | 0.5% (6/1246) | | Bleeding | | 0.2% (2/1156) | 0.7% (8/1156) | 0.9% (10/1156) | 0.2% (3/1246) | 0.3% (4/1246) | 0.6% (7/1246) | | | Epistaxis | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | GI | 0.1% (1/1156) | 0.3% (4/1156) | 0.4% (5/1156) | 0.2% (2/1246) | 0.1% (1/1246) | 0.2% (3/1246) | | | Other | 0.1% (1/1156) | 0.3% (3/1156) | 0.3% (4/1156) | 0.1% (1/1246) | 0.2% (3/1246) | 0.3% (4/1246) | | Blood Dyscrasia | | 0.4% (5/1156) | 0.6% (7/1156) | 1.0% (11/1156) | 0.3% (4/1246) | 0.6% (7/1246) | 0.9% (11/1246) | | Cancer | | 0.3% (3/1156) | 0.1% (1/1156) | 0.3% (4/1156) | 0.3% (4/1246) | 0.1% (1/1246) | 0.4% (5/1246) | | Cardiac | | 1.1% (13/1156) | 4.6% (53/1156) | 5.6% (65/1156) | 1.8% (22/1246) | 5.3% (66/1246) | 6.8% (85/1246) | | | Abnormal Lab Test | 0.0% (0/1156) | 2.9% (34/1156) | 2.9% (34/1156) | 0.0% (0/1246) | 3.5% (44/1246) | 3.5% (44/1246) | | | Arrhythmia | 0.3% (4/1156) | 0.4% (5/1156) | 0.8% (9/1156) | 0.6% (8/1246) | 0.9% (11/1246) | 1.5% (19/1246) | | | Cardiac Arrest | 0.1% (1/1156) | 0.0% (0/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Congestive Heart Failure | 0.2% (2/1156) | 0.1% (1/1156) | 0.3% (3/1156) | 0.3% (4/1246) | 0.1% (1/1246) | 0.4% (5/1246) | | | Coronary Artery Disease | 0.5% (6/1156) | 1.0% (12/1156) | 1.6% (18/1156) | 0.8% (10/1246) | 0.9% (11/1246) | 1.7% (21/1246) | | | Pulmonary Hypertension | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Structural Heart Disease | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 24 29 {24} Table 13 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1156 | | | First Attempted CEA^{1} N = 1246 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | Gastrointestinal | | 0.6% (7/1156) | 0.9% (10/1156) | 1.4% (16/1156) | 0.3% (4/1246) | 0.7% (9/1246) | 1.0% (13/1246) | | Genitourinary | | 0.3% (3/1156) | 0.7% (8/1156) | 1.0% (11/1156) | 0.2% (2/1246) | 0.7% (9/1246) | 0.9% (11/1246) | | Hemodynamic | | 0.3% (4/1156) | 0.2% (2/1156) | 0.5% (6/1156) | 0.2% (3/1246) | 1.2% (15/1246) | 1.4% (18/1246) | | | Hypertension | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1246) | 0.1% (1/1246) | 0.1% (1/1246) | | | Presyncope / Syncope | 0.3% (4/1156) | 0.2% (2/1156) | 0.5% (6/1156) | 0.2% (3/1246) | 1.1% (14/1246) | 1.4% (17/1246) | | Infection | | 1.3% (15/1156) | 0.9% (10/1156) | 2.1% (24/1156) | 0.8% (10/1246) | 1.3% (16/1246) | 2.1% (26/1246) | | Mental Health Related | | 0.2% (2/1156) | 0.5% (6/1156) | 0.7% (8/1156) | 0.1% (1/1246) | 0.6% (8/1246) | 0.7% (9/1246) | | Metabolic | | 0.1% (1/1156) | 0.8% (9/1156) | 0.9% (10/1156) | 0.2% (2/1246) | 1.0% (13/1246) | 1.2% (15/1246) | | Miscellaneous | | 0.0% (0/1156) | 1.6% (19/1156) | 1.6% (19/1156) | 0.0% (0/1246) | 2.1% (26/1246) | 2.1% (26/1246) | | Musculoskeletal | | 0.2% (2/1156) | 1.5% (17/1156) | 1.6% (19/1156) | 0.5% (6/1246) | 1.3% (16/1246) | 1.7% (21/1246) | | Neurologic Other Than Stroke | | 0.8% (9/1156) | 3.5% (41/1156) | 4.2% (49/1156) | 0.9% (11/1246) | 3.5% (43/1246) | 4.3% (54/1246) | | | Amaurosis Fugax | 0.0% (0/1156) | 0.5% (6/1156) | 0.5% (6/1156) | 0.1% (1/1246) | 0.6% (7/1246) | 0.6% (8/1246) | | | Confusion | 0.1% (1/1156) | 0.1% (1/1156) | 0.2% (2/1156) | 0.0% (0/1246) | 0.2% (2/1246) | 0.2% (2/1246) | | | Dementia | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Hyperperfusion Syndrome | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.1% (1/1246) | 0.0% (0/1246) | 0.1% (1/1246) | | | Migraine | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Neurologic Other | 0.0% (0/1156) | 0.4% (5/1156) | 0.4% (5/1156) | 0.0% (0/1246) | 0.6% (8/1246) | 0.6% (8/1246) | | | Peripheral Neuropathy | 0.0% (0/1156) | 0.2% (2/1156) | 0.2% (2/1156) | 0.1% (1/1246) | 0.1% (1/1246) | 0.2% (2/1246) | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 25 30 {25} Table 13 (continued) | Category | Subcategory | First Attempted CAS* N = 1156 | | | First Attempted CEA* N = 1246 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non- serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non- serious AEs | Subjects with any AE | | | Seizure | 0.2% (2/1156) | 0.0% (0/1156) | 0.2% (2/1156) | 0.2% (3/1246) | 0.1% (1/1246) | 0.3% (4/1246) | | | Sensory Deficit | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.3% (4/1246) | 0.3% (4/1246) | | | Speech Disturbance | 0.1% (1/1156) | 0.0% (0/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Subdural Hematoma | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.1% (1/1246) | 0.0% (0/1246) | 0.1% (1/1246) | | | TIA | 0.4% (5/1156) | 1.8% (21/1156) | 2.2% (25/1156) | 0.3% (4/1246) | 1.2% (15/1246) | 1.5% (19/1246) | | | Vertigo | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1246) | 0.1% (1/1246) | 0.1% (1/1246) | | | Visual Disturbance | 0.0% (0/1156) | 0.3% (3/1156) | 0.3% (3/1156) | 0.0% (0/1246) | 0.3% (4/1246) | 0.3% (4/1246) | | Procedure Related | | 6.3% (73/1156) | 25.7% (297/1156) | 29.8% (345/1156) | 4.7% (58/1246) | 27.4% (341/1246) | 31.1% (387/1246) | | | Anesthesia / Procedural Medication Related | 0.2% (2/1156) | 1.2% (14/1156) | 1.4% (16/1156) | 0.3% (4/1246) | 3.5% (43/1246) | 3.8% (47/1246) | | | Arrhythmia | 0.7% (8/1156) | 3.2% (37/1156) | 3.9% (45/1156) | 0.2% (2/1246) | 0.8% (10/1246) | 1.0% (12/1246) | | | Bleeding | 0.8% (9/1156) | 0.5% (6/1156) | 1.3% (15/1156) | 1.0% (13/1246) | 0.8% (10/1246) | 1.8% (23/1246) | | | Cranial Nerve Injury | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.4% (5/1246) | 4.6% (57/1246) | 5.0% (62/1246) | | | Fever | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.1% (1/1246) | 0.1% (1/1246) | | | Fluid Over Load | 0.1% (1/1156) | 0.0% (0/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.1% (1/1246) | 0.1% (1/1246) | | | Graft Infection | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.1% (1/1246) | 0.0% (0/1246) | 0.1% (1/1246) | | | Headache | 0.0% (0/1156) | 1.6% (19/1156) | 1.6% (19/1156) | 0.4% (5/1246) | 1.4% (18/1246) | 1.8% (23/1246) | | | Heparin Induced Thrombocytopenia | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Horners Syndrome | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1246) | 0.2% (2/1246) | 0.2% (2/1246) | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 26 31 {26} Table 13 (continued) | Category | Subcategory | First Attempted CAS^{a} N = 1156 | | | First Attempted CEA^{a} N = 1246 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | | Hypertension | 0.4% (5/1156) | 5.2% (60/1156) | 5.6% (65/1156) | 1.4% (17/1246) | 11.7% (146/1246) | 13.1% (163/1246) | | | Hypoperfusion | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.1% (1/1246) | 0.0% (0/1246) | 0.1% (1/1246) | | | Hypotension | 4.5% (52/1156) | 16.9% (195/1156) | 21.4% (247/1156) | 1.0% (12/1246) | 8.7% (108/1246) | 9.6% (120/1246) | | | Pain | 0.0% (0/1156) | 1.1% (13/1156) | 1.1% (13/1156) | 0.0% (0/1246) | 2.4% (30/1246) | 2.4% (30/1246) | | | Spasm | 0.0% (0/1156) | 0.3% (4/1156) | 0.3% (4/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Urinary Retention | 0.2% (2/1156) | 0.5% (6/1156) | 0.7% (8/1156) | 0.2% (2/1246) | 1.4% (18/1246) | 1.6% (20/1246) | | | Vessel Trauma | 0.0% (0/1156) | 0.2% (2/1156) | 0.2% (2/1156) | 0.0% (0/1246) | 0.2% (2/1246) | 0.2% (2/1246) | | Respiratory | | 0.6% (7/1156) | 0.3% (4/1156) | 1.0% (11/1156) | 0.6% (7/1246) | 1.4% (18/1246) | 2.0% (25/1246) | | Trauma | | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.1% (1/1246) | 0.4% (5/1246) | 0.5% (6/1246) | | Unknown AE | | 0.2% (2/1156) | 0.0% (0/1156) | 0.2% (2/1156) | 0.1% (1/1246) | 0.0% (0/1246) | 0.1% (1/1246) | | Vascular | | 0.9% (10/1156) | 0.4% (5/1156) | 1.3% (15/1156) | 0.6% (7/1246) | 0.7% (9/1246) | 1.3% (16/1246) | | | Aneurysm | 0.1% (1/1156) | 0.0% (0/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.2% (2/1246) | 0.2% (2/1246) | | | Carotid Artery Disease | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1246) | 0.1% (1/1246) | 0.1% (1/1246) | | | Contralateral Stenosis | 0.1% (1/1156) | 0.1% (1/1156) | 0.2% (2/1156) | 0.2% (2/1246) | 0.1% (1/1246) | 0.2% (3/1246) | | | Deep Vein Thrombosis | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | | | Occlusion | 0.1% (1/1156) | 0.0% (0/1156) | 0.1% (1/1156) | 0.1% (1/1246) | 0.1% (1/1246) | 0.2% (2/1246) | | | Peripheral Vascular Disease | 0.5% (6/1156) | 0.3% (3/1156) | 0.8% (9/1156) | 0.0% (0/1246) | 0.2% (3/1246) | 0.2% (3/1246) | | | Renal Vascular Disease | 0.1% (1/1156) | 0.0% (0/1156) | 0.1% (1/1156) | 0.0% (0/1246) | 0.0% (0/1246) | 0.0% (0/1246) | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 27 32 {27} Table 13 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1156 | | | First Attempted CEA^{1} N = 1246 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | | Target Lesion Restenosis | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.1% (1/1246) | 0.1% (1/1246) | 0.2% (2/1246) | | | Target Lesion Thrombosis | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.2% (2/1246) | 0.0% (0/1246) | 0.2% (2/1246) | | | Thrombosis | 0.0% (0/1156) | 0.0% (0/1156) | 0.0% (0/1156) | 0.1% (1/1246) | 0.0% (0/1246) | 0.1% (1/1246) | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 28 33 {28} Table 14: All Reported Non-Primary Endpoint Adverse Events between 31 and 365 Days following the Study Procedure (All Randomized Subjects) | Category | Subcategory | First Attempted CAS^{1} N = 1145 | | | First Attempted CEA^{1} N = 1230 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | Access Site Complication Not Requiring Treatment | Incision Complication | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1230) | 0.1% (1/1230) | 0.1% (1/1230) | | Access Site Complication Requiring Treatment | Hematoma | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.1% (1/1230) | 0.0% (0/1230) | 0.1% (1/1230) | | Allergic Reaction | | 0.0% (0/1145) | 0.1% (1/1145) | 0.1% (1/1145) | 0.2% (3/1230) | 0.2% (2/1230) | 0.4% (5/1230) | | Bleeding | | 1.4% (16/1145) | 0.7% (8/1145) | 2.1% (24/1145) | 1.0% (12/1230) | 1.1% (13/1230) | 1.9% (23/1230) | | | Epistaxis | 0.0% (0/1145) | 0.3% (4/1145) | 0.3% (4/1145) | 0.0% (0/1230) | 0.1% (1/1230) | 0.1% (1/1230) | | | GI | 1.2% (14/1145) | 0.3% (3/1145) | 1.5% (17/1145) | 0.7% (9/1230) | 0.3% (4/1230) | 0.9% (11/1230) | | | Other | 0.2% (2/1145) | 0.1% (1/1145) | 0.3% (3/1145) | 0.2% (3/1230) | 0.7% (8/1230) | 0.9% (11/1230) | | Blood Dyscrasia | | 0.6% (7/1145) | 0.6% (7/1145) | 1.2% (14/1145) | 0.5% (6/1230) | 0.3% (4/1230) | 0.8% (10/1230) | | Cancer | | 1.5% (17/1145) | 0.2% (2/1145) | 1.7% (19/1145) | 1.2% (15/1230) | 0.2% (2/1230) | 1.4% (17/1230) | | Cardiac | | 4.5% (52/1145) | 2.6% (30/1145) | 6.8% (78/1145) | 4.7% (58/1230) | 3.2% (39/1230) | 7.1% (87/1230) | | | Abnormal Lab Test | 0.1% (1/1145) | 0.6% (7/1145) | 0.6% (7/1145) | 0.1% (1/1230) | 0.5% (6/1230) | 0.6% (7/1230) | | | Arrhythmia | 0.6% (7/1145) | 1.1% (13/1145) | 1.7% (20/1145) | 1.4% (17/1230) | 1.1% (14/1230) | 2.3% (28/1230) | | | Cardiac Arrest | 0.6% (7/1145) | 0.0% (0/1145) | 0.6% (7/1145) | 0.1% (1/1230) | 0.0% (0/1230) | 0.1% (1/1230) | | | Congestive Heart Failure | 0.4% (5/1145) | 0.1% (1/1145) | 0.5% (6/1145) | 0.6% (7/1230) | 0.2% (2/1230) | 0.7% (9/1230) | | | Coronary Artery Disease | 3.1% (36/1145) | 1.1% (13/1145) | 4.1% (47/1145) | 3.0% (37/1230) | 1.5% (18/1230) | 4.0% (49/1230) | | | Structural Heart Disease | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.1% (1/1230) | 0.0% (0/1230) | 0.1% (1/1230) | $^{1}$ Subjects first attempted study procedure was CAS or CEA and the subjects were in the study beyond 30 days post procedure. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 29 34 {29} Table 14 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1145 | | | First Attempted CEA^{1} N = 1230 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non- serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non- serious AEs | Subjects with any AE | | Gastrointestinal | | 1.5% (17/1145) | 1.6% (18/1145) | 2.9% (33/1145) | 1.1% (14/1230) | 1.1% (14/1230) | 2.3% (28/1230) | | Genitourinary | | 1.8% (21/1145) | 0.3% (3/1145) | 2.1% (24/1145) | 1.1% (14/1230) | 1.1% (14/1230) | 2.2% (27/1230) | | Hemodynamic | | 1.7% (19/1145) | 2.5% (29/1145) | 4.0% (46/1145) | 1.6% (20/1230) | 1.9% (23/1230) | 3.3% (41/1230) | | | Hypertension | 0.5% (6/1145) | 0.9% (10/1145) | 1.3% (15/1145) | 0.5% (6/1230) | 0.5% (6/1230) | 1.0% (12/1230) | | | Hypotension | 0.3% (3/1145) | 0.3% (4/1145) | 0.6% (7/1145) | 0.3% (4/1230) | 0.6% (7/1230) | 0.9% (11/1230) | | | Presyncope/Syncope | 0.9% (10/1145) | 1.4% (16/1145) | 2.2% (25/1145) | 0.9% (11/1230) | 0.8% (10/1230) | 1.7% (21/1230) | | Infection | | 1.7% (19/1145) | 1.9% (22/1145) | 3.5% (40/1145) | 1.9% (23/1230) | 2.0% (24/1230) | 3.4% (42/1230) | | Mental Health Related | | 0.3% (4/1145) | 0.3% (4/1145) | 0.7% (8/1145) | 0.2% (3/1230) | 0.6% (7/1230) | 0.8% (10/1230) | | Metabolic | | 0.8% (9/1145) | 1.4% (16/1145) | 2.2% (25/1145) | 0.5% (6/1230) | 0.7% (9/1230) | 1.1% (14/1230) | | Miscellaneous | | 0.5% (6/1145) | 2.8% (32/1145) | 3.3% (38/1145) | 0.3% (4/1230) | 2.8% (34/1230) | 3.1% (38/1230) | | Musculoskeletal | | 1.5% (17/1145) | 2.6% (30/1145) | 4.0% (46/1145) | 1.1% (13/1230) | 2.6% (32/1230) | 3.5% (43/1230) | | Myocardial Infarction^{2} | | 1.0% (12/1145) | 0.0% (0/1145) | 1.0% (12/1145) | 1.1% (13/1230) | 0.0% (0/1230) | 1.1% (13/1230) | $^{2}$ The MI or stroke in the table are not primary endpoint events based on the definition of one year primary endpoint. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 30 35 {30} Table 14 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1145 | | | First Attempted CEA^{1} N = 1230 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | Neurologic Other Than Stroke | | 2.5% (29/1145) | 3.8% (44/1145) | 6.2% (71/1145) | 2.4% (30/1230) | 4.4% (54/1230) | 6.5% (80/1230) | | | Amaurosis Fugax | 0.3% (3/1145) | 0.4% (5/1145) | 0.7% (8/1145) | 0.1% (1/1230) | 0.3% (4/1230) | 0.4% (5/1230) | | | Confusion | 0.0% (0/1145) | 0.2% (2/1145) | 0.2% (2/1145) | 0.0% (0/1230) | 0.0% (0/1230) | 0.0% (0/1230) | | | Contra-Lateral Cranial Nerve Injury | 0.0% (0/1145) | 0.1% (1/1145) | 0.1% (1/1145) | 0.0% (0/1230) | 0.1% (1/1230) | 0.1% (1/1230) | | | Cranial Nerve Injury | 0.0% (0/1145) | 0.1% (1/1145) | 0.1% (1/1145) | 0.0% (0/1230) | 0.2% (2/1230) | 0.2% (2/1230) | | | Dementia | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1230) | 0.2% (2/1230) | 0.2% (2/1230) | | | Migraine | 0.2% (2/1145) | 0.1% (1/1145) | 0.3% (3/1145) | 0.0% (0/1230) | 0.2% (3/1230) | 0.2% (3/1230) | | | Neurologic Other | 0.1% (1/1145) | 0.3% (4/1145) | 0.4% (5/1145) | 0.2% (3/1230) | 1.6% (20/1230) | 1.9% (23/1230) | | | Peripheral Neuropathy | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.1% (1/1230) | 0.2% (2/1230) | 0.2% (3/1230) | | | Seizure | 0.3% (4/1145) | 0.3% (4/1145) | 0.7% (8/1145) | 0.2% (3/1230) | 0.0% (0/1230) | 0.2% (3/1230) | | | Sensory Deficit | 0.0% (0/1145) | 0.3% (3/1145) | 0.3% (3/1145) | 0.1% (1/1230) | 0.3% (4/1230) | 0.4% (5/1230) | | | Speech Disturbance | 0.2% (2/1145) | 0.0% (0/1145) | 0.2% (2/1145) | 0.0% (0/1230) | 0.1% (1/1230) | 0.1% (1/1230) | | | Subdural Hematoma | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.1% (1/1230) | 0.0% (0/1230) | 0.1% (1/1230) | | | TIA | 1.4% (16/1145) | 1.2% (14/1145) | 2.5% (29/1145) | 1.5% (18/1230) | 1.0% (12/1230) | 2.4% (29/1230) | | | Vertigo | 0.0% (0/1145) | 0.3% (3/1145) | 0.3% (3/1145) | 0.1% (1/1230) | 0.3% (4/1230) | 0.4% (5/1230) | | | Visual Disturbance | 0.2% (2/1145) | 0.6% (7/1145) | 0.8% (9/1145) | 0.1% (1/1230) | 0.3% (4/1230) | 0.4% (5/1230) | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 31 36 {31} Table 14 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1145 | | | First Attempted CEA^{1} N = 1230 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non- serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non- serious AEs | Subjects with any AE | | Procedure Related | Cranial Nerve Injury | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1230) | 0.2% (3/1230) | 0.2% (3/1230) | | Respiratory | | 1.7% (19/1145) | 1.0% (12/1145) | 2.6% (30/1145) | 1.4% (17/1230) | 0.7% (8/1230) | 2.0% (25/1230) | | Stroke^{2} | | 0.6% (7/1145) | 0.0% (0/1145) | 0.6% (7/1145) | 0.5% (6/1230) | 0.0% (0/1230) | 0.5% (6/1230) | | | Cerebral Hemorrhage, Non-Ipsilateral | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.1% (1/1230) | 0.0% (0/1230) | 0.1% (1/1230) | | | Ischemic, Non-Ipsilateral | 0.6% (7/1145) | 0.0% (0/1145) | 0.6% (7/1145) | 0.4% (5/1230) | 0.0% (0/1230) | 0.4% (5/1230) | | Trauma | | 0.2% (2/1145) | 0.4% (5/1145) | 0.6% (7/1145) | 1.1% (14/1230) | 0.4% (5/1230) | 1.5% (19/1230) | | Unknown AE | | 0.3% (4/1145) | 0.0% (0/1145) | 0.3% (4/1145) | 0.3% (4/1230) | 0.1% (1/1230) | 0.4% (5/1230) | | Vascular | | 7.4% (85/1145) | 0.8% (9/1145) | 8.2% (94/1145) | 6.4% (79/1230) | 1.5% (19/1230) | 7.6% (93/1230) | | | Aneurysm | 0.1% (1/1145) | 0.0% (0/1145) | 0.1% (1/1145) | 0.2% (2/1230) | 0.0% (0/1230) | 0.2% (2/1230) | | | Carotid Artery Disease | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.1% (1/1230) | 0.0% (0/1230) | 0.1% (1/1230) | | | Cerebral Malformation | 0.1% (1/1145) | 0.0% (0/1145) | 0.1% (1/1145) | 0.0% (0/1230) | 0.0% (0/1230) | 0.0% (0/1230) | | | Contralateral Stenosis | 2.1% (24/1145) | 0.0% (0/1145) | 2.1% (24/1145) | 3.5% (43/1230) | 0.2% (2/1230) | 3.6% (44/1230) | | | Deep Vein Thrombosis | 0.0% (0/1145) | 0.0% (0/1145) | 0.0% (0/1145) | 0.2% (2/1230) | 0.0% (0/1230) | 0.2% (2/1230) | | | Fistula/Pseudoaneurysm/ Dissection | 0.1% (1/1145) | 0.0% (0/1145) | 0.1% (1/1145) | 0.0% (0/1230) | 0.1% (1/1230) | 0.1% (1/1230) | | | Peripheral Vascular Disease | 2.7% (31/1145) | 0.3% (4/1145) | 3.1% (35/1145) | 0.9% (11/1230) | 0.9% (11/1230) | 1.6% (20/1230) | | | Renal Vascular Disease | 0.5% (6/1145) | 0.0% (0/1145) | 0.5% (6/1145) | 0.3% (4/1230) | 0.0% (0/1230) | 0.3% (4/1230) | | | Target Lesion Restenosis | 1.8% (21/1145) | 0.4% (5/1145) | 2.3% (26/1145) | 1.6% (20/1230) | 0.4% (5/1230) | 2.0% (24/1230) | $^{2}$ The MI or stroke in the table are not primary endpoint events based on the definition of one year primary endpoint. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 32 37 {32} Table 14 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1145 | | | First Attempted CEA^{1} N = 1230 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | | Target Lesion Thrombosis | 0.1% (1/1145) | 0.0% (0/1145) | 0.1% (1/1145) | 0.0% (0/1230) | 0.0% (0/1230) | 0.0% (0/1230) | | | Thrombosis | 0.1% (1/1145) | 0.0% (0/1145) | 0.1% (1/1145) | 0.0% (0/1230) | 0.0% (0/1230) | 0.0% (0/1230) | Table 15: All Reported Non-Primary Endpoint Adverse Events after 365 Days Post Study Procedure (All Randomized Subjects) | Category | Subcategory | First Attempted CAS^{1} N = 1092 | | | First Attempted CEA^{1} N = 1175 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | Allergic Reaction | | 0 | 7 | 7 | 1 | 3 | 4 | | Bleeding | | 17 | 10 | 27 | 27 | 8 | 35 | | | Epistaxis | 0 | 1 | 1 | 0 | 0 | 0 | | | GI | 12 | 2 | 14 | 20 | 2 | 22 | | | Other | 5 | 7 | 12 | 7 | 6 | 13 | | Blood Dyscrasia | | 14 | 10 | 23 | 10 | 9 | 18 | | Cancer | | 33 | 9 | 40 | 31 | 6 | 37 | | Cardiac | | 104 | 29 | 121 | 114 | 37 | 138 | | | Abnormal Lab Test | 2 | 0 | 2 | 2 | 0 | 2 | | | Arrhythmia | 15 | 15 | 28 | 25 | 24 | 48 | | | Cardiac Arrest | 8 | 0 | 8 | 12 | 0 | 12 | | | Congestive Heart Failure | 14 | 3 | 17 | 21 | 5 | 26 | | | Coronary Artery Disease | 71 | 13 | 80 | 64 | 11 | 71 | | | Effusion | 0 | 0 | 0 | 1 | 0 | 1 | $^{1}$ Subjects first attempted study procedure was CAS or CEA and the subjects were in the study beyond 365 days post procedure. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 33 38 {33} Table 15 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1092 | | | First Attempted CEA^{1} N = 1175 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | | Pulmonary Hypertension | 0 | 0 | 0 | 1 | 0 | 1 | | | Structural Heart Disease | 4 | 0 | 4 | 1 | 1 | 2 | | Gastrointestinal | | 31 | 20 | 44 | 27 | 19 | 41 | | Genitourinary | | 18 | 8 | 25 | 24 | 10 | 33 | | Hemodynamic | | 25 | 25 | 46 | 21 | 28 | 47 | | | Hypertension | 5 | 6 | 10 | 6 | 11 | 16 | | | Hypotension | 10 | 6 | 15 | 4 | 6 | 10 | | | Presyncope/Syncope | 11 | 13 | 22 | 14 | 11 | 24 | | Infection | | 34 | 22 | 52 | 30 | 25 | 51 | | Mental Health Related | | 4 | 5 | 9 | 5 | 4 | 9 | | Metabolic | | 14 | 15 | 27 | 10 | 11 | 20 | | Miscellaneous | | 2 | 31 | 33 | 3 | 32 | 34 | | Musculoskeletal | | 32 | 35 | 61 | 33 | 37 | 68 | | Myocardial Infarction^{2} | | 25 | 0 | 25 | 34 | 0 | 34 | $^{2}$ The MI or stroke in the table are not primary endpoint events based on the definition of one year primary endpoint. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 34 39 {34} Table 15 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1092 | | | First Attempted CEA^{1} N = 1175 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | Neurologic Other Than Stroke | | 44 | 59 | 96 | 34 | 62 | 92 | | | Amaurosis Fugax | 9 | 4 | 12 | 1 | 7 | 8 | | | Confusion | 1 | 3 | 4 | 1 | 1 | 2 | | | Cranial Nerve Injury | 0 | 2 | 2 | 0 | 0 | 0 | | | Dementia | 3 | 0 | 3 | 1 | 4 | 5 | | | Migraine | 2 | 1 | 3 | 0 | 1 | 1 | | | Neurologic Other | 0 | 10 | 10 | 1 | 13 | 14 | | | Peripheral Neuropathy | 0 | 0 | 0 | 0 | 8 | 8 | | | Seizure | 3 | 0 | 3 | 5 | 1 | 6 | | | Sensory Deficit | 0 | 3 | 3 | 0 | 4 | 4 | | | Speech Disturbance | 3 | 4 | 7 | 0 | 1 | 1 | | | Subdural Hematoma | 0 | 0 | 0 | 1 | 0 | 1 | | | TIA | 23 | 30 | 51 | 21 | 20 | 40 | | | Vertigo | 3 | 1 | 4 | 2 | 3 | 4 | | | Visual Disturbance | 1 | 5 | 6 | 2 | 5 | 7 | | Respiratory | | 28 | 8 | 34 | 31 | 11 | 40 | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 35 HO {35} Table 15 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1092 | | | First Attempted CEA^{1} N = 1175 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | Stroke^{2} | | 32 | 0 | 32 | 28 | 0 | 28 | | | Cerebral Hemorrhage, Ipsilateral | 0 | 0 | 0 | 1 | 0 | 1 | | | Cerebral Hemorrhage, Non-Ipsilateral | 2 | 0 | 2 | 2 | 0 | 2 | | | Ischemic, Ipsilateral | 14 | 0 | 14 | 15 | 0 | 15 | | | Ischemic, Non-Ipsilateral | 16 | 0 | 16 | 11 | 0 | 11 | | Trauma | | 11 | 14 | 25 | 11 | 8 | 19 | | Unadjudicated Stroke^{2} | | 5 | 0 | 5 | 4 | 0 | 4 | | Unknown AE | | 6 | 1 | 7 | 6 | 0 | 6 | | Vascular | | 74 | 21 | 92 | 62 | 11 | 72 | | | Aneurysm | 4 | 1 | 5 | 2 | 1 | 3 | | | Aortic Dissection | 1 | 0 | 1 | 1 | 0 | 1 | | | Carotid Artery Disease | 2 | 0 | 2 | 0 | 1 | 1 | | | Cerebral Malformation | 0 | 0 | 0 | 0 | 1 | 1 | | | Contralateral Stenosis | 31 | 6 | 36 | 27 | 1 | 28 | | | Deep Vein Thrombosis | 1 | 1 | 2 | 2 | 0 | 2 | | | Peripheral Vascular Disease | 21 | 9 | 28 | 18 | 7 | 24 | | | Renal Vascular Disease | 1 | 0 | 1 | 6 | 0 | 6 | | | Target Lesion Restenosis | 14 | 4 | 18 | 9 | 2 | 11 | | | Target Lesion Thrombosis | 1 | 0 | 1 | 0 | 0 | 0 | | | Thrombosis | 1 | 0 | 1 | 1 | 0 | 1 | $^{2}$ The MI or stroke in the table are not primary endpoint events based on the definition of one year primary endpoint. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 36 41 {36} Table 15 (continued) | Category | Subcategory | First Attempted CAS^{1} N = 1092 | | | First Attempted CEA^{1} N = 1175 | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | Subjects with Serious AEs | Subjects with Non-serious AEs | Subjects with any AE | | | Vessel Trauma | 1 | 0 | 1 | 0 | 0 | 0 | Table 16: Cause of Deaths Reported for All Enrolled Subjects | | Cause of Death | CAS | CEA | | --- | --- | --- | --- | | Death to 30 days | | | | | | Stroke | 4 | 4 | | | Bleeding | 1 | 0 | | | Cardiac | 2 | 0 | | | Sepsis | 1 | 0 | | Death > 30 days | | | | | | Stroke | 3 | 5 | | | Bleeding | 1 | 2 | | | Cancer | 22 | 28 | | | Cardiac | 34 | 22 | | | Drug overdose | 1 | 0 | | | Gastrointestinal | 4 | 2 | | | Infection/Pneumonia | 5 | 5 | | | Neurologic other than Stroke | 3 | 2 | | | Renal Failure | 5 | 5 | | | Respiratory Failure | 12 | 9 | | | Sepsis | 5 | 6 | | | Suicide | 1 | 0 | | | Unknown AE outcome death | 7 | 11 | | | Vascular | 1 | 0 | | Total number of deaths | | 112 | 101 | PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 37 42 {37} ## 2. Effectiveness Results The analysis of effectiveness was based on the CREST randomized population treated with CAS or CEA, with follow-up data available for 96.0% (2365/2464) of subjects at 1 month, 90.3% (2140/2369) of subjects at 1 year post-procedure, and 72.4% (589/813) of subjects at 4 years post-procedure. Effectiveness was analyzed by evaluating one-year clinically-driven target lesion revascularization (TLR) and 4-year long-term outcomes of a composite measure of all death, stroke, and MI at 30 days plus ipsilateral stroke between 31 days and 4 years. Target Lesion Revascularization at 12 Months (PP population) The freedom from clinically-driven TLR at 12 months by Kaplan-Meier Survival Analysis is 98.8% in the CAS arm and 99.0% in the CEA arm. The Kaplan-Meier survival curves for the clinically-driven TLR in the CAS arm and the CEA arm at 12 months are comparable. The results demonstrate the long term durability of the CAS procedure compared to the conventional treatment with CEA in the standard surgical risk population requiring treatment for carotid stenosis. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 38 43 {38} Figure 7: CREST Freedom from Clinically-Driven Target Lesion Revascularization (TLR) at 12 Months (PP Population)  Solid line: CAS Subjects (n= 1131) Dashed line: CEA Subjects (n= 1370) Vertical bar: 95% Confidence Limit | Days Post Index Procedure | 0 | (0, 30] | (30, 180] | (180, 365] | (365, 407] | | --- | --- | --- | --- | --- | --- | | CAS | | | | | | | Subjects at Risk | 1131 | 1131 | 1119 | 1093 | 1060 | | Subjects Censored | 0 | 11 | 25 | 25 | 1057 | | Number of Events | 0 | 1 | 1 | 8 | 3 | | % Event Free | 100% | 99.9% | 99.8% | 99.1% | 98.8% | | % Standard Error | 0.0% | 0.1% | 0.1% | 0.3% | 0.3% | | CEA | | | | | | | Subjects at Risk | 1176 | 1175 | 1164 | 1141 | 1110 | | Subjects Censored | 0 | 10 | 22 | 22 | 1110 | | Number of Events | 1 | 1 | 1 | 9 | 0 | | % Event Free | 99.9% | 99.8% | 99.7% | 99.0% | 99.0% | | % Standard Error | 0.1% | 0.1% | 0.1% | 0.3% | 0.3% | | Tests Between Groups | Test | Chi-Square | DF | p-value | | | | Log-Rank | 0.096 | 1 | 0.7568 | | | | Wilcoxon | 0.080 | 1 | 0.7778 | | Note: Subjects at risk gives the number of subjects at risk of an event at the start of the interval, while subjects censored and number of events are the incremental counts of subjects censored or with events during the interval. The intervals are denoted as half-open bracket expression, where the start of interval 't' is exclusive and the end of the interval 'l' is inclusive. PMA P040012/S034: FDA Summary of Safety and Effectiveness Data page 39 HH {39} # Long-term Outcomes of a Composite Measure of all Death, Stroke and MI at 30 days plus Ipsilateral Stroke between 31 Days and 4 Years The long-term durability and…