Portico Transcatheter Aortic Valve Implantation System

P190023 · ABBOTT MEDICAL · NPT · Sep 17, 2021 · Cardiovascular

Device Facts

• Record ID: P190023
• Device Name: Portico Transcatheter Aortic Valve Implantation System
• Applicant: ABBOTT MEDICAL
• Product Code: NPT · Cardiovascular
• Decision Date: Sep 17, 2021
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The Portico Transcatheter Aortic Valve Implantation System is indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis 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 Portico System is a transcatheter aortic valve implantation (TAVI) device used to treat severe native calcific aortic stenosis without open-heart surgery. The system comprises a self-expanding nitinol stent with bovine pericardial leaflets and a porcine pericardial cuff, a FlexNav delivery system, and a loading system. The device is delivered percutaneously (transfemoral, subclavian/axillary, or transaortic) by a heart team including a cardiac surgeon. The delivery system allows for controlled valve deployment and re-sheathing/repositioning up to two times before full release. The valve functions by replacing the failed native valve, improving hemodynamic performance and reducing symptoms of heart failure. Clinical benefits include improved valve area, lower pressure gradients, and enhanced quality of life. The device is intended for patients at high or greater surgical risk.

Clinical Evidence

Evidence based on the PORTICO RCT (n=750, randomized 1:1) and supplemental FlexNav cohorts (n=100 and n=193). RCT primary safety endpoint (30-day composite) met non-inferiority (13.8% vs 9.6%, upper CI 8.1% < 8.5% margin). Primary effectiveness endpoint (1-year composite) met non-inferiority (14.9% vs 13.4%, upper CI 5.7% < 8.0% margin). Supplemental cohorts demonstrated improved major vascular complication rates (5.7-7.0%) compared to RCT Portico group (9.6%) and reduced paravalvular regurgitation. CT sub-study assessed leaflet mobility; no significant impact on mortality or neurological outcomes observed.

Technological Characteristics

Valve: Nitinol stent, bovine pericardial leaflets, porcine pericardial cuff. Cuff/leaflets preserved in glutaraldehyde and treated with Linx™ anticalcification technology. Sizes: 23, 25, 27, 29 mm. Delivery System: Over-the-wire, 0.035" compatible, integrated sheath (14F-15F). Sterilization: Multi-component liquid sterilant (ethanol, glutaraldehyde, formaldehyde) for valve; Ethylene Oxide (EtO) for delivery/loading systems. Connectivity: None.

Indications for Use

Indicated for patients ≥ 21 years with symptomatic severe native calcific aortic stenosis (mean gradient >40 mmHg, jet velocity >4.0 m/s, or AVA ≤1.0 cm²) at high or greater surgical risk (STS ≥8%). Contraindicated for patients unable to tolerate antiplatelet/anticoagulant therapy, with nitinol alloy hypersensitivity, or active infections including endocarditis.

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

• SAPIEN
• SAPIEN XT
• SAPIEN 3
• CoreValve
• CoreValve Evolut R
• CoreValve Evolut PRO

Submission Summary (Full Text)

{0}

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Aortic valve, prosthesis, percutaneously delivered

Device Trade Name: Portico™ Transcatheter Aortic Valve Implantation System: Portico™ Transcatheter Aortic Heart Valve, FlexNav™ Delivery System, FlexNav™ Loading System

Device Product Code: NPT

Applicant Name and Address: Abbott One St. Jude Medical Drive St. Paul, MN 55117

Date of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P190023

Date of FDA Notice of Approval: September 17, 2021

II. INDICATIONS FOR USE

The Portico Transcatheter Aortic Valve Implantation System is indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis 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 $\geq 8\%$ 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 valve is contraindicated for patients with inability to tolerate antiplatelet/ anticoagulant therapy, nitinol alloy (nickel and titanium), or who have active infections, including endocarditis.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Portico Transcatheter Aortic Valve Implantation System labeling.

{1}

# V. DEVICE DESCRIPTION

The Portico Transcatheter Aortic Valve Implantation System (Portico System) is designed to be implanted in the native aortic heart valve without open heart surgery and without concomitant surgical removal of the failed native valve. The Portico System consists of 3 components: (1) Portico Transcatheter Aortic Heart Valve (Portico valve), (2) FlexNav Delivery System (DS), and (3) FlexNav Loading System (LS). Refer to Table 1 for a list of model numbers for these components and their compatibility between the devices.

| Table 1: Portico System Model Numbers and Device Compatibility | | |
| --- | --- | --- |
| Portico Valve | FlexNav DS | FlexNav LS |
| PRT-23 | FNAV-DS-SM | FNAV-LS-SM |
| PRT-25 | | |
| PRT-27 | FNAV-DS-LG | FNAV-LS-LG |
| PRT-29 | | |

# A. Portico Valve

The Portico valve (Figure 1) is comprised of three main components: stent, cuff, and leaflets. The stent is made from nitinol, a nickel-titanium alloy that has self-expanding properties and is radiopaque. The cuff is made from porcine pericardium that is sutured to the stent frame. The cuff provides the sealing area for implantation. The leaflets are made from bovine pericardium and are sutured together into a tri-leaflet configuration on the stent frame.

The cuff and leaflet pericardial tissue is preserved and crosslinked in glutaraldehyde. Glutaraldehyde, formaldehyde and ethanol are used in the valve sterilization process. The valve's leaflets and cuff are processed using $\mathrm{Linx}^{\mathrm{TM}}$ anticalcification technology. The valve is supplied sterile and non-pyrogenic.

Figure 1: Portico Transcatheter Aortic Valve

The Portico valve is available in four different sizes (23 mm, 25 mm, 27 mm, and 29 mm) that are intended to treat patients with a native annulus size ranging from 19 - 27

{2}

mm, respectively. Refer to Table 2, for a detailed list of available sizes that are intended to treat patients with the anatomical measurements indicated below.

| Table 2: Patient Anatomical Measurements | | | | |
| --- | --- | --- | --- | --- |
| Portico valve Size | Model Number | Annulus Size Treated | Ascending Aorta Diameter | Minimum Vascular Access Diameter |
| 23 mm | PRT-23 | 19-21 mm | 26-36 mm | ≥ 5.0 mm |
| 25 mm | PRT-25 | 21-23 mm | 28-38 mm | ≥ 5.0 mm |
| 27 mm | PRT-27 | 23-25 mm | 30-40 mm | ≥ 5.5 mm |
| 29 mm | PRT-29 | 25-27 mm | 32-42 mm | ≥ 5.5 mm |

# B. FlexNav Delivery System

The FlexNav Delivery System (DS) (Figure 2) consists of a handle, integrated sheath, stability layer, and outer/inner member. It facilitates Portico valve implantation using transfemoral, subclavian/axillary, or transaortic access methods. The FlexNav DS is an over-the-wire, $0.035''$ compatible system designed to facilitate gradual, controlled deployment of the Portico valve. The valve is deployed annulus end first from the distal end of the delivery system. If needed, the valve may be re-sheathed and repositioned up to two times, provided the valve has not been fully deployed.

Figure 2: FlexNav Delivery System

Table 3 lists FlexNav DS model numbers, specifications, and compatibility requirements.

{3}

Table 3: FlexNav Delivery System Specifications

| Delivery System Model Number | Equivalent Integrated Sheath Diameter | Valve Capsule Outer Diameter | Integrated Sheath Working Length | Delivery System Working Length | Minimum Vessel Diameter Requirement | Compatible Guidewire |
| --- | --- | --- | --- | --- | --- | --- |
| FNAV-DS-SM | 14F | 6.0mm | 30 cm | 107 cm | ≥ 5.0 mm | 0.035” (0.89mm) |
| FNAV-DS-LG | 15F | 6.3mm | 30 cm | 107 cm | ≥ 5.5 mm | 0.035” (0.89mm) |

# C. FlexNav Loading System

The FlexNav Loading System (LS) (Figure 3) is an accessory used to facilitate valve preparation/loading onto the FlexNav DS. The LS includes a loading funnel, loading base, base insert, loading tube, and a leaflet tester.

Figure 3: FlexNav Loading System

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for patients with severe symptomatic native aortic valve stenosis who are deemed to be high or greater risk for surgical aortic valve replacement, including treatment with other commercially available transcatheter aortic valve implantation (TAVI) devices, surgical aortic valve replacement (SAVR), temporary relief using a percutaneous technique called balloon aortic valvuloplasty (BAV), or medical therapy (no obstruction-relieving intervention). Each alternative has its own advantages and disadvantages. Patients should fully discuss these alternatives with their physician to select the best method that best meets expectations and lifestyle.

{4}

# VII. MARKETING HISTORY

The Portico System is marketed in the following countries/geographies (Table 4).

| Table 4: Countries/Geographies where the Portico System is Marketed | | |
| --- | --- | --- |
| Argentina | Hong Kong | Philippines |
| Algeria | Israel | Russia |
| Australia | Jordan | Saudi Arabia |
| Belarus | Kuwait | Singapore |
| Bolivia | Lebanon | South Korea |
| Brazil | Malaysia | Taiwan |
| Chile | Mexico | Thailand |
| Colombia | Macedonia | Tunisia |
| Costa Rica | Morocco | Turkey |
| Ecuador | New Zealand | UAE |
| Egypt | Paraguay | Ukraine |
| Europe | Peru | Vietnam |

The Portico System has not been withdrawn from any market.

# 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:

- access site complications (e.g., pain, bleeding, infection, hematoma, pseudoaneurysm, etc.)
- acute coronary obstruction
- acute myocardial infarction
- allergic reaction to antiplatelet agents, contrast medium, or valve components
- aortic rupture
- ascending aorta trauma
- atrio-ventricular node block
- cardiac arrhythmias
- conduction system injury
- dissection
- embolism
- endocarditis
- heart failure
- hemodynamic compromise
- hemolysis
- hemolytic anemia
- hemorrhage
- hypotension or hypertension
- infection
- myocardial ischemia
- mitral valve insufficiency
- multi-organ failure
- non-structural dysfunction (i.e., entrapment by pannus, paravalvular leak, inappropriate sizing or positioning)
- pericardial effusion
- perforation of the myocardium, ventricle or a blood vessel

{5}

pannus
- regurgitation
- renal insufficiency or renal failure
- respiratory failure
sepsis
stroke
structural deterioration (i.e., calcification, leaflet tear)
thrombosis
- tamponade
- valve embolization or migration
- vessel dissection or spasm
- transfusion
- conversion to open surgical procedure
reoperation
emergent balloon valvuloplasty
emergent percutaneous coronary intervention (PCI)
emergent surgery (i.e., coronary artery bypass, heart valve replacement)
explantation
permanent disability
death
permanent pacemaker implantation

For the specific adverse events that occurred in the clinical studies, please see Sections X and XI below.

# IX. SUMMARY OF PRECLINICAL STUDIES

# A. Laboratory Testing

A series of non-clinical laboratory studies were performed on the Portico System as recommended per ISO 5840, Cardiovascular implants – Cardiac valve prostheses: part 1-General requirements (2015), and part 3- Heart valve substitutes implanted by Transcatheter techniques (2013) along with relevant FDA Guidance Documents.

# 1. Biocompatibility

Biocompatibility and Toxicology evaluations were completed on the device components that makeup the Portico System in accordance with ISO 10993-1: Biological Evaluation of Medical Devices Part 1: Evaluation and Testing. A summary of the tests and results conducted on the Portico Valve, FlexNav DS, and FlexNav LS are provided in Table 5 – Table 7 respectively. Test samples for the studies consisted of all patient-contacting portions of the device (direct and indirect) after all manufacturing processes, including sterilant exposure. All results were acceptable.

| Table 5: Summary of the Portico Valve Biocompatibility Testing/Results | | |
| --- | --- | --- |
| Biological Test | Test Method | Result |
| Cytotoxicity | MEM elution assay on L-929 mouse fibroblast cells; ISO 10993-5 | Pass Non-cytotoxic |

{6}

| Table 5: Summary of the Portico Valve Biocompatibility Testing/Results | | |
| --- | --- | --- |
| Biological Test | Test Method | Result |
| Sensitization | ISO Guinea Pig Maximization Method; ISO 10993-10 | Pass Non-sensitizing |
| Intracutaneous Reactivity (Rabbit) | ISO Intra-cutaneous Reactivity Test; ISO 10993-10 | Pass Non-irritant |
| Acute Systemic Toxicity – (Mouse) | ISO Acute Systematic Injection Test; ISO 10993-11 | Pass Non-toxic |
| Pyrogenicity | Materials Mediated Rabbit Pyrogen Test; ISO 10993-11 | Pass Non-pyrogenic |
| Genotoxicity - AMES | Bacterial Mutagenicity (Ames); ISO 10993-3 | Pass Non-Mutagenic |
| Genotoxicity – Mouse Lymphoma | In vitro mouse Lymphoma Assay; ISO 10993-3 | Pass Non-Mutagenic |
| Hemocompatibility | | |
| Hemolysis | ASTM Direct Contact; ISO 10993-4 | Pass Non-hemolytic |
| | ASTM Extract Method; ISO 10993-4 | |
| Partial Thromboplastin Time (PTT) | In vitro Hemocompatibility; ISO 10993-4 | Pass Non-coagulant |
| Leukocyte and Platelet | In vitro Hemocompatibility; ISO 10993-4 | Pass Hemocompatible |
| Complement Activation | C3a and SC5b-9 Assay; ISO 10993-4 | Pass Non-activator |
| Chemical Characterization | | |
| GC/MS Direct Inject | Gas Chromatography and Mass Spectrometry; ISO 10993-18 | Acceptable based on toxicological risk assessment of identified leachable/extractable compounds |
| LC/MS | Liquid Chromatography-Mass Spectrometry; ISO 10993-18 | Acceptable based on toxicological risk assessment of identified leachable/extractable compounds |
| ICP | Inductively Coupled Plasma; ISO 10993-18 | Acceptable based on toxicological risk assessment of identified leachable/extractable compounds |
| FTIR | Fourier Transform Infrared Spectroscopy; ISO 10993-18 | Confirmed Polymer identification |
| NVR | Non-volatile residual test; ISO 10993-18 | Pass |

{7}

| Table 6: Summary of the FlexNav Delivery System Biocompatibility Testing/Results | | |
| --- | --- | --- |
| Biological Test | Test Method | Result |
| Cytotoxicity | MEM elution assay on L-929 mouse fibroblast cells; ISO 10993-5 | Pass
Non-cytotoxic |
| Sensitization | ISO Guinea Pig Maximization; ISO 10993-10 | Pass
Non-sensitizing |
| Irritation – Rabbit Intracutaneous Reactivity | ISO Intra-cutaneous Reactivity Test; ISO 10993-10 | Pass
Non-irritant |
| Acute Systemic Toxicity – (Mouse) | ISO Acute Systematic Injection Test; ISO 10993-11 | Pass
Non-toxic |
| Pyrogenicity | Materials Mediated Rabbit Pyrogen; ISO 10993-11 | Pass
Non-pyrogenic |
| Hemocompatibility | | |
| Hemolysis | ASTM Direct Contact; ISO 10993-4 | Pass
Non-hemolytic |
| | ASTM Extract Method ASTM Direct Contact; ISO 10993-4 | |
| Partial Thromboplastin Time (PTT) | In vitro Hemocompatibility; ISO 10993-4 | Pass
Non-coagulant |
| Leukocyte and Platelet | In vitro Hemocompatibility; ISO 10993-4 | Pass
Hemocompatible |
| Thrombogenicity | In vivo swine model; ISO 10993-4 | Pass
Non-thrombogenic |
| Complement Activation | C3a and SC5b-9 Assay; ISO 10993-4 | Pass
Non-activator |
| Chemical Characterization | | |
| GC/MS Static and Dynamic headspace | Gas Chromatography and Mass Spectrometry; ISO 10993-18 | Pass
No leachable/extractable of toxicological concern |
| ICP | Inductively Coupled Plasma; ISO 10993-18 | Pass
Acceptable based on toxicological risk assessment of identified leachable/extractable compounds |
| FTIR | Fourier Transform Infrared Spectroscopy; ISO 10993-18 | Confirmed Polymer identification |
| NVR | Non-volatile residual test; ISO 10993-18 | Pass |

{8}

| Table 7: Summary of the FlexNav™ Loading System Biocompatibility Testing/Results | | |
| --- | --- | --- |
| Biological Test | Test Method | Result |
| Cytotoxicity | Agarose Overlay method using mouse fibroblast cells (L-929); ISO 10993-5 | Pass Non-cytotoxic |
| Heavy Metals | General polymers section of USP <661> physicochemical tests for plastics was followed. ISO 10993-18 | Pass |
| FTIR | Fourier Transform Infrared Spectroscopy; ISO 10993-18 | Confirmed Polymer identification |
| NVR | Non-volatile residual test; ISO 10993-18 | Pass Acceptable levels of residuals |

# 2. Bench Testing

Comprehensive preclinical bench testing and computational analysis was performed on the Portico System (i.e., Portico valve, FlexNav DS and FlexNav LS). All testing was conducted in accordance with national and international product standards (i.e., FDA guidance documents and ISO 5840-1, ISO 5840-3, and ISO 10555-1). Testing verified that all components of the Portico System were within design specifications and met its specified design performance requirements. The tests are summarized in Table 8 and Table 9.

| Table 8: Summary of Portico Valve In-Vitro Testing/Results | | | |
| --- | --- | --- | --- |
| Test | Attribute | Test Description | Results |
| Valve Testing: Hydrodynamic Assessment | | | |
| Hydrodynamic Assessment | Pressure Drop | To determine the hydrodynamic performance of the Portico valve in terms of Pd, EOA, Regurgitation under normal cardiac conditions. | Pass |
| | EOA | | |
| | Regurgitation | | |
| Variable Cardiac Conditions | Pressure Drop | To determine the hydrodynamic performance of the Portico valve in terms of Pd, EOA, Regurgitation under variable cardiac conditions. | Pass |
| | EOA | | |
| | Regurgitation | | |
| Steady Forward Flow | Pressure Drop | To determine the pressure drop at various steady forward flow rates. | Pass |
| Steady Backflow Leakage | Leakage | To determine the leakage rates at various steady forward flow rates. | |
| Bernoulli Relationship | Pressure drop measurement | To determine whether the Bernoulli relationship applies to clinical pressure drop measurements | Pass |
| | Doppler Velocity Measurement | | |
| Flow Visualization & Particular Image Velocimetry | Flow Characterization | To qualitatively investigate flow characteristics near the valve | Pass |
| Valve Testing: Migration | | | |

{9}

| Table 8: Summary of Portico Valve In-Vitro Testing/Results | | | |
| --- | --- | --- | --- |
| Test | Attribute | Test Description | Results |
| Chronic Outward Radial Force (COR) and Migration | Annulus & Aortic Chronic outward radial force | To determine the Portico stent is manufactured with acceptable COR to ensure migration resistance | Pass |
| Migration Resistance & Cadaver Calcified Annulus Pullout | Valve Migration Resistance | Verify the COR of the Portico valve is appropriate to assure valve migration resistance when exposed to simulated in-vitro conditions. | Pass |
| Valve: Post Dilatation Testing | | | |
| Balloon Valvuloplasty Post Dilatation | Pressure drop | Ensure post dilatation does not impact leaflet durability and functionality. | Pass |
| | EOA | | |
| | Regurgitation | | |
| | Functional | | |
| Valve Testing: Structural Performance | | | |
| Accelerated Wear Testing | Pressure drop | To assess long-term valve performance, 200 million cycles, through accelerated wear testing. | Pass |
| | EOA | | |
| | Regurgitation | | |
| | Functional | | |
| Dynamic Failure Mode Analysis | Pressure Drop | To obtain information about the failure mode affecting the durability of the valve. | Pass |
| | EOA | | |
| | Regurgitation | | |
| | Visual | | |
| Leaflet, Cuff, and stent Finite Element Analysis (FEA) | In Plane principle stress | FEA was used to characterize the structural behavior of the components of the Portico valve using computer analytics when subjected to anticipated in vivo operational conditions | Pass |
| Stent Testing | | | |
| Stent Fatigue Resistance | Freedom from fracture | Demonstrate the Portico stent has fatigue resistance to 600 million cycles. | Pass |
| Stent Corrosion | Nickel Leaching | Evaluate the corrosion resistance of the Portico stent in accordance with ASTM F2129 and ISO 16429. | Pass |
| | Corrosion Assessment | | |
| | Surface assessment | | |
| Stent length and Foreshortening | Valve Maximum Length | To evaluate the relationship of the Portico stent length and diameter when crimped and deployed. | Pass |
| | Stent Foreshortening | | |
| Magnetic Resonance Imaging | Displacement and Torque | To characterize the performance of the Portico valve in an MR field and determine the compatibility. | Pass |
| | 1.5T RF Heating | | |
| | 3.0T RF Heating | | |
| | MR Artifacts | | |
| | Visual | | |

{10}

| Table 9: Summary of FlexNav DS and FlexNav LS In Vitro Testing/Results | | |
| --- | --- | --- |
| Test | Purpose/Objective | Results |
| Delivery System Size Profile (Visual and Dimensional verification) | Verification that the manufacturing processes produce finish devices meeting design requirements for dimensions and the DS surface is free from defects. | Pass |
| Bond Strength | Verification that the bonds and tubing of the DS meet the strength specification when subjected to tensile testing. | Pass |
| Delivery System Kink Resistance | This test verifies the DS is resistant to kinks when subjected anatomical curvature expected in a clinical scenario. | Pass |
| Load and Re-sheath Forces | This test verifies when the Portico valve is loaded or re-sheathed into the FlexNav™ DS it meets the product force requirements. | Pass |
| Handle Function | Verification that the DS handle components (deployment lock button, deployment re-sheath wheel, macro slide release button and micro adjustment wheel) function as intended. | Pass |
| Radiopaque Feature and Delivery System Visibility | Verification that the DS and radiopaque features (tip and inner member marker band) are visible under fluoroscopy. | Pass |
| Deployment Accuracy | Verification that the DS can consistently deploy the Portico valve accurately. | Pass |
| Guidewire Compatibility | Verification that the DS is compatible to pass a 0.035” guidewire. | Pass |
| Hydrophilic effectiveness/Integrity | Verification that the integrity and effectiveness of the hydrophilic coating on the DS is maintained. | Pass |

# 3. Sterilization

The Portico valve is sterilized using a multi-component liquid sterilant (MCS), a mixture of ethanol, glutaraldehyde, and formaldehyde. Following sterilization, the valves are aseptically transferred from the sterilization container to the final jar. The validated aseptic transfer MCS sterilization process has demonstrated a Sterility Assurance Levels (SAL) of $10^{-6}$ , following ISO 14160 requirements.

The FlexNav DS and LS are sterilized via Ethylene Oxide (EtO) in accordance with ISO 11135 - Sterilization of health-care products - Ethylene oxide - Requirements for the development, validation and routine control of a sterilization process for medical devices. The validated EtO sterilization process has demonstrated Sterility Assurance Levels (SAL) of $10^{-6}$ .

{11}

# 4. Packaging and Shelf Life

The device components which make up the Portico System are all packaged separately. The Portico valve is stored in a jar filled with sterile $0.5\%$ formaldehyde storage solution which is tightly sealed with an integrated gasket lid to form the primary sterile barrier. The jar is contained within the inner packaging assembly which is contained within a shelf carton to complete the protective packaging system for the Portico valve. Non-clinical testing on Portico valves that were real time aged for three years following sterilization demonstrated the packaging integrity and valve performance are maintained following ISO 11607 (as applicable). Therefore, shelf life has been established at 3 years for the Portico valve.

The FlexNav DS is placed in a retainer tray to hold the DS in place. The retainer tray is covered with a formed cover lid and placed inside a pouch. The pouch is sealed to form the primary sterile barrier and is then placed in a shelf carton. The FlexNav LS is placed into a tray that is sealed with a Tyvek lid. Non-clinical testing of FlexNav DS/LS and related packaging, conducted on test articles accelerated aged for two years following sterilization, demonstrated that the FlexNav DS and LS performance and packaging integrity, in accordance with ISO 11607, are maintained. Therefore, shelf life has been established at 2 years for the FlexNav DS and LS.

# B. Animal Studies

Four animal studies were performed in support of the safety and performance of the Portico System (i.e., Portico valve, FlexNav DS, and FlexNav LS) and according to ISO 5840 parts 1 &amp; 3 product standard. One of the four studies was conducted to specifically evaluate the chronic in vivo safety and performance of the Portico valve in a domestic sheep model. The other three studies were conducted to evaluate the performance of FlexNav DS and the deployment/in vivo performance of the Portico valve using an acute in vivo porcine model. These studies are summarized in Table 10.

| Table 10: Portico Valve and FlexNav DS and LS Overview of Acute and Chronic Animal Studies | | | | |
| --- | --- | --- | --- | --- |
| Study Information | Chronic GLP Animal-Portico Valve Study | Acute GLP Animal - FlexNav DS Study | Acute GLP Animal - Subclavian Access Study | Acute non-GLP Animal - Transaortic Access Study |
| Device Evaluated | Portico valve | FlexNav DS (Small and Large Sizes) and Portico valve | Portico 18F DS and Portico valve | Portico 18F DS and Portico valve |
| Animal Model | Domestic Sheep | Domestic swine | Domestic swine | Domestic swine |

{12}

| Table 10: Portico Valve and FlexNav DS and LS Overview of Acute and Chronic Animal Studies | | | | |
| --- | --- | --- | --- | --- |
| Study Information | Chronic GLP Animal-Portico Valve Study | Acute GLP Animal - FlexNav DS Study | Acute GLP Animal - Subclavian Access Study | Acute non-GLP Animal - Transaortic Access Study |
| Methods | Implant the Portico valve (N=8) and control valves (N=3, commercially available surgical valves) into the native aortic valve in a domestic sheep model. An aortic band was placed around the aorta to simulate aortic stenosis. | Delivery performance of the FlexNav DS (N=6) was conducted using the transfemoral approach in a domestic swine model. | Delivery performance of the Portico DS (18F, N=7; 19F, N=6) was conducted using subclavian access in a domestic swine model. | Delivery performance of the Portico DS (N=2) was conducted using trans-aortic access in a domestic swine model. |
| Duration | Chronic 140 days | Acute (<24 hours) | Acute (<24 hours) | Acute (<24 hours) |
| Objective | • Evaluate the chronic in-vivo safety of the TAVI device with respect to the following items: o hemodynamic performance, o biostability, o calcification, o morbidity/ mortality, o valve migration, o pathological analysis. | • Evaluate the acute in-vivo safety of the FlexNav DS and Portico valve in terms of the following: o DS performance and valve deployment o In-vivo hemodynamic performance of the Portico valve o Pathological analysis | • Evaluate the acute in-vivo safety of the Portico DS deploying the Portico valve by subclavian access by the following endpoints: o DS performance and valve deployment o In-vivo hemodynamic performance of the Portico valve o Pathological analysis | • Evaluate the acute in-vivo safety of the Portico DS deploying the Portico valve by transaortic access by the following endpoints: o DS performance and valve deployment o In-vivo hemodynamic performance of the Portico valve o Pathological analysis. |

{13}

| Table 10: Portico Valve and FlexNav DS and LS Overview of Acute and Chronic Animal Studies | | | | |
| --- | --- | --- | --- | --- |
| Study Information | Chronic GLP Animal-Portico Valve Study | Acute GLP Animal - FlexNav DS Study | Acute GLP Animal - Subclavian Access Study | Acute non-GLP Animal - Transaortic Access Study |
| Results | The chronic animal study demonstrated the Portico valve performed as expected by meeting all study endpoints listed below: • The Portico valve demonstrated acceptable hemodynamic performance and migration resistance when compared to the control valve. • There were no significant variances between the Portico valve and control group with regards to clinical pathology parameters. • The overall morphologic findings of this study demonstrated a satisfactory tissue healing response and acceptable biocompatibility of the Portico valve. | The acute animal study demonstrated the FlexNav DS performed as expected by meeting all study endpoints listed below: • successfully deploying the Portico valve in all six animals • Acceptable device trackability, handling and functional performance of the DS, • Acceptable hemodynamic performance of the Portico valve, • Acceptable target organ pathology and no device related thrombus. | The acute animal study demonstrated the Portico DS performed as expected by meeting all study endpoints listed below: • successfully deploying the Portico valve in all animals • Acceptable device trackability, handling and functional performance of the DS, • Acceptable hemodynamic performance of the Portico valve, • Acceptable target organ pathology and no device related thrombus. | The acute animal study demonstrated the Portico DS performed as expected by meeting all study endpoints listed below: • successfully deploying the Portico valve in all animals • Acceptable device trackability, handling and functional performance of the DS, • Acceptable hemodynamic performance of the Portico valve, • Acceptable target organ pathology and no device related thrombus. |
| Conclusion | The Portico valve demonstrated acceptable hemodynamic performance with satisfactory healing response. The Portico valve was determined to be safe for clinical use. | The FlexNav DS demonstrated the delivery systems provides safe and effective deployment of the Portico valve within the aortic annulus and was determined to be safe for clinical use. | This acute study met the study endpoints and supports safe use of the Portico DS to deploy a valve using the subclavian access site. | This acute study met the study endpoints and supports safe use of the Portico DS to deploy a valve using the transaortic access site. |

{14}

# X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant performed a clinical study, the PORTICO randomized controlled trial (RCT), to establish a reasonable assurance of safety and effectiveness of transcatheter aortic valve implantation with the Portico Transcatheter Aortic Valve Implantation System in patients with symptomatic severe native aortic stenosis who are considered high or greater surgical risk in the United States and Australia under IDE # G120263.

The FlexNav Delivery System represents a design modification to the first-generation Portico Delivery System to improve the ease of use, reduce the occurrence of major vascular complications, and improve procedural safety outcomes observed in the RCT. The FlexNav Delivery System was evaluated in a non-randomized FlexNav DS Study arm added to the PORTICO study following completion of enrollment in the RCT cohort. The PORTICO FlexNav DS Study and a parallel study being conducted outside the U.S. (OUS) under a similar protocol, called the FlexNav EU CE Mark Study (NCT03724812), were combined to make two cohorts to supplement PORTICO RCT for the PMA approval decision: FlexNav PMA Analysis Cohort and FlexNav Global Cohort.

The FlexNav PMA Analysis Cohort was a prospective study group consisting of a subset of subjects from the PORTICO FlexNav DS Study and the FlexNav EU CE Mark Study. This cohort excludes roll-in subjects, continued access enrollees, and those enrolled after submission of the marketing application to FDA.

The Global FlexNav Cohort consists of all patients in the PORTICO FlexNav DS Study and the FlexNav EU CE Mark Study plus those enrolled after submission of the marketing application to FDA. The results of the Global FlexNav Cohort represent the totality of pre-market evidence on the FlexNav DS while the FlexNav PMA Analysis Cohort represents a subset of this evidence.

Table 11 captures the major characteristics of the primary RCT and supplemental studies. Figure 4 illustrates the relationship of the FlexNav DS studies and the composition of the supplemental FlexNav cohorts.

| Table 11: Summary of Clinical Studies | | | | |
| --- | --- | --- | --- | --- |
| Study/Cohort | N | Device | Geographies | Design and Endpoints |
| PORTICO RCT (ITT) • Portico Arm (n=381) • Control Arm (n=369) | 750 | Portico Valve vs. CAV Portico 1st Generation DS | US, AUS | Prospective Randomized (1:1) Primary Safety: Non-inferiority of a 5-component composite2 at 30 days. Primary Effectiveness: Non-inferiority of a 2-component composite3 at 1 year. |
| FlexNav PMA Analysis Cohort • PORTICO FlexNav DS Analysis Cohort (n=81) • FlexNav EU CE Mark Study (n=19) | 100 | Portico Valve FlexNav DS/LS | US, AUS, EU | Prospective Single Arm Primary Safety: Major vascular complication rate at 30 days. |
| Global FlexNav Cohort1 • FlexNav Roll-ins (n=34) • PORTICO FlexNav DS Analysis | 193 | Portico Valve FlexNav DS/LS | US, AUS, EU | Observational Single Arm There were no prespecified primary endpoints for this aggregate Global |

PMA P190023: FDA Summary of Safety and Effectiveness Data

{15}

Page 16

| Cohort (n=100) • FlexNav Continued Access Study (n=13) • FlexNav EU CE Mark Study (n=46) | | | | FlexNav cohort, however key PORTICO RCT and FlexNav Study endpoints were summarized descriptively. |
| --- | --- | --- | --- | --- |
| 1 The Global FlexNav Cohort is inclusive of the patients in the FlexNav PMA Analysis Cohort, including 81 patients in the FlexNav IDE Analysis cohort and 19 patients in the FlexNav EU CE Mark Study 2 The 5 components of the safety composite endpoint were all-cause mortality, disabling stroke, Acute Kidney Injury stage 3 requiring dialysis, life-threatening bleed requiring a transfusion and major vascular complications at 30 days. 3 The 2 components of the effectiveness composite endpoint were all-cause mortality and disabling stroke at 1 year. CAV = Commercially Available Valves, i.e. control group in RCT | | | | |

Figure 4: Supplemental FlexNav Studies &amp; Cohorts

1. Subjects enrolled prior to submission of marketing application to FDA were included in the FlexNav PMA Analysis Cohort
2. Subjects enrolled after submission of the marketing application to FDA were not included in the FlexNav PMA Analysis Cohort
3. FlexNav Roll-In and Continued Access Study (CAS) subjects were not included in the FlexNav IDE or PMA Analysis Cohorts
4. The Global FlexNav Cohort included all subjects from FlexNav DS Study and FlexNav EU CE Mark Study, including the FlexNav PMA Analysis Cohort.

A summary of the primary clinical study, PORTICO RCT, is presented below. Summaries of the supplemental clinical cohorts to evaluate the safety and performance of the FlexNav Delivery System design iteration (i.e., FlexNav PMA Analysis Cohort and Global FlexNav Cohort) are presented in Section XI. Data from the PORTICO RCT, in conjunction with supplemental data from the FlexNav PMA Analysis Cohort and Global FlexNav Cohort, were the basis for the PMA approval decision.

## A. Study Design

Patients in the PORTICO RCT study were enrolled between May 30, 2014 and October 10, 2017. The database for this PMA reflected data collected through July 31, 2019 and included 750 randomized patients enrolled at 52 investigational sites in the United States and Australia.

The study was a prospective, multicenter, randomized controlled, open label non-inferiority trial designed to evaluate the safety and effectiveness of the Portico

PMA P190023: FDA Summary of Safety and Effectiveness Data

{16}

Transcatheter Aortic Valve System for transcatheter aortic valve implantation (TAVI) via transfemoral, subclavian/axillary, or transaortic delivery for treatment of patients with symptomatic severe native aortic stenosis who are considered to be high or extreme surgical risk. All Portico valve implants in the PORTICO RCT were delivered with the Portico first-generation delivery system.

The control group was any FDA-approved and commercially available TAVI System for the treatment of severe symptomatic aortic stenosis in a high or extreme surgical risk patient population. The following commercially available TAVI Systems were used in the control group, referred to hereafter as "CAV" (Commercially Available Valves): SAPIEN, SAPIEN XT, SAPIEN 3, CoreValve, CoreValve Evolut R, and CoreValve Evolut PRO.

All patients were reviewed by an independent Subject Selection Committee (SSC) to confirm study eligibility and access route suitability. An independent Clinical Events Committee (CEC) adjudicated all primary endpoint clinical events according to Valve Academic Research Consortium (VARC)-2 criteria. Independent core laboratories assessed all echocardiographic and CT imaging data.

Patients were randomized in a 1:1 ratio to receive a Portico valve or CAV. Permuted block randomization was used and stratified by: (1) clinical investigational site, (2) surgical risk cohort (high vs extreme; as determined by the subject selection committee (SSC)), and (3) vascular access method (transfemoral or alternative access). Treatment assignment was not masked to the investigational site, implanting physician or study participant.

The analysis plan to demonstrate non-inferiority of the Portico Transcatheter Aortic Valve System compared to CAV in the safety and effectiveness endpoints was based on Kaplan-Meier estimates at the analysis timepoint and standard errors. Assuming 80% high risk and 20% extreme risk patients, and estimated event rates (in both Portico valve and CAV groups) of 30.81% for the primary safety endpoint at 30 days and 25.0% for the primary effectiveness endpoint at 1 year, 750 randomized patients were required to demonstrate non-inferiority with margins of 8.5% and 8.0% respectively.

A subset of consecutive randomized patients was enrolled in a computed tomography (CT) sub-study to investigate the prevalence of reduced leaflet motion (RLM). For these patients with interpretable 4D-CT, leaflet motion and Hypoattenuated Leaflet Thickening (HALT) were assessed by a CT core laboratory.

1. Clinical Inclusion and Exclusion Criteria

Inclusion Criteria

Enrollment in the PORTICO RCT was limited to patients who met the following inclusion criteria:

- Patients must have co-morbidities such that the surgeon and cardiologist Co-PMA P190023: FDA Summary of Safety and Effectiveness Data

{17}

Investigators concur that the predicted risk of operative mortality is ≥15% or a minimum STS score of 8%. A candidate who does not meet the STS score criteria of ≥8% can be included in the study if a peer review by at least two surgeons concludes and documents that the patient's predicted risk of operative mortality is ≥15%. The surgeon's assessment of operative comorbidities not captured by the STS score must be documented in the study case report form as well as in the patient medical record.

- Subject is 21 years of age or older at the time of consent.
- Subject has senile degenerative aortic valve stenosis with echocardiographically derived criteria: mean gradient &gt;40 mmHg or jet velocity greater than 4.0 m/s or Doppler Velocity Index &lt;0.25 and an initial aortic valve area (AVA) of ≤1.0 cm² (indexed EOA ≤0.6 cm²/m²). (Qualifying AVA baseline measurement must be within 60 days prior to informed consent).
- Subject has symptomatic aortic stenosis as demonstrated by NYHA Functional Classification of II, III, or IV.
- The subject has been informed of the nature of the study, agrees to its provisions and has provided written informed consent as approved by the Institutional Review Board (IRB) of the respective clinical site.
- The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits.
- Subject's aortic annulus is 19-27mm diameter as measured by CT conducted within 12 months prior to informed consent. Note: if CT is contraindicated and/or not possible to be obtained for certain patients, a 3D echo and non-contrast CT of chest and abdomen/pelvis may be accepted if approved by the subject selection committee.

For a subject to be considered an Extreme Risk candidate they must meet # 2, 3, 4, 5, 6, 7 of the above criteria, and:

- The subject, after formal consults by a cardiologist and two cardiovascular surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or serious, irreversible morbidity exceeds the probability of meaningful improvement. Specifically, the probability of death or serious, irreversible morbidity should exceed 50%. The surgeons' consult notes shall specify the medical or anatomic factors leading to that conclusion and include a printout of the calculation of the STS score to additionally identify the risks in these patients.

## Exclusion Criteria

Patients were not permitted to enroll in the PORTICO study if they met any of the following exclusion criteria:

- Evidence of an acute myocardial infarction (defined as: ST Segment Elevation as evidenced on 12 Lead ECG) within 30 days prior to index procedure.
- Aortic valve is a congenital unicuspid or congenital bicuspid valve or is non-

PMA P190023: FDA Summary of Safety and Effectiveness Data
Page 18

{18}

calcified as verified by echocardiography.

- Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation 3-4+).
- Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to index procedure.
- Pre-existing prosthetic heart valve or other implant in any valve position, prosthetic ring, severe circumferential mitral annular calcification (MAC) which is continuous with calcium in the LVOT, severe (greater than 3+) mitral insufficiency, or severe mitral stenosis with pulmonary compromise. Patients with pre-existing surgical bioprosthetic aortic heart valve should be considered for the Valve-in-Valve registry.
- Blood dyscrasias as defined: leukopenia (WBC&lt;3000 mm³), acute anemia (Hb &lt; 9 g/dL), thrombocytopenia (platelet count &lt;50,000 cells/mm³).
- History of bleeding diathesis or coagulopathy.
- Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support.
- Untreated clinically significant coronary artery disease requiring revascularization.
- Hemodynamic instability requiring inotropic support or mechanical heart assistance.
- Need for emergency surgery for any reason.
- Hypertrophic cardiomyopathy with or without obstruction (HOCM).
- Severe ventricular dysfunction with LVEF &lt;20% as measured by resting echocardiogram.
- Echocardiographic evidence of intracardiac mass, thrombus or vegetation.
- Active peptic ulcer or upper GI bleeding within 3 months prior to index procedure.
- A known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid), or clopidogrel (Plavix), or sensitivity to contrast media which cannot be adequately premedicated.
- Recent (within 6 months prior to index procedure date) cerebrovascular accident (CVA) or a transient ischemic attack (TIA).
- Renal insufficiency (creatinine &gt;3.0 mg/dL) and/or end stage renal disease requiring chronic dialysis.
- Life expectancy &lt; 12 months from the time of informed consent due to non-cardiac co-morbid conditions.
- Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal luminal diameter 5 cm or greater; marked tortuosity (hyperacute bend), aortic arch atheroma (especially if thick [&gt;5 mm], protruding or ulcerated) or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe "unfolding" and tortuosity of the thoracic aorta (applicable for transfemoral patients only).
- Native aortic annulus size &lt; 19 mm or &gt;27 mm per the baseline diagnostic imaging.

PMA P190023: FDA Summary of Safety and Effectiveness Data
Page 19

{19}

- Aortic root angulation &gt; 70° (applicable for transfemoral patients only).
- Currently participating in an investigational drug or device study.
- Active bacterial endocarditis within 6 months prior to the index procedure.
- Bulky calcified aortic valve leaflets in close proximity to coronary ostia.
- Non-calcified aortic annulus
- Iliofemoral vessel characteristics that would preclude safe placement of the introducer sheath such as severe obstructive calcification, or severe tortuosity (applicable for transfemoral patients only).

## Additional Exclusion Criteria (Transcatheter Access-Related)

For selection of an appropriate alternative access delivery method, patients were screened using the following transaortic access specific exclusion criteria:

- Subject has pre-existing patent right internal mammary arterial (RIMA) graft that would preclude access.
- Subject has a hostile chest or other condition that complicates transaortic access.
- Subject has a porcelain aorta, defined as an extensive circumferential calcification of the ascending aorta that would complicate transaortic access.

## Subclavian/Axillary Subject Cohort Specific Exclusion Criteria

- Subject’s access vessel (subclavian/axillary) diameter will not allow for introduction of the applicable 18 Fr or 19 Fr delivery system.
- Subject’s subclavian/axillary arteries have severe calcification and/or tortuosity.
- Subject’s aortic root angulation is:
- Left Subclavian/Left Axillary: &gt;70°
- Right Subclavian/Right Axillary: &gt;30°
- Subject has a history of patent LIMA/RIMA graft that would preclude access

## 2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at discharge, 30 days, 6 months, 12 months, and then annually for 5 years post-procedure. For patients who were unable to attend an in-person follow-up visit at 12 months, a vital status phone call to determine survival and any new adverse events within 12 months was permitted. RCT patients who did not receive a study valve were followed for 12 months and then allowed to withdraw.

Preoperatively, patients were screened by a local Heart team to confirm they met study eligibility criteria including CT and echocardiographic imaging assessments to assess severity of aortic stenosis and confirm transcatheter vascular access route suitability. Baseline assessments included laboratory tests, quality of life surveys, functional and cognitive tests, and neurological assessments.

Postoperatively, the objective parameters measured during the study included New

PMA P190023: FDA Summary of Safety and Effectiveness Data

{20}

York Heart Association (NYHA) functional classification, neurological assessments, transthoracic echocardiogram (TTE) evaluation and quality of life surveys. 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 non-hierarchical composite of all-cause mortality, disabling stroke, life threatening bleeding requiring blood transfusion, acute kidney injury requiring dialysis, or major vascular complications at 30 days. The primary hypothesis was as follows:

$$
\mathrm{H}_0: \lambda_{\text{test}} \geq \lambda_{\text{control}} + \Delta_{\mathrm{p1}}
$$

$$
\mathrm{H}_a: \lambda_{\text{test}} &lt; \lambda_{\text{control}} + \Delta_{\mathrm{p1}}
$$

where $\lambda_{\text{test}}$ is the probability of a subject experiencing a primary safety endpoint event by 30 days in the Portico valve (test) group, $\lambda_{\text{control}}$ is the probability of a subject experiencing a primary safety endpoint event in the CAV (control) group, and $\Delta_{\mathrm{p1}}$ is the non-inferiority margin for the primary safety endpoint pre-defined as 8.5%.

The hypothesis test was a non-inferiority test performed in the Intention-to-Treat (ITT) population by calculating a 95% one-sided upper confidence limit for the difference of ($\lambda_{\text{test}} - \lambda_{\text{control}}$), using Kaplan-Meier estimates for the event rates and standard errors. If the upper confidence limit for the difference was less than 8.5%, the Portico valve group was determined to be non-inferior to the CAV group. The endpoint was also analyzed for the As-Treated (AT) and Per Protocol (PP) populations.

### Primary Effectiveness Endpoint:

The primary effectiveness endpoint was a composite of all-cause mortality or disabling stroke assessed at 1 year. The primary hypothesis was as follows:

$$
\mathrm{H}_0: p_{\text{test}} \geq p_{\text{control}} + \Delta_{\mathrm{p2}}
$$

$$
\mathrm{H}_a: p_{\text{test}} &lt; p_{\text{control}} + \Delta_{\mathrm{p2}}
$$

where $p_{\text{test}}$ is the probability of a subject experiencing a primary effectiveness endpoint event by 1 year in the Portico valve (test) group, $p_{\text{control}}$ is the probability of a subject experiencing a primary effectiveness endpoint event by 1 year in the CAV (control) group, and $\Delta_{\mathrm{p2}}$ is the non-inferiority margin for the primary effectiveness endpoint pre-defined as 8.0%.

The hypothesis test was a non-inferiority test performed in the ITT population by calculating the 95% one-sided upper confidence limit for the difference of ($p_{\text{test}} - p_{\text{control}}$), using Kaplan-Meier estimates for the event rates and standard errors. If the

PMA P190023: FDA Summary of Safety and Effectiveness Data

{21}

upper confidence limit for the difference was less than 8.0%, the Portico valve group was determined to be non-inferior to the CAV group. The endpoint was also analyzed for the AT and PP populations.

## Secondary Endpoints:

Four pre-specified secondary endpoints were tested in a hierarchical testing scheme (as shown in Table 12 below). Non-inferiority tests were performed in the ITT population for each secondary endpoint. To claim non-inferiority, both secondary endpoints tested per group must be within the pre-specified non-inferiority margins.

| Group | Secondary Endpoint | Alternative Hypothesis Test | Non-inferiority Margin |
| --- | --- | --- | --- |
| 1 | Severe aortic regurgitation (AR) at 1 year^{1} | Ha: θtest,_{1} < θcontrol,_{1} + 0.04 | 4% |
| 1 | KCCQ Overall Score at 1 year^{2} | Ha: θtest,_{2} > θcontrol,_{2} - 10 | 10 points |
| 2 | Moderate or severe aortic regurgitation at 1 year^{1} | Ha: θtest,_{3} < θcontrol,_{3} + 0.06 | 6% |
| 2 | 6-minute walk at 1 year^{2} | Ha: θtest,_{4} > θcontrol,_{4} - 36 | 36m |
| 1 based on the Farrington-Manning method
2 based on a two-sample t-test | | | |

## Descriptive Endpoints:

Descriptive endpoints including acute device success, quality of life, NYHA functional classification, valve hemodynamics, and clinical outcomes were assessed at 30 days, 6 months, and 12 months post index procedure, unless otherwise specified. All descriptive endpoints were summarized using descriptive statistics.

- Acute device success defined as:
- Absence of procedural mortality AND
- Correct positioning of a single prosthetic heart valve into the proper anatomical location AND
- Intended performance of the prosthetic heart valve (mean aortic valve gradient &lt;20 mmHg or peak velocity &lt;3 m/s, no moderate or severe prosthetic valve regurgitation) AND
- Successful access was obtained as intended by group assignment

- Kansas City Cardiomyopathy Questionnaire (KCCQ) at 1 year
- Major vascular complications at 30 days
- NYHA functional classification at 30 days, 6 months, and 1 year
- Six-minute walk test at 30 days, 6 months, and 1 year
- Paravalvular Leak (PVL) at 30 days, 6 months, and 1 year
- Aortic insufficiency greater than trace at 30 days, 6 months, 1 year, and 2 years
- Reintervention to treat aortic insufficiency at 1 year and 2 years
- Permanent pacemaker insertion at 30 days
- Major bleeding at 30 days

PMA P190023: FDA Summary of Safety and Effectiveness Data
Page 22

{22}

- Acute kidney injury at 30 days
- Individual components of the primary effectiveness endpoint
- All-cause mortality at 30 days, 6 months, 1 year and 2 years
- Disabling stroke at 30 days, 6 months, 1 year and 2 years
- Non-disabling Stroke and Transient Ischemic Attack (TIA) at 30 days, 6 months, 1 year, and 2 years
- Atrial fibrillation at 1 year and 2 years
- Quality of Life (QOL) from baseline to 30 days, 6 months and 1 year

## B. Accountability of PORTICO RCT Cohort

At the time of database lock, a total of 750 patients were randomized in the study, including 381 Portico valve patients and 369 CAV patients.

There were four different analysis populations defined in the protocol: Intention-to-treat (ITT), As-Treated (AT), Modified As-Treated (mod AT), and Per Protocol (PP), as summarized in Table 13 and Figure 5 below. The primary analysis was based on the ITT population, with the date of randomization considered Day 0.

| Table 13: Summary of Analysis Populations and Patient Accountability | | | |
| --- | --- | --- | --- |
| Analysis Populations | Definition | Cohort | |
| | | Portico valve (N) | CAV (N) |
| Intention-to-Treat (ITT; primary) | All randomized patients, with the date of randomization considered Day 0 | 381 | 369 |
| As-Treated (AT) | All randomized patients in whom treatment was initiated (defined as entering the procedure room), with date of the index procedure considered Day 0. | 375 | 362 |
| Per protocol (PP) | All randomized patients who were successfully treated with the assigned valve implant and had no deviation for inclusion/exclusion in the study, with date of the index procedure considered Day 0 | 350 | 348 |
| Modified As-Treated (mod AT) | All randomized patients who were implanted with one or more valves per the assigned treatment (Portico valve or CAV) at the time of the index procedure. Patients that died during procedure, were converted to surgery or received a valve different than assigned were excluded. Date of the index procedure considered Day 0 | 366 | 361 |

PMA P190023: FDA Summary of Safety and Effectiveness Data
Page 23

{23}

Figure 5: Population Flowchart

Of the 750 randomized patients, $82.3\%$ were alive and available for follow-up (i.e. not withdrawn) at the 12-month post-operative visit. The overall disposition of the patients and compliance for each follow-up visit is presented by group in Table 14.

| Table 14: Overall Disposition and Study Compliance | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Group | Visit Interval | Completed Visits | Expected Visits1 | Missed Visits | Study Exits | | Follow-up Compliance % |
| | | | | | Death | Withdrawal2 | |
| Portico Valve (Intention-to-Treat) | Baseline | 381 | 381 | 0 | N/A | N/A | 100.0% |
| | Procedure | 375 | 375 | 0 | 0 | 6 | 100.0% |
| | Discharge | 368 | 369 | 1 | 6 | 0 | 99.7% |
| | 30 Days | 346 | 356 | 10 | 13 | 1 | 97.2% |
| | 6 Months | 307 | 330 | 23 | 19 | 7 | 93.0% |
| | 12 Months3 | 302 | 308 | 6 | 18 | 4 | 98.1% |
| CAV (Intention-to-Treat) | Baseline | 369 | 369 | N/A | N/A | N/A | 100.0% |
| | Procedure | 362 | 362 | 0 | 2 | 5 | 100.0% |
| | Discharge | 360 | 360 | 0 | 2 | 0 | 100.0% |
| | 30 Days | 347 | 356 | 9 | 4 | 0 | 97.5% |
| | 6 Months | 314 | 334 | 20 | 19 | 3 | 94.0% |

PMA P190023: FDA Summary of Safety and Effectiveness Data

{24}

PMA P190023: FDA Summary of Safety and Effectiveness Data
Page 25

# C. Study Population Demographics and Baseline Parameters

The baseline demographics of the study population are typical for a TAVI study performed in the United States and are summarized in Table 15. The treatment cohorts were generally well balanced with respect to age, gender, baseline NYHA classification, and STS risk score.

| Table 15: Study Population Demographics and Baseline Parameters (ITT population) | | | |
| --- | --- | --- | --- |
| | Portico valve (N=381) | CAV (N=369) | |
| Demographics | | | |
| Age, mean (SD), y | 83.0 (7.6) | 83.7 (7.0) | |
| Female | 198 (52.0%) | 197 (53.4%) | |
| NYHA functional class | | | |
| NYHA II | 109 (28.6%) | 100 (27.1%) | |
| NYHA III | 229 (60.1%) | 234 (63.4%) | |
| NYHA IV | 43 (11.3%) | 35 (9.5%) | |
| STS PROM Score^{1}, % | | | |
| Mean (SD) | 6.4 (3.4) | 6.6 (3.4) | |
| STS <4% | 102 (26.8%) | 88 (23.8%) | |
| STS 4-7.9% | 182 (47.8%) | 173 (46.9%) | |
| STS ≥8% | 97 (25.5%) | 108 (29.3%) | |
| EuroSCORE II, % | 6.8 (7.6) | 6.6 (5.8) | |
| Extreme risk | 70 (18.4%) | 63 (17.1%) | |
| High risk | 311 (81.6%) | 306 (82.9%) | |
| Comorbidities | | | |
| Hypertension | 358 (94.0%) | 331 (89.7%) | |
| Diabetes mellitus | 143 (37.5%) | 142 (38.5%) | |
| Oral controlled | 73/143 (51.0%) | 71/142 (50.0%) | |
| Kidney disease | 96 (25.2%) | 94 (25.5%) | |
| Atrial fibrillation | 125 (32.8%) | 145 (39.3%) | |
| Permanent pacemaker | 57 (15.0%) | 63 (17.1%) | |
| Pre-existing RBBB | 56 (14.7%) | 43 (11.7%) | |
| Prior stroke | 29 (7.6%) | 49 (13.3%) | |
| Prior transient ischemic attack | 33 (8.7%) | 25 (6.8%) | |
| Carotid artery disease | 93/380 (24.5%) | 82 (22.2%) | |
| Coronary artery disease | 266 (69.8%) | 256 (69.4%) | |
| Prior coronary stenting | 108 (28.3%) | 107 (29.0%) | |
| Prior bypass graft surgery | 88 (23.1%) | 76 (20.6%) | |

{25}

PMA P190023: FDA Summary of Safety and Effectiveness Data
Page 26

| Table 15: Study Population Demographics and Baseline Parameters (ITT population) | | |
| --- | --- | --- |
| | Portico valve (N=381) | CAV (N=369) |
| Prior myocardial infarction | 55 (14.4%) | 43 (11.7%) |
| Peripheral vascular disease | 72 (18.9%) | 65 (17.6%) |
| Chronic lung disease | 158 (41.5%) | 148 (40.1%) |
| Hostile chest/Prohibitive chest deformity | 11 (2.9%) | 19 (5.1%) |
| Porcelain aorta | 11 (2.9%) | 10 (2.7%) |
| Severe liver disease | 4 (1.0%) | 3 (0.8%) |
| Pulmonary hypertension | 131 (34.4%) | 126 (34.1%) |
| Total frailty score (out of 4), mean (SD) | 1.8 (0.9) | 1.9 (0.8) |
| Katz index of activities of daily living, ≤4 | 40 (10.5%) | 41 (11.1%) |
| Grip strength, <BMI and height-based cut-off | 298/379 (78.6%) | 302 (81.8%) |
| 15-foot (5m) walk test ≥Height and sex-based cut-off | 268/359 (74.7%) | 256/342 (74.9%) |
| Albumin < 3.5g/dl | 87/380 (22.9%) | 93/366 (25.4%) |
| KCCQ-OS score, mean (SD) | 55.0 (23.2) (375) | 53.9 (23.7) (358) |
| EQ-5D Index score, mean (SD) | 0.73 (0.19) (373) | 0.74 (0.19) (359) |
| Six-minute walk distance, mean (SD), m | 207.5 (116.5) (320) | 208.9 (110.2) (306) |
| Echocardiographic parameters^{2} | | |
| Aortic valve area, mean (SD), cm^{2} | 0.68 (0.17) | 0.67 (0.16) (367) |
| Mean gradient, mean (SD), mm Hg | 46.2 (11.2) (379) | 45.9 (11.9) (368) |
| Ejection fraction, mean (SD), % | 57.3 (11.5) (377) | 57.4 (11.1) (367) |
| Mitral insufficiency (moderate/severe) | 78/380 (20.5%) | 83/367 (22.6%) |
| Tricuspid insufficiency (moderate/severe) | 70/380 (18.4%) | 67/367 (18.3%) |
| Data are presented as n (%), mean (SD), n/N (%) or mean (SD) (n).
KCCQ-OS= Kansas City Cardiomyopathy Questionnaire Overall Summary. NYHA= New York Heart Association. STS PROM= Society of Thoracic Surgeons predicted risk of mortality. EuroSCORE= European System for Cardiac Operative Risk Evaluation. EQ-5D= EuroQol- 5 Dimension. RBBB= Right Bundle Branch Block.
^{1} Patients screened after November 15, 2018 were evaluated using risk models developed using STS data from 2011 to 2014 and validated using 2014 to 2016 data.
^{2} Site-reported echo data | | |

## D. Safety and Effectiveness Results

### 1. Primary Safety Endpoint

The composite rate of all-cause mortality, disabling stroke, life threatening bleeding requiring blood transfusion, acute kidney injury requiring dialysis, or major vascular complications at 30 days for the Intention-to-Treat (ITT) and As-Treated (AT) populations are shown in Table 16.

The primary analysis was prespecified for the ITT population, for which Kaplan-Meier analysis shows the composite rate at 30 days was 13.8% in the Portico valve group and 9.6% in the CAV group. The 95% upper confidence limit of the difference was 8.1% for the ITT population, which falls within the pre-specified non-inferiority

{26}

margin of 8.5%, indicating the study's primary safety endpoint was met for the primary analysis population. A confirmatory analysis was also pre-specified using the AT population; however, the 95% upper confidence limit of the difference for the AT population was 8.9%, which was not within the pre-specified non-inferiority margin. Thus, non-inferiority of the Portico valve for the primary safety endpoint was not confirmed by the AT population.

| Table 16: Primary Safety Endpoint Analysis (30 Days) | | | | | |
| --- | --- | --- | --- | --- | --- |
| Analysis Set | Kaplan-Meier Estimate (SE) of Event Rate | | Difference in event rate between groups | Upper limit of the one-sided 95% confidence interval of event rate difference^{1} | P-value |
| | Portico valve | CAV | | | |
| Intention-to-Treat (N=750) | 13.8% (1.8%) (N=381) | 9.6% (1.5%) (N=369) | 4.2% | 8.1% | 0.03 |
| As-Treated (N=737) | 14.4% (1.8%) (N=375) | 9.4% (1.5%) (N=362) | 5.0% | 8.9% | 0.07 |
| 1 Kaplan-Meier method was used to estimate the event rate (SE). If the upper limit of the one-sided 95% confidence interval for the difference of event rate (Portico – CAV) is < 8.5%, then non-inferiority is demonstrated.
Note: Endpoint is measured from Day of Randomization for ITT and from Day of Procedure for AT. | | | | | |

Event rates for individual components of the composite primary safety endpoint for the ITT and AT analysis populations are shown in Table 17, along with 95% confidence intervals. Event rates for all-cause mortality and major vascular complications are numerically higher in the Portico group (ITT: 3.5% and 9.6%, respectively) than in the CAV group (ITT: 1.9% and 6.3%, respectively). Comparison of the component event rate differences between Portico and CAV groups across the ITT population, which included all randomized subjects with follow-up beginning at randomization, and the AT population, which included all treated subjects with follow-up beginning at the index procedure, identified that the individual component event rate differences were consistent across the two populations, except for all-cause mortality. In the AT population, there were 2 fewer patient deaths in the CAV group (occurred before index procedure) and 4 more patient deaths in the Portico group (occurred after 30 days from randomization but within 30 days of index procedure). As a result, the all-cause mortality rate difference increased 1.5% from the ITT to AT population (+1.6% vs. +3.1%, respectively) in favor of the CAV group.

PMA P190023: FDA Summary of Safety and Effectiveness Data
Page 27

{27}

| Table 17: Components of Primary Safety Endpoint (30 Days) | | | | |
| --- | --- | --- | --- | --- |
| Component | PORTICO RCT (Intention-to-Treat) | | PORTICO RCT (As-Treated) | |
| | Portico valve (N=381) | CAV (N=369) | Portico valve (N=375) | CAV (N=362) |
| All-Cause Mortality1 [95% Confidence interval]2 | 3.5% (13/375) [1.86%, 5.86%] | 1.9% (7/364) [0.78%, 3.92%] | 4.5% (17/374) [2.67%, 7.18%] | 1.4% (5/362) [0.45%, 3.19%] |
| Disabling Stroke1 [95% Confidence interval]2 | 1.6% (6/375) [0.59%, 3.45%] | 1.1% (4/364) [0.30%, 2.79%] | 1.6% (6/374) [0.59%, 3.46%] | 0.8% (3/362) [0.17%, 2.40%] |
| Life Threatening Bleeding Requiring Blood Transfusion1 [95% Confidence interval]2 | 4.5% (17/375) [2.66%, 7.16%] | 3.6% (13/364) [1.92%, 6.03%] | 4.8% (18/374) [2.88%, 7.50%] | 3.6% (13/362) [1.93%, 6.06%] |
| Acute Kidney Injury Requiring Dialysis1 [95% Confidence interval]2 | 1.1% (4/375) [0.29%, 2.71%] | 0.8% (3/364) [0.17%, 2.39%] | 1.1% (4/374) [0.29%, 2.72%] | 0.8% (3/362) [0.17%, 2.40%] |
| Major Vascular Complications1 [95% Confidence interval]2 | 9.6% (36/375)3 [6.81%, 13.04%] | 6.3% (23/364)4 [4.05%, 9.33%] | 9.6% (36/374) [6.83%, 13.08%] | 6.6% (24/362) [4.29%, 9.70%] |
| 1 The proportion of patients who experienced each event was calculated. The numerator for the 30-day rate is the number of patients who experienced an event by 30 days (post randomization for ITT and post index procedure for AT). The denominator for each event type is the number of analysis patients excluding patients that have withdrawn before 30 days without an event. 2 By Clopper-Pearson exact confidence interval. 3 Of the 36 major vascular complications in the Portico ITT group, 19 (5.1%) occurred at an access site (3.2% TAVI, 1.9% non-TAVI access site), 16 (4.3%) did not occur at an access site, and 1 subject (0.3%) had multiple events (1 at the access site and 1 non-access site). 4 Of the 23 major vascular complications in the CAV ITT group, 16 (4.4%) occurred at an access site (3.0% TAVI, 1.4% non-TAVI access site), 6 (1.6%) did not occur at an access site, and 1 subject (0.3%) had multiple events (1 at the access site and 1 non-access site). | | | | |

# 2. Primary Effectiveness Endpoint

The composite rate of all-cause mortality or disabling stroke at 1 year for the Intention-to-Treat (ITT) and As-Treated (AT) populations are shown in Table 18.

The primary analysis was pre-specified for the ITT population, for which Kaplan-Meier analysis shows the composite rate was $14.9\%$ in the Portico valve group and $13.4\%$ in the CAV group. A confirmatory analysis was also pre-specified using the AT population. The $95\%$ upper confidence limit for the difference was $5.7\%$ in the ITT population and $6.2\%$ in the AT population, which both fall within the prespecified non-inferiority margin of $8.0\%$ , indicating the study's primary effectiveness endpoint was met.

PMA P190023: FDA Summary of Safety and Effectiveness Data

{28}

PMA P190023: FDA Summary of Safety and Effectiveness Data
Page 29

| Table 18: Primary Effectiveness Endpoint Analysis (1 Year) | | | | | |
| --- | --- | --- | --- | --- | --- |
| Analysis Set | Kaplan-Meier Estimate (SE) of Event Rate | | Difference in event rate between groups | Upper limit of the one-sided 95% confidence interval of event rate difference¹ | P-value |
| | Portico valve (N=381) | CAV (N=369) | | | |
| Intention-to-Treat (N=750)² | 14.9% (1.8%) (N=381) | 13.4% (1.8%) (N=369) | 1.5% | 5.7% | 0.006 |
| As-Treated (N=737)³ | 15.2% (1.9%) (N=375) | 13.2% (1.8%) (N=362) | 2.0% | 6.2% | 0.010 |
| ¹ Kaplan-Meier method was used to estimate the event rate (SE). If the upper limit of the one-sided 95% confidence interval for the difference of event rate (Portico – CAV) is < 8.0%, non-inferiority is demonstrated.
² Endpoint is measured from Day of Randomization
³ Endpoint is measured from Day of Procedure | | | | | |

Event rates for individual components of the composite primary effectiveness endpoint for the ITT and AT analysis populations are shown in Table 19 along with 95% confidence intervals. The individual component event rates of Portico and CAV groups were consistent across ITT and AT populations. While the mortality rate numerically favored the CAV group at 30-days and 1-year, the difference of all-cause mortality between Portico and CAV groups at 1-year was similar to the difference at 30 days (Table 17), suggesting the post-procedural mortality risk (beyond 30-days) is consistent between the Portico and CAV groups. Although the rate of disabling stroke at 30 days favored CAV (1.6% vs. 1.1%) (Table 17), the disabling stroke rate at 1 year numerically favored the Portico valve (1.6% vs. 2.9%).

| Table 19: Components of Primary Effectiveness Endpoint (1 Year) | | | | |
| --- | --- | --- | --- | --- |
| Component | PORTICO RCT (Intention-to-Treat) | | PORTICO RCT (As-Treated) | |
| | Portico valve (N=381) | CAV (N=369) | Portico valve (N=375) | CAV (N=362) |
| All-Cause Mortality¹ [95% Confidence interval]² | 14.4% (1.8%) [11.17%, 18.38%] | 12.0% (1.7%) [9.05%, 15.85%] | 14.7% (1.8%) [11.43%, 18.71%] | 11.8% (1.7%) [8.86%, 15.63%] |
| Disabling Stroke¹ [95% Confidence interval]² | 1.6% (0.7%) [0.73%, 3.58%] | 2.9% (0.9%) [1.56%, 5.29%] | 1.6% (0.7%) [0.73%, 3.54%] | 2.6% (0.9%) [1.36%, 4.94%] |
| ¹ Kaplan-Meier method was used to estimate the event rate (SE).
² The 95% confidence interval was estimated using KM method with Greenwood standard error. | | | | |

## 3. Secondary Endpoints

The analysis of predefined secondary endpoints in the RCT was based on the ITT analysis population of 750 randomized patients that had available data at 1 year.

As shown in Table 20, the Portico valve group was found to be non-inferior to CAV within the pre-specified non-inferiority margins for proportion of severe aortic regurgitation and overall KCCQ score at 1 year. However, the Portico valve group

{29}

did not meet the non-inferiority criterion for proportion of moderate or severe aortic regurgitation at 1 year with respect to the CAV group. The remaining secondary endpoint (6-minute walk) in the hierarchy test was not tested.

| Table 20: Non-Inferiority Testing of Secondary Endpoints (ITT population) | | | | | |
| --- | --- | --- | --- | --- | --- |
| Secondary Endpoints at 1 year | Portico valve (N=381) | CAV (N=369) | Difference (Portico-CAV) | 95% Upper or Lower Confidence Limit | P-value |
| Severe aortic regurgitation | 0.4% (1/269) | 0.0% (0/269) | 0.4% | 2.34%1 | 0.00125 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Score | 75.4 (274) | 75.9 (283) | -0.5 | -3.502 | <0.00016 |
| Moderate or severe aortic regurgitation | 7.8% (21/269) | 1.5% (4/269) | 6.3% | 9.24%3 | 0.57145 |
| 6-minute walk distance (m) | 235.0 (227) | 231.5 (225) | 3.5 | -15.364 | No test6 |
| Note: all available data for randomized patients 1 If the one-sided 95% upper confidence limit for the difference of proportions (Portico – CAV) is < 4%, then non-inferiority is demonstrated. 2 If the one-sided 95% lower confidence limit for the difference of score (Portico – CAV) is > -10, then non-inferiority is demonstrated. 3 If the one-sided 95% upper confidence limit for the difference of proportions (Portico – CAV is < 6%, then non-inferiority is demonstrated. 4 If the one-sided 95% lower confidence limit for the difference of score (Portico – CAV) is > -36m, then non-inferiority is demonstrated. 5 Farrington-Manning test 6 Hypothesis testing was stopped after non-inferiority was not met for moderate or severe aortic regurgitation non-inferiority. | | | | | |

# 4. Additional Effectiveness Results

# Valve Hemodynamics

Figure 6 presents mean aortic gradients and aortic valve areas at baseline through follow-up in the PORTICO RCT. Improvements in mean aortic gradients and valve areas from baseline to discharge were maintained through 30 days and through 1 year in both the Portico and CAV groups. The randomized Portico valve group reported numerically larger valve areas and smaller mean gradients compared to the randomized CAV group at 1 year.

PMA P190023: FDA Summary of Safety and Effectiveness Data

{30}

Figure 6: Valve Hemodynamics Through 1 Year (ITT population)

# Total Aortic Regurgitation &amp; Paravalvular Aortic Regurgitation

Figure 7 and Figure 8 present core laboratory observed rates of total aortic regurgitation and paravalvular aortic regurgitation at discharge through follow-up in the PORTICO RCT, respectively. As determined in the secondary endpoint analysis, clinically significant total aortic regurgitation after 1 year was lower in the CAV group (1.5%) than in the Portico group (7.8%). In the Portico group, all reported moderate or severe total aortic regurgitation was attributable to paravalvular regurgitation. Patients treated with the Portico valve reported a three-times higher rate of clinically significant paravalvular regurgitation (6.3%) compared to the patients in the CAV group (2.1%) at 30 days, which persisted through 1 year (7.5% vs. 1.5%, respectively).

PMA P190023: FDA Summary of Safety and Effectiveness Data

{31}

Figure 7: Total Aortic Regurgitation Through 1 Year (ITT population)

| Characteristic | Discharge n=348 | 30 Days n=335 | 6 Months n=291 | 12 Months n=269 | Discharge n=343 | 30 Days n=334 | 6 Months n=296 | 12 Months n=269 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| None/Trace | 49.4% | 37.6% | 40.5% | 44.2% | 65.3% | 58.1% | 53.4% | 57.2% |
| Mild | 46.3% | 55.5% | 52.6% | 48.0% | 34.1% | 44.9% | 44.9% | 41.3% |
| Moderate | 4.3% | 6.6% | 6.9% | 7.4% | 0.6% | 1.7% | 1.7% | 1.5% |
| Severe | 0.0% | 0.3% | 0.0% | 0.4% | 0.0% | 0.0% | 0.0% | 0.0% |

PMA P190023: FDA Summary of Safety and Effectiveness Data

{32}

Figure 8: Paravalvular Aortic Regurgitation Through 1 Year (ITT population)

| Characteristic | Discharge n=343 | 30 Days n=334 | 6 Months n=286 | 12 Months n=266 | Discharge n=339 | 30 Days n=329 | 6 Months n=291 | 12 Months n=262 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| None/Trace | 49.9% | 37.7% | 40.9% | 45.5% | 65.8% | 58.1% | 54.3% | 59.2% |
| Mild | 46.4% | 56.0% | 52.1% | 47.0% | 33.6% | 39.8% | 44.0% | 39.3% |
| Moderate | 3.8% | 6.0% | 7.0% | 7.1% | 0.6% | 2.1% | 1.7% | 1.5% |
| Severe | 0.0% | 0.3% | 0.0% | 0.4% | 0.0% | 0.0% | 0.0% | 0.0% |

# Reintervention to Treat Aortic Regurgitation

Table 21 presents the results for reintervention to treat aortic regurgitation (defined as moderate or greater paravalvular aortic regurgitation or transvalvular aortic insufficiency) among subjects after the TAVI procedure $(N = 732)$ .

A total of 9 subjects (8 Portico, 1 CAV) required reintervention to treat moderate or greater paravalvular aortic regurgitation within 365 days post-index procedure; no subjects reported transvalvular aortic insufficiency. Of the 8 Portico subjects that required reintervention to treat aortic regurgitation, 7 underwent a TAV-in-TAV procedure with a commercially available valve and 1 was implanted with an Amplatzer Vascular Plug. The CAV subject that required reintervention to treat aortic regurgitation underwent a balloon aortic valvuloplasty procedure.

PMA P190023: FDA Summary of Safety and Effectiveness Data

{33}

PMA P190023: FDA Summary of Safety and Effectiveness Data
Page 34

| Table 21: Reintervention to Treat Aortic Regurgitation at 1 Year | | |
| --- | --- | --- |
| Characteristic | Implanted Population | |
| | Portico (N=371) | CAV (N=361) |
| Reintervention for Aortic Regurgitation | 2.2% (8/371) | 0.3% (1/361) |

## NYHA Functional Classification

Figure 9 presents NYHA functional class of patients at baseline through 1 year. The presentation of severe cardiac symptoms (NYHA class III or IV) was reduced from 71.4% at baseline to 8.4% at 1 year in Portico patients and from 72.9% at baseline to 8.3% at 1 year in CAV patients, which represents a similar improvement of clinically significant heart failure classification in both treatment groups.

Figure 9: New York Heart Association (NYHA) Functional Class Through 1 Year (ITT population)

## Quality of Life

Table 22 summarizes self-reported quality of life over time as measured by KCCQ Overall Summary Score in the PORTICO RCT. KCCQ scores improved by approximately 20 points in both cohorts at 1 year.

{34}

| Table 22: KCCQ Quality of Life Scores Through 1 Year (ITT population) | | |
| --- | --- | --- |
| Characteristic | Portico valve (N=381) | CAV (N=369) |
| KCCQ score at Baseline | 54.99 ± 23.17 (375) | 53.93 ± 23.71 (358) |
| KCCQ score at 30 days | 69.59 ± 22.98 (335) | 72.05 ± 22.22 (340) |
| KCCQ score at 6 months | 73.49 ± 22.70 (297) | 75.66 ± 21.16 (302) |
| KCCQ score at 1 year | 75.43 ± 22.18 (274) | 75.94 ± 20.48 (283) |

# 5. Adverse Events

Table 23 presents VARC-2 defined endpoints in the PORTICO RCT at 30 days and 1 year.

| Table 23: VARC-2 Clinical Events (ITT population) | | |
| --- | --- | --- |
| Outcomes | Portico valve (N=381) | CAV (N=369) |
| At 30 Days1 | | |
| All-cause mortality | 13 (3.5%) | 7 (1.9%) |
| Cardiovascular | 12 (3.2%) | 6 (1.6%) |
| Non-cardiovascular | 1 (0.3%) | 1 (0.3%) |
| All stroke | 10 (2.7%) | 9 (2.5%) |
| Disabling stroke | 6 (1.6%) | 4 (1.1%) |
| Non-disabling stroke | 4 (1.1%) | 5 (1.4%) |
| Transient ischemic attack | 4 (1.1%) | 1 (0.3%) |
| All Bleeding | 40 (10.6%) | 30 (8.2%) |
| Life threatening or disabling bleeding | 22 (5.9%) | 14 (3.8%) |
| Life threatening or disabling bleeding requiring transfusion | 17 (4.5%) | 13 (3.6%) |
| Major bleeding | 19 (5.1%) | 16 (4.4%) |
| Minor bleeding | 33 (8.8%) | 34 (9.3%) |
| Major vascular complications | 36 (9.6%) | 23 (6.3%) |
| Minor vascular complications | 35 (9.3%) | 32 (8.8%) |
| Acute kidney injury | 22 (5.9%) | 26 (7.1%) |
| Stage 1 | 10 (2.7%) | 19 (5.2%) |
| Stage 2 | 5 (1.3%) | 3 (0.8%) |
| Stage 3 | 7 (1.9%) | 4 (1.1%) |
| Acute kidney injury requiring dialysis | 4 (1.1%) | 3 (0.8%) |
| Atrial fibrillation | 15 (4.0%) | 17 (4.7%) |
| New permanent pacemaker3 | 88 (27.7%) | 35 (11.6%) |
| Valve intervention due to prosthetic valve thrombosis4 | 0 (0%) | 0 (0%) |
| Valve intervention due to endocarditis4 | 0 (0%) | 0 (0%) |

PMA P190023: FDA Summary of Safety and Effectiveness Data

{35}

# 6. Other Results

# Procedural Outcomes and Implant Characteristics

Table 24 shows the procedural outcomes and implant characteristics of the 737 PORTICO RCT patients that attended the index procedure (As-Treated population).

| Table 24: Procedural Outcomes and Implant Characteristics (AT population) | | |
| --- | --- | --- |
| Outcome | Portico valve (N=375) | CAV (N=362) |
| Procedural outcomes (final disposition) | | |
| Procedural success1 | 359 (95.7%) | 356 (98.3%) |
| Procedural mortality | 2 (0.5%) | 0 (0%) |
| Conversion to open heart surgery | 1 (0.3%) | 1 (0.3%) |
| Need for second valve (TAV-in-TAV) | 10 (2.7%) | 5 (1.4%) |
| Unable to implant assigned valve type | 2 (0.5%) | 0 (0%) |
| Unable to gain vascular access, no TAVI implant | 1 (0.3%) | 0 (0%) |
| Implant characteristics | | |
| Conscious sedation anesthesia | 112 (29.9%) | 116 (32.0%) |
| Implantation time2, min | 13.3 (13.8) | 6.8 (13.7) |
| Pre-balloon valvuloplasty3 | 322/373 (86.3%) | 200/361 (55.4%) |
| PPCI | 10/375 (2.8%) | 10/362 (2.8%) |
| PPCI + TAVI | 1/375 (0.3%) | 1/362 (0.3%) |
| PPCI + TAVI + TAVI + CABG | 1/375 (0.3%) | 1/362 (0.3%) |
| PPCI + TAVI + TAVI + CABG + TIMI | 1/375 (0.3%) | 1/362 (0.3%) |
| PPCI + TAVI + TIMI + TIMI + TIMI + TIMI + TIMI + TIMI + TIMI | 1/375 (0.3%) | 1/362 (0.3%) |

PMA P190023: FDA Summary of Safety and Effectiveness Data

{36}

PMA P190023: FDA Summary of Safety and Effectiveness Data

| Resheathing performed | 144 (38.4%) | NR |
| --- | --- | --- |
| Post-implantation balloon valvuloplasty | 186 (49.6%) | 74 (20.4%) |
| Final TAVI Access route | | |
| Transfemoral | 347/371 (93.5%) | 343/361 (95.0%) |
| Subclavian/Axillary | 8/371 (2.2%) | 5/361 (1.4%) |
| Transaortic | 16/371 (4.3%) | 12/361 (3.3%) |
| Transapical | 0/371 (0%) | 1/361 (0.3%) |
| Implanted prosthesis size^{4} | | |
| 20 mm | .. | 7/361 (1.9%) |
| 23 mm | 14/371 (3.8%) | 97/361 (26.9%) |
| 25 mm | 77/371 (20.8%) | .. |
| 26 mm | .. | 151/361 (41.8%) |
| 27 mm | 135/371 (36.4%) | .. |
| 29 mm | 145/371 (39.1%) | 87/361 (24.1%) |
| 31 mm | .. | 7/361 (1.9%) |
| 34 mm | .. | 12/361 (3.3%) |
| Data presented as n/N (%) or mean (SD)^{1} Procedural success is defined as: absence of procedural mortality and successful delivery of a single TAVI valve placed in the desired location^{2} Total implant time: Implant Start Time is defined as delivery system from first attempted valve inserted into the body; Implant End Time is defined as the time of last attempted valve fully deployed^{3} Denominator is number of patients with implant attempted^{4} Device size based on last implanted (functioning) valve; note that some device sizes are not available across all valve brands | | |

## Computed Tomography (CT) Sub-study

A subset of RCT patients were enrolled in a CT sub-study to investigate the prevalence of Hypoattenuated Leaflet Thickening (HALT) and reduced leaflet motion (RLM). Per protocol, a minimum of 200 consecutive RCT patients implanted with either a Portico valve or CAV with an adequate multi-slice 4D CT scan (or TEE, if the CT scan is medically or technically contraindicated) for leaflet mobility assessment at both 30 days and 6 months were required. The sub-study's primary outcome measure was the prevalence of RLM in all sub-study patients, defined as moderate or severely reduced motion or immobility of at least one valve leaflet.

There were 313 randomized patients (165 Portico valve and 148 CAV) with an interpretable 30-day CT/TEE, and 202 patients (111 Portico valve and 91 CAV) with a corresponding interpretable 6-month CT/TEE. Presence of HALT and RLM imaging findings are summarized in Table 25 along with the associated mean aortic pressure gradients.

| Table 25: Leaflet Mobility Findings and Mean Gradients | | | | |
| --- | --- | --- | --- | --- |
| Findings | At 30 Days | | At 6 Months | |
| | Portico valve (N=165) | CAV (N=148) | Portico valve (N=111) | CAV (N=91) |
| Oral Anticoagulant Use | | | | |

Page…