1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DEVICES AND
RADIOLOGIC HEALTH
CIRCULATORY SYSTEM DEVICES PANEL
Thursday, March 18,
2004
9:00 a.m.
Hilton Gaithersburg Washington
D.C., North
Salons A, B and C
620 Perry Parkway
Gaithersburg,
Maryland
2
PARTICIPANTS
Cynthia Tracy, M.D., Acting Chair
Geretta Wood, Executive Secretary
MEMBERS:
Salim Aziz, M.D.
Mitchell Krucoff, M.D.
William Maisel, M.D., MPH
Christopher J. White, M.D.
CONSULTANTS:
Clyde Yancy, M.D.
Judah Z. Weinberger, M.D., Ph.D.
John W. Hirshfeld, M.D.
Thomas B. Ferguson, M.D.
Norman S. Kato, M.D.
Brent Blumenstein, Ph.D.
Charles Bridges, M.D.
L. Henry Edmunds, Jr., M.D.
INDUSTRY REPRESENTATIVE:
Michael Morton
CONSUMER REPRESENTATIVE:
Chrissy Wells
FDA:
Bram Zuckerman, M.D.
3
C O N T E N T S
Call to Order
Cynthia Tracy, M.D. 4
Conflict of Interest Statement
Geretta Wood 4
Introductions 6
FDA Presentation:
Julia Marders 8
Wolf Sapirstein, M.D., MPH,
FACS 17
Kachi Enyinna 26
Open Public Hearing:
Randall Wolfe, M.D. 31
Robert W. Emery, M.D. 41
G. Phillip Schoettle,
M.D. 50
Robert Frater, M.D., 55
Michael Mack, M.D., STS/AATS 66
Mark Slaughter, M.D. 76
Henry Frank Martin, M.D. 85
Bernard Hausen, M.D. 90
Prof. Uwe Klima 96
Open Committee Discussion 107
Summary
Cynthia Tracy, M.D. 262
4
1 P R O C E E D I N G S
2 Call to Order
3 DR. TRACY:
Good morning, everybody. I
4
would like to call to order this meeting of the
5
Circulatory System Devices Panel.
The topic today
6
is a discussion of type of data and study required
7
to effectively evaluate performance of aortic
8
anastomotic devices for marketing.
9 Conflict of Interest
10
MS. WOOD: The following announcement
11
addresses conflict of interest issues associated
12
with this meeting and is made a part of the record
13
to preclude even the appearance of an impropriety.
14 To determine if any conflict existed, the
15
agency reviewed the submitted agenda and all
16
financial interests reported by the committee
17
participants. The conflict of
interest statutes
18
prohibit special government employees from
19
participating in matters that could affect their or
20
their employers' financial interests.
However, the
21
agency has determined that participation of certain
22
members and consultants, the need for whose
23
services outweighs the potential conflict of
24 interest
involved, is in the best interest of the
25
government.
5
1 A waiver has been granted for Dr. Clyde
2
Yancy and a wavier was previously granted for Dr.
3
Judah Weinberger for their financial interests in
4
firms at issue that could potentially be affected
5
by the panel's recommendations.
The waivers allow
6
these individuals to participate fully in today's
7
deliberations. Copies of these
waivers may be
8
obtained from the agency's Freedom of Information
9
Office, Room 12A-15 of the Parklawn Building.
10 We would like to note for the record that
11
the agency took into consideration other matters
12 regarding
Drs. Thomas Ferguson, Mitchell Krucoff,
13
Cynthia Tracy, Judah Weinberger and Clyde Yancy.
14
These panelists reported past or current interests
15
involving firms at issue but in matters that are
16
not related to today's agenda.
The agency has
17
determined, therefore, that these individuals may
18
participate fully in the panel's deliberations.
19 In the event that the discussions involve
20
any other products or firms not already on the
21
agenda for which an FDA participant has a financial
22
interest, the participants should excuse him or
23
herself from such involvement and the exclusion
24
will be noted for the record.
25 With respect to all other participants, we
6
1
ask in the interest of fairness that all persons
2
making statements or presentations disclose any
3
current or previous financial involvement with any
4
firm whose products they may wish to comment upon.
5 DR. TRACY:
Just before we get started, I
6
would just like to ask everybody to be sure that
7
you are speaking directly into the microphone,
8
including the speakers who will be coming up later
9
in the open public hearing. A
transcript is being
10
made from these presentations today.
11 At this time I would like to ask the panel
12
members to introduce themselves.
13 Introductions
14 MR. MORTON: I
am Michael Morton. I am
15
the industry representative. I
am an employee of
16
CarboMedics.
17 DR. WEINBERGER:
Judah Weinberger,
18
Director of Interventional Cardiology at Columbia.
19
DR. YANCY: Clyde Yancy, Director of Heart
20
Failure and Transplantation at UT Southwestern, in
21
Dallas.
22 DR. WHITE:
Chris White. I am the Chief
23
of Cardiology at Ochsner Clinic Foundation.
24 DR. HIRSHFELD:
John Hirshfeld. I am an
25
interventional cardiologist in the University of
7
1
Pennsylvania.
2 DR. KATO:
Norman Kato, cardiovascular
3
surgeon, private practice, Encino, California.
4 MS. WOOD:
Geretta Wood, Executive
5
Secretary.
6 DR. TRACY: I
am Cindy Tracy,
7
electrophysiologist, George Washington University.
8 DR. EDMUNDS: I
am Hank Edmunds, Professor
9
of Surgery at the University of Pennsylvania.
10 DR. FERGUSON:
Tom Ferguson,
11
cardiovascular surgeon, Washington University St.
12
Louis.
13 DR. KRUCOFF:
Mitch Krucoff,
14
interventional cardiologist, Duke University
15
Medical Center; Director of Devices Trials, Duke
16
Clinical Research Institute.
17 DR. MAISEL:
William Maisel,
18
electrophysiologist, Brigham & Women's Hospital.
19 DR. BLUMENSTEIN:
Brent Blumenstein,
20
biostatistician, Seattle, Washington.
21 DR. BRIDGES:
Charles Bridges, Chief
22
Cardiovascular Surgery Pennsylvania Hospital,
23
University of Pennsylvania.
24 MS. WELLS:
Chrissy Wells. I am the
25
consumer representative on the panel.
8
1 DR. ZUCKERMAN:
Bram Zuckerman, Director,
2
FDA, Division of Cardiovascular Devices.
3 DR. TRACY:
Thank you. At this point we
4
will have the FDA presentation, and Julia Marders,
5
from the Office of Surveillance, will be the
6
opening speaker.
7 FDA Presentation
8 MS. MARDERS:
Good morning.
9 [Slide]
10 My name is Julia Marders, and I am a nurse
11
analyst in the Division of Postmarket Surveillance,
12
Office of Surveillance and Biometrics.
13 [Slide]
14 I will present an analysis of adverse
15
event reports received by the FDA on aortic
16
anastomotic devices. My
presentation will begin
17
with a brief description of the Medical Device
18
Reporting System, MDR, which is a system for
19
adverse events and product problems, and include a
20
discussion of its limitations.
21 Next, I will describe the database, search
22
methodology used to obtain the reports of aortic
23
anastomotic devices and provide a summary of
24
findings and analysis of conclusions.
Then I will
25
finish the presentation with conclusions,
9
1
considerations and questions for the panel to
2
contemplate.
3 [Slide]
4
The Medical Device
Reporting System is a
5
nationwide passive surveillance system which
6
includes both mandatory and voluntary reporting.
7
Since 1984 manufacturers and importers have been
8
required to submit reports to the FDA of
9
device-related deaths and serious injuries, as well
10
as events involving device malfunctions that may
11
cause or contribute to death or serious injury.
12 The Safe Medical Devices Act of 1990
13
introduced mandatory reporting of device-related
14
deaths and serious injuries by user facilities,
15
most notably hospitals and nursing homes.
16
Voluntary medical device adverse event and problem
17
product reports, most often submitted by healthcare
18 practitioners, consumers, patients or family
19
members, are received through the FDA's MedWatch
20
program. In general,
approximately 95 percent of
21
the reports received by FDA are from manufacturers,
22
one percent from importers, and the remainder is
23
equally split between voluntary and user
24
facilities.
25 [Slide]
10
1 The Medical Device System, which is the
2
MDR system as most people know it, while providing
3
signals of actual and potential device-related
4
problems, has some limitations.
Under-reporting of
5
adverse events to hospitals, manufacturers and the
6
FDA by healthcare practitioners is a well-known and
7
recognized phenomenon. Thus,
events reported
8
through MDR represent a subset of the total
9
occurrence of events.
10 In addition, manufacturers are not
11
required to submit denominator information such as
12
number of devices manufactured, distributed and
13
implanted. Thus, due to
under-reporting and lack
14
of denominator data accurate incidence rates are
15
unable to be determined based on MDR data alone.
16
Furthermore, reports received may not be
17
representative and reflective of a variety of
18
reporting biases. Thus, for
example, reporting may
19
vary by manufacturer or by the presence or absence
20
of publicity.
21 Although there is a regulatory requirement
22
for a minimum data set, event narrative
23
descriptions vary in completeness and complexity.
24
For example, one aortic anastomotic device report
25
indicates failure of the connector as the entire
11
1
event description and no further details are
2
provided. In addition, many
reports do not contain
3
results of manufacturer failure analyses. Often
4
devices are not returned to the manufacturer for
5
evaluation because they are discarded or remain
6
implanted. Thus, root causes for
reported events
7
are often unable to be determined.
8 [Slide]
9 Now I will describe the search methodology
10 used
to obtain the data set of aortic anastomotic
11
device reports in this presentation and present the
12
findings. First I searched the
database by product
13
code. All medical devices
approved or cleared for
14
marketing have a unique three-letter identifier
15
called the product code. Next, I
narrowed the
16
search by date. This search
includes events of
17
aortic anastomotic devices that were reported from
18
May 24, 2001, the first marketing clearance date
19
for these devices, to March 1, 2004.
I also
20
performed additional database queries by brand
21
names to validated that I had captured all aortic
22
anastomotic device reports that have been entered
23
into the database.
24 [Slide]
25 Now the findings, a total of 213 reports
12
1
are in the database and most reports were received
2
in 2003. The number of death
reports is 23;
3
injury, 185; and malfunction, 5.
The vast majority
4
of these reports, that is 203, came from
5
manufacturers, with 2 from user facilities and 8
6
voluntary.
7 [Slide]
8 Patient age was provided in 129 of the 213
9 reports and ranged from
ages 35 to 83 years, with
10
most in the 50-65 age range.
Slightly over half of
11
these events are noted in males, a quarter in
12
females and a quarter were gender unspecified. One
13
hundred and seventy-three events, or 81 percent,
14
occurred with patients in the U.S. and 14, which is
15 7
percent, with patients outside the U.S.; 26 event
16
reports, 12 percent, did not specify whether the
17
event is foreign or domestic.
18 [Slide]
19 Of the 23 death reports, 22 were from
20
manufacturers and one from a user facility. All
21
patient deaths occurred within 18 days of
22
implantation and 15 of the deaths occurred within 3
23
days of implantation. Interestingly,
one patient
24
actually had both a dissection operatively and a
25
detachment postoperatively and is included in 2 of
13
1
the problem categories listed on this slide.
2
Additionally, another patient had both thrombus and
3
aortic detachment that was discovered on
4
postoperative day 2 when the patient coded.
5 Twelve reports indicate the problem of
6
occlusion or thrombus at the connector site. One
7
report describes the patient was noted to have a
8
predisposing hypercoagulable state, and 2 reports
9
indicate that patients had atrial fibrillation.
10
Aortic dissection associated with deployment or
11
after the connector is placed was noted in 7
12
reports. Device detachment,
resulting in
13
hemorrhagic shock, occurred in 6 reports. None of
14
the devices associated with death were returned to
15
the manufacturer for evaluation and the
16
manufacturer has not been able to determine the
17
root cause of the events.
18 [Slide]
19 Now I will present an actual report to
20
illustrate these findings in a more clinically
21
relevant way. A patient was implanted
with an
22
aortic anastomotic device during an off-pump
23
procedure. No difficulties were
encountered with
24
loading or deployment of the device.
Recovery was
25
good for approximately 40 hours when the patient
14
1
suddenly lost consciousness after a dramatic drop
2
in blood pressure. CPR was
initiated and blood
3
appeared in the drains. At
re-operation, the
4
aortic connector was detached from the aorta and
5
the patient died after 10 minutes.
The autopsy
6
revealed the cause of death was hemorrhagic shock.
7 [Slide]
8 A total of 185 injuries were reported.
9
Stenosis and occlusion are overwhelmingly noted to
10
be the first and second most frequently reported
11
problems respectively. Although
infrequently
12
reported, events involving device detachment have
13
also resulted in serious injury.
Clinically, the
14
reported outcomes of stenosis and occlusion
15
resulted in life-threatening conditions resulting
16
in shortness of breath, chest pain, arrhythmias,
17
subsequent myocardial infarction and/or hemodynamic
18
instability requiring either surgical or
19
interventional treatment including catheterization
20
for PTCA and stenting.
21 The time from implantation to injury, as
22
noted in 37 of the 185 reports submitted, of the 30
23
noting stenosis or occlusion most, or about 60
24
percent, occurred within 90 days; 4 events occurred
25
within 4 days. The other 7 are
associated with a
15
1
variety of patient problems other than stenosis or
2
occlusion. Three reports of
device detachment
3
occurred within one day of surgery, and another
4
event atypically occurred after 97 days, possibly
5
due to a fragile aorta and placement of the
6
connector on a pseudoaneurysm.
Of all the
7
injuries, only 2 devices were returned to the
8
manufacturer for evaluation, both of which resulted
9
in manufacture evaluation indicating no device
10
failure detected.
11 [Slide]
12 Five reports indicated a device
13
malfunction. One report states
the device was not
14
able to be used because the anchor tip was closed.
15
Two reports indicate the aortic plug was not seen
16
by the surgeon upon inspection of the device. Both
17
of these patients have not experienced any adverse
18
consequences. The fourth report
indicates a device
19
malfunction resulting in an aortic laceration
20
requiring repair. It is not
clear why the user
21
facility reported this event as a malfunction
22
rather than an injury, and no information was
23
included about the patient's outcome.
Follow-up is
24
ongoing. The fifth report
indicates failure of the
25
connector, with no other details, other than
16
1
indicating no consequences to the patient.
2 [Slide]
3 Conclusions--the reports of serious
4
adverse outcomes related to aortic anastomotic
5
device use raises a signal of a potential public
6
health problem. Some of these
occurrences are
7
catastrophic, such as aortic dissection or device
8
detachment, and not expected.
Others, for example,
9
occlusion or stenosis, may be expected depending on
10
the patient's underlying condition of adequacy of
11
antiplatelet therapy, or may reflect device-related
12
events, for example, stenosis at the connection
13
site or thrombosis potentially related to
14
bioincompatibility or poor hemodynamics. Lastly,
15
the reported information to date reflects
16
short-term experience. Long-term
failure
17
information is also important.
18 [Slide]
19 Considerations--additionally, there are
20
two other important points to consider, first,
21
failure analyses of this adverse event data are
22
lacking or limited. The
underlying root cause of
23
these events, particularly occlusion and stenosis,
24
is unknown. Multiple factors may
be involved which
25
can make the evaluation of these events difficult.
17
1
Second, this adverse event data needs to be
2
factored into the risk/benefit profile for these
3
devices.
4 [Slide]
5 To conclude my presentation, I have the
6
following three questions for the panel to consider
7
that are based on adverse event report findings:
8 First is the question of collection of
9
long-term failure rate data.
Should a longer
10
period of time for manufacturer collection of
11
device performance data post implantation be
12
required to fully understand aortic anastomotic
13
device failures?
14 Next, should studies comparing short- and
15
long-term patient outcomes between standard
16
suturing versus sutureless aortic anastomotic
17
devices to address risk/benefit issues be
18
undertaken?
19 Finally, should further study of
20
device-related events be considered?
21 I encourage the panel to consider these
22
questions before making final recommendations.
23
That concludes my part of the presentation and now
24 I
will turn over to Wolf Sapirstein.
25 DR. SAPIRSTEIN:
Dr. Tracy, panel members,
18
1
good morning.
2 [Slide]
3 The people listed up there are members of
4
the Division of Cardiovascular Devices. My name
5
is Wolf Sapirstein. We are
mandated by statute to
6
regulate cardiovascular devices, and are hopeful
7
that this panel will generate guidance for us in
8
undertaking this activity for these new and unique
9
devices used in treatment of coronary-artery
10
disease.
11 [Slide]
12 Vascular suturing was introduced by Carrel
13
in 1903 and has changed little over the next 100
14
years, except for the replacement of catgut with
15
synthetic suture. After about 30
years of attempts
16
by various investigators internationally, an
17
automatic device to effect vascular anastomoses,
18
the Symmetry Aortic Connector, was cleared in 2001
19 for commercial use by the agency. The drive for
20
development of these devices has undoubtedly been
21
coronary arterial bypass graft procedure which also
22
underscores the clinical importance of assuring
23
safety and effectiveness for these devices.
24 Incremental modifications to the coronary
25
arterial bypass graft procedure are seminal to the
19
1
acceleration in development of these devices. The
2
surgeons among us will have the forbearance, I
3
hope, while I undertake a thumbnail sketch of the
4
changes that have taken place in the performance of
5
the coronary arterial bypass grafting procedure.
6 [Slide]
7 The CABG procedure was the earliest
8
surgical therapy validated with a randomized,
9
controlled trial, the Coronary Arterial Surgery
10
Study. Autogenous venous
conduits remain
11
extensively employed with anastomosis performed to
12
the aorta and the coronary artery distal to the
13
obstructive lesion. Induced
ventricular
14
fibrillation and anoxic cardiac arrest with
15
hypothermic protection were initially used to
16
provide the quiet field demanded by the challenge
17
of suturing vessels 1-2 mm in diameter.
18
Cardioplegia inducing perfusion of the coronary bed
19
has since produced cardiac standstill with improved
20
myocardial preservation during the ischemic period
21
of conduit anastomosis.
22 Resistance of the internal thoracic
23
artery, ITA, to the atherosclerotic degeneration
24
that seemed inexorable with vein conduits has led
25
to is preferential employment since the late 1980s.
20
1
This also provides the advantage of eliminating
2
need for an aortic anastomosis.
Patient survival
3
has since been shown in several studies to be
4
closely related to the effectiveness of
5
revascularization achieved for the anterior surface
6
of the heart and left ventricle.
These
7
developments, patency of the ITA and anterior
8
cardiac revascularization justified introduction of
9
the minimal access direct CABG procedure in the
10
1990s to perform an isolated LIMA-LAD bypass. This
11
was shortly followed by beating heart and finally
12
off-pump CABG with elimination of extracorporeal
13
circulatory support entirely.
Thus, were the ill
14
effects of cardiac arrest, extracorporeal
15
circulatory perfusion and aortic clamp manipulation
16
of the aorta obviated.
17 [Slide]
18 These modifications made to the CABG
19
procedure addressed its changing role in an era of
20
increasing catheter-mediated coronary treatment.
21
The MIDCAB is seen as reducing the morbidity of
22
incisional trauma, particularly in an increasingly
23
older patient cohort and patients with more
24
compromised coronary circulation not amenable to
25
percutaneous coronary interventions, and these
21
1
patients become candidates for operative
2
intervention. Dispensing with
cardiopulmonary
3
bypass eliminated a potent activator of both the
4
systemic inflammatory response and the various
5
immunological cascades.
6 There is also increasing recognition of
7
the frequency with which neurocognitive
8
deterioration, apart from the more overt cerebral
9
ischemic events, occur with CABG procedures.
10
Extracorporeal cardiopulmonary bypass and
11
manipulation of the atherosclerotic aorta for
12
cardiopulmonary bypass perfusion, as well as
13
conduit anastomosis, have been indicted as
14
etiologic factors for these complications.
15
Anastomotic devices, by facilitating the various
16
modifications to the CABG that address morbidity,
17
can certainly play a major role in reducing this
18
illness.
19 [Slide]
20 Several studies during the development
21
stage of CABG evaluated the effectiveness of this
22
revascularization procedure measured as durability
23
of patency. While this slide
presents a generally
24
accepted distillation of these study findings, it
25
should be noted that patency of CABG is dependent
22
1
on multifactorial elements that have likely been
2
affected by recent changes to the operation itself
3
that are still being evaluated, and by new measures
4
to inhibit the progression of coronary-artery
5
disease. This has to be
considered when evaluating
6 anastomotic
devices in a comparison to these
7
conduit patency rates.
8 [Slide]
9 Failure of the CABG conduit has been
10
attributed to several causes which are listed here.
11
They are broadly stratified by the period of their
12
most prominent effects: the perioperative failures;
13 6
months o 1 year, failure due to neointimal
14
hyperplasia; and the continuum from 6 months on are
15
both coronary-artery disease in the native vessel
16
and the conduit itself.
17 [Slide]
18 The advent of anastomotic devices carry a
19
promise for significant benefits in the performance
20
of the CABG procedure that go beyond simplifying
21
procedural mechanics for the benefit of the
22
operator. They have the
potential for eliminating
23
many of the factors contributing to poor patient
24
outcome. It must be recognized
that while the
25
precise benefit perceived for some of these recent
23
1
changes to the procedures, such as beating heart
2
and operations performed without cardiopulmonary
3
bypass, are as yet unresolved.
The use of
4
non-suture constructed anastomoses will certainly
5
facilitate and increase the frequency of their use.
6
These are some of the benefits that seem intuitive
7
with anastomotic devices.
8 [Slide]
9 Well, Woody Allen has said every silver
10
lining has a dark cloud, and this is exactly true
11
with these anastomotic devices.
Here are listed
12
some of the design characteristics that may
13
contribute to graft failure which do not obtain
14
with conventional sutured vascular connections.
15 [Slide]
16 In our evaluation of these devices for
17
clearance with a 510(k) notification, we have
18
required extensive preclinical data to support
19
limited clinical studies. The
clinical material
20 was required to substantiate equivalence to
21
historical data for conduit patency, which was a
22
surrogate for correcting the deficiency in
23
myocardial perfusion.
24 We encountered some disagreement regarding
25
the study design, the duration of follow-up, and
24
1
the instruments for assessing effectiveness. While
2
general agreement exists regarding the use of
3
suture anastomosis as the gold standard to control
4
for patency, there is considerable advocacy to
5
employ measures of coronary perfusion for
6
assessment of patency. This is a
reversal of the
7
original CABG use of patency as a surrogate for
8
perfusion.
9 With regard to duration of follow-up, the
10
initial concept was to take into consideration the
11
multifactorial causes of CABG failure by accepting
12 a
relatively short period, such as 6-9 months, that
13
focuses on the adequacy of the anastomosis
14
constructed rather than the other factors in graft
15
failure. The changes made to the
CABG procedure
16
itself and the introduction of measures aimed at
17
disease progression were not addressed.
It was
18
also felt that a distinction could be made for
19
devices used on the proximal aortic or on the
20
distal coronary artery.
21 [Slide]
22 The problem encountered in designing a
23
study to evaluate these anastomosis devices goes
24
beyond the inherent problem of the multifactorial
25
causes of CABG failure. They
involve in general
25
1
the device-specific variables listed here that may
2
frustrate attempts at one-design-fits-all study
3
design for the devices.
4 [Slide]
5 From our initial experience with cleared
6
devices, we now have the belief that the rigor of a
7
randomized trials may be required unless there are
8
very mitigating circumstances to justify otherwise.
9
To this end, we would like input on an appropriate
10
template for study design that could be modified to
11
accommodate some of the variables intrinsic to
12
their use. This slide lists some
of the
13
considerations we have encountered for designing a
14
study template and it is just put up for your
15
consideration as a straw man.
16 [Slide]
17 This slide represents a sample size
18
estimation for a one-armed study with the endpoint
19
for effectiveness based on the historical values
20
listed here for conduits performed with hand
21
suturing. For instance, a point
estimate of 95
22
percent patency, with a lower confidence level
23
accepted as 5 percent, would require a sample size
24
of 150 patients for study. This
is just placed
25
here for your consideration or evaluation for even
26
1 a
one-armed study.
2 This completes my introduction to the
3
FDA's request for this panel's input in formulating
4
an appropriate regulatory approach for devices that
5
present the potential for critically affecting the
6
treatment of coronary arterial disease, which is
7
the wound stripe of modern society.
8 Kachi Enyinna, our lead engineer reviewer
9
for these devices, will now present or crystallize
10
some of the comments that I have made in the form
11
of questions that we would like this panel to
12
address in helping us wrestle with the regulation
13
of these devices. Thank you very
much.
14 MR. ENYINNA:
Good morning. My name is
15
Kachi Enyinna, biomedical engineer and lead
16
reviewer, Division of Cardiovascular Devices. I
17
will be presenting the questions we have come up
18
with and seeking some kind of guidance from panel
19
on how to evaluate clinical studies of these
20
devices. I would like to remind
the panel members
21
to keep these questions in mind while I go over the
22
questions and to keep the questions in mind until
23
discussion time this afternoon allow members of the
24
medical community, as well as sponsors and industry
25
to speak before we discuss the questions.
27
1 [Slide]
2 Regarding trial design, the first
3
question, please comment on the choice of control
4
in the clinical trial required to evaluate vascular
5
anastomosis devices for CABG.
The gold standard of
6
sutured CABG anastomoses has a well-documented
7
history of over thirty years.
8 [Slide]
9 Can historical data from sutured CABG
10
anastomosis device trials be used as the control in
11
the device studies?
12 [Slide]
13 Alternatively, are concurrently performed
14
CABG controls necessary given the multifactorial
15
causes of CABG failure, for example, technical
16
construction, extent and progression of native
17
vessel disease, condition of conduit and
18
progression of intima hyperplastic and atheromatous
19
degeneration, and the introduction of drugs for
20
mitigation of atherosclerotic disease?
21 [Slide]
22 If these trial designs are inadequate,
23
should randomized, controlled clinical trials be
24
performed?
25 [Slide]
28
1 With regard to device placement and device
2
design, please address the following:
Given the
3
considerable differences between the proximal and
4
distal CABG anastomoses, what, if any, differences
5
in study criteria should be required?
6 [Slide]
7 Are there certain aspects of the clinical
8
study design, for example length of follow-up and
9
endpoints, that should be required for all devices
10
irrespective of device form and function? For
11
example, the U-clip performance closely duplicates
12
that of a suture, whereas the Symmetry has greater
13
similarity to a stent.
14 It is rarely possible to determine the
15
cause of conduit failure. Can
you suggest criteria
16
to determine whether failure is device related?
17 [Slide]
18 Number three, do you believe that the
19
significant differences between an arterial conduit
20
and a venous conduit warrant distinct study
21
criteria and assessment for each?
If so, please
22
identify these criteria and analyses.
23 [Slide]
24
Four, should the primary
effectiveness
25
endpoint be graft patency alone, or include both
29
1
graft patency and myocardial perfusion?
2 Five, with regard to device safety, what
3
criteria, that is, acceptable adverse event rates
4
as compared to that for suture should be applied to
5
the evaluation of device safety as distinguished
6
from device effectiveness? For
example, myocardial
7
infarction, reoperations, neurologic events,
8
incidence of aortic complications.
9 [Slide]
10 Regarding endpoint evaluation, number six,
11
with regard to appropriate patient follow-up, in
12
view of the possible persisting risk of failure of
13
some mechanical anastomosis sites, distinct from
14
the progression of native vessel disease, what
15
duration of follow-up is advisable for premarket
16
evaluation?
17 [Slide]
18
Should postmarket follow-up
be required to
19
assess long-term device effectiveness?
If so,
20
please define the appropriate length of follow-up
21
after primary patency evaluation.
22 [Slide]
23 The last question, can non-invasive
24
measuring instruments, for example,
25
echocardiography, ultrafast spiral CT, MRA, EBT,
30
1
etc., be used for primary assessment of graft
2
patency or is angiographic follow-up necessary? At
3
what time points should patency be assessed? Thank
4
you.
5 DR. TRACY:
Does that conclude the FDA
6
presentation? Does anybody on
the panel have a
7
question for the FDA at this point?
8 [No response]
9 At this point, we will move on to the open
10
public hearing. Both the Food
and Drug
11
Administration and the public believe in a
12
transparent process for information gathering and
13
decision-making. To ensure such
transparency at
14
the open public hearing session of the advisory
15
committee meeting, FDA believes that it is
16
important to understand the context of an
17
individual's presentation. For
this reason, FDA
18
encourages you, the open public hearing speaker, at
19
the beginning of your written or oral statement to
20
advise the committee of any financial relationship
21
that you may have with the sponsor, its product
22
and, if known, its direct competitors.
For
23
example, this financial information may include the
24
sponsor's payment of your travel, lodging or other
25
expenses in connection with your attendance at this
31
1
meeting. Likewise, FDA
encourages you at the
2
beginning of your statement to advise the committee
3
if you do not have any such financial
4
relationships. If you choose not
to address this
5
issue of financial relationships at the beginning
6
of your statement it will not preclude you from
7
speaking.
8 MS. WOOD: I
have just a couple of
9
announcements for the open public speakers. We
10
have asked today, due to the number of speakers
11
that have requested time, that you limit your
12
remarks to five minutes each. I
would also ask
13
that you provide me with either an electronic copy
14
or a hard copy of your presentation for the benefit
15 of
the summary writer and the transcriptionist.
If
16
you could see me at lunchtime, that would be great.
17
Thank you.
18 DR. TRACY:
There are a number of speakers
19
and I will call them in order.
The first is Dr.
20
Randall Wolfe, from University of Cincinnati.
21 Open Public Hearing
22 DR. WOLFE:
Members of the panel, ladies
23
and gentlemen, good morning.
24 [Slide]
25 Thank you for honoring my request to speak
32
1
before you. My disclosure is
that I was the
2
principal investigator on the multicenter U-clip
3
distal anastomotic trial. Those
results were
4
presented at AATS two years ago.
There is no
5
financial relationship.
6 I was a past consultant for Ethicon in
7
laboratory and clinical evaluation of proximal and
8
distal anastomotic devices, and in the past was a
9
consultant to Ventrica in helping set up their
10
clinical distal anastomotic connector trial.
11 I am currently on the steering committee
12
of the Prevent IV Core Gentech E2F Decoy trial
13
which uses synthetic DNA to prevent aortic coronary
14
venous graft atherosclerosis.
That study is closed
15
with over 3,000 patients enrolled.
I mention that
16
because I think we are going to be educated on true
17
graft patency of the results of that trial which
18
will be opened first quarter of next year.
19 [Slide]
20 My primary interest is that I have been
21
presenting summary of anastomotic devices at our
22
national meetings, both AATS, STS and ISMICS. In
23
the next five minutes I would like to summarize
24
some of the things that have been presented at
25
these meetings.
33
1 [Slide]
2 Overall, there are a lot of anastomotic
3
connector devices, and this shows a convenient way
4
to classify these into proximal and distal and
5
subsequently into automated versus manual. There
6
are 13 to 15 different devices in these different
7
categories but I find this a convenient way to look
8
at connectors.
9 [Slide]
10 There are different value propositions
11
with the connectors and they range from traditional
12
CABG all the way to total endoscopic CABG. I don't
13 have
time to go over this in detail but only to
14
point out that there is a possibility of
15
eliminating the heart-lung machine by using certain
16
connectors and also reducing ischemic time. In the
17
endoscopic evaluation there is a potential to
18
reduce patient pain and trauma and to truly enable
19
endoscopic surgery.
20 [Slide]
21 This is a summary that you will probably
22
hear more about from other presenters, but vein
23
graft failures could be a bad vein; the vein could
24
be too long; it could be too short; there could be
25 a
poor run-off bed; or it could be a distal or
34
1
proximal anastomotic problem.
2 [Slide]
3 I think this is an important slide. This
4
is some of the science and this is based on some of
5
the work of the E2F Decoy trial but there is an
6
initial wave of inflammation in a venous graft.
7
There is injury. There is
activation of smooth
8
muscle cells. There is migration
proliferation and
9
intimal soil, if you will, for atherosclerotic
10
plaque and ultimately accelerated atherosclerosis.
11
However, this initial wave is in the first two
12
weeks after the venous graft has been harvested
13
from the leg and placed on the heart.
14 [Slide]
15 This is a summary of how I look at graft
16
failure. I divided it into three
distinct
17
categories. The first is
immediate, that is a
18
technical graft failure. These
are all venous
19
grafts, by the way; it could be arterial as well.
20
Technical failure would be identified in the first
21
week. In other words, if one
obtained a
22
postoperative coronary angiogram in a patient in
23
one week technical failures would be disclosed.
24 The next is intermediate, and this is what
25 I
relate to devices. This is usually in
the first
35
1
six to eight weeks. So, a
six-month angiographic
2
evaluation should pick up device failures.
3 The third is chronic and this relates to
4
accelerated atherosclerosis and this really takes
5
years. In the E2F Decoy trial we
are looking at
6
one year but, in fact, it probably occurs over five
7
years. In my opinion, if the St.
Jude device had
8
been evaluated at six months by angiography
9
stenoses and occlusions would have been discovered
10
that related to the device. In
other words, the
11
intermediate category.
12 [Slide]
13 We now have second generation anastomotic
14
devices. They have proven to be more
reliable than
15
hand sewn. There is a consistent
orifice size.
16
They are easier to use. I think,
importantly,
17
another change that has happened with the second
18
generation is a lack of vein manipulation. So,
19
these should be evaluated with six-month
20
angiographic equivalency and we should also look at
21
performance outcomes.
22 [Slide]
23 In summary, I believe the science supports
24
six months angiographic data for the intermediate
25
or device failure area. Proximal
stainless steel
36
1
devices have demonstrated excellent patency, which
2
will probably be discussed. And,
second generation
3 distal
devices demonstrate excellent patency.
I
4
think we have to keep in mind as we think about
5
this is that unlike stents for coronary-artery
6
disease, these devices do not rearrange plaque
7
morphology. Thank you.
8
DR. TRACY: Thank you.
Are there any
9
brief questions for Dr. Wolfe from the panel?
10 DR. EDMUNDS:
What data do you have for
11
that last statement?
12 DR. WOLFE:
Which part of it?
13 DR. EDMUNDS:
The last statement, how do
14
you know that the device doesn't rearrange plaque?
15 I
mean I don't know. I would just be
interested in
16
your data.
17 DR. WOLFE: The
last statement is
18
concerning distal devices. This
is assuming that
19
the device is placed to a target site that is
20
relatively free of atherosclerotic debris. The
21
second bullet point is for the proximal devices.
22
The third bullet point is specifically for distal.
23 DR. EDMUNDS:
That is what I am talking
24
about. Are you talking about
magnetic coupling?
25 DR. WOLFE: Any
type. What I am trying to
37
1
relate is that stents and anastomotic devices are
2
not equal in that a stent is supposed to rearrange
3
plaque to open up a stenosis.
For devices that we
4
are using that is not their purpose.
We are not
5
rearranging the plaque. We are
connecting,
6 hopefully,
a fairly normal vein or artery to a
7
fairly normal coronary distal target.
8 DR. BRIDGES: I
have a question about the
9
second bullet point. Can you
also inform us what
10
data that is based on?
11 DR. WOLFE: I
think that will be presented
12
by others, but I believe that the difference is
13
that stainless steel is stronger, and in a proximal
14
position where there is atherosclerotic disease a
15
stainless steel device can actually hold the aorta
16
open, whereas a nitinol device may not; it may
17
buckle and close. So, it is
really the strength of
18
the material. The proximals are
different from the
19
distals. In fact, the people
that may need the
20
proximal devices the most are the ones who have the
21
worst aortas. They have disease
in a situation
22
where it is maybe not safe to clamp the aorta.
23 DR. AZIZ: With
the proximal devices, if
24
you do get narrowing, how do you propose that be
25
handled? Let's say in six months
you find that you
38
1
have osteal narrowing, how would you handle that?
2 DR. WOLFE: I
don't know the answer to
3 that.
4 DR. AZIZ: Can
they be dilated in the cath
5
lab?
6 DR. WOLFE: I
don't know the answer to
7
that.
8 DR. AZIZ: And
is there intimal
9
hyperplasia that you are seeing, if you do see it?
10 DR. WOLFE: I
believe so with the second
11
generation devices. With the
first generation
12
devices I think it was a more complicated situation
13
where the graft could actually embrocate over the
14
device. But in the second
generation devices it
15
should be more related to disease in the aorta.
16
However, if a large lumen is maintained then there
17
shouldn't be significant stenosis.
So, let's say
18
you get neointimal hyperplasia in every graft,
19
let's say you get a millimeter in every
20
graft--well, if you get a 1.5 mm opening, that is
21
significant. If you get a 3 mm
opening that is
22
maintained, it won't be significant.
23 DR. AZIZ: Let
me ask you one other thing,
24
with the proximal anastomotic devices, the angle
25
that the graft comes off is really at right angles
39
1
to the aorta. Right?
2 DR. WOLFE: In
some of the products, that
3
is true.
4 DR. AZIZ: You
mean there are ones where
5
you can have it coming off as a cobra head?
6 DR. WOLFE:
That is correct.
7 DR. KRUCOFF:
Have you actually retrieved
8
any of these devices and looked at them under a
9
microscope when they have failed?
10 DR. WOLFE: I
have not--well, I have seen
11
the slides, I certainly have.
12 DR. KRUCOFF:
Whose slides are those?
13
DR. WOLFE: St. Jude.
I did go over those
14
at one point and, again, that is a first generation
15
device and I believe the mode of failure of that is
16
different from anything you might see in the
17
future. It is multifactorial but
the occlusions
18
tend to be flush with the aorta.
There is
19
neointimal hyperplasia; there is thrombus. First
20
of all, the angiogram does not look like a typical
21
angiogram that you might see with an occluded vein
22
graft; it is completely different.
There is also
23
the possibility that the vein graft itself has
24
changed its position on the connector.
In
25
addition, that was a connector that had a high
40
1
profile. There is also the
possibility that there
2
could be a right angle kink right at the end of the
3
connector.
4 I think in summary, I give credit to the
5
pioneers for being the first ones out there. The
6
first eight patients who received a mitral valve
7
replacement all died.
Fortunately, we still do
8
mitral valve replacements and maybe with the first
9
generation connectors we are seeing some of the
10
same things, some of the mistakes.
I think many of
11
those have been changed by changes in device and
12
changes in material.
13 DR. YANCY: As
you have worked through
14
your clinical trials with these devices, have there
15
been concomitant improvements or changes in medical
16
management because of anticipated problems with
17
these connectors vis-avis antiplatelet therapy,
18
anticoagulation, aspirin, etc.?
19 DR. WOLFE: We
do have some data from the
20
E2F Decoy trial. The trial has
not opened but we
21
have some demographic data. It
has been shown that
22
when patients are followed more closely the chances
23
of them going home on antiplatelet agents are much
24
higher. Although most surgeons
say that they send
25
their patients home on aspirin or some antiplatelet
41
1
agent, in fact, many patients do not go home on
2
that but in a careful study situation they do.
3
There is a study bias.
4 DR. YANCY: So,
those anticipated events
5
that you thought would be predicted or captured at
6
six months, do you think they are product failures,
7
medical management failures or both?
8 DR.
WOLFE: I expect they are product
9
failures and they probably would be in an extreme
10
environment such as a very atherosclerotic aorta,
11
but I am not sure. I am not
sure.
12 DR. TRACY: I
think we are going to have
13
to move on at this point. There
is a number of
14
other speakers. Thanks very
much. Dr. Robert
15
Emery?
16 DR. EMERY:
While we are setting up my
17
disc here, I am Robert Emery. I
am in private
18
practice in Minneapolis-St. Paul, Minnesota. I am
19
not being sponsored by any companies but I have had
20
relationships in terms of research grants by St.
21
Jude Medical, ATS Medical, AtriCure, Congestive
22
Heart Failure Solutions. I have been
on research
23
advisory boards for St. Jude Medical, Medtronic,
24
Myocor, Percardia, CardioGenesis, Inc.; data safety
25
monitoring boards for Cardioblate and for Myocor,
42
1
and I have received speaking fees for several of
2
the aforementioned companies.
3 [Slide]
4 I would like to address our early
5
experience in the Minneapolis-St. Paul area looking
6
at why vein grafts fail, the new issues with aortic
7
connectors. We have been through
the etiology of
8
graft failures so I won't go into that, however,
9
there are several new issues that are introduced by
10
the currently used generation of connectors. There
11
can be overloading of the connector, that is, too
12
much vein graft placed below the prongs;
13
double-loading of the connector like putting on
14
your socks where you can invert the graft and load
15
that which inhibits flow through the graft. You
16
can skive the aortic punch and that make take out a
17
complete circle.
18 There are variations in operative
19
technique. For instance,
performing your proximals
20
first, as most surgical trainees in the United
21
States perform distals first you are radically
22
changing the way we have been trained in our
23
everyday use in conduct of the operation. Grafts
24
can move. After the patient is
closed the lungs
25
can push the grafts to various positions and this
43
1
can cause loss of the 90 degree angle, that has
2
been mentioned here, that is necessary for the
3
current generation St. Jude connector.
4 [Slide]
5 Let's look at some of these issues that we
6
have seen. Here is a surgical
technical error at
7
the distal anastomosis that would lead to graft
8
failure if not completed. I
don't think that could
9
be blamed on the connector but a connector was
10
utilized.
11 [Slide]
12 This is the first case I performed in the
13
United States, the second one done in the United
14
States after FDA approval. You
can see two
15
technical errors here that I learned over time and
16
if I had not changed my operative technique one
17
would have a consistent mode of failure that would
18
be uncorrected. That is, these
grafts are placed
19
on top of the aorta instead of further down the
20
side toward the pulmonary artery, therefore,
21
maintaining a 90 degree angle.
The grafts are also
22
reflected superiorly with some kinking at the
23
anastomotic site, not maintaining that 90 degree
24
angle. As I mentioned, these
grafts can move. All
25
grafts should be tacked to keep that important 90
44
1
degree angle. If you lose that
you can predict
2
some degree of graft failure.
3 [Slide]
4 There can be poor run-off, as shown on
5
this slide, to a patent vein graft but a poor
6
distal vessel.
7 [Slide]
8 Another example is shown here. The graft
9
can be too short, as mentioned.
Again, it may be a
10
variation in operative technique.
11 [Slide]
12 Here a graft is tethered across the
13
pulmonary artery and you can see the narrowing
14
several centimeters distant from the connector
15
device.
16 [Slide]
17 And a similar vein here wrapped around the
18
pulmonary artery more tightly than one would like
19
to see.
20 [Slide]
21 Improper placement of the graft is also
22
important.
23 [Slide]
24 Here is a vein graft that was placed on
25
the right side of the aorta as we traditionally
45
1
place our saphenous vein grafts when we suture
2
them, rather on the anterior surface of the aorta,
3
riding over the right ventricular outflow tract
4
maintaining the 90 degree angle.
You can see the
5
acute bend on the right side as this graft reflects
6
against the patient's pleural surface.
7 [Slide]
8 Aortic disease was mentioned and this can
9
be important. Here is an
occluded connector in a
10
diffusely diseased aorta and you can see, as Dr.
11
Wolfe mentioned, the flush occlusion of the aorta.
12 [Slide]
13 A combination of factors--here is a small
14
vein graft and poor run-off.
15 [Slide]
16 And here is a very small vein graft that
17
has become atretic over time to a small distal
18
vessel, still patent through the connector but,
19
nonetheless, narrowed.
20 [Slide]
21 Then there is the unknown. Here is the
22
occluded connector again flush at the angiographic
23
site.
24 [Slide]
25 Here is an occluded vein graft marked by
46
1
the stainless steel ring in the same patient. You
2
can see the connector graft slightly to the left
3
and one or two centimeters down in this example.
4
There are connector related issues that are key.
5 [Slide]
6 This is what was addressed a little bit in
7
the prior question, proximal anastomotic problems
8
in the face of appropriate graft and appropriate
9
distal connectors that need to be investigated.
10 [Slide]
11 Yet, there are technical issues. Here is
12
another proximal connector with a very good vein
13
graft and a large distal run-off system.
14 [Slide]
15 Improved and more extensive training may
16
obviate several of the modes of failure that we
17
have seen. We need to develop
indications and
18
contraindications for the use of these devices,
19
particularly as they come out not just general,
20
overall approval. There are
technical
21
considerations that need to be mentioned. Many
22
modes of failure are unstudied or unconfirmed.
23
Thus, prospective studies are warranted including
24
operative technical detail, both visual, such as
25
the photograph I showed you and verbal operative
47
1
reports, and improved mentoring may be necessary
2
even for devices that seem intuitively simple.
3 [Slide]
4 There are tips for success that I have
5
developed in my own practice based on my
6
experience.
7 [Slide]
8 What we do not want to do is throw the
9
baby out with the bath water because these
10
connecting devices offer us a great opportunity to
11
improve our service to our patients.
Thank you.
12 DR. TRACY:
Thank you. Are there any
13
brief questions from the panel members?
I do want
14
to remind you that there are a lot of people who
15
want to present today.
16 DR. KRUCOFF:
Just one question. The
17
angiograms you showed us, were they part of a study
18
protocol that required angiography or were these
19
clinical presentations of people who came back
20
sick?
21 DR. EMERY:
These were clinical
22
presentations in approximately our first eight
23
months of use, from May, 2001 through the first
24
eight months, and we have seen very few since we
25
have modified our surgical techniques.
48
1 DR. KRUCOFF:
And the denominator for
2
these eight months?
3 DR. EMERY: It
was about 160, and these
4
are not all of them. These are
representative
5
samples of technical errors that are correctable
6
with proper training and changing of your
7
techniques as you learn the process.
8 DR. AZIZ: When
you say you tack the
9
grafts, are you putting many anchoring stitches or
10
what do you do?
11 DR. EMERY:
Three or four generally on the
12
left side. I put one on the
pulmonary artery and,
13
again, depending on the length of the graft,
14
because you are doing proximals first with this
15
device, I will connect it so that it won't move
16
with respiration. On the right
side I connect it
17
down the body of the right ventricle as the graft
18
goes directly up from the aorta over the right
19
ventricle and down to the right coronary artery,
20
the posterior descending artery, just some 6-0
21
prolene suture tacking.
22 DR. AZIZ: We
normally do the regular
23
suturing technique; usually you don't have to do
24
that?
25 DR. EMERY: No,
I don't.
49
1 DR. AZIZ: So,
why do you think you need
2
to do it here?
3 DR. EMERY:
Because I learned doing this
4
distal first and I think my measurement of the
5
length of the vein graft to the aorta is better on
6 a
distal first process in my hands. So,
sometimes
7 I
would rather make my grafts too long than too
8
short because the shortness of the graft may be one
9
reason for disconnection of these connectors from
10
the aorta. As the pulmonary
artery fills, if the
11
graft is too short you can pull these off. I have
12
pulled them off myself in the operating room by
13
tugging a little bit too hard and I had to put my
14
finger over the hole. So, a
short graft can lead
15
to connector displacement from the aorta,
16
particularly as the patient moves or the heart
17
fills in the postoperative period.
18 DR. TRACY: Dr.
Hirshfeld?
19 DR. HIRSHFELD:
I would just like to say
20
as an angiographer who has probably taken pictures
21
of thousands of bypass grafts, I have heard a lot
22
about considerations that I was never aware of
23
before from your brief presentation, and I think it
24
calls for a sharing of information between
25
angiographers and surgeons about many of these
50
1
technical considerations that affect graft
2
performance. So, I would hope
that out of this
3
will come that kind of sharing of information.
4 DR. EMERY: I
have reviewed all the
5
angiographs of patients that failed in my hands.
6 DR. TRACY: I
think we have to move on; we
7
have a number of speakers. I am
sorry to cut this
8
short; it is very interesting.
To remind you,
9
there will be more time this afternoon to discuss
10
things in detail. Dr. Schoettle?
11 DR. SCHOETTLE:
Good morning. My name is
12
Dr. Phillip Schoettle. I am a
thoracic and
13
cardiovascular surgeon in practice at Methodist
14
University Hospital in Memphis, Tennessee.
15 I am here this morning to discuss my
16
experience with the Symmetry proximal anastomotic
17
device. I would like to disclose
at the outset
18
that I have no financial interest in this matter.
19 I
paid my own way to Washington, and I am not
20
employed by anyone, nor intend to be employed by
21
anybody with a financial stake in this issue.
22 In September of 2001 I was trained in the
23
use of the Symmetry proximal anastomotic device,
24
along with two of my scrub assistants, by St. Jude
25
Medical. I was attracted to the device
because of
51
1
the reasons mentioned previously which would allow
2
you to do a proximal anastomosis off the aorta
3
without the use of a partial occluding or
4 side-biting
clamp with its attendant risk of
5
embolic debris.
6 I rapidly incorporated that device into my
7
practice and used it almost exclusively for the
8
next eleven months. Initially I
was very pleased
9
with the results. I had minimal,
if any, technical
10
issues with the device and was not aware of any
11
acute or subacute saphenous vein closures.
12
Unfortunately, at approximately ten months we began
13
to see almost a deluge of patients returning to the
14
cardiac catheterization laboratory with vein graft
15
occlusions or high grade stenoses invariably
16
occurring in the connector site.
17 This occurrence was totally incompatible
18
with my previous surgical experience.
I reported
19
this to St. Jude Medical and I felt like it
20
warranted a distribution to the surgical community
21
and I began a review of my patients, resulting in
22
the paper that you see here.
This paper was
23
entitled, "Use of an Anastomotic Device in Coronary
24
Bypass Surgery: A Word of Caution." It was
25
published in the January edition of the Journal of
52
1
Thoracic and Cardiovascular Surgery.
2 Without going into great detail, I would
3
like to summarize the results of that paper. It
4
was a review of two years of experience. The first
5
year was the year prior to my beginning to use the
6
device, while proximal saphenous vein connections
7
off the aorta were done in the conventional manner,
8
that is, hand-sewn with a partial occlusion clamp.
9
Beginning in September of 2001, for the next eleven
10
months, comprises the next group of patients where
11
almost exclusively all proximal anastomoses were
12
done with the St. Jude Symmetry anastomotic device.
13 I divided the group in group A and group
14
B. Group A was the first group,
the prior year
15
with hand-sewn anastomoses. I
reviewed all
16
patients who required repeated cardiac
17
catheterization after coronary artery bypass
18
surgery. What we found was that
even though the
19
patients in group A had had a year longer of
20
exposure to my cardiology colleagues, less of those
21
required repeated cardiac catheterization, although
22
that number was not significant between the groups.
23 The number of grafts studied between group
24 A
and group B was also similar. However,
what we
25
did find was that the group A patients, those with
53
1
hand-sewn anastomoses, had an 80 percent patency
2
rate of vein grafts studied.
Remember, these were
3
symptomatic, or at least theoretically symptomatic
4
patients. So, 80 percent of the
grafts were widely
5
patent in the hand-sewn anastomoses, with no
6
significant stenoses, and 20 percent were
7
occluding.
8 Unfortunately, in the group B
patients,
9
those with the Symmetry proximal anastomotic
10
device, only 20 percent of the grafts studied were
11
patent. Fully 80 percent of the
grafts were either
12
totally occluded or had high grade stenoses
13
uniformly occurring at the connector site. The
14
significance in p value in favor or patency of the
15
hand-sewn anastomoses was standardly evaluated with
16 a
p value of 0.0001.
17 Based on my experience with the Symmetry
18
proximal anastomotic device and review of my own
19
patients, I have several observations and two
20
conclusions I would like to make.
The use of the
21
Symmetry St. Jude proximal anastomotic device in
22
its current generation results in a significantly
23
higher saphenous vein closure and occlusion rate
24
when compared to hand-sewn anastomoses.
25 I do not believe that technical issues are
54
1
the major factor. I can show you
arteriograms of
2
what appear to be perfectly laid out saphenous vein
3
grafts with a 90 degree angle off the aorta, with
4
no kinking, where the stenosis arises immediately
5
in the connector site off the aorta.
6 In two patients that I reoperated, I was
7
able to harvest the segment of aorta with the
8
connector and the saphenous vein.
This was looked
9
at microscopically by the pathologists in my
10
hospital who reported basically a foreign body
11
reaction in the connector site with associated
12
neointimal hyperplasia.
13 I would also point out that these
14
connector stenoses and occlusions are not
15
clinically insignificant. In
this group at least
16
six patients have required early reoperation.
17
Thirty patients, over a year ago, required PCI
18
stents and angioplasty. There
have been four
19
sudden deaths in these patients, two of which were
20
almost certainly related to myocardial infarction.
21 If I can have the liberty of making a
22
conclusion, I see no clinical indication for the
23
current generation of the St. Jude proximal
24
connector. The use of this
connector or any other
25
vascular anastomotic devices must be evaluated by
55
1
scientifically controlled, prospective clinical
2
trials.
3 I do not believe that uneducated surgeons
4
and uninformed patients should be the testing
5
ground for these devices that have not proven to be
6
clinically safe or effective. I
clearly am not
7
opposed to technological advances in coronary
8
bypass surgery. I have been an
early proponent of
9
off-pump surgery and less invasive coronary
10
surgery. I do not want to throw
the baby out with
11
the bath water. I do not
believe, however, that
12
the cause of less invasive coronary artery bypass
13
surgery is furthered by the ill-advised use of
14
these unproven devices. Thank
you. I would be
15
glad to answer questions if there is time.
16 DR. TRACY: Any
brief questions? Dr.
17
White?
18
DR. WHITE: Would you just clarify for me,
19
in the early part of your statement you said
20
something about follow-up at ten months. Was there
21 a
ten-month interval that was special to you?
22 DR. SCHOETTLE:
No, I believe it just
23
would have become apparent to me, you know, with
24
just the overwhelming evidence of patients. All of
25 a
sudden I was getting call after call from these
56
1 patients.
2 DR. WHITE:
Would six months not have
3
identified these patients? Would
a six-month
4
follow-up, do you think, not have been adequate?
5 DR. SCHOETTLE:
I was asked that question
6
last night. I don't have that
answer. My gut
7
feeling is that six months would probably be
8
appropriate but I don't know that answer based on
9
this review.
10 DR. BRIDGES: I
have a question. In the
11
brief study that you gave us I didn't see the
12
mortality in the two groups. You
said that there
13
were no sudden deaths in the hand-sewn group but
14
what was the overall mortality in the two groups
15
and are there any updates since this paper was
16
submitted?
17 DR. SCHOETTLE:
The operative mortality
18
was less than three percent but the overall
19
mortality long-term, I don't have that; there have
20
been no updates at this point although I intend to
21
do that.
22
DR. BRIDGES: But both groups--
23 DR. SCHOETTLE:
They were very similar.
24 DR. BRIDGES:
At least for the graft
25
connector patients, what would be medical therapy
57
1
for these?
2 DR. SCHOETTLE:
It is in the paper, but
3
all patients were discharged on aspirin and all
4
patients were discharged on Plavix for two months.
5 DR. AZIZ: But
when you had to reoperate
6
on them did you have to redo the whole anastomosis
7
or could you immobilize it and rehook it? How did
8
you do that?
9 DR. SCHOETTLE:
In a couple of cases I was
10
able to continue to use that vein segment. Conduit
11
length was an issue. Several of
the veins were
12
totally occluded and we just had to sacrifice those
13
veins.
14 DR. AZIZ: So,
the orifice was like the
15
whole length?
16 DR. SCHOETTLE:
That is correct.
17 DR. AZIZ: So,
you probably had intimal
18
hyperplasia proximally and you had full flow and
19
then thrombus--
20 DR. SCHOETTLE:
And then thrombus
21
distally, correct.
22 DR. AZIZ:
Obviously most people don't,
23
and they probably should use some flow techniques
24
to measure flows.
25 DR. SCHOETTLE:
All patients in both
58
1
groups had mediastinal transit time flow evaluation
2
at the time of surgery, and 95 percent of cases
3
were done off-pump.
4 DR. AZIZ: When
you did proximal
5
anastomoses with the device did you do any
6
sequential grafts--
7 DR. SCHOETTLE:
No, they were sequential
8
grafts but I don't have that number available to
9
me.
10 DR. TRACY:
Thank you.
11 DR. SCHOETTLE:
Thanks.
12 DR. TRACY: Dr.
Frater?
13 DR. FRATER: Let me state immediately I am
14
the Medical Director of St. Jude and, obviously,
15
have that as a conflict of interest.
16 I have a few points to make. I had
17
expected ten minutes so I am going to try and make
18
them quickly. I think we can all
agree that the
19
MDR system is a warning light that tells us nothing
20
about incidence and, unless we are very lucky,
21
doesn't give us much information on causality, hard
22
as we try to look into every single report that
23
comes in from the field. I shall
not elaborate on
24
that. I suspect the FDA feels
the same about the
25
MDR's utility as we do.
59
1 The question of comparing anastomotic
2
devices to historically published data for sutures
3
is an interesting one. The data
that was obtained
4
in the past has been cardiac surgeons who were
5
trying to find out what they were doing 30 years
6 ago when they were
making venous anastomoses. The
7
patients were younger. The
vessels were better.
8
The extra conditions, such as diabetes, were far
9
less common and it was a different group of
10
patients. Those patients have
long since been
11
captured by the interventionalists and the cardiac
12
surgeon today faces a very different patient.
13 We need to know what the patency rates are
14
today with the current set of patients.
We also
15
need to know what the difference may be between
16
off-pump and on-pump. There was
a paper presented
17
just a few weeks ago at the ACC, the so-called Prog
18
IV Trial, a randomized comparison between off-pump
19
and on-pump surgery with angiography at one year.
20
The patency rate of the cases performed on-pump at
21
one year was 59 percent; the patency rate of those
22
performed off-pump was 49 percent.
23 There is a paper being published in The
24
New England Journal of Medicine by Kahn. It came
25
out of Britain. Again, a
randomized study of
60
1
on-pump and off-pump anastomoses studied at three
2
months by angiography, which was performed in 80
3
percent of the patients in the trial.
The patency
4
rate of the on-pump cases was exemplary. At three
5
months they had a 98 percent patency rate but the
6
off-pump cases had an 88 percent patency rate at
7
three months.
8 I present this material, which is clearly
9
important in trying to assess what will be the
10
target of patency that we will be looking at in
11
future trials, and a recognition that times have
12
changed and circumstances are clearly very
13
different.
14 We have done a meta-analysis of some 7,000
15
patients in which angiograms were done between 6
16
and 12 months. We chose that 6-
and 12-month
17
period for the obvious reason that you have already
18
heard today, that after 12 months atherosclerosis
19
dominates the failure of vein grafts.
The mean
20
occlusion rate was 16 percent in this meta-analysis
21
between 6 and 12 months of sewn anastomoses. But
22
the range was from 9.5 to 26.5.
There is an
23
immense diversity from different institutions and
24
we can speculate forever, certainly not in five
25
minutes, as to what the reasons for those
61
1
differences are. I am sure that
the surgeons in
2
the Prog IV study have not suddenly become
3
incompetent; there are factors that we need to look
4
at.
5 The question of the extent to which
6
clinical utility data is considered to be
7
necessary, I think we have already begun to deal
8
with this. Six months seems to
be a period of time
9
that people are reaching, and that is not
10
unreasonable considering that stents are a Class
11
III device which may or may not be identical to
12
anastomotic devices--that is debatable--are being
13
evaluated with MACE and target vessel interventions
14
at six months.
15 Certainly, it is reasonable to state that
16
it should not be more than 12 months for the
17
obvious reason that by then atherosclerotic disease
18
dominates. There is intimal
damage and technical
19
factors in the first week, neointimal hyperplasia
20
for the next few months, blending finally into
21
atherosclerotic disease.
22 Now, it is essential that the FDA provide
23
clarity on the type of clearance that we need. If
24
the clinical data requirement reaches the point
25
which would normally be required for a PMA, then it
62
1
should be a PMA. If you are
required to produce
2
the data for a PMA, then the process should be done
3
under a PMA process. Thank you
very much.
4 DR. TRACY: Any
questions?
5 DR. WEINBERGER:
I have a question for
6
you. You said that you were
concerned that the
7
follow-up should be at six months because you
8
thought that atherosclerosis dominates the
9
subsequent natural history of graft failure. I am
10
concerned because we have a pretty good idea that
11
there is distinct biological heterogeneity in
12
different vascular beds in terms of the kinetics of
13
responses to manipulation. For
instance, we know
14
that for coronary interventions basically at six to
15
nine months the process is over.
But if you look
16
in the periphery, like the iliacs, the usual time
17
is three years. Do you have any
data to suggest
18
that the process to response to injury in vein
19
grafts is over at nine months?
20 DR. FRATER:
Well, if you look at the data
21
from peripheral vascular intervention where it is
22
far easier to follow the patients, it seems fairly
23
definite that while there is an acute phase, which
24
is partly technical and partly because of the
25
damage we do to the vein by the various things we
63
1
do when we take it out and manipulated it, it
2
starts in the first week. The
neointimal
3
hyperplasia seems to blend at 12 months in these
4
peripheral vascular studies with the
5
atherosclerotic process. It
would seem reasonable,
6
if there is an atherosclerotic process taking place
7
in veins after 12 months, not to attribute that to
8
how we handled the vein at the time of the initial
9
anastomosis.
10 DR. WEINBERGER:
Just one follow-up, if
11
there is any kinking in the vein and you have a
12
jet, that jet wouldn't lead to an accelerated
13
atherosclerotic process later on as well?
14 DR. FRATER: It
would happen far quicker
15
than that. Usually, if you leave
a kink in a vein
16
there is a consequence that is soon and definite.
17 DR. WEINBERGER:
Data?
18 DR. FRATER:
Data? Clinical experience.
19 I
am a cardiac surgeon.
20 DR. TRACY: Dr.
Bridges?
21 DR. BRIDGES: Yes, there are two points.
22
One is to echo Dr. Weinberger's point that I don't
23
think we know exactly. There is
nothing to suggest
24
that there can't be an interaction between
25
mechanical factors and atherosclerosis that extends
64
1
beyond one year. To say that you
can divide these
2
into two discrete processes that are technical,
3
device related and then atherosclerosis I think is
4
unsubstantiated and you can't really defend that.
5 Furthermore, I am sure we are going to
6
hear from Dr. Mack but his own data that was
7
presented at the STS meeting, just in January,
8
showed, at least in his series which I am sure he
9
will comment on, that it was not until you got out
10
beyond one year that you started to see a
11
difference in MACE, that is, you know,
12
cardiovascular events. So, that,
in and of itself,
13
also suggests that the idea of only looking at a
14
one-year or six-month time period is clearly going
15
to result in us missing failures.
16 DR. FRATER:
The obvious issue is how long
17
would you like it to be?
Clearly, it becomes
18 extraordinarily difficult if you are suggesting
19
that we should wait five years, or something like
20
that. Dr. Mack can speak for
himself but I believe
21
that in diabetes there was a difference and there
22
may well be factors like that that make a
23
difference.
24 DR. BRIDGES:
My point is not to suggest
25
how long we need to look, I am simply objecting to
65
1
the concept that we can definitively or
2
declaratively state at this point, based on what
3
evidence we have, that we know that six months or
4
nine months is an acceptable time frame in order to
5
exclude device-related issues.
6 DR. TRACY: Dr.
Yancy, and then if there
7
is time Dr. Maisel.
8 DR. YANCY:
Just a very short yes/no
9
question. I have not seen the
referred to NEJM
10
article comparing on-pump versus off-pump surgery.
11
Were connectors used in the off-pump cases?
12 DR. FRATER:
This was absolutely a study
13
of on-pump versus off-pump vein patency.
14 DR. TRACY: Dr.
Maisel?
15 DR. MAISEL:
You have eloquently stated
16
that times have changed and that historical
17
controls are just that, historical, and you stated
18
data that the patency rates vary greatly from
19
institution to institution. In
many respects that
20
is a strong argument for randomized trials but you
21
didn't come out and state that.
Are you a
22
proponent of randomized clinical trials to assess
23
these devices?
24 DR. FRATER:
You know, in the best of all
25
possible worlds, yes. I am
speaking as a cardiac
66
1
surgeon now.
2 DR. TRACY:
Thank you.
3 DR. EDMUNDS:
Did I hear you say that the
4
one-year patency rate for off-pump proximal veins,
5
the occlusion rate was 9-26 percent?
6 DR. FRATER: In
the meta-analysis that we
7
did between 6 and 12 months, there was a range from
8
9.5 to 26.5 percent in this meta-analysis of some
9
7,000 cases. In the Prog IV
study--
10 DR. EDMUNDS: For hand-sewn?
11 DR. FRATER:
Hand-sewn anastomoses, in the
12
Prog IV study the patency rate was 59 percent
13
patent at one year on pump, 49 percent patent
14
off-pump. It was just presented
at the ACC.
15 DR. TRACY: We
do have to move on, I am
16
sorry. Dr. Mack?
17 DR. MACK: My
name is Michael Mack and I
18
am a cardiac surgeon in Dallas.
By way of
19
disclosure, I am not sponsored by anybody today. I
20
paid my own way here. I have
served as a
21
consultant in the past at St. Jude, also to
22
Cardica. I have received
research grant support
23
from St. Jude regarding anastomotic devices, and I
24
am also on the scientific advisory board for
25
Medtronic and Guidant, both of which have equity
67
1
interests in anastomotic device companies.
2 The thrust of my presentation was to
3
discuss saphenous vein graft patency and not our
4
own St. Jude device paper, which has been
5
presented, in view of the fact that I only have
6
five minutes but I will try and get this done in
7
four and just spend the last minute discussing
8
that.
9 [Slide]
10 Specifically, what I would like to discuss
11
is I thought until I looked at all this that I knew
12
what the gold standard for saphenous vein graft
13
patency was. Eeverybody throws
around numbers but
14
until I did a meta-analysis of the literature I
15
really didn't know, and this is specifically to
16
address the trial design question number one of the
17
FDA, the gold standard of sutured anastomoses had a
18
well-documented history of over the past thirty
19
years, and I would like to go over those thirty
20
years right now--
21 [Slide]
22 --or the why of saphenous graft failure in
23
five minutes.
24 [Slide]
25 Since between 1979 and 2001 there have
68
1
been thirty studies published, analyzing a total of
2
28,081 grafts.
3 [Slide]
4 Factors impacting the studies are
5 angiogram
survivors. You lose early graft
6
occlusions resulting in death so, therefore, you
7
are automatically losing patency in any angiogram
8
series because you can only angiogram survivors.
9
Studies are impacted by the completeness of
10
follow-up, the percent of patients actually
11
undergoing angiograms, and whether the study was
12
done as a surveillance study or done for cause.
13 [Slide]
14 If we look at a meta-analysis of all
15
studies that looked at 30 days or less, there has
16
been a total of 11,000 grafts looked at. If you
17
just skip to the number at the bottom right, the
18
patency rate at 30 days in these 7 studies,
19
comprising 11,000 grafts, is 87.8 percent.
20 [Slide]
21 If you now look at 3 to 6 months and look
22
at the 10 studies published here, with a total of
23
2,290 grafts, at 3 to 6 months 84 percent is the
24
saphenous vein graft patency.
25 [Slide]
69
1 If we now go to 12 months and look at the
2
13 studies comprising almost 12,000 grafts, the
3
patency rate is 82.7 percent in the literature.
4
[Slide]
5 Lastly, if we look at 2 to 5 years, with a
6
total of 3,100 grafts in these 3 studies, the
7
patency rate between 2 and 5 years is 74.3 percent.
8 [Slide]
9 If we summarize all this, there is a
10
significant attrition in the literature of about 12
11
percent of vein grafts in the first 30 days.
12
Between 30 days and 3-6 months another 3 percent of
13
grafts are lost at that point.
If we go between
14
3-6 months to 12 months another 1.5 percent of
15
grafts are lost. Then there is a
slightly greater
16
attrition from 2 to 5 years. If
you look at
17
overall graft patency of all 28,000 grafts done at
18
any time, it is 84 percent.
19 [Slide]
20 Variables known to impact graft patency
21
include age, gender, diabetes and how well the
22
diabetes is controlled, obesity, which vessel is
23
bypassed, the LAD, the circ. or the right, the
24
target vessel size, the presence of distal disease,
25
the size of the vein graft, harvest injury, whether
70
1
an endarterectomy was done, what the graft flow at
2
time of implant was, individual versus sequential
3
vein grafts, how much myocardium was supplied, what
4
the ventricular function of the patient was,
5
whether lipid management was tightly controlled,
6
whether antiplatelets were used, surgeon
7
experience.
8 [Slide]
9 Variables that are not known how they
10
impact on graft patency has been alluded to.
11
Whether it is done on a beating heart or an
12
arrested heart. That recently
has been called into
13
question. And whether
anastomotic connectors
14
impact positively or negatively on the saphenous
15
vein graft patency.
16 [Slide]
17 I think how you design your study you can
18
get 100 percent patency at ten years if you do an
19
LAD, do it as a sequential and a three millimeter
20
target with no distal disease, use a small vein,
21
have a large run-off in a thin male that does not
22
have insulin-dependent diabetes and normal ejection
23
fraction, does not have a hypercoagulable state, is
24
on antiplatelet agents and is well controlled with
25
statins. On the other hand, you
can do the
71
1
converse of all those and you will end up with a 10
2
percent patency rate in less than 30 days.
3 [Slide]
4 In conclusion, I think that many variables
5
other than anastomotic connectors impact graft
6
patency. Angiography is the only
reliable method
7
to determine patency.
Meta-analysis reveals an
8
overall saphenous vein graft patency of 80-85
9
percent. There is no significant
difference from
10
3-6 months versus 12-16 months or, for that matter,
11
even between 30 days and the latter two endpoints.
12
An angiographically normal graft at the earlier
13
study times is often likely to develop occlusion on
14
later follow-up and, in my opinion, a 6-month
15
angiographic endpoint is adequate to evaluate graft
16
patency with anastomotic devices.
17 Real quickly regarding our experience, it
18
has been published on the St. Jude device. We did
19
find that there were events that happened after six
20
months. These were clinical
events. The study
21
that we performed was very similar to Dr.
22
Schoettle's. We took a one-year
experience with
23
the St. Jude device and compared it to one-year
24
previously with a similar cohort of patients and
25
found that there was a higher incidence of clinical
72
1
events in the St. Jude patients.
However, these
2
were all limited to diabetics.
We looked at the
3
non-diabetic population and we looked at all
4
possible variable by logistic regression diabetes
5
was the only thing that sorted out.
The
6
confounding variable in all this is that all these
7
procedures were also done on a beating heart.
8
Thank you.
9 DR. TRACY:
Thank you. Panel, you have 4
10
minutes and 36 seconds to ask questions. Any
11
questions? Dr. Weinberger?
12 DR. WEINBERGER:
In surgical literature
13
everyone seems to focus on patency.
Are you
14 interested at all in morphology, like quantitative
15
angiography looking at 30 percent stenosis, 40
16
percent stenosis? Is that
information valid to
17
surgeons?
18 DR. MACK:
Absolutely. Because I do think
19
that that is a precursor of potential total
20
occlusion.
21 DR. WEINBERGER:
And if that is the case,
22
are your angiographic colleagues who have looked at
23
these connectors able to assess the morphology
24
right around the metallic connector adequately?
25 DR. MACK: I
think the answer is yes.
73
1 DR. KRUCOFF:
Not being as familiar with
2
the surgical literature, in this list you sort of
3
ended with do you think there is sufficient data to
4
create a real propensity score in planning a trial?
5 DR. MACK: Yes.
6 DR. KRUCOFF:
To actually create risk
7
categories that could be sufficiently evaluated in
8
new populations?
9 DR. MACK: Yes,
I do. I think that
10
everything I listed there--one study or another has
11
listed those factors implicating graft patency and,
12
yes, I think you can develop a propensity score.
13 DR. TRACY: Dr.
Edmunds?
14 DR. EDMUNDS:
Mike, you said that all of
15
these were off-pump bypasses.
16 DR. MACK: In
our St. Jude experience,
17
yes.
18 DR. EDMUNDS:
Were they mostly right
19
grafts?
20 DR. MACK:
First of all, we did not have
21
any connectors placed to the LAD so they all went
22
to diagonal circumflexes or right, and which vessel
23
it went to, in our experience, did not sort out as
24 a
factor.
25 DR. EDMUNDS:
But non-LAD?
74
1 DR. MACK: All
non-LADs.
2 DR. EDMUNDS:
And these were surveillance
3
angiograms, not for symptoms?
4 DR. MACK: No,
the surveillance was
5
clinical events only. The only
angiograms--
6 DR. EDMUNDS:
So, you have bias towards
7
symptomatic patients.
8 DR. MACK: The
endpoint was not
9
angiography. The endpoint of our
study was
10
clinical events, major adverse events at now two
11
years of follow-up. We did not
do a specific study
12
angiogramming the patients. The
only angiograms we
13
had was in patients that were done for cause.
14 DR. EDMUNDS:
The 28,000 patients were
15
from 30 studies, weren't they?
16 DR MACK: Okay,
I am mixing up your
17
question then. Ask again, Hank.
18 DR. EDMUNDS:
Well, the cohort of 28,081
19
angiograms was from 30 papers--
20 DR MACK:
Right.
21 DR. EDMUNDS:
--and were those
22
surveillance angiograms or for symptoms?
23 DR. MACK: I am
sorry, I thought you were
24
talking about our own experience with the
25
connectors.
75
1 DR. EDMUNDS:
No, I am sorry, Mike.
2 DR. EDMUNDS:
No, all of those were
3
surveillance. Any that was done
for cause and I
4
did not include in that. All
those were
5
surveillance studies. Similarly,
there were a
6
couple of other studies that looked at just
7
saphenous vein graft, the LAD, I did not include
8
those because those were abnormally high.
9 DR. TRACY: Dr.
Bridges, did you have a
10
question?
11 DR. BRIDGES:
My question really is that
12
given that in the results you presented recently
13
there was a difference in major adverse
14
cardiovascular events, I guess in the manuscript
15
that I have seen a draft of it was limited to
16
diabetic patients. However,
those were non-insulin
17
dependent diabetics, I believe, and I was wondering
18
if you had a hypothesis as to why non-insulin
19
dependent diabetics would be different than insulin
20
dependent diabetics. Given that,
should we be then
21
separating diabetics from everyone else in terms of
22
determining the applicability of these devices?
23 DR. MACK: That
is an excellent question,
24
and we were a little bit surprised to find that
25
that was the case also because from the stent
76
1
experience you would expect it would be more so in
2
insulin dependent diabetics but such was not the
3
case. We have hypothesized that
perhaps it was due
4
to the fact that with non-insulin dependent
5
diabetic oral agents the blood sugar is not as
6
tightly controlled, but we have no proof; it is
7
total hypothesis.
8 I also think that the way that we look at
9
diabetes now, today, is totally blurring the line
10
between insulin dependence and non-insulin
11
dependent diabetics. I think we
have a lot of
12
metabolic syndrome patients who are actually Type 2
13
diabetics but are insulin dependent and we are
14
actually categorizing them as insulin dependent
15
when, in fact, they really should not be.
16 DR. TRACY:
Thank you. Dr. Slaughter?
17 DR. SLAUGHTER:
Thank you. I was asked to
18
speak today on behalf of Converge, and I am a U.S.
19
investigator for their ongoing trial for distal
20
anastomotic studies and they did pay my travel here
21
but I have no other financial relationship with
22
them.
23 [Slide]
24 To date so far we have heard predominantly
25
about proximal anastomotic devices and what I would
77
1
like to do is to tell you a little bit about a
2
current and ongoing look at distal anastomotic
3
devices.
4 [Slide]
5 Certainly, this comes up in many issues
6
and I don't think we need to belabor the fact but
7
perhaps at the end I will comment briefly on some
8
of the other questions asked, but there is still no
9
question, and it is really sort of one of the
10 unspoken issues for any outcome for the patient,
11
and that is, you know, the quality of anastomosis
12
and the overall revascularization and long-term
13
patency. Certainly surgeon skill
is very
14
important. There are also the
other issues of the
15
anatomy, disease state, access and visibility that
16
would affect these things. But
all these things
17
are very important in determining not only acute
18
but long-term graft patency and the overall outcome
19
for the patient.
20 [Slide]
21 This has been brought up now several times
22
and I think is very important.
This is just
23
another way of presenting it. It
is looking at
24
sort of the time scale injury.
That is, as was
25
brought up by Dr. Weinberger as well, there is no
78
1
question that there is good information and good
2
data as to the initiation of the injury,
3
inflammation and then subsequently intimal
4
hyperplasia. As a rule of thumb,
the idea is that
5
within, say, six to eight weeks the injury has
6
stopped. I don't think anybody
in their right mind
7
would argue that there is not heterogeneity and
8
certainly there are differences within patients.
9
Certainly that would show up as stenosis and
10
changes in morphology, as you mentioned.
11 But the idea is there is reasonably good
12
science and information to suggest that within
13
about 60 days a vascular anastomosis has healed,
14
particularly within the coronary-arterial tree.
15
So, beyond that time, if there are graft failures,
16
the question is what are they due to, and it is
17
generally due to ongoing atherosclerosis, intrinsic
18
patient factors and/or perhaps a lack of medical
19
therapy such as antiplatelet agents, aspirin and/or
20
Plavix.
21 So, you know, if hand-sewn anastomosis is
22
so perfect, why are we here today?
The issue is
23
they are not perfect and there certainly is room
24
for improvement. Certainly, by
hand sewing in a
25
bad distal vessel it is calcified in a diabetic.
79
1
They have lateral calcification.
By piercing them
2
with needles--we all had that experience, you end
3
up with plaque rupture. You have
hemorrhage within
4
the media. The idea is this is a
traumatic event.
5
[Slide]
6 The other is reliability. The issue is
7
how can you do it day to day, 20,000 a year. The
8
idea is you want to make it as
reliable as
9
possible and it needs to be reproducible between
10
different surgeons at different institutions.
11 The other is it must be reversible. The
12
idea is if you don't like it you have to cut the
13
suture, take it out and redo it.
You want to be
14
able to do the same thing, perhaps in a less
15 traumatic
fashion, with a coupler device.
16 The other is it must be easy to use. The
17
idea is if anybody walks up to the podium and is
18
giving you a talk, they basically should all be
19
able to have the same results without any
20
significant extensive training.
21 The other is I think we do need to realize
22
there are differences between proximals and
23
distals. I don't think we need
to spend a lot of
24
time on this today but the main two differences are
25
the flow dynamics which clearly are different at
80
1
the proximal and distal ends, as well as tissue
2
characteristics. On the tissue
characteristics, on
3
the right it is either going to the aorta or vein
4
aorta or artery depending on which you conduit you
5
use. Certainly for distal
anastomoses what you are
6
looking at is vein to coronary artery or an
7
arterial conduit to an artery but it is a very
8
different scenario.
9 Also, with flow dynamics there is no
10
question that the size or the shape of the opening
11
or the angle of the take-off is very important, the
12
pressure differential, as well as the vessel
13
diameter throughout the length.
14 [Slide]
15 I think one other issue which hasn't been
16
brought up today which does need to be mentioned,
17
at least just to bring it up, is actually the type
18
of material. I think this sort
of goes into the
19
heterogeneity or perhaps ongoing injury to intimal
20
hyperplasia. These are not new
materials. They
21
have all been used before. They
have all been used
22
in intravascular scenarios and the idea is there is
23
good evidence to suggest, whether it is nitinol,
24
stainless steel, titanium, that they are
25
compatible, and I don't think that we can sort of
81
1
imply or say that they are intrinsically the source
2
of perhaps later stenoses or some ongoing failures
3
beyond the eight-week time period.
Certainly there
4
is the heterogeneity of healing in some patients
5
but it is a relatively small number.
It is like a
6
cheloid. Some patients get
cheloids but not all.
7
The answer is you see it as it progresses. If you
8
follow them and you look for it you can identify
9
who those patients are.
10
[Slide]
11 I would like to just show you a histologic
12
series which I think is interesting in helps people
13
visualize. Really the sort of
best description I
14
think for the Converge distal anastomotic device is
15
that of sort of a compression clip.
The idea is it
16
is two frames which are expandable.
In the upper
17
right it sort of gives you the diagrammatic picture
18
of a graft into the artery. The
important thing
19
here is that you now are able to mechanically
20
manipulate flow dynamics as well as other
21
engineering aspects so you get a perfect 30 degree
22
take-off; you get perfect dynamics.
You won't get
23
turbulence at the site of the anastomosis.
24 The left side shows the bypass graft,
25
which is CABG going down to the circumflex artery.
82
1 I
think the important thing here is this was done
2
at 90 days but, once again, the idea is it is
3
completely endothelialized so the idea is if you
4
get an angiogram at six months and you have a
5
normal lumen you have no narrowing.
The idea is
6
are you going to have ongoing intimal hyperplasia
7
that would be an unexpected finding?
I think the
8
answer is no.
9 DR. TRACY: If
you could finish up in the
10
next few sentences.
11 DR. SLAUGHTER:
Sure, I can finish up in
12
about 30 seconds.
13 [Slide]
14 The idea is you see very clearly that it
15
is a well healed anastomosis and you have the
16
advantages.
17 [Slide]
18 This has already been brought up. The
19
idea is are historical controls acceptable? I
20
think the answer is yes.
21 [Slide]
22 There is no question there is lots of
23
existing data. We have also lots
of information to
24
suggest not only at seven days but at years out
25
that you can evaluate intimal hyperplasia.
83
1 [Slide]
2 Certainly angiography--we know the causes
3
of failure, early failure and what we need to do is
4
differentiate between a device failure and ongoing
5
atherosclerosis.
6 [Slide]
7 I will just show--
8 DR. TRACY: I
am sorry, we are just going
9
to have to cut this off if we are going to have
10
time for questions from the panel.
11 DR. SLAUGHTER:
I apologize.
12 DR. TRACY: We
have three minutes left for
13
questions from the panel.
Anybody? Dr. Hirshfeld?
14 DR. HIRSHFELD:
I would just point out
15
that in the coronary stent experience if we used a
16
two-month follow-up we never would have discovered
17
restenosis.
18 DR. TRACY: Dr.
Krucoff, did you have a
19
comment?
20 DR. KRUCOFF: I
would just also say that
21
in the stent experience I think if we started with
22
historical controls based on lung literature, we
23
would have left a lot of important information out.
24 DR. SLAUGHTER:
I think the one difference
25
though, and this has come up I think in other
84
1
discussions with the FDA panel, is that although it
2
uses a similar material and it is stent-like, it is
3
not a stent. The idea is it is
just the edges that
4
are present along the edges of the coronary artery.
5
It is not compressed plaque and the idea is it is
6
very different. It is really
sort of a compression
7
clip that applies the vein graft to the distal
8 coronary artery.
9 DR. TRACY: Dr.
White?
10 DR. WHITE: I
think there is no evidence
11
for that, and I think everything that we have heard
12
today sounds like it is a stent, although a stent
13
in a graft. So, the question
would be if you don't
14
believe it is a stent, then you should show us data
15
that suggested that intimal hyperplasia within the
16
tube is not the primary cause of these closures.
17 DR. SLAUGHTER:
Sure.
18
DR. YANCY: And because of that, I think
19
it is even more important to state that historical
20
controls would be really problematic I think.
21 DR. TRACY: Any
other comments from the
22
panel?
23 [No response]
24 Thank you. Is
Mr. Lotti here?
25 [No response]
85
1 We will move on then to Dr. Martin.
2 DR. MARTIN:
Good morning. As so many
3
members of the panel have already suggested,
4
including Dr. White, I can make my comments brief.
5
My name is Dr. Frank Martin. I
am Chairman of the
6
Department of Cardiology at Methodist Care in
7
Memphis, one of the largest private hospitals in
8
the country. I have no financial
ties with any
9
anastomotic device companies or, for that matter,
10
any stent companies.
11 My historical experience, I trained with
12
John Simpson back in 1985, '86, and have
13
relationships with many of the members of this
14
panel. I trained with people who
are icons today,
15
like Paul Yak, Paul Tierstien, Dean Keriakus, Met
16
Selman, Morris Bookbinder, Rock Califf, Eric Topal
17
and did interventional cardiology until
18
approximately four years ago and made a life style
19
change, and now I do only diagnostic caths and do
20
my chairmanship. Also as
discussed earlier, in the
21
late 1980s, with Dr. Chris White, we did brachy
22
therapy because some of the early DCA slides showed
23
needle intimal hyperproliferation similar to
24
cancer.
25 That having been said, I, as many of you
86
1
all, have honed this sixth sense of skill with
2
cardiology over the last 15 years of practice. Dr.
3
Phil Schoettle, who has already presented here
4
today, and I have worked collaboratively for the
5
last 20 years. We basically make
a good team
6
because he knows what I do and I know what he does.
7 Our group opened one of the first
8
outpatient cardiac cath labs and it was a labor of
9
trust on his part. Both of us
have a sixth sense
10
about when patient is dissected and needs to go to
11
surgery urgently, and have always had that sort of
12
feel. Obviously, in the early
days of intervention
13
with PRCA lots of patients went to CABG and, of
14
course, more and more patients went to CABG at that
15
time than do now.
16 So, imagine my chagrin in September of
17
2002 when I cath'd an ER nurse friend of mine and
18
found one occluded and two stented Symmetry aortic
19
connectors, the first patient I had ever seen.
20
When Dr. Schoettle referred to September, 2002 that
21
was the watershed moment. I
walked out of that
22
cath, called him and said, Dr. Schoettle, I don't
23
know what this device is but it is a stent and it
24
will act like a stent and it will always be a
25
stent. I said, what is it? What do we know about
87
1
it? And, he basically told me
his experience over
2
the last ten months.
3 At that point I found an interventional
4
colleague of mine and said, what are these devices?
5
He said he had been stenting them since April; he
6
didn't know much about them. I
did an Internet
7
search and found out they were made in nitinol, and
8
realized at that point in time that no
9
cardiologists were involved in either the research,
10
the design, the implementation or the roll-out of
11
this device basically because all the
12
cardiologists, interventional cardiologists,
13
especially know the problems associated with that.
14 It took me about 45 days, almost two
15
months, with multiple interventional colleagues of
16
mine and surgeons in Memphis to have it withdrawn
17
from all the shelves of all three hospitals in
18
Memphis, Tennessee, and that was in the latter part
19
of fall of 2002.
20 As patients have returned to the clinic,
21
dozens, and dozens, and dozens have been found to
22
have virtually total and/or subtotal occlusions of
23
these devices. The first contact
I had with St.
24
Jude was in December, 2002 after I had gone to TCT,
25
in September I believe, and HA in November, telling
88
1
them about the problem with these devices and why
2
they acted like stents. Finally,
they walked in on
3
me while I was cath'ing a 70 year-old ob/gyn who
4
had two patently occluded Symmetry aortic
5
connectors. Basically, I said
this is the problem.
6
You don't understand anginal syndrome because most
7
of these patients won't come back with chest pain
8
for multiple reasons--denervation of the heart;
9 more
LV dysfunction problem. You don't
understand
10
the role of clopidogrel or Plavix in these patients
11
because most of them go to surgery without Plavix
12
on board, and you don't understand the fact that in
13
stent pathology, which we obviously cath a lot, you
14
can have one patent graft, for instance the LIMA
15
which most of these patients get, and the other two
16
can subtotally occlude slowly and their only
17
symptom is LV dysfunction.
18 We, as cardiologists, as members of this
19
panel, diagnose ischemia. We
send these patients
20
to a surgeon for treatment and continue to reattach
21
and stent these folks. They will
come back for
22
years with their LIMAs. An
anecdotal experience of
23
one surgeon in Jonesboro, Arkansas, close by
24
Memphis, asked two of the cardiologists in his
25
community, "so what's up with this Symmetry aortic
89
1
connector?" And the
cardiologists response was,
2
"are you having any problems?" And he said, "well,
3 I
don't know." And they said,
"well, don't worry
4
about it."
5 He wasn't satisfied with that, came to
6
Memphis, we cath'd him and his two connectors were
7
occluded and his lumen was patent.
After
8
intervention he told me that as an oral surgeon he
9
uses nitinol every day to induce scar tissue
10
formation and keep bridge reconstruction in place.
11 The
fact that you auger a hole in the aorta, hold a
12
finger over it beginning the platelet clotting
13
cascade, implant a metallic device with hooks
14
without the benefit of loading doses of Plavix or
15
predictable absorption is inconceivable.
16 The idea of a connector makes sense for
17
improvement of stroke risk, however, I feel the
18
present device should be withdrawn and should have
19
been withdrawn years ago.
Basically, I think the
20
cardiologists need to be involved in any future
21
trials or designs and I think to do otherwise is a
22
violation of our sacred oath to our patients.
23
Thank you.
24 DR. TRACY:
Thank you. Any questions from
25
the panel? Comments?
90
1 [No response]
2 Thank you. Dr.
Hausen?
3 DR. HAUSEN: By
way of introduction, my
4
name is Bernard Hausen. I am the
present CEO of
5 Cardica.
My background, I am a cardiac surgeon by
6
training. My financial conflicts
are inherent with
7
my position, otherwise I have none other.
8 [Slide]
9 I want to use this opportunity to show you
10
new generation of products that we are developing
11
beyond the pioneers in this field that we have been
12
discussing so far.
13 [Slide]
14 We have two products in the pipeline. One
15
is a distal anastomosis system.
16 [Slide]
17 It is called C-Port and it is based on the
18
principle of simulating interrupted stitch distal
19
anastomosis by applying a set of eight implantable
20
clips, all simultaneously, and performing
21 arteriotomy
with the push of one button. This type
22
of a system results in a minimal amount of metal
23
exposure. It is a applied in
distal anastomosis
24
and it is in clinical evaluation as we speak.
25 [Slide]
91
1 This is just a video showing how it works.
2
This is a 1.5 mm LAD. You insert
the anvil; pull
3
it out and you are basically done; place one stitch
4
to close the anvil insertion
hole. This is a 1 mm
5
diagonal cadaver heart and shows how it works.
6 This technology, we believe, will enable
7
beating heart surgery as it is quick and does not
8
require any temporary ischemia of the myocardium
9
during placement.
10 [Slide]
11 We have a second device which is called
12
PAS-Port. It stands for proximal
anastomosis
13
system, and it is a second generation proximal
14
system. We have the advantage of
being a company
15
that is going to be able to take advantage of the
16
knowledge from the predecessors, predicate devices.
17 [Slide]
18 So we were able in our design to spend a
19
lot of time on key improvements from things we have
20
learned from the other devices.
We have focused on
21
trying to minimize or completely eliminate
22
endothelial trauma of the graft during loading. We
23
wanted to minimize blood-exposed non-endothelial
24
tissue, i.e., metal exposure. We
wanted to
25
maximize the orifice area and reduce the incidence
92
1
of kinking by a low profile.
2 [Slide]
3 We did that by basically having nothing
4
touch the endothelium of the vein during loading or
5
deployment. This is a
cross-section of the
6
implant.
7 [Slide]
8 We have a minimal amount of metal exposed
9
with the stainless steel device.
It is the same
10
material as is being used for coronary stents. And
11
we wanted to maximize the orifice, especially for
12
small vein grafts, and have a very low profile
13
height.
14 [Slide]
15 For all this we have done a clinical
16
trial. We have had a lab
cardiologist review our
17
data by QCA and determine what is the amount of
18
narrowing of the implant versus the graft body.
19
They first looked at some hand-sewns that were done
20
concurrently in those patients and, as you can see,
21
the average narrowing of a hand-sewn is about 5
22
percent at discharge and about 18 percent at 6
23
months. This is in agreement
with all the
24
published literature.
25 [Slide]
93
1 Then we asked them to look at the PAS-Port
2
data. What you find, and you can
hardly see this,
3
this is a minus 7 percent narrowing, i.e., the
4
grafts at the anastomosis are larger than they are
5
in the graft body and that is by design. That is
6
how the implant has been designed.
7 Now at 6 months, the most important
8
figure, the average narrowing is 3 percent compared
9
to 18 percent in hand-sewns. I
propose that if a
10
device had a problem at discharge or at 6 months
11
you would be seeing that in this quantitative
12
analysis. If you don't see it
because the
13 injurious
event was at the time of surgery, you are
14
very unlikely to see it going forward besides the
15
normal decay of a vein graft, as alluded to by the
16
previous speakers.
17 [Slide]
18 So, Cardica's regulatory position is we
19
are applying for 510(k) clearance based on
20
prospective multicenter non-randomized trials, and
21
our primary study endpoint for this distal device
22
is vessel patency at discharge and 6 months, and
23
for the proximal device performing a vessel patency
24
study at 6 months with QCA.
Thank you very much
25
for your attention.
94
1 DR. TRACY:
Thank you. Any questions?
2 Dr. White?
3 DR. WHITE: I
just noticed that on the
4
last slide you said you were going to do MRI
5
follow-up on these metal grafts.
How are you going
6
to do that?
7 DR. HAUSEN: We
have done that on the
8 proximal anastomotic
device. Basically, with the
9
gadolinium contrast injection you can see--the only
10
thing CTs and MRIs allow you to do is determine is
11
the graft patent or not. You
cannot evaluate the
12
degree of stenosis at the implant.
So, a preferred
13
method is a quantitative angiography.
14 DR. WHITE: Do
you have experience with
15
MRI?
16 DR. HAUSEN: We
have done five MRIs in the
17
patients in this study.
18 DR. WHITE: And
also CT?
19 DR. HAUSEN:
And CT too and MDCT.
20 DR. WHITE: And
there is no difference in
21
your hands?
22 DR. WHITE: I
like the MDCT much better.
23 I
think the image is much clearer. The
3-D
24
reconstructions are very impressive.
25 DR. AZIZ: And
how does that correlate
95
1
with angiograms?
2 DR. HAUSEN: It
depends on what your
3
outcome variable is. If you want
to just know if
4
the graft is patent or not, there is a very, very
5
good correlation. That has been
shown in the
6
literature. If you need more
than that, if you
7
need to know is there a degree of narrowing, that
8
will not suffice.
9 DR. AZIZ: If
you do distal anastomosis if
10
you have bleeding, how can you control that? Can
11
you put a regular stitch over that?
12 DR. HAUSEN:
Yes, you can. It is the same
13
as a steel device. It is very
firm. The pull-out
14
force of this device is very high because stainless
15
steel is three times stiffer than nitinol. So,
16
what you do, you just place the first string around
17
the anastomosis and slowly tighten it.
That brings
18
the aorta closer to the implant--
19 DR. AZIZ: If
you do distal anastomosis if
20
you have bleeding, can you do regular stitches?
21 DR. HAUSEN:
Yes.
22 DR. AZIZ: You
have obviously shown a vein
23
graft. If you had an arterial
graft can you use
24
your same distal anastomotic site for that?
25 DR. HAUSEN:
This generation of device,
96
1
no; the next generation, yes.
2 DR. TRACY: Dr.
Bridges?
3 DR. BRIDGES:
You showed differences in
4
percent stenosis of the proximal anastomoses at
5
discharge and at 6 months.
6
DR. HAUSEN: Yes.
7 DR. BRIDGES:
What about occlusion or
8
patency at the same time points?
9 DR. HAUSEN: We
have 87.9 percent patency
10
rate so we had 6 occlusions in 50 implants, which
11
is 100 percent in agreement with the historical
12
data from the meta-analysis you saw and we did too.
13 DR. BRIDGES:
So, how would you interpret
14
the fact that in spite of having a higher orifice
15
area or diameter you have the same patency at the
16
6-month time point?
17 DR. HAUSEN:
That is wonderful proof that
18
it has nothing to do with the connector. It is
19
probably your distal run-off or any of the other
20
200 factors that Dr. Mack said.
21
DR. AZIZ: If you had a very thick
22
proximal ascending aorta--
23 DR. HAUSEN:
Yes?
24 DR. AZIZ:
--sometimes you do a hand-sewn
25
vein graft that dunks in and obviously you don't
97
1
want that.
2 DR. HAUSEN:
Yes.
3 DR. AZIZ: Does
your anastomosis
4
technique--where would that fit in?
Would the vein
5
also dunk in?
6 DR HAUSEN: It
is inverted over the
7
implant so it is in the lumen but, because it is a
8
stainless steel implant, it props the anastomosis
9
open and you will not have lumen reduction, if that
10
is where you are heading towards.
And we have
11
shown that, minus 7 percent widening of the
12
anastomosis is evidence that that is exactly what
13
the implant does and it accommodates the varying
14
thickness of the aortic wall because it is like a
15
paper clip. It can adjust to
varying thicknesses.
16 DR. AZIZ: And
the angle at which it comes
17
off proximally, is that oblique or head-on?
18 DR. HAUSEN: It
is theoretically 90
19
degrees. We asked our core lab
to evaluate that
20
too. There are hardly any at 90
degrees. They
21
vary from 10-70 degree take-offs.
Because the
22
hinge point is so small, only 1.5 mm, the vein can
23
come off almost at any angle it wants to.
24 DR. AZIZ: So,
could you take the proximal
25 along through the transverse sinus and pull it
98
1
through?
2 DR. HAUSEN:
You could, yes.
3 DR. AZIZ: You
could?
4 DR. HAUSEN:
Yes.
5 DR. EDMUNDS:
What is the size of the shoe
6
inside the vessel?
7 DR. HAUSEN:
The shoe inside the vessel?
8 DR. EDMUNDS:
Against which you are
9
putting the clamps down. The
part of the device
10
that goes inside the vessel, what are the
11
dimensions of that shoe of the device?
12 DR. HAUSEN:
There is really nothing
13
inside the vessel. The vein is
pulled through the
14
implant and inverted so there is no metal inside,
15
except for the prongs that penetrated the vein and
16
then go outward. I would be more
than happy to sit
17
down afterwards and show you maybe some work. I am
18
kind of limited by the time here.
19 DR. AZIZ: Can
you do a sequential of this
20
for the distal anastomosis?
21 DR. HAUSEN:
No. Well, you could if you
22
did your side by side by hand, absolutely.
23 DR. TRACY:
Thank you very much. Prof.
24
Klima?
25 PROF. KLIMA:
Ladies and gentlemen,
99
1
members of the panel, my name is Uwe Klima.
2 [Slide]
3 I am a full professor at Hanover Medical
4
School for Cardiac Surgery. The
financial
5
disclosure I have to make is that Ventrica paid for
6
my trip here and my lodging, and Ventrica provided
7
us with an unrestricted grant for preclinical
8
testing of an anastomotic device three years ago.
9 [Slide]
10 I expected a talking time of ten minutes
11
and I will try to cut that down to five minutes.
12
Basically, what I want to talk about is mechanisms
13
of how wound healing takes place after an
14 anastomosis; give you some of our clinical
15
experience with hand-sewn anastomosis, especially
16
with our MIDCAB series; more update or experience
17
with our anastomotic devices; and I will have a
18
little discussion of appropriate methods and
19
follow-up time frames for CABG surgery.
20 [Slide]
21 As background, we all know that hand-sewn
22
anastomoses now are more or less on the market for
23
more than four decades.
Everything is pretty much
24
well tested and evaluated. We
have a pretty clear
25
understanding of what happens to an anastomosis.
100
1
What happens is a healing response--at what time
2
frame this will be stable. So, I
will go into
3
details with my next slide.
4 [Slide]
5 There are several publications out now
6
which tell us exactly what happens after an
7
anastomosis has been performed.
We know there is a
8
lot of trauma coming after surgery.
Cell
9
proliferation is coming out. And
the most
10
important message that comes out of this
11
publication, for example, is that the repair
12
process is about to be completed two months after
13
surgery.
14 [Slide]
15 We wanted to know what is happening with
16
anastomotic devices. Is it the
same response? Can
17
we expect the same thing to happen?
Filsoufi
18
published, from Boston. He tested
the Ventrica
19
device and what is happening after implantation two
20
months, three months and six months after surgery,
21
and we could see that there is a single layer of
22
endothelium covering after two months, three months
23
and after six months and there was no sign of any
24
inflammatory response at the site of the
25
anastomosis.
101
1 [Slide]
2 As a control group--I would like to speak
3 a
little bit about our MIDCAB experience in
4
Hanover. We have now enrolled
more than 700
5
patients. Out of the first 500
patients we did
6
angiographic follow-up in 6-7 percent of these
7
patients. The first group, which
was the big one
8
with 297 patients, had a pre-discharge angiogram.
9
What was pretty interesting was that in about 6
10
percent of these patients we had a highly
11
significant problem at the site of the anastomosis,
12
as you can see here. As a
Swedish colleague
13
presented his data with the same problem four years
14
ago at the ASCTS and recommended just to wait
15
because this is part of the healing response, we
16
changed our politics, which you will see on the
17
next slide, and just let the whole situation be as
18
it was; waited for 3-6 months, reevaluated these
19
patients and saw that the degree of stenosis or the
20
number of intimal hyperplasia went down without any
21
intervention from 6 percent to 1 percent.
22 [Slide]
23 There is another example here and, as you
24
can see again, there is a highly significant
25
stenosis here at the pre-discharge angiogram;
102
1
perfect anastomosis 3-6 months later when we
2
reevaluated the patients. What
we learned here is
3
that the healing response is still evolving in the
4
earlier time frame. We changed
our angiographic
5
follow-up from pre-discharge to a 6-month follow-up
6
so the remaining 203 patients were evaluated 6
7
months after surgery instead of having a
8
pre-discharge angiographic follow-up.
9 [Slide]
10
So, what is the Hanover
experience now
11
with anastomotic devices? Just
to give you a quick
12
overview, Hanover does approximately 2,000 open
13
heart procedures per year. It is
a large teaching
14
institution. We are affiliated
with several
15
research centers so we are exposed to new
16
technologies and clinical trials.
The studies I
17
have performed were with Ventrica, St. Jude and
18
Converge. In addition, I have a
little experience
19
also with Cardica and Coalescent, however, I just
20
want to present you the data where I have
21
angiographic follow-up.
22 [Slide]
23 St. Jude--we had a prospective, randomized
24
trial with 11 patients where every patient received
25
two proximal anastomoses. One
was hand-sewn and
103
1
the other one was an automatic anastomosis. This
2
is the strongest study design that you can create.
3
The data that we saw was that in 11 patients who
4
were enrolled in the study and came back after 6
5
months and there were 10 postoperative angiograms
6
showing that only 3 grafts were patent.
We had 6
7
occlusions and 1 highly significant stenosis at the
8
site of the anastomosis, with a consequent PTCA and
9
stent after graft. Even though
the patients were
10
asymptomatic, the study was stopped because the
11
data did not look the way we wanted to have it.
12 [Slide]
13 Even though all patients were
14
asymptomatic, due to several reasons that we can
15
discuss, I think independent of the cause a
16
prospective six-month angiographic evaluation was
17
sufficient in our study to detect performance
18
issues of the device.
19 [Slide]
20 Ventrica was part of a multicenter trial
21
that we did with two other centers.
We enrolled
22
100 patients, 48 came from Hanover--
23 DR. TRACY: Can
I ask you to start
24
wrapping up?
25 PROF. KLIMA:
Yes. The most important
104
1
information I want to give you here is that in the
2
first 48 patients we had a pre-discharge angiogram
3
and a 6-month angiogram to study efficacy of the
4
device and performance of the anastomosis after 6
5
months.
6 [Slide]
7 The last study we did was with Converge.
8
It was also a multicenter trial.
We had 8 weeks of