UNITED STATES OF AMERICA
	DEPARTMENT OF HEALTH AND HUMAN SERVICES

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	FOOD AND DRUG ADMINISTRATION

	OFFICE OF DEVICE EVALUATION

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	WORKSHOP ON PRE-CLINICAL TESTING FOR
	ENDOVASCULAR GRAFTS

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	Tuesday,

	July 31, 2001

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		The Workshop was called to order at 9:05 a.m., in Conference Room Number 1, of the Gaithersburg Holiday Inn, Two Montgomery Village Avenue, Gaithersburg, Maryland by Director Jim Dillard, presiding.

PRESENT:

HUGH G. BEEBE, M.D.          Steering Committee
DOROTHY ABEL                 Steering Committee
MEGAN MOYNAHAN               Steering Committee
LOU SMITH                    Steering Committee
MICHAEL MORTON               Steering Committee
MARK DEHDASHTIAN             Steering Committee
STEVE WEINBERG               Steering Committee
MARK FILLINGER, M.D.         Invited Participant
THOMAS FOGARTY, M.D.         Invited Participant
BARRY KATZEN, M.D.           Invited Participant
MICHAEL LAWRENCE-BROWN,M.D.  Invited Participant
JUAN PARODI, M.D.            Invited Participant
RODNEY WHITE, M.D.           Invited Participant
GEOFF WHITE, M.D.            Invited Participant

	C-O-N-T-E-N-T-S
	PAGE

I.	Administrative Remarks	3
	Director Jim Dillard

II.	Introductory Remarks	8

III.	Presentation by Dr. Huge G. Beebe	19

IV.	Presentation by Dr. Barry Katzen	28

V.	Comments and Summary Statement	41

VI.	Presentation by Dr. Juan Parodi	49

VII.	Comments and Summary Statement	54

VIII.	Presentation by Dr. Geoff White	63

IX.	Comments and Summary Statement	78

XI.	Presentation by	81
	Dr. Michael Lawrence-Brown

XI.	Day One Wrap-Up	101

	P-R-O-C-E-E-D-I-N-G-S
	(9:05 a.m.)
		DIRECTOR DILLARD:  Good morning.  My name is Jim Dillard, and I am the Director of the Division of Cardiovascular Respiratory Devices, in the Office of Device Evaluation, at the Center for Devices in Radiological Health.  
		And so we have put up only one of those little bit of acronyms because I think really from my perspective certainly in the Office of Device Evaluation, we rely very heavily on the other components within the center.
		Certainly our Office of Science and Technology, and a number of the other offices, that really pull together in combination with all of what we do -- pre-market, post-market, pre-clinical testing, and clinical testing, to try to come up with the best sort of test methodologies to bring products to the market.
		And I am very pleased to be here today, and I certainly wanted to welcome everybody.  I know that this has been a large effort.  Hopefully this will be the first annual Endovascular Graft Worksheet.
		It has been a large effort certainly not only on FDA's part, but I think from everybody's perspective here in the audience, and we really appreciate you making the time to come to today to talk about a very important issue, and a very important new technology.
		And I think one that is probably very revolutionary in everybody's minds here, or you probably wouldn't be here.  But also is in its infancy, I think, in its development stages.  And from the FDA's perspective, it is a technology that we need great help with.
		We have got a couple of very early designs that are on the market, and we have a number of other types of technologies for endovascular grafting that are under investigation.
		And when we look at that from the agency's perspective, and the types of test methods that we need to evaluate the technology, it is very crucial for us to understand pre-clinically how to do the right types of testing and what sort of test methodologies are the most appropriate.
		And I think that with that, what I would like to do is thank certainly Megan and Dorothy.  They are two of the best and brightest on my staff, and they had this great idea about 6 or 8 months ago to try to put together a workshop funded not exclusively, but to a large degree, with some sort of FDA money that didn't exist at the time.
		And they came and talked to me and said that this is really a great idea, and we think we can put the best and brightest around the world in a room, and talk about pre-clinical testing.
		And being the person that I am, I sort of shrugged my shoulders a little bit, and they beat up on me a little bit more and said, no, we can really do this, and we can do this fairly cheaply, and I think that was really the genesis of this, and moved on to get a lot of variable people to put this program together.  
		And in the next couple of days, I am very excited that we are going to be focusing at least in the next couple of days on pre-clinical testing, although I have seen on the agenda that the clinical relevance and the clinical significance of the pre-clinical testing is going to be a large focus.
		And I think with that that we will really have the right sort of approach, and we will take a look at what is going to be very important.  And I will just sort of end with one more comment.  
		And that is that we are really moving in the direction to try to pull together all components, pre-clinical testing, clinical testing, post-market evaluation, and the best possible way to take a look at technology.
		This technology I think is going to be a great example, because we have the opportunity in the next couple of days to look at what we have learned, and certainly in the early phases, and take a look at how to evaluate the technology, and then even most importantly, how do we take pre-clinical information, feed that back into the development of product so that we as a regulatory authority, and you as industry and clinicians, can get the most out of the technology at the earliest possible time so that it is available to patients in a very timely way.
		And I think that moving from exclusively a clinical kind of evaluation to something that might have great ties in the pre-clinical testing arena is something that we are very excited about, and very enthusiastic.
		And I have very high hopes that at the end of this conference, if we haven't at a bare minimum brought up the most important questions that need to be addressed, and hopefully also thought about the next steps about how do we really focus on addressing those issues, and what sort of tests can we utilize, and how do we get the most out of the pre-clinical testing environment, which I think is perhaps the most challenging in the next couple of days, is going to be very important.
		And so with that, again, I would say welcome.  Hopefully the hotel here is reasonable accommodations.  I don't know.  Many of you have probably come to panel members here, and the last 2 or 3 that we have had there has been a lot of construction going on, and I think they are getting pretty close to being complete.
		And hopefully you will find the accommodations and everything else reasonable.  If you have any questions, Anne Marie Williams is one of our greatest, too, of putting together these types of meetings.  Her and her staff will be available if you need anything.
		So please don't hesitate.  And Anne Marie, if you want to maybe wave.  Many of you may know Anne Marie.  Please don't hesitate to get her, and Megan and Dorothy can certainly help out, too.
		And with that, I think I will turn it over to the much more important people who are going to focus on in the next couple of days.  Dorothy, are you next?  Oh, Dr. Beebe.
		DR. BEEBE:  Thanks, Jim.  I guess I am going to make a few remarks on behalf of the steering committee.  We want to add our welcome to Jim's.  
		Change in clinical practice is usually incremental, and taken in conservative steps, and validated by empirical evidence.  And there is safety in this process, quite analogous to driving pitons in direct aid mountain climbing, but it is slow, and it is expensive, and it kind of inhibits true innovation.
		The advent of endovascular grafts can be considered a big leap, kind of like a lateral pendulum traverse, to continue the mountaineering analogy.  But it probably should still be considered incremental because it was based on the concepts of conventional open surgery.
		And these concepts did not prepare us for what was observed in practice.  Examples that prove this point abound.  Consider only that we didn't even know what the dimensions of aortic aneurysms were, or that Dr. Juan Parodi began without using a distal stent, or that we were all surprised to see that excluded aneurysms were shrinking, and we didn't know why.
		It is also important to acknowledge that endograft development has been seriously burdened by the lack of an appropriate and practical experimental model.  
		So here we were trying to do something completely new, and no relevant laboratory experienced, and somewhat inappropriate concepts, and certainly a situation that would predict a steep learning curve to climb.
		Well, what have we learned?  Well, one thing that we have learned is that the value of pre-clinical testing would be immense if we only knew how to do it.  
		In the beginning of endografting, preclinical testing standards didn't exist, and to have invented some would have been arbitrary, and certainly unsuccessful.  
		But today we have the accumulated experience of a decade of clinical application of endografts, and it is time to take a fresh look at preclinical testing.  
		There are two ultimate questions to ask.  Do we know enough to set uniform preclinical testing standards, and if we do, what should they be.  This workshop on preclinical testing begins the process of answering these questions.
		But along the way, we are going to discover a lot of other questions that need answers before approaching the two ultimate ones.  This workshop brings together a diverse group.  
		We have people here from different clinical disciplines who are investigators of endograft technology, with different perspectives and insight.  We have manufacturing industry, each with their own perspectives, and with their own proprietary interests.
		And we encourage you to take the risk of contributing to the commonwealth need of making all endografts better, and perhaps we can get into that a little bit outside the sessions, and talk about how we all stand or fall together at this point.
		And we have regulatory evaluators, and isn't it cool that we are all here in the same room, so that we can belay each other on the climb.  We should be capable of accomplishing a practical result at this conference, because there is a lot of talent in this room, and a lot of motivation to use it.
		And I think we should have as a goal to come out of this with a practical concrete result.  Progress to the summit of patient safety and endograft effectiveness, however, will take a lot of effort because we have a long way to go.  Thank you.
		(Applause.)
		DR. BEEBE:  Now here is the deal.  Some of you people who are giving introductory kind of talks have got stuff on CD.  Does anybody have slides?  Technology-challenged people from California can use a slide projector.
		And if you don't have Cds and you have not already discovered it, you can plug your laptop in over here, and that is kind of cool, too.  I have been -- for some reason Dr. Parodi has a really neat advertisement for Air France on his as a screen saver.  If any of you want to see that, you can come over and look at it.  
		And so that is the A/V thing, and now I think -- Dorothy, are you going to say some things about how the conference is going to work?  Megan is the only one who is out of uniform.  Dorothy is dressed in pink, and I wore my pink shirt, and I somehow forgot to tell Megan.  
		MS. ABEL:  Sorry about that, Megan. I am actually going to tell you about how this conference came to me, as opposed to how the next couple of days are going to run, and that is going to be Megan's job.
		But I don't want to take up too much time, and I think that Jim already set the stage, in terms of how we found out that there was funding, and we took advantage of it.  
		I just wanted to let you know that we thought that this workshop would be possible because of the dedication of all the different interested parties in this device area.  
		I think we have got a unique group, and it shows in the standards development, and in the professional society meetings, where there is a lot of sharing of information.  There is a lot of working together with a common goal.
		We even have clinicians talking to clinicians, and engineers talking to engineers at our regulatory meetings now, instead of reg affairs people talking to regulators.  
		So I think we are really at the point where we can all get together and try to work on improving the frequent field testing for these devices.
		In February, at the ISO meeting, we asked the standards group if there was an interest in having this type of a workshop, and there was.  So we pushed ahead.  We called for volunteers to help us plan the meeting, and they are going to show up on the screen here any minute now.  
		And the folks who showed up at the first planning meeting are the steering committee.  So obviously it wasn't hand-selected.  It was by volunteers, and they are listed here.  
		The exception is Dr. Beebe, who was an invited moderator due to his wonderful skills at that.  What we did with the steering committee was try to figure out how to lay out this workshop, and come up with the questions that needed to be answered, and worked on the work assignments.
		And we found that since we only had two days to do what we were trying to do, that it would be beneficial to send out the work assignment in advance, and try to get the compiled document that you now see before you.  
		The asterisks show who actually responded to the work assignment, and we would like to give them a round of applause because that was a hugh effort that the folks put into doing that.
		(Applause.)
		MS. ABEL:  Those without the asterisks were invited, but did not send in their work assignments, or they sent them yesterday morning.  So not all of them are reflected in the information that you have.
		We received 13 completed assignments in case you didn't want to count the little asterisks.  The other thing that I want to mention is that although we have listed individual goals for the separate sessions of the workshop, it is important to just acknowledge that what we are really trying to do is to improve the pre-clinical evaluation of these devices.
		We are hoping that this can be accomplished both through what the individuals walk away from this workshop with, and through feedback into the standards committee that is currently in the process of trying to develop test methods for these devices.
		And as a final note, I just wanted to acknowledge that the pre-clinical testing will never take the place of well-controlled clinical trials to really find out how well these devices are going to work.
		But we certainly want to learn as much as possible about each of these devices before we move into that ultimate test.  Now, Megan is going to tell you how the next couple of days are going to run.
		MS. MOYNAHAN:  Good morning.  And welcome.  Actually, I am very encouraged by the turnout today.  I have to say that we were a little intimidated as all the responses were coming in that we might not have a big enough place, but it looks like everyone is comfortably seated.
		I would like to explain a little bit about how the next two days are going to proceed.  Basically, the flow of the workshop is going to go through the entire work assignment that you have in front of you.
		If you know Dorothy and me, you know that we are very goal oriented, and we fully intend to finish all seven questions by the end of two days.  We have structured the workshop to have presentations that kind of kick off the discussion. 
		And really the purpose of the presentation is just to set the stage for the rest of the discussion that follows, and to bring up some clinical perspective on some of this pre-clinical testing.  
		After each presentation, Dorothy and I will spend a few minutes orienting you to the material that is in the binders, because we realize that a lot of you haven't seen this before.
		And then that will start the working participants and discussion over the working compiled assignment.  At the end of the working session, we will have a wrap-up comment by Dr. Beebe, and it will also be an opportunity for the audience if they want to add in.
		Our goal is really to have a version of the work assignment that reflects the input for the next two days, both from the participants' point of view, and also from the audience members' point of view.
		But I want to emphasize that this is really not designed to be a consensus conference, per se.  We are not really trying to get one consensus statement in one particular area. 
		If there are points though in agreement that we can all acknowledge, then that would be fine. 
The last thing just as a reminder is that we are having portions of this transcribed for the record.  We will be transcribing the presentations and the audience comments.
		We are not going to be documenting all the back and forth during the working session.  But that means that it is important as audience members when you do want to comment to use a microphone and to introduce yourselves for the purpose of the transcriptionist.  
		MS. ABEL:  And the agenda is really just a tentative agenda, and it certainly is subject to change.  
		MS. MOYNAHAN:  Right.  We want to have the most flexibility as possible.  If we feel that there are areas where we need to spend more time, let's go ahead and do that, and then we will try to shuffle things around a little bit later.  So the agenda is really just a tentative agenda.  All right.  Dr. Beebe.
		DR. BEEBE:  Okay.  Let's get started.  On the subject of times though, in some of these sessions, we have got an awful lot to cover, and so we are going to need to keep one eye on the clock.
		John, rather than me saying next slide, if I just point at it, would you please change it.  Thanks.  Clearly, morphology, which is -- we are kind of setting the stage for getting into this process here by talking about the standard aneurysm morphology, and how we assess it.  
		And so that is what Barry and I are going to talk about, and that is a big deal in all of these clinical areas, but it is also a big deal for free clinical testing.  
		And the method of assessing the morphology can be separated from understanding the data that we have, and Barry is going to address that subject in a while.
		But recognizing that there are some great differences here, and one of them from my perspective is that we are trying to solve a three dimensional issue with two dimensional tools in the past, and maybe it is time that we moved on a little bit.
		Rather than going through a kind of tiresome review of what actually are the morphologic characteristics of aneurysms, which I think everyone in this room probably knows very well, what I am going to try to do is just in a qualitative way review some thoughts about morphology to get us thinking about the difference between clinical and patient selection, and pre-clinic testing. 
		They are not always the same thing, and a lot of the morphology data that we have bears on the clinical issue of patient selection and device selection for a given patient, but maybe doesn't describe very well what we need to know for pre-clinical testing purposes.
		So that the basic thing that we know is to sort of look at, and I have put some examples, striking examples, that aneurysms come in lots of shapes and sizes, just as people do.  
		And I kind of think now that when I look at the classification that we devised in a consensus and that was published in JVS in 1997 is a little bit dated, and perhaps a little naive.  
		That is a personal bias, but I think particularly when you get around to thinking about pre-clinical testing, this classification system doesn't serve us particularly well.  Can you go back one, John.
		There was, for example, an enormous preoccupation with the distal neck.  Well, today we don't care a whole lot about the distal neck.  And there was a lot of focus on the simplistic, I think -- and I think we would all agree -- notion that there was a meaningful cut point at neck length.  
		And now I think we -- if we knew how to do it better, we would say, well, it just isn't length.  It is length plus angulation, plus diameter, and it is a more complex thing than just simple length.  Okay.  Next, please.
		And the angulation was described in a way that is a little different from the way that we usually talk about it today, but it is primarily the difference between the super renal axis of the aorta, and the neck end of the body angle, but doesn't describe at all the angle within the aneurysm.
		But they have got lots of different angles, and we didn't describe anything.  In fact, it is a pretty difficult task to describe iliac tortuosity.  But that is turning out to be a big deal in multiple ways.
		And there is nothing in our data, pretty much nothing, about lumen size.  And when you get to thinking about issues that are specific to pre-clinical testing, maybe this is pretty important.  Next, please.
		It may be important what is inside this lumen, and devices may behave differently between the empty aneurysm and what I am calling the full aneurysm, but most of the time we don't pay much attention to this, unless it is such a small lumen that we are worried about operating a modular device when it is that small, and that it is so small at the bottom that it is going to pinch the lumen of the endograft.
		This is essentially absent from the literature and so we don't have much data.  Well, there are a lot of anatomical factors important in patient selection, and the question is which of these -- next please -- are important for pre-clinical testing.
		And when you boil it down, the meat and potatoes are pretty much proximal neck factors, and all of these may be, and I think are, we would agree, very, very, important.  
		Iliac arteries, we don't describe tortuosity very well, and we are not describing the lumen size very well.  Calcification I will say something more about in a moment.  
		But all of these are clearly factors that impact on clinical selection, and which of these need to be taken into account for pre-clinical testing to be meaningful.  That is really the question.
		And we need to remember that this is unstable anatomy.  It does vary by gender and by age.  The older the patient, we are starting with generally a larger and different anatomy than a younger patient's.  Next, please.
		Now, there has been proposed a classification method for an aneurysm neck shape.  Next please.
		But most of the literature ignores this.  Here is an example of why we do so at our peril.  This is a cone shaped neck, but both the top and the bottom of the neck were within the diameter limits of inclusion and exclusion criteria for a clinical trial.
		We put an endograft in this patient, and 12 months later, it has migrated down 20 millimeters.  We were within the perimeters of the trial, but it was a poor patient selection in my opinion.  Next, please.
		When we talk about diameter and I think Barry will probably get into this a bit more, we have been fooling ourselves by measuring diameter simplistically by simply taking the least dimension on an axial slice as recommended in the literature.
		But if you use 3-D methods and reformat the slice, you find out that these necks are not all round.  In fact, they are clinically significant.  Here as an example is 6 millimeters.  Actually, this is the true shape of this lumen.
		It is not a round neck.  So sometimes we are mistaken, and calcification, we don't have a classification system that works in my opinion, and this circumference thing is whacko -- next, please --because they are not lined up.  
		The volume averaging effect of the CT slice is misleading us, and we have developed a kind of quirky classification system there that is based on an artifact.
		Neck filling defects.  They come in lots of different sizes and shapes.  Next please.  Papers have been written about how they don't matter.  A lot of people think they do matter.  For sure, it is not normal aortic wall.  Next, please.
		So what do we do about this in pre-clinical testing?  Do we ignore it or what is the deal here.  We really don't know.  Next, please.
		Type II endoleaks, do they affect device performance, and if they do, how, and should this be taken into account.  This is quite different from patient selection.  I think that most of us tend to ignore the patent lumbars, and perhaps patent IMAs, and wait to see what happens.  Next, please.
		Well, enough about anatomy.  A few thoughts about physiology.  Next, please.  A long time back, the 19th century, the idea that the aorta is a wind kessel.  It is kind of a neat concept, but there is a huge elastic recoil phenomenon and reflected ways that accompany the original left ventricular ejection wave.
		And these tend to summate where?  Right where we are trying to put in endografts, folks.  It is in the infrarenal aorta.  As a matter of fact, in an experimental animal, with short acting beta blockers, you can move where those waves summate up and down the aorta almost at will by tytrating the animal.  It is very interesting.  Next, please.
		If you look at the some of the experimental work that has come from Stanford, both in vitro and more recently exercise in vivo data, you find out that there is some very interesting things that happen in the infrarenal aorta.
		Here, if you can make it out, with exercise and the solid line is resting data, this is bicycle orgametry on an MR.  Look at how aortic flow changes with really not heavy exercise.
		Most of the endograft patients are not doing heavy exercise, but a lot of them are more active than we tend to think.  These are not just people that sit in a chair.  They are out doing stuff.
		And the flow rates change dramatically with very significant changes in shear stress.  Next please.
		So this is a complex stress strain curse in the infrarenal aorta, and there are a lot of factors that impact on it, and which of these are important, and how to take them into account is a big challenge.  But to ignore them is no longer tenable.  We just can't blow it off.  Next, please.
		So in conclusion, I would say that there are many characteristics of aortoiliac morphology and physiology that you can measure.  There is tons of stuff.
		The existing classifications maybe aren't quite suited, both to patient selection, but certainly to preclinical testing how.  Next, please.  So that the preclinical testing methods must select out the really valuable anatomical and physiologic factors that are going to influence the failure mode, inducers and promoters.
		And we probably should be taking into account from the beginning the usefulness of 3-D methods if we are ever going to get to the point of using computer simulation to help in preclinical testing, and graft performance predictions.
		So that is my remarks.  Now, Barry is going to heighten our awareness about how the imaging data that we are using sometimes needs a lot of interpretation.
		DR. KATZEN:  Thank you.  I am going to try and add briefly to what Jacque has already said, and I apologize for any redundancy, and where there is, I will just try and skip through things.  
		But I will try and give you a little insight into what I think we can and can't do with imaging, and a little bit -- and perhaps the future -- in the context of understanding aneurysms at least, and where some of the future may lie.  Next slide, please.
		(Brief Pause.)
		DR. KATZEN:  Well, Jacque has already talked a little bit about what we need to know, and I think the presumption is that we know what we need to know, and I think one of the things that we have learned certainly over the past decade of experience is that we probably don't really know what we need to know.
		And part of that is that we are learning and exploring as we go.  I think he has highlighted some of the critical areas that we have been at least assessing.  Next slide.  I am going to skip through some of this.
		There are a variety of imaging modalities available for interrogating aneurysms and trying to understand them.  I think that all of you are aware of these modalities, and how they are used in clinical practice.  
		While I think there was a lot of hope for ultrasound, it certainly has limited information, and we certainly learned about the pitfalls in conventional abdominal CT, because it really does not provide volumetric data in very thick slice thicknesses.  Next, please.
		And spiral CT has been the principal data source that we have been using to interrogate and understand aneurysms because it provides high resolution volumetric data, from which we can provide -- we can get accurate measurements.
		The problem is that in the 2-D formatting of volumetric data there is the same pitfalls of a sort of lesser imaging modality.  So if the volumetric basis of CT scanning is not used, then really we are settling back to a more basic 2-D types of information.  Next.
		The pitfalls of 2-D imaging include the compression of 3-D data into a flat display, and I think Jacque has alluded to this, and the need for us to think and understand more three dimensionally, and the elimination of curves and angles which can be dramatic, and affect a lot of very critical measurements.
		And it can all lead to inadequate measurements, including angles, diameters, and compressed lengths.  Next.  Some of the reformatting options that we use and that are available to us include maximum intensity projection types of images, surface renderings, which include an outer look at the aneurysm morphology, multiplanar reconstructions, which allows us to reconstruct images along the plane of the vessel, or a pre-defined vessel such as curve multiplanar reconstructions.
		And then you can get sophisticated combinations of these, including some of the proprietary services that are available.  Next, please.
		I want to mention just briefly MR, because we are not going to talk a lot about, and in talking about the future, I think it is important to discuss it.  MRA is being widely used in Europe now as an imaging modality for patient selection.
		It offers the benefit of non-ionizing radiation, and no use of renal toxic agents.  It has a fairly high-spatial		resolution, less than CT, but you can see that you can get very good quality images with modern fast MR scanners, and the use of MR contrast media, and the image quality is continually improving.
		And you can obtain the volumetric types of data that we are used to using more and more for AAA analysis.  Next.
		And here is an example in another application of one advantage that MR may offer us over CT, and that is the use of dynamic imaging.  And it relates to some extent to the physiologic parameters that Jacque is looking at.
		If there was some way that we could actually measure physiologically what is going on, and where stress is occurring, and where maximum diameter changes are occurring, and begin to look at the aorta itself in a dynamic fashion, it offers perhaps some opportunity for us in the future to understand where maximum stresses are going to be.
		MR also lends itself to many of the sophisticated software analyses, including virtual endoscopy, and many of the reformats that you are used to seeing in this particular case, negotiating up through a coar and looking at the suplavian artery.  Next.  
		So I think that in terms of future imaging that this is going to be something certainly that we are going to be interested in looking at.  And as I said, it is being used more and more certainly among our European colleagues.
		Well, how do you think in 3-D dimension, as Jacque likes to say.  Well, one way is to spend three years in a radiology residency, and you learn over time how to think in 3-D when you are looking at flat images.
		But the other is to use these powerful tools to make imagery simpler for all of us to look at and understand.  Next.
		Well, you have heard and seen some of the disadvantages of looking at flat images, and here is an example of a patient with an aortic aneurysm that has a sort of globular looking lumenagram on angio.
		And ordinarily most of us would look at this and think of it as a tear drop, round shape, but when you look at the axial image, you can see here that actually it is a very flat type of shape.  
		Now, does this have any real significance?  It may in terms of the device that we choose.  It may in terms of the deployment methods that we have to employ and so on.  Next.
		The presence or absence of calcium is something that cross-sectional imaging, particularly CT, provides over angiography.  And by the way, this is one of the disadvantages of MR, is the ability to detect calcification, and in which it is limited.
		But the presence of calcium is very important as Jacque mentioned.  Tortuosity in and of itself may not be an adverse predictor, or an adverse stress point.
		Whereas, tortuosity and the presence of calcium, will have a totally different affect both on the endograft and the ability to deploy it.  Next.
		A similar example here, with an underestimation of calcium by traditional angiographic techniques.  Next.
		Now, angiography -- I guess the question is whether there is a role for angiography, and I think that varies among investigators.  To some extent, for angiographers, you will hear them say that this is a little bit like driving a race track before the race.  
		So there is some value if the angiographer is the same person who is going to be the implanting physician.  But the angiography, per se, as an imaging modality, is probably having less and less value, depending on the quality of information you can derive from cross-sectional imaging.  
		You can get very a very interesting and accurate sense of diameters, as well as length measurements, though they are probably more accurate than traditional CT.  Next.
		Now, the advantages of reformat that I alluded to, here is an example of an aneurysm sac that has a very unusual looking limb that has migrated in this case, and assumed a very peculiar kind of orientation within the sac, and which is shown to be a kink in the reformatting.
		So reformatting allows us to see and understand things quite a bit easier than in the axial images.  Next.
		Surface renderings, which are a little bit less valuable to some extent, can be very valuable in sort of reproducing the angiogram, the appearance of an angiogram in a volumetric way.  
		And it allows us to very sensitively see branch arteries, and in this case, an atonic pelvic kidney, or identify branches that are occurring from other areas, and actually recreate an angiogram.  Next.
		Surface renderings also give us a very good visualization of angulation and allow us to do the calculations of angulation, and try and understand what the angulation is going to mean for deployment.
		What imaging cannot tell us is what the stresses are going to be relative to the angulation, and what the dynamics of the curve point are from a shear stress point of view.  Next.
		And by the way the shear stress models, you know, by and large, are generally done in straight tubes as well.  So they suffer the same problem.  If we could somehow transfer the imaging data and mix the physiologic data -- and that's why MR may offer some potential for that, and we might get better information.
		Again, as Jacque said, imaging cannot tell us what the makeup of luminal filling defect is.  Maybe someday it might be able to, but at least with current technologies it can't.  Next.
		The complex sac anatomy is another critical event that may -- a critical issue that may create both initial and long term problems.  Next.
		In this particular case, you can see that there is a so-called empty sac with a flow divider in it.  The question is how do you understand whether this is going to be a significant barrier, or whether it is a dissection that may be extending through the whole sac.
		And that may actually create to an acute conversion, or lead to an acute conversion.  And this is where the volumetric information becomes important.  Next.
		And in the final couple of minutes, I am not going to spend a lot of time on this, because I think that Jacque made the simple point, which is that the measurement of arteries in an off-axial way introduces error.  And this has been demonstrated in a lot of different ways as you see here.  Next.
		And here in this image that you have already seen before, we have become much more sensitive to the need to get true axial measurements.  Next.
		In the iliac artery, it is the same type of thing, and that is that measuring a circle with an off-axial image is going to introduce error, and depending on the device, this may be critical to both deployment and long term outcome.  Next.
		Angulation is very critical, and there are numbers that can be accurately measured by imaging, and we have been able to use these as inclusion and exclusion criteria.  Next.
		The other important thing to understand about measurements is the pitfalls involved in length measurements.  These are less important in modular devices where there is some operator flexibility, and you can shorten up devices.
		And so to one extent, this is somewhat device specific type of information, but as you see in the image on your right, you can see that if you just took all the axial images, and just added them up, you would probably be about 15 percent short here on device length.  Next.
		Angulation of the neck can be compensated for and all of this information can be determined in advance.  Next.  And this translates into real world problems, in terms of device failure.  Next slide, please.
		Or as you can see here, if you -- this is a device that was deployed in the AP or frontal projection, and when you do the correct angulation, you can see that actually there was an abundant amount of room still in the proximal neck for deployment.  Next.
		Obviously these kinds of technologies can allow us through not only preclinical testing, but we might be able to actually create virtual computer models for testing as well.  Next.  And not just for implantation.
		The final thing that imaging provides us is the ability to look at volumes, which may be important in ways that we really don't understand.  I just want to mention it for completeness.  
		And certainly for following performance of the device as we believe it is important, but is it important for inclusion and exclusion criteria is another thing that we may need to look at.  Next.
		Finally, I just want to introduce a concept.  We are tending to lump all the things and want all these issues in one barrel, and you might have an Indy car that is a great car, or a Formula One car, both of which are great performance models, but would not perform at the highest level in the same environments if they were both put in each other's environment.  
		And I think it is probably time as our state of knowledge has become sophisticated enough to begin to start looking at these things, and begin to think about different devices, and different specifications, and it may even require different testing.
		Self-expanding devices under current recommendations have greater latitude in measurements of diameter, or at least we are using them with greater latitude, in terms of oversizing and how we deploy these.
		Whereas, unsupported devices have tended to be more precisely measured, and more precisely implanted in terms of the size tolerances.  The same thing may be true in terms of ultimately response to stress, and response to curves, and so on.  Next.
		And so the effect or the interpretation of imaging findings themselves may be device dependent.  The effect of curves, and the effect of angulation as you see here, and here is a patient that had a fairly angulated neck, and is now seven years post-implantation, with quite an excellent result.
		And here is a patient with an angulated neck that ultimately had a device migration.  Next.  Is it angulation, or is it device, or is it a combination of angulation and device.  I think we need to begin to start looking at these things in a more compartmentalized way.  
		And so in conclusion, endografts require precision measurement for accurate deployment.  Volumetric imaging is critical to optimal treatment planning and understanding.
		And I think it is important for us to think and image in three dimensions, and probably to understand that there are limitations to what imaging can show us, particularly about the nature of the arterial wall and the stresses that are going on in the vessels over curves.  Thank you.
		(Applause.)
		(Working Session.)
		(Whereupon, at 9:49, a recess was taken, and the workshop was resumed at 11:05 a.m.)
		DR. BEEBE:  Other than invited participants who want to make a brief comment, has anybody got anything they are dying to say?
		MR. BRUCHMAN:  Yes, I have one comment.
		DR. BEEBE:  Please use the mike, and would you tell us who you are.
		MR. BRUCHMAN:  My name is Bill Bruchman, W.L. Gore and Associates, and I am having a hard time sitting in my seat during all this discussion.
		DR. BEEBE:  Good.  
		MR. BRUCHMAN:  But in any event, compliance is an irrelevant issue from the perspective of the device, you see, because what actually matters in the end is the strain to which the wire is subjected, okay?
		And that is the function of a whole lot of things.  But the compliance of the vessel is actually immaterial.  It is the compliance or the excursion that is encountered by the composite, okay?
		So while it is great to do all this modeling, in order to understand what really happens with the device, you have to know what the wire excursions are.  You have to know what the device compliance actually is, and how much it moves, and so on.
		So from the modeling standpoint, we are far past that at this point.  I think it is incumbent upon all of us to know what the actual excursions are.
		DR. BEEBE:  Okay.  Good point.
		WORKSHOP PARTICIPANT:  Isn't that going to depend on where you start your compliance number?  If you are start at 13 percent without a device in there, and then you put your device in, the composite is going to have a different compliance than had you started at 3 percent.
		MR. BRUCHMAN:  Right.  You are talking about modeling, and I am talking about clinically.
		WORKSHOP PARTICIPANT:  Well, are we trying to decide what kind of models we are going to use for pre-clinical testing?
		MR. BRUCHMAN:  I think you have got to go the other way.
		DR. BEEBE:  Eventually we are going to get to that.
		MR. BRUCHMAN:  As we talk about wire strains encountered from these diametric excursions, we ought to start wondering what they are from caking.
		DR. BEEBE:  Okay.  Thank you for that.  Any other comments?  Yes, sir.
		MR. KING:  My name is Martin King, University of Alberta, City of Canada.  Just a couple of quick comments, because we have been involved in the materials analysis for the Europe-stock program.  So when you look at 15 and you say where did this 22 millimeter aneurysm diameter come from, where that refers to the size of an iliac vessel aneurysm.
		And that is the reason why that number was in, and so the question then comes do you want 15 to be looking at aortic diameters or iliac diameters.
		DR. BEEBE:  Well, that question was specifically that 15 was aortic diameters, and we have iliac diameters ranked pretty high, too.
		MR. KING:  And the second point again is just to confirm what has previously been mentioned with respect to 16C was it, and whether it was an external abrasion to textile or metal components observed on clinical explants.
		DR. BEEBE:  Yes.
		MR. KING:  That is the question, and we have looked at a number of clinical explants, and looked at the failure mechanisms, and there is no evidence as far as we can see from what we have seen so far that there is abrasion between either metallic or textile clinical crossover.
		MR. BRUCHMAN:  And adjacent to iliac.
		DR. BEEBE:  Okay.  Confirming what we heard before, and that is useful  A comment?  Yes, sir.
		MR. BERGMAN:  Darren Bergman, from Terimed.  Just a couple of general comments while I was sitting in my seat there.  I think all of us know that there is a balance that is needed between what is ideal, and what is truly feasible, and I heard that come out just recently here.
		So really what we are looking for in pre-clinical testing is a level of robustness, that the device is robust to a bunch of different anatomical conditions.
		And as a manufacturer, when I hear these matrixes of 30 different angles and things, that scares the heck out of me.  And I think that the real value of the pre-clinical in vitro testing is to look at relative comparisons between one device and another, or one type of construct and another.  
		And that the best information that we can get in a session like this is really I think trying to go back to the clinical implants or explants that we are seeing, and look at the actual failures, and say could we come up with bench testing that can replicate that failure mode.
		And personally sitting here this morning, a lot of information that I heard, the most important one was when the manufacturers went around and said the iliac leg is rubbing, and I have never seen that failure.  
		That was huge, and I hope that in the next day that we hear more of those types of sharing of explants and what failures they have seen.  
		DR. BEEBE:  Thank you for that.  So, now, we have -- I am just going to summarize this first session by saying that we have ranked some anatomical data for the purpose of entering into the pre-clinical testing process, and we have also identified a few things that turn out to be pretty important, or of pretty important interest here, that we aren't doing a very good job of measuring.
		And we need to revisit that, and particularly compliance and calcification.  Now, having described the normal -- no, not the normal, but the pre-treatment anatomy, now we discover after we treat it that it doesn't stay the same.  
		And we are going to go into the next area, and Juan Parodi is going to talk a few minutes to introduce this subject of the changing morphology.
And because we are a little behind schedule, I am going to suggest that those of you who want to go up and go to the bathroom, just get up and go.
		And it seems like we say the same things over and over enough, at least in the first session, and so you will hear it again, and you didn't miss much.  And if you want a cup of coffee, just get up and get it.
		That worked pretty well in Ireland last week, and it will work well enough here.  So, Dr. Parodi.
		DR. PARODI:  I don't want to repeat things, but I want to emphasize about the environment that this endograft is going to be.  Without any question, the distal abdominal aorta is the worst place to place an endograft.
		It is a higher systolic pressure, and lower diastolic pressure, and a steeper rate of pressure rise than a thoracic aorta.  So the abdominal aorta is subjected to a very large pulsatile stress test.
		Why is this, and why the pressure wave is different in the abdominal proximal and the distal aorta?  The reason is that the aorta tapers, and the cross-sectional area diminishes as we reach the bifurcation, and it becomes stiffer and more collagen, and less lasting.  
		And also after 50 years of age, most of the patients reflect the pressure waves coming from the distal arteries, and this amplifies the pressure.  Next, please.
		So this is the environment -- high pulse, pressure, and also it has a foreign body reaction of the recipient of the endograft.  This implies enzymes, macrophages, fibroblasts, changes in Ph, electrolytes, et cetera.
		Corrosion is in this environment, and there are several causes of corrosion; changes in Ph, biological reactions, and also macro-motion between or among components, metal components, that eliminates the protective oxide layer, and then facilitates corrosion.
		Changes in the morphology and the remodeling.  So in general we can say that complex vector forces are acting in an uninterrupted fashion promote material fatigue and motion of the components of the endograft.  Next, please.
		To make things worse, this is not a one piece device.  It is a composite device, metal and fibroblast, and also it is interposed between two or three arteries of different sizes and compliances.
		And I am going to show the next slide, please.  So this is the environment, and this is a normal artery, and the patient with a normal compliance, and then the neck has a different compliance, and very little, because it is contained, and then we have the third situation, in which the graft is expanded if it is not totally supported, it expands more, and so there is a different stress and a different situation that adds the stress to the endograft.  Next, please.
		And this is a very simple, but in the initial testing this was not taken care of, and the  aneurysm forms never have a straight access.  Next.
This I took from Molina, and this is a motion, and we have seen this in fluoroscopy when we talk about compliance of the neck, and I can say that it can be seen very simply doing fluoroscopy that the balloon expandable doesn't expand during cylindrically, but with a self-expandable does expand.  
		So the motion exists remotely in the self-expandable, at the level of the neck, and in the middle of the -- motion.  There is a radial motion, and a longitudinal motion, and these motions can be pulsatile or continuous.
		For instance, we take radial motion, and we can have a pulsatile motion, and also an expansion of the neck as we are going to see with the self-expandable.  This is a radial continuous motion.  Next, please.
		What we need.  We need to have a permanent attachment and sealing of the endograft, and long lasting integrity of the structure, and a patient to remodeling.  Next please.
		We should take advantage of the experience we have had for the last 50 years doing open procedures.  Initially, device failures during the open procedure is very, very small.  
		We have seen some dilation of the graft using the needed graft, and a few cases of wearing, false aneurysms, but after an average of 17 years, almost one out of every five cases had complications.
		What is the difference between the open procedure and our procedure?  We should compare metal versus suture.  In the standard procedure, we don't have metal skeleton that we have in some endografts. 
		In some endografts, we are using a thinner fabric, and also remember that we leave the sac intact, and we replace the inside.  We don't remove it or we don't wrap the graft with a sac.  Next, please.
		So metal versus suture, I think that this is critical.  Without any question, the suture adapts much better to the wall, and to the fabric, than the metal.  Even if we use hooks, the hooks concentrates stress and discreet spots.  Next, please.
		A very, very short thing to show you is that most of the failures that we had using the open device were device related.  So we were very proud after four years, or I'm sorry, after three years of initiation, that we had no failures.  Next, please.
		But after two years, we started to have these kinds of failures that we all know, even ruptures.  Next, please.  So most of the failures were device related, and time related.  Next please.
		Without any question, we are dealing with a different situation than having -- and during the first two years the only complication that we had was related to remodeling.  Failures were time related, and the first failure after two years.  Next, please.
		But I can say that we were very happy with the endograft.  We were actually very proud saying that for two years that this is the best treatment that you can have.  Afterwards, you know, you are in trouble.  Next, please.
		I think that it is good to compare balloon expandable versus self-expandable.  Balloon expandable has a high radial force, and high conformability.  It is usually one piece.
		And what is important is that it produces immobilization of the recipient artery and the fibroblast.  Next.  The drawbacks are that it is rigid, and needs a balloon, does not follow neck dilation in the case of occurrence.  Next, please.
		Self-expandable, low profile, flexible, can support the whole length of the endograft, expands when the artery dilates.  We don't know which is first.  Next, please.
		Disadvantages.  Not completely adaptable to known cylindrical necks.  Less radial coarse, and tendency to expand the neck of the aneurysm.  This has been extensively studied with self-expandable stents in the coronary arteries.  Next, please.
		We also need to remember the basic components of the wall, of the aneurysm in the wall of the neck.  We have two main components, elastin and collagen.
		The elastin is a supported mesh-like structure that can be expanded 70 percent of the initial neck.  Collagen is composed of three helical polyceptide strains, tightly cross-linked, preventing extension of fibers.
		What is important is that the extensibility of collagen is less than one percent of elastin.  Under normal conditions, less than one percent of the collagen fibers are loaded.  Next, please.
		What happens with the balloon expandable?  The balloon expandables, we oversize 15 percent, depending on the neck.  The balloon expandable stretches the neck from the beginning and having continuous expansion.
		This effect is achieved loading the collagen fibers from the beginning.  With a self-expandable stent, we create a continuous force of expansion that ends when a nominal diameter is reached, or when the collagen fibers are loaded.  Next, please.
		So, self-expandable loads elastin in a progressive way, and dilates the neck, and when collagen is loaded, the dilation stops.  With a balloon expandable, the balloon expandable stent loads elastin and collagen from the beginning, and collagen, as I have shown before, is less expandable.  Thus, dilatation is less evident.  Next, please.
		We did a study with 30 patients, and this is half of the patients, of the neck diameter after five years, and in 30 patients, we found that with a balloon expandable that we had no neck dilatation.  Next, please.
		This is another basic study done using a study of compliance.  Next, please.  This study was done by Dubling, and I think it is a very interesting one.  This is pressure and this is diameter, and so it is compliance.  
		This is a normal curve and this is after subjecting this specimen -- this was a human fresh external iliac to elastin.  You can see that eliminating the elastin fibers, we expand the artery, and using collagens, you further expand these, and all of the specimens ruptured.  Next, please.
		So in summary with these balloon expandables, the neck becomes non-compliant, at least in our studies, and as well as seen in fluoroscopy, the neck does not move at all.  
		With self-expandables, and Molina did the study, you have movement in every case.  So this neck became especially compliant.  The elastin fibers are loaded, and collagen fibers are loaded.  This partially loaded the collagen fibers.  Next, please.
		And just to talk about endoleaks and pressures, I think this is very important.  This is a paper that was accepted for publication in General Vascular Surgery, and this is a model that we used for an artificially created aneurysm, with a side branch simulator, and lumbar arteries.  This was under a pulsatile flow.  Next, please.
		And this one we found systemic pressure and aneurysm pressure.  We excluded aneurysm.  This is systolic, much lower inside the sac, and diastolic, and mean pressure.  Next, please.
		In the presence of a Type One endoleak, making an orifice in the graft, we found that the systolic pressure was higher.  The systemic pressure was higher than the pressure inside the sac.
		But the diastolic and mean pressure was higher outside than inside.  This obviously is a dynamic pressure measurement.  Otherwise, the sac would collapse the lumen, and this is dynamic during
-- next, please.
		And we changed the size of the orifice, and making the orifice larger, this becomes more -- the pressure is much higher.  Next please.  So a small orifice, the pressure outside. Next, please.
		And this is with the outflow, which is simulated in the lumbar artery, and this is clinically relevant because we have an endoleak without flow, and with a very high outflow, and let's say several lumbars open.  
		So you have the diastolic pressure much lower than the pressure without any outflow.  And this patient, if this happens in a patient, you are going to have an acute rupture.  Next, please.
		So these are the pressures with less flow, with more flow, and so you have more outflow and less pressure obviously.  Next, please.
		And if you combine all of this, big orifice and different flows, with a small orifice and very high outflow, the pressure is very low.  So even in a patient with a Type One aneurysm, if we compare this with a clinical situation, very small flow, and Type One Endoleak, with several open lumbars, the pressure is going to be low.
		And probably this patient has a low risk of rupture.  On the other hand, with a big orifice, without outflow, the pressure is going to be much higher, and the risk of rupture is going to be higher.  Next, please.
		This is a combination, big orifice and small outflow; and small orifice, and a high outflow.  Next, please.  And this is what we have seen in clinical settings.  
		We have seen patients that the aneurysm decreases in size, and almost vanished, but after 2 or 3 years, if this patient develops an acute endoleak, this patient is in a big danger of a rupture.
		It has no outflow, and the wall of the aorta is atrophic.  So in testing, I think this could be interesting to see how the material fatigue behaves, in terms of having these dynamic changes inside the sac.  Thank you.
		(Applause.)
		(Working Session.)
		(Whereupon, at 12:10 p.m., the workshop was recessed.)

	A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N
	(1:30 p.m.)
		(Working Session.)
		DR. BEEBE:  Okay.  We are going to move on now to discuss failure modes of endovascular grafts. 
		MS. ABEL:  Audience comments.
		DR. BEEBE:  Well, we have got a lot of them already.  Does anybody else in the audience have a comment?
		MR. BIRKBY:  The one thing, irrespective of what we call it, whether we call it compliance, and it has all these different terminologies banded around, one thing that we really didn't focus on at all was the range that would be feasible to test within.
		And that has to be directly related to the range which would be expected to be seen in normal physiology.  Now, we saw two different -- I think we had two different numbers mention.  I think 7 to 13 or 5 to 13 percent.  
		I heard from testimony that some people test between 5 and 7, and what scares me is that if someone does a test that is between 5 and 7 percent, and that data is then submitted, perhaps some unnamed person from an unnamed regulated body may suggest that we should have tested at 13 percent.
		DR. BEEBE:  But what the reality is --
		WORKSHOP PARTICIPANT:  It depends on the size unsigned check that comes with the application.
		(Laughter.)
		DR. BEEBE:  The reality is that we don't have any physiologic data, or if we have, I have missed it.  But testing the human aorta under appropriate conditions of age, and aneurysm circumstances to meet Steven Weinberg's criterion.  We can't do that, or we could do it, I suppose, but we haven't done it.
		And so we can't do what you are suggesting.  There is no basis for that.
		MR. BIRKBY:  So can we agree on a range?  Can we agree on a maximum compliance, or can we agree on a range which would be reasonable go what within?
		DR. BEEBE:  I don't know.  Can we agree on that?
		WORKSHOP PARTICIPANT:  No, I don't think we can agree on whether compliance should even be tested, or if you can test it.
		DR. BEEBE:  All right.  We called the question.  So this is another great subject for five o'clock around the bar, or 5:30 around the bar.  Now we are going to move on to actually talking about what failure modes have we really seen.
		DR. WHITE:  Okay.  We are moving now from theory to reality, and as far as technology is concerned, this is where East meets West; California method here, and East Coast over here.
		What I am going to do is just show some slides illustrating failure modes that have been encountered clinically in our own practice and elsewhere, using some of our own slides, and some that I have stolen from various publications.
		So if I use your slide here, thank you very much.  Then I am going to go to the computer slides and just give a quick summary as to what I see as being the most important issues.
		To start with the most common failure mode we have encountered is probably endoleak, and I think it is a good place to start because it illustrates one very important feature, and that is endoleak may occur because of device failure.  
		It may occur because of poor patient selection, and what somebody recently termed as patient failure.  It may occur because of a procedural failure by the implanting physician, and it may occur because of diverse, anatomic variations within the patient, as we have already touched on.
		And just a quick summary of the current classification that we have been using, Type One of the attachment slides; and Type Two, any retrograde type of flow from side branch vessels, and Type Three, a defect in the graft wall or disconnection.
		This type probably mainly depends on the patient, but it obviously can also occur because of anatomic factors.  To confuse all of this, we have variations in graft construction, which can give the appearance of endoleak, and with the earlier version of the endograft, we have this mixture of perhaps porosity of the graft fabric, and little channels through the graft where the sutures go through, which on early CT scans gave it this appearance of like a jet of blood coming out form the graft.
		And this we had termed Type Four endoleak, because it seemed to close reliably within at least a month, and often quite earlier, but we are still not quite sure whether there may be long term consequences of these little channels.
		This is an illustration of another type of endoleak, and I am going to run through these fairly quickly.  This is one of the earlier seam separations, and I think this was the stentograph, where the seam was sewn and the suture broke with perforation of the graft limb.
		Here is another similar one, again with either the stent or the vanguard, showing leakage outside the graft, and this is the appearance after explant of the graft, and after attempted repair with another graft inside.  And again you can see the separation of the sutured seam.  
		Here is another type of graft erosion, or tear, or hole, a fairly subtle appearance on this view, but when you hold it up to the light, you can see the holes within the graft, which obviously can become significant channels, and can lead to repressurization of the graft, and much of the aneurysm.
		And I think it was Juan Parodi earlier who emphasized the fact that once the aneurysm is deemed depressurized, it may be far more liable to early rupture when it is repressurized.  
		In the direction of the metal components, and the fabric components, they obviously can have the same effect.  And with all modular grafts which are constructed inside the body by connecting various pieces, we can later have disconnection.
		This is a typical CT scan appearance, where one of the graft limbs is appearing sideways, like somebody crossing their knees, with the endoleak associated as you see here.  Here is the thrombus and here is the leak within the aneurysm sac.
		This is how it appears on the plain x-ray, which is extremely valuable for diagnosing this kind of dislocation, and where you see the limb here and the trunk here and these two points should be in contact with each other.
		And here is the angiographic appearance with contrast coming down and appearing in the aneurysm sac at that disconnection point.  Here is another form of disconnection, where approximal extension has become disconnected from the graft, and you see the two similar sized fragments here.  
		These are both the approximal ends of the graft and not limbs, and here they are laying side by side, instead of one inside the other.  Another common form of graft failure or complication is this kink of the limb seam, where the metallic fragments are angulated and very close together.
		And this typically would lead to occlusion of thrombosis of a graft limb, and or in some cases partly thrombosis, following by embolization, leading to trash foot and other complications.
		There have been attempts made to define this more scientifically if you like; buckling and any increase in angulation, kinking and acute localized angulation, and this comes from a publication of Peter Harris, the Journal of Endovascular Surgery.
		Importantly, they showed that late complications, that is, endoleak or lumen collusion, developed in 19 percent of the cases, all of whom exhibited graft buckling or kinking in a series of Vanguard grafts.
		So it was a very important association with those early signs, with late adverse effects on the patients.  Here is another example of graft buckling or kinking from our own practice, associated with displacement of the graft from the distal or the approximal neck of the aneurysm.
		And you can see that it slipped down 5 or 6 centimeters from the neck.  There is still good blood from the channel, and here is the plain x-ray of that patient showing you the angulation of the metallic components of the graft.
		We have also shown and published a variety of these grafts shortened considerably during the implant procedure, and with both the Vanguard and the aneurylextial (phonetic) stent, we observed a shortening of more than 10 percent, and close to 50 percent of case, probably caused by the forces needed to push the graft out of the deployment system so that the graft in the loader is this long, and in the patient is this long.  
		And that is another possible cause for acute or light device failure.  This slide was meant to demonstrate the fracture of a Y-Form, and I think it illustrates why it is an important point about Y-Form fractures, and those can be very difficult to detect.
		And in this case, we see that a tubular graft has dislocated from the distal aspect of the makeup of the so-called distal makeup on an aneurysm.  This is one of our early cases from about 1993, and I will come back to this later on the computer slides just to discuss some of the complexities of diagnosis and analysis.
		The other thing that is important to stress on these is variations in the angle between the various wires, which we feel may be associated with external pressure, but it may also be associated with variations in the compliance or the oscillations, or whatever you like to term it.
		This slide was just meant to show that analysis and searching for these Y-Form fractures can be extremely difficult.  Here is an electro x-ray of a patient with one of the Baxter endografts in place, and you can see the individual Y-Forms. 
		And to look at these is a very painstaking effort to determine whether or not these are actually fractured or not.  So a lot of these are probably being missed on diagnosis today for all graft types.
		And it is far more difficult to see the ones made of nyanom (phonetic).  In some cases, poor apposition of the graft, either because it has been placed too low, or because of thrombus, may lead to the complication which we now term endo-tension.
		And that is defined as continued or recurrent pressurization of the aneurysm sac without any evidence of endoleak.  And here you see a patient whose aneurysm was slightly more than five centimeters at the time of implant.
		And two years later the aneurysm is now close to seven centimeters in diameter, with no evidence of endoleak on any of the imaging studies that have been done.  
		So persistent or reoccurring pressurization without endoleak, and here is that same patient with an open surgical conversion, and these are the typical appearances we found now in seven cases.
		And with liquified thrombus, or semi-liquid, or plasma-jelled type thrombus, surrounding the graft, and this liquified component, and in most cases we feel that this is due to an endoposed layer of thrombus at the neck, and this thrombus, which you can see here after the graft being removed, probably transmits pressure in males who have osmotic effects leading to activity within the thrombus and within the sac.
		Whether or not this can be tested in a pre-clinical means is very doubtful.  However, the factors that lead to it may be identified, and perhaps can be tested.  
		We have heard a lot about variations in anatomy, and I would just like to finish off the slides just by talking a little bit about causal factors in variations in anatomy.
		Somebody asked earlier about the relevant incidents of the taper or reverse taper in a series of patients that we analyzed last year, and this was in 8 percent of the cases that we actually treated with an endograft, and probably far higher than in those that are not treated.  
		We have defined six different types of neck, and we have shown that in almost every case it can be fitted with this classification.  And we have used that to define what we feel is a practical anatomic risk grading.
		And in essence this depends on the neck and the iliac arteries, or the sac, with all favorable necks being defined -- correction, with all favorable necks being defined as Grade I, and unfavorable necks as Grade II, and severely unfavorable as Grade III.
		Whereas, if the iliacs or the sac are unfavorable, that led to it being changed from 1A to a 1B.  And another way to put this, Grade IA, the neck was favorable, and the iliacs and sac were favorable.
		And Grade 1B, the neck favorable, and iliacs and the sac unfavorable; and we come down to Grade III, the neck was severely unfavorable, and the iliacs and the sac were unfavorable.
		Now,I mentioned this because I think this might have relevance to pre-clinical testing, because I believe that we should have difficult grades of difficulty in the models that we use for our pre-clinical testing.
		We should be testing grafts in the Type 1-A anatomy as most of us have seen today, but we also should have different degrees of difficulty within the anatomic testing to simulate the human variation that we see.
		Now, these ones would not fit the criteria for any graft at present, and you can see in Grade III the incidents of earlier outcome failure; that is, endoleak was 50 percent.  But in fact all of these were sealed and were cured by subsequent removals.
		And we are now awaiting the long term results of studies such as this.  I would quickly now just kind of like cross to the other screen, because I would like to try and bring together what I have said from the clinical situation, to how it pertains to this meeting today.  If we could have the next slide.
		In an outline, I am just going to reiterate the frequent modes of endograft failure, and state which I think are the most critical modes of failure, and thereby come to some form of classification.
		And talk a little bit about causing factors, and emphasize the relationship of device failure to patient, and any other factors, and I will try to do all of that in about three minutes.  Next slide, please.
		The classification of failure may be according to many factors, and we can classify according to the component or device affected, and we can classify according to the cause, and we can differentiate device factors versus patient factors.
		We can talk about the timing, early versus late, the severity, and particularly with respect to clinical effects, and there are probably many other ways of classifying device failure.
		To date, most testing has really been relevant to acute device failure.  That is, being able to deploy the graft and analyze acute failure within the model, usually with fairly simple anatomy.
		And the things that are tested there, first, whether or not the device will deploy, which we are not ready to discuss today; and failure of the device to attach to the aortic wall; and failure of the device to seal or exclude the aneurysm; disconnection of modular components; and occlusion or thrombosis of the graft. 
		So I think that this represents a useful framework for a subsequent discussion.  Next slide.  If we now look at the chronic or long term modes of device failure, these are the ones which we really have difficulty in devising preclinical testing for, because it really pertains to device durability.  
		But these same factors really come up here.  The failure of the device to maintain its fixation to the aortic wall, and leading to displacement, loss of device seal, or it may have been previously sealed, disconnection of modular components, and again occlusion, or thrombosis of the graft again.
		And now device materials failure or durability rears its ugly head.  Next slide.  And when we are looking particularly at those device and materials durability factors, we are coming back to most of the things that we have already talked about today.  
		Fractures of the stents, or Y-Forms, and which hasn't really been mentioned too much, either due to fatigue or corrosion, or to most likely a combination of these.  
		Breakage or disconnections of sutures, which I didn't illustrate on those slides, but it has also been a frequent failure mode.  Graft fabric or material tears, metal erosion through the fabric, and device angulation or kinking.  Next slide.
		The critical effects of device failure are really those that affect the patient in the most critical ways, and causes, such as failure of the seal, or fabric tears, or device shift, or stent fractures, are really only relevant to the patient if they cause either an aneurysm enlargement, or aneurysm rupture.  
		Likewise, device kinking, buckling, and so on, is also only relevant to the patient if it is a precursor to these factors, or if it causes arterial blockage, or embolus.  
		So in looking at the critical effects, we are really talking about the effects on the patient rather than the bench top testing.  But naturally we need to devise bench top testing which can lead to earlier recognition of these potential failure modes.  Next slide, please.
		I would like to just quickly give a patient illustration, which I also used at the recent conference in Ireland, because I think it really shows the multifactorial nature very nicely. 
		This is a true case, and it involves a 73 year old male, who we initially treated in 1993 for an abdominal aortic aneurysm.  At that time, we only had two grafts available in a workable fashion, and so he received the tube endograft.
		And not surprisingly, two years later, he presented with distal endoleak, and the graft had pulled out of the distal end, and it was similar to that slide that I showed you where the graft had pulled out distally.
		And we put a second redistal tube extension in to seal it off.  Two years again later, he had a Type I distal endoleak, which occurred during an exercise test for his cardiac status, and this was treated by a third endograft.  Next slide.
		It may on the face of it seem very simple on what caused failure in this case, but here are the factors that really need to be analyzed in determining that, and I think that is part of the problem that we are struggling with here, because it is a very multifactorial question.
		The patient selection and device type obviously paid a role, because we think that distal disconnection may not have occurred if we used bifurcated graft rather than a tube graft.
		However, they weren't available.  Changes in the patient's anatomy may have contributed because the distal nick may have expanded, leading to that disconnection.  
		Activity and reactions in the  aneurysm sac seemed to be an important component, because the patient actually developed a coagolapathy at the time of his second endoleak.
		Endoleak forces, and the effect of exercise and extraneous factors, and perhaps there was also a device material failure, and interaction of the metal, and the fabric, and the graft.  Next slide.
		The patient factors, I think, we have done to death already, and so I won't dwell on those.  Next slide.  Device materials failure.  Again, all of these are the things that can lead to long term failure in the durability of devices.  Next slide.
		And to finish off, there have been some attempts within the various bodies to try and define these failure modes in a mode that is relative to reporting.  
		One is to classify endograft deformity, and you see an initial attempt here, which is due to be published in the SVS standards document hopefully later this year in the Journal of Vascular Surgery, with a grading of angulation or kinking of the graft from zero to three.
		And on the final slide, a further classification of device failure according to clinical severity, which from the patient's point of view is obviously the most relevant. 
		And with Grade Zero being no adverse or clinical effects, and down to Grade Three, resulting in conversion, rupture, major complications, or death of the patient.
		So I hope that will serve as a useful introduction to this section on modes of failure that have been observed in practical and clinical experience to date.  Thank you.
		(Applause.)
		(Working Session.)
		DR. BEEBE:  Okay.  Does anybody have any questions?
		(No response.)
		DR. BEEBE:  All right.  We will take a five minute break at this time.
		(Whereupon, at 4:07 p.m., the workshop was recessed, and was resumed at 4:14 p.m.)
		DR. BEEBE:  Okay.  We are going to go on now to Question Number 4, and to wrap it up to a much higher level by talking about Failure modes of endovascular grafts that may be simulated through pre-clinical testing, and the clinical characteristics that need additional consideration in these tests.
		And we are going to make this the Australia -- get the Southern Hemisphere guys more involved in this.  I have asked Geof White to moderate this session, and Michael Lawrence-Brown is going to lead us off.
		DR. LAWRENCE-BROWN:  Thank you for inviting me here.  I don't know if I am going to lift this to a higher level.  I have taken quite a beating already on this, and I wasn't really sure how to put the clinical characteristics, and so if I have taken some license, I hope you will forgive me, but it was the only way I could put it together.
		So what I looked at was proximal fixation versus seal, to prevent -- and we have looked at that, and the distal landing zone attachment and seals, I have put that separate, because it had separate problems.
		And they can be dealt with in a different way, and access is an image for failure, and graft and limb occlusion, and I will show you some of the testing that we did with that.  
		And deployment failure, and a device defect, either in short or long term, and it is the long term issues that are really coming to the fore now.  And we cannot divorce any of that from the physician induced problems which apply to the failure mode.
		And its inappropriate usage, and its technique defect, which can be an education defect on their part, or it can be a memory lapse, or it can just be a human factor.  
		And inadequate infrastructure, especially with imaging, and I have been to different places, and some of the imaging that I have seen, I can't see a dam thing on what is going on, and so how they can see where they are going I don't know.  But it is a real matter for failure.
		And then inadequate support.  So do you have someone there to give you the extra ancillary devices that you need to fix a problem that you can't fix at the time.  
		And planning.  If you plan it wrong, you get it wrong, and that is probably one of the most common failure modes.  And we all have a problem because this slide illustrates that the death rate per 100,000 has been reduced to almost half in Australia, but mainly through the work of the National Heart Foundation.
		And so you can see that all causes comes down by 46 percent, and pulmonary heart disease comes down by 68, and then it is followed by a stroke, which has a lesser impact.
		But for all cardiovascular disease, people are living longer, and aneurysmal disease emerges as an age related factor, and the heart for aneurysmal disease is age.
		And this was the paper presented in 1986 at the RSNA, with Jim and Lawrence, and it showed the stent with the graft, and the work was done in dogs.  We followed on with that to some extent, but we were limited by the materials that were available to be used.
		Now, there may be new materials, but it is not easy to use new materials.  So it was back on the polyester versus PDFE, and stainless steel versus notanole (phonetic), versus polyurethane, and the sutures were polypolprine and polyester nylon, and then the metal markers that existed.
		Now, people said that the better polyesters or better materials such as cylar and mylar, and it is my understanding that we can't use those because Dupont says that they are never to be implanted in a human being.
		So there are limitations imposed on us from all sides, and I stand corrected if necessary, but that was our understanding.  We found working on dogs and animals impossible, in terms of devising something that was feasible, and to be able to do something.
		And so we developed a model with a gelatin aneurysm from a real life model, a cast, a 
3-D CT scan, and day by day we lay it in resin, and then we attached the various ports, and constructed valves, because the first thing we needed was hemostatic valve.
		So this was our first simulated model, and this was an x-ray phantom, and so of course we called on Mr. Walker.  And there is the x-ray machine, and there was the pressure pump.
		And that is just a closer picture, and it was a fairly ideal sort of aneurysm.  It was the model of the first one that we ever treated with a tube graft.  But what we were looking at was to try and make a bifurcated graft.
		And what we needed to do was to test different methods to see if we could actually feasibly deliver a bifurcated graft, and see if we could do it and now lose total blood volume in the process.  
		So that was the first simulated test model that we had, and I am sure that we can make much better ones, but it is a start.  Then we looked at what metal we should use, and we looked at cyclic colonization, one hour equals one year.  
		And this is the simple diagrammatic method.  You put the sample in the solution, and you connect it to a variable potential, and you measure the electrode potential across it.
		And then this would be ideal, and so you would at the breakdown point when you start to get equilibrium, it moves all the way up, and it deforms at the breakdown point, and then it comes down along the same line.
		It is not a metal that we could use for lots of reasons.  So the next one was stainless steel, which comes along on a relative straight line up and down, but you get mesenteric curve once you go past the elastic point.  So you get a permanent deformation.
		And the notanols, there are different kinds of notanols, as it has been stated today.  The only one available to us showed some deformity right from the beginning, and so it never really came back along the same line, which meant that it would change its crystalline structure, which meant in the long term that it would probably fracture.
		So we were only left with stainless steel to use, and that's why we used stainless steel, but it a simulated pre-clinical test, and I am sure that it could be extended so that other metals or materials could be used pre-clinically to do that.
		And then we tried to improve on that by -- there is the stainless steel, and we had to look to see how we would join it.  So we looked at a welded sleeve, and we looked at soldering, and the welded sleeve was somewhat better than the soldering we could produce.
		But we were convinced by the engineers that the soldering could be improved and we went back to soldering, but it also shows that these things can be tested on how they get joined and so on.
		And we looked to see if we could improve it by plating it with gold, and we made it worse, which was interesting, and which was a surprise.  And so you can look at the various potentials and you can assess it, and we can go way above the corrosive time span for the lifetime of the people that we are dealing with.
		We are not dealing with pediatric patients.  We are dealing with people in the last -- probably 15 or 20 years of their lives.  So having done that, we then proceeded and used a graft, and after a period of time, we had a failure.  
		It was a failure of the migration, and it fell down into the aneurysm and it was explanted, and having a look at it, you can see there the stress fracture lines, and until it breaks.  
		And it didn't break at the joint or at the soldering point.  It broke at the stress point, and so it was a stress point fracture, a deep fracture.  And this is the point where it broke.  You can see the corrosion around it where it had occurred.
		But the fracture occurred here, and that was a stress-strain relationship.  The stress-strain relationship migration is very important as Dr. Parodi has done some very elegant experiments with this.
		And this was a very early sample that we used, and it was sent to me by a colleague, and he showed that the pressure wave inside the false lumen of a dissected aneurysm with no outflow was this, and with the true lumen it was this.
		And what it means is that in the false lumen where there is no outflow, but you have pressure, the pulse wave is higher, and the diastolic 
-- the pulse rate is wider, and the diastolic is higher.
		So the main pressure is somewhat higher in the false lumen than in the true lumen.  So we were very worried at that stage about endoleaks, and where there was no outflow, because if you increase the mean pressure, you increase the risk of rupture, and I think we all believe that now.
		So migration became a very important issue for us in that.  So with that, we got permission to change the hook structure.  You can see a long hook and there was a stress point there which fractured, and it got changed to a different soldering or hooks, stronger hooks, et cetera.
		And then it was tested, and so you can do some pre-clinical testing.  It is very simple.  Here is a spring gage, and the aorta is tied to a syringe top, and that is a cadaver aorta, and sometimes we use pigs in the beginning, but then we got permission to use cadaver aortas.
		And then the graft is affixed to an animal and it has an attachment device to the hooks, or no hooks as it may be inside, and we just pulled.  And the friction force alone to pull out is along here, and so it is 16 gage wire, or I'm sorry, 14 gage wire, and 16, 18, and 20. 
		And you get to 20 gage wire, and it becomes pretty bulky.  So it is not desirable, but you don't get much extra regular force anyway.  But if you add another attachment system, depending on the strength of the hook, and the number of hooks, you can lift your displacement detachment force from 10 or 12, and up to 40 or whatever, depending on what you want to put in there.  So you can test for that.
		But you can't -- whatever you are doing in designing that, you cannot forget about the problems of planning, and how the graft is going to fall.  So, a graft is always going to fall at right angles to the access.  
		And this is just a mirror image of that, in terms of where the renal arteries are, and you can see that -- well, not the mirror image of.  I'm sorry.  I have moved the renal arteries relative to the right and to the left.
		But the wall distance, or the length that you would assess the neck to be on an axial CT is the same, but the effect of putting a graft in is very different, because your wall contact area is very short here, whereas it is very long there.  So you can simulate that in any situation.
		And the diameter is important because just simple mathematics tells you that you have got a 28 millimeter diameter, and you can pull it at right angles and it is goes under the curve, you are going to lose at 45 degrees approximately 19.8 millimeters.
		So you can lose just about your whole wall on one side, and that is the minimum contact wall length that you require.  And here is an example.
		This is the 18th case that we ever did, and it is sharply angulated forward, and we thought that everything was fine, but on the posterial wall, you can see that the top crown of the cover stent has fallen into the sac of the aneurysm, and therefore, there is not adequate wall contact at that point.
		And that hole is sufficient to cause a rupture, and a rupture occurred in a large aneurysm, and it occurred in a couple of weeks.
		So migration and seal and all contact became issues, and that was the reason that we decided to go across the renal artery, because the region of the mesenteric and renal vessels is the strongest part of the aorta, and the last bit to start to dilate.
		And durability demands a secure fixation without migration, because migration as we said may repressurize.  But if you put a Y across the renal artery, you go across its surgical principle.  
		And you can see why here across the renal, and all the vortex shedding and so on that occurs, and all the canoeist is doing is keeping his canoe straight with the paddles.  He is not paddling up against that.  He is just balancing.
		So we were concerned obviously of putting a Y across a renal artery.  So we did some mathematical modeling, and then we did some computer computational flow dynamics, and then finally we put it into a flow model and looked at it.
		And they all come out fairly close for a 7 millimeter tube and a 5 millimeter Y, and as long as you don't get accretions on it, then you get a three percent decrease in flow, about that range.
		We have to look in the clinical characteristics and you cannot put that in our selection, because as people age, not only do they lose brain cells and can't remember things, but they also lose a certain number of neutrons, and so the creatinine levels are going to rise with age.
		And so you have to put it into some form of normal human context if you are going to follow these people over a period of time.  And you also have to look at the tortuosity as we discussed, and two issues arise.
		The first is that as soon as you put a rigid device, or send a rigid device in there, you are getting a knitting needle effect if there is severe tortuosity.
		And the more rigid there is, the more that will occur, and that will change all your length assessments.  And then when you release it, it may take up its previous shape or it may not.  
		Here is the issue of a kink and this is a very good examine of a kink, but the problem is that the following stent overrides the preceding stent.  And that is a major problem, and it was not an anticipated problem for that degree of deformity.
		And we could have avoided that and I admit that by just doing some better testing on what angle we wanted it to take, and the argument is that you have to put a gap in this type of stent arrangement to allow you to go around the curve.  It is a box car on a train effect.
		And it can be calculated, and so you can actually do that, and so you can calculate, say, to go around an angle on an aorta, or you can clinically test this.  
		You can make a design with a certain angle and you can do that, and plan it to go around, which brings up a really important issue, and that is that if you are simulating pre-clinically to design or make something, what limit are you going to put on it, because you are going to have to put some limit at some stage, and thereafter you are going to have to adapt.
		And you adapt before you put it, rather than trying to fix the problem afterwards.  So if you say, okay, we will set these limits, and so we will only use a device at these limits, and we have all done that, and we set guidelines.
		And we found that 69 percent of the devices inserted were outside the guidelines.  Now, to be fair, many of those that were inserted outside the guidelines had been custom made or adapted for the deviation from the guidelines.
		But we thought that the neck was the most critical part if we are going to get a failure, because it is the hardest to fix, and 63 percent were outside that.  
		So it does mean that we have a clinical problem, and the clinical characteristics of the people that we are treating, or the clinical characteristics of the people we are treating are going to impact on what you design to test.
		And we found when we looked at how it was -- how the failure being an endoleak rate, the flair and contour of greater than 3 millimeters was the greatest risk.
		And then length for the reasons that we described, and they are affected by diameter.  We found that angles up to 30 degrees was not a problem, and up to 60 degrees, you could cater for them with customizing, and after that, we had a problem.
		But the failing defect within the other limits, which is within 28 millimeters, didn't affect the situation, in terms of migration or endoleak.  But the contour was very important, and it is probably device specific.
		So there is a finite link to the graft and that is ideal, but in this one, if it were to fit to there, and just cover that length, then it would probably be okay.  And pre-clinical testing on the model on the bench would show conformity to that shape.
		But if it fits across there, then it is not going to have wall contact.  It is going to be separated here and there, and that is just the reverse of this.  So you might say that is the safe thing from the point of view of resisting detachment, but it is not, because if it fits in here, then you could have 30 graft flow here.
		And that is just a combination and that is just a dangerous situation as was already alluded to, because you don't get wall contact.  Now, compliance may come into it, because you may push the graft out and compliance of the aorta is going to be important.
		These points are often related to the number of arteries, and that's where a number of arteries come out.  So the point of narrowing as far as that top pair of arteries, you may be able to push it out, or you may not.
		And that is going to depend on other factors, such as calcification, and as people go outside two parameters, then they increase the risk of failure.  So in this situation, if there is contour with diameter, it is highly significant.
		And contour length is the next most significant thing, and neck diameter affects a  contour change in angle, of course, and is important, but less significant.
		This is an issue of imaging, and our first priority was to make sure that the imaging was the first prerequisite.  And we had to take the balance of imaging and infection.  
		And you should be able to angle, and so you get the best angle, and you get the best length, and so on and so forth.  And since I have had the pleasure of staying two days in Washington, I have seen some enormous people in Washington, and if you haven't got a good machine to get through them, it is going to be hard whether you operate on them or whether you -- or whatever you do, it is going to be really difficult.
		So imaging is essential and that is a clinical characteristic related to infrastructure.  Now, this is where I got beaten up today, and I don't know what the force is, but the force is going to be here, and it is going to move until it hits the wall.
		Or it is going to hit something that stops it, and when it moves, it is going to pull from the other two ends.  Pressure, of course, is something I accept as important, but pressure would change with exercise.
		So if you are going to pre-clinically test, you have got to be able to test by changing your pressure, and every time we exercise, people in exercise tests with endovascular disease, the pressure always goes up, especially when there is no compliance in the aortic wall with aging, because you lose the capacity.
		And we were concerned, rightly or wrongly, but we were concerned that if this was the area that was going to be a problem, and just maybe you could say it was intuition, but it was going to be at the bottom end and it was going to lift out.  And we still have that problem.
		And so we decided that if you are going to use a modular device, you have got to get the joint as close to the exit point as possible, and preferably inside the exit vessel.  
		So you can see that there are many forces at work, and as we said, there is a drag force, and if we have a 30 millimeter diameter neck at the top here, and 10 millimeters down at the bottom, the drug force is 10 Newtons.  
		Now, if you use regular force alone, you are going to drag it out, because the radial force alone, the stainless steel anyways, is an extra 10 Newtons.  And you are going to need a little bit of exercise, and it is going to pop out.
		In a thorastic aorta, you don't get that problem because just the flow through there doesn't give you a drag force.  If you come down below 26 millimeters, then the Newton pullout is only 3 to 4.
		So there is a huge difference if you change your diameter, and the relative diameters of the top and the bottom.  There is the perception of difficulty, and so you would think that people would go up the right side here to get a straight line, but that is merely the mirror image.
		So in implanting, people can use the same thing in a mirror image, and change their whole access of procedural plans.  So, perception is important.  And in open surgery, you can modify.  We tailor.
		To think that we go in there and do a specific operation every time and not have changes is naive.  We have the ability to tailor.  So if you are going to work from a remote site, you should have the ability to tailor in principle.
		And if we are going to pre-clinically test or set up these things, we have got to set it up for the different situations that we are going to encounter.  So we have to anticipate those situations.  You can't expect one device to perform all functions.
		And here is an example of tortuosity.  If you have tortuosity of the top and the bottom, you cannot orientate the top and the bottom at the same time, because as you deploy, it will take on a different twist.  
		So why not separate them so that then you can do different things with this one, and you can orientate that one separately.  It also means that you can -- that you don't have to worry about lengths so much, and so you can bring this one right down and put it into the other side if necessary and get stability.
		We talk about thrombosis and clotting, and here is a pre-clinical test that we did very early.  We soaked this in hundred-thousand units per liter, which is not a lot really.  It is only 5,000 units in 50 mils.
		And we put this bit of graft material into a bowl, and harvested it with some blood, in which the patient had 5,000 units of heparin, and this one was free of clot, and this one wasn't.
		Now, if you read the literature, there is no heparin bounding to that one, but experimentally it makes a difference.  So if people take a long time and they don't prime it properly, there is the potential for thrombosis, and we have had that problem.
		Animal testing is not to be forgotten, because it does have a place, but it depends on what you want to test, and in this situation we wanted to test what happens in a growing pig when we put Y's and things across orifices or vessels, and to see how much time it takes to narrow off the vessel.
		And there are limits.  You can only use the animal once, and if something goes wrong, or the anesthetic is wrong, or whatever, then it doesn't work. 
		In this case, we could only go on for six months, because the pig got so big because it was growing that they wouldn't feed it anymore.
		We need to be able to test the different devices in a situation, one against the other.  So you might test ancillary devices.  And you can see that this is just a simple experiment of putting a balloon expandable stent and putting one through a self-expanding stent.  
		But it shows you different properties, and that is so we can use these properties.  This is the current test rig that we are trying to set up to simulate these tests, and here is an artificial heart, and it goes through an artificial aneurysm, and there is an in-flow and out-flow, and we can change that.
		And we can position the graft in different situations inside there, and have a look to see what happens when we put pulsatile flow in through that area.  It is pretty crude, but it is a start that we didn't have a long time ago.
		We talked about laminated thrombus today, and I don't think we came up with any specific things, and lots of things have been written about it, but I don't think we understand it too much.
		Essentially, we regard it as having no structural strength whatsoever, and it will change.  Now, this is an experiment and we just put a little bit of the current through the laminated thrombus, and you can see after you run it for a while that it starts to cavitate.
		Now, maybe your artificial thromboses is not the same as laminated thromboses, and it has a slightly different structure.  They have tried the angi-fluid dynamics, and engineers are not allowed to work with human material.  
		And so we have simulated thrombus and we can't use real thrombus.  But it does suggest that if you start to get channels through laminated thrombus that it behaves in a strange way.  
		And we all know what the physics are to make an aneurysm expand, but this business of aneurysm contraction, especially length contraction, and compression length-wise, we didn't see any physical or mechanical reason why that should occur.
		So that is still debated and I left this morning feeling that that was probably the agreement around here.  And this is just Einstein, but I guess you all know that he died at the age of 75, and it was in 1955, and open surgery had been available since 1952.
		And having had a procedure that was open surgery with a graft, and having had a graft before and it hadn't worked too well, he turned down surgery even though he knew his aneurysm was ruptured and he lay in bed for about three days, and he was still working away with his mathematical formulas.
		So he is almost the patron of many thing, including aneurysmal disease.  But I want to put him up for another reason, and that is that he is a Northern European and he is old.
		If he were Chinese, his common iliacs would be very different, and because we are in Southeast Asia, when we are starting to look at that situation, we have to have a whole new set of pre-clinical tests, and so on and so forth, on the ethnic changes in the common iliacs.  And lift out from the common iliacs is a real problem, which is why we dwelt on it.  Thanks.
		(Applause.)
		(Working Session.)
		DR. BEEBE:  All right.  Thank you, Geof.  Dorothy just said it was time for me to get up and summarize today's discussion, and I tried to get out of it by saying why don't we start tomorrow morning's session by doing that, but she wouldn't let me off the hook.
		I will attempt some kind of summary here by asking you to help with it, and seeing if you think back now over the four fairly thorny wickets we have been through here.  
		We started with something pretty simple, just describing the disease, shape, and physiology that we are treating here.  What was the -- think back on that, and when we were first talking about that, and Barry and I were talking about the morphology and imaging methods, what was the best and the worst of that?  Anything that stands out in your mind, or is it all at this point a complete blur?
		Was there any news?  We didn't necessarily expect that it would be news.  We were just trying to pave the way for other discussion.  But I think that in my mind, anyway, to answer my own question since I don't see you all waving your hands frantically, it is that we seem to have a very solid opinion in the group that 3-dimensional stuff is where it is at now.
		And I thought that was kind of important.  We haven't always heard that over the last few years, but it is time now to move on to 3-dimensional imaging.  
		Was there any -- if we are going to talk about morphology, we have got to talk about 3-D.  If we don't talk about 3-D, we are just wasting time.  Does anybody disagree with that?
		DR. WHITE:  I don't think I disagree, John, but I think the other thing that came out in that session was that we do need standardized definitions of how we do all these measurements, because as it was pointed out, we don't have any standard definitions of what an angle is, and how you measure angulation, and how you measure tortuosity, how you measure the curve, et cetera.
		DR. BEEBE:  Yes, and as if that wasn't bad enough, when we got into the physiology, we really had a problem with non-standardization, and then when we went on into the morphology change, which was question number two, it got wrapped up to a higher level of at least exposing what we need to know and don't.
		And we need some more work there before we can just arbitrarily say things about that.  The physiologic environment of the excluded aneurysm was a pretty lively discussion, and I don't know whether we cleared the air, but we certainly clarified a lot of clear differences.
		We have some work to do there, but we did achieve meaningful consensus on the importance of pressure in provoking the cyclical loading of the device.  Is that a fair statement out of all that discussion?
		WORKSHOP PARTICIPANT:  Pressure and strain.
		DR. BEEBE:  Is there anything else?
		WORKSHOP PARTICIPANT:  Pressure and strain also.
		DR. BEEBE:  Pressure and strain.  Okay.  No disagreement there.  We went on to describe a very long list of failure modes, and at the end of that discussion, I think we identified a very useful distinction it seems to me without having kept notes about it.
		But what is sticking out in my mind is the importance of not placing an overemphasis on failures that resulted from extreme case selection.  It was sort of not exactly off-label, but very risky stuff that may have been perfectly appropriate clinically, but it was such a sick patient that you were willing to take that risk.
		But that should not be driving us, just to lump all failure modes together.  I felt that was extremely important, because most of our literature does not make that distinction.
		And a lot of what we think we know from reading that literature, and summarizing our experience needs maybe to be refined.  That was pretty powerful.  Anybody have any other powerful points on that issue?
		WORKSHOP PARTICIPANT:  The only thing I would add to that is very rarely do we have the opportunity for positive controls on clinical outcomes, and if you are trying to have performance requirements, it was mentioned that we do want to maybe pool clinical data if we can.
		And if we can jump the legal hurdles, I would try to capture those data to the extent possible because those are the ones that allow us to establish performance requirements.
		DR. BEEBE:  Dan's point is very strong.  Not so much the device analysis, but the morphology analysis of the device and of the patient failures that we have observed, and if we could work on that a little bit more, and maybe we have to come back to that in Session 7.
		But keep that in your mind, and be thinking about that overnight.  Is there a way that we could do that.  It seems to me that most people in this room ought to have a common interest in getting that data together at some neutral point.  
		We are talking about morphology and patient characteristics, and not about the device failure analysis.  And then we got into the discussion that was just concluded, and I am not going to try to summarize that, because we didn't get very much of it done.
		But we have got a couple of hours first thing in the morning to work on it, and come in here fresh, and enlightened, and full of bright ideas, and we have got to get through a whole lot of testing stuff tomorrow in the first couple of hours.  With that said, we are starting at nine o'clock tomorrow morning.  
		(Whereupon, at 5:42 p.m., the Workshop was adjourned, to reconvene at 9:00 a.m., on Wednesday, August 1st, 2001.)