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Most Sacred Heart of Jesus Cardiology and Valvular Institute

Nalini M. Rajamannan, MD, FACC


Visiting Scientist Mayo Clinic Telephone 920-451-4611
703 N 8th St Suite 303 Fax 920-451-4611
Sheboygan, WI
www.SacredCardiology.com

February 10, 2020

Honorable Senator Charles Grassley


President Pro Tempore
Chairman of the Senate Finance Committee
219 Dirksen Senate Office Building
Washington, DC 20510-6200

Dear Honorable Senator Grassley,

Today, February 10, 2020, I plan to update you on the missing evidence regarding concealment to the Senate
Finance Committee after you initiated an investigation on December 4, 2008 to help the thousands of US
Citizens who receive benefits from Medicare and Medicaid, and who rely on the FDA to have oversight of
medical devices placed in their hearts during surgery.

I am presenting evidence from the Illinois Supreme Court statements made by the Northwestern University
attorneys regarding the FDA status of the McCarthy Myxo Ring Model 5100. The status of the device was
the central focus of your Senate Investigation on December 4, 2008 on behalf of the hundreds of patients
who unknowingly received the device without consent, without FDA approval and without pre-authorization
from Medicare and Medicaid.

The attorneys claimed to the Illinois Supreme Court on December 6, 2019, and the Appellate court of Illinois
on June 13, 2019, that the device was “FDA approved” based on a two line email sent to the University from
the Edwards Lifesciences, Irvine CA, in 2007.

In 2009, the FDA confirmed in a letter sent to you the Chairman of the Senate Finance committee that the
device was never approved prior to March 4, 2009, and in fact was on recall as of December 5, 2008.

The 667 patients who received the device prior to the March 4, 2009 FDA determination, still do not know
that they received the McCarthy Myxo ETlogix Ring Model 5100 prior to FDA approval without Medicare
and Medicaid pre-authorization to use a non-approved FDA device, as reported by the FDA to Senator
Richard Lugar on November 5, 2009.

In fact, Congressman Glenn Grothman received a letter from the FDA in 2017 confirming the fact that the
FDA was not planning to inform patients, as the FDA representatives in the letter stated that:

“did not believe that notification would not provide a benefit to patients and instead could unnecessarily
alarm patients and raise unwarranted concerns. Therefore, FDA did not mandate the company to notify all
patients who received the device prior to is April 2009 clearance.”
FDA to Congressman Glenn Grothman on July 6, 2017, Congressman for Sheboygan WI

Furthermore, the FDA again wrote another patient on July 16, 2009, Ms. Antonitsa Vlahoulis stating that the
version of the Model 5100 the McCarthy Myxo Ring placed in her heart, is still considered investigational
and that Senator Richard Durbin would be contacting her on behalf of then Senator Barack Obama. The
patient is still waiting for a meeting with Senator Durbin. This letter arrived three months after the FDA
provided a 510(k) clearance for the Model 5100 with the new name and new indication, DEtlogix. This letter
confirms that the FDA never approved the device central to the Senate Finance Investigation, the Myxo
ETlogix Model 5100.

I am confident that this evidence of ongoing concealment of the status of the device from the patients by the
FDA/the hospital/the University and the device manufacturer will confirm that the device was tested in
patients and published without consent and without FDA authorization, in violation of the federal code.
46CFR45, and 21CFR820.30 federal laws require immediate notification of the surgical placement of
significant risk heart devices and immediate informed consent for the patients who were part of the research
and development study published in the leading journal for the American Association of Thoracic Surgeons,
in July of 2008.

Many of the patients have suffered significant injuries as outlined in the student newspaper, The Daily
Northwestern in May 23, 2019.

Only one patient was acknowledged by Northwestern University’s IRB after Dr. Edwards requested
information. In their response the University’s IRB under the FWA 1549, which is the human subject
assurance for protections, failed to report to Dr. Edwards that the device was never FDA approved and was
placed on recall as of December 2008. Again, furthering the ongoing concealment of evidence which is a
failure of the FWA 1549 to at least one patient.

I have attached the letter to the Illinois Supreme Court(12-6-2019), the FDA Congressional letter(3-2009)
and the published Daily Northwestern Story on the patients’ injuries and the other letters cited in this letter.

I hope that this evidence is enough to request the FDA, the hospital, the University and the device
manufacturer to inform the patients of the unauthorized human experiment.

Thank you for your hard work on behalf of the citizens of the United States of America.

Respectfully,

Nalini M. Rajamannan, MD
Most Sacred Heart of Jesus Cardiology and Valvular Institute
Corvita Valve Director
Visiting Scientist Mayo Clinic Biochemistry and Molecular Biology

Attachments in order : Northwestern University Letter to Illinois Supreme Court dated 12-6-2019
FDA Letter to Senator Charles Grassley dated 3-4-2009
FDA letter to Antonitsa Vlahoulis dated 7-16-2009
FDA letter to Senator Richard Lugar
FDA Letter to Congressman Glenn Grothman 7-6-2017
The Daily Northwestern May 23, 2019 publication
Unauthorized FDA study published in JTCVS the Myxo ETlogix human clinical trial
7-2008
Northwestern IRB letter to Dr. Al Edwards 6-17-2011
Edwards Lifesciences Recall sent to hospitals 12-5-2008
Senate Finance Investigation began 12-4-2008
DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration


Silver Spring, MD 20993

The Honorable Charles E. Grassley 4 MAR 2009


Ranking Member
Committee on Finance
United States Senate
Washington, D.C. 20510-6200

Dear Senator Grassley:

Thank you for your letter of December 3,2008, concerning the status with the Food and
Drug Administration (FDA or the Agency) of the model 5100 McCarthy Myxo ETlogix
Annuloplasty Ring for use in heart valve repair, manufactured by Edwards Lifesciences
LLC (Edwards). Below we have repeated the questions from your letter, followed by the
Agency's responses.

1. Has the FDA received any information and/or a 510(k) application from
Edwards regarding the Myxo Ring? Has the FDA ever reviewed this device.
for marketing? If so, what was FDA's decision regarding this device?

As Edwards has revealed publicly, they submitted a 5l0(k}to FDA in October, notifying
us of their intent to market the dETlogix (formerly called the Myxo ETlogix)
Annuloplasty Ring. FDA received thls submission on October 29,2008. FDA is
currently in the process of reviewing the submission.

2. According to Edwards' email to Dr. McCarthy, the Myxo Ring "is a minor
modification of model 4200, GeoForm Annnloplasty Ring." Did EdwardS
report that modification to the FDA? If so, on what date, to whom and how
was that information communicated to the Agency?

In a letter dated August 15, 2008, Edwards notified the Agency that they were indeed
marketing the Myxo ETlogix Annuloplasty Ring. The letter stated their belief that the
Myxo ETlogix was substantially equivalent to the Edwards GeoForm, Model 4200, and
Carpentier-Edwards Physio, Model 4450, Annuloplasty Rings, and that the Myxo Ring
represented only a minor modification to the predicate rings. This letter was addressed to
William MacFarland, Acting Chief of the Cardiovascular and Neurological Devices
Branch in the Office of Compliance (OC) of FDA's Center for Devices and Radiological
Health (CDRH).

3. Based on the information the Committee has received to date, the Myxo Ring
is not being used under an IDE. If it is in fact a device that has not been
Page 2 - The Honorable Charles E. Grassley

approved or cleared by the FDA, please explain whether or not implantation of


this device should be conducted under an IDE.

FDA has now determined that the Myxo ETlogix Annuloplasty Ring is not covered under
any 51 O(k) clearance. A significant risk device such as the Myxo ETlogix Annuloplasty
Ring that is not cleared or approved would be required to be studied under an
investigational device exemption (IDE). Edwards has not yet received 51O(k) clearance
or IDE approval for the Myxo ETlogix Annuloplasty Ring. The sponsor came in for a
regulatory meeting with CDRH's OC on October 14, 2008. At this meeting, the sponsor
stated that their firm had discontinued distribution of the device. Shortly thereafter,
Edwards submitted the 510(k), which FDA received on October 29,2008. Edwards also
stated publicly in October 2008 that the firm had discontinued distribution of the device.

4. According to an email from Ms. Vlahoulis to Don Workman at Northwestern,


dated October 19, 2008, the patient stated that she sent a report to the FDA
and the "FDA acknowledged to me that they never approved this ring and that
they are investigating this situation." See attached. I would appreciate a
brief"mg for my Committee staff as soon as the FDA concludes its investigation.

The information provided to Ms. Vlahoulis did not, as the quotation suggests, include the
clearance status of the Myxo ETlogix Annuloplasty Ring. As noted in our response to #1
above, the Agency received the 510(k) submission on October 29, 2008, and is in the
process of reviewing it.

5. FDA's website states that a 510(k) is required when "There is a change or


modification of a legally marketed device and that change could significantly
affect its safety or effectiveness. The burden is on the 510(k) holder to decide
whether or not a modification could significantly affect safety or effectiveness
of the device."

a. What type of reporting is required of 510(k) holders when they make


modifications to their devices?

A 51O(k) holder may make a modification to a device without filing a new 51O(k) after
concluding that the change does not significantly affect the safety or effectiveness of the
device or constitute a major change in the intended use of the device. Sponsors may refer
to FDA's 510(k) memorandum (dated January 10,1997) "Deciding When to Submit a
510(k) for a Change to an Existing Device" for assistance in determining whether
changes to a device require a new 51 O(k). This document
(http://www.fda.gov/cdrhlode/51Okmod.html) includes a flowchart to help manufacturers
through the logic scheme necessary to arrive at a decision on when to submit a 51O(k) for
a change to an existing device. The flowchart addresses labeling changes, technology or
performance specifications changes, and materials changes. This document recommends
that, if a sponsor concludes that a new 510(k) is not required, the sponsor should
document the analysis and file it for future reference. The following text is taken from
the definitions section of the FDA memorandum:
Page 3 - The Honorable Charles E. Grassley

For the purpose of this guidance, documentation means recording the results of applying the
model to proposed changes in a device. Consideration of each decision point should be recorded,
as well as the final conclusions reached. If testing or other engineering analysis is part of the
process, the results ofthis activity should be recorded or referenced. A copy of this documentation
should be maintained for future reference.

It should be noted that no formal reporting by the 51 O(k) holder to the Agency is required
ifthe sponsor concludes that a given change does not require a new 51O(k). However, a
5l0(k) holder is required to maintain the documentation and make it available to FDA
during an inspection.

b. How does FDA ensure that the StOCk) holder has made the appropriate
decision regarding whether or not to submit a StOCk) when the holder
makes modifications to a legally marketed device?

As stated above, the 51O(k) holder is not required to formally notify FDA after
concluding that a given change does not require a 51 O(k). Therefore, the Agency does
not have the opportunity to evaluate that decision in advance to determine if it was
appropriate. However, the Agency educates sponsors about how to make the correct
decision in this regard, e.g., the 51 O(k) memorandum referenced above. This document
provides guidance and decision flowcharts for the sponsor to use when making these
decisions. Furthermore, a 51O(k) holder is required to maintain records and make them
available during an inspection.

As mentioned in the FDA memorandum, there are bound to be some changes that fit into
a "gray area" as to whether a new 51 O(k) submission is required. In these cases, sponsors
are encouraged to contact the Agency if they have questions regarding the
appropriateness of a 51 O(k). Lastly, although a sponsor may conclude that a particular
change does not require a 5l0(k), the sponsor may subsequently make additional changes
to the same device that do require a new 51O(k). When this occurs, sponsors are required
to submit a 51 O(k) incorporating all the changes that have been made to the device since
clearance of the most recent 51O(k) for the device.

Thank you again for your interest in this matter. If we can be of further assistance, please
let us know.

y,

Stephen R. Mason
Acting Assistant Commissioner
for Legislation
The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

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In Focus: Years after surgery,


new documents renew
patients’ malpractice claims
against Northwestern
Memorial doctor
Amy Li (https://dailynorthwestern.com/staff_profile/amy-li-
development-and-recruitment-editor/), Web Editor
May 23, 2019
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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

Thirteen years ago, Northwestern Memorial Hospital’s renowned cardiac surgeon Patrick
M. McCarthy began operating on his patients’ hearts using a new invention.

McCarthy designed the Myxo-ETlogix 5100 annuloplasty ring, devised to treat the most
common form of heart disease, called “myxomatous mitral valve disease.”

The mitral valve regulates blood flow from one chamber of the heart to another. The
disease is characterized by lengthened or thickened leaflets that prevent the mitral valve
from opening and closing smoothly. If left untreated, small amounts of blood can leak
backward into the valve as the heart pumps, which could lead to complications like a heart
murmur, stroke or death. An annuloplasty ring reinforces and repairs the heart valve.

McCarthy’s annuloplasty ring was designed to improve his patients’ health, but just years
later, his invention was in deep water — it had faced a U.S. Food and Drug Administration
rebuke and several lawsuits from patients alleging the surgeon performed human trials for
the ring without their consent. It has also been subject to investigations by the FDA and
U.S. Senate, both of which ultimately fizzled out.

Former patients and their families said what they thought was a straightforward, one-time
operation led to years of heart problems. They’ve been waiting for a legal response in their
favor for over a decade.

Now, former patient Maureen Obermeier is trying her hand again.

In February, Obermeier filed a petition to overturn the dismissal of her 2008 lawsuit, which
alleged poor medical treatment by McCarthy. The petition is based on new information
revealed through a Freedom of Information Act request showing that, at the time of her
2006 surgery, McCarthy’s annuloplasty ring was not FDA-approved and the surgeon was
not given permission from Northwestern’s Institutional Review Board to operate with it.

The lawsuit names McCarthy, Northwestern Memorial, Edwards Lifesciences and


Northwestern Medical Group — formerly known as Northwestern Medical Faculty
Foundation — as defendants.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

“This started in 2006,” Obermeier said. “Now it’s 2019, and we’re still fighting the same
fight.”

Regulatory loopholes

During the initial stages of the ring’s development, its manufacturer, Edwards
Lifesciences, benefited from a FDA regulatory loophole that allowed it to skip the stringent
review process typically required for a potentially life-threatening device like an
annuloplasty ring.

The FDA categorizes


medical devices into three
groups based on increasing
risk to patients: Class I, II
and III. Devices classified
under Class III “support or
sustain human life, are of
substantial importance in
preventing impairment of
human health, or which
present a potential,
unreasonable risk of illness
or injury,” according to the
FDA. Common Class III
devices include implantable
(https://dailynorthwestern.com/wp-content/uploads/2019/05/Ring20140515.jpg)
pacemakers and breast
The McCarthy Annuloplasty Ring Model 5100.
implants. The FDA requires
Class III devices to undergo
the more rigorous “premarket approval,” which is the only route that requires clinical
testing.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

But in 2001, the Advanced Medical Technology Association successfully petitioned to


lower annuloplasty rings from Class III to Class II. The reclassification allowed McCarthy’s
invention to bypass “premarket approval” and go through a less rigorous process for FDA
approval.

When a device is similar enough to another previously FDA-approved model, the


manufacturer can claim “substantial equivalence” to forgo federal regulatory processes
altogether.

Edwards Lifesciences — for which McCarthy works as a consultant — said his invention
was similar enough to other annuloplasty rings, despite claiming 40 unique characteristics
on its patent application to the U.S. Patent and Trademark Office.

Companies like Edwards Lifesciences have received intense backlash from medical
professionals for using the loophole. They say similar models do not guarantee the same
safety or effectiveness.

McCarthy and Edwards Lifesciences did not respond to requests for comment.

After multiple patient allegations that the ring implant they had received had not
undergone FDA approval, a U.S. Senate investigation prompted a FDA rebuke that
required the ring to be submitted for Class II approval. The FDA disagreed with the
manufacturer’s original claim that the new ring was similar enough to past devices.

The application for FDA clearance was submitted in 2008 and in April 2009, the ring had
been cleared under a different name: the dETlogix annuloplasty ring 5100.

By that time, McCarthy was already three years into patient trials.

Pending lawsuit

One of those patients was Obermeier, who received the ring implant during her 2006
mitral valve repair at Northwestern Memorial. She called her surgery “the worst
experience” of her life.

“I felt so sick post-surgery, I could barely get out of bed,” she said.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

Northwestern Memorial also could not offer her an explanation, she said, and she begged
to be released because she felt so ill.

When her new cardiologist at the Advocate Christ Medical Center in Oak Lawn, Illinois,
asked her about the surgery, Obermeier said she wasn’t aware of any complications. The
only way she was able to find out was by requesting her medical records from
Northwestern Memorial.

After reviewing her hospitalization charts from 2006, the cardiologist found elevated
troponin values and concluded she suffered a heart attack during her surgery and multiple
episodes of cardiac arrest within 24 hours of the operation, Obermeier said.

Obermeier said McCarthy assured her that her surgery went smoothly, she received no
medical follow-up and was administered no treatment for her heart attack.

“He had nothing to say about what happened during the surgery,” Obermeier said of
McCarthy. “So it was like I got lied to.”

McCarthy later confirmed the heart attack in a 2011 court hearing and 2012 legal
deposition.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

A TIMELINE OF SOME OF PATRICK


MCCARTHY'S OPERATIONS — AND
THE FINDINGS THAT FOLLOWED !

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Timeline JS

After the surgery, Obermeier said she experienced multiple episodes of arrhythmia, or
irregular heartbeat. When she asked doctors at Advocate Christ to see if corrective
surgery was possible, she said they told her the severity of her heart attack damaged the
organ too greatly for additional operations.

Obermeier believes the experimental ring implantation and her untreated heart attack
contributed to her poor health post-surgery.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

“I didn’t have any answers until I had to file a lawsuit,” Obermeier said. “It’s scary that you
have to take your attorney with you just to get a surgery.”

Once she learned what happened during the procedure, Obermeier sued McCarthy,
Northwestern Memorial Hospital and Northwestern Medical Group in 2008. She alleged a
failure to adequately assess her cardiac status, as well as harm, damage and
traumatization to one or more of her coronary arteries.

Still, an Illinois state court jury ruled in favor of McCarthy and Northwestern Memorial-
affiliated defendants in April 2016, clearing him of allegations for negligence and operating
without informed consent.

Obermeier’s current lawsuit is based on a 2018 FOIA request filed by Nalini Rajamannan,
a cardiologist who formerly worked on McCarthy’s surgical team at Northwestern
Memorial.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

(https://dailynorthwestern.com/wp-
content/uploads/2019/05/pullquote2-
1.jpg)

Obermeier believes the FOIA


documents contain evidence proving
McCarthy guilty of performing
experiments without patient consent
and were kept secret by McCarthy
and Northwestern Memorial.

A FOIA to find more

With her FOIA request, Rajamannan


uncovered documents that she and
former patients believe are key to a
verdict in their favor.

Rajamannan, a former associate


professor at Northwestern’s
Feinberg School of Medicine, said she grew concerned with McCarthy’s surgical practices
after multiple patients, including Obermeier, came to her post-operation and said their
health problems were ignored by McCarthy.

That led to her challenging the ethics of McCarthy’s surgeries. She was denied tenure and
discharged from Northwestern, and in the time since, Rajamannan has worked with past
patients to seek legal action against the renowned Feinberg surgeon.

According to documents from her FOIA, the Northwestern Institutional Review Board — a
group responsible for protecting the rights and welfare of human subjects involved in
research at Northwestern — authorized McCarthy’s research on the ring in 2006. Its
understanding, documents show, was that his studies would be retrospective.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

That meant McCarthy was only authorized to review past medical records of patients who
had undergone mitral valve repair between April 2004 and June 2006. He was not granted
permission to operate with the Myxo ring.

However, The Daily obtained a 2005 Edwards Lifesciences document from Rajamannan
that recorded McCarthy’s input on the design of the ring at the initial stages of the device’s
development. The document said McCarthy intended to operate on at least 10 patients
with the prototype.

“Dr. McCarthy indicated that if the first 10 implants went well, he would feel comfortable
expanding the use of the device to other surgeons,” the document stated.

These operations were carried out without IRB approval and took place before McCarthy’s
IRB request to review past patient records.

When McCarthy filed a new request to expand his review into 2007 records, the board
determined his research was no longer retrospective and requested for additional
information. Instead of submitting details about his research to the IRB, he decided to
terminate it altogether.

In 2007 emails obtained by The Daily, a representative from McCarthy’s team confirmed to
the IRB that the research project would be closed.

“After further consideration, we have decided to terminate this project,” the email said. The
email also confirms that no research has been done since McCarthy’s approval for
retrospective reviews expired on June 27, 2007.

However, his 2008 publication in The Journal of Thoracic and Cardiovascular Surgery —
titled “Initial clinical experience with Myxo-ETlogix mitral valve repair ring” — stated that
“100 patients received the Myxo ring, which is a Food and Drug Administration-approved
ring.”

He had not been given permission to operate at the time, and the Myxo ring was not
cleared by the FDA until 2009.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

Obermeier believes she was one of the


patients whom McCarthy operated on after
the IRB’s expiration date.

Bringing it back to court

In light of the newly discovered findings,


Obermeier filed her current suit, alleging that
the defendants “concealed” information
during the 2008 trial.

Obermeier alleges her surgery proceeded


without informed consent — and after
McCarthy told the IRB he’d stop the research
after its request for additional information.
The IRB project Obermeier cited in her
petition was the medical record review
between April 2004 and June 2006 — but
she was operated on in November later that
(https://dailynorthwestern.com/wp-
year. content/uploads/2019/05/IFOneWEB.jpg)
Provided
In a March response, the defendants denied Patrick M. McCarthy, Nalini Rajamannan, and Robert
multiple claims Obermeier makes in the Bonow on the front cover of a 2007 Northwestern Memorial

ongoing suit, saying, they failed to see the Hospital cardiovascular review. Rajamannan, who used to
work with McCarthy, filed a FOIA in 2018 that Obermeier is
connection between the evidence cited and using in her new lawsuit.
Obermeier’s case due to gaps in the
timeline.

The defendants didn’t address Obermeier’s claim that she didn’t consent to McCarthy’s
human trials beyond the IRB-approved window of retrospective chart reviews.

Instead, they argued Obermeier has no claim to a suit because she had no involvement in
the 2004 to 2006 study she cited as evidence — and signed a consent form to take part in
a record of patient surgery outcomes.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

Northwestern-affiliated defendants cited Obermeier’s signature as evidence for informed


consent, but Obermeier said she wasn’t consenting to be implanted with an investigational
device.

Obermeier said she knew she was going to receive an annuloplasty ring, but McCarthy
never mentioned he invented the ring or that the ring had not undergone any federal
approval processes. The ring implant Obermeier received was called the “McCarthy
Annuloplasty Ring” on her device identifier card — it was the preclinical, rudimentary
version of the model that was later submitted for FDA clearance.

“There were many rings on the market at that time that had been used for years,”
Obermeier said. “I would never have agreed to what he did to me.”

In the defendants’ response, McCarthy maintained he used his invention during


Obermeier’s surgery because “he felt that it was the best device to address her problems.”

The defendants have the right to file a second motion within the next two weeks, and
Obermeier will have the right to file a response. Both sides will present arguments in an
appellate court on June 13.

Obermeier hasn’t been alone in filing legal challenges.

Former patient Antonitsa Vlahoulis, who claimed she was unaware until well after her
2006 operation that she was implanted with an experimental ring without her consent,
sued in 2008.

The lawsuit was ultimately dropped due to mounting legal fees. Vlahoulis filed a second
suit that was dismissed (https://dailynorthwestern.com/2014/05/16/top-stories/trial-of-the-
heart/) before it went to court.

A former patient’s death

Along with Obermeier’s ongoing suit, the recent death of one of McCarthy’s former
patients drew even more attention to his alleged wrongdoings.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

William Knotts received mitral valve repair


surgery with McCarthy in 2014. He died of
a stroke four years later on Nov. 22, 2018.

His son, Steven Knotts, remembers his


father before the surgery as one of the
healthiest people he knew. William Knotts
was an active man who, in his 70s, was
still able to go on skiing trips every year in
Colorado with his wife, his son said.

But after the surgery, Steven Knotts said


he watched his father grow progressively
weaker and face new health problems, like
lightheadedness and chronic low blood
pressure.

When his father reported his health


problems to McCarthy after the operation,
(https://dailynorthwestern.com/wp-
content/uploads/2019/05/IFThreeWEB.jpg) Steven Knotts said McCarthy assigned him
Provided by Steven Knotts a psychiatrist instead of running tests to
Lynne Knotts kisses her husband William Knotts on the determine the cause of his discomfort,
forehead after his corrective surgery. Doctors at Advocate
suggesting his health complications were
Christ Medical Center said a corrective surgery was needed
after William Knott’s 2014 procedure with McCarthy. “all in his head.”

The Knotts did not believe McCarthy’s


explanation, and with William Knotts’ condition worsening, his son and wife, Lynne Knotts,
felt they had no other choice but to try another hospital that might give them the answers
they needed.

After performing heart examinations at Advocate Christ Medical Center, his cardiologist
there found that William Knott’s mitral valve leaflet — a part of the heart valve that, when
functioning healthily, should be able to open and close freely — had been “crudely”

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

stitched closed.

McCarthy “thinks he can do whatever he wants and get away with it,” Steven Knotts said.

William Knotts was told he needed corrective surgery because of the stitching of the
leaflet and received the second operation at Advocate Christ in June 2018. Consecutive
surgeries weakened his heart before his death.

Knotts filed a Northwestern EthicsPoint complaint reporting suspected ethical misconduct


on behalf of his father in October. But Jay Walsh, Northwestern’s vice president for
research whose office oversees the IRB, said he said the University never received the
complaint, according to a 2018 email obtained by The Daily.

Lynne Knotts said she had asked for a face-to-face meeting with Walsh earlier this year,
but her request was never granted.

Walsh forwarded The Daily’s comment request to a University spokesman, who declined
to speak.

However, when he was presented with the released FOIA documents, Walsh said in a
email last year to the Knotts family that “there were no research interventions, device
testing, or experimental surgeries done as part of either of those studies.”

Finding a way forward

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

(https://dailynorthwestern.com/wp-
content/uploads/2019/05/Artboard-3-
copy.jpg)

For Obermeier, the Knotts family and


other patients who say they’ve been
hurt by McCarthy’s alleged human
trials, the FOIA documents represent
not only a legal pathway to
requesting another trial, but renewed
hope that something consequential
will finally come out of the years-long
fight.

“Everybody keeps protecting him,


circling the wagon,” Obermeier said.
“With this new evidence, it will be
much clearer what wrongs were
done to me and the other patients.”

Steven Knotts said he hopes McCarthy will receive some form of reprimand to make sure
nobody else is hurt in the future.

“The rules are black and white, and the violations are black and white,” Knotts said.

The outcome of the new lawsuit is still to be determined, but Obermeier said she is
hopeful that the FOIA documents are a turning point that will finally “end the cycle of
horrible behavior.”

But even if the lawsuit is settled in her favor, Obermeier has to deal with the ramifications
of her 2006 surgery for the rest of her life. She will continue to rely on a number of
medications and have to live a restricted lifestyle.

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The Daily Northwestern | In Focus: Years after surgery, new documen…w patientsʼ malpractice claims against Northwestern Memorial doctor 2/9/20, 10(30 AM

“My life is completely different now,” Obermeier said. “My cardiologist told me, ‘You’re alive
probably only because you’ve worked so hard at staying alive.’”

Email: amyli2021@u.northwestern.edu (mailto:amyli2021@u.northwestern.edu)

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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
Thoracic Surgeons National Cardiac Database. Ann Thorac Surg. 2003;
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


Ranking Member's News | Newsroom | The United States Senate Committee on Finance 2/9/20, 10(52 AM

DECEMBER 04,2008

Grassley seeks answers about the use of a


heart device in clinical research
WASHINGTON — Senator Chuck Grassley is asking questions about an Edwards
Lifesciences’ device used in heart valve repair that was implanted in some patients at
Northwestern Memorial Hospital. He is also asking the Food and Drug Administration
whether or not the agency has reviewed this device for marketing. Grassley said he has
received allegations that the device has not been approved for use in clinical research or
cleared by the FDA.

The text of the letters sent today from Grassley to Edwards Lifesciences, Northwestern
University/Northwestern Memorial Healthcare and the Food and Drug Administration
follows here.

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December 3, 2008

Dean M. Harrison
President and Chief Executive Officer
Northwestern Memorial Healthcare
251 East Huron Street
Chicago, IL 60611

Henry S. Bienen, PhD


President
Northwestern University
633 Clark Street
Evanston, IL 60208

Dear Dr. Bienen and Mr. Harrison:

The United States Senate Committee on Finance (Committee) has jurisdiction over the
Medicare and Medicaid programs. As a senior member of the United States Senate and as
Ranking Member of the Committee, I have a special responsibility to the more than 80
million
Americans who receive health care coverage under those programs to ensure that taxpayer
and
beneficiary dollars are appropriately spent on safe and effective drugs and devices.

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I recently received troubling allegations that the Myxo ETlogix 5100 Ring (Myxo Ring),
an annuloplasty ring used in heart valve repair, has not been approved and/or cleared for
marketing by the Food and Drug Administration (FDA). At the same time it appears that
the
Myxo Ring has been, and perhaps continues to be, implanted in patients by Dr. Patrick
McCarthy, a cardiothoracic surgeon at Northwestern Memorial Hospital. Furthermore, I
was
informed that the device is being implanted without an Investigational Device Exemption
(IDE),
which would allow the device to be used in a clinical study to collect data in support of an
application to the FDA for approval. It is my further understanding that Dr. McCarthy
invented
this device, which is manufactured by Edwards Lifesciences (Edwards), and receives
royalty
payments from Edwards.

These allegations were brought to my attention by Dr. Nalini Rajamannan, Associate


Professor and Valve Director of the Bluhm Cardiovascular Institute at Northwestern
University’s
(Northwestern/University) Feinberg School of Medicine. In addition, Antonitsa Vlahoulis,
one
of the patients who received the Myxo Ring during her operation in April 2006, expressed
concern to my Committee staff that this device had not been approved and/or cleared by
the FDA when it was implanted in her without her informed consent.

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Dr. Rajamannan and Ms. Vlahoulis also told my Committee staff that they have both
brought their concerns to Northwestern. According to a letter that the University sent to
Ms.
Vlahoulis, dated September 18, 2008, Northwestern’s Office for Research Integrity
completed its
own investigation of the allegations and concluded that the implantation of the device was
“not
research and did not require IRB approval.” The letter also stated that Edwards confirmed
in an
email to Northwestern that the device was commercially available.

I am also aware of the fact that Edwards Lifesciences wrote in an email to Dr. McCarthy
that “According to the FDA guidance document dated January 10, 1997…model 5100 is a
minor
modification of model 4200, GeoForm Annuloplasty Ring, cleared under K032250. The
applicable 510(k) number for model 5100 is K032250.” I cannot judge whether or not the
Myxo
Ring required FDA approval or clearance; however, Dr. Rajamannan told Committee staff
that,
in her opinion, the Myxo Ring is not a minor modification because, among other things, the
shape of the ring is triangular whereas other annuloplasty rings are oblong. She also told
my
staff that after bringing this matter to Northwestern’s attention, the University began to take
action against her.

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My Committee staff’s own search for the Myxo Ring on FDA’s website did not produce
any information regarding the Myxo Ring other than 8 adverse event reports that were
submitted
to FDA’s Manufacturer and User Device Experience Database (MAUDE).

In investigating these allegations, I would appreciate Northwestern’s response to the


following questions and requests for information. Please repeat the enumerated question
and
follow with the appropriate response.

1) Please provide the Committee with a copy of the report, memorandum, or


any other documentation of the internal investigation completed by Northwestern’s Office
for Research Integrity.

2) Please provide a copy of all internal communications and correspondence


regarding the Myxo Ring and the use of the device as part of an outcomes study. This
request covers the period of January 2006 through the date of this letter.

3) Please provide a copy of all communications and correspondence with


Edwards Lifesciences and FDA regarding the Myxo Ring. This request covers the period
of January 2006 through the date of this letter.

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4) What information regarding the Myxo Ring was provided to the


Institutional Review Board during its review of the protocol and consent form for the
outcomes study entitled, “Early and Late Outcomes Following Surgical Intervention for
Atrial Fibrillation Database”?

5) According to a July 24, 2008 letter to Dr. Rajamannan from Northwestern


Medical Faculty Foundation, Inc., pursuant to the Foundation’s request, Dr. Rajamannan
“agreed not to provide clinical care at Northwestern Medical Faculty Foundation and
Northwestern Memorial Hospital.”

a. Please explain why this request was made of Dr. Rajamannan.

b. Did the University and/or Northwestern Memorial Hospital have concerns


regarding her clinical performance?

c. Prior to bringing her concerns regarding implantation of the Myxo Ring to the
attention of the University, did Dr. Rajamannan receive any poor job performance
evaluations? Has the University taken any disciplinary actions against Dr.
Rajamannan in the past?

d. Please provide the Committee with a copy of Dr. Rajamannan’s personnel


records. Dr. Rajamannan provided a signed authorization on October 28, 2008,
for the release of her personal information.

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6) Please provide a copy of any forms filed with the University and
Northwestern Memorial Hospital detailing Dr. Patrick McCarthy’s outside income and
conflicts of interest from January 2004 through June 2008.

7) Because reporting practices vary widely from one institution to another, I


would appreciate you also placing this income into a chart, detailing compensation from
device companies to Dr. McCarthy. This request covers the period of January 2004
through June 2008. For each payment to Dr. McCarthy from a company, please provide
the following information:

a. Name of company;
b. Date of payment;
c. Payment description (CME, honorarium, research support, royalties, etc.); and
d. Amount of payment.

In cooperating with the Committee’s review, no documents, records, data or information


related to these matters shall be destroyed, modified, removed or otherwise made
inaccessible to the Committee.

I look forward to hearing from you by no later than January 5, 2009.

Sincerely,

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Charles E. Grassley
Ranking Member

Attachments

December 3, 2008

Michael A. Mussallem
Chairman and Chief Executive Officer
Edwards Lifesciences
One Edwards Way
Irvine, CA 92614

Dear Mr. Mussallem:

The United States Senate Committee on Finance (Committee) has jurisdiction over the
Medicare and Medicaid programs. As a senior member of the United States Senate and as
Ranking Member of the Committee, I have a special responsibility to the more than 80
million
Americans who receive health care coverage under those programs to ensure that taxpayer
and
beneficiary dollars are appropriately spent on safe and effective drugs and devices.

https://www.finance.senate.gov/ranking-members-news/grassley-seeks-answers-about-the-use-of-a-heart-device-in-clinical-research Page 8 of 19
Ranking Member's News | Newsroom | The United States Senate Committee on Finance 2/9/20, 10(52 AM

I recently received troubling allegations that Edwards Lifesciences’ (Edwards) Myxo


ETlogix 5100 Ring (Myxo Ring), an annuloplasty ring used in heart valve repair, has not
been
approved and/or cleared for marketing by the Food and Drug Administration (FDA). At the
same
time it appears that the Myxo Ring has been, and perhaps continues to be, implanted in
patients
by Dr. Patrick McCarthy, a cardiothoracic surgeon at Northwestern Memorial Hospital.
Furthermore, I was informed that the device is being implanted without an Investigational
Device Exemption (IDE). It is my further understanding that Dr. McCarthy invented this
device
and receives royalty payments from Edwards Lifesciences.

Antonitsa Vlahoulis, one of the patients who received the Myxo Ring during her
operation in April 2006, expressed concern to my Committee staff that this device had not
been
approved and/or cleared by the FDA when it was implanted in her without her informed
consent. Ms. Vlahoulis and her physician, Dr. Nalini Rajamannan, Associate Professor and
Valve Director of the Bluhm Cardiovascular Institute at Northwestern University’s
(Northwestern) Feinberg School of Medicine, also informed my staff that they have
brought their
concerns regarding the Myxo Ring to FDA and Northwestern.

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According to a letter that Northwestern sent to Ms. Vlahoulis, dated September 18, 2008,
Northwestern’s Office for Research Integrity completed its own investigation of the
allegations
and concluded that the implantation of the device was “not research and did not require
IRB
approval.” The letter also stated that Edwards confirmed in an email to Northwestern that
the
device was commercially available.

I am also aware of the fact that Edwards Lifesciences wrote in an email to Dr. McCarthy
that “According to the FDA guidance document dated January 10, 1997…model 5100 is a
minor
modification of model 4200, GeoForm Annuloplasty Ring, cleared under K032250. The
applicable 510(k) number for model 5100 is K032250.” I cannot judge whether or not the
Myxo
Ring required FDA approval or clearance; however, Dr. Rajamannan told Committee staff
that,
in her opinion, the Myxo Ring is not a minor modification because, among other things, the
shape of the ring is triangular whereas other annuloplasty rings are oblong.

My Committee staff’s own search for the Myxo Ring on FDA’s website did not produce
any information regarding the Myxo Ring other than 8 adverse event reports that were
submitted
to FDA’s Manufacturer and User Device Experience Database (MAUDE).

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In investigating these allegations, I would appreciate Edwards’ response to the following


questions and requests for information. Please repeat the enumerated question and follow
with
the appropriate response.

1) Did Edwards submit information and/or a 510(k) application to the FDA regarding its
Myxo Ring? If so, please provide a copy of what was submitted to the FDA.

2) On what date did the Myxo Ring become commercially available?

3) On what date was the first Myxo Ring implanted?

4) According to the company’s email to Dr. McCarthy, “model 5100 is a minor


modification of model 4200, GeoForm Annuloplasty Ring.” On what basis did Edwards
make that determination?

a. Was the modification to model 4200 reported to the FDA?


b. If so, on what date, to whom and how was that information communicated to the
FDA?
c. How many rings have been implanted by Dr. McCarthy?

5) Please provide a copy of all communications and correspondence with Northwestern and
Northwestern Memorial Hospital and with the FDA regarding the Myxo Ring. This
request covers the period of January 2006 through the date of this letter.

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6) Please identify each payment Edwards made to Dr. Patrick McCarthy for the period of
January 1, 2003 through October 31, 2008. Also, provide the annual amount paid to Dr.
McCarthy. For each payment to Dr. McCarthy, please provide the following
information:

e. Date of payment;
f. Payment description (CME, honorarium, research support, royalties, etc.); and
g. Amount of payment.

7) Please provide all internal and external communications and/or documents in Edwards’
possession regarding the outcomes study conducted by Dr. McCarthy entitled, “Early and
Late Outcomes Following Surgical Intervention for Atrial Fibrillation Database.” This
request covers the period of January 1, 2006 through October 31, 2008.

8) Please provide a detailed account of payments and/or benefits of any kind that Edwards
provided to Northwestern University, Northwestern Memorial Hospital, and
Northwestern Medical Faculty Foundation, Inc. for the period of January 1, 2003 through
October 31, 2008. For each payment, please provide the following:

a. Date of payment;
b. Payment description (CME, honorarium, research support, etc.);
c. Amount of payment; and
d. Whether the payment was provided to Northwestern University, Northwestern
Memorial Hospital, or Northwestern Medical Faculty Foundation, Inc.

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9) Please also provide the total annual amount of payments and/or benefits Northwestern
University, Northwestern Memorial Hospital, and Northwestern Medical Faculty
Foundation, Inc. received from Edwards.

In cooperating with the Committee’s review, no documents, records, data or information


related to these matters shall be destroyed, modified, removed or otherwise made
inaccessible to
the Committee.

I look forward to hearing from you by no later than January 5, 2009.

Sincerely,

Charles E. Grassley
Ranking Member

December 3, 2008

The Honorable Andrew C. von Eschenbach, M.D.


Commissioner
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

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Dear Commissioner von Eschenbach:

As Ranking Member of the United States Senate Committee on Finance (Committee), I


have a responsibility to the more than 80 million Americans who receive health care
coverage
under the Medicare and Medicaid programs to oversee the proper administration of these
programs and ensure that taxpayer dollars are appropriately spent on safe and effective
drugs and devices.

I recently received troubling allegations that the Myxo ETlogix 5100 Ring (Myxo Ring),
an annuloplasty ring used in heart valve repair manufactured by Edwards Lifesciences
(Edwards), has not been approved and/or cleared for marketing by the Food and Drug
Administration (FDA/Agency). At the same time it appears that the Myxo Ring has been,
and
perhaps continues to be, implanted in patients by Dr. Patrick McCarthy, a cardiothoracic
surgeon
at Northwestern Memorial Hospital. Furthermore, I was informed that the device is being
implanted without an Investigational Device Exemption (IDE), which would allow the
device to
be used in a clinical study to collect data in support of an application to the FDA for
approval.

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These allegations were brought to my attention by Dr. Nalini Rajamannan, Associate


Professor and Valve Director of the Bluhm Cardiovascular Institute at Northwestern
University’s
(Northwestern/University) Feinberg School of Medicine. In addition, Antonitsa Vlahoulis,
one
of the patients who received the Myxo Ring during her operation in April 2006, expressed
concern to my Committee staff that this device had not been approved and/or cleared by
the FDA when it was implanted in her without her informed consent.

Dr. Rajamannan and Ms. Vlahoulis also informed the Committee that they have both
brought their concerns to Northwestern. According to a letter that the University sent to
Ms.
Vlahoulis, dated September 18, 2008, Northwestern’s Office for Research Integrity
completed its
own investigation of the allegations and concluded that the implantation of the device was
“not
research and did not require IRB approval.” The letter also stated that Edwards
Lifesciences
confirmed in an email to Northwestern that the device was commercially available.
According
to that email from Edwards dated September 10, 2007, the Myxo Ring “has been marketed
in the US since March 2006 pursuant to the FDA’s 510K clearance process.”

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Edwards also wrote in an email to Dr. McCarthy that “According to the FDA guidance
document dated January 10, 1997…model 5100 is a minor modification of model 4200,
GeoForm Annuloplasty Ring, cleared under K032250. The applicable 510(k) number for
model
5100 is K032250.” I cannot judge whether or not the Myxo Ring required FDA approval or
clearance; however, Dr. Rajamannan told Committee staff that, in her opinion, the Myxo
Ring is
not a minor modification because, among other things, the shape of the ring is triangular
whereas other annuloplasty rings are oblong. The letter to Ms. Vlahoulis and the emails
from Edwards Lifesciences are attached.

My Committee staff’s search for the Myxo Ring on FDA’s website did not produce any
information regarding the Myxo Ring other than 8 adverse event reports that were
submitted to
FDA’s Manufacturer and User Device Experience Database (MAUDE). I understand that at
least 10 reports, however, have been submitted to MAUDE to date.

In investigating these allegations, I would appreciate FDA’s response to the following


questions and requests for information. Please repeat the enumerated question and follow
with
the appropriate response.

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1) Has the FDA received any information and/or a 510(k) application from Edwards
regarding the Myxo Ring? Has the FDA ever reviewed this device for marketing? If so,
what was FDA’s decision regarding this device?

2) According to Edwards’ email to Dr. McCarthy, the Myxo Ring “is a minor modification
of model 4200, GeoForm Annuloplasty Ring.” Did Edwards report that modification to
the FDA? If so, on what date, to whom and how was that information communicated to
the Agency?

3) Based on the information the Committee has received to date, the Myxo Ring is not
being
used under an IDE. If it is in fact a device that has not been approved or cleared by the
FDA, please explain whether or not implantation of this device should be conducted
under an IDE.

4) According to an email from Ms. Vlahoulis to Don Workman at Northwestern, dated


October 19, 2008, the patient stated that she sent a report to the FDA and the “FDA
acknowledged to me that they never approved this ring and that they are investigating this
situation.” See attached. I would appreciate a briefing for my Committee staff as soon as
the FDA concludes its investigation.

5) FDA’s website states that a 510(k) is required when “There is a change or modification
of a legally marketed device and that change could significantly affect its safety or
effectiveness. The burden is on the 510(k) holder to decide whether or not a modification

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could significantly affect safety or effectiveness of the device.

a. What type of reporting is required of 510(k) holders when they make


modifications to their devices?

b. How does FDA ensure that the 510(k) holder has made the appropriate decision
regarding whether or not to submit a 510(k) when the holder makes modifications
to a legally marketed device?

Thank you for your attention to this important matter. Please respond to the questions set
forth in this letter by no later than January 5, 2009.

Sincerely,

Charles E. Grassley
Ranking Member

Attachment

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