Edwards SAPIENIii Transcatheter Heart Valve with the RetroFlex 3Edwards Delivery SystemInstructions for Use The following table identifies the bioprosthesis size that should be

Caution: Federal (USA) law restricts this device used based on native valve annulus size, as measured byto sale by or on the order of a physician. transesophageal echocardiography (TEE).

Transfemoral Retrograde Approach Native Valve AnnulusImplantation of the transcatheter heart valve Size Bioprosthesisshould be performed only by physicians who (Tissue Annulus Diameterhave received Edwards Lifesciences training. The Diameter)implanting physician should be experienced in 18-22 mm 23 mmballoon aortic valvuloplasty. 21-25 mm 26 mm

Please verify that you have the latest version ofthe instructions for use prior to using the deviceby visiting http://THVIFU.edwards.com or by * RetroFlex 3 Delivery System - Model 9120FS23 for 23 mmcalling 1.800.822.9837. In order to access the valve procedure and 9120FS26 for 26 mm valve procedureinstructions for use, an IFU Code will be required. (Figure 2)STERILE: The bioprosthesis is supplied sterilizedwith gluteraldehyde solution. The delivery system The RetroFlex 3 delivery system includes a rotating wheel within thEis supplied sterilized with ethylene oxide gas. handle for articulation of flex catheter, a tapered tip at the distal end

of the delivery system to facilitate crossing the native valve, a1.0 Device Description balloon for deployment of the bioprosthesis, and radiopaque marker

Edwards SAPIEN Transcatheter Heart Valve - as indicated in Figure 2.

Model 9000TFX (Figure 1) Figure 2. RetroFlex 3 Delivery SystemThe Edwards SAPIEN transcatheter heart valve(bioprosthesis) is comprised of a balloon-expandable, radiopaque, stainless steel (316 L)frame, three bovine pericardial tissue leaflets, and apolyethylene terephthalate (PET) fabric. Thebioprosthesis is treated according to the Carpentier-Edwards ThermaFix process, packaged, andterminally sterilized in glutaraldehyde. Black dots indicate position of radiopaque markers.

Figure 1. Edwards SAPIEN Transcatheter Heart Valve NominalRBPBalloon Diameter

23 mm 7 ATM (709 kPa)26 mm 7 ATM (709 kPa)

The following table identifies the access vessel diameters thatshould be used for delivery system access.

Ilio-Femoral Vessel DelivDiameter

BioprosthesisDiameter Frame Height (Profile) 2 7 mm 23 mm

> 8mm 26 mm23 mm 14.3 mm26 mm 16.1 mm.

Edwards Lifesciences, the stylized E logo, Edwards,Edwards SAPIEN, RetroFlex, RetroFlex 3, and ThermaFixare trademarks of Edwards Lifesciences Corporation.

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2.0 Indications completely cover the bioprosthesis, thetemperature indicator has been activated, theThe Edwards SAPIEN Transcatheter Heart Valve, bioprosthesis is damaged, or the expiration datemodel 9000TFX, sizes 23 mm and 26 mm, is has elapsed.

indicated for transfemoral delivery in patients withsevere symptomatic native aortic valve stenosis who Do not mishandle the RetroFlex 3 delivery system orhave been determined by a cardiac surgeon to be use it if the packaging or any components are notinoperable for open aortic valve replacement and in sterile, have been opened or are damaged (e.g.whom existing co-morbidities would not preclude the elapsed.expected benefit from correction of the aorticstenosis. Use of excessive contrast media may lead to renalThe RetroFlex 3 Delivery System is indicated for the failure. Measure the patient's creatinine level priorThe etr~lex3 Dlivey Sste is ndiatedfortheto the procedure. Contrast media usage should be.-transfemoral delivery of the Edwards SAPIEN monitored.Transcatheter Heart Valve.

* Patient injury could occur if the delivery system is3.0 Contraindications not un-flexed prior to removal.

The bioprosthesis and delivery system arecontraindicated in patients who cannot tolerate an 5.0 Precautionsanticoagulation/antiplatelet regimen or who have Long-term durability has not been established for theactive bacterial endocarditis or other active infections. bioprosthesis. Regular medical follow-up is f

advised to evaluate bioprosthesis performance.4.0 Warnings * Glutaraldehyde may cause irritation of the skin,* Observation of the pacing lead throughout the eyes, nose and throat. Avoid prolonged or

Osedureiososseneaacingavead theopoteal rskrepeated exposure to, or breathing of, the solution.procedure is essential to avoid the potential risk of Use only with adequate ventilation. If skin contactpacing lead perforation. There is an increased risk us , n ly wlth te a t ed af ithoccurs, immediately flush the affected area withof stroke in transcatheter aortic valve replacement water; in the event of contact with eyes, seekprocedures, as compared to balloon aortic immediate medical attention. For more informationvalvuloplasty or other standard treatments. about glutaraldehyde exposure, refer to Material

* The devices are designed, intended, and distributed Safety Data Sheet available from Edwardsfor single use only. Do not re-sterilize or reuse Lifesciences.the devices. There are no data to support the * To maintain proper valve leaflet coaptation, do notsterility, non-pyrogenicity, and functionality of the overinflate the deployment balloon.devices after reprocessing. * Appropriate antibiotic prophylaxis is recommended

* Incorrect sizing of the bioprosthesis may lead to post-procedure in patients at risk for prostheticparavalvular leak, migration, embolization and/or valve infection and endocarditis.annular rupture.

a Bioprosthetic valve recipients should be maintained* Accelerated deterioration of the bioprosthesis may on anticoagulant and antiplatelet therapy (e.g.occur in patients with an altered calcium clopidogrel or ticlopidine [75 mg/day]) for 6 months

metabolism. Bioprosthesis must remain hydrated post procedure and aspirin (75-100 mg/day) forat all times and cannot be exposed to solutions life, except when contraindicated, as determinedother than its shipping storage solution and sterile by their physician.physiologic rinsing solution. Bioprosthesis leafletsmishandled or damaged during any part of the * The safety of the bioprosthesis implantation has notprocedure will require replacement of the been established in patients who have:bioprosthesis. Pre-existing prosthetic heart valve in the aortic

* Caution should be exercised in implanting a positionbioprosthesis in.patients with clinically significant * Severe ventricular dysfunction with ejectioncoronary artery disease. fraction <20%

* Patients with pre-existing mitral valve devices should Hypertrophic cardiomyopathy with or withoutbe carefully assessed prior to implantation of the obstruction (HOCM)bioprosthesis to ensure proper bioprosthesis * Safety and effectiveness have not been establishedpositioning and deployment. for patients who are candidates for surgical aortic

* Patients presenting with combination AV low flow, valve replacement.low gradient should undergo additional evaluation * Safety, effectiveness, and durability have not beento establish the degree of aortic stenosis. established for valve-in-valve procedures.

* Do not use the bioprosthesis if the tamper evident * Safety and effectiveness have not been establishedseal is broken, the storage solution does not for patients with the following

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characteristics/comorbidities: Stroke/transient ischemic attack clusters or* Non-calcified aortic annulus neurological deficit

* Congenital unicuspid or congenital bicuspid Paralysisaortic valve Permanent disability

* Mixed aortic valve disease (aortic stenosis and Respiratory insufficiency or respiratory failureaortic regurgitation with predominant aortic Hemorrhage requiring transfusion or interventionregurgitation >3+) * Cardiovascular injury including perforation or* Pre-existing prosthetic heart valve or prosthetic dissection of vessels, ventricle, myocardium orring in any position valvular structures that may require

* Severe mitral annular calcification (MAC), severe intervention(>3+) mitral insufficiency, or Gorelin syndrome Pericardial effusion or cardiac tamponade

* Blood dyscrasias defined as: leukopenia Embolization including air, calcific valve material(WBC<3000 mm3), acute anemia (Hb <9 or thrombusmg%), thrombocytopenia (platelet count<50,000 cells/mm3), or history of bleeding Infection including septicemia and endocarditisdiathesis or coagulopathy Heart failure

* Hypertrophic cardiomyopathy with or without Myocardial infarctionobstruction (HOCM) Renal insufficiency or renal failure

* Echocardiographic evidence of intracardiac Conduction system injury (defect) which maymass, thrombus, or vegetation require a permanent pacemaker

* A known hypersensitivity or contraindication to * Arrhythmiaaspirin, heparin, ticlopidine (Ticlid), orclopidogrel (Plavix), or sensitivity to contrast * Retroperitoneal bleedmedia, which cannot be adequately Femoral AV fistula or pseudoaneurysmpremedicated Reoperation

*Native aortic annulus size <18mm or >25mm as Peniheral ischemia or nerve mumeasured by echocardiogram p ry*Restenosis

* Patient has been offered surgery but has refusedsurgery Pulmonary edema

* Significant aortic disease, including abdominal Pleural effusionaortic or thoracic aneurysm defined as maximal - * Bleedingluminal diameter 5 cm or greater; marked - Anemiatortuosity (hyperacute bend), aortic archatheroma (especially if thick [> 5 mm], * Abnormal lab values (including electrolyteprotruding, or ulcerated) or narrowing imbalance)(especially with calcification and surface - Hypertension or hypotension;irregularities) of the abdominal or thoracic Hyertension o aypotesiotaorta, severe "unfolding" and tortuosity of the Allergic reaction to anesthesia or to contrastaortamediathoracic aorta

* Iliofemoral vessel characteristics that would - Hematomapreclude safe placement of 22F or 24F * Syncopeintroducer sheath such as severe obstructive * Pain or changes at the access sitecalcification, severe tortuosity or vessels sizeless than 7 mm in diameter * Exercise intolerance or weakness

Bulky calcified aortic valve leaflets in close * Inflammationproximity to coronary ostia * Angina

* Heart murmur

6.0 Potential Adverse Events -Fever

Potential risks associated with the overall procedure * Additional potential risks specifically associated

including potential access complications associated with the use of the bioprosthesis include, but

with standard cardiac catheterization for the may not be limited to the following:transfemoral access procedure, balloon * Cardiac arrestvalvuloplasty, and the potential risks of local and/or * Cardiogenic shockgeneral anesthesia: * Emergency cardiac surgery

Death * Cardiac failure or low cardiac output

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* Coronary flow obstruction/transvalvular flow RetroFlex Dilator Kit Model 9100DKS7disturbance * Crimper Model 91 00CR23 for 23 mm valve

* Device thrombosis requiring intervention procedure and- Model 9100CR26 for 26 mm valve* Valve thrombosis procedure

* Device embolization * Inflation device provided by Edwards Lifesciences

* Device migration or malposition requiring for this application

intervention 7.2 Bioprosthesis Handling and Preparation

* Valve deployment in unintended location Follow sterile technique during device preparation and* Valve stenosis implantation.*,Structural valve deterioration (wear, fracture, 7.2.1 Bioprosthesis Rinsing Procedure

calcification, leaflet tear/tearing from the stentposts, leaflets retraction, stent creep, suture The bioprosthesis is packaged sterile in a plastic jarline disruption of components of a prosthetic with a screw-cap closure and seal. Before opening,valve, thickening, stenosis) carefully examine the jar for evidence of damage

* Device degeneration (e.g., a cracked jar or lid, leakage, or broken or

* Paravalvular or transvalvular leak missing seals).

Valve regurgitation CAUTION: Bioprosthetic valves from containersfound to be damaged, leaking, without adequate

* Hemolysis sterilant, or missing intact seals must not be used* Device explants for implantation.

* Nonstructural dysfunction

* Non-emergent reoperation Step ProcedureSet up two (2) sterile bowls with at leastAll listed risks may include symptomns associated with 500 mL of sterile physiologic saline tothe above mentioned medical conditions. 1 thoroughly rinse the glutaraldehyde

sterilant from the bioprosthesis.The bioprosthesis is contained in the jar7.0 Directions for Use within a holder. Carefully remove the

7.1 Required Equipment bioprosthesis/holder assembly from the jar

2 without touching the tissue. The holder is* Standard cardiac catheterization lab equipment tagged with the bioprosthesis' serial

* Fluoroscopy (fixed, mobile or semi-mobile identification number. Inspect the

fluoroscopy systems appropriate for use in bioprosthesis for any signs of damage topercutaneous coronary interventions) the frame or tissue.

Rinse the bioprosthesis as follows: Place* Transesophageal or transthoracic echocardiography the bioprosthesis in the first bowl of sterile,

capabilities physiological saline. Be sure the saline* Exchange length 0.035 inch (0.89 mm) extra-stiff solution completely covers the

guidewire bioprosthesis and holder. With the

* Temporary pacemaker (PM) and pacing lead bioprosthesis and holder submerged,slowly agitate (to gently swirl the

* Sterile rinsing basins, physiological saline, bioprosthesis and holder) back and forthheparinized saline, and 15% diluted radiopaque for a minimum of 1 minute. Transfer thecontrast medium bioprosthesis and holder to the second

* 20 cc-or larger-luer-lock-syringe..... .rinsing-bowLof physiological.saline and--gently agitate for at least one more

* High-pressure 3-way stopcock 3 minute. Ensure the rinse solution in the* Edwards SAPIEN Transcatheter Heart Valve first bowl is not used. The bioprosthesis* RetroFlex 3 Delivery System should be left in the final rinse solution

until needed to prevent the tissue from* 20 mm and/or 23 mm balloon catheter such as: unting.

RetroFlex balloon catheter Model 9120BC20 for drying.use prior to 23 mm valve implantation and Model CAUTION: Do not allow the9120BC23 for use prior to 26 mm valve bioprosthesis to come in contact withimplantation the bottom or sides of the rinse bowl

* RetroFlex 3 Introducer Sheath Set Model 9120S23 during agitation or swirling of thefor 23 mm valve procedure and Model 9120S26 bioprosthesis. Care must be taken tofor 26 mm valve procedure ensure that the identification tag does

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Step Procedure Close the stopcock to the 20 mL syringe andnot come in contact with the tissue and verify the balloon is sized appropriately withdamage it. No other objects should be the gauge. Remove the syringe. Unlockplaced in the rinse bowls. The 10 inflation device and deflate the balloon whilebioprosthesis should be kept hydrated creating a three-wing fold configuration, andthroughout the rest of the preparation ensure no fluid is left behind. Lock theprocedure to prevent the tissue from inflation device.drying.

7.2.2 Prepare Transfemoral Procedure Components 7.2.3 Mount and Crimp the Bioprosthesis on the

Step Procedure Delivery System

Refer to RetroFlex Dilator Kit, RetroFlex 3

Introducer Sheath Set and Crimper Step Procedureinstructions for use on device preparation Remove the bioprosthesis from the holderand handling. 1 and gently place the bioprosthesis into the

2 Prime and flush the guidewire lumen of the crimper aperture.delivery system with heparinized saline. 2 Gradually crimp the bioprosthesis to aInsert an extra stiff guidewire [0.035 inch diameter of approximately 12 mm.(0.89 mm) and 150 cm long] in the Remove the bioprosthesis from the crimper

3 guidewire lumen, leaving a 2 to 3 cm and place it on the delivery system with thesegment of the guidewire protruding from inflow (fabric cuff end) of the bioprosthesisthe distal tip. 3 towards the distal end of the balloon

4 Flush the delivery system with heparinized catheter. Ensure that the inflow of thesaline through the flush port. bioprosthesis is aligned with the proximalPlace the loader cap onto the delivery end of the tapered catheter tip.

5 system, ensuring that the inside of the Place the bioprosthesis back in the crimperloader cap is in the same direction as the aperture, and completely crimp until it fitstapered tip. inside the crimp gauge.Prepare a 20 mL or larger luer-lock syringe 4with diluted contrast medium (15:85 contrast CAUTION: The physician must verify

6 to heparinized saline) and attach it to a 3- correct mountinglorientation of theway stopcock on the balloon inflation port. bioprosthesis prior to its implantation.Completely fill the inflation device provided Press on the balloon shouldersby Edwards and attach to 3-way stopcock. 5 circumferentially to facilitate insertion intoEnsure there are no air bubbles in the the flex catheter and loader.balloon. If an air bubble is detected, Pull the proximal end of the balloon into theeliminate it while deflating the balloon. Close 6 flex catheter until the proximal edge of thethe stopcock to the syringe. bioprosthesis is flush against the distal endInsert the balloon into the balloon gauge of the flex catheter.located on the crimper. Inflate the balloon Flush the loader with sterile heparinizedand verify its diameter fits the gauge with 7 saline and insert the crimped bioprosthesisminimal friction. While gently pulling and inside the loader.pushing the balloon, verify that the balloon Advance the bioprosthesis into the loadermoves with some resistance within the 8 until the distal end of the delivery systemgauge. If the balloon does not reach the tip is exposed.correct diameter when fully inflated, add or Screw the loader cap to the loader, re-flushdiscard some of the inflating solution in the the flex catheter and close the stopcock to

8 inflation device provided by Edwards until 9 the delivery system.the correct diameter is reached. Theinflation device must remain connected to Note: Keep bioprosthesis hydrated untilthe delivery system throughout the rest of ready for implantation.the procedure. Remove guidewire and flush guidewire

10 lumen.Note: Correct balloon sizing is critical tosuccessful valve deployment and valve 7function. 7.3 Valvuloplasty and Bioprosthesis DeliveryClose stopcock to the delivery system and Valvuloplasty and bioprosthesis delivery should be

9 remove any remaining contrast solution in performed under local and/or general anesthesiainflation device provided by Edwards with hemodynamic monitoring in a catheterizationLifesciences. Lock the inflation device. lab/hybrid operating room with fluoroscopic and

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s'O

electrocardiographic imaging capabilities. additional information on device

Administer heparin to maintain the ACT at 2250 sec. - preparation and handling:3 Insert the loader into the sheath.

CAUTION: Use of excessive contrast media may Push the delivery system through thelead to renal failure. Measure the patient's sheath. CAUTION: The bioprosthesiscreatinine level prior to the procedure. Contrast 4. should not be advanced through themedia usage should be monitored. sheath if the sheath tip is not past the

aortic bifurcation.CAUTION: Use of the retrograde approach may Retract loader to the proximalend ofrequire a femoral artery cut-down with surgical 5 RetroFlex 3 delivery system.closure of the puncture site due to the large size Tetete atu te i

of te arerioomy.The catheter articulates in a directionopposite from the flush port, and the flushport should be pointed away from the

6 physician. Advance the RetroFlex 37.3.1 Baseline Parameters delivery system up the descending aorta;

deflect the delivery system by rotating itsStep Procedure handle "clockwise".

Perform a supra-aortic angiogram with the Cross the native aortic valve and position1 projection of the native aortic valve 7 the bioprosthesis within the diseased

perpendicular to the view. valve.Evaluate the height between the inferior Maintain the position of the bioprosthesisaspect of the annulus and the inferior and retract the flex catheter, leaving the2 aspects of the lowest coronary ostium for bioprosthesis in position. Verify that thesubsequent prosthetic aortic valve 8 flex catheter is completely off of the balloonimplantation. before it is inflated and the bioprosthesis is

3 Introduce a pacemaker (PM) lead until its deployed.distal end is positioned in the right ventricle. Position the mid-point of the bioprosthesis

4 Set the stimulation parameters, and test 9 at the plane of the hinge points of thepacing. native valve leaflets.

Verify the correct location of the10 bioprosthesis with respect to the calcified

7.3.2 Valvuloplasty valve.Begin bioprosthesis deployment:

Refer to RetroFlex Balloon Catheter Instructions for * Unlock the inflation device.Use (IFU) for information on device preparation andhandling. * Begin rapid pacing; once arterial bloodNote: Rapid ventricular pacing should be performed pressure has decreased to 50 mmHg orwhen using the RetroFlex balloon catheter for below, balloon inflation can commence.valvuloplasty prior to aortic transcatheter valveimplantation. *Deploy the bioprosthesis by inflating the

balloon with the entire volume in theAfter placement of the balloon at the intended site, 11 inflation device. When the delivery systembegin rapid ventricular pacing. Once the blood has been completely deflated, turn off thepressure has decreased to 50 mmHg or below, pacemaker.balloon inflation can commence.

CAUTION: Prosthetic valve implantation should De-articulate the delivery system andnot be carried out if the balloon cannot be fully remove it from the sheath.inflated during valvuloplasty. CAUTION: Patient injury could occur if

the delivery system is not un-flexedprior to removal.

7.3.3 Bioprosthesis Delivery Remove sheath when the ACT level is12 appropriate (e.g., reaches < 150 sec).

Close puncture site.

Step ProcedureDilate the femoro-iliac vessel using the 8.0 How Supplied

1 RetroFlex dilator kit. Refer to RetroFlexDilator Kit IFU for information on device STERILE: The bioprosthesis is supplied sterilized with

- -preparation and handling. glutaraldehyde solution. The delivery system is

2 Insert the introducer sheath. Refer to the supplied sterilized with ethylene oxide gas.2 RetroFlex 3 Introducer Sheath Set IFU for

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8.1 Storage serial number and model number may be found onthe package.

The bioprosthesis must be stored between 10 C-250C (50 'F-77 'F). Each jar is shipped in an enclosure 11.0 Recovered Clinical Bioprosthesiscontaining a temperature indicator to detect exposure The explanted bioprosthesis should be placed into aof the bioprosthesis to extreme temperature. suitable histological fixative such as 10% formalin or

2% glutaraldehyde and returned to the company.The RetroFlex 3 delivery system should be stored in a Refrigeration is not necessary under thesecool, dry place. circumstances. Contact Edwards Lifesciences to

request an Explant Kit.9.0 MR Safety Disposal of Used Delivery Devices

A MR Conditional Used delivery devices may be disposed of in thesame manner that hospital waste and biohazardous

Non-clinical testing has demonstrated that the materials are handled. There are no special risksEdwards SAPIEN THV (implant) is MR Conditional. It related to the disposal of these devices.can be scanned safely under the following conditions:

12.0 Clinical Studies* Static magnetic field of 1.5 Tesla (T) or 3 Tesla. The Placement of Aortic Transcatheter Valves* Spatial gradient field of 2500 Gauss/cm or less. (PARTNER) trial (Cohort B), a prospective,* Maximum whole-body-averaged specific absorption randomized-controlled, multi-center pivotal trial,

rate (SAR) of 2 W/kg for 15 minutes of scanning. evaluated the safety and effectiveness of the Edwards* Normal mode operation, as defined in IEC 60601-2- SAPIENTm Transcatheter Heart Valve via

33 Ed. 3.0, of the MR system. transfemoral delivery to a group of inoperablepatients with severe symptomatic aortic stenosis.These inoperable patients were eligible for Cohort B

In non-clinical testing and analysis, the implant was due to coexisting conditions that resulted in thedetermined to produce a temperature rise of less than probability of death or irreversible morbidity exceeding1.1 0C above background for a whole body SAR of 50%. Patients in Cohort B were also evaluated for2.0 W/kg for 15 minutes of MR scanning in a 1.5 T vascular access and those meeting the criteria werecylindrical whole body MR system, assessed using a 1:1 randomized to either transfemoral delivery of theGE Signa whole body coil and a phantom designed to Edwards SAPIEN valve or to a control group. Patientssimulate human tissue. The phantom average SAR in the control group were treated with medicationcalculated using calorimetry was 2.2 W/kg and local and/or balloon valvuloplasty. Patients in Cohort B whobackground SAR at the site of the implant was 5.6 did not meet the criteria for vascular access were notW/kg. The measured rise above background was 0.7 eligible for the trial. The following data summarize the0C for a whole body SAR of 2 W/kg in a 3.0 T results from Cohort B.cylindrical bore whole body MR system, assessedusing a GE Signa HDx whole body active shield MR A total of 358 patients with severe aortic stenosis

scanner with software version 14/LX/MR and a underwent 1:1 randomization at 22 centers (18 in the

phantom designed to simulate human tissue. The United States) with baseline characteristics described

phantom average SAR calculated using calorimetry in Table 1. Severe aortic stenosis was defined as an

was 2.9 W/kg and local background SAR at the site of aortic-valve area of less than 0.8 cm2, a mean aortic-

the implant was 8.4 W/kg. valve gradient of 40 mmHg or more, or a peak aortic-jet velocity of 4.0 m per second or more. The primary

The image artifact extended as far as 15 mm from the end point was the rate of death from any cause overimplant for spin echo images and 40 mm for gradient the duration of the trial. At 1 year, the rate of deathimages when scanned in non-clinical testing in a 3.0 T from any cause (Kaplan-Meier analysis) was 30.7%GE Signa HDx MR system. The implant has not been with TAVR, as compared with 50.7% in the group notevaluated in MR systems other than 1.5 or 3.0 T. receiving the valve (hazard ratio with TAVR, 0.51;

10.0 Patient Information 95% confidence interval [Cl], 0.39 to 0.68; P <0.0001) (Figure 3). A total of 141 of the 179 (78.8%)

A patient implant card is provided in the patient patients in the control group underwent balloon aorticinformation brochure and should be given to every valvuloplasty (BAV). In addition, 11 patients (6.1%)patient after the procedure prior to discharge. The

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underwent aortic valve replacement. 5 patients (2.8%) endocarditis was 1.1% in the TAVR group, asreceived an LV-descending aortic conduit, and 4 compared to 0.6% in the control group. Mean totalpatients (2.2%) received a THV outside the US. The hospital stay was 18.4 days for the TAVR group, ascoprimary composite end point was time of death compared to 13.8 days for the control group. Meanfrom any cause or the time to the first occurrence of days alive out of hospital was 273.8 days for therepeat hospitalization. The rate of the composite end TAVR group and 210.2 days for the control group. Atpoint of death from any cause or repeat 1 year, rate of aortic regurgitation for the TAVR grouphospitalization was 43.6% with TAVR as compared was as follows: 2% of patients at 4+, 13% of patientswith 71.6% in the control group (hazard ratio, 0.45; at 3+, 50% of patients at 2+, 20% of patients at 1+,95% CI, 0.35 to 0.59; P < 0.0001) (Figure 4). and 11% of patients with no regurgitation. InPrespecified secondary end points included the rate comparison, rate of aortic regurgitation of the controlof death from cardiovascular causes (Figure 5), group was as follows: 17% of patients at 3+, 40% ofNYHA functional class (Figure 6), valve performance patients at 2+, 37% of patients at 1+, and 7% of(Figure 7, 8), and the distance covered during a 6- patients with no regurgitation. In the control group, theminute walk test. Among survivors at 1 year, the rate rate of AV reintervention was as follows: 66 patientsof cardiac symptoms (New York Heart Association (37%) had a cardiac reintervention with a BAV. 11class Ill or IV) was lower among patients who had patients (6.1%) underwent aortic valve replacement. 1undergone TAVR than among those in the control patient (0.6%) received an LV-descending aorticgroup (23.9% vs. 60.8%, P <0.001). When conduit. 4 patients (2.2%) received a THV outside theinterpreting NYHA results, consider that the US. In the TAVR group, at I year, 10 patients (5.6%)evaluation was unblinded. As with other heart valve had undergone reintervention of the aortic valve.trials, the patients are aware of their treatment group.Accordingly there is the potential for bias in the NYHA Procedure data for the TAVR group is summarized invalues, and there is no statistical method for Table 2. Clinical outcomes of TAVR as compared withestimating the bias. At 30 days, TAVR, as compared the control are summarized in Table 3. In the yearwith the control, was associated with a higher after TAVR, there was no deterioration in theincidence of strokes (7.3% vs. 1.7%, P = 0.02) and functioning of the bioprosthetic valve, as assessed bymajor vascular complications (16.8% vs. 1.1%, P < evidence of stenosis or regurgitation on an0.001). The time from index procedure to stroke in the echocardiogram.TAVR group was as follows: 1 stroke at 12 daysbefore .the index procedure but after randomization, 4 In patients with severe aortic stenosis who were not

strokes on the day of the index procedure, 2 strokes suitable candidates for surgery, TAVR, as compared

on the first post-operative day and 2 on the second with the control, significantly reduced the rates of

post-operative day, and one stroke each on days 3, 5, death from any cause, the composite end point of

10, 23, 39, 51, 75, 120, 136, and 151. At 1 year, the death from any cause or repeat hospitalization, and

rate of hemorrhagic vascular complication was 55.9% cardiac symptoms, despite the higher incidence of

in the TAVR group, as compared to 14.0% in the stroke and major vascular events.

control group. At 1 year, the rate of bleeding eventswas 17.3% in the TAVR group, as compared to 2.2%in the control group. Additionally, at 1 year, the rate of

These products are manufactured and sold under one or more of the following US patent(s): US Patent No. 5,411,552; 5,840,081; 5,931,969;6,168,614; 6,210,957; 6,214,054; 6,547,827; 6,561,970; 6,582,462; 6,893,460; 6,908,481; 7,214,344; 7,510,575; 7,530,253; 7,585,321; 7,618,446;7,780,723; 7,789,909; and RE40570 and corresponding foreign patents. Additional patents are pending.

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Table 1: Baseline Characteristics of the Patients and Echocardiographic Findings*___________________________ TAVR Control Group

Characteristic NN 9= 179 P ValueAe- y1 83.1 ± 8. 6 83 2 - 8.3 0.95Male sex-no (%) 82(45.8) 84 (46.9) 092STS scoret 11.2 ± 5.8 11 9 ± 4.8 .14NYHA class -n (0/) T 068I1 14 (7.8) 11 61)III or IV 165 (92.2) 168 (93 9)Coronary artery disease no (%) 121 (67.6) 133 743 0.20Previou s myocardial Infarction no /total 33/177 (1'86) 47/179 (26.3) 0 1no. (%)Previous intervention no /total no (%)CABG 58/179 (32.4) 73/1-79 (40-8) 0 12PCI 47/179 (26.3) 39/179 (21.8) 0.39Balloon aortic valvuloplasty 25/154 (16 2) 39/160 (24.4) 0.09Cerebral vascular disease - no /total no. 48/175 (27.4) 46/171 (26.9) 1.00

Peripheral vascular disease - no./tota 55/178 (30.9) 45/179 (25.1) 0.24

COPD-no. %:Any 74 (41.3) 94 (52 5) 0 04

Oxygen-dependent 38 (21.2) 46 (25.7) 038Creatinine > 2 mng/dL (177 pmol/liter) - 8/179 (4.5,: 16/178 (9.0) 01no./total no. )Atrial fibrillation - no./total no. % 28/85 (32.9) 39/80 (48.8) 0.04Permanent pacemaker - no./total no (%) 35/179 (19 6) 31/179 (17.3) 0 68Pulmonary hypertension - no./total no. 50/118 (42.4) 53/121 (43.8) 0.90(%)Extensively calcified aorta - no. (%) 34 (19.0) 20 (11.2) 0.05Deleterious effects of chest-wall 16 (8.9) 15 (8.4) 1.00irradiation - no.(%Chest-wall deformity - no. (%) 15 (8 4) 9 (50) 0 29Liver disease -no./total no,(%) 6/177 (3 4) 6/178 (3 4)1 00Echocardiographic findingsAortic-valve area - cm2 0.6 ± 0.2- 0.6 ± 0.2 0.97Mean aortic-valve gradient - mmHg 44.5 ± 15.7 43.0 ± 15.3 0.39Mean LVEF - % 53.9 ± 13.1 51.1 + 14 3 0.06Moderate or severe mitral regurgitation - 38/171 (22.2) 38/165 (23.0) 0.90no./total no. (%)I* Plus-minus values are means ± SD. To convert the value for creatinine to micromoles per liter, multiplyby 88.4. CABG denotes coronary-artery bypass grafting, COPD chronic obstructive pulmonary disease,LVEF left ventricular ejection fraction, NYHA New York Heart Association, PCI percutaneous coronaryintervention, and TAVR transcatheter aortic-valve replacement.t The Society of Thoracic Surgeons (STS) score measures patient risk at the time of cardiovascularsurgery on a scale that ranges from 0% to 100%, with higher numbers indicating greater risk. An STSscore higher than 10% indicates very high surgical risk.[ Moderate or severe mitral regurgitation was defined as regurgitation of grade 3+ or higher.

9

Table 2: TAVR Procedure Data

Variable Mean or % of patients (min - max)Total time of procedure (min) 262 (139-616)Skin to skin tme (min) 150 (34 -'553)Fluoroscopy time (mm) 29 (10-68)Volume of contrast (ml, 132 (10-450)Use of CPB 1.1%Use of general anesthesia 100%# of devices used

0 4.6%1 89.1%2 5.7%3 0.6%

Valve in Valve procedure %. 23

Einergent operation due to device or rocedure 1.1%

Adverse event during procedure . 39 4%Devicev malfunction 34O

Device Success (deployment, AVA >09 AI<3+,1 valve) 78.2%Proceduire Success (Device success no MACCE<30d) 71 8

10

Table 3. Clinical Outcomes at 30 Days and 1 Year (ITT Population)30 Days 1 Year

Transfemoral TransfemoralTAVR Control Group TAVR Control Group

Outcome N = 179 N = 179 N 179 N = 179Death 9 (5.0) 5 (2.8) 55 (30.7) 89 (49.7)

From any cause From 8(4.5) 3(1.7) 35(19.6) 75(41.9)cardiovascular cause8

Repeat hospitalization 10 (5,6) 18 (10.1) 40 (22.3)K 7Death from any cause orrepeat hospitalizationb 20 (11.2) 22 (12.3) 78 (43.6) 126 (70 4)TIA 0 0 1 (0.6) 0All Stroke' 13 (7.3) 3 1 20 (11.2) 8 (4.5)

Myocardial InfarctionAll 0 1 (0.6) 1 (0.6)Peri-procedural 0 0 0 0

Hemorrhagic VascularComplicatiori v (0.) 11(61 ) 50 ( .) 66 (36 )

Major Vascular Complication 30 (16.8) 2(1.1) 31 (17.3) 422Renal Failure 2 (1. 1) 2 (1, 1) 4 (2.2) _ 5 (2.8)Renal Insufficiency 1(6)0(0.0) 2 (1.1) 3(17Bleeding Event; 29 (16 2) 4 (2 2) 31 (17T3)_ 4 (2.2)Cardiac reintervention

Balloon aortic valvuloplasty 1 (0.6)' 11 (6.1) 5 (2.8) 66 (36.9)d'Repeat TAVRe 3 (1.7) NA 4 (2.2) NAAortic-valve replacement 0 3 (1.7) 1 (0.6)' 11 (6.1)

Endocarditis 0 0 2 (1 1) 1 (0.6)New Atrial Fibrillation 1 0.6 2 (1.1) -1 (0.6) 3(1.7)New pacemaker- 6(3.4) 9 (50 0 8 (4 5) 14 (78)NA = not applicable, TAVR = transcatheter aortic valve replacement, TIA = transient ischemic attack.Data presented as n (%).of patients.a. Deaths from unknown causes were assumed to be deaths from cardiovascular causes.b. Repeat hospitalizations were included if they were due to aortic stenosis or complications of the valve procedure

(e.g., TAVR).c. One patient in the TAVR group did not receive TAVR (because of failed access) and subsequently underwent

balloon aortic valvuloplasty, followed by aortic-valve replacement.d. 30 patients underwent repeat BAV after the index BAV procedure that had been performed in the first 30 days

after randomization, and 36 patients underwent a first BAV more than 30 days after randomization.e. Three patients underwent a repeat TAVR within 24 hours after the index TAVR procedure; four patients in the

control group who underwent TAVR at a nonparticipating, ex-US site are not included here.f. Stroke was defined as follows: Neurological deficit lasting 2 24 hours or lasting less than 24 hours with a brain

imaging study showing an infarction.g. Bleeding event is defined as ! 2 units within the index procedureh. Hemorrhagic vascular complications are defined as vascular complications that include hematoma at the access

site of > 5 cm, false aneurysm, arterio-venous fistula, retroperitoneal bleeding, peripheral ischemia/nerve injury,any transfusion or vascular surgical repair within 30 days of the procedure.

11

Figure 3 Primary Endpoint: All Cause Mortality(68% confidence limits displayed)

10%-

(.ontrol Paliens

40 0% 0, 7

TAVR Patients

1Oa0 7 ato 5 %' NNT 510 pts.

0 3 6 9 12 is is 21 24

11rn to £ve% (Mnonlhs)

Figure 4 Co-Primary Endpoint:Mortality or Repeat Hospitalization

(68% confidence limits displayed)

f Control Patients

40%- .... .. TAVRPatients

=04510,35,0541 NNT 3.6 pts.

0 2 6 9 12 Is 0 21 24

TWMe to £ewt (mo*t)

Figure 5 Secondary Endpoint:Death from Cardiovascular Cause

(68% confidence limits displayed)100.0% t2 910001

... Control Patients

Logrank PYAbo* <.owlf

240.0%TAVRPatents

Hira d RAA t95 C11

0 3 6 9 12 1 i s 24

nm to Ent lmotha)

Figure 6 Secondary Endpoint: NYHA Symptoms Over Time

P-Ohkt - 0.671 P-vW,5ke 00"i1 P-Akl 0 00o: P-vIlu# P(vUm -*w 001

6M

0.

TAVR Control TAVR Control TAVR Control TAVR Control TAVR (ontrolV4Cn* x Das 6 wMmhA I WaI 2 Yeo

NYHA CLIa C Ciss 1 MEMO ClaSS It Clit 8 C11 3 ss IV o.-It,

Figure 7 Secondary Endpoint: AVA Over Time(one standard deviation displayed)

L5' 153 LS

TAVR Patients

1.0 0,64

---- 6n _e ooh] ..... IContro Patienti

0"dono 30 O0y% 6 MAnths I Vow 2 Years

511vdle Vkft

Figure 8 Secondary Endpoint: Mean Gradient Over Time(one standard deviation displayed)

7o

44,440'.

44 9 , control Patients

11 113 12.5I' ;w 10.7

TAVR Patientr

sa$ 30 Dwys 6 MoWhs I You Z yew$

s004*d VIsA

13

RetroFlex Balloon Catheter

Edwards

Instructions for Use 2.0 IndicationsCaution: Federal (USA) law restricts this device The RetroFlex balloon catheter is indicated forto sale by or on the order of a physician. valvuloplasty of a stenotic cardiac valve prior toPlease verify that you have the latest version of implantation of a transcatheter heart valve.the instructions for use prior to using the deviceby visiting http://THVIFU.edwards.com or by 3.0 Contraindicationscalling 1.800.822.9837. In order to access theinstructions for use, an IFU Code will be required.

* Other than standard risks associated withSTERILE: The balloon catheter is supplied insertion of a cardiovascular catheter, there aresterilized by ethylene oxide. no known contraindications for valvuloplasty.

The patient's medical condition could affect1.0 Device Description successful use of this catheter.

The RetroFlex Balloon Catheter consists of a shaftand balloon with radiopaque markers indicating 4.0 Warningsworking length of the balloon. At the proximal end ofthe device, there is a standard "Y-connector" for * The device is designed, intended, andballoon inflation and the guidewire lumen. The distributed for single use only. Do notinflation parameters are as follows: resterilize or reuse the device. There are no

data to support the sterility, nonpyrogenicity,Table 1. Inflation Parameters and functionality of the device after

reprocessing.Balloon InflationModel Dimensions Volume * Do not mishandle the device or use it if the

9120BC20 20 mm x 3 cm 13 mL packaging or any components are-not sterile,9120BC23 23 mm x 3 cm 16 mL have been opened or are damaged

(e.g. kinked or stretched), or the expiration datehas elapsed.

RetroFlex Balloon Catheter

5.0 Precautions

* For special considerations associated with theuse of this device prior to transcatheter heartvalve implantation, refer to the bioprosthesisInstructions for Use.

Black dots indicate position of radiopaque markers. Use only appropriate balloon inflation medium.Do not use air or gaseous medium to inflate the

Device Compatibility: balloon.

* Maximum guidewire diameter: 0.035" (0.89 * The device is not intended for post-dilatation ofmm) d6ployed transcatheter heart valves.

* Minimum sheath compatibility: 14F (4.62 mm) * While exposed within the body, deviceNOTE: For proper volume sizing, the balloon catheter advancement and retrieval should not be done

should be used with the inflation device provided by without the aid of fluoroscopy. Do not advanceor retract the device unless the balloon is fully

Edwards Lifesciences. deflated under vacuum.

Edwards Lifesciences, the stylized E logo, Edwards andRetroFlex are trademarks of Edwards Lifesciences 6.0 Potential Adverse EventsCorporation.

Complications associated with standardcatheterization, balloon valvuloplasty, and the use ofangiography include, but are not limited to, allergic Step Procedurereaction to anesthesia or to contrast media, injury 8 Adaceteincluding perforation or dissection of vessels, 8 Advance the balloon catheter over thethrombus formation, plaque dislodgement and guidewire, through the introducer sheath,embolization that may result in myocardial across the valve, and position the ballooninfarction, stroke, distal peripheral occlusion and/or _ markers at the intended site.death, arrhythmia development, cardiac perforation, 9 Fully inflate the balloon with the inflationconduction system injury, hematoma, infundibulum device.injury, annular tear or rupture and/or valve leaflet 10 Completely deflate the balloon, and gentlydehiscence, severe valve insufficiency, valve withdraw the valvuloplasty balloon catheterrestenosis, valve damage, balloon rupture. and remove from the sheath.

7.0 Directions for Use8.0 How Supplied

Step Procedure1 Prepare vascular access site for STERILE: The balloon catheter is supplied sterilized

valvuloplasty balloon catheter insertion and by ethylene oxide.position guidewire using standardtechniques. 9.0 Storage

2 Flush the valvuloplasty balloon catheter withheparinized saline. Attach a high pressure Store in a cool, dry place.

I 3-way stopcock to the balloon inflation port.3 Prepare a 20 mL syringe with 5 mL diluted

contrast solution (15:85 contrast to 10.0 Device Disposalheparinized saline) and attach to thestopcock. Used devices may be handled and disposed of in

4 Completely fill the inflation device provided the same manner as hospital waste andby Edwards with diluted contrast solution biohazardous materials.There are no special risksand attach in the locked position to the related to the disposal of these devices.stopcock; close the stopcock to the inflationdevice.

5 Slowly pull vacuum with the 20 mL syringerepeatedly to remove air, leaving neutralpressure in the system.

6 Close the stopcock to the balloon catheter.Gradually remove contrast medium into the20 mL syringe to achieve the appropriatevolume by rotating the knob of the inflationdevice. Close the stopcock to the 20 mLsyringe and remove the 20 mL syringe fromthe system.

7 Remove balloon cover and hydrate thelength of the balloon catheter.

Crimpermn Model 9100CR23/ 9100CR26Edwards

4.0 WarningsInstructions for Use * The device is designed, intended, andCaution: Federal (USA) law restricts this device distributed for single use only. Do notto sale by or on the order of a physician. resterilize or reuse the device. There are no

data to support the sterility, nonpyrogenicity,Please verify that you have the latest version of and functionality of the device afterthe instructions for use prior to using the device reprocessing.by visiting http://THVIFU.edwards.com or bycalling 1.800.822.9837. In order to access theinstructions for use, an IFU Code will be required. * Do not mishandle the device or use it if the

packaging or any components are not sterile,STERILE: The crimper is supplied sterilized by have been opened or are damaged, or theethylene oxide. expiration date has elapsed.

1.0 Device Description5.0 Precautions

The Crimper is comprised of a housing and acompression mechanism, creating an aperture that For special considerations associated with the useis opened and closed by means of a handle. The of this device prior to transcatheter heart valveCrimper includes a balloon gauge to verify diameter implantation, refer to the bioprosthesis Instructionsof an inflated balloon catheter. The Crimper is for Use.available in two sizes, 23 mm and 26 mm, with acorresponding balloon gauge for each size. It also 6.0 Potential Adverse Eventsincludes a crimp gauge to verify collapsed diameterof the device. No known potential adverse events.

Figure 1. Crimper 7.0 Directions for UsesIT152 1. Remove the bioprosthesis from its package and

gently place the bioprosthesis into the crimperBalloon Gauge aperture.

2. Crimp the bioprosthesis by rotating the handleto close the aperture.

CrimpGauge 8.0 How SuppliedSTERILE: The Crimper is supplied sterilized by

CrimpAperture /ethylene oxide.

9.0 Storage2.0 Indications The Crimper should be stored in a cool, dry place.The Crimper is indicated for use in preparing the 10.0 Device DisposalEdwards SAPIEN Transcatheter HeartValve forimplantation. Used crimpers may be handled and disposed of in the

same manner as hospital waste and biohazardous0 Cmaterials. There are no special risks related to the

3.0 Contra indications disposal of these devices.No known contraindications. These products are manufactured and sold under one

or more of the following US patent(s): US Patent No.

Edwards Lifesciences, the stylized E logo and Edwards 7,530,253 and corresponding foreign patents.are trademarks of Edwards Lifesciences Corporation. Additional patents are pending.

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A MR ConditionalNon-clinical testing has demonstrated that the Edwards SAPIEN THV (implant) is MR Conditional.It can be scanned safely under the following conditions: LOW* Static magnetic field of 1.5Tesla (I) or 3.0 Testa.* Spatial gradient field of 2500 Gauss/cm or less.* Maximum whole-body-averaged specific absorption rate (WB-SAR of2 W/kg for 15 minutes of scanning.* Normal mode operation, as defined in IEC 60601-2-33 Ed. 3.0, of the MR system.In non-clinical testing and analysis, the device was determined to produce a temperature rise of lessthan 1.1 C above background for a W8-SAR of 2W/kg for 15 minutes of MR scanning in 1.5 T and3.0 T cylindrical bore whole body MR systems.The image artifact extended as far as 15 mm from the device for spin echo images and 40mm forgradient images when scanned in non-clinical testing in a 3 T GE Signa HDx MR system.The implant has not been evaluated in MR systems other than 1.5 or 3.0 T.

Edwards Lifesciences MRI information available at www.edwardsmri.com. - I -

Tel (USA) 800.424.3278 Tel (outside USA) 949.250.2500

Patient Device Description

Follow-up Physician Model

Implanting Physician Implant Date Serial No.

Hospital Position Size