Who is the manufacturer of LOTUS Edge Valve System?

Boston Scientific Corporation filed the PMA application for LOTUS Edge Valve System (P180029).

What is the FDA product code for LOTUS Edge Valve System?

NPT. as a Class 3 device in the Cardiovascular panel.

Who can help prepare an FDA PMA submission like LOTUS Edge Valve System?

Innolitics — a medical-device software consultancy — provides regulatory and engineering support for FDA PMA submissions. See https://innolitics.com/services/regulatory/ or contact https://innolitics.com/contact.

LOTUS Edge Valve System

P180029 · Boston Scientific Corporation · NPT · Apr 23, 2019 · Cardiovascular

Device Facts

Record ID	P180029
Device Name	LOTUS Edge Valve System
Applicant	Boston Scientific Corporation
Product Code	NPT · Cardiovascular
Decision Date	Apr 23, 2019
Decision	APWD
Device Class	Class 3
Attributes	Therapeutic

Indications for Use

The LOTUS Edge™ Valve System is indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis (aortic valve area [AVA] of ≤ 1.0 cm² or index of ≤ 0.6 cm²/m²) who are judged by a heart team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., predicted risk of surgical mortality ≥ 8% at 30 days, based on the Society of Thoracic Surgeons (STS) risk score and other clinical comorbidities unmeasured by the STS risk calculator).

Device Story

The LOTUS Edge™ Valve System is a transcatheter aortic valve replacement (TAVR) device. It consists of a glutaraldehyde-fixed bovine pericardial tissue valve mounted on a braided nitinol frame. The device is delivered percutaneously via a catheter system, which includes an outer sheath, inner catheter assembly, and a controller handle. The valve features a post-and-buckle locking mechanism for secure deployment and an outer seal to minimize paravalvular regurgitation. Radiopaque tantalum markers on the locking mechanism aid visualization under fluoroscopy. The device is used in a clinical setting by a heart team (interventionalist and cardiac surgeon). The physician uses fluoroscopy to guide, deploy, and lock the valve in the native annulus. The device provides a mechanical replacement for the stenotic aortic valve, improving hemodynamic performance and patient quality of life. The system includes Depth Guard™ technology to minimize frame depth in the left ventricular outflow tract.

Clinical Evidence

Evidence includes the REPRISE III randomized controlled trial (N=912) comparing the Lotus Valve to CoreValve, plus supplemental prospective single-arm studies (REPRISE NG DS, REPRISE Edge, and REPRISE III Nested Registry). Primary safety endpoint (30-day composite) met non-inferiority (Lotus 20.3% vs. CoreValve 17.2%, p=0.0027). Primary effectiveness endpoint (1-year composite) met non-inferiority and superiority (Lotus 15.4% vs. CoreValve 25.5%, p<0.0001). Lotus demonstrated superior reduction in moderate or greater paravalvular regurgitation (0.9% vs 6.9%, p<0.0001) but higher rates of new permanent pacemaker implantation (34.2% vs 18.5% at 1 year).

Technological Characteristics

Valve: bovine pericardial tissue leaflets, braided nitinol frame, tantalum markers. Delivery system: catheter-based, compatible with 0.035" guidewire. Materials: nitinol, tantalum, titanium, bovine tissue, polyurethanes. Standards: ISO 5840 (cardiovascular implants), ISO 10993 (biocompatibility), ISO 11137 (sterilization). Sterilization: liquid chemical (glutaraldehyde) followed by e-beam. Connectivity: none (mechanical).

Indications for Use

Indicated for patients with symptomatic severe native calcific aortic stenosis (AVA ≤ 1.0 cm² or index ≤ 0.6 cm²/m²) at high or greater surgical risk (STS score ≥ 8% or other clinical comorbidities). Contraindicated in patients with non-calcified aortic annulus, active systemic infection/sepsis/endocarditis, hypersensitivity to contrast or device materials (nickel, titanium, tantalum, bovine-derived materials, polyurethanes), or severe arterial tortuosity/calcification preventing introducer sheath placement.

Regulatory Classification

Identification

To replace a patient's aortic heart valve. They are different from the classified device (heart valves) in that they are placed percutaneously and do not require open chest surgery or a cardiotomy for placement.

Reference Devices

CoreValve Transcatheter Aortic Valve Replacement System
CoreValve Evolut R Recapturable TAVR System
Lotus Valve System (first-generation)

Submission Summary (Full Text)

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Aortic valve, prosthesis, percutaneously delivered Device Trade Name: LOTUS Edge™ Valve System Device Procode: NPT Applicant's Name and Address: Boston Scientific Corporation 300 Boston Scientific Way Marlborough, MA 01752-1234 Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P180029 Date of FDA Notice of Approval: April 23, 2019 II. INDICATIONS FOR USE The LOTUS Edge™ Valve System is indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis (aortic valve area [AVA] of ≤ 1.0 cm² or index of ≤ 0.6 cm²/m²) who are judged by a heart team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., predicted risk of surgical mortality ≥ 8% at 30 days, based on the Society of Thoracic Surgeons (STS) risk score and other clinical comorbidities unmeasured by the STS risk calculator). III. CONTRAINDICATIONS The LOTUS Edge™ Valve System is contraindicated in patients who have: a non-calcified aortic annulus; an active systemic infection, sepsis, or endocarditis; known hypersensitivity to contrast agents that cannot be adequately pre-medicated, or known hypersensitivity or contraindication to aspirin, thienopyridines, heparin, nickel, titanium, tantalum, bovine-derived materials or polyurethanes; or severe arterial tortuosity or calcification that would prevent safe placement of the introducer sheath. IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the LOTUS Edge™ Valve System labeling. V. DEVICE DESCRIPTION PMA P180029: FDA Summary of Safety and Effectiveness Data Page 1 The LOTUS Edge™ Valve System consists of a pre-loaded, stent-mounted tissue valve prosthesis that is delivered to the native annulus by a catheter delivery system. # LOTUS Edge™ Valve Implant The valve consists of three glutaraldehyde-fixed bovine pericardial tissue valve leaflets supported on a braided nitinol frame. The braided valve structure is designed to foreshorten and expand radially when delivered, and is then locked in position using a post-and-buckle locking mechanism. An outer seal around the lower inflow end of the device is designed to minimize paravalvular regurgitation. Radiopaque tantalum markers are present on the buckle and post components of the locking mechanism to aid in visualization of the locking procedure under fluoroscopy. The valve is available in 23 mm, 25 mm, and 27 mm diameters. ![img-0.jpeg](img-0.jpeg) Figure 1. LOTUS Edge™ Valve Implant # LOTUS Edge™ Delivery System The LOTUS Edge™ Valve System delivery catheter is used to deliver, deploy, and release the valve in the intended implant location. The delivery system is comprised of three main assemblies: An outer catheter assembly also referred to as the outer sheath An inner catheter assembly which consists of a Multi-Lumen Extrusion (MLE) and the delivery system locking assembly. The MLE houses delivery system components that interact with the valve implant including the push pull rods, release mandrel, the nosecone /nosecone extension and coupler finger, guide, collars and sheathing aids. A controller assembly (also referred to as delivery system handle), which is used to control placement and release of the valve. The delivery system is compatible with a 0.035" guidewire. The LOTUS Edge Valve System may be introduced at the access site using either the Lotus Introducer set or the iSLEEVE Introducer set. Both the Lotus and iSLEEVE Introducer sets are cleared for market under $510(\mathrm{k})$ . PMA P180029: FDA Summary of Safety and Effectiveness Data ![img-1.jpeg](img-1.jpeg) Figure 2. LOTUS Edge™ Valve System ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the correction of severe calcific aortic stenosis, including: treatment with other approved transcatheter aortic valve implantation devices, surgical aortic valve replacement, temporary relief using a percutaneous technique called balloon aortic valvuloplasty (BAV), or medical therapy. 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 LOTUS Edge™ Valve System is marketed in the following countries: - Germany - Great Britain - Austria - Finland - Czech Republic - Denmark - Sweden - Spain - Italy - Netherlands - Portugal - Switzerland - France The LOTUS Edge™ Valve System was voluntarily withdrawn from marketing on October 28, 2016 to implement design changes to improve device deliverability and deployment. The modified device was re-introduced to the market on March 20, 2019. ## 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. - Abnormal lab values (including electrolyte imbalance) PMA P180029: FDA Summary of Safety and Effectiveness Data - Access site complications (including arteriovenous (AV) fistula, hematoma or lymphatic problems) - Allergic reaction (including to medications, anesthesia, contrast, or device materials, including nickel, titanium, tantalum, bovine-derived materials or polyurethanes) - Anemia - Angina - Arrhythmia or new conduction system injury (including need for pacemaker insertion) - Bleeding or hemorrhage (possibly requiring transfusion or additional procedure) - Cardiac arrest - Cardiac failure / low cardiac output - Cerebrovascular accident, stroke, transient ischemic attack or cerebral infarction including asymptomatic neuroimaging findings - Coronary obstruction - Death - Device misplacement, migration or embolization - Emboli (including air, tissue, thrombus or device materials) - Endocarditis - Fever or inflammation - Heart failure - Hemodynamic instability or shock - Hemolysis and/or hemolytic anemia - Hypertension/hypotension - Infection (local and/or systemic) - Mitral valve insufficiency - Myocardial infarction - Myocardial or valvular injury (including perforation or rupture) - Nerve injury or neurological deficits (including encephalopathy) - Pain - Pericardial effusion or tamponade - Peripheral ischemia or infarction - Permanent disability - Pleural effusion - Pulmonary edema - Renal insufficiency or failure - Respiratory insufficiency or failure - Restenosis (including pannus formation) - Valve dysfunction, deterioration or failure - Valve or device thrombosis - Valvular stenosis or regurgitation (central or paravalvular) - Vessel injury (including spasm, trauma, dissection, perforation, rupture, pseudoaneurysm or arteriovenous fistula) PMA P180029: FDA Summary of Safety and Effectiveness Data Page 4 For the specific adverse events that occurred in the clinical studies, please see Section X below. ## IX. SUMMARY OF NONCLINICAL STUDIES In vitro studies on the LOTUS Edge™ Valve System were conducted in accordance with national and international standards and FDA guidance documents. Testing verified that all components of the LOTUS Edge™ Valve System met its product performance and design specifications and is summarized below. ## A. Laboratory Studies ### Biocompatibility A series of biocompatibility tests were conducted to demonstrate that the materials and components of the LOTUS Edge™ Valve System are biocompatible. Testing was conducted on the both the valve implant and the delivery system in accordance with EN ISO 10993-1 Biological Evaluation of Medical Devices - Part 1: Evaluation and Testing within a risk management process and FDA Guidance Use of International Standard ISO 10993-1 Biological Evaluation of Medical Devices - Part 1: Evaluation and Testing within a risk management process. Test samples for the studies consisted of all patient-contacting portions of the devices (direct and indirect contact) exposed to all manufacturing processes, including sterilization. All results were acceptable. Table 1. Summary of Biocompatibility Testing – LOTUS Edge™ Valve Implant | Test Name | Test Description | Test Article and Results | | --- | --- | --- | | MEM Elution Cytotoxicity/ ISO 10993-5 | MEM Elution Cytotoxicity: ISO 10993-5 | Pass, non-cytotoxic | | Guinea Pig Maximization Sensitization/ | Guinea Pig Maximization Sensitization: ISO 10093 - 10 | Pass, non-sensitizer | | Intracutaneous Reactivity | Intracutaneous Reactivity: ISO 10993-10 | Pass, non-irritant | | Acute Systemic Injection | Acute Systemic Injection: ISO 10993-11 | Pass, non-toxic | | Materials Mediated Rabbit Pyrogen | Materials Mediated Rabbit Pyrogen: ISO 10993-11 | Pass, non-pyrogenic | | Subacute Toxicity Intraperitoneal and Intravenous | Subacute Toxicity Intraperitoneal: ISO 10993-11 | Pass, non-toxic | | Ames Mutagenicity | Ames Mutagenicity: ISO 10993-3 | Pass, non-mutagenic | | Mouse Lymphoma | Mouse Lymphoma: ISO 10993-3 | Pass, non-mutagenic | | Mouse Micronucleus | Mouse Micronucleus: ISO 10993-3 | Pass | PMA P180029: FDA Summary of Safety and Effectiveness Data PMA P180029: FDA Summary of Safety and Effectiveness Data Page 6 | Test Name | Test Description | Test Article and Results | | --- | --- | --- | | Partial Thromboplastin Time | Partial Thromboplastin Time: ISO 10993-4 | Pass, non-activator | | Complement Activation | Complement Activation: ISO 10993-4 | Pass comparable to control device | | In Vitro Hemocompatibility | In Vitro Hemocompatibility: ISO 10993-4 | Pass | | Hemolysis Indirect / Extract & Direct Contact | Indirect / Extract Hemolysis: ISO 10993-4 | Pass, non-hemolytic | | Extractables & Leachables IR/GC-MS/UPLC-MS, ICP-MS | Extractables & Leachables: ISO 10993-18 | Acceptable based on toxicological risk assessment of identified residuals | | Glutaraldehyde residual analysis / Formaldehyde residual analysis | Glutaraldehyde residual analysis / Formaldehyde residual analysis: ISO 10993-4 | Acceptable based on toxicological risk assessment of identified residuals | Table 2. Summary of Biocompatibility Testing – LOTUS Edge™ Delivery System | Test Name | Test Description | Test Article and Results | | --- | --- | --- | | MEM Elution Cytotoxicity/ ISO 10993-5 | MEM Elution Cytotoxicity: ISO 10993-5 | Pass, non-cytotoxic | | Guinea Pig Maximization Sensitization/ | Guinea Pig Maximization Sensitization: ISO 10093 - 10 | Pass, non-sensitizer | | Intracutaneous Reactivity | Intracutaneous Reactivity: ISO 10993-10 | Pass, non-irritant | | Acute Systemic Injection | Acute Systemic Injection: ISO 10993-11 | Pass, non-toxic | | Materials Mediated Rabbit Pyrogen | Materials Mediated Rabbit Pyrogen: ISO 10993-11 | Pass, non-pyrogenic | | Ames Mutagenicity | Ames Mutagenicity: ISO 10993-3 | Pass, non-mutagenic | | Mouse Lymphoma | Mouse Lymphoma: ISO 10993-3 | Pass, non-mutagenic | | Complement Activation | Complement Activation: ISO 10993-4 | Pass comparable to control device | | In Vitro Hemocompatibility | In Vitro Hemocompatibility: ISO 10993-4 | Pass | | Test Name | Test Description | Test Article and Results | | --- | --- | --- | | Hemolysis Indirect / Extract & Direct Contact | Indirect / Extract Hemolysis: ISO 10993-4 | Pass, non-hemolytic | | In vivo Thromboresistance study | In vivo Thromboresistance study (in sheep):ISO 10993-4 | Pass | | USP Physicochemical <661> | USP Physicochemical <661>: ISO 10993-18 | Characterization of chemical residuals | # Design Performance Testing In vitro studies were conducted to evaluate the design and performance attributes of the LOTUS Edge™ Valve System. Testing included materials and mechanical property testing, corrosion assessment, hydrodynamic performance assessment, device durability and structural integrity assessment, device compatibility, delivery system performance, valve performance, and MRI compatibility testing. Where relevant, the studies were conducted in accordance with ISO 5840: Cardiovascular Implants-Cardiac Valve Prostheses. The matrix of the tests performed and the corresponding results are provided in Table 3 below. The results showed that LOTUS Edge™ Valve System meets its specified design performance requirements. Table 3. Summary of LOTUS Edge™ Valve System Design Performance Testing | In Vitro Test Description | Purpose/Acceptance Criteria | Result (Pass/ Fail) | | --- | --- | --- | | Materials and Mechanical Property Testing | | | | Raw Material Properties | Assess the properties of raw materials in accordance with ISO 5840-3, ASTM F2063-12, ASTM F560-13, ASTM F2516-07, and ASTM F2082-06. | N/A - Characterization | | Post-Processing Properties | Assess the properties of raw materials in the post processed condition in accordance with ISO 5840-3, ASTM F2063-12, ASTM F560-13, ASTM F2516-07, and ASTM F2082-06. | N/A - Characterization | | Corrosion Assessment | | | PMA P180029: FDA Summary of Safety and Effectiveness Data | In Vitro Test Description | Purpose/Acceptance Criteria | Result (Pass/ Fail) | | --- | --- | --- | | Corrosion Resistance | Verify the corrosion resistance of the valve in accordance with ISO 5840-3, ISO 25539-1, ASTM F3044-14, and per ASTM F2129-08. | Pass | | Nickel Leach | Determine the nickel ion release rate from the LOTUS Edge™ Valve through experimental and theoretical methods in accordance with FDA Guidance Document: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | Pass | | Surface Assessment | Assess the surface composition and visualize the surface finish of the LOTUS Edge™ Valve in accordance with FDA Guidance Document: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems April 2010. | N/A - Characterization | | Catheter Corrosion Assessment | Verify that the patient contacting and fluid contacting portions of the catheter are resistant to corrosion in accordance with ISO 10555-1. | Pass | | **Hydrodynamic Performance** | | | | Steady Backflow Leakage (Nominal) | Measure the static leakage of the valve under a range of applied static back pressures in accordance with ISO 5840-3 including Annex N. | N/A - Characterization | | Steady Backflow Leakage (Axisymmetric Deformation) | | | | Pulsatile Flow | Assess valve performance in clinically relevant shapes by simulating physiological pressure and flow waveforms in accordance with ISO 5840-3. | N/A - Characterization | | Bernoulli Equation | Verify the Bernoulli relationship under in vitro physiological pulsatile flow conditions across all sizes valve. | N/A - Characterization | | Flow Visualization | Assess valve performance under varying cardiac outputs in accordance with ISO 5840-3 including Annex N. | N/A - Characterization | | **Device Durability** | | | PMA P180029: FDA Summary of Safety and Effectiveness Data Page 8 | In Vitro Test Description | Purpose/Acceptance Criteria | Result (Pass/Fail) | | --- | --- | --- | | Accelerated Wear Testing | Assess the durability and continued function of the valve in clinically relevant shapes after 200 million cycles. Commercially available reference valves were also tested for comparative purposes and validation of the testing conditions in accordance with ISO 5840-3. | Pass | | Dynamic Failure Mode Testing | Identify the failure modes associated with the LOTUS Edge™ Valve, under extended Accelerated Wear Testing in accordance with ISO 5840-3. | N/A – Characterization | | Structural Reliability | | | | Material Fatigue Life Determination | Determine the fatigue limit of the Nitinol material used to make the structural components of the LOTUS Edge™ Valve in accordance with ISO 5840-3. | N/A – Inputs to the Factor of Safety (FOS) | | In Vivo Boundary Conditions | Use finite element analysis (FEA) using relevant in vivo boundary conditions to build a computational model of the deformations (fatigue stresses and strains) that occur within the device during clinical loading in accordance with ISO 5840-3. | | | Finite Element Analysis | | | | Factor of Safety (FOS) | Use FEA computational model to determine appropriate Factor of Safety (FOS) | Pass | | Fatigue Demonstration Test | Determination of frame fatigue resistance to 600 million cycles and evaluation of failure mode of the structural components of the LOTUS Edge™ Valve in accordance with ISO 5840-3. | Pass | | Fatigue Testing to Failure | | N/A - Characterization | | Device Compatibility | | | | Compatibility: Introducer | Assess the compatibility of the LOTUS Edge™ Valve with the relevant introducer and guidewire. | Pass | | Compatibility: Guidewire | | Pass | | Compatibility: Flush Ports | Assess compatibility of the flush ports in accordance with EN 1707 to demonstrate that the device flush ports conform to the requirements of EN 1707 and ISO 594-2. | Pass | | Compatibility: Catheter Effective Length | Verify the effective length in accordance with ISO 10555-1 Single use intravascular catheters – Part 1: General Requirements. | Pass | PMA P180029: FDA Summary of Safety and Effectiveness Data PMA P180029: FDA Summary of Safety and Effectiveness Data Page 10 | In Vitro Test Description | Purpose/Acceptance Criteria | Result (Pass/ Fail) | | --- | --- | --- | | Compatibility: Catheter OD | Verify the maximum catheter outer diameter inserted into the vessel in accordance with ISO 10555-1 Single use intravascular catheters – Part 1: General Requirements. | Pass | | **Delivery System Performance** | | | | **Device Deliverability** | | | | Deliverability (Trackability, Pushability, Kink Resistance) | Assess the ability to deliver the device to the target treatment site in a clinically relevant manner and function correctly in accordance with FDA Guidance Document: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems along with ISO 5840-3 and ISO 25539-1. | Pass | | Torquability | Assess the functionality of the LOTUS Edge™ Valve System following clinically challenging torsional loading. This testing ensures compliance to ISO 25539-1, ISO 5840-3 and FDA Guidance Document: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | Pass | | Torque Strength | Assess device torque to failure while secured in a model that mimics the vasculature of the aorta including the aortic arch. This is in accordance with FDA Guidance Document: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | Pass | | Retraction | Assess the ability to retract the delivery system with and without a sheathed valve attached in a clinically relevant manner in accordance with FDA Guidance Document: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | Pass | | In Vitro Test Description | Purpose/Acceptance Criteria | Result (Pass/ Fail) | | --- | --- | --- | | Delivery System/Valve Component Visibility - Fluoroscopy | Assess the delivery system and valve component visibility during the simulated use testing by fluoroscopy in accordance with ISO 5840-3, ISO 25539-1 and FDA Guidance Document: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | Pass | | Component and Bond assessment to enable sheathing and unsheathing | This testing of the relevant component and bonds to ensure compliance to ISO 10555-1 and FDA Guidance Document: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | Pass | | Unsheathing: System Performance | Measurement of the forces experienced by the catheter components to ensure they do not exceed the tensile and compressive strength of the delivery system and valve components. | Pass | | Sheathing: System Performance | Measurement of the displacement experienced by the catheter components to ensure they do not exceed the compressive strength of the delivery system and valve components. | Pass | | Freedom from Leakage | Pressurize the system and verify there are no unacceptable leaks. | Pass | | Particulate | Characterize the particulate levels of the LOTUS Edge™ device to ensure compliance to ISO 5840-3 and FDA Guidance Document: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | N/A - Characterization | | Catheter Coating Characterization | Characterize the catheter coating integrity to ensure compliance to ISO 5840-3 and FDA Guidance Document: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | N/A - Characterization | | Catheter Coating Thickness | Characterize the catheter coating thickness of the LOTUS Edge™ system. | N/A - Characterization | | Valve Deployment Requirements | | | PMA P180029: FDA Summary of Safety and Effectiveness Data Page 11 | In Vitro Test Description | Purpose/Acceptance Criteria | Result (Pass/ Fail) | | --- | --- | --- | | Component and Bond assessment to enable locking and unlocking | The ability to lock and unlock the device in accordance with ISO 5840-3 and FDA Guidance Document: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | Pass | | Component and Bond assessment to enable valve deployment/release | The ability to deploy/release the valve in accordance with ISO 5840-3 and FDA Guidance Document: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. | Pass | | Valve Performance | | | | Radial Outward Force | Determine the radial outward force of the valve when it is in the fully locked configuration in accordance with ISO 5840-3. | Pass | | Crush Resistance | Determine valve functionality after lateral compression testing when the valve is in the fully locked configuration in accordance with ISO 5840-3. | Pass | | Device Migration Resistance | Assess the resistance to valve migration under clinically relevant conditions in accordance with ISO 5840-3. | Pass | | Hydrodynamic Performance: Effective Orifice Area | Determine the effective orifice area under pulsatile flow in accordance with ISO 5840-3. | Pass | | Transvalvular and Total Regurgitant Fraction | Determine the transvalvular and total regurgitant fractions under pulsatile flow in accordance with ISO 5840-3. | Pass | | MRI Compatibility | Assess magnetically induced displacement force and torque, radio frequency (RF) heating, and image artifacts of the valve in accordance with ISO 5840-3, ASTM F2052-14, ASTM F2213-06, ASTM F2182-11a, and ASTM F2119-07. | Pass | ## Sterilization The LOTUS Edge™ Valve undergoes liquid chemical sterilization in a glutaraldehyde solution. The terminal sterilization process involves incubation of the bioprosthesis in sterilant solution at elevated temperature for a defined period of time. The validated PMA P180029: FDA Summary of Safety and Effectiveness Data terminal liquid chemical sterilization process has demonstrated a Sterility Assurance Level (SAL) of 10⁻⁶. Following the chemical sterilization, the final packaged device is sent to the contract sterilizer for e-beam sterilization. The e-beam sterilization cycle has been validated in accordance with ISO 11137-1 Sterilization of health care products - Radiation - Requirements for development, validation and routine control of a sterilization process for medical devices. The delivery system goes through e-beam sterilization using a dosage determined per the requirements of this standard. A routine sterilization dose has been validated to provide a minimum sterility assurance level (SAL) of at least 10⁻⁶ with an overall average product bioburden of ≤1000 CFU/device using the VDmax²⁵ method. ## Packaging and Shelf Life The packaging used for the LOTUS Edge™ Valve System is a single barrier package. Each individual LOTUS Edge device is placed in a thermoformed co-polyester tray/lid. A pouched Stylet (used during device preparation) is placed in the tray with the device. The closed tray is placed inside a sealed pouch comprised of an uncoated Tyvek® film layer on one side and clear poly Nylon on the opposite side. The sealed pouch assembly is inserted between two foam end caps and placed in a multi-layer corrugated carton. A patient guide booklet (including implant card), electronic directions for use card and a temperature logger (used to monitor temperature) are added within the carton. The LOTUS Edge™ Valve System is labeled with a 9-month shelf life based on real-time aging of the LOTUS Edge™ Valve implant and real-time and accelerated aging of the LOTUS Edge™ Valve System. Packaging and product integrity studies were conducted to ensure that the device meets specifications throughout the stated shelf life. ## B. Animal Studies The LOTUS Edge™ Valve System was evaluated in four animal studies. Safety, acute and chronic device performance, and biological response of the LOTUS Edge™ Valve System are supported by ovine study 12-024G. Calcification potential for the LOTUS Edge™ Valve System tissue compared to a commercially available control surgically implanted pericardial valve tissue is supported by rat implant studies TR5212 and TR5211. Thromboresistance of the LOTUS Edge™ Valve System is supported by ovine study TR4704. These studies are summarized in Table 4. PMA P180029: FDA Summary of Safety and Effectiveness Data Page 13 Table 4. Summary of LOTUS Edge Valve System In Vivo Studies | Study | Device and Number (N) | Device Size, Implant Location and Method | Species, Number of Animals Enrolled (N) and Age Category | Evaluation Time Points | Number of Animals Surviving to Evaluation Time Points (n/N) | Objectives | Testing Summary | | --- | --- | --- | --- | --- | --- | --- | --- | | Lotus Valve Ovine 90- and 140-Day Safety and Biological Response Study 12-024G | | | | | | | | | GLP Safety Study 12-024G | Lotus Valve (17) | 27 mm Aortic annulus TAVR, femoral access | Ovine (23) Adolescent | 90 and 140 days | (12/17) 90 days: 2 140 days: 10 | To assess safety and biological response of the Lotus valve over 20 weeks of percutaneous implantation in the orthotopic position in adolescent sheep. | Results: Of 23 animals prescreened for implantation, 6 were euthanized prior to valve introduction due to vascular dissection at the access site. Lotus valves were deployed in 17 animals, of which 12 survived to scheduled termination (2 at 90 days, 10 at 140 days) without major adverse clinical events, complications, or other evidence of functional impairment. There were 5 unscheduled deaths that were procedurally related: • Two procedural deaths due to complete AV block followed by ventricular fibrillation (VF). • One death from right coronary obstruction due to the short aortic root in the sheep. • One death occurred during recovery from VF of unknown cause. • One death from ventricular embolization of the device likely related to implantation in the elastic annulus of a non-diseased animal model. All animals surviving to termination demonstrated normal hemodynamic parameters that met all published clinical VARC-2 criteria for transvalvular gradients and EOA. Pathology showed findings representative of percutaneous bioprosthetic valves chronically implanted in sheep. Radiographic calcification analysis of Lotus valves compared with explanted human bioprosthetic valves demonstrated no significant difference in calcification scores. | PMA P180029: FDA Summary of Safety and Effectiveness Data | Study | Device and Number (N) | Device Size, Implant Location and Method | Species, Number of Animals Enrolled (N) and Age Category | Evaluation Time Points | Number of Animals Surviving to Evaluation Time Points (n/N) | Objectives | Testing Summary | | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | | | Conclusions: Percutaneous implantation of the 27 mm Lotus Valve can be performed in the native aortic annulus of healthy sheep with survival for duration of 140 days. Lotus valve calcification did not exceed that of comparative human explanted valves. Taken together, the hemodynamic performance and histologic analysis demonstrate the safety of the Lotus valve. | | Rat Calcification Studies TR5212 and TR5211 | | | | | | | | | Study TR5212 | Test: Lotus Valve bovine pericardial tissue (30) | 8 mm Diameter Pericardial Tissue Disk | Rat (10) Young | 30 and 90 days | 10/10 | To evaluate calcification potential of bovine pericardial tissue used in Lotus valve compared to tissue from Mitroflow pericardial valve. | Results: Histology: In the Lotus group no calcification was observed at 30 or 90 days. In the Mitroflow group calcification mild to moderate was observed at 30 days and moderate to severe at 90 days. Calcium Analysis: Calcification was substantially less in Lotus tissue than Mitroflow. Conclusions: Results demonstrate a substantially reduced tendency for calcification of Lotus valve tissue compared to Mitroflow valve tissue in the young rat subcutaneous model at 30 and 90 days. | | | Control: Mitroflow bovine pericardial valve tissue (30) | | | | | | | | Study TR5211 | Test 1: Lotus Valve bovine pericardial tissue, one-year aged (16) | 8 mm Diameter Pericardial Tissue Disk | Rat (8) Young | 60 days | 8/8 | To evaluate the effects of tissue aging on calcification potential of one-year aged | Results: Histology: No calcification was observed in 1-year aged and non-aged Lotus tissue groups. Moderate calcification was observed in Mitroflow group in 2 of 3 samples. | PMA P180029: FDA Summary of Safety and Effectiveness Data | Study | Device and Number (N) | Device Size, Implant Location and Method | Species, Number of Animals Enrolled (N) and Age Category | Evaluation Time Points | Number of Animals Surviving to Evaluation Time Points (n/N) | Objectives | Testing Summary | | --- | --- | --- | --- | --- | --- | --- | --- | | | Control 1: Lotus Valve bovine pericardial tissue, non-aged (16) | Dorsal subcutaneous Surgical implant-ation | | | | and non-aged adult bovine pericardial tissue used in Lotus valve compared to tissue from Mitroflow pericardial valve in the young rat subcutaneous model at 60 days. | Calcium Analysis: Calcification was substantially less in Lotus aged and non-aged tissues compared to Mitroflow. Conclusions: Results demonstrate reduced tendency for calcification of Lotus valve tissue, both aged and non-aged, compared to Mitroflow valve tissue in the young rat subcutaneous model at 60 days, and no impact of aging on the calcification potential of Lotus valve tissue. | | | Control 2: Mitroflow bovine pericardial valve tissue (16) | | | | | | | | Lotus Valve Ovine 90-Day Study TR4704 (Leveraged Support for Thrombogenicity Assessment) | | | | | | | | | Study TR4704 | Lotus Valve (8) | 27 mm Aortic annulus TAVR, femoral access | Ovine (8) Adolescent | 90 days | 3/8 | To assess the healing characteristics and calcification of the 27 mm Lotus valve in the adolescent ovine model for 90 days of implantation. | Results: Eight animals were implanted. There were 5 unscheduled deaths: 4 due to valve embolization and 1 due to VF during implantation. Three animals survived to scheduled termination at 90 days with no thrombus, hemolysis, systemic toxicity, or changes in valve shape or hemodynamics observed. Conclusions: CT prescreening allowed selection animals for implantation. Fixation of the valve was challenging in non-calcified annular tissue. Repositioning of valve was successfully performed. Complete valve and delivery system retrieval and removal can be performed if necessary. Normal healing and no evidence of hemolysis was observed. No patient safety risks were identified. | PMA P180029: FDA Summary of Safety and Effectiveness Data PMA P180029: FDA Summary of Safety and Effectiveness Data Page 17 # X. SUMMARY OF PRIMARY CLINICAL STUDIES The applicant performed a clinical study, REPRISE III, to establish a reasonable assurance of safety and effectiveness of transcatheter aortic valve replacement with the first-generation LOTUS Valve System in patients with calcific, severe, symptomatic, native aortic stenosis who were at high or extreme risk for open surgery. The study was conducted in the US, Canada, Western Europe, and Australia under IDE #G140090. Data from this clinical study were the basis for the PMA approval decision. The LOTUS Edge™ Valve System represents a modification to the first-generation LOTUS Valve System to improve flexibility and deliverability, and to reduce the profile of the delivery system. The device design modifications were primarily related to the delivery system. Compared to the LOTUS valve implant, the LOTUS Edge™ valve implant is similar with additional radiopaque tantalum markers on the buckle and post components of the locking mechanism to aid in visualization of the locking procedure under fluoroscopy. The safety and performance of the LOTUS Edge Valve System was supported by two prospective, single-arm studies conducted outside the US (OUS): the REPRISE NG DS (Cohort C) and REPRISE Edge studies. Following a voluntary field safety corrective action in October 2016, additional design modifications were made to the LOTUS Edge delivery system to improve deliverability and deployment. The safety and performance of the modified LOTUS Edge design were evaluated in a prospective, single-arm nested registry study in the US and Australia. A summary of the primary clinical study, REPRISE III, is presented below. A summary of the supplemental clinical studies to evaluate the safety and performance of the LOTUS Edge design modifications is presented in Section XI. ## A. Study Design Patients were treated between September 22, 2014 and December 24, 2015. The database for this PMA reflected data collected through March 8, 2017 and included 912 randomized patients enrolled at 55 investigational sites in the US, Germany, France, Australia, the Netherlands, and Canada. The REPRISE III clinical study was a prospective, multicenter, randomized controlled trial designed to evaluate the safety and effectiveness of the Lotus Valve System for transcatheter aortic valve replacement in symptomatic subjects with calcific, severe native aortic stenosis who were at high or extreme risk for open surgery. The control group was the CoreValve® Transcatheter Aortic Valve Replacement System. Subjects were randomized 2:1 to the Lotus Valve System (23 mm, 25 mm, and 27 mm valve sizes) or a commercially available CoreValve® (26 mm, 29 mm, and 31 mm valve sizes). A center was allowed to use CoreValve Evolut™ R Recapturable TAVR System with the aforementioned size matrix if the center no longer had access to CoreValve®. A frequentist analysis plan was used to demonstrate non-inferiority of the Lotus Valve System compared to the CoreValve® TAVR System in both safety and effectiveness endpoints. All potential eligible subjects were reviewed by a Case Review Committee to confirm suitability prior to enrollment. An independent Clinical Events Committee (CEC) adjudicated safety events. Independent core laboratories assessed echocardiography data; computed tomography (CT) and rotational X-ray angiography data; and electrocardiography data. Any explanted test devices were to be analyzed by an independent histopathology core laboratory. The primary and secondary endpoints and Valve Academic Research Consortium (VARC) clinical endpoints[1,2] were also validated by independent study statisticians. 1. Clinical Inclusion and Exclusion Criteria Enrollment in the REPRISE III study was limited to patients who met the following inclusion criteria: Table 5: REPRISE III Inclusion Criteria | IC1. Subject has documented calcific, severe native aortic stenosis with an initial AVA of ≤1.0 cm² (or AVA index of ≤0.6 cm²/m²) and a mean pressure gradient ≥40 mmHg or jet velocity ≥4.0 m/s, as measured by echocardiography and/or invasive hemodynamics. | | --- | | IC2. Subject has a documented aortic annulus size of ≥20 mm and ≤27 mm based on the center’s assessment of pre-procedure diagnostic imaging (and confirmed by the CRC) and, for the randomized cohort, is deemed treatable with an available size of both test and control device. | | IC3. Subject has symptomatic aortic valve stenosis with NYHA Functional Class ≥ II. | | IC4. There is agreement by the heart team (which must include a site investigator interventionalist and a site investigator cardiac surgeon) that subject is at high or extreme operative risk for surgical valve replacement (see Note 1 below for definitions of extreme and high risk, the required level of surgical assessment, and CRC confirmation) and that TAVR is appropriate. Additionally, subject has at least one of the following. | | • Society of Thoracic Surgeons (STS) score ≥8% -OR- | | • If STS <8, subject has at least one of the following conditions: | | ○ Hostile chest | | ○ Porcelain aorta | | ○ Severe pulmonary hypertension (>60 mmHg) | | ○ Prior chest radiation therapy | | ○ Coronary artery bypass graft(s) at risk with re-operation | | ○ Severe lung disease (need for supplemental oxygen, FEV₁ <50% of predicted, DLCO <60%, other evidence of major pulmonary dysfunction) | | ○ Neuromuscular disease that creates risk for mechanical ventilation or rehabilitation | PMA P180029: FDA Summary of Safety and Effectiveness Data Page 18 Table 5: REPRISE III Inclusion Criteria | after surgical aortic valve replacement ○ Orthopedic disease that creates risk for rehabilitation after surgical aortic valve replacement ○ Childs Class A or B liver disease (subjects with Childs Class C disease are not eligible for inclusion in this trial) ○ Frailty as indicated by at least one of the following: 5-meter walk >6 seconds, Katz ADL score of 3/6 or less, body mass index <21, wheelchair bound, unable to live independently ○ Age ≥90 years ○ Other evidence that subject is at high or extreme risk for surgical valve replacement (CRC must confirm agreement with site heart team that subject meets high or extreme risk definition) IC5. Heart team (which must include a cardiac interventionalist and an experienced cardiac surgeon) assessment that the subject is likely to benefit from valve replacement. IC6. Subject (or legal representative) understands the study requirements and the treatment procedures, and provides written informed consent. IC7. Subject, family member, and/or legal representative agree(s) and subject is capable of returning to the study hospital for all required scheduled follow up visits. | | --- | | Note 1: Extreme operative risk and high operative risk were defined as shown below. The risk of operative mortality and morbidity was to be assessed via an in-person evaluation by a center cardiac surgeon and was confirmed by the CRC (which included an experienced cardiac surgeon). Extreme Operative Risk: Predicted operative mortality or serious, irreversible morbidity risk ≥50% at 30 days. High Operative Risk: Predicted operative mortality or serious, irreversible morbidity risk ≥15% at 30 days. Abbreviations: AVA=aortic valve area; CRC=Case Review Committee; NYHA=New York Heart Association; RCT=randomized controlled trial; STS=Society of Thoracic Surgeons; TAVR=transcatheter aortic valve replacement | Patients were not permitted to enroll in the REPRISE III study if they met any of the following exclusion criteria: Table 6: REPRISE III Exclusion Criteria | EC1. Subject has a congenital unicuspid or bicuspid aortic valve. | | --- | | EC2. Subject has had an acute myocardial infarction within 30 days prior to the index procedure (defined as Q-wave MI or non-Q-wave MI with total CK elevation ≥ twice normal in the presence of CK-MB elevation and/or troponin elevation). | | EC3. Subject has had a cerebrovascular accident or transient ischemic attack within the past 6 months prior to study enrollment. | | EC4. Subject has end-stage renal disease or has GFR <20 (based on Cockcroft-Gault formula). | | EC5. Subject has a pre-existing prosthetic heart aortic or mitral valve. | PMA P180029: FDA Summary of Safety and Effectiveness Data Table 6: REPRISE III Exclusion Criteria | EC6. Subject has severe (4+) aortic, tricuspid, or mitral regurgitation. | | --- | | EC7. Subject has a need for emergency surgery for any reason. | | EC8. Subject has a history of endocarditis within 6 months of index procedure or evidence of an active systemic infection or sepsis. | | EC9. Subject has echocardiographic evidence of new intra-cardiac vegetation or intraventricular or paravalvular thrombus requiring intervention. | | EC10. Subject has Hgb <9 g/dL, platelet count <50,000 cells/mm3or >700,000 cells/mm3, or white blood cell count <1,000 cells/mm3. | | EC11. Subject requires chronic anticoagulation therapy after the implant procedure and cannot be treated with warfarin (other anticoagulants are not permitted in the first month) for at least 1 month concomitant with either aspirin or clopidogrela. | | EC12. Subject has had a gastrointestinal bleed requiring hospitalization or transfusion within the past 3 months, or has other clinically significant bleeding diathesis or coagulopathy that would preclude treatment with required antiplatelet regimen, or will refuse transfusions. | | EC13. Subject has known hypersensitivity to contrast agents that cannot be adequately pre-medicated, or has known hypersensitivity to aspirin, all P2Y12 inhibitors, heparin, nickel, tantalum, titanium, or polyurethanes. | | EC14. Subject has a life expectancy of less than 12 months due to non-cardiac, comorbid conditions based on the assessment of the investigator at the time of enrollment. | | EC15. Subject has hypertrophic obstructive cardiomyopathy. | | EC16. Subject has any therapeutic invasive cardiac or vascular procedure within 30 days prior to the index procedure (except for balloon aortic valvuloplasty or pacemaker implantation, which are allowed). | | EC17. Subject has untreated coronary artery disease, which in the opinion of the treating physician is clinically significant and requires revascularization. | | EC18. Subject has severe left ventricular dysfunction with ejection fraction <20%. | | EC19. Subject is in cardiogenic shock or has hemodynamic instability requiring inotropic support or mechanical support devices. | | EC20. Subject has severe vascular disease that would preclude safe access (e.g., aneurysm with thrombus that cannot be crossed safely, marked tortuosity, significant narrowing of the abdominal aorta, severe unfolding of the thoracic aorta, or symptomatic carotid or vertebral disease). | | EC21. Subject has thick (>5 mm) protruding or ulcerated atheroma in the aortic arch | | EC22. Subject has arterial access that is not acceptable for the test and control device delivery systems as defined in the device Instructions For Use. | | EC23. Subject has current problems with substance abuse (e.g., alcohol, etc.). | | EC24. Subject is participating in another investigational drug or device study that has not reached its primary endpoint. | PMA P180029: FDA Summary of Safety and Effectiveness Data Table 6: REPRISE III Exclusion Criteria | EC25. Subject has untreated conduction system disorder (e.g., Type II second degree atrioventricular block) that in the opinion of the treating physician is clinically significant and requires a pacemaker implantation. Enrollment is permissible after permanent pacemaker implantation. EC26. Subject has severe incapacitating dementia. | | --- | | a: An alternative P2Y12 inhibitor may be prescribed if subject is allergic to or intolerant of clopidogrel. Abbreviations: CK=creatine kinase; MI=myocardial infarction; PCI=percutaneous coronary intervention | 2. Follow-up Schedule All patients were scheduled to return for follow-up examinations at discharge or 7 days post-procedure (whichever comes first), 30 days, 6 months, 1 year, and then annually for 5 years post-procedure. Enrolled patients who did not receive a study valve (Lotus or CoreValve) were followed for 1 year. Preoperatively, patients were screened to confirm they met the eligibility criteria, including imaging assessments of valve function and arterial structure/disease. In addition, baseline assessments included neurological assessment, laboratory tests, and quality of life surveys. Postoperatively, the objective parameters measured during the study included New York Heart Association (NYHA) Classification, neurological physical examination, antiplatelet and anticoagulation medications (if applicable), transthoracic echocardiogram (TTE) evaluation, quality of life surveys, adverse event collection, and 4D CT imaging of the prosthetic valve (at 30 days and 1 year). Adverse events and complications were recorded at all visits. The key timepoints are shown below in the tables summarizing safety and effectiveness. 3. Clinical Endpoints Primary Safety Endpoint The primary safety endpoint was a composite of all-cause mortality, stroke, life-threatening and major bleeding events, stage 2 or 3 acute kidney injury, or major vascular complications at 30 days. The primary hypothesis was as follows: $$ H _ {0}: P _ {\mathrm {S} _ {-} \text {L o t u s}} - P _ {\mathrm {S} _ {-} \text {C o n t r o l}} \geq 10.5 \% $$ $$ H _ {A}: P _ {\mathrm {S} _ {-} \text {L o t u s}} - P _ {\mathrm {S} _ {-} \text {C o n t r o l}} < 10.5 \% $$ where $P_{\mathrm{S\_Lotus}}$ denotes the event proportion in the test arm, and $P_{\mathrm{S\_Control}}$ denotes the event proportion in the control arm. The test was performed as a one-sided test at $\alpha =$ PMA P180029: FDA Summary of Safety and Effectiveness Data 0.025. The primary analysis was a non-inferiority analysis in the implanted analysis set. The endpoint was also analyzed for the intent-to-treat (ITT) and as-treated analysis sets. ## Primary Effectiveness Endpoint The primary effectiveness endpoint was a composite of all-cause mortality, disabling stroke, or moderate or greater paravalvular aortic regurgitation (PVR; based on core lab assessment) at 1 year. The primary hypothesis was as follows: $$ H_0: P_{\mathrm{S\_Lotus}} - P_{\mathrm{S\_Control}} \geq 9.5\% $$ $$ H_A: P_{\mathrm{S\_Lotus}} - P_{\mathrm{S\_Control}} < 9.5\% $$ where $P_{\mathrm{S\_Lotus}}$ denotes the event proportion in the test arm, and $P_{\mathrm{S\_Control}}$ denotes the event proportion in the control arm. The test was performed as a one-sided test at $\alpha = 0.025$. The primary analysis was a non-inferiority analysis in the implanted analysis set. The endpoint was also analyzed for the intent-to-treat (ITT) and as-treated analysis sets. ## Secondary Endpoint The secondary endpoint was the rate of moderate or greater PVR based on core lab assessment at 1 year. A chi-square test was used to test the two-sided ($\alpha = 0.05$) hypothesis of superiority: $$ H_0: P_{\mathrm{AR-Lotus}} = P_{\mathrm{AR-Control}} $$ $$ H_A: P_{\mathrm{AR-Lotus}} \neq P_{\mathrm{AR-Control}} $$ Where $P_{\mathrm{AR-Lotus}}$ and $P_{\mathrm{AR-Control}}$ correspond to the moderate or greater PVR rates at 1 year for the Lotus Valve group (test) and the CoreValve group (control), respectively. The primary analysis set was the ITT analysis set. ## Additional Measurements Additional measurements based on the VARC endpoints and definitions were collected peri- and post-procedure, at discharge or 7 days post-procedure (whichever comes first), 30 days, 6 months, and 1, 2, 3, 4, and 5 years post index procedure, unless otherwise specified below. - Safety endpoints adjudicated by an independent Clinical Events Committee (CEC): - Mortality: all-cause, cardiovascular, and non-cardiovascular - Stroke: disabling and non-disabling - Myocardial infarction (MI): periprocedural (≤72 hours post index procedure) and spontaneous (>72 hours post index procedure) - Bleeding: life-threatening (or disabling) and major - Acute kidney injury (≤7 days post index procedure): based on the AKIN Stage 3 (including renal replacement therapy) or Stage 2 PMA P180029: FDA Summary of Safety and Effectiveness Data Page 22 Major vascular complication Repeat procedure for valve-related dysfunction (surgical or interventional therapy) o Hospitalization for valve-related symptoms or worsening congestive heart failure (CHF; New York Heart Association [NYHA] class III or IV) o New permanent pacemaker (PPM) implantation resulting from new or worsened conduction disturbances o New onset of atrial fibrillation or atrial flutter o Coronary obstruction: periprocedural (≤72 hours post index procedure) o Ventricular septal perforation: periprocedural (≤72 hours post index procedure) o Mitral apparatus damage: periprocedural (≤72 hours post index procedure) o Cardiac tamponade: periprocedural (≤72 hours post index procedure) o Prosthetic aortic valve malpositioning, including valve migration, valve embolization, or ectopic valve deployment o Transcatheter aortic valve (TAV)-in-TAV deployment o Prosthetic aortic valve thrombosis o Prosthetic aortic valve endocarditis - Device performance endpoints peri- and post-procedure: o Successful vascular access, delivery and deployment of the study valve and successful retrieval of the delivery system o Successful retrieval of the study valve if retrieval is attempted o Successful repositioning of the study valve if repositioning is attempted o Grade of aortic valve regurgitation: paravalvular, central and combined; overall distribution of PVR (none, trace/trivial, mild, moderate, severe), the percentage of subjects with moderate or severe PVR, and the percentage of subjects with mild, moderate or severe PVR - Clinical procedural success (30 days), defined as implantation of the study device in the absence of death, disabling stroke, major vascular complications, and life-threatening or major bleeding - Procedural success (30 days), defined as absence of procedural mortality, correct positioning of a single transcatheter valve into the proper anatomical location, intended performance of the study device (effective orifice area [EOA] >0.9 cm² for body surface area [BSA] <1.6 m² and EOA >1.1 cm² for BSA ≥1.6 m² plus either a mean aortic valve gradient <20 mmHg or a peak velocity <3m/sec, and no moderate or severe prosthetic valve aortic regurgitation) plus no serious adverse events at 30 days - Additional indications of prosthetic aortic valve performance as measured by transthoracic echocardiography (TTE) and assessed by an independent core laboratory, including EOA, mean and peak aortic gradients, peak aortic velocity, and grade of aortic regurgitation - Modified device success (30 days), reported for subjects randomized and implanted with an assigned study device and defined as follows: absence of mortality with the originally implanted transcatheter valve in the proper anatomical location, no additional aortic valve procedures, and with the intended performance of the prosthetic valve (either a mean aortic valve gradient PMA P180029: FDA Summary of Safety and Effectiveness Data Page 23 <20 mmHg or a peak velocity <3m/sec with no moderate or severe prosthetic valve aortic regurgitation) - Functional status as evaluated by the following: - 5-m gait speed test (at 1 year compared to baseline) - NYHA classification - Neurological status as determined by the following: - Neurological physical exam by a neurologist, neurology fellow, neurology physician assistant, or neurology nurse practitioner at discharge and 1 year - National Institutes of Health Stroke Scale (NIHSS) at discharge and 1 year - Modified Rankin Scale (mRS) at all time points - Health status as evaluated by Kansas City Cardiomyopathy and SF-12 Quality of Life (QOL) questionnaires at baseline; 1 and 6 months; and 1, 3, and 5 years ## B. Accountability of PMA Cohort At the time of database lock, of 912 patients enrolled in the PMA study (607 Lotus, 305 CoreValve), 97.4% (N=297) of CoreValve patients and 96.7% (N=587) of Lotus patients are available for analysis at the completion of the study, the 1-year post-operative visit. Table 7: REPRISE III Subject Disposition | Measure | Lotus | Core Valve^{a} | | --- | --- | --- | | Intent-to-treat analysis set | 607 | 305 | | Not treated with a study valve system (Lotus or CoreValve) | 20 | 8 | | Treated with a study valve system but not the assigned randomized study valve system (crossover) | 10 | 0 | | Implanted analysis set | 577 | 297^{b} | | As-treated analysis set (includes crossovers) | 577 | 307 | | Death before 365 days, no 12-month clinical follow-up performed | 70 | 39 | | Eligible for 12-month clinical follow-up^{c} | 537 | 266 | | 12-month clinical follow-up completed^{d} | 92.7% (498/537) | 88.7% (236/266) | | 12-month follow-up completed <335 days^{e} | 2 | 0 | | No 12-month clinical follow-up performed | 39 | 30 | | Premature discontinuation | 18 | 18 | | Withdrew consent | 13 | 14 | | Lost to follow-up | 1 | 1 | | Investigator discretion | 2 | 3 | | Completed study | 1 | 0 | | Other | 1 | 0 | | Missed 12-month follow-up visit | 21 | 12 | | With later follow-up visit performed | 0 | 0 | | No later follow-up visit performed | 21 | 12 | | 12-Month clinical follow-up or death^{f} | 93.6% (568/607) | 90.2% (275/305) | PMA P180029: FDA Summary of Safety and Effectiveness Data Page 24 Table 7: REPRISE III Subject Disposition | Measure | Lotus | Core Valvea | | --- | --- | --- | | Subjects with a VARC event | 364 | 164 | | Subjects with sufficient 12-month follow-up or had a VARC eventg | 96.7% (587/607) | 97.4% (297/305) | | 12-Month transthoracic echocardiography assessment | 482 | 228 | | Data are presented as n or % (count/sample size).Note: In one subject (randomized to the Lotus group) the index procedure was stopped prior to insertion of the delivery system. This subject subsequently underwent the valve implant procedure 361 days after randomization and was implanted with CoreValve Evolut R after an unsuccessful attempt with Lotus. This report does not include outcomes data at 1 year for this subject because the data snapshot was taken before the 1-year follow-up visit had occurred.a: The CoreValve group includes CoreValve and CoreValve Evolut R.b: Includes 153 subjects with CoreValve and 144 subjects with CoreValve Evolut R.c: Subjects who died prior to completion of follow-up window and prior to completing a 12-month clinical follow-up visit are considered ineligible and are excluded from calculation of proportion of subjects who completed the clinical follow-up visit.d: Based on subjects eligible for 12-month clinical follow-up (excludes deaths before 365 days post-procedure).e: Based on subjects without any event.f: Includes subjects who have died in both the numerator and the denominator; based on the intent-to-treat analysis set.g: Sufficient 12-month follow-up is defined as at least 335 days follow-up post randomization; a subject could have more than 1 VARC event.Abbreviation: VARC=Valve Academic Research Consortium | | | ![img-2.jpeg](img-2.jpeg) PMA P180029: FDA Summary of Safety and Effectiveness Data ![img-3.jpeg](img-3.jpeg) Figure 3. REPRISE III Randomized Subject Disposition (Intent-to-Treat) Figure 4. REPRISE III Randomized Subject Analysis Sets # C. Study Population Demographics and Baseline Parameters The demographics of the study population are summarized in Table 8, and are typical for a TAVR study performed in the US. Table 8: Demographics and Baseline Clinical Characteristics | Variable | Lotus (N=607) | CoreValve (N=305) | | --- | --- | --- | | Age at time of consent (years) | 82.8±7.1 (607) | 82.9±7.6 (305) | | Female | 50.1% (304/607) | 52.1% (159/305) | | Overall Risk Assessments | | | | Extreme risk | 23.1% (140/607) | 21.6% (66/305) | | High risk | 76.9% (467/607) | 78.4% (239/305) | | EuroSCORE 2011 (%) | 6.4±5.5 (605) | 6.4±5.5 (304) | | STS Score (%) | 6.7±4.0 (607) | 6.9±4.1 (305) | | STS Score ≥ 8 | 31.0% (188/607) | 29.5% (90/305) | | STS Score < 8 | 69.0% (419/607) | 70.5% (215/305) | | Porcelain aorta | 4.5% (19/419) | 3.3% (7/215) | | Severe pulmonary hypertension | 8.1% (34/419) | 8.4% (18/215) | | Orthopedic disease | 18.6% (78/419) | 12.6% (27/215) | | Neuromuscular disease | 1.4% (6/419) | 2.3% (5/215) | | Prior chest radiation therapy | 4.1% (17/419) | 3.7% (8/215) | | Hostile chest | 4.1% (17/419) | 4.7% (10/215) | | Severe lung disease | 15.3% (64/419) | 14.0% (30/215) | | CABG at risk with re-operation | 16.0% (67/419) | 20.0% (43/215) | | Childs Class A or B liver disease | 1.7% (7/419) | 1.9% (4/215) | PMA P180029: FDA Summary of Safety and Effectiveness Data Table 8: Demographics and Baseline Clinical Characteristics | Variable | Lotus (N=607) | CoreValve (N=305) | | --- | --- | --- | | Frailty | 72.6% (304/419) | 70.7% (152/215) | | Age ≥ 90 years | 10.0% (42/419) | 12.6% (27/215) | | Other | 4.1% (17/419) | 7.0% (15/215) | | General Medical History | | | | Diabetes mellitus (medically treated) | 30.9% (187/606) | 32.6% (99/304) | | History of hyperlipidemia (medically treated) | 74.6% (453/607) | 75.7% (230/304) | | History of hypertension | 91.8% (557/607) | 93.8% (286/305) | | History of peripheral vascular disease | 31.1% (187/602) | 25.7% (78/304) | | History of dialysis dependent renal failure | 0.2% (1/603) | 1.3% (4/305) | | COPD - Supplemental oxygen dependent | 6.5% (39/599) | 6.3% (19/303) | | Cardiac History | | | | History of coronary artery disease | 71.5% (433/606) | 73.4% (224/305) | | History of myocardial infarction | 18.3% (109/597) | 19.0% (58/305) | | History of congestive heart failure | 77.0% (463/601) | 79.8% (241/302) | | History of percutaneous coronary intervention | 33.1% (201/607) | 32.5% (99/305) | | History of CABG | 23.6% (143/606) | 23.3% (71/305) | | History of atrial fibrillation | 35.1% (213/606) | 31.6% (96/304) | | History of atrial flutter | 4.9% (29/594) | 6.7% (20/300) | | Prior pacemaker implant | 17.8% (108/607) | 19.0% (58/305) | | NYHA functional class | | | | Class I | 0.0% (0/607) | 0.0% (0/305) | | Class II | 28.7% (174/607) | 32.1% (98/305) | | Class III | 63.6% (386/607) | 61.0% (186/305) | | Class IV | 7.7% (47/607) | 6.9% (21/305) | | Neurological History | | | | History of transient ischemic attack | 8.3% (50/601) | 7.9% (24/303) | | History of cerebrovascular accident | 11.3% (68/603) | 14.5% (44/304) | | Cognitive and Daily Living Assessments | | | | Mini-cognitive assessment for dementia score | 3.6±1.4 (599) | 3.7±1.4 (304) | | Katz Index Activities of Daily Living score | 5.6±0.9 (605) | 5.6±1.0 (305) | | Strength and Balance Assessments | | | | Use of wheelchair | 5.8% (35/606) | 4.9% (15/305) | | Gait speed average to walk 5 meters (seconds) | 8.7±5.2 (565) | 8.7±4.2 (285) | | Falls in the past 6 months | 0.4±1.1 (604) | 0.5±1.8 (304) | | Maximal grip strength average (kg) | 21.1±10.1 (605) | 20.4±9.7 (303) | PMA P180029: FDA Summary of Safety and Effectiveness Data Table 8: Demographics and Baseline Clinical Characteristics | Variable | Lotus (N=607) | CoreValve (N=305) | | --- | --- | --- | | Echocardiographic Findings | | | | Aortic valve area (cm2) | 0.69±0.19 (541) | 0.70±0.19 (280) | | Mean aortic valve gradient (mmHg) | 44.64±13.35 (575) | 43.85±12.31 (294) | | Doppler velocity index | 0.22±0.05 (553) | 0.23±0.05 (292) | | Values are presented as mean±standard deviation (n) or % (count/sample size) Abbreviations: CABG=coronary artery bypass graft; COPD=chronic obstructive pulmonary disease; NYHA=New York Heart Association; STS=Society of Thoracic Surgeons | | | # D. Safety and Effectiveness Results # 1. Safety Results The primary safety endpoint was the composite of all-cause mortality, stroke, life-threatening and major bleeding events, stage 2 or 3 acute kidney injury, or major vascular complications at 30 days. The primary analysis set for the primary safety endpoint was the implanted analysis set, which includes all patients who signed an informed consent form, were enrolled in the trial, and were implanted with the assigned, randomized study device. The key safety outcomes for this study are presented below in Tables 9-10. Adverse effects are reported in Table 11. Table 9: Non-Inferiority Testing for the Primary Safety Endpoint | Analysis Set | Lotus | CoreValve | Difference [95% CI] | One-sided 97.5% UCB a | Non-Inferiority Margin | One-sided P value b | | --- | --- | --- | --- | --- | --- | --- | | Implanted (N=874) | (N=577) | (N=297) | 3.1% [-2.3%, 8.5%] | 8.32% | 10.5% | 0.0027 | | | 20.3% (117/576) | 17.2% (51/297) | | | | | | Intent-to-Treat (N=912) | (N=607) | (N=305) | 2.8% [-2.4%, 8.0%] | 7.75% | 10.5% | 0.0011 | | | 19.0% (114/601) | 16.2% (49/303) | | | | | | Rates are presented as % (count/sample size) a: Farrington-Manning upper confidence bound b: P value is from the Farrington-Manning test and based on the standard normal distribution Abbreviations: CI=confidence interval; UCB=upper confidence bound | | | | | | | Figure 5 shows that the safety composite of all-cause mortality, stroke, life-threatening and major bleeding events, stage 2 or 3 acute kidney injury, and major vascular complications was not different between the treatment and control groups to 1 year. PMA P180029: FDA Summary of Safety and Effectiveness Data ![img-4.jpeg](img-4.jpeg) Figure 5. Primary Safety Composite to 1-year, Intent-to-Treat Analysis Set Values are presented as cumulative event rate $\pm 1.5$ standard error Table 10 shows that the components of the 30-day primary safety endpoint were similar between the two groups. Table 10: Components of the 30-Day Primary Safety Endpoint, ITT Analysis Set | Outcome | Lotus (N=607) | CoreValve (N=305) | | --- | --- | --- | | All-cause mortality | 2.5% (15/601) | 2.3% (7/303) | | Stroke | 4.8% (29/601) | 4.3% (13/303) | | Disabling | 2.0% (12/601) | 3.3% (10/303) | | Life-threatening or disabling bleeding | 8.0% (48/601) | 5.0% (15/303) | | Major bleeding | 4.8% (29/601) | 5.9% (18/303) | | Major vascular complications | 7.0% (42/601) | 5.3% (16/303) | | Acute kidney injury | 2.5% (15/601) | 3.6% (11/303) | | Values are presented as % (count/sample size) | | | Time-to-event event curves (Kaplan-Meier analysis) to 1 year for all-cause death, all-cause death or disabling stroke, and disabling stroke are shown below for the ITT analysis set. The estimated event rate for all-cause death to 1 year was similar for the 2 cohorts (11.9% for Lotus and 13.7% for CoreValve; Figure 6). The combined outcome of all-cause death or disabling stroke to 1 year was 13.2% for Lotus compared to 17.9% for CoreValve (Figure 7). The estimated rate for disabling stroke to 1 year was 3.6% for Lotus compared to 7.3% for CoreValve (Figure 8). PMA P180029: FDA Summary of Safety and Effectiveness Data Figure 6: Kaplan-Meier Event Curve for All-Cause Death to 1 Year Post-Randomization, ITT Analysis Set ![img-5.jpeg](img-5.jpeg) Values are presented as cumulative event rate $\pm 1.5$ standard error Figure 7: Kaplan-Meier Event Curve for All-Cause Death or Disabling Stroke to 1 Year Post-Randomization, ITT Analysis Set ![img-6.jpeg](img-6.jpeg) Values are presented as cumulative event rate $\pm 1.5$ standard error PMA P180029: FDA Summary of Safety and Effectiveness Data Figure 8: Kaplan-Meier Event Curve for Disabling Stroke to 1 Year Post-Randomization, ITT Analysis Set ![img-7.jpeg](img-7.jpeg) Values are presented as cumulative event rate $\pm 1.5$ standard error # Adverse effects that occurred in the PMA clinical study: Table 11 shows binary rates of CEC-adjudicated, VARC-defined events occurring from randomization to 30 days and 1 year in the ITT analysis set. Table 11: VARC Events Through 30 Days and 1 Year; ITT Analysis Set, Binary Rates | Outcome | 30 Days | | 1 Year | | | --- | --- | --- | --- | --- | | | Lotus (N=607) | CoreValve (N=305) | Lotus (N=607) | CoreValve (N=305) | | All-cause mortality | 2.5% (15/601) | 2.3% (7/303) | 11.9% (70/587) | 13.5% (40/297) | | Cardiovascular | 2.3% (14/601) | 2.3% (7/303) | 7.7% (45/587) | 9.8% (29/297) | | Non-cardiovascular | 0.2% (1/601) | 0.0% (0/303) | 4.3% (25/587) | 3.7% (11/297) | | Stroke | 4.8% (29/601) | 4.3% (13/303) | 7.0% (41/587) | 9.4% (28/297) | | Disabling | 2.0% (12/601) | 3.3% (10/303) | 3.6% (21/587) | 7.1% (21/297) | | Ischemic | 1.8% (11/601) | 3.3% (10/303) | 2.9% (17/587) | 6.4% (19/297) | | Hemorrhagic | 0.2% (1/601) | 0.0% (0/303) | 0.7% (4/587) | 0.3% (1/297) | | Undetermined | 0.0% (0/601) | 0.0% (0/303) | 0.2% (1/587) | 0.3% (1/297) | | Non-disabling | 2.8% (17/601) | 1.0% (3/303) | 3.6% (21/587) | 2.4% (7/297) | | Ischemic | 2.3% (14/601) | 1.0% (3/303) | 3.1% (18/587) | 2.4% (7/297) | | Hemorrhagic | 0.2% (1/601) | 0.0% (0/303) | 0.2% (1/587) | 0.0% (0/297) | | Undetermined | 0.3% (2/601) | 0.0% (0/303) | 0.3% (2/587) | 0.0% (0/297) | | All-cause mortality or disabling stroke | 4.0% (24/601) | 5.3% (16/303) | 13.3% (78/587) | 17.8% (53/297) | | Cardiac death or disabling stroke | 3.8% (23/601) | 5.3% (16/303) | 9.5% (56/587) | 14.8% (44/297) | | Major vascular complications | 7.0% (42/601) | 5.3% (16/303) | 7.7% (45/587) | 6.1% (18/297) | PMA P180029: FDA Summary of Safety and Effectiveness Data Table 11: VARC Events Through 30 Days and 1 Year; ITT Analysis Set, Binary Rates | Outcome | 30 Days | | 1 Year | | | --- | --- | --- | --- | --- | | | Lotus (N=607) | CoreValve (N=305) | Lotus (N=607) | CoreValve (N=305) | | Access site related | 4.7% (28/601) | 3.3% (10/303) | 5.1% (30/587) | 3.7% (11/297) | | Not access site related | 2.5% (15/601) | 2.0% (6/303) | 2.7% (16/587) | 2.4% (7/297) | | New PPM implanteda | 29.1% (175/601) | 15.8% (48/303) | 34.2% (201/587) | 18.5% (55/297) | | No prior PPMa | 35.5% (175/493) | 19.6% (48/245) | 41.4% (201/485) | 23.0% (55/239) | | Bleeding | 12.8% (77/601) | 10.9% (33/303) | 18.1% (106/587) | 17.8% (53/297) | | Life-threatening or disabling | 8.0% (48/601) | 5.0% (15/303) | 9.9% (58/587) | 9.8% (29/297) | | Major | 4.8% (29/601) | 5.9% (18/303) | 8.3% (49/587) | 8.4% (25/297) | | Myocardial infarction | 0.7% (4/601) | 1.3% (4/303) | 3.2% (19/587) | 4.4% (13/297) | | Peri-procedural MI | 0.5% (3/601) | 1.0% (3/303) | 0.5% (3/587) | 1.3% (4/297) | | Spontaneous MI | 0.2% (1/601) | 0.3% (1/303) | 2.7% (16/587) | 3.4% (10/297) | | Acute kidney injury | 2.5% (15/601) | 3.6% (11/303) | 2.6% (15/587) | 3.7% (11/297) | | Stage 2 | 1.0% (6/601) | 1.3% (4/303) | 1.0% (6/587) | 1.3% (4/297) | | Stage 3 | 1.5% (9/601) | 2.3% (7/303) | 1.5% (9/587) | 2.4% (7/297) | | Repeat procedure for valve-related dysfunction | 0.0% (0/601) | 1.0% (3/303) | 0.2% (1/587) | 2.0% (6/297) | | TAVR | 0.0% (0/601) | 0.7% (2/303) | 0.0% (0/587) | 1.7% (5/297) | | Valvuloplasty | 0.0% (0/601) | 0.0% (0/303) | 0.0% (0/587) | 0.0% (0/297) | | SAVR | 0.0% (0/601) | 0.0% (0/303) | 0.2% (1/587) | 0.0% (0/297) | | Other | 0.0% (0/601) | 0.3% (1/303) | 0.0% (0/587) | 0.3% (1/297) | | Hospitalization | 1.7% (10/601) | 3.0% (9/303) | 11.2% (66/587) | 13.8% (41/297) | | New onset atrial fibrillation/flutter | 5.8% (35/601) | 4.3% (13/303) | 6.6% (39/587) | 4.7% (14/297) | | Atrial fibrillation | 5.8% (35/601) | 4.3% (13/303) | 6.6% (39/587) | 4.7% (14/297) | | Atrial flutter | 0.0% (0/601) | 0.0% (0/303) | 0.0% (0/587) | 0.0% (0/297) | | Coronary obstruction | 0.2% (1/601) | 0.3% (1/303) | 0.2% (1/587) | 0.7% (2/297) | | Cardiac tamponade | 2.5% (15/601) | 1.0% (3/303) | 2.6% (15/587) | 1.3% (4/297) | | Prosthetic aortic valve malpositioning | 0.0% (0/601) | 2.6% (8/303) | 0.0% (0/587) | 2.7% (8/297) | | Valve migration | 0.0% (0/601) | 0.7% (2/303) | 0.0% (0/587) | 0.7% (2/297) | | Valve embolization | 0.0% (0/601) | 2.0% (6/303) | 0.0% (0/587) | 2.0% (6/297) | | Ectopic valve deployment | 0.0% (0/601) | 0.3% (1/303) | 0.0% (0/587) | 0.3% (1/297) | | TAV-in-TAV deployment | 0.0% (0/601) | 3.0% (9/303) | 0.0% (0/587) | 3.7% (11/297) | | Prosthetic aortic valve thrombosis | 0.0% (0/601) | 0.0% (0/303) | 1.5% (9/587) | 0.0% (0/297) | | Prosthetic aortic valve endocarditis | 0.2% (1/601) | 0.0% (0/303) | 0.7% (4/587) | 0.0% (0/297) | | Values are presented as % (count/sample size).a: Resulting from new or worsened conduction disturbances; “no prior PPM” indicates subjects without a PPM before the index procedureAbbreviations: CEC=Clinical Events Committee; VARC=Valve Academic Research Consortium; MI=myocardial infarction; PPM=permanent pacemaker; SAVR=surgical aortic valve replacement; TAV=transcatheter aortic valve; TAVR=transcatheter aortic valve replacement | | | | | # 2. Effectiveness Results PMA P180029: FDA Summary of Safety and Effectiveness Data The primary effectiveness endpoint is the composite of all-cause mortality, disabling stroke, and moderate or greater PVR (based on independent core lab assessment) at 1 year. The primary analysis of effectiveness was based on the 874 evaluable patients at the 1-year time point in the implanted analysis set. Key effectiveness outcomes are presented in Table 12 and Figures 9-11. Table 12: Non-Inferiority Testing and Superiority Testing for the Primary Effectiveness Endpoint | Analysis Set | Lotus | CoreValve | Difference [95%CI] | One-sided 97.5% UCBa | Non-Inferiority Margin | P valueb | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | | | | | Non-Inferiority | Superiority | | ITT (N=912) | (N=607) | (N=305) | -10.2% [-16.3%, -4.0%] | -4.54% | 9.5% | <0.0001 | 0.0006 | | | 15.8% (82/520) | 26.0% (68/262) | | | | | | | Implanted (N=874) | (N=577) | (N=297) | -10.1% [-16.2%, -3.9%] | -4.41% | 9.5% | <0.0001 | 0.0007 | | | 15.4% (78/506) | 25.5% (66/259) | | | | | | | Rates are presented as % (count/sample size). a: Farrington-Manning upper confidence bound b: P value is from the Farrington-Manning test and is based on the standard normal distribution for the non-inferiority testing and from the Chi-square test for the superiority testing. Abbreviations: CI=confidence interval; ITT=intent-to-treat; UCB=upper confidence bound | | | | | | | | As shown in Table 12, the Lotus Valve System demonstrated non-inferiority to the control (P<0.0001) and further met superiority in a subsequent analysis in both the ITT and Implanted analysis cohorts. Figure 9 shows that mean aortic gradient improved in both cohorts from baseline to discharge and remained generally constant out to 1 year. Mean effective orifice area (EOA) improved in both cohorts from baseline to discharge and remained above baseline with a slight reduction at 1 year. The Lotus Valve System appears to demonstrate a slightly lower EOA and higher mean gradient compared to CoreValve at each time point. However, this result is anticipated due to the larger size range of CoreValve implants used in the study compared to Lotus implants (23-, 25-, and 27-mm Lotus valves vs. 26-, 29-, and 31-mm CoreValve). Despite these differences, the clinical effectiveness outcomes (as demonstrated in Table 12 and Figures 10-11) are comparable between the Lotus Valve and CoreValve systems. Furthermore, left ventricle mass was the same in both cohorts at 1 year. PMA P180029: FDA Summary of Safety and Effectiveness Data Figure 9: Mean Aortic Gradient and Effective Orifice Area to 1 Year, ITT Analysis Set ![img-8.jpeg](img-8.jpeg) Values are presented as mean $\pm$ standard deviation PVR over time is illustrated in Figure 10. At discharge, $87.4\%$ of evaluable patients in the Lotus cohort had no or trace PVR compared to $47.4\%$ in the CoreValve cohort. At 30 days, $88.1\%$ of evaluable patients in the Lotus group had no or trace PVR compared to $41.3\%$ in the CoreValve group. At 1 year, $87.6\%$ of evaluable patients in the Lotus cohort had no or trace PVR compared to $51.0\%$ in the CoreValve cohort. There was no severe PVR in either cohort at any time. PMA P180029: FDA Summary of Safety and Effectiveness Data Figure 10: PVR over Time, ITT Analysis Set ![img-9.jpeg](img-9.jpeg) (Figure shows results from evaluable echocardiograms that were gradable.) NYHA functional status of patients from baseline to 1 year is shown in Figure 11. While all patients were classified as NYHA Class II, III, or IV at baseline, the majority in both cohorts were Class I or II at 30 days and 1 year. ![img-10.jpeg](img-10.jpeg) Figure 11: NYHA Functional Status over Time, ITT Analysis Set PMA P180029: FDA Summary of Safety and Effectiveness Data Health status was evaluated using the SF-12 Quality of Life questionnaire and Kansas City Cardiomyopathy Questionnaire (KCCQ). ## SF-12 Among assessed patients in the Lotus cohort, the mean SF-12 physical summary score improved from 31.9±9.0 at baseline to 37.0±9.8 at 30 days and remained high at 1 year (36.9±10.6). The mental health summary scores were 49.6±11.6, 52.9±10.9, and 53.6±9.7 at baseline, 30 days, and 1 year, respectively. Similar results were seen in the CoreValve cohort. ## KCCQ Among assessed patients in the Lotus cohort, the overall summary score improved from 51.9±23.5 at baseline to 73.0±21.3 at 30 days and remained high at 1 year (74.9±21.0). The clinical summary score improved from 55.2±23.3 to 73.1±21.4 at 30 days and was 73.1±21.3 at 1 year. Similar results were seen in the CoreValve cohort. ## 3. Secondary Endpoint Results The secondary endpoint was the core-lab determined rate of moderate or greater PVR at 1 year. The primary analysis set for superiority testing of the secondary endpoint was the ITT analysis set. The secondary endpoint was met because in the ITT analysis set the rate of core-lab determined moderate or greater PVR for the Lotus group (0.9%) was superior to the rate for the CoreValve group (6.9%, P < 0.0001). Table 13: Superiority Testing for the Secondary Endpoint | Analysis Set | Lotus | CoreValve | Difference [95%CI] | P value^{a} | | --- | --- | --- | --- | --- | | Intent-to-Treat (N=912) | (N=607) | (N=305) | -6.1% [-9.6%, -2.6%] | <0.0001 | | | 0.9% (4/452) | 6.9% (15/216) | | | | Implanted (N=874) | (N=577) | (N=297) | -6.0% [-9.5%, -2.5%] | <0.0001 | | | 0.9% (4/443) | 6.9% (15/216) | | | | Rates are presented as % (count/sample size). a: P value is from the Chi-square test for the superiority testing. | | | | | ## 4. Other Results Table 14 below shows the procedural characteristics for Lotus implant procedures compared to CoreValve procedures. | Measure | Lotus (N=607) | CoreValve (N=305) | | --- | --- | --- | | Time from randomization to procedure (days) | 13.0 ± 17.7 (596) | 13.0 ± 12.6 (301) | PMA P180029: FDA Summary of Safety and Effectiveness Data | Total procedure time (min) | 86.8 ± 41.8 (596) | 76.7 ± 40.6 (299) | | --- | --- | --- | | Total time with study introducer (min) | 50.4 ± 24.1 (595) | 44.9 ± 36.9 (297) | | Total time with study valve delivery system (min) | 23.8 ± 17.6 (595) | 15.0 ± 17.0 (298) | | Total fluoroscopy time (min) | 27.1 ± 10.8 (595) | 22.2 ± 12.2 (299) | | Total contrast used for procedure (cc) | 110.6 ± 62.3 (593) | 120.9 ± 64.6 (299) | | Post-dilatation | 1.5% (9/596) | 31.2% (94/301) | | TEE used during implant procedure | 59.2% (353/596) | 55.7% (167/300) | | Successful vascular access, delivery and deployment of the study valve system, and successful retrieval of the delivery system | 97.8% (583/596) | 99.0% (297/300) | | Conversion to open heart surgery | 0.7% (4/596) | 0.7% (2/300) | | Unplanned use of cardiopulmonary bypass | 0.7% (4/596) | 1.0% (3/300) | | Values are presented as mean ± standard deviation (n) or % (count/sample size) Abbreviation: TEE = Transesophageal Echocardiography | | | # 5. Subgroup Analyses Mortality and stroke rates were also evaluated based on gender. A total of 449 male patients $(49.2\%)$ were enrolled in the ITT analysis set; 303 were randomized to Lotus and 146 were randomized to CoreValve. There were 463 female patients $(50.8\%)$ in the ITT analysis set; 304 were in the Lotus arm and 159 were in the CoreValve arm. Table 15 shows mortality and stroke rates in male and female patients at 1 year. The outcomes suggest that the rates of mortality and stroke are similar between male and female patients; however, the study is not powered to drawn conclusions from this analysis. Table 15: Mortality and Stroke to 1 Year by Gender; ITT Analysis Set | Outcome | Male Patients | | Female Patients | | | --- | --- | --- | --- | --- | | | Lotus (N=303) | CoreValve (N=146) | Lotus (N=304) | CoreValve (N=159) | | All-cause mortality | 11.5% (34/295) | 14.8% (21/142) | 12.3% (36/292) | 12.3% (19/155) | | Cardiovascular | 8.1% (24/295) | 12.0% (17/142) | 7.2% (21/292) | 7.7% (12/155) | | Non-cardiovascular | 3.4% (10/295) | 2.8% (4/142) | 5.1% (15/292) | 4.5% (7/155) | | Stroke | 6.1% (18/295) | 9.2% (13/142) | 7.9% (23/292) | 9.7% (15/155) | | Disabling | 2.7% (8/295) | 7.7% (11/142) | 4.5% (13/292) | 6.5% (10/155) | | Non-disabling | 3.4% (10/295) | 1.4% (2/142) | 3.8% (11/292) | 3.2% (5/155) | | All-cause mortality or disabling stroke | 12.9% (38/295) | 18.3% (26/142) | 13.7% (40/292) | 17.4% (27/155) | | Values are % (count/sample size) | | | | | # 6. Pediatric Extrapolation In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population. # E. Financial Disclosure PMA P180029: FDA Summary of Safety and Effectiveness Data 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 550 investigators of which none were full-time or part-time employees of the sponsor and 5 had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f) and described below: - Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0 - Significant payment of other sorts: 4 - Proprietary interest in the product tested held by the investigator: 0 - Significant equity interest held by investigator in sponsor of covered study: 2 The applicant has adequately disclosed the financial interest/arrangements with clinical investigators. Statistical analyses were conducted by FDA to determine whether the financial interests/arrangements had any impact on the clinical study outcome. The information provided does not raise any questions about the reliability of the data. ## XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION ### REPRISE NG DS (Cohort C) and REPRISE Edge Studies The LOTUS Edge Valve System is a design iteration of the Lotus™ Valve System which was modified to improve flexibility and deliverability, to reduce the profile of the delivery system, and to minimize how…

LOTUS Edge Valve System

Device Facts

Indications for Use

Device Story

Clinical Evidence

Technological Characteristics

Indications for Use

Regulatory Classification

Identification

Reference Devices

Submission Summary (Full Text)

Panel 1

Section Matches

Product Code Matches

Special Control Matches

My Alerts

LOTUS Edge Valve System

Device Facts

Indications for Use

Device Story

Clinical Evidence

Technological Characteristics

Indications for Use

Regulatory Classification

Identification

Reference Devices

Submission Summary (Full Text)

Panel 1

Section Matches

Product Code Matches

Special Control Matches

My Alerts

Create Alert

Search Filters

Agent Token

Welcome

Check your email

Welcome!