← Product Code NPT · P130009

# EDWARDS SAPIEN XT TRANSCATHETER HEART VALVE AND ACCESSORIES (P130009)

_Edwards Lifesciences, LLC · NPT · Jun 16, 2014 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P130009

## Device Facts

- **Applicant:** Edwards Lifesciences, LLC
- **Product Code:** NPT
- **Decision Date:** Jun 16, 2014
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic

## Intended Use

The Edwards SAPIEN XT Transcatheter Heart Valve, model 9300TFX, and accessories are indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis (aortic valve area ≤ 1.0 cm² or aortic valve area index ≤ 0.6 cm²/m², a mean aortic valve gradient of ≥ 40 mmHg, or a peak aortic-jet velocity of ≥ 4.0 m/s), and with native anatomy appropriate for the 23, 26, or 29 mm valve system, who are judged by a heart team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., Society of Thoracic Surgeons operative risk score ≥8% or at a ≥15% risk of mortality at 30 days).

## Device Story

Transcatheter heart valve (THV) system for percutaneous aortic valve replacement; replaces diseased native valve in high-risk patients. System includes balloon-expandable cobalt chromium frame with bovine pericardial leaflets; delivered via NovaFlex+ or Ascendra+ systems (transfemoral, transapical, or transaortic access). Physician team uses fluoroscopic guidance to position and deploy valve; balloon inflation expands frame to anchor valve in annulus. Device restores hemodynamic function; improves symptoms/quality of life. Used in hospital cath lab/OR; requires heart team (cardiac surgeon, interventionalist). Benefits include avoidance of open-heart surgery; reduced procedure time/vascular complications compared to previous generations.

## Clinical Evidence

Pivotal data from PARTNER II Cohort B (randomized, inoperable patients, N=560) showed SAPIEN XT non-inferior to SAPIEN THV for composite primary endpoint (death, major stroke, rehospitalization) at 1 year (RR 0.987, 95% CI 0.793-1.228, p=0.0024). Nested registries (NR1, NR4, NR5, NR6) provided data for 29mm valve and alternate access (TA/TAo). SOURCE XT registry (N=2688) supported high-risk indication, demonstrating consistent safety/effectiveness profiles. Primary endpoints met; secondary endpoints (NYHA, 6MWT, EOA) showed significant improvement.

## Technological Characteristics

Balloon-expandable radiopaque cobalt chromium frame; trileaflet bovine pericardial tissue (ThermaFix-treated); PET fabric skirt. Sizes: 23, 26, 29 mm. MR Conditional (1.5T/3.0T). Sterilization: TLS (valve) and EO (accessories). Connectivity: None. Software: None.

## Regulatory 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 THV ([P100041](/device/P100041.md), [P110021](/device/P110021.md))
- Carpentier-Edwards PERIMOUNT Pericardial Bioprosthesis ([P860057](/device/P860057.md))
- Cordis Palmaz Genesis stents

## Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA

I. GENERAL INFORMATION

Device Generic Name: Aortic valve, prosthesis, percutaneously delivered

Device Trade Name: Edwards SAPIEN XT™ Transcatheter Heart Valve, model 9300TFX, 23, 26, and 29 mm, and accessories
(NovaFlex+ delivery system, models 9355FS23, 9355FS26, and 9355FS29, with crimp stopper and Qualcrimp crimping accessory (laminated model or cloth model 9300QC);
Edwards Expandable Introducer Sheath Set, models 916ES23, 918ES26, and 920ES29;
Edwards balloon catheter, models 9350BC20, 9350BC23, and 9350BC25;
Ascendra+ delivery system with crimp stopper, models 9355AS23, 9355AS26, and 9355AS29;
Ascendra+ introducer sheath set, models 9350IS23, 9350IS26, and 9350IS29;
Ascendra balloon aortic valvuloplasty catheter, model 9100BAVC; and Edwards crimper, model 9350CR)

Device Procode: NPT

Applicant's Name and Address: Edwards Lifesciences LLC
One Edwards Way
Irvine, CA 92614

Date(s) of Panel Recommendation: None

Premarket Approval (PMA) Application Number: P130009

Date of FDA Notice of Approval: June 16, 2014

II. INDICATIONS FOR USE

The Edwards SAPIEN XT Transcatheter Heart Valve, model 9300TFX, and accessories are indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis (aortic valve area ≤ 1.0 cm² or aortic valve area index ≤ 0.6 cm²/m², a mean aortic valve gradient of ≥ 40 mmHg, or a peak aortic-jet velocity of ≥ 4.0 m/s), and with native anatomy appropriate for the 23, 26, or 29 mm valve system, who are judged by a heart team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., Society of Thoracic Surgeons operative risk score ≥8% or at a ≥15% risk of mortality at 30 days).

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# III. CONTRAINDICATIONS

The transcatheter heart valve (THV) and delivery systems are contraindicated in patients who cannot tolerate an anticoagulation/antiplatelet regimen or who have active bacterial endocarditis or other active infections.

# IV. WARNINGS AND PRECAUTIONS

Warnings and precautions can be found in the Edwards SAPIEN XT THV labeling.

# V. DEVICE DESCRIPTION

The Edwards SAPIEN XT THV, shown in Figure 1, is comprised of a balloon-expandable, radiopaque, cobalt chromium frame, trileaflet bovine pericardial tissue valve and polyethylene terephthalate (PET) fabric skirt. The leaflets are treated according to the Edwards ThermaFix™ process, and the valve is packaged and terminally sterilized in glutaraldehyde.

![img-0.jpeg](img-0.jpeg)
23mm and 26mm

![img-1.jpeg](img-1.jpeg)
29mm

Figure 1: SAPIEN XT Transcatheter Heart Valve

The NovaFlex+ delivery system, shown in Figure 2, includes a handle that provides a flex wheel for articulation of the flex catheter, a tapered tip at the distal end of the delivery system to facilitate crossing the native valve, a balloon catheter for deployment of the THV, and radiopaque markers.

![img-2.jpeg](img-2.jpeg)
Figure 2: NovaFlex+ Delivery System

The Edwards Expandable Introducer Sheath Set, shown in Figure 3, consists of a sheath, introducer, and loader.

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![img-3.jpeg](img-3.jpeg)
Figure 3: Edwards Expandable Introducer Sheath Set

The Edwards balloon catheter, shown in Figure 4, consists of a balloon, radiopaque marker bands, guidewire shaft, balloon catheter shaft, strain relief, and Y-connector.

![img-4.jpeg](img-4.jpeg)
Figure 4: Edwards Balloon Catheter

The Qualcrimp crimping accessory, shown in Figure 5, is a non patient-contacting device that is placed around the Edwards SAPIEN XT THV to protect the leaflets during the crimping process. It is available in two models. The cloth model is manufactured from ester-based polyurethane compressed foam encapsulated in a single piece of knitted polyester cloth that is wrapped around the foam and sutured at the top. The laminated model is manufactured of tubular polyester polyurethane foam that is laminated cylindrically on both the inner and outer surfaces with a polyether urethane material.

![img-5.jpeg](img-5.jpeg)
Cloth Model
Figure 5: Qualcrimp Crimping Accessory

![img-6.jpeg](img-6.jpeg)
Laminated Model

The Ascendra+ delivery system, shown in Figure 6, has radiopaque markers for visualization under fluoroscopy, a balloon for deployment of the THV and a handle. The system comes with a loader that is used to cover the THV during delivery. An extension tube is supplied for use with the delivery system during inflation.

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![img-7.jpeg](img-7.jpeg)
Figure 6: Ascendra+ Delivery System

The Ascendra+ introducer sheath set, shown in Figure 7, consists of an introducer and sheath.

![img-8.jpeg](img-8.jpeg)
Figure 7: Ascendra+ Introducer Sheath Set

The Ascendra balloon aortic valvuloplasty catheter, shown in Figure 8, is a coaxial catheter with a distal inflatable balloon intended to pre-dilate the stenotic aortic valve prior to implantation of the bioprosthesis. Two radiopaque marker bands indicate the dilating section of the balloon and aid in balloon placement. At the proximal end of the catheter, there is a standard "Y" connector for balloon inflation and a guidewire lumen. The Ascendra balloon aortic valvuloplasty catheter is supplied with optional extension tubing.

![img-9.jpeg](img-9.jpeg)
Figure 8: Ascendra Balloon Aortic Valvuloplasty Catheter

The Edwards crimper, shown in Figure 9, is comprised of various molded plastic components which compress the valve to a controlled aperture. The aperture is created by rotating the handle until it abuts the crimp stopper. The Edwards crimper includes a 2-piece crimp stopper (packaged with the NovaFlex+ delivery system) or a one-piece crimp stopper (packaged with the Ascendra+ delivery system) used to correctly crimp the THV.

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![img-10.jpeg](img-10.jpeg)
Figure 9: Edwards Crimper

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for patients with severe symptomatic native aortic valve stenosis deemed to be non-operable (non-surgical), including treatment with other commercially available transcatheter aortic valve replacement (TAVR) devices, temporary relief using percutaneous balloon aortic valvuloplasty (BAV) or medical therapy (non obstruction-relieving intervention). For patients who are deemed operable, but at high risk, surgical aortic valve replacement (SAVR) or replacement with other commercially available TAVR devices are alternatives. 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 his/her needs.

## VII. MARKETING HISTORY

Commercial distribution of the SAPIEN XT THV, model 9300TFX, and accessories outside the U.S. began in March 2010. Currently, the device is approved in the 28 member states under the European Union (i.e., Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom) and other countries, including Azerbaijan, Belarus, Bosnia and Herzegovina, Brazil, Canada, Columbia, Egypt, Georgia, Iceland, Iran, Israel, Japan, Jordan, Korea, Kuwait, Lebanon, Maghreb, Moldova, Monaco, Montenegro, Norway, Oman, Russia, Saudi Arabia, South Africa, Switzerland, Turkey, United Arab Emirates, and Venezuela. The device is also commercially distributed in compliance with applicable local requirements in Chile and New Zealand.

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

The adverse effects listed below are associated with access complications relating to catheterization or valvuloplasty and local and/or general anesthesia:

- Death
- Stroke/transient ischemic attack, clusters or neurological deficit
- Paralysis

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- Permanent disability
- Respiratory insufficiency or respiratory failure
- Hemorrhage requiring transfusion or intervention
- Cardiovascular injury including perforation or dissection of vessels, ventricle, myocardium or valvular structures that may require intervention
- Pericardial effusion or cardiac tamponade
- Embolization including air, calcific valve material or thrombus
- Infection including septicemia and endocarditis
- Heart failure
- Myocardial infarction
- Renal insufficiency or renal failure
- Conduction system defect which may require a permanent pacemaker
- Arrhythmia
- Retroperitoneal bleed
- Femoral AV fistula or pseudoaneurysm
- Reoperation
- Peripheral ischemia or nerve injury
- Restenosis
- Pulmonary edema
- Pleural effusion
- Bleeding
- Anemia
- Abnormal lab values (including electrolyte imbalance)
- Hypertension or hypotension
- Allergic reaction to anesthesia, contrast media, or device materials
- Hematoma
- Syncope
- Pain or changes at the access site
- Exercise intolerance or weakness
- Inflammation
- Angina
- Heart murmur
- Fever

Additional potential risks associated with the use of the THV, delivery system and/or accessories include:

- Cardiac arrest
- Cardiogenic shock
- Emergency cardiac surgery
- Cardiac failure or low cardiac output
- Coronary flow obstruction/transvalvular flow disturbance
- Device thrombosis requiring intervention
- Valve thrombosis

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- Device embolization
- Device migration or malposition requiring intervention
- Valve deployment in unintended location
- Valve stenosis
- Structural valve deterioration (wear, fracture, calcification, leaflet tear/tearing from the stent posts, leaflet retraction, suture line disruption of components of a prosthetic valve, thickening, stenosis)
- Device degeneration
- Paravalvular or transvalvular leak
- Valve regurgitation
- Hemolysis
- Device explants
- Nonstructural dysfunction
- Mechanical failure of delivery system, and/or accessories
- Non-emergent reoperation

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

## IX. SUMMARY OF PRECLINICAL STUDIES

### A. Laboratory Studies

In vitro studies were performed on the Edwards SAPIEN XT THV, model 9300TFX, and non-implantable accessories. Valve testing was performed in conformity with FDA’s Draft Replacement Heart Valve Guidance (1994) and ISO 5840: Cardiovascular Implants-Cardiac Valve Prostheses (2005).

### 1. Biocompatibility Studies

Toxicology and biocompatibility testing for the SAPIEN XT THV, model 9300TFX, and accessories was conducted in accordance with ISO 10993-1: Biological Evaluation of Medical Devices Part 1: Evaluation and Testing. Summaries of the test results for the SAPIEN XT THV, NovaFlex+ delivery system, Ascendra+ delivery system, Edwards Expandable Introducer Sheath Set, Ascendra+ introducer sheath set, Edwards balloon catheter, Ascendra balloon aortic valvuloplasty catheter, Qualcrimp crimping accessories (cloth model and laminated model), and Edwards crimper are provided in Tables 1-6. Test samples for the studies consisted of all patient-contacting portions of the devices (direct and indirect contact) after all manufacturing processes, including sterilant exposure. All results were acceptable.

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Table 1: Summary of Biocompatibility Testing - SAPIEN XT THV (Model 9300TFX)

|  Test | Purpose | Results  |
| --- | --- | --- |
|  Cytotoxicity: Percent Inhibition of Cell Growth | Determine whether test article extract would inhibit cell growth. | Test article found to be non-inhibitory to cell growth at a sample concentration representative of the device's clinical application. Inhibitory to cell growth at elevated sample concentrations.  |
|  Cytotoxicity: Medium Eluate Method (MEM) | Determine whether test article extracts would cause cytotoxicity and cell lysis | Test article sample was non-cytotoxic. 0% cell lysis was observed with equivalent results to the negative control.  |
|  Cytotoxicity: Agar Overlay Test | Determine whether solid samples of test article would cause cytotoxicity and cell lysis. | Solid samples of the stent frame were non-cytotoxic. 0% cell lysis was observed with equivalent results to the negative control. Cytotoxicity was observed in solid samples of the cloth, suture, and tissue material due to glutaraldehyde and formaldehyde residuals present in the solid sample.  |
|  Sensitization: Guinea Pig Maximization | Investigate the potential for delayed dermal contact sensitization. | No irritation was present on any of the test or control animals at 24 or 48 hour readings using saline and vegetable oil extracts. Non-sensitizing.  |
|  Irritation/Intracutaneous Toxicity: Rabbit Intracutaneous Reactivity | Determine whether test article extracts would cause local dermal irritation or toxic effects. | No evidence of irritation or abnormal effects over a 72 hour period as compared to negative controls.  |
|  Systemic Toxicity: USP Mouse Systemic Injection | Determine whether test article extracts would cause acute systemic toxicity. | No weight differences or observed systemic effects as compared to negative controls over 72 hour test period.  |
|  Systemic Toxicity: Material Mediated (Rabbit) Pyrogen Test | Determine the presence of chemical pyrogens in test article extracts by measuring temperature rise in intravenously injected rabbits. | Temperature rise of ≤0.5°C and no abnormalities in any test or control animals.  |
|  Implantation: Subacute/Subchronic Toxicity Chronic Toxicity | Determine whether the test article would cause systemic toxicity affects after 7, 30, and 90 days intramuscular implantation in rabbits. | No microscopic evidence of cytotoxicity.  |
|  Genotoxicity: Ames Test - Plate Incorporation | Determine whether test article extracts would cause mutagenic changes in five S. typhimurium strains. | Test article extracts demonstrated no mutagenic potential under both the activated and non-activated conditions.  |
|  Genotoxicity: Chromosomal Aberration Assay | Determine whether test article extracts would cause genotoxicity in Chinese Hamster ovary cells. | Test article extracts demonstrated no mutagenic potential under both the activated and non-activated conditions.  |

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Table 2: Summary of Biocompatibility Testing – NovaFlex+ Delivery System, Edwards Balloon Catheter and Ascendra+ Delivery System, and Ascendra Balloon Aortic Valvuloplasty Catheter

|  Test | Purpose | Results  |
| --- | --- | --- |
|  Cytotoxicity: Medium Eluate Method (MEM) | Determine whether test article extracts would cause cytotoxicity and cell lysis | Test article sample was non-cytotoxic. 0% cell lysis was observed with equivalent results to the negative control.  |
|  Cytotoxicity: Agar Overlay Test | Determine whether solid samples of test article would cause cytotoxicity and cell lysis | Solid samples of test articles were non-cytotoxic. 0% cell lysis was observed with equivalent results to the negative control.  |
|  Sensitization: Guinea Pig Maximization | Investigate the potential for delayed dermal contact sensitization | No irritation was present on any of the test or control animals at 24 and 48 hour readings using saline and vegetable oil extracts (additional 72 hours readings were performed for NovaFlex+). Non-sensitizing.  |
|  Irritation/Intracutaneous Toxicity: Rabbit Intracutaneous Reactivity | Determine whether test article extracts would cause local dermal irritation or toxic effects | No evidence of irritation over a 72 hour period as compared to negative controls.  |
|  Systemic Toxicity: Mouse Systemic Injection | Determine whether test article extracts would cause acute systemic toxicity | No weight differences or observed systemic effects as compared to negative controls over 72 hour test period.  |
|  Systemic Toxicity: Material Mediated (Rabbit) Pyrogen Test | Determine the presence of chemical pyrogens in test article extracts by measuring temperature rise in intravenously injected rabbits. | Temperature rise of ≤ 0.5°C and no abnormalities in any test or control animals.  |
|  Hemocompatibility: Hemolysis | Determine whether the test article would cause hemolysis in vitro and determine the degree of inhibition or promotion of clotting time | No hemolytic effects observed under static conditions for both extract and solid samples. Material's extract did not adversely affect the clotting time and was determined to be compatible with plasma.  |
|  Hemocompatibility: Complement Activation | Evaluate the test article's potential to activate the C3 and C5 complement system | Test article was determined to be hemocompatible and not at risk to activate complement at a level of concern in a clinical application. Results equivalent to negative control.  |

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Table 3: Summary of Biocompatibility Testing – Edwards Expandable Introducer Sheath Set and Ascendra+ Introducer Sheath Set

|  Test | Purpose | Results  |
| --- | --- | --- |
|  Cytotoxicity: Medium Eluate Method (MEM) | Determine whether test article extracts would cause cytotoxicity and cell lysis | Test article sample was non-cytotoxic. 0% cell lysis was observed with equivalent results to the negative control.  |
|  Sensitization: Guinea Pig Maximization | Investigate the potential for delayed dermal contact sensitization. | No irritation was present on any of the test or control animals at 24 hour using saline and vegetable oil extracts. Non-sensitizing.  |
|  Irritation/Intracutaneous Toxicity: Rabbit Intracutaneous Reactivity | Determine whether test article extracts would cause local dermal irritation or toxic effects | No evidence of irritation or abnormal effects as compared to negative controls. Non-irritating.  |
|  Systemic Toxicity: Mouse Systemic Injection | Determine whether test article extracts would cause acute systemic toxicity | No significant systemic effects observed as compared to negative controls. Systemically non-toxic.  |
|  Systemic Toxicity: Material Mediated (Rabbit) Pyrogen Test | Determine the presence of chemical pyrogens in test article extracts by measuring temperature rise in intravenously injected rabbits. | No temperature rise or abnormalities in any test or control animals. Systemically non-toxic.  |
|  Hemocompatibility: Hemolysis | Determine whether the test article would cause hemolysis in vitro and determine the degree of inhibition or promotion of clotting time | No hemolytic effects observed under static conditions for both extract and solid samples. Material's extract did not adversely affect the clotting time and was determined to be compatible with plasma.  |
|  Hemocompatibility: Complement Activation | Evaluate the test article's potential to activate the C3 and C5 complement system | Test article was determined to be hemocompatible and not at risk to activate complement at a level of concern in a clinical application. Results equivalent to negative control.  |

Table 4: Summary of Biocompatibility Testing – Qualcrimp Crimping Accessory (Cloth Model)

|  Test | Purpose | Results  |
| --- | --- | --- |
|  Cytotoxicity: Medium Eluate Method (MEM) | Determine whether test article extracts would cause cytotoxicity and cell lysis | Test article sample was non-cytotoxic. 0% cell lysis was observed with equivalent results to the negative control.  |
|  Cytotoxicity: Agar Overlay Test | Determine whether solid samples of test article would cause cytotoxicity and cell lysis. | Solid samples of test articles were non-cytotoxic. 0% cell lysis was observed with equivalent results to the negative control.  |
|  Sensitization: Guinea Pig Maximization | Investigate the potential for delayed dermal contact sensitization. | No irritation was present on any of the test or control animals at 24 or 48 hour readings using saline and vegetable oil extracts. Non-sensitizing.  |
|  Irritation/Intracutaneous Toxicity: Rabbit Intracutaneous Reactivity | Determine whether test article extracts would cause local dermal irritation or toxic effects | No evidence of irritation or abnormal effects over a 72 hour period as compared to negative controls.  |

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Table 5: Summary of Biocompatibility Testing – Qualcrimp Crimping Accessory (Laminated Model)

|  Test | Purpose | Results  |
| --- | --- | --- |
|  Cytotoxicity: Medium Eluate Method (MEM) | Determine whether test article extracts would cause cytotoxicity and cell lysis | Test article sample was non-cytotoxic. 0% cell lysis was observed with equivalent results to the negative control.  |

Table 6: Summary of Biocompatibility Testing – Edwards Crimper (Model 9350CR)

|  Test | Purpose | Results  |
| --- | --- | --- |
|  Cytotoxicity: Medium Eluate Method (MEM) | Determine whether test article extracts would cause cytotoxicity and cell lysis | Test article sample was non-cytotoxic. 0% cell lysis was observed with equivalent results to the negative control.  |
|  Irritation/Intracutaneous Toxicity: Rabbit Intracutaneous Reactivity | Determine whether test article extracts would cause local dermal irritation or toxic effects | No evidence of irritation or abnormal effects over a 72 hour period as compared to negative controls.  |

2. SAPIEN XT THV Hydrodynamic Performance

In vitro hydrodynamic performance studies of the SAPIEN XT bioprosthesis (test valve) were completed to evaluate performance under steady and pulsatile flow testing conditions. Valves were evaluated after nominal deployment and after deployment into irregular shapes (i.e., under deployed, oval deployed, and over deployed). The studies were conducted in accordance with FDA’s Draft Replacement Heart Valve Guidance (1994) and/or ISO 5840: Cardiovascular Implants-Cardiac Valve Prostheses (2005). Reference articles for the nominally deployed SAPIEN XT valve studies consisted of commercially available aortic valves; reference articles for the irregular studies consisted of nominally deployed SAPIEN XT valves. A matrix of the tests performed and corresponding results is provided in Table 7.

Table 7: Hydrodynamic Testing and Results

|  Test | Purpose/Objective | Test/Reference Articles | Results  |
| --- | --- | --- | --- |
|  Steady Forward Flow | To determine the pressure drop at various steady forward flow rates. | Nominal
Test: SAPIEN XT Size 23mm, 26mm & 29mm
Reference: Nominal SAPIEN size 23mm, 26mm, & surgical Perimount Magna size 23mm, 27mm & 29mm valves; reference nozzle
Irregular
Test: Irregular SAPIEN XT size 23mm, 26mm & 29mm | The SAPIEN XT valve offers acceptable hemodynamics with pressure gradients and effective orifice areas (EOA) that are comparable to those offered by the reference valves.  |

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|  Test | Purpose/Objective | Test/Reference Articles | Results  |
| --- | --- | --- | --- |
|   |  | Reference: Nominal SAPIEN XT size 23mm, 26mm & 29mm; Nominal SAPIEN size 23mm & 26mm; reference nozzle |   |
|  Steady Backflow Leakage | To determine the leakage rate at various steady back flow pressures. | Nominal
Test: SAPIEN XT Size 23mm, 26mm & 29mm
Reference: Nominal SAPIEN size 23mm, 26mm, & surgical Perimount Magna size 23mm, 27mm & 29mm valves; reference nozzle

Irregular
Test: Irregular SAPIEN XT size 23mm, 26mm & 29mm
Reference: Nominal SAPIEN XT size 23mm, 26mm & 29mm; Nominal SAPIEN size 23mm & 26mm; reference nozzle | The SAPIEN XT valve offers satisfactory performance in terms of its competency to prevent significant transvalvular aortic back-flow during the diastolic phase.  |
|  Pulsatile Flow Pressure Drop | To determine pressure drop and effective orifice area performance under pulsatile flow conditions. | Nominal
Test: SAPIEN XT Size 23mm, 26mm & 29mm
Reference: Nominal SAPIEN size 23mm, 26mm, & surgical Perimount Magna size 23mm, 27mm & 29mm valves

Irregular
Test: Irregular SAPIEN XT size 23mm, 26mm & 29mm
Reference: Nominal SAPIEN XT size 23mm, 26mm & 29mm; Nominal SAPIEN size 23mm & 26mm | The SAPIEN XT valve offers acceptable hydrodynamics with a larger effective orifice area than those required by the ISO 5840:2005 acceptance criteria for aortic valves, and similar pressure drop to the reference valves.  |
|  Pulsatile Flow Regurgitation | To determine regurgitation performance under pulsatile flow conditions. | Nominal
Test: SAPIEN XT Size 23mm, 26mm & 29mm
Reference: Nominal SAPIEN size 23mm, 26mm, & surgical Perimount Magna size 23mm, 27mm & 29mm valves

Irregular
Test: Irregular SAPIEN XT size 23mm, 26mm & 29mm
Reference: Nominal SAPIEN XT size 23mm, 26mm & 29mm; | The SAPIEN XT valve offers acceptable hydrodynamics with regurgitant fractions that were lower than those required by the ISO 5840:2005 acceptance criteria.  |

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|  Test | Purpose/Objective | Test/Reference Articles | Results  |
| --- | --- | --- | --- |
|   |  | Nominal SAPIEN size 23mm & 26mm |   |
|  Flow Visualization | To qualitatively investigate flow characteristics in the vicinity of the valve. | **Nominal**
Test: SAPIEN XT Size 23mm
Reference: SAPIEN size 23mm
**Irregular**
Test: Irregular SAPIEN XT, sizes 23mm & 29mm
Reference: Nominal SAPIEN XT size 23mm & 29mm | The SAPIEN XT valve offers acceptable aortic flow patterns throughout the entire cardiac cycle.

Broad central jet-like flows with no flow stasis during opening were observed in all SAPIEN XT valves, with no retrograde jet-like flow.  |
|  Verification of Bernoulli Relationship | To determine whether the Bernoulli relationship applies to clinical pressure drop measurements. | **Nominal**
Test: SAPIEN XT Size 23mm, 26mm & 29mm
**Irregular**
Test: Irregular SAPIEN XT Size 23mm, 26mm & 29mm
Reference: Nominal SAPIEN XT size 29mm | Pressure drop results for the SAPIEN XT valve demonstrated correlation with the Bernoulli relationship.  |

## 3. SAPIEN XT THV Structural Performance

In vitro structural performance studies of the SAPIEN XT THV were performed. The studies were conducted in accordance with FDA's Draft Replacement Heart Valve Guidance (1994) and/or ISO 5840: Cardiovascular Implants-Cardiac Valve Prostheses (2005). Commercially available bioprosthetic aortic valves and Cordis Palmaz Genesis stents were used as control articles in studies requiring concurrent testing of devices marketed in the U.S. A matrix of tests performed and corresponding results are provided in Table 8.

Table 8: Structural Performance Evaluation

|  Test | Purpose/Objective | Test/Reference Articles | Results  |
| --- | --- | --- | --- |
|  Accelerated Wear | To assess long-term performance of the valve though accelerated wear. | **Nominal**
Test: SAPIEN XT size 23mm, 26mm & 29mm
Reference: Nominal SAPIEN size 23mm, 26mm, & surgical Perimount Magna size 23mm, 27mm & 29mm valves
**Irregular**
Test: SAPIEN XT size 23mm, 26mm & 29mm
Reference: PERIMOUNT size 23mm, 27mm & 29mm; Nominal | All valves survived durability testing to 200 million cycles in accelerated wear testers without excessive structural damage and/or functional impairment.

After testing to 200 million cycles, all valves met the minimum EOA and Total Regurgitation Fraction requirements of ISO 5840:2005.  |

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|  Test | Purpose/Objective | Test/Reference Articles | Results  |
| --- | --- | --- | --- |
|   |  | SAPIEN XT size 23mm and 26mm |   |
|  Dynamic Failure Mode | To obtain information about the failure modes affecting the durability of the valve. | Test: SAPIEN XT size 23mm, 26mm & 29mm
Reference: PERIMOUNT Size 23mm, 27mm & 29mm | All of the failures for both the test and reference valves occurred at pressures well beyond what would be experienced in vivo.  |
|  Frame Crush Resistance | To evaluate the resistance of the valve to lateral compressive loads. | SAPIEN XT frames size 23mm, 26mm & 29mm | Minimum force required to compress the frame was acceptable.  |
|  Frame Corrosion Resistance | To characterize the corrosion resistance of the valve frames and 4-hole bars in accordance with ASTMF2129-08 | Test: SAPIEN XT frames size 23mm, 26mm & 29mm, SAPIEN XT 4-hole bars
Reference: Cordis Palmaz Genesis stents | Corrosion resistance of SAPIEN XT cobalt chromium frames and 4-Hole Bars are equivalent to the commercially available stent.  |
|  Frame Fatigue | To determine frame fatigue resistance to 600 million cycles. | Test: SAPIEN XT frames size 23mm, 26mm & 29mm | No frame cracks or fractures were observed at 10x magnification following 600 million cycles of fatigue testing.  |
|  Stress Analysis (FEA) | To characterize mechanical behavior of the frame during deployment and operation. | Modeling based on in vitro and clinical data of 23mm, 26mm & 29mm SAPIEN XT frames. | Results indicate that the worst-case 26mm & 29mm SAPIEN XT frame should not fracture for 600 million cycles, even under the unlikely simultaneous combination of all the worst-case conditions.  |

## 4. SAPIEN XT THV Design Specific Performance Studies

Design specific in vitro performance studies of the SAPIEN XT THV were completed. The following studies were completed with acceptable results: percent surface area, frame overexpansion safety factor, frame foreshortening and recoil, frame radial strength, valve migration force, pulsatile flow migration, and radiopacity.

## 5. SAPIEN XT THV Magnetic Resonance Imaging (MRI) Compatibility

Testing of the size 23 mm, 26 mm, and 29 mm frames in magnetic fields of 1.5 and 3.0 Tesla has shown that the SAPIEN XT THV is MR Conditional. It can be scanned safely under the following conditions:

- Static magnetic field of 1.5 Tesla or 3.0 Tesla
- Spatial gradient field of 2500 Gauss/cm or less
- Maximum whole-body-averaged specific absorption rate (WB-SAR) of 2.0 W/kg for 15 minutes of scanning.
- Normal mode operation, as defined in IEC 60601-2-33, of the MR system

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6. Delivery System and Accessory Performance Testing

The following tests were performed for the NovaFlex+ delivery system and the Ascendra+ delivery system and showed acceptable results: dimensional verification, visual inspection, simulated use, balloon characterization, bond strength, and hemostasis. The NovaFlex+ delivery system was also subjected to valve retention testing.

The following tests were performed for the Edwards Expandable Introducer Sheath Set and the Ascendra+ introducer sheath set and showed acceptable results: dimensional verification, visual inspection, simulated use, bond strength, and hemostasis.

The following tests were performed for the Edwards balloon catheter and the Ascendra balloon aortic valvuloplasty catheter and showed acceptable results: dimensional verification, visual inspection, simulated use, balloon characterization, and bond strength.

The following tests were performed for the Qualcrimp and showed acceptable results: dimensional verification, visual inspection, and simulated use.

The following tests were performed for the Edwards crimper and showed acceptable results: dimensional verification, visual inspection, and simulated use.

7. Sterilization

The SAPIEN XT THV is sterilized by terminal liquid sterilization (TLS) in buffered glutaraldehyde solution. The NovaFlex+ delivery system, Ascendra+ delivery system, Edwards Expandable Introducer Sheath Set, Ascendra+ introducer sheath set, Edwards balloon catheter, Ascendra balloon aortic valvuloplasty catheter, Qualcrimp crimping accessory, and Edwards crimper are sterilized by ethylene oxide (EO). After sterilization, the devices are held in quarantine until sterility is verified per process specifications. The TLS and EO processes have demonstrated Sterility Assurance Levels (SAL) of $10^{-6}$ in validation studies.

8. Shelf Life

Packaging and product integrity studies were conducted to ensure that the shelf life for each package and product is maintained for a minimum of two (2) years for the NovaFlex+ delivery system, Ascendra+ delivery system, Edwards Expandable Introducer Sheath Set, Ascendra+ introducer sheath set, Edwards balloon catheter, Ascendra balloon aortic valvuloplasty catheter, Qualcrimp, and Edwards crimper.

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The 23mm and 26mm SAPIEN XT THVs are labeled with a two (2) year shelf life; the 29mm SAPIEN XT THV is currently labeled with a one (1) year shelf life.

## 9. Package Integrity

The packaging for the SAPIEN XT THV consists of a 3.8 oz jar, a lid and gasket closure system, and shelf and shipping containers. This system has been evaluated via physical testing and microbial challenge and was shown to maintain its sterile barrier following five years of real-time aging and exposure to temperature variations and simulated shipping conditions.

The NovaFlex+ delivery system, Ascendra+ delivery system, Edwards Expandable Introducer Sheath Set, Ascendra+ introducer sheath set, Edwards balloon catheter, Ascendra balloon aortic valvuloplasty catheter, Qualcrimp crimping accessory, and Edwards crimper are packaged in Tyvek pouches and shelf and shipping cartons. These systems have been evaluated and shown to maintain sterile barrier following two years of accelerated aging and exposure to temperature variations and simulated shipping conditions.

## 10. Product Integrity

### SAPIEN XT THV Biological Tissue

Edwards ThermaFix-processed bovine pericardial tissue has previously been validated and approved under PMA P860057 regarding the Carpentier-Edwards® PERIMOUNT® Pericardial Bioprosthesis product family, and PMA P100041 and P110021 for the SAPIEN THV. The tissue used for the SAPIEN XT THV is identical to the tissue used in the PERIMOUNT and SAPIEN valves.

Biochemical evaluation was conducted on tissue stored in glutaraldehyde solution for four years of real time aging. All device specifications were met for moisture content, ninhydrin content, shrinkage temperature, and enzymatic digestion of tissue.

Histological examination of leaflets was conducted on leaflet samples from whole valves at zero-time and after two years of real-time aging. Results demonstrated that aging of tissue does not appear to impact the microstructure of bovine pericardial tissue used in the SAPIEN XT THV. A stress relaxation study was completed to compare cyclic load decay for tissue leaflet samples at zero-time to tissue leaflets after three years of real-time aging. No statistically significant difference was observed between the two groups.

### SAPIEN XT THV Non-biological Components and Whole Valve Testing

Functionality of the SAPIEN XT THV's non-biologic components (polymers: valve holder, skirt, sleeve, and sutures; and metallics: frame) and whole-valve hydrodynamic and wear testing were completed after 2 years of real-time aging (for size 23 and 26mm valves).

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Tensile testing of the frame met acceptance criteria. Corrosion resistance of the frame demonstrated higher resistance than the zero-time reference. Tensile testing of all polymer components met acceptance criteria relative to zero-time reference strengths. All valves passed the minimum hydrodynamic performance requirements for EOA and Regurgitant Fraction per ISO 5840:2005. The 2 year real-time aged SAPIEN XT THVs (sizes 23mm and 26mm) survived durability testing out to 200 million cycles in accelerated wear testers under aortic pressure test conditions without failure, significant tissue wear or frame deformation and fracture. These valves offered a larger EOA and lower regurgitant fractions than those required per the minimum performance requirements of ISO 5840:2005 after 200 million cycles. The size 29 mm SAPIEN XT is currently labeled with a 1 year shelf life, which was substantiated based on in vitro testing of real time aged tissue and non-biologic components, as noted above.

## Delivery System and Accessories

Functionality and product integrity of the NovaFlex+ delivery system, Ascendra+ delivery system, Edwards Expandable Introducer Sheath Set, Ascendra+ introducer sheath set, Edwards balloon catheter, Ascendra balloon aortic valvuloplasty catheter, Qualcrimp crimping accessory, and Edwards crimper was demonstrated after two years of accelerated aging, exposure to temperature variations and simulated shipping conditions.

## B. SAPIEN XT THV Animal Studies

A chronic study was performed on the SAPIEN XT THV using 37 young adult male sheep implanted with annuloplasty rings in the aortic annulus to model the semi-rigid environment of the diseased aortic root found in the stenotic clinical situation. The THVs were surgically implanted, but deployed using a delivery system for simulated use. The study used the smallest size (23 mm) SAPIEN XT THVs due to anatomical limitations of the animal model. The endpoints of the animal study are a function of valve design and material interactions, and therefore the results of the study are applicable to all valve sizes. An overview of the study is provided in Table 9.

Table 9: GLP Chronic Study Overview

|  Sample Size/Animal Model | 37 young adult male sheep
Annuloplasty rings were surgically implanted into the aortic annulus to model the semi-rigid environment of the diseased aortic root found in the stenotic clinical situation.  |
| --- | --- |
|  Test Articles | Size 23 mm SAPIEN XT transcatheter heart valve, model 9300TFX.  |
|  Control Articles | Commercially available SAPIEN transcatheter heart valve (model 9000TFX) and Carpentier-Edwards PERIMOUNT pericardial bioprosthesis (model 2800TFX).  |

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A total of 34 SAPIEN XT and SAPIEN THVs were implanted for a 10 week and 20 week evaluation study: 6 animals (three SAPIEN XT and three SAPIEN) were electively sacrificed at 10 weeks, and 12 (six SAPIEN XT and six SAPIEN) survived to 20 weeks. Three (3) model 2800TFX surgical control articles were implanted in the aortic position of 3 adult male sheep: 2 survived to 20 weeks and were clinically normal prior to explant; 1 survived less than 14 days. The results of this study demonstrated that the SAPIEN XT THV has acceptable hemodynamic performance and is suitable for long-term implant. The three valve models were comparable for all parameters evaluated. A summary of the study results is provided in Table 10.

Table 10: GLP Chronic Study Summary

|  Evaluation Parameter | Summary of Results  |
| --- | --- |
|  Clinical History and Hematology | All six 10-week and thirteen of the fourteen 20-week sheep were clinically normal prior to explants. One animal experienced an increased respiratory rate and effort two weeks post operative and remained on diuretic therapy until sacrifice.

Clinical chemistry and complete blood count results were within normal limits for the majority of animals at implant and explant. Five animals, from test and control groups, showed moderately low platelet count. Among the remaining animals, some values were either slightly above or below the reported normal range but none was considered to clinically significant. Findings were comparable between all groups. None of the pre-implant and pre-explant abnormal hematology findings were considered to be clinically significant to affect the outcome of the study.  |
|  Hemodynamic Performance | In general, peak gradients and cardiac outputs at explants tended to be higher than at implant.

The 9300TFX and 9000TFX valves had evidence of valvular insufficiency by contrast angiography. The gaps were located between the annuloplasty ring and the aortic wall and were a failure of the model and not a problem with the valve delivery or performance. One 2800TFX control valve had paravalvular gap from possible suture tear.

Angiography evaluation at 20 weeks indicated that 5 of 6 test valves had grade 1-2 regurgitation and 1 of 6 had grade 3-4 regurgitation. For the 9000TFX control valve  |

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|  Evaluation Parameter | Summary of Results  |
| --- | --- |
|   | at 20 weeks, 4 of 6 had grade 1-2 regurgitation and 2 of 6 had grade 3-4 regurgitation. For the 2800TFX control valve at 20 weeks, 1 of 2 had grade 3-4 regurgitation and 1 of 2 had no evidence of regurgitation.  |
|  Histopathology | Histopathology results showed no apparent differences in tissue reactions (general healing, calcification, or morphology of the tissue/valve interface) between the test device and the control device. Tissue reactions towards the test and control devices were generally of low severity and were considered to be typical of this type of device implant.  |
|  Gross Observations | General healing results were comparable among the three valve models at 20 weeks. There were no thrombus, valvular mineralization and vegetative growths in 17 of 18 valves. There was no migration, leaflet damage, material wear, or structural failure in 17 of 18 valves. Minimal thrombus formation with unknown etiology was observed in the inflow aspect and minimal leaflet transparency observed on the outflow aspect of a model 9300TFX; attributable to compression lines caused by valve crimping. All valves showed no gross evidence of calcification deposits at 10 weeks, and only 1 in 12 valves at 20 weeks. Minimal to mild calcific deposits were observed in one valve model 9300TFX, possibly as a result of an individual animal response

The gross examination for the target organs (kidneys, liver, spleen, lung) at 10 and 20 weeks were all within normal limits, excluding one animal for the model 2800TFX at 20 weeks.  |
|  Clinical History and Hematology | All six 10-week and thirteen of the fourteen 20-week sheep were clinically normal prior to explants. One animal experienced an increased respiratory rate and effort two weeks post operative and remained on diuretic therapy until sacrifice.

Clinical chemistry and complete blood count results were within normal limits for the majority of animals at implant and explant. Five animals, from test and control groups, showed moderately low platelet count. Among the remaining animals, some values were either slightly above or below the reported normal range but none was considered to clinically significant. Findings were comparable between all groups. None of the pre-implant and pre-explant abnormal hematology findings were considered to be clinically significant to affect the outcome of the study.  |
|  Hemodynamic Performance | In general, peak gradients and cardiac outputs at explants tended to be higher than at implant.

The 9300TFX and 9000TFX valves had evidence of valvular insufficiency by contrast angiography. The gaps were located between the annuloplasty ring and the aortic wall and were a failure of the model and not a problem with the valve delivery or performance. One 2800TFX control valve had paravalvular gap from possible suture tear.

Angiography evaluation at 20 weeks indicated that 5 of 6 test valves had grade 1-2 regurgitation and 1 of 6 had grade 3-4 regurgitation. For the 9000TFX control valve at 20 weeks, 4 of 6 had grade 1-2 regurgitation and 2 of 6 had grade 3-4 regurgitation. For the 2800TFX control valve at 20 weeks, 1 of 2 had grade 3-4 regurgitation and 1 of 2 had no evidence of regurgitation.  |
|  Histopathology | Histopathology results showed no apparent differences in tissue reactions (general healing, calcification, or morphology of the tissue/valve interface) between the test device and the control device. Tissue reactions towards the test and control devices were generally of low severity and were considered to be typical of this type of device implant.  |

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|  Evaluation Parameter | Summary of Results  |
| --- | --- |
|  Gross Observations | General healing results were comparable among the three valve models at 20 weeks. There were no thrombus, valvular mineralization and vegetative growths in 17 of 18 valves. There was no migration, leaflet damage, material wear, or structural failure in 17 of 18 valves. Minimal thrombus formation with unknown etiology was observed in the inflow aspect and minimal leaflet transparency observed on the outflow aspect of a model 9300TFX; attributable to compression lines caused by valve crimping. All valves showed no gross evidence of calcification deposits at 10 weeks, and only 1 in 12 valves at 20 weeks. Minimal to mild calcific deposits were observed in one valve model 9300TFX, possibly as a result of an individual animal response

The gross examination for the target organs (kidneys, liver, spleen, lung) at 10 and 20 weeks were all within normal limits, excluding one animal for the model 2800TFX at 20 weeks.  |

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The clinical data presented in this section to establish a reasonable assurance of safety and effectiveness of the SAPIEN XT THV came from the following sources:

- Cohort B of the PARTNER II trial (G090216): randomized, inoperable patients, transfemoral (TF) delivery, 23 and 26 mm THVs (cf. section X.1)
- NR5: single-arm registry, inoperable patients, transfemoral delivery, 29 mm THV (cf. section X.2)
- NR1, NR4, and NR6: single-arm registry, inoperable patients, alternate access (NR1: transapical (TA) delivery of size 23 and 26 mm; NR4: transaortic (TAo) delivery of size 23 and 26 mm; and NR6: transapical delivery of size 29 mm; cf. section X.3)
- Edwards SOURCE XT Registry: single-arm, high risk patients, 23, 26, and 29 mm THVs, all access sites (cf. section X.4)

## X.1 SUMMARY OF THE RANDOMIZED CLINICAL TRIAL

### A. Study Design

Cohort B of the PARTNER 2 trial was a prospective, randomized, controlled, multicenter, pivotal trial study comparing the SAPIEN XT THV with the first generation SAPIEN THV in non-surgical patients who were candidates for the transfemoral approach. Patients were randomized in a 1:1 ratio to either TAVR with the SAPIEN XT THV (test arm) or TAVR with the SAPIEN THV (control arm). The valve sizes used in the trial included only the 23 and 26 mm ones.

The sample size was set to 500 patients based on a non-inferiority ratio of 1.35 at a one-sided alpha of 0.025, with the assumptions of a 1:1 randomization ratio, 43.6% event rate in both trial arms, 80% power, and 10% attrition rate, and other trial contingencies.

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The primary safety and effectiveness endpoint was a non-hierarchical composite of death (all cause), disabling (major) stroke, and rehospitalization for symptoms of aortic stenosis and/or complications of the valve procedure at one year (Day 365). Major stroke and rehospitalization were evaluated by the Clinical Event Committee (CEC). Events occurring on day 365 or earlier were included in the evaluation. Events occurring after day 365 were not included.

Pre-specified secondary endpoints included days alive and out of the hospital, NYHA functional class, the distance covered during a 6 minute walk test (6MWT), and valve performance (assessed by echocardiography).

The analysis was based on the ratio of proportions. Let $r_T$ denote the true event proportion in the test arm, and $r_C$ denote the true event proportion in the control arm. The hypotheses were:

$$
\mathrm{H}_0: r_T / r_C \geq 1 + \mathrm{D}
$$

$$
\mathrm{H}_A: r_T / r_C < 1 + \mathrm{D}
$$

where D was the non-inferiority margin, and was set at 0.35.

The primary analysis population is the intent-to-treat (ITT) population. The event proportions $r_T$ and $r_C$ were computed using the Kaplan-Meier algorithm. The standard errors $s_T$ and $s_C$ were computed using Greenwood's formula. A two-sided 95% confidence interval for the logarithm of the ratio under the null hypothesis was constructed and then transformed back to produce confidence limits for the ratio itself. The null hypothesis was rejected at alpha = 0.025 if the upper limit of the confidence interval was less than 1.35.

1. Inclusion and Exclusion Criteria

Enrollment in Cohort B was limited to patients who met the following inclusion criteria:

(1) Patient has senile degenerative aortic valve stenosis with echocardiographically derived criteria: mean gradient > 40 mmHg or jet velocity greater than 4.0 m/s and an initial aortic valve area (AVA) of ≤ 0.8 cm² or indexed EOA < 0.5 cm²/m². Qualifying echo must be within 45 days of the date of the procedure.

(2) Patient is symptomatic from his/her aortic valve stenosis, as demonstrated by NYHA Functional Class II or greater.

(3) The heart team agrees (and verified in the case review process) that valve implantation will likely benefit the patient.

(4) The study patient or the study patient's legal representative 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.

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(5) The study patient agrees to comply with all required post-procedure follow-up visits including annual visits through 5 years and analysis close date visits, which will be conducted as a phone follow-up.

(6) The heart team agrees 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 is ≥ 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 the patient. At least one of the cardiac surgeon assessors must have physically evaluated the patient. All Cohort B patients must be approved by the Patient Selection and Procedure Management Steering or Executive Committee (at least 2 member votes, one must be a cardiac surgeon).

(7) The heart team agrees the patient is likely to benefit from valve replacement.

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

(1) Evidence of an acute myocardial infarction ≤ 1 month (30 days) before the intended treatment [(defined as: Q wave MI, or non-Q wave MI with total CK elevation of CK-MB ≥ twice normal in the presence of MB elevation and/or troponin level elevation (WHO definition)].

(2) Aortic valve is a congenital unicuspid or congenital bicuspid valve, or is non-calcified.

(3) Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+).

(4) Preexisting mechanical or bioprosthetic valve in any position.

(5) Any therapeutic invasive cardiac procedure resulting in a permanent implant that is performed within 30 days of the index procedure (unless part of planned strategy for treatment of concomitant coronary artery disease) Implantation of a permanent pacemaker is not excluded.

(6) Any patient with a balloon valvuloplasty (BAV) within 30 days of the procedure (unless BAV is a bridge to procedure after a qualifying ECHO).

(7) Patients with planned concomitant surgical or transcatheter ablation for Atrial Fibrillation.

(8) Leukopenia (WBC < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), Thrombocytopenia (Plt < 50,000 cell/mL).

(9) Untreated clinically significant coronary artery disease requiring revascularization.

(10) Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or mechanical heart assistance within 30 days of screening evaluation.

(11) Need for emergency surgery for any reason.

(12) Hypertrophic cardiomyopathy with or without obstruction (HOCM).

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(13) Severe ventricular dysfunction with LVEF < 20%.
(14) Echocardiographic evidence of intracardiac mass, thrombus or vegetation.
(15) Active upper GI bleeding within 3 months (90 days) prior to procedure.
(16) A known contraindication or hypersensitivity to all anticoagulation regimens, or inability to be anticoagulated for the study procedure.
(17) Native aortic annulus size < 18 mm or > 25 mm as measured by echocardiogram.
(18) Clinically (by neurologist) or neuroimaging confirmed stroke or transient ischemic attack (TIA) within 6 months (180 days) of the procedure.
(19) Renal insufficiency (creatinine > 3.0 mg/dL) and/or renal replacement therapy at the time of screening.
(20) Estimated life expectancy < 24 months (730 days) due to carcinomas, chronic liver disease, chronic renal disease or chronic end stage pulmonary disease.
(21) Expectation that patient will not improve despite treatment of aortic stenosis.
(22) Significant aortic disease, including marked tortuosity (hyperacute bend), aortic arch atheroma [especially if thick (> 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.
(23) Iliofemoral vessel characteristics that would preclude safe placement of 22F or 24F introducer sheath such as severe obstructive calcification, severe tortuosity or minimum average vessel size less than 7 mm.
(24) Currently participating in an investigational drug or another device study. Note: Trials requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials.
(25) It is known that the patient is currently enrolled in the PARTNER I Trial or was withdrawn from the PARTNER I Trial prior to endpoint analysis.
(26) Active bacterial endocarditis within 6 months (180 days) of procedure

The study used the following: an independent Data Safety Monitoring Board (DSMB) that was instructed to notify Edwards Lifesciences of any safety or compliance issues; a CEC that was responsible for adjudicating endpoint related events reported during the trial per definitions established a priori; an ECG Core Lab for independent analysis of rhythm and occurrence of myocardial infarction; and an Echocardiographic Core Lab for independently analyzing all echocardiograms.

2. Follow-up Schedule

All patients were followed during the index hospitalization, at 30 days, 6 months, 1 year, and annually thereafter. The key time points and evaluations conducted at all time points in the study are shown in Table 11.

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Table 11: Schedule of Events - Cohort B

|   | Screening | Baseline | During procedure | Post Procedure | Discharge | Post Procedure | Post Procedure | 30 D Follow-Up (-7 days; +14 days) | Follow-Up (±60 days) | 1 Yr Follow-Up (±60 days) | Annual Follow-Up ≥5 Y (±60 days) | Telephone Follow-up after analysis close date (+30 days)  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Physical assessment and Patient interview |  |  |  |  |  |  |  |  |  |  |  |   |
|  Operability Risk Assessment | X |  |  |  |  |  |  |  |  |  |  |   |
|  Informed Consent | X |  |  |  |  |  |  |  |  |  |  |   |
|  Medical History | X |  |  |  |  |  |  |  |  |  |  |   |
|  Physical Exam | X |  |  |  | X | X | X | X |  |  |  | X  |
|  CCS Angina | X |  |  |  | X | X | X | X |  |  |  | X  |
|  NYHA Classification | X |  |  |  | X | X | X | X |  |  |  | X  |
|  Cardiac Medications |  | X | X | X | X | X | X | X |  | X |  | X  |
|  Adverse Event Assessment |  | X | X | X | X | X | X | X |  | X |  | X  |
|  NIH Stroke Score Assessment |  | X1 |  |  | X1 | X1 | X1 | X1 |  |  |  | X  |
|  Modified Rankin Scale |  | X1, |  |  | X1,2 | X1,2 | X1,2 | X1,2 |  |  |  | X  |
|  Barthel Index |  | X1,2 |  |  | X1,2 | X1,2 | X1,2 | X1,2 |  |  |  |   |
|  Risk Score Assessments: STS Risk Score Logistic EuroSCORE | X X |  |  |  |  |  |  |  |  |  |  |   |
|  Six Minute Walk Test (6MWT) |  | X |  |  |  | X |  | X |  |  |  |   |
|  MMSE | X |  |  |  |  |  |  |  |  |  |  |   |
|  Frailty Index |  | X |  |  |  |  |  |  |  |  |  |   |
|  Lab Measurements |  |  |  |  |  |  |  |  |  |  |  |   |
|  CBC with Differential and Platelet Count |  | X |  | X | X | X |  | X |  |  |  |   |
|  PTT or PT/INR |  | X |  | X | X |  |  |  |  |  |  |   |
|  CK/CKMB and/or Troponins |  | X3 |  | X4 |  |  |  |  |  |  |  |   |
|  Metabolic Panel (Sodium, Potassium, Creatinine, BUN) |  | X |  | X | X |  |  | X |  |  |  |   |
|  Liver Panel (ALT, AST) |  | X |  |  |  |  |  |  |  |  |  |   |
|  Albumin |  | X |  |  |  | X |  | X |  |  |  |   |
|  BNP |  | X |  |  | X | X |  | X |  |  |  | X  |
|  Plasma Free Hemoglobin & Haptoglobin |  | X |  |  |  | X |  | X |  |  |  |   |
|  Non-Invasive Tests |  |  |  |  |  |  |  |  |  |  |  |   |
|  ECG |  | X |  | X | X | X |  | X |  |  |  |   |
|  Chest X-ray |  | X |  |  | X | X |  | X |  |  |  | X  |
|  Transthoracic Echocardiogram (TTE) | X |  |  |  | X | X |  | X |  |  |  | X  |
|  Fluoroscopic imaging implanted valve |  |  | X |  |  | X5 |  | X5 |  |  |  | X5  |
|  Invasive Tests |  |  |  |  |  |  |  |  |  |  |  |   |

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|   | Screening | Baseline | During procedure | Post Procedure | Discharge | Discharge | 4 (2-30 days) Follow-up | 6 M (2-30 days) Follow-up | 1 Yr Follow-Up (≥ 60 days) | Telephone Follow-up after analysis close date (+30 days) | Annual Follow-Up ≥5 Y (≥ 60 days) | Telephone Follow-up after analysis close date (+30 days)  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  CT Thoracic/Abdomen with visualization of iliac and femoral arteries | X |  |  |  |  |  |  |  |  |  |  |   |
|  Cardiac Catheterization | X |  |  |  |  |  |  |  |  |  |  |   |
|  Supra-aortic angiogram or TEE |  |  | X |  |  |  |  |  |  |  |  |   |
|  Invasive Hemodynamics |  |  | X |  |  |  |  |  |  |  |  |   |
|  Quality of Life Questionnaire |  |  |  |  |  |  |  |  |  |  |  |   |
|  Cohort B KCCQ, EQ5D, SF12 |  | X |  |  |  | X |  | X |  |  | X |   |

1 A neurologist or a neurology fellow will assess the Cohort A and all Registries patients at Baseline, Post Procedure and Discharge. If the neurologist or neurology fellow is not available at the time of patient's baseline or discharge visit, a certified team member may perform the tests. A neurologist or neurology fellow must perform the Post Procedure assessment.
2. Barthel Index for any patient with a previous stroke.
3 Baseline CK/CKMB and/or Troponins are required  $< 72$  hours before the procedure.
Post Procedure CK/CKMB and/or Troponins are required at 3 different time intervals: 1) the first lab draw post procedure (within 8 hours of exiting the cath lab or operating room) 2) the second lab draw 6 - 8 hours after the first lab draw 3) the third lab draw 6 - 8 hours after the second lab draw.
For patients with abnormal chest x-ray findings related to valve integrity and position and patients with Adverse Events related to worsening valve function.

# B. Accountability of PMA Cohort

Patients were treated between April 27, 2011 and February 20, 2012. The database reflected data collected through July 23, 2013 and included 560 patients enrolled at 28 investigational sites in the U.S., as shown in Table 12. At the time of database lock, of 560 patients enrolled in the study, 420 were still alive and 392 have completed the 1-year post-operative visit within window.

Table 12: Patient Disposition at Follow-up (ITT Population)

|   | Intent-to-Treat (ITT) | As-Treated (AT) | Valve Implant (VI)  |
| --- | --- | --- | --- |
|  SAPIEN | 276 | 271 | 263  |
|  SAPIEN XT | 284 | 282 | 280  |
|  Total | 560 | 553 | 543  |

ITT= Intent To Treat population comprises of all patients randomized into one of the two treatment groups.
AT= As Treated population comprises of ITT patients who has a record of entry into Cath Lab
VI= Valve Implant population comprises of AT patients who has valve implanted

# C. Patient Demographics and Baseline Parameters

The demographics of the study population are typical for a TAVR study performed in the US. As summarized in Table 13, it can be seen that the two study arms were well matched.

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Table 13: Demographic and Baseline Characteristics (ITT Population)

|   | SAPIEN XT | SAPIEN |   |
| --- | --- | --- | --- |
|  Characteristic | (N= 284 ) | (N= 276 ) | P Value  |
|  Age – yr | 84.0 ± 8.65 | 84.6 ± 8.61 | 0.4439  |
|  Male sex — no. (%) | 141 (49.6%) | 142 (51.4%) | 0.6736  |
|  STS score† | 10.3 ± 5.38 | 11.0 ± 5.71 | 0.1461  |
|  Logistic EuroSCORE‡ | 18.8 ± 14.61 | 21.0 ± 16.92 | 0.2994  |
|  NYHA class — no. (%): |  |  |   |
|  I/II | 9 (3.2%) | 11 (4.0%) | 0.6539  |
|  III/IV | 275 (96.8%) | 265 (96.0%) |   |
|  Coronary artery disease — no. (%) | 186 (65.5%) | 186 (67.4%) | 0.6552  |
|  Previous myocardial infarction — no. (%) | 55 (19.4%) | 58 (21.0%) | 0.6740  |
|  Previous intervention — no. (%) |  |  |   |
|  CABG | 76 (26.8%) | 72 (26.1%) | 0.9237  |
|  PCI | 90 (31.7%) | 100 (36.2%) | 0.2843  |
|  Balloon aortic valvuloplasty | 51 (18.0%) | 55 (19.9%) | 0.5902  |
|  Cerebral vascular disease — no. (%) | 31 (10.9%) | 35 (12.7%) | 0.6004  |
|  Peripheral vascular disease — no.. (%) | 88 (31.0%) | 75 (27.2%) | 0.3524  |
|  COPD — no. (%): |  |  |   |
|  Any | 84 (29.6%) | 72 (26.1%) | 0.3963  |
|  Oxygen-dependent | 38 (13.4%) | 43 (15.6%) | 0.4734  |
|  Creatinine > 2 mg/dL (177 μmol/liter) — no. (%) | 31 (10.9%) | 33 (12.0%) | 0.7907  |
|  Atrial fibrillation — no. (%) | 104 (36.6%) | 112 (40.6%) | 0.3411  |
|  Permanent pacemaker — no. (%) | 59 (20.8%) | 47 (17.0%) | 0.2814  |
|  Pulmonary hypertension — no. (%) | 72 (25.4%) | 57 (20.7%) | 0.1934  |
|  Frailty§ — no. (%) | 168 (59.2%) | 166 (60.1%) | 0.8633  |
|  Extensively calcified aorta — no. (%) | 19 (6.7%) | 11 (4.0%) | 0.1896  |
|  Chest-wall deformity — no. (%) | 10 (3.5%) | 10 (3.6%) | >0.9999  |
|  Liver disease — no. (%) | 12 (4.2%) | 13 (4.7%) | 0.8396  |
|  Echocardiographic findings |  |  |   |
|  Aortic-valve area — cm2 | 0.6 ± 0.18 | 0.6 ± 0.17 | 0.7702  |
|  Mean aortic-valve gradient — mmHg | 45.1 ± 13.64 | 45.2 ± 14.28 | 0.9655  |
|  Mean LVEF — % | 52.3 ± 13.49 | 52.8 ± 13.80 | 0.7558  |
|  Moderate or severe mitral regurgitation** — no./total no. (%) | 71/265 (26.8%) | 79/255 (31.0%) | 0.3330  |
|  * Plus-minus values are means ± SD. To convert the value for creatinine to micromoles per liter, multiply by 88.4. ITT denotes intent to treat population, CABG denotes coronary-artery bypass grafting, COPD chronic obstructive pulmonary disease, LVEF left ventricular ejection fraction, NYHA New York Heart Association, PCI percutaneous coronary intervention, and TAVR transcatheter aortic-valve implantation.† The Society of Thoracic Surgeons (STS) score measures patient risk at the time of cardiovascular surgery on a scale that ranges from 0% to 100%, with higher numbers indicating greater risk. An STS score higher than 10% indicates very high surgical risk.‡ The logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE), which measures patient risk at the time of cardiovascular surgery, is calculated with the use of a logistic-regression equation. Scores range from 0% to 100%, with higher scores indicating greater risk. A logistic EuroSCORE higher than 20% indicates very high surgical risk.§ Frailty was determined by the surgeons according to prespecified criteria.** Moderate or severe mitral regurgitation was defined as regurgitation of grade 3+ or higher.  |   |   |   |

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D. Safety and Effectiveness Results

1. Safety Results

The analysis of safety was based on the AT cohort of 553 patients. The key safety outcomes for this study are presented below in Tables 14 and 15.

One unanticipated adverse device effects (UADEs) has been reported to date for the entire PARTNER II trial. The site's IRB determined valve migration into the left ventricle was not mentioned in the consent, and the consent was revised accordingly. However, both the Principal Investigator and Sponsor classified this event as "anticipated" based on the ICF, study protocol and IFU.

Four explants have been reported to date; three explants occurred at autopsy, and one SAPIEN XT valve was explanted on the day of the index procedure, which was complicated by aortic insufficiency and dissection of the aorta. CEC adjudicated endocarditis was reported for 3 patients (2 SAPIEN and one SAPIEN XT patient).

The composite adverse event rate involving CEC adjudicated major vascular complications and/or major stroke and/or minor stroke and/or TIA and/or acute stage 3 kidney injury to 30 days was not statistically different among trial arms at 30 days (p=0.3081), and neither were the individual components of this composite.

At 1 year, there was no significant difference between trial arms involving major stroke, minor stroke, life threatening/disabling bleeding, major bleeding, minor bleeding, acute kidney injury and permanent pacemaker.

CEC adjudicated serious adverse events are described in Table 14 and Table 15.

Table 14: CEC Adjudicated Serious Adverse Events at 30-days and 1-Year (AT Population)*

|  Outcome^{-1} | 30 Days |   | 1-Year  |   |
| --- | --- | --- | --- | --- |
|   |  SAPIEN XT | SAPIEN | SAPIEN XT | SAPIEN  |
|   |  (N=282) | (N=271) | (N=282) | (N=271)  |
|  Death^{b} |  |  |  |   |
|  From any cause | 10/282 (3.5%) | 12/271 (4.42%) | 63/282 (22.34%) | 61/271 (22.50%)  |
|  From cardiovascular cause | 9/282 (3.2%) | 10/271 (3.69%) | 46/282 (16.31%) | 46/271 (16.97%)  |
|  Major Stroke | 9/282 (3.2%) | 8/271 (2.95%) | 13/282 (4.61%) | 14/271 (5.17%)  |
|  Repeat hospitalization^{c} | 32/282 (11.3%) | 28/271 (10.33%) | 61/282 (21.63%) | 61/271 (22.51%)  |
|  Death from any cause or major stroke or repeat hospitalization | 48/282 (17.0%) | 43/271 (15.87%) | 105/282 (37.23%) | 100/271 (36.90%)  |
|  Myocardial Infarction | 5/282 (1.8%) | 2/271 (0.74%) | 19/282 (6.74%) | 8/271 (2.95%)  |
|  Major Vascular Complications | 32/282 (11.3%) | 43/271 (15.87%) | 35/282 (12.41%) | 47/271 (17.34%)  |
|  Renal Failure^{f} | 10/282 (3.5%) | 5/271 (1.85%) | 16/282 (5.67%) | 10/271 (3.69%)  |
|  Disabling Bleeding Event^{f} | 22/282 (7.8%) | 34/271 (12.55%) | 38/282 (13.48%) | 52/271 (19.19%)  |
|  Cardiac Reintervention^{f} | 9/282 (3.2%) | 13/271 (4.80%) | 10/282 (3.55%) | 13/271 (4.80%)  |

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Table 15: CEC Adjudicated Major Vascular Complications, Major Stroke, Minor Stroke, TIA and Acute Kidney Injury to 30 Days (AT Population)

|   | SAPIEN® (N=271) |   |   |   | SAPIEN XT® (N=282) |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  VARC Event[1] | Events | Patients with Event | No. Patients At Risk | KM Estimate [2] | Standard Error of KM | Events | Patients with Event | No. Patients At Risk | KM Estimate [2]  |
|  Major Vascular Complications and/or Major Stroke and/or Minor Stroke and/or TIA and/or Acute Stage 3 Kidney Injury | 71 | 56 | 209 | 0.207 | 0.025 | 59 | 49 | 228 | 0.174  |
|  Major Vascular Complications | 53 | 43 | 219 | 0.159 | 0.022 | 37 | 32 | 243 | 0.114  |
|  Major Stroke | 8 | 8 | 251 | 0.030 | 0.010 | 9 | 9 | 264 | 0.032  |
|  Minor Stroke | 3 | 3 | 253 | 0.011 | 0.006 | 3 | 3 | 269 | 0.011  |
|  TIA | 2 | 2 | 254 | 0.007 | 0.005 | 0 | 0 | 272 | 0.000  |
|  Acute Stage 3 Kidney Injury | 5 | 5 | 252 | 0.019 | 0.008 | 10 | 10 | 265 | 0.036  |

Note: Events with missing or incomplete onset dates are excluded from the analysis.
[1] Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials consensus from the Valve Academic Research Consortium (VARC)
[2] Kaplan-Meier estimates are provided at day 30 and use the first event per patient. Note: Events occurring after Day 30 are not included in the analysis.
[3] p-values comparing SAPIEN XT (Test) vs. SAPIEN (Control) are computed using the log-rank test.

# 2. Effectiveness Results

The KM estimate for the primary endpoint was 0.377 in the SAPIEN arm and 0.372 in the SAPIEN XT arm, resulting in a relative risk ratio of 0.987 (95% CI 0.793, 1.228) and  $p = 0.0024$ . Since the upper limit of the CI was  $< 1.35$ , non-inferiority was met (Figure 10). The same analyses were performed for the primary endpoint and the individual component of the composite events on the AT population, as demonstrated in Figures 11-19 for the primary endpoint, all

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cause mortality, all-cause mortality by STS score, landmark analysis of all cause mortality by STS score at 30-days (see discussion below), major stroke, and rehospitalization, respectively.

In the landmark analysis, the overall mortality at day 30 was reset to 0 for patients still at risk at day 30 and day 30 was relabeled as day 0 (i.e., re-zeroed). The Kaplan-Meier plots were produced based on the re-zeroed data, and all-cause mortality was analyzed to one year from the new day 0. Events that occurred before day 30 were not included in this analysis.

![img-11.jpeg](img-11.jpeg)
Figure 10: All-Cause Mortality and/or Major Stroke and/or Rehospitalization at 1 Year (ITT Population)

A tipping point analysis was conducted for the primary analysis to account for all possible combinations of missing data in the two trial arms. The non-inferiority was met, regardless of the imputation applied.

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![img-12.jpeg](img-12.jpeg)
Figure 11: All-Cause Mortality or Major Stroke or Re-hospitalization at One Year (As-Treated Population)

![img-13.jpeg](img-13.jpeg)
Figure 12: All-Cause Mortality at One Year (As-Treated Population)

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![img-14.jpeg](img-14.jpeg)
Figure 13: All-Cause Mortality by STS Score (SAPIEN), (Intent-to-Treat Population)

![img-15.jpeg](img-15.jpeg)
Figure 14: All-Cause Mortality by STS Score (SAPIEN XT), (Intent-to-Treat Population)

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![img-16.jpeg](img-16.jpeg)
Figure 15: All-Cause Mortality by STS Score Re-Zeroing at 30 Days (SAPIEN), (Intent-to-Treat Population)

![img-17.jpeg](img-17.jpeg)
Figure 16: All-Cause Mortality by STS Score Re-Zeroing at 30 Days (SAPIEN XT), (Intent-to-Treat Population)

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![img-18.jpeg](img-18.jpeg)
Figure 17: Major Stroke at One Year (As-Treated Population)

![img-19.jpeg](img-19.jpeg)
Figure 18: CEC Re-hospitalization at One Year (As-Treated Population)

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Procedural parameters showed a significant reduction in catheter lab time duration  $(207.0 \pm 57.8 \mathrm{~min}$  vs.  $220.8 \pm 70.2 \mathrm{~min}, \mathrm{p} = 0.0094)$  and total anesthesia time  $(197.6 \pm 60.8 \mathrm{~min}$  vs.  $212.0 \pm 75.7 \mathrm{~min}, \mathrm{p} = 0.0196)$  in the SAPIEN XT arm. The SAPIEN XT arm also had a shorter total procedure time and lower incidence of multiple valve implants and aborted procedures.

# a) Secondary Endpoints for Labeling that were Met

In the ITT population, the mean adjusted days alive and out of the hospital (DAOH) at 1 year was  $299.2 \pm 111.4$  days for the SAPIEN group and  $302.7 \pm 108.7$  days for the SAPIEN XT group. The difference between the two groups was 3.5 days (two sided  $95\%$  CI 1.8, 5.2) with  $p < 0.0001$ , indicating that non-inferiority was met.

In the SAPIEN group, the mean NYHA was  $3.5 \pm 0.6$  at baseline and  $1.8 \pm 0.8$  at 1 year, which constituted a reduction of  $1.7 \pm 0.9$ . In the SAPIEN XT group, the mean NYHA was  $3.4 \pm 0.6$  at baseline and  $1.7 \pm 0.7$  at 1 year, which constituted a reduction of  $1.8 \pm 0.9$ . The difference between the two groups was -0.13, (two sided  $95\%$  CI -0.32, 0.06) with  $p < 0.0001$ , indicating that non-inferiority was met. Figure 19 illustrates the NYHA classification by visit for the ITT population.

![img-20.jpeg](img-20.jpeg)
Figure 19: NYHA Class by Visit (ITT Population)

The hypothesis testing of the 6MWT at 1 year was based on a difference of 70 meters, which is considered clinically relevant. The mean 6MWT distance at 1 year was  $132.3 \pm 136.3$  meters in the SAPIEN group, and  $159.0 \pm 138.5$  meters in

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the SAPIEN XT group. The difference between the two groups was 26.7 meters (95% CI 24.2, 29.2) with p<0.0001; therefore, non-inferiority was met.

The 6MWT improvement in the SAPIEN XT arm from baseline to 1 year was also compared. The improvement for each subject was computed, and the comparison was evaluated by a two-sided paired sample t-test. The mean improvement was 52.7 ± 111.5 meters, which was statistically significant (p<0.0001).

Another secondary endpoint for labeling was the EOA at 1 year. The hypothesis testing was based on a difference of 0.2 cm². In the SAPIEN group, the mean EOA was 0.6 ± 0.17 cm² at baseline and 1.5 ± 0.40 cm² at 1 year, which was an improvement of 0.9 ± 0.38 cm². In the SAPIEN XT group, the mean EOA was 0.6 ± 0.18 cm² at baseline and 1.5 ± 0.43 cm² at 1 year, a mean increase of 0.9 ± 0.41 cm². The difference between groups in change from baseline to 1 year was -0.01 (95% CI -0.15, 0.13; p=0.0038); therefore, non-inferiority was met.

Device success was defined as successful vascular access, delivery, and deployment and retrieval of delivery system; correct positioning; intended performance (aortic valve area > 1.2 cm² and mean aortic valve gradient < 20 mmHg or peak velocity < 3 m/s, without moderate or severe prosthetic valve AR); and only one valve implanted. The proportion of device success was 45.3% in the SAPIEN group and 58.5% in the SAPIEN XT group. The relative risk ratio of SAPIEN XT vs. SAPIEN was 0.759 (95% CI 0.582, 0.990; p<0.0001), indicating that non-inferiority was met.

b) Secondary Endpoints for Labeling that were not Met

Total aortic regurgitation was assessed by the core lab as 0 = None, 1+ = Trace, 2+ = Mild, 3+ = Moderate, and 4+ = Severe. Total regurgitation at one year was analyzed in the valve implant population. The change in mean total aortic regurgitation from baseline to 1 year was 0.1 ± 1.23 in the SAPIEN group, and 0.2 ± 1.38 in the SAPIEN XT group. The difference between groups in change from baseline to 1 year was 0.09 (95% CI -0.16, 0.34; p=0.1027); therefore, non-inferiority was not met.

c) Valve Performance

In the SAPIEN arm, the mean EOA increased from 0.6 ± 0.17 cm² at screening to 1.5 ± 0.43 cm² at discharge, and then maintained at 1.5 ± 0.38 cm² at 30 days and 1.5 ± 0.39 cm² at 1 year. In the SAPIEN XT arm, the mean EOA increased from 0.6 ± 0.18 cm² at screening to 1.6 ± 0.43 cm² at discharge, and then maintained at 1.6 ± 0.44 cm² at 30 days and 1.5 ± 0.43 cm² at 1 year (Figure 20).

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![img-21.jpeg](img-21.jpeg)
Figure 20: Effective Orifice Area (VI Population)

In the SAPIEN arm, the average mean gradient decreased from $45.2 \pm 14.4 \mathrm{mmHg}$ at screening to $12.1 \pm 4.6 \mathrm{mmHg}$ at discharge, and maintained at $10.4 \pm 4.1 \mathrm{mmHg}$ at 30 days and $11.0 \pm 5.0 \mathrm{mmHg}$ at 1 year. In the SAPIEN XT arm, the average mean gradient decreased from $45.2 \pm 13.7 \mathrm{mmHg}$ at screening to $10.3 \pm 3.8 \mathrm{mmHg}$ at discharge, and maintained at $10.0 \pm 3.8 \mathrm{mmHg}$ at 30 days and $11.4 \pm 4.7 \mathrm{mmHg}$ at 1 year (Figure 21).

![img-22.jpeg](img-22.jpeg)
Figure 21: Mean Gradient (VI Population)

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In the SAPIEN arm, the mean peak gradient decreased from  $77.8 \pm 23.0 \mathrm{mmHg}$  at screening to  $23.6 \pm 8.8 \mathrm{mmHg}$  at discharge, and maintained at  $20.7 \pm 7.9 \mathrm{mmHg}$  at 30 days and  $21.7 \pm 9.4 \mathrm{mmHg}$  at 1 year. In the SAPIEN XT arm, the mean peak gradient decreased from  $78.8 \pm 22.8 \mathrm{mmHg}$  at screening to  $20.5 \pm 7.4 \mathrm{mmHg}$  at discharge, and maintained at  $19.8 \pm 7.6 \mathrm{mmHg}$  at 30 days and  $22.8 \pm 9.2 \mathrm{mmHg}$  at 1 year (Figure 22).

![img-23.jpeg](img-23.jpeg)
Figure 22: Mean Peak Gradient (VI Population)

In the SAPIEN arm, total aortic regurgitation was  $1.7 \pm 0.8$  at baseline, and  $1.8 \pm 1.0$  at 1 year. In the SAPIEN XT arm, total aortic regurgitation was  $1.7 \pm 0.9$  at baseline, and  $1.8 \pm 1.0$  at 1 year (Figure 23).

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![img-24.jpeg](img-24.jpeg)
Figure 23: Total Aortic Regurgitation (VI Population)

d) Other

Quality of life at different time points as measured by the KCCQ clinical summary score is shown in Figure 24. The improvement over time was similar between the SAPIEN XT and SAPIEN groups.

![img-25.jpeg](img-25.jpeg)
Figure 24: KCCQ Clinical Summary Score

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3. Subgroup Analyses

Subgroup analyses of sex and preoperative atrial fibrillation were conducted for their potential association with outcomes. The non-inferiority primary endpoint was met in males as well as in patients with or without atrial fibrillation, but not met in females. However, the study was not powered to demonstrate non-inferiority in any subset of the study population.

E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conduction clinical studies covered by the regulation. The pivotal clinical study included 187 investigators of which none were full-time or part-time employees of the sponsor and nine 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: none
- Significant payment of other sorts: 9 investigators
- Proprietary interest in the product tested held by the investigator: none
- Significant equity interest held by investigator in sponsor of covered study: none

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.

X.2 SUMMARY OF NESTED REGISTRY 5

A. Study Design

The 29 mm SAPIEN XT THV was not included in the randomized cohort of the trial because it was introduced later during the trial. A single arm, prospective observational nested registry, NR5, was designed to obtain data involving the 29 mm valve in inoperable, transfemoral access patients.

Patients were treated between October 12, 2012 and February 20, 2013. The database reflected data collected through July 22, 2013 and included 61 pat…

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