On-X Prosthetic Heart Valve

Transcription

1 O-X Prosthetic Heart Valve 0459 Istructios for Use Eglish Icludig Aortic Valve INR Update O-X Aortic Heart Valve with Stadard Sewig Rig - REF ONXA O-X Mitral Heart Valve with Stadard Sewig Rig - REF ONXM O-X Aortic Heart Valve with Coform-X Sewig Rig - REF ONXAC O-X Mitral Heart Valve with Coform-X Sewig Rig - REF ONXMC O-X Aortic Heart Valve with Aatomic Sewig Rig - REF ONXAN O-X Aortic Heart Valve ad Exteded Holder - REF ONXAE O-X Aortic Heart Valve with Coform-X Sewig Rig ad Exteded Holder - REF ONXACE O-X Aortic Heart Valve with Aatomic Sewig Rig ad Exteded Holder - REF ONXANE

2 ON-X PROSTHETIC HEART VALVE INSTRUCTIONS FOR USE O-X Aortic Heart Valve with Stadard Sewig Rig O-X Mitral Heart Valve with Stadard Sewig Rig O-X Aortic Heart Valve with Coform-X Sewig Rig O-X Mitral Heart Valve with Coform-X Sewig Rig O-X Aortic Heart Valve with Aatomic Sewig Rig O-X Aortic Heart Valve ad Exteded Holder O-X Aortic Heart Valve with Coform-X Sewig Rig ad Exteded Holder O-X Aortic Heart Valve with Aatomic Sewig Rig ad Exteded Holder The curret revisio of all O-X LTI IFUs may be foud at: TABLE OF CONTENTS ON-X PROSTHETIC HEART VALVE... 2 INSTRUCTION FOR USE DEVICE DESCRIPTION INDICATIONS FOR USE CONTRAINDICATIONS WARNINGS AND PRECAUTIONS WARNINGS PRECAUTIONS POTENTIAL ADVERSE EVENTS INDIVIDUALIZATION OF TREATMENT SPECIFIC PATIENT POPULATION PATIENT COUNSELING HOW SUPPLIED AVAILABLE MODELS AND SIZES PACKAGING STORAGE ACCESSORIES ACCESSORY CLEANING AND STERILIZATION DIRECTIONS FOR USE PHYSICIAN TRAINING STERILIZATION AND RESTERILIZATION HANDLING AND PREPARATION INSTRUCTIONS DEVICE IMPLANTATION SUTURING TECHNIQUES LEAFLET MOTION ASSESSMENT AND VALVE ROTATION VALVE ORIENTATION POSTOPERATIVE INFORMATION MAGNETIC RESONANCE IMAGING (MRI COMPATIBILITY RETURNED GOODS PATIENT INFORMATION PATIENT REGISTRATION PATIENT RECORD CARD PATIENT INFORMATION BOOKLET DISCLAIMER OF WARRANTIES APPENDIX A ADVERSE EVENTS OBSERVED ADVERSE EVENTS CLINICAL STUDIES PREMARKET TRIALS POSTMARKET TRIAL OF LOWER TARGET ANTICOAGULATION...14 O-X Prosthetic Heart Valve Istructios for Use 2

3 LIST OF FIGURES Figure 1: Aortic ad Mitral Profiles... 4 Figure 2: Stadard or Exteded Aortic Valve Holders... 6 Figure 3a: Sizer ad Replica Sizer... 7 Figure 3b: Sizer... 7 Figure 4: Istrumet Hadle... 8 Figure 5: Rotator... 8 Figure 6: Leaflet Probe... 8 Figure 7a. Twist-off outer lid... 9 Figure 7b. Remove by pull tab Figure 7c....or ivert o sterile field... 9 Figure 8a. Peel-off outer lid... 9 Figure 8b. Remove by pull tab... 9 Figure 8c....or ivert o sterile field... 9 Figure 9. Opeig the ier cotaier...10 Figure 10. Isertig the istrumet hadle...10 Figure 11. Aortic replica sizers verify the aortic valve...10 Figure 12. Supra-aular valve positioig...11 Figure 13. Sewig rig cross-sectios...11 Figure 14. Removig the valve holder...11 Figure 15. Isert valve rotator...12 Figure 16. Pivot axis of the mitral valve positioed ati-aatomically...12 Figure 17. INR Distributios...16 LIST OF CHARTS Chart 1: Patiet Follow-up Over Time...18 LIST OF TABLES Table 1: O-X Valve Specificatios (millimeters... 6 Table 2: Sizer Selectios - Regardless of Aortic Holder Type... 7 Table 3: Aortic Replacemet Observed Adverse Evet Rates...18 Table 4: Mitral Replacemet Observed Adverse Evet Rates...19 Table 5: Preoperative Patiet Demographics...19 Table 6: Operative Patiet Demographics Table 7: Number Implated ad Years by Valve Size...21 Table 8: Valve Effectiveess Outcomes...21 Table 9: Effectiveess Outcomes, Hemodyamic Results Table 10: Preoperative characteristics of test ad cotrol groups for high-risk AVR group Table 11: Post-Radomizatio Liearized Late Adverse Evet Rates For High-Risk AVR Group Table 12: No-Iferiority Aalyses...24 Table 13: Objective Performace Criteria Aalyses for Treatmet Group...24 Table 14: Defiitios...25 O-X Prosthetic Heart Valve Istructios for Use 3

4 INSTRUCTION FOR USE CAUTION: Federal law (USA restricts this device to sale by or o the order of a physicia. 1. DEVICE DESCRIPTION The O-X Prosthetic Heart Valve (Figure 1 is a bileaflet mechaical heart valve, which cosists of a orifice housig ad two leaflets. The orifice iflow area has a flared ilet desiged to reduce flow turbulece, ad the outflow rim cosists of leaflet guards desiged to protect the leaflets while i the closed positio. The leaflets rotate aroud tabs located withi the ier circumferece of the orifice rig. I the closed positio, each leaflet forms a omial agle of 40º relative to the plae of the orifice. I the ope positio, the plae of each leaflet forms a omial agle of 90º relative to the plae of the orifice. The leaflets have a travel arc of 50º to the closed positio. The orifice is composed of graphite substrate coated with O-X Carbo, a pure ualloyed form of pyrolytic carbo. The leaflets cosist of O-X Carbo deposited o a graphite substrate, which is impregated with 10 weight% tugste to provide radiopacity. The sewig rig is costructed of polytetrafluoroethylee (PTFE fabric mouted o the orifice usig titaium retaiig rigs ad 5-0 suture material. This form of sewig rig attachmet to the orifice allows for rotatio of the sewig rig i situ durig implatatio. Orietatio referece marks are provided o the sewig rig for valve orietatio. The O-X Prosthetic Heart Valve is available i 3 aortic ad 2 mitral sewig rig cofiguratios. All aortic cofiguratios are available i sizes 19, 21, 23, 25, ad 27/29 mm. The stadard mitral sewig rig is available i sizes 23, 25, 27/29 ad 31/33, while the mitral Coform-X sewig rig is available i size 25/33 oly. Aortic valves, size 19 mm through 25 mm, are desiged for itrasupra-aular sewig rig positio, while the valve size 27/29 mm is desiged for itra-aular sewig rig positio. All mitral valve sizes are desiged for the supra-aular sewig rig positio. Figure 1: Aortic ad Mitral Profiles (See Table 1 for correspodig dimesios (A AORTIC (ONXA, ONXAE orifice iteral diameter (D tissue aulus (moutig diameter (A profile height closed (h orifice iteral diameter (D tissue aulus (moutig diameter (A exteral sewig rig diameter (S profile height closed (h profile height closed (h profile height ope (H (B AORTIC CONFORM-X (ONXAC, ONXACE exteral sewig rig diameter (S orifice iteral diameter (D exteral sewig rig diameter (S orifice iteral diameter (D profile height ope (H (C AORTIC ANATOMIC (ONXAN, ONXANE tissue aulus (moutig diameter (A exteral sewig rig diameter (S (D MITRAL (ONXM tissue aulus (moutig diameter (A profile height closed (h profile height ope (H profile height ope (H 2. INDICATIONS FOR USE The O-X Prosthetic Heart Valve is idicated for the replacemet of diseased, damaged, or malfuctioig ative or prosthetic heart valves i the aortic ad mitral positios. (E MITRAL CONFORM-X (ONXMC exteral sewig rig diameter (S 3. CONTRAINDICATIONS The O-X Prosthetic Heart Valve is cotraidicated for patiets uable to tolerate aticoagulatio therapy. orifice iteral diameter (D tissue aulus (moutig diameter (A profile height ope (H profile height closed (h O-X Prosthetic Heart Valve Istructios for Use 4

5 4. WARNINGS AND PRECAUTIONS 4.1 Warigs FOR SINGLE USE ONLY. DO NOT use the O-X Prosthetic Heart Valve if: the prosthesis has bee dropped, damaged, or mishadled i ay way; the expiratio date has elapsed; the tamper evidet seal is broke; the serial umber tag does ot match the serial umber o the cotaier label. DO NOT pass a catheter, surgical istrumet, or trasveous pacig lead through the prosthesis as this may cause valvular isufficiecy, leaflet damage, leaflet dislodgmet, ad/or catheter/istrumet/lead etrapmet. DO NOT resterilize the O-X Prosthetic Heart Valve. 4.2 Precautios Hadle the prosthesis with oly O-X Life Techologies, Ic. (O-XLTI O-X Prosthetic Heart Valve Istrumets. Oly O-XLTI O-X Prosthetic Heart Valve sizers should be used durig the selectio of the valve size; other sizers may result i improper valve selectio. Avoid cotactig the carbo surfaces of the valve with gloved figers or ay metallic or abrasive istrumets as they may cause damage to the valve surface ot see with the uaided eye that may lead to accelerated valve structural dysfuctio, leaflet escape, or serve as a idus for thrombus formatio. Avoid damagig the prosthesis through the applicatio of excessive force to the valve orifice or leaflets. 5. POTENTIAL ADVERSE EVENTS Adverse evets potetially associated with the use of prosthetic heart valves (i alphabetical order iclude, but are ot limited to: agia cardiac arrhythmia edocarditis heart failure hemolysis hemolytic aemia hemorrhage myocardial ifarctio prosthesis leaflet etrapmet (impigemet prosthesis ostructural dysfuctio prosthesis paus prosthesis perivalvular leak prosthesis regurgitatio prosthesis structural dysfuctio prosthesis thrombosis stroke thromboembolism It is possible that these complicatios could lead to: reoperatio explatatio permaet disability death Mechaical prosthetic heart valves produce audible souds as a ormal fuctio of their operatio. I some patiets, these souds may be objectioable. Risk of Re-Use Statemet I accordace with the EU Medical Device Directive, 93/42/EEC, Aex I, Sectio 13.6h, the device maufacturer must provide iformatio o risks associated with re-use of a sigle use device. Therefore, the followig statemet is provided: The implated O-X prosthetic heart valve is desiged for sigle use oly. Do ot re-use the device. I additio to the risks listed i Sectio 5, re-use may cause procedural complicatios icludig device damage, compromised device biocompatibility, ad device cotamiatio. Re-use may result i ifectio, serious ijury, or patiet death. 6. INDIVIDUALIZATION OF TREATMENT Aticoagulatio Adequate aticoagulat or aticoagulat/atiplatelet therapy should be admiistered. Selectio of a aticoagulat or aticoagulat/atiplatelet regime is based o the particular eeds of the patiet ad the cliical situatio. Patiets with a O-X valve i the aortic valve positio should be maitaied o log-term warfari aticoagulatio which should achieve a Iteratioal Normalized Ratio (INR of for the first 3 moths after valve replacemet surgery, after which the INR should be reduced to Patiets with a O-X valve i the mitral valve positio or i multiple valve positios should be maitaied at a INR of cotiuously after valve replacemet surgery. The additio of a daily aspiri at a dose from 75 to 100 mg is also recommeded for patiets with a O-X valve i ay valve positio, uless there is a cotraidicatio to the use of aspiri. Studies show that stable cotrol of INR provides better cliical results ad that patiets should be regularly moitored. The use of home moitorig to accomplish stable INR cotrol is recommeded. 6.1 Specific Patiet Populatio The safety ad effectiveess of the O-X Prosthetic Heart Valve has ot bee established for the followig specific populatios because it has ot bee studied i these populatios: O-X Prosthetic Heart Valve Istructios for Use 5

6 patiets who are pregat; ursig mothers; patiets with chroic edocarditis; patiets requirig pulmoary or tricuspid replacemet. 7. PATIENT COUNSELING Prophylactic atibiotic treatmet must be provided to all patiets with prosthetic valves udergoig detal procedures or other potetially bacteremic procedures. Patiets require aticoagulatio or aticoagulat/ atiplatelet therapy. Patiets should be ecouraged to complete the Patiet ID card provided with the valve ad carry it with them at all times. 8. HOW SUPPLIED 8.1 Available Models ad Sizes The O-X Prosthetic Heart Valve is available i 3 aortic ad 2 mitral sewig rig cofiguratios. All aortic cofiguratios are available i sizes 19, 21, 23, 25, ad 27/29 mm. The stadard mitral sewig rig is available i sizes 23, 25, 27/29 ad 31/33 mm, while the Mitral Coform-X sewig rig is available i size 25/33 oly. Aortic valves, size 19 mm through 25 mm, are desiged for itrasupra-aular sewig rig positio, while the valve size 27/29 mm is desiged for itra-aular sewig rig positio. All mitral valve sizes are desiged for the supra-aular sewig rig positio. Aortic valves are available with either stadard or exteded valve holders (Figure 2. Figure 2: Stadard or Exteded Aortic Valve Holders Exteded Holder Stadard Holder The dimesioal ad model specificatios for all available sizes of the O-X Prosthetic Heart Valve are show i Table 1 ad Figure 1. The symbol SZ mm o the box, cotaier labels, ad implat registratio card refers to the tissue aulus diameter of the valve i millimeters. 8.2 Packagig The O-X Prosthetic Heart Valve is provided sterile, mouted o a holder, i a double-sealed plastic cotaier. The package cosists of the followig items: Outer box Patiet record card Plastic valve cotaier Implat registratio card Plastic valve holder Valve serial umber tag Istructios for use (booklet or Website Referece Card Table 1: O-X Valve Specificatios (millimeters Exteded Holder Model Desigator Stadard Holder Size/Type Tissue Aulus (moutig Diameter (A Orifice Iteral Diameter (D Exteral Sewig Rig Diameter (S Profile Height (closed (h Profile Height (ope (H Iteral Orifice Area (mm² ONXAE-19* ONXA Aortic ONXAE-21* ONXA Aortic ONXAE-23* ONXA Aortic ONXAE-25* ONXA Aortic ONXAE-27/29* ONXA-27/29 27/29 Aortic ONXACE-19* ONXAC-19* 19 Aortic Coform-X ONXACE-21* ONXAC-21* 21 Aortic Coform-X ONXACE-23* ONXAC-23* 23 Aortic Coform-X ONXACE-25* ONXAC-25* 25 Aortic Coform-X ONXACE-27/29* ONXAC-27/29* 27/29 Aortic Coform-X ONXANE-19* ONXAN-19* 19 Aortic Aatomic ONXANE-21* ONXAN-21* 21 Aortic Aatomic ONXANE-23* ONXAN-23* 23 Aortic Aatomic ONXANE-25* ONXAN-25* 25 Aortic Aatomic ONXANE-27/29* ONXAN-27/29* 27/29 Aortic Aatomic 27/ ONXM-23** 23 Mitral ONXM Mitral ONXM-27/29 27/29 Mitral ONXM-31/33 31/33 Mitral ONXMC-25/33 Mitral Coform-X * Not available i all markets ** Not available i the USA Refer to Figure 1 for locatio of measured dimesios. Values give are omial withi the tolerace bad. O-X Prosthetic Heart Valve Istructios for Use 6

7 Istrumets for implatatio of the O-X Prosthetic Heart Valve are supplied separately, NON-STERILE, ad must be cleaed ad sterilized prior to use as outlied i sectio Storage The sterility expiratio date of the O-X Prosthetic Heart Valve is recorded o the outer package label. Appropriate ivetory cotrol should be maitaied so that prostheses with earlier expiratio dates are preferetially implated ad expiratio is avoided. To protect the valve, it should be stored i its outer box util used. The storage eviromet should be clea, cool, ad dry. 8.4 Accessories The O-X Prosthetic Heart Valve is desiged to be used oly with O-XLTI O-X istrumets. The istrumets, supplied separately, are provided as a set, which icludes sizers, rotators, a istrumet hadle, ad a leaflet probe. The istrumets are reusable. Sizer The sizer is used to gauge the resultig tissue aulus diameter after the aulus is prepared for implat. The sizer has a bedable stem o each ed. The sizers are cylidrical for size 19 mm through 25 mm valves ad coical for size 27/29 mm ad 31/33 mm valves (Figure 3a ad 3b. To facilitate sizer selectio, refer to Table 2. Replica Sizers Aortic replica sizers are provided for all aortic valve sizes (Figure 3a. They model the O-X stadard aortic valve profile. They are used after sizig for stadard, Coform-X, ad Aatomic sewig rig cofiguratios to assure fit of the aortic valve without obstructio of the coroary arteries. The size 19 through 25 aortic replica sizers shape is iteded to model itrasupra-aular positioig. The size 27/29 aortic replica sizer is iteded to model itra-aular positioig. Figure 3a: Sizer ad Replica Sizer Cylidrical CAUTION: Sizers ad istrumet hadles have metallic regios that are bedable. Repeated bedig of these metallic regios ca lead to fatigue ad fracture. To avoid istrumet fracture durig use, the stem should be ispected for surface cracks before ad after each time it is bet. If metal fatigue surface cracks are preset, the sizer ad/or istrumet hadle should be discarded ad replaced. Cotact O-XLTI Customer Service to order replacemets. CAUTION: Leaflet probes ad rotators are flexible, but are ot iteded to be bet to a permaetly deformed state. Figure 3b: Sizer Aortic Replica Coical Table 2: Sizer Selectios - Regardless of Aortic Holder Type Sizer Choice Positio of sewig rig * Not available i all markets Size Valve Type Sizer Type Use Replicate Sizer 19 Aortic Cylidrical YES Itrasupra-aular 21 Aortic Cylidrical YES Itrasupra-aular 23 Aortic Cylidrical YES Itrasupra-aular 25 Aortic Cylidrical YES Itrasupra-aular 27/29 Aortic Coical YES Itra-aular 19* Aortic Coform-X Cylidrical YES Itrasupra-aular 21* Aortic Coform-X Cylidrical YES Itrasupra-aular 23* Aortic Coform-X Cylidrical YES Itrasupra-aular 25* Aortic Coform-X Cylidrical YES Itrasupra-aular 27/29* Aortic Coform-X Coical YES Itra-aular 19* Aortic Aatomic Cylidrical YES Itrasupra-aular 21* Aortic Aatomic Cylidrical YES Itrasupra-aular 23* Aortic Aatomic Cylidrical YES Itrasupra-aular 25* Aortic Aatomic Cylidrical YES Itrasupra-aular 27/29* Aortic Aatomic Coical YES Itra-aular 23* Mitral Cylidrical NO Supra-aular 25 Mitral Cylidrical NO Supra-aular 27/29 Mitral Coical NO Supra-aular 31/33 Mitral Coical NO Supra-aular 25/33 Mitral Coform-X Cylidrical or Coical NO Supra-aular O-X Prosthetic Heart Valve Istructios for Use 7

8 Istrumet Hadle The istrumet hadle (Figure 4 facilitates holdig the valve or the rotator durig surgery. The istrumet hadle is comprised of a grip, a bedable stem, ad a tip. Rotator The valve rotator (Figure 5 is used for reorietig a i situ valve ad may be used to verify leaflet mobility. The rotator cosists of a plastic head with a cetrally located leaflet probe ad a attached hadle. The rotator may be used with or without the istrumet hadle attached. To attach the rotator to the istrumet hadle, isert the istrumet hadle tip directly ito the slot o the ed of the rotator hadle. The rotator saps ito place after the applicatio of a light isertio force. Leaflet Probe The leaflet probe (Figure 6 is a flexible rod with tapered eds. The leaflet probe may be used to getly move the leaflets to verify that they ope ad close freely. Figure 4: Istrumet Hadle WARNING: DO NOT sterilize istrumets with ay method of sterilizatio other tha steam. Damage to some items could result from use of other sterilizatio methods. WARNING: The rotator must be removed from the hadle after use ad prior to cleaig. A force greater tha the isertio force is required to remove the rotator from the istrumet hadle. 9. DIRECTIONS FOR USE WARNING: DO NOT use the O-X Prosthetic Heart Valve if: the prosthesis has bee dropped, damaged, or mishadled i ay way; the expiratio date has elapsed; the tamper evidet seal is broke; the serial umber tag does ot match the serial umber o the cotaier label. 9.1 Physicia Traiig No special traiig is required to implat the O-X Prosthetic Heart Valve. The techiques for implatig this prosthesis are similar to those used for ay mechaical heart valve prosthesis. Figure 5: Rotator Figure 6: Leaflet Probe 9.2 Sterilizatio ad Resterilizatio The O-X Prosthetic Heart Valve is provided sterile. If the sterility expiratio date has passed or if upo removal from the outer box, the valve cotaier is damaged or the sterility barrier is broke, do ot use the valve. Call O-XLTI Customer Service ad arrage to retur the valve ad receive a replacemet. WARNING: If durig surgery the valve is removed from its cotaier but ot used, it must ot be repackaged or resterilized. I this situatio, the valve must be retured to O-XLTI. Call Customer Service for iformatio before ay retur is made. WARNING: Do ot resterilize the O-X Prosthetic Heart Valve. 8.5 Accessory Cleaig ad Sterilizatio Istrumets for implatatio of the O-X Prosthetic Heart Valve are supplied separately, NON-STERILE, ad must be cleaed ad sterilized prior to use. Stadard hospital surgical istrumet cleaig procedures must be used. Note: the metallic istrumets are made of titaium. The plastic istrumets are made of polypheylsulfoe. Materials used i these istrumets ca withstad stadard steam ad flash steam sterilizatio. WARNING: These istrumets are NOT provided sterile. They must be properly cleaed ad sterilized prior to each use. 9.3 Hadlig ad Preparatio Istructios CAUTION: Hadle the prosthesis with oly O-XLTI O-X Prosthetic Heart Valve Istrumets. Oly O- XLTI O-X Prosthetic Heart Valve sizers should be used durig the selectio of the valve size; other sizers may result i improper valve selectio. CAUTION: Avoid cotactig the carbo surfaces of the valve with gloved figers or ay metallic or abrasive istrumets as they may cause damage to the valve surface ot see with the uaided eye that may lead to accelerated valve structural dysfuctio, leaflet escape, or serve as a idus for thrombus formatio. CAUTION: Avoid damagig the prosthesis through the applicatio of excessive force to the valve orifice or leaflets. O-X Prosthetic Heart Valve Istructios for Use 8

9 Circulatig Nurse 1. Check the expiratio date o the outer box. WARNING: DO NOT use the O-X Prosthetic Heart Valve if the expiratio date has elapsed. If a valve is uused, its plastic cotaier is udamaged, ad the sterility expiratio date has passed, the valve should be retured to O-XLTI. 2. Remove the valve cotaier ad package iserts from the outer box. Ispect the cotaier for damage. WARNING: DO NOT use the O-X Prosthetic Heart Valve if the prosthesis has bee dropped, damaged, or mishadled i ay way. If ay damage is foud, use aother valve ad arrage for a retur through O-XLTI Customer Service. 3. Fill out the implat registratio card as completely as local law allows ad retur to O-XLTI as soo as possible. This allows the patiet to be etered ito the trackig database, which could be importat for future otices regardig the valve. Give the patiet record card to the patiet or place it i the patiet s records. 4. Ope the outer cotaier Twist-off outer lid package desig: Rotate the lid couter-clockwise util it stops, the lift the lid off off of the cotaier (Figure 7a. Twist-off Lid Desig Peel-off Tyvek lid package desig: Grasp the peel tab corer of the lid ad pull back towards the ceter of the cotaier (Figure 8a. Cotiue peelig util the lid is completely removed. 5. The scrub urse may remove the sterile ier cotaier from the outer cotaier by getly liftig the pull tab attached to the top of the ier cotaier (Figure 7b or Figure 8b. The ier cotaier is the placed oto the istrumet tray. Alterately, the ier cotaier ca be placed o the sterile field by getly ivertig the outer cotaier slightly above the sterile field (Figure 7c or Figure 8c ad allowig the ier cotaier to slip out oto the sterile field. Scrub Nurse/Surgeo: 1. Check the tamper evidet seal of the ier cotaier. WARNING: DO NOT use the O-X Prosthetic Heart Valve if the tamper evidet seal has bee broke. If the tamper evidet seal has bee broke, use aother valve ad arrage for retur through O- XLTI Customer Service. 2. Ope the ier cotaier by getly twistig the lid to break the tamper-proof seals (Figure 9 ad the liftig the lid off the base. Figure 7a. Twist-off outer lid Figure 7b. Remove by pull tab... Figure 7c....or ivert o sterile field Peel-off Lid Desig Figure 8a. Peel-off outer lid Figure 8b. Remove by pull tab... Figure 8c....or ivert o sterile field O-X Prosthetic Heart Valve Istructios for Use 9 O-X Prosthetic Heart Valve Istructios for Use

10 3. Press the istrumet hadle tip ito the slot o the valve holder util it saps firmly ito positio (Figure 10. Getly lift the valve out of the cotaier ad slide the holder plate off the holder. Carefully grasp the sewig rig with a gloved had usig a light grip ad getly tur the istrumet hadle i either directio. The valve should easily rotate withi the sewig rig. Stop rotatio testig with a orietatio mark aliged with the pivot axis. WARNING: DO NOT use the O-X Prosthetic Heart Valve if the valve does ot rotate easily. Use aother valve ad arrage for retur through O- XLTI Customer Service. Figure 9. Opeig the ier cotaier Figure 10. Isertig the istrumet hadle 4. Check the serial umber tag agaist the label o the outer cotaier. WARNING: DO NOT use the O-X Prosthetic Heart Valve if the serial umber tag does ot match the cotaier label. Use aother valve ad arrage for a retur through O-XLTI Customer Service. 5. Remove the serial umber tag by cuttig the suture that holds it o the valve. If desired, the tag ca be used to check for sterility by stadard culture techiques immediately after it is removed. 6. The valve is ow ready for implatatio. To ease positioig durig implatatio, the istrumet hadle stem ca be bet by graspig the eds of the hadle ad the stem, the bedig. Avoid graspig the valve. WARNING: DO NOT use the valve for leverage i bedig the istrumet hadle. This could damage the valve ad lead to mechaical failure. Sizig Use oly O-X Prosthetic Heart Valve sizers whe sizig the aulus. Sizers cotai cylidrical, coical, ad aortic replica eds. Refer to Table 2 to facilitate sizer selectio. Cylidrical sizers correspod to the valve sizes 19 mm through 25 mm. Coical sizers correspod to the valve size 27/29 mm ad 31/33 mm. These types of sizers may be used for both aortic ad mitral valves. The correct valve size is determied by obtaiig a comfortable, ot tight, fit of the sizer withi the aulus. Whe a comfortable fit is foud, the correspodig valve size is sigified by the idetificatio o the sizer. O-X Mitral Coform-X Prosthetic Heart Valves may be used whe a comfortable fit is at or betwee size 25 ad size 33. Aortic replica sizers are provided for all aortic valve sizes. For size 19 mm through 25 mm aortic valves, the aortic replica sizers are used to verify that the aortic valve ca be properly seated i the aulus ad that the coroary arteries remai uobstructed. Size 19 mm through 25 mm aortic valves of stadard, Coform-X, ad Aatomic sewig rig cofiguratios are desiged to fit withi the aulus at implat such that the exposed carbo flare rests i the aulus ad the sewig rig is itrasupraaular (Figure 11. WARNING: DO NOT size the sewig rig of the size 19 mm through 25 mm aortic valve to fit withi the aulus. Size 27/29 mm aortic valves of stadard, Coform-X, ad Aatomic sewig rig cofiguratios are desiged to be placed i a itra-aular positio ad have a replica sizer to mimic this placemet. All mitral valves, icludig the O-X Mitral Coform-X Prosthetic Heart Valve, are desiged to be placed i a supra-aular positio (Figure 12. CAUTION: Avoid oversizig the valve, as this could lead to iterferece with valve fuctio. Figure 11. Aortic replica sizers verify the aortic valve 9.4 Device Implatatio WARNING: All accessory istrumets must be cleaed ad sterilized prior to use accordig to the istrumet istructios. O-X Prosthetic Heart Valve Istructios for Use 10

11 9.5 Suturig Techiques The suturig techiques vary accordig to the prefereces of the implatig surgeo ad patiet coditio. The aortic valve is desiged to have the tissue aulus abut the orifice flare. The geeral cosesus amog surgeos is that the o-evertig iterrupted mattress suture techique, with or without pledgets, provides the best coformatio of the valve aulus to the outer surface of the flare. The mitral valves have geerally bee implated usig a pledgetted or o-pledgetted evertig mattress suture techique, although o-evertig ad cotiuous suture techiques have also bee used with success. CAUTION: Whe seatig the valve, esure that o suture material or aatomic structures iterfere with leaflet motio. The valve s rotatio capability may be helpful i avoidig abormal residual pathology that could iterfere with leaflet motio. Figure 12. Supra-aular valve positioig Figure 13. Sewig rig cross-sectios (A Aortic (C Mitral Coform-X Housig Titaium Rigs Layered Cloth Housig Titaium Rigs Layered Cloth (B Mitral (D Aortic Coform-X ad Aortic Aatomic The sutures should be passed through the mid-poit of the sewig rig. This allows the sewig rig to remai flexible ad coform to the aulus. It also prevets the suture eedle from cotactig the titaium rigs that lie withi the sewig rig (Figure 13. The orietatio marks o the sewig rig may be used to aid i suture placemet. CAUTION: For the Aatomic sewig rig, the sutures at the three valve commissures must correspod to the three orietatio marks o the sewig rig. Whe all the sutures are i place, the valve is advaced ito the aulus ad the sutures are tied dow. For aortic valves, it is suggested that the first 3 kots be tied equidistat to oe aother ad midway betwee the commissures to stabilize the valve i the aulus. The holder is removed from the valve by carefully cuttig the retaiig suture as show i Figure 14, the getly liftig the valve holder with hadle out of the valve. WARNING: Do NOT attempt to reisert the valve holder ito the valve oce it has bee removed. CAUTION: Suture ties should be cut short to avoid ay potetial iterferece with leaflet motio. Figure 14. Removig the valve holder O-X Prosthetic Heart Valve Istructios for Use 11

12 9.6 Leaflet Motio Assessmet ad Valve Rotatio Leaflet Motio Testig Oce the valve is i place, free motio of the leaflets must be tested. To test leaflet mobility, use the rotator probe or the leaflet probe to getly move the leaflets to verify that they ope ad close freely. WARNING: Test the leaflet mobility oly with the O- XLTI O-X leaflet probe or the leaflet probe o the ed of the rotator. Rotatio If the leaflets do ot move freely, getly rotate the valve i either directio util it reaches a positio where leaflet iterferece is ot ecoutered. CAUTION: Do ot attempt to rotate the valve if ay sigificat resistace to rotatio is ecoutered. The torque required to rotate the valve i situ should be about the same as that required whe testig rotatio before implatatio. If oticeably greater torque is required to rotate, stop attemptig rotatio. If rotatio is ecessary ad caot be performed, remove the valve. The rotator may be used with or without the istrumet hadle attached. As eeded, attach the istrumet hadle to the rotator by isertig the istrumet hadle tip ito the slot o the ed of the rotator hadle util it saps firmly ito positio. WARNING: Use oly the O-XLTI O-X rotator to rotate the valve i situ. Use oly the correspodigly sized rotator. Use of the wrog size rotator could damage the valve. With the rotator leaflet probe betwee the leaflets ad the cross-bar aliged with the leaflet pivot axis of the valve, carefully isert the valve rotator ito the valve util it seats easily i place (Figure 15. Figure 15. Isert valve rotator Cross-bar CAUTION: No resistace should be experieced whe isertig the rotator. If resistace is ecoutered, stop, remove, ad realig the rotator before attemptig to isert the rotator agai. Retest leaflet motio after rotatio. If free leaflet motio caot be achieved, remove the valve. 9.7 Valve Orietatio Aortic: Based o cliical studies, there is o preferred orietatio for the Aortic O-X Prosthetic Heart Valves with the stadard, Coform-X, or Aatomic sewig rig cofiguratios. CAUTION: Oce the valve is implated, visually cofirm that the coroary ostia are free from potetial iterferece. Mitral: Literature suggests that the pivot axis of the mitral valve should be positioed ati-aatomically. Refer to Figure 16. Figure 16. Pivot axis of the mitral valve positioed atiaatomically Mitral Stadard ad Coform-X 10. POSTOPERATIVE INFORMATION 10.1 Magetic Resoace Imagig (MRI Compatibility MR Coditioal: The O-X Prosthetic Heart Valve, Mitral Coform-X Heart Valve Prosthesis, Size 25-33*, was determied to be MRcoditioal accordig to the termiology specified i the America Society for Testig ad Materials (ASTM Iteratioal, Desigatio: F Stadard Practice for Markig Medical Devices ad Other Items for Safety i the Magetic Resoace Eviromet. ASTM Iteratioal, 100 Barr Harbor Drive, PO Box C700, West Coshohocke, Pesylvaia. No-cliical testig demostrated that the O-X Mitral Coform-X Heart Valve Prosthesis, Size 25-33, is MR Coditioal. A patiet with this device ca be scaed safely immediately after placemet uder the followig coditios: Static Magetic Field: Static magetic field of 3-Tesla or less O-X Prosthetic Heart Valve Istructios for Use 12

13 Maximum spatial gradiet magetic field of 720-Gauss/cm or less MRI-Related Heatig: I o-cliical testig, the O-X Prosthetic Heart Valve, Mitral Coform-X Heart Valve Prosthesis, Size 25-33, produced the followig temperature rise durig MRI performed for 15-mi of scaig (i.e., per pulse sequece i the 3-Tesla (3-Tesla/128-MHz, Excite, HDx, Software 14X.M5, Geeral Electric Healthcare, Milwaukee, WI MR system: Highest temperature chage +1.6 C Therefore, the MRI-related heatig experimets for the O-X Mitral Coform-X Heart Valve Prosthesis, Size 25-33, at 3-Tesla, usig a trasmit/receive RF body coil at a MR system reported whole body averaged SAR of 2.9-W/ kg (i.e., associated with a calorimetry measured whole body averaged value of 2.7-W/kg, idicated that the greatest amout of heatig that occurred i associatio with these specific coditios was equal to or less tha +1.6 C. Artifact Iformatio: MR image quality may be compromised if the area of iterest is i the exact same area or relatively close to the positio of the O-X Mitral Coform-X Heart Valve Prosthesis, Size Therefore, optimizatio of MR imagig parameters to compesate for the presece of this device may be ecessary. *The MRI fidigs apply to this specific largest heart valve prosthesis ad all other smaller sizes which are made from similar materials. Pulse Sequece Sigal Void Size (mm2 Plae Orietatio T1-SE 1,090 Parallel T1-SE 686 Perpedicular GRE 1,478 Parallel GRE 1,014 Perpedicular 10.2 Retured Goods Prior authorizatio from O-XLTI Customer Service is required for the retur of ay product. For ay questios regardig the valve or for retur authorizatio, please cotact Customer Service. Licesed uder U.S. Patet Nos. 5,308,361; 5,137,532; 5,545,216; 5,772,694; 5,641,324; 5,908,452; 5,284,676; 5,305,554; 5,328,713, 5,332,337; 5,336,259; 5,514,410; 5,677,061; 6,096,075; Serial No. 09/010,449 allowed; Serial No. 09/224,816 allowed; ad other permits ad patets pedig. 11. PATIENT INFORMATION 11.1 Patiet Registratio I each valve package, there is a Patiet Record Card ad a Implat Registratio Card. O-XLTI requests that the Implat Registratio Card be filled out immediately ad that the mailig copy be retured to O-XLTI Customer Service. For multiple valve implats, please fill out a card for each valve. O-XLTI will use these data for otificatio purposes ad to help with ivetory restockig i the hospital. All patiet iformatio remais strictly cofidetial, ad the release of patietidetifyig iformatio ca be refused if allowed by law Patiet Record Card A Patiet Record Card is provided with the prosthesis. Patiets should be ecouraged to complete the card ad carry it with them at all times Patiet Iformatio Booklet O-XLTI has made available a patiet iformatio booklet that the physicia may choose to provide to the patiet prior to discharge. Copies of this booklet are available o request from your O-XLTI sales represetative. 12. DISCLAIMER OF WARRANTIES Because of the complicatios listed previously that may occur with the use of ay heart valve prosthesis ad the possibilities of damage, also oted previously, before, durig or after implatatio, O-XLTI warrats oly that the product shall coform to O-XLTI s stadard specificatios. No other warraty is made by O-XLTI cocerig the fuctio of the product i use, ad O-XLTI assumes o risk whatsoever as to the results of the use of this product. The etire risk with use of the product is that of the buyer. O-XLTI disclaims all other warraties, respectig the product, expressed or implied, icludig but ot limited to those related to the product s merchatability or fitess for a particular purpose. O-XLTI shall ot be liable for ay direct, special, cosequetial or icidetal loss, damage or expese related to the use of the product. No perso has ay authority to alter ay of these coditios or to bid O-XLTI to ay additioal resposibility or warraty i coectio with the use of the product. O-X Prosthetic Heart Valve Istructios for Use 13

14 APPENDIX A Cliical iformatio as required by FDA (USA 1. ADVERSE EVENTS I the Europea premarket study a total of 184 aortic O-X Prosthetic Heart Valves were implated i 184 patiets at 11 ceters. The mea follow-up was 2.2 years (rage of 0 to 4.0 years with a total of patiet-years. I the mitral positio 229 valves were implated i 229 patiets at 16 ceters. Mea mitral follow-up was 1.8 years (rage of 0 to 4.5 years with a total of patietyears. I aortic patiets, a total of 7 deaths occurred durig the study ad 2 of these were characterized as valve-related. The causes of the aortic valve-related deaths were early thromboembolism (1 patiet ad sudde, uexplaied death (1 patiet. I mitral patiets, a total of 18 deaths occurred durig the study ad 3 of these were characterized as valve-related. The causes of the mitral valve-related deaths were early, ucotrolled bleedig (1 patiet ad sudde, uexplaied death (2 patiets. 1.1 Observed Adverse Evets Adverse evets were reported i the cliical study as show i Tables 3 ad 4 2. CLINICAL STUDIES 2.1 Premarket Trials The O-X Prosthetic Heart Valve premarket cliical trials were desiged to study the safety ad effectiveess of the valve i aortic ad mitral valve replacemet. Patiets requirig isolated aortic heart valve replacemet were erolled from 1996 to 2000 at 11 ceters i a iteratioal multiceter, prospective, o-radomized study with retrospective cotrols. Patiets requirig isolated mitral heart valve replacemet were erolled from 1996 to 2001 at 16 ceters i a iteratioal multiceter, prospective, o-radomized study with retrospective cotrols. The aortic cohort icluded 184 patiets (121 me, 63 wome, aged from 20 to 80 years (mea of 60.2 years. The cumulative follow-up was patiet-years with a mea follow-up of 2.2 years (SD = 0.8 years, rage = 0 to 4.0 years. The mitral cohort icluded 229 patiets (86 me, 143 wome, aged from 21 to 78 years (mea of 59.2 years. The cumulative follow-up was patiet-years with a mea follow-up of 1.8 years (SD = 1.3 years, rage = 0 to 4.5 years. Tables 5 ad 6 preset preoperative ad operative patiet demographics. Chart 1 shows the umber of patiets implated versus duratio of followup. Table 7 presets implat iformatio by valve size, icludig the umber of patiets implated ad the umber of patiet-years. Safety edpoits captured i the studies were complicatios; blood aalyses were used to cofirm the absece or presece of certai complicatios. Safety results are provided i Tables 3 ad 4. Effectiveess edpoits were New York Heart Associatio (NYHA classificatio ad echocardiographic assessmets. NYHA ad blood data were obtaied pre-operatively, itra-operatively, ad post-operatively at 3 to 6 moths, at oe year, ad aually thereafter. Hemodyamic data were obtaied at discharge ad at oe year. Tables 8 ad 9 preset these effectiveess results. 2.2 Postmarket Trial of Lower Target Aticoagulatio The Prospective Radomized O-X Aticoagulatio Cliical Trial (PROACT was desiged to evaluate whether it is safe ad effective to treat patiets implated with the O-X Prosthetic Heart Valve with less aggressive aticoagulat therapy tha curretly recommeded by the America College of Cardiology/ America Heart Associatio (ACC/AHA or America College of Chest Physicias (ACCP guidelies for patiets receivig a bileaflet mechaical valve prosthesis. The first cohort to complete erollmet ad aalysis was used to compare stadard aticoagulat therapy versus iteratioal ormalized ratio (INR goal of 1.5 to 2.0 i high-risk patiets requirig aortic valve replacemet (AVR. Study Desig ad Patiet Selectio The high-risk AVR arm of the PROACT study was a prospective, radomized, ublided, cotrolled trial comparig the outcomes after AVR with the O-X valve. It was a multiceter trial cosistig of 36 ceters i North America, of which 35 ceters were i the Uited States ad 1 ceter was i Caada. A total of 425 patiets were recruited i this cohort for AVR i patiets at high risk for valve thrombosis ad thromboembolism. Erollmet bega i Jue 2006 ad was closed for the high-risk AVR group i October Follow-up data through September 1, 2014 were available for this report. The primary edpoits were the rates of valve thrombosis, thromboembolism, bleedig, reoperatio, explat ad all-cause ad valve-related mortality, as defied by the Society of Thoracic Surgeos/America Associatio for Thoracic Surgery (STS/AATS guidelies for valve studies. No-iferiority betwee the 2 groups was to be evaluated usig the composite of valve thrombosis, thromboembolism, ad bleedig rate, ad a oiferiority margi of 1.5% (absolute. The sample size estimatio was determied usig a 1-sided proportio test with a type I error of 0.05 ad power of 80% to test the o-iferiority hypothesis. Patiet Iclusio Criteria The patiet iclusio criteria were as follows: 1. Patiets with a cliical idicatio for isolated AVR O-X Prosthetic Heart Valve Istructios for Use 14

15 2. Patiets with the followig coditios, which place a patiet i the "high-risk" group: chroic atrial fibrillatio, left vetricular ejectio fractio < 30%, elarged left atrium > 50 mm i diameter, spotaeous echocardiographic cotrasts i the left atrium, vascular pathologic features, eurologic evets, hypercoagulability (defied below, left or right vetricular aeurysm, lack of a platelet respose to aspiri or clopidogrel, ad wome receivig estroge replacemet therapy. 3. Cocomitat cardiac surgery, icludig coroary artery bypass graftig, mitral or tricuspid valve repair, ascedig aortic replacemet, ad maze procedure, was allowed 4. Adult patiets (at least 18 years old Patiet Exclusio Criteria The key patiet exclusio criteria were as follows: 1. Right-sided valve replacemet 2. Double (aortic plus mitral valve replacemet 3. Patiets with active edocarditis at the time of implatatio 4. Previous cofirmed or suspected thromboembolic evet or thrombophlebitis occurrig or resolvig withi the last year prior to erollmet 5. Patiets who are i a emergecy state Hypercoagulability i the AVR patiets was defied by the followig blood tests doe preoperatively ad before the iitiatio of warfari therapy: activated protei C resistace (factor V Leide mutatio, prothrombi mutatio, atithrombi III activity, protei C activity, protei S activity, factor VIII activity, ad lowdesity lipoprotei cholesterol. Resistace to aspiri or clopidogrel i AVR patiets was defied from cliical laboratory test results: urie 11-dehydro-thromboxae B2 (later chaged to blood thromboxae A2 for aspiri ad ihibitio of P2Y12 for clopidogrel. Radomizatio to Test ad Cotrol Groups All patiets received routie warfari with a target INR of 2.0 to 3.0, plus aspiri 81 mg daily for the first 3 postoperative moths. At 90 days postoperatively, radomizatio was performed usig a stadard radomizatio Mersee Twister algorithm through a o-lie radomizatio module. Test group: For the first 3 postoperative moths, warfari at a INR target of 2.0 to 3.0 with aspiri 81 mg/ day was used. After 3 moths, the warfari dose was reduced to a INR target of 1.5 to 2.0, with aspiri 81 mg/ day. Cotrol group: Postoperatively, warfari at a INR target of 2.0 to 3.0 with aspiri 81 mg/day was used throughout the study period. Ay patiet i the test group who experieced a thromboembolism evet was crossed over to stadard aticoagulatio therapy (INR, plus aspiri 81 mg/ day, although such patiets remaied i the test group by itetio-to-treat. Primary Edpoits The primary edpoits icluded major bleedig evets, mior bleedig evets, trasiet ischemic attack (TIA, ischemic stroke, peripheral thromboembolism, valve thrombosis, the composite of these evets, reoperatio, explat, ad all-cause ad valve-related mortality. Secodary Edpoits The secodary edpoits icluded edocarditis, hemolysis, hemolytic aemia, paravalvular leak, structural ad ostructural dysfuctio, postoperative New York Heart Associatio fuctioal class, ad echocardiographic hemodyamics (peak gradiet, mea gradiet, effective orifice area, ad valvular regurgitatio. Follow-up Schedule The patiets were followed up by i-perso visits to the study sites at 3 moths, 6 moths, ad 1 year after surgery ad the aually for 2 to 5 ad as much as 8 postoperative years to accrue the ecessary 800 patietyears of follow-up madated by the FDA. Durig these visits, electrocardiography or echocardiography was performed as required by the protocol ad as cliically idicated. All patiets maitaied with warfari therapy were followed up usig weekly home INR testig through a cetral telephoe or olie database. The follow-up period was through September 1, 2014 ad was complete i 98% of patiets. INR Maagemet All patiets received a home INR moitor at radomizatio. The INR cotrol was maitaied usig weekly home testig, with warfari dose adjustmets made by the cliical sites to miimize INR variability ad maximize the time i the INR target rage. Compliace to home moitorig was determied by the frequecy of the tests coducted mothly. Statistical Aalysis The descriptive statistics, icludig mea ad stadard deviatio, were reported for the umeric measures. Early adverse evets were those occurrig before radomizatio ad were calculated as percetages. Late (post-radomizatio liearized adverse evet rates i %/ patiet-year (pt-yr were calculated based o the safety populatio icludig all patiets who had received at least 1 dose of the study drug. Kapla-Meier life table curves were calculated for time to evet data, from the poit of radomizatio to the first evet The aalyses O-X Prosthetic Heart Valve Istructios for Use 15

16 were performed usig Statistical Aalysis Systems statistical software, versio 9.2 (SAS Istitute, Cary, NC. RESULTS From Jue 2006 to October 2009, 425 patiets were erolled i the high-risk AVR arm of the PROACT trial. Of these 425 patiets, 185 were radomized after 3 postoperative moths to the test group ad 190 were radomized to the cotrol group. The follow-up period averaged 3.82 years through September 1, 2014 (878.6 pt-yrs for the cotrol group ad pt-yrs for the test group. The remaiig 50 patiets were removed from the trial before radomizatio for the followig reasos: death ( = 8, adverse evet exclusio by protocol ( = l0, differet or o surgery performed ( = 14, withdrawal by patiet or physicia ( = 11, protocol criterio exclusio ( = 3, explatatio ( = 1, ad lost to follow-up ( = 3. The mea age at surgery was 55.8 ± 12.0 years (rage, for the cotrol group ad 54.1 ± 13.0 years (rage, for the test group (p =.187. I the cotrol ad test groups, 81% ad 80% of the patiets were me, respectively (p =.898. Comparisos betwee the 2 groups for ative valve pathologic features, valve lesio, preoperative New York Heart Associatio fuctioal classificatio, cliical risk factors, ad abormal laboratory test results are listed i Table 10. No statistically sigificat differeces were foud. The patiets were cosidered miimally compliat if their frequecy of testig was at least twice mothly, approximately twice as ofte as covetioal INR moitorig i a cliicia outpatiet office. The patiets were cosidered fully compliat whe their frequecy of testig was 2-3 times mothly. Ideal home moitorig would have resulted i a average iterval betwee the tests of 7 days. I the preset study, the average iterval betwee tests was 9 days i both groups. More tha 80% of the patiets were miimally compliat with the home moitorig procedures, >20% were ideally compliat, ad 96% of all patiets at least attempted to coduct home testig oce. Fially, 4% of patiets refused home INR moitorig altogether ad were moitored by their local physicias at cliic visits. The mea INR was l.89 ± 0.49 (media 1.80 for the test patiets (target, ad 2.50 ± 0.63(media 2.40 for the cotrol patiets (target, Figure 17 shows the distributio of INR measuremets by group, demostratig the lower INR levels maitaied i the test group. The percetage of INR measuremets i the target rage was 64.1% for the test group ad 70.4% for the cotrol group. The test group i-rage percetage was similar to that of the cotrol group, despite the arrower target rage. The mea ad media INR were withi the target rage for both groups. The percetage of readigs >3.0 or <l.5 was 17.3% i the cotrol group ad 13.5% i the test group, respectively. The results of the primary edpoit evets are preseted i Table 11. The liearized late evet rates showed that the test group experieced lower evet rates i both major ad mior bleedig. The rates of thrombotic evets betwee the 2 groups Figure 17. INR Distributios 60% 50% 40% Percet 30% 20% Cotrol Treatmet 10% 0% O-X Prosthetic Heart Valve Istructios for Use 16

17 appeared to be similar. The differece i bleedig evets betwee the 2 groups was oticeably i favor of the test group. Also, the mortality rates betwee the 2 groups were similar; the rates of other secodary valverelated evets ot show i Table 11 were all <1 %/pt-yr ad were also similar betwee the 2 groups. Before radomizatio, 4 patiets had died withi the first 30 days ad 4 more had died betwee 30 ad 90 days. The 4 early deaths were from cardiogeic shock, multiorga failure, bivetricular failure, ad atheroembolic shower leadig to real failure; all occurred withi 2 days of surgery. The 4 deaths occurrig at 30 to 90 postoperative days were from sudde death of ukow cause, prosthetic edocarditis, cerebral hemorrhage, ad arrhythmia. After radomizatio, the icidece of sudde death was similar i both groups (3 i each group. There were 3 cardiac deaths i the cotrol group ad oe i the test group. Valve-related deaths icluded 2 cerebral bleedig evets ad 1 gastroitestial bleedig evet i the cotrol group ad 1 ischemic stroke ad 1 cerebral bleedig evet i the test group. The remaiig late deaths were determied by idepedet adjudicatio to be ot valve-related ad there were 7 i each group. A qualitative evaluatio of reoperatio ad explats revealed that the types ad causes of the reoperatios ad explats were similar betwee the 2 groups. Before radomizatio, the most commo surgical procedure was re-exploratio for perioperative bleedig, which occurred 22 times (5.2% of 425 patiets, or about oe half of all perioperative bleedig evets. New pacemaker isertio withi 14 days was the secod most commo procedure ad occurred i 19 patiets (4.5% of 425 patiets. Other early procedures were for gastroitestial bleedig, prosthetic edocarditis, steral rewirig, ad a occult pregacy; each occurred oce. After radomizatio, valve-related reoperatios were related to prosthetic edocarditis, paravalvular leak, thrombosis, peripheral thrombectomy, bleedig, ad heart trasplatatio. Overall, the rate of postradomizatio reoperatios was 0.46%/pt-yr for the cotrol group ad 0.91%/pt-yr for the test group, ad the rate of explats was 0.34% i the cotrol group ad 0.91% i the test group The types ad umbers of reoperatios ad explats are similar betwee groups. TIA was defied as a eurologic deficit lastig 3 days. Seve (7 TIAs occurred i the cotrol group, with a average duratio of 1.6 days, ad 11 i the test group, averagig 1 day i duratio. These were all short-duratio blidess, umbess, weakess, or tiglig i patiets whose computed tomography or magetic resoace imagig scas showed o circulatio abormality or ew cerebral ifarctio. Seve (7 ischemic strokes occurred i the cotrol group ad 6 occurred i the test group. Of these, 3 each i the cotrol ad test groups had resolved withi 3 days but the computed tomography ad magetic resoace imagig results were positive. Four (4 cotrol patiets ad 2 test patiets experieced a permaet eurologic deficit, ad 1 test patiet died of stroke o the secod postoperative day. The icideces of eurologic thromboembolism evets i the 2 groups were similar as show i Table 11. Valve thrombosis was qualitatively differet from thromboembolism i that all 4 valve thrombosis evets occurred i patiets who had stopped takig warfari agaist medical advice. These cases were maaged by valve explatatio (1 cotrol ad 1 test, 1 thrombectomy, ad 1 spotaeous resolutio with the re-admiistratio of warfari. All 4 patiets recovered. Of the primary edpoit evets i the cotrol ad test groups combied, 46 were major bleedig evets, 44 were mior bleedig evets, 13 were ischemic strokes, ad 18 were TIAs. Major bleedig evets were further classified ito 5 cerebral bleedig evets, 27 gastroitestial bleedig evets, 3 hematomas, 2 osebleeds, ad 9 other bleedig evets. Cerebral bleedig evets resulted i 3 deaths ad 2 permaet deficits. Ischemic strokes resulted i 1 death ad 6 permaet deficits; 6 patiets recovered fully withi <3 days. Table 11 stratifies the bleedig ad cerebral evets ito those i the cotrol group ad those i the test group. To test the study hypotheses, aalyses of o-iferiority were coducted ad are show i Table 12. These aalyses establish that the test group is o-iferior to the cotrol group with a o-iferiority margi of 1.5% applied. Comparisos to Objective Performace Criteria (OPC were also required by the protocol ad are show i Table 13. The study was cosidered successful if the OPC evet rates must be less tha twice the correspodig OPC, which ca be see i the table. O-X Prosthetic Heart Valve Istructios for Use 17