AHDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
>
> CIRCULATORY SYSTEM DEVICES PANEL
>
> Wednesday, October 23, 2001
>
> 8:39 a.m.
>
> Walker/Whetstone Room
>
> Gaithersburg Holiday Inn
>
> 2 Montgomery Avenue
>
> Gaithersburg, Maryland
>
> [C O N T E N T S]{.underline}
>
> [AGENDA ITEM: PAGE]{.underline}
>
> Call to Order
>
> Dr. Cynthia M. Tracy, Chairperson 3
>
> Presentation: Dr. Dale R. Tavris, Office of
>
> Surveillance and Biometrics, FDA
>
> \"Adverse Events and Deaths Associated with
>
> Hemostasis Following Cardiac Catheterization:
>
> Comparison of Manual Compression versus
>
> Collagen Plug and Suture Hemostasis Devices\" 3
>
> Conflict of Interest Statement 23
>
> Open Public Session 28
>
> Sponsor Presentation
>
> Ms. Jean Chang, EMBOL-X, Mountain
>
> View, California 29
>
> Dr. Nicholas T. Kouchoukos, Study Co-
>
> Principal Investigator 32
>
> Dr. Richard E. Kuntz, Study Trial Design 41
>
> Dr. Keith B. Allen, Site Principal
>
> Investigator 54
>
> Questions and Answers 82
>
> FDA Presentation
>
> Catherine Wentz - Engineering Review 96
>
> Dr. Julie Swain - Clinical Review 100
>
> Dr. Gerry Gray - Statistical Review 110
>
> Questions and Answers 123
>
> Open Committee Discussion 134
>
> Open Committee Discussion - Continued 157
>
> Questions for Panel 212
>
> Adjournment 268
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order**
>
> DR. TRACY: Good morning. I\'d like to call to order this meeting of
> the Circulatory System Devices Panel.
>
> We are going to start with a presentation from the Office of
> Surveillance and Biometrics on \"Adverse Events and Deaths Associated
> with Hemostasis Following Cardiac Catheterization: Comparison of
> Manual Compression versus Collagen Plug and Suture Hemostasis
> Devices.\"
>
> If the presenter is present, would he please take the podium?
>
> **Presentation by Office of Surveillance**
>
> **and Biometrics**
>
> DR. TAVRIS: Thank you.
>
> This study was a collaborative effort between the FDA and the American
> College of Cardiology.
>
> \[Slide.\]
>
> Over the 5-year period between 1996 and 2000, 1,880 reports of serious
> injuries and 36 reports of deaths associated with the use of
> hemostasis devices used to prevent bleeding from the femoral artery
> following cardiac catheterization were reported to the FDA through its
> medical device reporting system.
>
> Most of these serious injuries and deaths involved hemorrhagic
> complications. It was also of interest that a large majority of injury
> and death reports involved women, even though cardiac catheterization
> is more common in men than in women.
>
> This study considered the earliest two types of hemostasis
> devices\--the suture device, Perclose, and the two collagen plug
> devices, VasoSeal and AngioSeal.
>
> Because of the continued receipt of adverse event reports involving
> injuries and deaths, the FDA was concerned about the safety of these
> devices. Of course, these reports themselves do not causally implicate
> these devices in the injuries and deaths, since these can also occur
> following manual compression, in which case the events would not be
> reported to the FDA.
>
> But the medical literature on this subject also gave us cause for
> concern. Of 13 studies that we could find that utilized manual
> compression control groups to assess risk of serious injury associated
> with hemostasis device use, 9 showed no difference in the rate of
> adverse events between device users and controls, and 4 demonstrated a
> higher rate in device users. None demonstrated a higher rate in
> controls than in device users.
>
> Two important weaknesses of the studies found in the medical
> literature are small sample sizes and the use of a single or small
> number of institutions. For example, the 13 studies referred to above
> utilized a total of 19,582 procedures, including a little over 15,000
> controls and a little over 4,000 device users. Most involved a single
> institution.
>
> By contrast, this study, which utilized the American College of
> Cardiology\'s National Cardiovascular Data Registry, involved 214
> participating institutions and 166,680 procedures, including over
> 113,000 controls and over 53,000 device users\--more than 7 times as
> many controls and 13 times as many device users than all the other
> studies combined.
>
> This study included information from all cardio catheterization lab
> admissions representing the 214 institutions included in the ACC\'s
> data registry from the year 2001. Excluded from the analysis were
> outpatients and any patient for whom critical data was not available.
>
> Outcomes assessed in these analyses included hemorrhage, arterial
> occlusion and loss of arterial pulses, artery dissection, the
> development of an AV fistula or pseudo-aneurysm, and death associated
> with any of these events. Hemorrhage, by far the most common of these
> events, was defined as \"blood loss requiring transfusion or
> prolonging the hospital stay or causing a drop in hemoglobin of
> greater than 3.\"
>
> Stepwise backward multiple logistic regression analysis was performed
> in order to control for the effects of potential confounding
> variables. The main independent variable of interest was hemostasis
> device use.
>
> Potential confounding variables that were assessed included
> demographic variables, comorbid conditions, type of procedure\--that
> is interventional versus diagnostic cardiac catheterization\--presence
> of left main coronary artery stenosis, and indications for the
> procedure.
>
> Of the more than 160,000 subjects in this analysis, by far the most
> frequent complication was hemorrhage. There were 1,756 episodes of
> this, a rate of 1.1 percent. This represented 73 percent of the
> subjects who were characterized by any adverse event in this study.
>
> The mortality rate for the 2,418 subjects in this study reported
> within the adverse event was 5.5 percent.
>
> First, I will present only the multivariate results that used the
> reporting of any adverse event as the outcome. Female gender and the
> use of interventional as compared to diagnostic cardiac caths were
> found to be the biggest risk factors, both with odds ratios of 2.3.
>
> Several comorbid conditions and indications for the procedure were
> also found to be associated with adverse events. These included an
> emergency indication for the procedure, plaque as an indication for
> the procedure, acute myocardial infarction, history of renal failure,
> New York Heart Association class, and peripheral vascular disease, all
> with odds ratios between 1.2 and 1.8.
>
> The use of a hemostasis device was found to be protective as compared
> with the use of no device, especially the use of the collagen plug
> devices, which demonstrated an odds ratio of 0.79, which was highly
> statistically significant.
>
> \[Slide.\]
>
> This table depicts odds ratios for those associations that were
> statistically significant at the P less than .05 level. To a large
> extent, the risks associated with any complication pertained to many
> of the specific complications as well.
>
> Female gender was associated with five of the seven specific
> complications, all with odds ratios of greater than 2 and P values of
> .0002 or less.
>
> The use of interventional cardiac catheterization was statistically
> associated with four of the seven specific complications.
>
> Of the nine comorbid conditions or indications for the procedure that
> were assessed in this analysis, six of them were associated with three
> to five of the seven specific outcomes in the multivariate analysis.
> Those that weren\'t associated with these outcomes were probably
> precluded from this by their close association with the other comorbid
> conditions.
>
> \[Slide.\]
>
> As for the hemostasis devices, the most pronounced protective effect
> pertained to pseudo-aneurysms. Both types of hemostasis devices were
> characterized by odds ratios of approximately one-half with respect to
> this outcome.
>
> The hemostasis devices as a group demonstrated a protective effect
> with regard to hemorrhage, with an odds ratio of 0.89, although this
> protective effect was not statistically significant.
>
> When the collagen plug devices alone were compared with manual
> compression, the odds ratio was 0.85 with a P value of .035.
>
> Neither hemostasis device demonstrated a statistically significant
> protective effect with regard to vascular complication-related deaths.
> The collagen plug devices demonstrated an odds ratio of 0.56 with
> respect to this outcome, but because there was only a total of 144 of
> these deaths, the study was not powerful enough to attain statistical
> significance even with that low odds ratio.
>
> The risks associated with female gender, interventional cardiac cath,
> and several of the comorbid conditions were not surprising, as these
> had been demonstrated previously. But we were surprised to note the
> protective effect of hemostasis devices given that concern over their
> safety was the main reason for conducting the study and that the
> medical literature had generally shown them to be associated either
> with a greater than or equal risk of adverse events compared to manual
> compression controls.
>
> Possible explanations for this apparent discrepancy are the following.
> First, confounding variables that were not controlled for in this
> analysis. However, this explanation seems unlikely to us given the
> large range of comorbid conditions that were controlled for in this
> study, although we did not control for coagulation status.
>
> Second, it could be that the medical providers who participated in
> this study were more skilled in the use of these devices than most
> other medical providers. This is a complicated issue. On the one hand,
> that explanation is made less convincing by the large number of
> participating institutions in this study; but on the other hand, the
> protective effect seen in this study was not very great\--only a 21
> percent decrease in total complication rate for the collagen plug
> devices and a 15 percent decrease for Perclose.
>
> None of the studies that we found in the medical literature was large
> enough to detect that small of a protective effect, even if one
> assumes that the skill of the providers was comparable to that found
> in this study. But that would still not explain why a minority of
> studies in the medical literature have demonstrated a harmful effect
> associated with hemostasis device use.
>
> Of course, since these studies generally involved a single
> institution, it is possible that the physicians involved in one or
> more of these studies were less experienced or skilled in the use of
> the hemostasis devices than average.
>
> Finally, a third possible explanation for the protective effect found
> in this study compared with other studies is that over time, the users
> of these devices have become more skilled and thus more likely to
> produce better results than those seen in other studies.
>
> That concludes my presentation, and I would be happy to answer
> questions.
>
> DR. TRACY: Dr. Krucoff?
>
> DR. KRUCOFF: Dale, with great respect for the noble intention here, I
> am really concerned that maybe we\'re just pouring worms into a can of
> worms.
>
> In a nonrandomized platform there is an enormous bias involved in how
> you and when you choose as an operator to use these things. Most of us
> will actually do a femoral injection before you position one of these,
> so anybody, where you are involved in a placque or at a bifurcation
> point or where you have had multiple sticks in a lesion, you don\'t
> even deploy these things.
>
> So immediately in this kind of registry, there is an intrinsic bias
> just by case selection. And I would certainly list that amongst your
> possible explanations for the findings that you are looking at.
>
> The other question I have is could you detail for us what you are
> aware of as far as any kind of quality control at the sites? Was the
> operator or somebody related to the operator who placed the device
> also the one who followed up on the patient and reported on
> complications, which of course is another source of bias\--if you put
> one of these things in, you may tend to look at a little oozing or
> bleeding as just something that is going on in the tract because the
> patient is anticoagulated, whereas if you with manual compression have
> subsequent bleeding, you may report it differently.
>
> How as the data quality-controlled at the site level?
>
> DR. TAVRIS: There were a number of quality control procedure that
> mostly included educational interventions to train the sites on how to
> record the data, and also overview of the data for completeness.
>
> As far as potential bias in the recording of data, I\'m not sure that
> any of the quality controls could have favorably influenced that.
>
> The earlier comment about potential selection bias sets\--part of what
> I meant when I talked about potential confounding variables that could
> have affected this\--do you feel that the selection of patients would
> work in a way that would make the patients who received the devices a
> group that was less likely to experience complications?
>
> DR. KRUCOFF: Definitely, absolutely, positively.
>
> Lastly, you called this a \"study.\" Did patients whose data were
> recorded in this registry provide informed consent?
>
> DR. TAVRIS: I\'m pretty sure they did. This was the American College
> of Cardiology\'s registry, and I\'m pretty sure they did.
>
> DR. KRUCOFF: We do not consent patients for registry data for the ACC.
>
> DR. TAVRIS: Okay.
>
> DR. TRACY: Dr. White?
>
> DR. WHITE: Thank you.
>
> I\'d like to echo Dr. Krucoff\'s statement. As a user of these
> devices, I think you cannot underestimate the selection bias that goes
> into this compared to a randomized device trial. The published
> literature\--our hands are tied about how patients are treated. You
> absolutely enroll the patients, they get one or the other, and you
> work very hard to make the patient fit the trial.
>
> In our regular practice, however, we don\'t poke skunks with sticks.
> If that groin doesn\'t look good, it doesn\'t get a device, and we
> don\'t look for that trouble, and I think that is a major reason to
> explain why it appears that devices are safer.
>
> The other thing is I think you may not completely understand the ACC
> Data Registry, which is a very voluntary, self-selected population. It
> certainly isn\'t a widely-adopted process. It doesn\'t even represent
> a majority of the catheterization laboratories in the U.S.\--not
> because it\'s not a good thing, it\'s just that it is expensive. For
> example, in my institution, I would love to participate, and my
> institution cannot afford to participate. So there is a lot of data
> missed, I think, if that is the database.
>
> Then, finally, I think that that database is used for quality control,
> not for scientific generally reporting, so I think patients generally
> are not consented that their data would be collected and used. And
> I\'m not sure what the implications are for that in terms of informed
> consent and the use of the data. That would be something that would be
> of concern, I think, to my local IRB that release of that kind of
> information.
>
> DR. TRACY: Dr. Laskey?
>
> DR. LASKEY: I would be very wary now and for the foreseeable future in
> using NCDR data. It is non-quality-assured. It is non-verified. There
> is no routine auditing as far as I can tell, as far as I know. And as
> Chris mentioned, it is an entirely voluntary registry which, maybe on
> one side of the coin bespeaks honesty on the part of the reporting
> sites, but it is extremely spotty, and-=
>
> DR. TAVRIS: When you say \"voluntary,\" doesn\'t that mean that it is
> voluntary as far as the institution, but the institutions that are
> participating in it do routinely collect data from all procedures?
>
> DR. LASKEY: Yes, but the rigor with which that data is collected
> cannot be vouched for, and it will vary from site to site.
>
> DR. WHITE: And the discipline should not be confused with the
> discipline for a randomized trial, which has audits, and you\'re
> pretty sure about that.
>
> DR. LASKEY: It has become very fashionable in the last few years to do
> things like propensity scores and all that to try to adjust away for
> some of these biases in these observational trials. I would bet if you
> did that, you would still be left with the same answer, but it is
> probably worthwhile going through the exercise since you have a number
> of people who didn\'t get the device.
>
> It has been our experience that it goes to more than the groin. If the
> groin or the artery doesn\'t look right, or if the patient doesn\'t
> look right at the end of the procedure, they do not get a closure
> device, either.
>
> DR. TAVRIS: What data would you use to calculate the propensity
> scores?
>
> DR. LASKEY: You have folks who got the device and folks who didn\'t
> get the device. That is your endpoint for the propensity score, and
> then you would put into the soup all the other variables that you just
> looked at as step one. And then, step two is to put the propensity
> scores into your final analysis. That is generally the way it is done.
> I am not supporting that as a way of verifying this data, but I think
> it is an interesting exercise.
>
> DR. TRACY: You mentioned that there was an exclusion of outpatients.
> Does that mean outpatient caths, and procedures and interventions were
> excluded from analysis\--because I think that in many institutions,
> most procedure are done as outpatient.
>
> DR. TAVRIS: In this database, most of them were not outpatients, but
> yes, the data that I showed excluded outpatients although before we
> excluded them, we did analyze the data with outpatients in it, and we
> got very similar results.
>
> The reason we excluded the outpatient afterward was that we felt that
> there might be some potential for additional bias because there might
> have been disproportionate followup in one group or the other. We
> couldn\'t be sure how good the followup was.
>
> DR. LASKEY: Dale, if available, just one other key variable which may
> not be in the database but that has clearly been associated with
> hemorrhagic complications is the extent of anticoagulation; what kinds
> of ACTs are in this patient population in a nonrandomized format.
>
> Again, that may actually affect whether or not an operator would
> deploy a device, so you may have your higher ACTs on IIb/IIIa\'s in
> the wrong group.
>
> DR. TAVRIS: We wanted to do that, but that data wasn\'t available. We
> do intend to do that in our next study. But from review of the medical
> literature, there is only one article, I believe, that did control for
> coagulation status, and in that article, those with hemostasis device
> use were more anticoagulated than those without use, and I would think
> that that would tend to make them look worse given that hemorrhage was
> the main complication here, and that group would have been more likely
> to experience higher hemorrhage rates.
>
> So that would have contributed bias, I would think, in a direction
> that would have made our results, the protective effects seen for the
> hemostasis devices even less likely.
>
> DR. TRACY: Dr. Zuckerman?
>
> DR. ZUCKERMAN: Just by way of background, the Agency is always
> interested in ways of potentially addressing the pre- and post-market
> balance in terms of what we require pre-market before PMA approval of
> a hemostasis device versus post-market. And certainly this has been
> one attempt at looking at post-market datasets given the controversial
> nature of some of these devices.
>
> Panel members have expressed problems with this particular registry,
> so the first question is are there any other datasets that might be
> useful to explore.
>
> The second question refers to some of the implications of the panel
> discussion for our pre-market approval data requirements for these PMA
> hemostasis devices. Because there are large opportunities for
> selection bias, et cetera, our general standard has been to require a
> randomized trial versus manual compression.
>
> Many sponsors have indicated that there is a large historical database
> of manual compression results and have suggested other trial designs.
> I would be interested in any comments on how to evaluate these devices
> and with minimization of bias.
>
> DR. KRUCOFF: I think one key question would be whether your issue is
> safety or efficacy. When you started the presentation, it seemed to me
> that the concern, because of the reporting mechanism that kicked all
> this in, was safety. And ultimately what your conclusions are leaning
> toward is are you demonstrating some kind of efficacy impact.
>
> I would at least start by being clear on what the question that is
> being addressed is, and if complication rates associated with these
> devices are what you need to learn about, then I think you need to
> make sure that the data is collected in a way that you can understand
> whether the complication rates are higher than your target.
>
> Now, in terms of manual compression, which I think has got to be the
> target, whether you could do a comprehensive job of characterizing an
> historic control where you understood that it was matched across
> important parameters to a study population where that device is
> deployed, I don\'t think an historic control would be out of the
> question, but I think with this kind of registry, the trouble is you
> are absorbing a selection bias that probably has as much or more to do
> with any observed results. At least an historic control, you could try
> to structure to a population so you wouldn\'t have that kind of
> implicit bias.
>
> DR. TRACY: It seems that maybe part of the problem is that there is
> selection bias for the type of device that is used in any given
> individual. It is going to be different, and the operator experience
> tremendously influences whether they do or do not use a particular
> device.
>
> So I think that if there were a new device that was coming along, the
> only control that you could use would either be manual compression in
> perhaps the ACC database versus one of the approved device studies.
>
> But I think it is just very difficult given the amount of bias that is
> inherent in this type of device to come up with a clean comparison.
>
> DR. WHITE: I think the true value of this trial is not whether or not
> your operators are more skilled than the PMA published papers are,
> because you can bet the people who are doing those trials are good at
> it. They wouldn\'t be doing those trials if they weren\'t fairly
> skilled, particularly at the randomized level. Those of us who do
> these trials get really good at these devices.
>
> I am reassured that in real use, people aren\'t getting hurt with
> these devices, and they are able to select patients and perhaps use
> these devices to some optimum. I mean, the fact that you found some
> benefit here, or some lower risk, reassures me that people know how to
> use these devices to their optimal ability. In the randomized trials,
> you have really skilled operators doing the best they can, and it is
> sort of an even ground.
>
> So I am reassured by your data, and I just think it means that out
> there in the real world, they are being used pretty well.
>
> I don\'t think you can use historical controls, because the patient
> populations are so highly variable. Whether we are talking about
> diagnostic catheterization, interventional catheterization, the level
> of anti-coagulation are huge impacts, and you can make things look
> better or make things look worse depending upon how you select. So the
> randomization here becomes a key.
>
> Now, if you want to accept randomization against another closure
> device, that would be an interesting model if there is enough data to
> make you convinced that you know\--if you want to randomize PercuSurge
> against the next level of device, that might be something I would be
> willing to do, but I would want to make sure that it was randomized so
> that the risks were evenly distributed in both populations.
>
> DR. TAVRIS: I certainly agree that randomization would be by far a
> preferable way of looking at this. The problem is that what randomized
> data we have is very, very small and would not be able to detect small
> differences.
>
> DR. WHITE: I agree.
>
> DR. TRACY: Are there any other comments?
>
> \[No response.\]
>
> DR. TRACY: If not, thank you very much for that presentation.
>
> We\'ll move on to the discussion of premarket notification of the
> Embol-X aortic filter.
>
> MS. WOOD: The following announcement addresses conflict of interest
> issues associated with this meeting and is made part of the record to
> preclude even the appearance of an impropriety.
>
> To determine if any conflict existed, the Agency reviewed the
> submitted agenda for this meeting and all financial interests reported
> by the Committee participants. The conflict of interest statutes
> prohibit Special Government Employees from participating in matters
> that could affect their or their employers\' financial interest.
>
> The Agency has determined, however, that the participation of certain
> members and consultants, the need for whose services outweighs the
> potential conflict of interest involved, is in the best interest of
> the Government.
>
> Therefore, a waiver has been granted for Dr. Thomas Ferguson for his
> interest in a firm that could be affected by the Panel\'s
> recommendation. The waiver involves a grant to his institution for the
> sponsor\'s product study in which he had no involvement and for which
> funding was less than \$100,000 per year. Copies of this waiver may be
> obtained from the Agency\'s Freedom of Information Office, Room
> 12A-15, in the Parklawn Building.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which an FDA participant has a financial
> interest, the participant should excuse him or herself from such
> involvement, and the exclusion will be noted for the record.
>
> With respect to all other participants, we ask in the interest of
> fairness that all persons making statements or presentations disclose
> any current or previous financial involvement with any firm whose
> products they may wish to comment upon.
>
> DR. TRACY: Thank you.
>
> I\'d like to ask the panel members to introduce themselves, starting
> with Mr. Morton.
>
> MR. MORTON: My name is Michael Morton. I am the industry
> representative, and I am employed by Soren Kolb \[phonetic\]
> Cardiovascular.
>
> DR. WHITE: Good morning. My name is Chris White. I am an
> interventional cardiologist from the Ochsner Clinic in New Orleans.
>
> DR. LASKEY: I am Warren Laskey, an interventional cardiologist from
> the National Naval Medical Center in Bethesda.
>
> DR. KRUCOFF: I am Mitch Krucoff, an interventional cardiologist from
> Duke University.
>
> DR. AZIZ: I am Samil Aziz, adult cardiac surgeon in Denver and
> associate clinical professor at the University of Colorado.
>
> DR. DeMETS: I am David DeMets. I am a biostatistician at the
> University of Wisconsin in Madison.
>
> DR. TRACY: I am Cindy Tracy. I am an electrophysiologist at Georgetown
> University Hospital.
>
> MS. WOOD: Geretta Wood, Executive Secretary.
>
> DR. EDMUNDS: I am Hank Edmunds, University of Pennsylvania, a surgeon.
>
> DR. MARLER: I am John Marler, Associate Director for Clinical Trials
> at the National Institute of Neurological Disorders and Stroke, and I
> am a neurologist.
>
> DR. FERGUSON: Tom Ferguson, a cardiac surgeon at Washington University
> in St. Louis.
>
> DR. PINA: Ileana Pina, heart failure transplant cardiologist, Case
> Western Reserve in Cleveland.
>
> MR. DACEY: Robert Dacey, Consumer Representative, from Boulder County,
> Colorado.
>
> DR. ZUCKERMAN: Bram Zuckerman, Director, Division of Cardiovascular
> Devices, Food and Drug Administration.
>
> DR. TRACY: Thank you.
>
> MS. WOOD: Pursuant to the authority granted under the Medical Devices
> Advisory Committee Charter dated October 27, 1990, and as amended
> August 18, 1999, I appoint the following individuals as voting members
> of the Circulatory System Devices Panel for this meeting on October
> 23, 2002: Christopher White, M.D.; L. Henry Edmunds, Jr., M.D.;
> Mitchell W. Krucoff, M.D.; John Marler, M.D.; Thomas B.Ferguson, M.D.;
> David L. DeMets, Ph.D.
>
> For the record, these people are Special Government Employees and are
> consultants to this panel and other panels under the Medical Devices
> Advisory Committee. They have undergone the customary conflict of
> interest review and have reviewed the material to be considered at
> this meeting.
>
> This is signed by David W. Feigel, Jr., M.D., M.P.H., Director, Center
> for Devices and Radiological Health, and dated October 10, 2002.
>
> Pursuant to the authority granted under the Medical Devices Advisory
> Committee Charter of the Center for Devices and Radiological Health
> dated October 27, 1990 and as amended August 18, 1999, I appoint the
> following individual as a voting member of the Circulatory System
> Devices Panel for the meeting on October 23, 2002: Ileana L. Pina,
> M.D.
>
> For the record, Dr. Pina is a consultant to the Cardiovascular and
> Renal Drugs Advisory Committee of the Center for Drug Evaluation and
> Research. She is a Special Government Employee who has undergone the
> customary conflict of interest review and has reviewed the material to
> be considered at this meeting.
>
> This is signed by William K. Hubbard, Senior Associate Commissioner
> for Quality Planning and Legislation, and it is dated October 18,
> 2002.
>
> DR. TRACY: Thank you.
>
> At this point, we\'ll move to the open public hearing. There were no
> scheduled speakers, but is there anyone in the audience who wishes to
> address the panel on today\'s topic or any other topic?
>
> \[No response.\]
>
> DR. TRACY: If not, we will close the open public hearing and move on
> to the presentation.
>
> MS. WOOD: I would just like to remind the speakers to introduce
> yourself and state your conflict of interest.
>
> **Sponsor Presentation**
>
> **EMBOL-X, Inc.**
>
> **K022071, EMBOL-X Aortic Filter**
>
> MS. CHANG: Thank you.
>
> My name is Jean Chang. I am the Chief Operating Officer for EMBOL-X,
> and I would like to thank the FDA, our panel reviewers, and all panel
> members for the opportunity to present our clinical results today.
>
> \[Slide.\]
>
> This is the presentation that we have planned. After I do a company
> overview, Dr. Nicholas Kouchoukos, Missouri Baptist Medical Center,
> the co-principal investigator, will give an overview of atheroembolism
> in cardiac surgery.
>
> Dr. Richard Kuntz, from Brigham and Women\'s, will present our EMBOL-X
> clinical trial design.
>
> And finally, Dr. Keith Allen, who is the site PI at Saint Vincent,
> will present the clinical study results.
>
> \[Slide.\]
>
> EMBOL-X is a small, privately-funded company that was founded in 1996
> by two physicians. It is in Northern California, and has less than 50
> employees.
>
> The product focus from the start has been intra-aortic filtration
> utilized during cardiac surgical procedures.
>
> The first clinicals were done at the end of 1997; CE marked the
> product in the end of 1998. And the product has been commercially
> available in Europe since 1999, with over 2,000 documented cases.
>
> \[Slide.\]
>
> What we show here are the two devices that make up the EMBOL-X
> intra-aortic filtration system. The top device there is the EMBOL-X
> aortic cannula, which has the premarket \[inaudible\] this past
> September is a modified standard cannula.
>
> The bottom device is the subject of our presentation, which is the
> EMBOL-X intra-aortic filter. The distal filter basket there is
> composed of two primary components. It is a polyester mesh with 120
> microns, and the polyester mesh is heparin coated with a duraflow
> heparin coating, which is the same heparin coating that is used
> \[inaudible\] filters.
>
> What this demonstrates is the principle of use of the filter in
> cardiac surgery. It has been inserted through the sideport in the
> cannula, and again, as you will note here, the filter captures
> particulates that arise from the heart up to and proximal to the
> arterial cannula. It does not capture particulate that is distal to
> the cannula, including arterial flow.
>
> What you see on the right there is a representative sample of the
> particulates that are captured. The grid marks there are 3 mm, and Dr.
> Allen will talk more about particulate capture as we go forward.
>
> \[Slide.\]
>
> Embolic protection, embolite capture, is not a new technology, and the
> EMBOL-X intra-aortic filter follows along the same lines as existing
> devices that are either currently approved or under investigation. And
> as we discussed earlier, the extracorporeal filter is standard in
> cardiac CPB surgery. The PercuSurge distal protection device is used
> for SVG, and Dr. Kuntz will talk a little about that.
>
> And finally, in other arterial beds, there are other distal filtration
> devices that filter particulate emboli in the \[inaudible\] vein area
> graft, which is for carotid intervention.
>
> And finally, in a different area, there are vena cava filters.
>
> \[Slide.\]
>
> All these devices capture particulate emboli, and it is the basis for
> the indications for our device. \"The EMBOL-X aortic filter is
> indicated for use with the EMBOL-X aortic cannula in cardiac surgery
> procedures to contain and remove particulate emboli.\" This is the
> basis for our clinical study design and for the clinical study results
> which you will hear later on today.
>
> I would now like to present Dr. Nicholas Kouchoukos from Missouri
> Baptist.
>
> DR. KOUCHOUKOS: Thank you very much, Madam Chairman, members of the
> panel.
>
> I am Nicholas Kouchoukos from the Missouri Baptist Medical Center in
> St. Louis, Missouri. I served as the co-principal investigator in this
> trial and was the principal investigator at the Missouri Baptist
> Medical Center.
>
> I have no financial interest in the company or any equity investment
> in the company. I have been reimbursed for my travel expenses, and a
> grant on my behalf for services rendered has been made to the
> Educational Research Foundation of the Missouri Baptist Medical
> Center.
>
> \[Slide.\]
>
> Since the beginning of open heart surgery, employing cardiopulmonary
> bypass has been recognized, and embolization of atheromatous debris
> from the atherosclerotic aorta is a cause of strike and other
> embolic-related complications.
>
> Until the last decade, there were scattered case reports implicating
> atherosclerosis. In 1992, in a landmark study published from the
> Cleveland Clinic by Christopher Blauth and colleagues, they autopsied
> 221 patients who had died following cardiac surgical procedures, and
> they observed a high prevalence of atheroembolism in these patients
> and were able to correlate the presence of atheroembolism with
> increasing age and aortic atherosclerosis, as well as the presence of
> peripheral vascular disease.
>
> \[Slide.\]
>
> Among the patients with atheroembolism who had atherosclerosis of the
> ascending aorta, the presence of atheroembolism to various organs was
> 37 percent; among the patients who had no significant atherosclerosis,
> the prevalence was 2 percent. This was a highly significant
> difference.
>
> \[Slide.\]
>
> There was a high correlation with increasing age and the presence of
> atherosclerotic disease in the ascending aorta.
>
> In a clinical trial we conducted at Washington University in St. Louis
> using epiaortic scanning to determine the severity of atherosclerosis
> in the ascending aorta, we also observed a substantial correlation
> between increasing age and the prevalence of severe atherosclerosis in
> the ascending aorta.
>
> Among the patients over the age of 80, for example, 33 percent of the
> patients had moderate or severe atherosclerosis.
>
> \[Slide.\]
>
> The prevalence of other risk factors for increased mortality and
> morbidity in patients undergoing cardiac surgical procedures such as
> coronary bypass grafting has increased over time.
>
> This is a study from the Society of Thoracic Surgeons Database looking
> at a subset of Medicare patients, that is, those over the age of 65,
> and looking at the prevalence of important risk factors for mortality
> and morbidity over a decade between 1990 and 1999. This involved over
> 620,000 patients.
>
> In this analysis, there was a substantial increase in many of the
> important risk factors associated with mortality and morbidity.
>
> \[Slide.\]
>
> This is an example of atherosclerosis in the ascending aorta with very
> friable material located circumferentially in this aorta, and this is
> the material that is at risk for dislodgement during cardiac surgical
> procedures where manipulation of the aorta with interventions such as
> cannulation or clamping is prone to dislodge this material.
>
> \[Slide.\]
>
> In the study by Blauth and colleagues looking at the organs that were
> affected with atheroembolism, the most common site was in the brain,
> and this was followed by the spleen and the kidney. This is not
> surprising because approximately 40 percent of the cardiac output is
> delivered to these two organs.
>
> \[Slide.\]
>
> These are some examples of small atheroemboli in the cerebral
> circulation, and below, in the presence of a large atheroembolism in a
> medium-sized artery. These are cortical infarcts in a patient
> following cardiac surgical procedure, and again, a large embolus of
> atheromatous material present in one of the renal arteries.
>
> \[Slide.\]
>
> We also looked in the early 1990s at the association of
> atherosclerosis as a predictor and the development of postoperative
> renal dysfunction. The index of renal dysfunction was the elevation of
> the keratinine to a level above 2.0, or an increase of 50 percent from
> baseline. And we correlated these changes in renal function with the
> presence of ascending atherosclerosis determined by epi-aortic
> scanning.
>
> There was a correlation with the severity of disease and the
> prevalence of renal dysfunction.
>
> \[Slide.\]
>
> The analyses were performed on Day 1 and Day 6, and using multivariate
> analysis on the first postoperative day, ascending atherosclerosis was
> the only independent predictor of renal dysfunction. On Day 6, it was
> one of three predictors of renal dysfunction, along with low
> postoperative cardiac output and preoperative left ventricular
> dysfunction.
>
> \[Slide.\]
>
> There are a number of interventions which have been designed and
> implemented in an attempt to reduce the frequency and severity of
> embolization from the ascending aorta.
>
> Extracorporeal filtration will remove embolic material, but it is not
> likely to remove any material from the ascending aorta.
>
> The interventions that are commonly used are those that involve
> minimal manipulation of the ascending atherosclerotic aorta. The use
> of a single cross-clamp rather than placement of multiple clamps
> reduces the frequency of manipulation of the aorta and, presumably,
> the dislodgement of atheromatous debris.
>
> The use of proximal anastomotic devices to avoid the placement of
> clamps on the aorta may have a protective effect.
>
> The use of off-pump surgery avoids placement of clamps on the
> ascending aorta, and other techniques such as hypothermic fibrillation
> and circulatory arrest have been utilized, again, to avoid clamping
> and other manipulation of the ascending aorta.
>
> Although these techniques may be effective, they have certain
> limitations. All of the atheroembolism cannot be eliminated with these
> techniques. For example, the proximal and anastomotic devices do
> involve manipulation of the ascending aorta with the potential for
> dislodgement. Off-pump surgery also involves manipulation of the heart
> and the aorta, despite the fact that no clamps are placed on the
> aorta.
>
> Furthermore, there are other sources of emboli. The left atrial
> appendage can release thrombus; there can be neural thrombus in the
> left ventricular cavity that can be released, and also debris from
> diseased mitral and aortic valves, and also surgical debris.
>
> The intra-aortic filter has the capacity to capture this debris as
> well.
>
> \[Slide.\]
>
> In a study by Dr. Denise Barbut and her colleagues, looking at
> embolization of particulate matter, they utilized transesophageal
> ecocardiography and transcranial doppler and identified the release of
> emboli during cardiac surgical procedures.
>
> This is just the distribution of the particle size of these emboli
> that were released in a study in 10 patients. And above is shown the
> diameters of various vessels in the intracranial circulatory
> system\--the leptomeningeal vessel, the small cortical arteries, the
> posterior cerebral artery, the branches of the middle cerebral, and
> here, the larger middle cerebral artery and the internal carotid
> artery.
>
> The diameters of these particles corresponds to the diameters of these
> arteries.
>
> \[Slide.\]
>
> In another study, Dr. Barbut and her colleagues looked at the temporal
> sequence of release of emboli from the aorta during the conduct of a
> cardiac surgical procedure. They found that the majority of these
> particles were released at the time of the release of the aortic
> cross-clamp from the ascending aorta.
>
> In fact, over 70 percent of the emboli were released in 20-second
> interval following the release of the clamp. This is the rationale for
> inserting the intra-aortic filter just before release of the aortic
> clamp during the cardiac procedure.
>
> \[Slide.\]
>
> As I have indicated, there are important complications that can result
> from atheroembolism.
>
> Stroke is the one that has caused the greatest concern because of the
> important mortality and morbidity that results from stroke. And it is
> now clearly recognized that atheroembolism is the principle cause of
> stroke following cardiac surgical procedures.
>
> There is also evidence for renal and other organ system dysfunction.
> Pathologic and clinical studies that we have presented suggest that
> embolization may be an important cause of renal dysfunction
> postoperatively.
>
> Embolization is also a possible contributing factor to postoperative
> neurocognitive dysfunction.
>
> There have been strategies employed to reduce serious embolic-related
> complications. Obviously, prevention would be the best option, and
> this would involve minimal or no manipulation of the aorta, but this
> is not 100 percent effective in eliminating embolization.
>
> Resection of the diseased aorta is a way to eliminate the emboli, but
> is only applicable to a very small percentage of patients.
>
> Reduction of the embolic load is an attractive way to reduce this
> embolization.
>
> Diversion is one option, to divert the material away from the central
> nervous system, but this would merely disseminate this material to
> other organs.
>
> And capture, using an intra-aortic filter, is an attractive method for
> capturing this embolic material.
>
> \[Slide.\]
>
> In the subsequent presentations, Dr. Kuntz and Dr. Allen will discuss
> the design and execution of a large, randomized clinical trial
> evaluating the safety and efficacy of the EMBOL-X intra-aortic filter.
> This study is well-designed, in my opinion, and clearly demonstrates
> that use of the EMBOL-X filter is a rational, safe, and beneficial
> intervention for removal of atheromatous and other embolic material
> from the ascending aorta of cardiac surgical patients.
>
> Thank you.
>
> DR. KUNTZ: Good morning. My name is Rick Kuntz. I am a cardiologist at
> Brigham and Women\'s Hospital in Boston.
>
> I got involved with this group about 3 years ago because of my
> interest in designing and working with trials on embolic protection in
> the heart, in the brain, and in the kidney. This afforded me an
> opportunity to work with a company who was looking at another way to
> impact on the reduction of embolic problems associated with cardiac
> surgery.
>
> My interest in this study is mainly academic. I have no financial
> interest in the company. I have no equity. I am being reimbursed for
> my travel, and a small grant was made to the Department of Medicine on
> behalf of this consultation.
>
> \[Slide.\]
>
> The purpose of this study\--and I am going to talk about the rationale
> as to how we came up with the design for the study\--was from the
> outset to demonstrate the ability of this device to safely and
> effectively remove visible particulate emboli during cardiac
> procedures.
>
> So at the outset, there was an assumption that these particles were
> bad\--that they floated around in the bloodstream, that they would be
> released with the cross-clamp, and that they probably don\'t do good
> things if they go around the arch of the aorta.
>
> So from the beginning, it was important to understand that we were
> trying to remove these things, and how to measure them clinically was
> the biggest challenge in trying to design the trial.
>
> \[Slide.\]
>
> So the goal was to design a clinical trial that evaluates the utility
> of the device aimed to prevent the dissemination of released emboli
> following cross-clamping.
>
> Now, here is the dilemma. We have particles that we can pull out, but
> the question is going to be what will these particles mean\--is it
> really important to take them out or not. So the bet way to correlate
> that is to try to find hard clinical endpoints that could be collated
> overall. And we were struck with trying to design a trial to
> demonstrate that, because we were dealing with a problem of embolic
> showers that might not manifest themselves as frank organ infarctions.
>
> So for example, if you have small particulate emboli that cause
> microvascular injury\--organs such as the brain, the kidney, the
> spleen, and others\--it might not be demonstrated as a frank, say,
> NIH-level major stroke or as a kidney infarction.
>
> And there was some stuff that we had learned from heart trials which I
> will talk about in a second, but ultimately, this was the biggest
> issue we had to deal with.
>
> One of the potential roles in looking at the impact of shower emboli
> was to measure cognitive dysfunction, and I will talk about the
> availability of instruments at the time of the trial design and
> whether there was consensus in the surgical community as to whether
> that could be applied or not.
>
> So these various study designs were explored and discussed with the
> FDA, and ultimately, in multiple discussions at which I was present,
> the focus was to demonstrate safety of this device with removal of
> particulate emboli as some demonstration of efficacy.
>
> Let me give you a parallel about the importance of shower emboli and
> how you can measure it in an organ that actually does give you a
> clinical outcome with shower emboli.
>
> \[Slide.\]
>
> There is a device on the market to protect emboli from intervention on
> vein grafts through the heart. This is a picture of the typical amount
> of emboli that is removed in the vein graft intervention, and they are
> manifested mainly by outcomes measured by cardiac enzyme elevation.
>
> So the heart is a nice organ, because it actually can show the impact
> of shower emboli, mainly manifested by elevations of cardiac enzymes.
>
> \[Slide.\]
>
> If we look at the primary endpoint of this study, which was 8 percent
> in those patients randomized to protection, where we actually removed
> particles, compared to nothing at all where particles were not
> removed, there was a 50 percent reduction in the major endpoint of the
> trial.
>
> \[Slide.\]
>
> But if we look at an index like frank organ infarction, which would be
> QMI, something we could pick up clinically, such as a change in the
> EKG or Q-wave, it only represented about 10 percent of the outcome.
> The majority of the outcome of this endpoint was measured by enzyme
> elevation which didn\'t manifest itself as a frank organ infarction.
>
> So it is important to understand that at least in the heart, shower
> emboli do have an impact that led to approval of the device, but
> wasn\'t mainly manifested in anything else other than a cardiac enzyme
> elevation.
>
> \[Slide.\]
>
> So if we look at this issue, the shower emboli from vein grant
> intervention, it does not usually manifest as a frank MI, and in the
> SAFER trial, the availability of cardiac enzyme rise is essentially
> used to show utility of the device.
>
> This reduction in myocardial infarction led to the approval of the
> device, and I think there was a general consensus across the
> interventional community that this was a good thing to use and now is
> considered to be a standard of care for vein grant intervention.
>
> Now, the same endpoints are also used in the heart to approve the
> whole classification of IIb/IIIa inhibitors. That is, another
> valuable, considered standard therapy, across our area was based on
> the reduction, mainly in emboli, that manifested themselves as cardiac
> enzyme elevations but not frank organ infarction.
>
> This was not applicable to the EMBOL-X system because it was north of
> the heart; this device wasn\'t designed to protect emboli in the
> coronary arteries following bypass surgery. And there were few
> parallel sensitive measures that were available for noncardiac end
> organs. That is, we don\'t have an enzyme elevation for the brian or
> for the kidney like we do for the heart to measure the impact of these
> emboli overall.
>
> \[Slide.\]
>
> So if we look at the distribution of organs that Dr. Kouchoukos showed
> that were targets for emboli from previous studies, we have a lot of
> important organs that we don\'t want in embolis, obviously, but we
> don\'t have good, readily available measures to demonstrate their
> injury pattern from shower emboli. And this was a conundrum that we
> were stuck with in trying to come up with an effective endpoint
> ultimately to demonstrate utility of this device by a clinical signal.
>
> \[Slide.\]
>
> So the issue raised by the FDA in our meeting was that there are few
> sensitive and specific measures available to look at the noncardiac
> end organs and their impact from shower emboli.
>
> Neurological assessment was obviously a very important one to
> evaluate, and there was much time spent look at all the available ways
> of looking at the neurological outcomes, because after all, the brain
> does receive approximately 20 percent of the circulation of the
> cardiac output and was obviously a target that we wanted to reduce.
>
> Well, if we wanted to look at frank reduction in stroke, as Dr.
> Kouchoukos showed\--that stroke is likely involved with emboli per
> se\--the instance of stroke following cardiac surgery was large enough
> that this would have to be a very, very large sample size in order for
> us to demonstrate a reduction. Now, a 20 percent reduction is pretty
> small, but still, if you are looking for 30 or 40 percent, we are
> talking about 5,000 to 10,000 patients minimum to demonstrate a
> reduction in the 2 to 3 percent stroke rate seen postoperatively.
>
> So what about measuring the cognitive function per se. Well, there are
> a lot of issues raised regarding using cognitive function as an
> endpoint in this study, and it is very controversial. First of all,
> the cell deficits may be due to diffuse small vessel embolism, to be
> sure, but there are other multifactorial causes of cognitive
> dysfunction after surgery that may involve general anesthesia.
>
> And even though it will be important to look at that at the time of
> the study and, I would even argue today to some degree, there is still
> no great consensus about instruments available for psychometric or
> neurological outcomes that measure cognitive dysfunction that has been
> accepted in the cardiovascular community, and at the time of this
> study, we couldn\'t get consensus along the lines of understanding
> whether to apply a battery of tests, most of which still have not been
> validated.
>
> \[Slide.\]
>
> So the practical approach was that the huge sample size to show a
> reduction of frank infarction such as stroke was just not feasible,
> because this is a large, randomized cardiac surgical trial, and it was
> unlikely that we could do a 5,000 to 10,000 patient study. Cognitive
> dysfunction could not be readily measured with mature, validated
> instruments was the conclusion that we reached in discussions with the
> FDA, and the proof of safety plus demonstration of captured emboli
> seemed to be the most feasible and logical approach to go forward.
>
> So when you look at this study to say why wasn\'t there a clear
> clinical measure of efficacy of this endpoint per se, it is because we
> wrestled with endpoints that had consensus to demonstrate true
> efficacy from a clinical perspective.
>
> And the final conclusion was that we would demonstrate safety by the
> safety endpoints to demonstrate this didn\'t cause any increases in
> those elements in the safety endpoints. And if we demonstrated that
> with removal of actual particulate emboli, at least there would be
> some measure of utility. Now, whether the utility would be enough for
> product approval, I think will be the discussion of this panel.
>
> Therefore, the approved IDE study design was safety equivalency for
> the composite primary endpoint and effectiveness through demonstration
> of particulate capture.
>
> \[Slide.\]
>
> So given that, there was a prospective study design; multi-center, 21
> sites; a sample size of 1,289 patients was calculated using a
> Blackwater \[phonetic\] formula for equivalency of an expected outcome
> of 15 percent plus a 5 percent delta; the EMBOL-X aortic catheter was
> randomized through Standard J tip cannula; and the primary endpoints
> again were effectiveness with the demonstration of particulate emboli
> capture and safety with equivalence of the safety profile using the
> current standard procedures.
>
> \[Slide.\]
>
> So this safety endpoint, which might be viewed as also a measure of
> efficacy, was necessarily not refined enough to demonstrate efficacy
> based on this sample size. It was mainly used to demonstrate that
> there would be no increase in problems associated with the instance of
> death, myocardial infarction, renal insufficiency, GI complications,
> limb-threatening embolisms, or neurologic deficit, either mild or
> severe, using the NIH Stroke Scale and other stroke measures.
>
> The safety endpoint was designed to demonstrate freedom from device
> complications.
>
> Now, it is important to point out that this is mainly a safety
> endpoint, and for example, the inclusion of myocardial infarction is
> important to have in a study looking for safety, but we wouldn\'t aim
> to actually improve myocardial infarctions, because the device is
> north of the heart, as it were.
>
> \[Slide.\]
>
> The effectiveness endpoint and hypothesis, therefore, was successful
> capture of the emboli, and this was defined as retrieved particles
> observed at 10X power at the operating table.
>
> And the hypothesis was that we would capture greater than 75 percent
> of the cases that would have emboli that was evident.
>
> \[Slide.\]
>
> The sample size was driven by the safety endpoint\--small sample size
> needed to demonstrate primary effectiveness endpoint of particulate
> capture, and the 1,286 patients were used to demonstrate safety, and
> there was a calculation for one interim analysis using a boundary
> condition under Bryant-Fleming \[phonetic\] for the Blackwater test.
>
> \[Slide.\]
>
> Safety was monitored by blinded, independent Clinical Events
> Adjudication Committees and the independent \[inaudible\] Monitoring
> Committee. There was an independent medical monitor. The Core
> Laboratories were blinded. Randomization was performed just prior to
> cannulation in the operating room, and a neurological examiner and the
> patients themselves were blinded to treatment assignment.
>
> \[Slide.\]
>
> We had independent EKG Core Laboratories and histological laboratories
> to evaluate the emboli.
>
> \[Slide.\]
>
> There was a separate ecocardiographic imaging core laboratory as well
> for the epi-aortic as well as TEE endpoints.
>
> \[Slide.\]
>
> And to put this into perspective, as large randomized trials in
> surgery are difficult to do, this ranks among the top enrolling
> randomized studies in the history of randomized trials in cardiac
> surgery. So this was quite an effort to do this well-designed trial in
> order to demonstrate the endpoints that Dr. Allen will review.
>
> \[Slide.\]
>
> So if we summarize this, safety was to be demonstrated under an
> equivalence endpoint in the agreed-upon IDE using a broad net
> composite safety endpoint chose, which included myocardial infarction,
> for example. The safety endpoint was not optimized to demonstrate
> clinical efficacy or superiority.
>
> Now, there is no question that this could be used if we had a huge
> sample size to demonstrate some reductions in embolic injury, but we
> didn\'t want to fool ourselves by thinking this initially would be the
> primary viewpoint of this endpoint overall to demonstrate utility.
>
> Therefore, the utility was focused on demonstrating safety first,
> followed by efficacy to show frequency of actual particulate removal
> from the operating room.
>
> Now I\'ll turn it over to Dr. Allen.
>
> DR. ALLEN: Thank you, Madam Chairman and members of the panel.
>
> My name is Keith Allen, and I was a site principal investigator. I
> practice as a cardiovascular and thoracic surgeon out of Saint Vincent
> Hospital in Indianapolis.
>
> \[Slide.\]
>
> From a financial disclosure standpoint, I have no financial interest
> in the country and certainly no equity investment in the company. I
> was reimbursed for my travel and time expenses to come today.
>
> \[Slide.\]
>
> On behalf of the 88 investigators at 22 centers across the U.S. and
> one Canadian site, I thank the panel for the opportunity to present
> our clinical results. I think, as you can see from our centers that
> were utilized in this study, they represent a broad spectrum of
> cardiac surgery in North America, involving both private, academic,
> and community centers across the board.
>
> \[Slide.\]
>
> The inclusion and exclusion criteria are summarized. Obviously, as
> with any large study like this, particularly when you are looking at
> safety as an endpoint, there are a number of exclusion criteria to
> confine your sample size to patients who are going to demonstrate
> safety for you.
>
> The inclusion criteria were confined to patients who were 60 years and
> older who either had primary CABG or primary valve procedure.
>
> Some of our exclusion criteria that we feel are important were
> dialysis dependent, a patient who had a previous stroke who had a
> residual deficit, or previous surgery or damage to the aorta.
>
> Obviously, the filter has various sizes and is part of the
> randomization process. To be included in the study, you had to have an
> internal diameter of the ascending aorta that would appropriately fit
> a filter that you could put in the patient.
>
> \[Slide.\]
>
> About 15 percent of patients screened for this study ultimately met
> inclusion and exclusion criteria, resulting in 1,394 patients
> available for the study.
>
> As is common with any study of this size and nature in which a new
> device is being placed in a clinician\'s hands, we had as a component
> of our study a roll-in phase. Each investigator was required to do at
> least one nonrandomized patient to gain familiarity with the device
> and understand how it could be used and inserted appropriately.
>
> While this does not impact the study results, I will concentrate the
> rest of our data analysis on patients who were actually randomized
> between filtered and nonfiltered arms.
>
> We ended up with 1,289 patients who were evenly distributed between
> filter with standard cannula or simply receiving the standard cannula
> alone, without intra-aortic filtration.
>
> It is important to understand our randomization stratification stream,
> and it really involved three components. Patients were stratified
> based on whether they were a valve or a primary CABG and, importantly,
> we randomized patients based on injection fraction.
>
> \[Slide.\]
>
> There were a number of key baseline and medical variables that were
> obviously evaluated in this study. There were four variables that
> differed between groups. One variable that favored a control arm was a
> patient-given history of aortic disease.
>
> There were three variables\--atrial fibrillation, valvular dysfunction
> and severe carotid disease\--which all favored the filter arm. It is
> important, though, when a multivariable analysis was done on these
> discrepant variables at the end of the study, there was no interaction
> or impact on our results.
>
> \[Slide.\]
>
> It is amazing, as different as cardiac surgeons are across the board
> how uniformly this operation was done across the centers that were
> involved in this study. There was a good distribution between CABG and
> valve patients. There was a good distribution between whether a
> partial clamp was used or whether a single-clamp technique was used.
>
> We tried to look at things like whether the aortic cross-clamp was
> repositioned as an impact on embolic release, and that was similar
> between arms. Things like cross-clamp time and cardiopulmonary bypass
> time were also familiar and similar between groups. And, importantly,
> we wanted to look at nuances like were the number of proximal
> anastomoses done between groups similar, because obviously, you are
> manipulating the ascending aorta, and we wanted to ensure that one
> group wasn\'t having more proximal anastomoses done than the other.
> And in fact, they were identical between the two arms.
>
> When we looked at filter dwell time, which obviously is not applicable
> to the control, the filter dwell time in our patients was
> approximately 21 minutes.
>
> \[Slide.\]
>
> As outlined very nicely by Dr. Kuntz our primary composite endpoint
> was a safety endpoint. It is important to reemphasize the fact that
> this was an equivalence safety endpoint, and I think we did achieve
> that safety endpoint. 17.1 percent of the treatment group compared to
> 18.9 percent of the control group had a composite event that was a
> priori defined. And once again, it is a safety endpoint, and it was
> not intended to capture clinical effectiveness of the device. It is
> important that the panel understand this and that they don\'t confuse
> this safety endpoint as a surrogate for clinical efficacy, because as
> Dr. Kuntz pointed out, if you were designing a composite endpoint to
> demonstrate clinical efficacy, you certainly would not have included
> myocardial infarction which the device can have no impact on and that
> occurred and represented approximately half of the events in our
> composite endpoint.
>
> \[Slide.\]
>
> Any time somebody presents or uses a composite endpoint, as an
> investigator, I always want to see the details of all the components
> that were involved in creating that composite endpoint to ensure that
> there are not trends favoring one or the other that even out when you
> do just the composite endpoint.
>
> When you look across-the-board at the components of our composite
> safety endpoint, we don\'t make claims of superiority in any area, but
> what you clearly see is equivalence and safety of the device in a very
> large prospective randomized trial, not only with the composite
> endpoint, but with the individual components of that composite
> endpoint.
>
> \[Slide.\]
>
> Clearly, in a trial like this where you are presenting people with a
> major surgical operation, you look at other serious adverse events,
> and once again, it is striking how evenly distributed these are across
> centers in this very large study. When you look at serious adverse
> events across the board, there was no statistical difference between
> either arm. And when you come down to actually tallying up whether or
> not patients had a serious adverse event in this very large study, the
> bottom line down at the bottom is that they were absolutely identical
> between both the control and the filter group.
>
> \[Slide.\]
>
> As an investigator who was asked to participate in this trial, one
> thing that we were interested in is that obviously, you are placing
> something inside the ascending aorta. So one of the key adverse events
> that I was interested in was does placing this device inside the
> ascending aorta potentially cause harm to the patient. And we captured
> that using, out of 18 of the 22 centers, sophisticated
> imaging\--primarily epi-aortic scanning, but also transesophageal
> ecocardiography\--to try to capture whether the device was leaving
> some type of footprint within the ascending aorta.
>
> And we looked at it as both did it cause ascending aortic dissections,
> and did it have ecocardiographic or imaging abnormalities that we
> might term aortic wall or intimal changes.
>
> \[Slide.\]
>
> I think that for the surgeons on the panel, this picture really
> doesn\'t need much explanation. As an investigator, this is what I was
> most concerned about when I was going to put this device in a
> patient\--was I going to cause a clinically significant and relevant
> aortic dissection?
>
> Clearly, on the left, the blue, engorged aorta that makes your heart
> skip as a cardiac surgeon when it occurs is a dreadful complication
> that has serious clinical implications.
>
> As a surgeon, this is very apparent, and while the TEE is dramatic in
> showing it, epi-aortic scanning or transesophageal ecocardiography
> aren\'t necessary for me to make this diagnosis.
>
> And it is interesting when we look at this serious clinical event,
> there were two ascending aortic dissections seen in the control arm,
> and there were no ascending aortic dissections in the EMBOL-X filter
> arm.
>
> \[Slide.\]
>
> What we did see was a footprint that may be left by the device. As I
> told you and as Dr. Kuntz pointed out in his study design, 18 of our
> 22 centers utilized either epi-aortic scanning or transesophageal
> ecocardiography peri-procedurally to look at the ascending aorta. And
> Dr. Weismann at the core lab for ecoocardiography did that very
> detailed blinded review. And, as will be pointed out later by the FDA,
> there was an incidence of endothelial disruptions or what I call
> intimal abnormalities seen more frequently in the filter group
> compared to the control arm.
>
> What were these endothelial disruptions, and what clinical context can
> we put them in?
>
> \[Slide.\]
>
> I think a series of images will hopefully clarify that.
>
> On your left is an epi-aortic scanning of the first endothelial
> disruption identified very early on in the study by a surgeon. There
> were three endothelial disruptions that were identified by surgeons
> early on in the study and that were elected to be repaired. One of
> those endothelial disruptions was an inadvertent stab from an 11-blade
> knife to the posterior wall of the ascending aorta. The filter
> certainly didn\'t cause that.
>
> But there were two endothelial disruptions, both occurring in the
> first four months of the study, both at the same center, in which
> surgeons elected to repair them. There was no historical basis for
> these. They weren\'t in the setting of an acute ascending dissection.
> But the surgeon had no background about what these endothelial
> disruptions are, and what you see\--and it is hard to see unless you
> turn the lights down and so forth\--is this small disruption or
> intimal flap that is right there.
>
> The patient had a 0.1-centimeter fibrinous strand removed after the
> ascending aorta was opened, sent for pathology, closed the ascending
> aorta, and the patient suffered no sequelae.
>
> DR. EDMUNDS: Could you point out the arch vessel?
>
> DR. ALLEN: This is actually mid-ascending aorta, so it is beyond; the
> arch vessels wouldn\'t be seen in this particular vein. It is not
> scanning farther on down there.
>
> DR. EDMUNDS: That is the pulmonary artery going across.
>
> DR. ALLEN: The pulmonary artery is right here.
>
> \[Slide.\]
>
> Here is another example. Once again, the surgeon identified this
> endothelial disruption, and you see it right here. It is a little
> easier to see it than on the last one. This occurred a little later on
> in the study after we had experience from the core lab telling us that
> we were seeing these ultrasound abnormalities, and in this case once
> again, there was no clinical dissection. The patient was doing fine.
> And this surgeon because he had been provided with some of this
> historical information didn\'t repair it. And in fact in 10 out of the
> 13 endothelial disruptions that were identified by surgeons, those
> surgeons decided not to repair it, and those patients didn\'t suffer
> sequelae from it.
>
> DR. TRACY: Before we leave this slide, I think Dr. Edmunds wants some
> clarification on a couple of things.
>
> DR. EDMUNDS: Can you point out the location or probable location of
> the deployed filter in relation to these so-called injuries?
>
> DR. ALLEN: I can tell you that we did an analysis on the location of
> the endothelial disruptions. In both of these cases, the endothelial
> disruptions were in the mid-ascending aorta. The filter was downstream
> from these devices, so they weren\'t in the area of\--
>
> DR. EDMUNDS: Where are you cannulating\--the sinuses of the falsalva
> \[phonetic\]? Where was the cannula, then?
>
> DR. ALLEN: The cannula was approximately right at the innominate
> \[phonetic\] artery.
>
> DR. EDMUNDS: So the filter is deployed upstream to the cannula tip?
>
> DR. ALLEN: No, sir.
>
> DR. EDMUNDS: I am totally confused.
>
> DR. ALLEN: The filter is deployed just proximal to the cannulation. It
> is part of the filtering process of the cannulation itself. It is part
> of the cannula that goes into the aorta.
>
> DR. EDMUNDS: Yes, but when it is deployed, like a parachute, where is
> that in relation to the nozzle of the bypass cannula?
>
> DR. ALLEN: It is posterior to it.
>
> DR. EDMUNDS: It is proximal to the aortic cannula spigot?
>
> DR. ALLEN: Yes, and it is distal to the cross-clamp.
>
> DR. TRACY: Maybe at the end, we will review your Slide 6.
>
> DR. ALLEN: I can show you another slide of that.
>
> DR. TRACY: Okay, but let\'s go ahead with your presentation.
>
> \[Slide.\]
>
> DR. ALLEN: This is an example of an interoperative photograph that I
> borrowed from Dr. Banberry \[phonetic\] at the Cleveland Clinic in a
> patient who was undergoing a routine aortic valve replacement in which
> we hypothesized what these endothelial disruptions might look like
> based on the one pathologic specimen that was sent and that was
> resected by a surgeon.
>
> \[Slide.\]
>
> These are two examples of epi-aortic scans, once again done at Dr.
> Kouchoukos\' center, one involving a filter patient, one involving a
> control patient. These are based on\--we asked the core lab to provide
> us with representative slides, and once again, without the lights
> turned down, it is difficult in this patient to see this, but the
> slight endothelial disruption here, and in a similar area, right here,
> that are tagged as being what we are calling these intimal injuries or
> endothelial disruptions.
>
> Once again, these were not identified by the surgeons at the time of
> the operation even in a center that has a vast experience with this
> technology and were not repaired by the surgeons and had no clinical
> sequelae because of that.
>
> \[Slide.\]
>
> Well, simply telling you that they weren\'t repaired and that they
> might not impact things isn\'t enough for me, and I certainly
> wouldn\'t think it is enough for you. And we asked that we do an
> analysis on was there a correlation between endothelial disruptions
> and adverse events.
>
> If you looked at, for example, patients in the filter arm and compared
> those patients who had EDS with those who didn\'t have EDS, there
> certainly was not a correlation with acute adverse composite events.
>
> If you similarly looked at the control patients, and one of the
> control patients had an endothelial disruption, or nine control
> patients had endothelial disruptions, and compared those with EDS to
> those without EDS, there certainly wasn\'t a correlation with EDS to
> an adverse event.
>
> And, more importantly, then, if you just forgot whether they were
> randomized or not and looked at all patients who had EDS and compared
> adverse composite events to those that didn\'t have EDS, there clearly
> is not a correlation to EDS with adverse acute events.
>
> \[Slide.\]
>
> Are there long-term consequences of EDS? And I think, as part of the
> presentation, it is important to understand that long-term followup in
> this study was not part of the protocol. But surgeons and
> investigators were interested in that, and we needed to know that what
> we were doing to our patients wasn\'t going to hurt them.
>
> So we developed a methodology to try to follow these patients and
> assess the long-term impact of EDS on composite and individual event
> rates. As I said, this is not part of the original protocol. But in
> order to obtain appropriate followup in the image patients, we
> targeted centers that had the imaging and centers that had EDS; we
> looked at centers that were high enrollers in order to have less
> variability between arms, and we also needed to be able to get timely
> IRB approval for this longer-term followup.
>
> \[Slide.\]
>
> We ultimately looked at four high-enrolling centers in which 90
> percent followup was obtained. We wanted, though, to look specifically
> at EDS, and obviously, there were some EDSs occurring outside of those
> four high-enrolling centers. So we wanted to get followup on all EDS,
> even patients who were roll-in. So we ended up trying to find followup
> on 58 patients.
>
> Seven patients couldn\'t have followup. Six of those were simply
> because we could not get appropriate IRB approval. We know the
> patients were alive, but we just couldn\'t get followup. There was one
> patient lost to followup.
>
> \[Slide.\]
>
> We ended up having a 360-day or almost one-year mean followup. And
> when you looked at composite event rates between filter and control
> patients out to 360 days mean, there were events occurring, but they
> were occurring absolutely identical at 6.1 percent between both arms.
>
> \[Slide.\]
>
> Once again, I asked the question\--well, that\'s great, but I want to
> know what about the patients who have EDS. And once again, when you
> look at the filter patients who had EDS compared to those who did not
> during long-term followup, there was no correlation to an adverse
> outcome. And when you look at all patients, once again, there wasn\'t
> a correlation during long-term followup.
>
> \[Slide.\]
>
> I come back to the issue of aortic dissections and the development of
> aneurysms, because while I tell you that long-term followup did not
> correlate with an acute composite event, what about the development of
> a late dissection or the development of an aneurysm.
>
> I told you that in the study, two dissections occurred acutely in the
> control arm and none in the filter. During followup, no patients were
> operated on for the development of acute dissections in either arm.
> There were three additional aneurysms that were seen in control
> patients\--two thoracic aortic aneurysms, one that was repaired, and
> one abdominal aortic aneurysm that was also repaired. Obviously, none
> of these were in areas where EDSs were identified, and in fact none of
> these three patients even had EDS.
>
> \[Slide.\]
>
> So from a summary standpoint\--and I think it is an important safety
> issue, and that is why we have spent time on this\--this was primarily
> a finding on aortic imaging. Seventy-eight percent of surgeons,
> despite using sophisticated epi-aortic scanning, were not able to
> identify these endothelial disruptions. They should not be classified
> as clinically significant aortic injuries, and while they were seen
> more frequently in the filter arm, they were seen in both arms.
>
> These are not aortic dissections, and I think our acute data
> demonstrates no correlation acutely to composite events, and I think
> our long-term data and due diligence in collecting that also does not
> demonstrate a safety issue.
>
> \[Slide.\]
>
> We had a second primary endpoint which, as Dr. Kuntz pointed out, was
> an effectiveness endpoint. The hypothesis was that we could capture
> particulate emboli in greater than 75 percent of the EMBOL-X aortic
> filters. And in that case, successful emboli capture was defined as
> retrieved particles observed at 10 times power before histologic
> processing.
>
> \[Slide.\]
>
> And I think as these photographs demonstrate, our primary
> effectiveness endpoint was indeed met. Ninety-six-point-eight percent
> of filters prior to histologic processing visualized, documented, and
> photographed captured particles.
>
> \[Slide.\]
>
> As surgeons, we were interested in what these particles might be
> composed of, and as part of the trial, we employed a pathologic core
> lab that would analyze this data.
>
> We anticipated, based on what the core lab was telling us, that
> because this small amount of tissue was going to go through extensive
> histologic processing and handling that there were going to be some
> specimens lost, displaced or dissolved and not available for analysis.
> And indeed that is what we found.
>
> We found that approximately 21 percent of previously photographed and
> visualized specimens were not ultimately available for histologic
> analysis. However, more than 85 percent of specimens that were
> available for analysis demonstrated that the material atheromatous in
> nature.
>
> \[Slide.\]
>
> There were various other things captured by the filters, and I show as
> this example RBC thrombus or clot, this polyploid structure in both
> specimens that, based on its organized nature on pathology, likely
> came from an intercavitary source, as Dr. Kouchoukos mentioned in his
> talk.
>
> \[Slide.\]
>
> It is important that we assure the panel that this device isn\'t
> causing what it captures and that it is not thrombogenic. And we did
> extensive bench-testing to demonstrate that with filters having the 95
> percent heparin bonding with a 2-hour dwell time, they were not
> thrombogenic. But what about in a human?
>
> \[Slide.\]
>
> And to assess for thrombogenicity, we used scanning electron
> microscopy, and it is important to note when the SEM was done.
>
> Unlike the histologic data, which was done obviously after processing,
> we looked at filters prior to histologic processing. The original
> intent of the study was to evaluate 10 percent of the filters, but
> after 5.6 percent of filters had been examined and presented to the
> FDA, the FDA agreed in a letter on October 12, 2001 that the scanning
> electron microscopy demonstrated no significant platelet thrombus
> formation, and we could discontinue doing additional scanning EMs.
>
> \[Slide.\]
>
> So from a summary standpoint, there certainly were captured particles
> that were documented and visualized as part of our a priori defined
> effectiveness endpoint that were not available for histologic
> analysis. But I contend that they are not available because of the
> extensive histologic processing that went on and the small amount of
> material that they represented, and that scanning electron microscopy
> does not demonstrate that filters are thrombogenic.
>
> \[Slide.\]
>
> What about the number of particles captured? I think Dr. Kuntz touched
> on that by what does it mean whether we capture one particle, five
> particles, or 20 particles.
>
> The study data demonstrate that there was a mean number of particles
> captured of 5.6.
>
> \[Slide.\]
>
> I think it is more interesting to look at the quantity of the
> particles that were captured, and here, you see a slide looking at the
> distribution of sizes of particles captured, and we superimposed the
> previous slide that Dr. Kouchoukos showed you of representative
> arteries such as middle cerebral artery branch or posterior
> circulation artery. And we also put in renal interlobular arteries
> versus the size of renal arcuate arteries, or intralobular renal
> arteries.
>
> And you see that the vast majority of the size of the particles that
> we captured are filtered or would be filtered by small arcuate or
> cortical cerebral arteries.
>
> \[Slide.\]
>
> So from a clinical study overview, we feel that we have met both of
> our primary endpoints successfully\--that effectiveness was
> demonstrated in that 96.8 percent of filters did capture emboli as
> documented under 10 times magnification; and we certainly feel that
> our safety endpoint of equivalence was met and that no clinical
> adverse events were associated with the findings of epi-aortic
> scanning.
>
> I think I reemphasized the point that our study was not powered nor
> was it designed to demonstrate superiority in this low-risk patient
> which was specifically selected to demonstrate safety.
>
> \[Slide.\]
>
> Following the completion of the study, the FDA, because this was a
> safety equivalency study, asked the company as well as the
> investigators whether study data could be extrapolated to clinical
> efficacy, and this was one of the questions that they had actually
> posed to the panel.
>
> And I think it is important that we in an attempt to answer this
> question did some additional analysis. But this additional analysis is
> in no way claims for labeling, and we don\'t make claims of
> superiority. It is simply an attempt to answer those questions raised
> by the FDA.
>
> From a surgeon\'s standpoint, we know that clinical outcomes are
> influenced by preoperative risk variables, so we felt that if you
> looked at the high-risk patients in our population, could we
> extrapolate some clinical benefit or efficacy.
>
> \[Slide.\]
>
> We utilized the Cleveland Clinic score, as published by Dr. Higgins in
> JAMA in 1992, to assess for preoperative risk. We specifically chose
> the Cleveland Clinic score because it looks at both morbidity and
> mortality unlike, for example, the STS or the New York State Index,
> which only look at mortality.
>
> The Cleveland Clinic score which is utilized at our center is a
> validated preoperative risk score that has been validated in over
> 9,000 patients, and a score of 5 or higher has been validated for
> increased morbidity and mortality.
>
> Eighteen-point-seven percent of the 1,289 patients randomized in this
> study met the criteria for moderate to high risk.
>
> \[Slide.\]
>
> When we looked at whether high- or low-risk patients had composite
> events, you will see that when we control filter to control in
> low-risk patients, a Cleveland Clinic score of zero to 4, there was
> absolutely no difference between the two groups.
>
> But when we looked at patients who had Cleveland Clinic scores greater
> than 5 as defined in that Higgins paper, we saw that the trend
> certainly favored statistically patients who received the filter.
>
> \[Slide.\]
>
> When we looked at components of that composite event and compared
> those to patients who had Cleveland Clinic scores greater than 5,
> across a broad range of all unselected components of the composite
> endpoints, there weren\'t statistical differences between groups
> except for renal insufficiency.
>
> I think it is important that we break it out as dialysis patients,
> patients without dialysis, or all patients who had renal insufficiency
> as defined in our study. And when you look at all patients with renal
> insufficiency, it was significantly less in the filter patients.
>
> \[Slide.\]
>
> Now, renal insufficiency is not as sexy and glamorous as preventing
> frank stroke, but I think renal insufficiency has a significant
> clinical impact. We know that based on the STS data base, renal
> insufficiency is a predictor of increased morbidity and mortality
> postoperatively, but when you look at patients who had renal events,
> their length of stay was a little under 15 days. For those patients
> who did not have renal insufficiency in this study, their length of
> stay was 7.2 days.
>
> And this looks at all patients with renal insufficiency. The data
> isn\'t simply driven by those who had dialysis. If you take out the
> dialysis patients, which you would expect to have an even longer
> length of stay, the length of stay only drops by one day.
>
> \[Slide.\]
>
> I think this slide has put it in perspective for a lot of the
> investigators in the study, because it helps us evaluate the
> risk-benefit of this device. It is an odds ratio comparison of
> baseline variables that, as surgeons, we know are predictive of
> increased postoperative morbidity and mortality.
>
> You can see the middle line demonstrating no benefit one way or the
> other; to the left, the filter arm tends to do better; to the right,
> the control patients tend to do better.
>
> Once again, we don\'t make claims of superiority, but it is
> interesting when you look at this odds ratio table that the vast
> majority of events are mitigated by placement of a filter.
>
> \[Slide.\]
>
> This additional analysis to address the possible clinical efficacy I
> think does demonstrate that at least in moderate- to high-risk
> patients, there may be a benefit\--and I underline \"may.\" Captured
> particles were predominantly of the size associated with cerebral and
> renal cortical arteries. The reduction in renal insufficiency events
> can be demonstrated with a sensitive marker in those high-risk
> patients. But the study was not designed to assess for neurocognitive
> dysfunction, and we make no claims for that.
>
> \[Slide.\]
>
> In summary, our study objective was to demonstrate that particular
> captured could be safely accomplished in lower-risk populations
> against the backdrop of known detrimental effects of particulate
> emboli.
>
> The risks of this device I think have been safely assured by the
> equivalency of our composite safety endpoint. Across this large
> prospective study, serious adverse events were identical between
> groups.
>
> Certainly, using epi-aortic imaging, we did demonstrate an increased
> incidence of these endothelial or intimal disruptions, but I think
> that certainly there was no acute correlation to adverse events, and
> our due diligence to try to provide you with some long-term clinical
> followup hopefully provides that there is not a correlation with
> long-term events.
>
> The benefits of this are that particulate capture was clearly
> demonstrated in 97 percent of filters, and we feel that the additional
> analysis asked for by the FDA does demonstrate that clinical efficacy
> can be reasonably extrapolated from particulate capture.
>
> MS. CHANG: I would like to thank Dr. Allen, Kouchoukos, and Dr. Kuntz
> for the presentation today.
>
> We believe that the study design and clinical \[inaudible\] supports
> the following indications for the study, and, Dr. Edmunds, if you
> would like me to answer your earlier question, I can do that for you,
> as to location of the epi-aortic imaging.
>
> DR. EDMUNDS: I think you have done that.
>
> MS. CHANG: Okay.
>
> DR. EDMUNDS: I have to say I missed it\--it was in the writeup, but
> your diagram was a little misleading, or at least I didn\'t interpret
> it right.
>
> MS. CHANG: Sorry.
>
> **Questions and Answers**
>
> DR. TRACY: Okay. I would like to ask the panel if they have any brief
> clarifying questions for the sponsor at this time. This is not the
> open committee discussion, but just clarifying questions.
>
> Yes?
>
> DR. MARLER: I was interested in the details of the discussion that led
> to the conclusion that there were not cognitive outcomes that could be
> used, and who participated.
>
> DR. KUNTZ: In the discussion with whom? With the FDA?
>
> DR. MARLER: You mentioned that you reached the conclusion that there
> was no outcome that could be agreed upon, and I was just wanting to
> hear some more details about that and who couldn\'t agree.
>
> DR. KUNTZ: All right. I may refer this to \[inaudible\] who is an
> expert in this area, but we reviewed\--I think the Stump \[phonetic\]
> battery of criteria at that time, which I think was probably the best
> candidate overall, but they were a collection of approximately 6 to 12
> instruments and batteries, and at that time, we didn\'t think there
> was a consensus or a study that had demonstrated or validated that
> those outcomes could be correlated with changes in cognitive
> dysfunction in 1999, and we were not aware of any validations of that
> emerging battery of tests, which I think is being refined and is
> probably a good set, but at that time, it was difficult to say if
> there was consensus.
>
> Maybe I could call up two other people who may want to make some
> comments.
>
> Dr. Gold?
>
> DR. GOLD: Thank you.
>
> My name is Jeff Gold, and I am a cardiac surgeon from New York, and I
> do indeed own some stock options in EMBOL-X and have been involved in
> a study of neurologic and cognitive function associated with cardiac
> surgery for perhaps longer than I care to remember sometimes.
>
> The definition of cognitive changes associated with cardiac surgery
> has bee a complex and moving target for an extremely long time. There
> have been, as I am sure you are all aware, at least one consensus
> panel and several others looking at development of a battery of tests.
>
> However, at the time that this study was conceived, not only was there
> not a defined battery of tests that cardiac surgeons across the board
> could agree upon, let alone psychometricians and neurologists, but the
> etiology of cognitive abnormalities was also highly controversial at
> the time.
>
> You might recall a very interesting study published by a Dr. Rousseau,
> who looked at the incidence of cognitive function abnormalities in
> patients undergoing total knee replacement surgery under local
> anesthesia. The incidence of cognitive abnormalities in that
> 524-patient cohort was exactly equal to an equivalent study done in
> patients undergoing coronary bypass surgery.
>
> So perhaps the art has improved. Perhaps if we were to redo this at a
> time in the future, we could agree upon a panel of tests. But if you
> were to ask about the significance of cognitive abnormalities among
> practicing cardiac surgeons today, and our ability to reliably
> demonstrate them, I would say they are poor.
>
> DR. TRACY: Dr. Aziz?
>
> DR. AZIZ: From what I understand, the way that you place this
> catheter, this could not protect against the sandblast effect of
> emboli being dispersed; is that right?
>
> DR. ALLEN: Yes, sir.
>
> DR. AZIZ: Okay. And secondly, so this cannula has to be inserted
> proximal to the enormid \[phonetic\] artery; is that right?
>
> DR. ALLEN: The cannula is inserted identically. There is no difference
> in what you do. If you were to, for example, cannulate the arch, as we
> sometimes have to, yes, you wouldn\'t use this cannula in somebody,
> for example, that you were going to cannulate the mid-arch.
>
> DR. TRACY: Dr. Laskey?
>
> DR. LASKEY: Dr. Allen, these ECO-abnormalities detected in the core
> lab, I am assume that there are pre-/post-placement ECOs. is this a
> serial analysis where the ecocardiogram is obtained only at one time,
> or was there some protocol that people adhered to where you had
> baseline ECOs and then ECOs during place and ECOs after placement? How
> was that done?
>
> DR. ALLEN: That\'s a very good question. It was quite laborious to do
> this. Actually, our center did not do imaging. I will let Dr.
> Kouchoukos\' center answer that, because his study was actually doing
> epi-aortic scanning.
>
> DR. KOUCHOUKOS: The epi-aortic scanning was performed after the
> pericardium was opened, before instituting cardiopulmonary bypass, and
> at the completion of the procedure, after removal of all the cannulas,
> administration of protamine, another scan was performed in the
> longitudinal and transverse planes for the whole ascending aorta.
>
> DR. EDMUNDS: Nick, could you explain how this was deployed? You say
> you didn\'t leave the filter up for 60 minutes, and you deployed it
> when you first started to manipulate and got the cannula in so you
> could deploy it.
>
> DR. KOUCHOUKOS: Yes. The cannula was deployed immediately before
> removal of the aortic cross-clamp\--in other words, after completion
> of the proximal and distal anastomosis and the bypass operation or
> closure of the aorta or the left mitral valve replacement\--
>
> DR. EDMUNDS: It was removed.
>
> DR. KOUCHOUKOS: \--it was removed. And then it was left in place
> generally until the protamine was administered. And the safety
> analyses indicate it could be left for an hour, but it was left on
> average for 20 minutes.
>
> DR. EDMUNDS: So you put the aortic cross-clamp on without the filter
> deployed?
>
> DR. KOUCHOUKOS: That\'s correct. The filter was deployed into the
> aortic cannula immediately before removal of the cross-clamp.
>
> DR. EDMUNDS: So you are not claiming that you got all the emboli; you
> just got what you got.
>
> DR. KOUCHOUKOS: Well, based on the analyses that I presented, the
> majority of these emboli are released at the time of removal of the
> cross-clamp, and that was the logic for deploying the filter
> immediately before release of the clamp.
>
> DR. EDMUNDS: Well, you did the studies, but on Dick Clark\'s study, I
> thought you got a shower of emboli when you put the clamp on, also; is
> that not correct?
>
> DR. KOUCHOUKOS: Well, I think I showed you a slide showing that there
> are emboli released at various times during the course of a cardiac
> surgical procedure, but that the majority of the emboli are released
> at the time of release of the cross-clamp.
>
> DR. EDMUNDS: Oh, I agree with that, yes.
>
> DR. TRACY: Okay. Are there any other clarifying questions? We\'ll have
> the open committee discussion in a few minutes after the FDA
> presentation, but are there any other clarifying questions?
>
> DR. KRUCOFF: Just a pluming question. Relative to, say, any other
> commercial cannula that you would use routinely, is this cannula
> different from a flexibility or a dimensional perspective?
>
> MS. CHANG: Let me show a picture of the product again.
>
> \[Slide.\]
>
> MS. CHANG: Actually, this main body is what a standard cannula looks
> like, and we have modified it so that we have added a sideport there.
> There is still only one hole, so it is actually virtually identical to
> existing commercial cannulas. So the big difference is the sideport.
>
> DR. KRUCOFF: Okay. So my question is does the presence of the sideport
> affect in any way the portion of the cannula that actually goes
> through the aorta relative to a commercial, in either dimension, or
> just how it feels?
>
> DR. ALLEN: The short answer is \"No,\" and I think Dr. Kouchoukos
> would concur with that.
>
> DR. TRACY: Okay. One more question.
>
> DR. DeMETS: I would like to ask what about the randomization process.
> You didn\'t describe it in your presentation, but your writeup, as I
> understand it, there were some patients who did not get treated as
> randomized.
>
> Could you walk me through that process so I can understand exactly
> what happened and what you did about it?
>
> DR. ALLEN: The specific details\--the patient was obviously net
> inclusion and exclusion criteria. The one exclusion criterion that
> couldn\'t be determined until you actually got in the operating room
> was whether his ascending aorta was of an appropriate size. So the
> patient had a stronotomy \[phonetic\], and then you measured the
> ascending aorta approximately 1.5 centimeters below the nominid
> \[phonetic\] artery, which is about where the filter would be
> deployed, and if it fell into an appropriate range, then a
> randomization card was opened, and the patient then was either
> randomized to have a standard J-tip cannula or a modified J-tip
> cannula inserted.
>
> There were nine patients who, when the card was opened early on in the
> study, the way the card read at the top was \"The EMBOL-X Study,\" and
> actually, the very first patient that I randomized, our coordinators
> read the patient was in the EMBOL-X study, and they assumed he was a
> filter patient when indeed, you had to read the line below it, which
> said whether he was a control or a filter patient.
>
> Those happened very early on in the study, and once they were educated
> about it, they ceased to happen. And in fact, in three of those nine,
> we actually caught the mistake before we actually put one device or
> the other in.
>
> Does that clarify that for you?
>
> DR. DeMETS: That clarifies the first part. The second part is given
> that that happened, which I now understand how it happened, in which
> group were the patients left?
>
> DR. ALLEN: Intent to treat.
>
> DR. DeMETS: So they were left in the group that they should have been
> randomized to?
>
> DR. ALLEN: Correct. And they represent a very small proportion of the
> number of patients that we put in the study, but we did an intent to
> treat analysis.
>
> DR. DeMETS: Thank you.
>
> DR. TRACY: Dr. Ferguson?
>
> DR. FERGUSON: I missed one point about the cannula. I thought from my
> reading that you used the cannula with the sideport even in the
> control group. That is not the case?
>
> DR. ALLEN: No. The standard cannula is the cannula that I trained with
> in Chicago, which is just a standard J-tip cannula. So essentially, if
> you take the\--
>
> DR. FERGUSON: Is that a cannula manufactured by this company?
>
> DR. ALLEN: No. That\'s a standard J-tip cannula.
>
> DR. FERGUSON: Did everybody use\--
>
> DR. ALLEN: Everybody.
>
> DR. FERGUSON: \--were they instructed to use that same cannula?
>
> DR. ALLEN: Yes. Everybody used the same cannula. So all control
> patients, regardless of what your standard cannula was at your site,
> you had to use the same standardized cannula.
>
> DR. FERGUSON: And I would ask again, if I may, when the standard
> cannula and then this cannula are affixed to the aorta, the aortic
> size and so forth at that point of entry into the aorta are both the
> same size?
>
> DR. ALLEN: It is identical. The only part that is inside the ascending
> aorta is right there.
>
> DR. FERGUSON: I understand that, but I just want to be sure that the
> impact of the sidebar does not enlarge that\--
>
> DR. ALLEN: No, sir, it doesn\'t. That\'s a great question, but no,
> sir, it doesn\'t.
>
> DR. TRACY: Mr. Morton?
>
> MR. MORTON: Madam Chair, does the sponsor have an example available,
> and would you mind if the panel could see it?
>
> DR. TRACY: No. Are we allowed to do that?
>
> DR. ZUCKERMAN: Yes. We can take a look at an example.
>
> DR. TRACY: Okay. Do you have that available?
>
> DR. ALLEN: \[Handing.\] I\'ll give it to the cardiac surgeons first.
>
> \[Laughter.\]
>
> DR. EDMUNDS: Can I ask a question? Is there any connection between the
> flow path from the pump and the deployment path of this filter?
>
> DR. ALLEN: If I\'m understanding you\--
>
> DR. EDMUNDS: In other words, this sort of filter deployment apparatus
> is just riding shotgun on the cannula. There is really no hole between
> the two.
>
> DR. ALLEN: Yes.
>
> DR. EDMUNDS: You vent the air out by blood coming around the wire that
> is around the filter.
>
> DR. ALLEN: Actually, that\'s a great question, and it involves a
> safety issue with how the air is vented.
>
> The filter\--I don\'t know if we actually have a filter to show
> you\--there is a plug, much like is on the standard cannula, which
> allows air to be vented. So when you put the filter in, you see the
> white plug turn red, indicating that blood has come up and evacuated
> in the air. And obviously, if you don\'t see that, you need to change
> filters or do something differently.
>
> DR. MARLER: I had a question on page 68, Tables 7-18 and 7-19\--and
> I\'m sure there is an explanation, but I just didn\'t understand why
> there were adverse events, NIH Stroke Scale greater than 4, 13 in the
> control group, with 644 patients\--
>
> DR. TRACY: I think this may actually be more appropriate for the open
> committee discussion. Unless there are some very brief clarification
> questions, I\'d like to stop at this point for a break.
>
> DR. EDMUNDS: Where does the damn thing come out? Does it come out this
> hole or some other hole?
>
> \[Dr. Allen handing sample to Dr. Edmunds.\]
>
> DR. EDMUNDS: Why don\'t you show everybody, because I can\'t be the
> only one confused.
>
> DR. ALLEN: The cannula is inserted as you would any other cannula; the
> cannulation is no different. Once the cannula is inserted, patients
> are put on cardiopulmonary bypass, everything is done\--you manipulate
> the heart, you do your proximals, you do your distals, and so forth.
> Just before you release the cross-clamp, you take out this plug, and
> you insert the filter, and the filter goes in like this.
>
> The air venting that you alluded to, for those of you\--and I will
> pass this around\--there is a white hemostatic pump that allows fluid
> to vent out and push the air out just like our cannulas do today. Once
> you confirm that it is vented appropriately, the device is deployed,
> just like this.
>
> DR. EDMUNDS: Why don\'t you pass that around?
>
> DR. ALLEN: And then the cross-clamp is released.
>
> DR. TRACY: While that thing is making its way around\--Dr. Aziz?
>
> DR. AZIZ: So during the time that you take the stop off to put the
> actual filter in, could air get in, or is there a one-way valve that
> is\--
>
> DR. ALLEN: No. It\'s one-way. It is a one-way valve.
>
> DR. TRACY: Okay. I think at this point, while that is working its way
> around, we\'ll take a 15-minute break and resume at approximately 20
> of 11.
>
> DR. ALLEN: Thank you.
>
> \[Break.\]
>
> DR. TRACY: I\'d like to reconvene the meeting at this point and ask
> the FDA to begin their presentation.
>
> **FDA Presentation**
>
> MS. WENTZ: Good morning. My name is Catherine Wentz, and I\'ll be
> opening up the FDA presentation for the EMBOL-X aortic filter.
>
> This will be done in four parts. I will do an introduction. Dr. Julie
> Swain will follow up with her clinical summary. Dr. Gerry Gray will
> then do his statistical summary, and I will then close with the
> questions to the panel.
>
> \[Slide.\]
>
> I\'ll start with a brief description. EMBOL-X gave you a better one
> than I can, but this is just a short reiteration.
>
> The EMBOL-X aortic filter is used in conjunction with the EMBOL-X
> aortic cannula which was cleared this past September and is \"intended
> to contain and remove particulate emboli from the ascending aorta
> during and following cross-clamp removal and as the heart resumes
> ejection.\"
>
> The heparin-coated filter has a pore size of 120 microns and is
> mounted on a nitinol frame. The filter is inserted into the ascending
> aorta via a sideport on the EMBOL-X cannula. The flexible wire filter
> frame expands upon insertion into the vessel and is available in five
> sizes. The filter is then retracted back through the same sideport at
> the end of the procedure.
>
> \[Slide.\]
>
> In the next three slides, I would just like to reiterate briefly some
> regulatory information that I think you all received in your training
> this morning.
>
> I would also like to reiterate that this is just for your information
> and should not enter into the discussion of the EMBOL-X study. It will
> be FDA\'s responsibility to take the recommendations made today at the
> panel meeting to make a final decision within the 510(k) realm.
>
> So just to reiterate some definitions, the 510(k) requires a
> manufacturer to demonstrate substantial equivalence or SE to a legally
> marketed predicate device.
>
> To further define substantial equivalence, substantial equivalence
> basically means that the two devices have the same intended use,
> similar technology, and if the technology is not similar, there are
> means by which to demonstrate that the new technology does not affect
> equivalent performance or the risk profile.
>
> \[Slide.\]
>
> A PMA is defined as a process where the FDA evaluates Class III
> medical devices. Class III devices are usually those that support or
> sustain human life, are of substantial importance in preventing
> impairment of human health or which present a potential unreasonable
> risk of illness or injury.
>
> \[Slide.\]
>
> Now, to put this submission into that context, the EMBOL-X aortic
> filter originally underwent a clinical study to demonstrate the safety
> and effectiveness of the device in support of a PMA application.
>
> However, in June of 2001, the PercuSurge device, which is also an
> embolic protection device, was cleared through the 510(k) regulatory
> pathway opening the doors for the EMBOL-X aortic filter to be reviewed
> under the 510(k) regulations.
>
> The PercuSurge device, which has a similar intended use to EMBOL-X, in
> conjunction with cardiopulmonary bypass arterial line blood filters,
> which has similar technology to the EMBOL-X device, will be used as a
> combination predicate for the EMBOL-X device in the determination of
> substantial equivalence under the 510(k) regulations.
>
> \[Slide.\]
>
> To go over a little bit of the history of how the endpoints for this
> study were developed, at the beginning, the sponsor wanted a
> nonclinical effectiveness endpoint\--that is, to capture debris\--and
> an equivalence safety study. The FDA consistently expressed concerns
> regarding the interpretability of the proposed endpoints.
>
> FDA, however, agreed to the proposed effectiveness endpoint assuming
> that the safety endpoint, which included some neurologic outcomes and
> other embolic-related events, would capture the clinical effectiveness
> of the device; and that the device labeling would be restricted to
> only the facts from the study. No clinical implications could be made
> from the capture of debris since none was evaluated.
>
> \[Slide.\]
>
> And briefly, just one slide of engineering\--that is my background; I
> performed the engineering review of the submission.
>
> Overall, on the bench studies, there were some design concerns and/or
> test method concerns that remain that may be related to the
> endothelial injuries observed with this device. These concerns are
> presently being addressed.
>
> Both the biocompatibility and sterilization, packaging, and shelf-life
> had no further questions; they were all fine.
>
> I think this is the point where I turn it over to Julie for her
> clinical review.
>
> DR. SWAIN: Thank you for the opportunity to present.
>
> Let me make a comment first, that I am at somewhat of a disadvantage
> in that we traditionally exchange presentations with the sponsors
> before the talk so we can mold our presentations, and we provided our
> slides to the sponsor, and the sponsor chose not to provide theirs, so
> I think that some of the comments that I will make are a little bit
> off-the-cuff in response to some of the presentations that I had no
> knowledge that these items were going to be presented.
>
> \[Slide.\]
>
> The clinical review was done by both Wolf Sapirstein and myself, and
> we are both cardiothoracic surgeons. I am a consultant to the FDA.
>
> \[Slide.\]
>
> The study design, as you have seen, was randomized, which is important
> in I think one of the discussions that we will have about the
> neuropsych\--it is a randomized, multicenter trial and one of the
> largest trials done\--control arm, patients without filter; and an
> interim data analysis was planned at 50 percent of the patients.
>
> \[Slide.\]
>
> In the study plan, it was said that \"If the hypothesis tests
> performed at the interim are statistically significant, indicating
> emboli capture and equivalent safety, the study will be terminated.\"
>
> However, the study was continued with the attempt to show safety
> superiority, and that is some of the data that we will discuss.
>
> \[Slide.\]
>
> Inclusion/exclusion criteria are patients with elective operations;
> isolated coronary bypass or valve; greater than age 60; and there were
> a total of 24 exclusion criteria. One was neurological deficit; one
> was a history of major stroke as defined by the clinical history of a
> fixed, focal neurological deficit attributable to stroke; redo
> operations; and renal failure on dialysis.
>
> \[Slide.\]
>
> Neurological evaluation was essentially gross neurologic
> testing\--history, physical exam; NIH stroke score; and no
> neuropsychological testing. And I have to say that I disagree with
> some of the comments made. Dr. Kuntz was talking about reviewing this
> 3 years. I have spent probably a quarter of a century as my major
> interest in the neurological effects on cardiac surgery, and the
> consensus conference, the Key West Conference in 1995, published in
> the Annals of Thoracic Surgery when Dr. Ferguson was the editor, and
> then the updates published when Dr. Edmunds is now the editor, listed
> the problems and the suggestions of the tests that could be done. And
> the comment was made that cardiac surgeons now still don\'t agree.
>
> There was a very nice conference about 5 months ago, sponsored by the
> NIH, where the leaders in the field were invited to discuss this
> problem. I attended the conference, and we essentially had subgroups,
> and the subgroup that I was in was a neuropsych group\--I don\'t
> believe anyone else in this room that I recognize was at that
> conference in that particular area\--and I disagree that there were no
> neuropsychological tests 3 years ago and that there is none now.
>
> And again, this is a randomized study, so we know that a lot of things
> cause changes after cardiac surgery or knee operations or
> whatever\--but that\'s the beauty of a randomized study, that one can
> then look at the changes.
>
> And when you look at a device that perhaps you have difficulty showing
> efficacy, it may be that it is not efficacious or that you didn\'t
> measure the most sensitive measures. And that may be relevant to the
> discussion here.
>
> \[Slide.\]
>
> What are the endpoints? Efficacy is that greater than 75 percent of
> the filters would capture at least one particle. And there was a
> composite primary safety endpoint composing several items, essentially
> saying that it wouldn\'t be worse than normal cardiac surgery, more
> than 5 percent worse.
>
> One of the secondary safeties was aortic injury, which was not really
> part of the composite safety primary endpoint.
>
> \[Slide.\]
>
> On patient demographics, there are really no statistical differences
> in the baseline. It was a well-randomized study. The treatment group
> was 73 percent male, 91 percent Caucasian, an average age of 71, and
> 84 percent of patients had an isolated coronary bypass operation.
>
> \[Slide.\]
>
> The composite safety endpoint comprised the items that are seen here.
> Renal were an elevation of creatinine, and then, a new dialysis
> requirement. Neurological divided into stroke, TIAs, nonmetabolics.
> Cardiac is Q-wave MI and non-Q-wave MI.
>
> \[Slide.\]
>
> We looked at the number of particles trapped, and the average was, I
> believe, 5.6 mean particles per filter. The problem is\--a denominator
> has been mentioned by the panel members\--you don\'t know how many
> particles are liberated\--there was no middle cerebral doppler or
> carotid measurements made, and that probably wouldn\'t help a lot.
>
> We also know that particulate matter and gaseous emboli are the two
> main causes of neurological dysfunction. This does nothing to gaseous;
> we are talking about particulate, as Dr. Kouchoukos said.
>
> \[Slide.\]
>
> When you look at the maximum number trapped in some filters, it was 25
> in the regular study and 38 in the roll-in patients, so maybe that
> gives you an idea of what the denominator is, because you would love
> to know the percentage of particles trapped, but you really can\'t
> know that information. That may also have an influence on the efficacy
> of this device or the clinical utility.
>
> \[Slide.\]
>
> I picked out just selected events\--in neurological, I picked out
> stroke; in renal failure, I picked out dialysis; in MIs, I picked out
> Q-wave MIs. And I think as the comment was made yesterday by Dr.
> Kuntz, you like to see a trend of everything in the same direction,
> and you really don\'t see a lot of trends here in these events.
>
> Now, the comment was made by two of the three speakers, and certainly
> not Dr. Kouchoukos, that MI is irrelevant here. Well, it is highly
> relevant\--it is actually the first adverse event that I would think
> of.
>
> When you have that\--I don\'t know where that device is\--but the
> filter is between the outflow cannula and the aortic cross-clamp.
> Well, we all know that you get retrograde flow in the aorta. You get
> it in many instances; that\'s how we close aortic valves and get
> aortic insufficiency\--but in cardiac surgery, when you take an aortic
> cross-clamp off, you\'ve got an essentially normally pressured aorta,
> or we drop the pressure transiently, and you\'ve got very often a
> sucked-on aorta that has collapsed with very minimal pressure, so you
> always get retrograde flow.
>
> So I would look at myocardial infarction as a physiologist as being
> one of the more interesting adverse events in this. And then, the
> first branch of the aorta is the coronary artery, the second branch is
> the neuro-feeding vessels. So those are the areas that I tend to be
> most concerned with.
>
> \[Slide.\]
>
> We looked at\--I use the term \"manipulation-related aortic injury.\"
> It is used in the literature, and in fact it is used in the literature
> quoted by the sponsor. So when you look at manipulation-related aortic
> injury, we can see that there are changes, and we really don\'t know
> what this means, as the sponsor pointed out.
>
> In this acute study, the patients were followed an average\--a median
> followup was 7.0 days\--it was during their hospitalization\--and what
> that implies to whether you find an injury.
>
> This occurred in 9.2 percent of the filter patients\--42\--in the
> regular study. Three of the filter patients, as has been said,
> required aortic repair. I know that the dissection ones that the
> control group had were the only ones placed up there in the table.
> However, three of the patients, the surgeons did choose to do an
> aortic repair, which is a fairly major procedure to add onto an
> isolated coronary bypass. Whether that was a correct decision or not,
> it is the data.
>
> \[Slide.\]
>
> The study protocol showed 30-day followup or hospital discharge,
> whichever occurred first; so the median was 7.0 days to study these
> patients.
>
> And then there is the post hoc study that was a telephone followup
> that followed up 43 of the 49 aortic injury patients and 18 of them
> were followed for greater than one year by telephone followup.
>
> So I think it was a good effort by the sponsor to see if you could
> find in this type of study whether there were adverse events, and
> again, none was found. Also, there was no apparent training effect in
> that you didn\'t get more of these at the beginning. They were pretty
> evenly distributed throughout the study.
>
> And again, they were not associated with the adverse events that were
> measured in this study.
>
> \[Slide.\]
>
> When we looked at the post hoc data analysis\--I was not present at
> the FDA when this was discussed, but I don\'t think that the exact
> type of analysis was specified\--in fact, I know it wasn\'t. The
> problem of a post hoc data analysis is that they are not planned
> actively in the investigational plan, so the statistical treatment
> that Dr. Gray will talk about is somewhat difficult in that a .05 P
> value is probably not the P value that would be interesting for you.
> And nominal P values do not account for multiplicity; you can do
> multiple analyses and find something that has a P value. And there is
> really no way to know how much adjustment should be applied when
> judging the significance of this.
>
> \[Slide.\]
>
> We looked at Higgins score, and Higgins score was chosen because it is
> generally used at one institution; it is a lot less used than some of
> the more common, SDS database or New York Heart, and although those
> two don\'t look at adverse events so much, they really do tell you how
> sick a patient you have, because it is an estimation of mortality.
>
> I have spent 24 years with the STS database, and I think that that is
> probably an interesting way to look at the data, and we don\'t have
> the results of that analysis.
>
> However, when we look at the Higgins score greater than 5, again you
> can see that when you look at death, slightly favored in the filter
> group, and stroke, slightly favored in the control group, there is
> really no consistent trend in these data.
>
> \[Slide.\]
>
> So in summary, the filter trapped at least one particle in 97 percent
> of the cases. The composite safety endpoints were really not different
> between the two, as the hypothesis was. The individual safety events,
> there were no significant differences; and the only difference was in
> the manipulation-related aortic injury.
>
> \[Slide.\]
>
> Conclusions: The filter traps particles; a correlation with clinical
> improvement was not shown; there were additional concerns raised by
> the occurrence of aortic injuries.
>
> Thank you.
>
> DR. GRAY: Good morning. My name is Gerry Gray, and I was the
> statistical reviewer for this submission.
>
> \[Slide.\]
>
> I am going to just address a few issues. First, I am going to talk a
> little bit about judging the results of the trial, because I think
> that\'s really the crux of any kind of disagreement we might have with
> this trial.
>
> Next, I\'m going to talk a bit about particulate capture as a
> surrogate endpoint; and finally, I will finish up with the subgroup
> analyses and the Higgins risk scores.
>
> \[Slide.\]
>
> The first issue is how are we going to judge the results of the trial,
> and of course, the bottom line is always the tradeoff between a
> probable benefit and a potential risk. I would say that both of those
> things are kind of hazy in this case.
>
> And the other thing you have to think about is what the appropriate
> set of endpoints to be using, and what is the appropriate
> control/comparator group.
>
> \[Slide.\]
>
> So, really, in this case, there are three main ways that you might
> judge the results. The first one being the most compelling is that the
> results are judged internally to the study, with clinical outcomes
> compared to a control group in a randomized trial, and at that level,
> you can really make pretty sound causal inferences.
>
> The next level might be to judge the results in comparison to other
> similar devices and/or studies that you might have.
>
> And the third way that you might think about it is judging the results
> narrowly, based purely on proposed claims, thinking of the device as a
> \"tool,\" in effect, and comparing that to some predefined criteria
> you might have for effectiveness of that tool. And in this scenario,
> really, there is no demonstration of clinical effectiveness.
>
> \[Slide.\]
>
> So, internally, using the adverse event composite as the endpoint,
> again, we had 1,289 patients randomized to the EMBOL-X versus control,
> the outcome being the major composite adverse event rate. We had 17.1
> percent of events in the EMBOL-X arm and 18.9 percent in the control.
>
> The first statistical test is for noninferiority, and that was with an
> equivalence delta of 5 percent. So in other words, we are testing
> whether the EMBOL-X is no more than 5 percent worse than the control.
> And that is strongly rejected, so that certainly we can say that the
> EMBOL-X device is equivalent to the control if you measure that as 5
> percent.
>
> And contrary to what I heard in the sponsor\'s presentation, there as
> an amendment to the IDE that specified that we would do another test
> for superiority for this adverse event composite, and you can do that
> without any worries about alpha penalty, but that test is not at all
> significant; the P value is 0.38.
>
> So the bottom line is, as you have probably already come to a similar
> conclusion, for the adverse event rates, the devices are equivalent
> but not superior in terms of this endpoint.
>
> \[Slide.\]
>
> Internally to the study, using the endpoint of particulate capture,
> the outcome is the proportion of the filters that capture at least one
> particle. And for this endpoint, there is no way to judge internally,
> because there was no comparison group that we had.
>
> \[Slide.\]
>
> For the other safety endpoint, to me, it looks like the results for
> safety are actually remarkably similar. Of all the types of serious
> adverse events, all 32 that we saw that the sponsor presented in one
> of their tables, there was none that came even close to being
> significant in either direction.
>
> So for all the other safety endpoints, there is no evidence of any
> difference between the device arm and the control arm.
>
> And finally, there was a secondary endpoint, as has been discussed, on
> aortic endothelial injury that was significantly higher in the EMBOL-X
> arm, but again, there is no detectable effect or outcome from those
> aortic injuries on any clinical adverse events. For short-term
> followup, there were 42 randomized patients.
>
> \[Slide.\]
>
> You might think you could compare the results of this study to some
> other device or a similar device. The predicate for the EMBOL-X device
> is the PercuSurge balloon aspiration catheter for SVG patients
> combined with the meshes in the CPB arterial filters.
>
> Unfortunately, though, the two devices are really fairly different in
> terms of their mechanism action, and they are fairly different in
> terms of the patient populations that were studied.
>
> So really, from my point of view, this is sort of a dead end; you
> can\'t really make a comparison with this device.
>
> \[Slide.\]
>
> Finally, based on the proposed claims, the evaluation of the device as
> a tool, the claim says \"to contain and remove particulate emboli,\"
> and certainly the device is successful in that regard because it was
> successfully deployed in about 96 percent of the patients, and
> depending on the denominator that you use\--either the number of
> filters or the number of patients\--it captured one or more particle
> in either 97 or 92.5 percent of the time.
>
> So that easily meets the predefined criteria of particulate capture in
> 75 percent of the filtered patients.
>
> \[Slide.\]
>
> So to summarize, the internal evidence is for equivalent safety, and
> there is no evidence of any effect on adverse event rates.
>
> Externally, it is very difficult to make any comparison, and as a
> tool, the device certainly captures particulate material, and from the
> sponsor\'s summary slide, they said \"Clinical efficacy can be
> reasonably extrapolated.\" So if you choose that route, you may get
> extrapolation.
>
> \[Slide.\]
>
> Let me just talk a little bit about particular capture as a surrogate,
> because one way you might justify the particulate capture is to think
> it is a surrogate for some clinically meaningful endpoint. And the
> question here in bullet number two\--is particulate capture, however
> you measure that, a valid surrogate for clinical adverse events?
>
> Really, to be a valid surrogate, the endpoint has to be somehow
> correlated with the outcome of interest, and somehow it has to capture
> the effect of the treatment on that outcome.
>
> \[Slide.\]
>
> So just going down that path a little bit, here is a two-by-two table
> that shows whether or not particles were captured and then whether or
> not a composite event was observed. And as you can see, the
> correlation coefficient is quite small there. There is really no
> obvious correlation that I can see between particulate capture and
> whether or not there was a composite event.
>
> It is the same if you do number of particles captured, whether it
> captured any particle or not, or if you measured the total surface
> area of particles captured.
>
> \[Slide.\]
>
> Looking at that a little further, this is called an Q-Q \[phonetic\]
> plot, and it plots the quantiles of two distributions.
>
> Here, on the X axis is the number of particles captured in patients
> who had no composite event, and the Y axis shows the number of
> particles captured in patients who did have a composite event. And if
> the two distributions are the same, we would expect that to be a
> straight 45-degree lines, and indeed, it is almost entirely a straight
> 45-degree line. So there is no real evidence that there is any
> difference, except potentially out in the fair tail there, where you
> have more than 12 or 15 particles captured.countries
>
> \[Slide.\]
>
> So I did a little bit of\--well, actually, first of all, here is the
> same kind of plot that is using particle area instead of number of
> particles, and it looks the same, visually.
>
> The only thing that would make you think there might be a relationship
> would e what is going on in the extreme tails here, where you have
> more than 10, 12, 15 particles captured. So I did a little bit of
> data-dredging of my own to try to figure out if there was anything
> going on out there, and that represents about 46 patients, I think it
> was, out of the 1,200 in the trial. It is relatively low numbers, and
> from a statistical point of view, you can\'t really draw any
> conclusions from those.
>
> \[Slide.\]
>
> So in regard to particulate capture as a surrogate, it really doesn\'t
> meet the condition that it is correlated with the outcome of interest.
>
> And similar results hold if you use other endpoints, or other kinds of
> adverse events not included in the composite.
>
> It is possible, of course, as Rick Kuntz pointed out, that there could
> be effects that are so subtle that they were not measured in this
> trial, and therefore, we have no way of knowing whether there is any
> effect on them.
>
> \[Slide.\]
>
> The third and final topic is just covering the basis on the subgroup
> analyses. The sponsor acknowledged this, that on Table 6 of their
> panel package, they have 36 different subgroup analyses that they
> performed, and certainly, when you look at them through the
> statistical viewpoint, the P values are small, but given the number of
> subgroups that we have gone through, that really is not surprising at
> all.
>
> \[Slide.\]
>
> And finally, for the preoperative Higgins risk score, really, that is
> in a sense another subgroup analysis, because we have used the Higgins
> risk\--we tried several cuts on the Higgins risk score and found one
> where the P value was slightly less than .05. But in order to make any
> strong statistical conclusion from that, we would need to know how
> small the P value has to be to be significant, and .047 really isn\'t
> it if you do any reasonable adjustment for multiplicity.
>
> \[Slide.\]
>
> So to summarize the last subject, the subgroup analyses really don\'t
> provide any evidence of superiority in terms of adverse event rates.
> And again, I heard this pretty clearly from the sponsor\'s
> presentation as well.
>
> That concludes my presentation.
>
> MS. WENTZ: Thanks very much.
>
> At this point, I just want to review the Questions to the Panel, and I
> believe there are six.
>
> Question 1. The primary safety endpoint for this study was a composite
> of seven clinical adverse events including death, neurologic deficit
> mild and severe, renal insufficiency, perioperative myocardial
> infarction, gastrointestinal complications, and limb-threatening
> peripheral embolism, evaluated at hospital discharge or 30 days,
> whichever was shorter. The median followup time was seven days.
>
> Some facts from the study are: The observed overall composite event
> rates were 17.1 percent in the EMBOL-X arm and 18.9 percent in the
> control.
>
> The composite event rate for the EMBOL-X arm was shown to be
> equivalent\--not more than 5 percent higher\--than the control.
>
> Also as specified in the protocol, a separate test for a lower event
> rate in the EMBOL-X arm was not statistically significant.
>
> The EMBOL-X arm demonstrated a significantly higher incidence of
> aortic endothelial injury\--9.2 percent versus 2.0 percent. Although
> these patients did not appear to have any short-term clinical sequelae
> resulting from the injuries, the long-term effects are unknown.
>
> And the final question being: Do these data support the safety of the
> EMBOL-X intra-aortic filter?
>
> Question 2. The primary effectiveness endpoint in this trial was to
> demonstrate that 75 percent of the devices would capture at least one
> particle during elective CABG or single-valve procedures. This was
> demonstrated in the study.
>
> There was no demonstrated reduction in any category of clinical
> adverse event in this well-controlled 1,289-patient trial. Please
> address the following concerns:
>
> 1\) Can this method of embolic entrapment, from this study or
> elsewhere, be extrapolated to clinical efficacy?
>
> 2\) Do these data support the effectiveness of the EMBOL-X
> intra-aortic filter?
>
> Question 3. Do the study data support an appropriate risk/benefit
> profile?
>
> Question 4. One aspect of the 510(k) review of a new product is the
> review of its labeling. The labeling must indicate which patients are
> appropriate for treatment, identify potential adverse events with the
> use of the device, and explain how the product should be used to
> maximize benefits and minimize adverse effects.
>
> Please address the following questions regarding product labeling:
>
> 1\) Do the Indications for Use adequately define the patient
> population studied? For example, should the patient population
> receiving this device be limited to the same patient population
> utilized in the study\--for example, nonemergent, patients over age
> 60, and first-time isolated valve or CABG patients.
>
> 2\) Are there any other restrictions that should be placed on the
> patient population receiving this device?
>
> 3\) Based on the clinical experience, should there be additional
> Contraindications, Warnings, and Precautions for the use of the
> EMBOL-X intra-aortic filter?
>
> 4\) Should the labeling include specific study information such as: no
> reduction of clinical events were noted in a 1,289-patient clinical
> study; and the EMBOL-X device appears to increase the rate of
> endothelial injury?
>
> 5\) What should the labeling include regarding the use of ultrasound
> both before\--for assessment of the aorta\--and after\--monitoring of
> injury\--the use of the device?
>
> Question 5. Please provide any other recommendations or comments
> regarding the labeling of this device.
>
> Question 6. If the data provided are not adequate to support safety
> and/or effectiveness, what additional data, analyses, or study would
> you require?
>
> Thank you.
>
> **Questions and Answers**
>
> DR. TRACY: Does that complete the FDA presentation?
>
> MS. WENTZ: Yes.
>
> DR. TRACY: Does the panel have any questions for the FDA before we
> move on?
>
> DR. LASKEY: I have one question to the engineer. Maybe it is trivial,
> maybe not.
>
> Nitinol and its thermal properties\--there is a nitinol frame here.
> Patients are generally cooled when they are put on bypass, hearts are
> cooled, and so on and so forth. Is there anything happening with
> the\--should we be concerned about any change in function or
> configuration of the frame here?
>
> MS. WENTZ: That is a very good question, and actually, that was
> brought up in a few of the stent studies a few years ago, when you
> place stents that have nitinol in them because patients are cooled
> down as well. And I believe from that, I did not review that from a
> material standpoint\--our OST scientists did\--but that was looked at,
> and the temperature that the patients are cooled down to does not
> affect the nitinol.
>
> DR. TRACY: Dr. Marler?
>
> DR. MARLER: In Dr. Swain\'s discussion of the myocardial infarction
> data, I may not have been able to see the complete slide, but I
> didn\'t have the impression of the same difference between the groups
> and the incidence of MI, and I was wondering where that information
> came from.
>
> DR. SWAIN: I think in your pack, you can talk about total MIs or
> Q-wave versus non-Q-wave MIs. So that is the difference. I believe the
> sponsor\'s presentation was total MIs, and my presentation was to pick
> out Q-wave MIs and stroke versus the lesser injury.
>
> Do you want that slide back up? I might be able to do that.
>
> DR. MARLER: I might be looking at the wrong table; I am looking on
> page 35, Table 62.
>
> \[Slide.\]
>
> DR. MARLER: Okay. It was a problem of not being able to read the
> slide, because I couldn\'t read the X axis. So it is clear now. I\'m
> sorry.
>
> DR. TRACY: Dr. Krucoff?
>
> DR. EDMUNDS: Julie, when they did these epi-aortic ecograms, did they
> look at the area of the cross-clamp with the core laboratory look,
> where they were able to see things that nobody else could see?
>
> DR. TRACY: Can we ask that during the open committee discussion,
> please? We haven\'t quite gotten there yet. I just don\'t want to mix
> the FDA with the sponsor.
>
> DR. EDMUNDS: I just asked Dr. Swain. I don\'t know why\--
>
> DR. TRACY: If she doesn\'t know the answer, then, let\'s just hold the
> question.
>
> DR. SWAIN: Yes, it was looked at. And the injuries are not seen by the
> surgeon\--I didn\'t look at my screens very much when I was busy
> closing up and getting up pumps. It was identified at the institution,
> I guess.
>
> DR. TRACY: Dr. Krucoff?
>
> DR. KRUCOFF: I have a question for Dr. Gray.
>
> Gerry, in your particles analysis\--I probably just didn\'t connect
> when it started\--but to me somehow, the elimination of particles by
> the filter would ostensibly be associated with a reduction in clinical
> events; if you got them out with the filter, presumably, you are
> saving the patient that avalanche effect.
>
> And somehow as I looked at these\--is that where the divergence in
> total number of particles captured\--well, I\'m confused.
>
> DR. GRAY: Let\'s go back to Slide 2.
>
> DR. KRUCOFF: Yes, because that\'s where it started.
>
> \[Slide.\]
>
> DR. KRUCOFF: So is your expectation\--is what you are testing here
> that if you get more particles out with the filter, you are more
> likely to have a composite event?
>
> DR. GRAY: We have a problem here with the endpoint, because we all
> would like to see the clinical endpoint, and what we have is the
> particulate capture. My line of reasoning here was let\'s see if
> somehow we can justify using particulate capture as a surrogate for
> some clinical outcome that we are interested in, in this case being
> the composite adverse events.
>
> So I am trying to see if there is some correlation between whether or
> not particles were captured in a patient and did that patient have an
> adverse event or not.
>
> DR. KRUCOFF: Okay, but the assumption here is what I am trying to get
> at, Gary\--
>
> DR. GRAY: I guess the assumption is that if removing particles does
> anything, we would expect that where the particles were removed, we
> would be reducing the composite adverse event rate. That is my
> assumption.
>
> DR. KRUCOFF: Well, I would suggest that the assumption is if particles
> are a surrogate for bad things happening, that that is what happens in
> a control population\--if you have 1,000 patients with no protection,
> some of them are going to have very few particles, and they would have
> fewer events; others are going to have showers of particles or big
> particles, and those would have clinical events.
>
> The trouble is that as you start removing particles, if you capture
> very few particles, those may be patients who have very few particles,
> and if you capture a lot of particles, those might be patients who
> would be high risk whom you are protecting.
>
> I just don\'t see how this would even begin to test that, because the
> assumption is that somehow particles removed would correlate with
> badness in the same patient population, and\--
>
> DR. GRAY: I agree that\--we wish we knew the denominator here, right;
> we wish we knew for any patient how many particles really there were
> present, and then we would have some idea of the effectiveness of
> removing those particles, so we could say that somehow, the amount of
> particles released in that patient is some indication of their
> potential risk for an adverse event, and then we could try to figure
> out, okay, if we remove a certain proportion of them or if this device
> can remove some proportion of them, what effect would that have on the
> outcome. That\'s what I wish we knew. But we don\'t know that. We
> don\'t really know at all\--and you are right, we don\'t know for any
> patient\--if the device captured one particle, that could be the only
> one that was released, or it could be one out of thousands. There is
> no way to tell that with the data that we have.
>
> So I admit I was on a bit of a stretch here to try to figure out is
> there any way to take the data that we do have, which is purely the
> number of particles captured, and relate that to whether or not there
> was an adverse event. That\'s why I went on to the next slide, which
> was just that.
>
> What is missing here is\--you are right\--what we really would love to
> know is the underlying information for each patient as to how many
> particles were actually released and how much risk was that patient
> exposed to. But we have nothing to tell us that as far as I know.
>
> DR. KRUCOFF: Okay. Can I ask you\--because when I actually walked
> through these slides, what I ended up sitting here thinking, which I
> took as different from what you were suggesting, is that although I
> agree it is a stretch, this might be taking as an imputation that you
> can take patients who are at much higher risk, i.e., the higher
> -particle group, and pull them down to a line of identify with
> patients who are at much lower risk, i.e., patients who have fewer
> particles, in a population where you are not allowing these particles
> into the systemic circulation\--you are removing them.
>
> Is that wrong?
>
> DR. GRAY: I can\'t say whether that is wrong or right, because if I
> understand correctly, what you are thinking is that somehow this mesh
> puts a limit on the amount of particles that are released, that
> actually escape through into the circulation, and therefore, that
> would be nothing but a good thing.
>
> Is that a correct interpretation of what you said?
>
> DR. KRUCOFF: But that would be one notion, I think, of the whole
> generation of distal protection devices, that basically, the more you
> get out with the device represents some sort of surrogate incremental
> protection afforded the patient.
>
> DR. GRAY: Yes. And that sort of gets back to my first set of ways of
> judging the results of the trial. And you can infer in your own mind
> that removing particles is undoubtedly a good thing and that the
> device only needs to be shown effective as a tool that removes
> particles, and that\'s all they care about, therefore, I\'m happy
> with.
>
> On the other hand, we have the internal to the study comparison
> between the treatment and the control group, where it was remarkably
> uniform, remarkable similarity in the adverse event rates across the
> board.
>
> So how do we make that judgment\--that\'s why I started out with that,
> because I think that is really the whole crux of the\--
>
> DR. TRACY: The less kind interpretation, Mitch, would be that it
> doesn\'t matter if you remove particles\--the risk is the same\--
>
> DR. KRUCOFF: Yes.
>
> DR. GRAY: That\'s right.
>
> DR. KRUCOFF: Understood.
>
> DR. TRACY: Okay. Can I ask Dr. Wentz to clarify\--you mentioned that
> bench study, some design concerns and/or test method concerns remained
> that may be related to the endothelial injuries. Could you expand on
> that just a little bit?
>
> MS. WENTZ: First of all, it is not \"Doctor\" but thank you.
>
> When this submission first came in, we looked at the test methods and
> the results and procedures and all that, and everything looked okay,
> and we let the study go on. It wasn\'t until we started focusing on
> these endothelial injuries that we backtracked and said, okay, what
> could some of the possibilities be for these injuries.
>
> Dr. Sapirstein and myself re-reviewed all of those test methods and
> found that there were a number of them that could possibly be related
> to those endothelial injuries. So we just sent those questions to the
> company in the form of a 510(k) Additional Information Letter\--and
> did that come back already\--no\--they are still formulating the
> answers to those.
>
> Does that answer your question?
>
> DR. TRACY: I guess so. I\'m not sure what the design questions
> are\--whether it is that the thing is too stiff or is too\--is there
> some fundamental problem with this thing that you are asking them to
> clarify?
>
> MS. WENTZ: Yes, that\'s basically it. When we tried to repeat their
> test methods using the sample device that we had, some of the forces
> that we felt were not anywhere near some of the forces that were on
> the paper that they said they had recorded. So we just asked them to
> clarify some of their test methods and procedures in light of the
> endothelial injuries.
>
> DR. TRACY: Thank you.
>
> Are there any other questions?
>
> Dr. Aziz?
>
> DR. AZIZ: Let me ask Julie a question.
>
> Julie, these endothelial disruptions\--I\'m sure the company will
> focus on that later\--in your review of the data, where were they
> occurring? Was it at the tip of where the net is? Where is it, and
> what do you think is causing it?
>
> DR. SWAIN: Right. You know what you can see on a TEE; essentially, you
> are blocked off because of the airways so that in the area examined of
> the ascending aorta, they occurred. Some of them occurred proximal,
> where the clamp was, but I didn\'t see it, or don\'t recall it being
> broken out that much; but they certainly did occur in the area where
> you have aortic manipulation.
>
> And I think also, in answer to Dr. Krucoff\'s question, the patients
> who had the biggest amount of atherosclerosis were screened out\--that
> group wasn\'t studied. So the kind of catch-22 is that maybe they
> would benefit more, but again, aortic manipulation in the presence of
> known atherosclerosis, from all the data and the work of 20 years from
> Dr. Kouchoukos, is what we all learned we shouldn\'t do.
>
> DR. AZIZ: And then actually looking at the ECO that was presented
> earlier, it seems like there were two different types. You had this
> fibrinous strand sort of waving at you, and then you had like an
> intramural hematoma on the wall. Maybe we\'ll look at that later.
>
> DR. SWAIN: Yes. You may ask the sponsor about the intramural. I
> didn\'t remember seeing that. It\'s kind of like in surfing, we use
> the term \"dings\"\--it is an aortic \"ding\"\--no clinical
> consequence as evaluated in this short-term study.
>
> **Open Committee Discussion**
>
> DR. TRACY: At this point, let\'s move on to the open committee
> discussion. I think there are lots of questions waiting to be asked.
>
> I would just like to remind everyone that this is a premarket
> notification or a 510(k) submission that is being brought to the panel
> at this time. And at the end, the FDA is asking for recommendations
> and advice. There will not be a final vote. And the two lead reviewers
> were Dr. Marler and Dr. Edmunds.
>
> Dr. Marler, if you would like to lead off with questions for the
> sponsor.
>
> DR. MARLER: Okay. I guess this very technical\--I still have this
> question comparing table 7-18 and 7-19. I tried to read and
> understand, and I\'m sure there is an explanation, but for adverse
> event under NIH Score greater than 4 in the control group, there are
> 13 in table 7-18 with 644 patients, and then, when the sample size is
> reduced to 620, there are more\--16. Is that because you are including
> events that occurred after the first exam?
>
> DR. ALLEN: I think it\'s a very good observation. There were very
> little times when the initial NIH score was applied. In the initial
> design of the study, we had hoped to have a 24-hour evaluation on
> every patient, but it became quite obvious as the study progressed
> that that wasn\'t practical. Patients were \[inaudible\] and so forth.
>
> So discussions then allowed us to do our first evaluation at 3 plus or
> minus one day. So that initial evaluation is variable in time.
>
> When you look at the 7-day evaluation which is applied evenly among
> both groups\--call it the end evaluation of the New York Stroke
> Scale\--the rates were essentially identical between the groups\--2.6
> was \[inaudible\].
>
> DR. MARLER: So, then, which one do you think most accurately reflects
> the strokes that were due to the cardiopulmonary bypass procedure and
> the surgery? Is it Table 7-18?
>
> DR. ALLEN: That\'s a very interesting question, because when you look
> at actual frank stroke after cardiopulmonary bypass, Dr. Kuntz in his
> presentation outlined the multiplicity of reasons for why patients
> have strokes. The stroke rate overall in our study was about 2.5
> percent. It is interesting that if you look at the time course as to
> when those strokes occurred, only about half of them actually occurred
> greater than 24 hours\--the patients woke up neurologically intact,
> and at day 2 or day 3 had an event.
>
> So the device\'s potential to impact frank stroke is with the
> operation. When we did an analysis, for example, on the impact of
> atrial fibrillation, 60 percent of patients who had stroke also had
> atrial fibrillation, which we know is a potential indicator for
> stroke.
>
> Dr. MARLER: The neurologist was looking throughout this for any
> description of the strokes or any further analysis, even breakdown as
> to hemorrhagic or ischemic\--did I miss it? Is it somewhere in the
> writeup, or was there data available to me on how the strokes were
> diagnosed as to their type?
>
> DR. ALLEN: I don\'t believe we broke the strokes down, and I don\'t\--
>
> DR. MARLER: For severity?
>
> DR. ALLEN: \--for severity as far as whether it is a hemorrhagic
> stroke or\--
>
> MS. CHANG: These are all ischemic strokes.
>
> DR. ALLEN: \--but they were adjudicated by a blinded events committee
> and felt to be related to surgery.
>
> MS. CHANG: We provided narratives in the 510(k) filing on these.
>
> DR. MARLER: Okay. But those aren\'t in the packet here.
>
> MS. CHANG: No.
>
> DR. MARLER: Okay. They are not very interesting reading to the
> cardiovascular surgeon, I\'m sure.
>
> \[Laughter.\]
>
> DR. MARLER: So, what I am looking for is an argument as to the logic
> of\--I mean, we have said that there is not a surrogate marker for
> safety. What is the clinical efficacy\--what is the benefit to the
> patient\--I mean, what\'s the talk on this? What are you
> expecting\--why do this? It seems to me the study has shown that it is
> as good as doing nothing. But why is it better, and what are you
> thinking?
>
> I was concerned that the discussion about the cognitive outcomes
> indicated\--which I thought would be an obvious possible benefit\--it
> was stated that that wasn\'t really thought of as a potential benefit.
> So I am a little unclear on the thinking of really what this study
> means to the patient.
>
> DR. ALLEN: We grappled with that, and I thought Dr. Kuntz tried to
> outline that in his presentation with regard to study design.
>
> You know, intuitively, reducing the particulate emboli load is a good
> thing, but we grappled in the design of the study with the very
> question that you are asking: How can we demonstrate an efficacy
> endpoint?
>
> And the conclusion was that, for example, unlike the SAFER trial where
> you had a very specific marker\--CPK isoenzymes that affected a very
> specific end organ\--with the exception of perhaps serum creatinine,
> we didn\'t have specific sensitive markers that might detect subtle
> clinical changes in patients\' outcome. So we ended up with a design
> trial that essentially looked at safety equivalency to show that the
> device wasn\'t causing harm and that the particulate capture was the
> efficacy endpoint, and that capture of particles was a good thing.
>
> You know, the difficulty of designing a trial comes down to what can
> be practically applied and logistically applied across multiple
> centers, and the one power calculation that Dr. Kuntz did\--if you
> look at just, for example, frank stroke and assume you have a 3
> percent incidence of frank stroke, not all of those strokes occurred
> in the operating room, so you wouldn\'t even expect that the device
> would prevent all of those strokes, but let\'s assume for argument
> that the event rate was 3 percent. A 20 percent reduction in that 3
> percent rate would require a sample size of a little over 22,000
> patients to demonstrate that.
>
> So you weigh what seems clinically intuitive with the practical
> aspects of designing a trial that demonstrates that clinical efficacy.
> And I think the additional analysis that we provided\--and I make full
> disclaimer\--I take my mea culpa in that I don\'t make claims of
> superiority when we look at that additional analysis, but it does
> provide some element of risk-benefit as to what population this may
> truly benefit, and it is the higher-risk group that we know as
> surgeons have an increased risk for morbidity and mortality
> postoperatively that, intuitively, reducing that embolic load in those
> patients seems very reasonable, and that additional analysis, when you
> looked at an endpoint that has a specific marker, i.e., serum
> creatinine, you began to see clinical ticks that, yes, there is
> something maybe going on there.
>
> But I agree with the FDA, and I don\'t want to make claims of
> superiority. We simply rely on the clinician\'s intuitiveness that a
> reduction of this embolic load is a good thing.
>
> DR. MARLER: What can you say that would reassure me or the
> committee\--I mean, we have knowledge that there are instances where
> something that is really intuitively obvious\--blood pressure,
> arrhythmias, I hesitate to mention, but ECIC bypass I am pretty
> confident of, in which there is a real obvious case in which the
> intervention did what it was supposed to do but it wasn\'t clear at
> all, and some people still think it may have actually been harmful but
> hiding underneath the obvious clinical benefit.
>
> Is there something different about this that would\--is there any
> reassurance you can offer?
>
> DR. ALLEN: No, and I think the panel members are grappling with the
> same things that I grapple with when I think about this data.
>
> You are absolutely right. There are many instances where your
> intuition tells you something is good, and a well-designed trial tells
> you that now your intuition wasn\'t as good as you thought it was.
>
> In this particular trial, it was designed as a safety study to
> demonstrate that the device, compared to current cannulation
> techniques that we use every day in open heart operations, isn\'t
> worse, and that particulate capture was the clinical efficacy
> endpoint.
>
> DR. MARLER: Thank you.
>
> DR. TRACY: Dr. Edmunds?
>
> DR. EDMUNDS: Keith, are you going to be the one who responds, or
> someone else? On this injury, if we discount the three, one of which
> was the scalpel and the other one, a surgeon took a stitch or two, and
> just concentrate on the 42, most of which were not surgeon-noticed at
> the time, or anesthesiologist reading the ecocardiogram, whoever it
> was, how many of those were more than just the endothelium? How many
> actually got into the media?
>
> DR. ALLEN: I think Dr. Kouchoukos is experienced in this field, so
> I\'ll let him answer that question.
>
> DR. KOUCHOUKOS: These were all basically endothelial disruptions. In
> other words, they are just small fragments of intima.
>
> DR. EDMUNDS: And do you think they were scratches from the nitinol
> wire?
>
> DR. KOUCHOUKOS: Well, the question was raised earlier about in the
> filter group, where these intimal disruptions were located, and they
> were distributed throughout the ascending aorta. Some of them were
> clearly related to the filter, but others occurred in the mid-aorta or
> perhaps in the more proximal part. So they would be expected to have
> resulted from other manipulations of the aorta, and that\'s basically
> why they occurred in the control group.
>
> DR. EDMUNDS: And that\'s why they occurred in the control group, too.
>
> DR. KOUCHOUKOS: That\'s what I said; that\'s why they were present in
> the\--they were present in 2 percent of the control group. And I
> think\--
>
> DR. EDMUNDS: right. So how long do you think it took for that to heal?
>
> DR. KOUCHOUKOS: Well, we don\'t have followup ecocardiograms or
> epi-aortic images to know the answer to that. It is also important to
> note that only one of these was detected by transesophageal
> ecocardiography. They were all detected for the most part by
> epi-aortic scanning. So you wouldn\'t see one of these with a
> transesophageal, and certainly not with a two-dimensional surface ECO.
>
> DR. EDMUNDS: Isn\'t it a stretch to call this an \"injury\"?
>
> DR. KOUCHOUKOS: Well, it\'s a good question. We termed it a
> \"disruption,\" but I think others would term it an \"injury.\"
>
> DR. EDMUNDS: Gosh, I would consider it an overinterpretation of the
> ecocardiogram myself, if it were one of my cases.
>
> Does anyone really think that this will progress to any problem
> downstream for the patient?
>
> DR. KOUCHOUKOS: I think, again, it is important to put it in
> historical context. These endothelial disruptions have been occurring
> since we started doing cardiac surgery.
>
> DR. EDMUNDS: Exactly.
>
> DR. KOUCHOUKOS: They have been there forever. And from what we know
> about the outcomes of patients who have cardiac surgery, they are
> probably of no significance. We know that an intra-aortic dissection
> is a catastrophic event, and we know how frequently that occurs, and
> it is very rare. And I think to extrapolate to what happens to the
> endothelial disruptions is hard, because they are not as significant
> as the others, and we really have no way of following what happens to
> them. We would surmise that they probably heal eventually, but we have
> no hard data to support that.
>
> DR. EDMUNDS: In your experience as a very busy cardiac surgeon over
> the long period, which is the greater injury\--the cross-clamp injury
> to the endothelium, or produced by this filter\--in your opinion? I
> know you don\'t have data, but you have a lot of clinical experience.
>
> DR. KOUCHOUKOS: Well, I think that what, if anything, we have learned
> from this study, and as we have learned from our own clinical
> experience, is that we want to manipulate the ascending aorta as
> little as possible. And certainly a cross-clamp is a major insult, if
> you will, to the ascending aorta. It is exposed to a lot of surface of
> the aorta, with the potential for dislodgment of atheromatous debris,
> and a side-butting clamp is the same.
>
> DR. EDMUNDS: So you think the clamps are a bigger injury?
>
> DR. KOUCHOUKOS: I do.
>
> DR. EDMUNDS: Now, as I understand it, the company does not intend to
> make any statement on the labeling about\--am I out of order
> already\--
>
> DR. TRACY: No\--not yet.
>
> \[Laughter.\]
>
> DR. EDMUNDS: \--okay\--about clinical benefit; is that correct?
>
> MS. CHANG: To both of them, yes.
>
> DR. EDMUNDS: Okay. There is no evidence that particulate emboli to the
> brain is good, so it is logical to assume that reducing it is at least
> not bad and is probably good.
>
> What percentage of the atherosclerotic emboli to the brain would you
> guess this filter when it is deployed decreases from some unknown
> hole? What would be your clinical estimate? I have one in my head.
>
> DR. KOUCHOUKOS: I\'m not sure I understand your question, Dr. Edmunds.
>
> DR. EDMUNDS: What percentage of all the emboli that go to the head
> from surgical manipulation doing a case do you think this filter
> catches?
>
> DR. KOUCHOUKOS: Well, it catches a different amount of material from
> each patient, and I think you saw that. There are patients who release
> small numbers and small sizes of particulate matter and others who
> release large amounts.
>
> From what we know from Dr. Barbut\'s studies and from our own
> experience, I think about 20 percent of those have the potential to go
> to the cerebral circulation, and a percentage of those would probably
> be dispersed to the brachial arteries and not enter the brain, but in
> her study, I think on overage, about 9 percent of the emboli in one
> small study that were released went to the brain.
>
> DR. EDMUNDS: Well, I would answer the question a little bit
> differently. Fourteen percent of the cardiac output goes to the brain.
> That is physiology. So we would presume that the amount of emboli
> would be the same, unless there is some streaming.
>
> We also know that the injury to the brain is due to a whole lot more
> than atherosclerotic emboli\--complement activation, cytokines,
> regional profusion differences, temperature movement, and all that
> sort of thing go into cumulative brain injury\--but from what I know,
> I think you are only catching a fraction of the total exposure of the
> brain to atherosclerotic emboli. I have no idea what the fraction is
> exactly, but I suspect it is less than 50 percent. Would you disagree
> strongly with that, any of you?
>
> DR. KOUCHOUKOS: No.
>
> MS. CHANG: No.
>
> DR. EDMUNDS: My case rests.
>
> DR. TRACY: Thank you.
>
> We\'ll go around the table with panel members to allow them to ask any
> questions they have for the sponsor, and we\'ll begin with Dr. Pina.
>
> DR. PINA: I have a question about the renal dysfunction. I see your
> definition of renal insufficiency being an increase of greater than 2
> or 50 percent increase, and I may have missed it here, but do you
> actually have the values of the creatinines? Do you have the mean
> values\--because so many things happen around surgery with drugs that
> we give that can alter renal function back and forth, and yet to those
> of us who take care of these patients afterward, that is a very
> significant point, the rental function.
>
> DR. ALLEN: I think the important aspect of that is that it is 50
> percent above baseline. I think one of the things that the
> investigators wanted to put into this study is that if you start out
> at a creatinine of 1.8 and go to 2.0, it\'s not fair to count that as
> a patient who has renal insufficiency, but it is a 50 percent increase
> from baseline or any increase above 2 that is important.
>
> DR. PINA: But I can also do that if I give a lot of diuretics to a
> patient in a perioperative period.
>
> I would like to know what happens to those patients later. Do you have
> any followup after those 7 days about the renal function?
>
> DR. ALLEN: Actually, what you see is that renal function, as you well
> know, worsens after cardiac surgery. There were some patients who
> required dialysis, but renal function returns to normal.
>
> The beauty of this is that this was in a randomized trial, so the same
> variables like did you start Altase postoperatively, at a time when
> you are diuresing a patient. You make the assumption\--and it is the
> reason you do the randomized trial, to allow for those variables to be
> adjudicated.
>
> DR. PINA: My point about followup with the renal function is it may
> help to differentiate the things that are strictly just the drugs that
> we do, or is it really emboli events to the kidneys, which may not
> result.
>
> DR. ALLEN: I guess I don\'t know that our data can help you answer
> that. All I know is that in a randomized trial, when you look at the
> safety endpoint, one of the endpoints in the composite was renal
> insufficiency, and you can\'t make a statement that renal
> insufficiency was significantly reduced. Only when you look at the
> higher-risk patients do you begin to see trends or ticks in favor of a
> reduction of renal insufficiency. But you have to assume that if you
> did everything identical in the two groups except one got a filter and
> one didn\'t, and you see the impact that renal insufficiency has on
> length of stay\--and you know that from your clinical experience\--in
> our situation, if you had renal insufficiency in our study, your
> length of stay was almost 15 days compared to 7 if you didn\'t have
> renal insufficiency. So it does have a dramatic impact.
>
> DR. PINA: I have no further questions.
>
> DR. TRACY: Dr. Ferguson?
>
> DR. FERGUSON: First, I want to congratulate the presenters, both your
> group and the FDA, for very lucid presentations.
>
> I have a couple of questions that relate to the particulate matter.
> The difficult is, as has been mentioned many times before, that we
> don\'t know what the denominator is, whether in the total spectrum of
> open heart surgery on a person who has atherosclerosis or some clot in
> the ventricle, whether a total screen would capture 1,000 particles,
> 500,000, whatever. So that is of a little concern, and I will get back
> to it in a second, relative to the time that you deploy.
>
> But first I want to ask about in the Higgins above-5 group, did you
> note that there were more numbers of particles in that than you would
> expect? I missed that; I\'m sorry.
>
> DR. ALLEN: I think that\'s a very good question. to be honest, I\'m
> not sure we did that analysis. We looked at the Cleveland Clinic score
> that was prespecified in those papers, picked their number of 5 and
> used that number.
>
> DR. FERGUSON: You would expect that would be the case. And that gets
> to my second question, which is that the instrument was not stressed
> to the max, if you will, because it was not purposely p ut in the
> kinds of aortas that everybody is seeing today. I think that\'s a fair
> statement\--or is it?
>
> DR. ALLEN: Yes, sir, and part of the exclusion\--although we didn\'t
> specifically exclude patients with, for example, Grade 4 aortas\--the
> exclusion criterion is that if you did your stronotomy and opened the
> patient, and it was an aorta that the surgeon did not feel that he
> could clamp or wanted to clamp, then, patients were excluded.
>
> So you are absolutely right, it did not necessarily even apply to the
> worst patients.
>
> DR. FERGUSON: The issue, then, for us is that\--I don\'t know how we
> would approach this, and FDA will tell us\--but this obviously is
> going to be used in the very severe aortas all the way up to the
> porcelain aorta.
>
> Nick, do you want to respond?
>
> DR. KOUCHOUKOS: Well, there is certainly the potential to use it in
> those patients. I think it would depend on the comfort level of the
> individual surgeon. But I see no reason why it would not be used in
> severely atherosclerotic aortas. We didn\'t encounter many patients
> who fell into that category by virtue of the patient group that we
> were elected to study.
>
> DR. FERGUSON: It gets to the disruption issue and whether there are
> going to be more disruptions in that group. I suspect there will be,
> because you say they\--that gets to my next question, if I could go on
> to that, and that is you have had more experience with epi-aortic ECO
> than anybody in the world, I suspect. Have you seen these disruptions
> in the series that you did prior to this study?
>
> DR. KOUCHOUKOS: One of the interesting things about epi-aortic
> scanning is that we have been using it for a long time, but we never
> for the most part until we began this study or until we became aware
> of some other publications did another scan after the completion of
> the procedure. You see, that\'s the difference with this study and how
> we have come to identify these endothelial disruptions.
>
> The point I made earlier is that it is quite likely that if we did
> epi-aortic scans on patients after the procedure, we would have found
> these endothelial disruptions a long time ago.
>
> DR. FERGUSON: So my next extension of that would be in your opinion,
> the group\'s opinion, should epi-aortic scanning before and after use
> of this device be recommended in the use of the device.
>
> I know that a lot of people don\'t use epi-aortic scanning, and I
> understand the ramifications there, but from a safety standpoint, I am
> just bringing that up.
>
> DR. KOUCHOUKOS: Currently, epi-aortic scanning is not standard of
> care, and it is my impression that it probably won\'t be for the
> foreseeable future. And based on what we know about the outcomes of
> the patients who develop endothelial disruptions, I would say it would
> not be necessary.
>
> DR. ALLEN: I think as a side that Dr. Ferguson did not use epi-aortic
> scanning\--we do 1,800 pumps a year at our hospital, and epi-aortic
> scanning certainly is not standard of care by any means. My personal
> belief and how I would use this device, epi-aortic scanning is not
> additive.
>
> The thing that I would\--
>
> DR. FERGUSON: If the disruptions are only seen with epi-aortic
> scanning, and if most people in the study didn\'t use it, you don\'t
> know what the real incidence of that is. That\'s what I\'m getting to.
>
> DR. ALLEN: I think, though, that the corollary to that is that we did
> see endothelial disruptions, and\--
>
> DR. FERGUSON: You did with\--
>
> DR. ALLEN: \--with epi-aortic scanning\--and you are right, those did
> occur\--but I think you have to put that in the clinical context of
> what those mean, and the two endothelial disruptions that were
> repaired at the single center very early on in the series were\--as
> Dr. Kouchoukos said, there was really no historical background as to
> what those meant, and they acted upon their\--I won\'t say clinical
> inexperience\--but their lack of historical background about them.
>
> The 10 endothelial disruptions that were subsequently identified by
> surgeons, none of those surgeons acted on those, because they had been
> educated and kind of knew now what they were seeing, and they didn\'t
> overreact to\--I won\'t use Dr. Edmunds\' term\--but as an
> overinterpretation of a very sophisticated imaging technique.
>
> DR. FERGUSON: I understand the data very well. The next question is
> what percent of the sites used epiaortic scanning before and after,
> because that to me would be the gold standard to really define whether
> this is going to turn out to be significant.
>
> DR. KOUCHOUKOS: Someone can provide me with the exact number of
> patients who had scanning in this study, but I think it is over\--is
> it 500 or thereabouts\--
>
> MS. CHANG: It\'s over 500.
>
> DR. KOUCHOUKOS: So about 500 of the patients had epiaortic scanning.
> And again, I think it is important to emphasize that 78 percent of
> these endothelial disruptions were not seen either by the operating
> surgeon or by the anesthesiologist, who is taking perhaps a little
> closer look at these ecocardiograms intraoperatively. They were not
> recognized. They were only recognized by the core laboratory.
>
> DR. FERGUSON: I see. Thank you.
>
> That\'s all I have.
>
> DR. KOUCHOUKOS: Four hundred and nineteen patients had epiaortic
> scanning.
>
> DR. TRACY: It\'s exactly 12 o\'clock now, so at this point, let\'s
> take an intermission for lunch and resume at 1 o\'clock.
>
> \[Whereupon, at 12 o\'clock p.m., the proceedings were recessed, to
> reconvene at 1:06 p.m. this same day.\]
>
> AFTERNOON SESSION
>
> \[1:06 p.m.\]
>
> DR. TRACY: If everybody is ready, I\'d like to resume the open
> committee discussion.
>
> Dr. Ferguson, were you finished with your questions?
>
> DR. FERGUSON: Yes, thank you.
>
> DR. TRACY: Okay. I\'ll pass it on, then, to Dr. DeMets.
>
> **Open Committee Discussion - Continued**
>
> DR. DeMETS: Thank you.
>
> Some of the questions I had have either been addressed earlier or
> addressed in the questions, but I still have a coupe more.
>
> Could you tell me a bit more about the rationale for the particular
> delta, the 5 percent that was decided? Obviously, that\'s very
> critical in the size of the study you came up with and the goal that
> you were after. So could you comment on how that rationale went?
>
> DR. ALLEN: Dr. DeMets, I apologize, but if I could have Dr. Kuntz
> answer your questions, I would appreciate it.
>
> Thanks.
>
> MS. CHANG: Dr. Kuntz can provide more detail, but that delta was
> decided on after several meetings with the FDA, and it was mutually
> agreed upon.
>
> DR. DeMETS: Okay. So this was not something that was based on clinical
> considerations or what would be important to rule out as a safety
> issue, or\--
>
> MS. CHANG: Not being a statistician, I\--
>
> DR. DeMETS: Well, it\'s not a statistical question. It\'s actually
> what clinical difference do you want to rule out, and I\'m just trying
> to understand how the 5 percent was arrived at. There are a lot of
> statistical implications about that, but how you got to that decision
> is what I\'m trying to understand.
>
> MS. CHANG: The delta of 5 percent.
>
> DR. DeMETS: Why 5 percent.
>
> DR. KUNTZ: The deltas are always inexactly determined in general, and
> I think that in our decision, with the baseline rate of 15 percent as
> established, 5 percent is already 33 percent delta, which is kind of
> on the high end of deltas to begin with, but has been in the range for
> devices in the cardiovascular arena. But I think that overall, the
> final arbitrator was that the clinicians felt that if they could
> remove emboli and have a plus or minus 5 percent overall event rate,
> they would accept that the device would remove the emboli, and that
> was the thing that we passed around, and that seemed to be the logical
> background to the 5 percent decision.
>
> DR. DeMETS: Okay. I asked you about the \[inaudible\] issue earlier;
> perhaps I jumped the gun. I am trying to understand as a non-surgeon
> what percent of patients who have this surgery in fact release
> particles. Is it 100 percent of them, or is it half of them?
>
> DR. KOUCHOUKOS: We don\'t know the answer to that question because we
> have had until now no way to assess that. Dr. Barbet, who is here, has
> done some studies with ecocardiography and transcranial doppler
> suggesting that there is a large number of particles. The issue there
> is that some of these particles are gaseous and some of them are
> particulate, so it is difficult to tell.
>
> DR. DeMETS: Well, my question actually has two parts. One, when it is
> released, how much is there in a patient, but how many patients is
> it\--is it almost always? Is it rarely? I don\'t know as a
> non-surgeon.
>
> DR. KOUCHOUKOS: Well, this study would suggest that almost all the
> patients release\--or, at least over the age of 60\--release some
> particulate matter, and it is a spectrum, obviously, depending to a
> great extent on the severity of atheromatous disease in the ascending
> aorta would determinate how many particles and their size are
> released.
>
> DR. DeMETS: The second part of the question which is important is
> given that they are released, what percent does this device capture.
> And at least in the FDA review, there was a suggestion that if you
> average 5 to 5.6, whatever it was, and it was 25 to 30 particles, that
> suggests a 20 percent or so capture rate. Is it higher or lower than
> that, because if there is a lot of it, and you aren\'t getting much of
> it, then, what are you really accomplishing, I guess is what I am
> trying to understand.
>
> DR. KOUCHOUKOS: Well, again, it is hard to say. This filter is
> occlusive, so theoretically, at least, it should capture all of the
> particles that are released proximal to where the filter is located.
> So we would think that the capture rate should be high.
>
> DR. DeMETS: Okay, thank you.
>
> Another question is that this trial obviously is not blinded, and when
> you are trying to establish equivalence, or at least safety
> equivalency, one of the challenges is always that you have to do a
> high-quality study. If you don\'t do a high-quality study, then it is
> easy to show or easier to show two things being equivalent, whatever
> you define as equivalent.
>
> So my question is given that this is clearly an ongoing study, what
> comments can you make about that there wasn\'t some bias between the
> two procedures, if you will. I\'m not sure it is possible to introduce
> bias, but at least the potential seems to me to be to do that. So can
> you help me on that a little bit?
>
> DR. KUNTZ: Yes, sir. It\'s an excellent question.
>
> In any study where we are using a device, especially a surgical study,
> it is impossible to blind because the ethics would make it a sham and
> impossible.
>
> So most of the time\--and this goes to the question about our endpoint
> per se\--the endpoint had always been focused on safety. And we talked
> earlier about the fact that we had included the myocardial infarction
> part because that is a safety endpoint that you would be interested
> in\--not necessarily an efficacy endpoint, because the filter is north
> of the heart there.
>
> But the bottom line is that the components of the endpoints were all
> hard endpoints, that is, they could be determined by an external
> adjudication committee that would hardly be malleable by someone who
> had a conflict of interest. That is, myocardial infarction is a new
> enzyme elevation or change in the EKG, death is death, stroke is
> stroke. These are very hard, nonsubjective endpoints, and they tend to
> help minimize the influence of bias of unblindedness.
>
> So we tried to make sure that the constellation of \[inaudible\]
> endpoints were in fact hard endpoints, none of which would be too
> subjective or that would lend itself to too much bias.
>
> DR. KOUCHOUKOS: Can I amplify on that for just a moment?
>
> DR. DeMETS: Sure.
>
> DR. KOUCHOUKOS: The examiners for the neurologic events were blinded
> as were the patients. So at least the neurological assessment as
> blinded.
>
> DR. DeMETS: Well, I think that to your credit, you worked very hard on
> that end of the process. Again, I ask the question as a non-surgeon,
> but one can imagine that if you had a bias about a device, you could
> be more careful or more careless, if you will, in actually doing the
> surgery and therefore artificially introducing one group looking
> better than the other. And like I said, maybe that\'s an ignorant
> question for a non-surgeon, but the issue is how you deliver it also
> affects\--even if you have everything blinded, and the ascertainment
> bias is minimized\--how you deliver the therapies can also introduce
> bias, and I\'m just trying to understand that process.
>
> DR. ALLEN: Let me give you a real example where what you are saying
> could be totally true. Let\'s say, for example, as a surgeon, I
> randomize my patient to not a filter. I could change my technique, for
> example, of the operation and do less proximal anastomosis or, for
> example, not use a side-biting clamp, or do things that might do what
> you are saying; but you will recall that in the demographics, we
> really specifically looked at those things, so that the things that
> the operator could vary that might impact the outcome, such as doing
> T-graphs off the mammary instead of putting them on the aorta, were
> not occurring, or not using a side-biting clamp, were not occurring.
>
> It is a very valid question, and I think the size and scope of the
> study, we did the very best job we could, not only from a design
> standpoint but then from an analysis standpoint of the operative data,
> to ensure that that wasn\'t going on.
>
> DR. DeMETS: Okay. I think that answers most of the questions I
> had\--and I still struggle with the issue of the clinical relevancy in
> the surrogate, but I\'m not sure what you can say that you haven\'t
> already said.
>
> Thanks.
>
> DR. TRACY: Dr. Aziz?
>
> DR. AZIZ: I just have a few questions, some sort of technically
> related.
>
> When I look at the cannula, you have the side arm, and when you
> cannulate, do you get air in that side arm, and how do you de-air
> that?
>
> DR. ALLEN: The concern about air comes from two things, primarily in
> that the filter is set in a heparin solution and then retracted up
> into the device. That still doesn\'t ensure that there couldn\'t be
> air within this cannula\--
>
> DR. AZIZ: But when you initially cannulate, when you put that cannula
> in right away, the first time around\--
>
> DR. ALLEN: You de-air by taking\--there is an opterator that goes in
> the sideport, and it is de-aired through that, through that one-way
> valve, so when you pull that out, the opterator allows the air to
> flush out, and then, the cannula itself is de-aired as I described
> earlier, with venting through this air release plug.
>
> The opterator also has the little\--I call it an air release plug\--it
> is the little wet plug that allows the air to go through it, so it
> actually vents through that plug when you put it in.
>
> DR. AZIZ: And that filter comes up at the time that you have taken the
> aorta cross-clamp off, so whatever is there in the ascending aorta,
> you capture.
>
> DR. ALLEN: Right. The filter is inserted and deployed right before you
> take the cross-clamp off.
>
> DR. AZIZ: So at the time that the protamine is being given, this
> filter is down, or is the filter mesh still up?
>
> DR. ALLEN: No. The filter has been withdrawn, and most of the time,
> patients have been decannulated. In my center, we decannulate before
> we give protamine. But if you leave your cannula in when you are
> giving protamine, the filter has been withdrawn.
>
> DR. AZIZ: It has been withdrawn. All right.
>
> Let me just ask a few more questions, then. When you were giving your
> talk, you showed, obviously, two extremes\--one with the flap of the
> aortic dissection, which I think anybody could see. The other
> side-by-side sort of TE, the surface ECO that you had, there were
> two\--one that had these strands sort of waving at you\--it could be
> fibrin\--but the other one\--and maybe we could have one of the ECO
> guys look at that with us\--it seemed to me like there wasn\'t a
> disruption in the intima, but that there was a gap or a gray zone in
> the actual media itself.
>
> Could we look at that?
>
> DR. ALLEN: Dr. Weissman, who was our\--while we are teeing that up, if
> you would like us to show that, we can have Dr. Weissman go over that
> specifically, and Dr. Kouchoukos might comment on that since he does
> an extensive amount of epiaortic imaging.
>
> DR. KOUCHOUKOS: All of these ECOs were reviewed by Dr. Weissman, and
> he indicated to me and I think will indicate to you if there is any
> question about it that there are no medial injuries at all that were
> identified. These were all endothelial or intimal injury.
>
> DR. WEISSMAN: That is correct.
>
> I am Neil Weissman, and I was the director of the ECO core lab for
> this study. I am a cardiologist at Washington Hospital Center.
>
> I have no financial conflict of interest; they gave a grant to the
> hospital for my work on this.
>
> There have been a number of different points brought up, and I think
> they have been answered very well, methodological issues and the
> extent of these endothelial disruptions and what they look like. So as
> we boot this up, let me just go through a couple of those things.
>
> DR. AZIZ: Sure.
>
> DR. WEISSMAN: People are asking about the methodology, and the
> methodology\--and I wrote the protocol\--was to do the scanning in a
> transverse manner, starting right proximally and capturing proximally
> at least 5 beats, and then moving one centimeter at a time, capturing
> 5 beats one centimeter, and so forth. So it was pretty methodological.
> And then, you do transverse imaging across the ascending aorta.
>
> As that was done, it had to be annotated on the screen or verbally to
> let me know where they are, and that\'s how we got location
> information.
>
> What you saw\--were you referring to this picture or earlier on\--
>
> \[Slide.\]
>
> DR. AZIZ: There was another one.
>
> DR. WEISSMAN: Yes. I think one of the things\--I don\'t know if it
> came through completely\--was that this is the more typical thing,
> which I have to admit I have trouble seeing here. There is a little
> wiggly right over there\--and you have got to turn the lights down.
>
> These images in the core lab were reviewed three times\--once by a
> technician, who would write down their preliminary results; then,
> independently by me; then, after I reviewed it, I looked at what the
> technician said to see if I missed anything and went to the spot where
> the technician thought they might have seen something to see if I
> missed anything.
>
> That is why I think 78 percent of these things were not seen by the
> anesthesiologists or the surgeons at the time.
>
> So I think the terms used here\--\"strands\" and \"dings\" and
> \"footprints\"\--are all pretty accurate.
>
> \[Slide.\]
>
> DR. WEISSMAN: So this is worst case scenario here. Where you see that
> thing sort of flipping is definitely among the worst case scenario.
> These, you could see from across the room on a projection with the
> lights on, okay? This was not the typical thing.
>
> So, show me what area you are concerned about?
>
> \[Dr. Aziz indicating.\]
>
> DR. WEISSMAN: Actually, you can tell that that is coming away from the
> wall. Right there, you see it is coming away from the wall. That is
> not even part of the wall. The intima is that very light ECO within
> it. The intima there is probably on the order of 2 or 3 millimeters
> thick, and it is the ECO-density of the flap that is being lifted up.
>
> That is essentially a monolayer, because the intima is so thin that
> you aren\'t seeing it. That is extra-aortic that you are seeing that
> little lifting.
>
> DR. AZIZ: Okay, good. Again, now that in a sense we have identified
> that you do have these endothelial disruptions, in my own mind, apart
> from the sites where you have an aortic cross-clamp on them, it could
> happen either in the control group or in the other group, but in the
> group where the filter is in place, how do you think that is causing
> that? Do you think it is the tip of the sheath that you are putting
> in, and is it occurring at the posterior wall of the aorta?
>
> For me, that is an important issue.
>
> DR. WEISSMAN: And I\'m going to defer\--since I was not in the
> operating room, I\'m going to defer that to the surgeons to comment
> on. Again, the results show that there were these little disruptions
> distributed along the whole ascending aorta. To conjecture how they
> arose, I\'m not going to do that; I just read the images.
>
> DR. KOUCHOUKOS: One has to assume that some of these were caused by
> the filter itself, although clearly not all of them were, even in the
> filter groups, because we saw them distributed in areas where the
> filter was not located.
>
> The metal rim of the filter, it is conceivable, could create a small
> intimal disruption, and that is probably the explanation for why they
> occurred.
>
> DR. AZIZ: But clearly, the goal of the filter is to prevent the emboli
> going upstream when you take the cross-clamp off. But I think as was
> mentioned in the FDA presentation, you could envision where
> particulate matter is caught in that mesh. You take the aortic
> cross-clamp off, and blood from upstream obviously hits the mesh on
> the other side and dislodges particles going downward, and maybe that
> is what is responsible for the Q-wave MI.
>
> What do you think about that?
>
> DR. KOUCHOUKOS: It is theoretically possible, and I think that is
> one\--it is fortuitous that we didn\'t look at myocardial infarction,
> but again, we found no difference in the prevalence of myocardial
> infarction\--
>
> DR. AZIZ: But theoretically, it doesn\'t protect against that, and it
> could predispose to something going in the reverse direction.
>
> DR. ALLEN: Actually, I spoke with Dr. Ferguson, and the design of the
> filter is a windsock design. Myocardial infarction was specifically
> put in as a safety endpoint for concerns for that very point. But in
> designing that windsock which drapes down over\--it is like my son
> does when fishing for tadpoles\--you are catching them in the windsock
> that falls down below, and you wouldn\'t expect when you have that
> pressure change for that to blow it out of that windsock as you would,
> for example, if it were a flat filter, like a seine. And that\'s why
> it was designed like that.
>
> DR. AZIZ: Okay. I have just a couple of other questions.
>
> Clearly, the majority of patients\--we all do bypass cases,and again,
> the case mix here was mainly patients who came for bypass
> surgery\--patients who come in for valve operations, particularly
> aortic valve operations, obviously, you had more calcium and bits of
> material that could come off there. When you analyzed your particulate
> trapping, did you find that it was higher in patients having valve
> operations, aortic valve versus mitral versus\--did you look at that
> subset?
>
> DR. ALLEN: We did, and what we primarily found was that the vast
> majority of the histologic material that we have treated was
> atheromatous.
>
> There is a wide range of material such as calcific material, organized
> clot that looked like it came from LV or left atrial appendage. We
> didn\'t specifically see a correlation between if you had a valve and
> you had more, for example, calcium versus atheromatous.
>
> DR. AZIZ: Particularly in aortic valve.
>
> The other thing\--and I know you can\'t do it now\--but in the study
> design, the reason you decided not to use TCD monitoring was
> because\--
>
> DR. KUNTZ: I am not an expert in TCD monitoring, but we have discussed
> this with other trials. It is not clear even in carotid interventions
> that TCD monitoring can be very helpful, because the high-intensity
> transience that occurs with that occurs, for example, in every
> operation for carotid enterectomy, so it is clearly possibly an overly
> sensitive measure of high-intensity transience, whatever that is, with
> respect to ultrasound as a measure of emboli.
>
> Clearly, they do measure emboli, but they may be measuring other
> things as well, because it is so frequent. Now, there is a lot of
> interest in looking at transcranial dopplers, and you have to do
> bilateral transcranial dopplers during that, and I think that might
> have also been logistically a little bit difficult during the
> operation. But I think because of the lack of a good sensitivity
> specificity profile for that test per se, it wasn\'t used.
>
> DR. AZIZ: Looking at it, you could have seen, for example, compared
> with the control group\--just take the CABs, where you are operating
> up the aorta\--you might have seen less numbers. Clearly, it has been
> shown that there is a correlation between the number of hits you get
> on TCD and cognitive dysfunction.
>
> DR. ALLEN: I think the difference is it is hard to know\--we can
> actually see that certainly the filter doesn\'t capture air or gaseous
> emboli; it captures particulate matter. And I think that\'s the hard
> thing with transcutaneous dopplers, that it lumps everything as to
> specks on a spectrum, and whether it is a particulate material or a
> gaseous emboli, they all look the same.
>
> DR. AZIZ: One other thing\--did you see any correlation in people who
> did get these endothelial let\'s say injuries\--was there a
> correlation between the thinness of the aortic wall and the size of
> the aorta\--in other words, big, dilated aortas were more prone to
> getting it?
>
> DR. ALLEN: That\'s a great question, and actually, what we looked at
> was whether the size of the filter, which obviously corresponds to the
> size of the aorta, correlated to an increase or decrease in
> endothelial disruptions, and it didn\'t. It just wasn\'t correlated.
> So was a larger filter size more prone to causing endothelial
> disruptions\--no. Was a smaller filter size less prone\--no.
>
> DR. AZIZ: Thank you.
>
> DR. TRACY: Dr. Krucoff?
>
> DR. KRUCOFF: Let me just ask a couple of quick questions. First, you
> mentioned at the very beginning of your presentation, I believe, a
> number for the percentage of patients who were screened relative to
> those actually enrolled.
>
> DR. ALLEN: Yes. About 15 percent of patients who were screened were
> eventually enrolled in the study.
>
> DR. KRUCOFF: Do you have any sense of who the other 85 percent were or
> why they were\--were they eligible but just didn\'t want to be in a
> research protocol, or are we really talking about a patient population
> that comes from 15 percent of the open heart surgery universe?
>
> DR. ALLEN: I think there are a lot of reasons, and you touched on both
> of them. I think Dr. Kouchoukos\' slide showing the types of patients
> that cardiac surgeons are operating on any more, the cardiologists
> just don\'t send us patients who are low-risk, and this was a safety
> study looking specifically at low-risk patients, and although we
> enrolled a lot of patients, it took us 20 months to do that. Even in
> the low-risk group, there certainly would be some patients who opted
> not to do it, but quite honestly, the enrollment\--as surgeons became
> familiar with this device and saw what they were capturing, enrollment
> in the study was pretty accelerated, and surgeons wanted to
> participate in the study.
>
> DR. KRUCOFF: I also just wanted to ask\--and thank you for passing the
> model around, because that helped me compared to the pictures\--as I
> look at the actual retraction process\--and I want to ask you a little
> bit about the windsock design\--when that pulls back in, it seems to
> me that there is a point when it is partially retracted where not the
> tip of the windsock but the upper part is actually just kind of
> flattened. And I would worry about whether that was capable of dumping
> debris that was not down in the windsock but that was higher up. Have
> you all\--and I just wasn\'t aware, at least in our panel pack, of any
> sort or bench-testing or preclinical modeling that has been done to
> see at what point or what size particles would be dumped rather than
> captured.
>
> DR. ALLEN: It is a preclinical test, and I\'ll let Jean speak to that.
>
> MS. CHANG: Yes. We did extensive preclinical tests, and our
> \[inaudible\] with the panel package includes the clinical information
> there. Our preclinical test was with little polyester beads,
> polystyrene beads. They are like little pinballs, so that when you do
> this, when you capture, you measure percent capture. And our capture
> rate was well above 80 percent.
>
> DR. KRUCOFF: Eighty percent. Are these sticky beads?
>
> MS. CHANG: No. So it is worst case.
>
> DR. KRUCOFF: Because one thing that I take\--and this is from looking
> at your own pictures\--is that a lot of the particles that you
> photographed are not down in the windsock; they are up in the sort of
> billowing part of the material. When I look at these pictures, and
> just thinking about what sticky particles, lipid particles or thrombus
> particles\--there is no question that when you get the big one in
> here, that\'s down at the tip of the windsock, but a lot of these
> others are not.
>
> DR. KOUCHOUKOS: When these were removed, the technician who was in the
> operating room was responsible to collect it, to flatten it out, and
> to display it; and I suspect that part of that is a flattening effect
> that was done so that we could get a photograph of the material in the
> filter. So it is partially related to that.
>
> To the question about possible loss of material, the filter is removed
> after 20 or 30 minutes, so we would surmise that most of the
> embolization would have occurred, so it\'s possible that we missed
> some of the material that might have passed through the filter as you
> are removing it, but I think the probability of that resulting in the
> loss of a large number of particles would be very, very strong.
>
> DR. KRUCOFF: Okay, I take your point, Dr. Kouchoukos. I was just
> sitting here looking at this and was thinking about, for example, some
> of the pressure shifts that Dr. Swain described, and if that was
> actually not trapped down in the tail but was sitting up in the
> higher, whether a sudden shift of pressure would dislodge it and do
> something else.
>
> I think most of my comments have been mentioned. I think the real
> issue here is a denominator one. In a very complex array of end organ
> problems, and even the precedents that Dr. Kuntz mentioned in the
> SAFER study, where the PercuSurge device was used, actually, there was
> no actual or even attempt to measure particulate capture in that
> study; that was driven entirely by a clinical measure of an end organ
> whose effect could be imputed to probably particle capture, but
> actually, it was purely a clinical measure\--and the IIb/IIIa is the
> same thing. We all sort of suspect in the angioplasty environment that
> we may create particulate matter that is responsible for end organ
> wounds to the heart, but the fact that a IIb/IIIa inhibitor corrects
> the wounds to the heart to some degree, or that a distal protection
> system in a vein graft protects the wounds to the heart, we have never
> really directly measured the role of particles. And what you all deal
> with in the brain and renal failure and all of the end organ effects,
> again, I think has been clearly recognized as multifactorial. Some of
> that is probably particulate embolization, and some of it is probably
> noncirculatory arrest and predisposing factors and transient
> hypertension and everything else in the world that comes with that.
>
> So I think that even if we start with the end organ denominator where,
> obviously, from a patient misery point of view, you would love to find
> a better way of bringing patients through open heart, the particulate
> component may only be a subset of that.
>
> And then, my difficulty with the other denominator is that, based on
> your data, it sounds to me like at least 96.8 percent of patients who
> undergo open heart surgery have something capturable in a filter, and
> certainly, 96.8 percent don\'t have measurable end organ effects. And
> again, there is no question when you look at a thrombus as huge as the
> one you have pictured in one of these pictures, you\'ve got to believe
> intuitively that you have benefitted the patient by pulling that out
> of his body rather than letting it go wherever the heck it was going
> to go.
>
> Ultimately, sorting this out is tough, and I think that point has been
> made.
>
> And then, the safety issues become more preeminent, because understand
> what is efficacy is hard.
>
> One suggestion that I would like to amplify as my last comment is if
> you could in fact correlate\--and this is just speaking from my own
> seat\--but if you could correlate that descriptors that you would
> think, prospectively, for a patient preoperatively, would identify a
> higher likelihood of having an embolic untoward event, whether they
> are morphologic descriptors of the aorta or low EFs or whatever you
> would think would be the ones that would say this population is likely
> to have more particles, or more frequency of particles, or whatever,
> and correlate that in your own dataset to a higher capture rate of
> particles with the filter, to me, that would be at least a first step
> toward saying maybe what this filter is able to do is to take
> higher-risk patients\--and again, this is my question to the FDA
> statistician\--one of the things that I think is at least a possible
> interpretation of what Gerry actually did was to say that what you\'re
> doing is taking the highest-risk patients and creating a more linear
> risk by capturing more particles. It\'s just that we don\'t have the
> descriptors match or really know what the descriptors model would be
> to say are those really the higher-risk patients or is that just sort
> of an \[inaudible\] finding.
>
> I think if you could build that model somewhat, that higher risk of
> whatever you think would predict embolic events and a higher capture
> of particles is a correlation, then you could start to think about
> what would you look for in a smaller venue as a way of really showing
> a benefit to putting a filter in.
>
> I just want to acknowledge that what is very clear, particularly from
> our two surgeons presenting, is a clear desire to try to prevent these
> types of untoward events with an intuitively obvious kind of
> mechanical approach, but in the face of a real difficult trial
> planning environment to the point where I\'m not sure that this one
> study achieves everything that you would want out of it.
>
> DR. KUNTZ: Mitch, can I make a few points about your comments? I think
> I would actually like to amplify some of your points.
>
> If we look at the SAFER trial per se, there were actually two studies
> that demonstrated a relationship between the emboli and the outcome.
> There is the initial John Webb study done, where he actually counted
> the number of particles, and that was associated with the amount of
> CK-MB that was elevated. That was the pilot study before the SAFER
> study.
>
> The second one was done in my institution by Campbell Rogers and
> compared the amount of emboli removed by the EPI device compared to
> that by the SAFER device, showing that the devices were equivalent
> once you controlled for the amount of particles and their enzyme
> elevations.
>
> So we do start to see some connection between emboli and what is
> causing damage to the heart. The other thing about the SAFER trial was
> that the device that was used to remove particles, the PercuSurge
> device, compared to doing nothing at all, the main and only difference
> was that one device removed particles and one didn\'t, and there was a
> 50 percent reduction in MI.
>
> So I think that that is actually pretty solid proof that the emboli
> were measurable in their impact on the heart. It\'s about as solid as
> you can get, I think, from an 800-patient randomized trial.
>
> So we do know that when using the heart as a surrogate, as an organ
> that has small vessels, like all organs do, that can be clogged up by
> emboli that have necrosis and damage as demonstrated by IIb/IIIa
> inhibitor trials and so on, that means something to the organ with a
> readily available measurable outcome, that we actually do prevent cell
> death by removing emboli, at least in that \[inaudible\].
>
> So the next transition to say that actually capturing emboli in the
> body in general is not so much of a high-falluting notion or theory as
> something, as Dr. Marler mentioned earlier, like ECIC bypass or other
> things that are intuitive but maybe don\'t have as much connection.
>
> So I think the evidence is growing, and there are lots of different
> venues now for investigations in which the notion of putting a filter
> on a device is actually already intuitively being planned. For
> example, many carotid stents are now being packaged with filters where
> there is no attempt to look at the filter component part of safety; it
> just makes sense to put a filter on there, because emboli don\'t make
> any sense if they go to the brain, for example.
>
> The same is starting to be done with studies in the rental area as
> well.
>
> So I think there is a growing body of evidence that small emboli are
> not good for organs; in the heart, I think it is established; and as
> we start to look at other organs, that notion is starting to grow. And
> this trial was caught in the middle of that in having technology
> available for surgery using background information, like Dr.
> Kouchoukos had shown for years that this was a problem, and we were
> caught in the crosshairs of being able to demonstrate the emboli being
> removed with the growing idea that emboli can be measured in some
> organs but not in all organs, and potentially, if this trial were to
> be repeated in a year or two, maybe we would have much more sensitive
> measures. But that\'s kind of how we put that in perspective.
>
> DR. KRUCOFF: I understand, and I take many of your points, Rick. On
> the coronary distal protection, as you well know, there is still
> ongoing dialogue about occlusive and nonocclusive and whether there
> are other elements besides particles. I don\'t want to intimate for a
> second that there is any proof that particles are good for anything.
>
> I think the reverse side here, and particularly in a large vessel that
> feeds virtually every other vessel in the body, is what size of
> particles, how many of them, and at what cost is unfortunately where I
> think \"caught in the middle\" is probably a good phrase.
>
> DR. TRACY: Dr. Laskey?
>
> DR. LASKEY: When one gets to this end of the table, one had better be
> brief\--or insightful. I\'ll be both.
>
> \[Laughter.\]
>
> Rick, you can\'t compare PercuSurge and IIb/IIIa inhibitors in the
> same breath. I mean, IIb/IIIa inhibitors don\'t do anything for large
> embolic goobers, yet they decrease the rate of necrosis.
>
> So this is, I think, without being dismissive, a rare outcome of a
> very prevalent disease. Atherosclerosis is diffuse, and without
> simplifying this any further, if you do diagnostic catheterization,
> you take a wire out of the body that has been in the body for 30
> seconds, you are wiping of thrombi, you are wiping off platelets, you
> are wiping off clots\--and yet the rate of stroke or embolization or
> other horrible things during cath is so acceptable that we don\'t even
> think about it. So we are not thinking about putting filters on our
> diagnostic caths, but those clots are there\--let there be no debate
> about that\--and it is a question of how sensitive the test is to look
> for them. So if you do scanning EM on your guidewires, you are going
> to find it.
>
> And if we parlay that to where we are today, atherosclerosis in the
> ascending aorta is virtually present in 100 percent of the patients
> that you all operate on, yet the event rate\--thank goodness\--is
> acceptably low\--1 to 2 percent, maybe 3 percent adverse embolic-type
> event rate. Now, it would be great if that were zero, but I don\'t
> think that\'s why we are here today. But I think we do need to be
> careful about signal and noise and reducing an event rate which
> agreeably is low but could be lower.
>
> So I am not entirely sure what we are all about here, and we are
> putting an instrument to the ascending aorta purportedly with the aim
> of collecting debris, but it is in there transiently, it is in there
> at a moment in time that you just sort of arbitrarily said is the
> moment of risk, and yet introducing the trocar \[phonetic\] into the
> ascending aorta could just as well release debris.
> Case-in-point\--virtually every, single brachial arteriotomy I have
> ever done in a patient over 50 \[inaudible\] catheterization, you open
> the artery, and there is placque right there. I mean, it is a
> universally present disease in these patients, and yet the dread
> sequelae are fairly infrequent, and developing sensitive tools is
> critical\--you have heard that; I don\'t need to repeat that. Assays
> for efficacy are sorely needed in this. And certainly, capturing the
> universe of the period of risk is critical. I think you need to be in
> there for the whole period at which the patient is at risk, and that
> includes from the moment you instrument or manipulate the aorta to the
> time that you go on or off bypass and give protamine.
>
> Those are just more editorial-type comments, but that is what we are
> all grappling with here, and I\'m sure it has a lot to do with why we
> are not and may not ever, until we have developed an incredibly
> sensitive test, be able to demonstrate the efficacy of these tools.
>
> But my one question to you is why 75 percent. Why did you pick that?
> Why didn\'t you pick 95 percent? Seventy-five percent is so little to
> my mind, given the prevalence, the universal prevalence, of this stuff
> in these aortas. Why not go for a higher figure?
>
> DR. ALLEN: We certainly could have gone for a higher figure, and if it
> had been anything under 96.8, we would have met that higher figure.
> There isn\'t a historical background. We have never had the ability to
> place a filter in the ascending aorta before, so we don\'t know what
> those numbers are.
>
> I think Dr. Edmunds early on was quite astute when he said the device
> isn\'t designed to capture all emboli, but is it better to have a
> device that captures some emboli or just not have the device at all,
> and we let those emboli go.
>
> I guess that\'s the crux of the philosophical debate. I guess as a
> surgeon, having put this device in over 100 patients and seen what it
> pulls out, I\'d rather have something that I can use to pull out some
> of those emboli. You\'re right\--I\'d love to have a device that
> captured everything, but that\'s not what I have. I\'ve got a device
> that captures a lot of emboli, and that has intuitively got to be good
> for the patient, and as you pointed out, the event rates that we are
> measuring are so small that to power a study to show pertinent and
> important reductions in those event rates would require such a huge
> study that from a practicality standpoint, it is not reasonable. So
> you design the trial to capture particles and show the device is safe.
> And I think that we have accomplished that by meeting both of our
> primary endpoints.
>
> DR. KUNTZ: Just one statistical thing, too\--you have to have a little
> bit of room for your \[inaudible\] about the number that you\'re
> trying to show so that you can demonstrate that the number you have
> has a lower battery that is above 75 percent.
>
> DR. LASKEY: I understand that, Rick, but really, a device which is 75
> percent efficient is nothing that I would want to fiddle around with.
>
> I think that what we\'re talking about is efficiency on two levels,
> but certainly, the efficiency of retrieval\--we have no idea what the
> efficiency of retrieval is. Is it 2 percent? Is it 20 percent? Is it
> close to something on the order of 90 percent?
>
> Don\'t equate the measure of efficacy that you have here with the
> measure of efficiency of the device. We don\'t know how much of that
> stuff at risk of embolization is actually retrieved. Yes, 96 percent
> of your device have done so, but that\'s not the same as how much of
> the stuff which is at risk of embolizing is actually retrievable ergo
> how much do you lower the risk of embolization.
>
> Dr. White, it\'s all yours.
>
> DR. WHITE: I can\'t be insightful, so I will be brief.
>
> \[Laughter.\]
>
> I am intrigued by emboli protection. I am involved with emboli
> protection in multiple organs, as Rick knows, and I like the intuitive
> argument that I never saw an emboli that I liked. I think the problem
> is\--and you guys probably know this better than I do, but for the
> rest of our panel members\--as Dr. Laskey just said, taking five
> emboli out of circulation is a great idea, but not if 500 get by. And
> I think there is a threshold at which we would decide that there is
> efficiency or efficacy in taking those\--even partial prevention is
> better than no prevention\--but there is a threshold where the partial
> prevention meets the road, and that is, I think\--we have heard from
> multiple people who keep trying to get to this denominator.
>
> The only thing I found in the whole pack\--and tell me if I am wrong
> about this\--it is under agency review for us; I don\'t know where you
> guys have it\--it is under \"Summary of FDA Methods\" on page 3. At
> the very bottom, it says that you did an in vitro study with these
> 120-micron beads, and that your acceptance criterion was to capture 50
> percent of those beads. Am I\--I don\'t want to go faster than you can
> go\--it is Number 5 in the Agency\'s summary. I don\'t know where it
> came from in the primary pack. Do they have the Agency summary?
>
> DR. ZUCKERMAN: Yes. It is in Dr. Wentz\' initial review.
>
> DR. WHITE: On page 3\--do you see what I am referring to? It is Number
> 5 at the bottom of that page. And what it shows is that in vitro, I
> guess this is, if you said 50 percent was captured, and that was your
> goal, that was your acceptance rate. Is that what you set up?
>
> MS. CHANG: That was the lower threshold.
>
> DR. WHITE: So you would have been happy with a 50 percent capture
> rate?
>
> MS. CHANG: These were polystyrene beads. We were testing the worst
> case. So they were literally like pinballs.
>
> DR. WHITE: Yes.
>
> MS. CHANG: Now, in the body, the particulates would be more sticky. So
> yes, we chose that lower threshold\--this is based on initial
> bench-testing. Our values ranged from the large filters to small
> filters, so it was sometimes as high as 80, 90 percent.
>
> DR. WHITE: Right. The design itself looks to me like it would be
> better than 50 percent. If I put that in a plastic tube and blew balls
> to it, just as you mentioned with the windsock, we ought to capture
> those balls. So when you start to talk about the failure mechanism,
> the reason that you would fail to capture them, is that because you
> are not getting uniform deployment of the ring in the aorta? Are the
> balls sneaking around the ring? Why do you fail to capture a ball?
>
> MS. CHANG: There is a little bit of a teeny gap right here, so again,
> on the smaller filter, this gap percentage is smaller. In a larger
> filter, it is a lower percentage. And it is just the way the filter is
> deployed, because again, there is a little bit of\--
>
> DR. WHITE: Because the next question I have for you that again goes to
> the clinical arena is could the surgeons judge the adequacy of the
> deployment. For example, the only experience I have like this is the
> EPI filter, which is a nitinol ring. And we image that radiologically
> and actually find a reasonable number of times that we have to adjust
> that filter to get it to actually oppose the wall; otherwise, it cants
> and tilts, and we don\'t have apposition.
>
> Do you guys have any direct control over the apposition of this
> filter? Do you know if it is cocked, or do you know if it is\--do you
> know what I mean\--canted in one way?
>
> DR. ALLEN: I understand what you are asking, and I think the answer to
> that is that there is a tactile sense to the device that you can tell
> when it is certainly deployed, and when you are having problems with
> deployment, if you had a problem with deployment, that tactile
> sensation gives you that feedback, and you need to make adjustments.
>
> DR. WHITE: But you don\'t actually look at the ring. You are not
> seeing it; it is going through the wall of the aorta.
>
> DR. ALLEN: No.
>
> DR. WHITE: And your ultrasound\--Dr. Kouchoukos, when you image these
> with your imaging, can you actually see the ring on ultrasound?
>
> DR. KOUCHOUKOS: It would be very difficult, because the probe is a
> 7-megahertz probe that sits on top of the aorta, and it would be
> impossible, really, to effectively image that area. And TEE doesn\'t
> give you a good image of that particular part of the aorta, as you
> well know.
>
> DR. WHITE: And then\--do you want to say something else?
>
> DR. ALLEN: I just wanted to come back to your comment about do things
> go around. I think Jean talked about the small area at the top, but
> you all know when you look at femoral arteries or, as surgeons, you
> look at the ascending aorta, that these aren\'t perfect manufactured
> tubes, particularly when you have disease in them\--they have nooks
> and crannies and stalactites and stalagmites\--and placing the device
> down in here, you wouldn\'t expect to get perfect apposition of the
> nitinol ring to the inside diameter of the vessel wall.
>
> DR. WHITE: I agree, but that\'s the whole purpose of reaching the
> threshold where\--your argument which you are trying to make it, which
> is that without measurable efficacy, less emboli are better than more
> emboli. And I would like to get comfortable that we are taking out
> most of the emboli, because taking out one out of 300 million\--I
> wouldn\'t agree with your argument if you were taking out a vast
> minority of the emboli.
>
> The other thing is in sizing\--I notice that your device comes in 3 mm
> and 4 mm increments, and you size the aorta with a device that
> measures the outside diameter of the aorta. Have you looked at or
> measured any internal consistency among operators at being able to fit
> the aorta and get it right? Are you able to judge the right size of
> that aorta? How much do you miss? What is the variability there?
>
> DR. ALLEN: Actually, we make estimates of the thickness of the
> ascending aorta, and when you are sizing the device, you step down so
> that you take into account the internal diameter\--
>
> DR. WHITE: My question is is there any measurement of how accurate any
> given surgeon is, or between surgeons, at making the right choice for
> the filter in order to fit that aorta, because if you are going to
> have high-efficiency capture, you really want to be measuring very
> carefully, or at least be very on-the-money about the right size.
>
> Do you have any measurement of that consistency or accuracy or the
> ability to correctly deploy the filter?
>
> DR. ALLEN: I don\'t have specific measures where we measured how
> effective the surgeons were at measuring the device. The devices that
> you use to measure the size of the ascending aorta are graft-sizers
> that vascular and cardiac surgeons use every day, and to measure the
> size of the ascending aorta, it\'s not rocket science.
>
> DR. WHITE: But with a 3 mm sensitivity, a little bit of mistakes make
> for incomplete loops, and again, if we are talking about that less
> emboli are better than more emboli, I would want to know that you are
> accurately doing the best you can to screen all of those out.
>
> DR. ALLEN: I can just tell you that as a surgeon, I think I do a
> pretty accurate job of using the vascular sizers to tell me what the
> size of the ascending aorta is and in choosing the appropriate filter
> size.
>
> DR. WHITE: It would be an interesting experiment to actually do it in
> a model, even an animal model, and measure your emboli three different
> times or two different surgeons or take a couple of your fellows\--you
> could tell us that, \"Do you know what\--we have five guys do it, and
> it\'s an easy thing to do; this thing fits no problem,\" or you could
> tell us that there is a tremendous amount of variability between
> surgeons and your ability to capture these or fit this device
> appropriately.
>
> MS. CHANG: Dr. White, actually, I\'m sorry\--in Europe when we did our
> first cases in the early 1990s, we did that correlation, and that\'s
> how we came up with the aortic sizer. So we would have the
> surgeons\--these were the first 20 or so cases\--do the aortic sizers
> and also do MJ \[phonetic\], and they correlated.
>
> DR. WHITE: How did you measure that?
>
> MS. CHANG: I think they did imaging.
>
> DR. WHITE: They imagined the loop?
>
> MS. CHANG: The cross-section.
>
> DR. WHITE: With what?
>
> MS. CHANG: Epi-aortic.
>
> DR. WHITE: With what\--ultrasound?
>
> MS. CHANG: Yes.
>
> DR. WHITE: Okay.
>
> The only other issue is that, again going back to the efficiency, the
> filters only filter everything bigger than they are, and that\'s a
> debate that we all have about distal protection devices. If you choose
> a filter which is nice to use, and you can have flow and all those
> things, you have to give up everything smaller than the 120 microns if
> that is the size you pick, or if you pick a smaller pore size, you get
> problems with that as well.
>
> But that goes to the efficiency of fewer emboli, and that is that we
> really don\'t know that the big emboli are the problem. As you have
> shown in your graph, the smaller emboli block the smaller brain
> arteries. So you may be picking out the big chunks, and the little
> stuff is still causing a problem, which is why I think we get back to
> if there is a threshold where taking emboli out is good, then we would
> like to get some measure of that efficacy. That is why I think just
> the rationale for me that taking out some emboli is better than no
> emboli is difficult to get enthusiastic about.
>
> That\'s all I have.
>
> DR. TRACY: I have just a couple of quick questions.
>
> This study was specifically not done in people with very severe aortic
> disease, and yet it did show, whether these things are clinically
> relevant or not, more evidence for aortic disruption than not having a
> device deployed.
>
> What is there that tells us that if we move into people with much more
> severe aortic disease that we won\'t have greater consequences of an
> increased number of aortic disruptions? Why would it be safe?
>
> DR. ALLEN: If you recall the odds ratio table that I showed you at the
> very end of the slides, for example, in the higher-risk patients,
> there was a specific component there that looked at imaged placque
> what grade the aorta was, and there was a correlation between grades
> of placque versus whether or not an EDS was occurring.
>
> I can give you that assurance, that there didn\'t appear to be an
> increased incidence of EDS in patients who had worse aortas. What I
> can\'t come back to is that it is an assumption that more
> atheroembolism is generated in patients who have worse aortas\--but I
> can\'t give you the denominator, as Dr. Laskey and Dr. White have both
> asked.
>
> DR. TRACY: And the other question or comment I have is that there are
> other things that cause neurologic events. How do we know that the
> things that aren\'t getting by aren\'t the things that would be
> causing problems? I am struck by this lack of any kind of endpoint to
> look at that with.
>
> DR. ALLEN: I think the whole flavor of particularly the last several
> questions illustrates the struggle that the panel has with the
> intuitive notion that particle removal is bad, but the study, because
> it is a safety equivalence study, doesn\'t show this dramatic
> reduction in events. And it relates, as we tried to go through, and it
> is\--you want this device to be able to demonstrate a reduction of
> events, but as Dr. Laskey pointed out, the events that fortunately
> occur with excellent cardiac surgical care today are not that high. So
> to power and design studies that can appropriately measure those
> events is very difficult.
>
> I think the issue is that the composite events, or the events that
> comprise that composite, were chosen to look at the device as far as
> the safety standpoint, and that\'s how the study was powered. That\'s
> how the study was done, and as an investigator, I am pretty proud of
> how that study was done.
>
> DR. KOUCHOUKOS: I think it\'s also important to recognize that the
> stroke rate in 80-year-old patients is not 2 percent or 3 percent. It
> is more like 8 or 10 percent. And the prevalence of significant renal
> dysfunction is also higher. We did not have a large percentage of our
> patients in this study, for obvious reasons, who were in that
> category, but one can assume that it might be possible to demonstrate
> efficacy in this high-risk group because of the higher prevalence of
> both of these major complications.
>
> DR. TRACY: Dr. Aziz?
>
> DR. AZIZ: The size of the filter in the heart-lung machine is usually
> about 20 microns. The size of the pores here is about 120 microns, if
> I am right. In your testing and design before you came up with this,
> did you try filters with smaller pores?
>
> MS. CHANG: Yes, we did. We looked at 85-micron pores, and the issue is
> the back-pressure, which then starts to create arterial resistance. So
> the 120 allows for basically almost virtually no pressure drop between
> the filter, and also to catch particulates of a size that\-- again,
> Dr. Barbut and Yao \[phonetic\] did a study where they looked at
> embolic size with regard to neurologic outcomes, and there seemed to
> be a collection of larger sizes at about the 120 mark.
>
> DR. AZIZ: This is has obviously been available in Europe since 1998 or
> so. Outside the group of patients that we have discussed today, is
> there a general feeling that in the older patients that are being done
> there\--over 80\--that there has been a clinical benefit?
>
> DR. ALLEN: The short answer to that is yes, the European data would
> suggest that there is a risk reduction particularly in high-risk
> patients, but you\'ll note we haven\'t shown any of that data, because
> it is not randomized data. I think it is not appropriate data, and I
> think you have to stand on the randomized control data, but you asked
> the question, and\--
>
> DR. AZIZ: And that\'s published, or was that just an impression?
>
> DR. ALLEN: That\'s published data\--European Journal of Cardiovascular
> and Thoracic Surgery.
>
> DR. AZIZ: This is actually a question for future trials that involve
> neuro-protective sorts of mechanisms. Can the S-100 protein be used as
> a marker? Some people have done that for brain injury on
> cardiopulmonary bypass.
>
> DR. ALLEN: I can\'t\--Dr. Kouchoukos and Dr. Kuntz are both eager to
> answer that question.
>
> DR. KUNTZ: And I\'d love to hear Dr. Marler on that, because we would
> love to use something for carotid studies as well. I don\'t know if he
> knows about that.
>
> DR. MARLER: No.
>
> DR. KOUCHOUKOS: There is data in the cardiopulmonary literature, and
> Dr. Edmunds, who is the current editor of one of our journals, can
> probably address it. But it is a very insensitive marker in patients
> who are undergoing cardiopulmonary bypass with neurologic injury.
> That\'s the short answer.
>
> DR. EDMUNDS: The S-100 protein is a marker of neurologic injury, but
> it is also a marker of macrophage \[inaudible\] activation, and since
> these operations are all contaminated with field suction, reclaiming
> field blood, the marker is not a reliable index of neurologic injury.
>
> DR. TRACY: Are there any other questions from the panel for the
> sponsor?
>
> DR. MARLER: Could I ask one more question?
>
> DR. TRACY: Yes.
>
> DR. MARLER: I haven\'t heard much about the indications and the
> precautions, and we are asked about that. Could you walk me through
> your thinking on going from the selection criteria in the trial to
> what you are recommending as indications for use?
>
> It seems to me that the trial selected patients at, at least
> neurologically, a lower risk of events, and yet, it seems you are
> actually intending to use this for a much broader range of patients.
> Is that correct, and could you walk me through at least some of the
> exclusion criteria to explain why you wouldn\'t continue to apply them
> when it is actually used?
>
> DR. ALLEN: I think from a practical standpoint, the device, except in
> aortas that couldn\'t be cross-clamped or that the surgeon chose not
> to cross-clamp, you are right, the device would probably be more
> broadly applied.
>
> I think you do have an opportunity when you look at the subset of
> patients that were considered higher-risk that you saw some mitigating
> effect in those patients with the filter, so those patients were
> deriving a benefit.
>
> It is an inference, and I don\'t draw superiority in those
> patients\--I don\'t make that claim at all\--but it does allow us to
> show that there is a subset of higher-risk patients whom we certainly
> didn\'t harm, and actually, some of the data suggests that we saw some
> benefit.
>
> DR. MARLER: But I think you made reference that those patients at
> higher risk were excluded for obvious reasons from the trial, and they
> are not so obvious to me if you then intend to use the device in them.
>
> DR. ALLEN: The patients\--we specifically wanted to look at\--when you
> design a trial for safety, to demonstrate safety of a device, I don\'t
> choose patients who are going to have tons and tons of complications.
> If I want to demonstrate superiority, I choose a population that is
> going to have a lot of complications so I don\'t have to enroll as
> many patients, and I can demonstrate that.
>
> So the trial, for all the reasons that we have discussed\--and it is
> still a very large trial just to demonstrate that equivalency\--was
> designed in that fashion.
>
> There were patients, though, who were at moderate or high risk as
> measured by the Cleveland Clinic Score, 20 percent of our population,
> and in those patients, certainly the device was safe, and in that
> subset analysis, there may have been some benefit shown.
>
> So I think surgeons are going to have to use their judgment as to whom
> they are going to use this in. The only patients from an aortic
> standpoint who were excluded were if you couldn\'t cross-clamp the
> ascending aorta. If they met inclusion and exclusion criteria, and you
> got to the operating room, and the patient unfortunately had a
> porcelain ascending aorta, those patients weren\'t included.
>
> So I think some of the precautions you are asking me to come to,
> clearly, if you can\'t put a clamp on the aorta, you are probably
> going to have to try to figure out some other method to revascularize
> these patients, and the filter isn\'t going to be appropriate in that
> population, because it is obviously attached to a cardiopulmonary
> bypass cannula.
>
> DR. EDMUNDS: If I might just comment, I think the Higgins Score is
> almost irrelevant to this problem, because there are lots of ways to
> die, and the Higgins Score will be influenced by whether or not
> somebody has emphysematous \[phonetic\] lungs, and I can\'t see how
> this device is going to affect that\--and a lot of other factors. I
> think that local factors are the ones that are relevant here\--things
> that directly produce particulate emboli.
>
> DR. ALLEN: I don\'t disagree with you, Dr. Edmunds.
>
> DR. EDMUNDS: I hope not.
>
> \[Laughter.\]
>
> DR. TRACY: Dr. Krucoff?
>
> DR. KRUCOFF: I just have one question, really, to Dr. Allen and Dr.
> Kouchoukos, and accepting that this is not going to be a data-based
> answer. But if this device were approved and came on the market
> commercially, as two of the individuals who have obviously had their
> hands on it in human application more than anybody else, can you tell
> me just what ball park of your total clinical practice of open heart
> surgery you think you would use this thing in? In what percentage of
> patient would you actually pull this off the shelf and use it?
>
> DR. KOUCHOUKOS: Based on what we know from epi-aortic scanning, as I
> showed you, we know that the prevalence of atherosclerosis begins to
> go up at age 60 or 65. The cut-off in this study was 60. I would
> consider using it in every patient over the age of 60.
>
> In this study, we retrieved emboli in 96 percent of the patients.
> There is every expectation that as you apply this to older and older
> patients, we would retrieve more debris. So I would use it in any
> adult patient over the age of 60 undergoing a cardiac procedure.
>
> DR. KRUCOFF: And again, Dr. Kouchoukos, in a very broad sense, is that
> 30 percent, 50 percent, 70 percent of your practice?
>
> DR. KOUCHOUKOS: Well, it depends on an individual\'s practice, but in
> an average adult practice, that would probably encompass probably 85
> to 90 percent of patients who have cardiac surgical procedures.
>
> DR. KRUCOFF: Dr. Allen?
>
> DR. ALLEN: I\'m sure it\'s the same in your institutions. I don\'t
> have cardiologists referring me too many young, healthy patients
> anymore. Most of my patients are over the age of 64. The median age in
> my practice is 72.
>
> I would agree with Dr. Kouchoukos. About 20 percent of my patient are
> done off-pump. I am not a huge advocate of off-pump, but I use it
> selectively in appropriate patients, so you can already take my number
> down to about 80 percent. I am going to use it in a lot of patients.
>
> DR. KRUCOFF: So most of the patients in whom you would cannulate the
> aorta, you would use this device.
>
> DR. ALLEN: Patients that I would put on cardiopulmonary bypass and
> cannulate the ascending aorta, I think the device is very safe, and
> the stuff you see on the filter, it\'s hard to say that it\'s not a
> good thing to take these things out; so I would be using it pretty
> frequently.
>
> DR. TRACY: It\'s hard to say it\'s not a good thing to take it out,
> but it\'s not easy to say that it is a good thing to take it out.
>
> DR. ALLEN: Yes.
>
> DR. TRACY: I mean, we have very little that says it is a good thing to
> take it out. I\'d just like to make that point.
>
> DR. ALLEN: Dr. Tracy, you are absolutely right, and I think that gets
> back to the whole issue that it is a safety study and not an efficacy
> study.
>
> DR. TRACY: Right.
>
> Are there any other questions from the panel at this point?
>
> \[No response.\]
>
> DR. TRACY: If not, we\'ll take a 15-minute break and then reconvene.
>
> \[Break.\]
>
> DR. TRACY: If everybody would take their seats, we can reconvene.
>
> There have been a number of questions regarding the efficiency of this
> device at collecting whatever \"goobers\" it is collecting, and I
> believe the sponsor may have some additional information that might
> help us understand the efficiency of this device.
>
> MS. CHANG: Yes. We just got our bench test results from California,
> and the average in the bench test is 80 to 90 percent.
>
> DR. WHITE: Is that the experiment with the 120-micron beads?
>
> MS. CHANG: Yes\--the pinballs flying all over.
>
> DR. TRACY: And there were no studies done with something that was more
> similar to atheromatous or to blood clots; is that correct?
>
> MS. CHANG: Yes.
>
> DR. TRACY: All right. At this point, we\'ll start going through the
> questions that were posed to us by the FDA.
>
> **Questions for the Panel**
>
> DR. TRACY: The first question: The primary safety endpoint for this
> study was a composite of seven adverse clinical events detailed on
> this slide. The median followup was 7 days. Some facts from the study
> are: The observed overall composite event rates were 17.1 percent in
> the EMBOL-X arm and 18.9 percent in the control; the composite event
> rate for the EMBOL-X arm was shown to be equivalent or not different
> from that in the control; also as specified in the protocol, a
> separate test for a lower event rate in the EMBOL-X arm was not
> statistically significant; the EMBOL-X arm demonstrated a
> significantly higher incidence of aortic endothelial injury\--9.2
> percent versus 2.0 percent. Although these patients did not appear to
> have any short-term clinical sequelae resulting from these injuries,
> long-term effects are unknown.
>
> So the first question posed to us is: \"Do these data support the
> safety of the EMBOL-X intra-aortic filter?\"
>
> I am supposed to summarize the discussion, and I really have no idea.
> I think in terms of being equivalent, if that is equivalent to doing
> nothing, then, I suppose it is equivalent to doing nothing. I really
> don\'t know how to answer that question. I\'ll have to ask the other
> panel members if they can be more articulate than I on this question.
>
> DR. KRUCOFF: Isn\'t safety and issue of doing harm? I think from what
> I heard discussed, other than the scanning finding of the \"ding\" or
> whatever we are calling the little flap of tissue, which it seemed
> pretty unclear is related to any kind of clinical sequelae, it sounded
> like there was reasonable information to support that no harm was
> being done. The non-inferiority statistic actually also, to my
> understanding\--and David, maybe you can chime in\--implies that at
> least no harm is being done.
>
> DR. DeMETS: Yes. My assessment of that would be that it certainly met
> the criteria that were established for the clinical delta that you
> were after, and moreover, the rates are actually lower in the
> treatment arm; overall, the composite is lower; and when you examine
> the individual components, most of them are at least in the
> direction\--a few are in the wrong direction, but just by a little
> bit. So we would like to have more data on that, of course, but this
> is what you have.
>
> So for the issue of safety within the criteria that were set up, I
> think they have met those goals.
>
> DR. TRACY: Yes. I guess the thing that I\'m struggling with is that I
> question whether this was an appropriate safety endpoint, but it was
> what was predetermined to be the endpoint of the study.
>
> Bram?
>
> DR. ZUCKERMAN: Right. Dr. Tracy, I think multiple people have
> commented that in the year 2002, they might design a different-type
> trial, but we have to appreciate how FDA and the sponsor designed the
> safety primary endpoint when the trial was first designed. And I
> believe safety was really designed the way Dr. DeMets just summarized.
> They met the delta. The trends were in the right direction. And our
> third concern, which the panel has commented on, was that the aortic
> disruptions did not have significant clinical sequelae, and if that is
> the agreement of this panel, then, for our purposes, it has met a
> safety definition.
>
> DR. TRACY: I think it has met it in the patients that it was tested
> in. I don\'t think you can extrapolate beyond the patients who were
> tested. I don\'t think there are data that would support expanding
> into a different group of people, for example, people with greater
> degrees of aortic disease. There are no data that support that.
>
> DR. ZUCKERMAN: And I am glad that you mention that, because multiple
> panelists asked about that this morning, and that question of labeling
> is a critical one that we will get to in Question 4.
>
> DR. EDMUNDS: Yes, but this was a random sample of a population of
> patients that has been well-characterized and defined. The mean age
> was 71. So I do think that if statistics apply to anything, they apply
> to a set of patients that fit these descriptors.
>
> DR. TRACY: It applies to the patients that were included in this
> study. It doesn\'t apply to another type of patient. So I would agree
> with you. But that has\--
>
> DR. EDMUNDS: Other type of patients.
>
> DR. TRACY: Right\--that were not studied.
>
> Are there any other comments regarding this first question?
>
> \[No response.\]
>
> DR. TRACY: If not, we\'ll move to Question 2.
>
> \"The primary effectiveness endpoint in this trial was to demonstrate
> that 75 percent of the devices would capture at least one particle
> during elective CABG or single-valve procedures. This was demonstrated
> in the study. There was no demonstrated reduction in any category of
> clinical adverse event in this well-controlled patient trial.\"
>
> \"Please address the following concerns: 1) Can this method of embolic
> entrapment, from this study or elsewhere, be extrapolated to clinical
> efficacy?\"
>
> I think that the answer to that is that we probably cannot extrapolate
> beyond what data we have. We do see that it is efficiency in
> retrieving material from patients undergoing surgery. We don\'t have
> data that would support clinical advantage to that. We don\'t have
> data that it is harmful to retrieve this material. But I would be
> cautious about extrapolating on the basis of intuition.
>
> DR. LASKEY: I\'m not sure that we know it is efficient. We know that
> it does. We don\'t know the efficiency. So perhaps it\'s best just not
> to use that term.
>
> DR. WHITE: The confusion comes from the fact that 90 percent of the
> patients had some; so I think that\'s where you say that a high rate
> of recovery. But the number of total emboli that was recovered is
> unknown, and I tend to think of that as the efficiency of the filter,
> so it is an unknown efficiency rate.
>
> DR. TRACY: Okay. Good point.
>
> Are there any other comments on that particular bullet?
>
> DR. KRUCOFF: Well, there are sort of two parts\--clinical efficacy and
> efficiency. On clinical efficacy, it would seem like we were pretty
> consistently clear there is no demonstration of an obvious
> relationship other than thinking that emboli are bad. There is no
> relationship in the data to clinical efficacy.
>
> And the second part is really about effectiveness or efficiency of
> thrombi, and there, I think we have, as Chris said, the denominator
> issues.
>
> DR. TRACY: And the second part: \"Do these data support the
> effectiveness of the EMBOL-X intra-aortic filter?\"
>
> I think you are hearing comments on that that we don\'t know how much
> was missed that was not captured. There is no way to know what was not
> captured by the device.
>
> DR. FERGUSON: Does the fact that it captures a known quantity that we
> know about give them a plus? I think it does.
>
> DR. TRACY: I think the problem again is that we don\'t know what it
> doesn\'t capture. There is no bench data that tells us exactly what it
> doesn\'t capture with something that would be bioequivalent to human
> atheromatous material or clot.
>
> We know that it captures something, but we don\'t know if there is
> 1,000 times or one time or 10 times as much that is getting past the
> filter.
>
> DR. FERGUSON: But you are posing that as a negative, and what I am
> looking at is the positive, which is that it captures a known quantity
> that we know it captures over the non-use of the filter.
>
> DR. EDMUNDS: Yes\--you have distorted the question.
>
> DR. FERGUSON: No.
>
> DR. MARLER: I don\'t think he has. My concern is that my common sense
> and intuition tell me that using the word \"effectiveness\" and not
> meaning \"clinical benefit\" is distorting the question. Whether the
> filter pulls back objects or not, I don\'t think there is any
> question.
>
> DR. TRACY: Maybe the FDA can clarify what they are actually asking us
> here.
>
> DR. ZUCKERMAN: In an ideal world, certainly, we would have liked to
> have been able to say yes to clinical efficacy; it makes it a much
> easier decision for everyone concerned. But I think everyone agrees
> that those aren\'t the data that we have in front of us, so what we
> are looking for is expert clinical opinion. For example, the fact that
> we have this device, this tool, that can be used in cardiac surgery to
> take out a certain number of particles, for the cardiac surgeons on
> the panel, is that an effective device? We won\'t be able to give you
> the denominator, but we would like your clinical impression.
>
> Certainly for those who don\'t do this procedure every day, we may
> have a different impression, but we are interested especially in the
> cardiac surgical perspective.
>
> DR. EDMUNDS: Well, the term \"clinical efficacy\" is a very ambiguous
> term. It\'s a bad term. Does this method of embolic entrapment remove
> particulate emboli from the circulation? That is unambiguous. That\'s
> what the question should be.
>
> The second question is does it have clinical effectiveness, if that\'s
> what you want to ask. But you have got to have an unambiguous
> question.
>
> DR. ZUCKERMAN: Okay, then, how would you answer those two questions?
>
> DR. EDMUNDS: You would like me to answer?
>
> DR. ZUCKERMAN: Yes.
>
> DR. EDMUNDS: I\'d be delighted to answer. Do you want it in half an
> hour or less?
>
> DR. ZUCKERMAN: Yes.
>
> DR. EDMUNDS: It does remove emboli, and they have not shown any
> clinical effectiveness in this study.
>
> DR. FERGUSON: I would agree with that. I don\'t think we have data to
> support the clinical effectiveness. They have said that, and we have
> said it here, so that\'s easy to answer.
>
> But I do think that we still have to say that in the sum total of
> taking care of patients in the operating room, anything that you can
> do where you can prove that you are taking out this material, but
> anything you can do like putting a filter in the arterial pressure
> line of the heart-lung machine, and we see the material that is
> trapped in that filter, we know that that\'s a good thing for the
> patient. And I view this as the same sort of thing.
>
> DR. ZUCKERMAN: And, Dr. Aziz, do we have consensus there?
>
> DR. AZIZ: Yes, I think I would agree with the other two surgical
> members of the team.
>
> DR. TRACY: Okay. So I think you have heard the spectrum of answers on
> that. We don\'t know how much is left behind, but it\'s a good thing
> to take away something.
>
> DR. WHITE: Do you want to hear the other side of that argument?
>
> DR. TRACY: Absolutely. Dr. White?
>
> DR. WHITE: I think that that is not clear. I could put anything into
> this patient\'s body and have a few bits stick to it and say, \"Look,
> I got one.\" Is it a tool that takes out emboli? Yes\--I got one out
> of 150,000 emboli.
>
> My problem is\--I won\'t argue that 97 percent of these patients had
> emboli removed\--what I am concerned about is that I have no idea
> whether that is doing the patient any good. I think that I would feel
> much more happy with partial capture and a clinical benefit than to
> support the efficacy of a tool that may not have any benefit.
>
> So the question then is are we denying the surgeons a tool that they
> might want to use. I think that\'s a much more difficult question. But
> I don\'t want anybody to get confused that I have some understanding
> that the tool that removes some benefits is something that I could say
> is a good thing to use in the next patient that has bypass. I think
> that\'s the difference between that and the bypass filter. The bypass
> filter is very small; it captures lots of bits. The question of
> efficacy there is much more easily satisfied, because you can look at
> the other side of the filter and see what it misses. What these guys
> can\'t tell us is what is on the other side of the filter, what is
> being missed\--plus the filter is partially filterable, and there is
> disease distal to the filter that causes these events, both renal and
> neurologic, multifactorial disease. So I think we don\'t have a very
> good handle on this.
>
> DR. TRACY: I think these are very difficult questions to answer, and
> the problems are the difference between clinical efficacy, and I think
> the answer is pretty clear on that part that we don\'t have
> demonstrate of clinical efficacy, and the problem with effectiveness
> of the device\--it removes something, and the surgical feeling is that
> it is a good thing to remove something, and the other side of the coin
> is that we don\'t know if it is removing one one-thousandth or 90
> percent of what is there available to be retrieved. That is the
> ambiguity that I think\--
>
> DR. LASKEY: Can\'t we do better than that? It is so disingenuous to
> let us go on the record as saying that taking something out is a good
> thing. It\'s just so disingenuous, it makes me very uncomfortable.
>
> Suppressing PVCs is a good thing. It also kills people.
>
> I just can\'t accept that. Can we change the language? Taking
> something out is a good thing\--no.
>
> DR. EDMUNDS: Warren, we have got to put this problem in the context
> that it really is. Embolization to the brain has been known since
> Lee\'s paper in 1960. It has been a huge problem in cardiothoracic
> surgery with bypass since that time.
>
> The improvements that we made that allow us to have the cognitive
> deficits that we have today are small, incremental
> improvements\--heparin dosage, antifibrinalitics, protenine\--all
> those sorts of things. It is going to be incremental. This is just a
> little baby step, perhaps, but it is a step in the right direction
> because you are dragging out some garbage.
>
> I think you have to look at it in that context. That means that there
> is a lot of garbage still in there. We know that. But we are going to
> be taking it out spoonful-by-spoonful. That\'s what it has been for
> the last 42 years.
>
> DR. TRACY: I have the feeling there is not going to be consensus on
> this.
>
> DR. MARLER: No. I think that the question about whether it is good or
> not to remove the emboli in a way is kind of independent of this
> discussion. I mean, that could be answered by different studies or
> looking at the literature and forming an opinion that way, which we
> really have not done.
>
> I thought we were looking at the results of a particular trial.
>
> DR. TRACY: If we remove the question of whether it is good or not,
> then I think the answer becomes even more difficult, because if we
> don\'t assume that there may be value to removing it, we have an
> unknown percentage of something that is being removed, and it becomes
> even more difficult to answer the second bullet.
>
> So I think I respect the surgical opinion that removal of material
> that would otherwise have gone somewhere probably is a good thing,
> although we do not have that clinical efficacy answer.
>
> It is unfortunate that there is not a better endpoint in this study to
> look at. I\'m not sure we\'re going to get much farther than where we
> are with this question.
>
> DR. KRUCOFF: I\'ll just make one comment and probably end up having to
> change specialties, because I actually lean toward the surgical group
> on this one.
>
> I think it would concern me if we felt that these little intimal
> \"dings\" or that some other significant safety issue or that some
> technical element that really made you redo or do differently the
> basic procedure of cannulating the aorta were a part of this device.
> Then I would feel very conservative about all the issues that have
> been so much discussed, about whether pulling grunge out of the
> \[inaudible\] meant anything.
>
> I guess, based on our consensus on the first point, if there is really
> no significant safety issue\--and my understanding of the discussion
> this morning, including all of us surgeons on both sides of the table,
> is that you put this thing in, you cannulate the aorta the same way
> you would for another purpose, and you basically slide the filter in
> with a pretty straightforward\--essentially, with no real technical
> change from how you would do a routine open heart procedure\--then, if
> debris is bad, and you are pulling it out, is that the first
> spoonful\--it sounds to me like the surgeons from both sides of the
> table feel like it probably is. And it is very clear that we aren\'t
> going to see any answer to that question in the dataset. But if there
> is not a significant safety issue, then, to me, a lot of the judgment
> about whether or not to use this probably ought to come not from the
> panel but from a community of surgeons who do this in live patients,
> and the only way they can do that is if it is available.
>
> DR. TRACY: Other comments on this question?
>
> \[No response.\]
>
> DR. TRACY: If not, we\'ll move to Question 3.
>
> \"Do the study data support an appropriate risk/benefit profile?\"
>
> I think you have\--I\'m not sure what the question is, really.
>
> DR. ZUCKERMAN: Okay. Dr. Krucoff just gave an answer to the question.
> He is looking at the data in this study as well as general experience,
> literature, et cetera, to try to come up with a risk/benefit profile
> which he judges to be positive.
>
> We are asking for other comments. At the end of the day, one needs to
> cut to the chase. Is there enough data within this study and external
> data to agree with Dr. Krucoff\'s comments?
>
> DR. TRACY: I think you\'re going to hear the same kind of debate back
> and forth among the panel members. I think within the confines of the
> type of patient who was involved in this particular study, Dr.
> Krucoff\'s answer probably is the correct answer. But I would caution
> again not to extrapolate too widely, and I am having the sense that
> there would be wide extrapolation if the device were clinically
> available.
>
> DR. MARLER: I guess I can say that it\'s hard to compute a
> risk-benefit when you have no indication of any benefit. I am
> extremely cautious about, quote, \"approving,\" whatever that means,
> something for which there is no evidence of any benefit. And there is
> some risk\--we have discussed it\--and there were a lot of questions
> about whom it is going to be applied in.
>
> So I would say that you can\'t say that the study data support a
> risk-benefit profile because they don\'t support any benefit.
>
> DR. EDMUNDS: I think I can disagree with that. It does not support any
> clinically demonstrable benefit except that it removes a filter full
> of garbage, and that\'s a benefit.
>
> DR. TRACY: Accepting that on, basically\--at this point, we have been
> asked to accept that on intuition, and I have a hard time accepting
> that on the basis of intuition, because we still struggle with not
> knowing what got by. So it is very difficult, I agree.
>
> DR. WHITE: The problem is it only takes one piece to cause a stroke.
> You can get an endpoint with one piece. That is why it is hard to know
> that if you got 60 percent of them, there is a clinical benefit
> associated with that, when it only takes one to cause an endpoint.
>
> DR. EDMUNDS: I am just really frustrated. For 42 years, we have been
> doing open heart surgery, and we have known that we have been
> circulating emboli. We\'re going to do it tomorrow, with or without
> the filter, circulating emboli. So there is no argument that there are
> no more emboli going to circulate if you use this device. There are
> going to be lots, but there are going to be less. The amount less is
> what is on the filter. That\'s the benefit. It is not a clinically
> demonstrable benefit.
>
> They didn\'t measure clinical benefit in this study. They didn\'t say
> they measured it, they didn\'t intend to measure it. We can\'t hold
> them to that standard.
>
> DR. TRACY: I think it\'s a little more than that. I think it\'s the
> whole issue of what is not known about what gets by. That\'s a very, I
> think, unknowable thing. There is something appealing about removing
> debris, but we don\'t know how much is being removed.
>
> Dr. Laskey?
>
> DR. LASKEY: I think what Hank says is absolutely on the money. I would
> agree with it 100 percent. It is just unfortunate that most people
> when they hear \"risk-benefit\" think about clinical benefit. They
> think about the risk of harm, and they think about the risk of
> clinical benefit.
>
> So perhaps again, the language could be softened here somewhat. But
> \"benefit\" here needs to be strictly qualified that this is not an
> artifactual benefit, but it is a benefit in terms of the study, which
> is strictly defined as catching stuff on the filter. But it is not a
> clinical benefit. When people see \"risk-benefit,\" that\'s what they
> think of.
>
> DR. WHITE: Do you need to consider the potential risks because you
> didn\'t measure a clinical risk in these patients; are there other
> theoretical or potential risks? We had a lot of discussion about air.
> We had discussion about disruptions, use in people with more sick
> aortas.
>
> If we are going to hypothesize about a possible benefit, should we
> hypothesize about how potentially dangerous this could be if the
> device were misused?
>
> DR. LASKEY: Thank you, Chris.
>
> One point I wanted to mention is that we don\'t know that these
> disruptions are the triponine \[phonetic\] of cardiac surgery. We
> didn\'t know about triponine until we started looking at these very,
> very subtle markers of injury. I\'m not sure we know\--none of us
> wants to believe that they are bad, but they may be, and it may be a
> very subtle marker of injury that we just don\'t have a handle on,
> just like triponine was in the early days.
>
> So I wouldn\'t dismiss it, and I would certainly keep it in the mix. I
> agree with you.
>
> DR. TRACY: Dr. Ferguson?
>
> DR. FERGUSON: I agree totally with the concept that this question is
> bad in the sense that \"risk-benefit\" does convey something other
> than what we did.
>
> I think we have all agreed that the risk is no greater than the
> control in this, and the benefit is that it takes out some clot, which
> we know is bad. And that\'s a better way to put it, I think, than the
> way it is written.
>
> DR. TRACY: Are there any other comments on this question?
>
> \[No response.\]
>
> DR. TRACY: Does that satisfy your question, Dr. Zuckerman?
>
> DR. ZUCKERMAN: Well, I think it is important for the record to know if
> the other two cardiac surgeons agree with Dr. Ferguson\'s last
> statement, that if we more precisely define what we are trying to get
> at here, if they would agree.
>
> DR. EDMUNDS: Well, we are splitting hairs, and I have on my loop, so
> that first of all, it is not clots that tare being taken out. It is
> atherosclerotic debris, principally. And I don\'t think that we have
> demonstrated clinical benefit, but we have demonstrated a benefit, and
> we have discussed that.
>
> There is a risk. The risk is exceedingly low. It is the EDS risk. And
> while it isn\'t zero, it is the number next to zero.
>
> DR. AZIZ: I think\--how can I put it\--clearly, I think that those two
> things are both in a sense true, and I hope they are connected in the
> sense that we do believe that removing clot will give us reduced brain
> injury, and I agree with what Chris is saying that we don\'t know how
> much is getting through on the other hand, and you really don\'t need
> to have a lot going through.
>
> But to sort of crystallize it, I think the wording of this statement
> is a little fuzzy. I think that what one should say is that clearly,
> this device has some risks, but at the same time, it reduces some
> other risks\--namely, the risks associated with the lot.
>
> So I think I would agree with what Dr. Ferguson is saying.
>
> DR. TRACY: Okay. We\'ll move on, then, to the fourth question.
>
> We are being asked in this question to review the labeling. \"The
> labeling must indicate which patients are appropriate for treatment,
> identify potential adverse events with the use of the device, and
> explain how the product should be used to maximize benefits and
> minimize adverse effects. Please address the following questions
> regarding product labeling: Do the Indications for Use adequately
> define the patient population studied? For example, should the patient
> population receiving this device be limited to the same patient
> population utilized in the study. For example, non-emergent; patients
> over the age of 60; first-time isolated valve or CABG patients.\"
>
> We\'ll take that first piece first. I think that there may be some
> sense that it would be applicable in other patient populations, but we
> have pretty scanty information as it stands, and I would be very
> cautious about expanding beyond the population that was studied in
> this protocol.
>
> DR. AZIZ: Well, I don\'t know quite how to take that, because we know
> that certain patients are at higher risk of getting this sort of
> problem, particularly the guys who are over 85, and although that
> didn\'t form a large percentage of the cohort, I think it comes back
> to what happened in a sense yesterday. Although you may say that, I
> think that in clinical practice, if I wanted to use this device, I
> would probably want to use it in a patient group that I know is at
> increased risk of having a neurological event.
>
> So no matter what we say, I think that in clinical reality, you
> probably would target the higher-risk patient anyway.
>
> DR. TRACY: Yes. My only point is not to extend it to the porcelain
> aortas or beyond the scope of this particular study. There did seem to
> be a group in whom there might be greater benefit, and that was the
> higher-risk patient population within this study. I think we have no
> data beyond this patient population, which did include some
> higher-risk but not the extraordinarily high-risk patients.
>
> I think you have what you have.
>
> DR. EDMUNDS: Dr. Tracy, I would like to take two words or two phrases
> out of that. I would like to take \"non-emergent\" and \"first-time\"
> out of that statement. Otherwise I can live with it. But there is no
> sense in handicapping the surgeons when they are doing more difficult
> cases who are otherwise over 60 and at risk of this problem.
>
> DR. TRACY: Do either of the other surgeons have any comments?
>
> DR. FERGUSON: We\'re talking about labeling here, and the question to
> me would be\--and you have a good point, I think, Cynthia\--or what I
> am wrestling with is should the labeling say that this device was
> tested under these conditions, and put those conditions in, which
> would work for the FDA and work for our consciences and so forth. Now,
> the way the device is going to be used is of concern to us, but it is
> of no concern, because it is going to be used\--Dr. Kouchoukos already
> said the ones he is going to define and use\--
>
> DR. ZUCKERMAN: Maybe we can have a time-out here and talk briefly
> about what we are getting at in this question.
>
> Certainly the agency doesn\'t regulate the practice of medicine, and
> if the device is approved, there will be surgeons who will use it as
> they want to. But what we are talking about today is truthful and
> accurate labeling in an indications statement, and then, part and
> parcel, we traditionally describe the clinical trial that was
> performed in the Clinical Trials section.
>
> I guess the main question that FDA has is when we look at the
> indications and intended use, it says that \"The EMBOL-X aortic filter
> is indicated for us with the EMBOL-X aortic cannula in cardiac surgery
> procedures to contain and remove particulate emboli.\"
>
> Based on the data that we discussed this morning, should there be
> additional qualifiers that better describe who was actually studied?
>
> DR. TRACY: You can refer to that in the \"Proposed Labeling\" section;
> page 2 of 10 at the top has the proposed indications for intended use.
> And then, on page 4 of 10, it begins the description of the patient
> population.
>
> DR. FERGUSON: What was the first reference?
>
> DR. TRACY: It is in the section titled, \"Proposed Labeling,\" page 2
> of 10, down at the bottom. And it is at the very top, Number 2, and it
> is exactly what Dr. Zuckerman said.
>
> \"The EMBOL-X aortic filter is indicated for use with the EMBOL-X
> aortic cannula in cardiac surgery procedures to contain or remove
> particulate emboli.\"
>
> And the question is do you then add the phraseology \"in patients over
> the age of 60 who are undergoing first-time surgery for isolated valve
> or CABG\"\--I think that\'s the question, or is it adequate on page 4
> to state the description of the patient population that was studied.
>
> My instinct would be that in general, we state the indication, unless
> there is a particular reason to put a qualification on it, and usually
> put those caveats in in the description of the patient population.
> I\'m not sure that it is critical to put that up front in the
> labeling, but I think it has to be somehow there that that is the
> patient population that was studied.
>
> DR. MARLER: So we are talking about indications now?
>
> DR. TRACY: Right.
>
> DR. MARLER: I guess it depends on whether you think your
> recommendations need to be driven by data, or not. I would personally
> be concerned, because my knowledge is that if you exclude patients who
> have had prior stroke in the study, you are very unlikely to get any
> estimate of the risk of stroke from a procedure, because that\'s one
> of the highest-risk groups of patients.
>
> And we heard from the sponsor that the reason this population was
> chosen\--at least, my interpretation of the response\--was because
> they wanted to select a group of patients in whom it was safe, or most
> likely to be safe.
>
> So I think to take it beyond that without any data to support it would
> be against my understanding of what we are doing here today, which
> should be driven by data from the study that we are presented.
>
> DR. TRACY: So are you supporting adding the phrases in \"Indications
> and Intended Use,\" \"non-emergent; patients over age 60; first-time
> isolated valve or CABG patients\"? Would you propose putting that in
> the indications statement?
>
> DR. MARLER: Well, because on some of those exclusion criteria, I
> don\'t have the expertise to interpret them, I would certainly think
> that you are changing the game if you include patients who had prior
> stroke or carotid stenosis. I don\'t know how the filter could
> possibly relate to that.
>
> What I would say is that I think each of the exclusions need to be
> discussed carefully in terms of whether there is any indication that
> it is also safe in those patients.
>
> DR. TRACY: Maybe a more detailed description of the exclusion criteria
> would be helpful in there. That doesn\'t seem to be particularly
> well-detailed in the proposed labeling. And I think perhaps in the
> section entitled \"Indications and Intended Use,\" if there were some
> reference specifically to \"Please see below for specific patient
> population inclusion and exclusion criteria\" and a statement that the
> device was tested in these patients only, would be appropriate.
>
> DR. FERGUSON: Yes. As data?
>
> DR. MARLER: Right\--whatever. I just think that if you make the
> decision that intuition is going to drive this whole process, there is
> almost no purpose to even do the trial beyond the first few number of
> patients where you show it catches some emboli.
>
> So I think that the basis of approval for anything should have to do
> with data that show that it is safe and effective.
>
> DR. TRACY: Okay?
>
> DR. ZUCKERMAN: Well, there are still a lot of question marks for these
> other potential patient populations. Sometimes, what we do in our
> labeling is after the \"Clinical Trials\" section, in what would be
> before Section 8, we have a discussion of individual patient
> considerations where we could talk about some of these sub-populations
> and the lack of known data right now.
>
> Do you think that it would be appropriate to add that section?
>
> DR. TRACY: I think that that would perhaps be helpful to somehow, if
> you can, capture some of the questions about the other patient
> populations. I think that would be appropriate, and reference to that
> in the original Number 2, \"Indications and Intended Use.\"
>
> DR. EDMUNDS: I think it would be more concise just to say what the
> study was done on, and that is what is up there, and then put that in
> as data, and then put a disclaimer that the manufacturer does not
> extrapolate these data to anybody. They probably wouldn\'t say it just
> that way.
>
> \[Laughter.\]
>
> DR. TRACY: Let\'s move on to the other bullets, and maybe it will help
> us clarify.
>
> The second bullet is: \" Are there any other restrictions that should
> be placed on the patient population receiving this device?\" And I
> guess that means in terms of contraindications. I think rather than
> contraindications, simply stating that other patient populations were
> not studied would be the more appropriate way of stating it.
>
> DR. FERGUSON: Contraindications are in the next bullet.
>
> DR. TRACY: Right.
>
> DR. KRUCOFF: Yes, and one that has come up that I didn\'t see in their
> labeling is the porcelain aorta as at least one morphologic descriptor
> that has come up a couple of times today that at least in my version
> is not specifically listed as someone who would probably not want
> to\--I wonder, is there a broader range, or is it worth saying the
> obvious, which is that in patients in whom you would simply not want
> to cannulate the aorta, those are patients who are obviously not
> candidates for this?
>
> DR. TRACY: The next section is, \"Based on the clinical experience,
> should there be additional Contraindications, Warnings, and
> Precautions for the use of the EMBOL-X intra-aortic filter?\"
>
> DR. MARLER: I want to back up a little bit. On these indications and
> contraindications, aren\'t we more deciding not what an individual
> physician can do in his or her practice, but what the company can
> advertise as what the FDA has looked at and approved as an indication,
> presumably, following the meaning of FDA approval, that it is driven
> by data and good evidence?
>
> MR. MORTON: Madam Chair, a couple of points, not to supersede Dr.
> Zuckerman.
>
> DR. TRACY: Yes.
>
> MR. MORTON: There is a difference between approving and clearing a
> 510(k), and that\'s what the FDA action will be; it will be a
> clearance. So the sponsor or the manufacturer will represent the
> device as \"cleared,\" not as \"approved,\" and that is significantly
> different.
>
> Additionally, there is a tremendous difference in the regulatory
> burden on indications and changing indications once those are locked
> into a clearance. It requires data and could even require another
> 510(k).
>
> DR. MARLER: But the impact of the indications is primarily the way the
> product can be advertised and sold, not the way it is used by the
> physician; is that correct?
>
> MR. MORTON: That is a practice of medicine issue; correct.
>
> DR. ZUCKERMAN: Okay, but the point that we are trying to get at is
> what is a truthful way to describe the dataset that has been discussed
> here and other external data that is potentially of importance, Dr.
> Marler. So that the indications statement doesn\'t need to necessarily
> follow, dot by dot, the clinical trial guidelines if it is reasonable
> to extrapolate farther. That is where we need your help; it may not
> be.
>
> DR. TRACY: Yes. I think it is very hard to extrapolate the way this
> particular study is constructed. It is hard to extrapolate, to expand
> on the indications. I think that the indications as stated in
> the\--I\'m not sure I would want to be more restrictive than what is
> stated here, other than to say that somewhere in the subsequent body,
> there has to be a statement of exactly who was studied and exactly who
> was not included. I think the exclusion criteria have to be more
> clearly stated than they are in the current proposed labeling.
>
> As far as placing additional restrictions, I don\'t think we need to
> place additional restrictions beyond clearly reiterating what was
> studied and what was not studied.
>
> Dr. Pina?
>
> DR. PINA: Let me go beyond the inclusion criteria. I would like to see
> a table with the baseline values of the patients. They were over the
> age of 60, but the age was up there, so I think that whomever is going
> to use this needs to see the mean values of the population that was
> actually studied. And it can be very simple\--age, gender, type of
> surgery, even number of vessels involved. That information should be
> available. But that\'s a descriptor that I think a surgeon needs to
> look at to make a decision about whether they want to use this or not.
>
> It\'s not just the inclusion criteria; it is what the data actually
> are.
>
> DR. TRACY: So that is there in paragraph 4 on page 4 of 10 and perhaps
> would benefit from expanding that into a more inclusive table.
>
> DR. MARLER: And I guess I would want to add that I thought I pretty
> clear asked for an explanation of how to extrapolate, and I did not
> hear anything except that emboli are bad.
>
> DR. EDMUNDS: I don\'t think we can extrapolate, and I don\'t think we
> can say the negatives, either, because the negative list will be long.
> You start out with dissecting aneurysms, marfands \[phonetic\],
> airlos-dolos \[phonetic\], Siamese twins\--you can keep going in an
> endless list. I think we have got to just stick to what this trial
> was. The use of this product is based on the demonstration that this
> filter captures embolic material when used in these patients, and
> that\'s where I would recommend that you stop, because that\'s all the
> data that we have.
>
> DR. LASKEY: And it is exceedingly difficult to stretch things beyond
> the equivalence. If we had evidence of benefit, it could conceivably
> stretch this to another sample, but with equivalence, that\'s a long
> way.
>
> DR. KRUCOFF: I would even amplify that to emphasize that since part of
> what I think makes this whole consideration reasonable is the absence
> of safety concerns, pushing the envelope in directions to new,
> untested populations, I think whether you encounter safety issues
> would be an important question that would be outside of this
> discussion.
>
> DR. ZUCKERMAN: Good. So you know what the present indications
> statement reads. How do you make it in a concise fashion more
> applicable to the data that have been presented?
>
> DR. TRACY: I think you have to simply state, \"See patient selection
> criteria for patients involved in this protocol.\" I think you have to
> refer to some other section. Otherwise, you end up with a
> 15-paragraph\--you have to refer to other areas in the labeling and
> then perhaps a statement that this device simply was not tested in
> other patient populations.
>
> DR. ZUCKERMAN: Okay. Another option that we sometimes use\--the one
> that you have suggested is just to put, \"(See Clinical Trials
> section)\" in parentheses. Another option that we sometimes use is to
> indicate some key clinical parameters right in the indications
> statement of which there aren\'t any right now.
>
> Are there any that are real show-stoppers that should be up front?
>
> DR. TRACY: I think they are all relevant, and I think you just have to
> refer to who was involved in this study and specifically who was not
> involved in this study.
>
> Dr. Ferguson?
>
> DR. FERGUSON: Are we through with that? I want to bring up another
> point.
>
> DR. TRACY: Yes.
>
> DR. FERGUSON: I think it belongs here; maybe not. That is that as I
> read through these\--and correct me if I am wrong\--I see nothing at
> all in the deployment and use of the device that indicates that you
> should use imaging as a guide. I know that you don\'t need it to put
> the instrument in, but is there any reason\--I am just bringing it up
> as a question, because half of the patients had either TEE or the
> epiaortic.
>
> I would like to have some discussion about whether that should be
> somehow included here.
>
> MS. WENTZ: That\'s actually the last part of the question.
>
> DR. FERGUSON: Oh, okay. I jumped the gun. It\'s not in there now;
> right?
>
> DR. KRUCOFF: My understanding from the comments from the investigators
> was that it just would not be conceivably or technically feasible to
> do that on a routine basis.
>
> DR. TRACY: I think their point on the TEE was that you wouldn\'t pick
> up these small disruptions.
>
> DR. FERGUSON: TEE isn\'t available for everybody.
>
> DR. TRACY: It is available, but it may not pick up these small
> disruptions that we don\'t know, as Dr. Laskey said, what the clinical
> relevance of these are. We know that they are occurring at a higher
> rate, and short-term, we don\'t see any increased adverse outcome
> related to it.
>
> DR. FERGUSON: Excuse me. That jumps the point. I\'m not talking about
> that. I was referring to the fact that it is very useful when you are
> getting ready to put an aortic cannula in, as Dr. Kouchoukos has done
> in monumental studies, it is very useful to have some sort of
> visualization of the arteriosclerotic aorta before you put the cannula
> in. I would like to have some discussion of that.
>
> DR. EDMUNDS: Well, that adds a little bit of a burden and delays the
> operation by about 10 minutes, because first of all, you have to get
> the probe sterilized, and then you have to find an anesthetist who
> knows where it is, and it take about 10 minutes to do the study.
>
> DR. FERGUSON: And probably if you do that, and you put the cannula in
> a spot that is not arteriosclerotic, you are probably doing the
> patient more good maybe even than the filter. That\'s my point.
>
> DR. PINA: Dr. Tracy, let me go back to Dr. Zuckerman\'s point, because
> I don\'t think we answered that first statement for you.
>
> In your statement of indications, I think you can very easily say,
> just like it says now, for cardiac surgical procedures that are
> non-emergent and in patients over the age of 60, for either bypass or
> valve surgery\--you can say all of those indications in one sentence,
> and that will describe generally the population, and then say \"Refer
> to Table such-and-such.\"
>
> DR. TRACY: I think you are going to have some argument from your
> surgical colleagues that that is appropriate to limit the surgeons\'
> ability to do this in emergency cases. So that was why I was holding
> back from making that particular statement. I think it is important to
> say that that is the patient population that was involved, but I
> don\'t know that I would put that pu front.
>
> DR. PINA: Yes, but the FDA will not regulate medical practice. They
> are going to do whatever they want anyway. The surgeons are going to
> use it any way they want, but I think the truth-in-labeling has to be
> the population that was studied. And the surgeons will make their
> decisions clinically, as we have always done with everything we do.
>
> DR. TRACY: I think that is going beyond the scope of\--I think to put
> that in there in the indications creates some liability issues that I
> would rather not open up to. I think we need to have it very clear
> that this is the patient population that was studied, and these are
> the people who were excluded. I\'m not sure that it belongs as an
> additional sentence in the indications for usage.
>
> DR. EDMUNDS: I agree with you. I think that\'s the data-supported
> course.
>
> DR. TRACY: But the reference needs to be there.
>
> Just to try to get through these other issues, \"Are there any other
> restrictions that should be placed on the patient population receiving
> this device?\"
>
> No, there are no other\--I cannot think of any other restrictions that
> we have discussed here that need to be placed. Again, it has got to be
> clear who was excluded from the patient population.
>
> And finally, on the third bullet of this question, \"Should there be
> additional Contraindications, Warnings, and Precautions for the use of
> the EMBOL-X intra-aortic filter?\"
>
> I think, with the exception of the porcelain aorta, which has come up
> a couple of times, the contraindications as stated are fair, and I
> think somewhere, the idea of the porcelain aorta has to come up,
> either as a warning or as a precaution.
>
> Dr. Krucoff?
>
> DR. KRUCOFF: I have a question, and there may not be a precedent to
> make this helpful, but I wonder if it would be worth, given the whole
> spirit of this discussion, separating out technical effectiveness from
> clinical effectiveness and to label this as a device that, with
> reasonable safety, has been shown to be technically effective at
> retrieving particulate matter in the setting of cannulation of the
> aorta, but in a precaution sort of environment, or make a statement
> that while this has been shown to be technically effective at removing
> particular matter, it has not been shown to be clinically beneficial,
> and therefore, caution in the use of this device would be warranted.
>
> DR. TRACY: I think it is difficult to go in that direction since we
> don\'t even know that it has been shown to be effective at removing
> particulate material. We don\'t know what percentage it is removing. I
> think that to introduce that into the labeling would be confusing, at
> the very least.
>
> DR. KRUCOFF: I was actually just wondering from a precedent, because I
> can think back as far as a day where an indication for reducing
> ischemia during angioplasty was sort of a technical achievement that,
> actually, devices and biologics were both ultimately approved for,
> even though the full clinical ramifications of reducing ischemia as a
> technical feat were never implied or demonstrated. And I just wondered
> whether there was a precedent that we could get clearer language for
> docs who are considering using this in their patients to make it very
> clear why this is on the market, but also the limitations of what we
> can understand about its clinical utility.
>
> DR. TRACY: The study results are pretty clear as they are stated here.
> I think it doesn\'t have to be expanded beyond the study results. I
> think it is explained in here what the study results are, and I think
> it is fair to leave that open to interpretation for the operator
> whether that study results supports the use for them in their
> individual patients.
>
> DR. AZIZ: If I could just make one point about the porcelain aorta, I
> think that shouldn\'t be put as a contraindication. I think I would
> just use it as a precaution, because you could probably see a case
> where you do a beating heart on-pump case where you won\'t cross-clamp
> the aorta, so you could still put the mesh inside.
>
> So I would say that that should be a precaution but shouldn\'t be a
> contraindication.
>
> DR. LASKEY: How about if you\'re just not willing to cross-clamp the
> aorta if it\'s a contraindication?
>
> DR. FERGUSON: And I\'ll get back to the point again about the
> ECO\--nobody wants to talk about it\--many times, you can\'t tell if
> you\'ve got a porcelain aorta or not until you actually do the TEE.
> You don\'t want to do this, you don\'t want to do that, because
> that\'s going to be bad.
>
> DR. TRACY: Shall we flip the page?
>
> DR. MARLER: So, at least at a minimum, I hear that as a precaution, we
> could specifically notify the clinician that certain patients were
> excluded from the study, and there is no evidence of the safety in
> patients that\--and then list the clinical exclusions.
>
> DR. TRACY: I think it\'s very clear that more detailed description of
> clinical exclusion needs to be included in the labeling.
>
> DR. MARLER: Rather than just referring to the protocol.
>
> DR. TRACY: Right.
>
> The next bullet, then, is: \"Should the labeling include specific
> study information such as no reduction of clinical events were noted
> in a 1,289-patient clinical study; and the EMBOL-X device appears to
> increase the rate of endothelial injury?\"
>
> The study results on page 4 of 10 do indicate that none of the
> surgical procedure differences between the randomized group achieved
> statistical significance. So that is there, I believe. And yes, I
> think it is important that those pieces of information be conveyed
> very clearly and in a fashion that can be readily picked up in the
> labeling.
>
> And then, to grapple a little more with \"What should the labeling
> include regarding the use of ultrasound both before\--for assessment
> of the aorta\--and after\--monitoring of injury\--the use of the
> device?\" there are data provided on the use of TEE or epiaortic
> imaging, and that is presented on page 5. Is there something peculiar
> about this device that would make it necessary to mandate the use of
> TEE?
>
> DR. FERGUSON: My suggestion would be something in the instructions for
> use of how helpful TEE can be in assessing the aorta both at the time
> the cannula is put in and also assessing the aorta before and after,
> but not to make it a mandatory part of the situation.
>
> DR. TRACY: I think that\'s reasonable. It is stated here, but perhaps
> that could be clarified a little bit as to exactly what was seen with
> the two modalities of assessment, and then, certainly in the
> instructions for use, that should be emphasized.
>
> DR. LASKEY: What is the standard of care? Are all patients generally
> getting TEEs now?
>
> DR. EDMUNDS: No. Could we go back to a previous slide? Number 2 of the
> first paragraph, you kind of went over, but I take objection to that
> statement, because \"endothelial injury\" is not defined. If you are
> going to use the term, I think you have to define it. We have
> discussed this, and we have been unable to demonstrate that this is a
> harmful finding, and we have shown, or the study showed, that 78
> percent of OR personnel were unable to detect it at all.
>
> So I think we have got to back off a little bit about that unless you
> start to raise a whole bunch of thorns that really don\'t need to be
> raised.
>
> DR. TRACY: The thorns are there, though, unfortunately, and that was
> found, and it is defined on page 5 of 10, the presence of
> ecocardiographically-evident endothelial disruption is noted\" and the
> statement is made \"did not put the patient at a statistically greater
> risk for composite endpoint event.\" I think that\'s fairly stated. It
> was there. There was no evidence that it increased the composite risk.
>
> So it has to be there, and perhaps something that needs to be observed
> over time, because we certainly have very limited information about
> what the prognostic significance of this is, and in particular as more
> diseased aortas are approached with this device, I wouldn\'t be
> surprised if there were a greater risk of disruption in those
> patients. So we need to be tracking something like this.
>
> Are there any other comments on this?
>
> \[No response.\]
>
> DR. TRACY: I think we are on to Number 5.
>
> \"Please provide any other recommendations or comments regarding the
> labeling of this device.\"
>
> I think we touched on\--Dr. Pina?
>
> DR. PINA: I just want to go back and ask a question of the sponsor.
> Somewhere along the way, you stated that the endothelial injury was
> almost center-specific and operator-specific, or you saw it several
> times in the same operator, so that perhaps experience may have a lot
> to do with lack thereof.
>
> Am I correct? Did I hear that right?
>
> DR. TRACY: I don\'t think that was my impression.
>
> DR. ALLEN: Actually, a good recollection. The two that were repaired
> were from the same center very early on in the experience, and then,
> after an historical basis for what we were seeing, and realizing they
> weren\'t causing clinical events, the additional 10 that were actually
> observed by surgeons weren\'t intervened on.
>
> DR. PINA: Again, I don\'t know if it would pay to say something in
> there that, first of all, they are not that common. We don\'t know how
> many times this happens, as Dr. Edmunds said, and we don\'t even know
> about them. So something to take a little bit away from the fear, even
> though I know it is there, but not to cause undo alarm may have
> something to do with the experience of the surgeon or the surgeon\'s
> ability to see this, just to kind of temper a little bit the fear of
> the endothelial injury.
>
> DR. TRACY: Wasn\'t it the repairs were done early on because people
> didn\'t understand the lack of clinical importance. It is not that the
> number of disruptions decreased over time.
>
> DR. MARLER: Wait a minute, now. Intuition is ruling today; right?
>
> DR. TRACY: I\'m sorry?
>
> DR. MARLER: Emboli are bad. Endothelial injury is likewise bad. I
> don\'t see why there is any discussion of this.
>
> DR. KRUCOFF: I think there is a reason, because I think you have to be
> fundamentally consistent about our assessment of the safety of the
> safety of this thing. To me, that\'s actually the much more rigorous
> part of this than the efficacy issue. And if we have all reached the
> consensus that this is safe, part of that is clearly based on our
> assessment that for the data presented, the significantly increased
> incidence of this finding in fact doesn\'t translate into significant
> clinical sequelae once, at least, you get enough competence in the
> surgical group to stop putting stitches into the darn things.
>
> DR. TRACY: But I certainly wouldn\'t advocate removing page 5 of 10.
>
> DR. PINA: No, no, I\'m not advocating that, either.
>
> DR. KRUCOFF: No, no. I think this is just consistent with what was
> brought up before about the statement if we are going to say
> \"endothelial injury,\" that implies something that is unsafe or bad.
> I think if we say this is a finding that has not appeared to translate
> into a clinically significant finding, that to me is consistent with
> our saying this is safe. And I think that\'s one where we can and need
> to be rigorous, particularly if we are unanimous.
>
> DR. EDMUNDS: If you use the term \"endothelial injury,\" detectable
> only on post-repair epiaortic ecocardiography one-quarter of the time
> that it is there by the OR personnel. In other words, I think this is
> totally impractical.
>
> DR. TRACY: But it is there, and it is part of the description of the
> patient study. The phrase, I believe, is fair the way it is described,
> and I believe it should be left in the labeling. Okay.
>
> Question 5. \"Please provide any other recommendations or comments
> regarding the labeling of this device.\"
>
> I think we along the course made other comments. Unless anybody else
> has additional comments to make regarding the labeling, I think we
> have covered this one.
>
> Okay. And Question 6: \"If the data provided are not adequate to
> support safety and/or effectiveness, what additional data analysis or
> study would you require?\"
>
> I think we are going to get back into the same discussion about what
> we need by safety and effectiveness. I think everybody would be happy
> if there were some other cognitive endpoint that could be analyzed at
> some point, obviously not in this dataset since it was not collected,
> but I think that would be something that we would be looking for in
> future studies, other measures that might be more appropriate than the
> composite endpoint that a priori is going to miss the thing that you
> are looking for, or you are hoping to reduce.
>
> DR. ZUCKERMAN: Dr. Marler, can you be more specific regarding what
> measurements of neurocognitive dysfunction you would be looking for in
> future studies?
>
> DR. MARLER: Given a menu, can I pick my favorite neuropsychological
> tests? Yes, I can. I like several tests because they are easy to
> administer, take little time, and cause minimal irritation to the
> patient and presumably the surgeon.
>
> But I think that we have found it possible in the research that I have
> sponsored in this from Wake Forest and now Johns Hopkins that if you
> put them in a room and don\'t let them out, it gives them specified
> limits that a neuropsychologist can reach some agreement on how to do
> neuropsychological evaluation in an efficient and cost-effective way.
>
> It is not answering your question, but to say Trailmaking B or
> Trailmaking A or this or that test I don\'t think is helpful in this
> situation. I think there is a way to come up with cognitive
> evaluation, and I think it has been done before, and I think it would
> move the field forward.
>
> You read different things in the newspaper from year to year.
> Sometimes it has cognitive effects, and I think most recently in the
> newspaper, it doesn\'t, at least, long-term effects.
>
> Sorry to be so unhelpful. I think it is a question that can be
> answered; I\'m not going to answer it now.
>
> DR. TRACY: The other piece of effectiveness is what percentage of
> material is the device capturing. And it seems like there might be
> some other bench test that could be better designed other than
> non-sticky things being passed through the system. There must be some
> other biologic way of testing to get a better idea of what percentage
> of material is being missed or picked up by the device.
>
> I would suggest that being part of the mechanical effectiveness
> assessment that should be done. And I am still a little troubled by
> your original question about is there some design problem here with
> the device that is resulting in whatever these disruptions are. We
> need to somewhere along the line satisfy the FDA on that with this
> device and certainly with any future device.
>
> Dr. Krucoff?
>
> DR. KRUCOFF: I would also suggest at least for future work, because I
> think one of the things that Chris mentioned that we have seen in
> other filters, since these are circular devices, and whether they are
> aligned, whether they are rotationally aligned and actually transverse
> across the aorta or whether they are cockeyed, that at that level, if
> there were a way\--imaging or otherwise\--to get a sense of how
> frequently these things simply are or are not aligned the way you
> would ideally envision them, to me, that would be useful information
> somewhere along the line in the evolution of these things.
>
> DR. MARLER: I wanted to add to my comment that my intuition\--since
> intuition is important today\--is that the way to find effects on the
> brain is not to look at low-risk patients but to include patients who
> have had prior stroke, have atrial fibrillation, have high risk of
> stroke, and they are usually the ones who show the effects of
> interventions. It is easier to see an effect.
>
> I would say that what you have is the baseline stroke rate that goes
> with the whole procedure here, and there was no increase or decrease,
> but in particularly risky patients, you might be more likely to see
> the cognitive effects and the stroke effects. That is based on a
> number of trials that I am saying that.
>
> DR. AZIZ: I think the problem with that would be to read lighting up
> of the stroke in those patients may be unrelated to emboli. It may be
> hypertensive episodes. So the protective effects\--
>
> DR. MARLER: We are having increasing evidence\--well, okay\--stroke is
> a systemic problem, and what triggers it varies from individual and
> from time to time, and what we are seeing here is these emboli may be
> more of a trigger of a whole cascade of events rather than the entire
> event itself.
>
> DR. EDMUNDS: I think this will come out if this is approved and used
> over time, but we don\'t have the data to say anything about it now,
> and that\'s why I think we have to wait. But I\'m sure that clinicians
> will want to use it in the high-risk patients; it\'s just horse sense.
>
> DR. MARLER: I\'m just trying to provide advice where I would go if I
> had to find clinical benefit. I am saying that the higher-risk
> patients, certainly with cognitive measures, but go where the things
> are happening.
>
> DR. TRACY: Are there any other comments on this question?
>
> DR. FERGUSON: I have one question. With the PMAs, we talk a lot about
> post-market approval studies. That is not an issue with the 510(k) as
> I understand; right?
>
> DR. ZUCKERMAN: That\'s correct.
>
> DR. FERGUSON: Thank you very much.
>
> DR. TRACY: Are there additional questions or comments that the FDA
> would like to make?
>
> DR. ZUCKERMAN: No.
>
> DR. TRACY: Does the sponsor have any additional comments or questions
> at this time?
>
> MS. CHANG: No, thank you.
>
> DR. TRACY: Mr. Dacey, any comments or questions?
>
> MR. DACEY: After over 4 years, this is my first 510(k) experience, and
> I certainly can\'t bring any clinical experience or intuition to this
> process, but speaking for the consumer, I am awfully glad that this
> process is taking place.
>
> That\'s all that I have to say.
>
> DR. TRACY: Thank you.
>
> I guess Mr. Morton, by the fact that he is not here, apparently has no
> additional comments.
>
> So at this point, we will have another open public hearing.
>
> Is there anyone in the audience who wishes to address the panel on
> today\'s topic?
>
> \[No response.\]
>
> DR. TRACY: If not, we\'ll close the open public hearing.
>
> Are there any final recommendations from the panel?
>
> \[No response.\]
>
> DR. TRACY: Dr. Zuckerman?
>
> DR. ZUCKERMAN: Geretta, do you have something to read about finding
> out about each panel participant\'s view on this topic?
>
> MS. WOOD: No.
>
> DR. ZUCKERMAN: I stand corrected. Thank you.
>
> DR. TRACY: I think you heard them.
>
> The meeting is adjourned.
>
> Thank you all very much.
>
> \[Whereupon, at 3:42 p.m., the proceedings were concluded.\]
>
> \- - -