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Research and Development of the Model 1155 calipers

1) August 2005, IRB 1532-003 Atrial Fibrillation Outcomes Database Dr. Patrick McCarthy minimal risk
database.
2) October 13, 2005 Design Input Memo for the Model 5100 ring, holder and Model 1155 Caliper.
3) February 26, 2006 First Justification to File DFU for the Model 5100 similar to previous annuloplasty rings.
4) April 26, 2006, Toni Vlahoulis Surgery causes severe mitral valve stenosis and Pacemaker
5) November 6, 2006, Maureen Obermeier Surgery causes severe heart attack and Defibrillator
6) June 2006, Dr. McCarthy applies for a HIPPA waiver to publish data from the database 1532-004, Expedited
Waiver for retrospective data is granted by Eileen Yates for protocol to study the Model 4100, the Model
5100, and the caliper measurements as part of a direct surgical analysis of the mitral valve and compare
the measurements to echo measurements of the mitral valve, AATS abstract
7) November 20, 2006, Second Justification to File Standard sizer methods and then turning the sizer 90
degrees for the Model 5100 ring.
8) January 2007, US Trademark Office Directions for use Myxo ETlogix Model 5100. See DFU.
9) May 21, 2007, Vlahoulis second surgery to replace stenosed valve and remove model 5100 ring, and asks
why she got the McCarthy Annuloplasty ring which is not listed in the Edwards Lifesciences Brochure.
10) I reported to the NU Dean’s office, Chief of Cardiology, IRB, General Counsel lack of consent in May 2007
and removed my name from the study.
11) May 2007, Dr. McCarthy requests another expedited HIPPA waiver from Northwestern University IRB
coordinator Tasha Osafo. Tasha Osafo recognizes that the study protocol is prospective, and not
retrospective as indicated in the June 2006 expedited waiver, and IRB Coordinator Osafo requests more
data for the IRB as 1532-004 is now a prospective study and not retrospective.
12) June 28, 2007 IRB Coordinator Tasha Osafo issues a cease and desist of the protocol 1532-004.
13) July 13, 2007 Dr. McCarthy prepares documents to terminate protocol 1532-004 on July 12, 2007 which
includes his checking the box with an agreement signed by Dr. McCarthy with the Northwestern University
IRB, under the Federal Wide Assurance 0001549, signed by Jay Walsh, with HHS, the NIH and the FDA, of
“no further contact with human subjects is planned: no subjects are, or will be, treated or followed; all data
are gathered and analyzed; and there are no further sponsor reports or publications to submit to the IRB.”
14) February 2007, Al Edwards surgery causes heart attack and pacemaker
15) January 8, 2008, Brian Warshawsky surgery causes severe heart attack and defibrillator
16) July 2008, Dr. McCarthy and colleagues publishes the study despite termination record, on the Myxo ETlogix
Ring and the model 1155 calipers study, he continued the protocol for the publication until November 2007.
Vlahoulis and myself report to the FDA the existence of the Model 5100, Myxo ETlogix Ring.
17) April 2009, US Trademark Office Directions for the use DETlogix Model 5100, See DFU. FDA 510k clears
device. 27 MAUDE Events related to the model 5100 including 2 deaths, 2 heart attacks and reoperations.
18) FDA confirms to Vlahoulis in July 2009, the Myxo ETlogix is significant risk and considered under an IDE.
19) September 25, 2014 William Knotts Surgery results in Severe Mitral Stenosis Short of breath
20) June 1, 2018 William Knotts undergoes surgery to replace the mitral valve and discovery of severe stenosis
with the anterior leaflet sewn shut to the ring. 174 day hospitalization which ends with his death at
Northwestern Memorial Hospital.
21) All patients listed in this chronology underwent protocol 1532-004 sizing method with the experimental
calipers, and not the DFU as listed in the Edwards Lifesciences Documents.
22) Meeting with FDA December 19, 2018 at noon to discuss the experimental calipers, and outcomes for
patients who received the calipers and not the established Directions for use as listed in Edwards
Lifesciences manufactured Rings.
Point One

1) August 2005, IRB 1532-003 Atrial Fibrillation Outcomes Database Dr. Patrick McCarthy minimal risk
database.
Point Two

2) October 13, 2005 Design Input Memo for the Model 5100 ring, holder and Model 1155 Caliper.
liIIIillllYAIIl\

IIDI Edwards Lifesciences


1lll1Iil!III~
Interoffice Memorandum - For Internal Use Only

To: Model 5100 File Date: November 11, 2005

cc: From: Vaso Adzich


Proje~~\1anage~,/.!
f/aoo ~ iY/'1 OJ-
Aaron Ingle
Staff Engineer
Matthe-;W--in-6---=;:::-~ II/JI/05

Subject:
: ' . Engin~
Design input for the Model 5100 ring, holder, and Model 1155 Mitral Valve Caliper
ii05
Purpose

This document is to record the desig'n input obtained from Dr. McCarthy in relation to the model 5100 ring,
holder, and Model 1155. Mitral Valve Caliper.

Background

On October 13, 2005, a discussion was held between Dr. McCarthy, Vaso Adzich, Jinny Lee, Aaron Ingle, and-
Matthew Winston. The discussion was in regards to the model 5100 ring and associated products, and took
place at Tommy Bahama's Restaurant in Newport Beach, CA.

Discussion

Model 5100 Ring: During the discussion, Dr. McCarthy was presented with the following prototype samples:
Metal cores of size 36mm myxomatous rings with (1) a closed "GeoForm type" cross-section, and (2)'
an open triangular cross-section.
Completed 36mm myxomatous rings with (1) a clOsed "GeoForm type" cross-section, and (2) an
open triangular cross-section (constructed with most recent Secant cloth and a silicone rubber band).
Completed rings, with a closed shape, a "GeoForm type" cross-section made of SLA material, the
most recent Secant cloth, and a silicone rubber band, in the following sizes: 26mm, 30mm, 38mm,
and 40mm.
Size 36m holder, with a 25 degree angle and a closed ring attached.
A 40mm Physio ring for size comparison purposes.
Samples of 2-0 Ethibond excel braided polyester suture (wI RB-1 taper 1/2 17mm needle) for needle
penetration/parachuting evaluation.

In comparing the metal cores of the open and closed design, Dr. McCarthy preferred the closed design due to
the reduced cross-section permitted by the design, and explained that he preferred a large sewing margin-to-
metal proportion in the ring.

In the discussion of the ring sizes, Dr. McCarthy felt that a 40mm ring was very large and said that the largest
size he used was a 36mm. However, he felt that if surgeons were requesting larger sizes, then we maywant
to make those sizes available (i.e. 38mm and 40mm).

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Ii =1 Edwards Lifesciences
lfiIrRllllI!!';/
Interoffice Memorandum - For Internal Use Only

To determine sew-ability, Dr. McCarthy placed a suture through the sewing area of a closed ring sample and
pulled the suture back and forth a few times to see how well the suture slid through. Based on this review, he
felt that the sewing area was adequate, though there was no specific mention of parachuting.

In regards to the holder he did not provide any significant feedback, but indicated that he liked it.

At the conclusion of the ring discussion, he requested samples of the closed ring design (with and without
cloth), and was told that he would be sent samples in a few weeks. He was also informed that we needed to
confirm the intellectual property status of the ring with Edwards legal before he could have outside
discussions regarding the rings design.

Mitral Valve Calipers and Sizing: After the ring discussion, Dr. McCarthy was shown a prototype mitral valve
caliper that closely resembled the design used for design verification testing.

Dr. McCarthy's response was positive. He had some brief trouble establishing the correct initial hand position
and managed to get the ruler off of the track, but was able to quickly figure it out. In trying to use the device,
he was OK with the measurement method and with his ability to adequately read the measurements. He had
some initial questions on the device resistance, but after some use of the device, he seemed to feel that it
was adequate. In regards to device sterilization, he was pleased with the ability to flash sterilize the device,
so that it could more easily be used in successive procedures. .

In terms of annuloplasty ring sizing, Dr. McCarthy indicated that he might want to use the calipers to measure
the posterior leaflet. His current evaluation of the posterior leaflet length is based on qualitative visual
assessment and the calipers may allow for that assessment to be quantified (at a previous discussion Dr.
McCarthy indicated that he upsized by one for large posterior leaflets and downsized by one for small
posterior leaflets).

The engineering team indicated that they would try to make the caliper available to him by the end of the
month.

Implant Schedule: Dr. McCarthy indicated that if the first 10 implants went well, he would feel comfortable
expanding the use of the device to other surgeons and listed a number of surgeons that he felt may be good
choices for expanded use of the ring.

In regards to the ring's availability, Dr. McCarthy was told that we would try to have the ring available by the
end of February.

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EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX." EW-S-20000169


Point Three

3) February 26, 2006 First Justification to File DFU for the Model 5100 similar to previous annuloplasty
rings.
Edwards Lifesciences
Justification to File
Notification of Product Modific ;ons made to
The GeoForm Annulopl ." (K032250)
McCart,hy Myxo ETI~. ~~ 0. i.sty Ring, Model 5100
'/'OLlme
I 1 0f 1
~arY27l 2006 .
Copy: RA File

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000037


interoffice Memorandum
Edwards Lifesciences For Internal Use Only

To: RA File Date: February 27, 2006

cc: From: Susan Reynolds


RA Associate III

Subject: Decision for Notification of Product Modification

Purpose

The purpose of this justification to the file is to document modifications made to the
GeoForm Annuloplasty Ring. The modifications resulted in the McCarthy Type II
Annuloplasty Ring, Mitral Model 5100.

Trade Name

McCarthy Type II Annuloplasty Ring, Mitral Model 5100

Device Description

The McCarthy Type II Annuloplasty Ring, Mitral Model 5100, is constructed of titanium
alloy and has a sewing ring margin that consists of a layer of silicone rubber covered
with a polyester velour cloth that is sewn with a single seam. Design objectives include:
retention of the natural valve apparatus, remodeling of the annulus, prevention of
secondary distension of the annulus (frequently the cause of recurrent incompetence
after conventional valvuloplasties) and retain the anterior to posterior dimension. The
small size and profile of the ring minimize the exposure of foreign material in the atrium
and may account for the reduced thromboembolic incidence as compared with prosthetic
valves.

Transverse colored threads indicate the anterior and posterior commissures.

Description of Product Modifications

Please refer to Table 1 for a comparison of the modifications between rings:

Model 5100, McCarthy Type II Mitral.doc Page 1 of9

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Ta bl e 1 - Companson 0 fth e G eo F orm an d Mc Ca rthIY Type 11Kmg.


GeoForm Type II
K# K032250
Cloth Material Polyester Velour Polyester Velour
Ring Material Titanium Alloy Titanium Alloy
Sewing Sewing ring margin consists of a Sewing ring margin consists of a
Ring/Silicone layer of silicone rubber covered layer of silicone rubber covered
with polyester velour cloth with polyester velour cloth
Opaque silicone band with Opaque silicone band with barium
barium sulfate additive sulfate additive
Intended Use Correction of mitral valve Correction of mitral valve
insufficiency insufficiency_
Flex/Rigid RigJd Rigid
Open Closed Closed Closed
Position Mitral Mitral
3-D Yes Yes

Change to the GeoForm Ring:


The change to the ring is as follows:
~ The McCarthy Type II Annuloplasty Ring, Mitral Model 5100 has an outward .
extension and upward lift in the central posterior (P2) portion of the ring when
compared to a Physio annuloplasty ring. Also, the anterior portion of the ring
includes an accentuated saddle shape .

.. Product Labeling Changes

Proposed labels and Directions for Use can be found in the section entitled "Labels".
The labeling for the McCarthy Type II Annuloplasty Ring is identical to that of the
GeoForm Annuloplasty Ring (K032250) with the following exceptions:
»- A new name and model number have been created for the modified
annuloplasty ring. The new name is the McCarthy Type II Annuloplasty Ring,
Model 5100. The new name and model number will be identified on all
applicable package labels and Directions For Use.
);> There is a minor change in the device description, in that the GeoForm states
that there is a decrease in the anterior to posterior dimension. The Type II
retains the anterior to posterior dimension.
);> All references regarding a holder were removed. A holder will be added at a
later date.

Safety and Effectiveness of Modified Product

The McCarthy Type II Annuloplasty Ring was evaluated by bench testing. The devices
were subjected to the maximum number of production steam sterilization cycles (3) as

Model 5100, McCarthy Type [I Mitral.doc Page 2 of9

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allowed by ELS 4013 Rev BP and maximum number of autoclave sterilization cycles (5)
as allowed by the DFU (PN 195678001) in order to simulate a worse case scenario.

The three production steam sterilization cycles were performed per ELS 4013 Rev BP,
cycle 45:
Temperature 121.0 - 123.0 °C
Time 46 ± 1 minutes
Dry Time 30 ± 10 minutes

As illustrated in Table 1, the parameters for the five autoclave sterilization cycles were
chosen to exceed the worst-case combination of par~meters allowed per the DFU (P/N
195678001) instructions for autoclave sterilization.

Table 1 Autoclave sterilization cycle parameters


Wrapped/U nwrapped Cycle Temp Cycle Time
DFU Wrapped 132-135°C 10-15 minutes
Wrapped/Standard
Cycle Specification
DFU Flash Cycle Unwrapped 132°C 3 minutes
Specification
Actual Test Cycles Unwrapped 137°C 18 minutes
Parameters

Additionally, a dry time of 5.0 minutes was utilized for this testing. This dry time was
determined to have no significant effect on the conditioning of the ring for testing.

The following testing was performed in Protocol 7430 and a copy is attached in the
Appendices.

Ring Tensile Test:


Method:
This test utilized a Universal Mechanical Test Machine to assess the load at which the
ring permanently deformed (yield strength). The complete assembled ring was tested.
The ring is positioned in the tensile tester along the anterior-to-posterior (short) axis of
the ring. The speed that the ring is to be pulled is 10mm/minute. Thirty rings were
pulled beyond the yield point and the force at the yield point was recorded.

Results:
The results from this test are used to determine if the ring strength is greater than the in-
vivo forces of 2.06 Ibs. The safety of the ring is assessed at the point where the ring is
permanently deformed (yield strength).

All rings were tested to a max load of 190 Ibf (86182.55 grams) and the test was
stopped. Acceptance criteria is that the lower 95% normal statistical tolerance limit
(Xbar - ks) is equal to or greater than 1000 grams (which is 65.6 grams greater than the

Model 5100, McCarthy Type II Mitral.doc Page 3 of9

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maximum published data), where k = 3.064 for a on-sided normal tolerance limit where
N =30.

Based on a sample size of 30, the 95% one-sided, lower, normal statistical tolerance
limits on performance that 99% of the population of devices is compliant is:
Xbar - k*s = 13671.410 - 3.064(735.683) -11417.277 grams

All of the rings exceeded the acceptance criteria. The rings average yield strength was
13671.41 grams. The statistical tolerance recorded was 11417.277 grams, which is
roughly 11 times larger than the acceptance criteria of 1000 grams.

Conclusion: The acceptance criterion was met because the one-sided, lower, normal
tolerance limit (11417.277 grams) was greater than 1000 grams.

Deviations: The flash autoclave sterilization cycle included a drying time of 5 minutes.
The original protocol stated that no drying time was required, as it has no effect on the
test samples. Therefore, this deviation does not affect the results from the testing.

Thirty-three rings were tested for yield strength. The data from 2 of the rings was saved
incorrectly and could not be analyzed. The data from ring #88 could not be analyzed
because the pro-load force on the ring was so high that the resultant graph did not
provide enough data points to be able to identify the elastic range of the ring. Since
there were still 30 rings successfully tested and analyzed, these deviations do not affect
the overall results and conclusions of this report. There is no indication that any of these
rings yielded in any different way than the remaining units; this was simply a technical
error.

The yield strength for Ring #94 was lower than the rest of the test samples (22.825 Ibf).
It was thought that this may be due to slippage of the ring in the fixture during the test.
The test graph confirmed the theory. All supporting documentation are contained in the
Appendix for Final Report #7430.

The acceptance criterion in section 6.1.3 of the original protocol was stated as ... "upper
95% ... " which is incorrect. It should have stated ... "lower 95% .... " to match the statistical
equation. The sample analysis was performed based on the protocol equation and
therefore this deviation does not affect the results of this report.

The Technical Summary was originally numbered #7424, but is actually numbered
#7477. .

Suture Pull Out


The velour cloth used for the McCarthy Type II Annuloplasty Ring, Model 5100 is the
same as that used for the GeoForm Ring (K032250). The single velour cloth was
previously qualified for suture retention strength in Protocol #6112. The lower tolerance
interval 0.894 of the natural log transformed suture retention result is greater than the
speCification limit of 0.0. Therefore, the suture retention strength of the velour cloth is
acceptable.

Model 5100, McCarthy Type II Mitral.doc Page 4 of 9

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Computational Structure Analysis of the Mitral Ring Model 5100 under distributed
compression force:
Method:
Finite Elemental Analysis (Software ABAQUS C3D81 Hexahedron element is used to
mesh the models of the Type II model 5100 geometry and the Carpentier-Edwards
Classic mitral ring model 4400 for stresses on these rings. The Carpentier-Edwards
Classic ring, which uses a titanium ring support, has been on the market for 19 years
and, to date, there have been no reports of structural ring failure. A comparison was
made from the results of the stress analysis for both models.

Results:
The Maximum Principal Stress in the model 5100 ring with a 2 Ib distributed
compression force is 15.75 ksi for the Anterior-Posterior direction. The Maximum
Principal Stress for the Carpentier-Edwards Classic mitral ring model 4400 is 53.33 ksi
(as reported in R&D report 1199).
Therefore, since the maximum stresses in the Type II are less than the maximum
stresses in the Classic ring, one can expect that the Type II ring will not be subjected to
structural failure in the clinical environment. In conclusion, the results demonstrate that
the acceptance criteria were met.

Computational Structural Analysis of Mitral Ring Model 5100 under Distributed


Tensile Force:
Method:
Finite Elemental Analysis (Software ABAQUS C3D81) Hexahedron element is used to
mesh the models of the Type II model 5100 geometry and the Carpentier-Edwards
Classic mitral ring model 4400 for stresses on these rings. The Carpentier-Edwards
Classic ring, which uses a titanium ring support, has been on the market for 19 years
and, to date, there have been no reports of structural ring failure. A comparison was
made from the results of the stress analysis for both models.

Results:
The results for the Maximum Principal Stress with the distributed tension force of 2 Ib are
found in Table 2:
Ta bl e 2 - Resu Its f or th e MaXlmum Prmci
. pa I Stress Mo d eI 4400 an d Mo d eI 5100
Anterior-Posterior Direction Major Axis Direction
Model 4400 Model 5100 Model 4400 Model 5100
(36mm) (40mm) (36mm) (40mmj
22.89 ksi 17.09 ksi 53.33 ksi 15.90 ksi

Therefore, since the maximum stresses in the Type II are less than the maximum
stresses in the Classic ring, one can expect that the Type II ring will not be subjected to
structural failure in the clinical environment. In conclusion, the results demonstrate that
the acceptance criteria were met.

Model 5100, McCarthy Type II Mitral.doc Page 5 of9

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M/B/C # 0751
The materials used for this device were evaluated by the Edwards
Microbiology/Biology/Chemistry Laboratory (see attached) and were shown to be
biocompatible for their intended use.

Sterilization: Sterilization method is conducted in accordance with an "overkill" method.


An "overkill" method is sterilizer cycle conditions that are established to kill the
microbiological challenge with an additional safety factor. The cycle conditions rendered
are more severe than required to inactivate the product bioburden. The following testing
procedures were conducted to qualify the McCarthy Type II Annuloplasty Ring, Mitral
Model 5100 for steam sterilization:
);> Bioburden - Product pre-sterilization bioburden was evaluated to determine the
level of microbial contamination present on product prior to sterilization. Levels
are within the control limits set forth for the predicate device.
}> Load Configuration Density - The product load density was determined to be
comparable to other existing steam sterilized products.
}> Relative Moist Heat Resistance - A representative equivalent product model was
qualified to determine comparable resistance to the validated Process Challenge
Device.

Summary:
Testing performed for the Model 5100 demonstrated:
}> Bioburden levels are within the control limits set forth for the device
);> The product load density was determined to be comparable to previously
validated steam sterilized products
);> Configuration of assembled materials in the ring and packaging is the same as
I quaIT
prevIously I Ied annu Ioplasty rings:
Component Classic Tricuspid Type II Model 5100
Metal RinjJ Titanium Titanium
Cloth Polyethylene Terepthalate (PET) Polyethylene T erepthalate (PET)
Tubing Silicone w/14% BAS04 Silicone w/14% BASP4
Packaging Polycarbonate Double Tyvek Polycarbonate Double Tyvek

o value for previously qualified comparable rings; reference Protocol 2896: (MOist
Heat Resistance Study performed, the 010 value was comparable to the appropriate
Process Challenge Device and demonstrated SAL that exceeds 10 -6). Therefore,
the Model 5100 can be incorporated into the steam sterilization process identified as
Cycle 45.

Pyrogen: Pyrogen testing was performed per the in vitro Limulus Amebocyte Lysate
(LAL) method on representative samples of the Model 5100. Testing was performed in
accordance with the FDA "Guidance for Validation of the Limulus Amebocyte Lysate
Test as an End-Product Endotoxin Test for Human and Animal Parental Drugs,
Biological Products, and Medical Device, 1987." Product is judged to be non-pyrogenic
if the endpoint indicates a bacterial endotoxin level of less than 20 EU (endotoxin units).
Only those devices from lots judged non-pyrogenic according to this criterion are
released for distribution.

Model 5100, McCarthy Type II Mitral.doc Page 6 of 9

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Summary:
Testing performed for the McCarthy Type II Annuloplasty Ring, Model 5100,
demonstrated non-pyrogenic levels of bacterial endotoxin.

Biocompatibility: The McCarthy Type II Annuloplasty Ring, Model 5100, uses the
same components as currently utilized in other approved Edwards annuloplasty rings:
~ Titanium Ring (Classic Ring: K831949)
~ Siloxane Polymer, Dow Corning Q7-4750 with 13% BaS04, Clear, Radiopaque
Tubing (Physio Ring K926138)
~ Polyethylene Terephthalate (PET), White, Woven Bias Cloth (Physio Ring
K926138)
~ Polytetrafluoroethylene (PTFE), White, Thread - (Physio Ring K926138)
~ Polytetrafluoroethylene (PTFE) Coated Polyethylene Terephthalate (PET),
Green, Deknatel Tevdek II Thread (Physio Ring K926138)
The implantable components have already been approved for implantable purposes.
The McCarthy Type II Annuloplasty Ring (Mitral Model 5100) will be exposed to the
same manufacturing and sterilization processes as are currently being used on the
approved devices listed above. A review of the biocompatibility and chemical
acceptability of each component was completed. The final device has been reviewed to
ensure sterility and microbiological acceptance. Biocompatibility and Chemistry reports
are in the Appendix.

Packaging Shelf Life/Accelerated Aging:


The McCarthy Type II Annuloplasty Ring, Model 5100 will use the same packaging as
the Cosgrove (K923367/ MC 3 (K020864) Annuloplasty Ring(s), Model 4600 and 4900,
therefore testing for shelf life studies/accelerated aging are applicable to this ring.
Previous testing performed on the Cosgrove (K923367) Annuloplasty Ring demonstrated
integrity of the 1073B Tyvek/24 Oliver Adhesive / Polycarbonate Tray package to meet
all physical test requirements and maintain sterility of contents following five (5) years of
accelerated aging and three (3) years of real time aging studies. Therefore, since the
materials used in the McCarthy Type II Annuloplasty Ring, Model 5100 are identical to
the Cosgrove Annuloplasty System (K923367), the McCarthy Type II Annuloplasty Ring,
Model 5100 is considered to meet the requirements for five years of accelerated aging
and three years real time.

Manufacturing Process:
The McCarthy Type II Annuloplasty Rings will be manufactured in the same stringent
and reliable process as the current annuloplasty rings with appropriate training, SOP
manufacturing documents and inspection documents in place. Both rings (GeoForm and
Type II) are machined from the same raw material and have similar processing. The
component rings are 100% inspected on all critical dimensions only after all machining
and polishing are completed to ensure consistently good parts. The final assembly
processes are very similar to current ring processes and employ either validations or
100% inspection of various operations to ensure consistent and reliable good product.

Model 5100, McCarthy Type II Mitral.doc Page 7 of9

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.. Conclusions
The modified annuloplasty ring is identical to the GeoForm Annuloplasty Ring (K032250)
with respect to the following:
» Intended Use
» Basic Design
» Materials
» Operating Principle
» Shelf Life
>-- Packaging and sterilization process

The modifications made to the McCarthy Type II Annuloplasty Ring, Mitral Model 5100
do not result in changes to the safety and efficacy of the new device. The intended use
is the same as that documented in the Special 510(k) for the GeoForm Ring (K032250),
which was determined to be substantially equivalent to previously marketed devices.

Regulatory Assessment

The need for FDA notification of the modifications described above were evaluated
based on the FDA's 510(k) Memorandum (January 10, 1997) 'Deciding When to Submit
a 510(k) for a Change to an Existing Device'. No FDA 510(k) premarket notification is
required for the product modifications described in this document. .

Applicable Regulatory Documents


K032250 GeoForm™ Annuloplasty Ring, Model 4200, cleared August 26, 2003

Model 5100, McCarthy Type II Mitral.doc Page 8 of 9

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Written by: Reviewed by:

~t1 /0Jv~ct<:v
Susan ReynOkii ''';;1.f6r7jot.c>
.stmYJ~W-
33/00
Susan Gamble
Regulatory Affairs Associate III Director, HVT Regulatory

Attachments:
Design Requirements Document
Main Flow Chart When to File a 51 O(k) After a Change to a Legally Marketed
Device
Design Validation of the Model 5100 Annuloplasty Ring (memo)
Protocol #7430
RD1177
RD1199
Suture Pull Out Justification
5 Year Shelf Life - in #7430
MRI Statement Memo
Implantation Characteristics JTF for Model 5100 (R&D)
Risk Assessment
Design FMEA #6988
Process FMEA #6989
Cleaning #1653
Drying #96000161
MBC 0751
Biocompatibility - Memo from Chem
Chemistry - Memo from Chem
Sterilization - Memo from Micro
Pyrogen - Memo from Micro MLT2652
Shelf Life/Acc Age- Pkg - Memo from Micro
Technical Summary - Packaging #7477
DFU
Drawing
Demonstration of Model 5100 Ring Drawing Equivalence

Model 5100, McCarthy Type \I Mitra\.doc Page 9 of 9

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EW-S-20000046
m
o
~
:::0
o
(f)
Regulatory Checklist for the Model 5100 Annuloplasty Ring
o
oZ Dated 02/16/06
"'Tl
o Testing Required Pass/Fail Document Supporting Documentation Comments
m
z Number
-I
» FEA
r Computational Structure Pass RD #1199
"'U Analysis - Tensile
:::0 Computational Structure Pass RD #1177
o
< i Analysis - Compression
o R&D Reports
m i

o I Tensile Testing Pass Design Verification


!
"'U #7430
C Suture Pull Out! Suture Pass Design Verification Protocol #6112
:::0
(f) Retention #7430
C Memo To Susan Reynolds from Aaron
»
z Ingle dated 02/16/06
-I, Ring Removal Force No holder - not applicable
-I
o Shelf Life for Ring
Assembly, Silicone, Suture
Pass Design Verification
#7430
Protocol #95-0038
(f)
m Threads, and Cloth
z
»
-I
Protocol #736
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Moist Heat Resistance Pass MBC #0751 Memo to Susan Reynolds From Micro
Pyr~gen Pass MBC #07.51 Memo to Susan Reynolds From Micro
Chemistry Acceptability Pass MBC #0751
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EDWARDS CONFIDENTIAL, PROVIDED PURSUANT TO SENATE RULE XXIX, EW-S-20000049


Edwards Lifesciences
MyxoLogix Mitral Annuloplasty Ring
Model 5100
(Sizes: 26mm - 36mm)
First Human Use Approval Sheet
DHF# 6994

The signatures below indicate approval for "First Human Use" of the MyxoLogix mitral
annuloplasty ring without holder.

Project Team Approvals:


_---;r-=====-=' '~
~:~~~i~:~~eam Leader R&D~~.K3~~~
Matthew Winston
R&D I
~ <71;.dJ 0
Susan Reynolds ~t1cpM~ 3)3)Ob
Regulatory Affairs

Holly Baran
Quality
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Guillermo Cardenas ~/5>/a~
Manufacturing

Tammy Huntley o3/tJs/rl,o


Manufacturing Engineering

Brian Brutcher
Manufacturing Engineering
3/3/oh
I ,

Alison Curtis
Marketing

Christine Cabiling 03 ·01· of::.:,


Project Management

Page 1 of 2

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX.


EW-S-20000050
Edwards Lifesciences
MyxoLogix Mitral Annuloplasty Ring
Model 5100
(Sizes: 26mm - 36mm)
First Human Use Approval Sheet
DHF# 6994

The signatures below indicate approval for "First Human Use" of the MyxoLogix mitral
annuloplasty ring without holder.

Management Approvals:

Vaso Adzich
R&D

Susan Gamble 3Jro){)0


Regulatory

Elise Gosme 03/{;(p/00


I
Quality

Sue Katz
Marketing

Sid Chung ~~ ~.
Manufacturing Engineering

Mark Konno
R&D

Page 2 of 2

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000051


Design Requirements Document

Myxo = Logix Annuloplasty Ring, Model 5100

DHF #6994

Rev.B

January 10, 2006

Approvals:

06
Research and Development:
Aaron
1/'Oi
Dat~:

Quality Engineer: \(IDIDV


Date:

Marketing: ~ -::::::;::;:;;: ::?'S 1- If) - (J ft,


Alison Curtis, Product Manager Date:

Manufacturing Engineering: \,.' --A1.J-D'-l4P<tJI-+-fM,.4-1A~+-:------=------:--- Qt I


/ lD DG
nior Engineer Date:

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000052


Design Requirements Document
DHF #6994

Myxomatous Annuloplasty Ring, Model 5100

Design Input Elements:

1.0 OBJECTIVE/ SCOPE:


1.1 The Mitral Opportunities Team will design a ring based on the surgeon's input, to
treat patients with myxomatous disease of the mitral valve.

2.0 USER! PATIENT/ CLINICAL:


2.1 Customers include: Referring cardiologists, echo cardiologists, cardiac surgeons,
and patients who receive the Myxomatous Annuloplasty Ring. This customer base
is worldwide.
2.2 Patients: The patient population includes patients with Type II Carpentier's
functional classification of the mitral valve evidenced by a billowing and/or
prolapsed valve.
2.3 Clinical: Clinical studies are not required for the Myxomatous Annuloplasty Ring.
2.4 Implantation: Implantation techniques will be equivalent to current Edwards
Lifesciences annuloplasty rings.

3.0 PERFORMANCE CHARACTERISTICS:


The key technical objectives of this design are as follows:

3.1 Move the posterior portion of the mitral annulus posteriorly and superiorly to
accommodate the excess leaflet tissue present in myxomatous tissue disease in an
effort to reduce the likelihood of Systolic Anterior Motion (SAM).
3.2 Radiopaque ring.
3.3 Cloth in-growth characteristics to be similar to current Edwards Lifesciences
annuloplasty rings.
3.4 Suture pull out force to be similar to current Edwards Lifesciences annuloplasty
rings: greater than or equal to 467 gm.
3.5 Ring design will be compatible with current Edwards Lifesciences annuloplasty ring
Slzers.
3.6 Forces required to parachute the ring down to the annulus should be less than or
equal to that of current Edwards Lifesciences annuloplasty rings.

4.0 SAFETY:
4.1 The Myxomatous Annuloplasty Ring is designed to have comparable durability to
all current Edwards Lifesciences annuloplasty rings.
4.2 Design verification data must not show safety issues that would require clinical
assessment.

Edwards Lifesciences Confidential Page 2 of 4

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX.


EW-S-20000053
Design Requirements Document
DHF#6994

5.0 LIMITS/ TOLERANCES:


5.1 Any operationa1limits imposed by the user operating environment will be defined
under the Directions For Use (DFU)

6.0 RISK ANALYSIS:


6.1 Refer to IS014971 Risk Analysis
6.2 Refer to Clinical Risk Analysis
6.3 Refer to Design FMEA #6988: "Design FMEA for Myxomatous Ring, Model 5100"
6.4 Refer to Process FMEA #6989: "Process FMEA for Myxomatous Ring, Model
5100"

7.0 TOXICITY/ BIOCOMPATIBILITY:


7.1 Implantable sterile device
7.2 The MBC report will define the biocompatibility requirements.

8.0 HUMAN FACTORS:


8.1 Ring size should be clearly labeled on the ring and/or ring packaging.
8.2 Implant orientation of the ring must be obvious to the surgeon and must be clearly
defined in the DFUs.
8.3 Ease of correct needle placement and penetration resistance of the needle through
the ring should be similar to current Edwards Lifesciences annu10plasty rings.

9.0 PHYSICAL/ CHEMICAL:


9.1 Ring cloth to be velour
9.2 Ring to be MRI compatible
9.3 Ring to be biocompatib1e
9.4 Sizes 26-36mm

10.0 LABELING/ PACKAGING:


10.1 The Myxomatous Annuloplasty Ring will be packaged in a qualified Edwards
Lifesciences packaging system that will protect the ring and allow it to remain
sterile.
10.2 Labeling will be similar to current Edwards Lifesciences annu10plasty rings in
reference to FDA Guidance for Annuloplasty Rings Special 51 O(K) submissions.

11.0 RELIABILITY:
11.1 Device expected to maintain its shape and structural integrity in the annulus for the
life of the patient.
11.2 There is no anticipated maintenance or repair of the device.
11.3 Shelf life is expected to be the same as current Edwards Lifesciences annu10plasty
nngs.

12.0 STATUTORY/ REGULATORY:


12.1 Justification to File (JTF) for United States
12.2 Change notification to TUV (Europe)

Edwards Lifesciences Confidential Page 3 of 4

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000054


Design Requirements Document
DHF #6994

12.3 Health Canada License Application (Canada)


12.4 Ministry of Health, Labor, and Welfare (MHLW) (Japan)
12.5 TGA (Australia)
12.6 Rest of World (ROW) will be assessed on an as country basis.

13.0 INTERNAL/ EXTERNAL STANDARDS:


13.1 Edwards GP 1051 "Design Verification and Process Validation"
13.2 Edwards GPl134 "Design Control"
13.3 Edwards GP1164 "Failure Modes and Effects Analysis"
13.4 Guidance for Annuloplasty Rings 51 O(K) Submissions - Jan. 31, 2001.
13.5 ISO 5840 and CE Mark requirements
13.6 Regulatory requirements of Canada, Japan, Australia, and Rest of World (ROW).

14.0 MANUFACTURABILITY:
14.1 The design and manufacturing process to be incorporated into the product are
proprietary to Edwards Lifesciences.
14.2 Assemble in cleanroom.
14.3 Manufacturing processes to be considered ergonomically acceptable by Edwards
Environmental Health and Safety (EHS).
14.4 Design must be cost effective.
14.5 Final materials selected that are incorporated into the manufacturing design shall be
procured from Supply Chain approved vendors.

15.0 STERILITY:
15.1 Maintain current sterility assurance level as current Edwards Lifesciences
annuloplasty rings.
15.2 Steam steri lizab Ie

16.0 COMPLAINT HISTORY:


16.1 There is no impact or change to the procedure for review of complaints for the
Myxomatous Annuloplasty Ring, Model 5100.

17.0 DESIGN HISTORY FILES:


17.1 DHF #6994 will compile all relevant documents for the Myxomatous Annuloplasty
Ring, Model 5100 per the guidelines of GP1051 and GPl134.

18.0 ENVIRONMENTAL COMPATIBILITY:


18.1 Device to be stored in a dry and contamination free environment.
18.2 There are no changes in environmental, health, and safety requirements from current
Edwards Lifesciences annuloplasty rings.

19.0 COMPATIBLE DEVICES:


19.1 Sizer Model 1174
19.2 Sizer handles Models 1111, 1117, and 1126.

Edwards Lifesciences Confidential Page 4 of4

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000055


m
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rings
10 Sterilization --- ---

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PDM

18 Assemble in c\eanroom 14.0 Assembly requirements Will build the final PIN 692952-026 Engineering
to be similar to current assembly in the thru 036, process sheet and
Edwards Lifesciences cleanroom Engineering SOP3674 for the
annuloplasty rings Process Sheets final assembly
19 Materials used must be procured from 14.0 Vendors approved by SQRs for the vendors DHF #6994 SQR reports
m Supply Chain approved vendors Supplier Quality using used throughout the
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Health Canada License and are communicated
Application Japan: to the team.
MHLW Australia: TGA
ROW: On a per country
basis

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Point Four

4) April 26, 2006, Toni Vlahoulis Surgery causes severe mitral valve stenosis and Pacemaker
Point Five

5) November 6, 2006, Maureen Obermeier Surgery causes severe heart attack and Defibrillator
Point Six

6) June 2006, Dr. McCarthy applies for a HIPPA waiver to publish data from the database 1532-004,
Expedited Waiver for retrospective data is granted by Eileen Yates for protocol to study the Model
4100, the Model 5100, and the caliper measurements as part of a direct surgical analysis of the mitral
valve and compare the measurements to echo measurements of the mitral valve, AATS abstract
AATS: Novel Surgical Approach to Myxomatous Mitral Valve Repair 11/26/12 10:45 AM

Home | Association | Membership | Publications | CME Meetings | For CT Surgeon | For Resident | For Medical Student

Members Only Area Apply for Membership Find a CT Surgeon

Novel Surgical Approach to Myxomatous Mitral Valve Repair

Patrick M. McCarthy1, Nalini M. Rajamannan2, Edwin C. McGee1, Vera H. Rigolin2, Qiong Zhao2, Anna L. Huskin2, Haris Subacius2,
Stacie Landron2, Susan Underwood2, Robert O. Bonow2; 1Division of Cardiothoracic Surgery, Northwestern University/Northwestern
Memorial Hospital, Chicago, IL; 2Northwestern University, Chicago, IL

Objective: Patients with myxomatous (Myxo) mitral regurgitation (MR) can present complex surgical challenges. This study was designed
to assess a new surgical strategy and ring technology in patients who underwent surgery for Myxo mitral disease.

Methods: From 4/2004 to 9/2006, 128 patients underwent primary mitral valve repair (MVR) for Myxo MR. In Group I, 92
patients underwent repair with conventional annuloplasty rings (Physio, n=70) and surgical techniques. In Group II, 36 patients
(3/06 to 9/06) underwent MVR with a new Myxo ETlogix ring. This ring has a larger orifice to accommodate elongated leaflets, a
29% increase in AP diameter, and a 3D design that pulls the posterior leaflet away from the outflow tract to reduce systolic
anterior motion (SAM). Ring sizing for Group II was calculated by direct measurement of the anterior and posterior leaflet
heights. Baseline patient characteristics between the groups were similar, except for gender (76.1% males in Group I vs. 55.6%
in Group II; p=0.022).

Results: Myxo MR was repaired in all patients. Quadrangular resection was performed in 77.2% vs. 75.0% of cases in Groups I
and II, respectively. Sliding annuloplasty was performed in 28.3% of Group I patients and was not required in Group II
(p<0.001). One operative mortality occurred in Group I (1.1%) and 0 in Group II. Median ring size was 32mm (range 26-40) and
34mm (range 26-36) in Groups I and II, respectively. After repair, overlap of the leaflet coaptation at A2 was 5.7±2.1mm and at
P2 was 6.2±1.8mm in Group II. By echo, the mean distance from the coaptation point to the septum was 17.3±3.4mm (range
11-24) in Group II. Median gradient was 3.5mmHg at discharge and 3.4mmHg at follow-up and did not differ between groups. In
Group I, mitral leaflet SAM occurred in 4 patients and chordal SAM in 1 patient (5.4% overall). In Group II, mitral leaflet SAM
was not observed and chordal SAM occurred in 1 patient at late follow-up (2.8% overall). SAM in Group I resulted in early
reoperation for 2 patients (2.2%), 1 requiring valve replacement, and 2 additional patients await reoperation. MR is depicted in
the table (mean ±SD).

Conclusion: Surgical repair of Myxo mitral disease with this etiology-specific ring significantly reduced MR, simplified the repair
technique by eliminating the need for sliding annuloplasty, without the subsequent development of SAM.

Back to Annual Meeting


Back to Program Outline

Policies | Find a Surgeon | About | Contact We Model Excellence


Copyright © 2012 American Association for Thoracic Surgery
All rights reserved. IMPORTANT REMINDER: The preceding information is intended only to provide
general guidance and not as a definitive basis for diagnosis or treatment in any particular case.
It is very important that you consult a doctor about any specific medical problem or question.

http://aats.org/annualmeeting/Abstracts/2007/T9.cgi Page 1 of 1
Point Seven

7) November 20, 2006, Second Justification to File Standard sizer methods and then turning the sizer 90
degrees for the Model 5100 ring.
Edwards Lifesciences
Myxo ET Logix Annuloplasty Ring
& Holder Model 5100
JTF: Decision for Notification of Product Modification

November 20, 2006


EW RACopy

-
EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000348
Interoffice Memorandum
, Edwards Lifesciences For Internal Use Only

To: RA File Date: November 20, 2006

cc: From: Susan Reynolds


Sr. Regulatory Affairs Specialist

Subject: Decision for Notification of Product Modification

Product Name

Edwards Myxo ETlogix Annuloplasty Ring with Holder, Mitral Model 5100

Regulatory Status

A Justification to File was written for the Edwards Myxo ETlogix Annuloplasty Ring on
February 27,2006.
The Edwards Myxo ETlogix ring is a modification of the GeoForm Annuloplasty Ring
which was cleared on August 26, 2003, K032250.

Description of Change(s)

The change(s) described in this justification include the following:

• Document the addition of a holder to the Edwards Myxo ETlogix Annuloplasty


Ring. (The handle is a Class 1- Exempt device per CFR 870.3935)

• Document the redesigned ring core.

• Document the addition of size 38mm and 40 mm.

• Document the change in packaging.

• Document the green center mark change to the ring.

• Document the green slash mark change to the ring

• Document the clarification of verbiage in the directions for use, specifically


addressing the "Measurement and Selection of the Appropriate Ring Size"
section.

Model 5100, MYXO ETLOGIX HOLDER, RING CORE, 38 & 40mm, PACKAGING, MARK, DFU JTF.doc Page 1 of 22

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000349


Interoffice Memorandum
Edwards Lifesciences For Internal Use Only

Intended Use

The intended use has not changed for any of the above mentioned changes.

Regulatory Evaluation

Holder Change-
Class I Exempt

Redesigned Ring Core and addition of size 38 and 40mm


In accordance with the document "Deciding when to Submit a 510(k) for a Change to an
Existing Device", the following flow chart questions were addressed for each change:
Main Flowchart
Was the change due to a recall or corrective action? - NO
Labeling change? - NO
Technology or performance change? - YES
Go to Chart B

Chart B
Control Mechanism Change? NO
Operating Principles Change? -NO
Energy Type Change? - NO
Environmental specifications? - NO
Performance specifications? - NO
Ergonomics of patent-user interface? - NO
Dimensional specification? - YES
Affect indication for use? - NO
Are clinical data necessary to establish S&E for purposes of substantial equivalence? -
NO
Do results of design validation raise new issues of S&E? - NO
Documentation

Change in Packaging
Change due to a recall or corrective action? - NO
Labeling change? - NO
Technology or performance change? - YES
Go to Chart B

Chart B
Control Mechanism Change? NO
Operating Principles Change? -NO
Energy Type Change? - NO
Environmental specifications? - NO
Performance specifications? - NO
Ergonomics of patent-user interface? - NO

Model 5100, MYXO ETLOGIX HOLDER, RING CORE, 38 & 40mm, PACKAGING, MARK, DFU JTF.doc Page 2 of 22

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000350


Interoffice Memorandum
Edwards Lifesciences For Internal Use Only

Dimensional specification? - NO
Software or firmware change? - NO
Change in packaging or expiration dating? - YES
Documentation

Green Center Mark/Green Slash Mark


Change due to a recall or corrective action? - NO
Labeling change? - NO
Technology or performance change? - YES
Go to Chart B

Chart B
Control Mechanism Change? NO
Operating Principles Change? -NO
Energy Type Change? - NO
Environmental specifications? - NO
Performance specifications? - NO
Ergonomics of patent-user interface? - YES
Affect indication for use? - NO
Are clinical data necessary to establish S&E for purposes of sUbstantial equivalence? -
NO
Do results of design validation raise new issues of S&E? - NO
Documentation

Clarification of Verbiage for the DFU


Change due to a recall or corrective action? - NO
Labeling change? - YES
Go to Chart A

Chart A
Does the change affect the indications for use? - NO
Change in warnings and precautions? - NO
Add a contraindication? - NO
Delete a contraindication? - NO
Is the labeling being revised for clarity to insure safer or more effective use? - YES
Documentation

Model 5100, MYXO ETLOGIX HOLDER, RING CORE, 38 & 40mm, PACKAGING, MARK, DFU JTF.doc Page 3 of 22

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000351


Interoffice Memorandum
Edwards Lifesciences For Internal Use Only

Change addition of the HOLDER and PACKAGING


Qualification Report(s)

Protocol #8271
This protocol qualified the performance characteristics of the ring and ring holder
assembly for the Edwards Myxo ETlogix Annuloplasty Ring, model 5100. The holder for
the model 5100 is molded from Amoco P1700 CL2611 polysulfone, which is the same
material used in the holder for the Physio, model 4450. The material was previously
qualified in Protocol #737.

The Myxo ETlogix ring has been previously qualified for performance characteristics in
Protocol #7430 Addendum A and was not retested.

The ring holder was functionally evaluated by determining the force required to remove
the ring holder from the Myxo ETlogix ring after the three attaching sutures have been
cut. The greatest contact surface area is the size 40 mm ring and holder. Therefore, the
size 40 mm ring and holder system is considered to be the worst case scenario for
removal. Since the size 40 mm ring and holder is considered to be worst case, the size
40 mm was tested and was used to qualify all sizes for the Myxo ETlogix ring.

The strength of the Myxo ETlogix holder was evaluated by determining the force
required to deform or break the holder under simulated use conditions.

Analysis of the holder design indicates that the P2 arm is the weakest area of the
component. The length of the holder arm is the greatest in the size 40mm assembly.
Longer arms produce the greatest lever arms and as a result the size 40 mm ring holder
is considered the worst case scenario in terms of strength. For this evaluation, the size
40 mm was tested.

Testing to measure holder to handle (Model 1150) snap-fit force has previously been
qualified for the model 4450 in Protocol #737. The portions of the holder mold used to
create handle engagement features are common for both model 5100 and model 4450
holders. The material used in each of these holders is also the same. While the
engagement features of each holder remains in specification, the holder to handle snap-
fit force will be similar. As a result, the holder to handle snap-fit force will not be tested
in this protocol.

The materials used in the model 5100 holder and the associated attaching suture have
previously been qualified in five-year or greater shelf life studies as listed below:
Attaching Suture Material Protocol # 95-0038
Holder Materials Protocol #737

Final Report #8271


Ring Removal Force
A total of fifteen (15) samples were tested.

Model 5100, MYXO ETLOGIX HOLDER, RING CORE, 38 & 40mm, PACKAGING, MARK, DFU JTF.doc Page 4 of 22

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Statistical Test: 95% confidence that the one-sided upper tolerance limit not be
exceeded by at least 99% of the population for this testing, the one-sided upper
tolerance limit is 1000 grams force.

Results:
All holders were pulled until they were completely disengaged from the ring and the
maximum removal force was recorded. The results of the testing are seen in Table 1.

Tabl e 1 R"lO_aRemovaIF oree Resu ts


Number of Samples Mean Removal Force Standard Deviation
Tested (Rm)/Newtons
15 48.47g (.48Nt 8.40g (.08N)_

The acceptance criterion for this test is that the upper 95% normal statistical tolerance
limit (Xbar + ks) is less than or equal to 1000 grams, where Xbar is the sample average,
s is the sample standard deviation, and k is the factor for one-sided tolerance limits for
99% of the population.

From the results obtained during testing, Xbar equaled 48.47 grams and s equaled 8.40
grams. The k value for a sample size of 15 equals 3.520. The resulting upper statistical
tolerance limit is 78.05 grams (48.47 + 8.40 * 3.520 = 78.05), which is below the criterion
of 1000 grams, and provides a 95% confidence that at least 99% of the population of
devices are compliant.

Holder Parachuting Strength


A total of fifteen (15) samples were tested. This sample size was justified based on the
feasibility testing performed on 8 Myxo ETlogix assemblies.

Statistical Test: According to the Design FMEA #6988 Rev D line 63, breakage of the
holder during parachuting is considered to be a Major A defect. As a result, it requires
that there be a 95% confidence that the one-sided lower tolerance limit is to be
exceeded by at least 99% of the population. For this testing, the one-sided lower
tolerance limit is 1000 grams force.

Results:
During testing, the failure mode for all of the holders was yielding. The results of the
testing are summarized in Table 2.

Tabl e 2 Ho Ider Parae hUf 109 Strenglth Resuts


Number of Samples Tested Mean Parachuting Yield Standard Deviation
Force Jgmsl (Newtons)
15 3697.45gsamsi36.26 Nl 50.44 grams (49N)

The acceptance criterion for this test is that the lower 95% normal statistical tolerance
limit (Xbar - ks) is greater than 1000 grams, where Xbar is the sample average, s is the
sample standard deviation and k is the factor for one-sided tolerance limits for 99% of
the population.

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From the results obtained during testing, X bar equaled 3697.45 grams and s equaled
50.44 grams. The k value for a sample size of 15 equals 3.52. The resulting lower
statistical tolerance limit is 3519.89 grams (3697.45 - 50.44 * 3.52 = 3519.89), which is
above our criterion of 1000 grams and provides a 95% confidence that at least 99% of
the population of devices are compliant.

P2 Retention Strength
A total of fifteen (15) samples were tested.

Statistical Test: According to the Design FMEA #6988, Rev. D, the fracture of the holder
is considered to be a Major A defect based on the severity ranking of 3. A Major A
defect requires that there be 95% confidence that the one-sided lower tolerance limit is
to be exceeded by at least 99% of the population. For this testing, the one-sided upper
tolerance limit is 2000 grams force.

Results:
The holders were loaded until the P2 arm fractured of the force reached 25 Ibf. Seven
(7) out of the 15 tests were stopped because the units fractured. In these seven cases
the P2 arm yielded and deformed significantly prior to fracture. In the remaining 8 units,
the arm continued to yield until it was vertical and the force reached 25 Ibf. All of the
calculations were done based on the yield point of the units using the 0.2% offset
method. The results of the testing are summarized in Table 3.

Tabl e 3 P2 R t fIon Strenglth


e en
Number of Samples Tested Mean P2 Retention Yield Standard Deviation
Force (gms) (Newtons)
15 5582.71 grams (54.75 N) 384.88 grams 13.77N)

The acceptance criterion for this test is that the lower 95% normal statistical tolerance
limit (x bar - ks) is greater than 2000 grams, where Xbar is the sample average, s is the
sample standard deviation, and k is the factor for one-sided tolerance limits for 99% of
the population.

From the results obtained during testing, X bar equaled 5582.71 grams and s equaled
384.88 grams. The k value for a sample size of 15 equals 3.52. The resulting lower
statistical tolerance limit is 4227.92 grams (5582.71 - 384.88 * 3.52 = 4227.92) which is
above our criterion of 2000 grams and provides a 95% confidence that at least 99% of
the population of devices are compliant.

Please note that because yielding of the holder was used for the failure data points, the
testing criterion for the P2 Retention test is considered to be conservative for the
following two reasons:
1) Yielding of the holder during surgeon use is considered to have a lower severity
(customer dissatisfaction - Major 8) than the fracture of a holder (possible
patient injury - Major A). Therefore per GP 113S Statistical Techniques, a

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"Major B" class defect only requires a one-sided normal tolerance limit with 95%
confidence for 95% of the population. To be conservative, the Major A class
defect specification was used for the acceptance criterion, which requires a one-
sided normal tolerance limit with 95% confidence for 99% of the population.
2) In all cases the force required for yielding of the holder was lower than the
fracture or ultimate strength. Therefore, the P2 retention testing is considered to
be conservative because the yield strengths of the holder components were
used as the failure data points, instead of the ultimate strengths (used for
fracture).

Deviations
1. Packaging
The ring removal test units were packaged in a single Cosgrove-style outer tray, instead
of the packaging configuration specified by the drawing and BOM.

New packaging components have been designed for the Myxo ETlogix assembly,
because of its overall size. At the time that the assembled test units were completed,
these new packaging components were not available. Since the ring removal test units
did not undergo shipping simulation, they were packaged for sterilization in the
Cosgrove-style outer trays so that testing could begin in parallel with development of the
new packaging. Per the assembly instructions, the ring-holder assemblies are placed in
the packaging right before they are steam sterilized. The Cosgrove-style outer trays do
not provide any added insulation or heat resistance in comparison to the new packaging
components. All of the ring removal units experienced the same exposure during the
production sterilization cycles compared to the units placed in the new packaging
configuration packaging.

2. Ring Removal Testing Fixture


Because of the overall size and the 3-dimensional geometry of the Myxo ETlogix
assembly, the flat silicone sheet called out in QCOP T1 024 could not be used for the
ring removal test, as it did not allow for the holder to be positioned vertically on the test
stand. In order to achieve this positioning an SLA fixture was designed and fabricated to
aid the testing.

The SLA fixture was described to position the ring-holder assembly in the vertical
position by pinning the ring to a rubber insert on the underside of the fixture. Since the
fixture only holds the ring in place while the holder is removed and does not come into
contact with either the holder or attaching suture, it does not affect the force required to
remove the holder from the ring. Therefore, the fixture does not affect the results of the
ring removal test.

3. Ring Removal Test of Sample #315


The initial ring removal testing of sample #315 resulted in a relatively higher peak
removal force, compared to the remaining 14 samples tested. This was due to the fact
that the load cell used for the testing was zeroed out before the Instron connecting
fixture and subsequent pins were attached to it. Therefore, the weight of the connecting
fixture and pins was measured by the Instron during the ring removal test for sample

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#315. This resulted in an offset of the test data. To determine the degree by which the
testing data was offset, the connection fixture and pins were each weighed individually
on a calibrated scale and totaled together. This total weight of the fixture components
was 75.82 grams.

Therefore, due to the weight of the connection fixture and pins the ring removal test for
sample #315 was offset by 75.82 grams. To correct this, 75.82 grams was subtracted
from its peak removal force, which resulted in a peak removal force of 43.48 grams.
This value was then used for the statistical analysis of the ring removal data shown in
Table 1.

CONCLUSION
The Myxo ETlogix annuloplasty ring with holder met all acceptance criteria with respect
to the ring removal force and holder strength tests (parachuting and P2 retention). Since
all tests met the acceptance criteria, one can conclude that the Myxo ETlogix
annuloplasty ring with holder has been qualified for use.

Because the requirements of protocol #8371 were met, the Myxo ETlogix annuloplasty
ring and holder also met the holder-related design input and the 2 nd tier requirements
from the Design Requirements Document, Rev E for the Myxo ETlogix assembly. The
holder specific inputs from the ORO which the design verification testing addressed are
listed below:

Holder to be compatible with the ring design


Holder to withstand forces seen during normal use with out failure
Holder to be able to engage and be removable from the model 1150 handle

A copy of protocol and final report #8271 are in Appendix A.

MBC 0835 - Qualification of the new Myxo ETlogix Annuloplasty Ring Holder
(P/N195845)

The configuration of the holder with ring is similar to existing annuloplasty rings which
have been previously qualified. The holder is composed of polysulfone material which
was qualified under MBC 97-230. The configuration of the polysulfone holder and the
previously qualified Myxo ETlogix ring was evaluated per MBC 0835.

The holder is used to hold the Myxo ETlogix Annuloplasty Ring (Model 5100: PIN
693401).

The holder is made of Amoco Udel P1700-NT11 Amber Polysulfone (PIN 400157-001) &
printed with Markem 2410 black ink.

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Sterilization
Myxo ETlogix Ring undergoes sterilization in the same manner as the previously
qualified Myxo ETlogix Ring (without holder). To confirm the holder will not affect the
validation, load density was evaluated.

Summary:
Product load density with the holder was calculated and determined not to impact
previously calculated worst-case sterilization loads.

Bioburden is routinely monitored and controlled to meet Edwards Lifesciences action


levels.

Shelf Life
The Myxo ETlogix ring with holder will use similar packaging materials as the
Cosgrove/Physio/MC3I1MRlGeoForm Annuloplasty Rings, however the configuration of
the packaging is different. Previous testing performed on these packaging materials
(which included accelerated aging/shelf life studies) are applicable to this ring.

Summary:
Tests performed for the demonstrated integrity of the 1073 B Tyvek®/24 AL Oliver
Adhesive/ Polycarbonate Tray package to meet all physical test requirements and
maintain sterility of contents following five (5) years of accelerated aging and> 5 years
real-time aging studies. Therefore, since the materials used are identical to the
predicate device, the model 5100 is considered to meet the requirements for 5 years of
accelerated aging and> 5 years real time aged shelf life with environmental challenges.
SL33-56 Microbiology Shelf Life Report is attached to the memo from Micro found in
Appendix B.

Pyrogen Control
Pyrogen testing is performed per the in vitro Limulus Amebocyte Lysate (LAL) method
on representative samples of the model 5100. Testing was performed in accordance
with the FDA "Guidance for Validation of the Limulus Amebocyte Lysate Test as an End-
product Endotoxin Test for Human and Animal Parental Drugs, Biological Products, and
Medical Device, 1987." Product is judged to be non-pyrogenic if the endpoint indicates a
bacterial endotoxin level of less than 20 EU (endotoxin units).

Summary:
Testing performed for the Myxo ETlogix ring with holder demonstrated non-pyrogenic
levels of bacterial endotoxin. A copy of the MBC and memo is in Appendix B.

FMEA
Both the Design FMEA - 6988 Rev E and Process FMEA - 6989 Rev C have been
updated to reflect the above mentioned additions. Copies of these FMEA's are in
Appendix C.
All the FMEA(s) were reviewed and updated to include the potential risks associated to
the following changes: addition of the holder/handle, redesigned ring core, addition of
size 38 and 40, packaging, green suture mark, and DFU update for the model 5100.

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These risks have been determined to be acceptable per the guidelines established in
GP1164 Revision B.

A copy of the Design and Process FMEA is in Appendix C.

PACKAGING
Technical Summary #8371
This report validates the Myxo ETlogix ring line with holder in the newly designed tray-in-
tray, double sterile barrier packaging with blank outer Tyvek lid. This newly designed
tray is to prevent product damage.

The report verifies that the sealing process parameters, previously qualified for the
Cosgrove inner and outer Tyvek-lidded trays are also acceptable for the Myxo ETlogix
inner and outer trays, when sealed with Belco 2020 machines. This verification includes
use of a new inner tray sealing nest tool and use of either of tow current outer tray
sealing nest tools. Addition or replacement of sealing nest tools in manufacturing may
require re-verification of the sealing process parameters. A sealing performance
qualification (PO) of the new package has been performed (#9098).

Background:
The primary packaging configuration for the Myxo ETlogix product line is a double sterile
barrier, tray-in-a-tray, Tyvek lidded system. Table 4 contains the packaging components
for the ETlogix annuloplasty ring.

T abl e 4 - Pac k agmg C om ponen t s


Description Material Part Number
Inner Tray Clear polycarbonate, .040" 195917001
3.56" x 3.04" x 1.48" thick
Outer Tray Clear polycarbonate, .040" 195916001
4.75" x 4.34" x 1.53" thick
Inner Lid, 3.58" x 3.18" 1073B Tyvek with Oliver 141664001
24AL autoclavable
adhesive coating
Bland Outer Lid, 4.36 x 1073B Tyvek with Oliver 24 141663002
4.76" AL autoclavable adhesive (only)
coating
Folding Carton .020 Recycled, clay coated 195920001
news

Protocol #8371 validates the entire Myxo ETlogix product family including size(s) 26-
40mm rings attached to a holder. Size 40mm ring on a holder was used for this report
because it was determined to be the worst case packaging configuration. The size
40mm ring on the holder is the heaviest and largest of all the Myxo ETlogix rings, which
would challenge the sterile barrier more than any other ring and holder size.

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Belco tray sealers, Model BM2020, serial numbers 8128 and 8055 are validated to run in
Edwards Lifesciences Irvine, CA manufacturing facility. Two sealing nest tools for the
outer tray, PN 300169 are qualified per this report to run on these Belco machines with
the Myxo ETlogix product family. The inner tray sealing nest tool, PN 394551, is
qualified per this report to run on Belco tray sealers, BM2020, serial numbers 8128 and
8055.

The inner tray and Tyvek and outer tray and blank Tyvek are qualified per this report to
the same sealing parameters and burst specification as used in Protocol 368 for the
Cosgrove trays and Tyvek lids. Sealing parameters and minimum burst specifications
were qualified for the Cosgrove ring trays per Protocol 368. It was demonstrated that
the packages sealed at the minimum burst specification were sufficient to ensure sterile
barrier throughout Edwards Lifesciences distribution environment. Because the Myxo
ETlogix inner and outer Tyvek lidded trays utilize the same materials, lid design, seal
design, and shipping conditions, seals at the same burst specifications will maintain a
sterile barrier. (If the burst strength for the Myxo ETlogix inner and outer Tyvek-lidded
trays remains above the minimum burst specification, and the visual seal characteristics
are acceptable per ELS4003, the seal will maintain a sterile barrier.)

This report validates that the Myxo ETlogix ring assembly with holder remains intact after
going through Edwards Lifesciences Distribution Environment.

Shelf Life Report # 33-56, study of the 1773B Tyvek/24 Oliver Adhesive with Prent
Polyarbonate trays for 5 years is valid for use with the new trays and Tyvek lids in Table
4. Since the Myxo ETlogix inner and outer Tyvek lidded trays utilize the same materials,
lid design, seal design and shipping conditions as the originally qualified package, the
Shelf-Life study 33-56 applies to these trays and Tyvek lids.
Simulated assemblies were used for this protocol, representing production assemblies
for the purposes of this testing.

Please note, the preprinted outer Tyvek lids (PN195901001) have not been qualified as
originally intended in the protocol. An addendum report will be performed to qualify the
preprinted outer Tyvek lid for use with the Myxo ETlogix package.

Deviations:
The preprinted Tyvek lid is not qualified for this report. The lot of Tyvek received did not
pass the Incoming Inspection. However, all requirements for the protocol with respect to
the blank outer Tyvek lid have been met.

Dye penetration testing per SOP3060 was added to the sterile barrier testing due to the
visual inspection failure of the preprinted Tyvek lid in the sealing process qualification as
described in Report# 8317. Dye penetration testing was performed prior to leak
submersion testing, and does not interfere with the accuracy of the leak submersion
testing. This test was added to allow a visual indication of quality of seal. While dye
penetration testing was included in this instance, specifically in response to the
preprinted Tyvek visual seal inspection failure, this testing is required for future sterile
barrier testing of this protocol

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A one-cavity tray mold was built by Prent for PN 195917001 after it was determined that
a 3-cavity tray mold could not effectively product parts to meet the design requirements
established by Edwards. Only the one cavity was sent through First Article, which is a
deviation from the protocol. Measurements for this report were performed on the 1-
cavity mold.

Prent's sampling plan for the inner tray was increased to 5 trays every 15 minutes in
order to tighten their process monitoring and reduce the possibility of non-conforming
trays being fabricated and shipped. This action was taken to monitor process variation
that was observed at Prent during development and qualification of the new tooling and
process.

Sampling of the trays at Prent was not able to occur every 15 minutes due to downtime
in the production of the trays.

In Section 3.5.4 of the protocol, the test method should be SOP 1097, which is the SOP
for Package Submersion Integrity Testing.

In Section 2.3 of the protocol, the protocol referenced is 368 not 386.

Drilling into the tray was deemed not necessary to perform Submersion Leak Testing by
Packaging Engineering and the Corporate Packaging Laboratory because the test probe
was able to be inserted into the outer try without damaging the inner tray.

First Articles are available in PDM. First Articles are referenced only, not included in the
report.

One shop order did not have final assembly inspection performed, which corresponds to
packaging samples 25 to 60. Although these samples are considered uncontrolled
samples for use with the Product Damage Section of the protocol, they will still be used
in order to have the statistical confidence needed per the protocol for the Product
Damage Section. Sterile barrier testing of the package is not affected by the missing
ring assembly final inspection, as the controls on the component materials and assembly
method are sufficient to ensure representative units.

Minimum sealing flange thickness was added as a measurement for the inner trays in
offer to better monitor the process variation of the inner trays in the sealing area.

Sterile Barrier and Product Damage Testing


A total of 120 packaging assemblies were sent through packaging testing and subjected
to sterile barrier testing (dye penetration and submersion leak testing).

All 120 samples passed. Passing sterile barrier testing integrity is defined as no
substrate breaches (tray and Tyvek) and no seal breaches.

Product Damage Testing


A total of 120 rings on holders were sent through package testing and subjected to
sterile barrier testing were inspected.

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27 of the 120 rings inspected had fibers. One shop order was not inspected prior to
packaging the rings. Although the 8 rings that had fibers were packaged per shop order
58244104 are considered uncontrolled samples, they will be used for the report.

One ring on the holder, sample 45, did not have the suture tail tucked. This ring was
part of the shop order that was not inspected before packaging. Therefore it is not
known whether this defect was due to simulated distribution or was an error in the
assembly process.

Fifteen holders showed distortion of the P2 arm, twenty -nine holders did not have pad
printing and one holder had no radiopaque pin molded into the holder. An explanation of
the follow up reason to these observations is mentioned in the final report.

First Article
A copy of the First Article reports is found in PDM.

Process Capability
Inner Trays
The Cpk calculation of each dimension of the inner tray was above the requirement of
0.86. Dimensions 2 and 4 were found to be out of spec for the Cpk values. Since the
trays used for sterile barrier testing and sealing performance testing had these
measurements, the drawing was updated to include the correct dimension of the
inspection dimensions 2 and 4. With the dimensions updated, all dimensions measured
for the outer tray passed the Process Capability Study by having a Cpk above 0.86.

Outer Trays
The Cpk calculation of each dimension of the outer tray per cavity was above the
requirement of 0.86. Dimensions 5, 6, and 7 were found to be out of spec for the Cpk
values. Since the trays used for sterile barrier testing and sealing performance testing
had these measurements, the drawing was updated to include the correct dimension of
the inspection dimensions 2 and 4. With the dimensions updated, all dimensions
measured for the outer tray passed the Process Capability Study by having a Cpk
above 0.86.

Sealing Process Parameter Verification


Outer Trays with Blank Tyvek Lidstock
All outer trays sealed to blank Tyvek lid passed the visual inspection of the seals. All 4
runs of the outer tray with blank Tyvek had a Lower Tolerance Limit (LTL) above the
minimum burst specification of 27 in H20.

Outer Trays with Preprinted Tyvek Lidstock


Six outer trays sealed to the preprinted Tyvek Lidstock using the lower parameters on
Belco Number 1 when sealed with sealing tool. All other outer trays sealed to preprinted
Tyvek lidstock passed visual inspection. All 4 runs of the outer tray with preprinted
Tyvek had an LTL above the minimum burst specification of 27 in H2 0.

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Inner Trays
All inner trays sealed to blank Tyvek lid passed the visual inspection of the seals. All 4
runs of the inner tray with blank Tyvek had an LTL above the minimum burst
specification of 71 in H20.

Summary and Analysis


Sterile Barrier Testing
All 120 samples subjected to packaging pre-conditioning and packaging distribution
testing passed sterile barrier testing, including the additional testing (dye penetration). It
can be stated with 95% confidence that at least 95% of the Myxo ETlogix ring with
holders shipped through Edwards Lifesciences distribution environment will maintain
sterile barrier integrity.

Product Damage Testing


All of the packaging/ring assembly units were visually inspected for signs of product or
packaging damage. Of 120 test units, 92 rings passed visual inspection. 27 rings failed
due to the presence of fibers around the ring and 1 ring failed due to a suture tail not
being tucked.

The rings that were rejected due to the presence of fibers were individually inspected
and a distribution diagram was created to show the general distribution of the identified
fibers. In addition to the distribution diagram, a feasibility test of 12 rings on holders was
performed to determine whether the packaging validation testing procedures were a
possible cause of the fibers. The results of these follow up studies can be found in
report #8371.

One unit was rejected for an un-tucked holder suture tail. This was also addressed in
report #8371. By tucking the suture tails on the Myxo ETlogix ring, even if suture tails
occasionally come un-tucked, the risk of holder suture tails interfering with implant is
significantly reduced from current production rings, and therefore is acceptable.

All 120 assemblies passed product damage testing. Therefore, it can be stated with
95% confidence that at least 95% of Myxo ETlogix rings with holders shipped through
Edwards Lifesciences' distribution environment will not be damaged.

CONCLUSION
The Myxo ETlogix product family is validated to maintain a double sterile barrier with the
packaging materials discussed in final report #8371. .

Part Numbers 195917001 and 195916001 have been verified to meet all Edwards'
design requirements when run at Prent.

Sealing of the inner tray with Tyvek lid on sealing tool and sealing of the outer tray with
blank outer Tyvek lid on sealing tools on Belco 1 and 2 in Edwards Lifesciences Plant 2
cleanroom has been validated by this report.

Due to the failure of the sealing parameter qualification using the preprinted outer Tyvek
lid, this lid is not qualified for use on this package. To qualify the preprinted lid and/or a

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new sealing tool, an addendum report may be issued to include the following testing on
the preprinted lid and sealing tool.

• Sealing parameter qualification and Sterile barrier testing

A Sealing performance qualification (PO) of the new inner and outer trays is required
and will be performed per Protocol 9098.

A copy of this report #8371 can be found in Appendix D.

Performance Qualification #9098


The purpose of this report (interim) is to document the sealing process qualification of
the Myxo ETlogix ring line with holder inner and outer Tyvek-lidded trays with one Belco
and one sealing tool for the inner tray and one sealing tool for the outer tray. The
performance qualification demonstrates that the sealing process of the Myxo ETlogix
ring line with holder will consistently produce an acceptable sterile barrier by
demonstrating that the seal integrity of the trays meets the minimum burst specifications
across a variety of production conditions (using only Belco Number 2 inner sealing tool
and one outer sealing tool).

The interim report validates only the machines and tools listed in Table 5 and material
listed in Table 4. One Belco sealer and one sealing tool have been qualified per this
interim report. Two Tyvek lids for outer trays were proposed for use with the Myxo
ETlogix product line. This interim report only validates the use of the blank outer Tyvek
for use with the Myxo ETlogix product line. Process sheets and SOP's will be updated
to reflect the use of only those machines and tools. An interim report may be written to
qualify the sealing process using one Tyvek lid, one Belco sealer, or one outer tray
sealing tool.

T a bl e 5 M ac h"mes an dT00 s qua IT


I Ied"m thOIS repo rt
Sealer Belco Number 2 (Serial Number 8055)
Inner Tray Nesting Tool Part Number 394551
Outer Tray Nesting Tool Part Number 300169 (Belco PN 170424)

The primary packaging configuration for the Myxo ETlogix product line is a double sterile
barrier, tray-in-a tray, Tyvek-lidded system.

This sealing performance qualification is part of the sealing process validation which
includes the 10/00 for the sealing equipment for sealer serial number 8128 and sealer
serial number 8055, and the packaging validation per protocol 8371. Successful
completion of this PO will constitute a complete sealing process validation for the tested
package configuration, sealing process and sealing equipment. This is an interim report
which only validates the materials listed in Table 4 to be used with the equipment listed
in Table 5. A final report will be issued to qualify all equipment and materials.

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This PO encompasses the sealing PO of the entire Myxo ETlogix product family
including ranges in size from 26 to 40 mm rings attached to a holder.

This PO specifically addresses the sterile barrier of the seal between the inner and outer
Tyvek lids and trays. The Tyvek lids and polycarbonate trays are qualified to provide a
sterile barrier per protocol 8371.

Sealing parameters and minimum burst specifications were qualified for the Cosgrove
ring trays per Protocol 368. This protocol demonstrated that packages sealed at the
minimum burst specification were sufficient to ensure sterile barrier throughout normal
distribution conditions. Because Myxo ETlogix inner and outer Tyvek lidded trays utilize
the same materials, lid design, seal design, and shipping conditions, seals at the same
burst specification will maintain a sterile barrier.

Burst testing is a seal strength test in which a package is inflated at a uniform rate until
the seal separates at the point of greatest weakness. Seal strength testing evaluates
the mechanical strength of the seal, assuring proper bonding to maintain package
integrity throughout the life of the product.

Deviations:
One inner tray from the 5:45am to 8:00am run was opened before it could be visually
inspected or burst tested. One hundred and eleven inner trays were visually inspected
and burst tested during this run. The inability to test 1 tray out of 112 trays for this run is
not likely to affect the ability of the lot to meet the statistical criteria for the run and the
run still exceeded the minimum quantity requirement.

Testing Performed:
Three production runs utilizing the material listed in Table 4 on the equipment listed in
Table 5 were performed in this interim report. The ring assemblies used for these test
runs were the same simulated assemblies used in protocol 8371.

Parts were run per sections 5.1 to 5.5 of this protocol. The original results of the runs
are found in the attachments.

A list of operators is found in PO 9098. Training transcripts of the sealing operators


used for the interim report are also found in the attachment.

The Burst Lower Tolerance Limit (LTL) from each production run was calculated per PO
9098.

The Burst LTL of the three combined production runs using the equipment in Table 5
was calculated. See attachments for results.

A k value for n=40 (3.242) per protocol was used for the calculation of the LTL for all
individual and combined runs even though in some instances n was greater than 40.
This makes the LTL a conservative calculation for the individual and combined runs
where n was greater than 40.

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Visual inspection was completed on each tray seal before burst testing, for reference
only. The trays that failed visual inspection were sent through burst testing. Seals are
100% visually inspected on-line during normal production per ELS4003 and SOP2827.
Visual inspection failures are reworked by Manufacturing. All trays that had visual
inspection failures passed burst testing. Therefore, these units are all acceptable per
this interim final report.

Out of 215 inner trays and Tyvek lids inspected, 33 failed visual inspection
• 29 samples failed due to fibers/contamination. Fibers were not removed before
sealing for the empty trays.
• 2 trays failed due to the Tyvek being sealed off-center on the tray
• 2 trays failed due to the Tyvek being "burned"

Out of 200 outer trays and Tyvek lids inspected, 13 failed visual inspection
• 9 samples failed due to fibers/contamination. Fibers were not removed before
sealing for the empty trays.
• 2 samples failed due to the Tyvek being sealed off-center on the tray
• 1 sample failed due to voids

CONCLUSION
Each production run performed in this interim report for the inner tray achieved a burst
test LTL higher than the specification level of 71 inches H20. Each production run
performed per this interim report for the outer tray achieved a burst test LTL higher than
the specification level of 27 inches H2 0. Each production run passed the acceptance
criteria per the protocol. Therefore, it can be stated with 95% confidence that no more
than 0.5% of the population of each lot will be below the specified burst strength.

The combined burst testing LTL of the three production runs per this interim report for
the inner tray was higher than the specification level of 71 inches H20. The combined
burst testing LTL of the three production runs per this interim report for the outer tray
was higher than the specification level of 27 inches H2 0. Therefore, it can be stated with
95% confidence that no more than 0.5% of the combined population will be below the
specified burst strength.

Based on the successful completion of the three production runs performed per this
interim report, the sealing process for the Myxo ETlogix product line packaging is
qualified to consistently produce an acceptable sterile barrier across a variety of
production conditions (using only Belco number 2, inner sealing tool PN 394551 and one
outer sealing tool PN 300169).

Based on successful completion of all the items listed in the protocol, the sealing
process of the Myxo ETlogix product line is validated for use with the materials listed in
Table 4 on the equipment listed in Table 5.

All requirements for the protocol when using the equipment laid out in Table 5 were met.
The material used in Table 4 is qualified to run on the equipment listed in Table 4. A
final report will be issued to validate all material and equipment established in the

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protocol. Production process sheets and SOP's will be updated to limit the sealing of the
Myxo ETlogix product line to only the equipment listed in Table 5.

The MBC for the packaging change is MBC0835 which is referenced in the holder
change section.

All the FMEA(s) were reviewed and updated to include the potential risks associated to
the change in packaging. The risks have been determined to be acceptable per the
guidelines established in GP1164 Revision B.

A copy of PO 9098 can be found in Appendix E.

REDESIGNED RING-CORE CHANGE & ADDITION OF SIZE 38 and 40


Qualification Report
Addendum Report A #7430
The purpose of the addendum report is to qualify the performance characteristics of the
modified annuloplasty ring, model 5100. The 3-D geometry of the titanium core has
been modified with respect to the original core design to allow the ring to rest in a stable
position when placed on a flat surface. This stable position provides a reference
orientation for the ring, where the anterior lift is greater than the posterior lift. The
complete size range (26 mm to 40 mm) of the modified model 5100 ring is qualified in
this addendum report.

A total of thirteen (13) rings were manufactured for evaluation. The sample size was
decreased from thirty to thirteen due to historical experience with the tensile testing of
titanium annuloplasty rings.
The model 5100 size 40 mm was evaluated in this addendum report.

Statistical Test: Given a sample size of thirty (30) rings and a confidence level of 95%,
99% of the population will be above the lower confidence limit of 1000 grams where X
bar =13671.410 grams and s =735.683 grams. This information was used to calculate
the acceptable sample size via StatGraphics. A sample size of seven (7) would provide
sufficient support for this confidence level. A sample size of thirteen (13) was used to
represent at least 99% of the population.

All test articles were subjected to the maximum number of steam and flash sterilization
cycles allowed by the DFU (PN 195678001) in order to simulate the worst case scenario.
Test articles were subjected to three (3) normal, production cycles following ELS4013,
Rev BT, "General Specification for Steam Sterilization at Edwards (Irvine)". Test
articles were removed from their packaging and subjected to five consecutive flash
cycles per the following parameters:

Test Cycle Parameters


Temperature: 137 - 139 °C
Time: 18.0 minutes
Dry Time: 5.0 minutes

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Please note, the test protocol determined the test cycle temperature to be 137 - 139°C
based on the proposed DFU (PN 195678001) at that time. The DFU has since been
modified to specify a temperature of 132 - 135°C. Therefore, the maximum test
parameter of 135 °C is required. The testing proceeded at the original range of 137 -
139°C, which represents a worst case scenario. This is considered to be 'worst case'
because this is the maximum temperature and sterilization allowed for the product.

Method:
This test utilized a Universal Mechanical Test Machine to assess the load at which the
ring permanently deformed (yield strength). The complete assembled ring was tested.
The ring is positioned in the tensile tester along the anterior-to-posterior (short) axis of
the ring. The speed that the ring is to be pulled is 10mm/minute. The rings were pulled
beyond the yield point and the force at the yield point was recorded.

Results:
All rings were tested to a max load of 100 pounds of force (Ibf) (45395.2 grams) and the
test was stopped. This load was arbitrarily selected to be significantly greater than the
expected yield range «30 Ibf) to ensure that the yield point was adequately captured.

Acceptance criteria is that the lower 95% normal statistical tolerance limit (Xbar - ks) is
equal to or greater than 1000 grams (which is 65.6 grams greater than the maximum
published data), where k =3.659 for a on-sided normal tolerance limit where N = 13.

Based on a sample size of 13, the 95% one-sided, lower, normal statistical tolerance
limits on performance that 99% of the population of devices is compliant is:
Xbar- k*s = 9319.579 - 3.0659(663.449) =6892.019

All of the rings exceeded the acceptance criteria. The rings average yield strength was
9319.579 grams. The statistical tolerance recorded was 6892.019 grams, which is
roughly 6.8 times larger than the acceptance criteria of 1000 grams.

Conclusion: The acceptance criterion was met because the one-sided, lower, normal
tolerance limit (6892.019 grams) was greater than 1000 grams.

Deviations:
The commissure marking and commissure inspection fixtures were constructed of a
rapid-prototype SLA resin instead of the specified stainless steel. These fixtures are
used in the assembly of the ring to place the cloth butt joint and the commissure marks.
The use of these SLA fixtures could result in some slight dimensional non-conformances
of the tooling and could cause some inaccuracies in the placement of the butt joint and
the commissures. This does not affect the results of this protocol because they are
cosmetic features and do not affect the tensile strength of the ring.

The flash autoclave sterilization cycle included a drying time of 5 minutes. The original
protocol stated that no drying time was required, as it has no effect on the test samples.
Therefore, this deviation does not affect the testing results.

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The acceptance criterion in the original protocol was stated as "upper 95% .... " which is
not correct. It should have stated "lower 95% .... " to match the statistical equation. The
sample analysis was performed based on the protocol equation and therefore this
deviation does not affect the results of this report.

Conclusion for the redesigned ring core and size 38 and 40 mm:
The design verification testing for the modified ring model 5100 meets all acceptance
criteria. The ring tensile test demonstrates that the modified model 5100 ring strength is
sufficiently greater than the published in-vivo forces. The ring strength is roughly 6.8
times greater than the in-vivo forces. Thus, the structural strength of the ring is
considered sufficient to withstand the in-vivo forces. Based on the successful
completion of this testing, the annuloplasty ring up to size 40 mm is considered to be
qualified.

Final product is qualified under MBC submission MBC0814.

All the FMEA(s) were reviewed and updated to include the potential risks associated to
the redesigned ring core and addition of size 38 and 40 mm. The risks have been
determined to be acceptable per the guidelines established in GP1164 Revision B.

A copy of the qualification addendum report #7430 is in Appendix F.

Product Shelf Life has been addressed in Protocol 7430. This protocol references
report(s) 950038 (Silicone Band, suture materials)
736 Titanium
737 Duraflo material and holder
These reports are One and Five Year Shelf Life Studies for the Physio, Cosgrove and
Classic Rings.

Micro information for the addition of size 38 mm and 40 mm including sterilization have
been addressed in the memo from Micro dated 11/21/06. See Appendix B.

GREEN SUTURE MARK (ECR 54962)


SOP 3862 was updated to include the following:
• The addition of a center mark to guide the P2 suture placement.
• Single direction green mark to aid in manufacturing cost reduction was
implemented.
• Holder attachment - tuck suture tails at the attachment.

No qualification tests are necessary.


No MBC was necessary for this change.
The respective FMEA's were reviewed and updated. The green suture marks aid in the
orientation of the ring.
A copy of ECR 54962 can be found in Appendix G.

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CLARIFY DFU - Measurement and Selection of the Appropriate Ring Size section

The directions for use have been updated. Current text of the section 'Measurement
and Selection of the Appropriate Ring Size' is as follows:

Because the intention of the technique of the valvular remodeling is to restore mitral
competency, measurement and ring selection is based on the measurement of the
anterior leaflet attachment by using sizers with two notches on their linear segments
(Figure 5). Since the delineation of the anterior leaflet may be difficult, the ring may also
be selected by measuring the surface of the anterior leaflet with the same sizers (Figure
6).

To facilitate this measurement, the chordae tendineae may be placed on tension, thus
spreading the leaflet.

The proposed text, to be added at the end of this section, is as follows:

Appropriate leaflet coaptation is necessary to restore mitral competency.


Therefore the height and/or surface area of the posterior leaflet should also be
considered in ring selection.

The AP (anterior-posterior) dimension of the Myxo ETlogix ring can be visualized


prior to the insertion of the ring by rotating the sizer 90 degrees. The length of
the sizer in this orientation generally corresponds to the AP (anterior-posterior)
distance of the Myxo ring.

Each of the two statements above is intended to clarify the DFU instructions for
measurement and selection of the appropriate Myxo ETlogix ring size to ensure a more
effective use of the ring.

The two statements are justified in a memo to the file in Appendix H.


Also included in this Appendix is a memo on 'Implantation Characteristics of the Myxo
ETlogix Annuloplasty Ring with Holder. This memo provides a detailed explanation and
comparison of the Myxo ETlogix ring to other annuloplasty rings currently on the market.

Disposition

In summary, this correspondence serves as a written notification to document the


decision that no regulatory submission is required for the addition of the holder to the
Myxo ETlogix Annuloplasty Ring, Model 5100, the redesigned ring core, the addition of
size(s) 38mm and 40mm, the change in packaging, the green center mark, the green
slash mark, the clarification of verbiage to the Directions For Use for the Model 5100,
Myxo ETlogix Annuloplasty Ring.

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Appendices

Appendix A- Protocol and Final Report #8271

Appendix B MBC0835 and Memo

Appendix C Design FMEA 6988


Process FMEA 6989

Appendix 0 Packaging Validation, Myxo ETlogix Annuloplasty Rings #8371

Appendix E Packaging PO, Model 5100, Myxo ETlogix, #9098

Appendix F Design Verification of Annuloplasty Ring, Model 5100, Addendum Report


A #7430

Appendix G ECR 54962

Appendix H Memo on DFU Verbiage Change and Memo on Implant Characteristics

Appendix I Applicable flowcharts from lOP 3100 and the FDA guidance document,
"Deciding When to Submit a 510(k) For a Change to an Existing Device"

Written by: Reviewed by:

~
',LLc;OfYJ ~. ~ ~ble.. 2 J )\jt)\I E>~
~ Susan Re y noJCiSl 0 Susan Gamble
Sr. Regulatory Affairs Specialist Sr. Director, HVT Regulatory

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DESIGN VERIFICATION OF THE MYXO
ETLOGIX, MODEL 5100, HOLDER
FINAL REPORT

Protocol No. 8271

Prepared By:_-..!..!.!WdA.....:.-!:.J£........L---?-Z..L..lb)=-.w:.
__•_ _ _ __ Date:~Db
101. _ ~
Matt Winston, HVT R&D Engineering

Approved By: _ _ _-,£-_"r---""=--_ _ _ __ Date: ld/2</O~


Aaron Ingl H

Approved By: "Walt~ Date: I b 12-"f/D~?


HolIYBaran, HVT Quality Engineering
.J

Approved By:,-\-/'"~:...I,..lL.jL...l.lU..'::~-If--f~~~--­ Date: fO 12,110 ~


Ta ngineering

Approved BY:~/)'\ ~<d-­ Date: iaJaS/~


Susan Reynolds, HVT Regulatory Affairs

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1 PURPOSE

1.1 The purpose of this Final Report is to verify the design and
functional characteristics of the Model 5100, Myxo ETlogix
Annuloplasty Ring with Holder (PIN 693401). The Myxo ETlogix
ring without a holder (PIN 693381) was previously verified under
Protocol #7430 and as a result, the focus of this protocol is on
the verification of the addition of the holder to the ring.

2 SCOPE

2.1 This Final Report summarizes and analyzes the data obtained
from Protocol #8271 which covers the specifications and test
procedures required to verify the performance characteristics of
the Myxo ETlogix Ring Holder (PIN 195845) for the Myxo
ETlogix, Model 5100 ring sizes 26-40mm (PIN 693401). Myxo
top assembly PIN 693381 does not include a holder and
therefore is not addressed in this protocol/report.

2.2 As justified in protocol #8271, certain tests were not repeated


because they were previously qualified on separate protocols. A
list of these tests and their corresponding protocol numbers is
listed in Table 1 below:

T a bl e 1 Prevlously Ieomple e T est s an dR es~ecrIve P ro toco S


ltd
PIN (if Previous Protocol
Test
applicable) #
Polysulfone Material 400157-003 737
Myxo Etlogix Model 5100 Ring
693381 7430
Assembly
Holder-Handle Snap_Fit N/A 737
AttachinQ Suture Material 440055-002 95-0038

3 Test Articles and Controls

3.1 A total of forty-five (45) Myxo ETlogix annuloplasty rings were


manufactured for evaluation (see respective test sections for
sample size justifications). Final assemblies (PIN 693401040)
were built by manufacturing, following the manufacturing shop
order system for traceability, and were subjected to the
maximum number of steam and flash sterilization cycles as
allowed by the DFU (PIN 196004001).

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4 Equipment

Metrology identifications are provided below. All instruments used


were in calibration per current calibration system requirements.

4.1 MTS universal tester - Sintech ReNew with TestWorks 4


software
4.1.1 Edwards Metrology Number: 105049
4.2 100N load cell (for Ring Removal Force)
4.2.1 Edwards metrology Number: 118006
4.3 1kN load cell (for Holder Strength)
4.3.1 Edwards Metrology Number: 118003
4.4 Production steam sterilizer
4.4.1 ID number 5070-01
4.5 Laboratory steam sterilizer
4.5.1 Edwards Metrology Number: 117629

The shipping simulation was performed by the Edward's Packaging


Department, and therefore the subsequent equipment identification
can be found in Appendix 2 with the shipping simulation report

5 Procedure, Specimen Conditioning

5.1 Test samples (PIN 693401040) were built and packaged under
the following two shop orders:

EG6F0848 (15 units)- Ring Removal Test Units (no shipping


simulation)
EG6F0847 (30 units)- Parachute and P2 Retention Test Units
(shipping simulation per section 5.2.1 of Protocol #8271)

Manufacturing records are listed in Appendix 1.

5.2 All samples were subjected to three (3) normal, production


cycles following ELS 4013, Rev BU, "General Specification for
Steam Sterilization at Edwards (Irvine)." Current sterilization
cycle 45. Sterilization records are listed with the manufacturing
records in Appendix 1.

5.3 Thirty (30) of the forty-five (45) units were chosen for Holder
Strength testing (Parachuting and P2 Retention) and were
therefore subjected to a shipping simulation and subsequent
inspection, as described in Protocol #8271. Records of the
shipping simulation and details of the environmental
conditioning are located in Appendix 2.

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5.4 After steam sterilization and shipping simulation (where
appropriate) all units were removed from their respective
packages and placed into a stainless steel tray. The units were
then flash sterilized as described in Protocol #8271. The
records of flash sterilization are located in Appendix 3.

6 Methods and Results

6.1 Ring Removal Force

6.1.1 Methods

A total of fifteen (15) samples were tested. This sample


size was justified based on previous testing performed on
3
the MC ring, Model 4900 (see Protocol #8271 section
6.1.2 for justification). Testing was performed per
Protocol #8271. The general test setup is shown in
Figure 1 below.

Figure 1: Ring Removal Test Setup

6.1.2 Results

A" holders were pulled until they were completely


disengaged from the ring and the maximum removal
force was recorded. The results of the testing are
summarized in Table 2 below. The complete data sheets
are located in Appendix 4.

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Table 2 - Rin Removal Data Summa
Number of Mean Removal Standard
Samples Tested Force Deviation
15 48.47

6.1.3 Analysis of Results

The acceptance criterion for this test is that the upper


95% normal statistical tolerance limit (Xbar + ks) is less
than or equal to 1000 grams (9.81 N), where Xbar is the
sample average, s is the sample standard deviation, and
k is the factor for one-sided tolerance limits for 99% of
the population.

From the results obtained during testing, Xbar equaled


48.47 grams (.48N) and s equaled 8.40 grams (.08N).
The k value for a sample size of 15 equals 3.52 (See
Table 6, GP1135). The resulting upper statistical
tolerance limit is 78.05 grams (48.47 + 8.40 * 3.52 =
78.05) or .77N, which is below our criterion of 1000
grams (9.81 N), and provides a 95% confidence that at
least 99% of the population of devices are compliant.

It should be noted that one of the data points (sample


#315) was identified as having a test method error and is
justified in the Deviations portion of this report (section
7.3).

6.2 Holder Parachuting Strength

6.2.1 Method

A total of fifteen (15) samples were tested. This sample


size was justified based on the feasibility testing
performed on 8 Myxo ETlogix assemblies (see Protocol
#8271 section 6.2.2 for justification) Testing was
performed per Protocol #8271. The general test setup is
shown in Figure 2 below.

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Figure 2: Parachute Strength Test Setup

6.2.2 Results

During testing, the failure mode for all of the holders was
yielding. The results of the testing are summarized in
Table 3 below. The complete data sheets are located in
Appendix 4.

T abl e 3 Parac hf
u mg TestOt
aa S umman
Mean
Number of Standard
Parachuting
Samples Tested Deviation
Yield Force
3697.45g
15 50.44g (.49N)
(36.26N)

6.2.3 Analysis of Results

The acceptance criterion for this test is that the lower


95% normal statistical tolerance limit (Xbar - ks) is
greater than 1000 grams (9.81 N), where Xbar is the
sample average, s is the sample standard deviation, and
k is the factor for one-sided tolerance limits for 99% of
the population.

From the results obtained during testing, Xbarequaled


3697.45 grams (36.26N) and s equaled 50.44 grams
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(.49N). The k value for a sample size of 15 equals 3.52
(See Table 6, GP1135). The resulting lower statistical
tolerance limit is 3519.89 grams (3697.45 - 50.44 * 3.52
=3519.89) or 34.52N, which is above our criterion of
1000 grams (9.81N), and provides a 95% confidence that
at least 99% of the population of devices are compliant.

6.3 P2 Retention Strength

6.3.1 Method

A total of fifteen (15) samples were tested. This sample


size was justified based on the feasibility testing
performed on 6 Myxo ETlogix assemblies (see Protocol
#8271 section 6.3.2 for justification). Testing was
performed per Protocol #8271. The general test setup is
shown in Figure 3 below.

Figure 3: P2 Retention Test Setup

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6.3.2 Results

As stated in protocol #8271 (section 6.3.1), the holders


were loaded until the P2 arm fractured or the force
reached 251bf (111.2N). Seven (7) out of the 15 tests
were stopped because the units fractured (test unit #'s
1,5,9,10,13,14, & 15). In these 7 cases the P2 arm
yielded and deformed significantly prior to fracture. In the
remaining 8 units, the arm continued to yield until it was
vertical and the force reached 251bf (111.2N). As stated
in protocol #8271 (section 2.5), all of the calculations
were done based on the yield point of the units using the
0.2% offset method. The results of the testing are
summarized in Table 4 below. The complete data sheets
are located in Appendix 4.

T a bl e 4 e en
P2 R t fIon T est D aa
t S ummary
Number of
Mean P2 Retention Standard
Samples
Yield Force Deviation
Tested
384.88g
15 5582.71g(54.75N)
13.77NJ

6.3.3 Analysis of Results

The acceptance criterion for this test is that the lower


95% normal statistical tolerance limit (Xbar - ks) is
greater than 2000 grams (19.61 N), where Xbar is the
sample average, s is the sample standard deviation, and
k is the factor for one-sided tolerance limits for 99% of
the population.

From the results obtained during testing, Xbar equaled


5582.71 grams (54.75N) and s equaled 384.88 grams
(3.77N). The k value for a sample size of 15 equals 3.52
(See Table 6,GP1135). The resulting lower statistical
tolerance limit is 4227.92 grams (5582.71 - 384.88 *
=
3.52 4227.92) or 41.46N, which is above our criterion
of 2000 grams (19.61 N), and provides a 95% confidence
that at least 99% of the population of devices are
compliant.

It should also be noted that because yielding of the


holder was used for the failure data points, the testing

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criterion for the P2 Retention test is considered to be
conservative for the following two reasons:

1) Yielding of the holder during surgeon use is


considered to have a lower severity (customer
dissatisfaction, Major B) than fracture of the holder
(possible patient injury, Major A). Therefore per
GP 1135 Statistical Techniques, a "Major B" class
defect only requires a one sided normal tolerance
limit with 95% confidence for 95% of the population.
To be conservative the "Major A" class defect
specification was used for the acceptance criterion,
which requires a one-sided normal tolerance limit with
95% confidence for 99% of the population.

2) In all cases the force required for yielding of the


holder was lower than the fracture or ultimate
strength. Therefore, the P2 retention testing is
considered to be conservative because the yield
strengths of the holder components were used as the
failure data points, instead of the ultimate strengths
(used for fracture).

7 Deviations

7.1 Packaging

The ring removal test units (shop order EG6F0848) were packaged in
a single Cosgrove-style outer tray (PIN 141925001), instead of the
packaging configuration specified by the drawing and BOM (inner tray
PIN 195917001 and outer tray PIN 195916001).

New packaging components have been designed for the Myxo ETlogix
assembly, because of its' overall size. At the time that the assembled
test units were completed, these new packaging components were not
available. Since the ring removal test units did not undergo shipping
simulation (see protocol #8271 for justification), they were packaged
for sterilization in the Cosgrove-style outer trays (PIN 141925001) so
that testing could begin in parallel with development of the new
packaging (the assemblies were too big to fit in the Cosgrove-style
inner trays). Per the assembly instructions (SOP 3862, Rev C), the
ring-holder assemblies are placed in the packaging right before they
are steam sterilized. Since the Cosgrove-style outer trays do not
provide any added insulation or heat resistance in comparison to the
Page 10 of 18

Confidential - This document is the property 01 Edwards Lilesciences LLC, and is intended solely lor their internal use.

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000380


new packaging components, all of the ring removal units saw the same
amount of exposure during the production sterilization cycles
compared the units placed in the new packaging configuration. From
this, it can be concluded that packaging the ring removal units in the
Cosgrove-style outer tray does not affect the fit, form, or function of the
assembled devices. Therefore, this deviation does not affect the
results of the ring removal test.

It should be noted that the remaining units (shop order EG6F0847)


that underwent shipping simulation (per section 5.2.1 of protocol
#8271) were packaged in the new configuration packaging (PIN's
195917 and 195916).

7.2 Ring Removal Testing Fixture

Because of the overall size and 3-dimensional geometry of the Myxo


ETlogix assembly, the flat silicone sheet called out in QCOP T1024
(standard procedure for ring removal testing) could not be used for the
ring removal test, as it did not allow for the holder to be positioned
vertically on the test stand. In order to achieve this positioning an SLA
fixture was designed and fabricated to aid the testing (see Figure 4
below).

Figure 4: Isometric and Side View of Ring Removal Fixture

The SLA fixture was designed to position the ring-holder assembly in


the vertical position by pinning the ring to a rubber insert on the
underside of the fixture. Since the fixture only holds the ring in place
while the holder is removed and does not come into contact with either
the holder or attaching suture, it does not affect the force required to
remove the holder from the ring. Therefore, the fixture does not affect
the results of the ring removal test. An engineering drawing for the
fixture can be located in Appendix 5 of this report.

Page 11 of 18

Confidential - This document is the property of Edwards Lifesciences LLC, and is intended solely for their internal US8.

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000381


7.3 Ring Removal Test of Sample #315

The initial ring removal testing of sample #315 (built on shop order #
EG6F0847) resulted in a relatively higher peak removal force (119.30
grams or 1.17N), compared to the remaining 14 samples tested (14
sample average= 48.82 grams or .48N). This was due to the fact that
the load cell used for the testing (MET 10 #118003) was zeroed out
before the instron connecting fixture and subsequent pins were
attached to it. Therefore, the weight of the connecting fixture and pins
was measured by the instron during the ring removal test for sample
#315. This resulted in an offset of the test data (see sample #315
graph in Appendix 4). To determine the degree by which the testing
data was offset, the connection fixture and pins were each weighed
individual on a calibrated scale (Edwards's Metrology 10 # 101828)
and totaled together. The total weight of the fixture components was
75.82 grams (connection fixture: 62.00 grams, instron-fixture pin:8.66
grams, fixture-holder pin: 5.16 grams), see Figure 5 below for details.

Figure 5: Components of Connecting Fixture

Therefore, due to the weight of the connection fixture and pins the ring
removal test for sample #315 was offset by 75.82 grams (.74N).To
correct this, 75.82 grams (.74N) was subtracted from its' peak removal
force, which resulted in a peak removal force of 43.48 grams (.43N).
This value was then used for the statistical analysis of the ring removal
data shown in Table 2 (section 6.1.2).

8 Conclusion

The Myxo ETlogix Annuloplasty Ring with Holder met all acceptance
criteria with respect to Ring Removal Force and Holder Strength tests
(Parachuting and P2 Retention). Since all tests met the acceptance
Page 12 of 18

Confidential - This document is the property of Edwards Lifesciences LLC, and is intended solely for their internal use.

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000382


criteria, one can conclude that the Myxo ETlogix Annuloplasty Ring
with Holder has been verified per Protocol #8271.

By meeting the requirements of protocol #8271, the MyxoLogix


Annuloplasty Ring with Holder also met holder-related design input
n
and 2 tier requirements from the Design Requirements Document
(DRO) Rev.E for the Myxo ETLogix assembly (found in OHF#6994).
The holder specific inputs from the DRO which the design verification
testing addressed are listed below:

• Holder to be compatible with ring design: ring removal force


<1000 grams (section 6.1 of report).
• Holder to withstand forces seen during normal use without
failure: parachute strength >1000gram and P2 retention
strength>2000 grams (sections 6.2 and 6.3 of report).
• Holder to be able to engage and be removable from the
Model 1150 handle: justification for handle-holder snap fit
testing (section 2.7 of protocol #8271).

9 Records
Records to be maintained in the PDM system at Edwards
Lifesciences.

10 Reference Documents

10.1 Test Protocol #8271, "Design Verification of Myxo ETlogix,


Model 5100, Holder"

10.2 GP1135, Rev E, "Statistical Techniques"

10.3 SOP3862, Rev C, "HVT Assy & Inspn for Myxo ETlogix Ring,
Model 5100"

10.4 Test Protocol #737, "Five Year Accelerated Shelf Life for the
Carpentier-Edwards Physio Ring With Duraflo Treatment, PIN
640164 for Steam Sterilization"

10.5 Test Protocol #7430, "Design Verification of Myxo-Logix


Annuloplasty Ring, Model 5100"

10.6 Test Protocol #95-0038, "One and Five Year Shelf Life Studies
for Baxter Edwards CVS Division Phase II Product & Packaging
for Carpentier-Edwards Physio Ring, Model Number 4450 and
Cosgrove-Edwards ring, Model Number 4600"

Page 13 of 18

Confidential - This document is the property of Edwards Lifesciences LLC, and is intended solely for their internal use.

EDWARDS CONFIDENTIAL. PROVIDED PURSUANT TO SENATE RULE XXIX. EW-S-20000383


Point Eight

8) January 2007, US Trademark Office Directions for use Myxo ETlogix Model 5100. See DFU.
PTO Form 1553 (Rev 9/2005)
OMB No. 0651-0054 (Exp. 09/30/2011)

Trademark/Service Mark Statement of Use


(15 U.S.C. Section 1051(d))

The table below presents the data as entered.

Input Field Entered


SERIAL NUMBER 78952900
LAW OFFICE ASSIGNED LAW OFFICE 113
NOTICE OF ALLOWANCE YES
EXTENSION OF USE NO
REQUEST TO DIVIDE NO
MARK SECTION
STANDARD CHARACTERS YES
USPTO-GENERATED IMAGE YES
LITERAL ELEMENT MYXO ETLOGIX
OWNER SECTION (no change)
ATTORNEY SECTION (current)
NAME Debra D. Condino
FIRM NAME EDWARDS LIFESCIENCES LLC
STREET 1 EDWARDS WAY
CITY IRVINE
STATE California
POSTAL CODE 92614-5688
COUNTRY United States
PHONE 949-250-6832
FAX 949-250-6850
ATTORNEY SECTION (proposed)
NAME Rajiv Yadav
FIRM NAME EDWARDS LIFESCIENCES LLC
STREET 1 EDWARDS WAY
CITY IRVINE
STATE California
POSTAL CODE 92614-5688
COUNTRY United States
PHONE 949-250-6832
FAX 949-250-6850
GOODS AND/OR SERVICES SECTION
INTERNATIONAL CLASS 010
CURRENT IDENTIFICATION Medical device, namely annuloplasty ring
GOODS AND/OR SERVICES KEEP ALL LISTED
FIRST USE ANYWHERE DATE 01/24/2007
FIRST USE IN COMMERCE DATE 01/24/2007
\\TICRS2\EXPORT14\789\529
SPECIMEN FILE NAME(S)
\78952900\xml2\SOU0002.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0003.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0004.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0005.JP G

\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0006.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0007.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0008.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0009.JP G
SPECIMEN DESCRIPTION Product insert brochure
PAYMENT SECTION
NUMBER OF CLASSES 1
SUBTOTAL AMOUNT 100
TOTAL AMOUNT 100
SIGNATURE SECTION
SIGNATURE /Rajiv yadav/
SIGNATORY'S NAME Rajiv Yadav
SIGNATORY'S POSITION Attorney
DATE SIGNED 10/30/2007
FILING INFORMATION
SUBMIT DATE Tue Oct 30 18:12:35 EDT 2007
USPTO/SOU-216.65.215.213-
20071030181235361102-7895
TEAS STAMP 2900-4001a546d89e48e789fc
7aab31d8cf19a7a-DA-4313-2
0071030180324439406
PTO Form 1553 (Rev 9/2005)
OMB No. 0651-0054 (Exp. 09/30/2011)

Trademark/Service Mark Statement of Use


(15 U.S.C. Section 1051(d))
To the Commissioner for Trademarks:

MARK: MYXO ETLOGIX


SERIAL NUMBER: 78952900

This Allegation of Use is being filed after a Notice of Allowance has issued.

The applicant, Edwards Lifesciences Corporation, having an address of One Edwards Way, Irvine,
California United States 92614, is using or is using through a related company or licensee the mark in
commerce on or in connection with the goods and/or services as follows:

For International Class 010:


Current identification: Medical device, namely annuloplasty ring

The applicant, or the applicant's related company or licensee, is using the mark in commerce on or in
connection with all goods and/or services listed in the application or Notice of Allowance or as
subsequently modified.

The mark was first used by the applicant, or the applicant's related company, licensee, or predecessor in
interest at least as early as 01/24/2007, and first used in commerce at least as early as 01/24/2007, and is
now in use in such commerce. The applicant is submitting one specimen for the class showing the mark as
used in commerce on or in connection with any item in the class, consisting of a(n) Product insert
brochure.
Specimen File1
Specimen File2
Specimen File3
Specimen File4
Specimen File5
Specimen File6
Specimen File7
Specimen File8

The applicant hereby appoints Rajiv Yadav of EDWARDS LIFESCIENCES LLC, 1 EDWARDS WAY,
IRVINE, California United States 92614-5688 to submit this Trademark/Service Mark Statement of Use
on behalf of the applicant.

A fee payment in the amount of $100 will be submitted with the form, representing payment for 1 class.

Declaration

Applicant requests registration of the above-identified trademark/service mark in the United States Patent
and Trademark Office on the Principal Register established by the Act of July 5, 1946 (15 U.S.C. Section
1051 et seq., as amended). Applicant is the owner of the mark sought to be registered, and is using the
mark in commerce on or in connection with the goods/services identified above, as evidenced by the
attached specimen(s) showing the mark as used in commerce.

The undersigned being hereby warned that willful false statements and the like are punishable by fine or
imprisonment, or both, under 18 U.S.C. Section 1001, and that such willful false statements and the like
may jeopardize the validity of this document, declares that he/she is properly authorized to execute this
document on behalf of the Owner; and all statements made of his/her own knowledge are true and that all
statements made on information and belief are believed to be true.

Signature: /Rajiv yadav/ Date Signed: 10/30/2007


Signatory's Name: Rajiv Yadav
Signatory's Position: Attorney

Mailing Address:
EDWARDS LIFESCIENCES LLC

1 EDWARDS WAY
IRVINE, California 92614-5688

Mailing Address:
EDWARDS LIFESCIENCES LLC

1 EDWARDS WAY
IRVINE, California 92614-5688

RAM Sale Number: 4313


RAM Accounting Date: 10/31/2007

Serial Number: 78952900


Internet Transmission Date: Tue Oct 30 18:12:35 EDT 2007
TEAS Stamp: USPTO/SOU-216.65.215.213-200710301812353
61102-78952900-4001a546d89e48e789fc7aab3
1d8cf19a7a-DA-4313-20071030180324439406
Point Nine

8) May 21, 2007, Vlahoulis second surgery to replace stenosed valve and remove model 5100 ring, and
asks why she got the McCarthy Annuloplasty ring which is not listed in the Edwards Lifesciences
Brochure.
EVIDENCE:
DEVICE IDENTIFICATION CARD
McCarthy Annuloplasty Ring
Pre-Clinical Version of the Model 5100
February 26, 2006

Edwards Lifesciences
Justification to File
Notification of Product Modific ;ons made to
The GeoForm Annulopl ." (K032250)
McCart,hy Myxo 0. i.sty Ring, Model 5100

2006 .
'/'OLlme
I 1 0f 1 Copy: RA File
Device Identifier Card
Preclinical Version of the Model 5100 placed in Vlahoulis heart
without informed consent on 4-26-2006
ONE OF THE FIRST TEN IMPLANTS IN THE LIMITED RELEASE
TO MCCARTHY
Device Identifier Card Pre-Clinical Model 5100
Implanted in Obermeier on November 6, 2006
EVIDENCE:
Clinical Version of the Model 5100 with the New Name:
Myxo ETLogix Ring
November 20, 2006
14 Days after Obermeier’s pre-clinical testing surgery

Edwards Lifesciences
Myxo ET Logix Annuloplasty Ring
& Holder Model 5100
JTF: Decision for Notification of Product Modification

November 20, 2006


EW RACopy
Point Ten

10) I reported to the NU Dean’s office, Chief of Cardiology, IRB, General Counsel lack of consent in May
2007 and removed my name from the study.
Point Eleven

11) May 2007, Dr. McCarthy requests another expedited HIPPA waiver from Northwestern University IRB
coordinator Tasha Osafo. Tasha Osafo recognizes that the study protocol is prospective, and not
retrospective as indicated in the June 2006 expedited waiver, and IRB Coordinator Osafo requests
more data for the IRB as 1532-004 is now a prospective study and not retrospective.
Point Twelve

12) June 28, 2007 IRB Coordinator Tasha Osafo issues a cease and desist of the protocol 1532-004.
Point Thirteen

13) July 13, 2007 Dr. McCarthy prepares documents to terminate protocol 1532-004 on July 12, 2007 which
includes his checking the box with an agreement signed by Dr. McCarthy with the Northwestern
University IRB, under the Federal Wide Assurance 0001549, signed by Jay Walsh, with HHS, the NIH
and the FDA, of “no further contact with human subjects is planned: no subjects are, or will be, treated
or followed; all data are gathered and analyzed; and there are no further sponsor reports or
publications to submit to the IRB.”
Point Fourteen

14) February 2007, Al Edwards surgery causes heart attack and pacemaker
Point Fourteen

14) February 2007, Al Edwards surgery causes heart attack and pacemaker
Point Fifteen

15) January 8, 2008, Brian Warshawsky surgery causes severe heart attack and defibrillator
Point Sixteen

16) July 2008, Dr. McCarthy and colleagues publishes the study despite termination record, on the
Myxo ETlogix Ring and the model 1155 calipers study, he continued the protocol for the
publication until November 2007. Vlahoulis and myself report to the FDA the existence of the
Model 5100, Myxo ETlogix Ring.
McCarthy et al Surgery for Acquired Cardiovascular Disease

Initial clinical experience with Myxo-ETlogix* mitral


valve repair ring
P. M. McCarthy, MD,a E. C. McGee, MD,a V. H. Rigolin, MD,b Q. Zhao, MD,b H. Subacius, MA,c A. L. Huskin, RN,c
S. Underwood, RN,a B. J. Kane, RDCS,b I. Mikati, MD,b G. Gang, MD,a and R. O. Bonow, MDb

ACD
Objective: Complexity of mitral valve repair for myxomatous disease has led to low
adoption. We report initial experience with a new ring designed specifically for myx-
omatous disease, the Myxo-ETlogix (Edwards Lifesciences LLC, Irvine, Calif).

Methods: From March 15, 2006, through November 19, 2007, 129 patients underwent
mitral valve surgery for pure myxomatous disease, and 124 valves (96.1%) were re-
paired. The Myxo-ETlogix ring was used in 100 cases and the Physio ring (Edwards)
in 24. The Myxo-ETlogix design includes a 3-dimensional shape to reduce systolic
anterior motion and a larger orifice to accommodate elongated leaflets and decrease
need for sliding plasty. Direct mitral valve measurements were made. Sizing was
based on A2 height, and choice of ring type was based on unresected leaflet heights.

Results: There was no operative mortality or lasting perioperative morbidity. The


Myxo-ETlogix group had taller A2, P1, P2, and P3 leaflet segments than the Physio
group (P # .003). Only 1 sliding plasty was performed for asymmetry in the Myxo-
ETlogix group. Predischarge and follow-up echocardiograms (n 5 338 in 124
patients) disclosed transient nonobstructive chordal systolic anterior motion in 3
echocardiograms in 3 patients. No patients had 21 or greater mitral regurgitation.
At discharge, 5.7% had 11 mitral regurgitation; this proportion was 17.3% at last
follow-up (mean 6.1 6 4.4 months).

Conclusion: In initial experience with the Myxo-ETlogix ring, nonobstructive systolic


From the Bluhm Cardiovascular Institute, anterior motion has been rare and obstructive systolic anterior motion not observed.
Division of Cardiothoracic Surgery,a Cardi- Ongoing prospective echocardiographic and clinical studies will elucidate the role
ology,b and Clinical Trials Unit,c Northwest-
of this etiology-specific ring.
ern Memorial Hospital, Chicago, Ill.
Read in part at the Eighty-seventh Annual
Meeting of The American Association for

M
itral valve (MV) prolapse is common, occurring in 1% to 2.5% of the pop-
Thoracic Surgery, Washington, DC, May
5–9, 2007. ulation.1 Myxomatous mitral regurgitation (MR) is characterized by elon-
P.M.M. is the inventor of the Myxo-ETlogix
gation and thickening of the valve leaflets with annular and dilatation
ring and receives royalties. R.O.B. and prolapse (Carpentier type II).2 Numerous studies have demonstrated that mitral repair
P.M.M. are consultants for Edwards Life- generally gives a more favorable result than does MV replacement, but because of the
sciences LLC.
complexity of the pathology and therefore the procedure required, it is performed
* Myxo-ETlogix is a trade name of Edwards in fewer than 50% of cases according to data from the United States and Europe.3-6
Lifesciences LLC, Irvine, Calif.
Furthermore, the considerable interpatient variability has required the surgeon to
Received for publication June 15, 2007;
revisions received Dec 21, 2007; accepted approach valve repair as an art, and valve repair has been concentrated such that
for publication Feb 12, 2008. a minority of surgeons perform the majority of repairs. Consequently, it has been dif-
Address for reprints: Patrick M. McCarthy, ficult for a low- or medium-volume mitral repair surgeon to develop the numerous
MD, Northwestern University, Division of skills necessary for successful repair, considering the wide variety of surgical tech-
Cardiothoracic Surgery, 201 E Huron St,
Suite 11-140, Chicago, IL 60611-2908
niques that may be required for complex repairs.
(E-mail: pmccart@nmh.org). An additional repair problem specific to myxomatous disease is the development
J Thorac Cardiovasc Surg 2008;136:73-81 of systolic anterior motion (SAM), which has been reported in 2% to 16% of patients
0022-5223/$34.00 after mitral repair.7-10 Transient SAM may be seen during first weaning from cardio-
Copyright Ó 2008 by The American Asso-
pulmonary bypass and may be easily treated by volume infusion from the pump to
ciation for Thoracic Surgery increase the systemic blood pressure (afterload) if the patient is hypotensive and vaso-
doi:10.1016/j.jtcvs.2008.02.013 dilated and by stopping positive inotropes. More troublesome is persistent SAM,
which may require additional medical or surgical therapy. SAM is precipitated by

The Journal of Thoracic and Cardiovascular Surgery c Volume 136, Number 1 73


Surgery for Acquired Cardiovascular Disease McCarthy et al

Bluhm Cardiovascular Institute, which was approved by the North-


Abbreviations and Acronyms western University Institutional Review Board for use in research.
MR 5 mitral regurgitation The study ran from the date of first use of Myxo-ETlogix (March
MV 5 mitral valve 15, 2006) until the date of 100th Myxo-ETlogix implant (November
SAM 5 systolic anterior motion 19, 2007). For the purposes of this study, we analyzed only those
patients with MR caused by isolated myxomatous degenerative
MV disease (n 5 129). The diagnosis of myxomatous disease was de-
termined by echocardiographic and surgical findings of elongated
ACD

MV leaflets with prolapse (type II). Patients were excluded if they


elongated leaflets and may cause left ventricular outflow tract had rheumatic valve disease, ischemic valve disease, cardiomyopa-
obstruction and residual or recurrent MR. SAM may be thy, endocarditis, or mixed pathology. Among the 129 myxomatous
caused by a short distance between the point of leaflet coap- MR cases, MV repair was performed in 124 patients (96.1%), and
tation to the nearest point on the ventricular septum, which MV replacement was performed in 5 patients (3.9%). These 5 patients
had ages of 65, 72, 74, 78, and 84 years, and all had annular and leaflet
may be seen when the posterior leaflet is too tall or the annu-
calcification. Patients included in this analysis were operated on by
loplasty ring placed is too small.7,8 An elongated anterior
two surgeons at a single institution, Northwestern Memorial Hospital.
leaflet may also contribute to SAM, and numerous techniques In the repair group, 100 patients received the Myxo-ETlogix an-
can be used to avoid or eliminate SAM, such as shortening nuloplasty ring, which is a Food and Drug Administration–approved
the anterior leaflet, creating a double orifice (edge-to-edge ring for patients undergoing MV repair. During the same period, the
approximation), or even myectomy.2,11-16 Reducing the Carpentier–Edwards Physio ring was used to repair 24 valves in pa-
height of the posterior leaflet (sliding plasty) is the most com- tients with myxomatous MV disease. Thus 80.6% of the patients
mon technique.2,10,17 Although some would argue that SAM with myxomatous disease underwent repair with the Myxo-ETlogix
may be managed medically with long-term b-blocker therapy ring, and 19.4% underwent repair with a Physio ring. According to
and a low late need for reoperation, persistent SAM may be our practice, all patients in the group were prospectively followed up
associated with continuing MR, and a young patient requir- by a specific valve nurse who was available to answer patient ques-
tions, arrange follow-up visits, and facilitate entry into prospective
ing long-term b-blocker therapy has had an imperfect opera-
3-dimensional echocardiographic and other imaging studies. The
tion.18,19 In an age when surgery is being performed early, in
characteristics of the patients who received the Myxo-ETlogix
symptom-free patients, this result is less than ideal.1 Ideally, ring are compared with those of the patients who received a Physio
the repair procedure would avoid SAM altogether and not ring in Table 1. Overall, the age of the patients was 57 6 13 years,
require long-term medical management. and the Myxo-ETlogix patients were younger (P 5 .047). The
We sought to develop a new MV repair ring designed to Myxo-ETlogix patients had more MR (97% with 41, P , .001).
accommodate the specific pathologic conditions of myxoma- Other significant differences between the groups included smaller
tous disease. This etiology-specific ring, the Myxo-ETlogix body mass index and more white patients in the Myxo-ETlogix
(Edwards Lifesciences LLC, Irvine, Calif) ring has a larger group (patient self-report), whereas patients in the Physio group
orifice than does a Physio (Edwards Lifesciences) ring were more likely to have chronic obstructive pulmonary disease.
(which is based on normal anatomy) to accommodate the The 5 patients who underwent MV replacement were significantly
elongated leaflets. It also has a 3-dimensional shape that older than the 124 repair patients (P , .001), and their operative find-
ings precluded safe, durable MV repair. All these patients underwent
moves the coaptation point away from the septum (increasing
valve replacement with a bioprosthetic bovine pericardial valve. In
the distance between the point of leaflet coaptation to the keeping with the trend toward early repair in patients with myxoma-
nearest point on the ventricular septum), thereby reducing tous MV disease, most of the patients in the repair group were in New
the risk of SAM.8,14 Because this etiology-specific ring has York Heart Association functional class I or II (81.4%).
a larger orifice, a secondary advantage would be that exten-
sive leaflet reconstruction to reduce the size of the leaflets Characteristics of the Myxo-ETlogix Ring
back to ‘‘normal’’ (sliding plasty) would not be needed, or The Myxo-ETlogix ring was designed as a complete annular remod-
at least would be needed much less frequently. This would re- eling ring with etiology-specific variations from the Physio ring
duce the complexity of myxomatous valve repair and ideally (Figure 1).20 The anteroposterior dimension of the ring was
increased 29% to accommodate elongated myxomatous leaflets.
make it more generalizable. Furthermore, the larger orifice
Depending on the exact size of the ring, this led to an increase in
leads to a low or normal gradient. This is the first report of
anteroposterior diameter of 5 to 8 mm, designed to correspond to
the concepts behind the new Myxo-ETlogix, the impact typical reduction in posterior leaflet height in patients who undergo
that it had on our use of other mitral repair rings and tech- sliding plasty. Rather than the surgeon performing extensive recon-
niques, and the initial clinical results. struction to reduce the height of the posterior leaflet by 5 to 8 mm,
instead the ring pulls the posterior leaflet down by a corresponding
Materials and Methods amount. This also creates a 16% increase in the total orifice area for
Patient Characteristics the Myxo-ETlogix ring. The largest anteroposterior diameter of
Patient information and follow-up data were obtained from the pro- a size 40 Physio ring is 27.2 mm, which corresponds most closely
spectively maintained cardiac surgery outcomes registry of the to a size 32 Myxo-ETlogix ring (28.0 mm). A size 40 Myxo-ETlogix

74 The Journal of Thoracic and Cardiovascular Surgery c July 2008


McCarthy et al Surgery for Acquired Cardiovascular Disease

TABLE 1. Preoperative patient characteristics by annuloplasty type

Total (N 5 124) Physio (n 5 24) Myxo-ETlogix (n 5 100) P value

Age (y) .047*


Mean 6 SD 57.4 6 13.4 62.2 6 12.1 56.2 6 13.5
Range 22–85 41–81 22–85
Male (No.) 76 (61.2%) 14 (58.3%) 62 (62.0%) NS

ACD
Body mass index (kg/m2) .006y
Mean 6 SD 25.4 6 4.5 27.6 6 3.9 24.9 6 4.5
Range 15.1–39.5 20.2–34.2 15.1–39.5
White race (No.) 103 (83.1%) 16 (66.7%) 87 (87.0%) .017
Previous cardiac surgery (No.) 1 (0.8%) 0 (0.0%) 1 (1.0%) NS
Comorbidities (No.)
Previous myocardial infarction 2 (1.6%) 1 (4.2%) 1 (1.0%) NS
Congestive heart failure 16 (12.9%) 5 (20.8%) 11 (11.0%) NS
Coronary artery disease 19 (15.3%) 4 (16.7%) 15 (15.0%) NS
Diabetes 3 (2.4%) 0 (0.0%) 3 (3.0%) NS
Hypertension (systemic) 48 (38.7%) 13 (54.2%) 35 (35.0%) .083
Hypertension (pulmonary) 65 (52.9%) 13 (54.2%) 52 (52.0%) NS
Renal failure 0 (0.0%) 0 (0.0) 0 (0.0) NS
Chronic obstructive pulmonary disease 8 (6.5%) 4 (16.7%) 4 (4.0%) .045z
Hyperlipidemia 40 (32.3%) 9 (37.5%) 31 (31.0%) NS
Atrial fibrillation or flutter 26 (21.0%) 7 (29.2%) 19 (19.0%) NS
New York Heart Association functional class (No.) NS
I 35 (28.2%) 4 (16.7%) 31 (31.0%)
II 66 (53.2%) 13 (54.2%) 53 (53.0%)
III–IV 23 (18.6%) 7 (29.2%) 16 (16.0%)
Prolapse (No.) NS
Anterior 8 (6.5%) 2 (8.7%) 6 (6.0%)
Posterior 83 (67.5%) 19 (82.6%) 64 (64.0%)
Anterior and posterior 32 (26.0%) 2 (8.7%) 30 (30.0%)
Preoperative echocardiographic mitral ,.001
regurgitation (No.)
21 2 (1.6%) 2 (8.3%) 0 (0.0%)
31 7 (5.7%) 4 (16.7%) 3 (3.0%)
41 115 (92.7%) 18 (75.0%) 97 (97.0%)
LV ejection fraction (%) NS
Mean 6 SD 59.4% 6 7.5% 60.7% 6 7.0% 59.1% 6 7.6%
Range 35%–80% 50%–80% 35%–75%
LV end-systolic dimension (cm) NS
Mean 6 SD 3.6 6 0.6 3.6 6 0.6 3.6 6 0.6
Range 2.1–5.1 2.3–4.4 2.1–5.1
LV end-diastolic dimension (cm) NS
Mean 6 SD 5.5 6 0.7 5.5 6 0.6 5.5 6 0.7
Range 3.9–7.1 4.3–6.5 3.9–7.1
NS, not significant (P . .20); LV, left ventricular. *Squared transformation. yNatural log transformation. zFisher exact test.

ring has an anteroposterior diameter of 35.0 mm. The Myxo-ETlo- effect of these two changes is to pull the coaptation point down
gix ring was only available in sizes 26 through 36 until mid Novem- and away from the septum.
ber 2006, when sizes 38 and 40 became available but sizes 26 and 28
became unavailable. This shortage was due to production of a lim- Operative Techniques
ited quantity of early rings. Operative techniques were largely based on Carpentier’s time-tested
In addition to accommodating the larger leaflets, the Myxo-ET- concepts of resection of the prolapsing segment, chordal transfer if
logix ring was designed to move the coaptation point down, and also necessary, leaflet reconstruction, and complete remodeling annulo-
away from the septum, by means of a 4-mm shape change centered plasty ring.3,20 The Myxo-ETlogix ring was used for patients with
at the P2 region, pulling the ring into the left atrium (Figure 1) and elongated anterior leaflets or tall remaining posterior leaflet segments
resulting in an increase in the distance between the point of leaflet after resection. If the remaining posterior and anterior leaflets were
coaptation to the nearest point on the ventricular septum. The net normal after resection, then a Physio ring was used. Repair techniques

The Journal of Thoracic and Cardiovascular Surgery c Volume 136, Number 1 75


Surgery for Acquired Cardiovascular Disease McCarthy et al

Figure 1. Myxo-ETlogix ring designed for pa-


tients with leaflet elongation historically treated
with sliding plasty with risk of systolic anterior
motion. Ring has longer anteroposterior diameter
(typically 6 mm) to accommodate larger leaflets,
corresponding to typical posterior leaflet height
reduction from sliding plasty. P2 segment of ring
has 4-mm displacement into annulus. Net effect
ACD

of these two changes moves coaptation point


down and away from septum, reducing risk of
systolic anterior motion.

for both groups included leaflet resection, chordal transfer, commis- ETlogix and Physio rings. Ring size was true sized to A2 height
suroplasty, and ring annuloplasty. No artificial chords were used in in most cases. Occasionally, a larger Myxo-ETlogix ring was chosen
any patients. Before the Myxo-ETlogix ring was available, sliding an- because of an unusually tall (.20 mm) posterior leaflet, a smaller
nuloplasty was performed in 38% of cases of myxomatous disease Myxo-ETlogix ring was chosen if there was a short posterior leaflet
(according to our database) when the remaining posterior segments (,12 mm), or another size was chosen if the closest ring size was not
were longer than 20 mm by visual inspection (not by direct measure- available. Other measurements or judgments (commissure-to-com-
ment, which was not yet available) and sometimes when the posterior missure, trigone-to-trigone, anterior leaflet surface area) were not
leaflet was shorter than 20 mm but there was a wide resection. used for sizing.
Concomitant cardiac surgical procedures (Table 2) included The Physio ring was used for the subset of patients who had what
a maze procedure in 31 patients (25%), tricuspid valve annuloplasty Carpentier classifies as ‘‘fibroelastic deficiency.’’21 This group
in 12 patients (9.7%), coronary artery bypass grafting in 17 patients tended to be older, with associated comorbidities such as hyperten-
(13.7%), and aortic valve replacement in 3 patients (2.4%). There sion and chronic obstructive pulmonary disease, and the pathologic
was no difference in concomitant procedures between the Physio characteristics typically consisted of ruptured chords at the P2 seg-
and Myxo-ETlogix groups, but the ring size used in the Myxo-ET- ment with normal lengths of P1, P3, and A2. The pathology at P2
logix group was larger (P 5 .001). The 1 patient (in the Myxo-ET- was resected, and the remaining valve leaflet lengths were therefore
logix group) who underwent sliding plasty had an unresected normal, so the Physio ring was chosen as a design based on normal
remnant P2 height of 27 mm and a P3 height of 16 mm. Because valve anatomy.10 Patients who received a Myxo-ETlogix ring con-
of the extensive size discrepancy and a wide resection (22 mm), sisted of those with Barlow disease and those with lengthening of
the height of the remaining P2 was reduced with a short sliding unresected segments of the leaflet, the anterior leaflet, or both.
plasty. A second pump run was performed in 2 cases (1.6%) because Most patients did not fall into two distinct categories (Barlow dis-
of residual MR (11–21), with conversion from repair to replace- ease vs fibroelastic deficiency) and instead had more intermediate
ment in an 84-year-old patient and successful additional leaflet leaflet length, as depicted in Figure 2.
repair in another patient.
Echocardiographic Techniques
Direct MV Measurements and Choice of Myxo- MR was assessed as follows: none or trivial, 0; mild, 11; moderate,
ETlogix Versus Physio Ring 21; moderate to severe, 31; and severe, 41. Nonobstructive
Direct measurements of the MV were taken with a custom-designed (chordal) SAM was defined as anterior motion of the MV or sub-
set of measuring calipers. These distance measurements included valvular apparatus without an elevation of the peak velocity or
commissure-to-commissure, trigone-to-trigone, and heights of the a late peaking velocity profile in the Doppler waveforms in the
leaflet at P1, P2, P3, and A2 segments (Figure 2). Other measure- left ventricle or left ventricular outflow tract. Echocardiography
ments included width of the resected segment, width of the annulus was performed in 100% of patients intraoperatively, at discharge,
after compression sutures, height of the middle segment of the pos- and, according to our usual practice, at approximately 1 month
terior leaflet after reconstruction when applicable, and overlaps at and between 3 and 6 months after surgery, annually, and any other
P1, P2, P3, A1, A2, and A3. The results of these measurements time as clinically indicated.
are depicted in Figure 2. Table 3 compares the measures in patients
with Myxo-ETlogix rings with those of patients with Physio rings. Statistical Analysis
Measurements were available for 98 of 100 patients in the Myxo- Demographic and clinical patient characteristics in the Physio and
ETlogix group and 22 of 24 patients in the Physio group. Myxo-ETlogix groups were compared with t tests for continuous
Ring size was chosen according to A2 height. The measurement variables and c2 tests for categorical variables. Group differences
was referenced to a chart of the anteroposterior diameter of Myxo- in intraoperative variables were evaluated with the same

76 The Journal of Thoracic and Cardiovascular Surgery c July 2008


McCarthy et al Surgery for Acquired Cardiovascular Disease

TABLE 2. Operative results

Total (N 5 124) Physio (n 5 24) Myxo-ETlogix (n 5 100) P value

Ring size (mm) .001


Mean 6 SD 33.0 6 3.4 31.1 6 2.6 33.5 6 3.4
Range 26–40 26–36 26–40
Resection (No.) 110 (88.7%) 20 (83.3%) 90 (90.0%) NS

ACD
Width of resection (mm) ,.001
Mean 6 SD 15.5 6 6.4 11.3 6 3.5 16.6 6 6.5
Range 7–36 7–20 7–36
Sliding plasty (No.) 0 (0.8)% 0 (0.0%) 1 (1.0%) NS
Chordal transfer (No.) 20 (16.1%) 1 (4.2%) 19 (19.0%) .119*
Crossclamp time (min) .195y
Mean 6 SD 88.1 6 22.7 83.5 6 24.1 89.2 6 22.3
Range 52–169 52–138 55–169
Cardiopulmonary bypass time (min) NS
Mean 6 SD 104.7 6 26.1 101.0 6 26.5 105.6 6 26.0
Range 67–190 67–159 67–190
Commissuroplasty (No.) 7 (5.7%) 0 (0.00%) 7 (7.0%) NS
Concomitant procedures (No.)
Coronary artery bypass grafting 17 (13.7%) 3 (12.5%) 14 (14.0%) NS
Atrial valve replacement 3 (2.4%) 0 (0.00%) 3 (3.0%) NS
Tricuspid valve annuloplasty 12 (9.7%) 1 (4.2%) 11 (11.0%) NS
Maze 31 (25.0%) 8 (33.3%) 23 (23.0%) NS
Postoperative
Mortality, infection, myocardial infarction, 0 (0.0%) 0 (0.0%) 0 (0.0%) NS
or acute renal failure (No.)
Reoperation for bleeding (No.) 1 (0.8%) 0 (0.0%) 1 (1.0%) NS
Cerebrovascular accident (No.) 1 (0.8%) 0 (0.0%) 1 (1.0%) NS
Hospital stay (d) NS
Mean 6 SD 5.8 6 2.9 6.0 6 2.6 5.6 6 2.9
Range 3–24 4–15 3–24
Intraoperative echocardiography
Mitral regurgitation (No.) NS
0 121 (97.6%) 23 (95.8%) 98 (98.0%)
11 3 (2.4%) 1 (4.2%) 2 (2.0%)
Mean gradient (mm Hg) NS
Mean 6 SD 3.1 6 1.5 3.3 6 1.9 3.0 6 1.4
Range 0.6–10.0 1.4–10.0 0.6–9.0
Predischarge echocardiography
Mitral regurgitation (No.) NS
0 115 (92.7%) 23 (95.8%) 92 (93.9%)
11 7 (5.7%) 1 (4.2%) 6 (6.1%)
Mean gradient (mm Hg) .134y
Mean 6 SD 3.3 6 1.4 3.7 6 1.7 3.2 6 1.4
Range 1.2–8.6 1.5–8.0 1.2–8.6
NS, Not significant. *Fisher exact test. yNatural log transformation.

methodology. Continuous variables were appropriately transformed fibrillation that resolved before discharge. Follow-up was
if a better approximation of normal distribution could be achieved. 100% complete, and there were no late deaths.
Fisher exact test was used for comparisons of categorical variables Predischarge and follow-up echocardiograms totaled 338.
with a minimum cell count of 5 or less. No MR or trivial MR was present at discharge in 92.7% of
patients, and 11 was present in 5.7% (Table 2). Mean
Results gradient at discharge showed a trend toward being higher
Postoperative complications were low, with no deaths, no in- in the Physio group (3.7 6 1.7 mm Hg vs 3.2 6 1.4 mm
fections, no perioperative infarctions, 1 reoperation for bleed- Hg, P 5 .134, natural log transformation to normalize the
ing (0.8%), and 1 stroke on postoperative day 3 from atrial data). At most recent follow-up (mean 6.1 6 4.4 months)

The Journal of Thoracic and Cardiovascular Surgery c Volume 136, Number 1 77


Surgery for Acquired Cardiovascular Disease McCarthy et al
ACD

Figure 2. Direct measurement with custom calipers provided quantitative data on leaflet length in different seg-
ments documenting elongated leaflets in bell-shaped frequency curve. In particular, A2 height was very elongated;
this was used to choose appropriate ring type (Physio ring vs Myxo-ETlogix ring) and ring size.

11 MR was present in the Physio group in 1 patient (10%) ond pump run or revision. One patient (with a 28-mm
and in the Myxo-ETlogix group in 16 patients (18%, differ- Myxo-ETlogix valve with commissuroplasty) had an early
ences from baseline and between groups not significant). uneventful course after repair, with a low gradient (3.5 mm
There was no significant difference between MR at discharge Hg), but had an intense, generalized inflammatory reaction,
and last follow-up. No patients had 21 or greater MR. including both mitral leaflets, and required reoperative MV
After surgery, no obstructive SAM was seen, and nonob- replacement for mitral stenosis 13 months after repair. Table
structive chordal SAM was inconsistently seen in 3 patients. 2 summarizes operative results for both groups.
In 1 patient (with a 32-mm Myxo-ETlogix valve), SAM was
first detected 14 days after discharge, but subsequent echo- Discussion
cardiograms on days 82, 214, and 397 had negative results. Overall, in an age of early repair for myxomatous disease, our
In a second patient (with a 36-mm Myxo-ETlogix valve), results demonstrated a safe operation with low morbidity,
there was no SAM early (predischarge or day 12 after dis- a high rate of repair (96%), and excellent early results with
charge), SAM was recorded on day 160 after discharge, little residual or recurrent MR (none at least 21). We have
and at 1-year follow-up there was no SAM. In a third patient found clinical benefit in precise anatomic measurement of
(with a 34-mm Physio ring), discharge echocardiography the pathologic tissue, and these data drive our choice of
showed chordal SAM; this patient has not yet returned for ring size and type of ring prosthesis. This has led to predict-
follow-up. Transient intraoperative SAM shortly after wean- able coaptation of the leaflets, without rings or residual leaflet
ing from bypass was uncommon (3 patients), depended on heights we considered too small or too big. Our data indicate
volume status and blood pressure, and never required a sec- that although some patients’ leaflets fall into the extremes of

78 The Journal of Thoracic and Cardiovascular Surgery c July 2008


McCarthy et al Surgery for Acquired Cardiovascular Disease

TABLE 3. Direct preoperative and postoperative mitral valve measurements

Measurement (mm) Total Physio (n 5 22) Myxo-ETlogix (n 5 98) P value

A2 ,.001
Mean 6 SD 27.9 6 4.9 23.7 6 5.2 28.9 6 4.3
Range 15-41 17-34 15-41
P1 ,.001

ACD
Mean 6 SD 13.6 6 4.3 10.6 6 2.9 14.3 6 4.3
Range 6-27 6-20 6-27
P2 .003
Mean 6 SD 21.9 6 5.1 19.0 6 4.6 22.5 6 5.0
Range 7-34 9-30 7-34
P-middle* ,.001
Mean 6 SD 14.6 6 2.9 12.3 6 1.9 15.1 6 2.8
Range 8-23 10-16 8-23
P3 ,.001
Mean 6 SD 15.1 6 3.8 12.5 6 2.6 15.7 6 3.8
Range 6-24 8-18 6-24
Cusp-to cusp .007
Mean 6 SD 38.1 6 6.0 35.0 6 4.3 38.8 6 6.2
Range 27-51 27-45 27-51
Trigone-to-trigone .023
Mean 6 SD 24.6 6 4.2 22.8 6 3.4 25.0 6 4.3
Range 14-36 16-28 14-36
P2 overlap .003
Mean 6 SD 6.5 6 1.9 5.4 6 1.4 6.8 6 1.9
Range 2-13 4-9 2-13
A2 overlap .070
Mean 6 SD 5.7 6 1.9 5.0 6 1.6 5.8 6 1.9
Range 2-11 3-9 2-11
*P-middle is the height of the leaflet after P2 resection and reconstruction.

Barlow disease versus fibroelastic deficiency, most patients’ Quantitative data, other than from echocardiograms, have
leaflet lengths fall somewhere between these extremes. been hard to find in mitral repair series. Use of the Adams
Although an artistic, creative approach to complex valve ‘‘ink test’’ and direct measurement of valve segments should
problems with many different techniques is still valuable, help standardize our results and make it easier to compare re-
we hope to move toward a more standardized, generalizable, sults from different series.23-25 All these points are important,
reproducible repair that will lead to higher repair rates. Our because we now see symptom-free patients for whom the
current approach includes three steps: (1) trapezoidal resec- guidelines recommend repair at experienced centers if there
tion (mean 15.5 6 6.4 mm) of prolapsing posterior leaflet is a greater than 90% chance of repair without residual
segments with chordal transfer to extensive anterior prolaps- MR.1,24,25
ing segments if needed, (2) ring choice and sizing that is Large annuloplasty rings have been recommended for pa-
based on A2 and remaining posterior leaflet heights, and tients with Barlow disease.7 We agree that this is an important
(3) complete remodeling annuloplasty with a Physio ring consideration, and more practical than bileaflet resection or
for normal remaining leaflets or with a Myxo-ETlogix ring reconstruction to reduce leaflet height. The new Myxo-ETlo-
for elongated leaflets. Although sliding plasty (and other gix ring, designed for these patients, is significantly larger
complex techniques) should not be forgotten, in our institu- than existing commercial remodeling rings. Barlow disease
tion we reduced the use of sliding plasty from 38% before is not a distinct entity in most cases, however, and even
this series to less than 1% in this experience. After recon- histologic studies have shown a large group of disorders
struction, the ratio of A2 height to posterior leaflet was 1.9 intermediate between Barlow disease and fibroelastic
in both groups, which is thought to be optimal. Others deficiency.21 Whereas some surgeons may describe Barlow
routinely use resection without sliding plasty, but SAM disease in 1% of patients, others may use that term to describe
does appear to be more common in those series than in 50% of their patients with degenerative disease. Furthermore,
ours (2.4% transient nonobstructive SAM and SAM without our data show that some patients may have an elongated A2
left ventricular outflow tract obstruction).18,22 segment but normal posterior segments, or vice versa. The

The Journal of Thoracic and Cardiovascular Surgery c Volume 136, Number 1 79


Surgery for Acquired Cardiovascular Disease McCarthy et al

choice of a large ring thus is variable by surgeon. Although the 7. Adams DH, Anyanwu AC, Rahmanian PB, Abascal V, Salzberg SP,
Filsoufi F. Large annuloplasty rings facilitate mitral valve repair in Bar-
average A2 height in our series (29 mm) corresponds most low’s disease. Ann Thorac Surg. 2006;82:2096-101.
closely to a 34 Myxo-ETlogix ring, larger than the largest 8. Maslow AD, Regan MM, Haering JM, Johnson RG, Levine RA. Echo-
Physio ring (27 mm), we commonly used smaller Myxo- cardiographic predictors of left ventricular outflow tract obstruction and
systolic anterior motion of the mitral valve after mitral valve reconstruc-
ETlogix rings instead of large Physio rings because of the tion for myxomatous valve disease. J Am Coll Cardiol. 1999;34:
perceived benefit of the 4-mm P2 displacement with the Myxo- 2096-104.
ETlogix ring to reduce the risk of SAM. Whether it is the P2 9. Mihaileanu S, Marino JP, Chauvaud S, Perier P, Forman J, Vissoat J,
et al. Left ventricular outflow obstruction after mitral valve repair (Car-
ACD

displacement or the large size of the Myxo-ETlogix ring that pentier’s technique). Proposed mechanisms of disease. Circulation.
accounts for our low incidence of SAM is not yet clear. 1988;78(3 Pt 2):I78-84.
10. Jebara VA, Mihaileanu S, Acar C, Brizard C, Grare P, Latremouille C,
et al. Left ventricular outflow tract obstruction after mitral valve repair.
Study Limitations Results of the sliding leaflet technique. Circulation. 1993;88(5 Pt 2):
This was a nonrandomized study of the initial use of a new II30-4.
11. Deloche A, Jebara VA, Relland JY, Chauvaud S, Fabiani JN, Perier P,
commercially available ring, but not all ring sizes were avail- et al. Valve repair with Carpentier techniques. The second decade.
able during the study period. The inventor of the ring was the J Thorac Cardiovasc Surg. 1990;99:990-1002.
surgeon in the vast majority of cases, and we attempted to re- 12. Mascagni R, Al Attar N, Lamarra M, Calvi S, Tripodi A, Mebazaa A,
et al. Edge-to-edge technique to treat post-mitral valve repair systolic an-
duce this bias with direct quantitative measurements and terior motion and left ventricular outflow tract obstruction. Ann Thorac
standard echocardiographic reporting. The data in all tables Surg. 2005;79:471-4.
and figures therefore represent unbiased measurements and 13. Quigley RL. Prevention of systolic anterior motion after repair of the se-
verely myxomatous mitral valve with an anterior leaflet valvuloplasty.
clinical results. A randomized trial is certainly feasible but Ann Thorac Surg. 2005;80:179-82.
would be best performed at another institution, albeit with 14. Bhudia SK, McCarthy PMM, Smedira NG, Lam BK, Rajeswaran J,
experienced surgeons. Blackstone EH. Edge-to-edge (Alfieri) mitral repair: results in diverse
clinical settings. Ann Thorac Surg. 2004;77:1598-606.
In summary, a new ring was introduced with a change in 15. Civelek A, Szalay Z, Roght M, Arnold R, Klövekorn WP, Vogt PR, et al.
our clinical practice. The result was simpler MV repair pro- Post-mitral valve repair systolic anterior motion produced by non-
cedures, rare nonobstructive SAM, and excellent clinical obstructive septal bulge. Eur J Cardiothorac Surg. 2003;24:857-61.
16. Raney AA, Shah PM, Joyo CI. The ‘Pomeroy procedure’: a new method
and echocardiographic results. Further confirmation at other to correct post-mitral valve repair systolic anterior motion. J Heart Valve
centers is pending, and late echocardiographic follow-up is Dis. 2001;10:307-11.
ongoing. 17. Zegdi R, Carpentier A, Doguet F, Berrebi A, Khabbaz Z, Chauvaud S,
et al. Systolic anterior motion after mitral valve repair. J Thorac Cardi-
ovasc Surg. 2005;130:1453-4.
References 18. Brown ML, Abel MD, Click RL, Morford RG, Dearani JA, Sundt TM,
et al. Systolic anterior motion after mitral valve repair: is surgical inter-
1. American College of Cardiology/American Heart Association Task vention necessary? J Thorac Cardiovasc Surg. 2007;133:136-43.
Force on Practice Guidelines, Society of Cardiovascular Anesthesiolo- 19. Schiavone WA, Cosgrove DM, Lever HM, Steward WJ, Salcedo EE.
gists, Society for Cardiovascular Angiography and Interventions, Soci- Long-term follow-up of patients with left ventricular outflow tract ob-
ety of Thoracic Surgeons, Bonow RO, Carabello BA, et al. ACC/AHA struction after Carpentier ring mitral valvuloplasty. Circulation. 1998;
2006 guidelines for the management of patients with valvular heart dis- 78(3 Pt 2):I60-5.
ease: a report of the American College of Cardiology/American Heart 20. Carpentier AF, Lessana A, Relland JY, Belli E, Mihaileanu S,
Association Task Force on Practice Guidelines (writing committee to re- Berrebi AJ, et al. The ‘‘physio-ring’’: an advanced concept in mitral
vise the 1998 Guidelines for the Management of Patients With Valvular valve annuloplasty. Ann Thorac Surg. 1995;60:1177-86.
Heart Disease): developed in collaboration with the Society of Cardio- 21. Fornes P, Heudes D, Fuzellier JF, Tixier D, Bruneval P, Carpentier A.
vascular Anesthesiologists: endorsed by the Society for Cardiovascular Correlation between clinical and histologic patterns of degenerative
Angiography and Interventions and the Society of Thoracic Surgeons mitral valve insufficiency: a histomorphometric study of 130 excised
[Published erratum appears in Circulation. 2007;115(15):e409]. Circu- segments. Cardiovasc Pathol. 1999;8:81-92.
lation. 2006;114:e84-231. 22. Gazoni LM, Fedoruk LM, Kern JA, Dent JM, Reece TB, Tribble CG,
2. Adams DH, Anyanwu AC, Rahmanian PB, Filsoufi F. Current concepts et al. A simplified approach to degenerative disease: triangular resections
in mitral valve repair for degenerative disease. Heart Fail Rev. 2006;11: of the mitral valve. Ann Thorac Surg. 2007;83:1658-65.
241-57. 23. Anyanwu AC, Adams DH. The intraoperative ‘‘ink test’’: a novel assess-
3. Braunberger E, Deloche A, Berrebi A, Abdallah F, Celestin JA, ment tool in mitral valve repair. J Thorac Cardiovasc Surg. 2007;133:
Meimoun P, et al. Very long-term results (more than 20 years) of valve 1635-6.
repair with Carpentier’s techniques in nonrheumatic mitral valve insuf- 24. Adams DH, Anyanwu AC. Pitfalls and limitations in measuring and in-
ficiency. Circulation. 2001;104(12 Suppl):I8-11. terpreting the outcomes of mitral valve repair. J Thorac Cardiovasc
4. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Barwolf C, Surg. 2006;131:523-9.
Levang OW, et al. A prospective survey of patients with valvular heart 25. Bridgewater B, Hooper T, Munsch C, Hunter S, von Oppell U,
disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Livesey S, et al. Mitral repair best practice: proposed standards. Heart.
Eur Heart J. 2003;24:1231-43. 2006;92:939-44.
5. Savage EB, Ferguson TB Jr, DiSesa VJ. Use of mitral valve repair: anal-
ysis of contemporary United States experience reported to the Society of
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75:820-5. Discussion
6. Suri RM, Schaff HV, Dearani JA, Sundt TM 3rd, Daly RC, Mullany CJ,
et al. Survival advantage and improved durability of mitral repair for
Dr Aidan A. Raney (Newport Beach, Calif). I enjoyed this presen-
leaflet prolapse subsets in the current era. Ann Thorac Surg. 2006;82: tation very much. Dr McCarthy is making a major contribution. As
819-26. he mentioned, the repairability rate of valves in this country is in the

80 The Journal of Thoracic and Cardiovascular Surgery c July 2008


McCarthy et al Surgery for Acquired Cardiovascular Disease

40% to 50% range. However, if the most complex valves with ex- height of the anterior and posterior leaflets and we can then prescribe
cessive tissue are included, the overall repairability rate is probably the right sized ring.
going to be significantly lower, maybe in the 30% range. This device Dr Raney. We have used this ring now in 8 cases, and I have
is a tremendous advance. Not only does it simplify the procedure but been very impressed with the efficacy and the efficiency of the ring.
it also reduces the risk of SAM. Dr Michael Mack (Dallas, Tex). Dr McCarthy, do you have any
When we looked at our series of over 200 patients about 11/2 years experience using this ring with artificial chords and does that make
ago, we also had about a 5% incidence of SAM that required a sec- sense?
ond pump run and correction. Dr McCarthy. I think it makes sense. I do not really use artificial

ACD
I have a few questions for you. In your series, are you repairing chords very much. I am still pretty classic and I do chordal transfer.
all the myxomatous valves with the Myxo-ETlogix ring or do you However, some surgeons are using artificial chords with the ring. If
have a sense of certain valve characteristics that would preclude artificial chords are used on the posterior leaflet where there is an
using this device? elongated P2 segment that is not being replaced, I think this would
Dr McCarthy. Right now, we look at the leaflet and annulus make sense, because otherwise, as you could see from the AP diam-
size. In the majority of these patients with myxomatous leaflets, eter, a 40-mm Physio ring is not nearly big enough for that group of
something is elongated. The valves do not always fall into that cat- patients.
egory of fibroelastic deficiency, so that it may be an elongated ante- Dr Mack. Is this ring generally available?
rior leaflet but not a very elongated posterior, or the other way Dr McCarthy. It is in the United States now.
around. I use the Physio ring when the remaining valve is normal: Dr Jen-Ping Chang (Kaohsiung, Taiwan). We all know that
the anterior leaflet, P1 and P3, are normal, and we have resected Professor Carpentier repairs the Barlow valves by banding the septal
the abnormal part, which is usually a flail involving P2. portion of the classic ring anteriorly, and we know your ring is just
Dr Raney. Do you think that there is less modification of the like bending the posterior portion of the ring posteriorly. What is the
annulus with this device, that is, without quadrangular resection and difference between the anterior displacement and the posterior
a plication of the posterior annulus? Because sizing can be a prob- displacement of this ring?
lem, do you think that transesophageal echocardiography before Dr McCarthy. The anterior displacement that Dr Carpentier
the repair will provide a good indication of what size of a Myxo- does periodically is variable: he could bend it just a little bit or he
ETlogix ring to use? could bend it quite a bit. It seemed to us most of the reduction should
Dr McCarthy. We are collecting a big database on our MV be more posterior rather than anterior, and so when we designed the
repairs, and we are also going to correlate it with what echocardiog- ring, that is where we put it. Also, remember on the classic ring when
raphy measures. So far, it looks very good. When we measure A2 at Dr. Carpentier bends it that way, that is the only place he can bend it
29 mm, the echocardiographer measures it at roughly the same. We because that is where the break is in the ring. So it is the only part
hope to get to a point where the echocardiographer can identify the that is practical.

The Journal of Thoracic and Cardiovascular Surgery c Volume 136, Number 1 81


Point Seventeen

17) April 2009, US Trademark Office Directions for the use DETlogix Model 5100, See DFU. FDA 510k
clears device. 27 MAUDE Events related to the model 5100 including 2 deaths, 2 heart attacks
and reoperations.
PTO Form 1553 (Rev 9/2005)
OMB No. 0651-0054 (Exp. 09/30/2011)

Trademark/Service Mark Statement of Use


(15 U.S.C. Section 1051(d))

The table below presents the data as entered.

Input Field Entered


SERIAL NUMBER 78952900
LAW OFFICE ASSIGNED LAW OFFICE 113
NOTICE OF ALLOWANCE YES
EXTENSION OF USE NO
REQUEST TO DIVIDE NO
MARK SECTION
STANDARD CHARACTERS YES
USPTO-GENERATED IMAGE YES
LITERAL ELEMENT MYXO ETLOGIX
OWNER SECTION (no change)
ATTORNEY SECTION (current)
NAME Debra D. Condino
FIRM NAME EDWARDS LIFESCIENCES LLC
STREET 1 EDWARDS WAY
CITY IRVINE
STATE California
POSTAL CODE 92614-5688
COUNTRY United States
PHONE 949-250-6832
FAX 949-250-6850
ATTORNEY SECTION (proposed)
NAME Rajiv Yadav
FIRM NAME EDWARDS LIFESCIENCES LLC
STREET 1 EDWARDS WAY
CITY IRVINE
STATE California
POSTAL CODE 92614-5688
COUNTRY United States
PHONE 949-250-6832
FAX 949-250-6850
GOODS AND/OR SERVICES SECTION
INTERNATIONAL CLASS 010
CURRENT IDENTIFICATION Medical device, namely annuloplasty ring
GOODS AND/OR SERVICES KEEP ALL LISTED
FIRST USE ANYWHERE DATE 01/24/2007
FIRST USE IN COMMERCE DATE 01/24/2007
\\TICRS2\EXPORT14\789\529
SPECIMEN FILE NAME(S)
\78952900\xml2\SOU0002.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0003.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0004.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0005.JP G

\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0006.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0007.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0008.JP G
\\TICRS2\EXPORT14\789\529
\78952900\xml2\SOU0009.JP G
SPECIMEN DESCRIPTION Product insert brochure
PAYMENT SECTION
NUMBER OF CLASSES 1
SUBTOTAL AMOUNT 100
TOTAL AMOUNT 100
SIGNATURE SECTION
SIGNATURE /Rajiv yadav/
SIGNATORY'S NAME Rajiv Yadav
SIGNATORY'S POSITION Attorney
DATE SIGNED 10/30/2007
FILING INFORMATION
SUBMIT DATE Tue Oct 30 18:12:35 EDT 2007
USPTO/SOU-216.65.215.213-
20071030181235361102-7895
TEAS STAMP 2900-4001a546d89e48e789fc
7aab31d8cf19a7a-DA-4313-2
0071030180324439406
PTO Form 1553 (Rev 9/2005)
OMB No. 0651-0054 (Exp. 09/30/2011)

Trademark/Service Mark Statement of Use


(15 U.S.C. Section 1051(d))
To the Commissioner for Trademarks:

MARK: MYXO ETLOGIX


SERIAL NUMBER: 78952900

This Allegation of Use is being filed after a Notice of Allowance has issued.

The applicant, Edwards Lifesciences Corporation, having an address of One Edwards Way, Irvine,
California United States 92614, is using or is using through a related company or licensee the mark in
commerce on or in connection with the goods and/or services as follows:

For International Class 010:


Current identification: Medical device, namely annuloplasty ring

The applicant, or the applicant's related company or licensee, is using the mark in commerce on or in
connection with all goods and/or services listed in the application or Notice of Allowance or as
subsequently modified.

The mark was first used by the applicant, or the applicant's related company, licensee, or predecessor in
interest at least as early as 01/24/2007, and first used in commerce at least as early as 01/24/2007, and is
now in use in such commerce. The applicant is submitting one specimen for the class showing the mark as
used in commerce on or in connection with any item in the class, consisting of a(n) Product insert
brochure.
Specimen File1
Specimen File2
Specimen File3
Specimen File4
Specimen File5
Specimen File6
Specimen File7
Specimen File8

The applicant hereby appoints Rajiv Yadav of EDWARDS LIFESCIENCES LLC, 1 EDWARDS WAY,
IRVINE, California United States 92614-5688 to submit this Trademark/Service Mark Statement of Use
on behalf of the applicant.

A fee payment in the amount of $100 will be submitted with the form, representing payment for 1 class.

Declaration

Applicant requests registration of the above-identified trademark/service mark in the United States Patent
and Trademark Office on the Principal Register established by the Act of July 5, 1946 (15 U.S.C. Section
1051 et seq., as amended). Applicant is the owner of the mark sought to be registered, and is using the
mark in commerce on or in connection with the goods/services identified above, as evidenced by the
attached specimen(s) showing the mark as used in commerce.

The undersigned being hereby warned that willful false statements and the like are punishable by fine or
imprisonment, or both, under 18 U.S.C. Section 1001, and that such willful false statements and the like
may jeopardize the validity of this document, declares that he/she is properly authorized to execute this
document on behalf of the Owner; and all statements made of his/her own knowledge are true and that all
statements made on information and belief are believed to be true.

Signature: /Rajiv yadav/ Date Signed: 10/30/2007


Signatory's Name: Rajiv Yadav
Signatory's Position: Attorney

Mailing Address:
EDWARDS LIFESCIENCES LLC

1 EDWARDS WAY
IRVINE, California 92614-5688

Mailing Address:
EDWARDS LIFESCIENCES LLC

1 EDWARDS WAY
IRVINE, California 92614-5688

RAM Sale Number: 4313


RAM Accounting Date: 10/31/2007

Serial Number: 78952900


Internet Transmission Date: Tue Oct 30 18:12:35 EDT 2007
TEAS Stamp: USPTO/SOU-216.65.215.213-200710301812353
61102-78952900-4001a546d89e48e789fc7aab3
1d8cf19a7a-DA-4313-20071030180324439406
Point Eighteen

18) FDA confirms to Vlahoulis in July 2009, the Myxo ETlogix is significant risk and considered under an
IDE.
Point Nineteen

19) September 25, 2014 William Knotts Surgery results in Severe Mitral Stenosis Short of Breath
Point Twenty

20) June 1, 2018 William Knotts undergoes surgery to replace the mitral valve and discovery of severe
stenosis with the anterior leaflet sewn shut to the ring. 174 day hospitalization which ends with his
death at Northwestern Memorial Hospital.
Point Twenty-One

21) All patients listed in this chronology underwent protocol 1532-004 sizing method with the experimental
calipers, and not the DFU as listed in the Edwards Lifesciences Documents.
Point Twenty-Two

22) Meeting with FDA December 19, 2018 at noon to discuss the experimental calipers, and outcomes for
patients who received the calipers and not the established Directions for use as listed in Edwards
Lifesciences manufactured Rings.
Point Twenty-One

21) All patients listed in this chronology underwent protocol 1532-004 sizing method with the experimental
calipers, and not the DFU as listed in the Edwards Lifesciences Documents.
Point Twenty-Two

22) Meeting with FDA December 19, 2018 at noon to discuss the experimental calipers, and outcomes for
patients who received the calipers and not the established Directions for use as listed in Edwards
Lifesciences manufactured Rings.
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 1

Edwards Myxo ETlogix Annuloplasty Ring

Implantation Techniques
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 1

The Myxo ETlogix Annuloplasty Ring

Myxomatous disease is characterized by


elongated, thickened leaflets that result in
leaflet billowing, annular dilatation, ruptured
chords and mitral regurgitation (MR).1

Mitral valve repair for this patient restores


the normal survival curve while avoiding the
limitations of mechanical valve replacement.2

The Myxo ETlogix ring moves the posterior


leaflet inferiorly thereby reducing the
reconstruction required to decrease the
posterior leaflet height.3

The Myxo ring also extends the posterior


leaflet up and away from the left ventricular
outflow tract (LVOT) mitigating systolic
anterior motion (SAM) and LVOTO.3

1
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 2

IMPLANTATION TECHNIQUES

Mitral Valve Assessment

A2
Each valve segment is compared to P1 A3
A1

P1 P3
P2

Removal of Myxomatous P2

Good chords are isolated with suture and


the segment for resection is identified.

The quadrangular resection is performed.

2
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 3

Reduction of Resection Gap

Compression sutures are used to reduce the


resection width. Typically, this technique is
only required if the resection is (greater than
or equal to symbol) 10 mm in width.

A pledgeted plication is used to


reapproximate P1 to P3.

3
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 4

Water Test

Suture Placement for Annuloplasty

2.0 multifilament mattress sutures are placed


in the annulus 2 mm from the junction of the
leaflet and the annulus. Sutures are directed
toward the ventricle and back out to avoid
the circumflex artery and incorporate the
maximum amount of fibrous annulus. Each
suture bite is approximately 1 cm in length.

4
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 5

Sizing

The ring may be selected by measuring the


height and/or area of the anterior leaflet
with the mitral sizers

Double Check the length of the sizer generally


corresponds to the AP (anterior-posterior)
distance of the Myxo ring.

5
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 6

The annuloplasty ring is lowered on the


holder down into the heart. Proper orientation
with the natural physiology of the annulus
should be achieved to ensure optimal
ring-to-annulus fit.

The competency of the valve is checked


by distending the left ventricle with saline.
Repair is judged satisfactory if the line of
the leaflet closure is parallel to the mural
portion of the ring, indicating good
apposition of the leaflets.

6
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 7

BACKGROUND

Normal Mitral Valve Orifice

• In a normal mitral valve orifice, the angle


between the aortic annulus and the mitral
annulus is wide open and the flow during
diastole is oriented towards the apex

• Because of the optimal proportion between


the amount of leaflet tissue and the orifice
area, the line of closure of the leaflets is far
from the left outflow tract

7
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 8

Risk Factors for Systolic Anterior Motion (SAM) and


Left Ventricular Outflow Tract Obstruction (LVOTO)

Primary Risks
• Excess tissue of the posterior leaflet represents the main risk for SAM and LVOTO

• As a result, the posterior leaflet closes before the anterior leaflet and pushes it
towards the left ventricular outflow tract (LVOT)

• The coaptation line is therefore displaced towards the LVOT

Secondary Risks
• The mitroaortic angle is narrower than normal

• The left ventricle is small

After valve repair and annuloplasty, the large


posterior leaflet closes before the anterior
leaflet and pushes it towards the left outflow
tract, thus producing SAM.

Characteristic appearance of a mitral valve


repair with SAM – the line of closure is
displaced towards the left outflow tract.

8
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 9

Carpentier Technique for Preventing SAM:


“The Sliding Leaflet Technique“

In case of excess tissue of the mural leaflet, the quadrangular resectionused to correct the
prolapse must be completed by two triangular resections of the posterior leaflet remnants
to correct excess tissue.

The resection of both the prolapsed area and


excess tissue of the mural leaflet remnants.

Resection has been completed.

Mattress sutures are passed through


the annulus.

9
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 10

Traction on the mattress sutures allows


for circumferential reduction in the size
of the annulus. Traction on the leaflet
remnants permits adjustment of the
leaflets to the annulus.

The anterior remnant of the posterior leaflet


is sutured to the annulus.

10
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 11

After the posterior remnant has been sutured


to the annulus, leaflet continuity is restored
by inverted sutures.

A prosthetic ring is used in order to remodel the


annulus. This provides an optimal orifice area, a
normal geometry of both the valve orifice and the
line of closure, a reduction of the stress on the
sutures and stable reconstruction.

11
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 12

Other Techniques to Remove Myxomatous P2

Quadrangular Resection

Trapezoidal Resection

Triangular Resection

12
06 ED Myxo Implant AR02209 3/19/07 2:54 PM Page 13

The techniques described here in are the techniques used by Patrick M. McCarthy,
MD, and Alain Carpentier, M.D. Edwards Lifesciences does not endorse any
particular surgical technique.

Patrick M. McCarthy, MD is a paid consultant to Edwards Lifesciences. Additionally,


he receives royalties for the Myxo ETlogix annuloplasty ring.

Rx only. See instructions for use for full prescribing information.

REFERENCES Edwards Lifesciences devices placed on the European market meeting the essential
1. Perier P, et al. Valve repair for mitral regurgitation caused by isolated requirements referred to in Article 3 of the Medical Device Directive 93/42/EEC bear
prolapse of the posterior leaflet. Ann Thorac Surg 1997;64(2):445-50. the CE marking of conformity.
2. Braunberger E, et al. Very long-term results (more than 20 years) of
valve repair with Carpentier's techniques in nonrheumatic mitral Edwards and Myxo ETlogix are trademarks of Edwards Lifesciences Corporation.
valve insufficiency. Circulation 2001;104(12 Suppl 1):8-11. Edwards Lifesciences and the stylized E logo are trademarks of Edwards Lifesciences
3. Maslow AD, et al. Echocardiographic predictors of left ventricular Corporation and are registered in the U.S. Patent and Trademark Office.
outflow tract obstruction and systolic anterior motion of the mitral
valve after mitral valve reconstruction for myxomatous valve disease. © 2007 Edwards Lifesciences LLC.
J Am C Cardio 1999;34(7):2096-104. All rights reserved. AR02209

Edwards Lifesciences LLC · One Edwards Way · Irvine, CA 92614 USA · 949.250.2500 · 800.424.3278 · www.edwards.com
Edwards Lifesciences (Canada) Inc. · 1290 Central Pkwy West, Suite 300 · Mississauga, Ontario · Canada L5C 4R3 · 905.566.4220 · 800.268.3993
Edwards Lifesciences S.A. · Ch. du Glapin 6 · 1162 Saint-Prex · Switzerland · 41.21.823.4300
Edwards Lifesciences Japan · 2-8 Rokubancho · Chiyoda-ku, Tokyo 102-0085 · Japan · 81.3.5213.5700