← Product Code NPT · P140031 # SAPIEN 3 TRANSCATHETER HEART VALVE AND ACCESSORIES (P140031) _Edwards Lifesciences, LLC · NPT · Jun 17, 2015 · Cardiovascular · APPR_ **Canonical URL:** https://fda.innolitics.com/device/P140031 ## Device Facts - **Applicant:** Edwards Lifesciences, LLC - **Product Code:** NPT - **Decision Date:** Jun 17, 2015 - **Decision:** APPR - **Device Class:** Class 3 - **Review Panel:** Cardiovascular - **Attributes:** Therapeutic, Expedited Review ## Intended Use The Edwards SAPIEN 3 Transcatheter Heart Valve (THV), model 9600TFX, and accessories are 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., Society of Thoracic Surgeons operative risk score ≥8% or at a ≥15% risk of mortality at 30 days). ## Device Story The Edwards SAPIEN 3 THV is a balloon-expandable, radiopaque, cobalt-chromium (MP35N) frame with a trileaflet bovine pericardial tissue valve and PET skirts to reduce paravalvular leakage. It is delivered percutaneously via the Commander delivery system (transfemoral) or other compatible systems. The device is used in a catheterization lab or hybrid suite by a heart team including a cardiac surgeon. The valve is crimped onto a balloon catheter using the Edwards Crimper and Qualcrimp accessory, then advanced to the native aortic valve site. Balloon inflation deploys the valve, which functions to replace the stenotic native valve. This procedure aims to improve hemodynamic performance, reduce pressure gradients, and improve patient quality of life and functional status (NYHA class). ## Clinical Evidence Pivotal clinical study (PARTNER II, PIIS3HR cohort) enrolled 583 patients. Primary endpoint: composite of death, all stroke, and AI ≥ moderate at 30 days. SAPIEN 3 (6.7%) met non-inferiority against historical SAPIEN control (15.6%). Secondary endpoints showed SAPIEN 3 superior in AI ≥ moderate at 30 days (3.0% vs 14.3%, p=0.0051). Major vascular complications were 5.0% vs 10.1% (p=0.0578). Hemodynamic improvements observed: EOA increased from 0.7 to 1.6 cm², mean gradient decreased from 45.5 to 11.1 mmHg. Supplemental data from S3OUS study (102 patients) supported findings. ## Technological Characteristics Balloon-expandable cobalt-chromium (MP35N) frame; trileaflet bovine pericardial tissue valve; PET internal and external sealing skirts. Sizes: 20, 23, 26, 29 mm. Sterilization: terminal liquid sterilization (buffered glutaraldehyde) for valve; ethylene oxide for delivery system/accessories. Complies with ISO 5840 (valves) and ISO 10993-1 (biocompatibility). ## 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 - Edwards SAPIEN THV (model 9000TFX) - SAPIEN XT - Perimount Magna - Cordis Palmaz Genesis stents ## Submission Summary (Full Text) > This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com. > > Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/). SUMMARY OF SAFETY AND EFFECTIVENESS DATA I. GENERAL INFORMATION Device Generic Name: Aortic valve, prosthesis, percutaneously delivered Device Trade Name: Edwards SAPIEN 3™ Transcatheter Heart Valve, model 9600TFX, 20, 23, 26, and 29 mm, and accessories (Edwards Commander™ delivery system, models 9600LDS20, 9600LDS23, 9600LDS26, and 9600LDS29, with crimp stopper and Qualcrimp crimping accessory; Edwards eSheath Introducer Set, models 914ES and 916ES; and Edwards crimper, model 9600CR) Device Procode: NPT Applicant Name and Address: Edwards Lifesciences LLC One Edwards Way Irvine, CA 92614 Date of Panel Recommendation: None Premarket Approval Application (PMA) Number: P140031 Date of FDA Notice of Approval: June 17, 2015 Priority Review: Granted priority review status on January 20, 2015 because the availability of the device is in the best interest of the patients II. INDICATIONS FOR USE The Edwards SAPIEN 3 Transcatheter Heart Valve (THV), model 9600TFX, and accessories are 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., Society of Thoracic Surgeons operative risk score ≥8% or at a ≥15% risk of mortality at 30 days). III. CONTRAINDICATIONS The Edwards SAPIEN 3 THV is contraindicated in patients who cannot tolerate an anticoagulation/antiplatelet regimen or who have active bacterial endocarditis or other PMA P140031: FDA Summary of Safety and Effectiveness Data active infections. ## IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the Edwards SAPIEN 3 THV labeling. ## V. DEVICE DESCRIPTION The Edwards SAPIEN 3 THV, shown in Figure 1, is comprised of a balloon-expandable, radiopaque, cobalt-chromium frame (MP35N), a trileaflet bovine pericardial tissue valve, a polyethylene terephthalate (PET) internal fabric skirt, and a PET external sealing skirt for reduction of paravalvular leakage (PVL). ![img-0.jpeg](img-0.jpeg) Figure 1: SAPIEN 3 Transcatheter Heart Valve The Edwards Commander delivery system, as 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. The Commander delivery system is used for transfemoral access. ![img-1.jpeg](img-1.jpeg) Figure 2: Edwards Commander Delivery System The Edwards eSheath Introducer Set, shown in Figure 3, consists of a sheath and two introducers and is used to facilitate introduction of the SAPIEN 3 THV and accessories into the vasculature. PMA P140031: FDA Summary of Safety and Effectiveness Data ![img-2.jpeg](img-2.jpeg) Figure 3: Edwards eSheath Introducer Set The Qualcrimp crimping accessory, shown in Figure 4, is a non patient-contacting device that is placed around the Edwards SAPIEN 3 THV to protect the leaflets during the crimping process. It is manufactured of tubular polyester polyurethane foam and laminated cylindrically on both the inner and outer surfaces with a polyether urethane material. ![img-3.jpeg](img-3.jpeg) Figure 4: Qualcrimp Crimping Accessory The Edwards Crimper, as shown in Figure 5, 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 is used with a Crimp Stopper (packaged with the Commander delivery system) to correctly crimp the THV. ![img-4.jpeg](img-4.jpeg) Figure 5: Edwards Crimper VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for patients with severe symptomatic native aortic valve stenosis who are deemed to be non-operable (non-surgical), including treatment PMA P140031: FDA Summary of Safety and Effectiveness Data Page 3 with other commercially available transcatheter aortic valve replacement (TAVR) devices, temporary relief using percutaneous balloon aortic valvuloplasty (BAV), and 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. Patients should fully discuss these alternatives with their physicians to select the method that best meets their expectations and lifestyle. ## VII. MARKETING HISTORY Commercial distribution of the SAPIEN 3 THV and accessories outside the U.S. began in January 2014. 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 Iceland, Israel, Kuwait, Liechtenstein, Norway, Saudi Arabia, Switzerland, Turkey, and United Arab Emirates. The device has not been withdrawn from marketing for any reason related to its safety or effectiveness. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH The adverse effects listed below are associated with access complications associated with standard cardiac catheterization, balloon valvuloplasty, the potential risks of conscious sedation and/or general anesthesia, and the use of angiography: - Death - Stroke/transient ischemic attack, clusters or neurological deficit - Paralysis - 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 - AV fistula or pseudoaneurysm - Reoperation PMA P140031: FDA Summary of Safety and Effectiveness Data Page 4 - 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 - 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 PMA P140031: FDA Summary of Safety and Effectiveness Data Page 5 For the specific adverse events that occurred in the clinical study, please see Section X. # IX. SUMMARY OF PRECLINICAL STUDIES # A. Laboratory Studies In vitro studies on the Edwards SAPIEN 3 THV and non-implantable accessories were performed in conformity with ISO 5840: Cardiovascular Implants-Cardiac Valve Prostheses (2005). # Biocompatibility Studies Toxicology and biocompatibility testing for the SAPIEN 3 THV 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 3 THV, Commander delivery system, eSheath Introducer Set, Qualcrimp crimping accessory, and Crimper are provided in Tables 1-5, respectively. 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. Table 1: Summary of Biocompatibility Testing - SAPIEN 3 THV | 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 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. No 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. | The test article extracts elicited no reaction at the challenge (0% sensitization), following an induction phase and the test article was classified as having weak allergenic potential. | | Irritation/Intracutaneous Toxicity: Rabbit Intracutaneous Reactivity | Determine whether test article extracts would cause local dermal irritation or toxic effects. | The respective test article extracts injection sites did not show significantly greater biological reactions than the sites injected with the control articles. | PMA P140031: FDA Summary of Safety and Effectiveness Data | Test | Purpose | Results | | --- | --- | --- | | Systemic Toxicity: USP Mouse Systemic Injection | Determine whether test article extracts would cause acute systemic toxicity. | The respective test article extracts did not induce significantly greater biological reactions than the control extracts, when tested in Swiss Albino mice. | | 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 the test article was considered non-pyrogenic. | | 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. No abnormalities were observed in any of the implant sites for the test article upon macroscopic gross tissue examination. | | Genotoxicity: Reverse Mutation Assay | Determine whether test article extracts would cause mutagenic changes in strains of S. typhimurium and E. coli. | Test article extracts did not induce significant increases in the number of revertant colonies as compared to the negative controls under both the activated and non-activated conditions. Non-mutagenic. | | Genotoxicity: Chromosomal Aberration Assay | Determine whether test article extracts would cause genotoxicity in Chinese Hamster ovary cells. | Test article extracts did not induce statistically significant increases in the number of structural chromosome aberrations compared to the negative control under both the activated and non-activated conditions. | | Genotoxicity: Rodent Bone Marrow Micronucleus | Determine whether test article extracts would cause genotoxic changes as determined by induced micronucleated polychromatic erythrocytes. | Test article extracts did not induce significant increase in micronucleated erythrocytes as compared to negative controls. Non-clastogenic. | | Hemocompatibility: Hemolysis | Determine whether the test article would cause hemolysis in vitro and determine the degree of inhibition or promotion of clotting time. | No differences in hemolytic effects observed for both extract and solid samples as compared to negative controls. Material's extract did not adversely affect the clotting time and was determined to be compatible with plasma. | | Complement Activation Assay Direct Contact | Determine the potential activation of the complement system in human plasma in response to the test article | Test article was determined to be hemocompatible and not at risk to activate complement. Results equivalent to negative control and untreated plasma. | Table 2: Summary of Biocompatibility Testing - Edwards Commander Delivery System PMA P140031: FDA Summary of Safety and Effectiveness Data PMA P140031: FDA Summary of Safety and Effectiveness Data Page 8 | Test | Purpose | Results | | --- | --- | --- | | Cytotoxicity: Medium Eluate Method (MEM) | Determine potential biological reactivity of a mammalian cell culture in response to the test article extract. | Test article sample was non-cytotoxic. No reactivity was observed with equivalent results to the negative control. | | Hemolysis- Rabbit Blood Direct and Indirect Contact | Determine the potential hemolytic activity on rabbit blood in response to the test article and to its extract | Test article sample was not considered hemolytic. The hemolytic index above the negative control is less than 5%. | | Unactivated Partial Thromboplastin Time (UPTT) Assay Indirect Contact | Determine the potential induction of the coagulation of human plasma via measurement of the Unactivated Partial Thromboplastin Time (UPTT), in response to an extract of the test article | Test article sample was not considered to have an effect on the Unactivated Partial Thromboplastin Time (UPTT). No statistically significant decrease between the UPTT of the plasma exposed to the test article and that of the plasma exposed to the negative control. | | Complement Activation Assay Direct Contact | Determine the potential activation of the complement system in human plasma in response to the test article | Test article was determined to be hemocompatible and not at risk to activate complement. Results equivalent to negative control. | | Salmonella typhimurium and Escherichia coli Reverse Mutation Assay | Determine the potential mutagenicity of the test article extract in various strains of Salmonella typhimurium (S. typhimurium) and Escherichia coli (E. coli) bacteria, via a change in their dependence for histidine or tryptophan. | The test article was considered non-mutagenic. No statistically significant difference between the number of revertant colonies in the test article and that of the negative control. | | Systemic Injection Test | Determine the potential for toxic effects of the test article extract as a result of a single –dose systemic injection in mice | Extracts of the test article did not induce a significantly greater biological reaction than the control extracts when tested in Swiss Albino mice. | | Rabbit Pyrogen Test (Material Mediated) | Determine the presence of chemical pyrogens in test article extracts by measuring temperature rise in intravenously injected rabbits. | The test article was considered non-pyrogenic. No rabbit showed an individual rise in temperature of 0.5°C or more above the baseline temperature. | | Intracutaneous Injection Test | Determine the potential irritation effects of the test article extract as a result of an intracutaneous injection in New Zealand White Rabbits | The test article sites did not show a significantly greater biological reaction than the sites injected with the control article. | | Kligman Maximization Test | Evaluate the allergenic potential or sensitizing capacity of the test article. | Test article extracts elicited no reaction at the challenge (0%) sensitization following an induction phase and are classified as having weak allergenic potential. | Table 3: Summary of Biocompatibility Testing - Edwards eSheath Introducer 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. No 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. | All components non-cytotoxic to cells with 0% cell lysis. | | 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 or 48 hour readings. 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 weight loss or 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. | Temperature rise <0.3°C and no 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. Results equivalent to negative control. | Table 4: Summary of Biocompatibility Testing - Qualcrimp Crimping Accessory | 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. No cell lysis was observed with equivalent results to the negative control. | Table 5: Summary of Biocompatibility Testing - Edwards Crimper | 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. No 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. | PMA P140031: FDA Summary of Safety and Effectiveness Data SAPIEN 3 THV Hydrodynamic Performance In vitro studies were conducted to evaluate the hydrodynamic performance of the SAPIEN 3 THV 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 ISO 5840: Cardiovascular Implants-Cardiac Valve Prostheses (2005). Reference articles for the nominally deployed SAPIEN 3 valve studies consisted of commercially available aortic valves; reference articles for the irregular studies consisted of nominally deployed SAPIEN 3 valves. The matrix of the tests performed and the corresponding results are provided in Table 6. Table 6: 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 3 Size 20mm, 23mm, 26mm & 29mm Reference: Nominal SAPIEN size 23mm, 26mm, SAPIEN XT size 20mm, 23mm, 26mm, and 29mm, and Perimount Magna size 20mm and 29mm Irregular Test: SAPIEN 3 Size 20mm, 23mm, 26mm & 29mm Reference: Nominal SAPIEN size 23mm, 26mm, SAPIEN XT size 20mm, 23mm, 26mm, and 29mm, and Perimount Magna size 20mm and 29mm | The SAPIEN 3 valve offers acceptable hemodynamics with pressure gradients and effective orifice areas (EOA) that are comparable to those offered by the reference valves. | | Steady Backflow Leakage | To determine the leakage rate at various steady back flow pressures. | Nominal Test: SAPIEN 3 Size 20mm, 23mm, 26mm & 29mm Reference: Nominal SAPIEN size 23mm, 26mm, SAPIEN XT size 20mm, 23mm, 26mm, and 29mm, and Perimount Magna size 20mm and 29mm Irregular Test: SAPIEN 3 Size 20mm, 23mm, 26mm & 29mm Reference: Nominal SAPIEN size 23mm, 26mm, SAPIEN XT size 20mm, 23mm, 26mm, and 29mm, and Perimount Magna size 20mm and 29mm | The SAPIEN 3 valve offers satisfactory performance in terms of its competency to prevent significant transvalvular aortic back-flow during the diastolic phase. | PMA P140031: FDA Summary of Safety and Effectiveness Data | Test | Purpose/Objective | Test/Reference Articles | Results | | --- | --- | --- | --- | | Pulsatile Flow Pressure Drop | To determine pressure drop and effective orifice area performance under pulsatile flow conditions. | Nominal Test: SAPIEN 3 Size 20mm, 23mm, 26mm & 29mm Reference: Nominal SAPIEN size 23mm, 26mm, SAPIEN XT size 20mm, 23mm, 26mm, and 29mm, and Perimount Magna size 20mm and 29mm Irregular Test: SAPIEN 3 Size 20mm, 23mm, 26mm & 29mm Reference: Nominal SAPIEN size 23mm, 26mm, SAPIEN XT size 20mm, 23mm, 26mm, and 29mm, and Perimount Magna size 20mm and 29mm | The SAPIEN 3 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 3 Size 20mm, 23mm, 26mm & 29mm Reference: Nominal SAPIEN size 23mm, 26mm, SAPIEN XT size 20mm, 23mm, 26mm, and 29mm, and Perimount Magna size 20mm and 29mm Irregular Test: SAPIEN 3 Size 20mm, 23mm, 26mm & 29mm Reference: Nominal SAPIEN size 23mm, 26mm, SAPIEN XT size 20mm, 23mm, 26mm, and 29mm, and Perimount Magna size 20mm and 29mm | The SAPIEN 3 valve offers acceptable hydrodynamics with regurgitant fractions that were lower than those required by the ISO 5840:2005 acceptance criteria. | | Flow Visualization | To qualitatively investigate flow characteristics in the vicinity of the valve. | Nominal Test: SAPIEN 3 Size 20mm, 23mm Reference: SAPIEN XT size 20mm, 23mm, and Perimount Magna size 20mm Irregular Test: Irregular SAPIEN 3 size 20mm, 23mm Reference: Nominal SAPIEN XT size 20mm, 23mm, and Perimount size 20mm | The SAPIEN 3 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 3 valves, with no retrograde jet-like flow. | | Verification of Bernoulli | To determine whether the Bernoulli | Nominal Test: SAPIEN 3 Size 20mm, | Pressure drop results for the SAPIEN 3 valve | | | pulsatile flow conditions. | 23mm 26mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm | 23mm 26mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm 29mm | PMA P140031: FDA Summary of Safety and Effectiveness Data PMA P140031: FDA Summary of Safety and Effectiveness Data Page 12 ## SAPIEN 3 THV Structural Performance The in vitro structural performance studies of the SAPIEN 3 THV were conducted in accordance with 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. The matrix of tests performed and the corresponding results are provided in Table 7. Table 7: 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 3 size 20mm, 23mm, 26mm & 29mm Reference: Nominal SAPIEN size 23mm, 26mm, & Perimount Magna size 21m, 23mm, 27mm & 29mm valves Irregular Test: SAPIEN 3 size 20mm, 23mm, 26mm & 29mm Reference: SAPIEN size 23mm, 26mm, SAPIEN XT size 20mm, 23mm, 26mm, 29mm & Perimount Magna size 21mm, 23mm, 27mm & 29mm valves | 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. | | Dynamic Failure Mode | To obtain information about the failure modes affecting the durability of the valve. | Test: SAPIEN 3 size 20mm, 23mm, 26mm & 29mm Reference: SAPIEN XT size 20mm, 23mm, 26mm, and 29mm Perimount Magna Size 21mm, 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 3 frames size 20mm 23mm, 26mm & 29mm | Minimum force required to compress the frame was acceptable. | PMA P140031: FDA Summary of Safety and Effectiveness Data Page 13 ## SAPIEN 3 THV Design Specific Performance Studies Design specific in vitro performance studies of the SAPIEN 3 THV were completed based on recommendations in the FDA Intravascular Stent Guidance (2010) with acceptable results. The matrix of tests performed and the corresponding results are provided in Table 8. Table 8: Design Specific Performance Studies | Test | Purpose/Objective | Test Articles | Results | | --- | --- | --- | --- | | Percent Surface Area | Determination of frame metal surface in contact with native valve leaflets and annulus | N/A – computational analysis | N/A – Characterization testing | | Frame Overexpansion | Verification that the SAPIEN 3 frames can withstand an acceptable amount of overexpansion before fracture | SAPIEN 3 frames: sizes 20mm, 23mm, 26mm, and 29mm | PASS - Frames withstood expansion beyond expected over-deployment for an acceptable safety margin | | Frame Foreshortening and Recoil | Determination of expected foreshortening and recoil of the SAPIEN 3 THV when passed through compatible sheaths and deployed with the Commander delivery system | SAPIEN 3 valves: sizes 20mm, 23mm, 26mm, 29mm | N/A – Characterization testing | | Frame Radial Strength | Determination of the radial strength and characterization of the stiffness of the SAPIEN 3 frame | SAPIEN 3 frames: sizes 20mm, 23mm, 26mm, and 29mm | Radial strength: PASS - All sizes were within specifications Radial Stiffness: N/A – Characterization Testing | PMA P140031: FDA Summary of Safety and Effectiveness Data Page 14 ## SATISFYING PROCEDURES ### SATISFYING PROCEDURES #### General - **Purpose/Objective** The SATISFYING PROCEDURES is a comprehensive review of the safety and effectiveness of the products and services used in the past. The following are the key issues related to the safety of the products and services used in the past: - **Purpose/Objective**: To assess the safety and effectiveness of the products and services used in the past. - **Purpose/Objective 1**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 2**: To assess the effectiveness of the services used in the past. #### General - **Purpose/Objective 1**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 2**: To assess the effectiveness of the services used in the past. ## EXPERIMENTAL PROCEDURES ### EXPERIMENTAL PROCEDURES #### General - **Purpose/Objective**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 1**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 2**: To assess the effectiveness of the services used in the past. ## EXPERIMENTAL PROCEDURES ### EXPERIMENTAL PROCEDURES 1 #### General - **Purpose/Objective**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 1**: To assess the effectiveness of the services used in the past. ## EXPERIMENTAL PROCEDURES 2 ### EXPERIMENTAL PROCEDURES 3 #### General - **Purpose/Objective**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 2**: To assess the effectiveness of the services used in the past. ## EXPERIMENTAL PROCEDURES 4 ### EXPERIMENTAL PROCEDURES 5 #### General - **Purpose/Objective**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 1**: To assess the effectiveness of the services used in the past. ## EXPERIMENTAL PROCEDURES 6 ### EXPERIMENTAL PROCEDURES 7 #### General - **Purpose/Objective**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 2**: To assess the effectiveness of the services used in the past. ## EXPERIMENTAL PROCEDURES 8 ### EXPERIMENTAL PROCEDURES 9 #### General - **Purpose/Objective**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 1**: To assess the effectiveness of the services used in the past. ## EXPERIMENTAL PROCEDURES 10 ### EXPERIMENTAL PROCEDURES 11 #### General - **Purpose/Objective**: To assess the effectiveness of the services used in the past. - **Purpose/Objective 2**: To assess the effectiveness of the services used in the past. ## EXPERIMENTAL PROCEDURES 12 ### EXPERIMENTAL PROCEDURES 13 | Test | Purpose/Objective | Test Articles | Results | | --- | --- | --- | --- | | | | Crimper Qualcrimp Crimping Accessory/Crimp Stoppers | | | Balloon Performance | Verification that the Commander delivery system balloon functions as intended when subjected to the following testing: inflation/deflation, inflation pressure, burst pressure, balloon fatigue, deployed balloon dimensional inspection. | Commander delivery system: sizes 20mm, 23mm, 26mm, and 29mm | PASS - The Commander delivery system balloon performs as intended and met acceptance criteria. | | THV Interaction | Verification that the Commander delivery system and accessories are compatible with the SAPIEN 3 THV when used as intended. Testing included the following: crimping force, push force through sheath, THV alignment and fine adjustment, THV retention on delivery system, valve retrieval into sheath, deployed valve OD. | SAPIEN 3 valves: sizes 20mm, 23mm, 26mm, 29mm Commander delivery system: sizes 20mm, 23mm, 26mm, and 29mm eSheath Introducer Set: sizes 14F and 16F Crimper Qualcrimp Crimping Accessory/Crimp Stoppers | PASS - Delivery systems and accessories are compatible with the SAPIEN 3 THV and met design requirements and acceptance criteria. | | Bond Strength | Verification that the bonds and tubing of the Commander delivery system and eSheath introducer set remain intact when subjected to tensile testing and/or simulated use. | Commander delivery system: sizes 20mm, 23mm, 26mm, and 29mm eSheath Introducer Set: sizes 14F and 16F | PASS - All bonds met design requirements and acceptance criteria. | ## Sterilization The SAPIEN 3 THV is sterilized by terminal liquid sterilization (TLS) in buffered glutaraldehyde solution. The Commander delivery system, eSheath Introducer Sheath Set, Qualcrimp crimping accessory, and 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. ## Packaging and Shelf Life PMA P140031: FDA Summary of Safety and Effectiveness Data The packaging for the SAPIEN 3 THV consists of a 3.8 oz jar, a lid and gasket closure system, and shelf and shipping containers. The Commander delivery system, eSheath Introducer Sheath Set, Qualcrimp crimping accessory, and Crimper are packaged in Tyvek pouches and shelf and shipping cartons. The labeled shelf life is one (1) year for the SAPIEN 3 THV based on real-time aging, one (1) year for the eSheath Introducer Sheath Set and the Crimper based on accelerated aging, and two (2) years for the Commander delivery system and the Qualcrimp accessory based on accelerated aging. Packaging and product integrity studies were conducted to ensure that the components meet specifications throughout the stated shelf life. ## B. Animal Studies Three chronic animal studies were performed on the SAPIEN 3 THV: two to evaluate the in vivo functional performance of the valve (one at 20 and one at 40 weeks post implantation), and one to evaluate the thrombogenic potential of the PVL skirt at three weeks post implantation. The THVs were implanted using an open heart procedure, but were deployed using a delivery system for simulated use. The endpoints of the animal study are functions of valve design and material interactions; therefore, the results of the study are applicable to all valve sizes. An overview of these studies is provided in Table 10. Table 10: Chronic Animal Study Overview | GLP Chronic 20 Week Study | | | --- | --- | | Sample Size/Animal Model | 21 adult 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 | 16 size 23 mm SAPIEN 3 THV (Group A had a one time 10-second crimp, Group B had a three time 5-second crimp); 16 NovaFlex 4 (Commander) Delivery System and 15F sheath. | | Control Articles | Five (5) commercially available, size 23mm SAPIEN THV (model 9000TFX); five (5) 23F RetroFlex 3 Delivery System and Introducer Sheath. | | Technique | Open heart implant of valve in the aortic position under direct visualization within a modified aortic root (modified Cosgrove-Edwards Annuloplasty band/ring sutured into the aortic annulus). | | Results | 21 open heart implantations were performed; 12 test animals and 3 control animals were sacrificed at 20 weeks. The test and control valves met the acceptance criteria. Early deaths: One control animal died less than 24 hours post procedure due to cardiac complications unrelated to the implanted valve. Four (4) test animals and 1 control animal were removed from the study since the additional animals were not necessary to fulfill the intended sample size and reassigned to the 40 week study described below. | PMA P140031: FDA Summary of Safety and Effectiveness Data Page 16 | Conclusion | The SAPIEN 3 valve performance was comparable to that of the SAPIEN control valve. The two groups of the SAPIEN 3 and the SAPIEN control met the acceptance criteria and exhibited no embolism, structural valve deterioration, sewing ring dehiscence, material wear, thrombus, significant vegetative growths, significant calcification or significant leaflet damage. Similar healing response (including normal inflammation), tissue overgrowth and good suture integrity were observed in both test and control articles. | | --- | --- | | Non-GLP 40 week Chronic Animal Study | | | Sample Size/Animal Model | Five (5) adult sheep | | Test Articles | Four (4) size 23mm SAPIEN 3 THV (2 Group A experienced a one time ten second crimp, 2 Group B experienced a three time five second crimp); four (4) NovaFlex 4 (Commander) Delivery System and 15F sheath. | | Control Articles | One (1) size 23 mm SAPIEN THV; one (1) 23F RetroFlex 3 Delivery System and Introducer Sheath. | | Technique | Open heart implant of valve in the aortic position under direct visualization within a modified aortic root (modified Cosgrove-Edwards Annuloplasty band/ring sutured into the aortic annulus). | | Results | Five (5) open heart implants were performed; Four (4) test animals and one (1) control were sacrificed at 40 weeks. No early deaths or early euthanasia. Pericardial leaflets in the implanted devices showed varying degrees of collagen degeneration, which has been reported in pericardial prosthetic leaflets following implantation historically. This observation was not associated with calcification or any gross or hemodynamic performance changes. | | Conclusion | The performance of the SAPIEN 3 valve was comparable to that of the SAPIEN control valve. Both the SAPIEN 3 and the SAPIEN valves met the acceptance criteria and exhibited no embolism, structural valve deterioration, sewing ring dehiscence, material wear, thrombus, significant vegetative growths, significant calcification or significant leaflet damage. Similar healing response (including normal inflammation), tissue overgrowth and good suture integrity were observed in both test and control articles. | | Non-GLP 3 Week Study | | | Sample Size/Animal Model | Four (4) young adult sheep (9-12 months old, 54-64 kg) | | Test Articles | Three (3) 23mm SAPIEN 3 THV (each was crimped three times with a minimum of a 5-second hold); three (3) NovaFlex 4 Delivery System with a sheath and loader kit | | Control Articles | One (1) Cribier-Edwards 23 mm SAPIEN THV; one (1) RetroFlex 3 Delivery System and Introducer Sheath | | Technique | Open heart implant of valve in the aortic position under direct visualization within a modified aortic root (modified Cosgrove-Edwards Annuloplasty band/ring sutured into the aortic annulus). The modified Cosgrove-Edwards Annuloplasty band used in this study had added irregularities to model calcific nodules. | PMA P140031: FDA Summary of Safety and Effectiveness Data Page 17 The results of these studies demonstrated that the SAPIEN 3 THV has acceptable hemodynamic, healing and durability performance and is suitable for long-term implant. Further summaries of these studies are provided in Table 11. Table 11: Chronic Animal Study Summaries | Evaluation Parameter | Summary of Results | | --- | --- | | GLP Chronic 20 Week Study | | | Clinical History and Hematology | One control (SAPIEN) animal was found dead the morning after surgery. The cause of death at explant was suspected to be due to a new acute infarct or an arrhythmia from an infarct at surgery. Some degree of valve oversizing was suspected, as shown by bruising of the annulus at the anterior mitral leaflet. This animal died unexpectedly and was not weighed at explant. The animal was disqualified from the study. The cause of death was non-device related. Hematologic findings were largely unremarkable at implant and explant and were comparable between both test and control groups. At explant, plasma free hemoglobin results were, in most instances, similar or lower than those at implant. At explant, Haptoglobin results were, on average, slightly higher at explant than implant for all three groups. Both test and control devices were hemocompatible. There were no other indicators of on-going hemolysis, such as anemia. There was no evidence of thromboembolic complications. | PMA P140031: FDA Summary of Safety and Effectiveness Data PMA P140031: FDA Summary of Safety and Effectiveness Data Page 19 | Hemodynamic Performance | In general, peak gradients and cardiac outputs at explant tended to be higher than at implant. One control animal and seven test animals had evidence of valvular insufficiency by contrast angiography which corresponded with the gross finding of paravalvular gaps on gross exam. The gaps were located between the annuloplasty ring and the native annulus, and were a failure of the model and not a problem with the valve delivery or performance. Values for the average cardiac output, peak gradient post implant, and the average peak gradient with an induced cardiac output were consistent with improved cardiac function compared to immediately post-bypass. At explant the test valves and control valves were comparable for aortic insufficiency. Two valves in each group had no leak, three valves from the test groups and one in the control group had trace to mild leak, and one valve in the test group had moderate to severe leak. | | --- | --- | | 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 control and test groups at 20 weeks. There were no thrombus, valvular mineralization and vegetative growths in the valves of either the control or test groups. There was no migration, leaflet damage, material wear, or structural failure in the valves. Only two animals (one from the control group and one from the test group) had minimal to mild calcification deposits on gross exam. The gross examination for the target organs (kidneys, liver, spleen, lung) were similar between the test and control groups, and were all within normal limits. | | Non-GLP 40 week Chronic Animal Study | | | Clinical History and Hematology | All five animals (four tests and one control) were clinically normal prior to explant at 40 weeks. There were no early deaths. All animals were free of adverse clinical signs and displayed normal behavior and vital signs throughout the implant period. Findings were comparable between the test and control groups. None of the pre-implant and pre-explant abnormal hematology findings was considered to be clinically significant to affect the outcome of the study. Both test and control devices were hemocompatible. There were no indicators of on-going hemolysis, such as anemia, and no evidence of thromboembolic complications. | | Hemodynamic Performance | In general, the peak gradients and cardiac outputs at explant tended to be higher than those at implant. This observation was consistent with improved cardiac function, as compared to what would be anticipated immediately post-bypass, and was similar to other prosthetic heart valves tested in the past. Though angiography data could not be located for one animal, gross necropsy did not find any paravalvular gaps, leaflet damage or retraction, suggesting no leak would have been observed on fluoroscopy. | PMA P140031: FDA Summary of Safety and Effectiveness Data Page 20 | Histopathology | Histopathology results showed no apparent differences in tissue reactions (general healing, calcification, or morphology of the tissue/valve interface) between the test devices and the control device. Tissue reactions were generally of low severity and were considered to be typical of this type of devices. | | --- | --- | | Gross Observations | General healing results were comparable among valve types at 40 weeks. All valves had pliable leaflets and had no thrombus, coronary occlusion, material wear, frame fracture or valve migration. All had good suture integrity. The valves were securely seated with normal healing into the aortic root. Three test animals had minimal to moderate paravalvular space. One test animal and the control animal had minimal vegetative growths. One test animal had a small leaflet perforation, likely caused by a nearby elongated suture, and the control animal had minimal to moderate leaflet retraction on two leaflets, possibly from calcification. The gross examination for the target organs (kidneys, liver, spleen, lung) were similar between the test and control groups, and were all within normal limits. | | Non-GLP 3 Week Study | | | Clinical History and Hematology | All four animals (three tests and one control) were clinically normal prior to explant at 3 weeks. There were no early deaths. The pre-implant and pre-explant hematology findings were unremarkable, and were comparable between the control and test groups. | | Hemodynamic Performance | Intracardiac (ICE) or transthoracic (TTE) echocardiography was performed immediately post-implant and immediately prior to explant. Aortic insufficiency or paravalvular leaks (PVL), integrity of the subvalvular structures (chordae and papillary muscles) and mitral valve regurgitation (MR) were evaluated and recorded. All three test animals had paravalvular spaces located near cable ties which were affixed to the rings to intentionally facilitate PVL between the ring and the skirt to simulate a worst-case condition for thrombus formation; in two of the animals the gap was near the left coronary cusp, and in the third the gap was near the non-coronary cusp. At explant, no valve had thrombus on the skirt (the primary area of interest). | | Histopathology | Histopathology results showed no apparent differences in tissue reactions (general healing, calcification, or morphology of the tissue/valve interface) between the test group valves 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 four animals at 3 weeks with pliable leaflets, no coronary occlusion, material wear, leaflet retraction, or calcification. Two of the test articles had no thrombus or vegetations. One test article had a single area of moderate pink tan thrombus deposition on the sewing band leaflet interface of the non-coronary cusp on the outflow aspect. The material was firmly adhered to the underlying cloth and was considered to be mature (chronic) fibrin thrombus. No valve had thrombus on the primary area of interest, the PVL skirt. | PMA P140031: FDA Summary of Safety and Effectiveness Data Page 21 # X. SUMMARY OF PRIMARY CLINICAL STUDY The applicant performed a clinical study in the U.S. to establish a reasonable assurance of safety and effectiveness of transcatheter aortic valve replacement with the Edwards SAPIEN 3 THV in patients with severe native calcific aortic stenosis under IDE G090216 (entitled the "PARTNER II" trial). The pooled data from two separate cohorts of the clinical study, i.e., the PIIS3HR cohort and Nested Registry #7 (NR7), were the basis for the PMA approval decision. A summary of the clinical study is presented below. Note that both the Edwards Commander delivery system (for transfemoral [TF] access) and the Edwards Certitude delivery system (for transapical [TA] or transaortic [TAo] access) were used in the clinical study and the clinical results presented herein include all access routes. However, the Edwards Certitude delivery system is not included in this PMA application. ## A. Study Design The PIIS3HR Cohort of the PARTNER II trial was a single arm, non-randomized, historical-controlled study to compare the third generation Edwards SAPIEN 3 THV system with the first generation Edwards SAPIEN THV system in patients who either have high risk for surgery or cannot undergo surgery (inoperable). The valve sizes used in the PIIS3HR trial included only the 23, 26 and 29 mm sizes. The 20 mm valve size was introduced into the trial after enrollment was completed with the three larger sizes, thus a separate nested registry, NR7, with identical inclusion/exclusion criteria as the PIIS3HR Cohort except for the aortic annulus diameter, was created to collect data for the 20 mm valve. Data from the PIIS3HR cohort and NR7 are pooled for the statistical analyses. For convenience, this combined cohort is referred to as "PIIS3HR" hereafter. Patients were treated between October 1, 2013 and July 17, 2014. The database reflected data collected through November 21, 2014 and included 583 eligible patients enrolled at 29 investigational sites in the U.S. The study used an independent Data Safety Monitoring Board (DSMB) that was instructed to notify Edwards Lifesciences of any safety or compliance issues, a Clinical Events Committee (CEC) that was responsible for adjudicating endpoint related events reported during the trial per a priori established VARC 2 definitions,[1] an ECG core laboratory for independent analysis of rhythm, and an echocardiographic core laboratory for independently analyzing all echocardiograms. ### 1. Clinical Inclusion and Exclusion Criteria Enrollment in PIIS3HR was limited to patients who met the following inclusion criteria: - STS >8% (a candidate who did not meet the STS score criteria of >8% could be included in the study if a peer review by at least two investigators [excluding the enrolling surgeon] concluded and documented that the patient’s predicted risk of operative mortality was ≥ 50%. The surgeon's assessment of operative comorbidities not captured by the STS score had to be documented). - 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 ≤ 0.80 cm² or indexed effective orifice area (EOA) < 0.5 cm²/m². Qualifying echo was required to be within 60 days of the date of the procedure. - Symptomatic from aortic valve stenosis, as demonstrated by NYHA Functional Class II or greater. - The heart team agreed (and verified in the case review process) that valve implantation would likely benefit the patient. - The study patient or the study patient’s legal representative was informed of the nature of the study, agreed to its provisions and provided written informed consent as approved by the Institutional Review Board (IRB) of the respective clinical site. - The study patient agreed to comply with all required post-procedure follow-up visits including annual visits through 5 years and analysis close date visits, which were to be conducted as phone follow-up. - For inoperable patients: The heart team agreed that medical factors precluded operation, based on a conclusion that the probability of death or serious, irreversible morbidity exceeded the probability of meaningful improvement. Specifically, the probability of death or serious, irreversible morbidity was ≥ 50%. The surgeons' consult notes had to specify the medical or anatomic factors leading to that conclusion and had to 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 was required to physically evaluate the patient. Inoperable patients had to be approved by a member of one of the PARTNER II Leadership Committees. - Aortic valve annulus area range (273 mm² - 680 mm²) per 3D imaging (echo, CT, or magnetic resonance imaging [MRI]). Patients were not permitted to enroll in PIIS3HR if they met any of the following exclusion criteria: - Evidence of an acute myocardial infarction (MI) ≤ 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 (World Health Organization [WHO] definition)]. - Aortic valve was a congenital unicuspid or congenital bicuspid valve, or was non-calcified. - Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+). PMA P140031: FDA Summary of Safety and Effectiveness Data Page 22 - Pre-existing mechanical or bioprosthetic valve in any position. - Any therapeutic invasive cardiac procedure resulting in a permanent implant that was performed within 30 days of the index procedure. Implantation of a permanent pacemaker or implantable cardioverter defibrillator (ICD) was not considered exclusionary. - Any patient with a balloon valvuloplasty (BAV) within 30 days of the procedure (unless BAV was a bridge to procedure after a qualifying echo). - Patients with planned concomitant surgical or transcatheter ablation for atrial fibrillation. - Leukopenia (white blood cells [WBC] < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), thrombocytopenia (Plt < 50,000 cell/mL). - Untreated clinically significant coronary artery disease requiring revascularization. - Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or mechanical heart assistance within 30 days of screening evaluation. - Need for emergency surgery for any reason. - Hypertrophic cardiomyopathy with or without obstruction. - Severe ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20%. - Echocardiographic evidence of intracardiac mass, thrombus or vegetation. - Active upper gastro-intestinal (GI) bleeding within 3 months (90 days) prior to procedure. - A known contraindication or hypersensitivity to all anticoagulation regimens, or inability to be anticoagulated for the study procedure. - Native aortic annulus size < 16 mm or >28 mm as measured by echocardiogram. - Clinically (by neurologist) or neuroimaging confirmed stroke or transient ischemic attack (TIA) within 6 months (180 days) of the procedure. - Renal insufficiency (creatinine > 3.0 mg/dL) and/or renal replacement therapy at the time of screening. - Estimated life expectancy < 24 months (730 days) due to carcinoma, chronic liver disease, chronic renal disease or chronic end stage pulmonary disease. - Expectation that patient would not improve despite treatment of aortic stenosis. - 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. (Transfemoral) - Iliofemoral vessel characteristics that would preclude safe placement of 14F or 16F introducer sheath such as severe obstructive calcification, severe tortuosity or minimum average vessel size less than 5.5 mm. (Transfemoral) - Currently participating in an investigational drug or another device study. Note: Trials requiring extended follow-up for products that were PMA P140031: FDA Summary of Safety and Effectiveness Data Page 23 investigational, but had since become commercially available, were not considered investigational trials. - Known enrollment in the PARTNER I Trial. - Active bacterial endocarditis within 6 months (180 days) of procedure. ## 2. Follow-up Schedule Follow-up periods were discharge or 7 days, whichever comes first, 30 days, 6 months, 12 months, and annually thereafter to a minimum of 5 years post procedure. ## 3. Clinical Endpoints The primary endpoint was a non-hierarchical composite of death (all cause), all stroke, and aortic insufficiency (AI) ≥ moderate at 30 days. Stroke was evaluated by the CEC, and AI was assessed by the echocardiography core laboratory. Events occurring on day 30 or earlier were included in the evaluation. The primary hypothesis was as follows: $$ \begin{array}{l} H_{0}: P_{T} - P_{C} \geq 7.5\% \\ H_{A}: P_{T} - P_{C} < 7.5\% \end{array} $$ where $P_{T}$ denotes the event proportion in the test arm, and $P_{C}$ denotes the event proportion in the control arm. The test was performed as a one-sided test at $\alpha = 0.05$. The analysis was a non-inferiority analysis adjusted for propensity quintiles. There were two pre-specified hypothesis-driven secondary endpoints: AI ≥ moderate at 30 days and major vascular complications at 30 days. The hypothesis for each secondary endpoint was as follows: $$ \begin{array}{l} H_{0}: P_{T} = P_{C} \\ H_{A}: P_{T} \neq P_{C} \end{array} $$ where $P_{T}$ denotes the event proportion in the test arm, and $P_{C}$ denotes the event proportion in the control arm. The comparison is a two-sided test with $\alpha = 0.05$. The analyses were adjusted for the stratification of propensity quintiles first and then adjusted for the multiplicity. ## B. Accountability of the PMA Cohort All 583 eligible patients were successfully implanted with a SAPIEN 3 THV, which constitutes the Valve Implant (VI) population. Among the VI population, 491 patients were implanted via the TF access route, and 92 patients via the TA or TAo access route, as summarized in Table 12. At the time of database lock, 570 of the 583 VI patients were still alive, and 565 patients had completed the 30-day post-operative visit. PMA P140031: FDA Summary of Safety and Effectiveness Data Page 24 Table 12: Patient Accountability | | Overall | TF | TA /TAo | | --- | --- | --- | --- | | Eligible Patient Population (EPP) | 583 | 491 | 92 | | Valve Implant (VI) Population | 583 | 491 | 92 | Eligible Patient Population (EPP) consists of all enrolled patients who received treatment assignment from the database and entered into the catheterization laboratory/hybrid suite and who remained eligible to receive the implant. Valve Implant (VI) Population consists of all enrolled patients who received a SAPIEN 3 implant, and retained the valve upon leaving the catheterization laboratory/hybrid suite. # C. Study Population Demographics and Baseline Parameters The demographics of the study population are summarized in Table 13, which are typical of a TAVR study performed in the U.S. Table 13: Patient Demographics and Baseline Characteristics - PIIS3HR VI Population | Characteristic | Overall (N= 583) | TF (N= 491) | TA/TAo (N= 92) | | --- | --- | --- | --- | | Age, yr | 82.6 ± 8.1 | 82.8 ± 8.2 | 81.7 ± 7.5 | | Male sex, no. (%) | 338 (58.0%) | 277 (56.4%) | 61 (66.3%) | | STS score | 8.6 ± 3.7 | 8.4 ± 3.5 | 10.0 ± 4.3 | | New York Heart Association (NYHA) class, no. (%): | | | | | I/II | 58 (9.9%) | 51 (10.4%) | 7 (7.6%) | | III/IV | 525 (90.1%) | 440 (89.6%) | 85 (92.4%) | | Coronary artery disease, no. (%) | 444 (76.2%) | 360 (73.3%) | 84 (91.3%) | | Previous myocardial infarction, no. (%) | 117 (20.1%) | 87 (17.7%) | 30 (32.6%) | | Previous intervention, no. (%) | | | | | Coronary-artery bypass grafting (CABG) | 193 (33.1%) | 145 (29.5%) | 48 (52.2%) | | Percutaneous coronary intervention (PCI) | 199 (34.1%) | 163 (33.2%) | 36 (39.1%) | | Prior aortic valvuloplasty | 62 (10.6%) | 49 (10.0%) | 13 (14.1%) | | Cerebral vascular accident (CVA), no. (%) | 64 (11.0%) | 53 (10.8%) | 11 (12.0%) | | Peripheral vascular disease, no. (%) | 205 (35.2%) | 155 (31.6%) | 50 (54.3%) | | Chronic obstructive pulmonary disease (COPD), no. (%): | | | | | Any | 259 (44.6%) | 216 (44.1%) | 43 (47.3%) | | Oxygen-dependent | 68 (11.8%) | 58 (11.9%) | 10 (11.0%) | | Atrial fibrillation, no. (%) | 255 (43.7%) | 212 (43.2%) | 43 (46.7%) | | Permanent pacemaker, no. (%) | 95 (16.3%) | 78 (15.9%) | 17 (18.5%) | | Severe pulmonary hypertension, no. (%) | 30 (5.1%) | 24 (4.9%) | 6 (6.5%) | | Frailty, no. (%) | 180 (30.9%) | 162 (33.0%) | 18 (19.6%) | | Chest deformities that preclude an open chest procedure, no. (%) | 4 (0.7%) | 3 (0.6%) | 1 (1.1%) | | Cirrhosis, no. (%) | 11 (1.9%) | 9 (1.8%) | 2 (2.2%) | | Echocardiographic findings | | | | | Effective Orifice Area (EOA), cm2 | 0.7 ± 0.2 | 0.7 ± 0.2 | 0.7 ± 0.1 | PMA P140031: FDA Summary of Safety and Effectiveness Data | Characteristic | Overall (N= 583) | TF (N= 491) | TA/TAo (N= 92) | | --- | --- | --- | --- | | Mean aortic-valve gradient, mmHg | 45.5 ± 14.3 | 45.7 ± 14.4 | 44.0 ± 13.2 | | Mean left ventricular ejection fraction (LVEF), % | 56.4 ± 14.8 | 57.0 ± 14.5 | 53.2 ± 15.9 | | Moderate or severe mitral regurgitation, no./total no. (%) | 69/541 (12.8%) | 63/461 (13.7%) | 6/80 (7.5%) | Plus-minus values are means ± SD. ## D. Safety and Effectiveness Results ### 1. Primary Endpoint The composite rate of all-cause mortality, all stroke, and AI ≥ moderate at 30 days was 6.7% in the SAPIEN 3 cohort and 15.6% in the SAPIEN cohort, as shown in Table 14. The resulting proportion difference in the average treatment effect on the treated (ATT; see reference [2]) was -6.9% (90% CI: [-13.3%, -0.5%]). Since the upper limit of the CI was < 7.5%, the non-inferiority was met. Table 14: Primary Endpoint Analysis – Non-Inferiority Test SAPIEN 3 vs. SAPIEN (PIIS3HR VI Population) | Event at 30 days | SAPIEN 3 (N=583) | SAPIEN (N=326) | Weighted Proportion Difference in Average Treatment Effect on the Treated (ATT) | | --- | --- | --- | --- | | Composite of Death, Stroke and AI ≥ Moderate) | 6.7% [5.1%, 8.6%]¹ | 15.6% [12.6%, 19.5%]¹ | -6.9% [-13.3%, -0.5%]² | ¹For each individual study, the two-sided 90% stratified Wilson confidence interval was provided. ² The Wald-type two-sided 90% confidence interval using weighted mean and SD is provided The Kaplan-Meier (K-M) estimates for all-cause mortality, cardiac mortality, and all stroke at 30 days for the SAPIEN 3 cohort and the SAPIEN cohort are provided in Table 15. Table 15: Death and Stroke at 30 Days (SAPIEN 3 vs. SAPIEN VI Population) | | SAPIEN 3 (N= 583) | | | SAPIEN (N= 326) | | | | --- | --- | --- | --- | --- | --- | --- | | Event at 30 Days | No. Events | No. Pts with Events | K-M Estimated Event Rate¹ (95% CI) | No. Events | No. Pts with Events | K-M Estimated Event Rate (95% CI) | | Death | 13 | 13 | 2.2% ([1.3%, 3.8%]) | 15 | 15 | 4.6% ([2.8%, 7.5%]) | | Cardiac Death | 8 | 8 | 1.4% ([0.7%, 2.7%]) | 10 | 10 | 3.1% ([1.7%, 5.7%]) | | All Stroke | 9 | 9 | 1.6% ([0.8%, 3.0%]) | 14 | 14 | 4.3% ([2.6%, 7.2%]) | ¹ Kaplan-Meier (K-M) estimates at 30 days used time to first event for each patient. Events occurring after 30 days were not included in this analysis. PMA P140031: FDA Summary of Safety and Effectiveness Data # 2. Secondary Endpoints Aortic insufficiency by visit is provided in Figure 6. ![img-5.jpeg](img-5.jpeg) Figure 6: Aortic Insufficiency by Visit - SAPIEN 3 vs. SAPIEN (PIIS3HR VI Population) The proportion of patients with AI $\geq$ moderate at 30 days was $3.0\%$ in the SAPIEN 3 cohort and $14.3\%$ in the SAPIEN cohort, which were found to be statistically significantly different $(p = 0.0051$ ; Table 16). Table 16: Aortic Insufficiency at 30 Days (SAPIEN 3 vs. SAPIEN VI Population) | Event at 30 Days | SAPIEN 3 (N = 583) | SAPIEN (N = 326 ) | Weighted Proportion Difference in Average Treatment Effect on the Treated (ATT) | P-value | | --- | --- | --- | --- | --- | | AI ≥Moderate, n/Total no. (%) [95% CI] | 16/532 (3.0%) [1.7%, 4.8%]1 | 40/280 (14.3%) [10.4%, 18.9%]1 | -13.1% [-22.2%, -3.9%]2 | 0.0051 | $^{1}$ 95% Clopper-Pearson Exact confidence interval. 2The Wald-type two-sided $90\%$ confidence interval using weighted mean and SD is provided. The rate of major vascular complications at 30 days post implantation is shown in Figure 7. The rate was $5.0\%$ for the SAPIEN 3 cohort and $10.1\%$ for the SAPIEN cohort, which were found to be not statistically significantly different $(p = 0.0578$ ; Table 17). PMA P140031: FDA Summary of Safety and Effectiveness Data ![img-6.jpeg](img-6.jpeg) Figure 7: Major Vascular Complications at 30 Days - SAPIEN 3 vs. SAPIEN (VI Population) Table 17: Major Vascular Complications at 30 Days (SAPIEN 3 vs. SAPIEN VI Population) | Event at 30 Day | SAPIEN 3 (N=583) | SAPIEN (N=326) | Weighted Proportion Difference in Average Treatment Effect on the Treated (ATT) | P-value | | --- | --- | --- | --- | --- | | Major Vascular Complications, n/Total no. (%) [95% CI] | 29/583 (5.0%) [3.4%, 7.1%] | 33/326 (10.1%) [7.1%, 13.9%]1 | -8.0% [-16.2%, 0.3%]2 | 0.0578 | 1 95% Clopper-Pearson Exact confidence interval. 2The Wald-type two-sided 90% confidence interval using weighted mean and SD is provided. Table 18 lists the hypothesis testing of the two secondary endpoints conducted with p-values in descending order for the Hochberg multiplicity adjustment steps. The largest p-value (p=0.0578 from major vascular complications) was greater than 0.05. As such, the null hypothesis was not rejected for the testing of major vascular complications at 30 days. The subsequent testing of AI ≥ moderate at 30 days had a p-value of 0.0051, which was less than 0.025. As such, the null hypothesis was rejected for AI ≥ moderate at 30 days, indicating that SAPIEN 3 was superior over SAPIEN in regards to AI ≥ moderate at 30 days. Table 18: Secondary Endpoints for Labeling (SAPIEN 3 vs. SAPIEN VI Population) | Endpoints | Original p-value | Inference | | --- | --- | --- | | Major Vascular Complications at 30 Days | 0.0578 | >0.05; reject the alternative hypothesis. Proceed to the rest of testing | | AI at 30 Days | 0.0051 | <0.025; claim superiority | PMA P140031: FDA Summary of Safety and Effectiveness Data # 3. Adverse Events The key CEC adjudicated adverse events at 30 days are presented in Table 19. Table 19: CEC Adjudicated Adverse Events at 30 Days (PIIS3HR VI Population) | 30 Day Adverse Events | Overall | TF | TA/TAo | | --- | --- | --- | --- | | Composite Event Rate of Death, All Stroke and AI ≥ Moderate, n/N (%) | 37/545 (6.8 %) | 27/463 (5.8 %) | 10/82 (12.2 %) | | Death | | | | | From Any cause, n/N (%) | 13/583 (2.2%) | 8/491 (1.6%) | 5/92 (5.4%) | | From cardiovascular cause, n/N (%) | 8/583 (1.4%) | 5/491 (1.0%) | 3/92 (3.3%) | | Stroke, n/N (%) | 9/583 (1.5%) | 8/491 (1.6%) | 1/92 (1.1%) | | AI ≥ moderate, n/N (%) | 16/532 (3.0 %) | 12/455 (2.6 %) | 4 /77 (5.2 %) | | Myocardial Infarction, n/N (%) | 3/583 (0.5%) | 2/491 (0.4%) | 1/92 (1.1%) | | Major Vascular Complications, n/N (%) | 29/583 (5.0%) | 26/491 (5.3%) | 3/92 (3.3%) | | Acute Kidney Injury, Stage III, n/N (%) | 6/583 (1.0%) | 4/491 (0.8%) | 2/92 (2.2%) | | Disabling Bleeding Event, n/N (%) | 37/583 (6.3%) | 27/491 (5.5%) | 10/92 (10.9%) | | Aortic Valve Re-Intervention, n/N (%) | 6/583 (1.0%) | 4/491 (0.8%) | 2/92 (2.2%) | | Endocarditis, n/N (%) | 1/583 (0.2%) | 1/491 (0.2%) | 0/92 (0.0%) | | Conduction Disturbance Requiring Permanent Pacemaker, n/N (%) | 76/583 (13.0%) | 65/ 491 (13.2%) | 11/ 92 (12.0%) | # 4. Other Results # Procedural Information Overall, the mean duration in the catheterization laboratory/hybrid suite was $192.8 \pm 59.3$ min, the mean total procedure time was $86.3 \pm 44.2$ min, and the mean total anesthesia time was $193.7 \pm 62.9$ min. These duration times were slightly shorter in the TF group. General anesthesia was used in the vast majority of cases; $15.9\%$ of the TF patients had conscious sedation. Correct positioning of the valve was achieved in $99.1\%$ of the patients. Five patients $(0.9\%)$ ; including 3 TF patients) were implanted with a second valve. One patient $(0.2\%)$ experienced valve embolization following rupture of the delivery balloon on annular calcium. This patient was converted to surgical aortic valve replacement and later died from aortic dissection. # Valve Performance The mean EOA increased from $0.7 \pm 0.2 \, \text{cm}^2$ at baseline to $1.6 \pm 0.4 \, \text{cm}^2$ at 30 days, as shown in Figure 8. PMA P140031: FDA Summary of Safety and Effectiveness Data ![img-7.jpeg](img-7.jpeg) Figure 8: Effective Orifice Area (PIIS3HR VI Population) The average mean gradient decreased from $45.5 \pm 14.3 \mathrm{mmHg}$ at baseline to $11.1 \pm 4.5 \mathrm{mmHg}$ at 30 days, as shown in Figure 9. ![img-8.jpeg](img-8.jpeg) Figure 9: Mean Gradient (PIIS3HR VI Population) The mean peak gradient decreased from $75.8 \pm 22.6 \mathrm{mmHg}$ at baseline to $21.2 \pm 8.5 \mathrm{mmHg}$ at 30 days, as shown in Figure 10. PMA P140031: FDA Summary of Safety and Effectiveness Data ![img-9.jpeg](img-9.jpeg) Figure 10: Peak Gradient (PIIS3HR VI Population) The proportion of patients with AI $\geq$ moderate was $7.3\%$ at baseline and $3.0\%$ at 30 days, as shown in Figure 11. ![img-10.jpeg](img-10.jpeg) Figure 11: Aortic Insufficiency (PIIS3HR VI Population) The proportion of patients with aortic paravalvular leak (PVL) $\geq$ moderate was $2.9\%$ at 30 days, as shown in Figure 12. PMA P140031: FDA Summary of Safety and Effectiveness Data ![img-11.jpeg](img-11.jpeg) Figure 12: Aortic Paravalvular Leak (PIIS3HR VI Population) # NYHA The NYHA class by visit is shown in Figure 13. For all patients, the mean NYHA class was $3.2 \pm 0.6$ at baseline and $1.7 \pm 0.7$ at 30 days. ![img-12.jpeg](img-12.jpeg) Figure 13: NYHA Class by Visit (PIIS3HR VI Population) PMA P140031: FDA Summary of Safety and Effectiveness Data PMA P140031: FDA Summary of Safety and Effectiveness Data Page 33 ## Six Minute Walk Test (6MWT) The improvement in mean 6MWT distance was $38.5 \pm 110.2$ meters from baseline to 30 days for all patients, $42.6 \pm 107.8$ meters for all TF patients, and $15.9 \pm 121.2$ meters for all TA/TAo patients. ## Length of Stay (LoS) The overall mean LoS was $6.8 \pm 4.8$ days, which included $3.0 \pm 2.7$ days in the ICU. The mean LoS was $6.1 \pm 4.3$ days (including $2.7 \pm 2.3$ days in the ICU) for the TF patients and $10.4 \pm 5.4$ days (including $4.8 \pm 3.9$ days in the ICU) for the TA/TAo patients. ## Quality of Life (QoL) QoL was measured using the visual analog scale (VAS) of the EuroQoL (EQ-5D) measure. The VAS is a self-assessment in which patients rate their well-being on a scale from 0 to 100 where 0 is the worst state they can imagine and 100 is the best state. During the trial, the mean improvement in VAS scale from baseline to 30 days was $14.6 \pm 22.2$ for all patients, $15.1 \pm 21.5$ for the TF patients, and $11.5 \pm 25.7$ for the TA/TAo patients. ## Additional QoL instruments The mean overall Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score was $46.9 \pm 22.6$ at baseline, and $67.5 \pm 22.6$ at 30 days for the entire VI population. Except for self-efficacy which showed a small improvement, moderate to large improvements were observed in all other subscores at 30 days. In general, improvements in the TF group were slightly larger compared to those observed in the TA/TAo group. Using the SF-36 norm based questionnaire, the physical component score for all patients improved from $32.0 \pm 8.9$ at baseline to $37.1 \pm 9.7$ at 30 days, and the mental component score improved from $46.9 \pm 12.8$ at baseline to $50.0 \pm 12.5$ at 30 days. In the TF group, the physical component score improved from $31.8 \pm 8.7$ at baseline to $37.3 \pm 9.8$ at 30 days, and the mental component score improved from $46.8 \pm 13.1$ at baseline to $50.5 \pm 12.2$ at 30 days. In the TA/TAo group, the physical component score improved from $32.9 \pm 10.0$ at baseline to $35.9 \pm 9.4$ at 30 days, and the mental component scores were $47.2 \pm 11.1$ at baseline and $47.2 \pm 14.0$ at 30 days. ## 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 PIIS3HR pivotal clinical study involved 196 investigators of which none were full-time or part-time employees of the sponsor including six (6) investigators that 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: 6 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. ## XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION The supplemental clinical data to the PMA application came from a study (referred to as "S3OUS" hereafter) conducted in Europe and Canada to support the CE Mark. ## A. Study Design The S3OUS study was a non-randomized, prospective, multi-center study in inoperable, high surgical risk, and intermediate surgical risk patients who underwent implantation of the 23, 26, or 29 mm SAPIEN 3 THV. Except the intermediate surgical risk patients, the inclusion/exclusion criteria of the S3OUS trial were largely similar to those of the PIIS3HR trial. However, the S3OUS study had a minimum age requirement (≥ 75 years) and the upper limit for AVA was higher (< 1 cm² instead of ≤ 0.80 cm²). Additionally, the S3OUS study allowed for the inclusion of patients with the following: BAV within 30 days of the procedure (unless BAV was a bridge to procedure); planned concomitant surgical or transcatheter ablation for atrial fibrillation; hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or mechanical heart assistance within 30 days of screening; and the need for emergency surgery for any reason. Furthermore, the exclusion criteria in the S3OUS study excluded senile dementia and any neurologic disease which severely affected the ability to walk or perform everyday activities, and shortened the time interval regarding confirmed stroke or TIA (within 3 months instead of 6 month of the procedure). The follow-up periods were discharge or 7 days, whichever comes first, 30 days, 1 year, and annually thereafter to a minimum of 5 years post procedure. PMA P140031: FDA Summary of Safety and Effectiveness Data Page 34 # B. Accountability of the S3OUS Cohort Patients were treated between January 3, 2013 and October 23, 2013 at 14 investigational sites. Note that the intermediate risk patients enrolled in the S3OUS study were excluded from the analysis presented herein. The database reflects data collected through November 19, 2014 and included 102 "all treated" (AT) inoperable and high surgical risk patients. "All treated" population is defined to include all patients who were enrolled in the trial and for whom the study valve implantation procedures were started (i.e., the anesthesia was started). One patient was excluded from the VI population. This patient experienced an aortic root rupture caused by displacement of a large lump of calcium with sharp edges through the native aortic annulus following balloon expansion of the SAPIEN 3 THV. The patient was subsequently converted to SAVR. After the patient was weaned of cardiopulmonary bypass, bleeding in the region of the dorsal root occurred, and the patient died on the operating table. A total of 56 patients were successfully implanted with a SAPIEN 3 THV via the transfemoral access route, and 45 via the transapical/transaortic access route, as shown in Table 20. At the time of database lock, 80 of the 102 AT patients were still alive and had not withdrawn consent, and all had completed the 1-year post-operative visit. Table 20: Patient Accountability (S3OUS) | Overall | | TF | | TA/TAo | | | --- | --- | --- | --- | --- | --- | | All Treated (AT) Population | Valve Implant (VI) Population | All Treated (AT) Population | Valve Implant (VI) Population | All Treated (AT) Population | Valve Implant (VI) Population | | 102 | 101 | 57 | 56 | 45 | 45 | | All Treated (AT) Population consists of all patients who were enrolled in the trial and for whom the study valve implantation procedures were started (i.e., the anesthesia was started). Valve Implant (VI) Population consists of all enrolled patients who received a SAPIEN 3 implant, and retained the valve upon leaving the catheterization laboratory/hybrid suite. | | | | | | # C. Study Population Demographics and Baseline Parameters The demographics of the S3OUS study population are shown in Table 21. Table 21: Patient Demographics and Baseline Characteristics (S3OUS AT Population) | Demographics and Baseline Characteristics | Overall (N= 102) | TF (N= 57) | TA/TAo (N= 45) | | --- | --- | --- | --- | | Age, yr | 84.1 ± 5.0 | 85.1 ± 4.6 | 83.0 ± 5.3 | | Male sex, no.(%) | 40 (39.2%) | 23 (40.4%) | 17 (37.8%) | | STS score | 8.0 ± 4.7 | 8.2 ± 4.2 | 7.9 ± 5.2 | | Logistic EuroSCORE | 24.1 ± 13.0 | 22.3 ± 11.3 | 26.4 ± 14.7 | | New York Heart Association (NYHA) class, no.(%): | | | | | I/II | 11 (10.8%) | 6 (10.5%) | 5 (11.1%) | PMA P140031: FDA Summary of Safety and Effectiveness Data | Demographics and Baseline Characteristics | Overall (N= 102) | TF (N= 57) | TA/TAo (N= 45) | | --- | --- | --- | --- | | III/IV | 91 (89.2%) | 51 (89.5%) | 40 (88.9%) | | Coronary artery disease, no.(%) | 68 (66.7%) | 36 (63.2%) | 32 (71.1%) | | Previous myocardial infarction, no.(%) | 20 (19.6%) | 7 (12.3%) | 13 (28.9%) | | Previous intervention, no.(%) | | | | | Coronary-artery bypass grafting (CABG) | 24 (23.5%) | 10 (17.5%) | 14 (31.1%) | | Percutaneous coronary intervention (PCI) | 34 (33.3%) | 16 (28.1%) | 18 (40.0%) | | Prior aortic valvuloplasty | 10 (9.8%) | 8 (14.0%) | 2 (4.4%) | | Stroke, no.(%) | 7 (6.9%) | 4 (7.0%) | 3 (6.7%) | | Peripheral vascular disease, no.(%) | 27 (26.5%) | 10 (17.5%) | 17 (37.8%) | | Chronic obstructive pulmonary disease (COPD), no.(%): | | | | | Any | 25 (24.5%) | 13 (22.8%) | 12 (26.7%) | | Oxygen-dependent | 1 (1.0%) | 1 (1.8%) | 0 (0%) | | Atrial fibrillation, no.(%) | 48 (47.1%) | 22 (38.6%) | 26 (57.8%) | | Permanent pacemaker, no.(%) | 15 (14.7%) | 7 (12.3%) | 8 (17.8%) | | Severe pulmonary hypertension, no.(%) | 10 (9.8%) | 6 (10.5%) | 4 (8.9%) | | Severe liver disease / Cirrhosis, no.(%) | 1 (1.0%) | 1 (1.8%) | 0 (0%) | | Echocardiographic findings | | | | | Effective Orifice Area (EOA), cm2 | 0.6 ± 0.2 | 0.6 ± 0.2 | 0.6 ± 0.1 | | Mean aortic-valve gradient, mmHg | 44.8 ± 15.3 | 45.2 ± 14.7 | 44.2 ± 16.1 | | Mean left ventricular ejection fraction (LVEF), % | 56.7 ± 9.1 | 57.7 ± 9.3 | 55.3 ± 8.7 | | Moderate or severe mitral regurgitation, no./total no. (%) | 23/85 (27.1%) | 9/48 (18.8%) | 14/37 (37.8%) | Plus-minus values are means ± SD. ## D. Safety and Effectiveness Results ### Key Adverse Events Key adverse events as adjudicated by the CEC are presented in Table 22. Table 22: CEC Adjudicated Adverse Events at 1 Year (S3OUS AT Population) | | 30 Day | | | 1 Year | | | | --- | --- | --- | --- | --- | --- | --- | | Outcomes | Overall | TF | TA/TAo | Overall | TF | TA/TAo | | Composite Event Rate of Death, All Stroke and AI ≥ Moderate… --- **Source:** [https://fda.innolitics.com/device/P140031](https://fda.innolitics.com/device/P140031) **Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. 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