fda guidance for heart valve replacement
TRANSCRIPT
Draft Guidance for Industry and FDA
Staff !
Heart Valves - Investigational Device
Exemption (IDE) and Premarket
Approval (PMA) Applications
DRAFT GUIDANCE !
This guidance document is being distributed for comment purposes only.!!
Document issued on: January 20, 2010
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U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Circulatory Support and Prosthetic Devices Branch
Division of Cardiovascular Devices
Office of Device Evaluation
Contains Nonbinding Recommendations !
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Preface
Additional Copies!
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Contains Nonbinding Recommendations !
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Table of Contents
I.! INTRODUCTION.........................................................................................................................................1!
II.! BACKGROUND............................................................................................................................................2!
III.! SCOPE ...........................................................................................................................................................2!
IV.! RISK ANALYSIS..........................................................................................................................................3!
V.! THE PRE-SUBMISSION PROCESS..........................................................................................................4!
VI.! IDE AND PMA APPLICATIONS: GENERAL CONSIDERATIONS...................................................4!
VII.! TERMS AND DEFINITIONS......................................................................................................................5!
VIII.! DEVICE DESCRIPTION.............................................................................................................................5!
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IX.! PYROGENICITY .........................................................................................................................................8!
X.! STERILIZATION.........................................................................................................................................8!
XI.! PRECLINICAL IN VITRO ASSESSMENT .............................................................................................10!
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XII.! PRECLINICAL ANIMAL STUDIES .......................................................................................................14!
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XIII.! CLINICAL INVESTIGATIONS ...............................................................................................................18!
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Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
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XIV.! PMA SUPPLEMENTS ...............................................................................................................................25!
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XV.! PROFESSIONAL LABELING..................................................................................................................26!
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XVI.! PATIENT LABELING...............................................................................................................................27!
APPENDIX A. SHELF LIFE VALIDATION........................................................................................................28!
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APPENDIX B. CAVITATION TESTING FOR RIGID HEART VALVES.......................................................32!
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APPENDIX C. BERNOULLI VERIFICATION...................................................................................................34!
APPENDIX D. ECHOCARDIOGRAPHY PROTOCOL.....................................................................................35!
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Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
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Draft Guidance for Industry and FDA Staff !
Heart Valves - Investigational Device Exemption
(IDE) and Premarket Approval (PMA)
Applications !
This draft guidance, when finalized, will represent the Food and Drug Administration's
(FDA's) current thinking on this topic. It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public. You can use an alternative approach
if the approach satisfies the requirements of the applicable statutes and regulations. If you
want to discuss an alternative approach, contact the FDA staff responsible for implementing
this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
I. Introduction !
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Contains Nonbinding Recommendations !
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Classification
(21 CFR)
Class Product
Code
Description
MT6:D5LE! UUU! <WS! J%82)1%$%&'!/%).'!9)29%!
†! UUU! Icd! @%).'!9)29%G!$%1/)&-1)2!
† UUU! IcJ! @%).'!9)29%G!&#&C)22#,.)0'!'-((+%!
†J%P+-.%(!8.%$).=%'!)88.#9)2!)882-1)'-#&!3%0#.%!$).=%'-&,!?(%%!(%1'-#&!EKD?)F!#0!'/%!A%*%.)2!
A##*G!<.+,G!)&*!"#($%'-1!B1'!?LK!`:;:":!DH61?)FFF:!
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\/%!.%1#$$%&*)'-#&(!-&!'/-(!*#1+$%&'!$)7!)2(#!)8827!'#!&%4!'78%(!#0!/%).'!9)29%(!?%:,:G!'-((+%C
%&,-&%%.%*!9)29%(G!8#27$%.!2%)02%'!9)29%(F:!!!
!
\/-(!,+-*)&1%!)2(#!)882-%(!'#!8%.1+')&%#+(27!*%2-9%.%*!9)29%(k!/#4%9%.G!*-00%.%&'!#.!)**-'-#&)2!*5'
6*,$19'*5'6*61'8.%12-&-1)2G!)&*!12-&-1)2!('+*-%(!$)7!3%!)88.#8.-)'%!0#.!(+1/!*%9-1%(G!*%8%&*-&,!#&!
'/%!(8%1-0-1!*%9-1%!*%(-,&G!'/%!8.#8#(%*!-&*-1)'-#&(!0#.!+(%G!)&*!'/%!.%(+2'(!#0!7#+.!.-(=!)&)27(-(:Z!!
c%!.%1#$$%&*!7#+!1#&')1'!'/%!"-.1+2)'#.7!)&*![.#('/%'-1(!<%9-1%(!_.)&1/!'#!*-(1+((!82)&&%*!
(+3$-((-#&(!0#.!8%.1+')&%#+(27!*%2-9%.%*!9)29%(:!
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\/-(!,+-*)&1%!*#%(!&#'!)8827!'#!9)29%C.%8)-.!*%9-1%(!?%:,:G!)&&+2#82)('7!.-&,(!?8.#*+1'!1#*%!
]J@G!MT6:DM66FE!#.!$-'.)2!9)29%!.%8)-.!*%9-1%(!?8.#*+1'!1#*%!^]>FF:!!
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\/-(!,+-*)&1%!*#%(!&#'!)8827!'#!)22#,.)0'!/%).'!9)29%(:!![2%)(%!1#&')1'!A<Bf(!"%&'%.!0#.!
_-#2#,-1(G!S9)2+)'-#&!)&*!J%(%).1/!?"_SJF!0#.!-&0#.$)'-#&!)3#+'!'/%!.%,+2)'#.7!.%P+-.%$%&'(!
0#.!)22#,.)0'!/%).'!9)29%(:H!!!
!
\/-(!,+-*)&1%!*#%(!&#'!)8827!'#!$#.%!'/)&!$-&-$)227!$)&-8+2)'%*!)22#,.)0'!/%).'!9)29%(!?8.#*+1'!
1#*%!R@BFG!4/-1/!.%P+-.%!12%).)&1%!#0!)!EK6?=F!8.-#.!'#!$).=%'-&,:!!!
!
IV. Risk Analysis
J-(=!)&)27(-(!-(!)!0#.$)2!8.#1%*+.%!37!4/-1/!7#+!%('-$)'%!'/%!8.#3)3-2-'7!)&*!*%,.%%!#0!/).$!)!
*%9-1%!.%8.%(%&'(G!)&*!82)&!)88.#8.-)'%!-&9%('-,)'-#&(!)11#.*-&,27!'#!$-'-,)'%!'/#(%!.-(=(!'#!'/%!
%Y'%&'!8#((-32%:!!c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!)!.-(=!)&)27(-(!)(!*%(1.-3%*!-&!U;R!EMZ6NL66E!
#.!-'(!%P+-9)2%&'!?%:,:G!/)g).*!-*%&'-0-1)'-#&G!)((#1-)'%*!0)-2+.%!$#*%(G!.-(=!%('-$)'-#&G!.-(=!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Z!A#.!.%1#$$%&*)'-#&(!'/)'!$)7!3%!)882-1)32%!'#!('+*-%(!#0!*%2-9%.7!(7('%$(!0#.!8%.1+')&%#+(27!
*%2-9%.%*!9)29%(G!(%%!'/%!(%1'-#&(!.%2)'%*!'#!*%2-9%.7!(7('%$!'%('-&,!*%(1.-3%*!-&!'/%!A<B!
,+-*)&1%G!Non-Clinical Tests and Recommended Labeling for Intravascular Stents and
Associated Delivery Systems!)'!
/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6
TKMHD:/'$:! !E!;%%!'/%!A<B!,+-*)&1%G!Guidance for Annuloplasty Rings 510(k) Submissions!)'!
/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6
TDHZZ:/'$:! !H!;%%!/''8NOO444:0*):,#9O13%.O'-((:/'$:!
! D
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
%9)2+)'-#&G!.-(=!1#&'.#2G!)&*!.-(=!.%9-%4F:!!W#+.!U<S!)882-1)'-#&(!(/#+2*!-&12+*%!7#+.!-&-'-)2!.-(=!
)&)27(-(!0#.!7#+.!*%9-1%!)&*!7#+.![>B!(/#+2*!-&12+*%!)&!+8*)'%*!.-(=!)&)27(-(:!!!
V. The Pre-Submission Process
\#!+(%!'/-(!,+-*)&1%!%00%1'-9%27G!4%!%&1#+.),%!7#+!'#!/)9%!0.%P+%&'!)&*!%).27!-&'%.)1'-#&!4-'/!
A<B!.%9-%4%.(:!!c%!)2(#!%&1#+.),%!7#+!'#!+(%!A<Bj(!8.%C(+3$-((-#&!8.#1%*+.%!0#.!'/-(!
-&'%.)1'-#&:!!\/%!8+.8#(%!#0!)!8.%C(+3$-((-#&!-&'%.)1'-#&!-(!'#!8.#9-*%!)!$%1/)&-($!0#.!7#+!)&*!
A<B!'#!1#$$+&-1)'%!-&0#.$)227!)3#+'!8.%12-&-1)2!('+*-%(!?-:%:G!3%&1/!)&*O#.!)&-$)2F!3%0#.%!7#+!
1#&*+1'!'/%(%!('+*-%(G!#.!)3#+'!)!12-&-1)2!8.#'#1#2!3%0#.%!7#+!(+3$-'!)&!U<S!)882-1)'-#&:!!W#+.!
8.%C(+3$-((-#&!(/#+2*!-&12+*%!)!*%(1.-8'-#&!#0!'/%!*%9-1%G!-'(!-&'%&*%*!+(%G!)&*!)!.-(=!)&)27(-(:!!
W#+.!8.%C(+3$-((-#&!(/#+2*!)2(#!-&12+*%!(+$$).-%(!#0!7#+.!8.#8#(%*!'%('!82)&G!8.#'#1#2(G!)&*!
-&9%('-,)'-#&)2!82)&(:!!U&!)**-'-#&G!7#+.!8.%C(+3$-((-#&!(/#+2*!1#&')-&!12%).27!*%0-&%*!P+%('-#&(!
0#.!*-(1+((-#&!4-'/!A<B:!!W#+!(/#+2*!-&12+*%!8-1'+.%(G!(2-*%(G!9-*%#(G!#.!()$82%(G!-0!7#+!3%2-%9%!
'/%7!).%!+(%0+2!'#!+&*%.(')&*!7#+.!*%9-1%:!
!
VI. IDE and PMA Applications: General Considerations
"2-&-1)2!('+*-%(!1#&*+1'%*!-&!'/%!`&-'%*!;')'%(!-&!(+88#.'!#0!)![>B!)88.#9)2!$+('!3%!1#&*+1'%*!
+&*%.!'/%!U&9%('-,)'-#&)2!<%9-1%!SY%$8'-#&(!?U<SF!.%,+2)'-#&G!LK!"AJ![).'!MKL:!!A<B!3%2-%9%(!
*%9-1%(!)**.%((%*!37!'/-(!,+-*)&1%!*#1+$%&'!).%!(-,&-0-1)&'!.-(=!*%9-1%(!)(!*%0-&%*!-&!LK!"AJ!
MKL:D?$F:T!!U&!)**-'-#&!'#!'/%!.%P+-.%$%&'!#0!/)9-&,!)!A<BC)88.#9%*!U<SG!(8#&(#.(!$+('!
1#$827!4-'/!'/%!.%,+2)'-#&(!,#9%.&-&,!-&('-'+'-#&)2!.%9-%4!3#).*(!?LK!"AJ![).'!EHF!)&*!
-&0#.$%*!1#&(%&'!?LK!"AJ![).'!E6F:!
!
W#+.!U<S!)882-1)'-#&!$+('!-&12+*%!)!1#$82%'%!.%8#.'!#0!8.-#.!-&9%('-,)'-#&(!#0!'/%!*%9-1%!
-&12+*-&,!)22!8.-#.!12-&-1)2G!)&-$)2!)&*!2)3#.)'#.7!'%('-&,!?LK!"AJ!MKL:L6!?3F?LF!)&*!MKL:LT?)FF:!!
B!1#$82%'%!.%8#.'!4#+2*!-&12+*%!*5'6*,$1!2)3#.)'#.7!'%('-&,!.%(+2'(G!*5'6*61!)&-$)2!('+*7!'%('-&,!
.%(+2'(G!)&*!'/%!8.#'#1#2(!0#.!'/%!12-&-1)2!-&9%('-,)'-#&(!0#.!8.-#.!-&9%('-,)'-#&(:!!
!
U&!,%&%.)2G!4%!.%1#$$%&*!'/)'!7#+!1#$82%'%!*5'6*,$1!'%('-&,!#0!7#+.!.%82)1%$%&'!/%).'!9)29%!
3%0#.%!7#+!(+3$-'!7#+.!U<S:!!U'!$)7!3%!)88.#8.-)'%G!/#4%9%.G!'#!1#$82%'%!1%.')-&!2#&,C'%.$!*5'
6*,$1!'%('(!4/-2%!7#+!1#&*+1'!7#+.!12-&-1)2!('+*7:!!W#+!(/#+2*!*-(1+((!7#+.!.)'-#&)2%!0#.!
(+3$-((-#&!#0!)&7!'%('(!0#.!4/-1/!'%('-&,!-(!&#'!1#$82%'%!4-'/!'/%!.%9-%4!3.)&1/!3%0#.%!
(+3$-''-&,!7#+.!U<S:!!c%!3%2-%9%!'/)'!-&!)22!1)(%(!7#+!(/#+2*!1#$82%'%!7#+.!)11%2%.)'%*!4%).!
'%('-&,!3%0#.%!7#+!(+3$-'!7#+.!U<S:!!!
!
W#+.![>B!)882-1)'-#&!$+('!1#&')-&!*)')!)&*!-&0#.$)'-#&!-&!(+00-1-%&'!*%')-2!'#!8%.$-'!A<B!'#!
)88.#9%!#.!*%&7!)88.#9)2!#0!'/%!)882-1)'-#&G!-&12+*-&,!'/%!$%'/#*(!)&*!8.#'#1#2(!+(%*!-&!12-&-1)2!
-&9%('-,)'-#&(!-&9#29-&,!/+$)&!(+3l%1'(!?LK!"AJ!MKZ:L6?3F?HFF:!!W#+!$+('!8.#9-*%!'/%!.%(+2'(!
0.#$!)22!8.%12-&-1)2!*5'6*,$1G!8.%12-&-1)2!*5'6*61G!)&*!12-&-1)2!'%('-&,!7#+!/)9%!1#&*+1'%*:!!U*:!!
!
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!T!;%%!/''8NOO444:0*):,#9O#1O#/.'O-.3(O*%9-1%(:/'$2m.-(=:!
! Z
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
VII. Terms and Definitions
c%!.%1#$$%&*!'/)'!7#+!+(%!'/%!'%.$(!)&*!*%0-&-'-#&(!*%0-&%*!-&!U;R!EMZ6NL66E!4/%&!8.%8).-&,!
U<S(!)&*![>B(!0#.!.%82)1%$%&'!/%).'!9)29%(:!!U&!)**-'-#&G!A<B!+(%(!'/%!0#22#4-&,!'%.$(N!!!
!
Replacement Heart Valve:!!B2'/#+,/!U;R!EMZ6NL66E!+(%(!'/%!'%.$!h/%).'!9)29%!(+3('-'+'%i!
'#!$%)&!)!8.#('/%'-1!/%).'!9)29%G!4%!+(%!'/%!'%.$!h.%82)1%$%&'!/%).'!9)29%i!-&!LK!"AJ!
MT6:D5LE!)&*!-&!'/-(!,+-*)&1%:!!c%!+&*%.(')&*!'/%!'%.$!h.%82)1%$%&'!/%).'!9)29%i!'#!3%!
%P+-9)2%&'!'#!h/%).'!9)29%!(+3('-'+'%i!?+(%*!-&!U;R!EMZ6NL66EF!)&*!%P+-9)2%&'!'#!(+1/!'%.$(!
)(!h8.#('/%'-1!/%).'!9)29%i!)&*!h/%).'!9)29%!-$82)&'i!0#.!8+.8#(%(!#0!'/-(!,+-*)&1%:!
!
Pressure Gradient:!!B2'/#+,/!U;R!EMZ6NL66E!+(%(!'/%!'%.$(!h$%)&!8.%((+.%!*-00%.%&1%i!
)&*!h8%)=!8.%((+.%!*-00%.%&1%Gi!4%!+(%!'/%!'%.$!h$%)&!8.%((+.%!,.)*-%&'i!-&!'/-(!,+-*)&1%!
-&('%)*!#0!h$%)&!8.%((+.%!*-00%.%&1%i!)&*!'/%!'%.$!h8%)=!8.%((+.%!,.)*-%&'i!-&!'/-(!,+-*)&1%!
-&('%)*!#0!h8%)=!8.%((+.%!*-00%.%&1%i!3%1)+(%!'/%!'%.$!h8.%((+.%!,.)*-%&'i!-(!+(%*!)2$#('!
%Y12+(-9%27!-&!'/%!`:;:!12-&-1)2!).%&)!)&*!-&!'/%!4#.2*4-*%!12-&-1)2!/%).'!9)29%!2-'%.)'+.%:!!c%!
.%1#,&-g%!'/)'!'/%!'%.$!h8.%((+.%!,.)*-%&'i!/)(!)!9%.7!(8%1-0-1!*%0-&-'-#&!-&!%&,-&%%.-&,!?-:%:G!
8.%((+.%O*-(')&1%F!'/)'!-(!&#'!1#&(-('%&'!4-'/!'/%!+(%!#0!'/-(!'%.$!-&!'/-(!,+-*)&1%:!
!
Tissue Annulus Diameter:!!\/%!'-((+%!)&&+2+(!*-)$%'%.!?\B<F!-(!*%0-&%*!-&!U;R!EMZ6NL66E!
)(!'/%!*-)$%'%.!-&!$-22-$%'%.(!)'!'/%!($)22%('!02#4!).%)!4-'/-&!'/%!8)'-%&'f(!9)29%!)&&+2+(:!!
\/%!9)29%!(-g%!-(!!*-('-&1'27!1#..%2)'%*!4-'/!'/%!\B<!)'!-'(!&)..#4%('!#8%&-&,:!!B(!(+1/G!
7#+.!*%(-,&)'-#&!#0!)!.%82)1%$%&'!/%).'!9)29%!(/#+2*!-&*-1)'%!'/%!\B<!#0!'/%!.%1-8-%&'!-&!
$-22-$%'%.(!?-:%:G!\B<!-(!!.%0%..%*!'#!)(!'/%!*%(-,&)'%*!9)29%!(-g%F:!!c%!.%1#$$%&*!'/)'!
7#+!0#22#4!'/-(!(')&*).*-g%*!*%0-&-'-#&!'#!)((+.%!'/%!1#..%1'!(-g%*!9)29%!-(!+(%*:!
!
U0!7#+!+(%!)!'%.$G!*%0-&-'-#&!#.!)33.%9-)'-#&!'/)'!*-00%.(!0.#$!)&7!)3#9%!#.!0.#$!'/#(%!#0!U;R!
EMZ6NL66EG!4%!.%1#$$%&*!'/)'!7#+!-&12+*%!'/-(!-&0#.$)'-#&!-&!7#+.!)882-1)'-#&:!!!
VIII. Device Description
U&!7#+.!U<S!)&*![>B!)882-1)'-#&!7#+!$+('!-&12+*%!)!*%(1.-8'-#&!#0!'/%!*%9-1%!?LK!"AJ!
MKL:LE?*F!)&*!LK!"AJ!MKZ:L6?3F?DF?--FF:!!c%!.%1#$$%&*!'/)'!7#+!8.#9-*%!'/%!0#22#4-&,!
*%(1.-8'-9%!-&0#.$)'-#&!-&!7#+.!.%82)1%$%&'!/%).'!9)29%!U<S!#.![>B!)882-1)'-#&:!!!!
!
Device Parameters
W#+.!U<S!)&*![>B!)882-1)'-#&!(/#+2*!-&12+*%!)!*%(1.-8'-#&!#0!%)1/!#0!'/%!,%&%.)2!*%9-1%!
*%(-,&!8).)$%'%.(!2-('%*!3%2#4:!!B!')3+2).!0#.$)'!-(!*%(-.)32%G!(/#4&!-&!'/%!%Y)$82%!
0#22#4-&,!'/%!2-('!3%2#4:!
! U$82)&')'-#&G!-&12+*-&,!9)29%!2#1)'-#&(G!)&&+2+(!8#(-'-#&(G!)&*!(+'+.%!'%1/&-P+%!
! I%)02%'(OR112+*%.G!-&*-1)'-&,!'/%!&+$3%.G!$)'%.-)2G!)&*!0#.!.-,-*!.%82)1%$%&'!/%).'!
9)29%(G!'/%!0+227!#8%&%*!)&,2%G!0+227!12#(%*!)&,2%G!)&*!'.)9%2!).1!0.#$!#8%&%*!'#!
12#(%*!
! E
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
! J)*-#8)1-'7G!-*%&'-07-&,!'/%!.)*-#8)P+%!$)'%.-)2!)&*!2#1)'-#&!#0!.)*-#8)P+%!$)'%.-)2!
! @#+(-&,O;'%&'G!*%(1.-3-&,!'/%!2%)02%'!).'-1+2)'-#&!$%1/)&-($!)&*!('%&'!$)'%.-)2!
! ;%4-&,!1+00G!-&*-1)'-&,!4/%'/%.!'/%!(%4-&,!1+00!-(!.#')')32%!)&*!*%(1.-3-&,!'/%!
)'')1/$%&'!$%1/)&-($!)&*!$)'%.-)2!
! "#)'-&,(!)&*!'.%)'$%&'(G!-0!)&7G!%Y82)-&-&,!'/%!8+.8#(%!?%:,:G!!)&'-3-#'-1G!
)&'-'/.#$3#'-1G!)&'-1)21-0-1F!)&*!2#1)'-#&!
! B11%((#.-%(G!(+1/!)(!-$82)&')'-#&!'##2(!?%:,:G!/#2*%.G!.#')'#.G!2%)02%'!8.#3%G!(-g%.F:!
!
Valve General Design Parameters Tabular Format Example!GENERAL DESIGN FEATURES
PARAMETER DESCRIPTION
Valve locations(s):
Annulus position(s):
Implantation:
Suture technique:
No. leaflets/occluders:
Fully opened angle*:
Fully closed angle*:
Travel arc from opened to closed*:
Leaflets/ Occluder:
Material:
Radiopaque material: Radiopacity:
Location of radiopaque material:
Leaflet articulation mechanism: Housing/ Stent:
Material:
Rotatable/not:
Attachment mechanism:
Sewing cuff:
Material:
Purpose:
(antibiotic, antithrombotic, anticalcific, etc.)
Coatings/ Treatments:
Location:
Accessories: Implantation tools (holder, rotator, leaflet probe, sizer).
Other:
*Applicable only to rigid replacement heart valves.
!
W#+.!U<S!)&*![>B!)882-1)'-#&!(/#+2*!)2(#!-&12+*%!)!*%(1.-8'-#&!#0!%)1/!#0!'/%!*-$%&(-#&)2!
*%(-,&!8).)$%'%.(!2-('%*!3%2#4!0#.!%)1/!(-g%!7#+!82)&!'#!$).=%':!!!
! \-((+%!B&&+2+(!<-)$%'%.!?\B<F!?$$F!
! Q)29%!R+'%.!<-)$%'%.!?R<F!?*-1')'%*!37!1+00!R<F!?$$F! !
! H
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
! Q)29%!U&&%.!<-)$%'%.!?U<F!?*-1')'%*!37!/#+(-&,!U<F!?$$F!
! V%#$%'.-1!R.-0-1%!B.%)!?$$LF!
! [.#0-2%!@%-,/'?(F!?$$F:! !
!
Packaging Information
W#+.!U<S!)&*![>B!)882-1)'-#&!$+('!-&12+*%!)!*%(1.-8'-#&!#0!'/%!8)1=-&,!$%'/#*(!+(%*!?LK!
"AJ!MKL:L6?3F?DF!)&*!LK!"AJ!MKZ:L6?3F?ZF?9FF:!!!c%!.%1#$$%&*!7#+!-&12+*%!8)1=),-&,!
*%(-,&!)&*!8%.0#.$)&1%!-&0#.$)'-#&!)(!*%(1.-3%*!3%2#4:!!B!')3+2).!0#.$)'!-(!*%(-.)32%G!)(!
(/#4&!-&!'/%!%Y)$82%!)'!'/%!%&*!#0!'/-(!(%1'-#&:!
!
1. Package Design!!
c%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!'/%!8)1=),%!*%(-,&!)&*!-&12+*%!$)((!)&*!9#2+$%!?0#.!
8+.8#(%(!#0!1)21+2)'-&,!2#)*!*%&(-'7!0#.!('%.-2-g)'-#&!9)2-*)'-#&FG!)22!1#$8#&%&'(G!)&*!)&7!
0%)'+.%!'/)'!-&*-1)'%(!4/%'/%.!'/%!8)1=),%!/)(!3%%&!#8%&%*:!!W#+.!*%(1.-8'-#&!(/#+2*!
-&12+*%!(%)2-&,!8).)$%'%.(G!(+1/!)(!'-$%G!'%$8%.)'+.%G!)&*!2-*!12#(+.%!'#.P+%:!!W#+.!
*%(1.-8'-#&!(/#+2*!)2(#!-&12+*%!8%.0#.$)&1%!(8%1-0-1)'-#&(!0#.!'/%!('%.-2-g)'-#&!1712%(G!2-*G!
(%)2G!9)1++$!2%)=!.%(-(')&1%G!)&*!)&7!(%)2-&,!')8%!#.!'%$8%.)'+.%!-&*-1)'#.(:!!!
!
2. Temperature Sensor
A#.!9)29%(!'/)'!1#&')-&!3-#2#,-1)2!'-((+%G!(+1/!)(!8#.1-&%G!3#9-&%G!#.!%P+-&%!9)29%(G!4%!
.%1#$$%&*!'/)'!7#+!+(%!)!'%$8%.)'+.%!(%&(#.:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!-&12+*%!
-&0#.$)'-#&!)3#+'!/#4!7#+!9)2-*)'%!'/%!(%&(-'-9-'7!#0!'/%!(%&(#.:!
!
3. Storage for Valves that Contain Biological Tissue
c%!.%1#$$%&*!'/)'!7#+!8.#9-*%!)!2-('!#0!'/%!1#$8#&%&'(!#0!'/%!('#.),%!(#2+'-#&:!!c%!
)2(#!.%1#$$%&*!'/)'!7#+!-&*-1)'%!'/%!)$#+&'!#0!'/%!.%(-*+)2!('#.),%!(#2+'-#&!2%0'!#&!'/%!
9)29%!'-((+%!)&*!-&!'/%!+(%*!.-&(%!(#2+'-#&!)0'%.!'/%!9)29%!/)(!3%%&!.-&(%*!)11#.*-&,!'#!'/%!
8.#1%*+.%!(8%1-0-%*!-&!7#+.!2)3%2-&,:!!!
Package Information – Tabular Format Example
Package Information
Package mass and volume
for purposes of calculating load density for sterilization validation
Package components i.e., container (jar), holder, lid and seal components (sealing tape), components or feature that indicates if the package has been opened
Storage solution amount of the residual storage solution left on the valve tissue and in the used rinse solution after the valve has been rinsed according to the procedure specified in your labeling
PARAMETER SPECIFICATION (average, min)
Seal time, temperature, and pressure
Sealing parameters
Lid closure torque
! T
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!Maximum no. of sterilization cycles
Tensile strength Sealing tape
Shrinkage
Minimum seal width
Peel force
Seal
Burst strength
Lid removal torque
Vacuum leak resistance
Composition Storage solution
pH
Performance specifications
Temperature indicators
IX. Pyrogenicity
W#+!$+('!%(')32-(/!)&*!$)-&')-&!8.#1%*+.%(!0#.!)11%8')&1%!)1'-9-'-%(!?LK!"AJ!ML6:M6F:!!W#+!
$+('!%(')32-(/!)&*!$)-&')-&!8.#1%*+.%(!0#.!0-&-(/%*!*%9-1%!)11%8')&1%!'#!%&(+.%!'/)'!%)1/!
8.#*+1'-#&!.+&G!2#'G!#.!3)'1/!#0!0-&-(/%*!*%9-1%(!$%%'(!)11%8')&1%!1.-'%.-)!?LK!"AJ!ML6:M6?*FF:!!
B!.%82)1%$%&'!/%).'!9)29%!-(!)&!-$82)&'%*!*%9-1%k!'/%.%0#.%!4%!.%1#$$%&*!'/)'!7#+!'%('!7#+.!
*%9-1%!0#.!87.#,%&-1-'7!?(8%1-0-1)227!0#.!%&*#'#Y-&(F:!!c%!.%1#$$%&*!'/)'!7#+!8.#9-*%N!
! *%(1.-8'-#&!#0!'/%!$%'/#*!+(%*!'#!$)=%!'/%!*%'%.$-&)'-#&G!%:,:G!I-$+2+(!)$%3#17'%!27()'%!?IBIF!
! -*%&'-0-1)'-#&!#0!'/%!'%('-&,!%&*8#-&'!.%)1/%*!)&*!.)'-#&)2%!0#.!(%2%1'-&,!'/)'!%&*8#-&'!
! *%(1.-8'-#&!#0!'/%!%Y'.)1'-#&!'%1/&-P+%!+(%*!'#!#3')-&!'/%!'%('!02+-*!0.#$!'/%!'%('!*%9-1%G!(/#4-&,!'/)'!)22!12-&-1)227!.%2%9)&'!1#&')1'!(+.0)1%(!#0!'/%!'%('!*%9-1%!4%.%!
)((%((%*!
! -*%&'-0-1)'-#&!#0!'/%!.%0%.%&1%!$%'/#*!+(%*G!%:,:G!`&-'%*!;')'%(![/).$)1#8%-)!?`;[FG!B^;UOBB>U!;\!TLNL66LG!_)1'%.-)2!%&*#'#Y-&(!C!\%('!$%'/#*#2#,-%(G!
.#+'-&%!$#&-'#.-&,G!)&*!)2'%.&)'-9%(!'#!3)'1/!'%('-&,!#.!A<B!,+-*)&1%:!
X. Sterilization
c%!.%1#$$%&*!'/)'!7#+!0#22#4!'/%!('%.-2-g)'-#&!$%'/#*(!*%(1.-3%*!-&!U;R!EMZ6NL66EG!#.!
%P+-9)2%&'!$%)(+.%(:!
!
1. Non-Sterile Devices
U0!7#+!-&'%&*!'#!(+8827!7#+.!*%9-1%!&#&C('%.-2%G!4%!.%1#$$%&*!'/)'!7#+!%Y82)-&!7#+.!
.)'-#&)2%:!!W#+!(/#+2*!-&*-1)'%!8.#$-&%&'27!#&!7#+.!2)3%2-&,!'/)'!'/%!*%9-1%!-(!(+882-%*!
&#&C('%.-2%!)&*!8.#9-*%!-&('.+1'-#&(!0#.!)11%8')32%!+(%!8).)$%'%.(G!(+1/!)(!'%$8%.)'+.%G!
8.%((+.%G!*4%22!'-$%(!0#.!'/%!-&-'-)2!('%.-2-g)'-#&:!!B**-'-#&)227G!7#+!(/#+2*!-&12+*%!-&!7#+.!
! M
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
2)3%2-&,!4/%'/%.!.%C('%.-2-g)'-#&G!+(-&,!'/%(%!8).)$%'%.(G!-(!)88.#8.-)'%:!!\/%!
*%'%.$-&)'-#&!4/%'/%.!.%C('%.-2-g)'-#&!-(!)88.#8.-)'%!(/#+2*!3%!3)(%*!#&!'/%!9)2-*)'-#&!
'%('-&,!0#.!'/%!(')'%*!8).)$%'%.(G!)&*!'/%!&+$3%.!#0!.%('%.-2-g)'-#&(:!!
2. Resterilization
W#+.!2)3%2-&,!(/#+2*!8.#9-*%!-&('.+1'-#&(!0#.!)11%8')32%!8).)$%'%.(!'#!3%!+(%*G!(+1/!)(!
'%$8%.)'+.%G!8.%((+.%G!*4%22!'-$%(G!3)(%*!#&!9)2-*)'-#&(!*#&%!'#!9)2-*)'%!'/%(%!8).)$%'%.(!
)&*!&+$3%.(!#0!.%('%.-2-g)'-#&(:!!U0!7#+.!2)3%2-&,!-&*-1)'%(!7#+.!*%9-1%!-(!.%('%.-2-g)32%!
?-:%:G!0#.!8)1=),%(!'/)'!).%!h#8%&!3+'!+&+(%*iFG!4%!.%1#$$%&*!'/)'!7#+.!)882-1)'-#&!
-&12+*%N!
! )!.)'-#&)2%!(+88#.'-&,!'/%!()0%!)&*!%00%1'-9%!8%.0#.$)&1%!#0!7#+.!*%9-1%!)0'%.!.%('%.-2-g)'-#&!
! )!*%(1.-8'-#&!'/)'!*-00%.%&'-)'%(!3%'4%%&!('%.-2-g)'-#&!1#&*+1'%*!)'!'/%!$)&+0)1'+.-&,!0)1-2-'7!)&*!('%.-2-g)'-#&!8%.0#.$%*!37!/#(8-')2!(')00!
! 9)2-*)'-#&!#0!'/%!%00%1'!#0!.%('%.-2-g)'-#&!#&!'/%!9)29%:!!?Q)2-*)'-#&!(/#+2*!*%$#&('.)'%!'/)'!'/%!$)Y-$+$!&+$3%.!#0!.%('%.-2-g)'-#&(!.%1#$$%&*%*!-&!7#+.!
2)3%2-&,!*#%(!&#'!)00%1'!'/%!()0%!)&*!%00%1'-9%!8%.0#.$)&1%!#0!'/%!9)29%:F!!!
3. Validation Study
c/%.%!'/%!.%(+2'(!#0!)!8.#1%((!1)&&#'!3%!0+227!9%.-0-%*!37!(+3(%P+%&'!-&(8%1'-#&!)&*!'%('G!
)(!4-'/!0-&-(/%*!*%9-1%!('%.-2-g)'-#&G!'/%!8.#1%((!$+('!3%!9)2-*)'%*!4-'/!)!/-,/!*%,.%%!#0!
)((+.)&1%!?LK!"AJ!ML6:TEF:!c%!.%1#$$%&*!'/)'!7#+!(+3$-'!.%(+2'(!#0!)!9)2-*)'-#&!('+*7!
'#!(/#4!'/)'!'/%!('%.-2-g)'-#&!8.#1%((!8.#9-*%(!)!('%.-2-'7!)((+.)&1%!2%9%2!?;BIF!#0!)'!2%)('!
K6CHG!-:%:G!'/%!8.#3)3-2-'7!#0!0-&*-&,!)&!+&('%.-2-g%*!*%9-1%!-(!#&%!-&!#&%!$-22-#&:!!\/%!
9)2-*)'-#&!(/#+2*!-&12+*%!+(%!#0!-+2)'%*!8.#*+1'!#.!-&*-1)'#.(!?3-#2#,-1)2!#.!#'/%.!
'78%(F!82)1%*!-&!'/%!2#1)'-#&!#0!'/%!*%9-1%!'/)'!-(!$#('!*-00-1+2'!'#!('%.-2-g%G!)&*!4-'/-&!'/%!
('%.-2-g)'-#&!1/)$3%.:!!Q-)32%!(8#.%!1#+&'!#&!3-#2#,-1)2!-&*-1)'#.(!(/#+2*!3%!9%.-0-%*!
3%0#.%!%)1/!+(%:!!\/%!#.,)&-($!1/#(%&!)(!'/%!-&*-1)'#.!(/#+2*!.%8.%(%&'!'/%!4#.('!1)(%!
#.,)&-($!0#.!'/%!8).'-1+2).!'78%!#0!('%.-2-g)'-#&!$%'/#*!1/#(%&:!!B22!%P+-8$%&'!+(%*!
*+.-&,!'/%!8.#1%((!'#!$#&-'#.!1#&*-'-#&(!?'/%.$#1#+82%(G!,)+,%(G!%'1:F!(/#+2*!/)9%!3%%&!
.%1%&'27!1)2-3.)'%*:!!<%$#&('.)'%!)&*!*#1+$%&'!'/)'!'/%!9)2-*)'-#&!$%'/#*(!1/#(%&!).%!
1#$8)'-32%!4-'/!'/%!*%9-1%!)&*!8)1=),-&,!$)'%.-)2(!'/+(!%(')32-(/-&,!'/%!/-,/!*%,.%%!#0!
)((+.)&1%:!
!
4. Controls
\/%!%&9-.#&$%&')2!1#&*-'-#&(!#0!7#+.!0)1-2-'7!1)&!.%)(#&)327!3%!%Y8%1'%*!'#!/)9%!)&!
)*9%.(%!%00%1'!#&!8.#*+1'!P+)2-'7:!!W#+!$+('!%(')32-(/!)&*!$)-&')-&!8.#1%*+.%(!'#!
)*%P+)'%27!1#&'.#2!'/%(%!%&9-.#&$%&')2!1#&*-'-#&(!?LK!"AJ!ML6:T6?1F!)&*!LK!"AJ!
ML6:T6?%FF:!c%!.%1#$$%&*!'/)'!7#+!-&12+*%!-&0#.$)'-#&!#&!'/%!1#&'.#2(!+(%*!'#!%&(+.%!
'/)'!'/%!3-#3+.*%&!#&!'/%!*%9-1%!-(!2#4!?%:,:G!'/%!12%)&-&,!(1/%*+2%!0#.!'/%!02##.(!)&*!
#'/%.!(+.0)1%(G!*-(-&0%1'-#&!8.#1%*+.%(G!$)&),%$%&'!#0!4)'%.!)&*!)-.!(7('%$(G!2)$-&).!
! 5
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
02#4!/##*(G!('%.-2-g%.(F:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!(8%1-07!'/%!4).&-&,!)&*!)1'-#&!
2-$-'(!0#.!3-#3+.*%&:!!!
!
5. Package Integrity
W#+!$+('!%&(+.%!'/)'!*%9-1%!8)1=),%(!).%!*%(-,&%*!)&*!1#&('.+1'%*!'#!8.#'%1'!'/%!*%9-1%!
0.#$!)2'%.)'-#&!#.!*)$),%G!-&12+*-&,!'/%!1#&')$-&)'-#&!#0!('%.-2%!*%9-1%(!?LK!"AJ!
ML6:KD6F:!!\%('-&,!(/#+2*!-&12+*%!)&!)((%(($%&'!#0!8)1=),%!-&'%,.-'7!?9-)!+(%!#0!)!
8/7(-1)2!$%'/#*G!(+1/!)(!)!2%)=!'%('G!#.!)!$-1.#3-)2!1/)22%&,%!0#22#4%*!37!('%.-2-'7!
)((%(($%&'!#0!'/%!1#&'%&'(F:!!c%!.%1#$$%&*!'/)'!7#+!'%('!'/%!0-&)2!4/#2%!8)1=),%!)0'%.!
(-$+2)'%*!#.!.%)2C'-$%!),-&,G!(/-8$%&'G!/)&*2-&,!)&*!%&9-.#&$%&')2!('.%((-&,:!!\%('-&,!
'/%!0-&)2!4/#2%!8)1=),%!-(!8.%0%..%*!#9%.!)((%((-&,!8)1=),%!1#$8#&%&'(!(%8).)'%27G!#.!
#&27!)((%((-&,!(%)2%*!).%)(:!!
!
XI. Preclinical In Vitro Assessment
_)(%*!#&!7#+.!.-(=!)&)27(-(G!4%!.%1#$$%&*!'/)'!7#+!8%.0#.$!8.%12-&-1)2!*5'6*,$1!'%('-&,!#&!7#+.!
.%82)1%$%&'!/%).'!9)29%!0#22#4-&,!'/%!$%'/#*(!*%(1.-3%*!-&!U;R!EMZ6NL66E!#.!%P+-9)2%&'!
$%'/#*(:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!8.#9-*%!%Y82)&)'-#&(!0#.!)&7!*5'6*,$1!'%('-&,!7#+!#$-':!!
W#+.!U<S!)&*![>B!)882-1)'-#&(!(/#+2*!-&12+*%!'/%!'%('!1#&*-'-#&(G!()$82%!(%2%1'-#&G!)&*!'%('!
.%8#.'(!0#.!'/%!0#22#4-&,N!
! $)'%.-)2!8.#8%.'7!'%('-&,!
! 3-#2#,-1)2!()0%'7!
! /7*.#*7&)$-1!8%.0#.$)&1%!
! ('.+1'+.)2!8%.0#.$)&1%!
! *%9-1%!*+.)3-2-'7!
! 1#$8#&%&'!0)'-,+%!)((%(($%&'(!
! *%9-1%!(8%1-0-1!'%('-&,:!
!
A#.!%)1/!'%('G!4%!.%1#$$%&*!'/)'!7#+.!'%('!.%8#.'!-&12+*%!'/%!8.#'#1#2G!)11%8')&1%!1.-'%.-)!)&*!
.%(+2'(!?%-'/%.!)(!*)')!#.!8)((O0)-2F:!!W#+.!8.#'#1#2!(/#+2*!-&12+*%!()$82%!(-g%G!%&9-.#&$%&')2!
1#&*-'-#&(G!'%('!8).)$%'%.(G!)&*!'%('!*+.)'-#&:!!B!')3+2).!0#.$)'!-(!*%(-.)32%G!(%%!'/%!%Y)$82%!
')32%!)'!'/%!%&*!#0!'/-(!(%1'-#&:!
!
U&!)**-'-#&G!*%(-,&!1#&'.#2(!)8827!'#!)22!/%).'!9)29%(:!!W#+!$+('!%(')32-(/!)&*!$)-&')-&!
8.#1%*+.%(!-&!#.*%.!'#!%&(+.%!'/)'!(8%1-0-%*!*%(-,&!.%P+-.%$%&'(!).%!$%'!?LK!"AJ!ML6:D6?)FF:!!
\/%(%!8.#1%*+.%(!$+('!-&12+*%!*%(-,&!9)2-*)'-#&!8.#1%*+.%(:!!<%(-,&!9)2-*)'-#&!$+('!%&(+.%!'/)'!
*%9-1%(!1#&0#.$!'#!*%0-&%*!+(%.!&%%*(!)&*!-&'%&*%*!+(%(!)&*!$+('!-&12+*%!'%('-&,!#0!8.#*+1'-#&!
+&-'(!+&*%.!)1'+)2!#.!(-$+2)'%*!+(%!1#&*-'-#&(:!!?;%%!LK!"AJ!ML6:D6?,FF:!!B11#.*-&,27G!4%!
.%1#$$%&*!'/)'!7#+!-&12+*%!'/%!-&0#.$)'-#&!*%(1.-3%*!3%2#4!-&!7#+.!U<S!#.![>B!)882-1)'-#&:!!!
!
!
! K6
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
A. Valve Samples
c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!)22!*5'6*,$1!'%('(!#&!0-&-(/%*!9)29%(G!#0!'/%!0-&)2!*%(-,&G!
%Y8#(%*!'#!'/%!$)Y-$+$!&+$3%.!#0!.%1#$$%&*%*!('%.-2-g)'-#&!1712%(:!
!
B. Reference Valves
A#.!)&7!'%('!'/)'!*#%(!&#'!/)9%!9)2-*)'%*!8)((O0)-2!1.-'%.-)G!4%!.%1#$$%&*!'/)'!7#+!-&12+*%!
'/%!+(%!#0!)!2%,)227!$).=%'%*!.%0%.%&1%!/%).'!9)29%!#0!(-$-2).!1#$8#(-'-#&!)(!'/%!9)29%!7#+!
).%!'%('-&,:!
!
C. Biocompatibility
A<B!.%1#$$%&*(!'/)'!7#+!1#&*+1'!3-#1#$8)'-3-2-'7!'%('-&,!)(!*%(1.-3%*!-&!'/%!A<B!
,+-*)&1%G!Use of International Standard ISO-10993, Biological Evaluation of Medical
Devices Part-1: Evaluation and TestingGM!0#.!32##*C1#&')1'-&,G!2#&,C'%.$!-$82)&'%*!
*%9-1%(:!!U0!7#+!0#22#4!)!9#2+&').7!(')&*).*!'/)'!-(!.%2%9)&'!'#!)&7!)(8%1'!#0!'/%!()0%'7!#.!
%00%1'-9%&%((!#0!'/%!*%9-1%!'/)'!-(!=&G!#.!'/)'!(/#+2*!.%)(#&)327!3%!=&G!'#!7#+G!7#+!
$+('!%Y82)-&!)&7!*%9-)'-#&!0.#$!(+1/!(')&*).*!?LK!"AJ!MKZ:L6!?3F?EF?--FF:!!>)'%.-)2C
$%*-)'%*!87.#,%&-1-'7!'%('-&,!+(-&,!'/%!.)33-'!87.#,%&!'%('!(/#+2*!3%!8%.0#.$%*!)(!8).'!#0!'/%!
3-#1#$8)'-3-2-'7!3)''%.7!#0!'%('-&,:!!B!')3+2).!0#.$)'!-(!*%(-.)32%G!)(!(/#4&!3%2#4: !
!
Biocompatibility Information – Tabular Format Example!TEST PERFORMED/
LAB REPORT #
(literature citation, standard reference)
EXTRACT(S) IF USED
(polar, non-polar), or animal model/cell line
EXTRACT CONDITIONS
(time, temperature, area or mass to volume
ratio compared to in-use conditions)
TEST AND CONTROL(S)
USED
RESULTS/COMMENTS
(include units when appropriate, and include
descriptions for all deviations from the standard/protocol
Cytotoxicity
Sensitization
Irritation / Intracutaneous Toxicity
Systemic toxicity
Sub-chronic toxicity
Genotoxicity
gene mutation
chromosome aberration
DNA damage
In vivo assay
Implantation
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!M!\/-(!,+-*)&1%!*#1+$%&'!1)&!3%!#3')-&%*!)'N!
/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6
M6TDE:/'$! !
! KK
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!Hemocompatibility
hemolysis
complement
activation
in vivo thrombogenicity*
Pyrogenicity
Chronic toxicity
Carcinogenicity
Biodegradation
Reproductive or Developmental toxicity
*You may assess thrombogenicity in animal studies in place of this test.
D. Valve Durability Testing
c%!.%1#$$%&*!'/)'!7#+!)((%((!'/%!*+.)3-2-'7!#0!.%82)1%$%&'!/%).'!9)29%(!+(-&,!)11%2%.)'%*!
4%).!'%('-&,!?Bc\F!$%'/#*(!*-(1+((%*!-&!U;R!EMZ6NL66E!#.!%P+-9)2%&'!$%'/#*(:!!Bc\!
(/#+2*!1#&'-&+%!0#.!H66!$-22-#&!1712%(!0#.!.-,-*!9)29%(!)&*!L66!$-22-#&!1712%(!0#.!02%Y-32%!
9)29%(G!+(-&,!)!3)1=!8.%((+.%!3%'4%%&!KLE!)&*!KE6!$$@,G!'#!'%('!'/%!*+.)3-2-'7!#0!'/%!
1#$8#&%&'(!+&*%.!8+2()'-2%!02#4!)&*!8/7(-#2#,-1!2#)*-&,:!!c%!.%1#$$%&*!'/)'!7#+!0+227!
*%(1.-3%!)22!1#&*-'-#&(!*+.-&,!Bc\G!-&12+*-&,!.)'-#&)2%!0#.!'/%!1#&*-'-#&(!1/#(%&G!0#.!'/%!
0#22#4-&,N!
! '/%!02+-*!+(%*!!! '/%!02#4!.)'%(!'/.#+,/!'/%!9)29%(!!! '/%!8.%((+.%!2#)*-&,!-&12+*-&,!3)1=!8.%((+.%:!
!
E. Component Fatigue Testing
"#$8#&%&'(!#0!.-,-*!.%82)1%$%&'!/%).'!9)29%(!)&*!'/%!2#)*!3%).-&,G!&#&C3-#2#,-1)2!
1#$8#&%&'(!#0!02%Y-32%!.%82)1%$%&'!/%).'!9)29%(!?%:,:G!('%&'!4-.%F!(/#+2*!3%!-&*-9-*+)227!
0)'-,+%!'%('%*!'#!H66!$-22-#&!1712%(:!!!
!
F. Dynamic Failure Mode Testing
c%!.%1#$$%&*!'/)'!7#+!(+3l%1'!)!(%2%1'-#&!#0!9)29%(!'/)'!/)9%!(+.9-9%*!'/%!Bc\!'#!
)**-'-#&)2!'%('(!'#!*%'%.$-&%!'/%!$#*%!-&!4/-1/!'/%!9)29%(!4-22!0)-2:!!c%!.%1#$$%&*!'/)'!7#+!
8.#9-*%!P+)2-')'-9%!)&*!P+)&'-')'-9%!)((%(($%&'(!#0!'/%!0)-2+.%!$#*%(!)&*!/-,/!('.%((!).%)(!-&!
'/%!9)29%!?-:%:G!$#*%!)&*!2#1)'-#&!#0!'/%!0)-2+.%F:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!+(%!'/%(%!
.%(+2'(!'#!(+88#.'!)&7!)&)27'-1)2!9)2-*)'-#&!#.!1#$8+')'-#&)2!$#*%2-&,!#0!('.%((!)&)27(%(!#0!
'/%!1#$8#&%&'(:!
!
G. Cavitation
c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!1)9-')'-#&!'%('-&,!#0!.-,-*!/%).'!9)29%(!)(!*%(1.-3%*!-&!
B88%&*-Y!_:!
! KL
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
H. Corrosion Resistance
c%!.%1#$$%&*!'/)'!7#+!*%'%.$-&%!'/%!1#..#(-#&!.%(-(')&1%!#0!'/%!$%')22-1!$)'%.-)2(!37!
'%('-&,!'/%!0-&)2!0-&-(/%*!*%9-1%!-&!)!8/7(-#2#,-1)2!%&9-.#&$%&'!)&*G!-0!)88.#8.-)'%G!+&*%.!
('.%((:!!U0!7#+!8%.0#.$!'%('-&,!+&*%.!1712-1!2#)*-&,G!4%!.%1#$$%&*!'/)'!7#+!1#&*+1'!'%('(!
+&*%.!'/%!()$%!'78%!#0!2#)*-&,!)'!)!0.%P+%&17!'/)'!4-22!&#'!$)(=!2#1)2-g%*!)'')1=:!!c%!
.%1#$$%&*!'/)'!7#+!8%.0#.$!1#..#(-#&!'%('-&,!3#'/!3%0#.%!)&*!)0'%.!7#+.!0)'-,+%!'%('-&,:!!
c%-,/'!2#((!$%'/#*(!(/#+2*!&#'!3%!+(%*!'#!%9)2+)'%!2#1)2-g%*!)'')1=!?%:,:G!8-''-&,F!+&2%((!7#+!
).%!)32%!'#!%(')32-(/!'/)'!7#+.!%Y8%.-$%&')2!'%1/&-P+%!-(!(+00-1-%&'27!(%&(-'-9%:!!c%!
.%1#$$%&*!'/)'!7#+!1#&*+1'!)22!1#..#(-#&!'%('-&,!#&!0-&)2!0-&-(/%*!8.#*+1':!!!
!
I. Flammability of Valved Conduits
U0!7#+.!2)3%2-&,!.%1#$$%&*(!+(-&,!)&!%2%1'.#1)+'%.7!*%9-1%!'#!1+'!'/%!1#&*+-'!$)'%.-)2G!7#+!
(/#+2*!)((%((!'/%!02)$$)3-2-'7!#0!'/%!1#&*+-':!!!
!
J. Hemodynamic Performance - Verification of the Bernoulli
Relationship
c%!.%1#$$%&*!'/)'!7#+!)((%((!'/%!12-&-1)2!/%$#*7&)$-1!8%.0#.$)&1%!37!<#882%.!
+2'.)(#+&*G!+(-&,!'/%!_%.&#+22-!.%2)'-#&(/-8G!
!
![!n!]?Q*L!C!Q8
LF!
!
4/%.%N!!
]!-(!)!1#&(')&'!
![!-(!'/%!8.%((+.%!,.)*-%&'!
Q*!-(!'/%!*-(')2!9%2#1-'7!$%)(+.%*!37!1#&'-&+#+(!4)9%!<#882%.!
Q8!-(!'/%!8.#Y-$)2!9%2#1-'7!$%)(+.%*!37!8+2(%*!<#882%.!!!
!
\/%!9)2+%!#0!'/%!1#&(')&'!]!1)&!9).7!*%8%&*-&,!#&!9)29%!'78%:!!;%%!Appendix C. Bernoulli
Verification!0#.!)**-'-#&)2!.%1#$$%&*)'-#&(:!!
!
K. Magnetic Resonance (MR) Safety Testing
A#.!-&0#.$)'-#&!.%,).*-&,!>),&%'-1!J%(#&)&1%!?>JF!()0%'7!'%('-&,G!82%)(%!(%%!A<B!
,+-*)&1%!*#1+$%&'!%&'-'2%*G!hS(')32-(/-&,!;)0%'7!)&*!"#$8)'-3-2-'7!#0![)((-9%!U$82)&'(!-&!
'/%!>),&%'-1!J%(#&)&1%!?>JF!S&9-.#&$%&':i5!!
!
;%%!)2(#!XVI. Professional Labeling:!
!5!!\/-(!,+-*)&1%!*#1+$%&'!1)&!3%!#3')-&%*!)'N!
/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1
$K6TT6E:/'$!0#.!,+-*)&1%!#&!>J!()0%'7!'%('-&,!#0!7#+.!*%9-1%:!!!!!!!
! KD
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
!
L. Shelf Life
c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!'/%!(/%20!2-0%!('+*-%(!*%(1.-3%*!-&!B88%&*-Y!B!#0!'/-(!
,+-*)&1%:!
!
XII. Preclinical Animal Studies
A<B!.%1#$$%&*(!'/)'!)&-$)2!('+*-%(!3%!1#&*+1'%*!'#!%9)2+)'%!$#('!&%4!.%82)1%$%&'!/%).'!
9)29%!*%(-,&(!)&*!'/)'!'/%(%!('+*-%(!$)..7!3%('!8.)1'-1%(!#0!3-#$%*-1)2!.%(%).1/G!-&12+*-&,!
#3(%.9)&1%!#0!DJ!8.-&1-82%(!?-:%:G!.%*+1%G!.%0-&%G!#.!.%82)1%FG!4/%&%9%.!-'!4-22!&#'!1#$8.#$-(%!'/%!
-&9%('-,)'-#&!#0!()0%'7:K6!!\/%.%0#.%G!4%!.%1#$$%&*!'/)'!7#+!8%.0#.$!*5'6*61!)&-$)2!'%('-&,!#&!
7#+.!.%82)1%$%&'!/%).'!9)29%!0#22#4-&,!'/%!$%'/#*(!*%(1.-3%*!-&!U;R!EMZ6NL66E!)&*!U;R!
K655DNL66H!#.!%P+-9)2%&'!$%'/#*(:!!U0!7#+!+(%!*-00%.%&'!%&*8#-&'(!#.!*%9-)'%!0.#$!'/%!'%('-&,!
*%(1.-3%*!-&!'/-(!,+-*)&1%!#.!)!(')&*).*!7#+!0#22#4G!4%!.%1#$$%&*!'/)'!7#+!%Y82)-&!4/7!7#+.!
)88.#)1/!-(!(1-%&'-0-1)227!9)2-*:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!8.#9-*%!%Y82)&)'-#&(!0#.!)&7!*5'
6*61!)&-$)2!'%('-&,!7#+!#$-':!![.-#.!'#!8%.0#.$-&,!)&-$)2!('+*-%(G!7#+!$)7!4)&'!'#!#3')-&!A<B!
-&8+'!#&!7#+.!)&-$)2!('+*7!8.#'#1#2!9-)!'/%!8.%C(+3$-((-#&!8.#1%((:!!W#+.!&#&12-&-1)2!2)3#.)'#.7!
('+*-%(!$+('!3%!1#&*+1'%*!-&!)11#.*)&1%!4-'/!LK!"AJ![).'!EMG!V##*!I)3#.)'#.7![.)1'-1%!0#.!
^#&12-&-1)2!I)3#.)'#.7!;'+*-%(:!!c%!.%0%.!7#+!'#!'/#(%!.%,+2)'-#&(!0#.!1#$8.%/%&(-9%!.%,+2)'-#&!
#0!V##*!I)3#.)'#.7![.)1'-1%G!3+'!*-(1+((!(%9%.)2!)(8%1'(!#0!)&-$)2!('+*-%(!/%.%:!
!
A. Methods
U0!'%1/&-1)227!0%)(-32%G!4%!.%1#$$%&*!1/.#&-1!)((%(($%&'!#0!7#+.!.%82)1%$%&'!/%).'!9)29%!-&!
)22!)&)'#$-1)2!8#(-'-#&(!.%02%1'%*!-&!'/%!-&*-1)'-#&(!0#.!+(%:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!
%Y82)-&!7#+.!.)'-#&)2%!0#.!'/%!)&-$)2!$#*%2!7#+!/)9%!(%2%1'%*:!!U;R!EMZ6NL66E!,%&%.)227!
.%1#$$%&*(!+(-&,!#&27!'/%!()$%!(8%1-%(G!)&*!(+,,%('(!+(-&,!)&-$)2(!#0!'/%!()$%!,%&*%.!)&*!
),%!-&!)&-$)2!('+*-%(k!/#4%9%.G!4%!3%2-%9%!'/-(!$)7!&#'!3%!)*%P+)'%!'#!%9)2+)'%!)22!)1+'%!)&*!
1/.#&-1!('+*-%(!#0!)!&%4!9)29%!*%(-,&:!!\/%.%0#.%G!4%!$)7!.%1#$$%&*!)**-'-#&)2!)&-$)2!
'%('-&,!3%7#&*!'/)'!*%(1.-3%*!-&!U;R!EMZ6NL66E:!!!
!
B. Study Design
c%!.%1#$$%&*!'/)'!7#+!%9)2+)'%!'/%!0-&)2!0-&-(/%*!8.#*+1'!-&!7#+.!)&-$)2!('+*-%(:!!c%!
.%1#$$%&*!'/)'!7#+!)((%((!'/%!)&-$)2!)&*!'/%!*%9-1%!-$$%*-)'%27!)0'%.!-$82)&')'-#&!?)1+'%!
/%$#*7&)$-1!8%.0#.$)&1%k!-$82)&')'-#&!/)&*2-&,!1/).)1'%.-('-1(F!)&*!)'!L6!4%%=(!?1/.#&-1!
/%$#*7&)$-1!8%.0#.$)&1%k!%Y82)&'!8)'/#2#,7F:!!c%!$)7G!/#4%9%.G!.%1#$$%&*!'/)'!7#+.!
1/.#&-1!('+*7!1#&'-&+%!$#.%!'/)&!L6!4%%=(G!-0!'/%!.-(=!)((%(($%&'!#0!7#+.!*%9-1%!-&*-1)'%(!
'/)'!)!,.%)'%.!*+.)'-#&!-(!)88.#8.-)'%:!!c%!)2(#!.%1#$$%&*!'/)'!7#+.!('+*-%(!1#&(-('!#0!)!
!K6!;%%![+32-1!@%)2'/!;%.9-1%![#2-17!#&!@+$)&%!").%!)&*!`(%!#0!I)3#.)'#.7!B&-$)2(:!!
/''8NOO,.)&'(:&-/:,#9O,.)&'(O#2)4O.%0%.%&1%(O8/(8#2:/'$m@%)2'/oL6J%(%).1/oL6SY'%&(-#&oL
6B1'oL6#0oL6K5ME! !!! !!
! KZ
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
C.
8.#(8%1'-9%27C*%0-&%*!&+$3%.!#0!)&-$)2(!0#.!'/%!)1+'%G!1/.#&-1!)&*!1#&'.#2(!).$(!#0!7#+.!
('+*7:!!c%!.%1#$$%&*!'/)'!)!.)'-#&)2%!0#.!(%2%1'-#&!#0!'/%!&+$3%.!#0!)&-$)2(!3%!8.#9-*%*:!!!
!
R+.!V##*!I)3#.)'#.7![.)1'-1%!.%,+2)'-#&(!.%P+-.%!'/)'G!0#.!%)1/!('+*7G!7#+!$+('!/)9%!)&!
)88.#9%*!4.-''%&!8.#'#1#2!'/)'!12%).27!-&*-1)'%(!'/%!#3l%1'-9%(!)&*!)22!$%'/#*(!0#.!'/%!
1#&*+1'!#0!'/%!('+*7!?LK!"AJ!EM:KL6?)FF:!
!
c%!)2(#!.%1#$$%&*!)((%(($%&'!#0!)1+'%!)&*!1/.#&-1!/%$#*7&)$-1!8%.0#.$)&1%G!9)29%C
.%2)'%*!8)'/#2#,7!-&!%-'/%.!)&!#.'/#'#8-1!#.!&#&C#.'/#'#8-1!8#(-'-#&G!)&*!1/.#&-1!8%.0#.$)&1%!
#0!)&'-1)21-0-1)'-#&!'.%)'$%&'(!?-0!)882-1)32%F:!!U&!)**-'-#&G!4%!.%1#$$%&*!L6!#.!$#.%!4%%=(!
#0!0#22#4C+8!0#.!1/.#&-1!-$82)&')'-#&:!
!
Data Collection
c%!.%1#$$%&*!'/)'!7#+!1#22%1'!'/%!*)')!2-('%*!3%2#4:!
!
1. Study of Acute Hemodynamic Performance
U&!7#+.!)1+'%!('+*7G!4%!.%1#$$%&*!'/)'!7#+!1#22%1'N!!
! %)(%!#0!/)&*2-&,!)&*!(+.,-1)2!-$82)&')'-#&!!
! /%$#*7&)$-1!8%.0#.$)&1%!?1)'/%'%.!*)')!)(!4%22!)(!%1/#1).*-#,.)8/7F!
! 2%)02%'!$#'-#&!?37!%1/#1).*-#,.)8/7!)&*!)&,-#,.)8/7F!
! 8.%(%&1%!#0!('%&#(-(!#.!.%,+.,-')'-#&:!!!
!
2. Study of Chronic Hemodynamic Performance
U&!7#+.!1/.#&-1!('+*7G!4%!.%1#$$%&*!'/)'!7#+!1#22%1'N!!
! %)(%!#0!/)&*2-&,!)&*!(+.,-1)2!-$82)&')'-#&!!
! /%$#*7&)$-1!8%.0#.$)&1%!?1)'/%'%.!*)')!)(!4%22!)(!%1/#1).*-#,.)8/7F!
! 2%)02%'!$#'-#&!?37!%1/#1).*-#,.)8/7!)&*!)&,-#,.)8/7F!!
! 8.%(%&1%!#0!('%&#(-(!#.!.%,+.,-')'-#&!
! 32##*!('+*-%(G!-$),-&,!('+*-%(!#0!2%)02%'!$#'-#&!)&*!.%,+.,-')'-#&!!
! *5'+*,8'8/#'#(!#0!-&02#4!)&*!#+'02#4!.%,-#&(!)&*!9)29%!(+.0)1%(!!
! &%1.#8(7!)&*!,.#((!8)'/#2#,7!
! %Y82)&'%*!9)29%!)&)27(-(!?-&12+*-&,!/-('#2#,7!#0!'/%!9)29%!)&*!(+..#+&*-&,!'-((+%F:!
!
3. Hemodynamic Performance Assessment
A#.!'/%!/%$#*7&)$-1!8%.0#.$)&1%!)((%(($%&'G!4%!.%1#$$%&*!'/)'!7#+!-&12+*%N!!
! 8%)=!)&*!$%)&!8.%((+.%!,.)*-%&'!
! %00%1'-9%!#.-0-1%!).%)!?SRBF!.%,+.,-')'-#&!
! )!*%(1.-8'-#&!#0!-&('.+$%&')'-#&!)&*!'%('!$%'/#*(:!!!
!
! KE
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
D.
4. Laboratory Results
"#$82%'%!32##*!1#+&'!?"_"F!)&*!1/%$-('.7!)&)27(-(!(/#+2*!-&12+*%N!!
! .%*!32##*!1%22!1#+&'!
! 4/-'%!32##*!1%22!1#+&'!?4-'/!*-00%.%&'-)2F!
! /%$)'#1.-'!
! 0.%%!/%$#,2#3-&!
! (%.+$!2)1')'%!*%/7*.#,%&)(%!
! /)8'#,2#3-&!
! .%'-1+2#17'%!1#+&'!
! 82)'%2%'!1#+&':!
!
A#.!02%Y-32%!2%)02%'!9)29%(G!-&!)**-'-#&!'#!'/%!'%('(!2-('%*!)3#9%G!7#+!(/#+2*!-&12+*%N!
! (%.+$!1)21-+$!
! (%.+$!8/#(8/#.#+(!
! 2%)02%'!1)21-+$!
! 8/#(8/)'%:!!!
!
Data Analysis
U&!)**-'-#&!'#!'/%!-&0#.$)'-#&!*%(1.-3%*!-&!U;R!EMZ6NL66EG!7#+.!'%('!.%8#.'!(/#+2*!-&12+*%N!!!
! )88%&*-1%(!4-'/!12-&-1)2!)&*!/%$)'#2#,-1)2!2)3#.)'#.7!.%(+2'(!
! /%$#*7&)$-1!0-&*-&,(!
! '/%!0-&)2!8)'/#2#,7!.%8#.'!?-&12+*-&,!,.#((!8)'/#2#,7!4-'/!$)1.#(1#8-1!8/#'#,.)8/(G!
.)*-#,.)8/(G!('.+1'+.)2!-&'%,.-'7!)((%(($%&'!0#.!.-,-*!)&*!8%.1+')&%#+(!*%2-9%.%*!
9)29%(G!)&*!/-('#8)'/#2#,7!4-'/!.%8.%(%&')'-9%!$-1.#,.)8/(F!
!
E. Final Report of Animal Study
W#+!$+('!8.%8).%!)!0-&)2!.%8#.'!0#.!%)1/!&#&12-&-1)2!2)3#.)'#.7!('+*7!?LK!"AJ!EM:KMEF:!!
B$#&,!#'/%.!'/-&,(G!7#+.!0-&)2!.%8#.'!$+('!-*%&'-07!)&*!*%(1.-3%!'/%!'%('!)&*!1#&'.#2!*%9-1%!
7#+!+(%*!-&!'/%!)&-$)2!('+*-%(!?LK!"AJ!EM:KME?)F?ZFF:!!!
!
W#+!$+('!)2(#!-&12+*%!'/%!&+$3%.(!#0!)&-$)2(!+(%*!'#!#3')-&!'/%(%!*)')!?LK!"AJ!
EM:KME?)F?TFF:!
!
\#!$%%'!'/%!0-&)2!.%8#.'!.%P+-.%$%&'(G!'/%!.%8#.'!$+('!-&12+*%N
! 9)29%!$#*%2?(F!
! 9)29%!(-g%?(F!
! 4/%'/%.!'/%!*%9-1%!4)(!('%.-2%!#.!&#&C('%.-2%!
! 4/%'/%.!'/%!*%9-1%!4)(!),%*!3%0#.%!-$82)&')'-#&!
! KH
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
! 1#&'.#2!*%9-1%!!
! -$82)&'!2#1)'-#&:!
!
\/%!0-&)2!.%8#.'!(/#+2*!)2(#!*%(1.-3%!)&-$)2!0#22#4!+8:!!\/%!*%(1.-8'-#&!(/#+2*!-&12+*%!
0.%P+%&17G!*+.)'-#&G!)&*!%9)2+)'-#&!$%'/#*?(F:!
!
W#+.!.%8#.'!(/#+2*!*%0-&%!0)-2+.%(!?%:,:G!*%9-1%!0)-2+.%(!(+1/!)(!2%)02%'!'%).G!('%&'!0.)1'+.%G!
3)22##&!.+8'+.%F:!!W#+!(/#+2*!-&*-1)'%!'/%!'#')2!&+$3%.!#0!*%9-1%!0)-2+.%(!)&*!-&12+*%!)!
1#$82%'%!*%(1.-8'-#&!0#.!%)1/:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!%Y82)-&!)&7!8.#1%*+.)2!0)-2+.%(!
(+1/!)(!9)29%!$-()2-,&$%&'G!-$8.#8%.!(+'+.-&,G!#.!(-g%!$-($)'1/G!)&*!'/)'!7#+!8.#9-*%!)!
1#$82%'%!*%(1.-8'-#&!#0!%)1/:!!\/%!.%8#.'!(/#+2*!(/#4!'/%!'#')2!&+$3%.!#0!0)-2+.%(G!('.)'-0-%*!
37!7#+.!*%0-&-'-#&(:
!
W#+.!'%('!.%8#.'!$+('!-&12+*%!)!*%(1.-8'-#&!#0!)22!1-.1+$(')&1%(!'/)'!$)7!/)9%!)00%1'%*!'/%!
P+)2-'7!#.!-&'%,.-'7!#0!'/%!*)')G!-&12+*-&,!)!2-('-&,!#0!)22!8.#'#1#2!*%9-)'-#&(!)&*!'/%-.!-$8)1'!
#&!('+*7!0-&*-&,(!?LK!"AJ!EM:KME?)F?5FF:!!!
!
F. Submitting Animal Study Information to your IDE and
PMA
W#+!$+('!(+3$-'!7#+.!0-&)2!.%8#.'!#0!)22!)&-$)2!('+*-%(!'#!7#+.!U<S!)&*![>B!?MKL:LT?)FG!
MKZ:L6?3F?HF?-FF: W#+!(/#+2*!8.#9-*%!0#.!%)1/!('+*7N!
! ('+*7!*)'%(!
! %&*8#-&'(!!
! 0)-2+.%!)&*!(+11%((!1.-'%.-)!
! 8/7(-#2#,-1)2!.%(8#&(%(!'%('%*!?%:,:G!1).*-)1!#+'8+'!?"RFF!!!
! )&7!-&#'.#8-1!*.+,!)*$-&-('%.%*!?)&*!*#(%F!
! )&-$)2!$#*%2?(F!%$82#7%*!
! &+$3%.!#0!)&-$)2(!+(%*!
! )&-$)2!),%!)&*!9%.-0-1)'-#&!?-0!3-.'/!.%1#.*(!).%!&#'!)9)-2)32%G!4%!.%1#$$%&*!+(-&,!
*%&')2!%.+8'-#&!'-$%!)&*!$#.8/#2#,-1)2!1/)&,%(!#0!'/%!*%&')2!')32%F!
! $%*-1)'-#&(!)&*!*#(%(!,-9%&!0#.!8.%C8.#1%*+.%G!*+.-&,!8.#1%*+.%G!)&*!8#('C
8.#1%*+.%:!
c%!)2(#!.%1#$$%&*!'/)'!7#+!%Y82)-&!/#4!'/%!)&-$)2!$#*%2(!)&*!$%*-1)'-#&(!)*%P+)'%27!
.%8.%(%&'!'/%!-&'%&*%*!8)'-%&'!8#8+2)'-#&!)&*!)&'-1-8)'%*!12-&-1)2!%Y8%.-%&1%:!
!
U0!'/%!*%9-1%!7#+!-&'%&*!'#!$).=%'!*-00%.(!0.#$!'/%!9%.(-#&!+(%*!-&!'/%!)&-$)2!('+*-%(G!4%!
.%1#$$%&*!'/)'!7#+!*%(1.-3%!)22!1/)&,%(!-&!*%(-,&!)&*!$)&+0)1'+.-&,!0#22#4-&,!'/%!('+*-%(!
)&*!'/)'!7#+!8.#9-*%!)!.)'-#&)2%!'#!(+88#.'!+(-&,!)!*%9-1%!'/)'!-(!*-00%.%&'!0.#$!'/%!#&%!'/)'!-(!
-&'%&*%*!'#!3%!$).=%'%*:!
!
! KT
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
XIII. Clinical Investigations
"2-&-1)2!('+*-%(!).%!&%1%(().7!'#!%9)2+)'%!$#('!&%4!.%82)1%$%&'!/%).'!9)29%!*%(-,&(:!!c%!
.%1#$$%&*!'/)'!7#+!8%.0#.$!12-&-1)2!-&9%('-,)'-#&(!#0!7#+.!.%82)1%$%&'!/%).'!9)29%!0#22#4-&,!
'/%!$%'/#*(!*%(1.-3%*!-&!U;R!EMZ6NL66E!#.!%P+-9)2%&'!$%'/#*(:!![.-#.!'#!(+3$-''-&,!7#+.!U<S!
)882-1)'-#&G!7#+!$)7!4)&'!'#!#3')-&!A<B!-&8+'!#&!7#+.!12-&-1)2!('+*7!8.#'#1#2!9-)!'/%!8.%C
(+3$-((-#&!8.#1%((:!
!
[2%)(%!(%%!B88%&*-Y!<!#0!'/-(!,+-*)&1%!0#.!)**-'-#&)2!.%1#$$%&*)'-#&(!)3#+'!%1/#1).*-#,.)8/7!
4/%&!+(%*!-&!'/%!12-&-1)2!%9)2+)'-#&!#0!.%82)1%$%&'!/%).'!9)29%(:!!\/%!8.#'#1#2!(+3$-''%*!-&!7#+.!
U<S!)&*!'/%!0-&)2!12-&-1)2!.%8#.'!(+3$-''%*!-&!7#+.![>B!)882-1)'-#&(!(/#+2*!)**.%((!'/%!-((+%(!
*%(1.-3%*!3%2#4:!
!
A. Data Safety Monitoring Board
;8#&(#.(!).%!.%(8#&(-32%!0#.!%&(+.-&,!8.#8%.!$#&-'#.-&,!#0!'/%!-&9%('-,)'-#&!)&*!$+('!(%2%1'!
$#&-'#.(!P+)2-0-%*!37!'.)-&-&,!)&*!%Y8%.-%&1%!?LK!"AJ!MKL:Z6!)&*!LK!"AJ!MKL:ZD?*FF:!c%!
.%1#$$%&*!'/)'!7#+!%(')32-(/!)!<)')!;)0%'7!>#&-'#.-&,!_#).*!?<;>_FKK!'#!.%9-%4!)*9%.(%!
%9%&'(!)&*!.%1#$$%&*!('+*7!'%.$-&)'-#&!-0!()0%'7!1#&1%.&(!4)..)&':!!\/%!<;>_!(/#+2*!
%(')32-(/!1.-'%.-)!0#.!.%1#$$%&*-&,!('+*7!'%.$-&)'-#&!0#.!()0%'7!.%)(#&(!3%0#.%!'/%!('+*7!
3%,-&(!)&*!(/#+2*!$%%'!)'!2%)('!'4#!'-$%(!*+.-&,!'/%!('+*7!'#!$#&-'#.!)*9%.(%!%9%&'(:!!\/%!
<;>_!(/#+2*!/)9%!$%$3%.(!4/#!).%!-&*%8%&*%&'!0.#$!'/%!('+*7!(8#&(#.(!)&*!
-&9%('-,)'#.(:!!\4#!#.!$#.%!$%$3%.(!(/#+2*!3%!8/7(-1-)&(G!-&12+*-&,!)!1).*-#'/#.)1-1!
(+.,%#&!)&*!)!1).*-#2#,-(':!!U0!'/%!('+*7!-&12+*%(!(')'-('-1)2!)&)27(%(G!#&%!$%$3%.!(/#+2*!3%!)!
(')'-('-1-)&:!
!
B. Clinical Events Committee
c%!.%1#$$%&*!'/)'!7#+!%(')32-(/!)!"2-&-1)2!S9%&'(!"#$$-''%%!?"S"F!0#.!'/%!12-&-1)2!
-&9%('-,)'-#&!-&!#.*%.!'#!)*l+*-1)'%!)*9%.(%!%9%&'(!)(!3%-&,!9)29%C.%2)'%*!#.!&#'G!)&*!'#!
12)((-07!'/%!(%9%.-'7!#0!)*9%.(%!%9%&'(:!!\/%!"S"!(/#+2*!/)9%!$%$3%.(!4/#!).%!-&*%8%&*%&'!
0.#$!'/%!('+*7!(8#&(#.(!)&*!-&9%('-,)'#.(:!
!
C. Number of Investigators
U0!7#+.!('+*7!+(%(!#&27!#&%!12-&-1)2!-&9%('-,)'#.G!4%!.%1#$$%&*!'/)'!7#+!8.#9-*%!7#+.!
.)'-#&)2%!'#!(/#4!4/7!%Y8%.-%&1%!0.#$!'/-(!#&%!12-&-1)2!-&9%('-,)'#.!-(!(+00-1-%&'!'#!
*%$#&('.)'%!'/%!()0%'7!)&*!%00%1'-9%&%((!#0!7#+.!*%9-1%!)&*!'#!%&(+.%!.%8.#*+1-3-2-'7!#0!'%('!
.%(+2'(!)1.#((!$+2'-82%!*%9-1%!+(%.(:!
!
!
!
!KK!;%%!V+-*)&1%!0#.!12-&-1)2!'.-)2!(8#&(#.(!#&!:+,%;&*+73"5,'%5#'<4"$%,*15'1.'=&*5*>%&'?$*%&'-%,%'
@15*,1$*5)'=133*,,""+G!>).1/!L66H:!!
/''8NOO444:0*):,#9OJ%,+2)'#.7U&0#.$)'-#&OV+-*)&1%(O+1$KLT6H5:/'$:! !
! KM
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
D. Investigational Sites
U&9%('-,)'-#&)2!(-'%(!).%!)22!'/%!1%&'%.(!-$82)&'-&,!'/%!9)29%!-&!'/%!`&-'%*!;')'%(G!)&*!)22!'/%!
0#.%-,&!1%&'%.(!-$82)&'-&,!'/%!9)29%!'/)'!(+3$-'!*)')!)(!8).'!#0!'/%!-&9%('-,)'-#&:!!B22!(+3l%1'(!
(/#+2*!3%!1#$82%'%27!)11#+&'%*!0#.!-&!'/%!0-&)2!12-&-1)2!.%8#.':!!c%!.%1#$$%&*!'/)'!7#+!
8.#9-*%!1#$82%'%!(+3l%1'!)11#+&'-&,!#&!)!8%.!(+3l%1'!3)(-(!0#.!%)1/!1#/#.':!!W#+!(/#+2*!
-&12+*%!'/%!&+$3%.!#0!(+3l%1'(!%Y8%1'%*!0#.!0#22#4C+8G!*-(1#&'-&+%*!3%1)+(%!#0!*%)'/!#.!
*%9-1%!.%$#9)2G!)&*!)1'+)227!%9)2+)'%*!)'!%)1/!%9)2+)'-#&!'-$%!8#-&':!!!
!
E. Data Collection
\/%!(8#&(#.!4/#!*-(1#9%.(!'/)'!)&!-&9%('-,)'#.!-(!&#'!1#$827-&,!4-'/!'/%!(-,&%*!),.%%$%&'G!
'/%!-&9%('-,)'-#&)2!82)&G!.%P+-.%$%&'(!-&!LK!"AJ![).'!MKL!#.!#'/%.!)882-1)32%!A<B!
.%,+2)'-#&(G!#.!)&7!1#&*-'-#&(!#0!)88.#9)2!-$8#(%*!37!'/%!.%9-%4-&,!-&9%('-,)'-#&)2!.%9-%4!
3#).*!#.!A<B!-(!.%(8#&(-32%!0#.!8.#$8'27!(%1+.-&,!'/%!-&9%('-,)'#.(!1#$82-)&1%!#.!
*-(1#&'-&+-&,!(/-8$%&'!#0!'/%!*%9-1%!'#!'/%!-&9%('-,)'#.!)&*!'%.$-&)'-&,!'/%!-&9%('-,)'#.f(!
8).'-1-8)'-#&!-&!'/%!-&9%('-,)'-#&!?LK!"AJ!MKL:ZH?)FF:!!W#+.!8.#'#1#2!$+('!%&(+.%!'/)'!'/%!
-&9%('-,)'-#&!-(!(1-%&'-0-1)227!(#+&*!37!%&(+.-&,!1#&(-('%&17!3%'4%%&!'/%!-&*-1)'-#&!('+*-%*G!
)&*!'/%!(+3l%1'!-&12+(-#&!)&*!%Y12+(-#&!1.-'%.-)!?LK!"AJ!MKL:LE?3FF:!!U&!)22!('+*7!*%(-,&(G!7#+!
(/#+2*!%&(+.%!'/)'!-&9%('-,)'#.(!1#22%1'!'/%!)88.#8.-)'%!-&0#.$)'-#&:!!;8%1-0-1)227G!7#+!(/#+2*!
%&(+.%!'/)'!'/%!12-&-1)2!*)')!1#22%1'-#&!0#.$(!+(%*!37!'/%!-&9%('-,)'#.(!)&*!-&('-'+'-#&(!).%!
1#&(-('%&'!4-'/!'/%!12-&-1)2!8.#'#1#2:!!W#+!(/#+2*!)2(#!%&(+.%!'/)'!-&0#.$%*!1#&(%&'!
*#1+$%&'?(F!).%!1#&(-('%&'!4-'/!'/%!12-&-1)2!8.#'#1#2:!
!
F. Control Data
_)(%*!#&!#+.!2#&,!/-('#.7!-&!'/%!%9)2+)'-#&!#0!/%).'!9)29%(!)&*!'/%!%Y'%&(-9%!.%8#.'-&,!-&!'/%!
2-'%.)'+.%G!A<B!3%2-%9%(!'/)'!)!(-&,2%C).$!('+*7!4-'/!2-'%.)'+.%C3)(%*!1#&'.#2(!-(!'/%!2%)('!
3+.*%&(#$%!)88.#)1/!'#!12-&-1)2!%9)2+)'-#&!#0!)!.%82)1%$%&'!/%).'!9)29%:!!W#+.!12-&-1)2!('+*7!
(/#+2*!-&12+*%!)88.#8.-)'%!1#&'.#2(!-&12+*-&,!2-'%.)'+.%C3)(%*!#3l%1'-9%!8%.0#.$)&1%!1.-'%.-)!
?R["(F!0#.!()0%'7!*)')G!)&*!2-'%.)'+.%!).'-12%(!)&*!.%8#.'(!0#.!3#'/!()0%'7!)&*!%00%1'-9%&%((!
*)'):!!\/%!R["(!(/#+2*!3%!%(')32-(/%*!0.#$!*)')!,%&%.)'%*!0#.!)!(-$-2).!'78%!#0!.%82)1%$%&'!
/%).'!9)29%G!)&*!'/%!).'-12%(!)&*!.%8#.'(!(/#+2*!)**.%((!)!(-$-2).!'78%!#0!.%82)1%$%&'!/%).'!
9)29%!-&!'/%!()$%!9)29%!8#(-'-#&:!!\/%!1#&'.#2!*)')!0.#$!2-'%.)'+.%!).'-12%(!)&*!.%8#.'(!(/#+2*!
3%!1#22%1'%*!0.#$!('+*-%(!8+32-(/%*!-&!8%%.C.%9-%4%*!l#+.&)2(!*+.-&,!'/%!8)('!E!7%).(:!!\/%!
2-'%.)'+.%!1#&'.#2!()0%'7!*)')!(/#+2*!-&12+*%!%).27!)*9%.(%!%9%&'!.)'%!*)')G!2-&%).-g%*!2)'%!
)*9%.(%!%9%&'!.)'%!*)')G!)&*!)1'+).-)2!?+(+)227!])82)&C>%-%.F!)*9%.(%!%9%&'!.)'%!*)'):!!\/%!
2-'%.)'+.%!1#&'.#2!%00%1'-9%&%((!*)')!(/#+2*!-&12+*%!^%4!W#.=!@%).'!B((#1-)'-#&!?^W@BF!
0+&1'-#&)2!12)((-0-1)'-#&12!*)')!)&*!/%$#*7&)$-1!*)'):!!;%%!)2(#!(%1'-#&!I. Follow-Up Data
3%2#4 0#.!.%1#$$%&*)'-#&(!#&!/%$#*7&)$-1!('+*-%(!*)'):!
!
!KL!\/%!".-'%.-)!"#$$-''%%!#0!'/%!^%4!W#.=!@%).'!B((#1-)'-#&:!^#$%&12)'+.%!)&*!".-'%.-)!0#.!
<-),&#(-(!#0!<-(%)(%(!#0!'/%!@%).'!)&*!V.%)'!Q%((%2(:!5'/!%*:!_#('#&G!>)((N!I-''2%G!_.#4&!p!"#k!
K55ZNLEDCLEH:!
! K5
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
A#.!-&0)&'(!)&*!7#+&,!1/-2*.%&!.%1%-9-&,!.%82)1%$%&'!9)29%(!#.!9)29%*!1#&*+-'(!?(+1/!)(!
8+2$#&-1!9)29%*!1#&*+-'(F!-&!12-&-1)2!('+*-%(G!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!*)')!).%!&#'!
)88.#8.-)'%:!!R3')-&-&,!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!*)')!#&!-&0)&'(!)&*!7#+&,!1/-2*.%&!-(!
,%&%.)227!&#'!0%)(-32%!3%1)+(%!'/%(%!(+3l%1'(!).%!'##!7#+&,!'#!8.#9-*%!'/%!(7$8'#$!
-&0#.$)'-#&!&%1%(().7!0#.!(+1/!12)((-0-1)'-#&:!!A#.!'/%(%!(+3l%1'(!'/%!%9)2+)'-#&!#0!
%00%1'-9%&%((!-(!'78-1)227!3)(%*!(#2%27!#&!'/%!/%$#*7&)$-1!*)')G!4/-1/!$)7!3%!9).-#+(27!
(+882%$%&'%*!4-'/!#'/%.!%00%1'-9%&%((!*)')!(+1/!)(!1).*-)1!-$),-&,!*)')!)&*!%Y%.1-(%!'%('-&,!
*)'):!!!!
!
A<B!.%1#$$%&*(!'/%!+(%!#0!'/%!R["(!)(!2-('%*!-&!\)32%!J:K!#0!U;R!EMZ6NL66E!B&&%Y!J!
(-&1%!'/%(%!R["(!).%!3)(%*!#&!)&!%Y'%&(-9%!2-'%.)'+.%C3)(%*!.%9-%4!#0!$)&7!).'-12%(!0.#$!
*-00%.%&'!-&('-'+'-#&(:!!c%!*#!&#'!.%1#$$%&*!'/%!+(%!#0!'/%!R["(!-&!\)32%!J:L!#0!B&&%Y!J!
(-&1%!'/%(%!2)''%.!R["(!).%!3)(%*!#&!#&27!#&%!(%.-%(!#0!(+3l%1'(!?)23%-'!)!2).,%!(%.-%(F!)'!#&%!
-&('-'+'-#&:!!@#4%9%.G!-0!7#+!4-(/!'#!-&12+*%!)!1#&1+..%&'!1#&'.#2!,.#+8!-&!7#+.!('+*7G!4%!
.%1#$$%&*!'/)'!7#+!1#&')1'!'/%!<-9-(-#&!#0!").*-#9)(1+2).!<%9-1%(:!!
!
G. Sample Size and Follow-Up Effect on Complication Rate !
1. Patient-Years
c%!.%1#$$%&*!'/)'!7#+!$%)(+.%!0#22#4C+8!-&!h8)'-%&'C7%).(i!-&('%)*!#0!'/%!h9)29%C
7%).(i!3%1)+(%!*#+32%!9)29%!.%82)1%$%&'!?<QJF!(+3l%1'(G!4/#(%!0#22#4C+8!-(!%Y8.%((%*!
-&!9)29%C7%).(G!).%!'78-1)227!%Y12+*%*!0.#$!'/%!$)-&!)&)27(%(!#0!()0%'7!*)')!)&*!^W@B!
0+&1'-#&)2!12)((-0-1)'-#&!*)'):!!c%!)2(#!.%1#$$%&*!'/)'!7#+!%Y12+*%!<QJ!(+3l%1'(!0.#$!
'/%!$)-&!)&)27(-(!3%1)+(%!)*9%.(%!%9%&'(!)&*!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!1)&&#'!3%!
12%).27!)*l+*-1)'%*!'#!)!8).'-1+2).!9)29%!8#(-'-#&!-&!<QJ!(+3l%1'(:!!!
!
2. Duration of Follow-Up
U&!#.*%.!'#!8.#9-*%!)!12-&-1)227!(+00-1-%&'!)$#+&'!#0!*)')!#&!'/%!-&9%('-,)'-#&)2!
.%82)1%$%&'!/%).'!9)29%G!4%!.%1#$$%&*!'/)'!)22!(+3l%1'(!3%!0#22#4%*!0#.!K 7%).!#.!$#.%:!!!
!
U0!7#+.!12-&-1)2!-&9%('-,)'-#&!-(!0#.!#&%!9)29%!8#(-'-#&G!4%!.%1#$$%&*!'/)'!7#+!0#22#4!
D66!#.!$#.%!(+3l%1'(!0#.!K!7%).!#.!$#.% 0#.!)!'#')2!#0!M66!8)'-%&'C7%).(!#0!0#22#4C+8:KD!
!
U0!'/%!('+*7!-(!0#.!'4#!9)29%!8#(-'-#&(!?-:%:G!)#.'-1!)&*!$-'.)2FG!4%!.%1#$$%&*!'/)'!7#+!
0#22#4!KE6!(+3l%1'(!0#.!#&%!7%).!#.!$#.% 0#.!%)1/!9)29%!8#(-'-#&!0#.!)!'#')2!#0!Z66!8)'-%&'C
7%).(!#0!0#22#4C+8!8%.!9)29%!8#(-'-#&:!
!KD!\/%!.%1#$$%&*%*!0#22#4C+8!#0!M66!8)'-%&'C7%).(!-(!(')'-('-1)227!*%.-9%*!)(!0#22#4(N!!;-&,2%!
()$82%!#&%C(-*%*!/78#'/%(-(!'%('-&,!1)&!3%!+(%*!'#!*%$#&('.)'%!'/)'!%)1/!#0!'/%!1#$82-1)'-#&!
.)'%(!)((#1-)'%*!4-'/!'/%!-&9%('-,)'-#&)2!*%9-1%!-(!2%((!'/)&!L!'-$%(!'/%!R["!0#.!'/)'!
1#$82-1)'-#&:!!\/%!)88.#8.-)'%!&+22!/78#'/%(-(!-(!'/)'!'/%!'.+%!.)'%!)((#1-)'%*!4-'/!'/%!
-&9%('-,)'-#&)2!*%9-1%!-(!L!#.!$#.%!'-$%(!-'(!R[":!!\#!.%l%1'!'/-(!&+22!/78#'/%(-(!-(!'#!)11%8'!'/%!
)2'%.&)'-9%!/78#'/%(-(!'/)'!'/%!'.+%!.)'%!)((#1-)'%*!4-'/!'/%!-&9%('-,)'-#&)2!*%9-1%!-(!2%((!'/)&!L!
'-$%(!-'(!R[":!!!
! L6
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
!
c%!.%1#$$%&*!'/)'!7#+!1#&*+1'!'/%!12-&-1)2!('+*7!)'!%-,/'!#.!$#.%!8.-$).7!1%&'%.(G!4-'/!
D6!#.!$#.%!(+3l%1'(!-$82)&'%*!)'!%)1/!1%&'%.!0#.!)!#&%C8#(-'-#&!('+*7!)&*!KE!#.!$#.%!
(+3l%1'(!-$82)&'%*!)'!%)1/!1%&'%.!0#.!)!'4#C8#(-'-#&!('+*7:!!c%!3%2-%9%!'/)'!+(-&,!0%4%.!
'/)&!%-,/'!8.-$).7!1%&'%.(!1)&!-&'.#*+1%!3-)(!-&'#!'/%!('+*7:!
!
A#.!3#'/!#&%!8#(-'-#&!)&*!'4#!8#(-'-#&!('+*-%(G!4%!.%1#$$%&*!-$82)&'-&,!KE!#.!$#.%!
(+3l%1'(!0#.!%)1/!(-g%!)&*!%)1/!8#(-'-#&!0#.!)22!9)29%!(-g%(:!!U&!#'/%.!4#.*(G!-0!7#+.!('+*7!
)((%((%(!3#'/!)#.'-1!)&*!$-'.)2!.%82)1%$%&'(G!7#+.!('+*7!(/#+2*!%&.#22!KE!#.!$#.%!
(+3l%1'(!)'!'/%!)#.'-1!8#(-'-#&!)&*!)&!)**-'-#&)2!KE!#.!$#.%!(+3l%1'(!)'!'/%!$-'.)2!8#(-'-#&G!
0#.!%)1/!9)29%!(-g%:!!\/%!KE!(+3l%1'(!-$82)&'%*!8%.!(-g%!8%.!8#(-'-#&!1.-'%.-#&!-(!3)(%*!#&!
(')'-('-1)2!1)21+2)'-#&(!0#.!%1/#1).*-#,.)8/-1!%00%1'-9%!#.-0-1%!).%)!?SRBF!*)'):!!\/%(%!
1)21+2)'-#&(!(/#4!'/)'!-&!#.*%.!'#!)((+.%!)!(+00-1-%&'27!&)..#4!5Eo!1#&0-*%&1%!-&'%.9)2G!
'/%!$-&-$+$!&+$3%.!#0!(+3l%1'(!-$82)&'%*!4-'/!%)1/!9)29%!(-g%!-(!KE:!!U0!7#+!#$-'!)&7!
(-g%(G!4%!.%1#$$%&*!'/)'!7#+!%Y82)-&!/#4!'/%!*)')!7#+!1#22%1'!).%!.%8.%(%&')'-9%!#0!)22!
'/%!(-g%(!'/)'!7#+!-&'%&*!'#!$).=%':!
!
3. Complication Rates
B((+$-&,!'/%![#-((#&!*-('.-3+'-#&!)&*!'/%!'.+%!.)'%!3%-&,!%P+)2!'#!-'(!R["G!)&*!4-'/!
8.#3)3-2-'-%(!#0!\78%!U!%..#.!#0!6:6E!)&*!\78%!UU!%..#.!#0!6:L6G!'/%!)$#+&'!#0!*)')!
&%1%(().7!'#!)1/-%9%!'/%!($)22%('!R["!#0!K:Lo!8%.!8)'-%&'C7%).!?%Y12+*-&,!'/%!R["(!0#.!
9)29%!'/.#$3#(-(G!$)l#.!/%$#../),%G!)&*!$)l#.!8%.-9)29+2).!2%)=G!4/-1/!).%!)22!2%((!'/)&!
K:Lo!8%.!8)'-%&'C7%).F!-(!M66!8)'-%&'C7%).(!?)#.'-1!)&*!$-'.)2!8#(-'-#&(!1#$3-&%*F:KD!!\/%!
&+22!/78#'/%(-(!0#.!)!1#$82-1)'-#&!.)'%!1)&!3%!.%l%1'%*!)'!'/%!#&%C(-*%*!(-,&-0-1)&1%!2%9%2!
#0!6:6E!-0!'/%!+88%.!5Eo!1#&0-*%&1%!2-$-'!0#.!'/%!1#$82-1)'-#&!.)'%!-(!2%((!'/)&!L!'-$%(!'/%!
R["!0#.!'/)'!1#$82-1)'-#&:KZGKE
!
4. Complications
c%!.%1#$$%&*!'/)'!'/%!1#$82-1)'-#&!*)')!-&12+*%!/%$#../),%(!.%(+2'-&,!0.#$!)22!1)+(%(!
?)22C1)+(%!/%$#../),%F!.)'/%.!'/)&!l+('!/%$#../),%!.%2)'%*!'#!)&'-1#),+2)&'!'/%.)87!
?)&'-1#),+2)&'C.%2)'%*!/%$#../),%F:!!B**-'-#&)227G!4%!.%1#$$%&*!'/)'!'/%!1#$82-1)'-#&!
*)')!-&12+*%!)22C1)+(%!.%#8%.)'-#&G!9)29%C.%2)'%*!.%#8%.)'-#&G!%Y82)&'G!)22C1)+(%!*%)'/G!)&*!
9)29%C.%2)'%*!*%)'/:!!!
!
H. Pre-Operative Data
\/%!*-),&#('-1!8.%C#8%.)'-9%!*)')!1#22%1'%*!(/#+2*!-&12+*%!'/%!&#.$)2!.)&,%(!0#.!'/%!12-&-1)2!
2)3#.)'#.7!32##*!'%('(!'/)'!).%!%9)2+)'%*G!4-'/!'/%!&#.$)2!.)&,%(!3%-&,!*%'%.$-&%*!37!'/%!
2)3#.)'#.-%(!+(%*:!!
!
!KZ!V.+&=%$%-%.!VIG!a#/&(#&!<>G!)&*!^)0'%2!<"G!;)$82%!(-g%!.%P+-.%$%&'(!0#.!%9)2+)'-&,!/%).'!
9)29%(!4-'/!1#&(')&'!.-(=!%9%&'(:!A'B"%$,'C%&6"'-*+!DNEDCEMG!K55Z:!KE!S*$+&*(!I@G!a.G!",'%&D!V+-*%2-&%(!0#.!.%8#.'-&,!$#.3-*-'7!)&*!$#.')2-'7!)0'%.!1).*-)1!9)29+2).!
#8%.)'-#&(:!A'?71$%>'=%$#*16%+>'E8$)!KKLNT6MCTKKG!K55H:!
! LK
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
I. Follow-Up Data
S)1/!(+3l%1'!%&'%.%*!-&'#!'/%!('+*7!(/#+2*!3%!0#22#4%*!)11#.*-&,!'#!'/%!('+*7!8.#'#1#2:!!
B**-'-#&)227G!0#22#4C+8!*)')!(/#+2*!3%!1#22%1'%*!0#.!%)1/!(+3l%1'!+&'-2!'/%!%&'-.%!('+*7!-(!
'%.$-&)'%*!0#.!)22!(+3l%1'(:!!\/-(!0#22#4C+8!*)')!(/#+2*!3%!1#22%1'%*!37!#00-1%G!12-&-1G!#.!
/#(8-')2!9-(-'k!'%2%8/#&%!0#22#4C+8!(/#+2*!3%!+(%*!#&27!'#!9%.-07!*%)'/!#.!2#((!'#!0#22#4C+8:!!
B(!'/-(!0#22#4C+8!*)')!(/#+2*!3%!1#22%1'%*!+&'-2!'/%!%&'-.%!('+*7!-(!'%.$-&)'%*!0#.!)22!8)'-%&'(G!
'/%!0#22#4C+8!8%.-#*!$)7!3%!(-,&-0-1)&'27!2#&,%.!'/)&!(')'%*!-&!'/%!('+*7!8.#'#1#2!0#.!$#('!
8)'-%&'(:!!B11#.*-&,27G!7#+!$+('!.%1%-9%!-&0#.$%*!1#&(%&'!'#!(+1/!0#22#4C+8!8%.-#*!0.#$!)22!
(+3l%1'(!?LK!"AJ!E6:LE?)F?KFF:!!B&7!(+3l%1'!&#'!4-22-&,!'#!0+227!8).'-1-8)'%!-&!'/%!('+*7G!
-&12+*-&,!'/%!0#22#4C+8!8%.-#*G!(/#+2*!&#'!3%!%&'%.%*:KH!!!!!!
A#22#4C+8!*)')!(/#+2*!-&12+*%!'/%!&#.$)2!.)&,%(!0#.!'/%!12-&-1)2!2)3#.)'#.7!32##*!'%('(!
%9)2+)'%*!)11#.*-&,!'#!'/%!&#.$)2!.)&,%(!+(%*!37!'/%!2)3#.)'#.-%(!'/)'!1#&*+1'%*!'/%!'%('-&,:!!
[2)($)!0.%%!/%$#,2#3-&!-(!8.%0%.)32%!'#!(%.+$!2)1')'%!*%/7*.#,%&)(%G!/)8'#,2#3-&G!)&*!
.%'-1+2#17'%!1#+&'!0#.!'/%!%9)2+)'-#&!0#.!/%$#27(-(!3%1)+(%!4%!3%2-%9%!82)($)!0.%%!
/%$#,2#3-&!/)(!/-,/%.!12-&-1)2!(%&(-'-9-'7!0#.!'/%!*%'%1'-#&!#0!/%$#27(-(!'/)&!'/%!#'/%.!'/.%%!
2)3#.)'#.7!'%('(:!!
c%!.%1#$$%&*!'/)'!7#+!8.#9-*%!'/%!0#22#4-&,!%1/#1).*-#,.)8/-1!/%$#*7&)$-1!*)')G!
('.)'-0-%*!37!9)29%!(-g%N!!
! 8%)=!8.%((+.%!,.)*-%&'!
! $%)&!8.%((+.%!,.)*-%&'!
! %00%1'-9%!#.-0-1%!).%)!
! 9)29+2).!.%,+.,-')'-#&!
! %00%1'-9%!#.-0-1%!).%)!-&*%YKT!
! 8%.0#.$)&1%!-&*%Y!
! 1).*-)1!#+'8+'!
! 1).*-)1!-&*%Y:!
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!KH!R0'%&!8)'-%&'(!).%!0#22#4%*!37!'/%-.!8%.(#&)2!1).*-#2#,-('G!&#'!'/%!(+.,%#&k!'/%.%0#.%G!'/%!
-&9%('-,)'#.!(/#+2*!4#.=!-&!1#&l+&1'-#&!4-'/!'/%!8/7(-1-)&!.%(8#&(-32%!0#.!0#22#4-&,!'/%!8)'-%&'!
'#!%&(+.%!'/)'!'/%!-&9%('-,)'#.!1#22%1'(!'/%!)88.#8.-)'%!*)')!)'!'/%!1#..%1'!'-$%!8%.-#*(:!!\/-(!$)7!
3%!3%''%.!)11#$82-(/%*!-0!%-'/%.!'/%!-&9%('-,)'#.!#.!'/%!(8#&(#.!#3')-&(!1#&')1'!-&0#.$)'-#&!0#.!
'/%!0#22#4-&,!8/7(-1-)&G!(#!/%O(/%!1)&!3%!)*9-(%*!#0!'/%!)1'+)2!('+*7!8.#'#1#2:!KT!A#.!.%82)1%$%&'!8+2$#&-1!9)29%(!)&*!8+2$#&-1!9)29%*!1#&*+-'(G!4%!*#!&#'!.%1#$$%&*!'/)'!
7#+!1)21+2)'%!'/%!%00%1'-9%!#.-0-1%!).%)G!(-&1%!'/%!1#&%!(/)8%!#0!'/%!.-,/'!9%&'.-1+2).!#+'02#4!'.)1'!
$)=%(!%1/#1).*-#,.)8/-1!$%)(+.%$%&'!#0!'/%!.-,/'!9%&'.-1+2).!#+'02#4!'.)1'!*-)$%'%.!*-00-1+2':!!
\/-(!*-00-1+2'!$%)(+.%$%&'!2%)*(!'#!8#'%&'-)2!-&)11+.)'%!1)21+2)'-#&!#0!'/%!8+2$#&-1!9)29%!
%00%1'-9%!#.-0-1%!).%)!9-)!'/%!1#&'-&+-'7!%P+)'-#&!$%'/#*:!!;-$-2).27G!0#.!.%82)1%$%&'!8+2$#&-1!
9)29%(!)&*!8+2$#&-1!9)29%*!1#&*+-'(G!4%!*#!&#'!.%1#$$%&*!'/)'!7#+!1)21+2)'%!%00%1'-9%!#.-0-1%!
).%)!-&*%Y!)&*!8%.0#.$)&1%!-&*%Y!*)')G!4/-1/!).%!1)21+2)'%*!+(-&,!%00%1'-9%!#.-0-1%!).%)!*)'):!!
! LL
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
J. Clinical Laboratory Results in Children
"2-&-1)2!2)3#.)'#.7!1#22%1'-#&(!).%!9%.7!('.%((0+2!0#.!-&0)&'(!)&*!7#+&,!1/-2*.%&!.%1%-9-&,!
.%82)1%$%&'!9)29%(!#.!9)29%*!1#&*+-'(!?%:,:G!8+2$#&-1!9)29%*!1#&*+-'(F:!!\/%.%0#.%G!-'!$)7!3%!
)88.#8.-)'%!'#!#$-'!12-&-1)2!2)3#.)'#.7!1#22%1'-#&(!0#.!/%$#27(-(!%9)2+)'-#&!)'!/#(8-')2!
*-(1/).,%!)&*!D!$#&'/(!8#('C-$82)&'!-&!'/%(%!8#8+2)'-#&(:!!@#4%9%.G!4%!.%1#$$%&*!'/)'!
7#+!('-22!8%.0#.$!12-&-1)2!2)3#.)'#.7!1#22%1'-#&(!)'!H!$#&'/(!)&*!K!7%).!8#('C-$82)&'G!)&*!
)&&+)227!'/%.%)0'%.!)(!(8%1-0-%*!-&!7#+.!8.#'#1#2:!!A#.!-&0)&'(!)&*!7#+&,!1/-2*.%&!4/#!).%!
+&)32%!'#!/)9%!)22!#0!'/%!12-&-1)2!2)3#.)'#.7!32##*!'%('!1#22%1'-#&(!)11#.*-&,!'#!'/%!&#.$)2!
.)&,%(!+(%*!37!'/%!2)3#.)'#.-%(!'/)'!1#&*+1'%*!'/%!'%('-&,G!(8#'!+.-&%!+.#3-2-&#,%&!-(!)&!
)11%8')32%!'%('!0#.!/%$#27(-(!%9)2+)'-#&:!
!
K. Imaging Data
c%!.%1#$$%&*!'/)'!'/%!-$),-&,!*)')!4-'/-&!'/%!0#22#4C+8!*)')!-&12+*%!.%8#.'(!#0N!!
! %1/#1).*-#,.)$(!
! 1).*-)1!1)'/%'%.-g)'-#&(!
! )&7!#'/%.!1).*-#9)(1+2).!-$),-&,!8.#1%*+.%(G!-&12+*-&,!"\!)&*!>J!(1)&(!
! 1/%('!YC.)7(:!
!
L. Additional Information
U&!)11#.*)&1%!4-'/!LK!"AJ!MKZ:L6?3F?DF?9F?_FG!7#+.![>B!$+('!-&12+*%!)!(+$$).7!#0!'/%!
12-&-1)2!-&9%('-,)'-#&(G!-&12+*-&,!)*9%.(%!.%)1'-#&(!)&*!1#$82-1)'-#&(:!!c%!.%1#$$%&*!7#+.!
(+$$).7!(8%1-0-1)227!-&12+*%N!!
! 1)(%!(+$$).-%(!#0!%)1/!*%)'/!4-'/!)!*%'%.$-&)'-#&!#0!4/%'/%.!'/%!*%)'/!.%8.%(%&'(!)&!
%).27!#.!)!2)'%!*%)'/KMk!)&*!
! '/%!(+$$).7!#0!(+3l%1'(!&#'!1#$82%'-&,!('+*7!('.)'-0-%*!37!2#('C'#C0#22#4!+8G!*%)'/G!#.!
%Y82)&'F:!
!
c%!.%1#$$%&*!'/)'!7#+!)2(#!-&12+*%!'/%!0#22#4-&,!-&0#.$)'-#&G!-0!)9)-2)32%N!
! 2#1)'-#&(!#0!'/%!-&9%('-,)'-#&)2!(-'%(k!
! 1#$8).-(#&!#0!8.%#8%.)'-9%!)&*!8#('#8%.)'-9%!^W@B!0+&1'-#&)2!12)((!?8.%(%&'%*!)(!
'/%!8%.1%&'),%!#0!(+3l%1'(!-&!%)1/!12)((!)'!3)(%2-&%G!)'!%)1/!0#22#4C+8!'-$%C8#-&'G!)&*!
)(!'/%!8%.1%&'),%!#0!(+3l%1'(!)'!%)1/!0#22#4C+8!'-$%C8#-&'!4/#!-$8.#9%*G!4#.(%&%*G!
#.!*-*!&#'!1/)&,%!-&!12)((Fk!
! '/%!q8.%C-$82)&'q!%00%1'-9%!#.-0-1%!).%)!#0!'/%!.%82)1%$%&'!/%).'!9)29%k!!
!KM!A<B!1#&(-*%.(!)!*%)'/!#11+..-&,!4-'/-&!D6!*)7(!#0!-$82)&')'-#&!#.!*+.-&,!'/%!-&-'-)2!
/#(8-')2-g)'-#&G!4/-1/%9%.!'-$%!8%.-#*!-(!2#&,%.G!'#!3%!)&!%).27!*%)'/:!!A<B!1#&(-*%.(!)22!#'/%.!
*%)'/(!'#!3%!2)'%!*%)'/(:!
! LD
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
! &+$3%.(!#0!-$82)&'%*!(+3l%1'(!('.)'-0-%*!37!-&9%('-,)'-#&)2!(-'%G!.%82)1%$%&'!9)29%!
8#(-'-#&!?%:,:G!)#.'-1G!$-'.)2G!#.!*#+32%!9)29%!.%82)1%$%&'FG!)&*!9)29%!(-g%k!
! &+$3%.(!#0!-$82)&'%*!(+3l%1'(!0#22#4%*!'#!K!7%).!8#('C-$82)&'!('.)'-0-%*!37!
-&9%('-,)'-#&)2!(-'%G!.%82)1%$%&'!9)29%!8#(-'-#&!?%:,:G!)#.'-1G!$-'.)2G!#.!*#+32%!9)29%!
.%82)1%$%&'FG!)&*!9)29%!(-g%k!
! 0#22#4C+8!*+.)'-#&!-&0#.$)'-#&!?'#')2!)&*!37!9)29%!8#(-'-#&FG!-&12+*-&,!$%)&!0#22#4C
+8G!(')&*).*!*%9-)'-#&!)&*!.)&,%!#0!0#22#4C+8G!)&*!1+$+2)'-9%!0#22#4C+8!-&!8)'-%&'C
7%).(k!
! 1#&0#+&*-&,!0)1'#.(!37!/)g).*!.%,.%((-#&!)&)27(-(!)882-%*!'#!-*%&'-07!.-(=!0)1'#.(!
?%:,:G!,%&*%.G!),%!)'!-$82)&'G!8.%C#8%.)'-9%!^W@B!0+&1'-#&)2!12)((-0-1)'-#&G!8.%9-#+(!
9)29%!(+.,%.7G!1#&1#$-')&'!1#.#&).7!).'%.7!378)((!(+.,%.7G!-$82)&'!8#(-'-#&G!)&*!
-$82)&'!(-g%FG!4/-1/!$-,/'!)00%1'!'/%!-&1-*%&1%!#0!.%#8%.)'-#&G!%Y82)&'G!)&*!*%)'/k!!
! 8)'-%&'!1#$82-)&1%!*)')!0#.!0#22#4C+8!9-(-'(G!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!*)')G!
%1/#1).*-#,.)8/-1!*)')G!)&*!12-&-1)2!2)3#.)'#.7!.%(+2'(k !
! 2-('!#0!1#$82-1)'-#&(!37!8)'-%&'!-*%&'-0-1)'-#&!&+$3%.k!
! (+$$).7!#0!(+3l%1'!1#$82)-&'(!.%1%-9%*k!
! 1)(%!.%8#.'!0#.$(!0#.!)!K6o!.)&*#$!()$82-&,!#0!'/%!(+3l%1'!8#8+2)'-#&k !
! 1#8-%(!#0!1)(%!.%8#.'!0#.$(!0#.!)22!(+3l%1'(!&#'!1#$82%'-&,!'/%!('+*7k!
! %Y82)&'!)&)27(-(!-&!)22!1)(%(!4/%&!)!9)29%!-(!%Y82)&'%*!#.!)&!)+'#8(7!-(!8%.0#.$%*k!
)&*!
! *%)'/!.%8#.'(!-&12+*-&,!)+'#8(7!.%8#.'(G!4/%&!)9)-2)32%G!%(8%1-)227!4/%&!'/%!1)+(%!#0!
*%)'/!/)(!3%%&!12)((-0-%*!)(!&#&C9)29%!.%2)'%*:!
!
M. Database Closure
\/%!12-&-1)2!*)')!-&!7#+.![>B!)882-1)'-#&!(/#+2*!3%!1+..%&'!'#!4-'/-&!(-Y!$#&'/(!#0!'/%!*)'%!
#0!(+3$-((-#&:!!W#+!$+('!)2(#!8%.-#*-1)227!+8*)'%!7#+.!8%&*-&,!)882-1)'-#&!4-'/!&%4!()0%'7!
)&*!%00%1'-9%&%((!-&0#.$)'-#&!2%).&%*!0.#$!#&,#-&,!#.!1#$82%'%*!('+*-%(!?LK!"AJ!MKZ:L6?%FF!
!
N. Subject Compliance
;+3l%1'!1#$82-)&1%!(/#+2*!3%!1)21+2)'%*!)(!'/%!0#22#4-&,!0#+.!8%.1%&'),%(N!'/%!&+$3%.!#0!
(+3l%1'(!/)9-&,!1#$82%'%*!0#22#4C+8!9-(-'(G!4-'/!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!*)')G!4-'/!
%1/#1).*-#,.)8/-1!*)')G!)&*!4-'/!12-&-1)2!2)3#.)'#.7!.%(+2'(!)'!%)1/!0#22#4C+8!'-$%C8#-&'G!
*-9-*%*!37!'/%!'#')2!&+$3%.!#0!-$82)&'%*!(+3l%1'(!)9)-2)32%!?-:%:G!4/#!/)9%!&#'!*-%*!#.!/)*!
'/%-.!9)29%!%Y82)&'%*F!)&*!%2-,-32%!?-:%:G!4/#!/)9%!.%)1/%*!'/%!,-9%&!'-$%C8#-&'F!0#.!0#22#4C+8!
)'!'/)'!8).'-1+2).!'-$%C8#-&':!!\/%!'#')2!&+$3%.!#0!(+3l%1'(!/)9-&,!%1/#1).*-#,.)8/7!%Y)$(!
(/#+2*!3%!'/%!()$%!)(!'/%!'#')2!&+$3%.!#0!(+3l%1'(!4-'/!*)')!0#.!%)1/!(8%1-0-1!
%1/#1).*-#,.)8/-1!/%$#*7&)$-1!8).)$%'%.!?-:%:G!8%)=!8.%((+.%!,.)*-%&'G!$%)&!8.%((+.%!
! LZ
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
,.)*-%&'G!%00%1'-9%!#.-0-1%!).%)G!%00%1'-9%!#.-0-1%!).%)!-&*%YGKT!8%.0#.$)&1%!-&*%YG!1).*-)1!
#+'8+'G!1).*-)1!-&*%YG!)&*!9)29+2).!.%,+.,-')'-#&F:!
!
O. Data Pooling
c%!3%2-%9%!'/)'!8##2-&,!*)')!0.#$!$#.%!'/)&!#&%!9)29%!8#(-'-#&G!(+1/!)(!8##2-&,!'/%!*)')!
0.#$!'/%!)#.'-1!)&*!$-'.)2!9)29%!8#(-'-#&(G!$)(=(!8#'%&'-)2!*-00%.%&1%(!-&!9)29%!0+&1'-#&!)&*!
9)29%C.%2)'%*!)*9%.(%!%9%&'(:!!\/%.%0#.%G!7#+!(/#+2*!('.)'-07!'/%!*)')!37!9)29%!8#(-'-#&!
-&('%)*!#0!8##2-&,!'/%(%!*)'):!
!
P. Adverse Events and Complication Rates
W#+.![>B!(/#+2*!-&12+*%!'/%!)1'+)2!&+$3%.!#0!)*9%.(%!%9%&'(:!!U&!)**-'-#&G!4%!.%1#$$%&*!
'/)'!7#+!%Y8.%((!%).27!1#$82-1)'-#&!.)'%(!)(!'/%!&+$3%.!#0!)*9%.(%!%9%&'(!*-9-*%*!37!'/%!'#')2!
&+$3%.!#0!(+3l%1'(G!)(!.%1#$$%&*%*!37!S*$+&*(!",'%&DKE!c%!.%1#$$%&*!'/)'!7#+!-&12+*%!
2-&%).-g%*!2)'%!1#$82-1)'-#&!.)'%(:!!I-&%).-g%*!2)'%!1#$82-1)'-#&!.)'%(!).%!1)21+2)'%*!)(!'/%!
&+$3%.!#0!2)'%!)*9%.(%!%9%&'(!*-9-*%*!37!'/%!'#')2!&+$3%.!#0!2)'%!8)'-%&'C7%).(:!!
!!
Q. Foreign Data
B&7!0#.%-,&!*)')!(+3$-''%*!-&!(+88#.'!#0!7#+.![>B!)882-1)'-#&!$+('!1#$827!4-'/!LK!"AJ!
MKZ:KE:!
!
U0!7#+!).%!.%27-&,!(#2%27!#&!0#.%-,&!*)')!'#!(+88#.'!7#+.![>B!)882-1)'-#&!0#.!)!.%82)1%$%&'!
/%).'!9)29%G!4%!.%1#$$%&*!7#+!8.#9-*%!'/%!+(+)2!#&%C7%).!*)')!)(!4%22!)(!+8C'#C*)'%!
-&0#.$)'-#&!-&12+*-&,!)&&+)2!0#22#4C+8!?%:,:G!^%4!W#.=!@%).'!B((#1-)'-#&!?^W@BF!/%).'!
0)-2+.%!12)((-0-1)'-#&!(1/%$%GKL!%1/#1).*-#,.)$G!)&*!32##*!'%('(!)11#.*-&,!'#!'/%!&#.$)2!
.)&,%(!+(%*!37!'/%!2)3#.)'#.-%(!'/)'!1#&*+1'%*!'/%!'%('-&,:!!W#+.!*)')!(/#+2*!*%$#&('.)'%!
2#&,C'%.$!8%.0#.$)&1%!)&*!0)-2+.%!$#*%G!)&*!-&12+*%!)+'#8(7!#.!%Y82)&'!)&)27(%(G!4/%&!
)9)-2)32%:!
XIV. PMA Supplements
B&!)88.#9%*![>B!(+882%$%&'!-(!,%&%.)227!.%P+-.%*!8.-#.!'#!$)=-&,!)!1/)&,%!)00%1'-&,!'/%!
()0%'7!#.!%00%1'-9%&%((!#0!7#+.!*%9-1%:!?LK!"AJ!MKZ:D5F:K5!!J%1#$$%&*)'-#&(!3%2#4!)**.%((!
(8%1-)2!1#&(-*%.)'-#&(!.%2)'%*!'#!$#*-0-1)'-#&(!#0!'/%!(%4-&,!.-&,!1#&0-,+.)'-#&!)&*!9)29%*!
1#&*+-'(:!
!
!
!
!
!K5!;%%!Modifications to Devices Subject to Premarket Approval (PMA) - The PMA
Supplement Decision-Making ProcessG!
/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6
M5LTZ:/'$:!
! LE
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
A. Modifications to the Sewing Ring Configuration
V%&%.)227G!12-&-1)2!*)')!$)7!&#'!3%!&%%*%*!'#!%(')32-(/!'/%!()0%'7!)&*!%00%1'-9%&%((!#0!
)2'%.&)'%!(%4-&,!.-&,!1#&0-,+.)'-#&(!8.#9-*%*!7#+!/)9%!&#'!)2'%.%*!'/%!(+3('.+1'+.%(!#0!'/%!
9)29%:!!c%!.%1#$$%&*!'/)'!7#+!9)2-*)'%!1/)&,%(!'#!7#+.!(%4-&,!.-&,!1#&0-,+.)'-#&!37!
1#&*+1'-&,!*5'6*,$1!('+*-%(!'#!12%).27!%(')32-(/!'/)'!'/%!&%4!(%4-&,!.-&,!1)&!(+88#.'!'/%!
8/7(-#2#,-1)2!2#)*-&,:!!c%!.%1#$$%&*!'/)'!7#+!1#$8).%!'/%!(8%1-0-1!$)'%.-)2!?$)&+0)1'+.%.G!
4%)9%G!%'1:F!4-'/!'/%!$)'%.-)2!+(%*!-&!7#+.!)88.#9%*![>B:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!
9)2-*)'%!1#$$#&G!12-&-1)227C)11%8'%*!(%4-&,!.-&,!$)'%.-)2(!?8#27'%'.)02+#.#%'/72%&%!r[\ASsG!
8#27%'/72%&%!'%.%8/'/)2)'%!r[S\sF!4-'/!)&-$)2!/%)2-&,!*)')!(+882%$%&'%*!4-'/!%Y82)&'!*)'):!!
A#.!)&7!(%4-&,!.-&,!$)'%.-)2(!#'/%.!'/)&![\AS!)&*![S\G!/#4%9%.G!4%!.%1#$$%&*!'/)'!7#+!
9)2-*)'%!'/%!$#*-0-1)'-#&!4-'/!12-&-1)2!*)'):!
!
B. Valved Conduits
c%!.%1#$$%&*!'/)'!7#+!1#&*+1'!12-&-1)2!-&9%('-,)'-#&(!0#.!.%82)1%$%&'!9)29%*!1#&*+-'(:!!
"2-&-1)2!-&9%('-,)'-#&(!$)7!&#'!3%!&%%*%*!4/%&!3#'/!'/%!9)29%!)&*!'/%!1#&*+-'!#.!,.)0'!).%!
2%,)227!$).=%'%*:!!U0!3#'/!).%!2%,)227!$).=%'%*G!*5'6*,$1!-&9%('-,)'-#&(!$)7!3%!(+00-1-%&':!!
c/%'/%.!)&!*5'6*,$1!-&9%('-,)'-#&!-(!)88.#8.-)'%!*%8%&*(!#&!7#+.!.-(=!)((%(($%&'k!%:,:G!'/%!
.-(=!)((%(($%&'!0#.!)!$#*-0-%*!*%(-,&!$)7!-&*-1)'%!'/%!)3-2-'7!#0!'/%!9)29%O,.)0'!-&'%.0)1%!'#!
4-'/(')&*!8/7(-#2#,-1)2!2#)*-&,!-(!8#'%&'-)227!*-00%.%&':!!U&!'/-(!1)(%G!*5'6*,$1!('+*-%(!$)7!3%!
)88.#8.-)'%!'#!9)2-*)'%!)!1/)&,%!-&!'/%!*%(-,&!#0!'/%!9)29%O,.)0'!-&'%.0)1%:!!R.G!0#.!-&(')&1%G!-0!
7#+!$#*-07!7#+.!*%9-1%!37!+(-&,!)!1#)'%*!,.)0'G!'/%!.-(=!)((%(($%&'!(/#+2*!)**.%((!4/%'/%.!
'/%.%!).%!)&7!8#'%&'-)2!)*9%.(%!%00%1'(!'#!'/%!1#)'-&,!?%:,:G!2#((!#0!1#)'-&,!-&'%,.-'7!2%)*-&,!'#!
32%%*-&,!*+%!'#!'/%!$)&+0)1'+.-&,!('%8(!)((#1-)'%*!4-'/!(%4-&,!'/%!9)29%!-&'#!'/%!,.)0'F:!
!
XV. Professional Labeling
I)3%2-&,!.%P+-.%$%&'(!0#.!$%*-1)2!*%9-1%(!).%!*%(1.-3%*!-&!LK!"AJ![).'!M6K:L6!!U&!)11#.*)&1%!
4-'/!LK!"AJ!MKZ:L6?3F?K6FG!7#+!$+('!(+3$-'!)22!8.#8#(%*!2)3%2-&,!-&!7#+.![>B:!!c%!
.%1#$$%&*!'/)'!7#+.!2)3%2-&,!-&12+*%!'/%!-&0#.$)'-#&!0#+&*!-&!;%1'-#&!H:L:D!)&*!B&&%Y!d!#0!
U;R!EMZ6NL66E!#.!%P+-9)2%&'!(+,,%('%*!0#.!-&12+(-#&!-&!2)3%2-&,!)&*!-&('.+1'-#&(!0#.!+(%. U&!
)**-'-#&G!7#+.!2)3%2-&,!(/#+2*!-&12+*%!'/%!-&0#.$)'-#&!*%(1.-3%*!3%2#4:!
!
A. Non-Sterile Devices!
U0!7#+!-&'%&*!'#!$).=%'!7#+.!*%9-1%!-&!&#&C('%.-2%!0#.$G!7#+!(/#+2*!8.#9-*%!12%).!)&*!
)*%P+)'%!-&('.+1'-#&(!0#.!('%.-2-g)'-#&!-&!7#+.!-&('.+1'-#&(!0#.!+(%!4-'/!)11%8')32%!8).)$%'%.(!
'#!3%!+(%*G!(+1/!)(!'%$8%.)'+.%G!8.%((+.%G!*4%22!'-$%(G!)&*!4/%'/%.!#.!&#'!.%C('%.-2-g)'-#&!
+(-&,!'/%(%!8).)$%'%.(!-(!)88.#8.-)'%G!!c%!)2(#!.%1#$$%&*!'/)'!7#+!8.#$-&%&'27!-&*-1)'%!-&!
7#+.!8)1=),%!2)3%2-&,!)&*!-&('.+1'-#&(!0#.!+(%!'/)'!7#+.!*%9-1%!-(!8.#9-*%*!&#&C('%.-2%:!
!L6!;%%!CDRH!Device Advice!)9)-2)32%!)'!
/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OR9%.9-%4O<%9-1%I)3%2-&,O
*%0)+2':/'$!0#.!)**-'-#&)2!-&0#.$)'-#&!)3#+'!*%9-1%!2)3%2-&,!.%P+-.%$%&'(:!
! LH
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
!
B. Resterilization
U0!'/%!*%9-1%!1)&!3%!.%('%.-2-g%*G!'/%&!'/%!2)3%2-&,!(/#+2*!-&12+*%!'/%!.%1#$$%&*%*!
('%.-2-g)'-#&!$%'/#*!)&*!8).)$%'%.(!'#!+(%:!
!
C. Magnetic Resonance Imaging (MRI)
A#.!-&0#.$)'-#&!.%,).*-&,!>),&%'-1!J%(#&)&1%!?>JF!()0%'7!'%('-&,G!82%)(%!(%%!A<B!
,+-*)&1%!*#1+$%&'!%&'-'2%*G!hS(')32-(/-&,!;)0%'7!)&*!"#$8)'-3-2-'7!#0![)((-9%!U$82)&'(!-&!
'/%!>),&%'-1!J%(#&)&1%!?>JF!S&9-.#&$%&':iLK!
XVI. Patient Labeling
U0!7#+!8.#8#(%!'#!8.#9-*%!8)'-%&'!2)3%2-&,G!%:,:G!!)!8)'-%&'!$)&+)2!#.!8)'-%&'!-*%&'-0-1)'-#&!1).*(!
4-'/!7#+.!*%9-1%G!7#+!$+('!(+3$-'!'/%!8.#8#(%*!2)3%2-&,!-&!)11#.*)&1%!4-'/!LK!"AJ!
MKZ:L6?3F?K6F:!!\/%!8)'-%&'!$)&+)2!(/#+2*!-&12+*%!)!*-(1+((-#&!#0!)&'-1#),+2)'-#&!'/%.)87!)&*!
'/%!-$8#.')&1%!#0!0#22#4C+8!9-(-'(:!!;%%!Guidance on Medical Device Patient LabelingLL!0#.!
$#.%!-&0#.$)'-#&!)3#+'!'/%!1#&'%&'(!#0!8)'-%&'!2)3%2-&,:!
\/%!8)'-%&'!-*%&'-0-1)'-#&!1).*!(/#+2*!(/#4!'/%!0#22#4-&,N!
! 8)'-%&'!&)$%!
! *)'%!#0!-$82)&'!
! &)$%!)&*!1#&')1'!-&0#.$)'-#&!0#.!'/%!-$82)&'-&,!8/7(-1-)&G!'/%!0#22#4-&,!8/7(-1-)&G!)&*!'/%!*%9-1%!$)&+0)1'+.%.!
! %$%.,%&17!1#&')1'!8%.(#&!
! *%9-1%!&)$%G!(-g%G!8#(-'-#&!)&*!(%.-)2!&+$3%.!
! )&7!$%*-1)'-#&(!)&*!*#(),%(!
! >J!;)0%!#.!>J!"#&*-'-#&)2!-&0#.$)'-#&LD:!
!LK!!\/-(!,+-*)&1%!*#1+$%&'!1)&!3%!#3')-&%*!)'N!
/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$K
6TT6E:/'$!0#.!,+-*)&1%!#&!>J!()0%'7!'%('-&,!#0!7#+.!*%9-1%:!!!!!!LL!\/-(!,+-*)&1%!*#1+$%&'!1)&!3%!#3')-&%*!)'N!
/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6
T6TML:/'$:! !LD!!A#.!)**-'-#&)2!-&0#.$)'-#&G!82%)(%!(%%G!hS(')32-(/-&,!;)0%'7!)&*!"#$8)'-3-2-'7!#0![)((-9%!
U$82)&'(!-&!'/%!>),&%'-1!J%(#&)&1%!?>JF!S&9-.#&$%&'i!)'!
/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$K
6TT6E:/'$:!
! LT
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
Appendix A. Shelf Life Validation
W#+.![>B!)882-1)'-#&!$+('!-&12+*%!)!'%1/&-1)2!(%1'-#&!4/-1/!(/)22!1#&')-&!*)')!)&*!
-&0#.$)'-#&G!-&12+*-&,!'/%!.%(+2'(!#0!'/%!(/%20!2-0%!'%('-&,G!-&!(+00-1-%&'!*%')-2!'#!8%.$-'!A<B!'#!
*%'%.$-&%!4/%'/%.!'#!)88.#9%!#.!*%&7!7#+.!)882-1)'-#&!?LK!"AJ!MKZ:L6?3F?HF?-FF:!!W#+!(/#+2*!
9)2-*)'%!7#+.!.%82)1%$%&'!/%).'!9)29%!)&*!8)1=),%!#9%.!'/%!(/%20!2-0%!#0!'/%!*%9-1%!3%1)+(%!#0!'/%!
8#'%&'-)2!0#.!9)29%!*%'%.-#.)'-#&!'/)'!-(!&#'!.%)*-27!9-(-32%!'#!'/%!(+.,%#&G!3+'!'/)'!1#+2*!
(+3(%P+%&'27!$)&-0%('!-&!'/%!8)'-%&'!)(!8.%$)'+.%!9)29%!0)-2+.%:!!A#.!)22!9)29%(G!4%!.%1#$$%&*!
'/)'!7#+!1#&*+1'!1#$8).)'-9%!8%.0#.$)&1%!'%('-&,!#0!),%*!)&*!+&),%*!4/#2%!9)29%(G!)(!
*%(1.-3%*!3%2#4:!
!
c%!.%1#,&-g%!'/)'!(#$%!(/%20!2-0%!9)2-*)'-#&!'%('(!-*%&'-0-%*!-&!'/-(!,+-*)&1%!).%!)882-1)32%!'#!
#&27!1%.')-&!9)29%(:!!U0!7#+!3%2-%9%!'/)'!)!8).'-1+2).!'%('!*#%(!&#'!)8827!'#!7#+.!*%9-1%G!4%!
.%1#$$%&*!'/)'!7#+!8.#9-*%!7#+.!.)'-#&)2%!0#.!#$-''-&,!'/%!'%(':!!!
!
A#.!(/%20!2-0%!9)2-*)'-#&G!4%!.%1#$$%&*!'/)'!7#+!%Y82)-&!/#4!%)1/!#0!'/%!0#22#4-&,!-(!12-&-1)227!
.%8.%(%&')'-9%!)&*!-&!),.%%$%&'!4-'/!'/%!#8%.)'-#&)2!(8%1-0-1)'-#&(!#0!'/%!*%9-1%N!
! '%('!8).)$%'%.(!?(7('%$-1!8.%((+.%G!3%)'!.)'%G!('.#=%!9#2+$%G!1).*-)1!#+'8+'!?"RFG!'-((+%!
1#$82-)&1%G!%'1:F!
! '%('!*+.)'-#&!!
! )882-1)32%!8%.0#.$)&1%!(8%1-0-1)'-#&:!
!
A. Test Valve Selection!!!
\#!%(')32-(/!)!(/%20!2-0%!0#.!7#+.!*%9-1%G!7#+!(/#+2*!%9)2+)'%!4/#2%!9)29%(!),%*!'#!'/%!2)3%2%*!
(/%20!2-0%!)&*!+&),%*!4/#2%!9)29%(!-&!)!(-*%!37!(-*%!$)&&%.!-&!#.*%.!'#!$)=%!)!1#$8).-(#&:!!
c%!.%1#$$%&*!'/)'!7#+!%9)2+)'%N!
! 9)29%(!#0!'/%!($)22%('G!-&'%.$%*-)'%G!)&*!2).,%('!(-g%(!
! 9)29%(!('%.-2-g%*!'#!'/%!$)Y-$+$!&+$3%.!#0!1712%(!-&!)11#.*)&1%!4-'/!'/%!%(')32-(/%*!
)&*!9)2-*)'%*!('%.-2-g)'-#&!8.#1%((!
! 0-&)2!0-&-(/%*!8.#*+1'!?-:%:G!(+3l%1'%*!'#!)22!$)&+0)1'+.-&,!8.#1%((%(G!-&12+*-&,!)&!
)&'-C1)21-0-1)'-#&!'.%)'$%&'G!-0!)882-1)32%F!
! 9)29%(!(+3l%1'%*!'#!(-$+2)'%*!*-('.-3+'-#&!)&*!/)&*2-&,!1#&*-'-#&(:!
!
B. Real-Time and Accelerated Aging
c%!,%&%.)227!.%1#$$%&*!.%)2C'-$%!),-&,!#0!'%('!9)29%(:!!@#4%9%.G!-0!7#+!+(%!)11%2%.)'%*!
),-&,!'%1/&-P+%(G!4%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!/#4!7#+!9)2-*)'%*!7#+.!)11%2%.)'%*!),-&,!
$%'/#*(!)&*!8.#9-*%!'/%!.%(+2'(!#0!)&7!9)2-*)'-#&!('+*-%(!1#&*+1'%*:!!c%!.%1#$$%&*!),-&,!
#0!'/%!4/#2%!9)29%G!-&12+*-&,!'/%!('%&'!0#.!'/#(%!9)29%(!4-'/!('%&'(G!3%1)+(%!'/%!('#.),%!
(#2+'-#&!1)&!/)9%!)&!-$8)1'!#&!'/%!-&'%,.-'7!#0!'/%!('%&':!!@#4%9%.G!'/%!('%&'!$)7!3%!.%$#9%*!
0#.!'%('-&,:!!B,-&,!('+*-%(G!4/%'/%.!.%)2C'-$%!#.!)11%2%.)'%*G!(/#+2*!)**.%((!'/%!%00%1'(!#0N!
! '%$8%.)'+.%!
! LM
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
! /+$-*-'7!
! 8.%((+.%!
! 2-,/'!%Y8#(+.%!
! (/-88-&,!)&*!/)&*2-&,:!!!
!
C. Device Stability
c%!.%1#$$%&*!'/)'!7#+!%9)2+)'%!'/%!0+&1'-#&)2!8%.0#.$)&1%G!('.+1'+.)2!-&'%,.-'7G!'-((+%!
$#.8/#2#,7G!-0!)882-1)32%G!)&*!8.#8%.'-%(!#0!'/%!*%9-1%!)'!g%.#!'-$%!)&*!)'!'/%!2)3%2%*!(/%20!
2-0%:!!c%!.%1#$$%&*!'/)'!7#+!%Y82)-&!7#+.!.)'-#&)2%!0#.!%)1/!'%('!$%'/#*!+(%*:!
!
1. Hydrodynamic Performance
\#!*%$#&('.)'%!/7*.#*7&)$-1!8%.0#.$)&1%G!4%!.%1#$$%&*!1#$8).-&,!*)')!0.#$!'/%!
0#22#4-&,!'%('(!#&!),%*!)&*!+&),%*!*%9-1%(N
! ('%)*7!0#.4).*!02#4!?"[G!SRBF!!
! 8+2()'-2%!0#.4).*!02#4!?"[G!SRBF!!
! 8+2()'-2%!.%,+.,-')'-#&!!
! )&'-C1)21-0-1)'-#&!%00%1'(G!-0!)882-1)32%G!?)(!*%'%.$-&%*!37!(+31+')&%#+(!
-$82)&')'-#&!-&!.)'(!#.!.)33-'(F:!
!
2. Structural Integrity
\#!*%$#&('.)'%!('.+1'+.)2!-&'%,.-'7G!4%!.%1#$$%&*!1#$8).-&,!*)')!0.#$!'/%!0#22#4-&,!
'%('(G!-0!)882-1)32%G!#&!),%*!)&*!+&),%*!*%9-1%(N!!
! 2%)02%'!*+.)3-2-'7!
! 2%)02%'!8.#2)8(%!?)(!*%'%.$-&%*!37!('%)*7!3)1=02#4!'%('-&,F:!
! (%4-&,!1+00!-&'%,.-'7!?8+22!'%('-&,F!
! (%4-&,!.-&,!-&'%,.-'7!?8+22!'%('-&,F!
! ('%&'!0)'-,+%!
! ('%&'!1.%%8!
! (1)&&-&,!%2%1'.#&!$-1.#(1#87!?;S>F!)&)27(%(!
! 8#27$%.-1!('%&'!1/%$-1)2!1#&1%&'.)'-#&!)&)27(%(:!
!
3. Tissue Morphology and Properties
\#!*%$#&('.)'%!'/)'!'/%!(/%20!2-0%!('#.),%!*#%(!&#'!)*9%.(%27!)00%1'!'-((+%!$#.8/#2#,7!)&*!
8.#8%.'-%(G!-0!)882-1)32%, 4%!.%1#$$%&*!1#$8).-&,!*)')!0.#$!'/%!0#22#4-&,!'%('(!#&!),%*!
)&*!+&),%*!*%9-1%(N!!
! /-('#2#,7!4-'/!(')-&-&,!
! L5
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
! 0-Y)'-#&!(')3-2-'7!?9-)!(/.-&=),%!'%$8%.)'+.%!#.!*-00%.%&'-)2!(1)&&-&,!1)2#.-$%'.7F!
! .%(-*+)2(!-&!('#.),%!(#2+'-#&!?%:,:G!)2*%/7*%!88$F!
! 3-#$%1/)&-1)2!8.#8%.'-%(!?3-)Y-)2!'%('-&,G!1.%%8!'%('-&,F:!
!
4. Storage Solution
c%!.%1#$$%&*!'/)'!7#+!)((%((!'/%!('#.),%!(#2+'-#&!)(!8).'!#0!'/%!(/%20!2-0%!9)2-*)'-#&:!!
"/)&,%(!-&!8@G!1/%$-1)2!1#$8#(-'-#&G!8#27$%.-g)'-#&!#.!3.%)=*#4&G!)(!4%22!)(!2%)=),%!
$)7!#11+.!)&*!(/#+2*!3%!%9)2+)'%*:!![.#2#&,%*!*%,.)*)'-#&!#0!'/%!('#.),%!(#2+'-#&!$)7!
/)9%!)&!%00%1'!#&!'-((+%!P+)2-'7:!!W#+.!)((%(($%&'!#0!'/%!('#.),%!(#2+'-#&!(/#+2*!-&12+*%!
)&!)&)27(-(!#0!'/%!.%(-*+)2(!-&!'/%!('#.),%!(#2+'-#&!)&*!)&)27(-(!#0!8)1=),%!1#$8#&%&'(!
2%)1/%*!-&'#!'/%!('#.),%!(#2+'-#&!)'!'/%!2)3%2%*!(/%20!2-0%!#0!'/%!*%9-1%:!!!
!
5. Package Integrity
W#+!$+('!%&(+.%!'/)'!*%9-1%!8)1=),%(!).%!*%(-,&%*!)&*!1#&('.+1'%*!'#!8.#'%1'!'/%!*%9-1%!
0.#$!)2'%.)'-#&!#.!*)$),%!*+.-&,!'/%!1+('#$).7!1#&*-'-#&(!#0!8.#1%((-&,G!('#.),%G!
/)&*2-&,G!)&*!*-('.-3+'-#&!?LK!"AJ!ML6:KD6F:!!c%!.%1#$$%&*!'/)'!7#+!%9)2+)'%!'/%!
8)1=),%!-&'%,.-'7!#0!'/%!8.#*+1'!8)1=),-&,!)'!g%.#!'-$%!)&*!)'!'/%!2)3%2%*!(/%20!2-0%G!
8.%0%.)327!+(-&,!)!$%'/#*!'/)'!%9)2+)'%(!'/%!4/#2%!8)1=),%!.)'/%.!'/)&!#&27!'/%!(%)2!).%):!!
\/%!8)1=),%!(/#+2*!1#&')-&!%-'/%.!'/%!.%)2!8.#*+1'G!#.!)!(-$+2)'%*!8.#*+1'!'/)'!/)(!
(-$-2).!$)((!)&*!,%#$%'.7:!!W#+!(/#+2*!-&12+*%!7#+.!.)'-#&)2%!0#.!'/%!'%('!$%'/#*(!
%$82#7%*:!
!
!
!
Shelf Life Validation Information – Tabular Format Example
SAMPLE PREPARATION PLANNED QUALIFICATION
& VALIDATION STUDIES
SAMPLE SIZE
[subject (control)] Sterilization Aging Distribution & Handling
Other (e.g., treatments)
ACCEPTANCE CRITERIA
Valve in vitro hydrodynamic performance:
Steady forward flow ("P, EOA)
Pulsatile forward flow
("P, EOA)
Pulsatile regurgitation
Anti-calcification effect (if applicable) determined by subcutaneous implantation in rats or rabbits
Valve structural integrity:
Leaflet durability
Leaflet prolapse determined by steady backflow testing
! D6
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!Sewing cuff integrity (pull testing)
Sewing ring integrity (pull testing)
Stent fatigue
Stent creep
Stent SEM analyses
Polymeric stent chemical concentration analyses
Valve tissue morphology & properties:
Histology (with staining)
Fixation stability (shrink temperature or differential scanning!calorimetry)
Residuals in storage solution (e.g., aldehyde ppm)
Biomechanical properties (biaxial testing, creep, and corrosion)
Storage solution:
Volume
Chemical composition
pH
Leaching analysis (of package components into storage solution, particularly if EtO sterilized)
Package integrity:
Test method used
Real or simulated product
!
! DK
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!
Appendix B. Cavitation Testing for Rigid Heart Valves
")9-')'-#&!%.#(-#&!?)&*!-&!(#$%!1)(%(G!1)')('.#8/-1!('.+1'+.%!0)-2+.%F!/)(!#11+..%*!-&!(#$%!.-,-*!
.%82)1%$%&'!/%).'!9)29%!*%(-,&(:!!B**-'-#&)227G!1)9-')'-#&!1)&!3%!-&*+1%*!-&!$#('!.-,-*!/%).'!
9)29%(!*5'6*,$1D!!\/+(G!4%!.%1#$$%&*!1)9-')'-#&!8#'%&'-)2!'%('-&,!0#.!.-,-*!9)29%(:!!;-&1%!&#!#&%!
'%('!-(!(+00-1-%&'!'#!)((%((!'/%!1)9-')'-#&!8#'%&'-)2!#0!)!&%4!.-,-*!.%82)1%$%&'!9)29%!*%(-,&G!4%!
.%1#$$%&*!'/)'!7#+!8%.0#.$!)!8.%12-&-1)2!*5'6*61!('+*7G!(-$+2)'%*!2#&,!'%.$!*5'6*,$1!('+*7!?-:%:G!
*+.)3-2-'7!'%('-&,F!'#!)((%((!8#((-32%!1)9-')'-#&!*)$),%G!)&*!%Y)$-&%!'/%!)&-$)2!('+*7!)&*!
12-&-1)2!?-0!)882-1)32%F!%Y82)&'%*!9)29%(!0#.!%9-*%&1%!#0!1)9-')'-#&:!!!
!
\/-(!)88%&*-Y!.%8.%(%&'(!#+.!+&*%.(')&*-&,!#0!*5'6*,$1'1)9-')'-#&!'%('!$%'/#*(!)'!'/%!'-$%!'/-(!
,+-*)&1%!4)(!-((+%*:!!W#+!(/#+2*!.%9-%4!(')'%!#0!'/%!).'!1)9-')'-#&!'%('-&,!3%0#.%!-$82%$%&'-&,!)!
8.#'#1#2:!!R+.!,%&%.)2!.%1#$$%&*)'-#&(!0#.!'%('!8).)$%'%.(!).%!,-9%&!3%2#4:!!!
!
A. Test Valve Selection!!!
c%!.%1#$$%&*!'/)'!7#+!'%('!'4#!#0!'/%!($)22%('!)&*!'4#!#0!'/%!2).,%('!9)29%!(-g%(:!
!
B. Test Valve Mounting!!!
A#.!1)9-')'-#&!'%('-&,G!'/%!9)29%(!(/#+2*!3%!.-,-*27!$#+&'%*!-&!'/%!$-'.)2!8#(-'-#&!#0!)!/%).'!
(-$+2)'#.:!!U0!&#!$-'.)2!9)29%!$#*%2!-(!+&*%.!%9)2+)'-#&G!)!'%('!8.#'#1#2!0#.!'/%!)#.'-1!8#(-'-#&!
(/#+2*!3%!*%9%2#8%*:!
!
C. Reference Valves!!!
c%!.%1#$$%&*!'/)'!7#+!+(%!'4#!()$82%(!#0!)&!A<BC)88.#9%*!9)29%!)(!.%0%.%&1%!9)29%(:!
!
D. Working Fluid!!!
\/%!4#.=-&,!02+-*!(/#+2*!3%!8/7(-#2#,-1)2!()2-&%!)22#4%*!'#!1#$%!'#!%P+-2-3.-+$!4-'/!.##$!
)'$#(8/%.%!0#.!LZ!/#+.(:!
!
E. Atrial Chamber!!!
\/%!)'.-)2!1/)$3%.!(/#+2*!3%!#8%&G!4-'/!)!1.#((!(%1'-#&)2!).%)!,.%)'%.!'/)&!TE!1$L:!
!
F. Atrial Pressure!!!
\/%!$%)&!)'.-)2!8.%((+.%!#&!'/%!'%('!9)29%!(/#+2*!3%!2%((!'/)&!T!$$@,:!
!
G. Cavitation Definition!!!
A<B!*%0-&%(!1)9-')'-#&!)(!)'!2%)('!#&%!-&(')&1%!#0!3+332%!0#.$)'-#&!&#'%*!#&!9)29%!12#(-&,!
#+'!#0!%9%.7!'%&!1712%(!('+*-%*:!
! DL
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
H. Description of Detector!!!
c%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!'/%!1)9-')'-#&!*%'%1'-#&!(7('%$!)&*!-&*-1)'%!-'(!(%&(-'-9-'7:!
!
I. Pressure Profile!!!
c%!.%1#$$%&*!'/)'!7#+!8.#9-*%!)!8.#0-2%!#0!'/%!8.%((+.%!9(:!'-$%!?)9%.),%*!#9%.!'%&!
1#&(%1+'-9%!(7('#2-1!1712%(F!)'!KL6!$$@,G!)&*!)'!)&7!8%)=!9%&'.-1+2).!8.%((+.%!)'!4/-1/!
1)9-')'-#&!-(!0#+&*!0#.!)&7!9)29%G!%-'/%.!(+3l%1'!#.!.%0%.%&1%:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!
.%8#.'!'/%!)9%.),%!8.%((+.%!#9%.!(7('#2%:!!!
!
J. Ventricular Pressure!!!
Q)29%(!(/#+2*!3%!'%('%*!)'!KL6!$$@,!8%)=!9%&'.-1+2).!1/)$3%.!8.%((+.%!)&*!)'!)!$)Y-$+$!
02#4!.)'%!#0!T:6!IO$-&:!!\/%!(7('#2-1!.)'-#!(/#+2*!3%!(%'!)'!DE!t!L!o:!
!
K. Maximum Ventricular Pressure!!!
U0!1)9-')'-#&!-(!&#'!#3(%.9%*!-&!%-'/%.!'/%!(%'!#0!(+3l%1'!9)29%(!#.!'/%!(%'!#0!.%0%.%&1%!9)29%(G!
'/%!8%)=!9%&'.-1+2).!8.%((+.%!(/#+2*!3%!-&1.%)(%*!+&'-2!1)9-')'-#&!-(!(%%&!-&!)'!2%)('!#&%!(%'!#0!
'/%!9)29%(G!#.!+&'-2!8%)=!9%&'.-1+2).!8.%((+.%!-(!%P+)2!'#!L66!$$@,:!!U0!7#+!9).7!(7('%$!
8).)$%'%.(!'#!)1/-%9%!1)9-')'-#&G!4%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!'/%!(7('%$!8).)$%'%.(!
7#+!1/)&,%*:!
! DD
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Appendix C. Bernoulli Verification!
!
"2-&-1)2!/%$#*7&)$-1!%9)2+)'-#&!#0!.%82)1%$%&'!/%).'!9)29%(!-&!12-&-1)2!'.-)2(!'78-1)227!-&12+*%(!
$%)(+.%$%&'!#0!'/%!8.%((+.%!,.)*-%&'!37!<#882%.!+2'.)(#+&*:!!<#882%.!9%2#1-'7!$%)(+.%$%&'(!
).%!1#&9%.'%*!-&'#!8.%((+.%!,.)*-%&'(!+(-&,!'/%!_%.&#+22-!%P+)'-#&G!![!n!]?Q*L!C!Q8
LF:!!
\/%#.%'-1)227G!'/%!1#&(')&'!]!4-22!%P+)2!ZG!3+'!9)29%C*%8%&*%&'!*%9-)'-#&(!0.#$!'/-(!9)2+%!/)9%!
3%%&!.%8#.'%*:LZGLEGLHGLT
!!c%!.%1#$$%&*!'/)'!7#+!*%'%.$-&%G!*5'6*,$1G!4/%'/%.!'/%!1#%00-1-%&'!Z!-(!
)88.#8.-)'%G!37!1#$8).-&,!![!$%)(+.%*!37!<#882%.!4-'/!'/)'!$%)(+.%*!*-.%1'27!37!)!8)-.!#0!8.%((+.%!'.)&(*+1%.(:!
!
\%('-&,!(/#+2*!-&12+*%!#&%!#0!'/%!2).,%('G!-&'%.$%*-)'%G!)&*!($)22%('!()$82%(!0#.!%)1/!9)29%!'78%G!
)(!4%22!)(!)&!)88.#8.-)'%!?()$%!(-g%!)&*!'78%F!2%,)227!$).=%'%*!9)29%!)(!.%0%.%&1%:!
!
c%!.%1#$$%&*!'/)'!7#+!82#'!'/%!9)2+%(!#0!![!)(!$%)(+.%*!37!8.%((+.%!'.)&(*+1%.(!),)-&('!?Q*L!C!
Q8LF!)(!$%)(+.%*!37!<#882%.G!0#.!02#4!.)'%(!'/)'!7#+!+(%*:!
!
c%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!/#4!'/%!.%(+2'-&,!%Y8%.-$%&')227!$%)(+.%*!1#&(')&'!]!$)7!
)00%1'!12-&-1)2!$%)(+.%$%&'(!#0!8.%((+.%!,.)*-%&'(G!0#.!*-),&#(-(!)&*!8.#,&#(-(.!
!
!LZ!W)$)(/-')!\G!>#.-7)$)!WG!;)')!^G!%'!)2:!<-(1.%8)&17!3%'4%%&!<#882%.!)&*!1)'/%'%.!
$%)(+.%$%&'(!#0!8.%((+.%!,.)*-%&'(!)1.#((!($)22C(-g%!8.#('/%'-1!9)29%:!!a8&!a!\/#.)1!").*-#9)(1!
;+.,:!L66EkEDNHZCM:!LE>)(1/%.3)+%.!aG!;1/-$)!@G!>)+.%.!VG!_)+$,).'&%.!@:!!<#882%.!)((%(($%&'!#0!$%1/)&-1)2!
)#.'-1!9)29%!8.#('/%(%(N!%00%1'!#0!9)29%!*%(-,&!)&*!(-g%!#0!'/%!)#.'):!!a!@%).'!Q)29%!<-(:!
L66ZkKDNMLDCD6:!!!LH;'%4).'!;AG!@%.$)&!_BG!^%22!<>G!J%'')!;>:!S00%1'(!#0!9)29%!1/).)1'%.-('-1(!#&!'/%!)11+.)17!
#0!'/%!_%.&#+22-!%P+)'-#&N!)!(+.9%7!#0!*)')!(+3$-''%*!'#!'/%!`:;:!A<B:!!a!@%).'!Q)29%!<-(:!
L66ZkKDNZHKCH:!LT_%1/C@)&((%&!RG!")-*)/2!]G!c)22%&'-&!UG!_.)&*3%.,!aG!c.)&&%!_G!B(=![:!!B#.'-1!8.#('/%'-1!
9)29%!*%(-,&!)&*!(-g%N!.%2)'-#&!'#!<#882%.!%1/#1).*-#,.)8/-1!0-&*-&,(!)&*!8.%((+.%!.%1#9%.7C!)&!
*5'6*,$1!('+*7:!!a!B$!;#1!S1/#1).*-#,.:!L666kKDND5CE6:!
! DZ
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
Appendix D. Echocardiography Protocol
!
W#+!$+('!(+3$-'!7#+.!12-&-1)2!8.#'#1#2(!4-'/!7#+.![>B!)882-1)'-#&!?LK!"AJ!MKZ:L6?3F?HF?--FF:!!
A#.!7#+.!U<S!)882-1)'-#&G!7#+!$+('!(+3$-'!)&!)11+.)'%!(+$$).7!#0!7#+.!8.#'#1#2(G!)&*!4%!$)7!
.%P+%('!)**-'-#&)2!-&0#.$)'-#&!1#&1%.&-&,!'/%!-&9%('-,)'-#&:!!LK!"AJ!MKL:L6?3F?LFG!?1FF:!!\/-(!
)88%&*-Y!*%(1.-3%(!A<Bf(!.%1#$$%&*)'-#&(!0#.!'/%!%1/#1).*-#,.)8/-1!%9)2+)'-#&!#0!
.%82)1%$%&'!/%).'!9)29%(!-&!12-&-1)2!('+*-%(:!!U&0#.$)'-#&!.%,).*-&,!'/%!%1/#1).*-#,.)8/7!
8.#'#1#2!?.%1#.*-&,!('+*-%(G!*)')!1#22%1'-#&G!)&*!1#.%!2)3#.)'#.7!1)21+2)'-#&(!)&*!)&)27(-(F!1)&!3%!
0#+&*!-&!B&&%Y!@!#0!U;R!EMZ6NL66E:!!!
!
c%!.%1#$$%&*!'/%!0#22#4-&,!-&!)**-'-#&!'#!U;R!EMZ6NL66E!B&&%Y!@G!(+3(%1'-#&!@:K:!!\/%!
.%1#$$%&*)'-#&(!)&*!$%'/#*#2#,-%(!).%!)882-1)32%!'#!)22!.%82)1%$%&'!/%).'!9)29%(!.%,).*2%((!#0!
-$82)&')'-#&!$%'/#*:!
!
B&!%1/#1).*-#,.)8/7!1#.%!2)3#.)'#.7!(/#+2*!8%.0#.$!'/%!1%&'.)2!.%9-%4!#0!)22!%1/#1).*-#,.)8/-1!
*)'):!!\/%!1#.%!2)3#.)'#.7!(/#+2*!/)9%!)!(+8%.9-(-&,!*-.%1'#.!4/#!-(!)&!%1/#1).*-#2#,-('!
%Y8%.-%&1%*!-&!%1/#1).*-#,.)8/-1!.%82)1%$%&'!9)29%!%9)2+)'-#&:!!\/%!1#.%!2)3#.)'#.7!(/#+2*!+(%!
)!4.-''%&!%1/#1).*-#,.)8/7!8.#'#1#2G!0#22#4%*!37!)22!(#&#,.)8/%.(!)&*!-&9%('-,)'#.(!-&9#29%*!-&!
'/%!12-&-1)2!('+*7:!!U&'%.8.%')'-#&!#0!'/%!%1/#1).*-#,.)$(!37!'/%!1#.%!2)3#.)'#.7!(/#+2*!3%!
$)(=%*:!!U0!'/%.%!).%!)&7!*-00%.%&1%(!3%'4%%&!'/%!('+*7!1%&'%.(!)&*!'/%!1#.%!2)3#.)'#.7!-&!'/%!
-&'%.8.%')'-#&!#0!%1/#1).*-#,.)$(G!'/%&!'/%!1#.%!2)3#.)'#.7!4-22!')=%!8.%1%*%&'!-&!A<Bf(!.%9-%4!
#0!'/%!%1/#1).*-#,.)$(:!!
!
c%!.%1#$$%&*!'/)'!7#+!('.)'-07!)22!%1/#1).*-#,.)8/-1!/%$#*7&)$-1!*)')G!-&12+*-&,!9)29+2).!
.%,+.,-')'-#&!*)')G!37!9)29%!8#(-'-#&!)&*!9)29%!(-g%:!
!
U0!7#+!1#22%1'!'.)&(%(#8/),%)2!%1/#1).*-#,.)8/7!?\SSF!*)')G!4%!.%1#$$%&*!+(-&,!)!$+2'-82)&%!
\SS!%Y)$(G!.)'/%.!'/)&!$#R)&%!#.!3-82)&%!\SS!%Y)$(:!!>)&7!(')&*).*!/%$#*7&)$-1!
$%)(+.%$%&'(G!(+1/!)(!)#.'-1!9)29%!8.%((+.%!,.)*-%&'(G!'/)'!).%!)9)-2)32%!4-'/!'/%!+(%!#0!
'.)&('/#.)1-1!%1/#1).*-#,.)8/7!?\\SF!$)7!&#'!3%!)9)-2)32%!-0!7#+!+(%!\SS:!!;-&1%!-'!-(!-$8#.')&'!
'#!+(%!'/%!()$%!%1/#1).*-#,.)8/-1!-$),-&,!$#*)2-'7!)'!)22!0#22#4C+8!'-$%C8#-&'(G!)&*!(-&1%!\\S!
-(!'/%!12-&-1)2!(')&*).*!)&*!2%)('!-&9)(-9%!$%'/#*!#0!%1/#1).*-#,.)8/7G!4%!.%1#$$%&*!'/)'!7#+!
8%.0#.$!\\S!%Y)$(!)'!)22!0#22#4C+8!'-$%!8#-&'(:!!\/%(%!'-$%!8#-&'(!(/#+2*!-&12+*%!h)'!/#(8-')2!
*-(1/).,%i!#.!)!'-$%!8#-&'!)'!D6!*)7(!#.!2%((!8#('C-$82)&'!-0!'/%!(+3l%1'!/)(!&#'!3%%&!*-(1/).,%*:!
!
A. Data Collected by the Study Center
U0!7#+!0#22#4!U;R!EMZ6NL66E!B&&%Y!@G!(+3(%1'-#&!@:DG!4%!.%1#$$%&*!'/%!)**-'-#&(!
*%(1.-3%*!3%2#4:!
!
<)')!1#22%1'%*!37!'/%!('+*7!1%&'%.!(/#+2*!-&12+*%N!!
! 8%)=!8.%((+.%!,.)*-%&'!
! $%)&!8.%((+.%!,.)*-%&'!
! DE
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
! %00%1'-9%!#.-0-1%!).%)!?SRB!#.!BSRF!
! %00%1'-9%!#.-0-1%!).%)!-&*%Y!?SRBU!#.!BSRUF!
! 8%.0#.$)&1%!-&*%Y!?[UF!
! 1).*-)1!#+'8+'!?"R!#.!R"F!
! 1).*-)1!-&*%Y!?"UF:!!!
!\/%!*)')!(/#+2*!1#&(-('!#0!(+3l%1'!&+$3%.(!)&*!$%)&!?)9%.),%FG!(')&*).*!*%9-)'-#&G!
$-&-$+$!9)2+%(G!)&*!$)Y-$+$!9)2+%(:!!c%!.%1#$$%&*!'/)'!7#+!('.)'-07!'/%!*)')!37!9)29%!
8#(-'-#&!)&*!9)29%!(-g%:!!!
!
B2'/#+,/!U;R!EMZ6NL66E!+(%(!'/%!'%.$(!h9%2#1-'7!-&'%,.)2i!)&*!hr*-)('#2-1s!9%2#1-'7!-&'%,.)2!
?<QUFGi!'/%!1#$$#&!`:;:!12-&-1)2!'%.$!-(!h9%2#1-'7!'-$%!-&'%,.)2!?Q\UFi!#.!h'-$%!9%2#1-'7!
-&'%,.)2!?\QUF:i
!
U;R!EMZ6NL66E!.%1#$$%&*(!)9%.),-&,!E!/%).'!3%)'(!4/%&!#3')-&-&,!%1/#1).*-#,.)8/-1!
/%$#*7&)$-1!$%)(+.%$%&'(!-&!(+3l%1'(!4-'/!)'.-)2!0-3.-22)'-#&:!!\/%(%!(+3l%1'(!$)7!/)9%!)!
/-,/27!9).-)32%!/%).'!.)'%!4/-1/!$)7!1)+(%!$%)(+.%$%&'(!'/)'!).%!%-'/%.!(%9%.)2!$-&+'%(!
)8).'!?(+1/!)(!IQR\!)&*!$-'.)2!9)29%!$%)(+.%$%&'(F!#.!#3')-&%*!#9%.!E!#.!$#.%!3%)'(:!!;+1/!
$%)(+.%$%&'(!$)7!3%!%..#&%#+(!3%1)+(%!'/%7!).%!(+3l%1'!'#!3#'/!/%).'!.)'%!9).-)'-#&!)&*!
.%(8-.)'#.7!)2'%.)'-#&:!!U&!#.*%.!'#!$-'-,)'%!$%)(+.%$%&'!%..#.(G!'/%!%1/#1).*-#,.)8/%.!(/#+2*!
(%2%1'!3%)'(!'/)'!0#22#4!)!8/7(-#2#,-1!8.%1%*-&,!1712%!2%&,'/!?%:,:G!M66!t!M6!$(!#.!TE!t!K6!
38$F!#.!3%)'(!4-'/!K6o!9).-)3-2-'7!-&!/%).'!.)'%:!!`(-&,!%-'/%.!#0!'/%(%!'4#!)88.#)1/%(G!'/%!
(')&*).*!$+2'-82%!3%)'(!?+(+)227!DF!1)&!3%!$%)(+.%*!)&*!)9%.),%*!.%,).*2%((!#0!'/%!
+&*%.27-&,!./7'/$:!
!
Q)29+2).!.%,+.,-')'-#&!*)')!(/#+2*!1#&(-('!#0!'/%!&+$3%.(!)&*!8%.1%&'),%(!#0!(+3l%1'(!0#.!
%)1/!,.)*%!#0!(%9%.-'7:!!c%!.%1#$$%&*!'/)'!7#+!('.)'-07!9)29+2).!.%,+.,-')'-#&!*)')!37!,.)*%!
#0!.%,+.,-')'-#&!(%9%.-'7G!9)29%!8#(-'-#&G!)&*!9)29%!(-g%:!
!
c%!.%1#$$%&*!'/)'!7#+!*#1+$%&'!#'/%.!*)')!'/)'!).%!.#+'-&%27!#3')-&%*!)(!8).'!#0!)!
1#$82%'%!%1/#1).*-#,.)8/-1!%Y)$-&)'-#&G!-&12+*-&,N!!
! &#&C('+*7!9)29%!?&)'-9%!#.!#'/%.!.%82)1%$%&'F!('.+1'+.%!)&*!0+&1'-#&!
! 2%0'!)&*!.-,/'!)'.-)2!(-g%!
! 2%0'!)&*!.-,/'!9%&'.-1+2).!(-g%!
! 2%0'!)&*!.-,/'!9%&'.-1+2).!0+&1'-#&!
! 9%&'.-1+2).!(%8')2!)&*!2%0'!9%&'.-1+2).!8#('%.-#.!4)22!'/-1=&%((!
! 1)9-').7!'/.#$3-!#.!#'/%.!$)((%(!
! 8%.-1).*-)2!)3&#.$)2-'-%(!?(+1/!)(!%00+(-#&F!
! )#.'-1!.##'!*-)$%'%.:!!
!
!
! DH
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
B. Calculations and Analysis by the Core Laboratory
!
1. Effective Orifice Area
c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!%1/#1).*-#,.)8/-1!('+*-%(!)(!*%(1.-3%*!-&!U;R!
EMZ6NL66E!B&&%Y!@G!(+3(%1'-#&!@:Z!#.!-'(!%P+-9)2%&':!!U&!)**-'-#&G!4%!.%1#$$%&*!'/)'!
7#+!8%.0#.$!'/%!1#.%!2)3#.)'#.7!1)21+2)'-#&(!)&*!)&)27(%(!)(!*%(1.-3%*!3%2#4:!!!
!
A#.!%00%1'-9%!#.-0-1%!).%)G!BSRG!4%!.%1#$$%&*!'/%!1#&'-&+-'7!%P+)'-#&!3%2#4:!
!
A#.!)#.'-1!9)29%(N!FC
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#$ : ! !
!
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#$ : ! !
4/%.%! F:<!! -(!'/%!%00%1'-9%!#.-0-1%!).%)!-&!1$L!
F=EDGC<?! -(!'/%!2%0'!9%&'.-1+2).!#+'02#4!'.)1'!?IQR\F!1.#((C(%1'-#&)2!
).%)!-&!1$LG!1)21+2)'%*!0.#$!'/%!*-)$%'%.!)((+$-&,!1-.1+2).!
1.#((C(%1'-#&!
C?2GC<?! -(!'/%!IQR\!9%2#1-'7!'-$%!-&'%,.)2!?Q\UF!-&!1$G!)(!$%)(+.%*!
37!8+2(%*!4)9%!?[cF!<#882%.!
C?2FC! -(!'/%!)#.'-1!9%2#1-'7!'-$%!-&'%,.)2!?Q\UF!-&!1$G!)(!$%)(+.%*!
37!1#&'-&+#+(!4)9%!?"cF!<#882%.!
C?2@C! -(!'/%!$-'.)2!9%2#1-'7!'-$%!-&'%,.)2!?Q\UF!-&!1$G!)(!$%)(+.%*!
37!"c!<#882%.!
!
U0!(-,&-0-1)&'!)#.'-1!.%,+.,-')'-#&!-(!8.%(%&'G!'/%!1#&'-&+-'7!%P+)'-#&!0#.!$-'.)2!9)29%(!4-22!
2-=%27!#9%.%('-$)'%!'/%!$-'.)2!9)29%!%00%1'-9%!#.-0-1%!).%)G!-0!7#+!+(%!'/%!IQR\!1.#((C
(%1'-#&)2!).%)!)&*!IQR\!9%2#1-'7!'-$%!-&'%,.)2:!!U&!'/-(!1)(%G!4%!.%1#$$%&*!'/)'!7#+!
(+3('-'+'%!'/%!IQR\!1.#((C(%1'-#&)2!).%)!)&*!IQR\!9%2#1-'7!'-$%!-&'%,.)2!-&!'/%!
1#&'-&+-'7!%P+)'-#&!)(!0#22#4(:!!c%!.%1#$$%&*!'/)'!7#+!+(%!'/%!(+3('-'+'-#&(!(/#4&!-&!
'/%!')32%!3%2#4:!!!
!
IN PLACE OF: USE:
IQR\!1.#((!(%1'-#&)2!).%)!?F=EDGC<?F! 8+2$#&-1!)&&+2+(!1.#((!(%1'-#&)2!).%)!?F=EDHCF!-&!
1$L!?1)21+2)'%*!0.#$!'/%!8+2$#&-1!)&&+2+(!
*-)$%'%.F!
IQR\!9%2#1-'7!'-$%!-&'%,.)2!?C?2GC<?F 8+2$#&-1!9)29%!9%2#1-'7!'-$%!-&'%,.)2!?C?2HCF!-&!
1$!?)(!$%)(+.%*!37!"c!<#882%.F!
!
! DT
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
\/%!$-'.)2!9)29%!%00%1'-9%!#.-0-1%!).%)!$)7!3%!1)21+2)'%*!37!'/%!8.%((+.%!/)20C'-$%!
$%'/#*!-&('%)*!#0!'/%!1#&'-&+-'7!%P+)'-#&:!!U0!(-,&-0-1)&'!$-'.)2!.%,+.,-')'-#&!-(!8.%(%&'G!
'/%!1#&'-&+-'7!%P+)'-#&!0#.!$-'.)2!9)29%(!4-22!2-=%27!+&*%.%('-$)'%!'/%!$-'.)2!9)29%!
%00%1'-9%!#.-0-1%!).%)!-0!'/%!IQR\!1.#((C(%1'-#&)2!).%)!)&*!IQR\!9%2#1-'7!'-$%!-&'%,.)2!
).%!+(%*:!!U&!'/-(!1)(%G!4%!.%1#$$%&*!'/)'!7#+!+(%!'/%!8.%((+.%!/)20C'-$%!$%'/#*!-&('%)*:!!!
\/%!8.%((+.%!/)20C'-$%!?[@\F!-(!*%0-&%*!)(!'/%!'-$%!?-&!$-22-(%1#&*(F!0#.!'/%!$)Y-$+$!
?8%)=F!%).27!*-)('#2-1!'.)&($-'.)2!8.%((+.%!,.)*-%&'!'#!*%1.%)(%!37!#&%C/)20!#.!0#.!'/%!
$)Y-$+$!?8%)=F!9%2#1-'7!'#!*%1.%)(%!37!KO"L!?n!KOK:ZF:!!\/%![@\!-(!*%'%.$-&%*!37!"c!<#882%.:!
!
A#.!$-'.)2!9)29%(N!!
!HB?
F:<LL6
$ ! !
!
! -?HB? #$ L5:6 ! !
!
4/%.%! HB?!! -(!'/%!8.%((+.%!/)20C'-$%!-&!$(!
!
-?' -(!'/%!*%1%2%.)'-#&!'-$%!-&!$('
!
B2'%.&)'-9%27G![@\!1)&!)2(#!3%!,.)8/-1)227!*%'%.$-&%*!)'!'/%!8#-&'!4/%.%!'/%!/)20C'-$%!
9%2#1-'7!?8%)=!9%2#1-'7OK:ZF!-&'%.(%1'(!'/%!2-&%).!9%2#1-'7!(2#8%!#&!'/%!"c!<#882%.!
(8%1'.)2!9%2#1-'7!'.)1%:!
!
c%!.%1#$$%&*!'/)'!7#+!-&*-1)'%!'/%!$%'/#*!#0!1)21+2)'-#&!#0!'/%!%00%1'-9%!#.-0-1%!).%)!
+(%*!0#.!%)1/!9)29%!8#(-'-#&:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!+(%!'/%!()$%!$%'/#*!#0!
1)21+2)'-#&!0#.!%)1/!9)29%!8#(-'-#&!0#.!)22!0#22#4C+8!'-$%C8#-&'(:!
!
R&%!.%0%.%&1%!1)+'-#&(!'/)'!'/%![@\!#9%.%('-$)'%(!'/%!%00%1'-9%!#.-0-1%!).%)!#0!&#.$)2!
.%82)1%$%&'!$-'.)2!9)29%(G!(-&1%!'/%!1#&(')&'!LL6!4)(!*%.-9%*!3)(%*!#&!&)'-9%!$-'.)2!
9)29%!('%&#(%(!.)'/%.!'/)&!.%82)1%$%&'!$-'.)2!9)29%!('%&#(%(:LM!!\/%.%0#.%G!4/%&!'/%.%!-(!
&#!(-,&-0-1)&'!$-'.)2!.%,+.,-')'-#&G!'/%!1#&'-&+-'7!%P+)'-#&!$)7!3%!)!3%''%.!$%'/#*!0#.!
*%'%.$-&-&,!'/%!%00%1'-9%!#.-0-1%!).%)!#0!.%82)1%$%&'!$-'.)2!9)29%(:
!
>#('!&#.$)227C0+&1'-#&-&,!.%82)1%$%&'!)#.'-1!)&*!$-'.)2!9)29%(!/)9%!(#$%!.%('.-1'-#&!'#!
02#4!*+%!'#!9).7-&,!*%,.%%(!#0!-&/%.%&'!('%&#(-(:!!"#&(%P+%&'27G!&#.$)227C0+&1'-#&-&,!
.%82)1%$%&'!$-'.)2!9)29%(!$)7!/)9%!/-,/!-&-'-)2!9%2#1-'-%(G!3+'!4-22!/)9%!)!.)8-*![@\G!)(!
1#$8).%*!'#!)&!#3('.+1'%*!.%82)1%$%&'!9)29%!4/-1/!4-22!/)9%!)!8.#2#&,%*![@\:!!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!LM!R/!a]G!;%4).*!a_G!)&*!\)l-=!Ba:!\/%!S1/#!>)&+)2G!L&*!%*:!I-88-&1#''CJ)9%&![+32-(/%.(G!
[/-2)*%28/-)G![BG!^%4!W#.=G!^WG!K555:!!!!
! DM
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
!
\/%!8.%((+.%!/)20C'-$%!$%'/#*!-(!+&.%2-)32%!-&!(-'+)'-#&(!-&!4/-1/!'/%!2%0'!9%&'.-1+2).!
?IQF!*-)('#2-1!8.%((+.%!.-(%(!.)8-*27!?*+%!'#!.%('.-1'-#&!'#!0-22-&,F!)(!4-'/!(-,&-0-1)&'!)#.'-1!
.%,+.,-')'-#&G!IQ!*-)('#2-1!&#&1#$82-)&1%G!#.!-(1/%$-):!!U&!'/%(%!(-'+)'-#&(!'/%!.)8-*!.-(%!
-&!IQ!*-)('#2-1!8.%((+.%!.%(+2'(!-&!.)8-*!%P+-2-3.)'-#&!#0!'/%!8.%((+.%!*-00%.%&1%!3%'4%%&!
'/%!2%0'!)'.-+$!)&*!'/%!2%0'!9%&'.-12%G!)&*!'/%![@\!-(!(/#.'%&%*:!!\/%!8.%((+.%!/)20C'-$%!
$%'/#*!-(!)2(#!+&.%2-)32%!-&!(-'+)'-#&(!-&!4/-1/!P+)2-'7!(8%1'.)2!<#882%.!4)9%!0#.$(!).%!
&#'!#3')-&%*G!(+1/!)(!-&!)'.-)2!')1/71).*-)!)&*!0-.('!*%,.%%!BQ!32#1=!?2#&,![J!-&'%.9)2F!
4/%.%!'/%!S!4)9%!)&*!'/%!B!4)9%!$%.,%G!)&*!-&!)'.-)2!02+''%.!4/%.%!'/%!02+''%.!4)9%!
<#882%.!8)''%.&(!$)7!1/)&,%!'/%!S!4)9%!*%1)7!8)''%.&:L5
!;+3l%1'(!4-'/!)3&#.$)2!
$7#1).*-)2!.%2)Y)'-#&!/)9%!)!8.#2#&,%*![@\G!3+'!'/%!8%)=!S!9%2#1-'7!-(!&#'!-&1.%)(%*!)&*!
-(!+(+)227!2#4%.!'/)&!K!$O(:LM!
!
U'!-(!)88.#8.-)'%!'#!1)21+2)'%!'/%!)#.'-1!9)29%!%00%1'-9%!#.-0-1%!).%)!37!'/%!1#&'-&+-'7!
%P+)'-#&!#&27!-0!7#+!/)9%!)&!)11+.)'%!IQR\!$%)(+.%$%&':!!U0!7#+!1)&&#'!#3')-&!)&!
)11+.)'%!IQR\!$%)(+.%$%&'G!4%!.%1#$$%&*!'/)'!7#+!.%8#.'!'/%!<#882%.!9%2#1-'7!-&*%Y!)(!
)!(+..#,)'%!0#.!'/%!)#.'-1!9)29%!%00%1'-9%!#.-0-1%!).%):!!\/%!<#882%.!9%2#1-'7!-&*%Y!?)2(#!
1)22%*!'/%!*-$%&(-#&2%((!-&*%YF!-(!'/%!.)'-#!QIQR\OQBQG!4/%.%!QIQR\!-(!'/%!IQR\!9%2#1-'7!
)&*!QBQ!-(!'/%!)#.'-1!9%2#1-'7:!!B!<#882%.!9%2#1-'7!-&*%Y!2%((!'/)&!6:L6!0#.!)!$%1/)&-1)2!
.%82)1%$%&'!9)29%!#.!2%((!'/)&!6:KE!0#.!)!/%'%.#,.)0'!3-#8.#('/%'-1!9)29%!-(!,%&%.)227!
1#&(-('%&'!4-'/!(%9%.%!.%82)1%$%&'!)#.'-1!9)29%!#3('.+1'-#&:L5!
!
A#.!.%82)1%$%&'!8+2$#&-1!9)29%(!)&*!8+2$#&-1!9)29%*!1#&*+-'(G!4%!*#!&#'!.%1#$$%&*!
'/)'!7#+!1)21+2)'%!'/%!%00%1'-9%!#.-0-1%!).%)G!(-&1%!'/%!1#&%!(/)8%!#0!'/%!.-,/'!9%&'.-1+2).!
#+'02#4!'.)1'!$)=%(!%1/#1).*-#,.)8/-1!$%)(+.%$%&'!#0!'/%!.-,/'!9%&'.-1+2).!#+'02#4!'.)1'!
*-)$%'%.!*-00-1+2':!!\/-(!*-00-1+2'!$%)(+.%$%&'!2%)*(!'#!8#'%&'-)2!-&)11+.)'%!1)21+2)'-#&!#0!
'/%!8+2$#&-1!9)29%!%00%1'-9%!#.-0-1%!).%)!9-)!'/%!1#&'-&+-'7!%P+)'-#&!$%'/#*:!!;-$-2).27G!
0#.!.%82)1%$%&'!8+2$#&-1!9)29%(!)&*!8+2$#&-1!9)29%*!1#&*+-'(G!4%!*#!&#'!.%1#$$%&*!
'/)'!7#+!1)21+2)'%!%00%1'-9%!#.-0-1%!).%)!-&*%Y!)&*!8%.0#.$)&1%!-&*%Y!*)')G!4/-1/!).%!
1)21+2)'%*!+(-&,!%00%1'-9%!#.-0-1%!).%)!*)'):!
!
@#4%9%.G!4%!('-22!.%1#$$%&*!'/)'!'/%!8+2$#&-1!8%)=!,.)*-%&'!)&*!$%)&!,.)*-%&'!3%!
1)21+2)'%*G!+(-&,!"c!<#882%.G!)(!*#&%!0#.!#'/%.!9)29%!8#(-'-#&(:!!
!
A#.!)#.'-1!)&*!$-'.)2!9)29%(G!4%!.%1#$$%&*!'/)'!7#+!-&*%Y!'/%!%00%1'-9%!#.-0-1%!).%)!'#!
3#*7!(+.0)1%!).%)!)(!(/#4&!3%2#4:!
!
!L5!]%.+'!S]G!>1U24)-&!SAG!)&*![2#'&-1=!V<:!@)&*3##=!#0!S1/#C<#882%.!U&'%.8.%')'-#&:!A+'+.)!
[+32-(/-&,!"#$8)&7G!U&1:G!B.$#&=G!^WG!K55H:!
! D5
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
A#.!)#.'-1!)&*!$-'.)2!9)29%(N!
!
!IE
:<:<
F
F2F $ ! !
!
4/%.%! F:<2! -(!'/%!-&*%Y%*!%00%1'-9%!#.-0-1%!).%)!-&!1$LO$
L:!
!
FIE! -(!'/%!3#*7!(+.0)1%!).%)!-&!$L!
!
2. Velocity Time Integral
\/%!9%2#1-'7!'-$%!-&'%,.)2!r#.!'-$%!9%2#1-'7!-&'%,.)2!?\QUFs!-(!*%0-&%*!)11#.*-&,!'#!'/%!
0#22#4-&,!%P+)'-#&N!!
!
! ! !!EK6%##$ :A3"%5 ,CC?2
!
!
4/%.%! C?2!! -(!'/%!9%2#1-'7!'-$%!-&'%,.)2!-&!1$!
!
! C$%)&!! -(!'/%!$%)&!9%2#1-'7!#0!0#.4).*!02#4!-&!$O(!
!
! ,Sa!! -(!'/%!%l%1'-#&!'-$%!-&!$(!
!
B2'%.&)'-9%27G!7#+!$)7!1)21+2)'%!'/%!9%2#1-'7!'-$%!-&'%,.)2!?Q\UF!37!'/%!3+-2'C-&!(#0'4).%!
#0!$#*%.&!%1/#1).*-#,.)8/7!+2'.)(#+&*!$)1/-&%(!+(-&,!'/%!'%1/&-1-)&f(!82)&-$%'.7!
?'.)1-&,F!#0!'/%!<#882%.!9%2#1-'7!(-,&)2:!
!
3. Peak Pressure Gradient
c%!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!8%)=!8.%((+.%!,.)*-%&'!)1.#((!'/%!.%82)1%$%&'!
9)29%!9-)!'/%!$#*-0-%*!_%.&#+22-!%P+)'-#&!3%2#4:!!B2'%.&)'-9%27G!7#+!$)7!1)21+2)'%!'/%!
8%)=!8.%((+.%!,.)*-%&'!+(-&,!$#*%.&!%1/#1).*-#,.)8/7!+2'.)(#+&*!$)1/-&%(!4-'/!3+-2'C-&!
(#0'4).%!'/)'!+(%(!'/%!%P+)'-#&!3%2#4:!
!
! & 'LKL
LZ CCHH"%J %$" ! !
!
4/%.%! H"%J'!H!! -(!'/%!8%)=!8.%((+.%!,.)*-%&'!-&!$$!@,!
! ! !
CL! -(!'/%!9%2#1-'7!*-(')2!'#!'/%!9)29%!-&!$O(!?)(!$%)(+.%*!37!
"c!<#882%.F!
! ! !
CK! -(!'/%!9%2#1-'7!8.#Y-$)2!'#!'/%!9)29%!-&!$O(!?)(!$%)(+.%*!37!
[c!<#882%.FG!$%)(+.%*!-&!'/%!IQR\!0#.!)&!)#.'-1!
8.#('/%(-(!!
!
! Z6
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
4. Mean Pressure Gradient
c%!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!$%)&!8.%((+.%!,.)*-%&'!)1.#((!'/%!.%82)1%$%&'!
9)29%!9-)!'/%!%P+)'-#&!3%2#4:!!c%!.%1#$$%&*!'/)'!7#+!+(%!'/%!3+-2'C-&!(#0'4).%!#0!
$#*%.&!%1/#1).*-#,.)8/7!+2'.)(#+&*!$)1/-&%(!'/)'!+(%!82)&-$%'.7!?'.)1-&,F!#0!'/%!"c!
<#882%.!(8%1'.)2!9%2#1-'7!(-,&)2!)&*!'/%!(-$82-0-%*!_%.&#+22-!%P+)'-#&!?#[!n!ZQLLF!'#!
#3')-&!$+2'-82%!-&(')&')&%#+(!8.%((+.%!,.)*-%&'(G!4/-1/!7#+!(/#+2*!'/%&!)9%.),%!'#!*%.-9%!
'/%!$%)&!8.%((+.%!,.)*-%&'G!)(!(/#4&!-&!'/%!0#22#4-&,!%P+)'-#&:!!!
!
!5
HHHH@"%5 5*** $$$ "(("("$"
:::LK ! !
4/%.%! @"%5'!H! -(!'/%!$%)&!8.%((+.%!,.)*-%&'!-&!$$@,!
! ! #H*nK! -(!'/%!K('!-&(')&')&%#+(!8.%((+.%!,.)*-%&'!-&!$$@,!
! ! #H*nL! -(!'/%!L&*!-&(')&')&%#+(!8.%((+.%!,.)*-%&'!-&!$$@,!
! ! #H*n5! -(!5'/!-&(')&')&%#+(!8.%((+.%!,.)*-%&'!-&!$$@,!
! ! 5! -(!'/%!&+$3%.!#0!-&(')&')&%#+(!8.%((+.%!,.)*-%&'(!
!
\/%!(-$82-0-%*!_%.&#+22-!%P+)'-#&!)((+$%(!&%,2-,-32%!8.#Y-$)2!9%2#1-'7:!!U&!#'/%.!4#.*(G!
-'!)((+$%(!QK!-(!2%((!'/)&!K$O(:!!U0!'/-(!)((+$8'-#&!-(!+&'.+%G!/#4%9%.G!'/%!%P+)'-#&!)3#9%!
$)7!#9%.%('-$)'%!'/%!$%)&!8.%((+.%!,.)*-%&':!
5. Transvalvular Flow
A#.!)#.'-1!)&*!$-'.)2!9)29%(G!4%!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'.)&(9)29+2).!02#4!)(!
0#22#4(N!!!
!
! DK6#$:A
+
,
C!&1K ! !
4/%.%! !&1K!! ! -(!'/%!'.)&(9)29+2).!02#4!-&!$2O(!
! ,Sa!! -(!'/%!%l%1'-#&!'-$%!-&!$(!
C;!!! -(!'/%!('.#=%!9#2+$%!-&!$2G!1)21+2)'%*!+(-&,!'/%!0#22#4-&,!
('.#=%!9#2+$%!%P+)'-#&N!
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01
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! !
! ZK
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
4/%.%! F";!! -(!'/%!1.#((C(%1'-#&)2!).%)!#0!'/%!IQR\!-&!1$L!0#.!'/%!)#.'-1!
('.#=%!9#2+$%!1)21+2)'-#&G!#.!'/%!1.#((C(%1'-#&)2!).%)!#0!'/%!
$-'.)2!9)29%!)&&+2+(!-&!1$L!0#.!'/%!$-'.)2!('.#=%!9#2+$%!
1)21+2)'-#&!
-! -(!'/%!*-)$%'%.!#0!'/%!IQR\!-&!1$!0#.!'/%!)#.'-1!('.#=%!
9#2+$%!1)21+2)'-#&G!#.!'/%!*-)$%'%.!#0!'/%!$-'.)2!9)29%!
)&&+2+(!-&!1$!0#.!'/%!$-'.)2!('.#=%!9#2+$%!1)21+2)'-#&!
C?2! -(!'/%!IQR\!9%2#1-'7!'-$%!-&'%,.)2!-&!1$!0#.!'/%!)#.'-1!
('.#=%!9#2+$%!1)21+2)'-#&G!#.!'/%!$-'.)2!9%2#1-'7!'-$%!
-&'%,.)2!-&!1$!0#.!'/%!$-'.)2!('.#=%!9#2+$%!1)21+2)'-#&!
!
6. Cardiac Index
c%!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!1).*-)1!-&*%Y!)(!0#22#4(N!
!
!IE
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<=2 $ ! !
!
4/%.%! =2!! ! -(!'/%!1).*-)1!-&*%Y!-&!2O$-&O$L!
!
! <"!! ! -(!'/%!1).*-)1!#+'8+'!-&!2O$-&!
!
F_;!! ! -(!'/%!3#*7!(+.0)1%!).%)!-&!$L!
!
7. Performance Index
c%!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!8%.0#.$)&1%!-&*%Y!)(!0#22#4(N!
!
!HC
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2<F
F6*61*5H2 $ ! !
!
4/%.%! H2'! ! -(!'/%!8%.0#.$)&1%!-&*%YG!4/-1/!/)(!&#!*-$%&(-#&(!
!
*5'6*61!FSR! -(!'/%!*5'6*61!%00%1'-9%!#.-0-1%!).%)!-&!1$L!
!
2<F[Q! -(!'/%!8.%C-$82)&'!-&'%.&)2!#.-0-1%!).%)!#0!'/%!.%82)1%$%&'!
9)29%!-&!1$LG!#3')-&%*!0.#$!'/%!.%82)1%$%&'!9)29%!
(8%1-0-1)'-#&(!
!
A#.!.%82)1%$%&'!8+2$#&-1!9)29%(!)&*!8+2$#&-1!9)29%*!1#&*+-'(G!4%!*#!&#'!.%1#$$%&*!
'/)'!7#+!1)21+2)'%!'/%!8%.0#.$)&1%!-&*%YG!4/-1/!-(!1)21+2)'%*!+(-&,!%00%1'-9%!#.-0-1%!).%)!
*)')G!(-&1%!'/%!1#&%!(/)8%!#0!'/%!.-,/'!9%&'.-1+2).!#+'02#4!'.)1'!$)=%(!%1/#1).*-#,.)8/-1!
$%)(+.%$%&'!#0!'/%!.-,/'!9%&'.-1+2).!#+'02#4!'.)1'!*-)$%'%.!*-00-1+2':!!\/-(!*-00-1+2'!
! ZL
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
$%)(+.%$%&'!2%)*(!'#!8#'%&'-)2!-&)11+.)'%!1)21+2)'-#&!#0!'/%!8+2$#&-1!9)29%!%00%1'-9%!
#.-0-1%!).%)!9-)!'/%!1#&'-&+-'7!%P+)'-#&!$%'/#*:!
!
C. Valvular Regurgitation
U&!)**-'-#&!'#!U;R!EMZ6NL66EG!;%1'-#&!@:ZG!(+3(%1'-#&!@:Z:TG!4%!.%1#$$%&*!'/)'!7#+!
-&12+*%!'/%!-&0#.$)'-#&!*%(1.-3%*!3%2#4!-&!7#+.!%9)2+)'-#&!#0!9)29+2).!.%,+.,-')'-#&:!
!
c%!.%1#$$%&*!'/)'!7#+!-*%&'-07!%)1/!l%'!)(!8%.-9)29+2).G!'.)&(9)29+2).G!3#'/G!#.!+&1%.')-&:!!
c%!)2(#!.%1#$$%&*!'/)'!7#+!(/#4!'/%!(-'%!#0!%)1/!8%.-9)29+2).!l%'!#&!'/%!(%4-&,!.-&,G!0#.!
%Y)$82%G!)(!)!q12#1=C0)1%q!*-),.)$:!!!
\/%!%9)2+)'-#&!#0!9)29+2).!.%,+.,-')'-#&!(/#+2*!-&9#29%!)&!-&'%,.)'%*!)88.#)1/!-&!4/-1/!7#+!
+(%!$+2'-82%!%1/#1).*-#,.)8/-1!$%'/#*(!'#!)((%((!.%,+.,-')'-#&!)'!%)1/!0#22#4C+8!'-$%C8#-&':!!
;-&1%!1%.')-&!$%'/#*(!$)7!&#'!3%!)9)-2)32%!)'!%9%.7!0#22#4C+8!9-(-'G!'/-(!)88.#)1/!)22#4(!7#+!
'#!1#$8).%!(%P+%&'-)2!.%(+2'(!0#.!'/%!%&'-.%!*+.)'-#&!#0!0#22#4C+8G!4-'/!'/%!.%(+2'(!#3')-&%*!37!
'/%!()$%!$%'/#*!#.!$%'/#*(:!!c%!.%1#$$%&*G!/#4%9%.G!'/)'!7#+!(+3$-'!)22!0#22#4C+8!
.%(+2'(G!-&12+*-&,!'/#(%!#3')-&%*!37!$%'/#*(!4-'/!$-((-&,!'-$%C8#-&'(:!!B88.#8.-)'%!$%'/#*(!
0#.!%9)2+)'-&,!.%,+.,-')'-#&!).%!(+$$).-g%*!3%2#4!)&*!*-(1+((%*!-&!0+.'/%.!*%')-2!-&!'/%!
2-'%.)'+.%:D6GDK
!
1. Aortic Regurgitation
c%!.%1#$$%&*!'/)'!7#+!,.)*%!)#.'-1!.%,+.,-')'-#&!37!)&!-&'%,.)'%*!%9)2+)'-#&!3)(%*!#&!
0)1'#.(!-&12+*-&,N!!
! -&('.+$%&'!(%''-&,!
! l%'!4-*'/!
! l%'!).%)!
! l%'!*%8'/!
! '/%!(/)8%!?1#&'#+.F!)&*!'/%!*%&(-'7!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!?%:,:G!'/%!
*%1%2%.)'-#&!'-$%!)&*!8.%((+.%!/)20C'-$%!3#'/!*%1.%)(%!4-'/!-&1.%)(-&,!BJ!(%9%.-'7k!
-&1.%)(%*!(-,&)2!*%&(-'7!,%&%.)227!-&*-1)'%(!$#.%!(%9%.%!BJF!
! '/%!*+.)'-#&!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!?%:,:G!)!3.-%0!*-)('#2-1!*+.)'-#&!+(+)227!
-&*-1)'%(!8/7(-#2#,-1!#.!$-2*!BJF!
!D6!b#,/3-!cBG!S&.-P+%gC;).)&#!>G!A#('%.!SG!V.)73+.&![BG!].)0'!"<G!I%9-&%!JBG!
^-/#7)&#+2#(![G!R''#!">G!d+-&#&%(!>BG!J)=#4(=-!@G!;'%4).'!caG!c),,#&%.!BG!)&*!
c%-(($)&!^a:!J%1#$$%&*)'-#&(!0#.!%9)2+)'-#&!#0!'/%!(%9%.-'7!#0!&)'-9%!9)29+2).!.%,+.,-')'-#&!
4-'/!'4#C*-$%&(-#&)2!)&*!<#882%.!%1/#1).*-#,.)8/7:!a!B$!;#1!S1/#1).*-#,.!KHNTTTCM6LG!
L66D:!DK!V#''*-%&%.!a;G!_%*&).g!aG!<%9%.%+Y!JG!V).*-&!aG!]2%-&!BG!>)&&-&,!caG!>#.%/%)*!BG!]-'g$)&!
<G!R/!aG!d+-&#&%(!>G!;1/-22%.!^_G!;'%-&!a@G!)&*!c%-(($)&!^a:!B$%.-1)&!;#1-%'7!#0!
S1/#1).*-#,.)8/7!.%1#$$%&*)'-#&(!0#.!+(%!#0!%1/#1).*-#,.)8/7!-&!12-&-1)2!'.-)2(G!a!B$!;#1!
S1/#1).*-#,.!KTNK6MHCKKK5G!L66Z:!
! ZD
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
! '/%!('.+1'+.%!#0!'/%!)#.'-1!9)29%!
! '/%!(-g%!)&*!0+&1'-#&!#0!'/%!2%0'!9%&'.-12%!
! /#4!0).!*-)('#2-1!02#4!.%9%.()2!1)&!3%!9-(+)2-g%*!4-'/-&!'/%!)#.'):DL!!!
!
R0!'/%(%!,.)*-&,!0)1'#.(G!'/%!4-*'/!#0!'/%!)#.'-1!l%'!)(!)!8.#8#.'-#&!#0!'/%!2%0'!9%&'.-1+2).!
#+'02#4!'.)1'!*-)$%'%.!-(!'/%!$#('!0.%P+%&'27!+(%*!(-&,2%!$%)(+.%:DD!!@#4%9%.G!l%'!4-*'/!
(/#+2*!3%!)882-%*!1).%0+227!0#.!%11%&'.-1!l%'(:!!!
!
c%!.%1#$$%&*!'/)'!7#+!)2(#!,.)*%!)#.'-1!.%,+.,-')'-#&!37!'/%!)88%).)&1%!#0!'/%!*-)('#2-1!
0-22-&,!8)''%.&!-&!$-'.)2!-&02#4!?%:,:G!(%9%.%!)#.'-1!.%,+.,-')'-#&!.%(+2'(!-&!)!.%('.-1'-9%!$-'.)2!
0-22-&,!8)''%.&!4-'/!/-,/!S!9%2#1-'7G!2#4!B!9%2#1-'7G!-&1.%)(%*!SOB!9%2#1-'7!.)'-#G!)&*!(/#.'!
*%1%2%.)'-#&!'-$%F:!!!
!
c%!)2(#!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!.%,+.,-')&'!9#2+$%G!.%,+.,-')&'!0.)1'-#&G!)&*!
%00%1'-9%!.%,+.,-')&'!#.-0-1%G!'#!#3')-&!)!$#.%!#3l%1'-9%!P+)&'-g)'-#&!#0!'/%!(%9%.-'7!#0!)#.'-1!
.%,+.,-')'-#&:!!\/%!.%,+.,-')&'!9#2+$%G!.%,+.,-')&'!0.)1'-#&G!)&*!%00%1'-9%!.%,+.,-')&'!
#.-0-1%!).%)!1)&!3%!1)21+2)'%*!37!'/%!9#2+$%'.-1!#.!8.#Y-$)2!-(#9%2#1-'7!(+.0)1%!).%)!?[U;BF!
$%'/#*(:!!^#.$)2!.%,+.,-')'-#&!*+%!'#!3)1=02#4!(/#+2*!3%!*-('-&,+-(/%*!0.#$!8)'/#2#,-1!
.%,+.,-')'-#&:!!\/%!+(+)2!*-('-&,+-(/-&,!0%)'+.%(!#0!&#.$)2!.%,+.,-')'-#&!).%!)!+&-0#.$!1#2#.!
8)''%.&!)&*!($)22!l%'(!4-'/!&#.$)2!.%,+.,-')'-#&:!!\/%!+(+)2!*-('-&,+-(/-&,!0%)'+.%(!#0!
8)'/#2#,-1!.%,+.,-')'-#&!).%!)!$#()-1!1#2#.!8)''%.&!)&*!2).,%.!l%'(:!!!
!
2. Mitral Regurgitation
c%!.%1#$$%&*!'/)'!7#+!,.)*%!$-'.)2!.%,+.,-')'-#&!37!)&!-&'%,.)'%*!%9)2+)'-#&!3)(%*!#&!
0)1'#.(G!-&12+*-&,N!
! -&('.+$%&'!(%''-&,!
! l%'!4-*'/!
! l%'!).%)!
! l%'!*%8'/!
! l%'!%11%&'.-1-'7!
! '/%!(/)8%!?1#&'#+.F!)&*!'/%!*%&(-'7!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!?%:,:G!(%9%.%!$-'.)2!
.%,+.,-')'-#&!$)7!.%(+2'!-&!)!q1+'C#00!(-,&i!*+%!'#!)!2).,%!9!4)9%k!-&1.%)(%*!(-,&)2!
*%&(-'7!,%&%.)227!-&*-1)'%(!$#.%!(%9%.%!>JF!
! '/%!8%)=!9%2#1-'7!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!?%:,:G!8%)=!9%2#1-'7!*%1.%)(%(!4-'/!
-&1.%)(-&,!$-'.)2!.%,+.,-')'-#&!(%9%.-'7!*+%!'#!-&1.%)(%*!2%0'!)'.-)2!8.%((+.%F!
! '/%!*+.)'-#&!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!
! '/%!('.+1'+.%!#0!'/%!$-'.)2!9)29%!
!DL!;-$8(#&!UBG!<%!_%2*%.!>BG!]%&&7!BG!>).'-&!>G!)&*!^-/#7)&#+2#(![G!@#4!'#!P+)&'-')'%*!
9)29%!.%,+.,-')'-#&!37!%1/#!<#882%.!'%1/&-P+%(G!_.-'!@%).'!a!!TD?E!;+882!LFNKC5G!K55E:!DD![%..7!VaG!@%2$1=%!AG!^)&*)!^"G!_7).*!"G!)&*!;#'#!_:!!S9)2+)'-#&!#0!)#.'-1!-&(+00-1-%&17!37!
<#882%.!1#2#.!02#4!$)88-&,G!a!B$!"#22!").*-#2!5N5ELC5E5G!K5MT:!
! ZZ
Contains Nonbinding Recommendations !
-$%.,'/'01,'.1$'234&"3"5,%,*15'
!
! ZE
! '/%!(-g%!)&*!0+&1'-#&!#0!'/%!2%0'!9%&'.-12%!
! '/%!(-g%!#0!'/%!2%0'!)'.-+$!
! -$8-&,%$%&'!#0!'/%!l%'!#&!'/%!2%0'!)'.-)2!4)22!
! '/%!*-.%1'-#&!#0!(7('#2-1!02#4!-&!'/%!8+2$#&).7!9%-&(!?%:,:G!(%9%.%!$-'.)2!.%,+.,-')'-#&!
$)7!.%(+2'!-&!(7('#2-1!02#4!.%9%.()2F!
! '/%!4-*'/!#0!'/%!9%&)!1#&'.)1')!?'/%!&)..#4%('!8#.'-#&!#0!'/%!$-'.)2!.%,+.,-')'-#&!l%'!
*#4&('.%)$!0.#$!'/%!#.-0-1%F:!!!
!
>-'.)2!.%,+.,-')'-#&!$)7!)2(#!3%!,.)*%*!37!'/%!)88%).)&1%!#0!'/%!*-)('#2-1!0-22-&,!8)''%.&!-&!
$-'.)2!-&02#4!?%:,:G!(%9%.%!$-'.)2!.%,+.,-')'-#&!.%(+2'(!-&!)!.%('.-1'-9%!0-22-&,!8)''%.&!4-'/!
/-,/!S!9%2#1-'7G!2#4!B!9%2#1-'7G!-&1.%)(%*!SOB!.)'-#G!)&*!(/#.'!*%1%2%.)'-#&!'-$%F:!!!
!
c%!)2(#!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!.%,+.,-')&'!9#2+$%G!.%,+.,-')&'!0.)1'-#&G!)&*!
%00%1'-9%!.%,+.,-')&'!#.-0-1%!'#!#3')-&!)!$#.%!#3l%1'-9%!P+)&'-')'-#&!#0!'/%!(%9%.-'7!#0!$-'.)2!
.%,+.,-')'-#&:!!\/%!.%,+.,-')&'!9#2+$%G!.%,+.,-')&'!0.)1'-#&G!)&*!%00%1'-9%!.%,+.,-')&'!
#.-0-1%!1)&!3%!1)21+2)'%*!37!'/%!9#2+$%'.-1!#.![U;B!$%'/#*(:!!^#.$)2!.%,+.,-')'-#&!*+%!'#!
3)1=02#4!(/#+2*!3%!*-('-&,+-(/%*!0.#$!8)'/#2#,-1!.%,+.,-')'-#&:!!\/%!+(+)2!*-('-&,+-(/-&,!
0%)'+.%(!#0!&#.$)2!.%,+.,-')'-#&!).%!)!+&-0#.$!1#2#.!8)''%.&!)&*!($)22!l%'(!4-'/!&#.$)2!
.%,+.,-')'-#&:!!\/%!+(+)2!*-('-&,+-(/-&,!0%)'+.%(!#0!8)'/#2#,-1!.%,+.,-')'-#&!).%!)!$#()-1!
1#2#.!8)''%.&!)&*!2).,%.!l%'(:!!!