FOOD AND DRUG ADMINISTRATION














                        Thursday, March 18, 2004


                               9:00 a.m.




               Hilton Gaithersburg Washington D.C., North

                           Salons A, B and C

                           620 Perry Parkway

                         Gaithersburg, Maryland






         Cynthia Tracy, M.D., Acting Chair

         Geretta Wood, Executive Secretary




         Salim Aziz, M.D.

         Mitchell Krucoff, M.D.

         William Maisel, M.D., MPH

         Christopher J. White, M.D.




         Clyde Yancy, M.D.

         Judah Z. Weinberger, M.D., Ph.D.

         John W. Hirshfeld, M.D.

         Thomas B. Ferguson, M.D.

         Norman S. Kato, M.D.

         Brent Blumenstein, Ph.D.

         Charles Bridges, M.D.

         L. Henry Edmunds, Jr., M.D.




         Michael Morton




         Chrissy Wells




         Bram Zuckerman, M.D.




                            C O N T E N T S


      Call to Order

                Cynthia Tracy, M.D.                              4


      Conflict of Interest Statement

                Geretta Wood                                     4


      Introductions                                              6


      FDA Presentation:

                Julia Marders                                    8

                Wolf Sapirstein, M.D., MPH, FACS                17

                Kachi Enyinna                                   26

      Open Public Hearing:


                Randall Wolfe, M.D.                             31

                Robert W. Emery, M.D.                           41

                G. Phillip Schoettle, M.D.                      50

                Robert Frater, M.D.,                            55

                Michael Mack, M.D., STS/AATS                    66

                Mark Slaughter, M.D.                            76

                Henry Frank Martin, M.D.                        85

                Bernard Hausen, M.D.                            90

                Prof. Uwe Klima                                 96


      Open Committee Discussion                                107



                Cynthia Tracy, M.D.                            262




  1                      P R O C E E D I N G S


  2                          Call to Order


  3             DR. TRACY:  Good morning, everybody.  I


  4   would like to call to order this meeting of the


  5   Circulatory System Devices Panel.  The topic today


  6   is a discussion of type of data and study required


  7   to effectively evaluate performance of aortic


  8   anastomotic devices for marketing.


  9                       Conflict of Interest


 10             MS. WOOD:  The following announcement


 11   addresses conflict of interest issues associated


 12   with this meeting and is made a part of the record


 13   to preclude even the appearance of an impropriety.


 14             To determine if any conflict existed, the


 15   agency reviewed the submitted agenda and all


 16   financial interests reported by the committee


 17   participants.  The conflict of interest statutes


 18   prohibit special government employees from


 19   participating in matters that could affect their or


 20   their employers' financial interests.  However, the


 21   agency has determined that participation of certain


 22   members and consultants, the need for whose


 23   services outweighs the potential conflict of


 24   interest involved, is in the best interest of the


 25   government.




  1             A waiver has been granted for Dr. Clyde


  2   Yancy and a wavier was previously granted for Dr.


  3   Judah Weinberger for their financial interests in


  4   firms at issue that could potentially be affected


  5   by the panel's recommendations.  The waivers allow


  6   these individuals to participate fully in today's


  7   deliberations.  Copies of these waivers may be


  8   obtained from the agency's Freedom of Information


  9   Office, Room 12A-15 of the Parklawn Building.


 10             We would like to note for the record that


 11   the agency took into consideration other matters


 12   regarding Drs. Thomas Ferguson, Mitchell Krucoff,


 13   Cynthia Tracy, Judah Weinberger and Clyde Yancy.


 14   These panelists reported past or current interests


 15   involving firms at issue but in matters that are


 16   not related to today's agenda.  The agency has


 17   determined, therefore, that these individuals may


 18   participate fully in the panel's deliberations.


 19             In the event that the discussions involve


 20   any other products or firms not already on the


 21   agenda for which an FDA participant has a financial


 22   interest, the participants should excuse him or


 23   herself from such involvement and the exclusion


 24   will be noted for the record.


 25             With respect to all other participants, we




  1   ask in the interest of fairness that all persons


  2   making statements or presentations disclose any


  3   current or previous financial involvement with any


  4   firm whose products they may wish to comment upon.


  5             DR. TRACY:  Just before we get started, I


  6   would just like to ask everybody to be sure that


  7   you are speaking directly into the microphone,


  8   including the speakers who will be coming up later


  9   in the open public hearing.  A transcript is being


 10   made from these presentations today.


 11             At this time I would like to ask the panel


 12   members to introduce themselves.


 13                          Introductions


 14             MR. MORTON:  I am Michael Morton.  I am


 15   the industry representative.  I am an employee of


 16   CarboMedics.


 17             DR. WEINBERGER:  Judah Weinberger,


 18   Director of Interventional Cardiology at Columbia.


 19             DR. YANCY:  Clyde Yancy, Director of Heart


 20   Failure and Transplantation at UT Southwestern, in


 21   Dallas.


 22             DR. WHITE:  Chris White.  I am the Chief


 23   of Cardiology at Ochsner Clinic Foundation.


 24             DR. HIRSHFELD:  John Hirshfeld.  I am an


 25   interventional cardiologist in the University of




  1   Pennsylvania.


  2             DR. KATO:  Norman Kato, cardiovascular


  3   surgeon, private practice, Encino, California.


  4             MS. WOOD:  Geretta Wood, Executive


  5   Secretary.


  6             DR. TRACY:  I am Cindy Tracy,


  7   electrophysiologist, George Washington University.


  8             DR. EDMUNDS:  I am Hank Edmunds, Professor


  9   of Surgery at the University of Pennsylvania.


 10             DR. FERGUSON:  Tom Ferguson,


 11   cardiovascular surgeon, Washington University St.


 12   Louis.


 13             DR. KRUCOFF:  Mitch Krucoff,


 14   interventional cardiologist, Duke University


 15   Medical Center; Director of Devices Trials, Duke


 16   Clinical Research Institute.


 17             DR. MAISEL:  William Maisel,


 18   electrophysiologist, Brigham & Women's Hospital.


 19             DR. BLUMENSTEIN:  Brent Blumenstein,


 20   biostatistician, Seattle, Washington.


 21             DR. BRIDGES:  Charles Bridges, Chief


 22   Cardiovascular Surgery Pennsylvania Hospital,


 23   University of Pennsylvania.


 24             MS. WELLS:  Chrissy Wells.  I am the


 25   consumer representative on the panel.




  1             DR. ZUCKERMAN:  Bram Zuckerman, Director,


  2   FDA, Division of Cardiovascular Devices.


  3             DR. TRACY:  Thank you.  At this point we


  4   will have the FDA presentation, and Julia Marders,


  5   from the Office of Surveillance, will be the


  6   opening speaker.


  7                         FDA Presentation


  8             MS. MARDERS:  Good morning.


  9             [Slide]


 10             My name is Julia Marders, and I am a nurse


 11   analyst in the Division of Postmarket Surveillance,


 12   Office of Surveillance and Biometrics.


 13             [Slide]


 14             I will present an analysis of adverse


 15   event reports received by the FDA on aortic


 16   anastomotic devices.  My presentation will begin


 17   with a brief description of the Medical Device


 18   Reporting System, MDR, which is a system for


 19   adverse events and product problems, and include a


 20   discussion of its limitations.


 21             Next, I will describe the database, search


 22   methodology used to obtain the reports of aortic


 23   anastomotic devices and provide a summary of


 24   findings and analysis of conclusions.  Then I will


 25   finish the presentation with conclusions,




  1   considerations and questions for the panel to


  2   contemplate.


  3             [Slide]


  4             The Medical Device Reporting System is a


  5   nationwide passive surveillance system which


  6   includes both mandatory and voluntary reporting.


  7   Since 1984 manufacturers and importers have been


  8   required to submit reports to the FDA of


  9   device-related deaths and serious injuries, as well


 10   as events involving device malfunctions that may


 11   cause or contribute to death or serious injury.


 12             The Safe Medical Devices Act of 1990


 13   introduced mandatory reporting of device-related


 14   deaths and serious injuries by user facilities,


 15   most notably hospitals and nursing homes.


 16   Voluntary medical device adverse event and problem


 17   product reports, most often submitted by healthcare


 18   practitioners, consumers, patients or family


 19   members, are received through the FDA's MedWatch


 20   program.  In general, approximately 95 percent of


 21   the reports received by FDA are from manufacturers,


 22   one percent from importers, and the remainder is


 23   equally split between voluntary and user


 24   facilities.


 25             [Slide]




  1             The Medical Device System, which is the


  2   MDR system as most people know it, while providing


  3   signals of actual and potential device-related


  4   problems, has some limitations.  Under-reporting of


  5   adverse events to hospitals, manufacturers and the


  6   FDA by healthcare practitioners is a well-known and


  7   recognized phenomenon.  Thus, events reported


  8   through MDR represent a subset of the total


  9   occurrence of events.


 10             In addition, manufacturers are not


 11   required to submit denominator information such as


 12   number of devices manufactured, distributed and


 13   implanted.  Thus, due to under-reporting and lack


 14   of denominator data accurate incidence rates are


 15   unable to be determined based on MDR data alone.


 16   Furthermore, reports received may not be


 17   representative and reflective of a variety of


 18   reporting biases.  Thus, for example, reporting may


 19   vary by manufacturer or by the presence or absence


 20   of publicity.


 21             Although there is a regulatory requirement


 22   for a minimum data set, event narrative


 23   descriptions vary in completeness and complexity.


 24   For example, one aortic anastomotic device report


 25   indicates failure of the connector as the entire




  1   event description and no further details are


  2   provided.  In addition, many reports do not contain


  3   results of manufacturer failure analyses.  Often


  4   devices are not returned to the manufacturer for


  5   evaluation because they are discarded or remain


  6   implanted.  Thus, root causes for reported events


  7   are often unable to be determined.


  8             [Slide]


  9             Now I will describe the search methodology


 10   used to obtain the data set of aortic anastomotic


 11   device reports in this presentation and present the


 12   findings.  First I searched the database by product


 13   code.  All medical devices approved or cleared for


 14   marketing have a unique three-letter identifier


 15   called the product code.  Next, I narrowed the


 16   search by date.  This search includes events of


 17   aortic anastomotic devices that were reported from


 18   May 24, 2001, the first marketing clearance date


 19   for these devices, to March 1, 2004.  I also


 20   performed additional database queries by brand


 21   names to validated that I had captured all aortic


 22   anastomotic device reports that have been entered


 23   into the database.


 24             [Slide]


 25             Now the findings, a total of 213 reports




  1   are in the database and most reports were received


  2   in 2003.  The number of death reports is 23;


  3   injury, 185; and malfunction, 5.  The vast majority


  4   of these reports, that is 203, came from


  5   manufacturers, with 2 from user facilities and 8


  6   voluntary.


  7             [Slide]


  8             Patient age was provided in 129 of the 213


  9   reports and ranged from ages 35 to 83 years, with


 10   most in the 50-65 age range.  Slightly over half of


 11   these events are noted in males, a quarter in


 12   females and a quarter were gender unspecified.  One


 13   hundred and seventy-three events, or 81 percent,


 14   occurred with patients in the U.S. and 14, which is


 15   7 percent, with patients outside the U.S.; 26 event


 16   reports, 12 percent, did not specify whether the


 17   event is foreign or domestic.


 18             [Slide]


 19             Of the 23 death reports, 22 were from


 20   manufacturers and one from a user facility.  All


 21   patient deaths occurred within 18 days of


 22   implantation and 15 of the deaths occurred within 3


 23   days of implantation.  Interestingly, one patient


 24   actually had both a dissection operatively and a


 25   detachment postoperatively and is included in 2 of




  1   the problem categories listed on this slide.


  2   Additionally, another patient had both thrombus and


  3   aortic detachment that was discovered on


  4   postoperative day 2 when the patient coded.


  5             Twelve reports indicate the problem of


  6   occlusion or thrombus at the connector site.  One


  7   report describes the patient was noted to have a


  8   predisposing hypercoagulable state, and 2 reports


  9   indicate that patients had atrial fibrillation.


 10   Aortic dissection associated with deployment or


 11   after the connector is placed was noted in 7


 12   reports.  Device detachment, resulting in


 13   hemorrhagic shock, occurred in 6 reports.  None of


 14   the devices associated with death were returned to


 15   the manufacturer for evaluation and the


 16   manufacturer has not been able to determine the


 17   root cause of the events.


 18             [Slide]


 19             Now I will present an actual report to


 20   illustrate these findings in a more clinically


 21   relevant way.  A patient was implanted with an


 22   aortic anastomotic device during an off-pump


 23   procedure.  No difficulties were encountered with


 24   loading or deployment of the device.  Recovery was


 25   good for approximately 40 hours when the patient




  1   suddenly lost consciousness after a dramatic drop


  2   in blood pressure.  CPR was initiated and blood


  3   appeared in the drains.  At re-operation, the


  4   aortic connector was detached from the aorta and


  5   the patient died after 10 minutes.  The autopsy


  6   revealed the cause of death was hemorrhagic shock.


  7             [Slide]


  8             A total of 185 injuries were reported.


  9   Stenosis and occlusion are overwhelmingly noted to


 10   be the first and second most frequently reported


 11   problems respectively.  Although infrequently


 12   reported, events involving device detachment have


 13   also resulted in serious injury.  Clinically, the


 14   reported outcomes of stenosis and occlusion


 15   resulted in life-threatening conditions resulting


 16   in shortness of breath, chest pain, arrhythmias,


 17   subsequent myocardial infarction and/or hemodynamic


 18   instability requiring either surgical or


 19   interventional treatment including catheterization


 20   for PTCA and stenting.


 21             The time from implantation to injury, as


 22   noted in 37 of the 185 reports submitted, of the 30


 23   noting stenosis or occlusion most, or about 60


 24   percent, occurred within 90 days; 4 events occurred


 25   within 4 days.  The other 7 are associated with a




  1   variety of patient problems other than stenosis or


  2   occlusion.  Three reports of device detachment


  3   occurred within one day of surgery, and another


  4   event atypically occurred after 97 days, possibly


  5   due to a fragile aorta and placement of the


  6   connector on a pseudoaneurysm.  Of all the


  7   injuries, only 2 devices were returned to the


  8   manufacturer for evaluation, both of which resulted


  9   in manufacture evaluation indicating no device


 10   failure detected.


 11             [Slide]


 12             Five reports indicated a device


 13   malfunction.  One report states the device was not


 14   able to be used because the anchor tip was closed.


 15   Two reports indicate the aortic plug was not seen


 16   by the surgeon upon inspection of the device.  Both


 17   of these patients have not experienced any adverse


 18   consequences.  The fourth report indicates a device


 19   malfunction resulting in an aortic laceration


 20   requiring repair.  It is not clear why the user


 21   facility reported this event as a malfunction


 22   rather than an injury, and no information was


 23   included about the patient's outcome.  Follow-up is


 24   ongoing.  The fifth report indicates failure of the


 25   connector, with no other details, other than




  1   indicating no consequences to the patient.


  2             [Slide]


  3             Conclusions--the reports of serious


  4   adverse outcomes related to aortic anastomotic


  5   device use raises a signal of a potential public


  6   health problem.  Some of these occurrences are


  7   catastrophic, such as aortic dissection or device


  8   detachment, and not expected.  Others, for example,


  9   occlusion or stenosis, may be expected depending on


 10   the patient's underlying condition of adequacy of


 11   antiplatelet therapy, or may reflect device-related


 12   events, for example, stenosis at the connection


 13   site or thrombosis potentially related to


 14   bioincompatibility or poor hemodynamics.  Lastly,


 15   the reported information to date reflects


 16   short-term experience.  Long-term failure


 17   information is also important.


 18             [Slide]


 19             Considerations--additionally, there are


 20   two other important points to consider, first,


 21   failure analyses of this adverse event data are


 22   lacking or limited.  The underlying root cause of


 23   these events, particularly occlusion and stenosis,


 24   is unknown.  Multiple factors may be involved which


 25   can make the evaluation of these events difficult. 




  1   Second, this adverse event data needs to be


  2   factored into the risk/benefit profile for these


  3   devices.


  4             [Slide]


  5             To conclude my presentation, I have the


  6   following three questions for the panel to consider


  7   that are based on adverse event report findings:


  8             First is the question of collection of


  9   long-term failure rate data.  Should a longer


 10   period of time for manufacturer collection of


 11   device performance data post implantation be


 12   required to fully understand aortic anastomotic


 13   device failures?


 14             Next, should studies comparing short- and


 15   long-term patient outcomes between standard


 16   suturing versus sutureless aortic anastomotic


 17   devices to address risk/benefit issues be


 18   undertaken?


 19             Finally, should further study of


 20   device-related events be considered?


 21             I encourage the panel to consider these


 22   questions before making final recommendations.


 23   That concludes my part of the presentation and now


 24   I will turn over to Wolf Sapirstein.


 25             DR. SAPIRSTEIN:  Dr. Tracy, panel members,




  1   good morning.


  2             [Slide]


  3             The people listed up there are members of


  4   the Division of Cardiovascular Devices.   My name


  5   is Wolf Sapirstein.  We are mandated by statute to


  6   regulate cardiovascular devices, and are hopeful


  7   that this panel will generate guidance for us in


  8   undertaking this activity for these new and unique


  9   devices used in treatment of coronary-artery


 10   disease.


 11             [Slide]


 12             Vascular suturing was introduced by Carrel


 13   in 1903 and has changed little over the next 100


 14   years, except for the replacement of catgut with


 15   synthetic suture.  After about 30 years of attempts


 16   by various investigators internationally, an


 17   automatic device to effect vascular anastomoses,


 18   the Symmetry Aortic Connector, was cleared in 2001


 19   for commercial use by the agency.  The drive for


 20   development of these devices has undoubtedly been


 21   coronary arterial bypass graft procedure which also


 22   underscores the clinical importance of assuring


 23   safety and effectiveness for these devices.


 24             Incremental modifications to the coronary


 25   arterial bypass graft procedure are seminal to the




  1   acceleration in development of these devices.  The


  2   surgeons among us will have the forbearance, I


  3   hope, while I undertake a thumbnail sketch of the


  4   changes that have taken place in the performance of


  5   the coronary arterial bypass grafting procedure.


  6             [Slide]


  7             The CABG procedure was the earliest


  8   surgical therapy validated with a randomized,


  9   controlled trial, the Coronary Arterial Surgery


 10   Study.  Autogenous venous conduits remain


 11   extensively employed with anastomosis performed to


 12   the aorta and the coronary artery distal to the


 13   obstructive lesion.  Induced ventricular


 14   fibrillation and anoxic cardiac arrest with


 15   hypothermic protection were initially used to


 16   provide the quiet field demanded by the challenge


 17   of suturing vessels 1-2 mm in diameter.


 18   Cardioplegia inducing perfusion of the coronary bed


 19   has since produced cardiac standstill with improved


 20   myocardial preservation during the ischemic period


 21   of conduit anastomosis.


 22             Resistance of the internal thoracic


 23   artery, ITA, to the atherosclerotic degeneration


 24   that seemed inexorable with vein conduits has led


 25   to is preferential employment since the late 1980s.




  1   This also provides the advantage of eliminating


  2   need for an aortic anastomosis.  Patient survival


  3   has since been shown in several studies to be


  4   closely related to the effectiveness of


  5   revascularization achieved for the anterior surface


  6   of the heart and left ventricle.  These


  7   developments, patency of the ITA and anterior


  8   cardiac revascularization justified introduction of


  9   the minimal access direct CABG procedure in the


 10   1990s to perform an isolated LIMA-LAD bypass.  This


 11   was shortly followed by beating heart and finally


 12   off-pump CABG with elimination of extracorporeal


 13   circulatory support entirely.  Thus, were the ill


 14   effects of cardiac arrest, extracorporeal


 15   circulatory perfusion and aortic clamp manipulation


 16   of the aorta obviated.


 17             [Slide]


 18             These modifications made to the CABG


 19   procedure addressed its changing role in an era of


 20   increasing catheter-mediated coronary treatment.


 21   The MIDCAB is seen as reducing the morbidity of


 22   incisional trauma, particularly in an increasingly


 23   older patient cohort and patients with more


 24   compromised coronary circulation not amenable to


 25   percutaneous coronary interventions, and these




  1   patients become candidates for operative


  2   intervention.  Dispensing with cardiopulmonary


  3   bypass eliminated a potent activator of both the


  4   systemic inflammatory response and the various


  5   immunological cascades.


  6             There is also increasing recognition of


  7   the frequency with which neurocognitive


  8   deterioration, apart from the more overt cerebral


  9   ischemic events, occur with CABG procedures.


 10   Extracorporeal cardiopulmonary bypass and


 11   manipulation of the atherosclerotic aorta for


 12   cardiopulmonary bypass perfusion, as well as


 13   conduit anastomosis, have been indicted as


 14   etiologic factors for these complications.


 15   Anastomotic devices, by facilitating the various


 16   modifications to the CABG that address morbidity,


 17   can certainly play a major role in reducing this


 18   illness.


 19             [Slide]


 20             Several studies during the development


 21   stage of CABG evaluated the effectiveness of this


 22   revascularization procedure measured as durability


 23   of patency.  While this slide presents a generally


 24   accepted distillation of these study findings, it


 25   should be noted that patency of CABG is dependent




  1   on multifactorial elements that have likely been


  2   affected by recent changes to the operation itself


  3   that are still being evaluated, and by new measures


  4   to inhibit the progression of coronary-artery


  5   disease.  This has to be considered when evaluating


  6   anastomotic devices in a comparison to these


  7   conduit patency rates.


  8             [Slide]


  9             Failure of the CABG conduit has been


 10   attributed to several causes which are listed here.


 11   They are broadly stratified by the period of their


 12   most prominent effects: the perioperative failures;


 13   6 months o 1 year, failure due to neointimal


 14   hyperplasia; and the continuum from 6 months on are


 15   both coronary-artery disease in the native vessel


 16   and the conduit itself.


 17             [Slide]


 18             The advent of anastomotic devices carry a


 19   promise for significant benefits in the performance


 20   of the CABG procedure that go beyond simplifying


 21   procedural mechanics for the benefit of the


 22   operator.  They have the potential for eliminating


 23   many of the factors contributing to poor patient


 24   outcome.  It must be recognized that while the


 25   precise benefit perceived for some of these recent




  1   changes to the procedures, such as beating heart


  2   and operations performed without cardiopulmonary


  3   bypass, are as yet unresolved.  The use of


  4   non-suture constructed anastomoses will certainly


  5   facilitate and increase the frequency of their use.


  6   These are some of the benefits that seem intuitive


  7   with anastomotic devices.


  8             [Slide]


  9             Well, Woody Allen has said every silver


 10   lining has a dark cloud, and this is exactly true


 11   with these anastomotic devices.  Here are listed


 12   some of the design characteristics that may


 13   contribute to graft failure which do not obtain


 14   with conventional sutured vascular connections.


 15             [Slide]


 16             In our evaluation of these devices for


 17   clearance with a 510(k) notification, we have


 18   required extensive preclinical data to support


 19   limited clinical studies.  The clinical material


 20   was required to substantiate equivalence to


 21   historical data for conduit patency, which was a


 22   surrogate for correcting the deficiency in


 23   myocardial perfusion.


 24             We encountered some disagreement regarding


 25   the study design, the duration of follow-up, and




  1   the instruments for assessing effectiveness.  While


  2   general agreement exists regarding the use of


  3   suture anastomosis as the gold standard to control


  4   for patency, there is considerable advocacy to


  5   employ measures of coronary perfusion for


  6   assessment of patency.  This is a reversal of the


  7   original CABG use of patency as a surrogate for


  8   perfusion.


  9             With regard to duration of follow-up, the


 10   initial concept was to take into consideration the


 11   multifactorial causes of CABG failure by accepting


 12   a relatively short period, such as 6-9 months, that


 13   focuses on the adequacy of the anastomosis


 14   constructed rather than the other factors in graft


 15   failure.  The changes made to the CABG procedure


 16   itself and the introduction of measures aimed at


 17   disease progression were not addressed.  It was


 18   also felt that a distinction could be made for


 19   devices used on the proximal aortic or on the


 20   distal coronary artery.


 21             [Slide]


 22             The problem encountered in designing a


 23   study to evaluate these anastomosis devices goes


 24   beyond the inherent problem of the multifactorial


 25   causes of CABG failure.  They involve in general




  1   the device-specific variables listed here that may


  2   frustrate attempts at one-design-fits-all study


  3   design for the devices.


  4             [Slide]


  5             From our initial experience with cleared


  6   devices, we now have the belief that the rigor of a


  7   randomized trials may be required unless there are


  8   very mitigating circumstances to justify otherwise.


  9   To this end, we would like input on an appropriate


 10   template for study design that could be modified to


 11   accommodate some of the variables intrinsic to


 12   their use.  This slide lists some of the


 13   considerations we have encountered for designing a


 14   study template and it is just put up for your


 15   consideration as a straw man.


 16             [Slide]


 17             This slide represents a sample size


 18   estimation for a one-armed study with the endpoint


 19   for effectiveness based on the historical values


 20   listed here for conduits performed with hand


 21   suturing.  For instance, a point estimate of 95


 22   percent patency, with a lower confidence level


 23   accepted as 5 percent, would require a sample size


 24   of 150 patients for study.  This is just placed


 25   here for your consideration or evaluation for even




  1   a one-armed study.


  2             This completes my introduction to the


  3   FDA's request for this panel's input in formulating


  4   an appropriate regulatory approach for devices that


  5   present the potential for critically affecting the


  6   treatment of coronary arterial disease, which is


  7   the wound stripe of modern society.


  8             Kachi Enyinna, our lead engineer reviewer


  9   for these devices, will now present or crystallize


 10   some of the comments that I have made in the form


 11   of questions that we would like this panel to


 12   address in helping us wrestle with the regulation


 13   of these devices.  Thank you very much.


 14             MR. ENYINNA:  Good morning.  My name is


 15   Kachi Enyinna, biomedical engineer and lead


 16   reviewer, Division of Cardiovascular Devices.  I


 17   will be presenting the questions we have come up


 18   with and seeking some kind of guidance from panel


 19   on how to evaluate clinical studies of these


 20   devices.  I would like to remind the panel members


 21   to keep these questions in mind while I go over the


 22   questions and to keep the questions in mind until


 23   discussion time this afternoon allow members of the


 24   medical community, as well as sponsors and industry


 25   to speak before we discuss the questions.




  1             [Slide]


  2             Regarding trial design, the first


  3   question, please comment on the choice of control


  4   in the clinical trial required to evaluate vascular


  5   anastomosis devices for CABG.  The gold standard of


  6   sutured CABG anastomoses has a well-documented


  7   history of over thirty years.


  8             [Slide]


  9             Can historical data from sutured CABG


 10   anastomosis device trials be used as the control in


 11   the device studies?


 12             [Slide]


 13             Alternatively, are concurrently performed


 14   CABG controls necessary given the multifactorial


 15   causes of CABG failure, for example, technical


 16   construction, extent and progression of native


 17   vessel disease, condition of conduit and


 18   progression of intima hyperplastic and atheromatous


 19   degeneration, and the introduction of drugs for


 20   mitigation of atherosclerotic disease?


 21             [Slide]


 22             If these trial designs are inadequate,


 23   should randomized, controlled clinical trials be


 24   performed?


 25             [Slide]




  1             With regard to device placement and device


  2   design, please address the following:  Given the


  3   considerable differences between the proximal and


  4   distal CABG anastomoses, what, if any, differences


  5   in study criteria should be required?


  6             [Slide]


  7             Are there certain aspects of the clinical


  8   study design, for example length of follow-up and


  9   endpoints, that should be required for all devices


 10   irrespective of device form and function?  For


 11   example, the U-clip performance closely duplicates


 12   that of a suture, whereas the Symmetry has greater


 13   similarity to a stent.


 14             It is rarely possible to determine the


 15   cause of conduit failure.  Can you suggest criteria


 16   to determine whether failure is device related?


 17             [Slide]


 18             Number three, do you believe that the


 19   significant differences between an arterial conduit


 20   and a venous conduit warrant distinct study


 21   criteria and assessment for each?  If so, please


 22   identify these criteria and analyses.


 23             [Slide]


 24             Four, should the primary effectiveness


 25   endpoint be graft patency alone, or include both




  1   graft patency and myocardial perfusion?


  2             Five, with regard to device safety, what


  3   criteria, that is, acceptable adverse event rates


  4   as compared to that for suture should be applied to


  5   the evaluation of device safety as distinguished


  6   from device effectiveness?  For example, myocardial


  7   infarction, reoperations, neurologic events,


  8   incidence of aortic complications.


  9             [Slide]


 10             Regarding endpoint evaluation, number six,


 11   with regard to appropriate patient follow-up, in


 12   view of the possible persisting risk of failure of


 13   some mechanical anastomosis sites, distinct from


 14   the progression of native vessel disease, what


 15   duration of follow-up is advisable for premarket


 16   evaluation?


 17             [Slide]


 18             Should postmarket follow-up be required to


 19   assess long-term device effectiveness?  If so,


 20   please define the appropriate length of follow-up


 21   after primary patency evaluation.


 22             [Slide]


 23             The last question, can non-invasive


 24   measuring instruments, for example,


 25   echocardiography, ultrafast spiral CT, MRA, EBT,




  1   etc., be used for primary assessment of graft


  2   patency or is angiographic follow-up necessary?  At


  3   what time points should patency be assessed?  Thank


  4   you.


  5             DR. TRACY:  Does that conclude the FDA


  6   presentation?  Does anybody on the panel have a


  7   question for the FDA at this point?


  8             [No response]


  9             At this point, we will move on to the open


 10   public hearing.  Both the Food and Drug


 11   Administration and the public believe in a


 12   transparent process for information gathering and


 13   decision-making.  To ensure such transparency at


 14   the open public hearing session of the advisory


 15   committee meeting, FDA believes that it is


 16   important to understand the context of an


 17   individual's presentation.  For this reason, FDA


 18   encourages you, the open public hearing speaker, at


 19   the beginning of your written or oral statement to


 20   advise the committee of any financial relationship


 21   that you may have with the sponsor, its product


 22   and, if known, its direct competitors.  For


 23   example, this financial information may include the


 24   sponsor's payment of your travel, lodging or other


 25   expenses in connection with your attendance at this




  1   meeting.  Likewise, FDA encourages you at the


  2   beginning of your statement to advise the committee


  3   if you do not have any such financial


  4   relationships.  If you choose not to address this


  5   issue of financial relationships at the beginning


  6   of your statement it will not preclude you from


  7   speaking.


  8             MS. WOOD:  I have just a couple of


  9   announcements for the open public speakers.  We


 10   have asked today, due to the number of speakers


 11   that have requested time, that you limit your


 12   remarks to five minutes each.  I would also ask


 13   that you provide me with either an electronic copy


 14   or a hard copy of your presentation for the benefit


 15   of the summary writer and the transcriptionist.  If


 16   you could see me at lunchtime, that would be great.


 17   Thank you.


 18             DR. TRACY:  There are a number of speakers


 19   and I will call them in order.  The first is Dr.


 20   Randall Wolfe, from University of Cincinnati.


 21                       Open Public Hearing


 22             DR. WOLFE:  Members of the panel, ladies


 23   and gentlemen, good morning.


 24             [Slide]


 25             Thank you for honoring my request to speak




  1   before you.  My disclosure is that I was the


  2   principal investigator on the multicenter U-clip


  3   distal anastomotic trial.  Those results were


  4   presented at AATS two years ago.  There is no


  5   financial relationship.


  6             I was a past consultant for Ethicon in


  7   laboratory and clinical evaluation of proximal and


  8   distal anastomotic devices, and in the past was a


  9   consultant to Ventrica in helping set up their


 10   clinical distal anastomotic connector trial.


 11             I am currently on the steering committee


 12   of the Prevent IV Core Gentech E2F Decoy trial


 13   which uses synthetic DNA to prevent aortic coronary


 14   venous graft atherosclerosis.  That study is closed


 15   with over 3,000 patients enrolled.  I mention that


 16   because I think we are going to be educated on true


 17   graft patency of the results of that trial which


 18   will be opened first quarter of next year.


 19             [Slide]


 20             My primary interest is that I have been


 21   presenting summary of anastomotic devices at our


 22   national meetings, both AATS, STS and ISMICS.  In


 23   the next five minutes I would like to summarize


 24   some of the things that have been presented at


 25   these meetings.




  1             [Slide]


  2             Overall, there are a lot of anastomotic


  3   connector devices, and this shows a convenient way


  4   to classify these into proximal and distal and


  5   subsequently into automated versus manual.  There


  6   are 13 to 15 different devices in these different


  7   categories but I find this a convenient way to look


  8   at connectors.


  9             [Slide]


 10             There are different value propositions


 11   with the connectors and they range from traditional


 12   CABG all the way to total endoscopic CABG.  I don't


 13   have time to go over this in detail but only to


 14   point out that there is a possibility of


 15   eliminating the heart-lung machine by using certain


 16   connectors and also reducing ischemic time.  In the


 17   endoscopic evaluation there is a potential to


 18   reduce patient pain and trauma and to truly enable


 19   endoscopic surgery.


 20             [Slide]


 21             This is a summary that you will probably


 22   hear more about from other presenters, but vein


 23   graft failures could be a bad vein; the vein could


 24   be too long; it could be too short; there could be


 25   a poor run-off bed; or it could be a distal or




  1   proximal anastomotic problem.


  2             [Slide]


  3             I think this is an important slide.  This


  4   is some of the science and this is based on some of


  5   the work of the E2F Decoy trial but there is an


  6   initial wave of inflammation in a venous graft.


  7   There is injury.  There is activation of smooth


  8   muscle cells.  There is migration proliferation and


  9   intimal soil, if you will, for atherosclerotic


 10   plaque and ultimately accelerated atherosclerosis.


 11   However, this initial wave is in the first two


 12   weeks after the venous graft has been harvested


 13   from the leg and placed on the heart.


 14             [Slide]


 15             This is a summary of how I look at graft


 16   failure.  I divided it into three distinct


 17   categories.  The first is immediate, that is a


 18   technical graft failure.  These are all venous


 19   grafts, by the way; it could be arterial as well.


 20   Technical failure would be identified in the first


 21   week.  In other words, if one obtained a


 22   postoperative coronary angiogram in a patient in


 23   one week technical failures would be disclosed.


 24             The next is intermediate, and this is what


 25   I relate to devices.  This is usually in the first




  1   six to eight weeks.  So, a six-month angiographic


  2   evaluation should pick up device failures.


  3             The third is chronic and this relates to


  4   accelerated atherosclerosis and this really takes


  5   years.  In the E2F Decoy trial we are looking at


  6   one year but, in fact, it probably occurs over five


  7   years.  In my opinion, if the St. Jude device had


  8   been evaluated at six months by angiography


  9   stenoses and occlusions would have been discovered


 10   that related to the device.  In other words, the


 11   intermediate category.


 12             [Slide]


 13             We now have second generation anastomotic


 14   devices.  They have proven to be more reliable than


 15   hand sewn.  There is a consistent orifice size.


 16   They are easier to use.  I think, importantly,


 17   another change that has happened with the second


 18   generation is a lack of vein manipulation.  So,


 19   these should be evaluated with six-month


 20   angiographic equivalency and we should also look at


 21   performance outcomes.


 22             [Slide]


 23             In summary, I believe the science supports


 24   six months angiographic data for the intermediate


 25   or device failure area.  Proximal stainless steel




  1   devices have demonstrated excellent patency, which


  2   will probably be discussed.  And, second generation


  3   distal devices demonstrate excellent patency.  I


  4   think we have to keep in mind as we think about


  5   this is that unlike stents for coronary-artery


  6   disease, these devices do not rearrange plaque


  7   morphology.  Thank you.


  8             DR. TRACY:  Thank you.  Are there any


  9   brief questions for Dr. Wolfe from the panel?


 10             DR. EDMUNDS:  What data do you have for


 11   that last statement?


 12             DR. WOLFE:  Which part of it?


 13             DR. EDMUNDS:  The last statement, how do


 14   you know that the device doesn't rearrange plaque?


 15   I mean I don't know.  I would just be interested in


 16   your data.


 17             DR. WOLFE:  The last statement is


 18   concerning distal devices.  This is assuming that


 19   the device is placed to a target site that is


 20   relatively free of atherosclerotic debris.  The


 21   second bullet point is for the proximal devices.


 22   The third bullet point is specifically for distal.


 23             DR. EDMUNDS:  That is what I am talking


 24   about.  Are you talking about magnetic coupling?


 25             DR. WOLFE:  Any type.  What I am trying to




  1   relate is that stents and anastomotic devices are


  2   not equal in that a stent is supposed to rearrange


  3   plaque to open up a stenosis.  For devices that we


  4   are using that is not their purpose.  We are not


  5   rearranging the plaque.  We are connecting,


  6   hopefully, a fairly normal vein or artery to a


  7   fairly normal coronary distal target.


  8             DR. BRIDGES:  I have a question about the


  9   second bullet point.  Can you also inform us what


 10   data that is based on?


 11             DR. WOLFE:  I think that will be presented


 12   by others, but I believe that the difference is


 13   that stainless steel is stronger, and in a proximal


 14   position where there is atherosclerotic disease a


 15   stainless steel device can actually hold the aorta


 16   open, whereas a nitinol device may not; it may


 17   buckle and close.  So, it is really the strength of


 18   the material.  The proximals are different from the


 19   distals.  In fact, the people that may need the


 20   proximal devices the most are the ones who have the


 21   worst aortas.  They have disease in a situation


 22   where it is maybe not safe to clamp the aorta.


 23             DR. AZIZ:  With the proximal devices, if


 24   you do get narrowing, how do you propose that be


 25   handled?  Let's say in six months you find that you




  1   have osteal narrowing, how would you handle that?


  2             DR. WOLFE:  I don't know the answer to


  3   that.


  4             DR. AZIZ:  Can they be dilated in the cath


  5   lab?


  6             DR. WOLFE:  I don't know the answer to


  7   that.


  8             DR. AZIZ:  And is there intimal


  9   hyperplasia that you are seeing, if you do see it?


 10             DR. WOLFE:  I believe so with the second


 11   generation devices.  With the first generation


 12   devices I think it was a more complicated situation


 13   where the graft could actually embrocate over the


 14   device.  But in the second generation devices it


 15   should be more related to disease in the aorta.


 16   However, if a large lumen is maintained then there


 17   shouldn't be significant stenosis.  So, let's say


 18   you get neointimal hyperplasia in every graft,


 19   let's say you get a millimeter in every


 20   graft--well, if you get a 1.5 mm opening, that is


 21   significant.  If you get a 3 mm opening that is


 22   maintained, it won't be significant.


 23             DR. AZIZ:  Let me ask you one other thing,


 24   with the proximal anastomotic devices, the angle


 25   that the graft comes off is really at right angles




  1   to the aorta.  Right?


  2             DR. WOLFE:  In some of the products, that


  3   is true.


  4             DR. AZIZ:  You mean there are ones where


  5   you can have it coming off as a cobra head?


  6             DR. WOLFE:  That is correct.


  7             DR. KRUCOFF:  Have you actually retrieved


  8   any of these devices and looked at them under a


  9   microscope when they have failed?


 10             DR. WOLFE:  I have not--well, I have seen


 11   the slides, I certainly have.


 12             DR. KRUCOFF:  Whose slides are those?


 13             DR. WOLFE:  St. Jude.  I did go over those


 14   at one point and, again, that is a first generation


 15   device and I believe the mode of failure of that is


 16   different from anything you might see in the


 17   future.  It is multifactorial but the occlusions


 18   tend to be flush with the aorta.  There is


 19   neointimal hyperplasia; there is thrombus.  First


 20   of all, the angiogram does not look like a typical


 21   angiogram that you might see with an occluded vein


 22   graft; it is completely different.  There is also


 23   the possibility that the vein graft itself has


 24   changed its position on the connector.  In


 25   addition, that was a connector that had a high




  1   profile.  There is also the possibility that there


  2   could be a right angle kink right at the end of the


  3   connector.


  4             I think in summary, I give credit to the


  5   pioneers for being the first ones out there.  The


  6   first eight patients who received a mitral valve


  7   replacement all died.  Fortunately, we still do


  8   mitral valve replacements and maybe with the first


  9   generation connectors we are seeing some of the


 10   same things, some of the mistakes.  I think many of


 11   those have been changed by changes in device and


 12   changes in material.


 13             DR. YANCY:  As you have worked through


 14   your clinical trials with these devices, have there


 15   been concomitant improvements or changes in medical


 16   management because of anticipated problems with


 17   these connectors vis-avis antiplatelet therapy,


 18   anticoagulation, aspirin, etc.?


 19             DR. WOLFE:  We do have some data from the


 20   E2F Decoy trial.  The trial has not opened but we


 21   have some demographic data.  It has been shown that


 22   when patients are followed more closely the chances


 23   of them going home on antiplatelet agents are much


 24   higher.  Although most surgeons say that they send


 25   their patients home on aspirin or some antiplatelet




  1   agent, in fact, many patients do not go home on


  2   that but in a careful study situation they do.


  3   There is a study bias.


  4             DR. YANCY:  So, those anticipated events


  5   that you thought would be predicted or captured at


  6   six months, do you think they are product failures,


  7   medical management failures or both?


  8             DR. WOLFE:  I expect they are product


  9   failures and they probably would be in an extreme


 10   environment such as a very atherosclerotic aorta,


 11   but I am not sure.  I am not sure.


 12             DR. TRACY:  I think we are going to have


 13   to move on at this point.  There is a number of


 14   other speakers.  Thanks very much.  Dr. Robert


 15   Emery?


 16             DR. EMERY:  While we are setting up my


 17   disc here, I am Robert Emery.  I am in private


 18   practice in Minneapolis-St. Paul, Minnesota.  I am


 19   not being sponsored by any companies but I have had


 20   relationships in terms of research grants by St.


 21   Jude Medical, ATS Medical, AtriCure, Congestive


 22   Heart Failure Solutions.  I have been on research


 23   advisory boards for St. Jude Medical, Medtronic,


 24   Myocor, Percardia, CardioGenesis, Inc.; data safety


 25   monitoring boards for Cardioblate and for Myocor,




  1   and I have received speaking fees for several of


  2   the aforementioned companies.


  3             [Slide]


  4             I would like to address our early


  5   experience in the Minneapolis-St. Paul area looking


  6   at why vein grafts fail, the new issues with aortic


  7   connectors.  We have been through the etiology of


  8   graft failures so I won't go into that, however,


  9   there are several new issues that are introduced by


 10   the currently used generation of connectors.  There


 11   can be overloading of the connector, that is, too


 12   much vein graft placed below the prongs;


 13   double-loading of the connector like putting on


 14   your socks where you can invert the graft and load


 15   that which inhibits flow through the graft.  You


 16   can skive the aortic punch and that make take out a


 17   complete circle.


 18             There are variations in operative


 19   technique.  For instance, performing your proximals


 20   first, as most surgical trainees in the United


 21   States perform distals first you are radically


 22   changing the way we have been trained in our


 23   everyday use in conduct of the operation.  Grafts


 24   can move.  After the patient is closed the lungs


 25   can push the grafts to various positions and this




  1   can cause loss of the 90 degree angle, that has


  2   been mentioned here, that is necessary for the


  3   current generation St. Jude connector.


  4             [Slide]


  5             Let's look at some of these issues that we


  6   have seen.  Here is a surgical technical error at


  7   the distal anastomosis that would lead to graft


  8   failure if not completed.  I don't think that could


  9   be blamed on the connector but a connector was


 10   utilized.


 11             [Slide]


 12             This is the first case I performed in the


 13   United States, the second one done in the United


 14   States after FDA approval.  You can see two


 15   technical errors here that I learned over time and


 16   if I had not changed my operative technique one


 17   would have a consistent mode of failure that would


 18   be uncorrected.  That is, these grafts are placed


 19   on top of the aorta instead of further down the


 20   side toward the pulmonary artery, therefore,


 21   maintaining a 90 degree angle.  The grafts are also


 22   reflected superiorly with some kinking at the


 23   anastomotic site, not maintaining that 90 degree


 24   angle.  As I mentioned, these grafts can move.  All


 25   grafts should be tacked to keep that important 90




  1   degree angle.  If you lose that you can predict


  2   some degree of graft failure.


  3             [Slide]


  4             There can be poor run-off, as shown on


  5   this slide, to a patent vein graft but a poor


  6   distal vessel.


  7             [Slide]


  8             Another example is shown here.  The graft


  9   can be too short, as mentioned.  Again, it may be a


 10   variation in operative technique.


 11             [Slide]


 12             Here a graft is tethered across the


 13   pulmonary artery and you can see the narrowing


 14   several centimeters distant from the connector


 15   device.


 16             [Slide]


 17             And a similar vein here wrapped around the


 18   pulmonary artery more tightly than one would like


 19   to see.


 20             [Slide]


 21             Improper placement of the graft is also


 22   important.


 23             [Slide]


 24             Here is a vein graft that was placed on


 25   the right side of the aorta as we traditionally




  1   place our saphenous vein grafts when we suture


  2   them, rather on the anterior surface of the aorta,


  3   riding over the right ventricular outflow tract


  4   maintaining the 90 degree angle.  You can see the


  5   acute bend on the right side as this graft reflects


  6   against the patient's pleural surface.


  7             [Slide]


  8             Aortic disease was mentioned and this can


  9   be important.  Here is an occluded connector in a


 10   diffusely diseased aorta and you can see, as Dr.


 11   Wolfe mentioned, the flush occlusion of the aorta.


 12             [Slide]


 13             A combination of factors--here is a small


 14   vein graft and poor run-off.


 15             [Slide]


 16             And here is a very small vein graft that


 17   has become atretic over time to a small distal


 18   vessel, still patent through the connector but,


 19   nonetheless, narrowed.


 20             [Slide]


 21             Then there is the unknown.  Here is the


 22   occluded connector again flush at the angiographic


 23   site.


 24             [Slide]


 25             Here is an occluded vein graft marked by




  1   the stainless steel ring in the same patient.  You


  2   can see the connector graft slightly to the left


  3   and one or two centimeters down in this example.


  4   There are connector related issues that are key.


  5             [Slide]


  6             This is what was addressed a little bit in


  7   the prior question, proximal anastomotic problems


  8   in the face of appropriate graft and appropriate


  9   distal connectors that need to be investigated.


 10             [Slide]


 11             Yet, there are technical issues.  Here is


 12   another proximal connector with a very good vein


 13   graft and a large distal run-off system.


 14             [Slide]


 15             Improved and more extensive training may


 16   obviate several of the modes of failure that we


 17   have seen.  We need to develop indications and


 18   contraindications for the use of these devices,


 19   particularly as they come out not just general,


 20   overall approval.  There are technical


 21   considerations that need to be mentioned.  Many


 22   modes of failure are unstudied or unconfirmed.


 23   Thus, prospective studies are warranted including


 24   operative technical detail, both visual, such as


 25   the photograph I showed you and verbal operative




  1   reports, and improved mentoring may be necessary


  2   even for devices that seem intuitively simple.


  3             [Slide]


  4             There are tips for success that I have


  5   developed in my own practice based on my


  6   experience.


  7             [Slide]


  8             What we do not want to do is throw the


  9   baby out with the bath water because these


 10   connecting devices offer us a great opportunity to


 11   improve our service to our patients.  Thank you.


 12             DR. TRACY:  Thank you.  Are there any


 13   brief questions from the panel members?  I do want


 14   to remind you that there are a lot of people who


 15   want to present today.


 16             DR. KRUCOFF:  Just one question.  The


 17   angiograms you showed us, were they part of a study


 18   protocol that required angiography or were these


 19   clinical presentations of people who came back


 20   sick?


 21             DR. EMERY:  These were clinical


 22   presentations in approximately our first eight


 23   months of use, from May, 2001 through the first


 24   eight months, and we have seen very few since we


 25   have modified our surgical techniques.




  1             DR. KRUCOFF:  And the denominator for


  2   these eight months?


  3             DR. EMERY:  It was about 160, and these


  4   are not all of them.  These are representative


  5   samples of technical errors that are correctable


  6   with proper training and changing of your


  7   techniques as you learn the process.


  8             DR. AZIZ:  When you say you tack the


  9   grafts, are you putting many anchoring stitches or


 10   what do you do?


 11             DR. EMERY:  Three or four generally on the


 12   left side.  I put one on the pulmonary artery and,


 13   again, depending on the length of the graft,


 14   because you are doing proximals first with this


 15   device, I will connect it so that it won't move


 16   with respiration.  On the right side I connect it


 17   down the body of the right ventricle as the graft


 18   goes directly up from the aorta over the right


 19   ventricle and down to the right coronary artery,


 20   the posterior descending artery, just some 6-0


 21   prolene suture tacking.


 22             DR. AZIZ:  We normally do the regular


 23   suturing technique; usually you don't have to do


 24   that?


 25             DR. EMERY:  No, I don't.




  1             DR. AZIZ:  So, why do you think you need


  2   to do it here?


  3             DR. EMERY:  Because I learned doing this


  4   distal first and I think my measurement of the


  5   length of the vein graft to the aorta is better on


  6   a distal first process in my hands.  So, sometimes


  7   I would rather make my grafts too long than too


  8   short because the shortness of the graft may be one


  9   reason for disconnection of these connectors from


 10   the aorta.  As the pulmonary artery fills, if the


 11   graft is too short you can pull these off.  I have


 12   pulled them off myself in the operating room by


 13   tugging a little bit too hard and I had to put my


 14   finger over the hole.  So, a short graft can lead


 15   to connector displacement from the aorta,


 16   particularly as the patient moves or the heart


 17   fills in the postoperative period.


 18             DR. TRACY:  Dr. Hirshfeld?


 19             DR. HIRSHFELD:  I would just like to say


 20   as an angiographer who has probably taken pictures


 21   of thousands of bypass grafts, I have heard a lot


 22   about considerations that I was never aware of


 23   before from your brief presentation, and I think it


 24   calls for a sharing of information between


 25   angiographers and surgeons about many of these




  1   technical considerations that affect graft


  2   performance.  So, I would hope that out of this


  3   will come that kind of sharing of information.


  4             DR. EMERY:  I have reviewed all the


  5   angiographs of patients that failed in my hands.


  6             DR. TRACY:  I think we have to move on; we


  7   have a number of speakers.  I am sorry to cut this


  8   short; it is very interesting.  To remind you,


  9   there will be more time this afternoon to discuss


 10   things in detail.  Dr. Schoettle?


 11             DR. SCHOETTLE:  Good morning.  My name is


 12   Dr. Phillip Schoettle.  I am a thoracic and


 13   cardiovascular surgeon in practice at Methodist


 14   University Hospital in Memphis, Tennessee.


 15             I am here this morning to discuss my


 16   experience with the Symmetry proximal anastomotic


 17   device.  I would like to disclose at the outset


 18   that I have no financial interest in this matter.


 19   I paid my own way to Washington, and I am not


 20   employed by anyone, nor intend to be employed by


 21   anybody with a financial stake in this issue.


 22             In September of 2001 I was trained in the


 23   use of the Symmetry proximal anastomotic device,


 24   along with two of my scrub assistants, by St. Jude


 25   Medical.  I was attracted to the device because of




  1   the reasons mentioned previously which would allow


  2   you to do a proximal anastomosis off the aorta


  3   without the use of a partial occluding or


  4   side-biting clamp with its attendant risk of


  5   embolic debris.


  6             I rapidly incorporated that device into my


  7   practice and used it almost exclusively for the


  8   next eleven months.  Initially I was very pleased


  9   with the results.  I had minimal, if any, technical


 10   issues with the device and was not aware of any


 11   acute or subacute saphenous vein closures.


 12   Unfortunately, at approximately ten months we began


 13   to see almost a deluge of patients returning to the


 14   cardiac catheterization laboratory with vein graft


 15   occlusions or high grade stenoses invariably


 16   occurring in the connector site.


 17             This occurrence was totally incompatible


 18   with my previous surgical experience.  I reported


 19   this to St. Jude Medical and I felt like it


 20   warranted a distribution to the surgical community


 21   and I began a review of my patients, resulting in


 22   the paper that you see here.  This paper was


 23   entitled, "Use of an Anastomotic Device in Coronary


 24   Bypass Surgery: A Word of Caution."  It was


 25   published in the January edition of the Journal of




  1   Thoracic and Cardiovascular Surgery.


  2             Without going into great detail, I would


  3   like to summarize the results of that paper.  It


  4   was a review of two years of experience.  The first


  5   year was the year prior to my beginning to use the


  6   device, while proximal saphenous vein connections


  7   off the aorta were done in the conventional manner,


  8   that is, hand-sewn with a partial occlusion clamp.


  9   Beginning in September of 2001, for the next eleven


 10   months, comprises the next group of patients where


 11   almost exclusively all proximal anastomoses were


 12   done with the St. Jude Symmetry anastomotic device.


 13             I divided the group in group A and group


 14   B.  Group A was the first group, the prior year


 15   with hand-sewn anastomoses.  I reviewed all


 16   patients who required repeated cardiac


 17   catheterization after coronary artery bypass


 18   surgery.  What we found was that even though the


 19   patients in group A had had a year longer of


 20   exposure to my cardiology colleagues, less of those


 21   required repeated cardiac catheterization, although


 22   that number was not significant between the groups.


 23             The number of grafts studied between group


 24   A and group B was also similar.  However, what we


 25   did find was that the group A patients, those with




  1   hand-sewn anastomoses, had an 80 percent patency


  2   rate of vein grafts studied.  Remember, these were


  3   symptomatic, or at least theoretically symptomatic


  4   patients.  So, 80 percent of the grafts were widely


  5   patent in the hand-sewn anastomoses, with no


  6   significant stenoses, and 20 percent were


  7   occluding.


  8             Unfortunately, in the group B patients,


  9   those with the Symmetry proximal anastomotic


 10   device, only 20 percent of the grafts studied were


 11   patent.  Fully 80 percent of the grafts were either


 12   totally occluded or had high grade stenoses


 13   uniformly occurring at the connector site.  The


 14   significance in p value in favor or patency of the


 15   hand-sewn anastomoses was standardly evaluated with


 16   a p value of 0.0001.


 17             Based on my experience with the Symmetry


 18   proximal anastomotic device and review of my own


 19   patients, I have several observations and two


 20   conclusions I would like to make.  The use of the


 21   Symmetry St. Jude proximal anastomotic device in


 22   its current generation results in a significantly


 23   higher saphenous vein closure and occlusion rate


 24   when compared to hand-sewn anastomoses.


 25             I do not believe that technical issues are




  1   the major factor.  I can show you arteriograms of


  2   what appear to be perfectly laid out saphenous vein


  3   grafts with a 90 degree angle off the aorta, with


  4   no kinking, where the stenosis arises immediately


  5   in the connector site off the aorta.


  6             In two patients that I reoperated, I was


  7   able to harvest the segment of aorta with the


  8   connector and the saphenous vein.  This was looked


  9   at microscopically by the pathologists in my


 10   hospital who reported basically a foreign body


 11   reaction in the connector site with associated


 12   neointimal hyperplasia.


 13             I would also point out that these


 14   connector stenoses and occlusions are not


 15   clinically insignificant.  In this group at least


 16   six patients have required early reoperation.


 17   Thirty patients, over a year ago, required PCI


 18   stents and angioplasty.  There have been four


 19   sudden deaths in these patients, two of which were


 20   almost certainly related to myocardial infarction.


 21             If I can have the liberty of making a


 22   conclusion, I see no clinical indication for the


 23   current generation of the St. Jude proximal


 24   connector.  The use of this connector or any other


 25   vascular anastomotic devices must be evaluated by




  1   scientifically controlled, prospective clinical


  2   trials.


  3             I do not believe that uneducated surgeons


  4   and uninformed patients should be the testing


  5   ground for these devices that have not proven to be


  6   clinically safe or effective.  I clearly am not


  7   opposed to technological advances in coronary


  8   bypass surgery.  I have been an early proponent of


  9   off-pump surgery and less invasive coronary


 10   surgery.  I do not want to throw the baby out with


 11   the bath water.  I do not believe, however, that


 12   the cause of less invasive coronary artery bypass


 13   surgery is furthered by the ill-advised use of


 14   these unproven devices.  Thank you.  I would be


 15   glad to answer questions if there is time.


 16             DR. TRACY:  Any brief questions?  Dr.


 17   White?


 18             DR. WHITE:  Would you just clarify for me,


 19   in the early part of your statement you said


 20   something about follow-up at ten months.  Was there


 21   a ten-month interval that was special to you?


 22             DR. SCHOETTLE:  No, I believe it just


 23   would have become apparent to me, you know, with


 24   just the overwhelming evidence of patients.  All of


 25   a sudden I was getting call after call from these




  1   patients.


  2             DR. WHITE:  Would six months not have


  3   identified these patients?  Would a six-month


  4   follow-up, do you think, not have been adequate?


  5             DR. SCHOETTLE:  I was asked that question


  6   last night.  I don't have that answer.  My gut


  7   feeling is that six months would probably be


  8   appropriate but I don't know that answer based on


  9   this review.


 10             DR. BRIDGES:  I have a question.  In the


 11   brief study that you gave us I didn't see the


 12   mortality in the two groups.  You said that there


 13   were no sudden deaths in the hand-sewn group but


 14   what was the overall mortality in the two groups


 15   and are there any updates since this paper was


 16   submitted?


 17             DR. SCHOETTLE:  The operative mortality


 18   was less than three percent but the overall


 19   mortality long-term, I don't have that; there have


 20   been no updates at this point although I intend to


 21   do that.


 22             DR. BRIDGES:  But both groups--


 23             DR. SCHOETTLE:  They were very similar.


 24             DR. BRIDGES:  At least for the graft


 25   connector patients, what would be medical therapy




  1   for these?


  2             DR. SCHOETTLE:  It is in the paper, but


  3   all patients were discharged on aspirin and all


  4   patients were discharged on Plavix for two months.


  5             DR. AZIZ:  But when you had to reoperate


  6   on them did you have to redo the whole anastomosis


  7   or could you immobilize it and rehook it?  How did


  8   you do that?


  9             DR. SCHOETTLE:  In a couple of cases I was


 10   able to continue to use that vein segment.  Conduit


 11   length was an issue.  Several of the veins were


 12   totally occluded and we just had to sacrifice those


 13   veins.


 14             DR. AZIZ:  So, the orifice was like the


 15   whole length?


 16             DR. SCHOETTLE:  That is correct.


 17             DR. AZIZ:  So, you probably had intimal


 18   hyperplasia proximally and you had full flow and


 19   then thrombus--


 20             DR. SCHOETTLE:  And then thrombus


 21   distally, correct.


 22             DR. AZIZ:  Obviously most people don't,


 23   and they probably should use some flow techniques


 24   to measure flows.


 25             DR. SCHOETTLE:  All patients in both




  1   groups had mediastinal transit time flow evaluation


  2   at the time of surgery, and 95 percent of cases


  3   were done off-pump.


  4             DR. AZIZ:  When you did proximal


  5   anastomoses with the device did you do any


  6   sequential grafts--


  7             DR. SCHOETTLE:  No, they were sequential


  8   grafts but I don't have that number available to


  9   me.


 10             DR. TRACY:  Thank you.


 11             DR. SCHOETTLE:  Thanks.


 12             DR. TRACY:  Dr. Frater?


 13             DR. FRATER:  Let me state immediately I am


 14   the Medical Director of St. Jude and, obviously,


 15   have that as a conflict of interest.


 16             I have a few points to make.  I had


 17   expected ten minutes so I am going to try and make


 18   them quickly.  I think we can all agree that the


 19   MDR system is a warning light that tells us nothing


 20   about incidence and, unless we are very lucky,


 21   doesn't give us much information on causality, hard


 22   as we try to look into every single report that


 23   comes in from the field.  I shall not elaborate on


 24   that.  I suspect the FDA feels the same about the


 25   MDR's utility as we do.




  1             The question of comparing anastomotic


  2   devices to historically published data for sutures


  3   is an interesting one.  The data that was obtained


  4   in the past has been cardiac surgeons who were


  5   trying to find out what they were doing 30 years


  6   ago when they were making venous anastomoses.  The


  7   patients were younger.  The vessels were better.


  8   The extra conditions, such as diabetes, were far


  9   less common and it was a different group of


 10   patients.  Those patients have long since been


 11   captured by the interventionalists and the cardiac


 12   surgeon today faces a very different patient.


 13             We need to know what the patency rates are


 14   today with the current set of patients.  We also


 15   need to know what the difference may be between


 16   off-pump and on-pump.  There was a paper presented


 17   just a few weeks ago at the ACC, the so-called Prog


 18   IV Trial, a randomized comparison between off-pump


 19   and on-pump surgery with angiography at one year.


 20   The patency rate of the cases performed on-pump at


 21   one year was 59 percent; the patency rate of those


 22   performed off-pump was 49 percent.


 23             There is a paper being published in The


 24   New England Journal of Medicine by Kahn.  It came


 25   out of Britain.  Again, a randomized study of




  1   on-pump and off-pump anastomoses studied at three


  2   months by angiography, which was performed in 80


  3   percent of the patients in the trial.  The patency


  4   rate of the on-pump cases was exemplary.  At three


  5   months they had a 98 percent patency rate but the


  6   off-pump cases had an 88 percent patency rate at


  7   three months.


  8             I present this material, which is clearly


  9   important in trying to assess what will be the


 10   target of patency that we will be looking at in


 11   future trials, and a recognition that times have


 12   changed and circumstances are clearly very


 13   different.


 14             We have done a meta-analysis of some 7,000


 15   patients in which angiograms were done between 6


 16   and 12 months.  We chose that 6- and 12-month


 17   period for the obvious reason that you have already


 18   heard today, that after 12 months atherosclerosis


 19   dominates the failure of vein grafts.   The mean


 20   occlusion rate was 16 percent in this meta-analysis


 21   between 6 and 12 months of sewn anastomoses.  But


 22   the range was from 9.5 to 26.5.  There is an


 23   immense diversity from different institutions and


 24   we can speculate forever, certainly not in five


 25   minutes, as to what the reasons for those




  1   differences are.  I am sure that the surgeons in


  2   the Prog IV study have not suddenly become


  3   incompetent; there are factors that we need to look


  4   at.


  5             The question of the extent to which


  6   clinical utility data is considered to be


  7   necessary, I think we have already begun to deal


  8   with this.  Six months seems to be a period of time


  9   that people are reaching, and that is not


 10   unreasonable considering that stents are a Class


 11   III device which may or may not be identical to


 12   anastomotic devices--that is debatable--are being


 13   evaluated with MACE and target vessel interventions


 14   at six months.


 15             Certainly, it is reasonable to state that


 16   it should not be more than 12 months for the


 17   obvious reason that by then atherosclerotic disease


 18   dominates.  There is intimal damage and technical


 19   factors in the first week, neointimal hyperplasia


 20   for the next few months, blending finally into


 21   atherosclerotic disease.


 22             Now, it is essential that the FDA provide


 23   clarity on the type of clearance that we need.  If


 24   the clinical data requirement reaches the point


 25   which would normally be required for a PMA, then it




  1   should be a PMA.  If you are required to produce


  2   the data for a PMA, then the process should be done


  3   under a PMA process.  Thank you very much.


  4             DR. TRACY:  Any questions?


  5             DR. WEINBERGER:  I have a question for


  6   you.  You said that you were concerned that the


  7   follow-up should be at six months because you


  8   thought that atherosclerosis dominates the


  9   subsequent natural history of graft failure.  I am


 10   concerned because we have a pretty good idea that


 11   there is distinct biological heterogeneity in


 12   different vascular beds in terms of the kinetics of


 13   responses to manipulation.  For instance, we know


 14   that for coronary interventions basically at six to


 15   nine months the process is over.  But if you look


 16   in the periphery, like the iliacs, the usual time


 17   is three years.  Do you have any data to suggest


 18   that the process to response to injury in vein


 19   grafts is over at nine months?


 20             DR. FRATER:  Well, if you look at the data


 21   from peripheral vascular intervention where it is


 22   far easier to follow the patients, it seems fairly


 23   definite that while there is an acute phase, which


 24   is partly technical and partly because of the


 25   damage we do to the vein by the various things we




  1   do when we take it out and manipulated it, it


  2   starts in the first week.  The neointimal


  3   hyperplasia seems to blend at 12 months in these


  4   peripheral vascular studies with the


  5   atherosclerotic process.  It would seem reasonable,


  6   if there is an atherosclerotic process taking place


  7   in veins after 12 months, not to attribute that to


  8   how we handled the vein at the time of the initial


  9   anastomosis.


 10             DR. WEINBERGER:  Just one follow-up, if


 11   there is any kinking in the vein and you have a


 12   jet, that jet wouldn't lead to an accelerated


 13   atherosclerotic process later on as well?


 14             DR. FRATER:  It would happen far quicker


 15   than that.  Usually, if you leave a kink in a vein


 16   there is a consequence that is soon and definite.


 17             DR. WEINBERGER:  Data?


 18             DR. FRATER:  Data?  Clinical experience.


 19   I am a cardiac surgeon.


 20             DR. TRACY:  Dr. Bridges?


 21             DR. BRIDGES:  Yes, there are two points.


 22   One is to echo Dr. Weinberger's point that I don't


 23   think we know exactly.  There is nothing to suggest


 24   that there can't be an interaction between


 25   mechanical factors and atherosclerosis that extends




  1   beyond one year.  To say that you can divide these


  2   into two discrete processes that are technical,


  3   device related and then atherosclerosis I think is


  4   unsubstantiated and you can't really defend that.


  5             Furthermore, I am sure we are going to


  6   hear from Dr. Mack but his own data that was


  7   presented at the STS meeting, just in January,


  8   showed, at least in his series which I am sure he


  9   will comment on, that it was not until you got out


 10   beyond one year that you started to see a


 11   difference in MACE, that is, you know,


 12   cardiovascular events.  So, that, in and of itself,


 13   also suggests that the idea of only looking at a


 14   one-year or six-month time period is clearly going


 15   to result in us missing failures.


 16             DR. FRATER:  The obvious issue is how long


 17   would you like it to be?  Clearly, it becomes


 18   extraordinarily difficult if you are suggesting


 19   that we should wait five years, or something like


 20   that.  Dr. Mack can speak for himself but I believe


 21   that in diabetes there was a difference and there


 22   may well be factors like that that make a


 23   difference.


 24             DR. BRIDGES:  My point is not to suggest


 25   how long we need to look, I am simply objecting to




  1   the concept that we can definitively or


  2   declaratively state at this point, based on what


  3   evidence we have, that we know that six months or


  4   nine months is an acceptable time frame in order to


  5   exclude device-related issues.


  6             DR. TRACY:  Dr. Yancy, and then if there


  7   is time Dr. Maisel.


  8             DR. YANCY:  Just a very short yes/no


  9   question.  I have not seen the referred to NEJM


 10   article comparing on-pump versus off-pump surgery.


 11   Were connectors used in the off-pump cases?


 12             DR. FRATER:  This was absolutely a study


 13   of on-pump versus off-pump vein patency.


 14             DR. TRACY:  Dr. Maisel?


 15             DR. MAISEL:  You have eloquently stated


 16   that times have changed and that historical


 17   controls are just that, historical, and you stated


 18   data that the patency rates vary greatly from


 19   institution to institution.  In many respects that


 20   is a strong argument for randomized trials but you


 21   didn't come out and state that.  Are you a


 22   proponent of randomized clinical trials to assess


 23   these devices?


 24             DR. FRATER:  You know, in the best of all


 25   possible worlds, yes.  I am speaking as a cardiac




  1   surgeon now.


  2             DR. TRACY:  Thank you.


  3             DR. EDMUNDS:  Did I hear you say that the


  4   one-year patency rate for off-pump proximal veins,


  5   the occlusion rate was 9-26 percent?


  6             DR. FRATER:  In the meta-analysis that we


  7   did between 6 and 12 months, there was a range from


  8   9.5 to 26.5 percent in this meta-analysis of some


  9   7,000 cases.  In the Prog IV study--


 10             DR. EDMUNDS:  For hand-sewn?


 11             DR. FRATER:  Hand-sewn anastomoses, in the


 12   Prog IV study the patency rate was 59 percent


 13   patent at one year on pump, 49 percent patent


 14   off-pump.  It was just presented at the ACC.


 15             DR. TRACY:  We do have to move on, I am


 16   sorry.  Dr. Mack?


 17             DR. MACK:  My name is Michael Mack and I


 18   am a cardiac surgeon in Dallas.  By way of


 19   disclosure, I am not sponsored by anybody today.  I


 20   paid my own way here.  I have served as a


 21   consultant in the past at St. Jude, also to


 22   Cardica.  I have received research grant support


 23   from St. Jude regarding anastomotic devices, and I


 24   am also on the scientific advisory board for


 25   Medtronic and Guidant, both of which have equity




  1   interests in anastomotic device companies.


  2             The thrust of my presentation was to


  3   discuss saphenous vein graft patency and not our


  4   own St. Jude device paper, which has been


  5   presented, in view of the fact that I only have


  6   five minutes but I will try and get this done in


  7   four and just spend the last minute discussing


  8   that.


  9             [Slide]


 10             Specifically, what I would like to discuss


 11   is I thought until I looked at all this that I knew


 12   what the gold standard for saphenous vein graft


 13   patency was.  Eeverybody throws around numbers but


 14   until I did a meta-analysis of the literature I


 15   really didn't know, and this is specifically to


 16   address the trial design question number one of the


 17   FDA, the gold standard of sutured anastomoses had a


 18   well-documented history of over the past thirty


 19   years, and I would like to go over those thirty


 20   years right now--


 21             [Slide]


 22             --or the why of saphenous graft failure in


 23   five minutes.


 24             [Slide]


 25             Since between 1979 and 2001 there have




  1   been thirty studies published, analyzing a total of


  2   28,081 grafts.


  3             [Slide]


  4             Factors impacting the studies are


  5   angiogram survivors.  You lose early graft


  6   occlusions resulting in death so, therefore, you


  7   are automatically losing patency in any angiogram


  8   series because you can only angiogram survivors.


  9   Studies are impacted by the completeness of


 10   follow-up, the percent of patients actually


 11   undergoing angiograms, and whether the study was


 12   done as a surveillance study or done for cause.


 13             [Slide]


 14             If we look at a meta-analysis of all


 15   studies that looked at 30 days or less, there has


 16   been a total of 11,000 grafts looked at.  If you


 17   just skip to the number at the bottom right, the


 18   patency rate at 30 days in these 7 studies,


 19   comprising 11,000 grafts, is 87.8 percent.


 20             [Slide]


 21             If you now look at 3 to 6 months and look


 22   at the 10 studies published here, with a total of


 23   2,290 grafts, at 3 to 6 months 84 percent is the


 24   saphenous vein graft patency.


 25             [Slide]




  1             If we now go to 12 months and look at the


  2   13 studies comprising almost 12,000 grafts, the


  3   patency rate is 82.7 percent in the literature.


  4             [Slide]


  5             Lastly, if we look at 2 to 5 years, with a


  6   total of 3,100 grafts in these 3 studies, the


  7   patency rate between 2 and 5 years is 74.3 percent.


  8             [Slide]


  9             If we summarize all this, there is a


 10   significant attrition in the literature of about 12


 11   percent of vein grafts in the first 30 days.


 12   Between 30 days and 3-6 months another 3 percent of


 13   grafts are lost at that point.  If we go between


 14   3-6 months to 12 months another 1.5 percent of


 15   grafts are lost.  Then there is a slightly greater


 16   attrition from 2 to 5 years.  If you look at


 17   overall graft patency of all 28,000 grafts done at


 18   any time, it is 84 percent.


 19             [Slide]


 20             Variables known to impact graft patency


 21   include age, gender, diabetes and how well the


 22   diabetes is controlled, obesity, which vessel is


 23   bypassed, the LAD, the circ. or the right, the


 24   target vessel size, the presence of distal disease,


 25   the size of the vein graft, harvest injury, whether




  1   an endarterectomy was done, what the graft flow at


  2   time of implant was, individual versus sequential


  3   vein grafts, how much myocardium was supplied, what


  4   the ventricular function of the patient was,


  5   whether lipid management was tightly controlled,


  6   whether antiplatelets were used, surgeon


  7   experience.


  8             [Slide]


  9             Variables that are not known how they


 10   impact on graft patency has been alluded to.


 11   Whether it is done on a beating heart or an


 12   arrested heart.  That recently has been called into


 13   question.  And whether anastomotic connectors


 14   impact positively or negatively on the saphenous


 15   vein graft patency.


 16             [Slide]


 17             I think how you design your study you can


 18   get 100 percent patency at ten years if you do an


 19   LAD, do it as a sequential and a three millimeter


 20   target with no distal disease, use a small vein,


 21   have a large run-off in a thin male that does not


 22   have insulin-dependent diabetes and normal ejection


 23   fraction, does not have a hypercoagulable state, is


 24   on antiplatelet agents and is well controlled with


 25   statins.  On the other hand, you can do the




  1   converse of all those and you will end up with a 10


  2   percent patency rate in less than 30 days.


  3             [Slide]


  4             In conclusion, I think that many variables


  5   other than anastomotic connectors impact graft


  6   patency.  Angiography is the only reliable method


  7   to determine patency.  Meta-analysis reveals an


  8   overall saphenous vein graft patency of 80-85


  9   percent.  There is no significant difference from


 10   3-6 months versus 12-16 months or, for that matter,


 11   even between 30 days and the latter two endpoints.


 12   An angiographically normal graft at the earlier


 13   study times is often likely to develop occlusion on


 14   later follow-up and, in my opinion, a 6-month


 15   angiographic endpoint is adequate to evaluate graft


 16   patency with anastomotic devices.


 17             Real quickly regarding our experience, it


 18   has been published on the St. Jude device.  We did


 19   find that there were events that happened after six


 20   months.  These were clinical events.  The study


 21   that we performed was very similar to Dr.


 22   Schoettle's.  We took a one-year experience with


 23   the St. Jude device and compared it to one-year


 24   previously with a similar cohort of patients and


 25   found that there was a higher incidence of clinical




  1   events in the St. Jude patients.  However, these


  2   were all limited to diabetics.  We looked at the


  3   non-diabetic population and we looked at all


  4   possible variable by logistic regression diabetes


  5   was the only thing that sorted out.  The


  6   confounding variable in all this is that all these


  7   procedures were also done on a beating heart.


  8   Thank you.


  9             DR. TRACY:  Thank you.  Panel, you have 4


 10   minutes and 36 seconds to ask questions.  Any


 11   questions?  Dr. Weinberger?


 12             DR. WEINBERGER:  In surgical literature


 13   everyone seems to focus on patency.  Are you


 14   interested at all in morphology, like quantitative


 15   angiography looking at 30 percent stenosis, 40


 16   percent stenosis?  Is that information valid to


 17   surgeons?


 18             DR. MACK:  Absolutely.  Because I do think


 19   that that is a precursor of potential total


 20   occlusion.


 21             DR. WEINBERGER:  And if that is the case,


 22   are your angiographic colleagues who have looked at


 23   these connectors able to assess the morphology


 24   right around the metallic connector adequately?


 25             DR. MACK:  I think the answer is yes.




  1             DR. KRUCOFF:  Not being as familiar with


  2   the surgical literature, in this list you sort of


  3   ended with do you think there is sufficient data to


  4   create a real propensity score in planning a trial?


  5             DR. MACK:  Yes.


  6             DR. KRUCOFF:  To actually create risk


  7   categories that could be sufficiently evaluated in


  8   new populations?


  9             DR. MACK:  Yes, I do.  I think that


 10   everything I listed there--one study or another has


 11   listed those factors implicating graft patency and,


 12   yes, I think you can develop a propensity score.


 13             DR. TRACY:  Dr. Edmunds?


 14             DR. EDMUNDS:  Mike, you said that all of


 15   these were off-pump bypasses.


 16             DR. MACK:  In our St. Jude experience,


 17   yes.


 18             DR. EDMUNDS:  Were they mostly right


 19   grafts?


 20             DR. MACK:  First of all, we did not have


 21   any connectors placed to the LAD so they all went


 22   to diagonal circumflexes or right, and which vessel


 23   it went to, in our experience, did not sort out as


 24   a factor.


 25             DR. EDMUNDS:  But non-LAD?




  1             DR. MACK:  All non-LADs.


  2             DR. EDMUNDS:  And these were surveillance


  3   angiograms, not for symptoms?


  4             DR. MACK:  No, the surveillance was


  5   clinical events only.  The only angiograms--


  6             DR. EDMUNDS:  So, you have bias towards


  7   symptomatic patients.


  8             DR. MACK:  The endpoint was not


  9   angiography.  The endpoint of our study was


 10   clinical events, major adverse events at now two


 11   years of follow-up.  We did not do a specific study


 12   angiogramming the patients.  The only angiograms we


 13   had was in patients that were done for cause.


 14             DR. EDMUNDS:  The 28,000 patients were


 15   from 30 studies, weren't they?


 16             DR MACK:  Okay, I am mixing up your


 17   question then.  Ask again, Hank.


 18             DR. EDMUNDS:  Well, the cohort of 28,081


 19   angiograms was from 30 papers--


 20             DR MACK:  Right.


 21             DR. EDMUNDS:  --and were those


 22   surveillance angiograms or for symptoms?


 23             DR. MACK:  I am sorry, I thought you were


 24   talking about our own experience with the


 25   connectors.




  1             DR. EDMUNDS:  No, I am sorry, Mike.


  2             DR. EDMUNDS:  No, all of those were


  3   surveillance.  Any that was done for cause and I


  4   did not include in that.  All those were


  5   surveillance studies.  Similarly, there were a


  6   couple of other studies that looked at just


  7   saphenous vein graft, the LAD, I did not include


  8   those because those were abnormally high.


  9             DR. TRACY:  Dr. Bridges, did you have a


 10   question?


 11             DR. BRIDGES:  My question really is that


 12   given that in the results you presented recently


 13   there was a difference in major adverse


 14   cardiovascular events, I guess in the manuscript


 15   that I have seen a draft of it was limited to


 16   diabetic patients.  However, those were non-insulin


 17   dependent diabetics, I believe, and I was wondering


 18   if you had a hypothesis as to why non-insulin


 19   dependent diabetics would be different than insulin


 20   dependent diabetics.  Given that, should we be then


 21   separating diabetics from everyone else in terms of


 22   determining the applicability of these devices?


 23             DR. MACK:  That is an excellent question,


 24   and we were a little bit surprised to find that


 25   that was the case also because from the stent




  1   experience you would expect it would be more so in


  2   insulin dependent diabetics but such was not the


  3   case.  We have hypothesized that perhaps it was due


  4   to the fact that with non-insulin dependent


  5   diabetic oral agents the blood sugar is not as


  6   tightly controlled, but we have no proof; it is


  7   total hypothesis.


  8             I also think that the way that we look at


  9   diabetes now, today, is totally blurring the line


 10   between insulin dependence and non-insulin


 11   dependent diabetics.  I think we have a lot of


 12   metabolic syndrome patients who are actually Type 2


 13   diabetics but are insulin dependent and we are


 14   actually categorizing them as insulin dependent


 15   when, in fact, they really should not be.


 16             DR. TRACY:  Thank you.  Dr. Slaughter?


 17             DR. SLAUGHTER:  Thank you.  I was asked to


 18   speak today on behalf of Converge, and I am a U.S.


 19   investigator for their ongoing trial for distal


 20   anastomotic studies and they did pay my travel here


 21   but I have no other financial relationship with


 22   them.


 23             [Slide]


 24             To date so far we have heard predominantly


 25   about proximal anastomotic devices and what I would




  1   like to do is to tell you a little bit about a


  2   current and ongoing look at distal anastomotic


  3   devices.


  4             [Slide]


  5             Certainly, this comes up in many issues


  6   and I don't think we need to belabor the fact but


  7   perhaps at the end I will comment briefly on some


  8   of the other questions asked, but there is still no


  9   question, and it is really sort of one of the


 10   unspoken issues for any outcome for the patient,


 11   and that is, you know, the quality of anastomosis


 12   and the overall revascularization and long-term


 13   patency.  Certainly surgeon skill is very


 14   important.  There are also the other issues of the


 15   anatomy, disease state, access and visibility that


 16   would affect these things.  But all these things


 17   are very important in determining not only acute


 18   but long-term graft patency and the overall outcome


 19   for the patient.


 20             [Slide]


 21             This has been brought up now several times


 22   and I think is very important.  This is just


 23   another way of presenting it.  It is looking at


 24   sort of the time scale injury.  That is, as was


 25   brought up by Dr. Weinberger as well, there is no




  1   question that there is good information and good


  2   data as to the initiation of the injury,


  3   inflammation and then subsequently intimal


  4   hyperplasia.  As a rule of thumb, the idea is that


  5   within, say, six to eight weeks the injury has


  6   stopped.  I don't think anybody in their right mind


  7   would argue that there is not heterogeneity and


  8   certainly there are differences within patients.


  9   Certainly that would show up as stenosis and


 10   changes in morphology, as you mentioned.


 11             But the idea is there is reasonably good


 12   science and information to suggest that within


 13   about 60 days a vascular anastomosis has healed,


 14   particularly within the coronary-arterial tree.


 15   So, beyond that time, if there are graft failures,


 16   the question is what are they due to, and it is


 17   generally due to ongoing atherosclerosis, intrinsic


 18   patient factors and/or perhaps a lack of medical


 19   therapy such as antiplatelet agents, aspirin and/or


 20   Plavix.


 21             So, you know, if hand-sewn anastomosis is


 22   so perfect, why are we here today?  The issue is


 23   they are not perfect and there certainly is room


 24   for improvement.  Certainly, by hand sewing in a


 25   bad distal vessel it is calcified in a diabetic. 




  1   They have lateral calcification.  By piercing them


  2   with needles--we all had that experience, you end


  3   up with plaque rupture.  You have hemorrhage within


  4   the media.  The idea is this is a traumatic event.


  5             [Slide]


  6             The other is reliability.  The issue is


  7   how can you do it day to day, 20,000 a year.  The


  8   idea is  you want to make it as reliable as


  9   possible and it needs to be reproducible between


 10   different surgeons at different institutions.


 11             The other is it must be reversible.  The


 12   idea is if you don't like it you have to cut the


 13   suture, take it out and redo it.  You want to be


 14   able to do the same thing, perhaps in a less


 15   traumatic fashion, with a coupler device.


 16             The other is it must be easy to use.  The


 17   idea is if anybody walks up to the podium and is


 18   giving you a talk, they basically should all be


 19   able to have the same results without any


 20   significant extensive training.


 21             The other is I think we do need to realize


 22   there are differences between proximals and


 23   distals.  I don't think we need to spend a lot of


 24   time on this today but the main two differences are


 25   the flow dynamics which clearly are different at




  1   the proximal and distal ends, as well as tissue


  2   characteristics.  On the tissue characteristics, on


  3   the right it is either going to the aorta or vein


  4   aorta or artery depending on which you conduit you


  5   use.  Certainly for distal anastomoses what you are


  6   looking at is vein to coronary artery or an


  7   arterial conduit to an artery but it is a very


  8   different scenario.


  9             Also, with flow dynamics there is no


 10   question that the size or the shape of the opening


 11   or the angle of the take-off is very important, the


 12   pressure differential, as well as the vessel


 13   diameter throughout the length.


 14             [Slide]


 15             I think one other issue which hasn't been


 16   brought up today which does need to be mentioned,


 17   at least just to bring it up, is actually the type


 18   of material.  I think this sort of goes into the


 19   heterogeneity or perhaps ongoing injury to intimal


 20   hyperplasia.  These are not new materials.  They


 21   have all been used before.  They have all been used


 22   in intravascular scenarios and the idea is there is


 23   good evidence to suggest, whether it is nitinol,


 24   stainless steel, titanium, that they are


 25   compatible, and I don't think that we can sort of




  1   imply or say that they are intrinsically the source


  2   of perhaps later stenoses or some ongoing failures


  3   beyond the eight-week time period.  Certainly there


  4   is the heterogeneity of healing in some patients


  5   but it is a relatively small number.  It is like a


  6   cheloid.  Some patients get cheloids but not all.


  7   The answer is you see it as it progresses.  If you


  8   follow them and you look for it you can identify


  9   who those patients are.


 10             [Slide]


 11             I would like to just show you a histologic


 12   series which I think is interesting in helps people


 13   visualize.  Really the sort of best description I


 14   think for the Converge distal anastomotic device is


 15   that of sort of a compression clip.  The idea is it


 16   is two frames which are expandable.  In the upper


 17   right it sort of gives you the diagrammatic picture


 18   of a graft into the artery.  The important thing


 19   here is that you now are able to mechanically


 20   manipulate flow dynamics as well as other


 21   engineering aspects so you get a perfect 30 degree


 22   take-off; you get perfect dynamics.  You won't get


 23   turbulence at the site of the anastomosis.


 24             The left side shows the bypass graft,


 25   which is CABG going down to the circumflex artery. 




  1   I think the important thing here is this was done


  2   at 90 days but, once again, the idea is it is


  3   completely endothelialized so the idea is if you


  4   get an angiogram at six months and you have a


  5   normal lumen you have no narrowing.  The idea is


  6   are you going to have ongoing intimal hyperplasia


  7   that would be an unexpected finding?  I think the


  8   answer is no.


  9             DR. TRACY:  If you could finish up in the


 10   next few sentences.


 11             DR. SLAUGHTER:  Sure, I can finish up in


 12   about 30 seconds.


 13             [Slide]


 14             The idea is you see very clearly that it


 15   is a well healed anastomosis and you have the


 16   advantages.


 17             [Slide]


 18             This has already been brought up.  The


 19   idea is are historical controls acceptable?  I


 20   think the answer is yes.


 21             [Slide]


 22             There is no question there is lots of


 23   existing data.  We have also lots of information to


 24   suggest not only at seven days but at years out


 25   that you can evaluate intimal hyperplasia.




  1             [Slide]


  2             Certainly angiography--we know the causes


  3   of failure, early failure and what we need to do is


  4   differentiate between a device failure and ongoing


  5   atherosclerosis.


  6             [Slide]


  7             I will just show--


  8             DR. TRACY:  I am sorry, we are just going


  9   to have to cut this off if we are going to have


 10   time for questions from the panel.


 11             DR. SLAUGHTER:  I apologize.


 12             DR. TRACY:  We have three minutes left for


 13   questions from the panel.  Anybody?  Dr. Hirshfeld?


 14             DR. HIRSHFELD:  I would just point out


 15   that in the coronary stent experience if we used a


 16   two-month follow-up we never would have discovered


 17   restenosis.


 18             DR. TRACY:  Dr. Krucoff, did you have a


 19   comment?


 20             DR. KRUCOFF:  I would just also say that


 21   in the stent experience I think if we started with


 22   historical controls based on lung literature, we


 23   would have left a lot of important information out.


 24             DR. SLAUGHTER:  I think the one difference


 25   though, and this has come up I think in other




  1   discussions with the FDA panel, is that although it


  2   uses a similar material and it is stent-like, it is


  3   not a stent.  The idea is it is just the edges that


  4   are present along the edges of the coronary artery.


  5   It is not compressed plaque and the idea is it is


  6   very different.  It is really sort of a compression


  7   clip that applies the vein graft to the distal


  8   coronary artery.


  9             DR. TRACY:  Dr. White?


 10             DR. WHITE:  I think there is no evidence


 11   for that, and I think everything that we have heard


 12   today sounds like it is a stent, although a stent


 13   in a graft.  So, the question would be if you don't


 14   believe it is a stent, then you should show us data


 15   that suggested that intimal hyperplasia within the


 16   tube is not the primary cause of these closures.


 17             DR. SLAUGHTER:  Sure.


 18             DR. YANCY:  And because of that, I think


 19   it is even more important to state that historical


 20   controls would be really problematic I think.


 21             DR. TRACY:  Any other comments from the


 22   panel?


 23             [No response]


 24             Thank you.  Is Mr. Lotti here?


 25             [No response]




  1             We will move on then to Dr. Martin.


  2             DR. MARTIN:  Good morning.  As so many


  3   members of the panel have already suggested,


  4   including Dr. White, I can make my comments brief.


  5   My name is Dr. Frank Martin.  I am Chairman of the


  6   Department of Cardiology at Methodist Care in


  7   Memphis, one of the largest private hospitals in


  8   the country.  I have no financial ties with any


  9   anastomotic device companies or, for that matter,


 10   any stent companies.


 11             My historical experience, I trained with


 12   John Simpson back in 1985, '86, and have


 13   relationships with many of the members of this


 14   panel.  I trained with people who are icons today,


 15   like Paul Yak, Paul Tierstien, Dean Keriakus, Met


 16   Selman, Morris Bookbinder, Rock Califf, Eric Topal


 17   and did interventional cardiology until


 18   approximately four years ago and made a life style


 19   change, and now I do only diagnostic caths and do


 20   my chairmanship.  Also as discussed earlier, in the


 21   late 1980s, with Dr. Chris White, we did brachy


 22   therapy because some of the early DCA slides showed


 23   needle intimal hyperproliferation similar to


 24   cancer.


 25             That having been said, I, as many of you




  1   all, have honed this sixth sense of skill with


  2   cardiology over the last 15 years of practice.  Dr.


  3   Phil Schoettle, who has already presented here


  4   today, and I have worked collaboratively for the


  5   last 20 years.  We basically make a good team


  6   because he knows what I do and I know what he does.


  7             Our group opened one of the first


  8   outpatient cardiac cath labs and it was a labor of


  9   trust on his part.  Both of us have a sixth sense


 10   about when patient is dissected and needs to go to


 11   surgery urgently, and have always had that sort of


 12   feel.  Obviously, in the early days of intervention


 13   with PRCA lots of patients went to CABG and, of


 14   course, more and more patients went to CABG at that


 15   time than do now.


 16             So, imagine my chagrin in September of


 17   2002 when I cath'd an ER nurse friend of mine and


 18   found one occluded and two stented Symmetry aortic


 19   connectors, the first patient I had ever seen.


 20   When Dr. Schoettle referred to September, 2002 that


 21   was the watershed moment.  I walked out of that


 22   cath, called him and said, Dr. Schoettle, I don't


 23   know what this device is but it is a stent and it


 24   will act like a stent and it will always be a


 25   stent.  I said, what is it?  What do we know about




  1   it?  And, he basically told me his experience over


  2   the last ten months.


  3             At that point I found an interventional


  4   colleague of mine and said, what are these devices?


  5   He said he had been stenting them since April; he


  6   didn't know much about them.  I did an Internet


  7   search and found out they were made in nitinol, and


  8   realized at that point in time that no


  9   cardiologists were involved in either the research,


 10   the design, the implementation or the roll-out of


 11   this device basically because all the


 12   cardiologists, interventional cardiologists,


 13   especially know the problems associated with that.


 14             It took me about 45 days, almost two


 15   months, with multiple interventional colleagues of


 16   mine and surgeons in Memphis to have it withdrawn


 17   from all the shelves of all three hospitals in


 18   Memphis, Tennessee, and that was in the latter part


 19   of fall of 2002.


 20             As patients have returned to the clinic,


 21   dozens, and dozens, and dozens have been found to


 22   have virtually total and/or subtotal occlusions of


 23   these devices.  The first contact I had with St.


 24   Jude was in December, 2002 after I had gone to TCT,


 25   in September I believe, and HA in November, telling




  1   them about the problem with these devices and why


  2   they acted like stents.  Finally, they walked in on


  3   me while I was cath'ing a 70 year-old ob/gyn who


  4   had two patently occluded Symmetry aortic


  5   connectors.  Basically, I said this is the problem.


  6   You don't understand anginal syndrome because most


  7   of these patients won't come back with chest pain


  8   for multiple reasons--denervation of the heart;


  9   more LV dysfunction problem.  You don't understand


 10   the role of clopidogrel or Plavix in these patients


 11   because most of them go to surgery without Plavix


 12   on board, and you don't understand the fact that in


 13   stent pathology, which we obviously cath a lot, you


 14   can have one patent graft, for instance the LIMA


 15   which most of these patients get, and the other two


 16   can subtotally occlude slowly and their only


 17   symptom is LV dysfunction.


 18             We, as cardiologists, as members of this


 19   panel, diagnose ischemia.  We send these patients


 20   to a surgeon for treatment and continue to reattach


 21   and stent these folks.  They will come back for


 22   years with their LIMAs.  An anecdotal experience of


 23   one surgeon in Jonesboro, Arkansas, close by


 24   Memphis, asked two of the cardiologists in his


 25   community, "so what's up with this Symmetry aortic




  1   connector?"  And the cardiologists response was,


  2   "are you having any problems?"  And he said, "well,


  3   I don't know."  And they said, "well, don't worry


  4   about it."


  5             He wasn't satisfied with that, came to


  6   Memphis, we cath'd him and his two connectors were


  7   occluded and his lumen was patent.  After


  8   intervention he told me that as an oral surgeon he


  9   uses nitinol every day to induce scar tissue


 10   formation and keep bridge reconstruction in place.


 11   The fact that you auger a hole in the aorta, hold a


 12   finger over it beginning the platelet clotting


 13   cascade, implant a metallic device with hooks


 14   without the benefit of loading doses of Plavix or


 15   predictable absorption is inconceivable.


 16             The idea of a connector makes sense for


 17   improvement of stroke risk, however, I feel the


 18   present device should be withdrawn and should have


 19   been withdrawn years ago.  Basically, I think the


 20   cardiologists need to be involved in any future


 21   trials or designs and I think to do otherwise is a


 22   violation of our sacred oath to our patients.


 23   Thank you.


 24             DR. TRACY:  Thank you.  Any questions from


 25   the panel?  Comments?




  1             [No response]


  2             Thank you.  Dr. Hausen?


  3             DR. HAUSEN:  By way of introduction, my


  4   name is Bernard Hausen.  I am the present CEO of


  5   Cardica.  My background, I am a cardiac surgeon by


  6   training.  My financial conflicts are inherent with


  7   my position, otherwise I have none other.


  8             [Slide]


  9             I want to use this opportunity to show you


 10   new generation of products that we are developing


 11   beyond the pioneers in this field that we have been


 12   discussing so far.


 13             [Slide]


 14             We have two products in the pipeline.  One


 15   is a distal anastomosis system.


 16             [Slide]


 17             It is called C-Port and it is based on the


 18   principle of simulating interrupted stitch distal


 19   anastomosis by applying a set of eight implantable


 20   clips, all simultaneously, and performing


 21   arteriotomy with the push of one button.  This type


 22   of a system results in a minimal amount of metal


 23   exposure.  It is a applied in distal anastomosis


 24   and it is in clinical evaluation as we speak.


 25             [Slide]




  1             This is just a video showing how it works.


  2   This is a 1.5 mm LAD.  You insert the anvil; pull


  3   it out and you are basically done; place one stitch


  4   to close the anvil insertion  hole.  This is a 1 mm


  5   diagonal cadaver heart and shows how it works.


  6             This technology, we believe, will enable


  7   beating heart surgery as it is quick and does not


  8   require any temporary ischemia of the myocardium


  9   during placement.


 10             [Slide]


 11             We have a second device which is called


 12   PAS-Port.  It stands for proximal anastomosis


 13   system, and it is a second generation proximal


 14   system.  We have the advantage of being a company


 15   that is going to be able to take advantage of the


 16   knowledge from the predecessors, predicate devices.


 17             [Slide]


 18             So we were able in our design to spend a


 19   lot of time on key improvements from things we have


 20   learned from the other devices.  We have focused on


 21   trying to minimize or completely eliminate


 22   endothelial trauma of the graft during loading.  We


 23   wanted to minimize blood-exposed non-endothelial


 24   tissue, i.e., metal exposure.  We wanted to


 25   maximize the orifice area and reduce the incidence




  1   of kinking by a low profile.


  2             [Slide]


  3             We did that by basically having nothing


  4   touch the endothelium of the vein during loading or


  5   deployment.  This is a cross-section of the


  6   implant.


  7             [Slide]


  8             We have a minimal amount of metal exposed


  9   with the stainless steel device.  It is the same


 10   material as is being used for coronary stents.  And


 11   we wanted to maximize the orifice, especially for


 12   small vein grafts, and have a very low profile


 13   height.


 14             [Slide]


 15             For all this we have done a clinical


 16   trial.  We have had a lab cardiologist review our


 17   data by QCA and determine what is the amount of


 18   narrowing of the implant versus the graft body.


 19   They first looked at some hand-sewns that were done


 20   concurrently in those patients and, as you can see,


 21   the average narrowing of a hand-sewn is about 5


 22   percent at discharge and about 18 percent at 6


 23   months.  This is in agreement with all the


 24   published literature.


 25             [Slide]




  1             Then we asked them to look at the PAS-Port


  2   data.  What you find, and you can hardly see this,


  3   this is a minus 7 percent narrowing, i.e., the


  4   grafts at the anastomosis are larger than they are


  5   in the graft body and that is by design.  That is


  6   how the implant has been designed.


  7             Now at 6 months, the most important


  8   figure, the average narrowing is 3 percent compared


  9   to 18 percent in hand-sewns.  I propose that if a


 10   device had a problem at discharge or at 6 months


 11   you would be seeing that in this quantitative


 12   analysis.  If you don't see it because the


 13   injurious event was at the time of surgery, you are


 14   very unlikely to see it going forward besides the


 15   normal decay of a vein graft, as alluded to by the


 16   previous speakers.


 17             [Slide]


 18             So, Cardica's regulatory position is we


 19   are applying for 510(k) clearance based on


 20   prospective multicenter non-randomized trials, and


 21   our primary study endpoint for this distal device


 22   is vessel patency at discharge and 6 months, and


 23   for the proximal device performing a vessel patency


 24   study at 6 months with QCA.  Thank you very much


 25   for your attention.




  1             DR. TRACY:  Thank you.  Any questions?


  2   Dr. White?


  3             DR. WHITE:  I just noticed that on the


  4   last slide you said you were going to do MRI


  5   follow-up on these metal grafts.  How are you going


  6   to do that?


  7             DR. HAUSEN:  We have done that on the


  8   proximal anastomotic device.  Basically, with the


  9   gadolinium contrast injection you can see--the only


 10   thing CTs and MRIs allow you to do is determine is


 11   the graft patent or not.  You cannot evaluate the


 12   degree of stenosis at the implant.  So, a preferred


 13   method is a quantitative angiography.


 14             DR. WHITE:  Do you have experience with


 15   MRI?


 16             DR. HAUSEN:  We have done five MRIs in the


 17   patients in this study.


 18             DR. WHITE:  And also CT?


 19             DR. HAUSEN:  And CT too and MDCT.


 20             DR. WHITE:  And there is no difference in


 21   your hands?


 22             DR. WHITE:  I like the MDCT much better.


 23   I think the image is much clearer.  The 3-D


 24   reconstructions are very impressive.


 25             DR. AZIZ:  And how does that correlate




  1   with angiograms?


  2             DR. HAUSEN:  It depends on what your


  3   outcome variable is.  If you want to just know if


  4   the graft is patent or not, there is a very, very


  5   good correlation.  That has been shown in the


  6   literature.  If you need more than that, if you


  7   need to know is there a degree of narrowing, that


  8   will not suffice.


  9             DR. AZIZ:  If you do distal anastomosis if


 10   you have bleeding, how can you control that?  Can


 11   you put a regular stitch over that?


 12             DR. HAUSEN:  Yes, you can.  It is the same


 13   as a steel device.  It is very firm.  The pull-out


 14   force of this device is very high because stainless


 15   steel is three times stiffer than nitinol.  So,


 16   what you do, you just place the first string around


 17   the anastomosis and slowly tighten it.  That brings


 18   the aorta closer to the implant--


 19             DR. AZIZ:  If you do distal anastomosis if


 20   you have bleeding, can you do regular stitches?


 21             DR. HAUSEN:  Yes.


 22             DR. AZIZ:  You have obviously shown a vein


 23   graft.  If you had an arterial graft can you use


 24   your same distal anastomotic site for that?


 25             DR. HAUSEN:  This generation of device,




  1   no; the next generation, yes.


  2             DR. TRACY:  Dr. Bridges?


  3             DR. BRIDGES:  You showed differences in


  4   percent stenosis of the proximal anastomoses at


  5   discharge and at 6 months.


  6             DR. HAUSEN:  Yes.


  7             DR. BRIDGES:  What about occlusion or


  8   patency at the same time points?


  9             DR. HAUSEN:  We have 87.9 percent patency


 10   rate so we had 6 occlusions in 50 implants, which


 11   is 100 percent in agreement with the historical


 12   data from the meta-analysis you saw and we did too.


 13             DR. BRIDGES:  So, how would you interpret


 14   the fact that in spite of having a higher orifice


 15   area or diameter you have the same patency at the


 16   6-month time point?


 17             DR. HAUSEN:  That is wonderful proof that


 18   it has nothing to do with the connector.  It is


 19   probably your distal run-off or any of the other


 20   200 factors that Dr. Mack said.


 21             DR. AZIZ:  If you had a very thick


 22   proximal ascending aorta--


 23             DR. HAUSEN:  Yes?


 24             DR. AZIZ:  --sometimes you do a hand-sewn


 25   vein graft that dunks in and obviously you don't




  1   want that.


  2             DR. HAUSEN:  Yes.


  3             DR. AZIZ:  Does your anastomosis


  4   technique--where would that fit in?  Would the vein


  5   also dunk in?


  6             DR HAUSEN:  It is inverted over the


  7   implant so it is in the lumen but, because it is a


  8   stainless steel implant, it props the anastomosis


  9   open and you will not have lumen reduction, if that


 10   is where you are heading towards.  And we have


 11   shown that, minus 7 percent widening of the


 12   anastomosis is evidence that that is exactly what


 13   the implant does and it accommodates the varying


 14   thickness of the aortic wall because it is like a


 15   paper clip.  It can adjust to varying thicknesses.


 16             DR. AZIZ:  And the angle at which it comes


 17   off proximally, is that oblique or head-on?


 18             DR. HAUSEN:  It is theoretically 90


 19   degrees.  We asked our core lab to evaluate that


 20   too.  There are hardly any at 90 degrees.  They


 21   vary from 10-70 degree take-offs.  Because the


 22   hinge point is so small, only 1.5 mm, the vein can


 23   come off almost at any angle it wants to.


 24             DR. AZIZ:  So, could you take the proximal


 25   along through the transverse sinus and pull it




  1   through?


  2             DR. HAUSEN:  You could, yes.


  3             DR. AZIZ:  You could?


  4             DR. HAUSEN:  Yes.


  5             DR. EDMUNDS:  What is the size of the shoe


  6   inside the vessel?


  7             DR. HAUSEN:  The shoe inside the vessel?


  8             DR. EDMUNDS:  Against which you are


  9   putting the clamps down.  The part of the device


 10   that goes inside the vessel, what are the


 11   dimensions of that shoe of the device?


 12             DR. HAUSEN:  There is really nothing


 13   inside the vessel.  The vein is pulled through the


 14   implant and inverted so there is no metal inside,


 15   except for the prongs that penetrated the vein and


 16   then go outward.  I would be more than happy to sit


 17   down afterwards and show you maybe some work.  I am


 18   kind of limited by the time here.


 19             DR. AZIZ:  Can you do a sequential of this


 20   for the distal anastomosis?


 21             DR. HAUSEN:  No.  Well, you could if you


 22   did your side by side by hand, absolutely.


 23             DR. TRACY:  Thank you very much.  Prof.


 24   Klima?


 25             PROF. KLIMA:  Ladies and gentlemen,




  1   members of the panel, my name is Uwe Klima.


  2             [Slide]


  3             I am a full professor at Hanover Medical


  4   School for Cardiac Surgery.  The financial


  5   disclosure I have to make is that Ventrica paid for


  6   my trip here and my lodging, and Ventrica provided


  7   us with an unrestricted grant for preclinical


  8   testing of an anastomotic device three years ago.


  9             [Slide]


 10             I expected a talking time of ten minutes


 11   and I will try to cut that down to five minutes.


 12   Basically, what I want to talk about is mechanisms


 13   of how wound healing takes place after an


 14   anastomosis; give you some of our clinical


 15   experience with hand-sewn anastomosis, especially


 16   with our MIDCAB series; more update or experience


 17   with our anastomotic devices; and I will have a


 18   little discussion of appropriate methods and


 19   follow-up time frames for CABG surgery.


 20             [Slide]


 21             As background, we all know that hand-sewn


 22   anastomoses now are more or less on the market for


 23   more than four decades.  Everything is pretty much


 24   well tested and evaluated.  We have a pretty clear


 25   understanding of what happens to an anastomosis. 




  1   What happens is a healing response--at what time


  2   frame this will be stable.  So, I will go into


  3   details with my next slide.


  4             [Slide]


  5             There are several publications out now


  6   which tell us exactly what happens after an


  7   anastomosis has been performed.  We know there is a


  8   lot of trauma coming after surgery.  Cell


  9   proliferation is coming out.  And the most


 10   important message that comes out of this


 11   publication, for example, is that the repair


 12   process is about to be completed two months after


 13   surgery.


 14             [Slide]


 15             We wanted to know what is happening with


 16   anastomotic devices.  Is it the same response?  Can


 17   we expect the same thing to happen?  Filsoufi


 18   published, from Boston.  He tested the Ventrica


 19   device and what is happening after implantation two


 20   months, three months and six months after surgery,


 21   and we could see that there is a single layer of


 22   endothelium covering after two months, three months


 23   and after six months and there was no sign of any


 24   inflammatory response at the site of the


 25   anastomosis.




  1             [Slide]


  2             As a control group--I would like to speak


  3   a little bit about our MIDCAB experience in


  4   Hanover.  We have now enrolled more than 700


  5   patients.  Out of the first 500 patients we did


  6   angiographic follow-up in 6-7 percent of these


  7   patients.  The first group, which was the big one


  8   with 297 patients, had a pre-discharge angiogram.


  9   What was pretty interesting was that in about 6


 10   percent of these patients we had a highly


 11   significant problem at the site of the anastomosis,


 12   as you can see here.  As a Swedish colleague


 13   presented his data with the same problem four years


 14   ago at the ASCTS and recommended just to wait


 15   because this is part of the healing response, we


 16   changed our politics, which you will see on the


 17   next slide, and just let the whole situation be as


 18   it was; waited for 3-6 months, reevaluated these


 19   patients and saw that the degree of stenosis or the


 20   number of intimal hyperplasia went down without any


 21   intervention from 6 percent to 1 percent.


 22             [Slide]


 23             There is another example here and, as you


 24   can see again, there is a highly significant


 25   stenosis here at the pre-discharge angiogram;




  1   perfect anastomosis 3-6 months later when we


  2   reevaluated the patients.  What we learned here is


  3   that the healing response is still evolving in the


  4   earlier time frame.  We changed our angiographic


  5   follow-up from pre-discharge to a 6-month follow-up


  6   so the remaining 203 patients were evaluated 6


  7   months after surgery instead of having a


  8   pre-discharge angiographic follow-up.


  9             [Slide]


 10             So, what is the Hanover experience now


 11   with anastomotic devices?  Just to give you a quick


 12   overview, Hanover does approximately 2,000 open


 13   heart procedures per year.  It is a large teaching


 14   institution.  We are affiliated with several


 15   research centers so we are exposed to new


 16   technologies and clinical trials.  The studies I


 17   have performed were with Ventrica, St. Jude and


 18   Converge.  In addition, I have a little experience


 19   also with Cardica and Coalescent, however, I just


 20   want to present you the data where I have


 21   angiographic follow-up.


 22             [Slide]


 23             St. Jude--we had a prospective, randomized


 24   trial with 11 patients where every patient received


 25   two proximal anastomoses.  One was hand-sewn and




  1   the other one was an automatic anastomosis.  This


  2   is the strongest study design that you can create.


  3   The data that we saw was that in 11 patients who


  4   were enrolled in the study and came back after 6


  5   months and there were 10 postoperative angiograms


  6   showing that only 3 grafts were patent.  We had 6


  7   occlusions and 1 highly significant stenosis at the


  8   site of the anastomosis, with a consequent PTCA and


  9   stent after graft.  Even though the patients were


 10   asymptomatic, the study was stopped because the


 11   data did not look the way we wanted to have it.


 12             [Slide]


 13             Even though all patients were


 14   asymptomatic, due to several reasons that we can


 15   discuss, I think independent of the cause a


 16   prospective six-month angiographic evaluation was


 17   sufficient in our study to detect performance


 18   issues of the device.


 19             [Slide]


 20             Ventrica was part of a multicenter trial


 21   that we did with two other centers.  We enrolled


 22   100 patients, 48 came from Hanover--


 23             DR. TRACY:  Can I ask you to start


 24   wrapping up?


 25             PROF. KLIMA:  Yes.  The most important




  1   information I want to give you here is that in the


  2   first 48 patients we had a pre-discharge angiogram


  3   and a 6-month angiogram to study efficacy of the


  4   device and performance of the anastomosis after 6


  5   months.


  6             [Slide]


  7             The last study we did was with Converge.


  8   It was also a multicenter trial.  We had 8 weeks of