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

9:06 a.m.

CHAIRMAN LASKEY: On the record. If we can have everybody take their seats please. This is a good sign. Everyone listens. Good morning. I=m Warren Laskey. I have the pleasure of calling this morning session to order. The topic this morning will be a discussion of the PMA for the Cordis PRECISE Nitinol Stent System P030047. I=d like to start with our Executive Secretary reading the conflict of interest statement.

MS. WOOD: AThe following announcement addresses conflict of interest issues associated with this meeting and is made a part of the record to preclude even the appearance of an impropriety. To determine if any conflict existed, the Agency reviewed the submitted agenda and all financial interests reported by the Committee participants.

The conflict of interest statutes prohibit special government employees from participating in manners that could affect their or their employers= financial interests. However, the Agency has determined that participation of certain members and consultants, the need for whose services outweighs the potential conflict of interest involved, is in the best interest of the Government.

Therefore, waivers have been granted for Drs. Mitchell Krucoff, Christopher White, and a waiver was previously granted for Dr. Judah Weinberger for their interests in firms that could potentially be affected by the panel=s recommendations. Dr. Krucoff=s waiver involves consulting with a competing firm on unrelated manners for which he receives an annual fee of less than $10,001.

Dr. White=s waiver involves grants to his institution for studies of the sponsor and several competing firms in which he had no involvement in data generation or analysis. Funding to the institution for the sponsor=s study was less than $100,000 per year. The total amount of funding for the competitors= studies was less than $100,000.

Dr. Weinberger=s waiver involves stock holdings in competing firms in which the values are between $25,001 and $50,000. The waivers allow these individuals to participate fully in today=s deliberations. Copies of these waivers may be obtained from the Agency=s Freedom of Information Office, Room 12A-15 of the Parklawn Building.

We would like to note for the record that the Agency took into consideration other matters regarding Drs. Andrew Comerota, Mitchell Krucoff, Kenneth Najarian, Michael Pentecost, Cynthia Tracy, and Judah Weinberger. These panelists reported past or current interest involving firms at issue but in matters that are not related to today=s agenda. The Agency has determined that these individuals may participate fully in the panel=s deliberations.

In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participant should excuse himself or herself from such involvement, and the exclusion will be noted for the record. With respect to all other participants, we ask in the interest of fairness that all persons making statements or presentations disclose any current or previous financial involvement with any firm whose products they may wish to comment upon.@

CHAIRMAN LASKEY: Thank you. If we can just go around the table and have everyone introduce themselves.

DR. ZUCKERMAN: Bram Zuckerman, Director, FDA Division of Cardiovascular Devices.

DR. AZIZ: Salim Aziz, Clinical Associate Professor at GW and private practice in Washington.

DR. KRUCOFF: Mitch Krucoff, Cardiology Division at Duke University and the Director of Devices Clinical Trials at the Duke Clinical Research Institute.

DR. TRACY: Cindy Tracy, the Director of Electrophysiology at George Washington University, Associate Director of the Division of Cardiology.

DR. COMEROTA: Anthony Comerota, Vascular Surgeon, Jobst Vascular Center in Toledo, Ohio.

DR. NICHOLAS: Gary Nicholas, Lehigh Valley Hospital, Professor of Surgery, Penn State.

DR. PENTECOST: Michael Pentecost, Chairman of Radiology at Georgetown.

MS. WOOD: Geretta Wood, Executive Secretary.

CHAIRMAN LASKEY: Warren Laskey, Interventional Cardiologist, Uniformed Services University.

DR. ABRAMS: Gary Abrams, Associate Professor of Neurology, University of California - San Francisco.

DR. WHITE: Chris White, Interventional Cardiology, Ochsner Clinic in New Orleans.

DR. WEINBERGER: Judah Weinberger, Director of Interventional Cardiology, Columbia, New York.

DR. MAISEL: William Maisel, Electrophysiologist, Cardiovascular Division at Brigham and Women=s Hospital.

DR. NAJARIAN: Ken Najarian, Interventional Radiologist, University of Vermont.

DR. HUGHES: Allen Hughes, Assistant Professor of MIS at George Mason University, the consumer representative.

MR. MORTON: Michael Morton, I=m the industry representative. I=m employed by Carbomedics.

CHAIRMAN LASKEY: And Geretta, if you could please read the voting status statement.

MS. WOOD: APursuant to the authority granted under the Medical Devices Advisory Committee charter dated October 27, 1990 and as amended August 18, 1999, I appoint the following individuals as voting members of the Circulatory System Devices Panel for this meeting on April 21, 2004: Judah Z. Weinberger, M.D., Ph.D.; Kenneth E. Najarian, M.D.; Michael J. Pentecost, M.D.; Anthony J. Comerota, M.D.; Gary M. Abrams, M.D.; Gary Nicholas, M.D.

For the record, these individuals are special government employees and are consultants to this panel under the Medical Devices Advisory Committee. They have undergone the customary conflict of interest review and have reviewed the material to be considered at this meeting, signed by David W. Feigal, Jr., M.D., M.P.H., Director, Center for Devices and Radiological Health and dated April 16, 2004.@

CHAIRMAN LASKEY: I=d like to begin this morning with the open public hearing portion of our session today. Prior to having the invited speakers come to the podium, I just want to read the following paragraph if I might.

ABoth the Food and Drug Administration and the public believe in a transparent process for information gathering and decision-making. To ensure such transparency at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual=s presentation.

For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the Committee of any financial relationship that you may have with the sponsor, its product, and if known its direct competitors. For example, this financial information may include the sponsor=s payment of your travel, lodging or other expenses in connection with your attendance at the meeting.

Likewise, FDA encourages you at the beginning of your statement to advise the Committee if you do not have any such financial relationships. If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.@ That being said, I would like to call our first speaker this morning for the open public session. That would be Dr. Janette Durham.

DR. DURHAM: Good morning. I am Dr. Janette Durham, a Professor of Radiology and an Interventional Radiologist from the University of Colorado Health Sciences Center. I have nothing to disclose or a conflict of interest. I am also the President of the Society of Interventional Radiology.

SIR is a non-profit, national, scientific organization of more than 4,000 physicians and Allied Health professionals committed to improving health and the quality of life through the practice of vascular and interventional radiology. This society promotes education, research, and communication while providing strong leadership in the development of health care policy.

SIR members have undergone training and cervico-cerebral angiography as part of our ACGME-approved residency program. Our members have extensive experience placing endovascular stents in multiple vascular beds. SIR recognizes the importance of carotid atherosclerosis and its appropriate management.

In a recent SIR member survey, 22 percent of respondents reported having performed 25 or more carotid stent cases and the collective total of carotid stent experience was over 5,000 cases performed. Of those surveyed, 90 percent responded that they are interested in training to perform carotid stenting.

SIR supports carotid stenting as an effective and beneficial new technology for appropriately selected patients. We believe that there is sufficient evidence to warrant approval of this technology. SIR has had an opportunity to review in a preliminary fashion the training program put forth by the sponsor. We feel it=s a sound program for device training.

We intend to participate as needed to provide educational content and proctors. Procedural safety and effectiveness will be equally as important to device safety and effectiveness. As a physician, I am involved in the diagnosis, prevention, and treatment of stroke.

In my practice, I recognize that stroke is one of the most devastating events a person can experience. Those who survive stroke are often disabled and have extensive health care needs. It is important that appropriately trained and skilled physicians treat patients who are being treated with a device to prevent stroke so that stroke is not the result of treatment.

It is important that labeling include the endovascular skills necessary to ensure high quality outcomes. Physicians are responsible for having undergone the necessary procedural training in addition to device training to qualify them to perform invasive procedures and utilize new technologies.

Hospitals are responsible for overseeing that physicians in fact have appropriate credentials to perform procedures safely. Industry need not share the responsibility for procedural training. To do this would unreasonably burden industry and add to the cost of advancing technology.

SIR has provided CME training and education on carotid stenting at our national meeting the past two years. We plan to continue this effort locally in the next year. In addition, SIR participated in the development of guidelines for the performance of carotid arteriography and most recently has developed a multi-society document for the appropriate quality and performance criteria for carotid artery stent placement which was published last September in The Journal of Vascular and Interventional Radiology and The American Society of Neuroradiology.

These guidelines are based on published science which recognizes a learning curve in the performance of carotid arteriography and carotid stent placement. In respect to stroke, SIR has also participated in developing a multi-society reporting standard for product stent technology assessment and uniformity of reporting in the literature. This will be published this May in Stroke and The Journal of Vascular and Interventional Radiology.

We recognize that carotid stenting is a dynamic area. As additional peer reviewed studies are published, SIR looks forward to working with all specialities involved in carotid stenting to refine these guidelines and further improve patient care. In closing, I thank the panel for the opportunity to provide comments. I am pleased to be available for any questions that you may have.

CHAIRMAN LASKEY: Thank you much, Dr. Durham. We=re going to try and minimize the Q and A, so I=m going to limit this to one question per speaker. Dr. Krucoff.

DR. KRUCOFF: Just a quick question. I=m sorry if I missed this. Is this a formal consensus or position statement on behalf of the society or is this an individual statement?

DR. DURHAM: It is on behalf of the society.

CHAIRMAN LASKEY: The next speaker who has requested time is Dr. Ken Rosenfield representing the ACC and SCA&I. Dr. Rosenfield. Please forgive the presence of the timer. We=re limiting these comments to ten minutes.

DR. ROSENFIELD: My understanding is that there is a shared presentation, SCA&I and ACC, is that correct?

CHAIRMAN LASKEY: That is correct. You will precede Dr. Gray.

DR. ROSENFIELD: Okay, members of the panel, FDA staff, and guests, my name is Dr. Kenneth Rosenfield. I am the Director of Cardiac and Vascular Services at Massachusetts General Hospital. I have the pleasure of standing along side Dr. William Gray who is the Director of Endovascular Interventions at Swedish Medical Center in Seattle.

Dr. Gray and I very much appreciate the opportunity to speak on behalf of two prominent organizations, the American College of Cardiology and the Society for Cardiovascular Angiography and Intervention or the SCA&I. As we embark on our comments, we disclose that we each have served in a consulting role for several companies, Cordis amongst them, whose products may be used for carotid stenting.

We have received modest compensation for time spent away from our practices while serving those consulting roles. In addition, Dr. Gray and I both have served actively as enrolling investigators in the SAPPHIRE trial. Our participation in this and several other trials of carotid stenting for high risk surgical patients as well as our role as busy and experienced cardiovascular clinicians caring for large numbers of patients with a high burden of atherosclerotic disease enables us to comment from an informed and seasoned perspective.

While we are formally here to represent physicians in our respective organizations, we believe that we are ultimately here to represent the patients we all treat. On behalf of those patients, many of whom are at risk for disabling stroke and who will benefit from the lowest risk carotid revascularization available, we, our college, and our society, come today in the strongest support for carotid stenting.

The position that we represent today is that of the ACC and SCA&I. The American College of Cardiology is a 30,890 member non-profit professional medical society and teaching institution whose mission is to advocate for quality cardiovascular care through education, research, promotion, development, and application of standards and guidelines and to influence health care policy. The college represents more than 90 percent of cardiovascular specialists practicing in the United States.

The SCA&I is a 3,150 member non-profit sub-speciality professional medical organization comprised of cardiovascular and vascular interventionalists from several specialities who care for patients with vascular disease and perform both cardiac and extra-cardiac invasive procedures. SCA&I=s mission is to promote excellence in catherization and angiography through physician education and representation, clinical guidelines, and quality assurance to enhance patient care.

On behalf of their members and the millions of patients for whom their members deliver care, the ACC and SCA&I both support treatments and approaches that promise to optimize and/or improve care while minimizing the negative effects and degree of invasiveness for patients. Furthermore, the approach for our organizations and their members has not necessarily been to accept the status quo but rather to pursue advances in treatment in order to accomplish our shared mission.

The ACC and SCA&I are here today in strong support of carotid angioplasty and stenting as an example of innovation and opportunity for less invasive treatment options for our patients. It is perhaps for this reason that more than any other speciality cardiologists have championed this new approach to carotid revascularization and stroke prevention.

There are numerous patients in every cardiology practice who are burdened with comorbid conditions that render conventional endarterectomy higher risk. Perhaps more than any other specialty, it is the patients cared for by cardiologists who have the most to gain if less invasive stroke prevention therapies are available which simultaneously offer reduction in peri-procedure MI and other surgical-related complications while providing for equivalent stroke prevention.

Conversely, it is these same higher risk patients who will suffer most if effective new therapies are withheld or stymied. The college and the society believe that the results of the SAPPHIRE trial along with other data now emerging provide the evidence base to support approval of carotid stenting with this protection for the subset of patients identified by the inclusion criteria for the trial. The ACC and SCA&I organizations strongly support that approval. We would like to focus on several specific areas in our comments to follow.

These include the role of the cardiovascular specialist in carotid artery disease management, secondly, the current gap in care and the lack of evidence base for patients with high risk features undergoing carotid vascularization, thirdly, our society=s interpretation of the SAPPHIRE and other data regarding carotid stenting, and fourthly, the ACC and SCA&I position regarding carotid stenting as an alternative for revascularization including the importance of training and post-market surveillance. A longer written version of our comments has been provided for the panel, the FDA staff, and the Register. With this, I=ll hand the podium over to Dr. Gray.

DR. GRAY: Thanks, Ken. Members of the panel, atherosclerotic disease states our core clinical competency of our two societies and of the more than 30,000 specialists that they represent. Our broad view of cardiovascular patients includes the critical recognition that atherosclerosis is a systemic disease and that the longitudinal clinical care and education of the patient and not episodic intervention is the key to effective reduction of morbid, life altering, and costly events such as myocardial infarction, sudden cardiac death, ischemic cardiomyopathy, renal failure, stroke, et cetera.

Specific to carotid stenting with embolic protection, cardiovascular specialists have been dominant among the vanguard of this new and promising technology for almost ten years and account for roughly 70 percent of all carotid stent procedures performed worldwide to date. In trials now before the panel as well as others to come, cardiologists form the important core of principal investigators and produce nothing short of spectacular results often in hostile, local, regulatory, and reimbursement environments but always in consideration of expanding the safety and effectiveness of the options available to the patient with extracranial carotid artery disease.

The cardiology community prides itself on practicing evidence-based medicine. It is in that spirit that we participate with our peers from other specialties to complete trials such as SAPPHIRE which are designed to clarify the role of carotid stenting vis a vie the existing standard of care endarterectomy.

The cardiology community has gone to great lengths to define the learning curve associated with carotid stenting so as to minimize the chances of causing harm to patients by indiscriminate performance of these procedures by unqualified interventionalists. It is on the background of this dedication to the evidence-based treatment, education, and research of cardiac and vascular diseases for our patients in general and stroke prevention specifically that ACC and SCA&I come before the panel today.

In practice for five decades, carotid endarterectomy for stroke prevention in a patient with extracranial bifurcation disease is an elegant and effective operation. However, not until 1991 with the publication of NASCET was endarterectomy shown to be effective in symptomatic patients versus medical therapy. The results of asymptomatic carotid trial, the ACAS trial, in 1995 extended surgical efficacy to the asymptomatic trial with severe carotid stenosis.

Based largely on these two trials, carotid endarterectomy is performed in over 150,000 patients every year in the United States. It is estimated that approximately two-thirds of these are asymptomatic. While the NASCET and ACAS landmark trials established surgical interventions effective in managing carotid stenosis, these studies excluded patients with significant comorbidities likely to increase their surgical risk.

Indeed, over 80 percent of the patients screened in NASCET and the majority of patients screened in ACAS were excluded mostly on the basis of one or more criteria which may have placed the patient at a higher risk of peri or post-operative procedural events. In high surgical risk patients, there are no randomized data comparing surgery to any alternative therapy. There are however data for multiple high risk surgical registries demonstrating that stroke and death rates are on average at least twice that of the aforementioned trials.

In spite of this lack of randomized control data, endarterectomy continues to be performed in these patients almost with a higher morbidity, mortality, and cost. In short, this patient cohort with endarterectomy has not been shown to be safe nor effective. This represents a significant national gap in the ability to offer these patients a proven therapy.

Endarterectomy has been clearly shown to vary widely with experience and volume. Even at NASCET investigational sites, outcomes are not as robust as those that were seen in the trial. This variability also represents a further gap in assuring predictable, quality outcomes for our high risk patients.

There is then, after review of available information, a clear and worrisome diversions between the clinical data available regarding the benefit of endarterectomy in patients without surgical risk and the current clinical practice of endarterectomy in patients with significant comorbidities in this country. It is on this background and with this gap in mind that we now consider the data in carotid stenting with embolic protection.

The panel is currently considering data from the SAPPHIRE trial, among other sources, in its deliberation regarding the application of Cordis Johnson & Johnson for premarket approval of its carotid stent and embolic protection device for the treatment of high risk patients in extracranial carotid artery disease. A presentation of the SAPPHIRE data has allowed several important observations.

This is the first randomized trial ever to explore any alternative to carotid endarterectomy in high risk patients. Although designed as a non-inferiority trial and in spite of its early stoppage, it appears to have demonstrated a significant advantage of stenting over surgery.

Late neurologic events after 30 days occur infrequently and demonstrate effective stroke prevention which is the goal of any effective carotid therapy. Repeated restorization rates for stenting are meaningfully lower then that for surgery, almost reaching statistical significance in this trial. These results, as sound as they are in and of themselves, are further supported by results already presented in print from other completed trials.

The results from those other trials, investigational carotid stenting in the U.S., demonstrate a remarkable uniformity in nearly 2,000 patients across devices, operators, and sites and endorse the results of SAPPHIRE as consistent and reproducible. It is useful noting that compared to the aforementioned trials ratifying endarterectomy as a standard of care in this country studies reporting outcomes in carotid stenting now total almost four times the number of patients in NASCET and several hundred more than the number of asymptomatic patients study in ACAS.

After reviewing these data, the college and society believe there is strong evidence that rigorous testing of carotid stenting has demonstrated comparable results and even superiority in some cases to carotid surgery in several important categories and in a significant number of patients to draw such a conclusion. I finish comments with Kenny.

DR. ROSENFIELD: Based on the current data available, the college and the society believe that carotid stenting with embolic protection should be made available as an option to patients with clinical or anatomical comorbidities as defined in the SAPPHIRE inclusion criteria in order that they may take advantage of this lower risk alternative to surgery and improve their outcomes. To deny these patients a clearly beneficial alternative to endarterectomy is neither in the best interest of the patient nor society as a whole.

The remarkable results from stenting, achieved in a fraction of the time that it took carotid surgery to mature, will only be replicated through continued expert application of the technology and procedure and with careful patient selection. The necessary skills transfer therefore is important once systems are available out of an IDE setting. Both the ACC and the SCA&I are committed to training and credentialing as a critical component of device and procedural approval.

Competency in carotid stenting requires acquisition of certain skill sets. These include cognitive, clinical, and technical skills. There is clearly a learning curve associated with achieving competence in carotid stenting.

The ACC and SCA&I are in favor of establishing rigorous but not prohibitive training and credentialing requirements. Specifically, we propose that training and certification be obtained within a rigorous, well-defined program which is based on thresholds for achievement of competence but does not present unreasonable barriers.

Several documents are currently under preparation by multi-specialty groups such as the AHA/ACC competency document as well as the AHA guidelines documents for cerebrovascular imaging. These documents will aid in identifying the requisite skills and numbers of procedures to achieve competence.

The college and society also understand the critical need for and support the implementation of careful ongoing tracking of outcomes post-PMA follow up using standardized definitions and measures. This ongoing surveillance will assure the adequacy of training and appropriateness of patient care.

Indeed, the ACC and the SCA&I have been at the forefront of developing standardized and systematized mechanisms by which key clinical and procedural data elements can be collected and analyzed to create new benchmarks and compare to existing benchmarks. As an example, the ACC NCDR, National Cardiovascular Data Registry, in conjunction with the Cardiothoracic Surgical Database represents the largest such effort to date.

ACC NCDR is already conducting two studies on behalf of the FDA. These are underway. We look forward to the opportunity to collaborate further in this regard. In spite of the robust nature of the SAPPHIRE and the other data at hand and the benefits already realized by the thousands of patients who have been treated thus far with carotid stenting in the United States and worldwide, there will be those who will be opposed to carotid stenting approval or critical of the trial design.

I would refer you to the longer version of our comments here, the written document, which would express our feelings about these various issues. Specifically the longer version addresses the issue of MI as an inclusion criteria in this trial, the issue of MI as an endpoint in this trial, the possible requirement for pre-approval by a surgeon before undergoing carotid stenting, and the absence of a medical arm for this trial.

Time precludes us from describing these sentiments in detail, but we would refer you to the written documents that we provided for the panel. We would like to focus on one key element or issue --

CHAIRMAN LASKEY: Dr. Rosenfield, excuse me, you have one minute remaining.

DR. ROSENFIELD: Okay, I=ll wrap up my comments then. The other issue that we would like to refer you to is the issue of the inclusion of asymptomatic patients in this trial and whether this should be applied to asymptomatic patients. ACC and SCA&I believe at this point that the focus should be on implementation and careful roll-out of the technique by ensuring that the procedure is made available to the appropriate patients and while at the same time making certain that its use is not overextended to those who are not high risk as defined in the trial and also recognizing the need for appropriate threshold criteria without creating barriers for talented operators of any specialty to ensure proper training for interventionalists.

Finally, the focus should be on instituting systems to enable meticulous monitoring results in the post-market phase to ensure compliance, proper patient selection, and integrity of the results as well as to provide a mechanism for continued quality improvement. Most importantly, we would like to reiterate that the ACC and SCA&I position regarding this procedure in the current era and as demonstrated by the SAPPHIRE trial is that this can provide a real and meaningful benefit for patients in this country who are at high risk for CEA or endarterectomy.

It is in the best interest of these patients, whose options are quite limited, to make the procedure available. We have been honored to be here today to represent our professional organization. We also are humbled by the opportunity to speak on behalf of the patients who have participated in carotid stent research and future patients who will benefit from its approval. Thank you very much.

CHAIRMAN LASKEY: Thank you both very much. It is clearly a full plate. In the interest of time, again, which is a precious commodity this morning, we will move on. The next speaker requesting time is Dr. Bacarach.

DR. BACARACH: Good morning, ladies and gentlemen of the panel. My name is Dr. Michael Bacarach. I=m very pleased to have the opportunity to present to you today on behalf of the Society of Vascular Medicine and Biology.

I=m a practicing interventional vascular medicine specialist. I=m currently the Director of the Heart Hospital in Sioux Falls, South Dakota. I=m also an Associate Professor of Clinical Medicine at the University of South Dakota. I=m the Treasurer of the Society of Vascular Medicine and Biology.

It=s my goal this morning to briefly describe the Society of Vascular Medicine and Biology, to present our society=s position regarding carotid stent support angioplasty, and the SAPPHIRE trial before you today. I wish to disclose that I did serve as an investigator for the SAPPHIRE trial. I have been an investigator in three additional carotid stent trials.

I have no financial relationship or conflict of interest with Cordis or Johnson & Johnson. I have received no compensation for my appearance today. I am here as an officer of the Society of Vascular Medicine and Biology to present our society=s position.

The Society of Vascular Medicine and Biology is an non-profit professional medical organization. It was founded in 1989 to foster a broad mission of patient care, education, and research in the field of vascular medicine. Our goal is to maintain a high standard of clinical practice and patient advocacy in vascular medicine.

The Society of Vascular Medicine and Biology is the only national professional medical society representing physicians with expertise in medical, surgical, and endovascular strategies for the treatment of these complex patients. Our membership includes individuals with expertise in vascular medicine, cardiology, vascular surgery, radiology, vascular nursing, vascular technology, and vascular biological research.

Extracranial carotid artery disease is an area of expertise of the physician members of the society. The development of endovascular therapy for vascular disease has been profound and has led to many advances which have improved the care of our patients with vascular disease. Specific use of less invasive therapies and strategies for revascularization have made treatment for many of my complex patients deemed suboptimal candidates for surgical revascularization life saving.

Carotid stent support angioplasty using cerebral embolic protection devices is one example of such innovation and advantage to our patients. My colleagues and I see many patients with carotid lesions that are inaccessible to standard endarterectomy or have prohibitive surgical risk from serious comorbid conditions making treatment difficult and risky.

Carotid stent support angioplasty represents a major advance in my ability to care for these patients. The SAPPHIRE trial was performed with sufficient scientific rigor and oversight to demonstrate convincingly that carotid stent support angioplasty with embolic protection is an appropriate first line therapy for high risk symptomatic and asymptomatic patients.

The society was impressed with the results of the SAPPHIRE trial. Our society strongly supports approval of carotid stent support angioplasty with embolic protection for high risk patients deemed to be in need of revascularization for the prevention of stroke.

The benefits of carotid stent support angioplasty by appropriately skilled, trained, and experienced operators and interventionalists are established. We do not support however broad adoption of this technology and technique without responsible and adequate training. As a national, professional medical society, the Society of Vascular Medicine and Biology urges you to approve carotid stent support angioplasty with embolic protection for high risk patients.

We urge you to assure that the proper training and experience is required prior to the adoption of this technique. Physician thought leaders must be involved in the development of this treatment breakthrough so that responsible, skilled, and experienced physicians treat our ill patients in the best, safe, and most appropriate manner. I thank you very much for the privilege of representing the society before you today. Thank you.

CHAIRMAN LASKEY: Thank you, sir. Any questions from the panel? Is there anyone else who wishes to come forth and address the panel on today=s topic or any other topic? Yes, sir, please come forward. Just identify yourself.

DR. HANLEY: Sure, I=m Daniel Hanley. I represent the American Academy of Neurology.

MS. WOOD: Do you have any financial disclosures?

DR. HANLEY: Certainly. I represent the American Academy of Neurology. They have paid for my transportation here. I have previous relationships with Jansen as a medical consultant. This is a Johnson & Johnson company. I have no relationship with Cordis.

I am a former board member of the National Institute of Health, American Academy of Neurology, and a current board member of the National Stroke Association. I=m a board member of a for-profit public company, NMT, which makes cardiologic devices which do not compete with this device.

Representing the academy, I wish to address the panel today. I bring to my comments 25 years of experience as a stroke physician and neurologist with an emphasis on acute care neurology, interventional procedures, their complications, and post-procedural care and recovery of stroke patients. I bring one decade of public advocacy for improved stroke care on the part of the American Academy of Neurology, American Heart Association, and the National Stroke Association.

I wish to comment in three areas: (1) to enforce the importance of the entire process today, (2) to make the panel aware of an academy white paper regarding training, and (3) to make a simple comment regarding the standards by which comparisons should be made.

The first issue, I=m pleased to be here while the FDA deliberates on a new industry sponsored trial data set that could lead to reduction in stroke events and the improvement or the addition to the armamentarium of interventions for Americans with stroke risks. The AAN, American Academy of Neurology, doesn=t presume to predict the outcome of today=s deliberation. Rather, we hope that patient safety and benefit are enhance by today=s outcome.

My second comment, we wish to make the Committee aware of the last three decades effort to improve stroke and stroke care by the systematic use of practitioner training pathways. The academy has not had the opportunity to comment on the training pathway suggested for this application but welcomes that opportunity now and hopes to submit its comments in the near future.

The specific neurovascular stroke coalition pathway has been developed and is brain-specific. It is to this that I wish to speak. Despite this pathway=s sponsorship by organized radiology, neurology, and neurosurgery, it is not as well known as similar heart-based pathways for coronary angiography and coronary procedures.

The pathway is articulated in the American Academy of Neurology=s white paper, a copy of which will be left today with this panel. The academy wishes to ask that the details of this pathway for training and competency in cranial-cervical angiography be incorporated into the decision-making today regarding the overall use of stenting devices and the protocol to place stents in patients with stroke.

The essence of the white paper is that patient safety is only protected when we apply to cranial-cervical angiography and carotid stenting the lessons we have learned in coronary angiography. These lessons have lead to improved heart outcomes. The deliberation today must consider how we can achieve a different goal, improved brain outcomes.

The lessons we believe are quite simple. (1) The procedure in question must be performed by practitioners with prolonged training times specific to diseases of the brain because patient selection, pre and post-procedure management, and procedure performance are all directed at brain processes. (2) The proceduralist must demonstrate both technical and cognitive competence prior to credentialing to select patients, perform carotid stenting, and organize the care of these patients after the procedure.

(3) Because stroke is the most feared medical complication, the standards for performance of brain vascular procedures should be at least as stringent and at least as specific as the standards for coronary angiography. Specifically, these are a minimum of experience of 100 procedures for technical competence and a minimum training period of one year in brain stroke patient care in an ACGME credentialed neurovascular program for cognitive training.

The issue of non-neurologically trained specialists is addressed in this white paper. We believe that these requirements should apply to all practitioners whether they are neurologically trained or not. We do not believe that training in coronary disease and coronary angiography alone prepare the practitioner for treatment of stroke.

We do not believe that short, CME courses, whether industry sponsored or otherwise, or simulation of procedures, not on patients, substitute for organized, credentialed training in brain vascular angiography. We make this recommendation because it is evidence-based and has been demonstrated in multiple brain angiographic domains to produce optimal patient safety.

We ask that the decision-making today regarding stroke, a brain disease, and this carotid stent device reflect our extensive knowledge about training and competency for brain angiography in the indications, in the labeling, and the instructions regarding competency of physicians who will perform this procedure. My third comment is directed towards the standards that should be applied today.

We suggest that the standard that protects patient well being be the current established medical therapy for stroke and that comparisons of the event rates for patients who are risk matched with medical treatments not requiring angiography or stent placement be considered in today=s deliberations. I thank you for your patience and I=m willing to answer any questions. We will provide you with a copy of the white paper which has been endorsed by all of the neuro-societies and radiology.

CHAIRMAN LASKEY: Thank you, sir. Any panel questions?

DR. HANLEY: Thank you.

CHAIRMAN LASKEY: Thank you again. Anyone else? Then at this point, I would like to close the open public hearing and move on to the sponsor presentation.

DR. COHEN: Mr. Chairperson, Committee Members, Dr. Zuckerman, representatives of the FDA, and representatives of the public, good morning. My name is Dr. Sidney Cohen. I=m Group Director of Clinical Research at Cordis Corporation. I=ll be presenting on behalf of Cordis this morning. I=m also an Adjunct Associate Professor of Medicine at the University of Pennsylvania.

In the next hour and 15 minutes, I would like to cover the following topics. I=d like to provide an overview of this project, go over some background information on stroke and carotid endarterectomy, provide a brief description of the devices that were studied, and provide an overview of the PMA clinical data which encompasses a total of 1,619 patients.

This includes both non-randomized carotid artery stent supportive data from two trials, the CASCADE study and a FEASIBILITY study done predominantly in the United States as well as the pivotal trial data from the SAPPHIRE trial which will be presented by Dr. Ken Ouriel. I will then briefly provide an overview of the training program that we have developed and discuss our plans for post-market surveillance study.

The requested indication is detailed here. I=m not going to read it for the sake of time. But to summarize, the Cordis PRECISE Nitinol Stent System used in conjunction with the ANGIOGUARD XP Emboli Capture Guidewire is indicated for the treatment of carotid artery disease in high risk patients. High risk is defined as at least 50 percent stenosis in patients with symptoms and at least 80 percent stenosis in patients without symptoms.

In addition patients both symptomatic and asymptomatic must have more than one condition or at least one condition that places them at high risk for carotid endarterectomy. We=ll go into what those risk factors are in the course of this presentation.

These studies started with a U.S. study called the U.S. FEASIBILITY study which was begun in September 1998. The SAPPHIRE pivotal study was begun in August 2000. The PMA was filed in October 2003. There are three conclusions from these studies that we plan to prove this morning, and that is (1) that we achieved our primary end point of non-inferiority of carotid artery stenting to carotid endarterectomy at one year for the major end point of major adverse events, (2) that carotid artery stenting provides improved outcomes in terms of reducing myocardial infarction, reducing the need for reinterventions and producing a statistically significant decrease in cranial nerve injuries, and (3) that the benefit of carotid artery stenting is sustained, and we will provide data up to three years from our studies.

Finally, the PMA was granted expedited review status in November 2003 being considered a significant therapeutic advance. You may be aware that Cordis was issued a warning letter on April 1. Cordis continues to work with the FDA on GMP and quality systems issues.

I have some background information on stroke and carotid disease. There are over 700,000 strokes that occur annually in the United States. Stroke is the third leading cause of death with an estimated 164,000 deaths per year. Up to 30 percent of strokes are caused by carotid artery disease. It=s the number one cause of disability in the United States.

The costs to take care of patients with stroke are in excess of $53 billion per year. If you are under the age of 65 and you have a stroke, you have an over 50 percent chance of dying within eight years. But by enlarge, this is a disease that affects the elderly and particularly those with comorbid medical conditions.

Carotid endarterectomy has a 50 year history of development and refinement to its present status. It=s currently the interventional standard of care in treating patients with carotid disease with the purpose of reducing stroke. There are up to 200,000 carotid endarterectomies performed each year in the United States.

It=s estimated that at least 20 percent of carotid endarterectomies are performed on high surgical risk patients annually in the United States with high surgical risk defined based on anatomic and medical comorbidities where the anatomic issues increase the risk of the procedure and the medical comorbidities increase the risk of having a myocardial infarction and death. There are a number of randomized clinical studies which have supported the superiority of carotid endarterectomy over best medical therapy that was available at the time the studies were undertaken.

These studies have led to carotid endarterectomy again being considered the standard of care for the interventional treatment of both symptomatic and asymptomatic carotid artery disease. It=s clear, however, that the current treatment of patient with carotid disease using carotid endarterectomy extends beyond the NASCET and ACAS inclusion criteria.

By enlarge, NASCET and ACAS studied a relatively healthy subset of patients. For example, ACAS screened 25 patients in order to enroll one patient whereas NASCET only enrolled one out of every three patients who underwent carotid endarterectomy at the participating institutions.

Patients considered at high risk for carotid endarterectomy, as defined by ineligibility, comprise up to 50 percent of patients in different published series. A study from the Ochsner Clinic encompassing 366 patients yielded 46.2 percent being trial ineligible. A study from the Cleveland Clinic encompassing over 3,000 patients indicated that just under 20 percent of patients were trial ineligible.

From a database for the Agency for Health Care Research and Quality, which encompasses over 7.5 million admission during the year 2001, there were 30,000 patients in that database who underwent carotid endarterectomy. And 35.1 percent of those had features that would have made them ineligible for NASCET and ACAS being considered them high risk.

The specific criteria that we=re talking about include anatomic and medical comorbidities. The anatomic risks include tandem lesions, previous carotid endarterectomy, previous radiation therapy to the neck, and status post-radical neck dissection. The medical comorbidities include age greater than 79, a previous stroke, a previous myocardial infarction, unstable angina, atrial fibrillation, symptomatic heart failure, valvular heart disease, cancer with a less than 50 percent five year survival, and renal pulmonary and liver failure.

The data on the next several slides will provide evidence in two regards; first, that outcomes in patients undergoing carotid endarterectomy do not match what is in the literature and in addition that there are patients that are at high risk that are undergoing carotid endarterectomy. This is a study published by Wennberg in which mortality in patients in a Medicare database of 113,000 patients treated with carotid endarterectomy from 1992 and 1993 was investigated.

On the left side, you can see the mortality rates from the ACAS study. For the NASCET study, you see that the mortality for patients undergoing carotid endarterectomy in the same hospitals that participated in ACAS and NASCET are more than two-fold higher than the mortalities reported in the literature for those two studies. And non-trial hospitals had somewhat higher mortality.

In addition, non-trial data from a number of centers that includes both single center, Ochsner Clinic, Ohio Registry which is a composite of Medicare database from that state, and New York Registry both symptomatic and asymptomatic patients, a composite of six hospitals, yielded incidents of rates of death of up to one percent, rates of stroke between two and a half and four and a half percent, giving rates of stroke and death between two and a half and five and a half percent.

Another study of academic medical centers in a retrospective analysis of 1,160 patients at 12 centers in the United States for patients undergoing carotid endarterectomy in the years 1988 through 1990, using an end point of in-hospital death, myocardial infarction, and stroke, and an end point that=s similar to that used in the SAPPHIRE trial, yielded an overall outcome of 6.9 percent. Patients who were over 75 who were symptomatic or had angina had higher event rates than those overall.

If we break out that 6.9 percent overall rate into its individual components, we see a death rate of 1.4 percent, non-fatal stroke rate of 3.4 percent yielding a combined death/non-fatal stroke rate of 4.8 percent and a MI rate of 2.1 percent. Certainly this study as well as the previous studies suggest both that patients currently undergoing carotid endarterectomy have risk factors that lead to outcomes that are not quite what is published in ACAS and NASCET.

In addition, there=s data that the patients currently undergoing therapy are actually comprised mostly of asymptomatic patients. Again, data from the same registries mentioned before or single site data indicates that a low of 25 percent or anywhere between 60 and 75 percent of patients currently going carotid endarterectomy in the United States are asymptomatic.

While there is no contemporary data that would allow us to understand the outcomes with medical therapy of patients who have carotid stenosis and who are asymptomatic, there is data that is more historical in nature that could be brought to bear on this. This is a study of asymptomatic patients totaling 1,196 which indicates that the stroke rate is fairly flat until you get to the 80 percent level where the stroke rate increases rapidly from one percent up to over five and a half percent.

This value of 80 percent to 99 percent actually is supported by data published from the European Carotid Surgery Trialists paper of asymptomatic patients which indicated that the three year stroke rate for the same cohort of patients for the 80 to 89 percent was 9.8 percent and for the 90 to 99 percent was 14.4 percent. In addition, I would remind you that of the patients enrolled in the ACAS trial, only one-third of those had an 80 percent or greater stenosis.

In fact, this data led to the choice of 80 percent as the minimum stenosis for asymptomatic patients in the SAPPHIRE trial. Thus, in the United States, the standard indications for surgical treatment of carotid disease include both NASCET and ACAS eligible as well as ineligible patients, symptomatic and asymptomatic patients, and higher risk patients with high risk being defined on anatomic and medical comorbidities and thus, SAPPHIRE trial study patients who currently are referred for treatment of their carotid disease.

We chose to study high surgical risk patients because in the initial evaluation of the new technology, it was decided to study it in a cohort of patients where carotid endarterectomy is technically demanding. It=s demanding based on anatomic factors which difficult access surgically may lead to increased local tissue and nerve injury as well as for the presence of medical comorbidities where patients would be less tolerant of general anesthesia and surgery. Thus, carotid artery stenting is studied as an alternative and less invasive method of therapy.

I=d like to move on now to a brief description of the devices used in these studies. The carotid artery stenting system consists of two devices; a stent delivery system and emboli protection device. The stent delivery system is comprised of a stent and a delivery catheter.

The Cordis PRECISE Nitinol Stent comes in two french sizes; 5.5 french and 6 french. The 5.5 french comes in diameters of 5, 6, 7, and 8 millimeters with lengths of 20, 30, and 40. The 6 french system has sizes of 9 and 10 millimeters diameter by 20, 30, and 40 millimeters in length.

In addition, tapered stents were studied. In the 5.5 system, that=s a 6 to 8 millimeter taper diameter by 30 millimeter length. For the 6 french system, 7 to 9 and 7 to 9 millimeter diameters with a 30 millimeter length. The stent delivery system has a usable length of 135 centimeters with a guidewire lumen of 0.018 inch.

Emboli protection is provided by the ANGIOGUARD XP Emboli Capture Guidewire. This is a polyurethane filter on a Nitinol frame. Basket diameters range from 4 to 8 millimeters. We oversize the basket in use by anywhere from 0.5 to 1.5 millimeters versus the reference vessel diameter. The pore size of the filter is 100 microns. The crossing profile is 3.5 french. The wire diameter again is 0.014.

I=d like to show an animation of the system in use. What you will see is, first, the inside view of the artery. That=s not good. What you would have seen is the inside view of the artery with first the ANGIOGUARD device being deployed past the lesion, the sheath being withdrawn, deploying the umbrella-shaped ANGIOGUARD. That would be followed by a balloon dilatation with release of material from the lesion being captured by the ANGIOGUARD which is distill to the lesion, the placement of the stent which is a Nitinol stent which self-expands upon withdrawal of the sheath, and then finally capture of the ANGIOGUARD device and then retrieval of that device from the body.

I=d like to move on now to an overview of the PMA clinical data which encompasses a total of 1,619 patients. Again, this is provided as supportive data from the CASCADE study done in Europe and the FEASIBILITY study done predominantly in the United States. The purpose of these two studies were to gain experience with the carotid stent system and provide a learning curve for investigators.

It allowed us to refine the stent delivery system and to evaluate the advantage of adding the ANGIOGUARD device. Two studies will be described. The CASCADE study done entirely in Europe was a non-randomized study of carotid artery stenting encompassing 121 patients. Even though the primary end point was 30 days, we have a one year follow up in those patients.

The FEASIBILITY study was done predominantly, again, in the United States. It=s a non-randomized study of carotid artery stenting. A total of 261 patients were enrolled. That has a three year follow up even though the primary end point was not at three years.

Let=s move on to the CASCADE study. The objective here was to evaluate the safety and performance of the SMART stent with and without ANGIOGUARD Emboli Capture in patients with high grade carotid artery stenosis. The primary end point was ipsilateral stroke or procedure-related death within 30 days of stent implantation.

This is a multi-center, prospective, non-randomized study in nine centers in Europe using the 7 french SMART system which is a predecessor to the PRECISE system, identical stent just a slightly different delivery system. There were 121 patients enrolled, 31 with ANGIOGUARD. It was conducted from September >98 through May 2002. It included symptomatic patients with greater than 70 percent stenosis, asymptomatic patients greater than 85 percent stenosis with the stenosis occurring between the origin of the origin of the common carotid and the extra-cranial segment of the internal carotid artery.

The primary end point is shown here. (Indicating.) There were no procedure-related deaths. Ipsilateral stroke occurred at a rate of 7.4 percent. If we divide the data between the patients who were treated with stent alone in blue and stent with an ANGIOGUARD in red, we see a reduction of events in the patients we used with ANGIOGUARD with ipsilateral stroke rate of 3.2 percent and no major ipsilateral strokes.

Conclusions. From the CASCADE study, which is carotid artery stenting, was found to be feasible for the treatment of carotid stenosis. The ANGIOGUARD distal protection device functioned well and appeared to reduce the risk of distal embolization resulting in fewer strokes such that use with the ANGIOGUARD the 30 day stroke rate was 3.2 percent with no major strokes.

The U.S. FEASIBILITY study=s objective was to assess the feasibility of carotid artery stenting in the treatment of obstructive carotid artery disease. It=s also to assess and standardize optimal operator techniques as this also served as the run-in phase for the clinical trial. It was designed as a non-randomized prospective study of 33 centers using the 6 and 7 french SMART system, again predecessors to the PRECISE system, and the 5.5 french PRECISE stent delivery system.

There were 261 patients enrolled, 85 of whom received stenting with the ANGIOGUARD device. They were enrolled from September >98 through July 2001. We have follow up out to three years. Inclusion criteria included patients who were symptomatic, needed to have at least 60 percent stenosis. Patients who were asymptomatic had to have at least 80 percent stenosis by ultrasound or angiography with again disease of the native common or internal carotid arteries.

Inclusion criteria here were somewhat different. They included anatomic risk factors which made the patients at somewhat higher risk for surgical endarterectomy. This included restenosis after carotid endarterectomy, a history of radical neck dissection, a history of contralateral carotid artery occlusion, a history of an ostial lesion of the common carotid, and a high take off carotid bifurcation disease.

The primary end point was 30 day major adverse events, MAE, defined as death, any stroke, and/or myocardial infarction. Key secondary end points included major clinical events at six months and yearly to three years, patency defined as less than 50 percent restenosis by carotid ultrasound at 48 hours, 30 days, six months, and yearly to three years, and neurologic assessments that were performed by an independent neurologist at 28 hours, 30 days, six months, and yearly to three years.

The end points are depicted here with a death rate of 0.8, MI of 1.1, stroke of 6.1 yielding a major adverse event rate of 6.9. Again, if we take the data and separate it out between the patients in blue who received a stent only versus patients in red who were treated with a stent and the ANGIOGUARD, you see that the stroke rate with ANGIOGUARD is 2.4. Once again, there were no major ipsilateral strokes.

We have here the cumulative incidents of major adverse events. I=d like to take a second to review this slide as you will be seeing this cumulative incidents curve several times during this presentation. At the very bottom of the curve - and I=m sorry, I don=t want to hit the gentleman=s head with the back of the pointer here - but you see the table that indicates the number of patients at risk at the different time periods.

On the Y axis is the cumulative percentage of major adverse events. The X axis is the time after the procedure. The end points are indicated at 30 days here by the numbers, one year, two years, and three years. Error bars are 1.5 times the standard error.

What you see here is an increase in the rate of adverse events over the three year follow up. When we look to see what the components of this increase in curve are, first, we look at the cumulative percentage of all stroke to 30 days and ipsilateral stroke from days 31 through three years. What you see is a rate at 30 days of 6.1 which increases to 8.7 at three years. That an increase of just under one percent per year.

On the other hand, if you look at the cumulative incidents rate percentage of death to three years, you see an increase in the curve over the course of this time period. It is this increased death that contributes to the increased rate of major adverse events. This increase of death rate or the deaths are likely due to the elderly age and the significant medical comorbidities of these patients.

In conclusion, for the U.S. FEASIBILITY study, we were able to demonstrate the feasibility of carotid stenting with the Cordis PRECISE Nitinol stent system. The ANGIOGUARD Emboli protection device appeared to reduce the incidents of stroke. Again, with use of the device, the stroke rate at 30 days was 2.4 percent and there were no major strokes. This also provided a run in to the pivotal SAPPHIRE study.

Because the number of patients in the FEASIBILITY study and the CASCADE study were small, we did an exploratory analysis to see whether combining the data from those two trials would yield significance. So on the right side of the slide here is the combined incidents of stroke without ANGIOGUARD and the combined incidents of stroke with ANGIOGUARD. You see the difference here, from 8.6 to 2.6, does reach statistical significance at the p = 0.02 level.

From these two studies, we were able to refine the carotid artery stent delivery system with a reduction in profile from 7 french to 5.5 french. That allowed us to improve the design of the delivery system. The data supports the benefits of the ANGIOGUARD Emboli protection device in reducing stroke. It has demonstrated the feasibility of performing carotid artery stenting. At this time, I would like to ask Dr. Ken Ouriel to come to the podium to present the pivotal SAPPHIRE trial data.

DR. OURIEL: Thank you, Sid. Good morning. I=m Dr. Kenneth Ouriel. I=m Chairman of the Division of Surgery at the Cleveland Clinic Foundation and Professor of Surgery at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University.

I=m one of the members of the executive committee of SAPPHIRE. I=m going to present the methodology and results of this pivotal trial. I=d like to disclose that my lodging for one night was paid by Cordis. My travel here was paid for by the Cleveland Clinic. I have no other conflicts to disclose at this time.

The objective of the SAPPHIRE study was to compare the safety and effectiveness of carotid stenting with emboli protection to endarterectomy in the treatment of carotid artery disease in high risk patients. There were a total of 2,294 patients screened for eligibility for the SAPPHIRE trial. Among these, roughly one-third or 747 patients met the inclusion and exclusion criteria as determined by concurrence between and interventionalist, a surgeon, and a neurologist at each site.

Within this cohort of 747 patients, both the surgeon and the interventionalist felt that either carotid stenting or endarterectomy were feasible in 334 patients. This group underwent randomization to stent treatment in exactly one-half or 167 patients and to endarterectomy in the other one-half.

There were 406 patients who the surgeons thought were unacceptable for carotid endarterectomy. These patients were not randomized. Rather, they were entered into a non-randomized stent treatment arm. There were seven patients who the interventionalists thought were at unacceptable risk for stenting. These patients were entered into a small, non-randomized endarterectomy treatment arm.

The primary end point of this trial was death (all cause), any stroke, and myocardial infarction to 30 days post-procedure plus death (all cause) and ipsilateral stroke between days 31 and 360 post-procedure. There are real differences between SAPPHIRE and previous surgical trials.

First, the primary end point of SAPPHIRE included all cause mortality rather than just peri-procedural or neurologic-related deaths. The composite end point of major adverse events included myocardial infarction in addition to death and stroke. The 24 hour post-procedure stroke evaluation was performed by a neurologist.

Stroke scales were utilized in addition to physical examination in the classification of stroke. Vessel restenosis and patency was documented by duplex ultrasound. Lastly, a multi-disciplinary team provided input on the treatment strategy including eligibility and appropriateness for randomization.

Some have asked why myocardial infarction was included in the primary end point of SAPPHIRE. Myocardial infarction leads to disability, death, prolonged hospitalization, and health care costs and as such is thought to be a key safety end point. In patients undergoing vascular surgery who sustain a perioperative non-Q wave MI, there is a six-fold increase in mortality over the subsequent six months.

Perioperative myocardial infarction predicts mortality at one year. There is a 27-fold increase in the risk of another myocardial infarction over the next six months. Therefore, perioperative myocardial infarction is a strong surrogate for long-term mortality after vascular surgical procedures. Lastly, perioperative myocardial infarction is part of the primary end point for other carotid artery stenting trials such as CREST and ARCHeR.

Myocardial infarction was defined as either Q-wave or non-Q-wave. The definition of Q-wave MI was relatively standard requiring acute symptoms and new pathologic Q-waves. Non-Q-wave MIs were defined using the WHO definition of a CK ratio of greater than two times the upper limit of normal and a CK-MB fraction greater than normal in the absence of new Q-waves.

The definition of stroke was standard requiring a focal deficit of abrupt onset lasting more than one day. While the presence or absence of a stroke was not determined using stroke scales, when a stroke did occur, it was classified as major or minor using the NIH, Rankin, and Barthel scales.

The SAPPHIRE study was designed as an equivalence or in statistical parlance non-inferiority trial. The design was based on the following parameters. This was a high risk study. The majority of events were expected to occur within 30 days for an overall one year event rate of 14 percent. The delta was chosen to be three percent, a definition that was agreeable to the clinicians and the Agency.

The statistical power was set at 90 percent. The one-sided type I error rate was set at 0.025 which is conventional. What this means is that we would expect the results to be equivalent if we could be 97.5 percent certain that stenting was no more than three percent worse than endarterectomy.

We employed an interim analysis plan so that we could terminate the trial early if we could demonstrate either non-inferiority or superiority. Given the fact that this was the first randomized FDA IDE trial and had a potential for slow enrollment, the triangular method that we employed allowed for flexibility in choosing the timing of sequential testing during enrollment.

Our initial plan was to allow the performance of interim analyses every 100 patients. This statistical plan was also flexible to allow enrollment of up to 2,400 patients, if needed. For example, this is roughly the sample size of CREST. Based on conservative efforts of the stent=s performance, we anticipated that a sample size of 600 to 800 patients would result in a decision to stop the trial for non-inferiority.

As the FDA has pointed out, the initial analysis plan was changed. All changes were done in accordance with the flexibility allowed with the triangular method. We decided to omit the first interim analyses since a sample size of anything less than 300 patients was thought to be unconvincing. Before the revised planned analysis in the fall 2001, it was clear that enrollment was proceeding so slowly that we were unlikely to reach 400 patients.

Therefore, with an expectation of the trial terminating for slow enrollment between 300 and 350 patients, we decided to omit all interim analyses and perform a single final analysis when enrollment was inevitably terminated. It is important to point out that this change in interim testing was permitted under the triangular method. Since interim analysis was not performed in the study, the first analysis was the final analysis. Therefore, standard testing without correction for interim looks was appropriate.

This is a graphical representation of the rate of enrollment. (Indicating.) Enrollment was robust for the first 12 months of the study. At that point, enrollment diminished concurrent with the availability of competing stenting registries from other companies. There were now outlets for patients to be treated with stenting outside of the randomized SAPPHIRE trial. In fact, the Cordis site IDEs began after the termination of randomization.

Importantly, all patients enrolled in SAPPHIRE were referred for treatment of their carotid disease. All randomized patients would have been treated likely with endarterectomy if not for the trial. Symptomatic patients were required to have a 50 percent or greater stenosis by duplex or angiography. Asymptomatic patients had to have a stenosis of 80 percent or greater.

Disease had to be located in the native common or internal carotid artery. Importantly, consensus agreement by a multi-disciplinary team was required which included an interventionalist, a neurologist, and a surgeon. A patient had to have at least one comorbid condition which increase the risk of endarterectomy. These comorbid conditions could be anatomic or medical.

Key anatomic inclusion criteria that assured a high risk subset included contralateral carotid occlusion, contralateral recurrent laryngeal nerve palsies, previous radiation therapy to the next, previous endarterectomy with the presence of a recurrent stenosis, difficult surgical access such as a high internal carotid artery lesion, or severe tandem lesions.

Key medical comorbidities that assured a high risk subset included the following: congestive heart failure, open heart surgery within six weeks, a recent myocardial infarction, angina at a low workload or unstable angina, severe COPD, or age greater than 80 years.

At this point, I would like to present the results of the randomized portion of the SAPPHIRE trial. Table 1 of any randomized trial is always a comparison of the demographics and comorbidities of the two treatment groups. The randomized stent and randomized endarterectomy arms of SAPPHIRE were similar with respect to all baseline variables except three: coronary artery disease, previous coronary bypass, and previous PTCA. These characteristics were more frequent in the stenting arm. So if anything, the randomized stent arm was slightly more ill than the randomized endarterectomy arm.

There was a high degree of procedural success in the stented patients. The stent was successfully delivered to its intended location more than 99 percent of the time. Deployment of the stent resulted in less than a 30 percent residual stenosis in approximately 90 percent of the cases. The 30 percent threshold is currently used for coronary stent trials however.

Using a 50 percent threshold, possibly more appropriate for a peripheral trial, approximately 99 percent of the patients were successfully treated. The ANGIOGUARD filter was deployed on the first attempt and retrieved successfully in over 95 percent of the subjects in the randomized stent arm and in over 91 percent of the patients in the non-randomized stent arm. Ultimately, 98 percent of the randomized stent and 95 percent of the non-randomized stent subjects had successful deployment and retrieval of the ANGIOGUARD device.

Let=s move on to study outcome presenting data on an intent to treat basis unless otherwise specified. Among the 167 patients randomized to stent, one year compliance was achieved with respect to clinical criteria in 93.5 percent of cases and with respect to duplex ultrasound in 80.6 percent of the cases.

In the endarterectomy group, complete clinical follow up was available at one year in 85.6 percent of the cases and duplex ultrasound in about 69 percent of the cases. To remind you, all clinical events were adjudicated by an independent clinical events committee and all angiograms and duplex studies by independent core laboratories.

This slide depicts 30 day data in the two randomized groups; endarterectomy in red and stenting in blue. There were no statistically significant differences in the rate of death, stroke, myocardial infarction, or the composite of major adverse events. At one year, again, there were no statistically significant differences in the frequency of death, stroke, myocardial infarction, or major adverse events. In each case, however, the data trended in favor of stenting over endarterectomy.

This is probably the most important slide that we=re going to show you today. This is the primary end point analysis. The percent difference in one year MAE is along the abscissa with a dotted red line demonstrating the target delta of three percent. The horizontal line is the point estimate for the MAE difference with a raw value of 7.2 percent in favor of stenting over endarterectomy.

As you can see, the 95 percent confidence interval is to the left of the margin of non-inferiority. In other words, the primary goal of the study was achieved. We were more than 95 percent certain that stenting was no more than three percent worse than endarterectomy. In fact and importantly, we were certain that non-inferiority was achieved with a p-value of 0.0035. In fact, with this particular test, had the 95 percent confidence bar been slightly to the left of zero rather than slightly to the right, stenting would actually have been statistically superior to endarterectomy with regard to the primary end point.

The FDA statisticians asked us to perform the analysis as if we had performed interim testing at 100, 200, 300, and 334 patients. This table displays the results of that retrospective interim analysis. There would have been three interim analyses and one final analysis. The recommendations are listed in the last column and would have been as follows.

We would have chosen to continue the trial after 100 patients. We would have chosen to continue the trial after 200 patients. We would have decided to stop the trial at 300 patients. There would have been some additional run on patients. We probably would have ended up with somewhere between 300 and 350 patients. The final analysis would have included the run ons.

The p-values for superiority would have been 0.066. Importantly, the p-value for non-inferiority would have been 0.003, well below our threshold of 0.025. So with interim analyses and with corrections for multiple sequential testing, our conclusion would have been exactly the same. Stenting is equivalent to endarterectomy.

Having demonstrated non-inferiority in the primary end point of one year major adverse events, it makes sense to look at the individual end points at one year. There were no statistically significant differences between the randomized groups. But again, as this slide demonstrates, all trends were in favor of stenting over endarterectomy.

Again, there was no statistically significant difference in the rate of stroke at one year, 7.2 percent in the endarterectomy arm and 6 percent in the stented arm. Diving strokes into major and minor ipsilateral events, it appeared as though the strokes that occurred in the endarterectomy patients were more often major, and the strokes that occurred in the stented patients were more often minor. But these differences did not attain statistical significance.

These two Kaplan-Meier curves represent the cumulative percentage of subjects experiencing a major adverse event over one year of follow up. The MAE rate was 20.1 percent in the endarterectomy group and 12.2 percent in the stented group. While the trial was designed to be a non-inferiority trial, stenting almost hit statistical significance for superiority. The p-value was 0.053 with a log rank test.

Data out to two years is displayed here. The trends continued through 720 days of follow up with an MAE rate of 26.7 percent in the endarterectomy group and 19.2 percent in the stent group.

When the composite adverse event rate is split out by its components, we see that the rate of perioperative stroke was relatively low at just over three percent in both treatment arms. Importantly, the rate of stroke remained relatively flat thereafter with roughly a one percent annual risk of subsequent stroke over the next two years.

These two Kaplan-Meier curves depict the risk of death over two years of follow up. The risk of perioperative death was relatively low at 2.5 percent in the endarterectomy group and 1.2 percent in the stent group. Over the next two years however, mortality increased to 20.9 percent in the endarterectomy group and 14.4 percent in the stent group, a rate representative of the comorbid conditions of the subjects enrolled in the trial.

Of note, the median survival for the stented patients was 8.5 years and for the endarterectomy patients was 5.0 years. The cause of death is broken out here. There were 33 total deaths over the first year of follow up; 21 in the endarterectomy group and 12 in the stent group. Only four of the 33 deaths were tied to a neurological event; three in the endarterectomy group and one in the stented group.

By far, non-neurologic deaths predominated. Twenty of the 33 deaths occurred as a result of other causes. Those other causes are broken down here. At the bottom of the slide, cardiac causes were the most common occurring in 18 of the 29 cases of non-neurologic death. Other causes are listed here without significant differences between the two treatment arms.

The complications in the randomized stent and endarterectomy subjects are listed here. Target lesion revascularization was performed in 0.6 percent of the stent group and 3.6 percent in the endarterectomy group, a difference that did not attain statistical difference. Vessel thrombosis, defined in the protocol as angiographically confirmed occlusion, was not documented in either group.

Major bleeding occurred in similar numbers of the stented and endarterectomy patients, nine and ten percent respectively. There was a greater number of cranial nerve injuries in the endarterectomy group; 4.9 percent and not unexpectedly zero in the stented patients, a difference that was significant at the 0.01 level.

The rate of restenosis, defined in the protocol as 50 percent or greater, was 19.7 percent in the stented group and 31.3 percent in the endarterectomy group, a difference that just missed statistical significance. But using more clinically applicable definitions of greater than 70 or 80 percent diameter reduction, the rate of restenosis was much lower. Using the 80 percent threshold, the rate of restenosis was 0.8 percent in the stent group and 4.2 percent in the endarterectomy group, again, a difference that did not attain statistical significance.

Clinically driven target lesion revascularization, which for all intensive purposes represents a result of critical restenosis, this occurred with very similar frequency to the presence of an 80 percent or greater stenosis. Well, we showed you an intent to treat analysis. But a small number of patients never underwent treatment.

Therefore, it=s interesting to present the outcome of the patients who were actually treated with a specified modality. The reasons subjects did not receive specified treatment included ineligibility found after the patient had been randomized, withdrawal of consent prior to treatment, and deterioration in the patient=s condition prior to treatment.

Interestingly in the treated patients, the frequency of major ipsilateral stroke and MI was significantly higher in the endarterectomy treatment arm. In the treated patients, by Kaplan-Meier analysis, the one year major adverse event rate was 20.1 percent in the endarterectomy group versus 12.0 percent in the stented group, a difference that was statistically significant by the log rank test with a p-value of 0.048.

We=ll move on to data from the 406 patients in the non-randomized stent arm, patients that met the criteria for inclusion but for whom the surgeon felt open surgical repair carried an unacceptably high risk. Initially, the intent was to compare data from the non-randomized stent arm to an objective performance criteria or OPC from the literature.

The pre-specified OPC was 12.94 percent. This was not met. In fact, from an evaluation of the data from the SAPPHIRE randomized carotid endarterectomy arm, it had been underestimated. The true MAE was 19.2 percent. The Agency was consulted in March of last year. A supplemental non-inferiority was suggested using data from the SAPPHIRE endarterectomy group and adjusting for differences in baseline demographics.

A propensity analysis was necessary because of the higher rate of comorbidities in the non-randomized stent group compared to the endarterectomy group with a statistically high rate of Class 3 or 4 CCS patients, previous neck radiation therapy, high cervical lesions, prior endarterectomy, and prior stroke.

These three Kaplan-Meier curves demonstrate the rate of MAE up to 360 days. Despite a higher severity of illness in the non-randomized stent group, outcome was as good or possibly better than that of the randomized endarterectomy treatment arm. In fact, the curve fell midway between the randomized stent and the randomized endarterectomy outcomes.

This is the analysis the Agency suggested. The outcome of the non-randomized stent group was non-inferior to that of the randomized endarterectomy group. The confidence interval falls just below the three percent delta that was pre-specified with a p-value of 0.05.

Looking at complications, the rate of target lesion revascularization and cranial nerve injury was significantly lower in the non-randomized stent arm. The rates of vessel thrombosis and major bleeding were similar in the two groups. Given the small number of patients in the non-randomized endarterectomy arm, data will not be covered.

While we will present data from subgroup analyses, the study was not powered for such analyses. I will now present data from the symptomatic and asymptomatic cohorts numbering 96 and 237 respectively. The 30 day MAE rate in the asymptomatic endarterectomy in red and asymptomatic stent patients in blue is illustrated here. There were no significant differences in any of the individual end points or in the composite MAE rate.

Corresponding data at one year is illustrated here. Again, there were no differences in the rate of the individual end points or in the rate of the composite end point. In each case, however, there were trends in favor of stent over endarterectomy. The p-value for the difference in the MAE rate by Fisher=s Exact high-score test was 0.07.

With Kaplan-Meier analyses of MAE to one year, asymptomatic patients randomized to stent did better than those randomized to endarterectomy, 10.5 percent versus 20.3 percent with a p-value by the log rank test of 0.04. The median survival of the stented asymptomatic patients was 12 years. The median survival of the endarterectomy asymptomatic patients was six years.

Moving on to symptomatic patients, the rates of the individual end points at 30 days were not statistically different in the two treatment groups. Point estimates favored the stented patients for all end points. At one year, similar results were observed without significant differences in any of the end points but with trends towards improvement in the stented groups for each of the end points.

These two Kaplan-Meier curves display the frequency of major adverse events in the symptomatic cohort estimated at 20 percent in the endarterectomy arm and 16.3 percent in the stent arm, a difference that was not statistically significant. Of note, the median survival for the symptomatic stent patients was five years and for the endarterectomy patients 3.5 years.

To assure the technical expertise of the surgeons in the SAPPHIRE trial and to convince ourselves that it was representative of surgeons throughout the United States, we evaluated volume and outcome. The 53 SAPPHIRE surgeons were high volume operators reporting a pre-trial experience averaging 36 carotid endarterectomies per year with a median of 28 endarterectomies per year.

This histogram depicts Medicare data from Wennberg published in JAMA about six years ago. Dividing the number of endarterectomies a surgeon performs into terciles, the lowest tercile performed, the cut off, was less than six carotid endarterectomies per year. The middle tercile was defined as between seven and 21 endarterectomies per year. The highest tercile was more than 21 endarterectomies per year.

As you can see from Wennberg=s data, the mortality rate for carotid endarterectomy decreased from 2.5 percent for surgeons performing less than seven cases annually to just over 1.5 percent for those Medicare surgeons performing more than 21 cases annually. Same data here but now adding the pre-trial volumes of the SAPPHIRE surgeons below the X axis.

With few exceptions, the SAPPHIRE surgeons= prior volume placed them in the highest tercile of experience. One index of surgical expertise is the rate of cranial nerve injuries. Despite the inclusion of re-do endarterectomies in the SAPPHIRE data set, the rate of cranial nerve injury was similar to both NASCET and the VA cooperative studies, studies that did not include repeat carotid endarterectomies.

To evaluate the SAPPHIRE surgeons= outcomes, the rate of 30 day ipsilateral stroke was used since this was one of the few end points available from each of the trials. Overall in SAPPHIRE, this rate was 1.8 percent. The SAPPHIRE symptomatic endarterectomy patients were compared with NASCET patients. While the numbers are small, the SAPPHIRE rate of zero is certainly no worse than the NASCET rate of 5.5 percent.

Comparing SAPPHIRE asymptomatic endarterectomy patients with ACAS, the rates were also very close, 2.5 percent versus 1.8 percent. These observations suggest that the surgical outcome for SAPPHIRE was quite similar to NASCET and ACAS for the end point of perioperative stroke despite the greater frequency of comorbidities in the SAPPHIRE data set.

We also compared the results of carotid stenting in SAPPHIRE to the outcomes of previously published surgical data. For symptomatic patients, there were no significant differences in the rate of ipsilateral stroke at 30 days between the SAPPHIRE randomized stent group, the non-randomized stent group, and the endarterectomy arm of the NASCET trial. For asymptomatic patients, there were no significant differences in the 30 day risk of ipsilateral stroke in the SAPPHIRE randomized stent arm, the SAPPHIRE non-randomized stent arm, and ACAS.

In symptomatic SAPPHIRE patients, the 30 day rate for all cause mortality was zero in the randomized stent arm and 0.8 percent in the non-randomized stent arm. For asymptomatic SAPPHIRE patients, the 30 day rate of all cause mortality was 1.7 percent in the randomized stent arm and 2.8 percent in the non-randomized stent arm. These data compare favorably with corresponding data from NASCET and ACAS.

In conclusion, the primary end point of the SAPPHIRE trial was achieved. Carotid artery stenting clearly was non-inferior to carotid endarterectomy in high risk patients. In fact, there were trends favoring stenting over endarterectomy with respect to major ipsilateral stroke, myocardial infarction, target lesion revascularization, and restenosis.

Further, there was a significant decrease in the rate of cranial nerve injuries in the stented group. In the symptomatic and asymptomatic subset analyses, there was significant improvement at 360 days in favor of stenting over endarterectomy in asymptomatic patients with a 50 percent reduction in the rate of major adverse events.

The MAE rate was similar in the symptomatic patients treated with stenting or endarterectomy. The risk of ipsilateral stroke in stented patients overlapped the risks from the NASCET and ACAS trials. In other words, the results of the SAPPHIRE trial was in keeping with previously published data.

With respect to the non-randomized carotid stent arm, there appeared to be risk factors that identified patients that may be at too high risk for endarterectomy. These risk factors were anatomic, medical, or both.

Interestingly, the patients entered into the non-randomized stent arm because the surgeon considered them to be at too high risk for endarterectomy had outcomes that were not inferior to the randomized endarterectomy patients even though the stented group had significantly more comorbidities. This was true for both the symptomatic and the asymptomatic patients. I would now like to reintroduce Dr. Sid Cohen to continue with training and post-marketing surveillance.

DR. COHEN: Thank you, Ken. I=d like to take the next couple of minutes just providing an overview of the training program that we=re proposing to undertake as well as the post-marketing surveillance study and finish with conclusions. The carotid artery stent training system is intended to build upon existing catheter-based expertise to develop the physician=s knowledge and technical abilities in performing carotid artery stenting.

The system was developed using a variety of experts including SAPPHIRE investigators, experts in Internet-based training, experts in simulator modeling, and experts in proficiency measurements. The process of this education encompasses five steps that are pretty traditional but with some modernization.

It includes an online didactic session, observation of actual cases, simulation using a simulator, a proctoring system, as well as training of adjunctive staff in performing the procedure. These trainings occur for the didactic at Internet delivery, for observation and simulation using regional education centers, for the proctoring network and staff training on-site training at the physician=s facility.

What=s unique here is that we have included very importantly a measurement of proficiency that occurs at each step to ensure that high quality patient outcomes would be generated from physicians trained in this system. For the online didactic training, the goal is to transfer expert knowledge through doing and decision-making as opposed to just reading. The goal is to ensure procedural success, providing a detailed understanding of carotid anatomy and brain anatomy, appropriate selection of cases, and high performance in terms of technical execution of the procedure.

Training at the regional educational center occurs in a small group setting where four modules are reviewed over two days. This includes both didactic presentations, observation of actual cases, simulation lab using a simulator, and a product lab to gain familiarity with the products used in carotid artery stenting. The physicians interact with realistic graphical simulations. Their task performance is formally assessed. The understanding of learning objectives is demonstrated.

On-site training at the physician=s facility by physician proctors utilizes a network of physicians who are experienced in performing carotid artery stenting using the Cordis system. These people act as proctors. The proctors either sign off the training and experience an application is adequate or suggest additional training recommendations in order to meet minimal proficiency standards.

The training program encompasses a total of 34 hours of training with exposure to a minimum of 15 cases. This serves as the foundation for hospital credentialing. In order to demonstrate outcomes of this training system in an earlier form, I would like to present outcomes from investigator IDE studies that were performed independent of Cordis but whose investigators were trained using an earlier version of this training system.

These investigator IDEs occurred at 36 centers, 30 of whom were non-SAPPHIRE investigators. All the investigators were trained and proctored on the use of the stent and the emboli protection system. Patient selection criteria was similar to that of the U.S. FEASIBILITY study. The neurologists evaluated the patients at 24 hours and at 30 days post-procedure. The data that I will be showing you is site-reported and unadjudicated.

Thirty day event rates, again site-reported, included a rate of death of 0.6 percent, stroke 2.6 percent, MI 1.4 percent yielding a major adverse event rate of 4.3 in 491 patients. Comparison of these outcomes with the data previously presented from CASCADE study in green, FEASIBILITY in yellow, SAPPHIRE in blue with the institutional IDEs in red shows that outcomes for both stroke as well as for death are very similar.

I=d like to move on now to the post-marketing surveillance study that we=re proposing to undertake. The goal here is to compare clinical outcomes with historical control data from SAPPHIRE in the early time period following approval and assess the effectiveness of the training program. It=s designed as a multi-center, prospective, non-randomized, open label study with a 30 day composite end point where major adverse events are defined as all death and all stroke.

Patients included will be those at high risk with de novo or restenotic lesions. We plan to enroll at least 1,000 patients with the inclusion criteria matching the labeled indications. Follow up will include neurologic exams at discharge and at 30 days performed by a neurologist and clinical events tracking through discharge by a 30 day office visit and a nine month telephone contact. There also will be monitoring with a stopping rule to ensure safety with electronic data capture to expedite review of outcomes.

I=d like to provide a summary and conclusions to this presentation. What we have discussed is that stroke is a disease that has significant morbidity and mortality. It=s due to carotid disease in up to 30 percent of patients. The goal is to prevent stroke and improve the quality of life.

Carotid endarterectomy is the current interventional standard of care for NASCET and ACAS eligible and ineligible patients, for symptomatic and asymptomatic patients, as well as for low, intermediate, and high risk patients. We acknowledge that there are no multi-center randomized studies that define outcomes in high risk medical or surgical risk patients. However, SAPPHIRE is intended as an objective comparison of carotid endarterectomy, the current interventional standard of care, with carotid artery stenting, a less invasive approach to therapy.

Again, Cordis is seeking an indication - I will not read this but summarize it - for use of the PRECISE Nitinol Stent System in conjunction with the ANGIOGUARD XP Emboli Capture Guidewire for use in the treatment of carotid artery disease in high risk patients with symptomatic patients having at least 50 percent atherosclerosis stenosis, asymptomatic at least 80 percent atherosclerosis stenosis with the symptomatic and asymptomatic patients having at least one of the conditions, either anatomic or medical comorbidities that place them at high risk.

This indication is supported by data that we=ve presented from the SAPPHIRE trial where we achieved our primary end point of non-inferiority of carotid artery stenting to carotid endarterectomy for the end point of major adverse events at one year with carotid artery stenting, improving outcomes in terms of reducing myocardial infarctions, reducing the need for reinterventions, and providing a statistically significant decrease, actually an absence, of cranial nerve injuries. We also have provided data in the supportive studies that the benefit of treatment is durable with data that we=ve presented with up to three year follow up.

Cordis will institute a training program to ensure that the outcomes of carotid stenting in the non-trial setting replicates the safety and effectiveness demonstrated in the SAPPHIRE trial. We will conduct a post-marketing surveillance study with the goal of quantifying patient outcomes and confirming the adequacy of physician training. Thank you very much. I would be happy to answer any questions.

CHAIRMAN LASKEY: Well, first of all, bravo for staying within the dreaded yellow and red lights. That was an excellent presentation from both of you. Realizing that each panel member will have an opportunity to query again this afternoon and that we=re coming up to a short break, are there particular areas of clarification that we can try and resolve now? Dr. Aziz.

DR. AZIZ: Just for clarification, once the stenosis was diagnosed by ultrasound, did the patient have an angiogram as well before surgery was done?

DR. COHEN: For the patients who received carotid stenting, obviously an angiogram was undertaken. For the patients who underwent carotid endarterectomy, no angiogram was required. A minority of patients actually underwent angiography because of the dangers of angiography.

DR. AZIZ: Interesting.

CHAIRMAN LASKEY: Tony.

DR. COMEROTA: Dr. Cohen, that was a very elegant presentation. Both you and Dr. Ouriel did it beautifully and very convincingly. In the FEASIBILITY study, could you tell us how many patients were symptomatic and how many were asymptomatic and how many had atherosclerotic disease and how many had recurrent stenosis?

DR. COHEN: I would need to check the data tables to be sure. My memory is that over 60 percent were symptomatic. I do not know that we gathered data on how many were native de novo lesions versus restenotic, but we can check on that and get back to you.

CHAIRMAN LASKEY: One question I had for Dr. Ouriel I guess. With respect to the surgical arm, was there a standardization of the surgical approach, i.e. general versus local? How was that decided? What was the standard surgical approach?

DR. OURIEL: Well, actually, it was left up to the surgeons. So we did not dictate that a surgeon had to use a patch or not use a patch, a shunt or no shunt, or general versus local anesthesia. I can tell you that most procedures were done with a patch and under general anesthesia.

DR. AZIZ: So none of them had an eversion endarterectomy. They had the standard endarterectomy.

DR. OURIEL: No, that=s not necessarily true. I don=t have those numbers, but again, it was left up to the surgeon. In fact, there were some cases that had vein patches, some prosthetic patches. Some re-do endarterectomies had a saphenous vein short interposition graph. So it was left up to the discretion of the operating surgeon.

DR. COHEN: If I could answer the question that was asked before for previous carotid endarterectomy with recurrent stenosis, that occurred in 22.4 percent in the patients in the FEASIBILITY study.

CHAIRMAN LASKEY: Okay, well, thank you both again. Let=s take a rigorous ten minute break. We=ll see you back in ten minutes. Off the record.

(Whereupon, the foregoing matter went off the record at 11:03 a.m. and went back on the record at 11:26 a.m.)

CHAIRMAN LASKEY: On the record. If we can all regroup again please. Thank you all very much for your compliance, another watchword. We would now like to proceed with the Agency=s presentation.

MS. KENNELL: Good morning, panel members and audience. Our FDA presentation --

MS. WOOD: Lisa, pull the mic a little closer.

MS. KENNELL: Thank you. I=m trying to juggle the laptop as well. Our FDA presentation will involve three presenters. I will be presenting some background information and comments about the non-clinical information in the file.

Our statistician Heng Li will present several slides detailing statistical issues and conclusions. Dr. Ronald Weintraub, a consultant to FDA on this project, will discuss issues relating to the clinical study. We have a substantial number of difficult questions for panel discussion, so I want to move through our presentation as quickly as possible.

I would like to acknowledge the people who helped me on this project. I had three engineers and three clinicians who provided input as well as Dr. Li, the statistician. I reviewed the remainder of the information in the submission as well as coordinating the reviews from the team members.

The next several slides detail configurations and sizes of the stent and embolic protection device that the sponsor proposes to offer for sale. The OTW, over the wire, configuration will be offered in either 6 or 5.5 french profile with the larger profile being for the larger stent diameters. Stent diameters in the OTW configuration will range from 5 to 10 millimeters in both tapered and straight configurations.

The sponsor also makes an RX, rapid exchange, configuration that is compatible with a 0.14 inch guidewire rather than the 0.18 inch needed for the OTW version in the same sizes as the OTW minus the tapered. However, due to a recent development, we are not considering this configuration today.

Similar to the stent, the ANGIOGUARD XP Emboli Capture Guidewire will also be made in both an OTW and an RX configuration. Filter sizes in both configurations will range from 4 to 8 millimeters. Again, the RX configuration will not be considered today.

There have been some recent developments relating to the RX configurations. The sponsor submitted an unsolicited amendment to the PMA just two weeks ago which proposed a change in the Instructions for Use for these devices. What prompted this submission were complaints received by Cordis relating to air being entrained in the RX configuration when used off-label in carotid and other indications.

While many of these instances resulted in no injury to the patient, there were a few that resulted in adverse events from air embolism. This rate has been increasing and is not up to an estimated 0.14 percent.

Cordis investigated these events to try to determine the root cause followed by some testing on the bench to try to simulate this problem and correct it. The problem seems to occur in the RX configuration because of the tolerance and the length of the pod in the RX. We are concerned that the bench testing performed by the sponsor to date is not optimal because saline was used in the testing and the viscosity of saline is different than that of blood.

We believe that additional animal and possibly clinical testing may need to be performed. After this slide was finalized, Cordis called to indicate that animal testing had been performed but it was not included in the amendment for review. Based on the bench and animal testing, the sponsor has proposed stipulating larger guiding catheters for introducer sheaths and more detailed instructions for preparing the delivery system.

FDA will continue to work with the sponsor to resolve this issue since we believe that further testing is probably warranted and the results of the animal studies will need to be submitted and reviewed. The indication sought by the sponsor is provided on this slide and provides options for patients with and without symptoms and stipulations relating to degree of stenosis as well as comorbidities making them a high risk for surgery.

The IDE for this device has had a long history beginning in 1998. Since the first submission, there have been many changes made to the device, materials of construction, sizes, and profile, with the most significant being the introduction of the ANGIOGUARD Embolic protection device during the latter part of the FEASIBILITY study, lowering the profile of the device, and the development of the RX configuration.

The sponsor terminated their randomized study early and gave the reasons detailed in this slide. Regarding the first bullet, these competing studies were facilitated by Cordis in that Cordis provided each investigator with a letter of authorization to allow FDA to access the Cordis file for background information. Cordis also supplied most, if not all, of the single investigators a copy of their FEASIBILITY protocol, which was a registry design, and the case report forms and consent that was developed for that study.

Most opted to follow this protocol with little modification, but Cordis was not privy to interactions between these single investigators and FDA. Most investigators were approved to perform somewhere between 50 and 100 carotid artery stenting cases.

While there was no contractual relationship between Cordis and these single investigators, a sponsor is required under the PMA regulation to provide FDA with all data known to them or that should be known to them. So Cordis coordinated with most of these investigators to obtain their 30 day data for inclusion into the PMA. It should be noted that all of these studies stipulate a minimum of 12 month follow up.

As stated earlier, there have been many design changes made throughout the history of the file. For each change the sponsor made, they provided testing appropriate to the specific change. Testing has included fatigue, simulated use, device specification, and integrity testing sometimes on the bench, sometimes in animals, sometimes in both.

We met with the firm just prior to the submission of the PMA and agreed that the RX configuration of the stent and ANGIOGUARD could be approved without clinical data since the working ends have not been modified. In the original animal testing results submitted prior to the proposed fix of using larger guiding catheters or sheaths, one comment in the report was that a larger guide would be needed for the 10 by 40 centimeter size.

While we did not suspect a problem with this statement, the new developments in humans, with devices being used off-label, may warrant further evaluation clinically and we may have to reconsider our agreement. To date, the engineering reviews have been completed, at least those performed prior to the proposal for larger guiding catheters and sheaths, as have biocompatibility. These are considered adequate and complete.

The review of the sterilization validation is not yet complete, but no major issues are anticipated from that review. As noted earlier, each additional bench, animal, and possible clinical data may be needed to fully validate the RX configuration.

Another non-clinical issue has arisen recently. The FDA issued Cordis a corporate warning letter on April 1, 2004. Our investigators noted many serious non-compliance issues with respect to the current Good Manufacturing Practices requirements. The letter quoted that there were systemic problems noted at many facilities.

Obviously these are going to need to be rectified before approval can be granted for the PRECISE and the ANGIOGUARD. I=m going to now turn over the podium to Dr. Heng Li, the FDA statistician for a brief discussion of the statistical issues.

DR. LI: In my presentation, I will make a few comments on the SAPPHIRE randomized trial, the SAPPHIRE stent registry, and the statistical procedure of propensities for analysis followed by some concluding remarks. First, let me talk about the SAPPHIRE randomized trial.

This randomized clinical trial, whose objective is to compare stenting with carotid endarterectomy, had a group sequential statistical plan in which the sequential triangular test was used. Unlike a fixed sample sized plan, the group sequential design does not pre-specify the sample size of the trial. Instead, the design establishes a set of stopping rules and schedules a series of interim analyses.

At each interim analyses, the available data are examined and the trial is either stopped or continued according to the stopping rules. The stopping rules and the schedule of interim analyses are specified so as to control the frequent error probabilities at their intended or specified levels. For the SAPPHIRE randomized trial, the interim analyses are scheduled at intervals of every 100 patients.

The maximum sample size was specified to be 2,400. In the original protocol, it was expected that the trial would be stopped at a sample size of at least 600. I will come back to discuss the original group sequential trial in some more detail for the SAPPHIRE randomized trial in a minute.

But before I do that, let me point out that the sponsor made no claims that the original group sequential protocol had been followed. As a matter of fact, in the current PMA submission, the message appeared to be that the original group sequential statistical plan had not been followed. In particular, the scheduled interim analyses had not been conducted. However, FDA was not aware of any change in the statistical plan.

In the current submission, data from SAPPHIRE randomized trial were used to make the declaration that stenting is non-inferior to CEA. This declaration is based upon statistical inference. We know that statistical inferences for design studies need to be made according to the statistical plan in the current study protocol. Otherwise, they are unplanned.

Therefore, the statistical inferences in the current PMA submission that led to the declaration of non-inferiority of stenting relative to CEA based on the SAPPHIRE randomized trial is unplanned since it made reference to a statistical plan that is not in the current study protocol, namely a fixed sample size design based on 334 patients, the number at which the trial happened to be discontinued. We all know that statistical inference based on unplanned analyses are less reliable. So we don=t think it=s necessary that the inference be based on an unreliable, unplanned analysis.

Now, let us describe the original group sequential protocol in a little more detail using a picture. In this picture, the label of the horizontal axis V represents the amount of information that has accumulated at a given time or before a given time. The label of the vertical axis Z represents the difference in treatment effect as reflected in the data at that time.

At any stage of the clinical trial, the values of V and Z can be calculated from the available data. So we can imagine that as the trial progresses, it traces out a sample path on the V-Z plane. Because the amount of information increases as more data became available, the sample path goes from left to right starting at V equal to zero.

As it moves to the right, it may wander up and down. The triangle on the graph defines the stopping rule in the original group sequential plan for the SAPPHIRE randomized trial. If the trial is continuously monitored, then when the sample paths cross one of the triangular boundaries the trial is stopped.

If the sample path crosses the upper triangular boundary, then the trial is stopped and the non-inferiority tested. When the sample path crosses the lower triangular boundary, the trial is stopped and no non-inferiority can be claimed. As long as the sample path is within the triangular region, the trial continues.

The inner boundaries are called the Christmas tree boundaries because of their shape. These reflect the adjustment necessary for discreet monitoring. Since the scheduled monitoring is discreet with interim analysis planned for every 100 patients, the Christmas tree boundaries would have been used for the SAPPHIRE randomized trial.

This slide summarizes the stopping rules described earlier according to the original protocol. For the SAPPHIRE randomized trial, based on the data contained in the PMA submission, we can calculate Z and V as mentioned before. So we can plot a point in the Z-V plane. Of course, this single point wouldn=t tell us what would have happened had the original group sequential protocol been followed.

In the sponsor=s presentation, there is one slide that contains very valuable information which is the attempt of reconstructing the group sequential plan or a reconstruction of what would have happened had the original protocol been followed to the best approximation. As far as I=m aware, this information wasn=t contained in the PMA submission. As far as I know, it wasn=t submitted. If it was submitted, it wasn=t submitted before 4:00 p.m. yesterday. I=m looking forward to reviewing this very valuable information in the near future.

Let me now turn to the SAPPHIRE stent registry. For the SAPPHIRE stent registry, the predefined objective performance criteria is to reject a null hypothesis that the 360 day major adverse event rate is greater than 16.94 percent. The observed 360 day major adverse event rate is 15.76 percent.

A 95 confidence interval for a 360 day major adverse event rate has a lower bound of 12.36 percent and an upper bound of 19.68 percent. The upper confidence limit, 19.68 percent, exceeds the OPC of 16.94 percent. The pre-specified OPC has not been met.

After realizing that the OPC is not met, the sponsor made unplanned comparisons between the stent registry and CEA arm of the randomized study. Since the patient characteristics of those two groups by the nature of how they are assigned are not necessarily the same, a straightforward comparison as was conducted in the current PMA submission is not appropriate.

To address this issue, the sponsor used a propensity score method to compare the two groups attempting to make post-hoc claim of non-inferiority of stent registry to randomized CEA. The phrase Apropensity score method,@ as it is commonly used, refers to a class of statistical procedures that can help evaluate difference in treatment effect when the treatment groups are not necessarily comparable by balancing a set of chosen covariates.

It works by first introducing a model for the probability of a subject being assigned to one of the treatment groups given the values of the covariates. This probability is called the propensity score, hence the name propensity score method. The issue of missing data in the modeling, the issue of missing covariates in propensity score modeling could be addressed by multiple imputation.

The result of propensity score modeling is that each subject is assigned a propensity score. One way of using propensity score analysis to compare treatment effects after a propensity score is calculated for each subject is to divide the patients into five strata according to their propensity scores.

The first stratum consists of patients with propensity scores in the top twentieth percentile and so on all the way down to the last stratum consisting of patients with propensity scores in the lowest twentieth percentile. It turns out that all the covariates included in the propensity score model could be simultaneously balanced to a great extent within each stratum. Therefore, bias due to imbalance of those covariates could be removed to a great extent when treatment comparison is made within each stratum.

The potential of being able to simultaneously balance a large number of covariates to a great extent is a very attractive feature of the propensity score method. However, the sponsor may not have taken full advantage of the propensity score analysis in carrying out their propensity score analysis.

The potential issues include not all observed, clinically relevant covariates were included in the propensity score model, not all patients are included in the treatment comparison, and of course the analysis itself is unplanned. Given the sensitivity of the results to any improvement of methodology, this is all the more of a concern.

Now, let me get to the concluding remarks. In conclusion, original group sequential protocol was not followed and FDA was not informed of any change in protocol for a new statistical plan. Evidence of non-inferiority under original group sequential protocol was not supplied in the current PMA submission.

For the stent registry, it fails to meet a pre-specified operating OPC, objective performance criteria. Any non-inferiority claim based on the sponsor=s post-hoc propensity score analysis is problematic for the reason mentioned above. Now, let me turn the podium to Dr. Weintraub.

DR. WEINTRAUB: Good morning. The SAPPHIRE pivotal clinical study was designed as a multi-center randomized group sequential study studied by intention to treat as a comparison between patients undergoing open operative carotid endarterectomy and those being treated with the carotid angioplasty in the Cordis PRECISE stent system. In addition to the 334 patients randomized to the stent and endarterectomy arms, there was an additional stent registry cohort.

This presentation will examine the comparative results of the randomized arms, compare subgroups within the randomized arms, examine the results of the non-randomized stent registry, and look at the relative clinical effectiveness of the stent and endarterectomy techniques. Finally, a brief survey of historical randomized trials comparing endarterectomy with medical management of carotid stenosis will be introduced as a frame of reference.

In order to be considered for enrollment in the SAPPHIRE study, patients were required to be considered high risk by a neurologic or anatomic criteria in addition to having one or more technical or medical comorbid features considered to present high risk for carotid endarterectomy. These include the following and are defined in greater detail in your panel packs. The sponsor also introduced these in detail earlier this morning.

There were a number of exclusion criteria which are also enumerated in these next two slides and in detail in your panel packs and again were discussed by the sponsor earlier. I=ll just take a second so you can look at them.

There were 167 patients in each arm. These serve as the basis of comparison in the pivotal trial. In the non-randomized registry, 406 patients met inclusion criteria but were determined by the surgeon at each site to be at too high a risk for carotid endarterectomy and inappropriate therefore for randomization.

First of all, I skipped a page obviously so I=m going to have to go back. The names of the various laboratories are provided in your panel packs. Data analysis was performed by the Harvard Clinical Research Institute which also provided the adjudication committee.

The primary end points. Please note that the composite of major adverse events at 30 days post-procedure includes myocardial infarctions. These are not included unless they were fatal in the historical randomized trials comparing endarterectomy and medical therapy. The second primary end point consists of the composite 30 day major adverse events plus death and/or ipsilateral stroke at one month to a year.

Secondary end points are listed in the next two slides. Again, they were detailed in your panel packs. For the pivotal randomized trial, 29 centers enrolled patients. A total of 334 patients were enrolled equally divided between stent and endarterectomy. Five centers however enrolled the majority of patients. The one year major adverse event rates are listed for those five centers in the slide shown here.

Let=s look at the primary events. The primary end point of 30 day adverse event rates for the randomized stent and endarterectomy arms are displayed here. Please note the confidence limits in the far right columns. Let me review for the panel as well as for myself that if the limits embraced by the brackets encompass zero, the values of the two arms are not considered to be statistically different. As shown here, several pairs of data points approach but do not reach statistical significance.

Here are the one year or 360 day major adverse event rates. There are no statistically significant differences between the two groups. Moving forward, we look at the two year major adverse event rates and again no statistical difference between the two groups.

In this slide, the data are presented in several ways. First, both randomized and registry data are presented. They are also divided into neurologically symptomatic and asymptomatic cohorts. Finally, the 30 day major adverse events are scrubbed of their non-fatal myocardial infarctions making them more comparable to historical randomized control trials. That=s done in this third column.

Again, there=s no significant difference between the randomized arms. The incidents and severity of myocardial infarctions in the randomized stent and endarterectomy arms was examined. It did not differ significantly. The same data for the registry are displayed though no formal statistical comparison can be made. Again, no differences.

As previously mentioned, a total of 406 patients were entered into the stent registry. The sponsor states that they were entered at the choice of the surgeon investigators who felt they were too high risk for randomization. On this slide are represented the reasons stated for surgical turndown. Note that the reasons were not enumerated in 50 percent of the patients. Please also note that approximately 70 percent of the patients were neurologically asymptomatic.

Represented here are the 30, 360, and 720 day adverse event rates among the registry patients. Take note especially, if you would, of this figure of 15.8 percent for major adverse event rates at one year. To briefly review Dr. Heng Li=s analysis, objective performance criteria were set at 12.94 percent.

This figure was determined by calculations derived from review of the literature of randomized, controlled, endarterectomy trials as well as site reviews of the relevant study populations of the SAPPHIRE trial. Since the original delta of four percent was specified, the null hypothesis assumed a 360 day major adverse event rate of the 12.94 percent plus four percent of 16.94 percent or higher.

The observed rate in the trial however was 15.76 percent as presented in the previous slide. Therefore, the sponsor could not reject the null hypothesis. In other words, the criterion for non-inferiority was not met. It=s clear that the propensity score method has not been thoroughly explored. Questions remain about the adequacy of analysis.

Let=s return to the randomized control study. The following slides show the patients subdivided into neurologically symptomatic and asymptomatic cohorts. Examination of the 30 day major adverse events demonstrated non-inferiority of the stent with respect to endarterectomy. I direct your attention to the number of patients in the symptomatic trials. Here=s the 30 day adverse event rates. Subgroup analysis at 360 days also showed non-inferiority of the stent.

Turning to the asymptomatic randomized patients, they were also compared with respect to 30 day major adverse event rates. Also note the rather larger number in these cohorts. There were over twice as many asymptomatic as symptomatic patients in randomized pivotal trial. Once again, there were no significant differences between randomized stent and randomized endarterectomy groups at the 30 day mark.

Results at one year were similar. There were no differences between the randomized stent patients and those who underwent endarterectomy, although the superiority of stent approached significance - you see the zero - at about the 0.07 level.

Subgroups other than symptomatic and asymptomatic were examined. Here are displayed male and female sex and diabetes in the randomized stent and endarterectomy arms and in the registry at 30 and 360 days. At 30 days, major adverse events in the diabetics occurred more frequently in endarterectomized patients actually reaching statistical significance with a p-value of 0.03.

One year major adverse events occurred more frequently in males almost reaching statistical significance. The subgroup of elderly patients was examined but the numbers were relatively small. No differences were noted. Recurrent stenosis occurred with similar frequency in all the groups.

Secondary end points were reviewed. In this table, lesion, procedure, and device success and protection for all patients randomized or selected for stent are displayed. Success defined by these various parameters ranged between 88 and 96 percent. The column to the far right represents the individual investigator sponsored trials.

Other secondary end points are shown in here in the different cohorts; trapped material, freedom from lesion restenosis, and freedom from major adverse events at one year. There=s probably no other surgically treated disease entity that has been studied so thoroughly in randomized control trials than carotid stenosis. Thus far, carotid endarterectomy has been compared with optimal medical therapy in a series of trials over the period of a decade or more.

Because the SAPPHIRE study is itself a randomized study comparing a new technology with carotid endarterectomy as the gold standard, it would be appropriate at this point to consider conclusions derived from those historical randomized studies which compare to endarterectomy with the then standard medical therapy. The best known studies are the asymptomatic carotid artery atherosclerosis study called ACAS which looked at patients with asymptomatic stenosis greater than 60 percent and the Veterans Administration study of asymptomatic males with greater than 50 percent stenosis.

The ECTS European study examined symptomatic patients. The NASCET, North American Symptomatic Carotid Endarterectomy Trial, also studied symptomatic patients. In the interest of time, I have condensed the conclusions of these several excellent studies into three slides. If the panel were to find it germane, we have more detailed slides available for the discussion period.

Here are the conclusions. For symptomatic patients, high grade stenosis carotid endarterectomy was very effective, greater than 50 percent reduction in the risk of stroke and any death at two years. Not only that but risk reduction varied with stenosis, that is, the greater the stenosis, the greater the risk reduction of operation.

For moderate stenosis, success was less certain. It was calculated that 23 operations were required to prevent each severe ipsilateral stroke at five years. Not only that but each two percent increase in 30 day perioperative event rate reduced the five year benefit by 20 percent.

In the asymptomatic patients with greater than 60 percent stenosis, endarterectomy was very effective with approximately a 50 percent reduction in the risk of ipsilateral stroke or perioperative stroke or death if the procedure could be performed with a perioperative, major adverse event rate of less than three percent. Not only that but angiography alone entailed a risk of stroke of 1.2 percent.

These conclusions are consonant with the American Heart Association guidelines for stroke prevention and for guidance for the appropriate use of endarterectomy published in 2001 and 1998 respectively. Finally, there are data that caution us about the indiscriminate employment of endarterectomy.

First, the risk of stroke in asymptomatic patients is statistically low. Second, in a study of NASCET patients who had asymptomatic stenosis in the artery contralateral to the symptomatic side, 45 percent of subsequent neurologic events were of lacunar or cardioembolic etiology. Both of these diagnoses are most common in those patients who are elderly or who have major medical comorbidities.

Finally, the application of mechanical technologies in patients with a limited life expectancy should be approached quite cautiously. In the following four slides, the respective symptomatic and asymptomatic historical randomized control data for endarterectomy cohorts are appended to the corresponding SAPPHIRE cohort.

Because the historical studies excluded non-fatal myocardial infarction in the definition of major adverse events, as pointed out by the sponsor, these have been scrubbed from the SAPPHIRE data or a range given where it was not entirely possible to get the exact numbers. I gave a range.

Some historical study data have been estimated for Kaplan-Meier curves. As you look at these tables, please understand that they are being offered merely as a frame of reference and not as a scientific comparison. Consider also the relative size of the cohorts.

For symptomatic patients, the NACSET cohort illustrated here is for the patients with high grade stenosis. The recruitment of these patients was discontinued at a mean follow up of 2.7 years because of the demonstrated superiority of endarterectomy compared to medical management. These are the same cohorts presented at the one year point. Remember these are symptomatic patients in the randomized control study stent arm and the carotid endarterectomy arm.

Moving to the asymptomatic patients, here the asymptomatic SAPPHIRE patients are displayed and juxtaposed to the ACAS asymptomatic trial patients. The same cohort groups are followed to one year. This completes the data presentation.

What are the limitations of the sponsor=s study? The pre-specified enrollment plan and study analysis was not carried to completion in the SAPPHIRE randomized study. This resulted in a smaller size study with small sample sizes in important subsets of carotid populations.

But what can we conclude? The randomized study suggests non-inferiority of the stent to the carotid endarterectomy. Registry cohort failed to meet the OPC pre-specified criteria. The comparability of the registry to the control endarterectomy patients has not been optimally defined or conducted. Thank you.

CHAIRMAN LASKEY: Are there questions from the panel to any of these three presentations? Mitch.

DR. KRUCOFF: A question for Dr. Li. I just want to make sure that I understand what you said with regard to your triangular method, Christmas tree slide that went onto a picture with a point with a dot on it. That was your sixth slide. So is that dot your data assessment from the randomized cohort at 334 patients that lie within the boundaries?

DR. LI: Right, it=s based on a Z and V value calculated from the 364 patients= data included in the PMA submission.

DR. KRUCOFF: Right, and so the next slide, you have a based on the above graph comment. Is what I understood that you are saying based on the information in the sponsor=s presentation today that was not present by 4:00 p.m. yesterday, would you change this conclusion? Is that what I=m understanding you to say?

DR. LI: Basically the short answer is yes. The sponsor, based on what I understand of the one slide presentation, is trying, to the best possible extent, to reconstruct what might have happened had the original group sequential protocol been followed.

My impression is that, based on the sponsor=s presentation, their conclusion is that had the group sequential protocol been followed then the trial would have been stopped at 300 patients and then subsequently non-inferiority can be declared. But it is important to make a distinction that in actuality the protocol hasn=t been followed as was implied by the presentation.

So it=s impossible to know what would actually have happened, but it=s to a best approximation. For example, had the protocol been followed to every detail, then enrollment, recruitment would have been stopped at the 300 patients, when 300 patients have had the 30 day data, which might not have been the case. So it=s not possible to repeat all the detail. But it=s only a rough approximation and this approximation needs to be verified.

DR. KRUCOFF: I take it you are talking about Dr. Cohen=s slide that had the outcome columns conclusion at 100 and --

DR. LI: Right, 100, 200, and 300.

DR. KRUCOFF: It was continue, continue, stop.

DR. LI: Continue, continue, stop, right.

DR. KRUCOFF: But you at 300 have a dot that=s still within the boundaries which would not imply stop. So I guess what I=m asking is - and understanding you haven=t had the chance to review this yet - do you have any sense of why one retrospective reconstruction of this would say stop and 300 where it appears your retrospective reconstruction of this would say continue at 300?

DR. LI: Okay, so remember when I described the group sequential protocol, I mentioned that the sample path may wander up and down. Although it always go from left to right, it wanders up and down. That dot in the previous slide is calculated at 334 patients. Apparently at 300 patients, if the sponsor=s calculation was right, then the boundary would have been crossed at that time, and it=s completely possible.

DR. KRUCOFF: Okay, thank you.

CHAIRMAN LASKEY: Other questions from the panel?

DR. ABRAMS: I have a question for Dr. Weintraub. In your additional slides, do you have data on the ACAS study for higher grade stenosis of asymptomatic?

DR. WEINTRAUB: I=m having trouble with a touchy mouse. I=m sorry, you asked for NACSET.

DR. ABRAMS: ACAS.

DR. WEINTRAUB: Oh, for ACAS. It should be pointed out in the European trial. The problem with the European and North American data are that the Europeans measured stenosis differently from the North Americans. But in an excellent editorial published at about the time that the final NASCET trial came out, the writer actually compared the two.

The take away message was that at moderate stenoses, which were about equivalent to about 40 to 50 percent stenosis in the American system, that results particularly in asymptomatic patients probably did not favor endarterectomy. Whether that would be different because endarterectomy is not the same as stent, we just don=t know. But certainly on the basis of the historical record, one has to approach moderate to less than 50 percent stenosis with a great deal of caution particularly in asymptomatic patients.

DR. ABRAMS: Is it actually possible from this data to do a subgroup analysis on the greater than 80 percent --

DR. WEINTRAUB: Yes, this was done. Unfortunately, it=s in there somewhere. To answer your question - and we can find that slide at the lunch break for you - in an NASCET, the degree of stenosis was broken down into three subsets.

Interestingly, the greatest effectiveness was in the middle subset. When it got up to 85 to 99 percent, it dropped off a little bit. But there was clearly a separation depending on the degree of stenosis. That was also certainly true in the European study. I think it was true in the ACAS but I would have to look at it again.

DR. COMEROTA: One question. I hate to belabor this point, Dr. Weintraub. And you don=t need to pull up the slide.

DR. WEINTRAUB: Very wise.

DR. COMEROTA: In your analysis, you compared the symptomatic patients with the NASCET group. Obviously we all know that there=s two publications for NASCET; the 70 to 99 percent stenosis and then the less than 70 percent stenosis. You compared the NASCET group greater than 70 percent. They all had arteriographic documentation of that degree of stenosis.

DR. WEINTRAUB: That is correct to my understanding, yes.

DR. COMEROTA: All of the patients in the SAPPHIRE had arteriographic documentation to the degree of stenosis. Was that compared on your slide, the definition of the arteriographic stenosis?

DR. WEINTRAUB: This is a question that I had raised in my original evaluation. I was told by the sponsors that angiography was not used routinely in those patients undergoing carotid endarterectomy.

DR. COMEROTA: Right, I=m talking about the registry and the randomized stent patients.

DR. WEINTRAUB: The randomized stent patients, of course, all had angiographic analysis preoperatively.

DR. COMEROTA: All patients having a stent had an arteriogram.

DR. WEINTRAUB: That=s correct.

DR. COMEROTA: But you are not sure what the distribution of the degree of stenosis was in the stented patients, correct?

DR. WEINTRAUB: I would really have to ask the sponsor about that. It=s in the panel pack because the degree of stenosis was broken down quite exactly. But in terms of grouping them, I can=t tell you that. The sponsor might be able to.

CHAIRMAN LASKEY: Well, if there are no further questions, since my hypoglycemia has taken hold, let=s break for an hour lunch. I have 12:25 p.m. Let=s resume at 1:25 p.m. Thank you. Off the record.

(Whereupon, at 12:22 p.m., the above-entitled matter recessed to reconvene at 1:34 p.m. the same day.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

1:34 p.m.

CHAIRMAN LASKEY: On the record. All right. I=d like to thank everybody for coming back. We=ll resume this afternoon=s session starting with Dr. Judah Weinberger=s queries. Judah.

DR. WEINBERGER: Thanks very much. First of all a comment to the sponsor. I think that the data presented is interesting, thought provoking and hopefully we can sort through it and figure out precisely what to do with it.

First an administrative question. I would just like to ask the sponsor to explain why the FDA wasn=t aware of the latest changes in terms of statistical analysis that was pointed out. It=s really hard for me to interpret a study when there=s a disagreement between the FDA and the sponsor as to statistical validity.

DR. COHEN: The answer to your question is that we were made aware that there was a question about the statistical methods being applied last Friday. We really did not have time to prepare materials to send to the Committee beforehand.

DR. WEINBERGER: So it is your position that there was no deviation from the original plan.

DR. COHEN: That=s correct.

DR. WEINBERGER: And it=s the FDA=s position that there was a significant deviation from the original plan. Is Dr. Li here?

DR. ZUCKERMAN: Ms. Kennell, would you come to the podium?

MS. KENNELL: You=re talking to the wrong person when you=re talking statistics, but I believe that that is our understanding about the original plan. I looked up the protocol last night just so I would make sure that it was fresh in my mind. The original protocol said that they were going to do interim analysis at every 100 patients and that was not done.

DR. WEINBERGER: All right. I=m not a statistician, but maybe you can explain to me how not doing an analysis prejudices the interpretation of the study. Rather I would imagine the less you look the more powerful the statistic is because we=re taught that repeated analyses actually require higher B-

MS. KENNELL: I don=t know that I would be comfortable answering that question. I don=t think I have enough statistical expertise. I can try to find out for our statistical session.

DR. ZUCKERMAN: Dr. Weinberger, let=s try to answer your questions. 1. The FDA and the sponsor had a protocol with a prespecified statistical analysis plan that has been reviewed by FDA. That prespecified statistical analysis plan was changed at some point. FDA was unaware of when it was changed and what went into making that change.

Usually we would expect a major supplement and meeting with FDA to discuss a major change in a clinical trial like that. As such because of the events that transpired, it becomes somewhat problematic to interpret the statistics as presented by the sponsor. It doesn=t mean it=s impossible, but it does throw another question mark. Dr. Greg Campbell, our Chief of Biostatistics, is also here and he may want to add a point.

DR. CAMPBELL: Greg Campbell, FDA. Dr. Weinberger, your question is a good question. It=s always a good idea to follow the original plan that a company has to analyze data. When they do not follow that plan or we at the FDA do not follow that plan, we=re doing post hoc analyses and those are not recommended. The issue as to how often you look is a very complicated one in this case and I think I would prefer not to try to comment on it only because it=s different if one looks all the time versus one looks at particular intervals.

DR. WEINBERGER: Okay. I=d like to dig around a little bit in the data if we might and deal with a couple of issues of trying to understand who=s getting the biggest bang for the buck or who is really benefitting in this trial compared to standard therapy. So if we understand the trial, the patients have to have been previously identified by their referring physician as people who need carotid revascularization. This comment is directed at the sponsors. Is that correct? So these are patients who are previously identified by their referring physician as needing revascularization.

DR. COHEN: That is correct.

DR. WEINBERGER: All right. So this is not anyone in the trial identifying the patient. Then that patient gets referred in for revascularization, has an anatomic study, has a clinical stratification and based upon that is eligible for the study.

DR. COHEN: That=s correct.

DR. WEINBERGER: All right. In that group of patients that are the symptomatic ones and the asymptomatic ones, you=ve done stratification of those two groups in your analysis as has the FDA. I=d like to focus on a different sort of a stratification that is among the patients who ultimately ended up in the registry, people who were not operated on because the vascular surgeon decided that this was inappropriate. Some of those patients ended up for anatomic reasons and some ended up for medical comorbidities.

One of the things that=s really counter-intuitive here is a statement that you have in Panel Pack where you said that the people ended in the registry group for anatomic reasons did better with surgery than they did with stenting. Let me read it to you correctly. AThere was significant differences in major adverse events at 360 days when patients were stratified by anatomic and medical criteria.@ I=m sorry. This is in the randomized group. AThe anatomic, high risk patients had major adverse events of 10.3 percent for stent patients and 5.6 percent for carotid endarterectomy patients.@ Now the reason that people are high risk if for anatomic reasons, how is it that they do better with surgery than they do with stenting?

DR. COHEN: One of the figures of the design of this trial if I understand your question correctly was that it allowed the surgeons to take patients that they felt were at high risk and not operate on them. Those patients then went into the non-randomized stent registry. That would be expected then to have the high risk surgery patients in the stent registry as opposed to the surgical arm.

DR. WEINBERGER: Let=s go back to the randomized trial.

DR. COHEN: Okay.

DR. WEINBERGER: In the randomized trial, you get into the randomized trial with having a high risk anatomic feature or high risk medical features.

DR. COHEN: That is correct.

DR. WEINBERGER: Okay. If you have high risk anatomic features, I would expect that you would do better with stenting than you would do with surgery. If you have high risk clinical features, it might be that you would do B- That=s unclear.

But certainly if you had high risk anatomic features, it would appear to be that you would be more likely to expect a good result from stenting. It=s rather counter-intuitive that patients with high risk anatomic features at least not appear to do significantly better, not in a statistical sense, but do much better in terms of major adverse events when they have a surgical approach rather than a percutaneous approach.

DR. COHEN: I=m sorry. Could I ask you to tell me where you=re looking at in the Panel Pack?

DR. WEINBERGER: Sure. This would be in the summary of FDA Review Memo and this is with the marked up memo that we got last week on page 12. That includes your comments.

DR. COHEN: I=m sorry. This is not in the Panel Pack.

DR. WEINBERGER: Geratta, do they have that in their Panel Pack now? That=s what I had Fed Ex=ed last week.

MS. WOOD: They should have that. It was the FDA Memo as edited per the company=s request.

DR. COHEN: I=d like to ask Dr. Ken Ouriel to answer this question.

DR. OURIEL: Okay. If I understood the question.

DR. WEINBERGER: All right. Let=s go through it slowly so it=s a point that=s at least important to me. I don=t know about the rest of the panel. If you take patients who are randomized in this study, they get into the study because they are either symptomatic or they are asymptomatic with high grade stenosis plus they have to have another feature that puts them at high risk.

DR. OURIEL: Correct.

DR. WEINBERGER: And that other feature can be either medical comorbidity or anatomic problems or radiation to the neck or both.

DR. OURIEL: Right.

DR. WEINBERGER: All right. So if you look among patients who get into the trial and you look at those people who get in for anatomic comorbidities primarily, those are the people you would expect would do worse with surgery because the anatomic comorbidities are defined as comorbidities that are important to a surgeon. That is radiation to the neck. That=s important to a surgeon, not to an endovascular therapy.

DR. OURIEL: Well, we know that it=s important for surgery. We didn=t know whether it was important or not for stenting. It may be that radiation arteritis is a high risk for stenting.

DR. WEINBERGER: Okay. Or a contralateral recurrent laryngeal nerve palsy, etc., all those things that push you anatomically to worry about doing that.

DR. OURIEL: Correct.

DR. WEINBERGER: All right. So in that anatomic high risk group, you report a major adverse event rate at 10.3 percent for stented patients and 5.6 percent for carotid endarterectomy. I=m not being critical of the surgeons. In fact, I=m congratulating the surgeons. I=m trying to understand how it is that stenting interacts negatively with anatomic comorbidities.

DR. OURIEL: I don=t have that data in front of me, but I wonder what the confidence intervals are there. The numbers get very small when you get down to the subgroups. I=m just wondering if those two numbers really are similar.

DR. COHEN: Can you tell us where this is again?

DR. WEINBERGER: Sure. This is page 12 of the section that=s labeled Section 4, Summary of FDA Review Memos. It=s in the revision of that section that came by last week. Do you have that? I don=t know what it was in the original document because the page numbers have changed.

DR. COHEN: Let me make a couple comments. First of all, only about 20 percent of the patients in the randomized portion of the trial had anatomic comorbidities. That means that the number of patients we=re talking about is very small. So when you=re then making a subgroup of that subgroup, a standard error on those endpoints alone, I=m sure it overlaps significantly. As you stated, there was no statistical significant difference. If you could point us to the exact sentence that you=re looking at.

DR. WEINBERGER: All right. There=s a page in my book that=s entitled AMinor Deficiencies (FDA Questions).@ Do you have that page?

DR. COHEN: Yes, this is page 12?

DR. WEINBERGER: This is page 12.

DR. COHEN: Questions 1, 2 and 3?

DR. WEINBERGER: Questions 1, 2 and 3. If you go down to the next to the last paragraph.

DR. COHEN: Yes.

DR. WEINBERGER: There were significant differences in major adverse events at 360 days. The flip side of that is actually a very complimentary finding for stenting and that is in patients with significant medical illnesses. There seems to be a very decided benefit to the stenting arm over the surgical arm. What I=m trying to tease out here is the statistics at least to a non-statistician are quite borderline. I=m trying to figure out who=s going to benefit from this approach.

What it seems to me is that based upon the data admittedly the subgroups may contain smaller number of patients. The patients who are more likely to benefit at least based upon what you=re reporting are the patients with medical comorbidities rather than anatomic problems.

DR. COHEN: I don=t think that=s a fair comment.

DR. WEINBERGER: You don=t think that=s a fair comment.

DR. COHEN: No.

DR. WEINBERGER: All right. Then let me ask you this. Why do surgeons refuse to operate on patients? You told us that 50 percent of the patients who were put in the registry got into the registry for reasons you could identify. Fifty percent had no identifiable reason for being in the registry.

DR. COHEN: Actually if I might just correct that statement. It=s not that we didn=t have information. We were asked this question three weeks ago to provide information on what were the factors that led to patients being entered into the non-randomized stent registry. That data is not on the case report forms. That=s on the screening logs and we had no database containing that data. In order to answer the question that was posed, we accumulated as many screening logs as we could. That=s why there is incomplete information.

What I would point out is that the items on that list are nearly identical to the list of demographic features which were at increased frequency in the patients in the non-randomized stent arm. So even though the data is incomplete which is more because of lack of time as opposed to not having the information necessarily, the factors that were identified were similar.

DR. WEINBERGER: So if you=re a vascular surgeon and you get a patient you is 75 years old with two or three medical comorbidities, is that sufficient in your practice not to operate on them?

DR. OURIEL: That would probably be a patient that would be eligible for the randomized portion of that study. Now if that patient had a lesion at the C1 vertebral body or if the patient had an MI within the last four weeks or other compounding things, then you might decide that this patient needed treatment but they were just too high a risk to have an endarterectomy. It really varied from site to site and surgeon to surgeon. Since some of the things are subjective, it=s very difficult to capture. Certainly you can=t capture it in a case report form.

DR. WEINBERGER: I think what I=m struggling with is that everything about this is very much interpretative. In other words, the decision to put someone in for revascularization is interpretative. The decision whether or not to push towards surgery is interpretative. Although we have some rigorous reasons that when patients accumulate enough of objective reasons to push them towards revascularization, that=s when the vascular surgeon will make some comment as to whether or not he wants to do it. Somehow they were eligible for the study without a vascular surgeon agreeing up front that they would do the case.

I was wondering why that was not a required part of the protocol. Why are patients eligible for enrollment and in fact enrolled before a vascular surgeon agrees that they would do the procedure if the patient is randomized?

DR. OURIEL: Well, in fact, they were not enrolled. They were actually eligible B- There was a certain number if you remember the slide was eligible for randomization and in those patients, you needed the surgeon and the interventionist to agree that they could have either form of therapy. Now if they were eligible by the criteria for enrollment, but the surgeon said that they did not want to do an endarterectomy then they ended up in the non-randomized stenting arm.

DR. WEINBERGER: All right. And the outcomes among those patients, those are patients who if we believe met the bulk of them, two-thirds of them are asymptomatic. Is that right?

DR. OURIEL: Correct. Roughly.

DR. WEINBERGER: Roughly. And ACAS would say that those asymptomatic patients would benefit from having an operation would have a revascularization under normal circumstances. But ACAS doesn=t report stroke frequencies that are anything close to what you are seeing with this patient population. So help me understand that particular conundrum.

DR. OURIEL: I think I can do that. ACAS, first of all, is a different set of patients because they didn=t have the medical comorbidities and probably didn=t have many of the anatomic comorbidities that this trial did. That said, if you remember some of the slides and you really look at the stroke rate which I think is what you mentioned despite the higher comorbidities in SAPPHIRE and the higher comorbidities for sure in the non-randomized stent arm, the 30-day stroke rates aren=t all that different.

DR. WEINBERGER: Okay. Then the last issue that I wanted to raise before I turn this over to somebody else is in terms of looking for subtle neurological deficits that occur post-procedure whether they be whatever the method of revascularization the nature of the neurological examination involved cognitive testing as well.

DR. COHEN: First of all, there=s an independent exam by an neurologist. Second, there are three tests that were used which are tests for deficiencies due to stroke, the NIH Stroke Scale, the Rankin and the Barthel. I think it would be best to have Dr. Pierre Fayad comment specifically on the components of those tests.

DR. FAYAD: Good afternoon. I=m Dr. Pierre Fayad. I=m a circ neurologist and professor and chairman of neurological sciences at the University of Nebraska. I am paid for my expenses today and for my time by Cordis. I am on the executive committee for the SAPPHIRE study. To answer the question, there were no specific neuropsychological testing that was requested as part of the SAPPHIRE trial. However, the neurologic exam would assess some basic neuropsychological functions and the NIH Stroke Scale would just direct the basic orientation and speech functions and so on. But there were no specific testing for neuropsychological function.

DR. WEINBERGER: Okay. Thanks very much.

DR. COHEN: May I? Just one little response. You had asked about the differences in outcomes on whether or not they were helping guide whether or not you should or should not enroll patients if this were approved. I would just like to point out that the numbers that you are referring to for anatomic reasons there were 35 patients who got carotid endarterectomy for anatomic reasons, 36 who received them who received the stent. The number of patients who actually had events in those two groups was two patients and four patients. So that=s why I say the difference between those are statistically meaningless. The numbers are so small.

DR. WEINBERGER: Thank you.

CHAIRMAN LASKEY: Thank you, Judah. Dr. Comerota.

DR. COMEROTA: Well, thank you, Dr. Laskey. I=m going to go about this a little bit differently. First of all, I think the sponsors are to be commended. They submitted detailed analyses from the studies that they have performed in bulk to the panel. They laid out a logical plan of investigation beginning with the FEASIBILITY study, moving to a randomized trial and then moving on to the registry for the reasons previously stated and then giving additional supporting documentation from IDE and CASCADE.

The pivotal clinical study as we saw was the SAPPHIRE trial which was performed under the IDE as you know. It did present supporting and safety data and the presentations were very elegant. At the end of those presentations, I thought this was going to be a very short day because the decisions would be quite obvious.

But let=s look at the studies a little bit and let=s look at some of the information. First of all, this began with the FEASIBILITY study which evaluated device and procedure safety and provided SAPPHIRE investigators experience with the angioplasty and the stent system. I would say in reviewing the investigators, the interventionalists, involved in this study, they are to be commended because these represent the top interventionalists in the country and I suspect if we were to rank them, they may fall within the top one to two percent of interventionalists in the world.

So the FEASIBILITY study was performed at 33 sites in the United States and it included 262 patients and 177 underwent angioplasty and stent and 85 patients had angioplasty and stenting with distal protection. They were followed for a year and then longer term follow-up was presented.

No demographic profile however was reported to us. Therefore, differentiation between symptomatic and asymptomatic patients as may have surfaced from this morning=s discussion was not presented. Subsequently we learned what the data were on atherosclerotic disease versus neoinitimal fibroplasia in this patient group.

Now it=s interesting that the stopping rules for the FEASIBILITY study were determined and were projected on the basis of the NASCET trial data of a major adverse events rate of 6.7 percent which was the second study from NASCET. The first study had a death and 30-day stroke and death rate of 5.8 percent. So that was chosen as the higher and perhaps the better number would have been the mean of the two if we=re dealing with symptomatic patients alone.

However, when we look at the data in the FEASIBILITY trial, major adverse events at 30 days was 6.9 percent and at one year, 10.7 percent. Death rate at 30 days was 0.8 percent and at one year was 3.8 percent. Stroke at 30 days was 6.1 percent and 8.4 percent at one year.

Now we did subsequently receive a differentiation of atherosclerotic patients versus recurrent stenosis or neoinitimal fibroplasic lesions. The major adverse event rate in the atherosclerotic patients was 10.8 percent. It was 8.5 percent in the recurrent stenosis group. The death rate was the same in both groups, 3.6 and 3.4 percents. Ipsilateral stroke was 7.7 percent in atherosclerotic lesions and 3.4 percent with recurrent stenosis. I think this is a trend and an appreciation that most of us have had that patients who have a recurrent carotid artery stenosis are a lesser risk for percutaneous interventions than patients with atherosclerotic disease. The mean pretreatment stenosis in the FEASIBILITY study was 66 percent and patients who had 50 percent or more restenosis at the end of the year numbered 24 percent of those treated with angioplasty and stenting.

So as I mentioned above, the distribution of patients was not given up front in the FEASIBILITY study. If, however, the distribution of the run-in patients were similar to SAPPHIRE patients in terms of disease and symptoms status, it can be assumed that nearly 70 percent of the patients would have been asymptomatic and about 25 percent would have had a recurrent carotid stenosis. Both of these groups are relatively low risk for ipsilateral stroke.

So if the stopping rule was actually calculated based upon lesion risk and if it was apportioned to the distribution of symptomatic versus asymptomatic patients, then the 30-day major adverse event rate should have calculated at about 2.9 to 3.0 percent rather than the 6.7 percent. If this were actually used as the guideline, the stopping rule would have been invoked and the FEASIBILITY study would have been terminated based upon that calculation.

When we look at the actual disease distribution in the patients in the FEASIBILITY study according to the angiographic description of the diameter percent stenosis, less than 10 percent of the patients had an 80 to 99 percent stenosis. About 38 percent of the patients had a 70 to 99 percent stenosis. The balance had less than 70 percent stenosis. So the magnitude of the severity of the disease was not too severe in terms of an angiographic diameter reduction stenosis.

As we move into the SAPPHIRE study, obviously these are the principal data supporting the submission for this IDE. The primary objective of the SAPPHIRE trial was to compare the safety and effectiveness of carotid stenting with distal protection using these devices versus carotid endarterectomy in the treatment of patients who are considered at high risk for carotid endarterectomy. It was an one-to-one randomization, multi-center trial.

The diagnosis initially was made on the basis of a duplex and I think the velocity criteria was certainly very appropriate. The primary endpoints which I think are very important to consider are the composite endpoints as clearly elucidated earlier including death and stroke and myocardial infarction at 30 days post procedure and then those additional data up to 12 months and beyond. The high risk criteria were well defined.

As we know, the SAPPHIRE trial was a randomized study and it was targeted for 600 to 900 patients, the thought with the interim analysis and that discussion has already proceeded so I won=t get into that. And we=ve seen the results in the randomized trial. We know that the death and stroke rate at 30 days in the stented patients was 4.2 percent and the death and stroke rate in the carotid endarterectomy patients was 4.8 percent. The overall stroke rate in the carotid angioplasty and stent patients was 3.6 percent. It was 3.0 percent in the carotid endarterectomy patients.

There were other associated events with procedures that didn=t surface in the discussion today as yet. A severe hypotension occurring during the procedure was 17.4 percent occurring in the carotid angioplasty and stent group and 3.0 percent in carotid endarterectomy patients. Bardycardia and/or asystole occurred in 8.4 percent in the carotid angioplasty and stent patients and 3.0 percent in the carotid endarterectomy patients. Those numbers barely reached statistical significance, not quite. That was 0.6 percent but the severe hypotension was very significant. Cranial nerve injury obviously 4.2 percent in the CEA patients and none in the angioplasty and stent patients. Distal vasospasm at the time of intervention occurred in 22 percent of the patients having carotid angioplasty and stenting. The analyses were presented and I think they were presented very well. I just supplemented some of those data with what I=ve reviewed.

Now when we look at the degree of stenosis of the lesion and I think we would all agree that a patient who has a high grade stenosis especially a patient who is symptomatic with a high grade stenosis is one who needs to have that carotid lesion corrected. If you look at the patients that we have data on that were submitted to us in the carotid angioplasty and stent group who had an 80 to 99 percent stenosis represented 22 percent of the patients in the randomized trial undergoing carotid angioplasty and stenting. Fifty-five percent had 70 to 99 percent stenosis. Therefore 45 percent of the patients who were randomized and received the stent had less than 70 percent stenosis.

Looking at the available data for carotid endarterectomy patients, 45 percent of the patients had an 80 to 99 percent stenosis. Eighty-five percent had an 70 to 99 percent stenosis. If we look at the registry data, 19 percent of the registry patients had an 80 to 99 percent stenosis. So we=re dealing with patients who underwent a percutaneous procedure that did not have relatively high grade stenosis in general.

A comparison was submitted to us regarding the registry patients and that comparison which was performed by the company compared the registry patients versus the carotid endarterectomy patients. They included of course death and stroke. When we look at the 30-day results of death and stroke, 5.9 percent in the stent patients versus 4.8 percent in the carotid endarterectomy patients.

If we look at overall registry patients versus carotid endarterectomy patients, ipsilateral stroke at 30 days 4.2 percent in the registry stented patients, 1.8 percent in the carotid endarterectomy patients. Then if we look at all strokes to 30 days, eight percent for stent and 5.8 percent for carotid endarterectomy.

If we look at symptomatic patients because this is real crux, I think, of what we=re dealing with, symptomatic patients with high grade stenosis, a death and stroke rate at 30 days is 8.1 percent in the stent patients and 6.5 percent in carotid endarterectomy patients. Ipsilateral stroke at 30 days, 6.5 percent in the stent patients and zero percent in carotid endarterectomy patients. And death or ipsilateral stroke 7.3 percent and 6.5 percent obviously. Then if we look at all strokes to 30 days, 8.1 percent in the carotid angioplasty and stent patients, two percent in the carotid endarterectomy and that one patient had a contralateral stroke.

Then if we move on to the asymptomatic patients, ipsilateral stroke was really no different, 3.2 percent and 2.5 percent respectively. Death and ipsilateral stroke at 30 days, 6.0 percent in the stented group and 3.3 percent in the carotid endarterectomy group. Death to 30 days in the stented group was 2.8 percent, 0.8 percent in the carotid endarterectomy group. So I think once we begin to look at the data, things do become clarified.

The CASCADE results were presented to us and 121 patients were reported in the CASCADE trial which was a European study. Ninety of those patients underwent angioplasty and stenting with no ANGIOGUARD protection and 31 of those patients had ANGIOGUARD protection. There were no deaths in the CASCADE study. There was an 8.2 percent stroke rate, ten percent in those patients who had no ANGIOGUARD protection and 3.2 percent in the 31 patients who had protection with ANGIOGUARD. Obviously we see a trend developing here that protection seemed to have been effective in that group. There were many more TIAs in the patients who had no ANGIOGUARD protection versus those who did have ANGIOGUARD protection.

Then the IDE data were presented. But I think since none of the IDE data were adjudicated, I think we have to look at it just as that. I don=t think we can accept the IDE data with very much vigor since it was not adjudicated. The FDA has asked us to address a number of questions. Warren, should I answer those questions from my perspective or should we wait until later?

CHAIRMAN LASKEY: We=ll have a turn at them as we go around. Do you have other queries or clarifications?

DR. COMEROTA: Well, yes. I have one other major point that I would like to address and it was asked by the FDA, but I would like to make it part of my preliminary comments. It has to do with the issue of myocardial infarction as an endpoint. I would just like to find my comments here.

The question was raised whether myocardial infarction either non-Q-wave or Q-wave myocardial infarction was a valid endpoint for this study. I think we just need to take a step back and look at what are we doing and why. Obviously the purpose of any procedure to treat carotid artery atherosclerosis is to reduce the risk of stroke, predominantly reduce the risk of ipsilateral stroke assuming that the procedure that we=re performing does not put the patient at risk for contralateral stroke.

Carotid endarterectomy has demonstrated its effectiveness in reducing stroke and death due to stroke in very large randomized trials and every one of them has been adjudicated by neurologists and compared to best medical care. Now this endpoint was achieved in reasonable risk patients.

If high risk patients were to have been included in these trials, the operation itself may not have proven beneficial compared to best medical care. If that were the case, carotid endarterectomy would not be available today for comparison to carotid angioplasty and stenting. The comparator would be best medical care.

In order to achieve equivalence with carotid endarterectomy in patients considered at high risk for operation, the SAPPHIRE included myocardial infarction as a component with major adverse events. None of us want our patients to have an MI and there is a substantial associated subsequent morbidity/mortality associated with anyone who suffers a myocardial infarction be it Q-wave or non-Q-wave.

However, if one looks at that as a endpoint obviously MI inherently favors a percutaneous procedure compared to an operative procedure in high risk patients. Furthermore, the premature termination of this study appears to bias this outcome in favor of carotid angioplasty and stenting. The reason why I say that is because it is well established that patients who have had a coronary artery bypass graft and who subsequently undergo noncardiac surgery have approximately a 50 percent risk reduction of a mortality associated with that operation. They have a 70 percent risk reduction of a nonfatal myocardial infarction.

In the SAPPHIRE trial in the randomized trial, 43 percent of the stented patients had a prior coronary artery bypass graft. 30.8 percent of the carotid endarterectomy patients had a prior coronary artery bypass graft. This difference is statistically significant. Furthermore, 35 percent of the stented patients had a prior percutaneous transluminal coronary angioplasty (PTCA) versus 23 percent of the carotid endarterectomy patients. This difference is statistically significant. The sum of that is that 80 percent of the stented patients had prior coronary revascularization versus 54 percent of the carotid endarterectomy patients.

So in the SAPPHIRE trial if coronary revascularization was equivalent and therefore the carotid endarterectomy patients were protected to the same degree as carotid angioplasty and stent patients were protected, would the difference in cardiac events have been observed? I think there=s a real chance that those difference would not have been observed.

The bias of prior coronary revascularization in favor of carotid angioplasty and stenting patients deflates the importance of the difference in myocardial infarction outcome between those two groups in the SAPPHIRE trial. Furthermore, carotid angioplasty and stent patients were treated with Clopidogrel in addition to aspirin. We all know that the combination of aspirin and Clopidogrel protects patients at high risk from coronary events.

This pharmacologic protection was not offered to patients undergoing carotid endarterectomy and perhaps for good reason. But there is now a revascularization bias and a pharmacotherapy bias in favor of the reduction of myocardial events in patients undergoing carotid angioplasty and stenting compared to carotid endarterectomy. I think that will conclude my comments for now. Thank you.

CHAIRMAN LASKEY: Did you wish the sponsor to respond to any of that or all of that?

DR. COMEROTA: Well these are observations based upon all the information that was presented in the Panel Pack. I had no additional information than what everybody else had.

CHAIRMAN LASKEY: Fair enough. Okay. Well, thank you. Let us go around the table for thoughts comments and queries. That=s right. Dr. Aziz. Thank you.

DR. AZIZ: Thank you. I would also like to commend the sponsor on an excellent presentation. Let me go straight to the topic of coronary artery disease in some of these patients and this is a question for the sponsors and maybe one of you could answer. Once a patient is identified as having carotid stenosis, what investigations are done to rule out underlying coronary artery disease particularly in patients who are going to go for a carotid endarterectomy? Do they have any noninvasive tests done or do they go straight to surgery?

DR. COHEN: Again, patients in this trial would have otherwise received the same type of preoperative evaluation that any patient undergoing either surgery or an interventional procedure would have undertaken, so whatever was appropriate given the individual patient=s history and physical exam, the EKG findings, whatever.

Having said that, I=d like to take the opportunity to mention that the distribution of patients with coronary disease in fact was equal between the different arms of the trial. Second of all, there was data captured in terms of patients who had a positive exercise test. So yes, that was obtained and those were equally distributed for patients who had positive exercise tests.

The other thing is that first you can=t simply sum the percentage of patients who have had bypass and who have had percutaneous coronary interventions because obviously those two groups overlap significantly. The other thing is that we actually looked to see whether the presence of coronary disease, the presence of bypass surgery or whatever played an important role in any of the individual outcomes as well as the composite outcomes and they did not.

DR. AZIZ: Let me see if I understand you. If a patient was found to have coronary artery disease or suggestive on the testing, would that patient have that corrected first before he had the carotid endarterectomy?

DR. COHEN: Yes, and it was explicitly stated in the protocol that if there was coexisting coronary disease or if another surgical procedure needed to be undertaken, be it, a carotid procedure or cardiac or otherwise, it could not occur with 30 days of the endarterectomy procedure.

DR. AZIZ: And then if a patient had, let=s say, carotid angioplasty and stenting done, obviously the patient would be put on Plavix I would presume for a long period of time. That would clearly delay him having coronary artery surgery for a number of months.

DR. COHEN: Actually the duration of Plavix was two weeks as mandated in the protocol.

DR. AZIZ: That=s one. Were there any patients who during the course of the carotid stenting develop carotid section?

DR. COHEN: I=ll ask Dr. Ouriel to answer this question.

DR. OURIEL: A long walk for a short answer. No.

DR. AZIZ: Now in terms of the emboli protection, I see these two groups of patients, clearly patients who are having intervention done on the carotid artery. The danger is obviously having emboli going in and you=ve obviously included an emboli protection device. I=m sure that the emboli protection device captures some of the emboli. But I guess we really had no way of knowing what percentage of the emboli it captures.

DR. COHEN: Actually there is data in the Panel Pack that speaks to that and I can summarize that. The percentage of emboli-capture devices, ANGIOGUARDs, actually had debris in it. It varied somewhat between the trials, but it was easily between 50 and 80 percent amongst the trials that we presented today. The average number of particles was six to eight particles per filter in filters that had debris, although the number ranged all the way up to, I believe, 20 particles per filter. The particles could be as large as 1 X 1-1/2 millimeters in size. The composition was basically what you would expect of an atherosclerotic plaque. There were smooth muscle cells, foam cells, cholesterol crystals, necrotic core, collagen, elastin and clot basically.

DR. AZIZ: Are you aware of any studies that were done, not necessarily for this trial, but patients may have had MRIs pre- and post-carotid extending procedure with or without protection devices?

DR. COHEN: No. There have been no studies that I=m aware of that have completed, although, I believe there are studies underway directed at neuropsychiatric changes as well as perhaps imaging studies.

DR. AZIZ: Okay. And you aren=t aware of any studies where TCD monitoring was being done at the time. Maybe you might be able to answer that question.

DR. OURIEL: You=re not talking about studies related to this particular panel.

DR. AZIZ: No.

DR. OURIEL: I=m sure there are TCD studies that are available. Of course, it=s a surrogate endpoint. There are studies that show that if you have protection that you get fewer hits, but it=s not part of this analysis.

DR. AZIZ: All right. I think I have one. Now I think it was earlier stated that there was a 17 percent incidence of hypotensive episodes during the placement of the stent. Do you have any ideas as to why that happened or what could be done to prevent that?

DR. OURIEL: Sure. I think of that as part and parcel of the stenting process just like for those of us who are surgeons what we know when the anesthesiologist puts our patient to sleep we get hypotension frequency. Now it=s not recorded in many cases, but we know that it occurs when the patient is put to sleep. We know that in a patient who has a carotid lesion that you stent especially a tight stenosis, maybe one with a lot of calcium, they are going to get a vagal impulse and it=s not surprising that you get hypotension and Bardycardia.

DR. AZIZ: Nothing else for the time being.

CHAIRMAN LASKEY: Dr. Krucoff.

DR. KRUCOFF: Dr. Cohen, you may as well hang around. Have a seat. Obviously one of the things we=re all wrestling with here is the statistical analysis plan, its origin and then what=s actually eventuated. Certainly I=ll echo everybody. You guys have done a great job in taking what=s a very complex dataset and at least presenting it in a very cogent and understandable fashion. In general, studies in this realm are conducted with Data Safety and Monitoring Board. Was there a DSMB for this trial?

DR. COHEN: Yes, there was.

DR. KRUCOFF: And did they have a role in the original triangular analysis plan or can you help me understand who was going to look at the data along the way in the original plan for these 100-patient cohorts and how was that originally envisioned from your perspective?

DR. COHEN: Perhaps what would be useful would be to have a little bit better understanding of exactly what this data analysis, interim analysis, plan was and how it played out. I think I would like to ask Dr. Rick Kuntz to come up and provide an explanation.

DR. KUNTZ: My name is Rick Kuntz. I=m a cardiologist in Boston. I=m mostly the chief of the Division of Clinical Biometrics at the Brigham Women=s Hospital. I functioned as the chief scientific officer and CRO run by Harvard which ran this trial.

The statistical interim analysis was contracted with a group in England called the Whitehead group. We have a representative from here who developed the triangular test that was used. We performed the analysis using that methodology. The sponsor and the group in England worked on the analysis plan and actually conducted the analysis plan.

Let me just explain my perspective on this, but being a clinician and having a little bit of background in statistics on this. It was clear from the beginning in the design of this trial that we didn=t know what the final sample size would be. There were a lot of unknown variables. An interim analysis was actually quite an effective way of potentially looking at this study. The study was going to be as large as 2400 patients if in fact our estimates were off and possibly as small as 300 or 400 patients if we had really good results. We estimated from our best analysis of the literature that probably 600 to 800 patients would result in a final analysis demonstrating non-inferiority. Maybe if there was a bang-up job done by the stents there would be superiority at some point, but our main goal was to look at non-inferiority.

In this analysis plan, the triangular test follows most interim analysis theory. That is in fact the more you look the more alpha there that you have to spend because you are rolling the dice each time to look for a positive result. In this study, the triangular test allows you to alter the times when you look during the conduct of the study. That is that you can actually use other cues to determine whether or not you want to look or not look and that=s part of the analysis plan and part of the textbooks that are written, part of the theory that=s been published in biostatistical literature and part of the program.

There were non-data driven reasons to not look at the first 200 patient intervals. That was because this was a new break-through therapy and it was very unlikely that regardless of the result of 100 or 200 patients that this would result in anything convincing to anybody because you just don=t have enough patients. The first reasonable time to look would be at 300 patients and that was decided at the beginning of this study. There was no data reviewed at all.

When it came to the point where the first planned interim analysis now, 300 patients, was going to be done, it was very clear on those curves that this study wasn=t going to be enrolling much more than 350 or 400 patients. So a decision was made to do the first look ever as the final look. The notion about not using the monitoring portion of the Whitehead test was omitted under the complete allowances of this Whitehead triangular test.

This was not communicated by the sponsor to the FDA. That probably was a mistake. They should have communicated that with the update and tell them what they were doing. But technically speaking as far as I understand it and as far as the program goes, this was all allowable in the analysis.

There was only one analysis done during the study and that was the final analysis. There were no decisions made anywhere based on any of the data and I can verify that. Nobody got any of the data except Data Safety and Monitoring Committee during this study.

So in the end, this study which started to peter out quickly at around 280 patients enrolled did peter out at about 350 patients, 334, when the enrollment was so slow that it wasn=t worth the money and the resources to continue and it was clear that it wouldn=t continue any further because many studies were having problems randomizing and there were the registries available that were chipping into the abilities randomized. So because of that, all analysis were presenting as a first time and final analysis as is appropriate.

There were irregularities with respect to the communication with the Food and Drug Administration about exactly what was going on, but I think the communications dealt with the fact that they didn=t know that this was appropriate to communication since it was all within the design of the triangular test. Looking back at it since this was a not typical traditional test that was used although very valid, there should have been better communication.

There is no doubt about it, but the statistical analysis we feel stands as is. It=s a one-time analysis. There were no increased chances to look at a positive result. Nobody rolled the dice more than once to understand whether results came up positive or not and these are the final results of the study. That is the best way that I think we can clarify on a clinical level what actually happened in this study with the interim analysis.

DR. KRUCOFF: Thank you. That at least for me clarifies some really key things. So what I=m hearing you say, Rick, is that nobody peaked at these data along the way. The original Whitehead triangular, somebody, not including the FDA, decided up front that the options for earlier interims which were within the statistical plan were going to be delayed until the 300 patient point. The decision was made before enrollment had begun.

DR. KUNTZ: No, actually I think that decision was made after enrollment was done, but within the allowances of the play of chance of the Whitehead triangular. That method can be explained theoretically by our statistician from England on this and he would be more than happy to explain that. But I think the key is that there were people looking at the data. We still use the 100-patient interval for the Data Safety and Monitoring Committee to review the data. They did see it at 100, 200, 300 patients to make sure that there were no safety concerns.

DR. KRUCOFF: But then just to make sure that I=m following you. Data and Safety who saw the data along the way, were they involved in the decision to go to 300 as a first formal Whitehead triangular look or were they independent of that decision?

DR. KUNTZ: They were independent. The decision to do the first interim analysis at 300 patients was a decision made by the sponsor.

DR. KRUCOFF: Okay. And last, was there anyone from the sponsor involved in the Data and Safety Board?

DR. KUNTZ: No. Nobody from the sponsor saw any of the data.

DR. KRUCOFF: Okay. Thank you. I=d like to shift gears a little bit and understand a little bit more about where angiograms were used and where they weren=t. As I understand for the randomized SAPPHIRE patients, Dr. Cohen, the patients would come in through whatever clinical evaluation recommended for carotid revascularization.

DR. COHEN: Correct.

DR. KRUCOFF: It sounds like there is a cohort of patients who were operated on based on ultrasound Doppler without a concomitant angiogram.

DR. COHEN: That=s correct.

DR. KRUCOFF: All of the patients on the percutaneous side had angiographic information. Do you know how many of them had a diagnostic angiogram independently from the interventional procedure? My questions are twofold. One is just how you knew whether a patient was a candidate for a stent or not in order to decide whether or not they were randomizable or should be put in the register without an angiogram.

DR. COHEN: My understanding is that for the surgical intervention or surgical treatment that because of the risk of doing angiography in patients who have significant carotid disease that it is usually omitted. So you go directly from ultrasound to surgery. I believe the majority of patients in this trial - we can conject to make sure that this is correct - their diagnostic angiogram was done at the time that they received their treatment with the stent and distal protection.

DR. KRUCOFF: So my only question is then how did you know you could randomize them if you didn=t have angiographic criteria to know whether they were tortuous of calcified or some of the things that would make you think stenting was not an option?

DR. OURIEL: Sure. In fact, some of the difference between the intent-to-treat and the treated is because you did an angiogram and you found out that this patient should not have been treated with the assigned therapy.

DR. KRUCOFF: Okay. So then if I understand, patients came in clinically. If they randomized to surgery, they could get operated on on the basis of the Doppler ultrasound data.

DR. OURIEL: Or could have an angiogram in the minority of patients.

DR. KRUCOFF: Okay. Or if they randomized to stenting, then most all of these patients had their first angiographic delineation of the anatomy at the time of their interventional procedure. Is that it?

DR. OURIEL: I can=t give you the numbers on that? But what I can tell you is that if a patient had an angiogram in preparation for a carotid stent and let=s say you found the stenosis was only 30 percent, then they would still stay in that arm intent-to-treat but they would not have been treated.

DR. KRUCOFF: Okay. And importantly then, patients who got angiograms with the 1.3 or so percent risk of a complication from that angiogram would already be in the intention to treat analysis. So complications from a diagnostic angiogram are in fact in the intention to treat.

DR. OURIEL: Sure. Once they are randomized. Although the 1.3 percent risk of stroke with angiography hopefully is no longer the case.

DR. KRUCOFF: Right. Understood. Then if I can, Dr. Cohen, ask you a little bit about the use of the ANGIOGUARD. As I look through the CASCADE and FEASIBILITY data at least my interpretation of what=s there is that patients who did not have the ANGIOGUARD didn=t have it because it wasn=t available.

DR. OURIEL: That=s correct.

DR. KRUCOFF: And then the percentage of the denominators that did receive it was presumably because it was available. Is that it?

DR. COHEN: That=s right. It became available later on in those trials.

DR. KRUCOFF: Okay. And I guess in looking at these data, one question that will come up that I=m just going to go ahead and ask is obviously the ANGIOGUARD seems to have an important function in all of this. What I=m wondering is whether it=s your inclination in the instructions for use to suggest that since that=s deployed first - you put the wire up, the distal protection system first - if you are for whatever reason unable to deploy the ANGIOGUARD, are you going to suggest that the procedure be terminated?

DR. COHEN: No, I don=t believe that=s what occurred in the trial. That would not be our suggestion.

DR. KRUCOFF: Okay. And yet is it fair to say that the data on stenting alone compared to stenting with distal protection looks like there=s a significant role for distal protection?

DR. COHEN: But I=d also offer that this was early in the learning curve for some of the physicians participating in the trials, so just the learning of doing coronary stenting. Second, this was with earlier generation devices. Third, I would say that there=s a cohort of physicians who do carotid stenting who do not believe in the benefit of distal protection.

The reason we did do exploratory analysis of combining both CASCADE and FEASIBILITY was to provide data that there is benefit to having distal protection. The reason that we collected the filters and had a pathology lab evaluate them was to demonstrate that there is material captured on them. However, the question I assume you=re getting at is if you are unable to pass it, should you not do the procedure.

I don=t know the percentage - and we can look that up - of patients who had to have predilatation before the ANGIOGUARD was actually placed, but that is a component of the dataset. My understanding is that those patients had outcomes that were not different than the overall trial outcomes.

DR. KRUCOFF: Okay. We can come back to this in discussions about labeling. At least the best that I could get out of the three sets of data, the CASCADE, FEASIBILITY and SAPPHIRE, SAPPHIRE, it seemed like, you probably had a more advanced iteration of the ANGIOGUARD end of the system because the deployment rate was fairly high.

DR. COHEN: That=s correct.

DR. KRUCOFF: And again I think you=ve shown some of it particularly in the randomized patients the noninferiority data for primary endpoint with regard to the 334 patients you have in intention to treat analysis. About 90 some percent of those had distal protection. What I=m concerned about is whether the data would look the same if the 334 patients had been randomized to unprotected stent versus not and what that ought to mean in terms of the real recommendations. But we can come back to that.

Do you know offhand -- And I don=t do carotid so I=m going to have to extrapolate from coronaries. In self-expanding platforms in the coronary arteries, there are times when all it takes is the structural strength of the Nitinol to dilate the lesion? There are times when you have to predilate the lesion to get the stent across and there are times when after deploying the self-expanding platform you have to post-dilate. Do you have - or if at least it was there, I=m sorry because I missed it - what percentage of the time was predilatation required and what percentage of the time was post-dilatation required?

DR. COHEN: I don=t have those percentages off the top of my head. I would need to look them up and we can see if we can get that. But both predilatation and post-dilatation were done in some cases.

DR. OURIEL: Well, I can tell you our practice at the Cleveland Clinic is to almost always predilate and always post-dilate because you do get a significant stenosis if you don=t post-dilate in almost every case.

DR. KRUCOFF: Okay. Because while I=m not going to go back to the marked hypertension and Bardycardia, in cases I=ve actually observed certainly the baroceptors in the neck is a pretty richly enervated territory managing patients. After carotid endarterectomy, you sure learn that lesson in patients. Obviously in a significant proportion of these patients how much manipulation is involved may also relate to that assault.

DR. OURIEL: And it=s always on the post-dil that it occurs.

DR. KRUCOFF: That is goes. Yes. But at Cleveland at least, you think that was most of the time you ended up post-dilating.

DR. OURIEL: Yes.

DR. KRUCOFF: Okay. Last two quick questions. One, it was pointed out in the distribution that out of the range of devices that you all manufactured the five millimeter device and the tapered seven to ten millimeter device was rarely used. Do you feel like you have sufficient data? Do you think a five millimeter flow channel to the brain, do we understand enough about that to say that=s going to behave identically to larger caliber vessels and do we have enough information to understand the tapered seven to ten?

DR. COHEN: I think it might be useful to understand why the five millimeters and the tapered are used. I would like to ask Dr. Nick Hopkins to make some comments.

DR. HOPKINS: Hi, I=m Nick Hopkins, neurosurgeon from Buffalo, chairman of the Department of Neurosurgery there and professor of radiology there. I=m kind of a hybrid. I=ve doing neurosurgery and carotid endarterectomy since 1979 and doing carotid stenting since the mid >90s. We have a large experience. Cortis did pay my way here and paid for my transportation and my lodging.

The question about the five millimeters. First of all, almost every carotid artery narrows down to somewhere near five millimeters somewhere near the skull base and a five millimeter opening, if I understand your question correctly, is plenty to provide normal flow. We don=t see significant reductions in flow until we have stenosis somewhere close to 60 percent. So a five millimeter opening is plenty large enough for that.

The reason for the seven to ten I think is the rare patient where you have a common carotid that is so large that you wouldn=t have good stent apposition if you didn=t have a ten millimeter stent. So a seven to ten taper takes care of that situation which is unusual, but it happens. So to not have those two sizes available I think would put us at a disadvantage. Does that help?

DR. KRUCOFF: I guess the conundrum for me is that five millimeters is the small end of carotid which would be the huge end for coronaries and again in my limited world of coronaries though smaller, longer term durability of stenting interventions is certainly different in smaller vessels than in larger vessels. As we get out into larger vessels, carotids and peripheral, there is some relatedness albeit the total flow volume is different. I guess one of the impressions I=ve gotten here is for ethical reasons more than anything. We don=t have a lot of angiographic follow-up or detailed follow-up in the whole cohort much less in how five millimeter stents behave in carotids. Is that fair?

DR. HOPKINS: I think that=s fair. You made the point that the average carotid carries 250 millimeters of flow per minute. It=s a huge difference in terms of the flow volume to the brain and the heart. A five millimeter stent, I think, is critically important in a situation where for example you have a lesion confined to the internal carotid. You want to limit your stent placement to the internal carotid and you have an internal carotid that may be relatively small. So you don=t want to greatly oversize, if you can avoid it, more than you have to. We like to oversize a millimeter or two, but I would hate to put a six or seven millimeter stent in three millimeter carotid. I think a five millimeter is extremely important for that situation.

DR. KRUCOFF: Okay. I lied. I actually have two last quick questions, one really quick one just to ask, your interpretation of the slide that you put up and when I asked the FDA, Dr. Li, earlier. You put up a slide for an FDA simulation of the V-Z approach that had 100 patients continue it, 200 patients continue it, 300 patients terminate. Dr. Li=s impression was that at 300 patients in that sawtooth, sort of, Christmas tree you were at a point that you would say would reach the recommendation to stop, whereas at 334, there was dot on his slide which was still within decision matrix boundaries which would be to continue. As far as you can tell, is that still appropriate? Did you all get your continue option at 300 and did you look in the same way at 334 as to whether you would have been inside or outside?

DR. COHEN: I think what I=d really like to do is have the expert here that we have available answer the question. I think if you don=t mind, Nigel, to come up. The short answer of that is that we=re trying to interpret this using our background which is not applicable to this specific analysis method.

DR. KRUCOFF: Maybe while he=s setting that up, can I ask you my last question? Why self-expanding, not balloon-expandable and is Nitinol a reasonable platform for a drug-eluding future?

DR. OURIEL: Well, we actually used to use balloon-expandable stents in the carotid, but as soon as the patient put their neck on their hand and rested their neck against some pressure, it would crush. So it=s clear that balloon-expandable stents aren=t going to be good in superficial locations. Nitinol right now is the best we have.

DR. COHEN: And just so people are aware of this, Nitinol has the ability to self-expand. Plus if you crush it, it will expand back to a predetermined size. That=s it=s major advantage and why we use it in areas that are compressible.

DR. KRUCOFF: Okay. So while they are setting up, have you all begun to explore whether Nitinol is a reasonable platform for polymer and drug-eluding configurations?

DR. COHEN: I=m not sure that=s an appropriate answer to give in this forum.

DR. KRUCOFF: Okay. Never mind. It might get you small vessel interest.

DR. STALLARD: Okay. I=m Dr. Nigel Stallard. I=m a principal research fellow at the Medical and Pharmaceutical Statistics Research Unit at the University of Reading. I=ve been paid as a consultant by Cortis and they=ve paid for me to come to this meeting and paid for my time?

MS. WOOD: Could you please pull the mike a little closer?

DR. STALLARD: I=m sorry. Okay. So just to briefly talk about the analysis that we would do had we performed those interim analyses at 100, 200 and 300 patients. But I want to start by just outlining how we analyze at the end of a sequential trial like this. Here=s just a picture of the triangular region and the triangular region is designed so that the probability of crossing the upper boundary during monitoring of the trial is controlled to be 0.025 when the treatment difference is actually the delta is the lower limit of the non-inferiority region that we=re interested in detecting. So that=s what we=re controlling when we do this test.

As has been explained, you can monitor at any time you wish so long as that time is chosen independently of any observed treatment difference. And the triangular region is calculated based on the assumption that you=re going to monitor continuously. As soon as you monitor the number of discrete points, the chance of stopping any one of those points is reduced or the chance of stopping in its total trial is reduced. So to control that to be at the 0.025 level, you need to bring in the boundaries further. So the solid lines that you just saw are, if you like, the most stringent ones. We actually adjust those bringing them in to allow for the analyses that we did. The more analyses you do, the less you have to bring them in because you=re looking more often.