Edwards SAPIEN XT Instructions For Use Manual

Edwards SAPIEN XT Transcatheter Heart Valve with the Ascendra+ Delivery System

Instructions for Use Caution: Federal (USA) law restricts this device to sale by or on the order of a physician. Implantation of the transcatheter heart valve should be performed only by physicians who

have received Edwards Lifesciences training. The implanting physician should be experienced in balloon aortic valvuloplasty.

Please verify that you have the latest version of the instructions for use prior to using the device by visiting http://THVIFU.edwards.com

or by calling 1.800.822.9837. In order to access

the instructions for use, an IFU Code will b e required. STERILE: The valve is supplied sterilized with glutaraldehyde solution. The delivery system is

supplied sterilized with ethylene oxide gas.

_________________________________________________________________________________________ Edwards, Edwards Lifesciences, the stylized E logo, Ascendra, Ascendra+, Carpentier-Edwards,

Edwards SAPIEN, Edwards SAPIEN XT, PARTNER and PARTNER II, SAPIEN, SAPIEN XT, TFX, and ThermaFix are trademarks of Edwards Lifesciences Corporation. All other trademarks are the property of their respective owners.

1.0 Device Description

Valve size recommendations are based on native valve annulus size, as measured by

Note: Risks associated with undersizing and oversizing should be considered.

Diameter

18-21 mm

23 mm

21-23.5 mm

26 mm

23.5-27 mm

29 mm

• Edwards SAPIEN XT Transcatheter Heart Valve – Model 9300TFX (Figure 1)

The Edwards SAPIEN XT transcatheter heart valve is comprised of a balloon-expandable, radiopaque, cobalt-chromium frame, trileaflet bovine pericardial tissue valve, and a polyethylene terephthalate (PET) fabric skirt. The leaflets are treated according to t he Car pe nti e r-Edwards ThermaFix process.

Table 1

Valve Size Height

23 mm 14.3 mm 26 mm 17.2 mm 29 mm 19.1 mm

Table 2

Native Valve Annulus

Size

(TEE)

18-22 mm 314 – 415 mm 21-25 mm 415 – 530 mm 24-27 mm 530 – 660 mm

Native Valve Annulus Size

(CT)

Area

Area Derived

Diameter

20-23 mm 23 mm 23-26 mm 26 mm

26-29 mm 29 mm

Valve Size

transesophageal echocardiography (TEE) or computed tomography (CT). Patient anatomical factors and multiple imaging modalities should be considered during valve size selection.

For transcatheter valve-in-surgical valve procedures, size recommendations for surgical bioprostheses with internal orifice diameters are shown in Table 3.

Bioprosthesis Internal Orifice

Table 3

SAPIEN XT Valve Size

NOTE: The internal orifice diameter o f th e surgical bioprosthesis must be determi n ed so that the appropriate valve size can be implanted. The bioprosthesis internal diameter of the primary implanted device is best determined by using computed tomography, magnetic resonance imaging, and/or tran sesophageal echocardiography to perfor m th e necessary measurements. The internal orifice diameter is a directly measured or area derived diameter measurement of the internal opening of the failed surgical valve.

NOTE: Exact volume required to deploy the valve may vary depending on the bioprosthesis internal orifice diameter. Do not exceed the rated burst pressure . See Table 4 for inflation parameters.

• Ascendra+ Delivery System (Figures 2a, 2b, 2c)

Diameter

Volume

(RBP)

The Ascendra+ delivery system (useable length 55 cm) is used for delivery of the Edwards SAPIEN XT transcatheter heart valve. The delivery system has radiopaque markers for visualization under fluoroscopy and a balloon for deployment of the valve. A balloon inflation hub, a guidewi re hub , and a pusher retraction feature are housed in the handle assembly. The handle is labeled “BALLOON” at the balloon inflation hub and “WIRE 0.035"” at the guidewire hub. The system also comes with a loader that is used to cover the valve during delivery. An extension tube is supplied for use with the delivery system during inflation.

Table 4

Model

9355AS23 23 mm 16 mL 7 atm 9355AS26 26 mm 20 mL 7 atm 9355AS29 29 mm 30 mL 7 atm

Nominal

Balloon

Nominal Inflation

Rated Burst

Pressure

2.0 Indications

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 who are judged by a Heart Team, including a cardiac surgeon, to be at intermediate or greater risk for open surgical therapy (i.e., predicted risk of surgical mortality ≥ 3% at 30 days, based on the Society of Thoracic Surgeons (STS) risk score and other clinical co-morbidities unmeasured by the STS risk calculator).

The Edwards SAPIEN XT transcatheter heart valve and accessories are also indicated for patients with symptomatic heart disease due to failure (steno sed, insufficient, or combined) of a surgical bioprosthetic aortic valve who are judged by a heart team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., STS operative risk score ≥8% or at a ≥15% risk of mortality at 30 days).

3.0 Contraindications

The valve and delivery system are contraindicated in patients who cannot tolerate an anticoagulation/antiplatelet regimen or who have active bacterial endocarditis or other active infections.

4.0 Warnings

• Observation of the pacing lead throughout the procedure is essential to avoid the potential risk of pacing lead perforation.

• There may b e an increased risk of stroke in transcatheter aortic valve replacement procedures, as compared to balloon aortic valvuloplasty or other standard treatments in high or greater risk patients.

• The devices are designed, intended, and distributed for single use only. Do not resterilize or reuse the devices. There are no data to support the sterility, nonpyrogenicity, and

functionality of the devices after reprocessing.

• Care should be exercised when sizing the native annulus or surgical valve; implanting a valve

that is too small may lead to paravalvular leak, migration or embolization, whereas implanting a valve that is too large may lead to residual gradient (patient-prosthesis mismatch) or annular rupture.

• Accelerated deterioration of the valve may occur in patients with an altered calcium metabolism.

• Prior to delivery, the valve must remain hydrated at all times and cannot be exposed to solutions other than its shipping storage solution and sterile physiologic rinsing solution. Valve leaflets mishandled or damaged during any part of the procedure will require replacement of the valve.

• Caution should be exercised in implanting a valve in patients with clinically significant coronary artery disease.

• Patients with pre-existing mitral valve devices should be carefully assessed prior to implantation of the valve to ensure proper valve positioning and deployment.

• Patients presenting with combination AV low flow, low gradient should undergo additional evaluation to establish the degree of aortic stenosis.

• Do not use the valve if the tamper evident seal is broken, the storage solution does not completely cover the valve, the temperature indicator has been activated, the valve is damaged, or the expiration date has elapsed.

• Do not mishandle the Ascendra+ delivery system or use it if the packaging or any components are not sterile, have been opened or are damaged (e.g. kinked or stretched), or the expiration date has elapsed.

• Care should be exercised in patients with hypersensitivities to cobalt, nickel, chromium, molybdenum, titanium, manganese, silicon, and/or polymeric materials.

• The procedure should be conducted under fluoroscopic guidance. Some fluoroscopically guided procedures are associated with a risk of radiation injury to the skin. These injuries may be painful, disfiguring, and long-lasting.

• Valve recipients should be maintained on anticoagulant/antiplatelet therapy, except when contraindicated, as determined by their physician. This device has not been tested for use without anticoagulation.

• Do not add or apply antibiotics to the storage solution, rinse solutions, or to the valve.

5.0 Precautions

• Long-term durability has not been established for the valve. Regular medical follow-up is advised to evaluate valve performance.

• Glutaraldehyde may cause irritation of the skin, eyes, nose and throat. Avoid prolonged or repeated exposure to, or breathing of, the solution. Use only with adequate ventilation. If skin contact occurs, immediately flush the affected area with water; in the event of contact with eyes, seek immediate medical attention. For more information about glutaraldehyde exposure, refer to the Material Safety Data Sheet available from Edwards Lifesciences.

• To maintain proper valve leaflet coaptation, do not overinflate the deployment balloon.

• Appropriate antibiotic prophylaxis is recommended post-procedure in patients at risk for

prosthetic valve infection and endocarditis.

• Safety, effectiveness, and durability have not been established for transcatheter valve in transcatheter valve procedures.

• Safety and effectiveness have not been established for patients with the following characteristics/comorbidities:

o Non-calcified aortic annulus o Severe ventricular dysfunction with ejection fraction < 20% o Congenital unicuspid or congenital bicuspid aortic valve o Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant

aortic regurgitation > 3+)

o Pre-existing prosthetic ring in any position o Severe mitral annular calcification (MAC), severe (> 3+) mitral insufficiency, or Gorlin

syndrome

o Blood dyscrasias defined as: leukopenia (WBC < 3000 cells/mL), acute anemia

(Hb < 9 g/dL), thrombocytopenia (platelet count < 50,000 cells/mL), or history of bleeding diathesis or coagulopathy

o Hypertrophic cardiomyopathy with or without obstruction (HOCM) o Echocardiographic evidence of intracardiac mass, thrombus, or vegetation o A known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid™), or

clopidogrel (Plavix™), or sensitivity to contrast media, which cannot be adequately premedicated

o Excessive calci fication of vessel at acce ss site o Bulky calcified aortic valve leaflets in close proximity to coronary ostia o A concomitant paravalvular leak where the surgical bioprosthesis is not securely fixed in

the native annulus or is not struc tur all y intact (e.g. w iref or m frame fracture)

o A partially detached leaflet of the surgical bioprosthesis that in the aortic position may

obstruct a coronary ostium

• The safety and effectiveness have not been established for implanting the transcatheter va lve inside a stented bioprosthetic valve < 21 mm (labeled size) or an unstented bioprosthetic aortic valve.

• Residual mean gradient may be higher in a "TAV-in-SAV" configuration than that observed following implantation of the valve inside a native aortic annulus using the same size device. Patients with elevated mean gradient post procedure should be carefully followed. It is important that the manufacturer, model and size of the preexisting surgical bioprosthetic aortic valve be determined, so that the appropriate valve can be implanted and a prosthesis-patient mismatch be avoided. Additionally, pre-procedure imaging modalities must be employed to make as accurate a determination of the internal orifice as possible.

6.0 Potential Adverse Events

Potential risks associated with the overall procedure including potential 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 incl ud ing air, c alcif ic valve material or thrombus

• Infection including septicemia and endocarditis

• Heart failure

• Myocardial infarc tion

• Renal insufficiency or renal failure

• Conduction system defect which may require a permanent pacemaker

• Arrhythmia

• Retroperitoneal bleed

• AV fistula or pseudoaneurysm

• Reoperation

• Ischemia or nerve injury

• Restenosis

• Pulmonary edem a

• 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 valve, 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

7.0 Directions for Use

7.1 Required Equipment Table 5

23 mm System

Product Name

Edwards SAPIEN XT

Transcatheter Heart Valve

Ascendra+ Delivery System* 9355AS23 9355AS26 9355AS29

Ascendra+ Introducer Sheath

Set

Ascendra Balloon Aortic

Valvuloplasty Catheter

Edwards Crimper 9350CR

* Includes the Crimp Stopper

(9355ASP23A)

9300TFX (23 mm) 9300TFX (26 mm) 9300TFX (29 mm)

9350IS23 9350IS26 9350IS29

Inflation devices provided by Edwards Lifesciences

26 mm System

(9355ASP26A)

Model

9100BAVC

29 mm System

(9355ASP29A)

Additional Equipment:

• 20 cc syringe or larger (x2)

• 50 cc syringe or larger

• Standard cardiac catheterization lab equipment

• Fluoroscopy (fixed, mobile or semi-mobile fluoroscopy systems appropriate for use in

percutaneous coronary interventions)

• Transesophagea l or transthoracic echocardiography capabilities

• Exchange length 0.035 inch (0.89 mm) extra-stiff guidewire

• Temporary pacemaker (PM) and pacing lead

• Sterile rinsing basins, physiological saline, heparinized saline, 15% diluted radiopaque contrast

medium

• Sterile table for valve and device preparation

7.2 Valve Handling and Preparation

Follow sterile technique during device preparation and im plantat ion.

7.2.1 Valve Rinsing Procedure

to come into contact with the bottom or sides of the rinse bowl

Flush loader through the distal end with heparinized saline and insert the delivery system (with proximal

Before opening the valve jar, carefully examine for evidence of damage (e.g., a cracked jar or lid, leakage, or broken or missing seals).

CAUTION: Valves from containers found to be damaged, leaking, without adequate sterilant, or missing intact seals must not be used for implantation.

Step Procedure

Set up two (2) sterile bowls with at least 500 mL of sterile physiological saline to thoroughly rinse the

glutaraldehyde sterilant from the valve. Carefully remove the valve/holder assembly from the jar without touching the tissue. Verify the valve

serial identification number with the number on the jar lid and record in the patient information documents. Inspect the valve for any signs of damage to the frame or tissue.

Rinse the valve as follows: Place the valve in the first bowl of sterile, physiological saline. Be sure the saline solution completely covers the valve and holder. With the valve and holder submerged, slowly agitate (to gently swirl the valve and holder) back and forth for a minimum of 1 minute. Transfer the valve and holder to the second rinsing bowl of physiological saline and gently agitate for at least one more minute. Ensure the rinse solution in the first bowl is not used. The valve should be left in the final

rinse solution until needed to prevent the tissue from drying.

CAUTION: Do not allow the valve during agitation or swirling in the rinse solution. Direct contact between the identification tag and valve is also to be avoided during the rinse procedure. No other objects should be placed in the rinse bowls. The valve should be kept hydrated to prevent the tissue from drying.

7.2.2 Prepare the Components

Step Procedure

Visually inspect all components for damage. Refer to Ascendra+ Introducer Sheath Set and Crimper instructions for use on device preparation and

handling. Ensure the delivery system pusher is in the distal locked position using the slider cap. I f the sto p co ck i s

not attached to the delivery system, attach st opc oc k to the flush port. Flush delivery system at the flush port with heparinized saline and close stopcock to delivery system.

Carefully remove distal balloon cover.

balloon cover on) into loader until loader is completely proximal.

Fully retract slider cap and rotate into proximal slot. Slide the proximal balloon cover onto the balloon shaft and carefully peel off the proximal balloon cover

from the delivery system.

Flush and attach balloon extension tube to the balloon inflation hub. Prepare a 50 cc or larger luer-lock syringe with diluted contrast solution (15:85 contrast to heparinized

saline) and attach to the extension tubing. Completely fill the inflation device provided by Edwards with diluted contrast and attach to the

extension tubing stopcock. Ensure there are no air bubbles in the balloon. If an air bubble is detected, eliminate it while deflating the balloon. Close the stopcock to the delivery system.

Step Procedure

Note: Correct balloon sizing is critical to successful valve deployment and valve function.

deployment.

Remove excess contrast medium from the inflation device provided by Edwards into the syringe to achieve the appropriate volume required to deploy the valve per the following. Then lock the inflation device:

Delivery System Valve Inflation

Model 9355AS23 23 mm 16 mL Model 9355AS26 26 mm 20 mL Model 9355AS29 29 mm 30 mL

Close the stopcock to the 50 cc or larger syringe and remov e the syringe.

CAUTION: Maintain the inflation device provided by Edwards in the locked position until valve

Volume

7.2.3 Mount and Crimp the Valve onto the Delivery System

Step Procedure

Rotate the crimper until the aperture is fully opened.

Remove the valve from the holder and remove ID tag using sterile scissors.

Place valve into crimper aperture and partially crimp so that it fits loosely over the prepared balloon. Remove the valve from the crimper and place it on the delivery system with the inflow (fabric cuff end)

of the valve proximally towards the pusher if accessing antegrade. If accessing retrograde, place the

valve on the delivery system with the inflow (fabric cuff end) of the valve towards the distal end away from the pusher. Ensure that the valve is aligned between the radiopaque markers.

Place the valve/balloon assembly in crimper aperture and gradually crimp. Periodically open crimper to verify correct placement of valve during crimping. Completely crimp until the handle contacts the crimp stopper.

CAUTION: The implanting physician must verify correct mounting/orientation of the valve prior to its implantation.

Advance the slider cap distally to allow the tip of the pusher to align with the proximal end of the

crimped valve. Advance the loader onto crimped valve until it reaches the balloon shoulder and the valve is full y

covered. While holding the loader in place, fully retract the slider cap and rotate into locked position. Flush

through the flush port to fill the loader and hydrate the valve. Once the valve is hydrated, advance the slider cap and rotate into distal locked position. Be sure to maintain position of the crimped valve between the radiopaque markers during hydration. Close the flush port stopcock to the delivery system.

Note: To facilitate flushing, keep the delivery system straight. CAUTION: To prevent possible leaflet damage, the valve should not remain in the loader over 30

minutes.

Ensure the slider cap is locked in the distal position and that the valve is still centered between radiopaque markers and fully inside the loader.

Note: Keep valve hydrated until ready for implantation.

Step Procedure

Minimum Required

Annulus to Sheath Tip

Model 9355AS23

23 mm

5.0 cm

Model 9355AS26

26 mm

5.5 cm

Model 9355AS29

29 mm

6.0 cm

Remove the stylet and flush the guidewire lumen of the delivery system.

CAUTION: The implanting physician must verify correct orientation of the valve prior to its implantation.

7.3 Valvuloplasty and Valve Delivery

Valvuloplasty and valve delivery should be performed under general anesthesia with hemodynamic monitoring in a catheterization lab/hybrid operating room with fluoroscopic and echocardiographic imaging capabilities.

The following table shows the minimum required distances from the native valve annulus to the distal tip of the Ascendra+ sheath to allow the Ascendra+ delivery system balloon to inflate properly during valve deployment. These distances should be considered during the transaortic approach when selecting the access site on the ascending aorta and determining the insertion depth of the Ascendra+ sheath into the aorta.

Delivery System Valve

Distance From

Administer heparin to maintain the ACT at ≥ 250 sec.

CAUTION: Contrast media use should be monitored to reduce the risk of renal injury.

7.3.1 B asel ine Par am ete rs

Step Procedure

Perform an angiogram with fluoroscopic view perpendicular to the valve. Evaluate the height between the inferior aspect of the annulus and the inferior aspects of the lowest

coronary ostium for subsequent prosthetic aortic valve implantation.

Introduce a pacemaker (PM) lead until its distal end is positioned in the right ventricle.

Set the stimulation parameters, and test pacing.

7.3.2 Valvuloplasty

Refer to Ascendra Balloon Aortic Valvuloplasty Catheter Instructions for Use (IFU) for information on device preparation and handling for a stenotic aortic valve.

Note: Rapid ventricular pacing s h o u ld be performed when using the Ascendra balloon aortic valvuloplasty catheter for valvuloplasty prior to transcatheter valve implantation.

After placement of the balloon at the intended site, begin rapid ventricular pacing. Once the blood pressure has decreased to 50 mmHg or below, balloon inflation can commence.

CAUTION: Valve implantation should no t b e carried out if the balloon cannot be fully inflated during valvuloplasty.

7.3.3 Valve Delivery

Retract pusher by rotating slider cap out of distal locked position and moving it proximally to ensure that

Step Procedure

Insert the introducer sheath. Refer to the Ascendra+ Introducer Sheath Set IFU for additional

information on device preparation and handling. Advance delivery system over guidewire. Engage loader into introducer sheath housing while

maintaining a firm grip. Tap lightly on the introducer sheath housing to release air to the proximal end of the loader. Lightly depress button valves on loader to aspirate the loader.

Cross the native aortic valve or bioprosthesis and position the transcatheter valve within the valve.

the tip of the pusher is retracted completely on to the balloon shaft.

CAUTION: The pusher must be pulled back completely on the balloon shaft for proper balloon inflation and valve deployment.

5 Verify the correct position of the valve with respect to the valve.

Begin valve deployment:

• Unlock the inflation device.

• Begin rapid pacing; once arterial blood pressure has decreased to 50 mmHg or below, balloon inflation can commence.

• Deploy the valve by inflating the balloon with the entire volume in the Inflation device provided by Edwards Lifesciences, hold for 3 seconds and confirm that the barrel of the inflation device is empty to ensure complete inflation of the balloon. When the balloon catheter has been completely deflated, turn off the pacemaker.

• Retract the delivery system into the introducer sheath.

Disengage loader from sheath and remove delivery system and loader.

Remove sheath when the ACT level is appropriate (e.g. reaches < 150 sec). Close access site.

8.0 How Supplied

STERILE: The valve is supplied sterilized with glutaraldehyde solution. The delivery system is supplied sterilized with ethylene oxide gas.

8.1 Storage

The valve must be stored at 10 °C to 25 °C (50 °F to 77 °F). Each jar is shipped in an enclosure containing a temperature indicator to detect exposure of the valve to extreme temperature.

The delivery system should be stored in a cool, dry place.

9.0 MR Safety

MR Conditional

Non-clinical testing has demonstrated that the Edwards SAPIEN XT transcatheter heart valve is MR Conditional. A patient with this device, when implanted in the native valve or a failed surgical bioprosthesis, can be scanned safely, immediately after placement of this device under the following conditions:

• Static magnetic field of 1.5 tesla or 3 tesla

• Maximum spatial gradient field of 2500 gauss/cm (25 T/m) or less

• Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 2 W/kg

(Normal Operating Mode) Under the scan conditions defined above, the SAPIEN XT transcatheter heart valve is expected to produce a maximum temperature rise of 2.6 °C after 15 minutes of continuous scanning.

In non-clinical testing, the image artifact caused by the device extends as far as 14.5 mm from the implant for spin echo images and 30 mm for gradient echo images when scanned in a 3.0 T MRI system. The artifact obscures the device lumen in gradient echo images. The implant has not been evaluated in MR systems other than 1.5 or 3.0 T. For valve-in-surgical valve implantation or in the presence of other implants, please refer to MRI safety information for the surgical valve or other devices prior to MR imaging.

10.0 Patient Information

Patient education brochures are provided to each site and should be given to the patient to inform them of the risks and benefits of the procedure and alternatives in adequate time before the procedure to be read and discussed with their physician. A copy of this brochure may also be obtained from Edwards Lifesciences by calling 1.800.822.9837. A patient implant card request form is provided with each transcatheter heart valve. After implantation, all requested information should be completed on this form. The serial number may be found on the package and on the identification tag attached to the transcatheter heart valve. The original form should be returned to the Edwards Lifesciences address indicated on the form and upon receipt, Edwards Lifesciences will provide an identification card to the patient.

11.0 Recovered valve and Device Disposal

The explanted valve should be placed into a suitable histological fixative such as 10% formalin or 2% glutaraldehyde and returned to the company. Refrigeration is not necessary under these circumstances. Contact Edwards Lifesciences to request an Explant Kit.

Used delivery system may be disposed of in the same manner that hospital waste and biohazardous materials are handled. There are no special risks related to the disposal of these devices.

12.0 Clinical Studies The PARTNER II Cohort B Registries

Cohort B of The Placement of Aortic Transcatheter Valves Trial II (PARTNER II) included registries for the transapical and transaortic delivery of the SAPIEN XT valve. These registries include the following:

• NR1: Inoperable Transapical (TA) Registry – transapical delivery of the 23 mm or 26 mm SAPIEN XT valve.

• NR3: Registry for Transcatheter Heart Valve in Aortic Surgical Valve Implantation (THV- SV). Patients with failing aortic bioprosthetic surgical valve with a surgical mortality or major morbidity ≥ 50% and meeting the sizing requirements for 23 mm or 26 mm SAPIEN XT valve.

• NR4: Inoperable Transaortic (TAo) Registry – transaortic delivery of the 23 mm or 26 mm SAPIEN XT valve.

• NR6: Inoperable Transapical Registry for the delivery of 29 mm SAPIEN XT valve in patients that did not have eligible transfemoral access.

Following completion of enrollment in the nested registries, the FDA approved continued access enrollment in the nested registries (CANRs).

SOURCE Registry XT: SOURCE Registry XT is an international multi-center prospective, consecutively enrolled,

observational registry. Consecutive patient data have been collected at discharge, 30 days, and 12 months post-implant, and will be collected annually thereafter up to 5 years post-implant.

Results of PARTNER II Cohort B Registries (NR1, NR4 and NR6)

A total of 265 patients were treated in PARTNER II Cohort B Nested Registries 1, 4, and 6. The primary safety and effectiveness endpoint was freedom from all-cause mortality at 1 year. The KM estimate at 30 days involving freedom from all-cause mortality was 92.0 ± 1.7%.

There were 1.9% major strokes, no incidence of endocarditis, 1.5% myocardial infarction, 5.7% major vascular complications, 11.3% disabling bleeding events, 3.0% cardiac intervention, and 4.5% new pacemaker at 30 days.

NYHA went from 3.2 ± 0.61 at baseline to 1.9 ± 0.88 at 30 days. The mean change was -1.3 ± 1.10. Device success was observed in 69.6% of patients (165/237). The mean hospitalization stay was

11.1 ± 8.96 days which included 4.5 ± 7.12 days in the ICU. The mean EOA was 0.7 ± 0.19 cm baseline and 1.6 ± 0.43 cm

at 30 days, and the average mean gradient decreased from

41.2 ± 12.17 mmHg at baseline to 8.6 ± 3.59 mmHg at 30 days. The mean peak gradient decreased from 73.2 ± 21.51 mmHg at baseline to 17.7 ± 7.30 mmHg at 30 days.

Results of SOURCE XT

A total of 2688 patients were enrolled. The vast majority of patients (96%) were treated with either the transapical (TA) or transfemoral (TF) approach. Only a small proportion of patients were treated with transaortic (TAo) or subclavian approaches. The implant approach was 62.7% for TF, 33.3% for TA,

3.76% for TAo and 0.3% for subclavian. The results only include the TF, TA and TAo approaches (n = 2680).

Using K-M event rates at 30 days post implant for the TF, TA/TAo population, 6.2% of patients had died, 3% due to a cardiac death, 3.6% of patients had suffered a stroke, and 6.6% had a major vascular complication. Major/life threatening bleeding had occurred in 14.9% of patients, major bleeding in 10.2%, and renal failure or AKI in 17.8%. Permanent pacemakers were implanted in 9.5% of patients. Using K-M event rates at 1 year post implant for the TF, TA/TAo population, 19.5% of patients had died, 9.5% of these from cardiac death, and 6.3% of patients had suffered a stroke. Major/life-threatening bleeding had occurred in 17.3% of patients, major bleeding in 12%, major vascular complications in 7.2%, renal failure or AKI in 20.5% and 11% of patients had a new pacemaker implanted.

Of the 2688 patients that were enrolled, fifty-seven (57) of these patients had the SAPIEN XT valve implanted into a failing surgical prosthesis. The TF approach was used in 23 patients, and the TA/TAo approach was used in 34 patients. The implanted valve size was 23 mm in 38 patients (66.7%), 26 mm in 14 patients (24.6%), and 29 mm in 5 patients (8.8%).

No deaths, no strokes, no major vascular complications, no life threatening bleedings, one (1) renal failure, and no new permanent pacemakers were reported at 30 days post implant for the TF population. At 1 year post implant, 3 deaths were reported for the TF population.

In the TA/TAo population, 3 deaths, 1 (major) stroke, 2 major vascular complications, 3 life threatening bleedings, and 4 new perm anent pacemakers were reported at 30 days. At 1 year post implant, 4 additional deaths, 1 additional (minor) stroke, 1 additional major vascular complication, and 1 additional new permanent pacemaker were reported for the TA/TAo population.

The PARTNER II Cohort B Aortic Valv e-in-Valve Registry (NR3/CANR3)

A clinical study was performed to establish a reasonable assurance of safety and effectiveness of transcatheter aortic valve replacement with the Edwards SAPIEN XT valve in patients with a failing surgical bioprosthetic aortic valve (i.e., “TAV-in-SAV”). The study was carried out as a single-arm registry nested (i.e., the PARTNER II Trial), which was designated as “NR3.” NR3 was originally approved for 100 patients and later expanded under a Continued Access Protocol (CAP). Data from the original NR3 cohort and the NR3 CAP (CANR3) cohort were pooled at 30 days and 1 year data was available for the NR3 cohort only.

Patients were treated at 40 investigational sites between June 12, 2012 and December 10, 2013. The database for this PMA supplement reflected data collected through February 26, 2015 and included 199 patients (2 patients withdrew prior to treatment). By the last database extract performed on February 26, 2015, all of these patients were included in the 30-day data analysis, and 97 patients were included in the 1-year analysis.

The NR3 study was a single arm, prospective, observational, descriptive study without formal hypothesis testing. The patients were limited to those who were deemed by a heart team to have a

mortality or major morbidity rate of ≥ 50% for replacement of a failing surgical aortic valve and met the

sizing requirements for the 23 mm or 26 mm SAPIEN XT valve. The specific sizing requirements were imposed because the 29 mm SAPIEN XT valve was not available whe n the study was initiated.

Contractors were utilized for analysis and interpretation of the clinical data, including an independent Data Safety Monitoring Board (DSMB) that was instructed to notify the applicant of any safety or compliance issues, a Clinical Event Committee (CEC) that was responsible for adjudicating endpointrelated events reported during the trial per definitions established a priori, an Electrocardiography (ECG) Core Lab for independent analysis of rhythm and occurrence of myocardial infarction, and an Echocardiography Core Lab for independent analysis of all echocardiograms.

Results of PARTNER II Cohort B Aortic Valve-in-Valve Registry (NR3/CANR3)

Since identical protocols were used in the pivotal and CAP cohort investigations, data from the two cohorts were pooled.

The “Attempted Implant” population consisted of all screen success patients for whom the index procedure was started. The “Valve Implant” population consisted of those patients for whom the valve implant process was completed. A total of 199 patients were screened for study participation. Two patients withdrew consent prior to treatment; therefore, there were 197 “Attempted Implant” patients. Two “Attempted Implant” patients were excluded from the “Valve Implant” population, because in one patient, intra-procedural TEE demonstrated a low transvalvular jet velocity (2.6 m/s) and gradient of 24 mmHg which did not meet the inclusion criteria, and in the other patient, the procedure was aborted due to inability to place the purse string sutures for transapical access. The patient disposition is summarized in Table 12.

The demographics of the pooled study population are summarized in the Table 13. The mean age was 78.5 years, and 60.4% were male. A high proportion of patients had significant comorbidities, frailty, and prior cardiac interventions. The mean STS score was 9.7, and 95.4% of all patients were in NYHA classes III or IV.

Table 14 provides a summary of the failed surgical valves treated, which consisted of 94.4% bioprosthesis, 4.6% homografts, and 1.0% other valve types. Aortic stenosis was the predominant cause of prosthetic failure (54.2%), followed by mixed lesion (23.4%) and insufficiency/regurgitation (22.4%).

The primary endpoint of all-cause mortality, all stroke, moderate or severe obstruction, or moderate or severe paravalvular leak was 16.9% at 30 days and 38.0% at 1 year, as shown in Table 15.

No unanticipated adverse device effects (UADEs) were reported throughout the trial. Three explants have been reported to date; one explant occurred at autopsy, and two during surgical aortic valve replacement due to severe aortic insufficiency on postoperative day 5 and day 18, respectively. No CEC adjudicated endocarditis was reported.

The key safety outcomes adjudicated by the CEC for this study are presented in Table 16 through Table 18.

Valve hemodynamics as assessed by echocardiography is summarized in Table 19 and Figure 11 through Figure 15. The mean DVI increased from 0.27 ± 0.10 at baseline to 0.37 ± 0.09 at 30 days and 0.39 ± 0.11 at 1 year. The mean gradient decreased from 36.1 ± 16.38 mmHg at baseline to 17.4 ± 7.37 mmHg at 30 days, which was maintained at 1 year. The mean peak gradient decreased from

65.0 ± 26.76 mmHg at baseline to 32.7 ±

12.90 mmHg at 30 days, which was maintained at 1 year. Moderate/severe aortic regurgitation was present in 43.7% of subjects at baseline, which decreased to 2.5% at 30 days and 1.9% at 1 year. Moderate/severe paravalvular leak was present in 6.8% of subjects at baseline, 2.5% at 30 days, and

1.9% at 1 year. It is important to note that although mean and peak gradients were significantly reduced as compared

to baseline for the “TAV-in-SAV” procedure, the residual mean and peak gradients were numerically higher than those observed for TAVR procedures performed for native valve stenosis.

The NYHA class by visit is shown in Figure 16. About 89% of subjects were in NYHA I/II at 30 days and 84% at 1 year as compared to 5% at baseline.

The mean improvement in 6MWD among the Attempted Implant population was 49.8 ± 169.9 meters from baseline to 30 days and 86.1 ± 142.0 meters from baseline to 1 year.

The mean hospitalization stay among the Attempted Implant population was 7.9 ± 7.0 days, which included 2.9 ± 5.0 days in the ICU.

The QoL at different time points as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score is shown in Figure 17. The mean KCCQ summary score among the Attempted Implant population improved from 45.5 ± 21.8 at baseline to 68.0 ± 22.0 at 30 days and

70.4 at 1 year. 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 cm

and mean aortic valve gradient < 20 mmHg or peak velocity < 3 m/s, without moderate or severe prosthetic valve aortic regurgitation. It was achieved in 61.5 % of patients. In the vast majority of device failure

subjects, the failure was due to unintended performance of the valve; specifically, mean gradient ≥ 20

mmHg or peak velocity ≥ 3 m/s was observed in 62 cases and moderate/severe aortic regurgitation in

5 cases.

PARTNER II Cohort B Registries Clinical Data

Table 6:

Baseline Characteristics and Echocardiographic Findings for NR1, NR4 and NR6 (AT Population)*

SAPIEN XT Valve (TA/TAo)

Characteristic

(N = 265)

Age - yr

82.0 ± 7.79

Male sex — no. (%)

141/265 (53.2%)

STS score†

10.3 ± 5.51

Logistic EuroSCORE‡

13.2 ± 11.96

NYHA class — no. (%):

I/II

24/264 (9.1%)

III/IV

240/264 (90.9%)

Coronary artery disease — no./total no. (%)

194/265 (73.2%)

Previous myocardial infarctio n — no./total no. (%)

56/265 (21.1%)

Previous intervention — no./total no. (%)

CABG

118/265 (44.5%)

PCI

107/265 (40.4%)

Balloon aortic valvuloplasty

72/265 (27.2%)

Peripheral vascular disease — no./total no. (%)

150/265 (56.6%)

COPD — no./total no. (%):

Any

101/265 (38.1%)

Oxygen-dependent

41/265 (15.5%)

Creatinine > 2 mg/dL (177 μmol/liter) — no./total no. (%)

28/265 (10.6%)

Atrial fibrillation — no./total no. (%)

95/265 (35.8%)

Permanent pacemaker — no./tot al no. (%)

43/265 (16.2%)

Pulmonary hypertension — no./total no. (%)

34/254 (13.4%)

Frailty§ — no./total no. (%)

97/254 (38.2%)

Extensively calcified aorta — no./total no. (%)

42/254 (16.5%)

Chest-wall deformity — no./total no. (%)

6/254 (2.4%)

Liver disease — no./total no. (%)

9/265 (3.4%)

Echocardiographic findings

Aortic-valve area — cm2

0.7 ± 0.19

Mean aortic-valve gradient — mmHg

41.2 ± 12.17

Mean LVEF — %

52.5 ± 13.37

Moderate or severe mitral regurgitation** — no./total no. (%)

70/232 (30.2%)

* Plus–minus values are mean ± SD. To convert the value for creatinine to micromoles per liter, multiply by 88.4.

** Moderate or severe mitral regurgitation was defined as regurgitation of grade 3+ or higher.

Cohort B (Inoperable)

AT denotes As Treated 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.

Table 7:

Cohort B (Inoperable) Clinical Outcomes at 30 days for NR1, NR4 and NR6

(AT Population)*

Death from any cause

21/265 (7.9%)

Major Stroke

5/265 (1.9%)

Repeat hospitalizationb

8/265 (3.0%)

Death from any cause or major stroke or repeat hospitalization

31/265 (11.7%)

Myocardial Infarction

4/265 (1.5%)

Major Vascular Complications

15/265 (5.7%)

Renal Failurec

7/265 (2.6%)

Disabling Bleeding Eventd

30/265 (11.3%)

Cardiac Reinterventione

8/265 (3.0%)

Endocarditis

0/265 (0.0%)

New Atrial Fibrillationf

9/167 (5.4%)

New pacemaker

12/265 (4.5%)

* AT = As Treated, NA = not applicable, TAVR = transcatheter aortic valve replacement. Dat a prese nted as n/N

f. Based on 167 patients at 30 days.

Table 8:

Population)

SAPIEN XT Valve

(N = 265)

Patients with

Event

12/265 (4.5%)

12/222 (5.4%)

Subjects with pacemaker or ICD at baseline are included (all patients included in denominator).

denominators.

Outcomea

SAPIEN XT Valve

(N = 265)

(%) of patients. a. CEC adjudicated. b. Repeat hospitalizations were included if they were due to aortic stenosis or complications of the valve procedure (e.g., TAVR). c. Renal failure is defined as stage III acute kidney injury: Increase in serum creatinine to ≥ 300% (3 x increase compared with baseline) or serum creatinine of ≥ 4 mg/d (≥ 354 μmol/L) with an acute increase of at least 0.5 mg/dl (44 μmol/L). d. Disabling bleeding: Fatal bleeding OR bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome OR bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or surgery OR overt source of bleeding with drop in hemoglobin of ≥ 5 g/dL or whole blood of packed red blood cells (RBC) transfusion ≥ 4 units. e. Cardiac reintervention includes any intervention that repairs, alters or replaces a previously operated valve OR balloon aortic valvuloplasty OR Surgical aortic valve replacement OR valve in valve

Conduction Disturbance Requiring Pacemaker to 30 Days for NR1, NR4 and NR6 (CEC Adjudicated) (AT

Event Events

New Permanent Pacemaker- All Patients1 0-30 Days New Permanent Pacemaker – Patients without pre-procedural pacemaker2 0-30 Days

Subjects with pacemaker or ICD at baseline are excluded (patients with baseline pacemaker/ICD subtracted

from denominator).

Note: The patients who received a new pacemaker in both rows are the same patients. The only difference is the

(TA/TAo)

Figure 3:

10%

20%

30%

40%

50%

60%

70%

0 5 10 15 20 25 30

All-Cause Mortality or M ajor Str oke or

Rehospitalization

Days Post-Procedure

SAPIEN XT

11.8%

No. at Risk

SAPIEN XT

265

250

247

245

241

240

234

All-Cause Mortality, Major Stroke or Re-Hospitalization to

30 Days, NR1, NR4, and NR6 – TA/TAo

(AT Population)

Figure 4:

10%

20%

30%

40%

50%

60%

70%

0 5 10 15 20 25 30

All-Cause Mortality

Days Post-Procedure

SAPIEN XT

8.0%

No. at Risk

SAPIEN XT

265

254

251

250

248

247

241

10%

15%

20%

0 5 10 15 20 25 30

Major Stroke

Days Post-Procedure

SAPIEN XT

1.9%

No. at Risk

SAPIEN XT

265

250

247

246

245

239

All-Cause Mortality to 30 Days, NR1, NR4, and NR6 –

TA/TAo

Figure 5:

Major Stroke at 30 Days, NR1, NR4, and NR6 – TA/TAo

(AT Population)

Figure 6:

10%

15%

20%

0 5 10

20 25 30

Rehospitalization

Days Post-Procedure

SAPIEN XT

3.2%

No. at Risk

SAPIEN XT

265

254

251

248

243

242

236

0.7

1.6

0.5

1.5

2.5

Baseline

30 Days

Effective Orifice Area (cm²)

SAPIEN XT

No. of Echos

SAPIEN XT

231

193

Re-Hospitalization at 30 Days, NR1, NR4, and NR6 –TA/TAo

(AT Population)

Figure 7:

Effective Orifice Area, NR1, NR4, and NR6 – TA/TAo

(Valve Implant Population)

41.2

8.6

Baseline

30 Days

Gradient (mmHg)

SAPIEN XT

No. of Echos

SAPIEN XT

244

200

Table 9:

(AT Population)

Figure 8:

Mean Gradient, NR1, NR4, and NR6 – TA/TAo

(Valve Implant Population)

NYHA Functional Class By Visit for NR1, NR4 and NR6

SAPIEN XT Valve (N = 265)

Visit I II III IV Total Baseline 1 23 158 82 264 30 Days 84 88 45 12 229

Figure 9:

0.4%

37.0%

10.1%

38.8%

58.1%

19.4%

31.3%

4.8%

20%

40%

60%

80%

100%

Percent

IIIIII

Baseline

TA/TAo

227

30 Days

TA/TAo

227

50.0

56.6

100

Baseline

30 Days

Mean Scores

SAPIEN XT

No. of Pts

SAPIEN XT

249

213

NYHA Class by Visit, NR1, NR4, and NR6 – TA/TAo

(Intent-to-Treat Population)

Figure 10:

KCCQ Clinical Summary Score, NR1, NR4, and NR6 – TA/TAo

(AT Population)

SOURCE XT Clinical Data

Table 10:

(AT Population)*

Transfemoral

TA/TAo Pooled

Characteristic

(N = 1685)

(N = 995)

Age - yr

82.0 ± 6.5

80.3 ± 6.5

Male sex — no. (%)

600 / 1685 (35.6%)

536 / 995 (53.9%)

STS score†

8.0 ± 6.8

7.9 ± 6.2

Logistic EuroSCORE‡

19.8 ± 11.6

21.6 ± 13.7

NYHA class

I/II — no./tot al no. (%)

377 / 1676 (22.5%)

242 / 992 (24.4%)

III/IV — no./total no. (%)

1299 / 1676 (77.5%)

750 / 992 (75.6%)

Coronary artery disease — no./total no. (%)

667 / 1685 (39.6%)

518 / 995 (52.1%)

Previous myocardial infarctio n — no./total no. (%)

205 / 1685 (12.2%)

197 / 995 (19.8%)

Previous intervention

CABG — no./total no. (%)

204 / 1685 (12.1%)

226 / 995 (22.7%)

PCI — no./total no. (%)

460 / 1685 (27.3%)

355 / 995 (35.7%)

Balloon aortic valvuloplasty — no./total no. (%)

128 / 1685 (7.6%)

66 / 995 (6.6%)

Cerebral vascular disease — no./tot al no. (%)

191 / 1685 (11.3%)

143 / 995 (14.4%)

Peripheral vascular disease — no./total no. (%)

248 / 1684 (14.7%)

320 / 995 (32.2%)

COPD

Pulmonary Artery Disease COPD — no./total no. (%)

327 / 1684 (19.4%)

218 / 995 (21.9%)

Pulmonary Artery Disease Oxygen Dependent — no./total no. (%)

31 / 1684 (1.8%)

11 / 995 (1.1%)

Creatinine > 2 mg/dL (177 μmol/liter) — no./total no. (%)

104 / 1681 (6.2%)

114 / 994 (11.5%)

Atrial fibrillation — no./total no.

395 / 1678 (23.5%)

289 / 990 (29.2%)

Permanent pacemaker — no./tot al no. (%)

170 / 1685 (10.1%)

134 / 995 (13.5%)

Pulmonary hypertension — no./total no. (%)

440 / 1684 (26.1%)

204 / 995 (20.5%)

Frailty§ — no./total no. (%)

896 / 932 (96.1%)

548 / 579 (94.6%)

Extensively calcified aorta — no./total no. (%)

71 / 1684 (4.2%)

103 / 995 (10.4%)

Chest-wall deformity — no./total no. (%)

18 / 1684 (1.1%)

6 / 995 (0.6%)

Liver disease — no./total no. (%)

52 / 1685 (3.1%)

27 / 995 (2.7%)

Echocardiographic findings

Aortic-valve area — cm2

0.7 ± 0.21

Mean aortic-valve gradient — mmHg

49.2 ± 16.54

45.0 ± 15.43

Mean LVEF — %

55.1 ± 12.48

53.2 ± 12.50

Moderate or severe mitral regurgitation** — no./total no. (%)

345 / 1633 (21.1%)

174 / 976 (17.8%)

* Plus–minus values are means ± SD. To conv ert the v alue for cr eatinine to m icromo les per li t er, multiply by 88.4. AT

** Moderate or severe mitral regurgitation was defined as regurgitation of grade 3+ or higher.

SOURCE XT (High Risk) Baseline Characteristics of the Patients and Echocardiographic Findings

denotes as treated population, CA BG denotes coronar y -artery bypass grafting, COPD chronic obstructive pul monary disease, LVEF left ventricular ejection fracti on, N Y H A New Y ork Heart Associati on, P CI percut aneous coron ar y intervention, and TAVR transcatheter aortic-valve implantation.

†

The Society of Thoracic Surgeons (ST S) score measures pa tient risk at the time of cardiovascular surgery on a scale that ranges from 0% to 100%, with higher numbers indicating gr ea ter risk. An S T S score higher th an 10% indicates very high surgical risk.

‡

The logistic European System for Car diac Oper ativ e Risk Evaluation ( Eur oSC OR E) , w hich measures patient ris k at the time of cardiovascular surgery, is calculated with the use of a logistic-regression eq uation. S c ores range fr om 0% to 100%, with higher scores indicating greater risk. A logistic EuroSCORE higher than 20% indicate s v ery high sur gical ris k.

Frailty was determined by the surgeons a ccording t o pr espe ci fied criter ia.

Table 11:

(AT Population)*

30 Days

1-Year

Transfemoral

TA/TAo

Transfemoral

TA/TAo

Outcome

(N = 1685)

(N = 995)

(N = 1685)

(N = 995)

All Cause Death

71 (4.2%)

96 (9.7%)

248 (15.0%)

266 (27.0%)

Cardiac Death

28 (1.7%)

51 (5.2%)

106 (6.7%)

132 (14.4%)

Stroke

All Stroke

56 (3.4%)

39 (4.1%)

90 (5.6%)

66 (7.6%)

Major Stroke

34 (2.0%)

27 (2.8%)

55 (3.5%)

44 (5.0%)

Repeat hospitalizationb

80 (4.9%)

83 (9.0%)

396 (25.5%)

314 (36.7%)

Myocardial Infarction

7 (0.4%)

9 (0.9%)

23 (1.5%)

21 (2.5%)

Major Vascular Complications

132 (7.9%)

43 (4.4%)

139 (8.3%)

52 (5.5%)

Renal Failured/AKI

197 (11.9%)

270 (28.0%)

240 (14.7%)

292 (30.6%)

Life-threatening bleedingc

63 (3.8%)

84 (8.6%)

74 (4.5%)

101 (10.6%)

Endocarditis

2 (0.1%)

2 (0.2%)

15 (1.0%)

10 (1.2%)

New Atrial Fibrillation

54 (3.3%)

83 (8.8%)

89 (5.6%)

109 (12.0%)

New pacemaker

145 (8.7%)

105 (10.8%)

165 (10.0%)

120 (12.7%)

* AT = As Treated, TAVR = transcatheter aortic valve replacement. Data presented as n (%) of patients where % is

(44 μmol/L)

Table 12:

Attempted Implant: All screen success patients for whom the Index Procedure

consisting of those patients for whom the valve implant process was completed.

SOURCE XT (High Risk) Clinical Outcomesa at 30 days and 1 year

the Kaplan-Meier event rate at 30-days and 1-year respectively. a. CEC adjudicated b. Repeat hospitalizations were included if they were due to aortic stenosis or complications of the valve procedure (e.g., TAVR). c. Disabling bleeding: Fatal bleeding OR bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome OR bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or surgery OR overt source of bleeding

with drop in hemoglobin of ≥ 5 g/dL or whole blood of packed red blood cells (RBC) transfusion ≥ 4 units d. Renal failure is defined as stage III acute kidney injury: Increase in serum creatinine to ≥ 300% (3 x increase compared with baseline) or serum creatinine of ≥ 4 mg/d (≥ 354 μmol/L) with an acute increase of at least 0.5 mg/dl

PARTNER II Nested Registry 3/ Continued Access Nested Registry 3 (NR3/CANR3) (Aortic Valve-in-Valve)

Patient Disposition

Attempted Implant1 Valve Implant2

Number of Patients 197 195

was started. Patients were analyzed according to the valve used in the initial implant attempt.

Valve Implant: This population was a subset of the Attempted Implant group,

Table 13:

Demographic and Baseline Characteristics

Results1 (N=197)

Age – yr

78.5 ± 11.001

Male sex

119/197 (60.4%)

STS score

9.7 ± 5.09

New York Heart Association (NYHA) class

I/II

9/197 (4.6%)

III/IV

188/197 (95.4%)

Coronary artery disease

139/197 (70.6%)

Previous myocardial infarctio n

25/197 (12.7%)

Previous intervention

Coronary artery bypass grafting (CABG)

97/197 (49.2%)

Percutaneous coronary intervention (PCI)

39/197 (19.8%)

Prior aortic valvuloplasty

17/197 (8.6%)

Cerebral vascular accident (CVA)

29/197 (14.7%)

Peripheral vascular disease

49/197 (24.9%)

Chronic obstructive pulmonary disease (COPD)

Any

65/197 (33.0%)

Oxygen-dependent

14/197 (7.1%)

Creatinine > 2 mg/dL (177 µmol/liter)2

25/197 (12.7%)

Atrial fibrillation

98/197 (49.7%)

Permanent pacemaker

51/197 (25.9%)

Pulmonary hypertension

26/197 (13.2%)

Frailty3

65/197 (33.0%)

Extensively calcified aorta

12/197 (6.1%)

Chest-wall deformity

4/197 (2.0%)

Liver disease

14/197 (7.1%)

Reason for Valve Replacement

Mixed Lesion

45/192 (23.4%)

Insufficiency/regur gita t ion O nly

43/192 (22.4%)

Stenosis Only

104/192 (54.2%)

Echocardiographic findings

Doppler Velocity Index (DVI)4

0.27 ± 0.10

Mean aortic-valve gradient — mmHg

35.9 ± 16.42

Mean left ventricular ejection fraction (LVEF) — %

49.8 ± 13.87

Moderate or severe mitral regurgitation5

62/171 (36.3%)

Moderate or severe mitral regurgitation was defined as regurgitation of grade 3+ or higher.

Attempted Implant Population

Characteristic

Quantitative data are expressed as mean ± SD (n). Categorical data are expressed as no./total no. (%).

To convert the value for creatinine to micromoles per liter, multiply by 88.4.

Frailty was determined by the surgeons according to pre-specified criteria.

DVI is a flow-dependent measure of orifice stenosis. A DVI < 0.25 suggests significant stenosis.

Table 14:

Summary of Failed Bioprosthetic Surgical Valves

Results1 (N=197)

Type of Failed Surgical Valve

Bioprosthesis

184 / 195 (94.4%)

Homograft

9 / 195 (4.6%)

Other 2

2 / 195 (1.0%)

Reason for Valve Replacement

Mixed Lesion

45/192 (23.4%)

Insufficiency/regurgitation Only

43/192 (22.4%)

Stenosis Only

104/192 (54.2%)

Table 15:

Valve Implant Population

Composite of all-cause mortality, all stroke, moderate or severe obstruction, moderate or severe paravalvular leak . Mortal i t y and

ion at

the 30-day follow-up visit.

Doppler velocity index (DVI) < 0.25 per the echo core lab read.

Confidence intervals calculated using exact binomial calculations. The confidence intervals are calc ul ated without multiplicity illustrate the variability only and should not be used to draw any statistical conclusion.

Attempted Implant Population

Categorical data are expressed as no./total no. (%).

Other includes an unidentified manufactured tissue valve and a St. Jude mechanical composite.

All-Cause Mortality, All Str ok e, Moderate o r Severe Obstruction, or Moderate or Severe

Paravalvular Leak

Events

30 Days

(N=195)

Patients with

Event

95% Confidence

Interval3

Patients with

Event

1 Year

(N=96)

95% Confidence

Interval

Composite Event1 28/166 (16.9%) [11.5%, 23.4%] 27/71 (38.0%) [26.8%, 50.3%] All-Cause Mortality 8/195 (4.1%) [1.8%, 7.9%] 19/96 (19.8%) [12.4%, 29.2%] All Stroke 5/195 (2.6%) [0.8%, 5.9%] 3/96 (3.1%) [0.6%, 8.9%] Moderate or Severe Obstruction2 12/169 (7.1%) [3.7%, 12.1%] 6/54 (11.1%) [4.2%, 22.6%] Moderate or Severe PV Leak 4/162 (2.5%) [0.7%, 6.2%] 1/53 (1.9%) [0.0%, 10.1%]

stroke are calculated at 30 days. The moderate or severe obstruction and paravalvular leak use the Echo core lab’s determinat

adjustment. The adjusted confidence intervals could be wider than presented here. As such, confidence intervals are provided to

Table 16:

CEC Adjudicated Adverse Events

Attempted Implant Population

Rate (no./total no. (%))

30 Days

(N=197)

1 Year (N=97)

Death1

From any cause

8/197 (4.1%)

19/97 (19.6%)

From cardiovascular cause

7/197 (3.6%)

15/97 (15.5%)

Major Stroke

5/197 (2.5%)

3/97 (3.1%)

Myocardial Infarction

5/197 (2.5%)

3/97 (3.1%)

Major Vascular Complications

8/197 (4.1%)

6/97 (6.2%)

Acute Kidney Injury, Stage III2

2/197 (1.0%)

N/A

Disabling Bleeding3

19/197 (9.6%)

16/97 (16.5%)

Cardiac Reintervention4

4/197 (2.0%)

2/97 (2.1%)

Endocarditis

0/197 (0.0%)

0/97 (0.0%)

New Atrial Fibrillation

4/135 (3.0%)

2/45 (4.4%)

New Pacemaker

3/197 (1.5%)

1/97 (1.0%)

Deaths from unknown causes were assumed to be deaths from cardiovascular causes.

least 0.5 mg/dl (44 µmol/L) within 72 hours of the procedure (per the VARC-1 definition).

Disabling bleeding: Fatal bleeding OR bleeding in a critical area or organ, such as intracranial,

blood of packed red blood cells (RBC) transfusion ≥ 4 units (Life-threatening per VARC-1 definitions).

Cardiac reintervention includes any intervention that repairs, alters or replaces a previously operated

valve OR balloon aortic valvuloplasty OR Surgical aortic valve replacement OR valve in valve.

Adverse Events

Acute kidney injury, stage III is defined as an increase in serum creatinine to ≥ 300% (3 x increase

compared with baseline) or serum creatinine of ≥ 4 mg/d (≥ 354 µmol/L) with an acute increase of at

intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome OR bleeding causing hypovolemic shock or severe hypotensi on requi ri ng

vasopressors or surgery OR overt source of bleeding with drop in hemoglobin of ≥ 5 g/dL or whole

Table 17:

Kaplan-Meier (KM) Event Rate for CEC Adjudicated Major Vascular Complications, Major Stroke, Minor

Attempted Implant Population

Patients

Estimate

Standardized endpoint definitions for transcatheter aortic valve im plantation cli nic al tri als cons ensus from t he Valve Academic

Kaplan-Meier estimates used the first event per patient. Events occurring after day 30 and day 365 were not included in the

Table 18:

Attempted Implant Population

30 Days

(N=197)

1 Year (N=97)

Patients

with Event

Patients

with Event

New Permanent Patients

3/197 (1.5%)

1/97 (1.0%)

New Permanent

pacemaker

3/146 (2.1%)

1/70 (1.4%)

Subjects with pacemaker or ICD at baseline were included (all patients included in denominator).

denominators.

Stroke, TIA, and Acute Kidney Injury

30 Days (N=197)

1 Year (N=97)

Patients

VARC Event1 Events

Major Vascular

15 14 0.071 (0.043, 0.117) 14 12 0.127 (0.074, 0.213)

with

Event

Estimate2 95% CI3 Events

with

Event

95% CI

Complications and/or Major Stroke and/or Minor Stroke and/or TIA and/or Acute Kidney Injury, Stage III

Major Vascular

8 8 0.041 (0.021, 0.080) 6 6 0.062 (0.029, 0.134)

Complications Major Stroke 5 5 0.025 (0.011, 0.060) 5 3 0.032 (0.010, 0.096) Minor Stroke 0 0 0.000 N/A 0 0 0.000 N/A TIA 0 0 0.000 N/A 1 1 0.013 (0.002, 0.089) Acute Kidney Injury,

2 2 0.010 (0.003, 0.040)

Stage III

Research Consortium (VARC). Events with missing or incomplete onset dates were excluded from the analysis.

analysis of the 30-day and 1-year results, respectively.

Confidence intervals calculated using Greenwood’s formula. The confidence intervals are calculated without multiplicity

adjustment. The adjusted confidence intervals could be wider than presented here. As such, confidence intervals are provided to illustrate the variability only and should not be used to draw any statistical conclusion.

Conduction Disturbance Requiring New Permanent Pacemaker

Events

Pacemaker- All

Pacemaker – Patients without preexisting

Subjects with pacemaker or ICD at baseline were excluded (patients with baseline pacemaker/ICD

subtracted from denominator).

Note: The patient who received a new pacemaker in both rows is the same patient. The only difference is the

Events

Table 19:

Valve Hemodynamics Measured by Echocardiography

Valve Implant Population

Baseline

(N=195)

Discharge

(N=195)

30 Days

(N=195)

1 Year (N=96)

Doppler Velocity Index - mean ± SD (n) All Valve Sizes 0.27 ± 0.10 (173) 0.37 ± 0.09 (161) 0.37 ± 0.09 (169) 0.39 ± 0.11 (54) 23 mm (N=140) 0.26 ± 0.09 (123) 0.36 ± 0.10 (114) 0.36 ± 0.09 (118) 0.38 ± 0.11 (38) 26 mm (N=55) 0.29 ± 0.13 (50) 0.40 ± 0.08 (47) 0.41 ± 0.11 (51) 0.44 ± 0.11 (16) Mean Gradient (mmHg) - mean ± SD (n) All Valve Sizes 36.1 ± 16.38 (179) 18.2 ± 7.79 (168) 17.4 ± 7.37 (176) 17.3 ± 8.76 (56) 23 mm (N=140) 37.2 ± 16.86 (129) 19.5 ± 8.19 (120) 19.0 ± 7.64 (125) 18.8 ± 9.32 (40) 26 mm (N=55) 33.2 ± 14.84 (50) 15.0 ± 5.51 (48) 13.4 ± 4.79 (51) 13.7 ± 5.91 (16) Peak Gradient (mmHg) - mean ± SD (n) All Valve Sizes 65.0 ± 26.76 (179) 34.3 ± 13.67 (168) 32.7 ± 12.90 (176) 32.8 ± 15.58 (56) 23 mm (N=140) 66.9 ± 27.49 (129) 36.5 ± 14.36 (120) 35.4 ± 13.30 (125) 35.2 ± 16.80 (40) 26 mm (N=55) 60.1 ± 24.34 (50) 29.0 ± 10.05 (48) 26.2 ± 9.09 (51) 26.7 ± 10.04 (16) Total Aortic Regurgitation - no./total no. (%) All Valve Sizes

None 22/174 (12.6%) 74/164 (45.1%) 86/163 (52.8%) 34/53 (64.2%) Trace 34/174 (19.5%) 64/164 (39.0%) 58/163 (35.6%) 15/53 (28.3%) Mild 42/174 (24.1%) 21/164 (12.8%) 15/163 (9.2%) 3/53 (5.7%) Moderate 47/174 (27.0%) 4/164 (2.4%) 3/163 (1.8%) 1/53 (1.9%) Severe 29/174 (16.7%) 1/164 (0.6%) 1/163 (0.6%) 0/53 (0.0%)

23 mm

None 21/124 (16.9%) 55/116 (47.4%) 63/115 (54.8%) 23/37 (62.2%) Trace 29/124 (23.4%) 43/116 (37.1%) 39/115 (33.9%) 12/37 (32.4%) Mild 32/124 (25.8%) 14/116 (12.1%) 10/115 (8.7%) 2/37 (5.4%) Moderate 29/124 (23.4%) 3/116 (2.6%) 2/115 (1.7%) 0/37 (0.0%) Severe 13/124 (10.5%) 1/116 (0.9%) 1/115 (0.9%) 0/37 (0.0%)

26 mm

None 1/50 (2.0%) 19/48 (39.6%) 23/48 (47.9%) 11/16 (68.8%) Trace 5/50 (10.0%) 21/48 (43.8%) 19/48 (39.6%) 3/16 (18.8%) Mild 10/50 (20.0%) 7/48 (14.6%) 5/48 (10.4%) 1/16 (6.3%) Moderate 18/50 (36.0%) 1/48 (2.1%) 1/48 (2.1%) 1/16 (6.3%)

Severe 16/50 (32.0%) 0/48 (0.0%) 0/48 (0.0%) 0/16 (0.0%) Paravalvular Leak - no./total no. (%) All Valve Sizes

None 121/162 (74.7%) 76/164 (46.3%) 91/162 (56.2%) 35/53 (66.0%)

Trace 18/162 (11.1%) 66/164 (40.2%) 56/162 (34.6%) 15/53 (28.3%)

Mild 12/162 (7.4%) 17/164 (10.4%) 11/162 (6.8%) 2/53 (3.8%)

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