Bioprosthesis Diameter
`23 mm
`26 mm
`
`Frame Height (Profile)
`14.3 mm
`16.1 mm
`
`
`
`The following table identifies the bioprosthesis size that
`should be used based on native valve annulus size, as
`measured by transesophageal echocardiography (TEE).
`
`Native Valve Annulus Size
`(Tissue Annulus Diameter)
`18-22 mm
`21-25 mm
`
`Bioprosthesis Diameter
`
`23 mm
`26 mm
`
` 
`
` Ascendra Balloon Catheter – Model 9100BCL23 for 23
`mm valve procedure and 9100BCL26 for 26 mm valve
`procedure (Figure 2)
`The Ascendra Balloon Catheter is used for delivery of the
`Edwards SAPIEN Transcatheter Heart Valve. The balloon
`catheter has radiopaque markers for visualization under
`fluoroscopy and a balloon for deployment of the
`bioprosthesis. The system also comes with a loader that is
`used to cover the bioprosthesis during delivery. An extension
`tubing is supplied for use with the balloon catheter during
`inflation.
`
`Figure 2. Ascendra Balloon Catheter
`
`
`
`
`2.0 Indications
`The Edwards SAPIEN™ Transcatheter Heart Valve, model
`9000TFX, sizes 23mm and 26mm, is indicated for
`transapical delivery in patients with severe symptomatic
`native aortic valve stenosis who have been determined by
`two cardiac surgeons to be at high risk for surgical aortic
`valve replacement, not suitable for transfemoral delivery per
`heart team decision, and in whom existing co-morbidities
`would not preclude the expected benefit from correction of
`the aortic stenosis.
`The Ascendra Balloon Catheter is indicated for the
`transapical delivery of the Edwards SAPIEN Transcatheter
`Heart Valve.
`
`1
`
`
`
`
`Edwards SAPIEN
`Transcatheter Heart Valve with
`the Ascendra Balloon Catheter
`Instructions for Use
`Caution: Federal (USA) law restricts this device to
`sale by or on the order of a physician.
`Transapical Approach
`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 be required.
`STERILE: The bioprosthesis is supplied sterilized with
`gluteraldehyde solution. The delivery system is supplied
`sterilized with ethylene oxide gas.
`
`1.0 Device Description
`• Edwards SAPIEN Transcatheter Heart Valve – Model
`9000TFX (Figure 1)
`The Edwards SAPIEN transcatheter heart valve
`(bioprosthesis) is comprised of a balloon-expandable,
`radiopaque, stainless steel (316 L) frame, three bovine
`pericardial tissue leaflets, and a polyethylene terephthalate
`(PET) fabric. The bioprosthesis is treated according to the
`Carpentier-Edwards ThermaFix process, packaged, and
`terminally sterilized in glutaraldehyde
`Figure 1. Edwards SAPIEN Transcatheter Heart Valve
`
`
`
`_______________________
`Edwards Lifesciences, the stylized E logo, Edwards,
`Ascendra, Carpentier-Edwards, PARTNER, ThermaFix and
`Edwards SAPIEN are trademarks of Edwards Lifesciences
`Corporation.
`
`
`
`001
`
`ENDOHEART AG, EX. 2006 Page 1
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
`Case No.: IPR2016-00299, U.S Patent No. 8,182,530
`
`

`
`
`
`
`3.0 Contraindications
`The bioprosthesis 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 is an increased risk of stroke in transcatheter
`aortic valve replacement procedures, as compared to
`balloon aortic valvuloplasty or other standard
`treatments.
` The devices are designed, intended, and distributed for
`single use only. Do not re-sterilize or reuse the
`devices. There are no data to support the sterility, non-
`pyrogenicity, and functionality of the devices after
`reprocessing.
`Incorrect sizing of the bioprosthesis may lead to
`paravalvular leak, migration, embolization and/or annular
`rupture.
` Accelerated deterioration of the bioprosthesis may occur
`in patients with an altered calcium
`metabolism.Bioprosthesis must remain hydrated at all
`times and cannot be exposed to solutions other than its
`shipping storage solution and sterile physiologic rinsing
`solution. Bioprosthesis leaflets mishandled or damaged
`during any part of the procedure will require replacement
`of the bioprosthesis.
` Caution should be exercised in implanting a
`bioprosthesis in patients with clinically significant
`coronary artery disease.
` Patients with pre-existing mitral valve devices should be
`carefully assessed prior to implantation of the
`bioprosthesis to ensure proper bioprosthesis 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 bioprosthesis if the tamper evident seal is
`broken, the storage solution does not completely cover
`the bioprosthesis, the temperature indicator has been
`activated, or the bioprosthesis is damaged, or the
`expiration date has elapsed.
` Do not mishandle the Ascendra Balloon Catheter 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.
` Use of excessive contrast media may lead to renal
`failure. Measure the patient’s creatinine level prior to
`the procedure. Contrast media usage should be
`monitored.
` Patient injury could occur if the delivery system is not un-
`flexed prior to removal.
` Care should be exercised in patients with
`hypersensitivities to chromium, nickel, molybdenum,
`manganese, copper, 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.
` The safety and efficacy of the transapical procedure has
`not been evaluated in for only those patient populations
`where the transfemoral procedure delivery is not suitable.
`
`5.0 Precautions
` Long-term durability has not been established for the
`bioprosthesis. Regular medical follow-up is advised to
`evaluate bioprosthesis 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
`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.
` Bioprosthetic valve recipients should be maintained on
`anticoagulant and antiplatelet therapy (e.g. clopidogrel or
`ticlopidine [75 mg/day]) for 6 months post procedure and
`aspirin (75-100 mg/day) for life, except when
`contraindicated, as determined by their physician.
` The safety of the bioprosthesis implantation has not been
`established in patients who have:
`o
`Pre-existing prosthetic heart valve in the
`aortic position
`Severe ventricular dysfunction with ejection
`fraction <20%
`o Hypertrophic cardiomyopathy with or without
`obstruction (HOCM)
`Safety, effectiveness, and durability have not been
`established for valve-in-valve procedures.
`Safety and effectiveness have not been established for
`patients with the following characteristics/comorbidities:
`o Non-calcified aortic annulus
`o Congenital unicuspid or congenital bicuspid
`aortic valve
`o Mixed aortic valve disease (aortic stenosis
`and aortic regurgitation with predominant
`aortic regurgitation >3+)
`Pre-existing prosthetic heart valve or
`prosthetic ring in any position
`Severe mitral annular calcification (MAC),
`severe (>3+) mitral insufficiency, or Gorelin
`syndrome
`Blood dyscrasias defined as: leukopenia
`(WBC<3000 mm3), acute anemia (Hb <9
`mg%), thrombocytopenia (platelet count
`<50,000 cells/mm3), or history of bleeding
`diathesis or coagulopathy
`o Hypertrophic cardiomyopathy with or without
`
`o
`
`
`
`
`
`o
`
`o
`
`o
`
`2
`
`
`
`002
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`ENDOHEART AG, EX. 2006 Page 2
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
`Case No.: IPR2016-00299, U.S Patent No. 8,182,530
`
`

`
`• Abnormal lab values (including electrolyte imbalance)
`• Hypertension or hypotension
`• Allergic reaction to anesthesia or to contrast media
`• Hematoma
`• Syncope
`• Pain or changes at the access site
`• Exercise intolerance or weakness
`• Inflammation
`• Angina
`• Heart murmur
`• Fever
`• Mechanical failure of delivery system and/or
`accessories
`
`
`Additional potential risks specifically associated with the use
`of the bioprosthesis include, but may not be limited to the
`following:
`
`
`Cardiac arrest
`
`Cardiogenic shock
`
`Emergency cardiac surgery
`
`Cardiac failure or low cardiac output
`
`Coronary flow obstruction/transvalvular flow
`disturbance
`
`
`
` 
`
`
`
` 
`
`
`
` 
`
`
`
`
`
` 
`
` 
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Injury at the site of ventricular access that may require
`repair
`
`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, stent creep, suture line disruption of
`components of a prosthetic valve, thickening, stenosis)
`
`Device degeneration
`
`Paravalvular or transvalvular leak
`
`Injury to the mitral valve
`
`Valve regurgitation
`
`Hemolysis
`
`Device explants
`
`Nonstructural dysfunction
`
`Non-emergent reoperation
`
`All listed risks may include symptoms associated with the
`above mentioned medical conditions.
`
`3
`
`
`
`o
`
`o
`
`o
`
`obstruction (HOCM)
`Echocardiographic evidence of intracardiac
`mass, thrombus, or vegetation
`A known hypersensitivity or contraindication
`to aspirin, heparin, ticlopidine (Ticlid), or
`clopidogrel (Plavix), or sensitivity to contrast
`media, which cannot be adequately
`premedicated
`o Native aortic annulus size <18 mm or >25
`mm as measured by echocardiogram
`Significant aortic disease, including
`abdominal aortic or thoracic aneurysm
`defined as maximal luminal diameter 5 cm or
`greater; marked tortuosity (hyperacute bend),
`aortic arch atheroma (especially if thick [> 5
`mm], protruding, or ulcerated) or narrowing
`(especially with calcification and surface
`irregularities) of the abdominal or thoracic
`aorta, severe “unfolding” and tortuosity of the
`thoracic aorta
`Bulky calcified aortic valve leaflets in close
`proximity to coronary ostia
`
`o
`
`
`6.0 Potential Adverse Events
`Potential risks associated with the overall procedure
`including potential access complications associated with
`standard cardiac catheterization for the transapical access
`procedure, balloon valvuloplasty, and the potential risks of
`local and/or general anesthesia
`
`
`• Death
`• Stroke/transient ischemic attack clusters or neurological
`deficit
`• Paralysis
`• Permanent disability
`• Respiratory insufficiency or respiratory failure
`• Hemorrhage requiring transfusion or intervention
`• Cardiovascular injury including perforation or dissection
`of vessels, ventricle, myocardium or valvular
`structures that may require intervention
`• Pericardial effusion or cardiac tamponade
`• Embolization including air, calcific valve material or
`thrombus
`• Infection including septicemia and endocarditis
`• Heart failure
`• Myocardial infarction
`• Renal insufficiency or renal failure
`• Conduction system injury (defect) which may require a
`permanent pacemaker
`• Arrhythmia
`• Retroperitoneal bleed
`• Femoral AV fistula or pseudoaneurysm
`• Reoperation
`• Peripheral ischemia or nerve injury
`• Restenosis
`• Pulmonary edema
`• Pleural effusion
`• Bleeding
`• Anemia
`
`003
`
`ENDOHEART AG, EX. 2006 Page 3
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
`Case No.: IPR2016-00299, U.S Patent No. 8,182,530
`
`

`
`7.0 Directions for Use
`7.1 Required Equipment
` Standard cardiac catheterization lab equipment
` Fluoroscopy (fixed, mobile or semi-mobile fluoroscopy
`systems appropriate for use in percutaneous coronary
`interventions)
` Transesophageal or transthoracic echocardiography
`capabilities
` Exchange length 0.035 inch (0.89 mm) soft, standard and
`extra-stiff guidewires
` Temporary pacemaker (PM) and pacing lead
` Sterile rinsing basins, physiological saline, heparinized
`saline, and 15% diluted radiopaque contrast medium
` 20 cc or larger luer-lock syringe
` 60 cc or larger luer-lock syringe
` High-pressure 3-way stopcock
` Edwards SAPIEN Transcatheter Heart Valve
` Ascendra Balloon Catheter
` 20 mm balloon valvuloplasty catheter such as Ascendra
`Balloon Aortic Valvuloplasty Catheter Model 9100BAVC
` Ascendra Introducer Sheath Set Model 9100IS
` Crimper Model 9100CR23 for 23 mm valve procedure
`and Model 9100CR26 for 26 mm valve procedure
`Inflation device provided by Edwards Lifesciences for this
`application
`7.2 Bioprosthesis Handling and Preparation
`Follow sterile technique during device preparation and
`implantation.
`7.2.1 Bioprosthesis Rinsing Procedure
`The bioprosthesis is packaged sterile in a plastic jar with a
`screw-cap closure and seal. Before opening, carefully
`examine the jar for evidence of damage (e.g. a cracked jar
`or lid, leakage, or broken or missing seals).
`CAUTION: Bioprostheses from containers found to be
`damaged, leaking, without adequate sterilant, or missing
`intact seals must not be used for implantation.
`
`
`
`Step Procedure
`1
`Set up two (2) sterile bowls with at least 500 mL of sterile
`physiological saline to thoroughly rinse the
`glutaraldehyde sterilant from the bioprosthesis.
`The bioprosthesis is contained in the jar within a holder.
`Carefully remove the bioprosthesis/holder assembly from
`the jar without touching the tissue. The holder is tagged
`with the bioprosthesis’ serial identification number.
`Inspect the bioprosthesis for any signs of damage to the
`frame or tissue.
`
`2
`
`3
`
`Rinse the bioprosthesis as follows:
`Place the bioprosthesis in the first bowl of sterile
`physiological saline. Be sure the saline solution
`completely covers the bioprosthesis and holder. With the
`bioprosthesis and holder submerged, slowly agitate (to
`gently swirl the bioprosthesis and holder) back and forth
`for a minimum of 1 minute. Transfer the bioprosthesis
`and holder to the second rinsing bowl of physiological
`saline and gently agitate for at least 1 more minute.
`Ensure the rinse solution in the first bowl is not used.
`The bioprosthesis should be left in the final rinse solution
`until needed to prevent the tissue from drying.
`CAUTION: Do not allow the bioprosthesis to come in
`contact with the bottom or sides of the rinse bowl
`during agitation or swirling of the bioprosthesis.
`Care must be taken to ensure that the identification
`tag does not come in contact with the tissue and
`damage it. No other objects should be placed in the
`rinse bowls. The bioprosthesis should be kept
`hydrated throughout the rest of the preparation
`procedure to prevent the tissue from drying.
`
`
`7.2.2 Prepare Transapical Procedure Components
`
`2
`
`3
`
`4
`
`5
`
`Step Procedure
`1
`Refer to Ascendra Introducer Sheath Set and
`Crimper instructions for use on device preparation
`and handling.
`Remove the balloon cover from the Ascendra
`Balloon Catheter
`Loosen the pusher nut and slide the pusher as far
`proximal as possible. Rotate the pusher nut to
`secure the pusher. Slide the loader cap, washers,
`and seal as far proximal as possible.
`CAUTION: Overtightening the pusher nut may
`result in improper balloon inflation.
`Prime and flush the guidewire lumen of the balloon
`catheter with heparinized saline.
`Insert an extra stiff guidewire (0.035” [0.89 mm] and
`≥ 100 cm long) in the guidewire lumen, leaving a 2 to
`3 cm segment of the guidewire protruding from the
`distal tip.
`Flush the balloon catheter with heparinized saline
`through the flush port.
`Attach extension tubing to balloon inflation port.
`Prepare a 60 mL or larger luer-lock syringe with
`diluted contrast medium (15:85 contrast to
`heparinized saline) and attach it to the balloon
`extension tubing.
`Completely fill the inflation device provided by
`Edwards Lifesciences with diluted contrast medium
`and attach to the balloon extension tubing.
`Close stopcock to inflation device. De-air the balloon
`catheter.
`Close the stopcock to the syringe. Insert the balloon
`into the balloon gauge located on the Crimper. Inflate
`the balloon and verify its diameter fits the gauge with
`minimal friction. While gently pulling and pushing the
`balloon, verify that the balloon moves with some
`resistance within the balloon gauge. If the balloon
`does not reach the correct diameter when fully
`inflated, add or discard some of the inflation solution
`in the inflation device provided by Edwards
`Lifesciences until the correct diameter is reached.
`
`6
`
`7
`8
`
`9
`
`10
`
`11
`
`4
`
`
`
`004
`
`ENDOHEART AG, EX. 2006 Page 4
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
`Case No.: IPR2016-00299, U.S Patent No. 8,182,530
`
`

`
`12
`
`Step Procedure
`The inflation device must remain connected to the
`balloon catheter throughout the rest of the
`procedure.
`
`Note: Correct balloon sizing is critical to successful
`valve deployment and valve function.
`Close stopcock to the balloon catheter and remove
`any remaining diluted contrast medium in the
`inflation device to the syringe. Lock the inflation
`device provided by Edwards Lifesciences.
`Close the stopcock to the syringe and verify the
`balloon is sized appropriately with the balloon gauge.
`Remove the syringe.
`Unlock inflation device provided by Edwards
`Lifesciences and deflate the balloon while creating a
`three-wing fold configuration, and ensure no diluted
`contrast medium is left behind. Lock the inflation
`device provided by Edwards Lifesciences.
`
`13
`
`14
`
`
`7.2.3 Mount and Crimp the Bioprosthesis on the Balloon
`Catheter
`
`Step
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Procedure
`Remove the bioprosthesis from the holder and
`gently place the bioprosthesis into the crimper
`aperture.
`Gradually crimp the bioprosthesis to a diameter of
`approximately 12 mm.
`Remove the bioprosthesis from the crimper and
`place it on the balloon catheter with the inflow
`(fabric cuff end) of the bioprosthesis towards the
`proximal end of the balloon catheter. Center
`bioprosthesis between the radiopaque markers.
`Place the bioprosthesis back in the crimper
`aperture, and completely crimp until it fits inside the
`crimp gauge.
`CAUTION: The physician must verify correct
`mounting/orientation of the bioprosthesis prior
`to its implantation.
`Loosen the pusher nut and advance the pusher to
`align the pusher tip with the proximal end of the
`crimped bioprosthesis. Rotate the pusher nut to
`secure the pusher in place.
`CAUTION: Overtightening the pusher nut may
`result in improper balloon inflation.
`Flush the loader with sterile heparinized saline and
`slide the threaded end of the loader over the
`crimped bioprosthesis.
`Slide the washers and seal on the balloon catheter
`shaft distally to the pusher. Insert into loader.
`Ensure washers and seal are flat against each
`other within the loader to prevent leakage. Slide
`loader cap distally over balloon catheter so it sits
`flat against the washers and seal and rotate the
`loader cap onto the base of loader. Check that the
`thread is not exposed. This indicates that the loader
`cap and seal are fully engaged around the pusher
`tubing. Do not overtighten the loader cap.
`Note: The loader must fully cover the bioprosthesis.
`
`8
`
`9
`
`Re-flush the balloon catheter through the flush port
`and close stopcock to the balloon catheter.
`Note: Keep bioprosthesis hydrated until ready for
`implantation.
`Remove guidewire and flush guidewire lumen.
`
`Valvuloplasty and Bioprosthesis Delivery
`7.3
`Valvuloplasty and bioprosthesis delivery should be
`performed under general anesthesia with hemodynamic
`monitoring in a catheterization lab/hybrid operating room
`with fluoroscopic and echocardiographic imaging
`capabilities.
`Administer heparin to maintain the ACT at ≥ 250 sec.
`CAUTION: Use of excessive contrast media may lead to
`renal failure. Measure the patient’s creatinine level prior
`to the procedure. Contrast media usage should be
`monitored.
`7.3.1 Baseline Parameters
`
`2
`
`Step Procedure
`1
`Perform a supra-aortic angiogram with the projection of the
`native aortic valve perpendicular to the view.
`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.
`
`3
`
`4
`
`
`7.3.2 Valvuloplasty
`Refer to Ascendra Balloon Aortic Valvuloplasty Catheter
`Instructions for Use (IFU) for information on device
`preparation and handling.
`Note: Rapid ventricular pacing should be performed when
`using the Ascendra Balloon Aortic Valvuloplasty Catheter for
`valvuloplasty prior to aortic 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: Prosthetic valve implantation should not be
`carried out if the balloon cannot be fully inflated during
`valvuloplasty.
`
`7.3.3 Bioprosthesis Delivery
`
`Step Procedure
`Insert the introducer sheath. Refer to the Ascendra
`1
`Introducer Sheath Set IFU for additional information on
`device preparation and handling.
`
`2
`
`3
`
`Insert loader into the sheath until it locks. Tap lightly on
`the loader and loosen the loader cap to de-air. Tighten
`cap until loader is sealed and catheter can move with
`minimal resistance. Check that the thread is not
`exposed. This indicates that the loader cap and seal are
`fully engaged around the pusher tubing. Do not
`overtighten.
`Cross the native aortic valve and position the
`bioprosthesis within the diseased valve.
`
`5
`
`
`
`005
`
`ENDOHEART AG, EX. 2006 Page 5
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
`Case No.: IPR2016-00299, U.S Patent No. 8,182,530
`
`

`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Loosen the pusher nut and retract the pusher, leaving
`the bioprosthesis in position. Rotate the pusher nut to
`secure the pusher. Verify that the pusher is completely
`off of the balloon before it is inflated and the
`bioprosthesis is deployed.
`CAUTION: The pusher must be pulled back for
`proper balloon inflation and bioprosthesis
`deployment.
`Position the mid-point of the bioprosthesis at the plane
`of the hinge points of the native valve leaflets.
`Verify the correct location of the bioprosthesis with
`respect to the calcified valve.
`Begin bioprosthesis 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 bioprosthesis by inflating the balloon with
`the entire volume in the inflation device. When the
`balloon catheter has been completely deflated, turn
`off the pacemaker.
`If deflection was used, straighten the catheter tip.
`
` Retract the balloon catheter into the introducer
`sheath.
`Disengage loader from sheath and remove balloon
`catheter.
`Remove sheath when the ACT level is appropriate (e.g.
`reaches < 150 sec). Close apical access site.
`
`
`8.0 How Supplied
`STERILE: The bioprosthesis is supplied sterilized with
`glutaraldehyde solution. The balloon catheter is supplied
`sterilized with ethylene oxide gas.
`8.1
`Storage
`The bioprosthesis must be stored between 10 C-25 C
`(50 F-77 F).Each jar is shipped in an enclosure containing
`a temperature indicator to detect exposure of the
`bioprosthesis to extreme temperature.
`The Ascendra Balloon Catheter should be stored in a cool,
`dry place.
`
`9.0 MR Safety
`
` MR Conditional
`Non-clinical testing has demonstrated that the Edwards
`SAPIEN THV (implant) is MR Conditional. It can be scanned
`safely under the following conditions:
`
`
`• Static magnetic field of 1.5 Tesla (T) or 3 Tesla.
`• Spatial gradient field of 2500 Gauss/cm or less.
`• Maximum whole-body-averaged specific absorption rate
`(SAR) of 2 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 implant was
`determined to produce a temperature rise of less than 1.1 °C
`above background for a whole body SAR of 2.0 W/kg for 15
`minutes of MR scanning in a 1.5 T cylindrical whole body
`
`MR system, assessed using a GE Signa whole body coil and
`a phantom designed to simulate human tissue. The phantom
`average SAR calculated using calorimetry was 2.2 W/kg and
`local background SAR at the site of the implant was 5.6
`W/kg. The measured rise above background was 0.7 °C for
`a whole body SAR of 2 W/kg in a 3.0 T cylindrical bore
`whole body MR system, assessed using a GE Signa HDx
`whole body active shield MR scanner with software version
`14/LX/MR and a phantom designed to simulate human
`tissue. The phantom average SAR calculated using
`calorimetry was 2.9 W/kg and local background SAR at the
`site of the implant was 8.4 W/kg
`The image artifact extended as far as 15 mm from the
`implant for spin echo images and 40 mm for gradient images
`when scanned in non-clinical testing in a 3.0 T GE Signa
`HDx MR system. The implant has not been evaluated in MR
`systems other than 1.5 or 3.0 T.
`
`10.0 Patient Information
`A patient registration 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 provide the
`temporary identification card to the patient prior to discharge.
`
`11.0 Recovered Clinical
`Bioprosthesis
`The explanted bioprosthesis 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.
`Disposal of Used Devices
`Used devices 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 Placement of Aortic Transcatheter Valves
`(PARTNER) trial, a prospective, randomized-
`controlled, multi-center pivotal trial, evaluated the
`safety and effectiveness of the Edwards SAPIEN
`Transcatheter Heart Valve via transfemoral and
`transapical delivery in a stratified population of high-
`risk and inoperable patients with severe symptomatic
`native aortic stenosis. Patients were stratified into two
`cohorts based on their risk of operability for standard
`aortic valve replacement surgery – those who were
`considered high surgical risk were eligible for Cohort
`A, while inoperable patients were eligible for Cohort B
`due to coexisting conditions that resulted in the
`probability of death or irreversible morbidity exceeding
`50%.
`
`
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`ENDOHEART AG, EX. 2006 Page 6
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
`Case No.: IPR2016-00299, U.S Patent No. 8,182,530
`
`

`
`Study Design – Cohort A
`
`This was a randomized study with the primary
`objective of ascertaining if TAVR is non-inferior to
`AVR surgery with respect to 12-month survival
`outcomes in high-risk surgical patients. Other
`objectives were focused on characterizing the benefit
`to risk ratio of TAVR relative to AVR.
`
`Patients in Cohort A were first evaluated for vascular
`access to determine whether their peripheral arteries
`could accommodate the 22 or 24 French sheaths
`required for the transfemoral TAVR approach to
`deliver the 23 mm or 26 mm Edwards SAPIEN valve
`sizes. Those patients who could accommodate these
`sheaths were then randomized 1:1 between
`transfemoral TAVR and surgical AVR. Those patients
`whose arteries could not accommodate these sheaths
`were randomized 1:1 between transapical TAVR and
`surgical AVR.
`
`The primary study endpoint was based on a pooled
`transapical and transfemoral analysis, and was
`defined as freedom from all-cause mortality at one
`year for the high-risk cohort. All patients were
`followed for at least 1 year, and cross-over from the
`surgical AVR group to the TAVR group was not
`permitted, except when findings or events during the
`assigned procedure prevented the planned
`treatment. Prespecified secondary endpoints included
`the following: time from randomization to the first
`occurrence of a Major Adverse Cardiac and
`Cerebrovascular Event (MACCE) within one year for
`which MACCE definition was comprised of death, MI,
`stroke, and renal failure as defined by protocol, total
`hospital days through one year, NYHA functional
`class at one year, and 6-minute walk test at one year.
`Additional prespecified efficacy endpoints were
`measured at 30 days, six months, and one year for
`the following: functional improvement from baseline
`as measured per (1) NYHA functional classification,
`(2) EOA, and (3) 6-minute walk test, freedom from
`MACCE, improved Quality of Life (QoL), and
`improved valve function demonstrated by an
`improvement in EOA.
`
`Study Design – Cohort B
`
`This was a randomized study with the primary
`objective of ascertaining if TAVR is superior to
`standard therapy in a control group for inoperable
`patients with respect to 12-month survival outcomes.
`Other objectives were focused on characterizing the
`benefit to risk ratio of TAVR relative to the standard
`therapy control group.
`
`Patients in Cohort B were also evaluated for vascular
`access and those meeting the criteria were
`randomized 1:1 to either transfemoral delivery of the
`Edwards SAPIEN valve or to a control group. Patients
`in the control group were treated with medication
`and/or balloon valvuloplasty. Patients in Cohort B who
`
`did not meet the criteria for vascular access were not
`eligible for the trial.
`
`Study Results – Cohort A
`
`A total of 699 (657 in the As-Treated [AT] population)
`high-risk patients with severe aortic stenosis were
`enrolled at 26 centers (23 in the United States) and
`assigned to TAVR (344 patients) or AVR (313
`patients) with baseline characteristics described in
`Table 1. Among the TAVR patents, 240 were treated
`using transfemoral access and 104 were treated
`using transapical access. Severe aortic stenosis was
`defined as a mean gradient > 40 mmHg, jet velocity >
`4.0 m per sec, or an initial aortic valve area (AVA) of
`0.8 cm2. The primary endpoint for the high-risk cohort
`was freedom from all-cause mortality at one year.
`Clinical outcomes of TAVR (transfemoral and
`transapical) as compared to AVR are summarized in
`Tables 5, 6, and 7. At day 365, the Kaplan-Meier
`estimate of all-cause death was 23.7% in the TAVR
`group, as compared to 25.2% in the AVR group. The
`estimated difference between these treatment groups
`is -1.5% with a one-sided lower 95% confidence
`interval of -4.0%, which is greater than the pre-
`specified margin of -7.5%. The non-inferiority p-value
`for this difference is 0.0037, indicating that TAVR is
`non-inferior to AVR with respect to all-cause death
`[Figure 3]. Pre-specified secondary endpoints
`included valve performance [Figures 6 and 7] and
`NYHA functional class [Figure 8]. When interpreting
`NYHA results, consider that the evaluation was
`unblinded. As with other heart valve trials, the
`patients are aware of their treatment group.
`Accordingly there is the potential for bias in the NYHA
`v