U.S. FOOD AND DRUG ADMINISTRATION

+ + + + +

CIRCULATORY SYSTEM DEVICES ADVISORY PANEL

+ + + + +

MEETING

+ + + + +

FRIDAY,
DECEMBER 8, 2006

+ + + + +

		The meeting convened at 8:00 a.m. at the Hilton Washington DC North/Gaithersburg, 620 Perry Parkway, Gaithersburg, Maryland, William H. Maisel, M.D., M.P.H., Chairperson, presiding.

PRESENT:

WILLIAM H. MAISEL, M.D., M.P.H., Chairperson
PAMELA W. ADAMS, Industry Representative
JEFFREY A. BRINKER, M.D., Consultant
MICHAEL J. DOMANSKI, M.D., Consultant
L. HENRY EDMUNDS, JR., M.D., Consultant
ROBERT HARRINGTON, M.D., FACC, Consultant
JOHN W. HIRSHFELD, M.D., Consultant
NORMAN S. KATO, M.D., Consultant
WARREN K. LASKEY, M.D., Consultant
JoANNE LINDENFELD, M.D., Consultant
DOUGLASS MORRISON, M.D., Consultant
LINDA A. MOTTLE, M.S.M., R., Consumer
	Representative
STEVE NISSEN, M.D., Consultant
SHARON LISE-NORMAND, Ph.D., Voting Member
RICHARD L. PAGE, M.D., Voting Member
JOHN C. SOMBERG, M.D., Voting Member
ERIC TOPOL, M.D., Consultant
GEORGE VETROVEC, M.D., Consultant

PRESENT: (cont.)

JUDAH Z. WEINBERGER, M.D., Ph.D, Consultant
CHRISTOPHER J. WHITE, M.D., Voting Member
CLYDE W. YANCY, M.D., Voting Member
FDA PARTICIPANTS:
JAMES P. SWINK, Executive Secretary
GERETTA WOOD, Director, Advisory Panel
	Program, CDRH
BRAM ZUCKERMAN, M.D., Director, Division of
	Cardiovascular Devices
ASHLEY BOAM
DANIEL SCHULTZ, M.D., Director, CDRH

PUBLIC SPEAKERS:

ALEXANDRE ABIZAID, M.D., Ph.D., Instituto
	Dante Pazzanese de Cardiologia,
	Sao Paulo
ROXANA MEHRAN, M.D., Columbia University
	Medical Center
DAVID KONG, M.D., Duke University Medical
	Center
DAVID MAGID, M.D., M.P.H., Kaiser Permanente
RALPH BRINDIS, M.D., Kaiser Permanente
DAVID O. WILLIAMS, M.D., Rhode Island
	Hospital
GREGORY MISHKEL, M.D., Prairie Heart
	Institute
RON WAKSMAN, M.D., Washington Hospital
	Center
SANJAY KAUL, M.D., Cedars-Sinai Medical
	Center
JEFFREY W. MOSES, M.D., Columbia University
	Medical Center
PETER K. SMITH, M.D., Duke University
ROBERT A. GUYTON, M.D., Emory University
	School of Medicine
T. BRUCE FERGUSON, JR., M.D., Brody School
	of Medicine at ECU
TIMOTHY HENRY, M.D., Director of Research,
	Minneapolis Heart Institute Foundation
JIM GUSTAFSON, M.D., Possis Medical
ROBERT S. HILLMAN, Ph.D., Accumetrics, Inc.

PUBLIC SPEAKERS (cont.)
 
RICK KUNTZ, M.D., M.Sc., Medtronic, Inc.
KRISHNA SUDHIR, M.D., Abbott Vascular
	Cardiac Therapies
LAURA MAURI, M.D., M.Sc., Chief Scientific
	Officer, Harvard Clinical Research
	Institute
JAMES T. DOVE, M.D., President-Elect,
	American College of Cardiology
GREGORY J. DEHMER, M.D., President, Society
	for Cardiovascular Angiography and
	Interventions
FREDERICK GROVER, M.D., President, The
	Society of Thoracic Surgeons
SIDNEY C. SMITH, M.D., FAHA, American Heart
	Association
MARK A. TURCO, M.D., FACC, FSCAI, Washington
	Adventist Hospital and Uniformed
	Services University of the Health
	Sciences

CORDIS CORPORATION:

DENNIS DONOHOE, M.D., Worldwide Vice President, Clinical Research and Regulatory
	Affairs

BOSTON SCIENTIFIC CORPORATION:

DONALD S. BAIM, M.D., Executive Vice
	President, Chief Medical and
	Scientific Officer

	I-N-D-E-X

Opening Remarks	5

Introductions	6

Discussion of Broader Use of DES and its
Implications, continued

	Open Public Hearing Session	

	Panel Q&A	

	Open Public Hearing Session, continued	

	Panel Q&A, round two	

	Open Public Hearing Session, continued
		(Dr. Kuntz)	

	Panel Q&A, round three	

	Clarification from Cordis	

	Clarification from Boston Scientific	

	Panel Q&A, round four	

Break

	P-R-O-C-E-E-D-I-N-G-S
		CHAIRPERSON MAISEL:  Good morning.  I'd like to call this meeting of the Circulatory System Devices Panel to order.  If you haven't already done so, please sign the attendance sheets sometime this morning that are on the tables by the doors.  If you wish to address this panel during one of the open sessions today, please provide your name to Ms. Ann Marie Williams at the registration table.  If you're presenting today in any of the open public sessions and have not previously provided an electronic copy of your presentation to FDA, please arrange to do so with Ms. Williams.
		I note for the record that the voting members present constitute a quorum as required by 21 CFR Part XIV.  My name is Dr. William MAISEL.  I'm a cardiologist at Beth Israel Deaconess, and I'd like to have the panel members introduce themselves.  And I'll start with Dr. Zuckerman, please.
		DR. ZUCKERMAN:  Bram Zuckerman, Director, FDA Division of Cardiovascular Devices.
		DR. DOMANSKI:  Mike Domanski, Interventional Cardiologist, NHLBI.  I'm head of the Coronary Artery Disease and Athrothrombis branch.
		DR. HARRINGTON:  Bob Harrington, Interventional Cardiologist at Duke University and Director of the Duke Clinical Research Institute.
		DR. NISSEN:  Steve Nissen, Chairman, Department of Cardiovascular Medicine, Cleveland Clinic.
		DR. WEINBERGER:  Judah Weinberger, interventional cardiology, New York Presbyterian Hospital.
		DR. VETROVEC:  George Vetrovec, Chairman of Cardiology, VCU Medical Center.
		DR. TOPOL:  Eric Topol.  I'm a cardiologist at Scripps Clinic and Scripps Research Institute.
		DR. MORRISON:  Good morning.  Doug Morrison, Interventional Cardiologist, Yakima Arts Center, Yakima, Washington.
		DR. LASKEY:  Warren Laskey, Chief Cardiology at the University of New Mexico.
		DR. LINDENFELD:  JoAnne Lindenfeld, Heart Failure-Heart Transplant Cardiologist at the University of Colorado.
		MS. WOOD:  Geretta Wood, Director of the Advisory Panel Program for Center for Devices Radiological Health.
		MR. SWINK:  James Swink, Executive Secretary for the Circulatory System Devices Panel.
		DR. NORMAND:  Sharon-Lise Norman, Professor of Health Care Policy and Biostatistics at Harvard Medical School and Harvard School of Public Health.
		DR. KATO:  Norman Kato, Cardiothoracic Surgery in private practice, Los Angeles, California.
		DR. PAGE:  Richard Page, head of cardiology, University of Washington on Seattle.
		DR. SOMBERG:  John Somberg, Professor of Medicine Pharmacology, Russia University, Chicago.
		DR. WHITE:  Chris White, Interventional Cardiology, New Orleans, Louisiana.
		DR. YANCY:  Clyde Yancy, Heart Failure-Heart Transplantation, Baylor University Medical Center, Director of Heath and Vascular Institute in Dallas, Texas.
		DR. BRINKER:  Jeff Brinker, Interventional Cardiologist, Johns Hopkins University.
		DR. HIRSHFELD:  John Hirshfeld, Interventional Cardiologist at University of Pennsylvania.
		MS. MOTTLE:  Linda Mottle, Director, Clinical Research Program, Gateway College and Arizona State University, Phoenix, Arizona.
		MS. ADAMS:  Pam Adams.  I'm the Industry Representative on the Orthopaedic Panel on loan to this panel.
		DR. EDMUNDS:  Dr. Edmunds, Department of Surgery, University of Pennsylvania.
		CHAIRPERSON MAISEL:  Thank you.  I'd like to remind people in attendance today to turn off or silence your pagers and cell phones.  I'd also like to ask that no one approach the front panel area unless you're on the panel or a member of the FDA.  At this time, Ms. Wood will read the conflict of interest statement.
		MS. WOOD:  The Food and Drug Administration is convening today's meeting on the Circulatory System Devices Panel of the Medical Devices Advisory Committee of the Center for Devices in Radiological Health under the authority of the Federal Advisory Committee Act of 1972.  With the exception of the industry representative, all members are consultants of the panel are special Government employees or regular federal employees from other agencies and are subject to federal conflict of interest laws and regulations.
		The following information on the status of this panel's compliance with federal ethics and conflict of interest laws covered by but not limited to those found in 18 U.S.C. 208 are being provided to participants in today's meeting and to the public.
		FDA has determined that members and consultants of this panel are in compliance with federal ethics and conflict of interest laws.  Under 18 U.S.C. 208, Congress has authorized FDA to grant waivers to special government employees who have financial conflicts when it is determined that the agency's need for a particular individual's services outweighs his or her potential financial conflict of interest.
		Members and consultants of the panel who are special government employees at today's meeting have been screened for potential financial conflicts of interest of their own as well as those imputed to them including those of their employer, spouse or minor child related to the discussions of today's meeting.  These interests may include investments, consulting, expert witness testimony, contracts, grants, CRADAs, teaching, speaking, writing, patents and royalties and primary employment.
		For today's agenda, the panel will discuss and make recommendations regarding issues related to stent thrombosis and coronary drug‑eluting stents.  Based on the agenda and all financial interests reported by the panel members and consultants, conflict of interest waivers have been issued in accordance with 18 U.S.C. Section 208(b)(3) to Doctors Robert Harrington, JoAnne Lindenfeld, Richard Page, George Vetrovec and Clyde Yancy.  The waivers allow these individuals to participate fully in today's deliberations.  Copies of these waivers may be obtained by visiting the agency's website at www.fda.gov/ohrms/docket/default.htm or by submitting a written request to the agency's Freedom of Information Office, Room 6-30 of the Parklawn Building.
		In addition, Dr. Judah Weinberger no longer holds a financial interest requiring a conflict of interest waiver.  A copy of the statement will be available for review at the registration table during this meeting and will be included as part of the official transcript.
		Ms. Pamela Adams is serving as the industry representative acting on behalf of all related industry and is employed by ETEX Corporation.
		We would like to remind members and consultants that if the discussions involve any other products or firms not already on the agenda for which an FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from such involvement, and their exclusion will be noted for the record.  FDA encourages all other participants to advise the panel of any financial relationships that they may have with any firms at issue.
		Transcripts of today's meeting will be available from Neal Gross & Company.  information on purchasing videos of today's meeting can be found on the table outside of the meeting room.  Presenters to the panel who have not already done so should provide FDA with a hard copy of their remarks including overheads.  The press contact for today is Heidi Valetkevitch.  Heidi are you here?
		MS. VALETKEVITCH:  (Off mic.)
		MS. WOOD:  Thank you.
		CHAIRPERSON MAISEL:  We have more than 20 scheduled public speakers today.  They'll each be allotted a maximum of 10 minutes.  There's a timer up at the front podium.  You'll get a warning as the time comes down.  We're going to be extremely strict with our time today as we have to be out of this room, because there's another scheduled event at the end of the day.
		So without further ado, we will open the public hearing session.  We'll proceed with the first open public hearing portion of the meeting.  Public attendees are given the opportunity to address the panel to present data, information or views relevant to the meeting agenda.  We have a number of speakers scheduled for this morning's session.  Once again, we ask that speakers be as brief as possible.  And I'm going to ask the panel to hold all questions until after the first group of speakers has presented.
		Both 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 sessions 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 any company or any group that may be affected by the topic of this meeting.  For example, this financial information may include a company's or a group'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 if you do not have any such 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.
		Today's fist scheduled speaker is Alex Abizaid.
		DR. ABIZAID:  Good morning.  I'd like to thank FDA for the opportunity.  I have to say that I'm also speaking on behalf of Professor Eduardo Sosa from San Paulo, Brazil.  And I have nothing to disclosure regarding this presentation.  In this next eight minutes, I'm going to divide my presentation into two parts.  First one I'll describe to you the Heath Hospital and Dante Pazzanese Registry on DES. and than the last two or three minutes will give you some insights of the potential mechanism of late thrombosis after DES according to our experience in San Paulo, Brazil.
		The registry includes 1,800 patients.  This summarizes the design of the registry.  The vast majority of the patients received the CYPHER stent, 75 percent.  It was approved one year before TAXUS.  And we also have one-fourth of the patients treated with TAXUS.  If you can appreciate, aspirin was given indefinitely and clopidogrel for 6 to 12 months to most of these patients.  We do have clinical followup, 1, 6, 12 months and now up to 5 years.  And I have to say that 98 percent of these patients were contacted and responded to this registry.
		This slide summarizes the main demographics.  You can see that 20 percent of our patients had diabetes, 21 previous myocardial infarction, 25 percent previous angioplasty, almost 30 percent with previous CABG, 2.2 stroke, and 5 percent peripheral disease.
		Some other important variables are included in this slide.  Almost 60 percent of the patients had multi-vessel disease.  LAD was the preferred target vessel in half of the patients; and the location, 93 percent native vessel; and we also treated 7 percent with SVG stenosis.
		This slide summarizes the 4-year MACE.  And again, in 98 percent that came back for follow-up, the stent thrombosis up to four years was 1.3 percent death; 3.4 cardiac; 1.9 non-cardiac, 1.4 Q and non-Q-wave MI; 2.2 percent target lesion revascularization; and 2.1 treated with bitiseay and most of the times 1.7 and with CABG .04 percent.  It was also treatment for lesion progression, 2.4 percent; 2.3 percent with percutaneous interventions and the vast minority with CABG. Therefore, the event-free survival in these almost 2,000 patients were 90 percent.
		Perhaps this is the most important slide of this presentation that describes the rates of SAT multiple times.  You can see that the first study days, we found .22 percent of the patients with stent thrombosis from one month to one year, .83 percent, so most of the patients presented with stent thrombosis in the first year; from 1 year to almost 4 years, .27, .03 percent, and the total, as I mentioned before, 1.32 percent.  We could document stent thrombosis in half of the patients by angiography 46 percent, 54 percent had sudden death, and 46 with acute MI.
		Now this is the last part of my presentation.  In these three minutes, I'll try to summarize.  The sudden analysis of almost 200 patients included at Dante Pazzanese in San Paulo, Brazil that we did intravascular ultrasound immediately post procedure and at the end of 6 to 12 months, so we, to try to explain it, to try to find reasons, the clinical reasons for this event, for stent thrombosis, so late incomplete apposition was identified in 10 patients out of this 195 patients or 5 percent of the patients had late acquired stent apposition, lack of apposition.  And the stent thrombosis in this cord of patients happened in only two patients, so .03 percent.
		But I was impressed to see that in these two patients that presented to us with stent thrombosis that you could document very well had late incomplete apposition.  One patient with CYPHER  and another one with TAXUS.  As you can appreciate, this patient was treated with this focal lesion in the RCA immediately post stent deployment, very good result, checked with IVUS.  The struts are completely apposed.  Eighteen months later, the patient came for a protocol, and we could evaluate again by IVUS, and you start to see incomplete apposition but the patient was doing well.  But 40 months later, so this is very late and was more than 3 years later, the patient comes back with stent thrombosis in the RCA and you can document that he had external elastic main vein growth, and this explains probably the mechanism of stent thrombosis in this patient.  Another patient now treated with TAXUS, you see the perfect result immediately stent deployment in this LAD; perfect apposition; 8 months later, positive remodeling with incomplete apposition; and the patient comes back with stent thrombosis, occluded LAD and we could again treat this patient -- the patient just had an MI, but we could open the vessel -- actually, there's two patients.
		So this is just a nation of sights and a small group of patients which I believe is going to be one of the mechanism of late thrombosis.  This is again after treatment with very good results, and both of the patients are doing well.
		So my two very short conclusions for this presentation is that stent thrombosis occurred in 1.3 percent in almost 2,000 patients, up to 4 years of stent thrombosis in our registry, and late IVUS observations suggest that late acquired incomplete apposition might be one of the most important mechanism of SAT.  Thank you for your attention.
		CHAIRPERSON MAISEL:  Thank you very much.  The next speaker is Roxanna Mehran.
		DR. MEHRAN:  Good morning.  I'll be presenting the Prospective "All Comers" Single Arm Study in Complex Patients:  The MATRIX Trial.  My name is Roxanna Mehran.  I'm an interventional cardiologist at Columbia University Medical Center and the Director of the Data Coordinating Center at the Cardiovascular Research Foundation.
		These are my disclosures pertaining to this talk.  The MATRIX Registry or Single Arm Study is a prospective study initiated in 2001 as a 3500 patient trial under a physician-driven IDE.  This was first submitted in October of 2003 with plans to include "all comers" with the Sirolimus-eluting stent, the stent that was approved at that time.  Both on and off label use of Sirolimus-eluting stent would thus be evaluated in this registry with clinical follow-up at 1 month, 6 months, 1 year and 2 years and yearly thereafter and an angiographic follow-up in a subset of patients, in patients with CTO, chronic total occlusions and acute myocardial infarction.
		Here's the study organization with independent clinical events committee and 100 percent monitoring of all data fields per request of the FDA in the first 1000 patients.  We were only allowed the first 750 patients enrollment, and once we submitted data on 30 days' outcomes of these patients, we were allowed to continue enrollment and now have full approval to continue enrollment in these patients.
		The pre-specified sub-studies to be evaluated in this registry are shown here on this slide including all complex patients and lesions, and I will show you some of these but will not be able to show all, because of the time constraints.  The medical regimen is also listed here.  Importantly, the post procedural recommendations for aspirin and clopidogrel therapy with aspirin at 325 milligrams for at least a month and 81 milligrams thereafter indefinitely, clopidogrel or ticlopidine if clopidogrel couldn't be given at 75 milligrams a day for at least 3 months but recommended up to 1 year, especially once we had more data on patients receiving 12 months of clopidogrel.
		This really is an all-inclusive registry.  There were no exclusions except for refusal to consent or to come back for followup, and I just want to show you that we've enrolled 1521 with follow-up of these patients available at 2 years.  That's 642 eligible for follow-up, so I will share with you all these data.  Almost every patient has had some contact except for 70 patients at Columbia University.  Here are the demographics of these patients.  The age is at 65 years of age, older than the normal population in randomized clinical trials with a large population of African American, Hispanic and immigrants just due to our location of Columbia Presbyterian Hospital.  There are 34 percent diabetic patients in this registry, and the target vessel and target lesion locations are shown here.  And I just want to draw your attention to the fact that there are chronic total occlusions, bifurcation lesions, multi vessel stenting as well as saphenous vein graft inclusion in these patients with an average of 2 stents per procedure, 1.2 stents per lesion, a majority of patients receiving Bivalirudin and IIb/IIIa's used only in 8 percent of the patients.
		Here are the 2-year data with a median follow-up of about 400 days.  We have an overall death rate of 2.8 percent with 1.1 percent cardiac death.  And you can see here that the target lesion and target vessel revascularization is at 9.4 and 12.5 percent.
		And I'm showing you here now the stent thrombosis data using the expanded definition according to ARC, although the ARC definitions were really placed for non-complex patients, patients for randomized prospective clinical trials.  We're hoping to expand on the ARC definitions.  But given what we have using definite and probable, we have an overall rate at 2 years of 1.2 percent with 12 patients experiencing this event.  And here, from time-to-time,  you can see where the patients are at 1521 patients.  And again, out to 2 years, we only have follow-up on 641 patients.  As I showed you, you can see here the K- curves of stent thrombosis.
		And the other very important issue that I think we were very vigilant about was regarding at follow-up their antiplatelet adherence.  We ascertained whether or not the patients were taking aspirin or clopidogrel therapy.  Interestingly, at discharge, 99.6 percent of the patients were on aspirin; 99 percent on Plavix, and you can see here who's available for follow-up.  And interestingly, up to 6 months, we drop down on the clopidogrel therapy to 78.8 percent, down to 69 percent at 1 year, and 60 percent at 2 years which I think is quite good.  Aspirin remains at about -- above 90 percent, which I also think is excellent adherence therapy to antiplatelet agents in this population.
		We also looked at the outcomes of the patients on and off clopidogrel at different time periods.  At 30 days, you can see the data of death, MI, and definite probable stent thrombosis, and we are not actually finding differences between the patients on or off Plavix here or at 1 year.  And you can see the confidence intervals are quite wide, so I'm not sure how much we can place on this, and as we get more and more data, we'll have a little bit more certainty regarding the effect of antiplatelet therapy on these patients.
		I also want to show you some of the subgroups, the diabetic patient population as we had promised to the FDA as a sub-study to present these data.  These patients do have higher incidents of death, myocardial infarction, target lesion and vessel revascularization.  However, in this small subgroup, although not powered to show the stent thrombosis late, there is no statistical significant difference, but the definite stent and probable stent thrombosis is 1.6 versus 1.0.  And you can see here patients with chronic kidney disease also have higher event rates, no differences in their stent thrombosis rates.  Patients with multi vessel disease, very interesting.  A large group of these patients, 473 of the 1500 patients had multi vessel stenting with no real incremental increase in their target lesion and vessel revascularization.  I think this is an important finding as well as the fact that patients who did receive more than 3 stents per patient did have higher rates of myocardial infarction, target lesion revascularization but no difference, again, in their definite or probable stent thrombosis rates.
		We also have data on the bifurcation lesions, as you can see here, with a definite probably stent thrombosis rate at 1.3 percent.
		So to conclude in this preliminary interim analysis of the first 1500 patients in the MATRIX Registry, which included patients with complex Coronary Artery Disease treated with the CYPHER stents, the frequency of early and late adverse events were low and similar to those previously reported with simple low-risk lesions.  However, the overall stent thrombosis incidence assessed, with the expanded definition, was at 1.2 percent.  And if we included the possible, it would e up to 2 percent, and late stent thrombosis up to 2 years is rare but observed.  And in patients with more complex lesions, we begin to see higher rates of important event rates.
		It's important to note that long-term outcome of these patients is ongoing, and we will be evaluating the antiplatelet regimen and looking at these patients in followup.  Thank you very much for your attention.
		CHAIRPERSON MAISEL:  Thank you very much.  Out next patient -- our next speaker --
		(Laughter.)
		CHAIRPERSON MAISEL:  -- and hopefully not patient is David Kong.
		DR. KONG:  Good morning.  I'm Dr. David Kong, an interventional cardiologist from Duke University Medical Center.  On behalf of Duke University Medical Center, Duke Clinical Research Institute, the Duke Translational Medicine Institute, the Duke DECIDE Network, and the Duke Center for Clinical Health Policy Research, I am pleased to present the results of  drug-eluting and bare metal stent outcomes from the Duke Cardiovascular Diseases Data Bank.  The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services as part of their Effective Healthcare program which develops unbiased scientific evidence on the effectiveness of medical interventions.
		I have no conflicts of interest to disclose.  The disclosures for the investigators are available on the DCIR website, www.dcir.org/research/coi.jsp.  The authors are responsible for the content of this report.  My statements should not be construed by endorsement by the Agency for Healthcare Research and Quality nor the United States Department of Health and Human Services.
		The safety and effectiveness of drug‑eluting stents was established in a series of controlled clinical trials on specific patient populations.  A continuing concern has been the extrapolation of these clinical trial results onto clinical practice where these devices are used in broader patient populations.  In addition, the BASKET-LATE study suggested that the currently recommended antiplatelet regimens, 3 months for CYPHER and 6 months for TAXUS, may be insufficient.  Our analysis examined long-term clinical outcomes for patients receiving drug-eluting and bare metal stent technologies, and the clinical outcomes of clopidogrel use beyond 6 months in these patients.
		Consecutive patients undergoing percutaneous coronary intervention at Duke Hospital were identified form the Duke cardiovascular diseases data bank.  These patients have received a bare metal stent between January 2000 and July 2005 or a drug‑eluting stent between April 2003 and July 2005.  Patients who received both bare metal and drug‑eluting stents were included in the drug‑eluting stent group.  Patients with congenital heart disease, moderate or severe valvular or heart disease, previous coronary artery bypass grafting or percutaneous coronary  intervention or with significant left main and coronary disease were excluded form the analysis.
		All patients had baseline demographic data, history and physical examination findings, and catheterization results recorded at the time of their initial procedure.  Patients were then followed using questionnaire and telephone contacts at 6 months, 1 year, and annually thereafter.  Each questionnaire asked patients to list their current medications.  Clinical events will be reported for up to 24 months.  All deaths were confirmed by an independent mortality committee.  Non-fatal myocardial infarction was based on clinical diagnoses assigned by the patient's medical providers and were not centrally adjudicated.  Follow-up was 98 percent complete for all scheduled contacts.  Patient with incomplete follow-up with censored at the time of last contact.  Median follow-up for the overall population was 3.1 years, 4 years for the bare mental stent group, and 1.6 years for the drug‑eluting stent group.
		There are a total 4,666 in the studied population.  One-third of patients received a drug‑eluting stent, and two-thirds of the patients received bare-metal stents.  The drug‑eluting stent patients were more likely to be diabetic and have more severe coronary disease as measured by the number of diseased vessels.  The drug‑eluting stents were significantly smaller in-stent diameter than bare metal.  Patients with bare-metal stents were more likely to have a history of previous myocardial infarction.  Differences between these groups were statistically adjusted using inverse probability weighted estimators.
		Adjusted cumulative incidents rates for death, non-fatal myocardial infarction, target vessel revascularization, and a composite major adverse cardiac event endpoint are shown here.  The drug‑eluting stent group is depicted in red, and the bare-metal stent group is shown in green.  Overall, the drug‑eluting stent group had less than 1 per 1,000 higher rate of mortality compared to bare-metal stents at 24 months, and this difference is not statistically significant.  There was a 1.5 percent lower rate of non-fatal myocardial infarction in the drug‑eluting stent group, and this was statistically significant at a p-value) of 0.022.  Overall, 2-year major adverse cardiac events were driven principally by fewer revascularization events in the drug‑eluting stent group, and these relationships are consistent with many other comparisons of drug‑eluting stent and bare-metal stent technologies.
		To evaluate the effect of clopidogrel on long-term stent outcomes, we performed a landmark analysis.  This is a form of survival analysis with a study cohort consisting of patients without death, myocardial infarction, or revascularization at a specific time-point after the initial placement, something that's terms the "landmark time-point".  Outcomes clinically are then evaluated from this landmark time-point.  Patients were categorized into one of four groups:  drug‑eluting stent with and without clopidogrel, and bare-metal stent with and without clopidogrel based upon the reporting of clopidogrel use in follow-up questionnaires.  The primary landmark analysis evaluated outcomes from six months forward and a secondary analysis was based on reported clopidogrel use at 12 months.  The comparison of the patients in the 6-month landmark analysis is shown in the slide.
		Again, patients in both groups who experienced a clinical event or failed to report medication use on the 6-month questionnaire were excluded.  Four treatment groups were identified based on the patient's initial stent type and the reported clopidogrel use at 6 months.  The outcomes of these four groups were evaluated at 24 month.  Baseline patient characteristics for the four groups were notable for significant differences in the prevalence of diabetes, congestive heart failure, myocardial infarction, and the number of diseased vessels.  Again, the effect of these differences on outcome were adjusted statistically using inverse probability weighting.
		Clopidogrel use in these patients was not randomized.  However, 55 percent of drug‑eluting stent patients and 62 percent of bare-metal stent patients who reported taking clopidogrel at 6 months continued to report taking clopidogrel at 24 months.  Conversely, patients who did not report taking clopidogrel at 6 months tended to remain of clopidogrel with 15 and 8 percent of drug‑eluting stent and bare-metal stent patients using the drug at 24 months respectively.  There was a strong interaction between clopidogrel and aspirin, particularly at 6 months.
		Drug-eluting stent patients who reported taking clopidogrel at 6 months had a 3.3 percent lower mortality rate at 24 months compared to drug‑eluting stent patients who did not report taking clopidogrel.  In addition, there is a significant 2.5 percent mortality difference between the bare-metal stent patients who were not taking clopidogrel and the drug‑eluting stent with clopidogrel group.
		The remainder of the differences between groups were not statistically significant with the drug‑eluting stent groups straddling both the bare-metal stent groups.  For the combined endpoint of death and non-fatal myocardial infarction, the drug‑eluting stent with clopidogrel group had a 4.1 percent lower event rate than the drug‑eluting stent without clopidogrel group; 3.1 percent versus 7.2 percent which was statistically significant at the 0.021 level.  The event rate in the drug‑eluting stent with clopidogrel group was also 2.9 percent lower than the bare-metal stent without clopidogrel group.
		Overall, the patients who received drug‑eluting stents and reported clopidogrel use at 6 months had the best overall outcome at 2 years while the patients with the least favorable outcomes had drug‑eluting stents without taking clopidogrel beyond 6 months.  This suggested the benefit or risk of drug‑eluting stents with respect to late death in myocardial infarction hinges on whether the patient was able to take clopidogrel beyond 6 months.
		Again, a similar secondary analysis was performed using a 12-month landmark view, and the results of that analysis are consistent with the 6-month findings.  Chief limitations of the study were that clopidogrel and drug‑eluting stent use were not randomized and the factors that may be important for determining prognosis in these patients might not have been measured or adjusted for statistically.  Clopidogrel use was identified by patient self-report and is subject to recall bias.  A 90-day window was used around each of the anniversary dates to determine follow-up contact and medication use when the analysis was done.  Using a 30-day window, the conclusions were similar.
		In conclusion, compared to bare-metal stents, drug‑eluting stents are associated with reduced rates of target vessel revascularization.  Death and non-fatal myocardial infarction were higher for drug‑eluting stent patients who stopped clopidogrel after 6 months.  As a result, the current recommendations for 3 to 6 months of clopidogrel after drug‑eluting stent placement are likely insufficient.  These results are consistent with the CREDO, BASKET-LATE and PREMIER studies, and rigorous clinical trials are still needed to address the optimal duration of clopidogrel therapy.
		These findings were published Tuesday in an online version of Journal of the  American Medical Association and the slides will be available from the Duke Clinical Research Institute website.  Thank you very much.
		CHAIRPERSON MAISEL:  Thank you very much.  Our next speaker is David Magid.
		DR. BRINDIS:  Distinguished panel, my name is Ralph Brindis.  I'm an Interventional Cardiologist and Senior Advisor for Cardiovascular Disease for Northern California Kaiser.  I'm here with David Magid who's a Director of Research at Colorado Kaiser.  We're also representing the work of Alan Go who's the Associate Clinical Director of the Division of Research in Northern California Kaiser.  None of us have any conflicts of interest or anything to disclose.
		We're here to present data related to drug‑eluting stent use at Colorado and San Francisco Kaiser for 2004 and 2006.  Kaiser Permanente is a physician-run healthcare system where we aggressively translate evidence-based medicine for the treatment of all of our patients, practicing a multidisciplinary approach for our cardiovascular patients with aggressive risk factor modification or use of appropriate adjunctive medications and therapies.
		We've embraced drug‑eluting stents as an important adjunct in the treatment of our Kaiser patients with coronary disease since the FDA release in 2003.  We've been impressed with the marked reduction in clinical restenosis and improvement in the quality of life of our patients.
		We're going to discuss the pattern of our drug‑eluting stent use, discuss the rate and timing of adverse events, myocardial infarction death and our drug‑eluting stent patients, attention to a chart review of AMI events in Colorado, discussion of predictors of adverse outcomes and also the relationship between drug‑eluting stent implantation and clopidogrel use and adverse outcomes.
		Our longitudinal Kaiser cohort, we utilize stent implantation in order 95 percent of our angioplasty patients of which over 95 percent are drug eluting.  The patients that we'll be discussing are 4,200 patients with having at least one implantation of a drug‑eluting stent.  And you can see the representation over the 3-year period.  We will be discussing outcomes from up to October 31st of this year of myocardial infarction and all causes of mortality.
		DR. MAGID:  In terms of our data sources, we enroll all of our patients in the ACC-NCDR Cath-PCI Registry.  Our pharmacy data is fairly unique. We have dispensing data on all medications that our patients receive.  And I think it's important to understand that about 98 percent of our patients have a drug benefit, which means they can obtain typically 2 to 3 months of a prescription for typically about $10.00 to $15.00 in co-payments.  So there's a strong financial incentive for them to obtain their medications within our system.  And we have very detailed data on the timing of receipt of those dispensing as well as the number of medications which allows us to carefully assess when patients are on and off medication.  We use hospital claims data to identify all patients with a primary discharge diagnosis of MI.  And we have our own Kaiser death registry files as well as state death registry files to look at the outcome of death.
		Briefly, to go through the patient characteristics, the mean age of the patients was 65; 30 percent were women.  You can see the racial and ethnic distribution of the patients in our registry.  In terms of medical history, 30 percent had diabetes; over half were either current or former smokers and a high percentage of hypertension and hyperlipidemia.  In terms of prior history, almost 30 percent with prior MI and prior PCI as well as events of prior CABG and heart failure.
		Importantly, the majority, over 70 percent of our patients are getting drug‑eluting stents in the setting of acute coronary syndromes.  And with regard to lesion characteristics, you can see that a large number of patients are receiving stents in the setting of non-FDA-approved indication, so 37 percent have high-risk C-lesions; almost 10 percent had a previously treated lesion; 7 percent had graft PCI; 10 percent in bifurcation lesions; and 18 percent in lesions over 30 millimeters.  This is a distribution of the numbers in stents implanted per case as well as the distribution by stent manufacturer.
		This is a life table analysis to give you a sense of the timing of both myocardial infarction and death over time.  I think the important finding from this slide is the high right of events in the first year which levels off thereafter.
		We did Cox proportional hazard regression analysis to identify independent predictors of both myocardial infarction and death.  These are the independent predictors of myocardial infarction after DES:  diabetes, graft PCI, lesions over 30 millimeters, heart failure, and lesion risk.  Again, note the number of lesion characteristics that don't have an FDA indication.  Similarly, with regard to predictors of death after stent implantation:  heart failure, bifurcation, lesions, older age, diabetes, acute coronary syndrome and current smoking.
		Perhaps the most interesting data we have relates to the issue of clopidogrel use and subsequent AMI, and I'd like to spend a few minutes on this slide.  Essentially, what we're looking at here is examining the association between Plavix and adverse events in each of 3-month windows.  I should say first off that almost all of our patients get the recommended of clopidogrel, so for patients receiving a CYPHER stent, that would be 3 months of therapy and for patients receiving a TAXUS stent, that would be six months, so well over 90 percent of patients, based on our pharmacy records, have received at least that much therapy.
		And so what we did in this analysis was we looked at the relationship between clopidogrel use beyond that recommended period and the occurrence of events.  So in the 1 to 3-month window, if the patient was on a CYPHER stent, that means we're looking at clopidogrel use in the 4 to 6-month window or 1 to 3 months after the recommended therapy.
		For the patients receiving TAXUS, the 1 to 3-month window rec is the 3 months following the 6 months recommended therapy.  We would be looking at adherence to Plavix in the 6 to 9 months.
		And essentially within each of these 3-month windows, patient's time is partitioned into an exposed and an unexposed period with regard to Plavix, and then we look at the events that occurred in those 3-months window with regard to whether patients were exposed and unexposed.  We use GEE to obtain relative risk adjusting for patient time as well as correlation between unexposed periods within a subject.  So as you can see, we have a statistically significant protective effect of Plavix in that 3-month period beyond the recommended period of time.  And there's also a trend towards protection in the second 3-month period.  There were no differences in terms of outcomes beyond that period of time.  And I haven't shown you specifically data for the period of time beyond 12 months, but I can just tell you that in all periods of time beyond that, there is no evidence of any protective effect associated with clopidogrel use in our population.
		Similar analysis with regard to death, again, reminding you that we're looking at an extended clopidogrel use, so we're looking at a period of time beyond that which is recommended for therapy.  And we see a similar protective effect in that first 3-month period as well as the second 3-month period beyond that which is recommended but nothing in the periods beyond that.  And again, in the periods beyond 12-month, we've seen no evidence of a protective effect.
		The last thing I wanted to tell you is that we did do a small review of all our MI cases in Colorado.  Of the 24 cases using the ARC definitions that people have talked about before, we identified 62 percent of cases as probable or definite stent thrombosis.  Twelve of the 15 cases of stent thrombosis occurred in the first year after stent implantations; 7 of the 12 cases occurred in the months 6 to 12 after the stent implantation.
		I think it's important to acknowledge several limitations with regard to our registry analysis.  We had limited long-term follow-up.  It's difficult to draw definitive conclusions of the efficacy of DES in subgroups, and the potential protective effects of clopidogrel that we see in the first 3 to 6 months in the extended analysis could be due to confounding factors.  Particularly, patients who adhere to therapies with clopidogrel also adhere to other therapies that may be beneficial.
		So in summary, we have a high proportion of DES implant in the setting of acute coronary syndrome.  DES implanted in lesions outside of current FDA indications are associated with an increased risk of adverse events.  Clopidogrel may be associated with a reduction in adverse outcomes in the 1 to 6 months passed current recommended therapy with no significant protective effect thereafter.  Thank you.
		CHAIRPERSON MAISEL:  Thank you very much.  Our next speaker is David Williams.
		DR. WILLIAMS:  Thank you, Dr. MAISEL, and good morning to panel and guests.  Today I'll be speaking with you about two registries, the DEScover Registry and the Dynamic Registry, and then I will focus on some very new data that relates to on-label use and off-label use.
		These are my disclosure information data.  In particular, I'm not involved in any speaker bureau and my travel today was not supported by anyone or else I would not be staying at the Hampton Inn which is eight miles away.
		(Laughter.)
		DR. WILLIAMS:  I'll tell you about DEScover first.  These data are also available in circulation and was published in the November 14th issue.  This is a United States study, a prospective observational trial at 140 sites, a broad sampling including academic medical centers and community hospitals.  Each site was asked to enroll at least 60 patients.  Our target was 7,500 patients.  We exceeded that slightly, and we enrolled consecutive patients undergoing PCI so that this included not only patients with drug‑eluting stents but those receiving bare-metal stents and plain old balloon angioplasty.
		The data collection and data management are shown on this slide.  The trial was supported by Cordis, but I think it's worth noting that the entire process of data collection and analysis were done independent of Cordis..  Only after this process was complete were those data shared with the sponsor.  The data analysis was performed under the direction of Kevin Kitt at the University of Pittsburgh.
		This is the source of our data.  We enrolled, as I said, slightly over 7,700 patients.  Of interest, 96 percent of PCI patients received at least one stent.  Of the patients who received a stent, 95 percent of those patients received at least one drug‑eluting stent indicating a strong preference for physicians to use drug‑eluting stents whenever possible.  Five percent received a bare-metal stent alone.  Of the patients who received a drug‑eluting stent, 55 percent received a Sirolimus stent, 38 percent a paclitaxel stent.  And for this analysis, we will be looking at the bare-metal stent patients, the Sirolimus only patients, and the paclitaxel stent only patients.  Obviously, a small proportion of patients received a bare-metal stent, and this is a registry, so we certainly need to be concerned about the possibility of selection bias in that group.
		Accordingly, I'm sharing with you some of the baseline characteristics of the three groups:  the bare-metal stent group, Sirolimus group and paclitaxel group.  And on the subsequent slides, the comparison between the bare-metal stent group and the drug‑eluting stent group are shown here, and between the two types of drug‑eluting stents on the far right.  Of these data, these particular endpoints and variables:  age, prior coronary bypass and prior angioplasty are different in their proportions between the bare-metal stent and drug‑eluting stent group.  So I think it's actually interesting that there were several factors that were not different including diabetes, smoking, hypertension, prior MI even though it was a relatively small sampling.
		It's also worth noting that when one looks at procedural features in terms of stent use and the types of lesions treated, there were more lesions attempted among the DES patients; there was more multi lesion intervention; there were more stents used; there was more stent overlap in these patients, and certainly there were complex lesions represented in both groups with more lesions, total occlusion type, certainly in the BMS group, but certainly a preponderance of de novo lesions in both groups seen here.
		Moving on to the outcome data, these are unadjusted raw data.  Looking at bare metal versus one year drug‑eluting stent results in terms of mortality, the bare-metal stent group had a 5.9 percent mortality versus 3.1.  This was significantly different.  There was no difference in the incidence of myocardial infarction.  Stent thrombosis was less than 1 percent for both groups, 0.8 and 0.6 percent.  If one looked at the need for target lesion revascularization, there's about a 30 percent reduction in that with the DES group as seen here, and that is highly significant.
		Trying to account for the differences in baseline features, we did an adjusted analysis.  I apologize.  The slide is a bit busy and tight.  The top line is the all patient group, so this is every patient and with adjustment, the hazard ratio is 0.74 in favor of drug‑eluting stents.  There is some overlap here.  It is not significant but approaches significant.  These are various subsets:  age; gender; whether a prior procedure had been done or not; whether the procedure was elective or urgent, and show certainly no excess of death and myocardial infarction for drug‑eluting stents.  If anything, the values are on the left side of this line favoring drug‑eluting stents.
		Looking at the efficacy side of drug‑eluting stents, that is the need to perform repeat revascularization for all patients comparing bare metal versus drug-eluting adjusted, we see a significant difference, 0.58, confidence interval .4 to .8, and again, for the various subsets in general a benefit for drug‑eluting stents.
		Moving on to the Dynamic Registry data, the -- this is a slightly different type of registry, and I'm going to move quickly here so we can have time.  But basically, this registry involves waves of enrollment.  And you can see the various period of time, we enroll approximately 2,000 patients.  And in this analysis, we've looked at the drug‑eluting stents in '04 versus the bare-metal stents in '02.  We did see significant differences here in this bare-metal stent group and thought that this would be a better group for comparison in that these patients would likely get a drug‑eluting stent if one had been available, 1,700 patients in the BMS group, 1,400 in the DES group.
		Again, baseline characteristics shown here.  Some differences but not major differences.  For example, diabetes 29 versus 34 percent but certainly some differences existing.  At one year, unadjusted, event rates:  death 4.3 for the bare-metal; 3.6 for drug-eluting; and again we see significant reductions in the need for target vessel revascularization and bypass surgery in these patients compared to the bare- metal group.  We did adjustment again here.  If one looks at the adjusted, for example, for death, 0.98.  No significant difference.  The only benefit being, again, in repeat revascularization, the only difference being a benefit for drug-eluting in those procedures.
		I want to spend a minute or two about the off-label versus on-label indication.  These data are brand new and have not been shown ever before.  These are the criteria by which we distinguished off-label use.  These are lesion based.  They're not patient based.  But that was our first cut at the data, and let me walk you through the slide.  In blue is bare-metal, standard meets on-label use.  Black is bare- metal off label; drug-eluting in red, standard; and in the sort of purple color, drug-eluting off-label.
		Let me just walk you through this.  This is 1-year cumulative mortality for these four groups of patients in the Dynamic Registry data.  So the numbers go 2.6, 3.3, 4.4, 5.8.  The highest is the bare-metal off-label.  The lowest two are the on-label DES and bare-metal.  So that's for mortality.  This distribution is significantly different.  If one looks at MI, one sees no significant difference according to these distinctions.  And if one looks at the efficacy side again, and this is a 1-year repeat revascularization, the lowest rate is a drug-eluting standard, the next is drug-eluting off-label.  The highest is bare-metal off-label and then bare-metal standard.  And this is the stent thrombosis data for the DES group.  We do not have it in the bare-metal group, because we didn't realize we needed to collect it at that point in time.  But based on off-label versus standard, we do see a difference with less than 1 percent, 0.05 percent, with on-label and 1.6 for DES off-label.
		So to conclude, we felt that the findings between these two independent real-world U.S. registries were similar.  There was no signal of excess death or MI among DES patients.  There was substantial reduction in the rates of TVR by either bypass surgery or PCI in the DES patients, and the off-label outcomes were worse than the on-label ones, and the bare-metal stent off-label patients fared worse in this analysis compared to the drug‑eluting stent on-label patients.  Thank you.
		CHAIRPERSON MAISEL:  Thank you very much.  Our next speaker is Gregory Mishkel.
		DR. MISHKEL:  Good morning.  My name is Gregory Mishkel, and I'm an Interventional Cardiologist and the Director of the Cardiac Catheterization Laboratory at Prairie Heart Institute at St. John's Hospital.  On behalf of my collaborator, Anna Moore, and the cardiologists of Springfield, Illinois, it's my pleasure to present to the FDA today the Prairie "Real World" Drug Eluting Stent Database.
		This database was funded by Boston Scientific, Cordis J&J and the Medicines Company.
		I'm sure many of you are wondering where is Springfield, Illinois.  Well, in fact, Springfield is in the central part of Illinois.  It's the state capital, lies on old Route 66 between Chicago and St. Louis.  Our group has a catchment area of roughly 17,000 square miles and additionally draws patients from other hospitals in the area.
		I am reporting on the patients who are enrolled at St. John's Hospital Prairie Heart Institute, which is the largest open heart program in the state of Illinois.  As any interventionalist in the audience will tell you, restenosis was the bane of our interventional existence.  Previously thought to be a benign phenomena, in fact, lately we've discovered that this might not be the case.  Indeed, we analyzed patients between July 1st of 2001 and May 1st of 2003 and found 420 patients who re-presented to the catheterization for repeat intervention for a bare-metal stent restenosis.  In fact, 7.5 percent of these patients presented with a STEMI, and 2.9 percent, almost 3 percent died prior to their hospital discharge.  We, therefore, embraced drug‑eluting stents with a penetration well over 95 percent in our cardiac catheterization laboratory from the time of commercial release, and we saw a concomitant fall in the rates of in-stent restenosis.  That was the good news.
		The bad news, unfortunately, for some patients, in this case a patient who was found dead at home, subsequently underwent autopsy, that he had a late drug‑eluting stent thrombosis in the LAD.
		We created the database at the time of commercial release which includes patients from May 1st of 2003 all the way to May 31st of 2006.  This database now contains 5,280 patients who received their first drug‑eluting stent.  Of note, more than 75 percent of these patients would have had one or more exclusion criteria from their major randomized controlled trials.  Clinical follow-up was obtained through various sources including telephone calls to patients and their primary doctor, contacting their Springfield cardiologist, mail surveys, electronic chart review, hospital re-admissions, both locally and distant, as well as death certificate review.  All deaths were independently adjudicated.  Patients were eligible for follow-up at 6 months, 1 year, 2 years, 3 years.  Of the 792 patients who were eligible for 3-year follow-up, we have completed follow-up on 89 percent of these patients.  The mean days to follow-up was 550.
		This is the baseline characteristics of patients who received a drug‑eluting stent.  Seventy-five percent of these patients received a Sirolimus stent; 1.7 to 1.8 drug‑eluting stents were implanted per procedure.  Diabetics represented 30 percent of the population, 10 percent of which were insulin-dependent diabetics.  CYPHER stents were over-represented in patients who had unstable angina, prior MI, prior PCI, or IIb/IIIa use.  Nine percent of the patients presented with a STEMI and received a drug‑eluting stent.  Twenty-five percent of the patients had moderate to severe renal insufficiency.
Not listed on this slide was the incidence of multi vessel disease which was 60 percent.  We recorded in follow-up 349 deaths.  All but 28 deaths were adjudicated.  Those 28 patients no longer reside in the state, were either traveling through the state at the time of their drug‑eluting stent and have been lost to follow-up or have been incarcerated and are not answering phone calls.
		This is the 3-year Kaplan-Meier curves for survival.  You can see that the all-cause mortality at 3 years was 86.4 percent and close to 95 percent for freedom from cardiac mortality.  Some European studies have suggested, in patients who died from non-cardiac causes, that there was an excess of deaths in the Sirolimus group.  Our study shows virtual super imposition of the Kaplan-Meier curve for patients who received either paclitaxel or Sirolimus and died from a non-cardiac cause.  This is the overall cardiac survival, Sirolimus versus paclitaxel; again, virtual super imposition of the two survival curves.
		Looking at the diabetic cohort, yes, we do see a lower survival in diabetic patients:  freedom from cardiac death, 91 percent at 3 years, significantly lower than those non-diabetic counterparts.  Looking at the diabetic subgroup, paclitaxel versus Sirolimus, freedom from cardiac death, we see virtual super imposition of the Sirolimus and paclitaxel curves.
		We identified 45 patients or .85 percent with a definite stent thrombosis.  Half to three-quarters of these patients presented with an ST elevation MI.  Eighteen patients presented early with a stent thrombosis, all of home were taking their Plavix.  Eleven patients presented late, and 16 patients very late.  Half to three-quarters of these patients were off their Plavix at that time.  Smokers were over-represented in the late and very late group.  Bifurcation lesions and overlapping stents were over-represented, particularly in the early stent thrombosis.  Thirty-day mortality started was 12 to 25 percent across the board.  Only no vein grafts occluded late.  The only vein graft closures were in the early patients.
		This is the distribution of definite stent thrombosis over time.  Once again, looking at the late and very late group, you can see that a large number of patients were on clopidogrel at the time of their stent thrombosis.  On those individuals who were off their clopidogrel, some presented quite remotely from the date of finishing their clopidogrel.  Indeed, the patients who presented the latest, beyond 3 years, had finished their clopidogrel some 2 years prior to their stent thrombosis.  Two of the definite stent thrombosis were found by autopsy reports.
		Some interesting observations were made looking at the patients' angiograms.  We found three patients who did not meet the definition by the ARC criteria of a definite stent thrombosis who had angiographically confirmed thrombus in a present in a previously placed DES but no accompanying acute coronary syndrome.  They had come back for stage drug‑eluting stent in another vessel.
		We also found several examples of multiple drug‑eluting stent thrombosis in the same patient.  Four patients had repeat drug‑eluting stent thrombosis in the same vessel, two patients in a different vessel.  Our probable stent thrombosis rate was .21 percent, and our possible stent thrombosis was .85 percent.
		I think it's important to note that just from simple death certificate review, our initial pass at the possible rate was 1.4 percent.  After independently adjudicating every death certificate, calling the patient's doctor, looking at out of town hospital records, we eliminated some 35 patients or so from the possible category.
		We created the logistic regression analysis for patients with definite or probable stent thrombosis, entered those that were significant to the univariate analysis and to the multivariate analysis, and only three features came out of a very weak model.  I think the most significant predictor, as we found it, was a left ventricular ejection fraction of less than 30 percent.
		This case study, I think, is instructive.  This individual had a 3-millimeter TAXUS stent implanted in a circumflex vessel and a type a lesion.  He had a preceding history of pulmonary embolism, had been treated with Coumadin, no evidence of a hypercoaguable state.  Two days later, compliant with aspirin, Plavix and re-institution of his Coumadin, he sustained a stent thrombosis for which he received a 3.5 millimeter proximal and a 2.75 millimeter distal TAXUS stent.  Some two months later, now compliant with increased dose of Plavix, Coumadin and aspirin, he sustained his second stent thrombosis, now a late stent thrombosis, and received a third 2.75 millimeter CYPHER stent distally only to present 14 months later with his third stent thrombosis, eight days after he discontinued his Plavix therapy for oral surgery.
		These are the ARC definitions for stent thrombosis:  definite and probable, freedom from death, and probable 98 percent at 3 years.  For all three categories, definite, probable and possible, freedom from stent thrombosis, 96 percent at three years.  The cumulative incidence of stent thrombosis per year after 30 days was .45 percent.
		Accordingly, after reviewing this data and other data that has come to light, this is the utilization data in our catheterization laboratory.  Our penetration of drug‑eluting stents was over 95 percent earlier in the year and has fallen off to closer to 80 percent as this data has been circulated.
		In summary, the total unadjusted rate of stent thrombosis for the Prairie Registry over 3 years is 1.9 percent.  However, the unadjusted rate of definite and probable over 3 years is only 1.1 percent.  The cumulative definite event rate is .45 percent per year after the first 30 days.  Possible stent thrombosis, in our mind, is an overly sensitive and non-specific indicator of stent thrombosis.  Late and very late stent thrombosis could not entirely be attributable to discontinuation of antiplatelet therapy.  Recurrent stent thrombosis in patients suggest other etiologies.  Any decision regarding drug‑eluting stent implantation must weigh the net clinical benefit of preventing in-stent restenosis and the associated morbidity and mortality versus late stent thrombosis.  Thank you very much.
		CHAIRPERSON MAISEL:  Thank you.  Our next speaker is Ron Waksman.
		DR. WAKSMAN:  Good morning.  Thank you very much.  I will present to you results for Contemporary Registries of the Washington Hospital Center.  These are my disclosures and also this presentation will be on our website.
		Washington Hospital Center is located actually a few miles south from here.  It's a single set registry here with 11 cath labs.  We have 31 independent interventional cardiologists, and all those registries conducted under local IRB approval.  All the patients underwent PCI per standard of care at Washington Hospital Center, and IVUS guided the PCI from -- in our institution in 70 percent fo the interventions.  All the patients were discharged on dual antiplatelet therapy for a minimum of 6 to 12 months with detailed instructions on the importance of long-term antiplatelet compliance.
		These are the statistical methods.  I'm not going to go through all of them, but I'll present you data which is partially on 7,266 patients.  Different registries are taken from this one.  First of all, I'd like to share with you the results of the REWARDS Registry.  This was TAXUS versus CYPHER.  We looked at the cumulative stent thrombosis.  This is the definite, by our definition, just angiographic stent thrombosis at 12 months, which was 1.6 percent.  See there was some differences between TAXUS and CYPHER, .8 to 1.9.  That was statistically significant.  And later on, I'll show you maybe a potential explanation for that.
		We all talked yesterday about the ARC definition.  I'm not going to dwell on the ARC definition, but I would share with you that we think that there is deficiencies in taking the possible element in the ARC definitions.  They're just simply too broad and will inflate the stent thrombosis rate and probably require modification.  So we'd like to keep either the definite, which is maybe too narrow, but, if possible, the definite and probable only and to drop the possible.
		The reason that possible should be dropped is because we do have deficiency or limitations on cause of death.  We are unable to locate cause of death for a patient in registries.  There are a lot of unexplained non-cardiac cause of death.  And what we tried to do is to look at some literature and epidemiological studies and found out that unexplained or sudden deaths range form 30 to 60 percent of all cardiac deaths of which 10 to 50 percent are attributable to unexplained atherosclerosis or acute ischemic heart disease.
		So we're counting actually with the situation that if we like to analyze all our data right now by definite, probable and possible, we're getting those enormous numbers of, if you look at the overall 24 months, about 12.2 percent, adding the 5.4 percent due to the possible.  So this is completely unrealistic and going to scare every patient if they hear that, with the possible complete definition, we're going to have in those registries 12.2 percent stent thrombosis over 24 months.
		This is how it is reflected in the Kaplan-Meier survivals.  You see here on the top the definite, the definite plus probable, and in the green this is including the possible, and you can see how this is exaggerating the situation.
		So what we're proposing is based on those epidemiological studies and questions in inaccuracy of stent thrombosis detection resulting in unexplained deaths, different weights should be applied to each of the definitions.
		We made a model, which I don't have the time to go through here, but this could be something that should be exercised further on -- to give 1 point to definite, probable .8, and possible .3.  And in the bottom, you see the formula of cumulative stent thrombosis.
		So that will turn out to, in this category for our studies, at least on the 12 months, to drop from 5.8 percent to 3.8 percent while in Hospital, we are almost about the same:  .9 and .8.  And also at the 30 days, we were at 2.1 and 1.8.  And at 24 months, instead of 12.2 percent, 7.7 percent.
		This is also true for the other trials that have been reported so far.  If you look at Endeavor, you can do the same exercise in the Registry.  The new definition, the modified ARC versus the black in the old definition as was reported by Kaplan -- by the ARC definition, and you can see that the numbers actually seem to be reasonable with this modified definition.  And this is also true for CYPHER.  If you took the total, it's exactly 2 percent for each versus 3.5 and 3.3 percent, just probably make more justice to what is late-stent thrombosis.
		Let's move to how long should we prescribe Plavix and clopidogrel compliance post drug‑eluting stent implantation be obtained and what is the impact on stent thrombosis.  Well, we know that there is a price to prolong Plavix, and this has been given us from three randomized studies in which Plavix was compared to aspirin alone.  And you can see here that all of them, CURE, CREDO AND CHARISMA, there was excess of bleeding.  And this is something that we are associating and confronting with our patients.  The compliance overall at Washington Hospital Center at discharge is 98.9 percent; at 1 month,  94.2 percent; and it goes to 78.7 percent at 12 months.  And the best compliance we have on are on patients with ACS.
		Now overall, we looked at our core and separated to complex population versus non-complex population.  In complex, we included ostial lesions, in-stent restenosis, non-artery native lesions, long lesions, type C lesions, CTO, more than two DES, AMI, insulin-dependent diabetes, chronic dialysis, and prior CABG.  So you can see here that overall, clopidogrel compliance at the time of stent thrombosis was pretty high.  We have here about 30.4 patients that were off Plavix during the stent thrombosis but 60 percent, and this is for CYPHER and TAXUS, similar numbers, patients were on Plavix and still we have some -- hard to get all the information on all those patients in those registries.
		We ran statistical analysis and you see here that you can look at stent thrombosis less than 6 months.  When we look at definite stent thrombosis and we look with clopidogrel, continuation was better or clopidogrel cessation was better.  Less than 6 months, clopidogrel continuation was better for the unadjusted overall parameters for the adjusted, for the complex, for the ACS.  Nothing on the diabetes.
		If you look between 6 to 12 months, we don't see any more adjustment for the unadjusted overall, adjusted overall complex, ACS or diabetes mellitus, and there is nothing here that clopidogrel continuation is prohibitive of stent thrombosis.
		One thing that we also see by those definitions is that are few predictors that come in on all the definitions.  This is presentation with acute MI, Type C lesions, a number of implanted stents.  What was also surprising to see in the probable, the lack of IVUS came also as a predictor for stent thrombosis.
		As I showed you before, we had differences between CYPHER and TAXUS in stent thrombosis, and we think that one of the explanations could be that you see here at the 6 month, we had less compliance or less patients on CYPHER that took clopidogrel, and that can explain those results.
		Let's move to restenosis.  We talked yesterday about the potential tradeoff from thrombosis, but let's go back to the data from Emory.  This is Bill Weintraub in 1993, so this is probable on 6-years follow-up between patients who had restenosis and no restenosis, and there was no difference in mortality according to the status at angiographic follow-up.  This was true in the days of the POBA.  Yesterday we heard that it may be different with the in-stent restenosis or bare-metal stent.  Since we ran so many radiation trials in our institution, we had the opportunity to look at our cohorts, how they presented, but 1.7 presented with STEMI, 5 percent non-STEMI, any-MI 6.7 percent.  And we looked also what happened at 30 days with those patients, and you can see here that Q-Wave MI was 1.4 percent, and death and Q-Wave MI all together was 2.3 percent.
		But if you look at the TAXUS ICR and if you look at the SISR trials, which were the sponsors' studies comparing the brachytherapy to TAXUS, you see here that actually the cardiac death, Q-Wave MI were nearly 0 at 9-month follow-up, and the non-Q-Wave MI was also relatively low.  This is also true for SISR.  And in fact, if you look at stent thrombosis, both brachytherapy and DES for in-stent restenosis, there were 0 in those sponsored trials.  So I would caution to draw some conclusions for small studies that are actually doing a post hoc analysis and finding potential explanation for these phenomena.
		Finally, I'll say a few words on off-label use.  We looked at off-label use, a cohort -- this are the baseline characteristics.  What I'd like to show you -- there is a big difference in terms in the results between the cohorts.  You see here much more events in the red, which is the off-label versus the label.  And also this is applying to TVR, and what is more important, to stent thrombosis.  The rates are almost doubled if you're looking at the off-label use versus the label use at 30 days and at 12 months.  And if we look at the predictors, off-label use, and all the other categories of left mains, saphenous vein graft, they're all coming as predictors of MACE at 12 months for off-label use.  We actually applied this to our practice.  As you can see, we reduced the drug‑eluting stents periodically.  This was also affected by the data in Barcelona.  Now we are 68 to 70 percent DES.
		So in conclusion, DES stent thrombosis in off-label use is higher when compared to the label use or to bare-metal stent.  The ARC definition inflates the rates of late stent thrombosis and should be modified.  We propose to drop the possible or to weight adjust it, and changing the definition will not resolve the problem.  Stent thrombosis of DES is associated with high mortality, 30 percent in morbidity, non-fatal MI 60 percent, and restenosis of BMS, although associated with low rates of death and MI, is not the sole explanation of the discordance between thrombosis, death and MI.  Careful patient selection for DES is mandatory, and off-label use should be reconsidered or restricted.  DES should be contraindicated for patients with poor compliance or allergic to Plavix or aspirin and need for upcoming surgery, and warning labeling should be considered for those when used off-label.  Diabetic patients with multi vessel disease should be liberally referred to surgery.  And finally, anecdote to platelet therapy beyond 6 months is not proven yet to be prohibitive to late stent thrombosis.  Thank you very much.
		CHAIRPERSON MAISEL:  Thank you very much.  I'd like to thank all of the speakers for excellent presentations, and I'd like to give the panel an opportunity to question these speakers this morning.  Dr. White?
		DR. WHITE:  I'd like to ask Ron a question if he'd come back to the microphone.  Just in the last conclusions, one of the top ones was that the drug‑eluting stents off-label had higher risk of stent thrombosis than on-label drug‑eluting stent use, but you also said bare-metal stents.  Are you saying that bare-metal stents on-label are safer than drug‑eluting stents off-label?  Or are you saying that bare-metal stents off-label are safer than drug‑eluting stents off-label?  Were you comparing apples and apples?
		DR. WAKSMAN:  No.  I think that in general, when we look at on-label and at off-label, the drug‑eluting stents are more thrombogenic than bare-metal stents.  So this is true for both.  For the label, we actually the analysis that shows that over time, late stent thrombosis is seen more in the DES versus the bare-metal stents, and that's also shown by our data.  But this is also true for the off-label.  We're seeing more tendency of stent thrombosis with the off-label DES versus off-label BMS.
		DR. WHITE:  That is different than Dr. Mishkel showed?
		DR. WAKSMAN:  Correct.
		CHAIRPERSON MAISEL:  Dr. Somberg.
		DR. SOMBERG:  I have a question for Dr. Williams as well as the Prairie.  Maybe they both want to come up so I can ask them very quickly.
		CHAIRPERSON MAISEL:  Let's do one at a time, please?
		DR. SOMBERG:  Okay.  Whatever the Chairman says.  Dr. Williams, your registry was started in '97, '98 I saw, but you only present 1-year follow-up?  Can you give us longer follow-up with the bare-metals versus the DES?
		DR. WILLIAMS:  The second registry was started earlier, that's right.  And typically -- and we have waves of enrollment, and the duration of follow-up varies according to the waves.  There's only one wave we have which has 5-year follow-up which will be a bare-metal wave, and we are asking -- we're actually going back to NIH to ask for extended follow-up for the group that I showed you -- we think that's valuable, but we were not funded for that so.  We think it's a great idea and support the idea.
		CHAIRPERSON MAISEL:  Dr. Topol?
		DR. TOPOL:  I'd like to ask Dr. Kong a question.  Actually, a couple of points on this recent JAMA paper that we had an opportunity to review.  First, of course, it's exemplary to have 98 percent follow-up, and that's actually perhaps overriding the ARC definition to have such excellent follow-up.  But one of the surprising findings which is discrepant with many of the studies that we've had a chance to review is that the drug‑eluting stent patients on clopidogrel actually did the best of the four groups.  I'd like you to comment further about that, because that's at odds with some of the other studies.
		But also, you didn't present the data with respect to on-label/off-label as some of the other presenters.  I suspect you may have done that analysis, so I'd like to get some insight from you about that, Dr. Kong.
		DR. KONG:  Briefly, we have not done an analysis on-label and off-label.  The way that the Duke University database has been constructed, there are certainly some parameters of off-label use such as the use in vein grafts or use in the setting of acute myocardial infarction that are relatively easy to identify.  In the way we've structured the database, captured things like overlapping stents or variances in vessel diameter, they're a little bit difficult.  And think it's one of the elements that we may consider for some of our ongoing research.
		With regard to the lower event rates in patients with drug‑eluting stent with clopidogrel use, certainly the leading hypothesis is that antiplatelet therapy reduces the likelihood of late thrombotic events.  Whether that's actually the mechanism or not requires additional study.  The reassuring thing is that the data even for relationships amongst bare-metal stent patients as well as drug‑eluting stents parallels your own CREDO study where albeit that we're not powered to detect mortality differences, there is the non-significant approximately 23 percent relative reduction in mortality associated with taking clopidogrel for extended durations.
		DR. TOPOL:  Just to follow-up, sir.  The data are so different, for example, from the Swedish registry that we heard yesterday, and obviously a lot of your analysis was adjusted.  There were marked differences and we've made some wrong turns in medicine because of using observational data and trying to make all sorts of adjustments, so I guess there's a level of confidence here when we have mixed data.  You know, you may wish to comment further about that.
		DR. KONG:  One of the key differences between our analysis and the Swedish analysis is that we're able to have reasonably detailed clopidogrel use among the four different arms.  So if we actually look at reports of drug‑eluting stent patients versus bare-metal stent patients, there is likely some admixture or blending of patients who are suspending clopidogrel use after 6 months versus who are using clopidogrel for expended periods of time.  And it became apparent even yesterday in the randomized clinical trials that there may actually be a mixture of patients who are using clopidogrel for extended durations of time.  So this blending of patient populations may account for some of the different conclusions that are raised when analysis are done simply on the basis of stent type as opposed to using these landmark settings.
		And I found it particularly interesting that Don Baim presented the landmark analysis from the TAXUS randomized stent trial showing similar parameters.  So certainly, as with any observational study, these generate questions that deserve to be answered in more formal and more rigorous settings, but there does appear to be sufficient robust signal that is worth additional investigation.
		CHAIRPERSON MAISEL:  Dr. Kong, while you're up there, I, likewise, would like to congratulate you on a very important study.  You highlighted some of the limitations of your data, to me, most importantly, the recall bias that may be associated with clopidogrel use or memory of clopidogrel use in drug‑eluting stent patients.  You also haven't been able to detail the bleeding complications associated with the clopidogrel use.  Based on your data, do you think this is sufficient to make a recommendation regarding clopidogrel use in drug‑eluting stent patients?  How long should they be on it?
		DR. KONG:  As many people would agree, the exact duration or optimal duration of clopidogrel use is something that is yet to be determined.  And in my opinion, there is still continuing evidence needs for determining what the optimal duration should be.  Certainly, because we've detected a mortality difference amongst patients who are on extended dose clopidogrel compared to those who are not, it is reasonable to suggest that the AHA recommendation of 12 months as a minimum would provide a more optimum balance of reduction of risk for death in non-fatal myocardial infarction.  We have not, as of yet, compiled detailed data regarding the bleeding risk from this particular stratification.
		CHAIRPERSON MAISEL:  Thank you very much.  Dr. Normand.
		DR. NORMAND:  I have a question for you as well.  I was looking at the numbers that you presented, and I believe there were a number of patients where you said there was no report of medication use.
		DR. KONG:  That's correct.
		DR. NORMAND:  Are they eliminated from your analysis?
		DR. KONG:  From the 6-month landmark analysis, if the patient did not submit a list of their medications on their questionnaire, they were excluded from the analysis population, yes.
		DR. NORMAND:  And could you just give a sense of what percent were eliminated on that basis?
		DR. KONG:  I'll show you the slide.
		DR. NORMAND:  All right.  That's okay.  I don't want to take up too much time, but if you -- I could look in the paper and you'll give us the numbers.  Is it about 10 percent, 5 percent?
		DR. KONG:  The number is fairly small, approximately 8 percent.
		DR. NORMAND:  Eight percent?
		DR. KONG:  Yes.
		DR. NORMAND:  Eight percent.  So they're excluded.
		DR. KONG:  Yes.
		DR. NORMAND:  Okay.  Thank you.
		DR. KONG:  And similarly, patients with revascularization, patients with non-fatal myocardial infarction, patients with death, all events happening before 6 months would have been excluded from the landmark analysis.
		DR. NORMAND:  Another question is really about whether or not they had the information to talk about clopidogrel abuse?
		DR. KONG:  Right.
		DR. NORMAND:  Right.
		DR. KONG:  So there are other exclusions beyond just the questionnaire.  Obviously, you don't complete the questionnaire if you're dead, but there are other elements, yes.
		DR. NORMAND:  That's the main point you're looking at is the drug use.  I just wanted to get a sense of that.  My second question is for, I think it's Dr. Mishkel.  I think it's for you.  I just want to get a sense of your sense and whether or not you had any information collected regarding why an interventionalist would use a CYPHER stent versus a TAXUS stent?  I'm trying to get a sense of that.  Is that basically availability, or is there a clinical reason?
		CHAIRPERSON MAISEL:  Turn your microphone on.
		DR. MISHKEL:  Well, that's a complex question.  In the first year, it was easy, there was only CYPHER.  So that was an easy decision.  There were supply issues associated with CYPHER at one point in time.  That sort of drove people to TAXUS.  There was at least one recall of the TAXUS stent that interfered with some people's confidence, and that drove people back to CYPHER.  And then I expect to some extent, the continued preponderance of CYPHER is a reflection of potentially marketing practices in the area and/or cardiologists who like to use a product that has a longer track record perhaps.
		DR. NORMAND:  Because I may have recalled correctly, but I think there were some differences in the patient characteristics between the two stents?
		DR. KONG:  Patients who received the CYPHER were more apt to have had unstable angina or prior MI and received more IIb/IIIa inhibitor, but those were really the only --
		DR. NORMAND:  And you think that's related to availability?
		DR. KONG:  When you looked at the numbers, I don't think those differences were actually clinically significant.
		DR. NORMAND:  You commented on them so.
		DR. KONG:  Beg your pardon?
		DR. NORMAND:  You commented on them, so I'm just trying to get a sense --
		DR. KONG:  Because they were statistically significant.
		DR. NORMAND:  Yes.  Okay.  So generally, your belief is just basically availability?
		DR. KONG:  Well, I think I would say that there is also a general belief that in tough anatomical subsets, TAXUS may be more deliverable and that might drive somebody to deliver a TAXUS stent.
		DR. NORMAND:  Thank you.
		CHAIRPERSON MAISEL:  Dr. Yancy?
		DR. YANCY:  I have two questions.  First is to Dr. Kong, please?  I too would applaud you on a very good data set and presentation, but my question regards something we've not heard in the last day and a half, and that has to do with concomitant other evidence-based medical therapies.  Since we're discussing endpoints of death and the current myocardial infarction, I'm fairly certain that this has been looked at, but if you could just state, for the purpose of completeness, what the adequacy of adherence to other medical therapies were in this patient population, that would be helpful.
		DR. KONG:  As we had mentioned in the core presentation, the chief concomitant medication we examined was aspirin use which, from a mechanistic standpoint, would have been important to us from the standpoint of antiplatelet therapy.  And indeed, there was a high correlation between use of clopidogrel and aspirin.
		DR. YANCY:  What about beta blockers, ARVs, ACE inhibitors?
		DR. KONG:  I don't have that information for you, sir.
		DR. YANCY:  I think it would be helpful when we're talking about coronary syndromes and chronic ischemic heart disease.  Let me extend that question then and say have you looked at a data cut referable to left ventricular dysfunction?  Because, again, that would apply to real world scenarios.
		DR. KONG:  That's an interesting question.  No, we have not.
		DR. YANCY:  May I ask my second question to the MATRIX investigators?  You demonstrated a very elaborate data cut that define gender, and you were the first to have really good information on the ethnic makeup, and I'd like to know the outcomes vis-a-vis those groups, less with regards to the adequacy of stent deployment and thrombosis but more so in the context of clopidogrel.  I would hate for us to get this process too far along and discover there is some group differences in response to stent antiplatelet therapy.  Do you have any feel for that initially?  Are you doing any analyses along that line?
		DR. MEHRAN:  We actually do and I think that's a critical, very, very important question is we evaluate patients who may or may not be fit for drug‑eluting stents and adherence to antiplatelet therapy is an important question.  So looking at our minority population, we are seeing some less adherence and actually less follow-up in those patients, especially amongst our immigrant population where we're having a very difficult time finding these individuals, not responding, wrong addresses, disconnected phones, and this has really been a challenge for our group that works very, very hard and diligently on finding these.  So unfortunately, we can't get enough follow-up on those patients to know that they are adherent to their medication.  We suspect that they may not be, and we have a program at Columbia where there is education before discharge and then a nurse calls the patients back 3 days after discharge, and that has really enhanced, especially in the minority population --
		DR. YANCY:  Thank you
		CHAIRPERSON MAISEL:  Thank you.  At this point, we're going to move on with additional public hearing speakers, and the next speaker is Sanjay Kaul.
		DR. KAUL:  Good morning.  On behalf of my collaborator, George Diamond and myself, I'd like to thank the committee for inviting me to share our Prospective on Drug‑eluting Stents:  Balancing Risks and Benefits, which I believe is the crux of the matter.  In the interest of full disclosure, I have received a one-time honorarium of $2,500.00 for an advisory board from Bristol Myers in the past.
		I'd like to start off with summarizing what we know about drug‑eluting stents.  They represent a quantum leap in interventional cardiology, they reduce angiographic and clinical restenosis; however, they do not confer benefits with respect to hard clinical outcomes, and they may even predispose, through stent thrombosis, a rare but potentially life-threatening outcome.
		What we don't know:  There is uncertainty regarding benefit with regards to restenosis.  Do clinical trials really reflect the real world practice, and a lot of this has been debated, so I'm not going to belabor this.  Do drug‑eluting stents prevent or forestall restenosis.  There is some animal evidence to suggest a catch-up phenomenon.  We don't see this consistently in clinical trials although I'm concerned that the curves are converging in case of  RAVEL at 5-year follow-up.  What about late complications such as aneurysms?  What is the clinical relevance of late loss?  Is less late loss necessarily a better outcome?
		Uncertainty regarding risk of stent thrombosis.  What is the magnitude of the problem in real world?  What is the duration of risk?  Does the risk abate with time or continue to rise?  What is the exact mechanism?  We have heard about multi-factorial mechanisms for stent thrombosis.  Whenever I hear the word multi-factorial, it's a euphemism for I don't know.
		Who's most at risk?  Do we have tools to predict who is at risk for stent thrombosis?  What are the safe and effective ways to mitigate risk.  I think there is no dispute about the evidence at hand.  The drug‑eluting stents reduce restenosis, but there is a problem with stent thrombosis.  And reducing restenosis is desirable as long as we have abilities to mitigate the risk of stent thrombosis.  Unfortunately, the current state of the art has significant limitations.  It increases risk of bleeding.  There is a monetary cost which may be prohibitive for some of our patients.  The optimal duration is unknown.  The best available evidence we have so far comes from one observational study that did not account for safety outcomes.  Moderate to low compliance is an issue, and along with it, the affordability.  And strictly speaking, the use of clopidogrel for non-emergency stenting is off-label.  Thus, risk benefit costs of dual antiplatelet therapy is not clear enough to warrant definitive recommendations.
		So how do we mitigate risk at acceptable benefit?  By avoiding drug‑eluting stent in patients unable or unlikely to take dual antiplatelet therapy or in need of immediate non-cardiac procedures, maybe extend antiplatelet therapy beyond 6 to 12 months, perhaps indefinitely in patients at low-risk for bleeding.  And some of you may have rightly argued that this is a bandaid solution.  Sometimes they are necessary, and perhaps sometimes they might even work.
		How do we accentuate benefit at acceptable risk?  I think through advocating a judicious selective evidence-based use, ideally reserved for patients at highest risk for restenosis such as longer lesions or smaller vessels.
		Now the science of medicine speaks to us through the language of data, and shown here are the analytic estimates, the patient-level estimates for the two stent programs.  While the data speak to us clearly with regards to the restenosis benefits simply because these trials were powered to address restenosis, they speak to us with less clarity with regards to late stent thrombosis, or death, or Q-MI, myocardial infarctions, and you can see what the hazard ratios are there.  And the reason why they speak to us with less clarity is because those trials were simply not powered to address this, and these are some conservative estimates of what the beta errors are: .6 to .7.  In other words, the post hoc power is about 30 to 40 percent, and the conservative sample size estimates for stent thrombosis are about 6,000 to 8,000; and for death of Q-MI myocardial infarction, it's about 20,000 to 25,000.
		So robust scientific inference to guide clinical practice is not possible based on inconclusive information.  So what do we do in the face of uncertainty.  And that's where the art of medicine comes into play.  And the challenge for us is how do we balance the high frequency-less important benefit vis-a-vis restenosis against the low frequency-more serious risk of thrombosis?  Is trading off a long-term safety for a short-term benefit an acceptable tradeoff.  And that sort of judgment can only be based on an individual patient assessment.
		The current drug‑eluting stent utilization rate is about 80 percent, and we have learned that nearly 60 percent of it is off-label.  We've also learned from the off-label use that the risk of stent thrombosis is higher, 2 to 3 percent, and in some subsets, like insulin-requiring diabetics, as high as 5 to 6 percent.  But the evidence-based threshold for optimal drug‑eluting stent utilization is somewhere in the range of 35 to 50 percent.
		So what I'd like to do is offer some recommended regulatory solutions more in the spirit of soul searching rather than finger pointing.  And I'll talk about four such recommendations.
		With regards to the approval recommendations, I think if nothing else, what we have learned from the last 24 hours is that we need larger and longer pre-approval to do randomized clinical trials that include a broad spectrum of patients that are more representative of the real world, that assess hard clinical endpoints, all-cause death and Q-wave myocardial infarction, and that are adequately powered to address death or Q-wave myocardial infarction.
		For post approval device registries, we need extended follow-up and greater and timely public access to data.  I think we will all agree that the approval process is likely to benefit from greater rigor than the current standard of least burdensome pathway enacted by the FDA in the modern Act in 1997.
		With regards to operational recommendations, we need explicit standards of evidence that require robust trial design and statistical methodology that emphasize clinical importance over statistically significant.  Over the last 24 hours, we all have witnesses the fine art of post hoc science being elevated to a much higher level.  What happened to the good old fashioned, you know, the hypothesis driving the data and not the other way around?  We need to have universal criteria adopted by principle stakeholders alike, sponsors, investigators, regulators, reimbursers, professional societies and guideline committees.
		With regard to the administrative recommendations, we need a comprehensive post marketing surveillance, and the FDA ought to be commended for taking the initiative; accurate, user-friendly point of care; easily trackable and perhaps electronic.  We need to balance private versus public interests.  We need to encourage innovation without compromising public policy, which is the original mandate of the FDA.  We need incentives to encourage compliance and education.  I realize the FDA does not have the mandate to guide clinical practice, but they can leverage their relationship with the industry and the professional societies to come up with so me best practice guidelines that mitigate unnecessary risk.  We need to have consistent public policies.
		Off-label use fo drug to optimize on-label use of drug is somewhat inconsistent.  And what's bad for spinach may also be back for stents occasionally.  The additional targets:   therapeutic reform.  The crux of the debate here is the over-utilization of revascularization -- the medical therapy versus revascularization therapy.  We cannot have a debate between bare-metal stent and drug‑eluting stent without addressing the root cause.
		We need tort reform.  We need to change the current standard of evidence from the community to evidence-based best clinical practice standard.  We need fiscal reform.  We need reimbursement incentives to encourage optimal utilization and reward evidence-based clinical practice.
		All of this is going to take a lot of resolve amongst all the principle stakeholders.  And that will take a lot of willpower.  And willpower is rather ethereal as Mark Twain observed nearly 100 years ago.  Willpower lasts about two weeks and is soluble in alcohol.  And I'm going to conclude with a with a caveat.  We should not allow inflated expectations of benefit to preclude objectivity or the need for vigilance against unanticipated harm.  Thank you very much.
		CHAIRPERSON MAISEL:  Thank you very much for your comments.  The next speaker is Jeffrey Moses.
		DR. MOSES:  Thank you.  I am here substituting for Marty Leon which is not an infrequent role I play.  These are my disclosures.
		I'm hear really to speak as a practicing interventional cardiologist deeply involved in the clinical care of patients. And first of all, I just wanted to thank the FDA for convening this panel, because the environment out there because of the negative characteristics portrayed in the press has really has really frightened and referring physicians and is now,, at this moment, I believe seriously compromising the interventionalist's ability to deliver optimal therapy to very many patients.  So I think we ought to think about four questions.
		First of all, the first question is, what are the alternatives to DES treatment.  Now let's go back to bare-metal stents, and let's not lose perspective on what in-stent restenosis was about. This is diffuse in-stent restenosis, unique pathophysiologic process.  Those were introduced by bare-metal stents that we struggled with for well over a decade.
		The cost of it, if applied to a current utilization of PCI would lead to worldwide 300,000 clinical events a year and ultimately to about 100,000 bypass surgeries with refractory restenosis in tens of thousands of patients.  The economic burden is non-trivial.  With a 70 percent use of bare-metal stents and current utilization rates, with a recurrence rate estimated from at least the Centers of Medicare and Medicaid of 14 percent, the burden within the healthcare system would be over $1 billion dollars.
		Now there's been data presented here, and there's some recent data also, recently published in peer review journals indicating that, you know, ISR is not a benign entity with approximately 10 percent of patients in a recent series presenting with unstable angina or not, or infarction non-Q and Q-wave here in the 10 percent range.  Importantly, from a large center, the Cleveland clinic, again, with about a 10 percent MI rate, the consequences of treatment yielded 8 procedural deaths, a .7 percent mortality rate indicating this is indeed not a benign entity.
	But I think something that's lost here as well is not just the frequency of restenosis but the quality of restenosis.  All restenosis isn't the same.  Dr. Mehran, seven years ago, proposed a categorization between diffuse and focal restenosis, and we know the consequences of the different restenosis patterns are non-trivial.  The majority of restenosis in bare-metal was diffuse, and as you can see, the recurrence rates with diffuse patterns range from 35 to 80 percent in that case.  And if you look at MACE rates here, from one study of 500 patients going out to 2 years, whatever solution you selected in terms of interventional or surgical solutions, the MACE rate for restenosis was over 50 percent at 2 years indicating the hazards that this entity actually produces.
		Importantly, our primary solution beyond just interventional procedures in radiation turned out to be a temporary one at 5 years.  As you can see, the TLR rates and the MACE rates converged between radiation therapy and placebo.  We didn't have that solution.  And importantly, in the refractory patients, even when we introduced, secondarily, drug‑eluting stents in non-radiation failure patients, as you can see, the TVR rate in this registry was high in the range of 30 percent.
		Now what is the incremental efficacy of DES with on-label and off-label cohorts?  We've seen a lot of data today.  These slides, of course, are familiar in terms of the randomized trials.  And unfortunately, all we're going to have for the foreseeable future are these 9 randomized cohorts in terms of well qualified data to really analyze the difference between bare-metal and drug‑eluting stents.
		But importantly and no matter what your debate is about, real world or non-real world, these whisker plots of a 4-year follow-up in terms of the sustainability from the CYPHER trials which are also reproduced in the TAXUS trials demonstrate a profound effect rarely not seen in clinical medicine in terms of the reduction of this clinical entity.  Expanding it to "off-label use", I think the most complex cohort we can cite that we know of in a well-characterized registry is the ARTS II data, now extended out to 3 years, and this is a group of patients compared to the randomized ARTS I trial; however, in migration of technology and clinical practice, this group had a much higher rate of three vessel disease, diffuse disease an, importantly, had an average of 3.7 stents per patient.  In spite of this, when you compare it to the bare-metal era, you can see a profound reduction in restenosis and MACE rates extending out now to 3 years that are comparable to that of bypass surgery with no evident compromise in safety.  This is replicated in real world registries here in the United States.  This is the stent registry.  Almost 800 multi vessel patients, again, in the real world had only a 5 percent TVR rate with no difference between the two drug‑eluting stents.
		Now how do we balance safety and efficacy?  Do we believe it's still in favor of drug‑eluting stents?  Well, these plots are certainly very familiar to everyone on the panel.  After two days of hearings, here are the thrombosis rates with 4-year follow-up in the 9 trials.  And, of course, after 1 year, there were 14 events versus 2 events.
		But when we look at it differently from intention to cheat perspective, which is really all you care about when you're dealing with your patients, suddenly with the definite and probable ARC definitions, we see that the overall thrombosis rates are not very different.  As a matter of fact, over 4 years, it still slightly favors the drug‑eluting stent here in CYPHER, and the differences in very late are actually narrowed.  There are 7 events here and 4 events here.
		Now why is that?  Well, the difference here is because under the analyses of the trials, all patients were censored after an intervention, and secondary events, which predominantly happened obviously in the bare-metal group, were eliminated from the analysis.  When you include them, the consequences of the treatment of that actually yields a much narrower difference between these two in this randomized cohort.
		Now we have our clinical practice example from our database at CRF.  When we analyzed Dr. Roxanna Mehran analyzed this 6 months before the introduction of the CYPHER into our clinical practice, we had 282 patients with 311 ISR lesions that we treated.  Starting 6 months after the introduction of CYPHER, it was down to 39 percent patients, an 86 percent reduction.  Now this reflects a bias of a referral center that was noted for treating refractory in-stent restenosis.
		But importantly, again, emphasizing the difference in the qualify of the restenosis, we have diffuse in-stent restenosis in the bare-metal group of 64 percent.  This has clinical consequences:  4.2 percent death, TLR rate of 27 percent, a total MACE rate at 1 year of 34 percent in that group.  In contradistinction, when we looked at the restenosis in the CYPHER stents, again, as per actually the clinical trials, 86 percent of it was focal.  And consistently with the classification scheme, when you looked at those 39 patients at 1 year, there was no MACE.
		So the secondary event rates have consequences, and I think when we analyze the data and look at the balance between risk and benefit, I think  you have to take that into the calculation.  Importantly, David Cohen has done a risk cost benefit analysis with more contemporary data.  As you can see, the green, is the diabetics and the non-diabetics shows that in 15 to 20 percent of the patients only is it not cost effective.  And this pretty much parallels the high-risk groups in our clinical practice.
		So what's the current dilemma for clinicians?  We don't know which patients are at the highest risk.  We don't know the optimal duration of antiplatelet therapy.  We don't know the consequences, and we will don't know that, even after the hearings today, of using long-term antiplatelet, dual antiplatelet therapy.  We don't know if it's a continuous linear hazard function, and does it happen more frequently in the real world, and are there other patient-related factors such as drug resistance besides adherence which relate to it.  So DES, I believe, are unquestionably the standard of care.  The treatment alternatives are not good when comparing it to bare-metal stents.  Given the data available, there does not seem to be evidence that DES causes a higher frequency of overall death and MI.  But DES are different and they do have a slightly higher frequency of very late thrombosis, and the prolonged obligatory dual antiplatelet therapy use and the attendant anxiety is causing clinical practice problems.
		What should we do?  Well, we certainly are recommending a more considered use of DES, not one stent with bifurcations, a very specific scrutiny of the ability of the patients to adhere to dual antiplatelet therapy.  And there are significant data gaps which we're trying to fill requiring new, much larger clinical trials, as the previous speaker enumerated.  And there are new DES technology which may reduce these allayed safety concerns, and we should bring them to clinical practice as soon as we have the evidence.  Thank you very much.
		CHAIRPERSON MAISEL:  Thank you very much.  Our next speaker is Peter Smith.
		DR. SMITH:  Thank you.  Here are my disclosures.  We've heard a lot about comparing one stent to another in the last two days.  We're here to talk about the issue of not being stent safety and benefit but patient safety and benefit.
		Here is a description of the treatment choices at Duke University for the last 20 years showing initially in the early era 20 percent of patients were treated with PCI.  The landmark introduction of bare-metal stenting and drug‑eluting stenting led to marked increase of such that now 60 percent of patients are being treated initially with intervention percutaneously.  Only 15 percent with coronary bypass in these 26, 000 patients.
		A current perspective is that America's number one killer is predominantly treated with percutaneous methodology that has not been demonstrated to provide a survival advantage.  Drug-eluting stent introduction has broadened the indications and increased the frequency of percutaneous intervention.  And this is particularly important for the treatment of multi vessel coronary disease where substantial quality of life and survival benefits have been conclusively demonstrated for bypass grafting.
		There's a growing body of evidence that indicates that drug‑eluting stenting associated with increased mortality risk compared to BMS.  And for the most important clinical outcome, DES is, at best, non-inferior to bare-metal stenting.  Therefore, comparisons of BMS to CABG, the standard of care is the relevant issue.  And fortunately, there's abundant long-term data available.
		Here's one of four peer-reviewed published observational trials, this one published in circulation from Northern New England:  14,000 patients, Kaplan-Meier curves demonstrating significant survival advantage for coronary bypass grafting compared to PCI in three vessel disease.
		Here's data from the ROBUST New York State audited database:  23,000 patients with three vessel disease published in the New England Journal of Medicine showing a significant survival advantage for coronary bypass grafting treatment compared to stenting at 3 years.
		At Duke we've analyzed 18,000 patients treated in 1986 to 2000 with significant coronary disease, each treatment applied fairly equally between initially medical therapy, percutaneous intervention or bypass grafting.  This was published two months ago.  We evaluated these patients by grouping them according to coronary artery severity creating groups of low, intermediate and high severity roughly corresponding to one, two and three vessel disease.
		And here's the Kaplan Meier outcome data for high severity coronary disease.  Bare-mental stenting versus coronary bypass grafting -- bypass grafting in red show it is significant and increasing over time.  Survival advantage compared to bare-metal stenting in the black -- up to 7 years of follow up.
		Why is bypass grafting better than PCI?  PCI treats the isolated proximal lesions.  Coronary bypass grafting bypasses the proximal two-thirds of the vessel where current lesion and future threatening lesions occur.  This advantage of bypass grafting will persist even if stent restenosis is 0.  CABG provides complete revascularization.  Grafting and graft failure does not effect the native coronary circulation which persists.  Coronary bypass risk increase little with increasing coronary disease severity.  PCI risk appears to be additive increasing arithmetically with each stent unlike CABG.  And CABG survival has been shown to benefit increase, to increase with increasing severity of coronary disease.
		Are we making an impact on patients?  In this period of time at Duke, we obviously are making an impact with either PCI or CABG.  You can see that for a low severity disease, we're adding some months, not significantly.  Intermediate severity sees a significant increase.  But the majority of the benefit is occurring in high severity disease patients where we're adding about two years of life for every 17 years of follow-up in this series.
		And what modality is providing this benefit.  You can see that comparing bypass grafting to intervention here, for low severity disease and intermediate severity disease, there's really not much difference in impact, but coronary bypass grafting is providing the benefit for the high severity disease patients here shown significantly.
		And how has this changed as both techniques have advanced over time?  In the early angioplasty ere shown here, there really wasn't much significant impact difference between coronary bypass grafting and percutaneous intervention, a slight trend toward CABG in high severity disease.  As both techniques advance, the significant advantage of coronary bypass grafting compared to percutaneous intervention became apparent in the severity disease patients.  And then surprisingly, when we looked at the bare-metal stent era data, we saw point estimate trends favoring bypass grafting even for low and intermediate severity disease, and an extension of the significant advantage that bypass grafting provides compared to intervention for high severity coronary disease.
		Thus, we were as surprised as the author of this quote appearing on the cover of Lancet, "In view of the survival benefits shown for coronary bypass grafting, the real controversy is why patients with symptoms and anatomy known to benefit from the procedure are still submitted to percutaneous coronary intervention."  And that's what's happening.
	Here is what's happened at Duke.  In 25 percent of the patients who under cath who have high severity disease.  That's the incidence.  There are 6,000 patients.  In the angioplasty era, only 10 percent of patients were receiving PTCA, 60 percent CABG in high severity coronary disease.  The introduction of bare-metal stenting did not impact this.  It was still only 10 percent, but the introduction of drug‑eluting stent and its promises led to a tripling of the application of percutaneous intervention for high severity coronary disease.  And for the first time, less than half the patients were initially offered coronary bypass grafting.
		How can this happen with the absolute survival advantage that I've shown you from these observational data on 40,000 patients showing that at 1 year, there's a 2.3 percent advantage, absolute advantage in bypass grafting versus stenting; 4.3 percent at 3 years; 5.1 percent at 5 years.  That's 1 out of every 20 patients who are treated with PCI that would have survived if they had had coronary bypass grafting.
		Thus, the significant benefit for CABG has been demonstrated and appears to increase with increasing follow-up.  When you translate into real world application, assuming that drug‑eluting stents are equivalent to bare-metal stents for the important mortality outcome, we get the following figures:  approximately 1.5 million drug‑eluting stents are implanted worldwide, 850,000 in the U.S.  Using data from the DEScover trial about stents per patient in the incidence of PCI and three vessel disease, we estimate that 160,000 are treated worldwide and 92,000 in the U.S. with drug‑eluting stents.  This translates into premature death at 1 year 3,800 patients worldwide, 2,000 in the U.S. premature death, and 16,000 patients at 3 years, 9,000 in the U.S.  Annualized this is 6,500 worldwide, 3,600 in the U.S.
		And I call your attention to this figure.  We heard a lot about rare outcomes yesterday.  This is not rare at all.  And I'll rephrase the question that was asked yesterday.  Am I more likely to be dead if I am treated with a drug‑eluting stent?  We would answer that the answer is yes if you have three vessel disease and are unable to have an off-label drug‑eluting stent or bare-metal stent implantation rather than CABG.
		I'm going to leave you with this figure from the preceding slide and talk about industry comments yesterday where we leaved that off-label extension was meeting an unserved need.  We're not certain whose unserved need that is, but we're fairly certain that it's not the need of our patients.  Thank you.
		CHAIRPERSON MAISEL:  Thank you very much for your comments.  Our next speaker is Robert Guyton.
		DR. GUYTON:  Thank you.  I appreciate the opportunity today to talk about the history of evidence-based coronary revascularization.  Can we identify our mistakes and not repeat them?  There are problems with randomized trials of PCI.  They're underpowered with low-risk patients, carefully selected with surrogated composite endpoints, and importantly misinterpretation of trial results.  The problems began with the BARI trial.  Of the administratively suitable patients, 72 percent were excluded because they were not good PCI candidates.  BARI was really a study of the 25 percent of multi vessel disease patients most suitable for PCI.  And even then, less than half of these were enrolled.  BARI also had a problem with power.  BARI was powered to detect a 2.5 percent mortality difference with 2,400 patients intended for enrollment, but only 1,829 were actually enrolled.
		Overall, the 5-year mortality difference was 2.9 percent favoring coronary  bypass, higher than the targeted difference.  But this was not statistically different because enrollment was lower than originally intended.  The erroneous conclusion of clinicians in the media was no mortality difference between PCI and coronary bypass in multi vessel disease.  In the world of statistics, this is not a misdemeanor, this is a felony.
		BARI had continued problems.  At 7 years, the PCI mortality was statistically higher than coronary bypass by 15 percent.  The response of the PCI advocates was this:  Let's take out the diabetic patients.  And I've heard this statement a thousand times.  Once we take out the diabetic patients, BARI shows us that PCI survival is equal to CABG survival in multi vessel disease.  This, my friends, is a compound felony.  The meta analysis of 9 randomized trials of PCI versus CABG support the 7-year BARI data, and as you can see, it takes 5 years to get these significant improvement with benefit from coronary bypass.  The response to this data:  That's owed to technology, stents have changed the world.
	What about stents?  Let's look at the most quoted trial of stenting versus coronary bypass,  The ARTS trial.  This was mostly European funded by industry.  It was a very PCI-friendly trial; enrollment only if equivalent revascularization could be achieved with either method.  Only 5 percent enrollment.  There was a problem with timeliness of therapy.  Treatment with stents occurred 11 days after randomization.  Treatment with coronary bypass, 27 days after randomization with 3 deaths, 4 MIs, and 1 stroke in the coronary bypass group, a .5 percent mortality, and more than 1 percent MACE before treatment, but not in the stent group.
		If you look at the 5-year outcomes, looking at outcomes after the procedure, there was a relative risk for mortality favoring coronary bypass of 1.13.  For the composite endpoint of death, MI or stroke, the relative risk favoring bypass was 1.33.  At the conclusion of the paper, the abstract was this:  At 5 years, there was no difference in mortality between stenting and surgery for multi vessel disease period.  Furthermore, the instance of stroke and myocardial infarction was not significantly different between the groups.
		This unqualified statement ignores the fact that the study was not powered to evaluate death or MI or stroke and ignores the trends post procedure favoring coronary bypass.  This conclusion is not justified.  It's worse than wrong.  It's powerfully misleading.
		Now one of the coauthors of the 5-year trial was the vice president of the sponsoring stent company.  I don't fault him.  He did his job well.  I do fault the other authors and the editor of the journal for this unqualified statement.
		Another important but unpublicized study was the stent or surgery trial.  A thousand patients from Europe and Canada, also funded by industry, revascularization was indicated and appropriate by either strategy.  A broader selection of multi-vessel disease patients than the equivalent revascularization of the ARTS trial, at 2 years, a 2 percent mortality in the coronary bypass group, a 5 percent mortality in the PCI group.  A 5-year follow-up recently showed that this 3 percent difference at two years had increased 4.3 percent at 5 years.
		Now we owe this 5-year follow-up to a small grant from the British government.  The stent companies that funded the trial declined to fund the longer follow-up of this trial.  The response to the early stent or surgery results?  "But those were bare-metal stents, drug-eluting stents have changed the world."  This is not so.  There is no mortality benefit of drug‑eluting stents compared to bare-metal stents.
		A final problem with randomized trials:  Surrogate endpoints can be hazardous.  The RAVEL trial showed a dramatic decrease in restenosis, 0 restenosis.  Yet this doesn't translate into a survival benefit at 5 years.  The stents are working but the patients are dying, and that's why we're here today.
		Are stents excessively utilized?  We must look to robust comprehensive databases allowing risk-adjusted review of patient subsets.  The most important, I think, is the New York State registry which showed a relative excess mortality at 3 years with initial stenting versus initial bypass in all subgroups of patients with multi vessel disease from the simplest two vessel disease at 24 percent excess mortality to complex triple vessel disease with 46 percent excess mortality.  Two Mayo Clinic cardiologists commented on this paper:  "We are reminded of the limitations of underpowered trials, particularly in lower risk patients, and these data show an impressive advantage of surgery in the overall cohort and most subgroups."
		Where is the answer?  Do we need more randomized trials?  The basic problem, my friends, is that in clinical trials of high-risk procedures, clinicians are advocates for their patients, and they honor their moral obligation from development report to first, "do no harm" and secondly, to "not injure one person regardless of the benefits that might come to others."  The patient is enrolled only if the clinician honestly believes that the patient will not be harmed by randomization.  The result is selected enrollment of low-risk patients.  I personally witnessed in CASS in the EAST trial and now in the FREEDOM trial.  But these selected patients do not represent the broader population for whom data is needed.
		There will be limited benefit from more randomized trials.  We need a comprehensive database for treatment of coronary disease that is sufficiently inclusive that appropriate therapy can be determined in various patient subsets.  Emphatically, we do not need just another registry of stent thrombosis.  The last thing we need is a registry that focuses on yet another surrogate endpoint.
		A final point, the issue of informed consent.  In 1981, I stood outside the room of a patient, and I heard Andreas Gruentzig say, I can fix your blockage with this catheter, or I can have Dr. Guyton crack your chest.  In 1981, I had no counterpoint.  There were no data.  In 2006, the PCI operator says, the drug‑eluting stents have solved the problem we used to have with restenosis.  Let us fix your blockages, now plural blockages, with the stents.  There is no difference in mortality, and we can always go back and do a coronary bypass if we have to.  I just don't want to crack your chest.  Notice Dr. Guyton is no longer in the picture.  I don't speak to the patient.  This is wrong.  The mortality is the same.  There are data.  Now all of us would choose stenting as the first procedure if mortality were the same as patients are being led to believe, but many patients would rethink their options if they could hear the surgeon say, for triple vessel disease, coronary bypass is the procedure that gives you the best chance of being free from angina, and if you have stenting as your first procedure, you have a 46 percent chance of dying in three years compared to coronary bypass as your first procedure.
		In conclusion, to guide future decisions, we need robust comprehensive databases of therapy in multi vessel disease patients, not more randomized trials of selected low-risk patients.  But patient protection and safety issues need attention now.  Drug-eluting stenting is inferior to coronary bypass in multi vessel disease.  The FDA has asked a specific question about labeling.  The labeling for drug‑eluting stents lists patient subgroups in whom the safety and effectiveness of stents have not been demonstrated.  The pivotal trials were single-vessel stenting procedures, but multi vessel disease not one of the subgroups listed.  It should be.  At the very least, better patient information is of paramount importance.  Thank you.
		CHAIRPERSON MAISEL:  Thank you very much.  At this point, I'd actually like to take a 15-minute break.  And Dr. Ferguson, we'll begin with you right after the break.
		(Whereupon, the above-entitled matter went off the record at 10:14 a.m. and resumed at 10:28 a.m.)
		CHAIRPERSON MAISEL:  Our next speaker is Bruce Ferguson.
		DR. FERGUSON:  Thank you.  The current situation with drug‑eluting stents, and in particular the possible increased mortality with the use of drug‑eluting stents, highlights several more generic issues for discussion.  The first centers around patient safety, what to do about existing patients and what to do about ongoing patients who would be candidates for drug‑eluting stents.  The second is the inability of RCT design and data to provide adequate information to address the problems that are coming up, highlighting the minimal post market data that are available and the high incidence off-label use.  And the third is the fact that unclear mortality data status mandates evaluation of on and off label drug‑eluting stent use versus other therapies for the same condition including medical, PCI, and surgical and the need for long-term outcomes.  Each of these issues has consequences.
		The first consequence has to do with a profound impact on patient safety related to the possible increased mortality with use of drug‑eluting stents.  There are uncertainties about patient management, which therapies to select, how to deal with Plavix and its discontinuation in a variety of non-cardiac conditions, uncertainties about focus of treatment, to what degree is there a patient-centric focus in current PCI practice, uncertainties about how data will address this issue should it come from randomized trials or registries or other data sources, and perhaps most importantly, uncertainties about patient communication.
		What are the drivers for current communication and what are the therapeutic risks and benefits that are currently being discussed with these patients?  The Society of Thoracic Surgeons is going to make three recommendations today, and the first is that informed consent communication that is accurate and complete is essential for patient safety.  A patient-centric focus of communication as mandated by the Institute of Medicine earlier this year is key.  Full and complete disclosure of risks and benefits should take place after diagnosis but before intervention.  Information disclosed should include all available objective data including long-term data and not just RCT data.  And this patient-centric communication is ideally conducted by a multidisciplinary team approach when there are multiple therapeutic options with presumed clinical equipoise as in medical, PCI, and CABG therapy for an underlying medical condition such as multi vessel coronary artery disease.
		The second consequence is that of a liability of incomplete information.  Indeed, the life cycle of potentially effective therapies is so short now that it is equal to or even less than the validation cycles for randomized clinical trial data and their dissemination and validation in the real world.  Moreover, expansion of indications off-label beyond RCTs compounds this information liability and, therefore, increases patient level risk.  For example, FDA labeling is based on pivotal RCTs of single-vessel stenting.  What are the implications of this for patients undergoing multi-vessel intervention.
		This liability of incomplete information highlights the need for new and more complete information.  We need contemporaneous real world technology use data, and we need observational populations representative of clinical practice to more completely assess medical and financial effectiveness of therapies.
		Indeed, CDRH's Postmarket Transformation Leadership Team Report from November 9th of this year highlighted this in Initiative #3.  And I quote:  "Maximize the FDA's ability to communicate information clearly and quickly to practitioners, patients, and consumers."
		The Society would like to suggest that there is an opportunity to share clinical information between specialty societies and the FDA to this end.  Indeed, this has already happened in the context of a Medicare FDA post-market evaluation of trans-myocardial laser revascularization from about 2 years ago where Medicare recognized at the end of the process that follow-up through the Society of Thoracic Surgeons' database was a mechanism that could be important and useful for follow-up.
		This FDA-Society information collaboration has a number of potential advantages.  First, there are major observational database systems already in place.  The Society of Thoracic Surgeons' Adult Cardiac database is a validated, audited data repository of over 3 million patient records collected routinely from over 750 sites doing cardiac surgery in this country.  This database has documented that the overall risk-adjusted mortality in 2005 for all-comers for coronary bypass surgery was less than 2 percent, and the mortality for elective multi vessel intervention was less than 1 percent.
		There is already established collaboration with multiple state databases and reporting systems such as Massachusetts, California, and New Jersey.  There's a track record of robust scientific analyses.  These databases have been the basis for society-led quality improvement efforts and are now the basis for pay for performance and public reporting initiatives.  They are representative of real world clinical practice.  And they have a greater degree of objectivity and scientific integrity than the registries sponsored by device companies.
		The second STS recommendation is that the FDA, as part of their postmarket transformation, should develop data partnerships with professional society-led databases to provide data on important new technologies where available.  And moreover, the FDA should influence and engage technology companies in the support of these follow-up efforts.
		The third consequence merits additional consideration.  The absolute excess mortality with stent therapy versus coronary bypass grafting in multi vessel disease to the tune of greater than 3,600 deaths per year, as indicated by Dr. Smith, highlights an unacknowledged lack of clinical equipoise that's existent.  At the patient-centric level, survival advantage is being withheld.  At the FDA and Medicare level, the ability to assess effectiveness of new technology will continue to be limited until all aspects of equipoise, including long-term outcomes data, can ultimately be evaluated.  This unacknowledged lack of clinical equipoise is now established as clearly important in considerations of multi vessel coronary artery disease therapy.
		FDA professional society partnerships would strengthen the postmarket transformation program as follows:  Information for this program and its quality will, in part, be based upon the consistency of use of new technology in evolving every day clinical practice.  For example, a multidisciplinary informed consent process would positively influence this huge consistency.  There are challenges to this idea, but they can be solved.  Long-term follow-up data will be necessary to evaluate new therapies with clinical equipoise to existing therapies.  Funding is a challenge in that currently these provider-led databases are entirely supported by the providers.  And long-term patient follow-up mechanisms in the United States are effected by current HIPAA and other regulations which make long-term patient follow-up difficult.
		Nevertheless, the STS would like to recommend active robust comprehensive databases should be developed between the FDA and professional societies as part of the transformation program.  In these partnerships, the FDA can influence funding and regulatory issues for the societies, and the societies can influence adoption and consistency of use of the new technologies for the FDA.
		Finally, the excess mortality in multi-vessel disease with PCI versus CABG mandates that in the FDA labeling, multi-vessel disease should be included in the patient subsets in whom the safety and effectiveness of stenting has not been established.
		In summary, a multidisciplinary patient-centric disclosure prior to intervention will optimize patient safety surrounding new technology introduction and adoption.  Secondly, the FDA should explore information collaboration opportunities with society-led databases where they exists.  And finally, active robust comprehensive databases should be the bases of partnerships between the FDA and professional societies to assist the FDA in evaluation of patient safety and clinical benefit issues surrounding new technology adoption into every day clinical practice.  This is a way, and maybe the only way, that patients, providers, industry, and the FDA will get the data that they need.  Thank you.
		CHAIRPERSON MAISEL:  Thank you very much.  Our next speaker is Timothy Henry.
		DR. HENRY:  Good morning.  My names' Tim Henry form the Minneapolis Heart Institute, and I appreciate the opportunity to discuss the impact of drug‑eluting stents in ST-elevation MI in data from the Minneapolis Heath Institute Level 1 MI Program.  This is a program for comprehensive of ST-elevation MI that was developed initially in a pilot program in 2002.  The current program began in 2003.
		The goals were to standardize care, which we felt would improve outcomes; importantly, to develop a research network of community and real hospital, so there's a comprehensive database that's been involved since 2003.  It would allow the implementation in the data as well as including a quality improvement program.  The overall goal is to allow safe transfer of ST- elevation MI patients with a total door to balloon time of less than 120 minutes, which was the AHA recommendations at the time.
		The key to the program is the diagnosis is made by an emergency physician.  There are currently hospitals that have been trained.  The data that I'll show you today is 1,121 consecutive patients over 39 months.  Importantly, we currently are treating more than 50 ST- elevation MI patients per month, and the inclusion criteria are all patients with an ST- elevation MI less than 24 hours from treatment or a new left bundle branch block, and there are no exclusions including out-of-hospital cardiac arrest and cardiogenic shock.
		The data shown here, the 30 hospitals in blue, is what we call Zone 1, which is out to 60 miles, and Zone 2 is 210 miles away from Minneapolis.  The demographics are here and are important in that 14 percent of the patients are over 80 years old, 12 percent of the patients have cardiogenic shock, 10 percent of the patients have had a cardiac arrest to arrival in a cath lab, and 7 percent have actually been intubated prior to BCI.  So it's the sickest registry of ST- elevation MI patients that's been reported, because it includes all patients.
		The overall mortality at 1 year has been quite remarkable with a standardized approach and rapid transfer.  The overall mortality at 1 year is 7.6 percent, but the cardiovascular-related mortality is 5.8 percent.  On that background, we look at two questions on the role of drug‑eluting stents in these patient population.  First, the percent of patients with ST- elevation MI who now present with stent thrombosis, and the second will be to determine the safety and efficacy of the use of drug‑eluting stents in these patients.
		So the first is, again, of the 1,177 consecutive patients, 218 patients have had a prior PCI, and of those, again, all patients with documented ST- elevation MI, 54 had a culprit lesion that was within a previously placed stint.  If you look at the data on here, over time, you see that in 2003, the percentage of our ST- elevation MIs that were due to stent thrombosis was 3.5 percent and actually included 1.8 percent drug‑eluting stents, mostly those patients that were in clinical trials.  That dropped slightly in 2004 to 3 percent, but then increased in 2005 to 4.6 percent.  And in 2006, currently it's 6.7 percent of our ST- elevation MIs are related to stent thrombosis.  And you can see the contribution of bare-metal stents and drug‑eluting stents there.
		Shown here on the graph, you'll see that the incidence of bare-metal stents has stayed relatively stable at the 1.5 to 2 percent whereas it has climbed with drug‑eluting stents.  Now importantly, the timing of stent thrombosis with the two groups, I think, provides some interesting insights.  You'll see on this slide that 80 percent of the patients who present with bare-metal stent thrombosis occur at greater than 1 year including patients who present out to 5 and 6 years post bare-metal stent placement, which is not really current knowledge.
		If you look at the drug‑eluting stents in contrast, 1/3 occur less than 30 days, 1/3 occur between 30 days to 1 year, and 1/3 occurred greater than one year.  Now the important point that is in contrary to what patients have previously reported is the overall mortality of the patients who presented with stent thrombosis is actually only 1.9 percent, which is only 1 death, in contrast to the total group, which is 4.8 percent.
		So in conclusion of the first half is the percentage of patients with ST- elevation MI due to stent thrombosis clearly has significantly increased from 2003 to 2006, but it occurs in both bare-metal and drug‑eluting stents and the timing and pathophysiology is different.  In contrast to previous reports, the mortality does not appear to be higher, but in fact would appear to be lower by this presentation.
		The second point then was to look at the long-term outcome of drug‑eluting stents in the patients who were initially placed for presentation of ST- elevation MI, and this includes 858 consecutive patients with ST- elevation MI patient during the same time period.  The stent type and the IIb/IIIa inhibitor use was at the discretion of the interventionalist.  The patients are classified on the stent that was deployed in the culprit vessel.  We kept track of, and continue to keep track of for 5 years, the major adverse cardiac events as well as stent thrombosis defined as in basically all three:  definite, probable, and possible.
		If you look at it, there is some baseline differences in that patients that had bare-metal stents were older, had less likelihood to have dyslipedemia.  Importantly on this, there are no statistical differences, but you'll see there are strong trends for higher incidence of cardiogenic shock in the bare-metal stents, cardiac arrest in patients with bare-metal as well as higher peak CKs, although non-statistically significant.  And no significant differences between those who got a CYPHER or a Sirolimus or paclitaxel stents.
		The overall event rates of the patients who had stents placed are shown here, and you'll note that the mortality is significantly for bare-metal stents at both 30 days and 1 year.  No significant difference between the two drug‑eluting.  If you look at major adverse cardiac events, again, significantly higher with bare-metal stents as well as higher with paclitaxel stents versus Sirolimus at 1 year.  And finally, if you look at stent thrombosis which includes all three definitions, the incidence is actually quite low with Sirolimus in particular and significantly lower than the other two groups.
		So if you look at the Kaplan-Meier curves, you'll note here the immortality in red for the bare-metal stents compared to the two drug‑eluting stents is significantly higher than both.  If you look at the MACE rates, you'll see a likewise similarity as what was shown on the previous slide.  And finally, if you see the stent thrombosis curves, it is important.  Because if you'll note the curves in paclitaxel, there is an increase but it occurs predominantly after one year.  The majority of these patients were not on clopidogrel at the time.
		We then did a propensity analysis to, as best we can, control for the covariates, and the covariates that you see that were included were here.  Because of some missing data, the propensity is on a slightly reduced cohort of 747 patients.  Overall, when you do the propensity analysis and you do the adjustment, you'll see in terms of the mortality, there is a significant reduction with the Sirolimus stent compared to bare-metal stents that is actually very similar, both that and with MACE, which is very similar to what you saw in the randomized with both TYPHOON and SESAMI.  And likewise with MACE, you'll note that there is a significant reduction with Sirolimus.  There's also a reduction of Sirolimus compared to paclitaxel.
		And finally, in terms of stent thrombosis, when adjusted by the propensity score, you see again the slight increase in the paclitaxel which is related to events that occurred after 1 year and patients who are not on clopidogrel.
		So the caveats, of course, are that this is non-randomized data, but it is the largest registry for ST- elevation MI that I'm aware of, and there are significant baseline differences between groups.  It's clear that the patients receiving bare-metal stents were at higher risk relative to the patients who were on drug‑eluting stents which certainly could influence outcomes and which may not be completely controlled for by the propensity analysis.
		So in summary, in our experience, the drug‑eluting stents did reduce all-cause mortality compared to bare-metal stents and that the use also reduces MACE, and stent thrombosis was slightly higher, particularly in the paclitaxel group which occurred predominantly after 1 year.  After adjusting for propensity, it does appear that the Sirolimus, in particular, improved mortality and MACE.  Thank you very much.
		CHAIRPERSON MAISEL:  Thank you for your comments.  Our next speaker is Jim Gustafson.
		DR. GUSTAFSON:  Good morning.  My name is Jim Gustafson.  I'm with Possis Medical, a medical device maker in Minneapolis.  I want to address a specific patient subset for drug‑eluting stents, that is patients with thrombosed lesions.  The common consent of trialists is that large intracoronary thrombus makes for higher risk intervention and poorer clinical outcomes.  Those quotes appear in presentation slides that are available on the TCT MD website.
		The current approved IFUs for both CYPHER and TAXUS have a list of lesion and vessel characteristics that are off-label.  In both of these IFUs, the very first item on the list is patients with unresolved thrombus at the lesion site and number six on both lists also mentions thrombus.  It says, "Patients with a recent AMI where there's evidence of thrombus or poor flow."  We've heard several presentations in the last two days that address various off-label subsets but none have yet specifically addressed patients with thrombosed lesions.
		This is of interest to my company because Possis Medical makes the Angio-Jet Rheolytic thrombectomy catheter system.  This product was approved by FDA in 1999 for removal of coronary thrombus in native vessels and SVGs prior to stenting.  It's also marketed in the U.S. for thrombectomy in peripheral arteries, AV access grafts and just recently peripheral veins.  To date, nearly 300,000 Angio-Jet thrombectomy procedures have been performed worldwide.  More than half of these have been to treat coronary thrombus.
		Angio-Jet action uses tiny high-velocity water jets contained inside the catheter shaft to create powerful low pressure venturi forces that suck thrombus into the catheter tip and out of the patient's body.  This mechanism is called rheolytic thrombectomy.
		So, what evidence is there, including real world clinical experience, that characterizes the clinical risk associated with drug‑eluting stents in thrombosed lesions, and what does the evidence say about mitigating that risk.  Ths is what I will now briefly summarize, and I should point out here that all the information I have to present is public.  It's all been published in the medical literature or presented at major medical meetings or both.
		The first is this pre-clinical work by Dr. Elazar Edelman and his colleagues at MIT and Harvard published in circulation 2005.  This paper reports results of computational, in vitro and in vivo modeling of drug capacity, diffusivity and convective velocity in the presence of thrombus.  The conclusion of this work states thrombus opposed on stents creates large variations in drug uptake and can act to either increase or decrease wall deposition according to the clot and stent geometry.  Arterial deposition of drug from stents deployed in clots will be highly variable and unpredictable unless the clot can be adequately controlled or removed.  So this work suggests that intracoronary thrombus can alter drug deliver in unpredictable and undesirable ways and that to avoid this, presenting thrombus should be removed before placing a drug‑eluting stent.
		As for clinical experience, in July of 2006, a supplement was published in the Journal of Invasive Cardiology on the subject "Current Experience and Role of Rheolytic Thrombectomy and the Management of Acute MI with Large Thrombus Burden."  This supplement presented a compendium of real-world clinical experiences from several high-volume centers.  Specifically, the supplement presented 6 independent clinical experiences including 4 retrospective, 2 prospective, 5 single-site, 1 multi-site, 4 single-arm with concurrent reference samples, 1 case control, and 1 randomized.
		Overall, these experiences comprised 625 Angio-Jet patients and over 2,400 reference sample patients.  All the patients in both groups had STEMI.  About 2/3 of the patients in each group received drug‑eluting stents.  But since most of these experiences involved elective use of Angio-Jet thrombectomy, the Angio-Jet patients had thrombus at baseline suggesting that the Angio-Jet patients had a higher baseline risk profile.
		This chart displays in-hospital mortality, a common endpoint for the various experience as reported.  The Angio-Jet patients are in blue, and the reference patients who did not receive Angio-Jet are in red.  And as you see, in every experience, in-hospital mortality is lower for Angio-Jet patients.  And if you just add up the patients and the events, the patients who receive Angio-Jet thrombectomy before stenting exhibited lower in-hospital mortality, 2.6 percent versus 4.6 percent for the reference sample, a significant difference.  This is, of course, just a simple first cut sort of look, but these observations are now the subject of a larger and much more formal meta analysis that we hope to see published in 2007.
		Now within the JIC supplement was a large patient experience authored by Dr. George Sianos and his colleagues of the Thorax Center in Rotterdam.  This experience offers a more detailed look at how Angio-Jet thrombectomy may improve outcomes in patients with thrombosed lesions who receive drug‑eluting stents.  To date, this experience from the Rotterdam center has been presented in these five venues in 2006 and what I will now summarize is an amalgamation of those various presentations.
		The analysis considered 900 sequential patients treated from April 2002 through December 2004.  All of these 900 patients had  STEMI less than 12 hours, 90 percent received drug‑eluting stents.  The drug‑eluting stents patients received standard antiplatelet therapy as shown on this slide.  The average follow-up was 18 months.  Also, of these 900 patients, 266, 30 percent, had baseline TIMI thrombus grade 4 after wiring and before treatment.  This grade of thrombus means that on angiogram, the longest thrombus diameter is at least as long as twice the vessel diameter.  This is typically called large thrombus.  And of these 266 patients with large thrombus, 75 received Rheolytic thrombectomy with Angio-Jet followed by direct stenting.  The other 191 patients received direct stenting without Angio-Jet.  Angio-Jet use was at the discretion of the operator, and it was the only thrombectomy used at the Thorax Center during this time.
		In this experience, stent thrombosis was defined as an acute clinical ischemic event with angiographic confirmation of complete or partial occlusion within the stented segment and with evidence of thrombus and reduced antegrade flow.  This definition is very similar to the one that ARC has developed for definite thrombus.
		The analysis observed first that patients with thrombus grades lower than 4 exhibited the same results, same outcomes with regard to stent thrombosis.  Therefore, those patients were put together into a single unified group.  Here we see the Kaplan Meier estimates of the stent thrombosis rates compared between the two groups.  The patients with large thrombus grade 4 at baseline experienced a higher rate of stent thrombosis than did the patients with smaller or no baseline thrombus, 8.2 percent versus 1.3 percent out to 2 years, a significant difference.  These results suggest that large presenting thrombus is an important risk factor for subsequent stent thrombosis.
		Then the analysis looked at just these large thrombus patients and split them out by whether or not they received Angio-Jet thrombectomy and compared them.  And here you see the Kaplan Meier actuarial estimates of the occurrence of stent thrombosis in these large thrombus patients at baseline.  In the 75 patients who received Angio-Jet thrombectomy before drug‑eluting stent, there were no stent thrombosis events out to 2 years, but in the  191 patients who did not receive Angio-Jet thrombectomy, the 2-year stent thrombosis rate was 11.3 percent, a statistically significant difference that favored the Angio-Jet arm.
		Here we see the results for survival in these same patients.  Again, a statistically significant difference favoring Angio-Jet thrombectomy for the patients with large presenting thrombus who receive Angio-Jet before treating with a drug‑eluting stents.  And these are the overall MACE results combining death and repeat MI and any revascularization including for stent thrombosis.  Again, the difference is significant and favors the Angio-Jet arm.
		The conclusions from this Thorax Center experience include that in STEMI patients receiving drug‑eluting stents, large unresolved thrombus at baseline is a major risk factor for stent thrombosis and a driver of higher MACE.  Angio-Jet thrombectomy before DES in STEMI patients with large presenting thrombus significantly reduces stent thrombosis and MACE.
		In simple terms, we believe this pre-clinical and real-world clinical experience supports these conclusions:  Presenting thrombus complicates PCI; unresolved presenting thrombus negatively effects drug deliver in DES use; in real-world STEMI patients, large presenting thrombus is a risk for higher rates of MACE and stent thrombosis, but in these same real-world patients, Angio-Jet thrombectomy reduces stent thrombosis and MACE.
		Basically, to us these results suggest that for the patient subset with thrombosed coronary lesions, Angio-Jet thrombectomy can turn a high-risk off-label lesion into a lower risk lesion that is on-label for drug‑eluting stent use.  Possis Medical welcomes any opportunity to study additional real-world experiences to further confirm these findings.  Thank you for your attention.
		CHAIRPERSON MAISEL:  Thank you very much.  Our next speaker is Robert Hillman.
		DR. HILLMAN:  I want to thank the committee for the opportunity to present today and build on Dr. Michelson's excellent presentation yesterday.  My disclosure is I'm employed by Accumetrics, the manufacturer of VerifyNow^TM, the point-of-care assay for monitoring platelet function.
		As discussed by the panel yesterday, data from many studies, one analysis which is shown here from the CURE trial, have demonstrated there's a clear risk-benefit ration with the use of antiplatelet agents; namely, balancing efficacy and bleeding risk.  Therefore, it's important to understand the dose duration and timing of antiplatelet therapy used in conjunction with drug‑eluting stents.
		I think it's safe to say that noone here would consider warfarin chronically to patients without carefully monitoring the INR and adjusting the dose because of its significant intrapatient variability in therapy and consequences of it.
		Several publications have shown that clopidogrel therapy results in larger intraindividual variability in platelet inhibition in patients receiving both chronic and acute doses.  On the left panel, you would see the distribution of response after chronic dosing with 75 milligrams of Plavix.  On the right panel, you see the variability after a 600 milligram loading does prior to PCI with the red dots being non-responders as specified by the author.  Of particular relevance to the discussion of this panel, this variability in response has been shown to have clinical consequences including but not limited to stent thrombosis.
		Here's a case study from Professor Frans Norman in Munich that patients that underwent PCI for an occlusion in the LAD and circumflex.  The patient was sent home with 75 milligrams Plavix and exhibited no chest pain post treatment.  About three weeks later, the patient came in with a positive troponin and thrombus shown here in the circumflex.  The patient's platelet aggregation was tested and showed no response to any of the platelet agonists -- on the left, you can see the curves are actually just all very flat -- and then was loaded with 150 milligrams on the right, retested and showed a robust platelet inhibition to ADP.
		There have been several publications, which I don't have the time to discuss, some of which are highlighted here which link clopidogrel non-responsiveness to stent thrombosis as well as other cardiac events.  As a result of this and other data, the 2005 PCI Guidelines by the AHA, ACC and SCAI have recommended for the first time that patients at risk for subacute stent thrombosis be tested and their dose potentially increased if they are non-responsive.
		One of the stumbling blocks to routine measurement of platelet function at the bedside has been the absence of a simple-to-use quick and accurate way to measure it.  The VerifyNow^TM system, an FDA-cleared device, has been correlated to the reference standard, light transmission aggregometry provides one such alternative.  Running the instrument is a simple three-step processing using the dedicated instrument shown above (indicating.)  There are assays for aspirin, clopidogrel, and GP2b3a inhibitors.  You simply insert an assay device with all the re-agents, insert a vacutainer, and read the results in less than 5 minutes.
		I want to share with you data from an interim analysis of an ongoing registry that was recently published at the American Heath Association performed by Dr. Paul Tierstein and Matt Price of Scripps Clinic in La Jolla.  Very briefly, patients received Sirolimus eluting stents; platelet function was measured both at baseline and 12 hours post procedure; and the operator was blinded to results at all times.  These results show that patients with low inhibition and high platelet reactivity showed a significant association with stent thrombosis.
		And let me take you through this slide for a minute.  What you're looking at here on the left is the degree of platelet inhibition.  Here the post treatment reactivity, and you can see 3 of the 4 patients with high post-treatment reactivity and low inhibition exhibited stent thrombosis.  While this is far from definitive evidence, it illustrates the powerful information that can be obtained on this issue with a simple blood test.
		So what can be done about it?  One potential strategy proposed by Scripps, and in line with the guidelines that I spoke about a minute ago, is to increase the dose in non-responders.  In fact, data from Kastrati and colleagues in the ISAAR-CHOICE trial that was published at the ESC meeting as well as the recent AHA meeting showed that increasing the dose of Plavix to 150 milligrams decreases aggregation or increases inhibition in most, but not all, patients.  If you think about it, there are a few drugs:  statins, unfractionated heparin or warfarin where one size fits all.
		Switching briefly to aspirin, in discussions of dual antiplatelet therapy at the panel, there has been very little discussion of aspirin.  This slide from Chen of 464 patients followed post-PCI for almost 2 years show an increasing level of events in patients who are not responsive to aspirin as measured by VerifyNow^TM as compared to patients that are aspirin responsive.  So here's the aspirin non-responsive/responsive group and cumulative events as a function of time.  The question that this data raises is are these patients who are non-responsive to aspirin a subset of patients that need to be left on clopidogrel for a longer duration versus those patients who are responsive, and after a given time period, do not require dual antiplatelet therapy.
		In conclusion, the level of platelet inhibition at the time of PCI has a clinically relevant impact on outcome.  Even after appropriate loading or chronic administration of clopidogrel, platelet inhibition is sub-optimal in a large proportion of patients.  Monitoring of platelet inhibition at the bedside is now possible for the first time.  Monitoring will at least yield insights into the optimal dose, timing, and duration of antiplatelet therapy in conjunction with drug‑eluting stents.  To that end, we've sponsored the first major antiplatelet study called RESISTOR that's being run by Dr. Daniel Simon at Case Western Reserve.  And as announced a TCT, we are working in collaboration with Boston Scientific's stent registry in a study led by Dr. Greg Stone and sponsored, as I said, by Boston Scientific.  But there is still a tremendous amount of information that needs to be gathered in this area.  Thank you very much.
		CHAIRPERSON MAISEL:  Thank you very much.  At this point, I'd like to the panel discussion for questions for our previous eight speakers, the four right after the break and the four right before the break, if anyone has any questions.  Dr. Harrington?
		DR. HARRINGTON:  I have a question for Dr. Moses if he's still here.  Jeff, on one of your final slides, you put up some work from David Cohen looking at the cost effectiveness issue, and I think I recorded this right that you said approximately 10 to 15 percent of lesions may not be cost effective to treat with drug‑eluting stenting.  Could you explain that a bit more to me.  And particularly what I'm interested in is, how would that translate that into patients?  How many patient -- right now we've seen anywhere from 80 to 95 percent use of drug‑eluting stents in some of the registries form individual centers.  And I'm curious from the analysis that you quote how much that might translate into in terms of not cost effective to use drug‑eluting stents in what percent of patients?
		CHAIRPERSON MAISEL:  Before you answer, I'll just remind the panel that we are not charged with cost effectiveness or considering cost in our discussions today, but I appreciate your question and he can certainly answer.
		DR. MOSES:  Well, I mean the data really presented in order to emphasize given the, you know, the dynamics of the marketplace.  How -- with a -- that the low-risk patients are becoming less and less cost effectively treated with the bare-metal and that line is moving.  That's a separate issue from which patients are at high-risk in a clinical practice.  That's pretty much designed from the Caitlin Ho analysis which is really restricted to most of the patients enrolled in randomized trials almost from day one of the bare-metal.  But if you look a our clinical data from the patients that, say, we treat in a large medical center, those, you know, low-risk patients that I think are really the controversy here about who are you going to treat with bare-metal and not besides the ACS patients, that really constitutes a similar percentage.  But that's sort of a coincidence that the numbers are pretty much the same.
		CHAIRPERSON MAISEL:  Dr. Edmunds.
		DR. EDMUNDS:  This question is directed to Dr. Ferguson.  Yesterday, Dr. Baim of Boston Scientific alleged that the operative mortality of the coronary bypass surgery is between 5 and 6 percent based on historical data.  These are his slides.  Can you tell us, the panel, what the operative mortality is for coronary artery bypass surgery, all-comers, and if you have the data, three-vessel disease, according to the STS database and when this data was accrued and how many patients approximately it's based on?
		DR. FERGUSON:  The STS database has demonstrated a steady and relentless decline in operative mortality over the past 15 years for surgical revascularization both overall and in every single subset of patients.  As I indicated in the latest analysis which is a composite of 3 years worth of data, risk adjusted, 30-day mortality, from over 700 hospitals doing heart surgery in this country.  Overall, the risk-adjusted mortality is 1.95 percent, in that range.  And for elective cases, which are predominantly now multi-vessel disease, because we do so few single-vessel cases, it is just ticking under 1 percent.  And that's a national representative sample that combines data from all those hospitals.
		CHAIRPERSON MAISEL:  Dr. Lindenfeld?
		DR. LINDENFELD:  If I could ask Dr. Kong one more question?  I know you were -- it was previously but I'm just -- in your very nice study, there's a big difference in aspirin use at 6 months in the patients who used clopidogrel and those who were off clopidogrel, 20 percent, 94 versus 74.  That difference doesn't exist in the bare-metal stents.  And although I know you somehow factored that into the analysis, it just bothers me there's that big of a difference and I'm uncomfortable that some of your results may not be explained by that big difference.  Can you give me a little more comfort there?
		DR. KONG:  Yes.  Certainly, one of the elements that occurred in our patient population was that clopidogrel therapy and reported aspirin therapy were very highly correlated together with the highest use of aspirin as a concomitant medication in the drug‑eluting stent plus the clopidogrel group, 95 percent and certainly a lower use of approximately 75 percent at 6 months in the bare-metal stent groups.  On the whole, over 80 percent of patients were taking aspirin by the 24-month endpoint.  So on the whole, looking at overall aspirin use, aspirin use was certainly common as far as an aggregate, but certainly patients who did not report clopidogrel use also tended not to report aspirin use in the groupings.
		So certainly when we make recommendations, it's a prudent thing to recommend dual antiplatelet therapy, recommending clopidogrel and aspirin together.  We did a separate subgroup analysis looking at aspirin patients that's part of the JAMA manuscript, and the results are consistent with the primary analysis.
		CHAIRPERSON MAISEL:  Dr. Page?
		DR. PAGE:  My first question is for Dr. Henry.  Just two brief questions if I may?  Dr. Henry?
		CHAIRPERSON MAISEL:  Dr. Henry told me that he was not going to be here for the question and answer period.
		DR. PAGE:  Okay.  My question, I'll ask it rhetorically then, is was the Angio-Jet used in any of his acute MI patients that he reported.  Did anybody hear whether he commented on that one way or the other?
		CHAIRPERSON MAISEL:  I don't think we have that information.
		DR. PAGE:  And my next question, just briefly, is for Dr. Ferguson.  Dr. Ferguson, I'm impressed by the low mortality of coronary artery bypass grafting.  Dr. Guyton mentioned a relative benefit over 3 years for surgery, a 46 percent survival for bypass grafting over PCI.  I was wondering if you could comment on the absolute benefit that that reflects?
		DR. FERGUSON:  Four point six percent.  Thank you, Dr. Guyton.  Four point six percent absolute benefit.
		DR. PAGE:  Over three years?
		DR. FERGUSON:  Yes.
		DR. PAGE:  Thank you
		CHAIRPERSON MAISEL:  Dr. Laskey?
		DR. LASKEY:  Some questions for -- or theme -- for Doctors Kong, Mehran and Mishkel.  Heard frequencies of stent thrombosis all over the place this morning, especially with respect to the time, the variation over time.  There clearly is a time-dependent risk to this, but I'm getting mixed messages with respect to very low rates in Mehran and Mishkel data, different rates in Kong.
		And you keep going back to the patient population here and whether you have an enriched population in the Duke study of ACS, so certainly clopidogrel therapy in that population is bound to give you some bang for your buck as well in terms of death MI.  BASKET-LATE was an AMI population.  Again, the clopidogrel story and the benefit conferred by clopidogrel in that population.
		Is that what we're seeing here in terms of the hazard of clopidogrel discontinuation after the fact then?  Is that why we're seeing such discordant numbers?  I'm not going to even use the word rate, because I've not heard any rates presented here in the last 36 hours in terms of numbers for patient per unit of time.  Well, we talked about frequencies.  But just help me understand why they're so pristine in Mehran and Mishkel and they're a little messier in these different higher-risk patient populations?
		DR. KONG:  Part of the answer to your question is implicit within.  Real-world data are often less clear than randomized controlled data.  To emphasize, one of the initial questions addressed by the committee was the question of definitions.  And I'll remind the committee that our analysis looked at death and non-fatal myocardial infarction, so all-cause death and non-fatal MI, as opposed to stent thrombosis as might be defined in some versions of the ARC definition.  That being said, as a real-world registry, the absolute proportions of patients experiencing death or non-fatal myocardial infarction are higher than was reported in the randomized controlled clinical trials.  We suspect this reflects a broader population and less patient selection and potentially higher patient risk subsets.
		DR. LASKEY:  Consecutive series from Roxanna and Mishkel speak to a different outcome rate.
		DR. MEHRAN:  I think I can only --
		CHAIRPERSON MAISEL:  Excuse me.  Could you sit for a moment?  Warren, did you have a specific question you were asking someone or making a comment?
		DR. LASKEY:  Well, I had to put Dr. Mehran on the spot, but it is more directed towards her.  Can you explain to me, at least to help me to understand, some of these differences between what is a more acceptable rate in your series as well as in Waksman's series as well as in Mishkel's series compared to what where' hearing otherwise?
		DR. MEHRAN:  Excuse me, Mr. Chairman, I apologize for that, but certainly I think there's no question that -- you know, I can only speak for the MATRIX data, and what we have here is first of all, there's a limitation to looking at the MATRIX data and that is that the patients out to 2 years, we don't have complete follow-up on.  I just want to make sure that everyone understands that on the panel.  We only have 640 of the 1,500 patients eligible for the 2-year follow-up so that as we collect more information, we may start to see -- the Kong data has 3-year, 98 percent follow-up -- and that may reflect that.
		The second thing I think is crucial, if I may, is that I still think we don't understand the aspirin-clopidogrel story, because the discontinuation of aspirin and clopidogrel may be secondary to bleeding issues that are not being discussed in any of these trials that were presented and that those patients are at a higher risk for morbidity like death, etcetera.
		CHAIRPERSON MAISEL:  Thank you.  Dr. Morrison?
		DR. MORRISON:  Well, actually, I wanted to ask Tim Henry, but since he has left, I'd like to ask either Dr. Guyton or Smith.  You've rightly pointed out to us some of the limitations of randomized trials and making inferences from underpowered trials of low-risk patients.  I am curious what you do about the recognized limitations of registries, namely selection bias, confounding and information bias, whether or not you think that correcting them is possible when you don't measure all of the appropriate parameters, and I will list only one that I'm aware of, namely diffuse disease, as either a contraindication or even prohibition for CABG.
		Given that, how sure are you that CABG prolongs life in the patients that you presented from Duke or the State of New York.
		DR. GUYTON:  Right.  I think this is a very important question and going forward, I think that our recommendation is that a robust comprehensive database be developed that includes some of the anatomic predictors of success or failure of PCI or surgery.  I don't think the existing databases are sufficient to go forward.
		Now we don't need the whole nation.  It could be that we just use the State of Massachusetts and the State of California which both already have existing databases, and we seek to add to the 400 or so fields that already being collected, an additional 200 fields in those two states.  And then we would have a comprehensive database in those patient populations that are capturing the whole state maybe.  And then we would have a sufficiently large database with a sufficient number of fields to determine which patient subsets are best served by which therapy.  And I think that's the end game and the long-term benefit.
		Currently, we do the best we can with propensity analysis with the fields that are available which, in the surgical series, is about 300 fields of preoperative descriptors.  And as you say, this does not include coronary anatomy, and that's a very important consideration.
		CHAIRPERSON MAISEL:  Thank you for your comments.  At this point, we'll move on in the open public hearing session for the next speaker who is Rick Kuntz.
		DR. KUNTZ:  Good morning.  My name is Rick Kuntz, and I'm working for Medtronic.  I'm going to review the Medtronic experience so far with their Endeavor stent.
		This is going to represent a next wave of stents, and it gives you a chance to look at the type of process that these stents are going through at this point.  This is the overall dossier on the Endeavor experience to date,  including our pilot study that started a few years ago to a planned study that's going to start in a few months, of 8,000 patients looking specifically at stent thrombosis.
		This is the data that was submitted for PMA application just recently.  And this data I'll review today with respect to stent thrombosis.  And this is the publicly available data that we have, that we feel comfortable presenting with respect to not violating the PMA submission.  It representative a pilot study, a randomized study against bare-metal stents and a randomized study against another stent.
		Now to frame the safety analysis, especially with respect to what we talked about yesterday, the data presented yesterday for the available drug‑eluting stents in the U.S. indicated that these devices are important advancements.  At least that was one of the arguments.  And that advancement and argument was made by the drug‑eluting stents reducing the need for revascularization without a statistical increase of the overall incidence of myocardial infarction and death.  Any increased incidence of late-stent thrombosis appeared to be offset by a reduction in downstream revascularization events prevented by drug‑eluting stents.  An ideal drug‑eluting stent is something I think we should all aim for and is one that both reduces the incidence of revascularization and its downstream events and provides an equivalent or better safety result compared to bare-metal stents.  Such an ideal stent would be associated with a lower overall death and MI rate compared to bare-metal stents.
		Now one of the barriers to these next generation stents is to not lump them all together into a specific drug‑eluting stent class.  This is far from a class.  There are different platforms.  There are different polymers.  There are different drugs and so on.
		Just to review, this is the best evidence so far for this particular stent.  It was a randomized study against its bare-metal cohort or companion, the Driver stent, demonstrating the overall reduction, as we've seen in other drug‑eluting stents, of restenosis manifested by clinical revascularization or target lesion revascularization with a rate of approximately 4.5 percent, typically seen in the drug‑eluting stents.  This difference was maintained out to 2 years so far in that follow-up.
		Now we've been asked to process this stent thrombosis both with the initial protocol definitions we heard about and with respect to the ARC.  The initial protocols that were submitted in the protocol was reviewed by HCRI and come very close to the definite and probable definitions that are shown here.
		The main differences between the definite and probable ARC definitions that you heard about yesterday was that the protocol definitions ruled out or censored intervening target lesion revascularization for all of the reasons that were brought up yesterday.  Also, there was a difference in the clinical events committee's thresholds for review and how they attributed target vessel myocardial infarction with EKGs.
		If we look overall at the protocol definition to date in the pool data so far of these three studies, we see that stent thrombosis was qualified in 4 patients within 30 days; in the period called late-stent thrombosis, in 30 days to 1 year; and the very late stent thrombosis, which is greater than 1 year, there have been no incidences of stent thrombosis with this stent.
		This is the Kaplan Meier estimates of the results so far comparing the pool results of these randomized studies against the bare-metal stent cohort demonstrating a difference that reached statistically significance.  And what's interesting here is that the safest stent, that is the one that has the highest event-free survival, is in fact the drug‑eluting stent.
		When we re-analyzed the data using the ARC definitions, and this is the most popular definition that appears, which is the definite and probable qualifications, we see the incremental increase of qualifications of stent thrombosis on both slides.  So now there are 7 that qualify, as we saw in the other definitions as well, for the Endeavor side and 8 for the bare-metal stent side.  Now the size of the denominators are larger for Endeavor, so the rates are .5 percent out to 3 years for the Endeavor side and 2.3 percent for the Driver side.
		This is the overall Kaplan Meier estimates at 3 years looking at the censored data, and we see that the estimate at 3 years based on available data is 99.4 percent freedom from stent thrombosis for the drug‑eluting stent, Endeavor; and 98.7 percent for the bare-metal cohort.
		When we broaden the definition to include possible, which we all know increases the sensitivity, we still see further cases that qualify on both sides, and now the number is 12 out of 1,300 in the Endeavor side, and 14 out of 596 for corresponding rates of 1 percent at 3 years versus 3.3.  The Kaplan Meier estimates here are showing a 99 percent freedom from stent thrombosis in this broader definition including the possibles versus 96.9, again demonstrating the safer performance of the drug‑eluting stent compared to its bare-metal stent counterpart.
		If we remove the or deal with the censored TLR issue, as you know, the ARC definition does not censor target lesion revascularizations.  Just to show that if we bring back in censoring for this broader definition, it doesn't change the overall results.  So if we look at the definitions of stent thrombosis with the increasing sensitivity, we see the typical response that you would expect; starting with the protocol definition, .3 percent; with the broader definition of the ARC, .54 percent; and the one that includes all possible events, .97 percent.
		The density of follow-up is such that we can put now 95 percent confidence intervals on these estimates so that, for example, we take the middle graph, which is the .54 percent, the 98 percent Greenwood confidence interval above that survival estimate is slightly less than 1 percent.  This should translate into an overall difference in overall mortality in the myocardial infarction if, in fact, there is a benefit seen in the stent thrombosis side.  And that trend is starting to appear in the pool data so far so that by 2 years, we're getting estimates now that the overall myocardial infarction and death rate is, in fact, lower for the drug‑eluting stent than that for the bare-metal side.
		I caution you that that does not reach statistically significant, but the estimates are starting to separate.  I also think that this data has a little bit more noise because it's all definite MI, but it should start to separate the results as we see now.  And hopefully, if we have more data, we'll get better separation.
		One way to test that is to do more randomized controlled studies and the commitment in this program is to do a single-arm registry which is called E-5 which will look at all- comers and a randomized controlled study against another stent for all-comers which will test the hypothesis of stent thrombosis safety in a broader population under a randomized controlled study of 8,000 patients.
		So in summary, I think it's important to point out that drug‑eluting stents are not a class, that is, there are too much variability with respect to the platform, the polymer itself, and the drug to classify that.  Available Endeavor data so far demonstrates prevention of restenosis without an increased safety risk under the ARC definitions, and this company is committed to ongoing follow-up studies to try to balance the turnover new technologies but at the same time do some randomized studies that are large enough to look for new signals in the future.  Thank you.
		CHAIRPERSON MAISEL:  Thank you very much.  Our next speaker is Krishna Sudhir.
		DR. SUDHIR:  Good morning, ladies and gentlemen.  My name is Krishna Sudhir.  I am Medical Director of Global Clinical Science at Abbott Vascular - Cardiac Therapies.  I'm a cardiologist by training and continue to have a visiting academic appointment at Stanford University.
		We are here today, Abbott and I, because Abbott has a drug‑eluting stent, the XIENCE V, which has been approved on the market in the EEU and a few other countries and has just entered the PMA approval process in the United States.  The XIENCE V has the following components shown on this slide -- a couple of these are familiar to most interventionalists in the audience:  The MULTI-LINK VISION stent and the MULTI-LINK VISION stent delivery system.  In addition, the drug on XIENCE V is Everolimus, and we have a durable fluoropolymer for release of the stent.
		We had a lot of debate yesterday, but it seemed to be general consensus that the benefits of drug‑eluting stents outweigh potential risks.  Having said that, all drug‑eluting stents are not the same.  Clearly, there are differences in platforms, polymers, drugs, and elution rates.  We believe that new therapies are best understood and advanced through robust pre-clinical, pre-market and post-market clinical research and believe history has shown us that as these new technologies evolve, efficacy and safety profiles are likely to improve over time.
		Several studies were presented yesterday, and I won't belabor the point.  One such study was the analysis of 9 databases from the Cardiovascular Research Foundation that Doctors Stone, Leon, Mehran and colleagues presented at TCT.  They used a pre-specified analysis of safety and efficacy variables, and no differences were observed in death and MI out to 4 years for CYPHER and TAXUS compared to bare-metal stents.
		Now one of the things we firmly believe is that in future analysis of drug‑eluting stents, pre-clinical assessment of these stents becomes pretty crucial in the development of these technologies.  Acute safety is achieved via minimal vessel injury, complete stent apposition, and perhaps the development of thromboresistant materials.  Long-term safety probably requires rapid re-endothelialization, a functional endothelial layer, minimal chronic inflammation and perhaps the absence of persistent fibrin.
		Now clearly there are differences in platforms, polymers, drugs, and elution rates, but even at the physical level, these stents differ quite considerably from each other.  If you look at simple parameters, for example, like strut thickness, there's quite a range of strut thicknesses across the four drug‑eluting stents.  There are also some differences in terms of polymer thickness.  So it's quite possible that in addition to the differences in platforms, polymers and drugs, the very physical differences in these stents may actually yield different pre-clinical data and possibly, over time, translate to differences in clinical endpoints.
		Shown on this slide are 14-day rabbit iliac re-endothelialization data that we have gathered in collaboration with Dr. Renu Virmani.  In this particular model, the animals are sacrificed at 14 and 28 days, and the stent surface is examined for the extent of endothelialization, and in some studies, for the quality of the endothelium.  So shown on the extreme left panel on the slide are the data from the XIENCE stent showing endothelial paving over both the struts of the stents as well as between the struts.  And the comparator data are shown for the other stents.
		The question was raised yesterday morning as to whether this endothelial lining is actually functional.  We believe that's quite important.  And again, in collaboration with Dr. Virmani, we have looked at a range of functional variables such as INOS, VEGF receptor expression, VEGF expression, thrombomodulin, CD31, and so on.  And again, in general, these parameters go up in a favorable direction when examining the data from the XIENCE V stents.  Some of these data were actually presented at TCT, and we'll be presenting updates at future academic meetings.
		When you quantitate the extent of endothelialization from these four different stents, these are the data that emerge.  With the XIENCE V stent, there's about a 78 percent endothelialization at 14 days.  When you look over the struts and between the struts, it's in the order of about 97 percent.  So two messages from the slide:  Clearly there are differences between the different stents, and the second message is that XIENCE appears to do relatively well when you look at this particular parameter.
		In addition, we've also done chronic studies in a pig coronary artery model where we've looked at the inflammatory burden in the arterial wall of the coronary arteries.  Again, this has been in collaboration with Dr. Virmani, and we've been able to show that at 360 and 720 days, there is minimum chronic inflammation in the wall of the pig coronary artery.  In fact, the degree of inflammation is really no different from what we observe with the VISION stent in these long-term studies.
		So we've seen some differences in pre-clinical data that may be related to differences in design of these stents.  But I think the key question is do these data translate to potentially different clinical results.  Now we are fairly early in our clinical program.  This is the SPIRIT family of trials that will evaluate XIENCE V.  SPIRIT was the first-in-man study, a safety and performance study from Europe.  SPIRIT II was the study that was used to support launch in the EU.  Professor Patrick Serruys was the PI on both those studies.  SPIRIT III and SPIRIT IV are both underway.  SPIRIT III is the U.S. and Japan approval study.  SPIRIT IV is an additional U.S. peri-approval study.  SPIRIT V, a post-marketing study OUS has just commenced and has started to recruit in the EU.  This has a diabetic substudy built into it, a randomized diabetic substudy.  And then, of course, we are planning U.S. post-approval studies labeled on the slide as SPIRIT VI and beyond.
		In the aggregate, the SPIRIT family of trials has over 10,000 patients.  In addition, we are participating in other registries such as Dr. Stone's Stent Thrombosis Registry which will follow patients for five years looking at stent thrombosis event rates.  Our data is early as we are fairly early in our clinical program.  These are the SPIRIT FIRST data that are probably well-known to many in the audience.  They primary endpoint was in-stent late loss where the data from XIENCE showed superiority to VISION in terms of this endpoint.  Similar data in SPIRIT II here.  The comparator was TAXUS.  Again, when we looked at the primary endpoint of in-stent late loss, it was not only non-inferior to the TAXUS data but in fact tested positive to superiority.  When we superimposed data from SPIRIT I and SPIRIT II, I think the one point I'd like to make is that the data from the XIENCE stent are virtually superimposable in both those studies.
		Germane to the discussions that we've been having yesterday and today, here are the data on stent thrombosis from SPIRIT FIRST and SPIRIT II.  In SPIRIT FIRST, there was no thrombosis in either the XIENCE or the VISION arm out to 2 years.  And SPIRIT II, as far as 9-month follow-up goes, there was on thrombotic event in each group within 60 days.  Both patients were on dual antiplatelet therapy at the time.  We are committed to re-adjudication of SPIRIT FIRST and SPIRIT II stent thrombosis data using the Dublin ARC definitions and this re-adjudication is currently ongoing.
		In conclusion then, the Abbott vascular XIENCE stent has a well-studied bare-metal stent platform, the MULTI-LINK VISION.  Our pre-clinical data for XIENCE have shown pretty endothelialization and limited chronic inflammation data.  SPIRIT FIRST and SPIRIT II have shown superior efficacy and encouraging safety data for XIENCE V.  And the SPIRIT family of trials will evaluate over 10,000 patients with long-term, up to 5-year, follow-up.  Thank you for your attention.
		CHAIRPERSON MAISEL:  Thank you very much.  Our next speaker is Laura Mauri.
		DR. MAURI:  Good morning.  Thanks for the opportunity to present. I'm an Interventional Cardiologist at the Brigham Women's Hospital, and I'm involved in the clinical trial design of many drug‑eluting stent trials.  I'll be presenting to you, not data, but an analysis plan for several drug‑eluting stent trial programs that involve a common drug and polymer.
		We're all aware that there are many challenges to evaluating rare adverse events such as stent thrombosis and that there are strengths and limitations to both the randomized trial approach as well as the observational or registry approaches.  I'm not presenting data because these programs are in earlier stages of their clinical development, but I'm hoping to present a method that can give us greater certainty in terms of rare adverse event rates.
		So the question of stent thrombosis is difficult to answer in clinical trials.  The events are rare.  The predictors remain poorly defined and as has been said earlier today, the results can't be generalized from one drug polymer combination to another.  They vary too widely in terms of their elution characteristics and completely different mechanisms of action.
		The current regulatory evaluation of new molecular entities has required at least 2,000 patients exposed based on the following assumptions:  The expected stent thrombosis rates were approximately 1 percent from the history of bare-metal stenting, and to have sufficient power to detect a doubling in the rate of this estimate, one would need approximately that number of patients.  In going forward, there may be an interest in increasing the power to detect these adverse events that occur infrequently and late through studies with a larger total exposure.  Where we have stent platforms that use the same drug and polymer combination, it would be useful to be able to combine data in some way to improve the power to detect these rare events whether they are anticipated or unanticipated.
		The Biolimus A9 drug and biodegradable polymer system is under investigation in several stent platforms described here.  Each stent platform has a series of trials that's designed to demonstrate safety and effectiveness on its own.  The trials vary widely according to the stent type used and the target patient population.  This is just to introduce the drug that's being used.  Biolimus, is from the limus family of compounds and acts, we think, similarly to inhibit smooth muscle cell proliferation.  This is a sketch of the various different companies that share a common drug and polymer.  And you can see that they vary widely, in terms of the stent platform, ranging from stainless steel to nitinol to cobalt chromium stents but have similar dosing and the same polymer across these different platforms.
		Each of these has its own independent PK studies and pre-clinical evaluations as well as first-in-man feasibility studies.  The data is really too early to present detailed safety information.  I'm not here to compare the safety or the effectiveness at ths point as these are early in development.  But looking forward to the pivotal trials that are intended to make these comparisons, you can see the total number of patients across these devices is over 5,000 patients, more than any of the single programs that have been designed for a single stent platform approval.  And finally, that there are additional planned post-market studies.
		So the common thread you can see across these studies is the drug and the polymer, and combining the data across these trials might increase our power to detect rare adverse events.  The objectives of such an analysis would be to provide a secondary safety analysis to combine data from the individual studies and yield a more precise estimate.  It's an exploratory analysis by its nature, of safety that's not intended to replace the requirements or be definitive but more to be hypothesis generating.
		The comparison of independent effects due to the drug and polymer combination would be a main objective and to isolate this compared to the various patient and trial level covariates.  This is not simple because of the differences in the platforms and the patient characteristics.  Simple pooling or exchangeability is not possible, and there are certain basic minimum requirements.  As has been discussed throughout these meetings, it's necessary to consider common definitions, and particularly in an analysis such as this, so that we're comparing apples to apples across the different trials.
		In addition, we've seen today a wide variation in rates of stent thrombosis but also of myocardial infarction.  And much of that variation is not just attributable to patient characteristics but also the methods of data acquisition which vary widely from study to study and the adjudication process.  So that needs to be consistent for any information to be shared across different studies.
		In addition, the presence of common controls in the studies is necessary in order to be able to make any kind of comparisons across the different platforms.
		And finally, precise definition of what the covariates are that may be confounding variables both at a patient and trial level will be important.  And common definitions for these are, of course, just as important.
		So this type of a mega-analysis would combine randomized trial and registry data of de novo coronary artery stenosis treatment to estimate the safety of the Biolimus stent platforms as a group and potentially each device in comparison to the controls that are available.  This would use survival methods in order to account for varying durations of follow-up and require adjustment for confounders on a patient and trial level.  This analysis would link the predictor variables that I've just mentioned to the outcomes related to safety, specifically stent thrombosis would be a concern but the same methods could be applied to other rare adverse events or a death or a myocardial infarction.
		Since there is very little prior information to be applied either a frequentist or Bayesian method could be considered.  And some of the important confounders, there are the same list of variables that have been identified by many of the investigators earlier today.  But at a trial level, I think it's important to consider variables that may be at least as important:  systematic differences according to the sites; differences in the conduct of the study that would have different levels of blinding; differences in the platforms, of course, is a major variable; and the lesion characteristics included for enrollment and consideration of interactions that might be present between the platform and the drug- polymer combination.  There are also potentially differences between the registry and the randomized trials, and propensity score methods could be used to match the registry patients to the randomized patients.
		Finally, a sensitivity analysis would be required to exclude registry patients in order to see the impact on the conclusions.  The anticipated results would be to provide estimates of safety for the Biolimus stents as a group, the individual platforms, and within patient subsets, and in comparison, where possible, to the controls that were used in these trials.
		So in conclusion, this type of a pre-specified combined safety analysis is one method that could be performed at varying durations of follow-up yields greater precision regarding safety.  It could identify predictors of stent thrombosis with greater certainty, because we would intend to account for many of the between-study covariates.  And if a consistent effect was attributable to the specific drug polymer combination across platforms, this type of analysis could increase the power to detect this effect.
		So I hope that this provides to the panel one topic for conversation for methods for going forward for drug polymer combinations on stents that may be evaluated in the future.  Thank you.
		CHAIRPERSON MAISEL:  Thank you very much.  At this point, I'd like to open up the panel discussion to these three previous speakers.  Dr. Somberg?
		DR. ZUCKERMAN:  Excuse me, Dr. Maisel.
		CHAIRPERSON MAISEL:  Dr. Zuckerman, I understand.  We're actually going to do this presentation a little later to allow your previous request to be accommodated.  So, Dr. Somberg?
		DR. SOMBERG:  Dr. Kuntz, from Medtronic, if you could answer my question about what antiplatelet therapy recommendation and protocol requirements in the ENDEAVOR studies?
		DR. KUNTZ:  Yes.  The ENDEAVOR studies all used the requirement of 3 months.  In the ENDEAVOR II, study which went against the bare-metal stent, 29 percent were on at 1 year, so the requirement mandated 3 months.  That was for all the studies.  In the future PROTECT study, which is an 8,000-patient randomized study, that will be a 6-month therapy, because we'll be going against another stent that has a 6-month requirement.
		CHAIRPERSON MAISEL:  Dr. Normand?
		DR. ZUCKERMAN:  Dr. Kuntz, before you leave, could I ask you another question on the PROTECT study, because it's certainly an important step that has been shown today just regarding the trial design, size, choice of primary endpoint, et cetera.  But on your slide your slide, you have listed as antiplatelet therapy, dual antiplatelet therapy greater than 3 to less than 12 months.  Now you've decided potentially on 6 months for both groups?
		DR. KUNTZ:  Six months is the protocol as I understand at this point.
		DR. ZUCKERMAN:  But based on what you've heard over the last two days, would you reconsider that?
		DR. KUNTZ:  That's an interesting question.  I think that there will be a lot of processing of the information from this panel.  I think that at first blush, I'm not quite sure that we have enough evidence that extending antiplatelet therapy beyond what's been proven so far, you know, at least in the type of patients that have been studied in the classical randomized studies, is going to be of value.  PROTECT is a study that will look at a broader group of all-comers.  I think that one could probably justify that because the risk would be higher that maybe it would be judicious to go to 1 year.  So I think that at this point, the plan is for 6 months, but I think that your recommendations are probably good to consider for something longer.
		CHAIRPERSON MAISEL:  Dr. Normand?
		DR. NORMAND:  I have a question for Dr. Kuntz.  I had asked an earlier question regarding the choice of using different types of drug‑eluting stents, and the answer, if I understood it correctly, was it really had to do with availability.  Now I think I heard you say and the other speakers in this little series that we just had saying that, you know, the drug‑eluting stents, indeed, aren't exchangeable, that they are different, and it really isn't related to availability.  Is that a fair characterization of what you said, that they aren't exchangeable?
		DR. KUNTZ:  I think they aren't.  I think that even with the two stents that have been available, there are different perceptions on how they perform, both in the patients themselves.  The issue of deliverability is something that a lot of cardiologists have opinions on, with respect to how easy it is to put it at a certain place in the coronary tree.  I think that is a platform issue, and that alone could probably generate a lot of different opinions about how people choose devices.
		I think the notion about the profound reduction in restenosis that these new therapies have brought have been lumped together as a class of drug‑eluting stents.  And I think people talk about that.  So with respect to the restenosis prevention and the safety demonstrated in the stents that are currently available, I think people have considered that as probably exchangeable on that basis.
		Maybe some slight differences in the way we measure restenosis but probably, and I'm just speaking for myself as an older interventional cardiologist, that there are a lot of opinions on choices, on deliverability and other features.
		So while historically there may not have been a complete exchangeable view of the two existing stents, I think when things go forward, there will be a less of a notion of exchangeability between these products as one starts to exploit the different components of these drug‑eluting stents and try to refine them to optimize them in the future.
		DR. NORMAND:  So patient characteristics obviously are going into play, region characteristics, patient characteristics --
		DR. KUNTZ:  That's a good question.  One would think that if you optimize the stent for one risk category, why would you ever chose a less optimum stent for anybody else.  So one would have to understand whether or not these risks are uniform and linear or if, in fact, they are no so linear.  So I think the data to be able to show that once that worked in one population but didn't work in another would require a lot of analysis.  My guess is that most people will try to understand what's the best stent overall and probably hook onto that.  But again, that's just my opinion, and I think that it might be a question for other practicing interventional cardiologists.
				DR. NORMAND:  So the question for Dr. Mauri right now, Laura, I think you were talking about -- I really liked your proposal.  That's probably no surprise.  But I did have a question.  You were saying that earlier on that these new stents would not be exchangeable, yet you can't fill a higher comodel if they're not exchangeable.  So I'm a little confused about your plan to use a higher comodel if indeed you're thinking they're not exchangeable.  So can you help me understand?  It seems like two contradictory statements.  I probably misunderstood.
		DR. MAURI:  I think at a simple level, they're not exchangeable for the same reasons that Rick just referred to.  These are different stent platforms.  They have different metals, different -- they're similar.  The ones that I described are similar based on drug and polymer, but their construction is quite different.  And so at the simplest level, they're not.  I think the issue of exchangeability applies to the question of whether, from the standpoint of just the drug and polymer whether it's possible to consider them as a class.  And that's where I think I would look into whether they are exchangeable and examine that.
		DR. NORMAND:  And then I have a second question regarding your statement about greater precision using the hierarchal regression frailty models if you're doing survival modeling.  You were indicating greater precision.  Are you talking about the overall rates over all the stents or for each study?
		DR. MAURI:  I'm mainly talking about for the drug and polymer combination.  As I said, I think this is really an exploratory secondary analysis that is to be -- you know, I think it could be very valuable if there is a signal that's in common to the drug and polymer combination.  It would give the power to detect it sooner.  As you can see, some of the stent platforms have a smaller sample size and some have a larger sample size, so as group, it would benefit our understanding of whether there are unique characteristics for the drug and polymer.
		DR. NORMAND:  Again, I think it's a good idea that the overall estimate will have inflated confidence intervals because of the extra between study variation.  However, the individual studies will have more precision, and I like that idea of borrowing information from drugs with similar drug and polymer combinations.  So thank you for the clarifications.
		DR. MAURI:  You're welcome.
		CHAIRPERSON MAISEL:  Thank you.  Dr. Yancy?
		DR. YANCY:  Thank you.  My question is for Dr. Sudhir from the Abbott data group.  I think we've heard several discussions about new stents, and I just have a question about the development of the stents, and it would be a question that's akin to dose response curve for drugs.  You obviously selected Everolimus.
		DR. SUDHIR:  Yes.
		DR. YANCY:  I didn't see the drug selection for the Medtronic stent.  It may or may not be the same.  But as you were designing your stent, did you consider different doses or different ways of eluting the drug from your stent?  Obviously, in Dr. Mauri's presentation, she showed a number of different doses for Biolimus, so it would seem as if it is theoretically possible to consider dose and one wonders if one can find a lesser dose that would prevent early restenosis without any downstream consequences.  So what was your thought process?  And in view of the last two deliberations, is that something worthwhile reviewing yet again?
		DR. SUDHIR:  Yes.  I'll make one comment and there are others in the company more knowledgeable about the drug dose choice than I am, so I can refer the question to them and, through the FDA, get back to you.  But I'll make one comment.  Everolimus has a slightly lower potency than Sirolimus.  So if you look at 100 micrograms of Everolimus versus 104 micrograms of Sirolimus, you're talking about probably a concentration that's equal to about 80 micrograms, one could argue.  So we're already at a slightly lower dose.
		But you do raise an important point:  Is some of what we're seeing sort of drug-dependent, dose-related toxicity?  And I think in the future, we should probably pay greater attention to this.  If I get a more exact answer from my basic science colleagues back at the company, I will work with the FDA to get that response to you.
		DR. YANCY:  One of the reasons I'm raising the question to you specifically regarding Everolimus is that, as you know, it's not yet been utilized for heart transplant recipients as an immunosuppressant because of concerns of some toxicity.  So I would think that especially with this compound, there were would be unique attention on this issue of dose.
		CHAIRPERSON MAISEL:  Thank you.  Dr. Harrington?
		DR. HARRINGTON:  Just a quick question for Dr. Mauri.  I, too, appreciate the plan to combine data and try to get the best estimate of what the risk might be.  I'm curious; have all the individual sponsors signed off on this plan, and have they agree to, at the end of the day, share their data with the other sponsors?
		DR. MAURI:  I don't think it would require necessarily that they share their data with the other sponsors, you know, in terms of sending their data from one sponsor to another.  It would require an independent analysis done by a central CRO.
		DR. HARRINGTON:  Without the plan to send back the analysis set to the individual sponsors?  In other words, you'll take all the different pieces of data, you'll put it into one common data set, you will perform the independent analysis.  And will you provide the individual sponsors back SAS tables?  Will you provide them actually the aggregated raw data?
		DR. MAURI:  I don't think there would be an intention to share data from one sponsor with another unless that was agreed upon by all sponsors involved.
		DR. HARRINGTON:  So they've not agreed to do this yet?  This is a proposal?
		DR. MAURI:  It is a proposal.  That's correct.  And the proposal would not require that data be given from one sponsor to another but that an independent group be able to analyze the data.
		CHAIRPERSON MAISEL:  Thank you.  Dr. Laskey?
		DR. LASKEY:  Just a quick, hopefully, question for Rick Kuntz.  Back to stent thrombosis, the theme of this meeting, you came as close as anybody to perhaps establishing the linkage that we've been missing between stent thrombosis and the death MI.  Are you going to pursue that and the downstream benefit?  Or are you of the school of thought that by preventing restenosis, that's where the gap is coming from?
		DR. KUNTZ:  Yes.  Thanks for asking that question, Warren.  I don't think it's actually much of a missing link.  I think it's pretty straightforward.  When you adjudicate these things, it's pretty obvious what happens.  I think what we have is an event, stent thrombosis, which is related with about a 60 to 70 percent of a major myocardial infarction and about a 20 to 25 percent chance, based on the literature, of death.  So if we look at things like myocardial infarction and death, we'll pick up 60 percent of the signal of stent thrombosis.  And if we look at mortality, we'll pick you 1 in 5 or 1 in 4.  So this linkage might just be an issue of noise, signal noise ratio issues that as you start to get differences in stent thrombosis, you'll start to get slower catch-up and differences in those more specific endpoints as they're linked.
		I think that the notion about restenosis causing downstream events is also one of these situations where for every restenosis, there's only a small portion that have a death or myocardial infarction associated with them, probably even much smaller than stent thrombosis.  I think this is pretty obvious.  So changes in reduction in restenosis linked to death and myocardial infarction for revascularization prevention will have a smaller impact than changes in stent thrombosis overall.  But still, if the sample sizes are large enough and one can provide safety that matches the bare-metal stent, hopefully this technology can even improve that safety, maybe the coding is better than bare-metal stents in the future, and that's the promise of technology.  And if we can maintain the reductions in revascularization, then it is logical that you'll start to see a signal in the overall death and myocardial infarction rate.
		And so, so far, the data is fortunate enough that we're starting a little bit of a signal in safety with respect to this stent's experience, and it is translating into separation of the estimators.  And I think that that's the linkages that we're seeing.
		CHAIRPERSON MAISEL:  Thank you very much.  At this time, I would like to close the open public hearing session.  And in the few minutes that remain before lunch, I've received a request form Boston Scientific and Johnson & Johnson to address the panel and provide some clarification on points from yesterday afternoon.  First, we will have Cordis and then Boston Scientific, and they'll each be allotted five minutes.
		DR. DONOHOE:  My name is Dennis DONOHOE.  I'm the Vice President of Clinical and Regulatory Affairs for Cordis.  I want to thank the FDA and the panel for the chance to address the panel a second time.  Yesterday there were two items or questions that came up, and I wanted to respond to those questions from the panel.
		This first slide, and I think you have a hard copy in front of you, the request was could we conduct the same type of analysis that was presented yesterday by Dr. Baim, and we have talked to our colleagues at Boston Scientific.  Based on how long that slide was up, we were not able to gather exactly how they did the analysis, but they promised to send us the methodology.
		What we have done -- there was a similar presentation by Dr. Stone looking at the same issue.  And I believe the question was, what was the contribution of death and MI from patients who had stent thrombosis and TLRs in both treatment groups.  And Dr. Stone presented this model using the same TAXUS data, and we wanted a chance to present this to the panel.  Now as you recall, yesterday, we presented total mortality and MI rates.  This is looking a the subset of patients in each group who had a stent thrombosis or target lesion revascularization.  Green is obviously the control group, and CYPHER is in yellow.
		As you see, there were, and this is going down the left side, 67 TLRs in the CYPHER treatment group and 13 stent thromboses.  There were 3 deaths, 1 cardiac and 2 non-cardiac, 1 MI in the CYPHER group following a TLR.  And looking at the total composite, that's 4 events as a composite of death and MI.  If we look at the TLR group, the 202 patients on the bare-metal stent side, there were 5 deaths, 3 cardiac, 2 non-cardiac, 9 MIs, and in counting those events up and not double-counting patients who had an MI and a later mortality, there were a total of 13 patients with death and non-fatal MI.
		Looking at the stent thrombosis column on the CYPHER side, out of the 13 stent thromboses, there were 4 deaths, 13 MIs for a total of 13 deaths and non-fatal MIs.  And then finally on the bare-metal stents side, there were 15 stent thromboses, 5 of which resulted in mortality, 13 MIs for a total number of 15 patients having a death or non-fatal MI.
		In adding those values up then, you'd see the rates are fairly comparable.  On the CYPHER side, there were 7 deaths, 5 of which were cardiac and 2 non-cardiac, 14 MIs for a total count of 17 death or non-fatal MIs.  On the bare-metal side, there were 10 deaths, 8 cardiac, 2 non-cardiac, 22 MIs in a total number of 28 patients.  Just to indicate again, this is a subset looking at the reasons for mortality and MI extending out of those who had stent thrombosis or a TLR.
		The other question or comment that had come up yesterday -- there was discussion about the possibility suggesting the FDA use some of the observational data that's been presented in the registries in labeling.  And just to clarify, while the presentation by Cordis yesterday on available registry data extended out to one year, I did want to make note that there is other data summarized here that extends the information on mortality rates, myocardial infarction rates out to the 3 to 4-year time period.  These are a combination of randomized, non-randomized and registry data sets as listed here, a total of about 2,600 patients, not counting the randomized data we presented yesterday that extend out to 4 to 5 years.
		Some of these studies are totally independent of Cordis.  Others were supported by Cordis, but is being conducted independent of Cordis, and that's why we were not presenting the data yesterday.  And this includes the MATRIX data as well as the Prairie Heart registries which Cordis helped to support.  And the last slides just show you the summary of MI rates over the 3-year time period.  So we do have available data from this type of data set if the panel decided that this kind of information should be included in the label.
		CHAIRPERSON MAISEL:  Thank you very much for your comments.  I'd like to invite Boston Scientific to the podium for five minutes.
		DR. BAIM:  Thanks.  It's a pleasure to be able to have some additional comments, but just to caution, these should not be construed as promotion of off-label use.  And with that preface, let me go back to my introduction about PCI.  POBA, plain old balloon angioplasty began with proximal discrete single-vessel lesions and accounted for maybe 5 percent of all revascularization, but through progressive improvements in technology, balloon stents and now drug‑eluting stents, we've seen progressive improvements in safety, success and durability which have naturally led to expansion and to broader anatomic and clinical areas, multi-vessel disease, acute myocardial infarction, chronic total occlusion, et cetera.
		Comparing PCI to medical therapy and stable angina, there's really no advantage beyond the relief of symptoms and the already good survival of patients on medical therapy.  But in unstable angina and acute myocardial infarction, there's evidence that acute use of percutaneous intervention can improve death and myocardial infarction.  For AMI, that's been shown for  primary angioplasty.  It's been shown for bare-metal stents in Cadillac and other trials, and for drug‑eluting stents, there is suggestive evidence from small trials.  I mentioned yesterday the HORIZONS trial.
		In terms of the comparison to bypass surgery, there are 7 randomized trials that show no clear difference in two and limited three-vessel disease suitable for intervention.  The issue now, though, is three-vessel disease and left main disease where bypass surgery has traditional advantages over medical therapy.  It's only recently that improvements with drug‑eluting stent restenosis have made entertaining use in these patients more challenging.
		The off-label data on the TAXUS use from the ARRIVE registry, and I'll show you again in a second, has provided some supportive data.  The performance of randomized clinical  trials comparing PCI to bypass surgery, including BARI, indicate a great deal of difficulty in doing this, yet we are almost done with enrollment in the SYNTAX trial randomizing TAXUS use to surgery in left main and three-vessel disease.  There is certainly room for big risk-adjusted registries to further address optimal revascularization.
		But I want to go back for a second to a slide that I think has been perhaps misquoted.  This slide looked at the death outcomes at 1 and 2 years, not 30 days, not in-hospital, of bypass surgery in complex populations as well as complex PCI as available.  I point out that the surgical results include the Duke trials as well as the Northern New England Database.  And the statement was that the bypass surgery mortality at 2 years ranged from 4 to 8 percent.  Those data are, in fact, correct.  We were not talking about operative mortality.  And when we look at the ARRIVE real-world registry, in fact, the overall death rates are entirely consistent with the other real-world registries and with the range of surgical 2-year mortality as described from the available surgical literature.
		So, in closing, I think I would point out that product labels are not a static thing.  Traditionally, we start with relatively simple indications compared to some indexed therapy, accepted therapy, and in this case, in both available drug‑eluting stents, the comparison was a comparison to bare-metal stents in relatively straightforward lesions.
		But then after the initial approval, each company has expanded to more complex lesions through so-called label expansion studies:  for small-vessel disease, for longer lesions, as we've done in the TAXUS V study, and then to other indications such as acute myocardial infarction.
		These further indications are frequently scouted with real-world, post-approval registries like the ARRIVE registry I've shown you, to find out if there are any areas where the performance of a new device shows concerning results in terms of high complications that should not be pursued for a label indication via additional studies.
		On the other hand, it may show areas where performance looks very good, and that should be supported by additional trials for label expansion.
		What I've shown you is that those real-world data remain supportive, and we await new indication expansion trials such as SYNTAX.  Thank you.
		CHAIRPERSON MAISEL:  Thank you, Dr. Baim.  At this point, we have a few minutes before lunch.  I'd like to open up questions for the panel for either Cordis or Boston Scientific.  I have a question for Dr. Donohoe if he could please come up to the --  I appreciate you showing a little bit of registry data out past 1 year.  I note that Cordis has sponsored six registries as noted in your presentation yesterday, and the first one began in 2002, and they were designed to have at least yearly follow-up.  When this panel approved the CYPHER stent in 2003, one of the conditions of approval was a post-market registry because of the panel's concern about long-term safety.
		I appreciate the issues of adjudication and the relatively recent development of the ARC definitions, but we now sit here three years later, and you have failed to provide this panel with any information from your registry data past 1 year.  TAXUS, which was approved a year later, has follow-up out to 2 years.  So in trying to reconcile why we don't have that data in front of us, I'm a little bit at a loss to explain why you've failed to show us that data, and I could come up with two explanations, and you can pick one or come up with one of your own.  The two I could come up with is that you've chosen not to show us the data, which I doubt is true.  Or the second one is that you haven't done your due diligence in analyzing this data and presenting it to the panel.  So I'd appreciate your comments, because this is critical data for us to make decisions and have the discussion we need to have.
		DR. DONOHOE:  Certainly, if we had the data, it would have been presented.  The follow-up on that post-market surveillance study that was tied to the conditional approval was only for one year.  I do understand there was a presentation yesterday indicating the follow-up was to be extended longer; but actually, that protocol was written indicating 1-year follow-up, and that's how it was approved.  And our understanding at that point was 1-year follow-up was the endpoint.  So that's where we had conducted the study.
		CHAIRPERSON MAISEL:  So your contention is that Cordis does not have any registry data out past 1 year?
		DR. DONOHOE:  We have other registry data, the studies that we have direct control over, the ones we presented yesterday, and they were terminated at 1 year except for the 2 in Japan which were still under way and are being extended out.
		CHAIRPERSON MAISEL:  I find it extremely concerning that we don't have any registry data from Cordis out past 1 year.  I'd like to open up to the panel for additional questions of the sponsors if anyone has one.  Dr. Somberg?
		DR. SOMBERG:  I mean I understand your frustration and mine and just for clarification, are you saying that this protocol was designed for 1 year, submitted to the FDA and the FDA agreed with that 1-year follow-up as --
		DR. DONOHOE:  That's what I'm saying, yes.
		DR. SOMBERG:  It's the only follow-up?
		DR. DONOHOE:  Yes.
		CHAIRPERSON MAISEL:  Dr. Zuckerman, would you like to comment on that?  I don't have the panel transcripts in front of me, but my recollection is the panel had concern about years of follow-up with these devices.
		DR. ZUCKERMAN:  That's right.  And I think since you and Dr. Somberg were at the panel meeting also, you also recognize that when post-approval studies are planned, there's always a balance between getting all the data that we would all like to see versus doing something that's reasonable and can answer the safety questions at hand.
		If we harken back to 2003, the knowledge base at that time, which was an incomplete knowledge base, and we all learn as we do appropriate science, was that stent thrombosis was something that would occur primarily within the 1-year timeframe.  We were using the bare-metal stent model.  And that's why the registry was designed as Dr. Donohoe has explained.
		In retrospect, certainly the Agency and Cordis would have liked to have done it differently, but this doesn't mean that when we discuss this afternoon, question 6, that if there are legitimate safety concerns right now, that continued work in the post-approval arena can't be done with this particular sponsor or any others.
		CHAIRPERSON MAISEL:  Dr. Somberg?
		DR. SOMBERG:  I just want to say I did not want to imply that either myself or I'll speak for Dr. Maisel, too, is we knew that there would be late stent thrombosis.  I think the discussion was, if I remember it correctly, was durability of the stent.  And there was worry about the polymer and the materials, et cetera, lasting, you know, for long periods of time.  So those were the concerns if I remember, and was chairman here as well at that point, so I'm just -- just as a general -- anyway, what is it -- it was a general --
		DR. ZUCKERMAN:  In the traditional model, which was the bare-metal stent model used at that time, was follow-up of the IDE cohort to five years?  And I believe the sponsor is doing --
		DR. SOMBERG:  Yes.
		DR. ZUCKERMAN:  -- due diligence with respect to that phenomenon.  What's new here and what the panel needs to recognize is that we're in a different day and age where we truly are reckoning with transforming technology that has reshaped the landscape of interventional cardiology in our understanding of the science.  And that's why we're all here today.  And if we do need to make adjustments in our post-approval strategies, that's more than legitimate if that's the advice of the advisory panel.
		CHAIRPERSON MAISEL:  Dr. Domanski?
		DR. DOMANSKI:  You know, in that regard, I'd like to make a comment.  I think it would be nice to have all of these data, but it is interesting to track through -- I mean I think the FDA has done a remarkable job in terms of their efforts at approval of these things.  In fact, I'm not so sure that their original approach, even in the light of new data, is going to stand.  And I must say, the panel, if it asked for -- you know, if it talked about a longer period of time, based on a concern that turned out not to be an issue, you know, hardly represents a failing by either the FDA or then by the sponsor for whom it was required.   I mean we'd like to have more data, but I worry about the sense that could go out, perhaps not yours, that this is a real criticism of the FDA, or for that matter, the sponsor.  It just doesn't seem fair.
		CHAIRPERSON MAISEL:  Well, I mean I think we have to take into consideration the number of patients who are exposed to a given therapy, and for a therapy, that's going to be formerly in patients or has been implanted in millions of patients and is going to be in there for the rest of their lives.  I think it's incumbent upon everyone involved to have a better understanding of the long-term implications of that therapy.
		DR. DOMANSKI:  I think if that had been the original rationale, it might have been more compelling.
		CHAIRPERSON MAISEL:  Dr. Nissen?
		DR. NISSEN:  Yes.  And keep in mind that we also have independent registries.  It's not like the data never happens.  I mean when the device is used in huge numbers of patients, independent people, we'll examine it.  And that's why I found very helpful the Swedish registry yesterday which was done, you know, very large, high level of follow-up.  And so for me, I'm actually much more interested in us looking at those independent efforts rather than efforts that are company-sponsored, because I think they're more likely to be objective.
		CHAIRPERSON MAISEL:  Dr. Somberg?
		DR. SOMBERG:  Well, Dr. Nissen, I think it's nice to have independent.  We never know if they do not occur.  And we don't have the same level of scrutiny.  I must say they're two levels of information that advisory panels in general get, that is the material we get from a drug company that is first reviewed by the FDA, and I always find the FDA reviewers' comments extremely helpful.  They spend months on it, and I spend a weekend on it, at best.  So I have lots of reservations about the series of data we've been bombarded with the last two days, especially the OUS data which becomes even more difficult.
		And, you know, just to give you an idea is what type of clopidogrel they use.  There's generic clopidogrels all over the place in Europe, and there are papers in the pharmaceutical industry.  Yes, in Europe, there are generic clopidogrels, and there's a paper from the University of Luann, Division of Pharmaceutical Sciences that there are tremendous differences in their solution capabilities, etcetera, and I'll share that with you at lunch if you'd like.
		But suffice it to say, those are the type of data we don't grab.  So I thought the purpose of a registry to develop a real-world experience versus the randomized, controlled trials, and the registry would have more patients because it's easier, it's cheaper, et cetera, and you would follow out for a long period of time, and you would demand things like, you know, a certain amount of monetary, et cetera to validate it, but that would be an extra thing.
		So I'm not trying to find fault.  I'm just trying to say, you know, we learn from what we learn, and we move forward on that.  And, therefore, in the future, I think I would like to see large registries in almost all areas, larger than the randomized, controlled trials, followed out for a long period of time.  And I was extremely -- you know, I mean let's go to the positive now -- I was extremely reassured by hearing from a company that's well along in its process -- I heard numbers like 5,000 and 10,000 patients to 5 years follow-up, and I think that is to be commended very highly.  So maybe industry's way ahead of this committee anyway.
		CHAIRPERSON MAISEL:  Dr. Zuckerman?
		DR. ZUCKERMAN:  Since we're talking about post-approval registry strategy in this country, I want to, again, go back to some of the things we learned from the Cordis experience.  Number one, to quickly initiate condition of approval studies is a challenge, not just for FDA and the sponsor, but for the whole healthcare community.  I think you may remember that in the initial rollout of the Cordis product, within 3 months, the Agency needed to get a Web notice up in collaboration with the sponsor.  One of the difficulties was that there isn't yet a real appreciation that with approval of a product, the FDA and sponsor may still need to have post-approval studies going and initiated quickly, post-approval.  And this is a real issue that we need to figure out how to work better with IRBs and professional societies on.
		The second issue that we've found with just the design of post-approval studies in general, and it's a note to the industry in attendance, is that they really should be ready to roll once the FDA approves the product.  To really make that a reality means that the Agency is more than willing during the PMA review process to interact with the sponsor on the condition of approval registry so that it doesn't take another year just to finalize post- approval registries as has been a common pattern in the past.
		CHAIRPERSON MAISEL:  Dr. Normand.
		DR. NORMAND:  This is along the same lines as was just mentioned.  I'm finding it very difficult to use the registries that the FDA is mandating to make conclusions because there's no control group.  And it's very difficult because what we're hearing from the sponsors today is that -- well, first of all, you can't use bare-metal stents, they're too old; we can't use CABG because the rates aren't there, or there's a discussion about using historical numbers, so I really think that if -- and I'm going to argue very strongly about this -- it's for the patient, it's not whether I get a drug‑eluting stent or not, it's what are the alternatives, and not having information about a control group in the database is very difficult for us to actually look at that.  And so I think that if someone is going to mandate registries to be collected by the sponsor, than I'm going to argue very strongly they better have a control group in there whether -- you know, it's real-world and that's the real world.  There are alternatives.  That's the cost of business I would argue.
		CHAIRPERSON MAISEL:  Dr. Donohoe, would you like to comment before we break for lunch regarding any of these statements?
		DR. DONOHOE:  Yes.  Thank you.  One more opportunity on this -- the point of summarizing the available data through registries or other studies to the panel was to highlight that when the questions about thrombosis and longer term safety issues came up, Cordis did move to support other registries, either partially funding them that were already running or to get those registries up and running that would provide longer term follow-up data.  Some of those registries you've already heard.  They're being conducted independently of Cordis, and that's why we didn't represent the data.  As a composite, the data we showed you yesterday with a total of over 45,000 patients entered into different studies and registries with the longest period of follow-up after 5 years, acknowledging that number is falling off, was an attempt to generate a large amount of data so we could look more closely at rare events.
		CHAIRPERSON MAISEL:  Great.  Thank you very much for your comments.  At this point, we're going to break for lunch.  We will reconvene at 1:20.
		(Whereupon, off the record for a luncheon break.)
		CHAIRPERSON MAISEL: Good afternoon.  I'd like to begin this afternoon's session, which will begin with open public hearing session, and the first speaker will be James Dove on behalf of the ACC.  Dr. Dove.
		DR. DOVE: Okay.  Good afternoon.  I'm James T. Dove.  I'm President-elect, American College of Cardiology.  I have no disclosures to make.  I'm happy to represent the 35,000 members of ACC worldwide about ACC's point of view on some of the testimonies taking place at this hearing.
		We prepared considerable documents prior to the hearing and actually have changed the testimony considerably to sort of get to the point of what ACC is concerned about and the recommendations that ACC would like for the Committee to consider.  So rather than reviewing in detail a lot of scientific information that you've already heard, I elected to basically talk about some of the recommendations from the College.
		Just to go through some of the high points, because they're significant in terms of how they point to the recommendations, is we heard lots of comments regarding randomized control trials, registries, and various meta-analyses.  We realized that there were problems with lots of those studies in terms of definitions and criteria and inter-criteria and the event criteria, et cetera.
		We heard a lot of discussion about the fact that the event rates were low and that many of the studies were under powered.  We heard data yesterday that suggested, at least, that the incidence of stent thrombosis out to one year was about equal for bare metal, but we've had varying testimony regarding the incidents beyond one year and whether that's a continuing problem going forward past two, three, and four years.
		We talked about clopidogrel and the fact that it was good in some studies, but we were unclear, even as the panel talked about clopidogrel, as to how long the drug should be continued and what the risk benefits of continuing beyond one year really were.  
		And we talked a lot about off-label use of coated stents but realized that there wasn't great comparison groups for bare metal stents, nor was there really a great comparison group for CABG in the studies that had been done.  So there was a lot of information that we just didn't have and that you don't have as you try to make decisions about where to go and what the recommendation should be.
		It was interesting yesterday this morning that one of the comments was that multi-factorial suggested that we really don't know, and I'd have to agree with that.  Many times we don't know what the complicating issues are for stent thrombosis.  I've listed on this slide, obviously, just a few.  There are many of these that we need to have much more information about in order to decide what the recommendation should be in these various  areas.
		I also heard that you discussed yesterday as I was here about what you needed to do for labeling purposes and what maybe the profession should do as far as the practice of cardiovascular medicine was concerned.  Now they want to say to you that the College as a professional society is willing to step in and help with those decision-making processes where it becomes a professional responsibility to educate the membership and all cardiovascular specialists.  We certainly want to be at the table to help do that.
		If it's important to educate patients, then we want to also be able to do that with our other colleagues in professional societies so that we can reach the best therapy and the best strategies for all patients.
		We also found out the late events in non-target vessels, actually, are much more common than they are in target vessels, so we're looking in one small part of the elephant in this whole discussion.  What is clear is that the complications of bare metal stents and drug-eluting stents are a huge improvement over what we had with bone angioplasty in the past.
		But I also caution the presenters, as well as the panel, about what I call data hysteria, meaning that we take small results and blow them way out of proportion.  So, for instance, we've seen in the literature that .05 is five times greater than .1, and .005 is  five times greater as is this, and we can take those numbers and magnify them by just changing the sample size so that suddenly something becomes 50,000 patients or 5,000 patients, depending on whether we're talking about a million or ten million patients, and we really out to stick to the science and not try to magnify what the projections of those outcomes are by trying to state something that really isn't proven or true.
		I think by the same token, in a very publicized event such as this hearing, it's critical that we watch the words that we use, so the words of significance when they're not referring to true science literature should be used carefully.  Words that say significant and extraordinary or sometimes that overstate what the literature is, we need to be careful about how we use those words and not upset the public as we try to decide what the best therapy is.
		So ACC's recommendation is combined basically of three strategies, sort of a short-term strategy to reiterate patient selection and to help determine what best treatment is; best treatment whether it's medical, PCI and stents, or CABG; to reiterate to the public and the physicians that the approval indications were for very small and selected subsets and not necessary for some of the complex things that we've talked about.  Having said that, though, we need to have better data on those complex patients so that we have a better understanding of what the outcomes are in those patients as we treat them.
		We need to have some recommendation on the duration of anti-platelet therapy, and I can tell you we do sympathize with the difficult of trying to make that recommendation.  I heard you yesterday deliberate in trying to decide whether it should be six months or 12 months or forever, and I don't think we have the information on that, so we need to think about that very carefully.
		We need to strategize on policies that will help patients be better compliant, and likewise has been said before, to educate all health care professionals about why Plavix, or clopidogrel in this case, and aspirin are important for that patient and shouldn't be just stopped indiscriminately without talking to the cardiovascular specialist in that regard.
		So those are the short-term strategies that the members are actually looking to hear from the FDA about what they should be doing with their patients.  As I said, in those areas where there's not enough information for you to make that decision or recommendation or where you think it's more in the light of practicing medicine, the ACC would help step forward to help bring a panel together of practicing physicians to help make those decisions and recommendations to the physicians in the interim while we wait for additional data.
		There are nearer term strategies where we need to better define patient selection, particularly when we're using the stents and off-labels.  We would agree that we need better informed consent for both medical PCI and CABG, that there needs to be a better discussion with the patients and their families regarding what their choices are, and we need to look at designing trials that help us to answer the questions to which we don't have answers to now.
		The real crux of ACC's recommendations beyond that is the need for longitudinal database.  We need a unique patient identifier so we can track patients wherever they are, whether they've had CABG or a stent or medical therapy.  We need to have common data standards so that data is collected consistently, and we need independent funding.
		One of the issues that's been passed around is perhaps funding by surcharges of some sort on devices and pharmaceuticals.  Some of this can be built on databases that the STS and ACC already have in place, and those particular databases have over 7.5 million patients in them.  They're not longitudinal at this point, so it does take financial support in order to make them longitudinal, and we need to figure out a way to do that.
		Actually, when you look at all the things you're considering, the most important and exciting thing is the longitudinal database.  It'll benefit patients far greater than anything we've discussed here today.  The value of the positive data collected is much more important than the negative data that we've been talking about, and unique patient identifiers are essential for electronic records going forward.
 		So whether it's beyond the scope of this panel or not, I don't know, but clearly longitudinal databases are needed for device, pharmaceutical, and procedure follow up. Thank you.
		CHAIRPERSON MAISEL: Dr. Dove, please - are you finished?
		DR. DOVE: Yes.
		CHAIRPERSON MAISEL: Great. Perfect.  Thank you.  Our next speaker is Gregory Dehmer from SCAI.
		DR. DEHMER: I'm Gregory Dehmer, practicing interventional cardiologist and President of the Society for Cardiovascular Angiography and Interventions.  On behalf of the Society, I appreciate the opportunity to provide comments to the panel on this important topic.
		I have no personal disclosures, and the Society funded my travel to this meeting.  Like many professional organizations, the Society receives support from industry for its educational programs.
		The Society for Cardiovascular Angiography and Interventions, or SCAI, is a professional association now representing over 3,700 invasive and interventional cardiologists.  As the main professional organization dedicated to the subspecialty of invasive and interventional cardiology, it is the goal of SCAI to provide the best possible information to physicians and patients.  
		For the past 30 years, the Society has diligently promoted excellence in invasive cardiology and quality standards to enhance patient care.  In fulfillment of that mission,  SCAI has been and will continue to be at the forefront in providing guidance to physicians regarding the use of drug-eluting stents.
		Our first position statement was released in 2003, shortly before drug-eluting stents were released for use.  Subsequently, we organized a task force to review critical issues surrounding drug-eluting stents and their introduction into clinical practice.  The report of this task force was published in 2004.
		We later joined the American College of Cardiology and the American Heart Association on updated guidelines for percutaneous coronary interventions, and a third clinical alert on drug-eluting stents is currently under development in collaboration with the ACC and the AHA and will be issued later this month.  As is true of all SCAI official statements, these represent a consensus of our profession's leading experts based an objective review of current research and best practices with the goal of providing the best quality care for our patients.
		Recent analyses of late follow-up data from initial randomized trials of drug-eluting stents suggest the infrequent occurrence of late stent thrombosis after implantation of a drug-eluting stent, but it rates lower than observed for bare metal stents.  
		Since these observations have come into light, there have been diverse comments about the safety of drug-eluting stents.  These concerns have been highlighted in the high profile news reports, causing some patients who have received these stents to become unduly alarmed.  My goal is to put these recent observations and reports into perspective and present what SCAI believes are reasonable actions for the Advisory Panel to consider.
		Over the past two days, there have been many presentations with various estimates of the occurrence of late stent thrombosis and discussions about whether these observations or real or a statistical fluke.  Despite concerns and the potential limitations of these data, SCAI believes this is a real but infrequent event.  Concern for this event is magnified by the fact that late stent thrombosis frequently presents as an acute myocardial infarction.  		Although concern about late stent thrombosis was the motivation for this meeting, we cannot focus on the risk side of this equation without appropriately considering the benefit side.  Like nearly everything else in medicine, the risks must be compared to the benefits.  
		At this point, no cardiologist has refuted the benefits of drug-eluting stents, but we are now asking if the benefits outweigh the risks and by how much.  Weighing the risks versus the benefits is something every physician does in the care of patients.  
		I will further emphasize this point by considering the potential serious complications of warfarin, another drug used widely in patients with cardiovascular disease.  The rate of major complications varies widely from zero to as high as 25 per 100 patient years in some studies.  
		The occurrence of fatal complications also varies from zero to 6.6 per 100 patient years among studies.  Thus, the rate of fatal events from this commonly used therapy are of the same or greater magnitude as those we are now considering as the newly identified risk of drug-eluting stents.
		Perhaps we could derive some lessons from what we teach medical students about using warfarin and applying these to drug-eluting stents.  We do not teach them warfarin is a bad drug that should not be used, but we teach them respect for warfarin and its potential hazards.  
		We teach them four practical things.  First, and this is perhaps self-evident, we teach them not to use this drug unless there is a good indication, because there are risks.  Second, although there may be a good clinical indication, we teach them not to use warfarin if the patient is at high risk for bleeding complications, because the risk outweighs the benefits.
		Third, we teach them how to use warfarin properly, with careful monitoring and anticoagulation.  And finally, we teach them that they must educate the patient about the risks and benefits of warfarin and if possible involve the patient in the decision process. 
		With this example, derived from a drug used in clinical practice for years as a template, SCAI makes the following recommendations.  Some of these are beyond the scope of this panel, beyond the scope that this panel can address.  It's fine to call for reforms in the system, but on Monday morning, many of us will be back in the cath lab or the clinic and need reasonable guidance that will be meaningful to our patients.
		First, physicians should adhere to established guidelines for percutaneous coronary intervention.  Similar to warfarin, physicians must use appropriate indications for PCI, even before considering whether or not to use a drug-eluting stent.  The current  treatment guidelines developed jointly by ACC, AHA, and SCAI outline the clinical situations where PCI is appropriate and inappropriate for use, and these remain a valid guideline to clinicians for selecting patients for PCI. 
		Lesions of intermediate severity may require further evaluation in the catheterization laboratory using techniques such as intravascular ultrasound or fractional flow reserve.  As noted in the guidelines, recommendations apply to most patients but may require modification by existing situations that only the primary treating health care provide can evaluate.
		Outside of the pivotal trials that include a predominance of non-complex lesions, we have gained considerable experience using drug-eluting stents in complex lesions considered to be off label.  These lesions have a higher risk of restenosis and have been shown to derive the greatest benefit from drug-eluting stents.
		After consideration of the risk-benefit ration for specific patients, many of these lesions may be best treated by a drug-eluting stent, and it would be unfortunate for the panel to restrict the use of drug-eluting stents to the non-complex lesions studied in the pivotal trials.
		Second, we should determine if the patient is an appropriate candidate for drug-eluting stents.  Patients may have appropriate clinical indications for PCI and drug-eluting stent placement but may not be an appropriate candidate for this therapy.  Similar to assessing whether the patient is an appropriate candidate for warfarin, clinicians must determine whether the patient is an appropriate candidate for prolonged dual anti-platelet therapy.  
		Strict adherence to dual anti-platelet therapy is necessary, and we support the Class I ACC/AHA/SCAI guideline recommendation that this therapy be continued for 12 months in patients who are not at a high risk of bleeding.  At this time, we do not believe it necessary to mandate the indefinite use of anti-platelet therapy in patients with drug-eluting stents and believe this option is best left to the clinician.  
		Third, drug-eluting stents must be implanted properly, and we need to adhere to the many lessons we have learned from the implantation of earlier stents.
		Fourth, we should increase patient and physician education about drug-eluting stents.  Physicians need to advise their patients or the most current information about the risks and benefits of drug-eluting stents and involve them in their health care decisions.  
		There are several unresolved issues.  One is the incidence of stent thrombosis with drug-eluting stents.  We have heard many excellent presentations but with conflicting results.  Clearly, we need better information in this area.  Second, we do not understand completely the role of drug resistance, and finally, what do we tell our patients with a drug-eluting stent?
		We will be encouraging all patients to read and consider our upcoming clinical alert when advising their patients.  We are developing this in collaboration with the ACC and the AHA and hope to have this available online within the next two weeks.  Thank you.
		CHAIRPERSON MAISEL: Thank you very much, Dr. Dehmer.  The next speaker is Frederick Grover on behalf of STS.
		DR. GROVER: Thank you.  On behalf of the STS, I would like thank the FDA for allowing us to speak today.  The STS is a society that represents over 90 percent of practicing cardiothoracic surgeons with a membership of over 5,000.  I have no disclosures to reveal.
		I think one of the questions that we have to revisit here is why was this panel convened.  Yesterday this presentation or data from the FDA highlighted the fact that the reason for this convening of this panel is stent thrombosis in the drug-eluting stent population.  They noted that there was a higher incidence of stent thrombosis in the drug-eluting stents in both brands in patients that are in the high risk disease or multi-vessel disease group.  In fact, this shows seven times higher.
		But is this what we really out to be focusing on.  It may be the object of this meeting, but I think we're missing the broad picture and the magnitude of the problem, and we're getting too much focused on the pure technology of this treatment and not on the patients themselves and the multiple options that you have for the treatment of patients with ischemic heart disease.
		The magnitude is that there are 3,600 excessive deaths per year in patients with multi-vessel disease or relief stents instead of coronary bypass despite the proven long-term survival of coronary bypass, as noted by my colleague Dr Smith this morning. 
		In addition, Sangay Kaul has previously noted that there are 2,200 additional deaths per year approximately from stent thrombosis, and we now face a $7 billion additional annual cost and potential morbidity and mortality of anti-platelet therapy to treat an iatrogenic disease caused by drug-eluting states, as noted yesterday.
		Well, how did we get here?  The approval of drug-eluting stents was based on comparison trials with a strawman, that is, bare metal stents and the idea of comparing, focusing on restenosis instead of comparing to all options of treatment available, including coronary bypass surgery.  
		Coronary bypass surgery has been performed for approximately 40-plus years and is probably the most heavily studied procedure in the history of the world, and yet these other therapies were not compared to that baseline therapy, which had shown to be highly successful over a number of years.
		There was a highly selected patient enrollment in the randomized clinical trials, as a matter of fact, only about four percent of patients screened.  The pivotal trails were inadequately -- in addition, they were inadequately powered for patient benefit end points using instead surrogate end points and were in short duration.
		The results of these select few trials are generalized to the population as a whole, and what's somewhat amazing to me is that greater than 60 percent of patients receiving stents are receiving drug-eluting stents for off-label multi-vessel disease, and as we heard this morning, it may be 80 percent.  And you could wonder how can this happen without comparing it to other modes of therapy?  Where were we when we were watching this develop, because it's taken off with a life of its own, I think, much, much greater than was probably anticipated.
		Th other issue that we have serious concern with, and Jim Dove covered this very nicely a few minutes ago, is that patients do not receive adequate informed consent after the diagnostic catheterization, before entering into an interventional procedure.  
		There has been misrepresentation of current coronary bypass results, as we heard yesterday, but most importantly, there is inadequate opportunity for other care givers, surgeons, non-interventional cardiologists, primary care physicians, to render an opinion regarding each therapy, especially regarding long-term survival and benefit, and I think this is a real moral and ethical problem.  
		If there's anything that's really important in medicine it is transparency, and it's having fully informed patients that fully understand the multiple options available to them, and I certainly hope that personally I'm very -- try to be as honest about the various options of therapy and try not to just push what procedure I happen to do myself, and I thin we all need to take a hard look at that and try to do better with that, and that's something our professional societies can work on.
		There are common problems in patients with drug-eluting stents that I think surgeons perhaps see more than a lot of other people, and yesterday and today you've heard a lot of discussion about the potential complications of clopidogrel usage with bleeding or what happens if you stop it with sudden thrombosis of stents.  As chairman of a department of surgery with eight divisions and 120 faculty, a lot of different specialities, I can tell you that a lot of operations are being postponed now, operations that need to be done because patients are on clopidogrel, and there's no antidote for that.  You have to wait for it to wear off unless you go into a lot of blood transfusions and platelet transfusions for those patients that absolutely can't wait and have to be done, and that increases the risk of those procedures, and that's something that really needs to be studied, as well.
		The additional complexity that we face, those of us doing coronary bypass after drug-eluting stents have been placed I think is underestimated at times.  There are frequently decreased left ventricular function in these patients, and in some patients there's actually -- it's impossible to find a place to put a bypass graph, because the vessel has what we call a full metal jacket, and this affects that patient's prognosis.
		It's interesting to note that six of the last 50 patients -- that's 12 percent -- who received a heart transplant at Duke University Medical Center had that heart transplant as a result of stent thrombosis, and there have recently been two more patients added to the list.
		Now I want to point that, as Jim Dove has, that the STS and the ACC have considerable database experience.  The STS database has over three million patients.  Over 2.5 million of those patients are coronary bypass patients from 80 percent of U.S. cardiac surgical centers, and we've had preliminary discussions.  
		And this is a database that's voluntary, and it is paid for by our membership and has been in place since 1989 and has demonstrated marked reduction in risk adjusted mortality for coronary bypass and other adult cardiac procedures in the decade of the nineties and the first five years of this decade.  We've had preliminary discussions with the leadership of the ACC and the STS about joint database usage, linking our database to track outcomes of cardiovascular interventions, and I think ths particular topic we're talking about today will lend itself to that opportunity.
		Now just shifting gears a little bit, yesterday evening we picked this up on the internet, and I must say this was very disturbing to me.  The headline, "FDA: Heart Stents Don't Up the Risk of Death."  Now this is coming out with no specification of what patient groups, not even 50 percent into a very important hearing.  
		So I think it shows that how we behave or how we conduct these hearings really affects what's put out to the public and patient education.  Now we would agree that this headline is probably correct in the context of single vessel disease as demonstrated in the pivotal trials.  
		However, off-label use of drug-eluting stents, particularly in multi-vessel disease, is a major public health problem causing unnecessary deaths, and this did not recognize that, and we seek to help solve this problem by the following recommendations: the labeling change for drug-eluting stents to reflect the fact that the safety and effectiveness of stenting in multi-vessel disease has not been established; adequate informed consent of all patients of all treatment options by a multi disciplinary team before intervention in multi-vessel disease; use of robust, comprehensive databases to assist the FDA, clinicians, and industry to determine appropriate therapy in various subsets of patients with coronary artery disease; and finally, and this is a request, a stronger FDA-specialties society partnership utilizing the combined strengths of the FDA, the STS, the ACC, and the medical device industry working to deliver better and safer care to our patients.  Thank you.
		CHAIRPERSON MAISEL: Thank you very much for your comments.  Our next speaker is Sidney Smith on behalf of the AHA.
		DR. SMITH: Dr. Maisel, distinguished panelists, FDA colleagues, and concerned members of the public, I'm Dr. Sidney Smith.  I'm a cardiologist with experience in research and clinical care of adults with cardiovascular disease, and I speak today on behalf of the American Heart Association, a voluntary health organization with over 22 million volunteers and supporters dedicated since 1924 to the reduction of disability and death from cardiovascular disease.
		The AHA engages in a broad range of activities, which includes research, patient and provider education, community-based programs, advocacy initiatives, and our guideline efforts with the ACC, and that's what brings me to the podium today.  I should mention that my travel expenses were paid by AHA.  
		The relationship with industry for the guidelines that I'll be referring to are published.  All members of the committee and reviewers can be found in the publication, and the AHA, should note, receives 3.6 percent of its revenues from industry contributions, one percent from the biomedical pharmaceutical industry.  The majority of AHA money comes from small donors around the country, as I mentioned, over 22 million volunteers.
		Our multi-stakeholder evidence-based clinical practice guidelines are particularly relevant to today's discussion.  I currently chair the task force on practice guidelines for the ACC and AHA, and I chaired the task force writing group for the guidelines on PCI.
		We feel that it's important for the AHA to be involved in the guideline effort and especially pertinent with regard to the PCI guidelines today.  The development of these guidelines involved a rigorous use of evidence-based medicine.  We weigh very carefully the benefits and risk that are involved in patient care, and I'll discuss later our specific recommendations regarding PCI that are pertinent to the drug-eluting stent issues.
		We have jointly been involved, the AHA and ACC, in the development guidelines since 1984, and this process is overseen by the task force which I currently chair and have mentioned to you.  Experts with specific experience in the guidelines being developed are selected, as well as knowledgeable others to perform a formal literature review, weigh the strength of evidence, and develop a consensus recommendation focusing on health outcomes.
		Wherever possible, cost is evaluated, but the safety and efficacy of patient care are primary considerations.  The guidelines are intended to assist health care providers in clinical decision-making by describing a range of acceptable approaches for the management or prevention of conditions.
		They attempted to find practices that meet the needs of most patients in most circumstances, but ultimately, however, the appropriate plan of care for an individual patient must be developed by the patient and their provider in the light of all clinically pertinent considerations available.
		Now this meeting is intended to address the issues that pertain to the function of a particular medical device, that is, the coronary artery drug-eluting stent.  My testimony will focus on what the AHA feels is a particularly serious risk regarding the clinical management of these devices, the substantial potential for thrombi to form when anti-platelet drugs are stopped prematurely during the first year after stent placement.
		After careful review of the scientific evidence, these are our recommendations as they now stand in 2005 for patients undergoing PCI.  One, patients who undergo placement of a bare metal stent should be treated with aspirin, 325 milligrams, and clopidogrel, 75 milligrams, for one month after stent placement.  
		Two, patients who undergo sirolimus-eluting stents should be treated with the same regimen for three months.  Three, patients undergoing paclitaxel-eluting stents should be treated with the same regimen for six months.  Four, patients at low risk for bleeding should be maintained on the above regimen for 12 months.
		The current recommendations then are for 12 months with the minimal criteria that I just specified.  Patients who have undergone any type of stent for coronary disease should be maintained on aspirin indefinitely.
		Although the initial study suggested the risk of in-stent thrombosis was small, the clinical trials that led to the FDA approval were conducted in a narrow range of low risk patients by experienced investigators who carefully followed detailed experimental protocols.  These conditions are rarely duplicated in day-to-day clinical practice, an important point, I believe, where off-label use is common.
		Mortality rates due to coronary stent thrombosis are substantial, but the incidence of thrombosis is only one percent if anti-platelet medications are taken as indicated.  Thrombosis risk increases substantially when thienopyridines are stopped too early.
		In the PREMIER registry, a multi-center database of patients with myocardial infarction who had received drug-eluting stents and discontinued thienopyridine therapy within 30 days following stent placement, patients were much more likely to die than those who continued as directed, the difference being striking, 7.5 percent mortality versus .7 percent.  Indeed, premature discontinuation of thienopyridine therapy is the single most important predictor of stent thrombosis.
		In the PREMIER study, 13.6 percent, or about one in seven, discontinued standard recommended anti-platelet therapy within a month of the procedure.  Technical factors make it possible that this is an underestimate.  
		As a group, these patients were older, sicker, poorer, less well educated, and lacking in social support.  They were also less likely to have received discharge instructions regarding their medications.  We believe this discontinuation of therapy is a serious problem, which should be addressed by this committee.
		Many reasons could explain why patients who have undergone coronary artery stenting stop taking their drugs.  For some, the cost of medication is prohibitive, and a falsely economy dictates its discontinuation.  The cost of their drugs is a real concern to many Americans.
		Patients and their providers may misunderstand the risk or be unaware of the guidelines for anti-platelet therapy.  Well intentioned patients and their physicians may overestimate the risk of bleeding when patients taking these drugs undergo an invasive procedure.  That's important particularly with dental work these days.
		An unrealistic fear of bleeding, coupled with ignorance of the consequence of coronary artery stent thrombosis can be lethal.  Lower educational achievement may also contribute to a fatal misunderstanding.
		We believe that the FDA, this panel, and all those participating in these hearings have a great opportunity to publicize and address the problem of premature discontinuation of thienopyridine therapy for the first year following placement of a drug-eluting stent.  Physicians who place coronary artery stents should take great care that they communicate the rationale for this drug regimen to their patients and particularly the risk of prematurely discontinuing the medication.
 		Other providers planning to perform invasive procedures on these patients should carefully balance the risk and benefits of discontinuing anti-platelet therapy.  Patients share responsibility for their care.  Particularly responsibility to thoroughly understand the plan of care should be communicated by the physician.
		During the entire first year following stent placement, patients and all providers participating in their care should consult the interventional cardiologist who placed the stent before stopping aspirin and clopidogrel.  The data clearly indicate that any decision to modify recommended anti-platelet therapy during the first year must be regarded as a highly individualized form of therapy which requires thoroughly balancing the benefits with considerable risk attendant to that choice.  
		The AHA is working with other multiple major organizations to issue and advisory on this matter, which Dr. Dehmer referenced.  The ACC/AHA/SCAI guidelines for percutaneous coronary intervention define the regimen of anti-platelet therapy most likely to prevent stent thrombosis.  Studies are now defining the incidence of risk factors for late stent thrombosis.
		As the panel knows, one study regarding this issue was published last week, and I just would like to say that at this point, from a guidelines standpoint, it's inappropriate for me to predict the outcome, but we will be following the deliberations of this committee very closely and be convening our group upon the completion of this procedure to determine whether a change in guidelines might be necessary.
		Though the risk of myocardial infarction or death with stent thrombosis is substantial, the actual number of patients is small.  The research questions which we feel are important include a refined selection criteria for the devices, technical approaches to complex interventions, the proper duration of dual anti-platelet therapy, and methods to promote good communication in clinical decision-making.  And I want to thank you for the opportunity to be here and will be available for questions at the conclusion.
		CHAIRPERSON MAISEL: Thank you very much.  Our next speaker is Mark Turco.
		DR. TURCO: Thank you.  My name is Mark Turco.  I am a interventional cardiologist at Washington Adventist Hospital and also Director of Center for Cardiac and Vascular Research of Washington Adventist Hospital.  I have no conflicts to report with respect to this presentation, and I would like to make some very brief comments with respect to the field of interventional cardiology and where we have come with drug-eluting stents and how it may be pertinent to some of the discussions that we have had over the last two days.
		As you can see, we started with our first angioplasty back in 1977, moving on to the first stent implant in 1986, and then the results of the stent and BENESTENT data from 1994, first in manned results with the CYPHER stent in 2000, 2001 with Ravel.  2002, we entered the drug-eluting stent era, and then the commercial availability of the CYPHER stent in 2003 and the TAXUS stent in the United States in 2004.
		And I present this historical background as a way to understand that we have had hiccups along the say as we have approached the evolution of our interventional treatments.  We are now to 2005 and beyond, and we are learning newer and newer things about the current drug-eluting stent platforms and will hopefully look forward to the new generation drug-eluting stent platforms that will play a role in treating out patients.
		If we go back and look at the history of stent thrombosis in the bare metal stent era, you can see that, again, we started with the PALMA stent era in 1991 with a very high incidence of stent thrombosis, upwards of 16 percent.  And then as we learned over the years, and as we modified our techniques, you can see that the incidence of stent thrombosis clearly dropped off as we learned more and more about our technologies.
		So what do we know about considerations for drug-eluting stent utilization?  Well, safety is obviously very paramount with regards to death, myocardial infarction, and stent thrombosis, efficacy from the standpoint of biological activity, the suppression of in-stent intimal hyperplasia, and the clinical benefit prevention of repeat revascularization events.
		Deliverability, we need user friendly features, the durability of the system, sustained efficacy over time.  Indication and patient selection is paramount, and deployment techniques as we continue to refine these over the years.
		As you can see, if we look at the bare metal stent to the current first generation stent, drug-eluting stent platforms, you can see where they fit, and this is my own iterations of efficacy, safety, deliverability, and durability, and you can see that bare metal stents may have a slight advantage, may have a slight advantage in safety.  
		There are bare metal stents that are clearly more deliverable than some of the first generation drug-eluting stents, and some bare metal stents may show increased durability over the first generation drug-eluting stents.  So clearly we have potential areas for improvement in our future technologies.
		As we all know, there has been a ravenous use of drug-eluting stents, and you can see over the years the fall-off of balloon angioplasty in red.  You can see the fall-off  of bare metal stent, although if we take it out to the year 2006, you would probably see  an upward turn in bare metal stent utilization, given all of the stent thrombosis frenzy that is occurring, and you can see the drug-eluting stent utilization increase over the years.
		I will not spend much time on the next three slides, because you have seen these over and over again, but this is the independent CRF analysis of the protocol-driven stent thrombosis results, and you can see that from years one to three for both CYPHER and TAXUS there is a slight statistically increased rate of subacute stent thrombosis.  
		However, we also see that this does not affect ischemic driven target lesion revascularization, which is clearly in benefit of the drug-eluting stent, and from a safety standpoint, you can see that there is clear cut no difference between death or myocardial infarction between drug-eluting stents and bare metal stents.
		So it has been mentioned the drug-eluting stents in high risk patients and lesions subsets, which in some cases encompasses over 60 percent of the patients that are currently being treated, and these include the patient subsets listed here.  The stent thrombosis issue is quite a complex interaction.  There are procedural issues, there are device issues, and there are patient  related issues that lead into our stent thrombosis problems.
		And looking at it on this slide with regards to the four possible areas leading into stent thrombosis, one, and certainly probably the most important is the discontinuation of anti-platelet therapy, the delay endothelialization that occurs, the polymer hypersensitivity and inflammation that occurs, and the possibility that late incomplete stent apposition affects late stent thrombosis.  And these are all areas that we can improve upon with newer generation drug-eluting stent platforms.
		Is the answer just to increase the Plavix duration?  Well, if we look at what we know from the Plavix studies, from CURE, CREDO, and CHARISMA, you can see that the -- with aspirin and clopidogrel there is a slight but statistically significant increase in complications, specifically bleeding.
		So if we look at where we are with our technology life cycle, you can see I like to look at it as a two wave phenomenon.  We started off with incredible enthusiasm with more perception of drug-eluting stents than actual data.  That moved to rapid adoption of the technologies with significant amounts of data from both companies that are currently available.
		And then we have moved to a second wave, where now we have a perception issue which is likely greater than the actual data, and that perception issue of untold complications.  Soon we will hopefully move to a realistic application where the data will far outweigh the perception.
		We still, as I have mentioned, have significant unmet clinical needs in the interventional community for treatment of the diabetic patient with vascular disease, for treatment of the patient with multi-vessel diffuse disease, for bifurcation lesions, for chronic total occlusions, and for left, main, and osteal disease.  These are all areas where we still have clinical and unmet needs for drug-eluting stents.
		As has been mentioned, there are many answers to come as we move forward with post-market data.  The stent thrombosis registry will look at 10,000 patients.  The E-Select registry will look at over 30,000 patients, and the PROTECT trial will look at 8,000 patients, and this should give us some further answers and hep with the evolution of some of the unknown answers to some of the questions that we currently have.
		So in conclusion, we must weigh the risks and benefits when using drug-eluting stents.  We have clear-cut benefits, and I would say that the risks of the use of drug-eluting stents are quite small.  
		The DES device-related contribution to late stent thrombosis are poorly understand but certainly need to be determined.  We must focus on safety first and solve any dilemma of late stent thrombosis associated with drug-eluting stents while preserving clinical efficacy.  
		New drug carrier systems need to be appropriately and aggressively evaluated, and if we do not continue to push forward and add to the advances of drug-eluting stents that we currently have, we'll be left with needs that we have not met.  Thank you, and I appreciate the opportunity to address the panel.
		CHAIRPERSON MAISEL: Thank you very much.  At this point we'll move on to our unscheduled speakers, who will be allotted five minutes each.  The first one is Ryszard Rokicki.
		MR. ROKICKI: Good afternoon.  My name is Ryszard Rokicki.  I'm electrochemist involved in electropolishing medical device.  I would like to read my challenge letter entitled --
		CHAIRPERSON MAISEL: Can you move your microphone down?  Can you speak into the microphone?  Thank you.
		MR. ROKICKI: -- "When Changing One Word Can Save a Life: Bare Instead of Eluting," in which I try to raise awareness with probably is a simpler and cheaper way to resolve problem of stent restenosis and stent thrombosis simultaneously by modifying surface of bare metal stents.
		I'd like to add some comments and challenge the established authorities, the stent producers, medical academic professionals, FDA regulators, and also medical insurance companies to reconsider the usage and undertake additional research in direction to help improvement of bare stent metal.
		In the last two decades, stents, which are used in over 90 percent of percutaneous coronary intervention revolutionized balloon angioplasty by cutting the rate of post procedural stenosis.  This tremendous reduction  was again cut in recent years by using drug-eluting stent. 
		It seems the perfect solution had been reached, but unfortunately, this was only an illusion.  Some researcher and practitioner cautioned their concern about long-term outcome of drug-eluting stent almost from the beginning of their approval by FDA.  They are recommending them only for high risk patient or for very specific vessels.
		Recently these concerns have started to resonate more strongly as more detailed data arrive, BASKET, BASKET-LATE.  These trials suggest with the unrestrictive and overwhelming use of drug-eluting stents has created a trade-off between stent restenosis versus death or main health hazard of late thrombosis.
		Even the primary stent producer, Boston Scientific, recently acknowledged the greater risk of late stent thrombosis from usage of their TAXUS drug-eluting stents.  Also, all these events concerning drug-eluting stent influence FDA to hold this public meeting.
  		I write these comments both as inventor, as a potential future recipient of stents.  Eighteen months ago, I underwent quintuple coronary bypass surgery.  When it comes to human health, I, like everyone else, have unquestionable rights to demand the best available treatment, which in this case means the best stent.
		As an inventor for last several years, I have worked on improvement of metallic surfaces toward better bio- and heamocompatibility.  I came up with patent pending process, which I called magneto-electropolishing.  
		The main advantage of this process over standard electropolishing used as finishing step in production of bare metal stent is the profound improvement of surface wetability, about 25 percent for 316L stainless steel and even more for Nitinol.
		According to a lot of research, more wetable surfaces are more thromboresistant.  There is good guide wire data to supporting this, and also more favorable to faster and more complete integration with connective tissue. 
		Some thromboresistivity tests have shown the superiority of magneto-electropolish 316L stainless steel over electropolished one.  The hypothesis is that more wetable surfaces are more hydrated when they come in contact with blood and that this factor is probably responsible for minimizing protein absorption and conformation, which eventually minimize platelet adhesion, leading to better thromboresistivity.
		I have reason to suspect that metallic surfaces with increased wetability could be more favorable to faster and more perfect endothelialization, which subsequently should lead to minimization in stent restenosis.  I challenge stent producer, medical academic professional, FDA authorities and medical insurance company to rethink drug-eluting stent programs and to work on bare metal stent improvement for health benefits of stent recipients and also for cost reduction.
		Maybe the old saying "More expensive doesn't mean better" will prove itself again, and the often used phrase "next generation of drug-eluting stents" will be replaced by the next generation of bare metal stents, with better results.
		CHAIRPERSON MAISEL: Thank you very much for your comments.  I'd like to move on now to the next speaker, Rich Dulin.  Is Mr. Dulin here?
		MR. DULIN: Good afternoon.  My name is Rick --
		CHAIRPERSON MAISEL: Can you press the button on the bottom right of your mic?
		MR. DULIN: Good afternoon.  My name is Rick Dulin.  Rick.  In November of 1997, after experiencing chest pain for several weeks, I went to the hospital and learned that I had distal heart disease and blockage in all of my vessels.  This required that I undergo a three-vessel bypass.  
		I was doing fine, I thought, until I experienced angina in March of 2006.  I went again to the same hospital, and a cardiac cath was performed.  Immediately after the procedure, while I lay on the OR recovery table with a compress on my -- with a compress on my groin, I was introduced to a cardiologist and a research coordinator.
		They began to explain to me that the three vessels had closed and that I required a stent.  They recommended, because of the condition of my arteries, that I elect to participate in a clinical trial with a new type of stent that released a medicine that prevented clotting.
		Did I ask questions?  No.  Did I fully comprehend what was happening?  No.  I only knew that I wanted to live.  They had clipboards and many forms for me to sign, and I signed them all from my flat position on the recovery table.  I was then officially enrolled in the SPIRIT III clinical trial where the XIENCE and TAXUS stents are being evaluated.
		Since March of this year, I have had many instances where I have needed some level of support, especially in the last few months, with all of the information regarding the safety of the devices, their impact on us with heart disease, and how I am to carry on with my life.  When I feel somewhat discomfort, this need for support is really obvious.
		On last week, I logged onto MSNBC and read an article that stated something along the lines of tiny time bombs ticking in the hearts of patients and experienced a fear like none other that I have had in my life.  I immediately called the telephone number of the research coordinator listed on my card that I've carried in my wallet since March and got her voicemail, stating that she was on vacation until the next week and was given another number to call.  I called it and left a message.
		The next day, someone called me back, listened to my concerns, and noted that they had not heard of any issues with the stent, and I shouldn't be alarmed.  I asked for the person's email address and sent an email of the link to the article that had prompted me to call.  I was then called back two days later, right before Thanksgiving, and the research coordinator asked if I would come in for a follow-up appointment, which I did.
		What I would like for the panel to please hear and to realize from this experience is this very lack of support services available to persons who are experiencing adverse emotional or physical responses from this.  Patients report that they get this device and are left to figure out the rest by themselves.  The disconnect is huge.
		On my last visit to a web site, there were about 300 paragraphs of responses to this article regarding the fear raised about this event from actual patients.  The vast majority of the persons who had written had experienced some type of adverse event and note the lack of support services.
		My questions to unanswered, other than I was able to find a web site online called angioplasty.com or .org, and they had another set of responses that I could read.  But for those who don't have internet access and are just not a part of this new electronic communication generation, please, panel, examine how those patients can also have access to this very important information and needed support.
		Finally, may I suggest that the panel examine how this, for me, highly complex information can be presented in a culturally accurate, linguistically diverse, and accurate literacy level for the millions of persons in our country who are impacted by this so that support services can be developed and provided to the entire patient population that have received one of these stents.
		On yesterday, I requested to speak in the unannounced segment of the meeting, but I left out of a fear that I had experienced on learning so much confusing information, which I know to be indicative of what others are also feeling based on the posted responses on so many different websites.  I went home and got in my bed.
		As a patient with this device in my heart, I ask that the panel please take under consideration how the implantation of these devices must be coordinated to also include the development and provision of compassionate care, supportive services via a provision of accurate information that will reach each patient.  
		This will serve as a means of educating those of us who are living with the fear of not knowing what's next and reading articles that prompt us to be alarmed.  This will also assist physicians responsible for monitoring these devices.
		On yesterday I learned that the percentage of stents implanted off label was approximately 60 percent, and then I read it in an article, and I'm still trying to figure out exactly what it means.  How can these services not be provided?  
		I've read that fear is false evidence appearing real, but if these stents are really doing what they are supposed to do, please help alleviate the fear that many persons such as myself are experiencing.  Thank you for the opportunity to speak.
		CHAIRPERSON MAISEL: Thank you very much for your eloquent comments, and I'm glad that you chose to come back today and share that with this panel.  I am going to open up the panel for panel discussion of asking any of the previous speakers questions and perhaps, Ms. Mottle, I can start with you.  Maybe you can comment on Mr. Dulin's comments or anything else that's on your mind.
		MS. MOTTLE: They were wonderful, Mr. Dulin.  Thank you.  First, I'd like to thank many of our global presenters for providing this panel with the copious and yet current data regarding DES stents.  
		What is heartening in all of this confusing information is, in the data analysis, is that the continuous and persistent scrutiny to obtain the most relevant and real world applicable safety and efficacy data to appropriately evaluate these emerging combination products that continue to substantially impact millions of heart patients worldwide.
		These DES products have proven clinical efficacy with dramatic reductions in restenosis and the need for revascularization procedures, yet the data remains conflicting, primarily on the safety side of the equation, especially for ST, risk occurrence, relationships between subset of populations, high risk patients, selection criteria, optimal utilization, and the off-label usage that continues to rise.
		It's evident that we must have better data sets over longer time periods that are comparable, with adequate power to detect the more complex risk profile in both pre- and post-marketing data sets and encourage sponsor financing, both public and private, coordination among our professional societies, and public registries for developing these appropriate data sets.
  		Of concern to me are the outstanding issues of higher risk patient selection criterias.  Should all of the subset patient categories have repeated DES, and how many times? Do we need full jackets in everybody?  What are the drug-to-drug interactions?  What are the bleeding risks for long-term anti-platelet therapy with higher risk subset of patients?
  		What are the complication rates in reality for these high risk patients for non-compliance, and how do we determine those appropriately and select the right patient candidates for these products that are a package deal, as was so said?  
		And of personal concern is the concern regarding informed consent.  As was just stated by a patient who has received a stent, there are times when we have very poor processes for informed consent, true informed consent of our patients.  
		My own brother has two different DES stents, neither of which he was told about until after they were in, and I think that that is something we really need to look at, informing our professionals and the entire health care community to help educate our consumers and have them participate whenever possible in the selection of the appropriate therapy and treatment indication for their particular circumstances.
		CHAIRPERSON MAISEL: Ms. Mottle, I'm going to interrupt you for now.  We'll have other opportunity for panel members to speak, but I want to let the panel question the speakers we just had.  So, Dr. Domanski?
		DR. DOMANSKI: You know, I'd like to ask Dr. Smith a question, if I could.  You know, thank you for coming today.  You know, I have -- I do have a question about the clopidogrel.  It appears to be -- there's at least a hint that it indeed is protective with regard to stent thrombosis, perhaps even long term, and I'm intrigued by the fact that you settle on 12 months, and I guess I'm wondering about the rationale for stopping at 12.  I mean, why not 11 months or 14 months or even 38 or as long as the patient tolerates it?
		DR. SMITH: Thank you.  Yes, I think we hit it just about right.  In listening, from what I've heard here it was PCI, CURE, CREDO that really sort of resulted in the nine-month to 12-month discussion, and we decided if everything is fine, and that is you're not having bleeding problems, and you can continue the medication for up to a year, that would be desirable.
		We then relied on the qualification for the FDA, which was one month for bare metal, three for sirolimus, and six for paclitaxel as the minimal duration, and I think that overall we came out pretty well with the guideline recommendations, all of which are Class I.  We, of course, were interested in CHARISMA, which was a different group of patients but really didn't have data out beyond a year to support a strong recommendation there. 
		Now we're confronted with what we know, and that is people who don't do this have significant problems, and we need to correct that.  That's easily preventable, and then what we don't know is the significance of a small incidence of stent thrombosis late and how we might approach that, whether we need to define subsets where there's an increased risk or whether we increase the duration of the dual anti-platelet therapy.
		CHAIRPERSON MAISEL: Dr. Domanski, did you have a follow-up question?
		DR. DOMANSKI: Yes, I was just -- I was just going to pursue that for one more second. 
		CHAIRPERSON MAISEL: Sure.
		DR. DOMANSKI: So you're -- I just want to make sure.  I thought I heard you say it, but let me make sure that you contemplate revisiting those guidelines with the -- anticipating that you're at least going to have to consider extending the time frame for the clopidogrel.  Did I hear that, or maybe I didn't?
		DR. SMITH: Well, you heard me correctly, and I don't want to understate my enthusiasm for the fact that the folks are here around the table and that you're pulling this testimony together.  The ACC/AHA guideline group will look very carefully at your deliberations, weigh all the evidence presented, and see if it looks like a change or additional guidelines are necessary.
		I wouldn't want to preempt that process by telling you want I think will happen, but, you know, among the possibilities are a better definition of subsets that are at increased risk and possibly a change in the recommendation for the duration of therapy.
		We have to learn, figure out exactly how long it's going to go on and what the periods of risk are.  There's some tricky questions there, but the deliberations here of this group are extremely important to the guideline process of ACC and AHA.
		CHAIRPERSON MAISEL: Thank you.  Dr. Harrington?
		DR. HARRINGTON: Dr. Smith, my question is for you, as well.  In your remarks, you note that you're going to -- you are focusing on the recommendations regarding discontinuation of anti-platelet therapy.  That's assuming that the clinician has already chosen to put some sort of stent in, either DES or bare metal.
		Is the AHA going to make recommendations around choice of bare metal versus drug-eluting stent?  In other words, if patients are felt to be at high risk of bleeding, needing another surgery, at high risk of non-compliance, et cetera, will the AHA weigh in on that?
		DR. SMITH: Well, first of all, it'll be the ACC, AHA, and SCAI, but it's the three groups in the process, and I think that if evidence emerges where that's important, we will.  Initially, the concern that came up as we wrote the guidelines was whether or not there was evidence about the safety of DES in acute coronary syndromes, and that was a long discussion.  
		Secondly, it certainly is something that all of us do in recommending the bare metal stents if patients have upcoming surgery, and you need to have surgery quickly.  So I think that there might well be a refinement of recommendations on stent selection that would apply to certain clinical conditions.  That gets right at your question.
		CHAIRPERSON MAISEL: Thank you very much.  At this point, we're going to move on to the FDA questions and the consideration of real world clinical use of drug-eluting stents. 
		Before we put the first question up, I was hoping, Dr. Zuckerman, that maybe you could put this all in perspective.  It's a little unusual for the FDA to convene a panel meeting to talk about off-label use, as the FDA does not regulate the practice of medicine, and perhaps provide some guidance for this panel as to what is and is not within our purview here.
		DR. ZUCKERMAN: Thank you.  As Dr. Farb indicated in his opening comments yesterday, FDA is an important component of HHS, and first and foremost, we have an important public health mission.  While it is not our usual structure to extensively regulate the practice of medicine, and the relationship between a physician and patient and choice of device used is an extremely important one that we don't want to tamper with, when there is a significant public health problem, the Agency, FDA, as well as HHS, cannot ignore it, and I think in our two days of deliberations we've heard that we have signals that need to be very seriously looked at, and hence we've convened this very important scientific body and post-panel advisory meeting.
		In your work over the next two hours, we look forward to hearing the best scientific advice.  I'm sure that there will be some discussions regarding whether this should -- this particular recommendation or that particular recommendation should go in a label versus, perhaps, a different type of FDA notification.
		I think that those considerations the Agency can continue to deliberate on post-panel, but what we're most interested in is, one, what do the data say for off-label use right now, what current scientific recommendations can be based on these data, and what subsequent steps can the Agency take with professional societies, investigators, and the industry to gather data in the form of new trials to better answer these questions?  So yes, this isn't the usual type of panel meeting, but it's an extremely important one.
		CHAIRPERSON MAISEL: Thank you very much for your comments, and I'll ask Ashley Boam to put up today's first question, which is question three, and to read the first paragraph.
		MS. BOAM: "The pivotal randomized trials of CYPHER and TAXUS submitted for FDA approval primarily involved use of drug-eluting stents in non-complex patients and lesions.  Following these approvals, it is estimated that a majority of drug-eluting stents are implanted in lesions outside of their current indications for use, such as in in-stent restenosis lesions, bifurcation lesions, coronary artery bypass grafts, acute myocardial infarction, chronic total occlusions, overlapping and multiple stents per vessel, and in patients with multi-vessel disease and chronic renal insufficiency.
		Given the currently available data, are there safety concerns regarding stent thrombosis, death, and myocardial infarction rates for drug-eluting stent use in these complex patients and lesions?"
		CHAIRPERSON MAISEL: And can you read question A, as well?
		MS. BOAM: Question A is, "If so, can lesion subsets or patient populations at a particularly higher risk of drug-eluting stent thrombosis within the `off-label' patient population be identified?"
		CHAIRPERSON MAISEL: Thank you. So I'd like to open it up for panel discussion regarding these questions, the safety concerns regarding stent thrombosis, death, and MI in off-label use.
		DR. NORMAND: Bill, can you -- I'm sorry, but I don't think -- I think it would be productive if we had a conversation knowing relative to what.  It's just very difficult to have this discussion without knowing --
		CHAIRPERSON MAISEL: That is part of the discussion.
		DR. NORMAND: Okay.
		CHAIRPERSON MAISEL: So we're talking about safety concerns regarding stent thrombosis, death and myocardial infarction, and part of that conversation is with regard to what, and we -- Dr. Nissen had his hand up first.
		DR. NISSEN: Okay, so the first question in think we have to answer is do we have reason to believe, based upon what we've heard over the last two days, that the relative efficacy and safety of drug-eluting stents compared -- I want to compare it to bare metal stents, because that is the most germane alternative.  
		Do we have evidence that that safety-efficacy balance might be different in the off-label use?  And I think that we've heard enough to suggest that that's the case, that we know these are more complex lesions.  We know multi-vessel left main.  We know that increases the incidence of these safety concerns.
		We also know from all kinds of data that people that participate in clinical trials are generally healthier.  They tend to be more compliant, take their medication better, and we know that premature discontinuation of clopidogrel is a major risk factor.
		And we know, for example, that in the real world, when you have to pay for your medicines, you may be less likely to take them, so cost has an effect on compliance.  So for all kinds of reasons, what we saw in the clinical trials probably represents a best case scenario for that safety-efficacy balance.
		So the first part of this is I would have to conclude that there are likely to be differences and that what we saw in the randomized trial experience, which was essentially equivalents, is likely to be the best that we're going to see with these comparisons.
     	So then the question is, you know, what do we know?  Well the problem with almost all the registry data that we saw here is that there's no comparison.  It's one-armed, as I think several of you pointed out, but there are some examples where they're not single-armed, and that's the Swedish data.
		And I know, John, you're concerned about the OUS and all that, but it's 60,000 patients, very well studied.  Dr. Topol makes the point about follow-up, and these folks were very well followed up.  And if you look at it critically, what you see is there is approximately a 20 percent higher mortality in real world use in individuals that got drug-eluting stents compared to bare metal stents, so I cannot exclude that there is an increased mortality in patients that get drug-eluting stents in the real world.
		Having said that, therefore, I would put on the table for your consideration the possibility that using its various means of communication that the Agency should clearly communicate that the efficacy versus safety relationship has not been established for patient subsets not included in the randomized trials that led to the approval of drug-eluting stents and that further studies need to be done in those populations in order to determine whether the efficacy exceeds the safety concerns.
		CHAIRPERSON MAISEL: Dr. Somberg.
		DR. SOMBERG: Well, it's always interesting how different people look at this situation.  I hear what Dr. Nissen is saying, but at the same time, I look at it differently, that I noticed that there was increased risk of stent thrombosis with complexity being bifurcations or being low ejection fraction or what have you, and that increased risk was with bare metal stents, and it was with drug-eluting stents.
		And I also noticed that there was, and this is a perplexing problem that I don't think we have a resolution to, but there is a difference between, and it's not outside the U.S.  It's European and Scandinavian databases and U.S. databases, and while, yes, the Swedish study is very large, there are a number of small ones we were presented which do show very marked differences in constant increments, you know, almost exponential curve here of increment in risk that is multi times what we see in the United States.  So there's something different here in what we're seeing.
		Certainly nothing's been established in terms of safety and efficacy, because it's off-label.  This was in randomized controlled studies to begin with, and there's no labeling of product, but there is a risk.  I think it should be so stated. 
		It's increased, and at the same time, I think that has implications for two important areas. One is future stent development, and two is what remedies do we have to offer, and there have been very good studies -- 
		CHAIRPERSON MAISEL: Dr. Somberg, do you mean an increased compared to on-label use or increase compared to bare metal stent?
		DR. SOMBERG: Increase compared to  -- first of all, higher complexity of problems, et cetera, off-label use is increased compared to lower complexity on-label use.  That's true for bare metal and for drug-eluting stents, but I think it certainly goes up for drug-eluting stents even more, especially in the outside U.S. studies.
		So anyway, I was trying to say is I think we have things that we can address and discuss in terms of remedy, in terms of future direction.
		CHAIRPERSON MAISEL: Dr. Harrington.
		DR. HARRINGTON: So to look first at the question of off-label use, I want to draw our attention again to the magnitude of the issue here.  The FDA quoted us 60 percent of the stents implanted being off-label, and the Prairie Heart presentation suggests in their practice it may be as high as 75 percent, so for me, Bill, these are the real critical discussions, because this is the vast majority of the patients.
		And then having said that, like Dr. Norman I'm troubled by the state of the data, that we have a whole lot of registries which are small, underpowered.  Dr. Topol and others have pointed out the relatively poor follow-up in many of them, the incomplete nature of it, et cetera, the characterization of the patient populations.
		But despite the weakness of those data, there is a consistency that emerges from the NHLBI dynamic follow-up, from the Prairie Heart Data, from the Washington Hospital Center, from the Minnesota data that off-label use is associated with a higher risk of bad outcomes, stent thrombosis, death, MI, relative to on-label use.
		And then we have this interesting question of the Swedish data, which likely reflects real world, a mixture of on-label and off-label and that at approximately a year that the survival curves separate, and what's strong about the Swedish data is, in addition to its well characterized follow-up, they have a large enough size to detect very small differences.  
		I think they pointed out yesterday that the risk is .5 percent per year in increased risk of mortality.  I think that that's something that needs to be thought about and that I would also conclude that the risk and benefit of off-label indications has not been well characterized and should be done so.
		CHAIRPERSON MAISEL: Thank you.  Dr. Topol, and if I could ask if people are not speaking or have not been called on, please turn off your microphone.  Dr. Topol.
		DR. TOPOL: Well, I'd like to just extend some of these comments.  I think the realization about this very late stent thrombosis is precisely the issue that we've been dealing with, first in the randomized control trials and then, of course, outside that important arena.
		Now this is something that is new in interventional cardiology.  That is, many of us have practiced this for over 20 years.  We have not faced something that would be of consequence and potentially a fatal consequence two, three, or four years later after the indexed procedure.
		So this is something that there are consistent data, and we heard the update of that today from Cordis with respect to the four-year follow-up of the randomized trials, that indeed there was no excess of death or MI, even though there is a significant very late state thrombosis, stent thrombosis, beyond one year that's across both of the stents, the CYPHER and TAXUS today.
		So I think the issue that we have to confront now are how about the inconsistencies in the data that are addressing this?  There are no randomized trials.  Dr. Harrington has just reviewed and others the gnawing concerns that exist, because, in a sense, although no question that drug-eluting stents were a great advance, they also created a new entity.  Some could say created a monster, which is this very small but significant and statistically significant, even in the ideal patient population, of late thrombosis.
		So it would be inappropriate, I believe, to extrapolate that late thrombosis, which does not attract with death and MI in randomized trials -- I am not prepared to make that big leap in the off-label use.  That is, it very well, and, in fact, the Swedish data and others suggest that late thrombosis may well be associated with increased death and MI in the off-label patient.
		So I think there's a very different read on the data, and I also think that if it weren't for the FDA to have organized this extraordinary exhibit of data worldwide, we wouldn't have the advantage of basically being up-to-date on everything.  
		And I should also mention the eminent Lancet publication that Dr. Serruys presented yesterday, which too reinforces the same concern of the increased and incremental over time as was certainly brought out by the Swedish registry and others. So I think there are multiple data sets that reinforce significant concern in the off-label use.
		CHAIRPERSON MAISEL: Dr. Domanski.
		DR. DOMANSKI: Yes, actually, I guess I have some, you know, I have some questions about some of this reasoning, as well.  Let me talk about two different -- talk about it from two different directions.  The first of all is from first principles.  
		You know, one anticipates that there is -- there's no question that there's a big improvement in restenosis, and, in fact, that may be a mechanism by which drug-eluting stents reduce the risk of death and MI and, in fact, may mitigate any increase in the risk of stent thrombosis, which is, you know, which is really not well -- you know, which is not, in fact, well validated.
		The second thing is the Swedish study -- I share your concern about the Swedish study, but in addition, it's really not true that it's a 20 percent difference. I mean, it depends on what you look at.  In fact, there's a statistically insignificant difference only when you split it out and somehow break this into two curves do you get any kind of significant difference.
		There's no significant difference if you just plain look at the data, so I think it's being misquoted or at least if not misquoted, it's certainly selectively quoted.  So I have some real concern.
		So summarizing, A, from first principles, one might anticipate that the more complex and more likely to restenose patients, we get more benefit, not less.  We don't know that.  And the Swedish study is not particularly supportive of the opposite view.
		CHAIRPERSON MAISEL: Dr. Normand.
		DR. NORMAND: Thanks.  I'd like to make two comments relative to the questions that were raised.  First of all, I think the question of off-label versus on-label is a confusing one, because we need to say compared to what.  
		I keep pushing this, because I think we'll all agree that off-label is going to have a higher rate of bad events, just because it's a more complex patient, so that's the first point.  Now that may seem simple-minded, but I think it relates to my second statement.
		So first of all, off-label versus on-label, I don't recall -- and, again, we all have different opinions about the data that we saw -- but for the last two days, I don't think I saw a lot of good comparisons on off-label use with CABG or with bare metal stents.  So first of all, we have no data about that.  Most of the data relate to off-label use, just talking about rates, overall rates of stent thrombosis.
		The second question, and I just want to step back for a second, about the relative control group or comparison group.  Help me to understand, my clinical colleagues, because I understand the simple patient using a bare metal stent as a comparison group, and so I can understand that comparison.
		If we're talking about off-label now, who's the right comparison group?  I would argue I don't think it's the bare metal stent group.  I probably think it would be CABG, so I do think the comparison group needs to be really clearly articulated, because unless I misunderstand, there's a clinical trial right now trying to answer the question  about use of drug-eluting stents in more complex patients.
		So I disagree very strongly with saying -- well, let me not say that.  I think it's important that the committee notes that not everybody agrees that the comparison group should be bare metal stents, and that statement depends on the comparison group, depends on the population.  		You've got complex patients.  I don't think bare metal stent is the right comparison group, and thus, we do not have any information in my mind, statistically, subjectively, to characterize off-label use relative to any comparison and relative to the comparison group I conjecture is the relative one, and that is CABG.
		CHAIRPERSON MAISEL: Dr. Kato.
		DR. KATO: What I've been impressed with is the fact that this is a very new technology, which has come to the forefront, and as many speakers have said, this has, including the FDA, this has been a transformational technology, which has really grabbed clinicians and patients both by force because of this issue with trying to do the least to get the most benefit.
		On the other hand, I think that the concern that we are having from this off-label use I think is critically important for device -- for drug-eluting stents, as well as for devices in general, and I'm particularly happy that we have an international forum, because I think that one comment Dr. Nissen said yesterday about how these outcome lines are really diverging, they're not coming together, the mortality risk is going up in a linear fashion and may be accelerating at the end points, is making me very, very nervous about proceeding with drug-eluting stents in general.
		Now I think that it's fairly safe to say that on-label use, as we said yesterday, I think is safe and effective.  I don't think that we have enough data at all to say that the other reasons for putting in a stent, a drug-eluting stent, are safe and effective, and therefore not only can it not be -- how should we say this -- not it's off-label, but it needs to be said more forcefully, contraindicated.
		In the, you know, in the regulatory world, that would be considered to be, I guess, equivalent to like a black box warning, but I think that this is a very important technology that is being utilized at a very rapid rate, and we just don't know enough to say that it's safe, given the fact that its adoption has been so rapid.
		CHAIRPERSON MAISEL: Thank you.  I'd like to try to summarize some of the things, the recurring themes that we're hearing.  Is there anyone who disagrees with the statement that off-label use of drug-eluting stents is associated with a higher risk of stent thrombosis, MI, and death compared to on-label use?  You disagree with that statement, Dr. Morrison?
		DR. MORRISON: Yes, I'm beside myself to disagree with that statement.  I think the operative concept is compared to what, and one of the most incredible things I'll take away from this meeting was the experiment where the device we're talking about was compared to bare metal stents for the very complication we're talking about, namely when Tim Henry presented data on acute thrombotic occlusion of an artery STEMI.
		More of the STEMIs that presented at Minneapolis were from bare metal stents than from drug-eluting stents.  The worst MIs were bare metal stents.  There was a higher proportion of cardiogenic shock and out-of-hospital arrest, and the mortality was higher with bare metal stents.
		So here is a very small registry experience with all the weaknesses of registry, but it's actually a comparison in the very entity we're talking about, and that's --
		CHAIRPERSON MAISEL: You're answering a slightly different question than what I just said.  I'm asking the question is there anyone who disagrees with the statement that off-label use of drug-eluting stents is associated with a higher risk of stent thrombosis, death, and MI compared to on-label use of drug-eluting stents.  Is there anyone who disagrees with that statement?
		DR. LASKEY: Yes, I think methodologically if we're going to be rigorous here, the answer is I disagree because the differences, if any, are likely to be confounded by differences in different population.
		CHAIRPERSON MAISEL: But that's exactly the point.  I agree.  They are confounded by differences in patient populations.  That is exactly the difference between on-label and off-label.  Dr. Domanski.
		DR. DOMANSKI: I think I may have a formula for peace here.  I understand what you're saying, and I think you could get everybody on board if you'd say that that's true for both bare metal stents and drug-eluting stents.
		CHAIRPERSON MAISEL: I agree that that is probably true for bare metal stents, as well, and if it makes people more comfortable to say that publicly, and I think we all -- is there anyone who disagrees that both bare metal stents and drug-eluting stents are associated with higher complication rates of stent thrombosis, MI, and death?
		The problem with saying that here  is that we haven't seen a lot of data on the bare metal stent at this panel meeting.
		DR. SOMBERG: And you also have a label issue, because bare metal stents have a broader label than drug-eluting stents.  Well, for acute MI it does.
		CHAIRPERSON MAISEL: So let's just focus on the drug-eluting -- your point is well taken, Dr. Domanski.  I'm trying to find out if anyone -- are there other objections to that --
		DR. DOMANSKI: Some formula for peace in our time.
		CHAIRPERSON MAISEL: Let's go over here to Pam.
		MS. ADAMS: Just very briefly, it's one thing to say it in the meeting.  It's another thing to talk about what the implications of them are, so I know we're going to be coming back to what goes in the label, what goes out in public health notices, and let's just be reminded that sponsors can only talk about what they've studied, all right, so but that's the thing.
		CHAIRPERSON MAISEL: We're here -- I appreciate that point.  We're here to talk about what we know and don't know.  Dr. Edmunds.
		DR. EDMUNDS: I'd like to have the panel refocused on the mechanisms and just point out that the stent lesion, regardless bare metal, DES, is an ongoing pro-thrombotic lesion, and the word endothelialization does not mean that the segment of the artery is lined with functional endothelial cells.  That is not proven.  
		That is not even a good hypothesis, probably, so that this is an ongoing risk, and I agree with Dr. Nissen, who first said that there is evidence that there is increased stent thrombosis going forward.  We have no idea whether this hazard is constant or whether it is variable.
		CHAIRPERSON MAISEL: Dr. Nissen.
		DR. NISSEN: Yes, like Mike Domanski, I grew up in the sixties, so I like to make love, not war, but all we're saying, all you're saying, Bill, is that sicker patients do worse, and I can't see how anybody can disagree with that, that basically if you're more complex, and you're sicker, as we know these real world patients are, you're going to have a worse outcome.  To me, that's an easy one.
		CHAIRPERSON MAISEL: Dr. Yancy.
		DR. YANCY: I fully appreciate the comments that have just been made, but the nature of your statement, Bill, was that the use of the stent is associated with less good outcomes in off-label circumstances.  The observation is one thing, but to link the presumption of cause and effect is something that's troublesome.  
		There are more events, as Dr. Nissen said.  These are sicker patients, but to use the language the use of a stent is associated with less good outcomes in this off-label population, we just haven't seen those data.
		CHAIRPERSON MAISEL: So maybe we should turn the statement around.  Less good outcomes are observed in patients in whom the drug-eluting stent is used off-label compared to on-label.
		DR. YANCY: I would support that.
		DR. DOMANSKI: Well, yes, I'm having a little bit of a problem, because it sounds like it's going to go out to the public.  I understand the logical train, but I'm worried about it going out to the public in a way that is technically true but suggests that somehow the drug-eluting stent is not -- you know, we don't even know that it's not the right thing to use in that setting, and it's very important not to send the message that you do.
		CHAIRPERSON MAISEL: Well, I'd like to take baby steps here.  I'm trying to -- you know, we're trying to build consensus, and I'm trying to establish that we all feel essentially the same way about off-label use of drug-eluting stents.  At the end of the day, we'll need to come back and make sure the message is absolutely clear.
		DR. DOMANSKI: You could also drop the statement, because it doesn't add too much to the sort of therapeutic recommendations.
		CHAIRPERSON MAISEL: Well, I disagree.  I mean, I think this is the crux of why we're here.  The off-label use is occurring in 60 percent of people.  The label doesn't address this issue at all, and we're here to establish that off-label use is associated with worse outcomes.  Whether that's directly related to the stent is -- we don't know.  It's related to the complexity of the patients.  Dr. Weinberger.
		DR. WEINBERGER: I think that everyone who has worse disease believes that even if they got the best available therapy they will not do as well as people who have less severe disease.  I think that the problem that we have is that when patients -- if a patient were to get a package insert, they would believe that they were going to get an outcome that's explained in the package insert.
		What I think our obligation with the package insert to do is to let the patient know that you don't fit into the data set that's printed in the package insert.  If you don't fit into that data set, you can't expect to get that particular outcome.
		What your outcome is is poorly defined, given the data that we have today.  We know it's certainly not as good as the people who have more moderate disease.  We don't know what the long-term risk is to that patient, whether that risk, that integrated risk, goes on -- goes up and up and up forever.
		So I would think that the purpose  of the package insert, if we're going to reach some consensus, is to let the patient know that if you fall into Class A, you can have the outcomes that are explained, and if you fall into Class B, your outcomes will not be as good.  So I think that that's supported by the statement you made.
		CHAIRPERSON MAISEL: I'd like to move on now to the comparison group.  Is there anyone here who thinks we have adequate data for drug-eluting stent off-label use compared to either bare metal stent or CABG?
		PARTICIPANT: What was he saying?
		CHAIRPERSON MAISEL: Does anyone think we have seen adequate data to make any statement regarding drug-eluting stent use off-label compared to bare metal stent use in that off-label population or compared to CABG in the off-label population.
		DR. SOMBERG: Bill?
		CHAIRPERSON MAISEL: Dr. Somberg, and then Dr. Edmunds.
		DR. SOMBERG: I think we've seen a good deal of data.  I'm not sure if we can make and should make any solid conclusions, but I do want to throw out in here -- some of my colleagues may comment, because it's hard to make consensus before we have some -- I know the time is pressing, but some sort of discussion on this, and that is that I heard two very interesting data points presented, one from the Duke database, which I thought was a very good and powerful study that if you're on anti-platelet therapy -- you see, I mean, I know you want to separate these things, but if you're on dual anti-platelet therapy and get a bare metal stent, you do the best.  
		And I also heard data -- pardon me?
		PARTICIPANT: Drug-eluting and --
		DR. SOMBERG: No, I meant drug-eluting.  That's my dyslexia.  Thank you very much.  I've got a --
		PARTICIPANT: Are you finished now?
		DR. SOMBERG: And the other aspect is that I've heard data from Dr. Baim and the TAXUS program also that went along those lines.  I was just wondering do we not have some good control data that if you think of the stent as a stent-medical therapy combination device -- you know, it's a pharmaceutical inside you.  
		It's a pharmaceutical you take daily.  When it's done right, maybe it is the best, and maybe that is, with a comparitor and the appropriate comparitor, which is the bare metal stent.
		CHAIRPERSON MAISEL: Dr. Edmunds.
		DR. EDMUNDS: I agree with Dr. Normand that it is imperative that the CABG be one of the comparison groups for comparing DES stents in the off-label group of patients so identified by this panel.  We still have to acknowledge that we really do not know what the hazard is going forward with the DES stent, whether the stent thrombosis problem will to away with therapy or without therapy, or whether it will get worse.  So I think we have to have a legitimate comparison group, and that is not bare metal stent, because you won't use it because of the restenosis rate.
	CHAIRPERSON MAISEL: Dr. Nissen, then Dr. Brinker.
		DR. NISSEN: I also want to make the comment about CABG and say that I think our surgical colleagues made, I think, a fairly impressive case that we know a lot about CABG.  We know that it has life-saving  -- it actually prolongs life in certain subsets.  It's extremely well categorized, not just with two-year and three-year outcomes but with ten-year outcomes.
		And so in making these comparisons, I think we have to be careful, because we've got a therapy, well established, that has profound, you know, effects on patient outcomes that are favorable that we understand extremely well, and, you know, I think that it's important to come back to earth here, you know, because, in fact, what is the use?  What is the off-label use?  What's driving the off-label use?
		It's using multi-vessel drug-eluting stenting as an alternative to sending the people to bypass surgery.  Well, we know what bypass surgery does long-term, but we do not know what multi-vessel drug-eluting stenting does long-term, and that's a real deficiency here.
		CHAIRPERSON MAISEL: Dr. Brinker.
		DR. BRINKER: So one issue is I don't think that we have the ability, because we didn't look at data, and there is some, looking at off-label use compared to surgery, and certain subgroups like left main disease that are high risk for surgery, et cetera.  We haven't looked at that.
		I think the purpose of your question, I think, was to get the confirmation that there's nothing in what we've heard that would change the off-label citing for these indications to something better than off-label.  In other words, we should leave those situations that are off-label as being non-qualified on the basis of available evidence for being on-label.
		There is one issue, though, about off-label stenting, and I think that's the only one we should consider here, and that is whether there is the suggestion that even if it is off-label, is there enough evidence to say that if off-label stenting is done, it needs more careful and perhaps more prolonged anti-platelet therapy.
		CHAIRPERSON MAISEL: We'll get to the anti-platelet therapy question in a second.  Are there -- I'd like to address specifically the issue of stent thrombosis in the off-label population.  Do people -- we had an extensive discussion about this yesterday.  
		Are there qualities of stent thrombosis in the off-label population that are somehow different than in the on-label population, other than because patients are more complex it appears that the rate is higher?  Is there something uniquely high about it for drug-eluting stents?
		DR. BRINKER: So I don't think so, and, in fact, I think this whole issue of stent thrombosis is not all that novel, and you heard it again today about bare metal stents and, I think, late thrombosis.
		The issue is becoming more to the fore, because what we were really worried about with bare metal stents, because the frequency was 20 times that of thrombosis, was restenosis, and now when we don't have restenosis being 20 times more, the issue of one percent or .2 percent per year becomes more on our radar. 
		So I am not sure that it is the issue specifically of thrombosis in these more complex cases that's so novel.  It is more, and it is more even in bare metal stents.
		CHAIRPERSON MAISEL: So I've had an excellent question posed to me that I will propose to the panel, which is to potentially cut to the chase which is does anyone have a proposal for an off-label use that they know that, based on the data we've seen, they find acceptable?
		DR. EDMUNDS: Bill, can I respond to your --
		CHAIRPERSON MAISEL: Hang on.
		DR. EDMUNDS: -- question before you asked that question?
		CHAIRPERSON MAISEL: Not quite yet, so we're moving.  Does anyone looking at the data see an off-label use that they feel comfortable should be on the -- 
		DR. WHITE: Yes, but the other way.
		CHAIRPERSON MAISEL: What is the other way?
		DR. WHITE: The other way is is  there anything you really think shouldn't be done.
		CHAIRPERSON MAISEL: Put on your mic, please, Dr. White.
		DR. WHITE: I think it should be asked another way, because I haven't heard anything today that's going to change my practice on Monday morning when I go back, unless there is some subset of these patients in whom we ought to be very wary of and perhaps bifurcation lesions I've heard.  Particularly in my mind Monday, my first bifurcation I run into is not going to get two drug-eluting stents in it.
		So that's the kind of thing that's moving my clinical practice.  I will not argue that I need more information, and I'm concerned about the Swedes, and I've always been worried about Swedes, but when you talk about what are we going to say here that's going to impact, you know, what we do or what I'm going to send messages to patients, you heard how we can do such unintended consequences of what we say, but clearly are there subsets of patients we've heard that are going to influence our practice?  Do we want to warn somebody about what we do?  And I would suggest that we heard yesterday from Dr. Columbo about some bifurcation issues that got my attention.
		CHAIRPERSON MAISEL: So let's talk about bifurcation lesions, overlapping stents, thrombosis in vessels, diabetics, comments on that.  Dr. Kato and then Dr. Somber.
		PARTICIPANT: And people who can't continue therapy.
		CHAIRPERSON MAISEL: And people who cannot continue therapy, their anti-platelet therapy.  Dr. Kato.
		DR. KATO: I'm going to -- this is a short answer to your questions.  No, I don't see any off-label -- there's no evidence to support the use of off-label use of drug-eluting stents in these off-label indications that Dr. Nissen is --
		DR. EDMUNDS: Bill, I disagree with that.
		CHAIRPERSON MAISEL: Okay, well, I'll give you a chance to speak in one moment.  Your moment has arrived.
		DR. EDMUNDS: Do I need to bow?  You asked if there was a possibility that there may be an increased risk in the off-label group of patients, and I answered that question yes, and that possibility, which is the hypothesis now, is that that set of patients have higher levels of circulating plasma tissue factor than do the first group, the on-label group.  Now that's a hypothesis now, but it does raise the possibility that there may be a greater hazard for the off-label group.
		CHAIRPERSON MAISEL: Are there particular subgroups of patients in the off-label group that we should be restricting drug-eluting stent use to, compared to a bare metal stent, should they be going to CABG, what have you?  Dr. Domanski?
		DR. DOMANSKI: You know, I certainly agree that we don't have the basis for adding, for representing that any these off-label indications we should say in a label have shown safety and efficacy, but I also don't think that any of them have reached the level in this testimony, in these data that have been put before us, so that you should be prescribing their use in clinical practice.  I would leave that to the ACC.  I don't think you've got the data to do it.
		CHAIRPERSON MAISEL: Dr. Vetrovec?
		DR. VETROVEC: I have to agree with Chris White.  It seems to me that when I go back Monday morning and have to decide about stents, I think what I'm carrying with me from this is a recognition that I ought to try to simplify everything I do, and less stent is probably better, but I'm not sure it's going to change any patient that I treat.
		And I think we have to be very careful in these arguments about surgery versus angioplasty and stents and so forth, not to forget that some of the people that we're pushed in the corner to treat are patients that have been turned down for surgery, and they're still having symptoms.  		So I think to give patients a perspective of this, there really are all directions of this, and the outcome for surgery that we heard is really the optimal, not the -- not in the highest risk subgroups, which is what we've been looking at.
		I think you have to realize that it's risk dependent on all of these patients, and so we need to make sure they can take long-term, whatever that time frame is, clopidogrel, but I don't think we're in a position to exclude anybody that we're currently doing.
		CHAIRPERSON MAISEL: Dr. Hirshfeld.
		DR. HIRSHFELD: I think what's giving us a hard time in trying to figure out how to approach this is we're trying to be data driven, and to be data driven we're getting into excessive lumping.  We're trying to sort of lump all the patients who are off-label together and say they're all the same and all the patients who are on-label together and say they're all the same, and I think I've heard a number of people say that they realize that that's not the case, and that's how they make their choices when they're in the lab and they have to decide which stent to take off the shelf.  
		And I think if we look at the pooled data that what we see is that in the off-label patients, there's a very small number of patients who probably have an injury related to having received a drug-eluting stent.  We don't know, but I expect that it's a very large number of patients who had a very beneficial outcome, because they received a drug-eluting stent, and what we don't know,  and what we can't tease out from the data right now is who's in which cohort.
		And this sort of comes right out of what Dr. Normand said, that she said compared to what, but my sense is and I think all of those of us who practice is that there are a lot of people out there whom we have treated in an off-label fashion, and at least to two to three, four years out, they've been benefitted by this.  So I think we have to be careful not to lump everybody together and say that we can't treat anybody off-label.
		CHAIRPERSON MAISEL: Dr. Nissen.
		DR. NISSEN: Yes, John, I can't agree with you.  I mean, we don't know that we've benefitted those patients, and that is the problem.  You know, we don't know whether any of those off-label patients have been benefitted versus being harmed, because we have insufficient data in that group to actually answer the question.
		And so I would ask those of you that say, "Well, I'm not going to change my practice," are you comfortable going back and putting three drug-eluting stents in, one in the LAD, one in the circumflex, and one in the proximal right, as an alternative to bypass surgery, given everything that you've heard over the last two days?  I would be very curious of those practicing interventionists whether -- how you might answer that question.
		CHAIRPERSON MAISEL: Dr. Page.
		DR. PAGE: I don't think we have enough data to support any new indications.  Likewise, I have trouble with the different subgroupings, but one group I think we need to emphasize and I think we can probably agree on would be if a patient is unable to understand, unable to comply, or unable to afford anti-platelet therapy.  
		That is a patient I think we need to really think about and, frankly, need a strong warning that that's a patient that is off-label or certainly is inconsistent with the way the clinical trials were performed, but that's a patient who should not have a drug-eluting stent.
		CHAIRPERSON MAISEL: I agree with all of that except the afford part.  I think we should try to find other avenues to get them their medication if --
		DR. PAGE: I agree.  If there was some way to guarantee at the time you get the stent that you have the medicine to take for the prescribed period of time, then that make the issue moot.
		CHAIRPERSON MAISEL: We can say it more generically that if they are -- if it is not expected that they will be able to continue their medication throughout the pre-specified duration.
		DR. PAGE: Right.
		CHAIRPERSON MAISEL: Dr. Yancy.
		DR. YANCY: I'm concerned, Bill, about this ongoing discussion regarding off-label use and stretching limited data to try to decide in whom it might benefit and who might not be benefitted.  I hope the message that goes forward on Monday morning is that any application of stent technology that is off-label should give someone pause, because we don't know whether true benefit has been experienced, and I would remind all of us of the drug domain.
		If we were here talking about a relatively recent medical intervention for which 60 percent or more of the use is off-label, the flavor of these comments would be vastly different, and I think we've learned important lessons in that arena, and we should pause if we're using off-label therapy.  
		I wouldn't use the word restrict, because we have to make patient-by-patient decisions, but trying to tease out the best group or the worst group with what we have available, I can't support that.  I think off-label is off-label.
		CHAIRPERSON MAISEL: I'd like to try to answer the first part of question three, which is, "Given currently available data, are there safety concerns regarding stent thrombosis, death, and myocardial infarction rates for drug-eluting stents used in these complex patients and lesions?"  		I would propose that we say that the rates of stent thrombosis, MI, and death are higher when drug-eluting stents are used in off-label as compared to on-label use.  If so, can lesion subsets or patient populations at particularly higher risk of DES thrombosis within the off-label patient populations be identified?  We've seen a lot of data.  There are a lot of hypotheses. 
		I don't think we've seen data of the rigor that we would change a label or make a broad, sweeping recommendation other than to say there are populations we're concerned about such as the things we've heard, overlapping stents, bifurcation lesions, thrombosis, all the things that we've defined as particularly higher risk.  I don' think we have the data to make a sweeping recommendation regarding drug-eluting stent in these populations.
		Dr. Topol.
		DR. TOPOL: I would agree, Bill.  I think the point that we need to make and hopefully it would be nice to settle on is that there are significant uncertainties, so while Dr. White or Dr. Vetrovec or others here might not change their practice on Monday, hopefully they would acknowledge that the data are inconsistent.  They don't address a lot of these questions, and as Dr. Yancy just asserted, we have significant uncertainties, and I think that would be the most important message here in response to the question.
		CHAIRPERSON MAISEL: Among the off-label population with the anti-platelet therapy modifications -- I'm going to skip that one for a second.  "If DES thrombosis concerns regarding more complex lesions or patient subsets have been identified, do they apply equally to both of the currently approved DES?"  I don't think we've seen any data that suggests one is any different than the other in the off-label population.  Does anyone disagree with that?  
		And although diabetic patients were included in the randomized controlled trials submitted for DES approval, neither of the approved DES devices have a specific labeled indication for use in diabetics, either insulin-requiring or non-insulin requiring.  		Is there a DES thrombosis safety concern for this important high-risk cardiovascular subgroup?  Anyone have concern about the diabetic group?  Dr. Domanski?
		DR. DOMANSKI: Well, you know, that's the subject -- that's the subject of an ongoing major trial that's going to answer that question, FREEDOM, so, I mean, we, A, don't have the answer, and B, we're going to down the pike, and I would let FREEDOM just answer it.
		CHAIRPERSON MAISEL: Dr. Edmunds.
		DR. EDMUNDS: I would like to go back to 3A and just say --
		CHAIRPERSON MAISEL: You're moving in the wrong direction.
		DR. EDMUNDS: I'm moving for clarity, though, and that is, if so, can a lesion subset or patient population at particularly higher risk, higher risk than what?  Higher risk than the on-label group should be added.
		CHAIRPERSON MAISEL: So in the diabetic population, is there anyone who has specific concern about off-label use of drug-eluting stents in diabetic patients, that we should be making some recommendations or statements other than we need additional information?  Okay.
		So now let's try to focus on the anti-platelet issue if --
		PARTICIPANT: Can you summarize what your statement is for 3A?
		CHAIRPERSON MAISEL: For 3A, can lesion subsets or patient populations of particularly higher risk of DES thrombosis within the off-label patient population be identified?  We feel that there are significant uncertainties, and it's difficult to make conclusive judgements regarding this issue.  
		There is potentially a suggestion that certain subgroup populations such as overlapping stents, bifurcation lesions, vessels with thrombus, et cetera, may be at higher risk, but we don't have adequate data to definitively say or to tell people not to, to or not to put in drug-eluting stents in these patients.
		Dr. Domanski?
		DR. DOMANSKI: Yes, I think that that statement's okay, but you need -- as long as you include bare metal stents and not just the drug-eluting stents.
		CHAIRPERSON MAISEL: Dr. Zuckerman.
		DR. ZUCKERMAN: If I had to do this over again, I wouldn't have written the question this way, but given that it is, perhaps a better way -- Bill, what you're hearing is a degree of uncertainty, because we don't have the best data possible.  I think your summary statement was a very good one personally, but perhaps you can use the mechanism you used yesterday to just go around the table and ask people yes or no regarding that statement, so we see how much uncertainty there is for your summarization of Point 3.
		CHAIRPERSON MAISEL: Are we talking about 3A or all of the --
		DR. ZUCKERMAN: I think you just summarized question 3, given the uncertainty regarding the data.  If you could just try to restate it.
		CHAIRPERSON MAISEL: Before we do that, and we will do that, I just want to get into -- I want to finish question three, which is, "Among the off-label population with the anti-platelet therapy modifications discussed previously for on-label use apply differently to this population or include other patient subgroups?"
		Well, we discussed for on-label use, and what we've heard today in testimony from AHA describing the AHA/ACC/SCAI guidelines is that the on-label anti-platelet therapy, dual anti-platelet therapy for three months with CYPHER, six months for TAXUS, should be followed and that patients should be continued on dual anti-platelet therapy for up to 12 months if they do not have a contraindication.
		Dr. Nissen?
		DR. NISSEN: I was persuaded by the Duke and the Kaiser data, which really do seem to indicate that up to 12 months of therapy is probably beneficial, and, you know, again, we're having to make decisions today under conditions of great uncertainty, but in that realm of uncertainty, I think risk versus benefit looks pretty good up to 12 months.  
		I don't see any compelling evidence that there's benefits beyond 12 months, at least not now, but up to 12 months there is, and so I think that it's reasonable to suggest that patients with drug-eluting stents, if they are not experiencing complications from their therapy, should be treated up to 12 months.
		CHAIRPERSON MAISEL: Dr. Normand?
		DR. NORMAND: I'm sorry, but I had my hand up a while ago, so this may go back a little bit, and that is I'm having -- if you go around and ask this question again, as was suggested, I'm going to have a difficult time answering it, because, A, if we're talking about comparing the complex group to the simple group in terms of the questions such as benefits, it's a nonsensical comparison to make, because they're completely two different groups of patients.
		So you can't do that, and so then the question would be, okay, we're comparing different patient groups.  We can't talk about benefits versus risks, because they're completely confounded, those two groups.  So if you say, "Let's talk about, then, the comparison of the off-label group of drug-eluting stents to bare metal stents," we've not really seen any data on that.
		So I just want to echo that it's very difficult, and I'm sorry to restate this, but the comparison groups are driving this on who's the control group, and so if we say complex versus simple, as Dr. Laskey said, it's two completely different patient groups.  We would treat them completely different, and so hence it makes no sense to talk about it, statistically, anyway.
		CHAIRPERSON MAISEL: So getting back to the anti-platelet question and Dr. Nissen's comments, is there anyone who feels that we should recommend something other than following the current AHA/ACC/SCAI guidelines?  Dr. Harrington?
		DR. HARRINGTON: Yes, I too find the one-year argument compelling based on four things, the first of all, I think that there has been a misperception that people were on for three or six months.  All the data we've seen from follow-up knowledge suggests, in fact, that three or six months was an option, and the vast majority of patients, if you look at the TAXUS landmark analysis, continued beyond six months.  I just want to point that out.  I think we've misled people to believe that three or six months is the therapy duration.  
		Second is that are at least three pieces of evidence we've heard, the Duke data, the Kaiser data, and the TAXUS landmark analysis, which would all suggest out to a year.  I feel uncomfortable after a year.  Let me rephrase that.  
		I feel uncertain after a year, and the reason, Bill, I'd like to change it to a year as the recommended, because I think that doing so will give people pause to say, "Do I really think this person could take it for a year?"
		CHAIRPERSON MAISEL: I think it's a little beyond our panel to "change the recommendation."  I don't -- I'm having a little trouble understanding why we need to do something more than what the AHA/ACC/SCAI has already done, which says patients at low risk for bleeding should be maintained on the above regimen for 12 months. 
		DR. HARRINGTON: Because I think when you put in the three- or the six-month minimum, you give people an out that has been misunderstood.  In fact, the vast majority of patients are going beyond the three and six months, and they went beyond the three or six months in the original trials.
		CHAIRPERSON MAISEL: So the AHA, the AHA/ACC/SCAI guidelines have three months for sirolimus stents, six months for paclitaxel, and they make that statement about 12 months for low risk patients for bleeding.
		DR. HARRINGTON: I'm not on that particular guideline committee.  I would recommend that it be tightened up.
		CHAIRPERSON MAISEL: Do people agree with Dr. Harrington, or would they rather go with what we have as our AHA/ACC/SCAI guidelines?  Dr. Kato?
		DR. KATO: Well, I mean, in addition to what Dr. Harrington said, I think the statement also has to be made that continuation of either -- of dual anti-platelet therapy, particularly clopidogrel, may or may not be associated with an improvement in, reduction in risk of stent thrombosis.
		I believe that there are a lot of -- I believe that there are a lot of people, a lot of the public, who believe that, "Well, gee, if 12 months is good, then I should really stay on this forever, and if I don't have a risk, then why not?"  But I think it's also important to actively state -- instead of not putting a statement in there, I think it's better to be proactive and state that continuation of clopidogrel is not -- it may or may not be associated with a reduction in risk of stent thrombosis.
		CHAIRPERSON MAISEL: Dr. White then Somberg.
		DR. WHITE: Bill, I don't see any reason to revise or change the guideline statement.  I think it facilitates treatment.  I think we could encourage the statement.  It's a Class I recommendation that low risk patients get plavix.  
		I don't know how much stronger we  want to be.  I don't want to force people who are at risk for bleeding perhaps.  I think that's a physician's decision, and why do you want to rewrite the guidelines without any specific data to support that?
		CHAIRPERSON MAISEL: How about a statement that we concur with the current guidelines and that patients at low risk for bleeding should be maintained on anti-platelet therapy for 12 months?  Dr. Somberg?
		DR. SOMBERG: No, Bill, I disagree with that, because I think with -- I mean, this panel is today.  The guidelines were yesterday, and there'll be some more things.  You know, in the next meeting we'll convene and do that, but right now we see that -- I think there's an appearing body of data that shows that 12 months for those people at risk who can tolerate dual therapy should receive it, and when you go back to the irrational three months here and six months there, that's not based on very much, but this is based on more data.
		Now I have one other suggestion.  I don't think you just stop there.  I think you have to say that those people who have off-label uses who are at high risk for events should consider staying on dual therapy for longer periods of time, those people at high risk.  
		Those people at the lowest risk or who have discontinued one may consider lower durations of therapy.  So it's not just, hey, everybody gets 12.  It should be based on risk and judgment.
		CHAIRPERSON MAISEL: Dr. Topol.
		DR. TOPOL: Well, I think just like there's uncertainties, there are uncertainties with respect to the whole stent-related clinical events, there's equally, symmetrically uncertainties about the anti-platelets, and some of the data have been misquoted.  So, for example, CREDO, the trial I chaired, was only in bare metal stent patients, so to extrapolate anything to drug-eluting stents, I think, is wrong.  
		Secondly, the CHARISMA trial is the largest trial with three-year follow up, over 16,000 patients, and of those, 4,000 patients had coronary disease.  The majority had a stent, and it was a mixture of the different types of stents, and there was a benefit in that subgroup, a non-specified subgroup with respect to reduction of death or MI, but it was offset by bleeding, and so there was a very narrow benefit if you take into account transfusions and significant over three years with the clinical protection from death or MI.  That's CHARISMA.
		And so the guidelines group that came up with this one year, that is very much arbitrary.  There are no data to support that.  For example, the Duke data that was presented today, that didn't stop the anti-platelets at one year.  That was for the duration of the follow-up.  In many cases, those patients took clopidogrel and an aspirin for multiple years.
		So I don't see how you can come out with one year.  That's just pulling it out of the air.  I think that this is -- while I respect the three societies for coming up with this recommendation, I don't think it's based on any data.
		CHAIRPERSON MAISEL: Dr. Zuckerman.  Dr. Zuckerman.
		DR. ZUCKERMAN: This is my recommendation, Dr. Harrington.  Again, to rephrase the question so I can get a sense of what the best scientific advice of the panel is today, and I like the way that Dr. Topol just stated it.
		He indicated that the American Heart Association has given us their best guess in collaboration with other professional societies based on the existing data and the uncertainties associated with it.  He's also indicated that this is a moving target, but what -- 
		And it would be very nice if the appropriate drug companies are interested in actually doing randomized control trials in this area, but what the Agency needs to know today is, given all these uncertainties, have we taken a step forward here with the AHA present guidelines with the caveat that we will continue to work with the AHA and other appropriate professional societies to update recommendations as more data become available.
		Dr. Topol?
		DR. TOPOL: Yes, I think that's very reasonable.  I think that there is a trend for longer duration with better outcomes, but we certainly don't know what that outer temporal window ought to be, so I think Dr. Zuckerman's summary is right on.
		CHAIRPERSON MAISEL: So we've heard from a lot of people on this issue, so just so we can understand how the panel's feeling about it, how many people are comfortable with the statement that off-label use anti-platelet therapy should be guided by the current AHA/ACC/SCAI guidelines?  
		We're not going to  officially vote, but the majority -- we're not voting, but the -- are there people who are uncomfortable with that statement?  Okay.  A non-vote.  So there are three or four people who are -- four or five or six, and -- seven or eight or nine or ten.  No.
		Okay, so we're not voting.  What I'm trying to under -- I'm trying to understand how panel members are feeling about the current guidelines and our recommendation or support of them.  So the question is, "Among the off-label population would anti-platelet therapy modifications assessed previously for on-label use apply differently to this population or include other patient subgroups?"
		So I think we do have some concerns that the off-label population may be a little bit different than the on-label population.  Does that recommendation -- among the panel members, it sounds like many are saying we should have at least 12 months of anti-platelet therapy.  Is there anyone who feels we should not have 12 months of anti-platelet therapy?
		PARTICIPANT: Come on.
		CHAIRPERSON MAISEL: Just hang on for a second, please.  Is there anyone who feels we should not have 12 months of anti-platelet therapy?  So everyone agrees on that point.  Pam.
		MS. ADAMS: The only point I wanted to make is you all have over and over again over the last two days said valid evidence, data-driven decisions, and I'm not hearing that anybody feels that we have that.  That's number one, and the only second point is what are we going to do with these statements is my other concern.
		DR. LINDENFELD: Yes, I -- can I just --
		CHAIRPERSON MAISEL: Okay.  Dr. Lindenfeld.
		DR. LINDENFELD: -- chime in here for a second?  I think that the data-driven -- I don't know what the average age was in CHARISMA.  I don't remember, but 62.  This data is driven by -- if we're going to say that, I think we need to say that, and people who were included in the trials that we've looked at, that's not the population that's out there, and if the bleeding was greater, do we really think there's going to be less thrombosis in the older folks that will balance more bleeding?  I don't think we know that at all so --
		CHAIRPERSON MAISEL: So there's unquestionably a number of unanswered questions.  We just asked the question of whether anyone on the panel thought that anti-platelet therapy should be stopped before 12 months, and no one raised their hand.  Does anyone want to have a chance to raise their hand now?  Okay, let's move on.
		So let's try to summarize question three, and we'll go around the table quickly and let make people make additional comments about it.  Given currently available data, are there safety concerns regarding stent thrombosis, death, and myocardial infarction rates for DES use in these complex patients and lesions.  Rates of stent thrombosis, MI and death are higher when DES is used in off-label as compared to on-label patients.
		If so, can lesion subsets or patient populations at a particularly higher risk of DES thrombosis within the off-label population be identified, given the significant uncertainties and limitations of the data?  We cannot definitively talk about specific patient subsets.  There are subgroups including but not limited to bifurcation lesions, overlapping stents, and thrombus that may be at higher risk, but further study is warranted.
		Among the off-label population would the anti-platelet therapy modifications discussed previously for on-label use apply differently to this population or include other patient subgroups?  There may be differences in off-label population, because they're higher risk patients.  It was the consensus of the panel that patients at low risk for bleeding should be maintained on at least 12 months of dual anti-platelet therapy.
		If DES thrombosis concerns regarding more complex lesions or patient subsets have been identified, do they apply equally to both of the currently approved DES?  We've seen no data to suggest there is a difference from one stent to the other, and although diabetic patients were included in the randomized control trial submitted for DES approval, neither of the approved DES have a specified label indication for use in diabetics, either insulin-requiring or non-insulin-requiring.  
		Is there a DES thrombosis safety concern for this important high-risk cardiovascular subgroup?  We haven't seen data that allows us to make that determination, although we certainly would be interested in the results of ongoing trials.
		Let's start with John Hirshfeld, and if we could briefly only highlight major problems you have with those statements.
		DR. HIRSHFELD: I don't have any problems.  I think the big unanswered question is the optimal duration.
		CHAIRPERSON MAISEL: Thank you.  Dr. Brinker.
		DR. BRINKER: I agree.  I think there's a gut feeling.  You know, physicians vote with their feet, just like everybody else, and most of us have gone for prolonged anti-platelet therapy before the AHA guidelines were published because of perception.  I think that there'll be even bigger perception of this after this panel meeting gets published or made more public.
		The fact of the matter is there is a gut feeling that the higher risk, more complex patients might benefit from a more prolonged than one year.  However, having said that, we don't have definitive data, and the fact of the matter is that the majority of thrombotic events occurred actually within the therapeutic window.
		When we look at all the studies, it was just that the later events are not the majority of events, so I'm happy for the time being with the comment as it stands, that is up to one year if tolerated, but would encourage further controlled studies before any of these off-label indications present themselves to the FDA for a labeled indication.
		CHAIRPERSON MAISEL: Dr. Yancy.
		DR. YANCY: For the totality of what you said, I don't have a major problem, but I would continue to emphasize that this is off-label.  We don't have sufficient data.  We need more data, and there should be some statement that we need new trials.
		CHAIRPERSON MAISEL: Dr. White.
		DR. WHITE: I'm in global agreement, Bill.  I would ask you to reconsider on the 3A to use the term stent, rather than extended drug-eluting stent, because I think that the statement is true for all stents, and I would not want to drive a patient to choose a bare metal stent because he had read that drug-eluting stents were worse than off-label.  So I would like the patient to understand that it's all high risk and not better for a bare metal than for a drug-eluting.
		CHAIRPERSON MAISEL: Dr. Somberg.
		DR. SOMBERG: I think we do need more data.  I think the key is what is mentioned as anti-platelet therapy, and I agree with the statements, but I would ask that maybe FDA can go to arbitration and resolution between this division and CDER and see if you can have -- I'm joking about -- don't worry, Bram, but the --
		DR. ZUCKERMAN: It's a very important point, and we're actively working with our CDER colleagues.  That's why your general point of getting a real drug trial done in this arena is an extremely important one.   
		DR. SOMBERG: Well, thank you, and the last thing is I do think we have seen a lot of data on that people still have stent thrombosis with what is considered optimum dual anti-platelet therapy, and we must remember clopidogrel, which is the one that's used in the United States, is an inactive drug.  It must be activated.  
		Twenty percent of the population are very poor to non-activators, so we have an issue here, and there's also a genetic polymorphism, and there's interaction with other three or four agents here, so once we just say that it should be for 12 months, there are subsections that need to be done, but I think you've done a nice job of summarizing how I feel.
		CHAIRPERSON MAISEL: Dr. Page.
		DR. PAGE: I agree with the statements as put forward, my only caveat being in 3A that, again, the drug-eluting stent be contraindicated if the patient is unable or unwilling to take their anti-platelet therapy.
		CHAIRPERSON MAISEL: Excellent.  Dr. Kato.
		DR. KATO: I basically agree, also. I would echo Dr. Somberg's comment, because I believe that clopidogrel is, at least in the way defined, that we're going to be recommending its use is off-label also.
		CHAIRPERSON MAISEL: Dr. Normand.
		DR. NORMAND: I'm going to be the person who disagrees, and the reason why I'm disagreeing is I don't think it's a well posed question, and the reason why I'm saying that is we're talking about off-label use, and I think you need to give the patient the choice of the options, and we have no data that I've seen that talk about the relevant options for them, and so hence I can't agree with the statements that have been made.
		CHAIRPERSON MAISEL: Dr. Lindenfeld.
		DR. LINDENFELD: I agree with the statements.  I agree with Dr. White about including stents in A, and I agree with the one year, but I think there may need to be just a caveat that says that specific patient groups, not all patient groups, may benefit from the one year or something.  I think that that's more, but I'm concerned that we're applying clinical trial data to a much broader population there.
		CHAIRPERSON MAISEL: Dr. Laskey.
		DR. LASKEY: You get around to this corner of the table, and there's little say, so I, A, I agree in spirit with what's been said.  B, we shouldn't forget the fact that this is a combo deal, that it's not just the stent.  It's the stent plus the drug, so they have to be viewed not in isolation but together.  
		And C, I find it a little ironic. I had my hand raised numerically as many times as others, but I guess numerically doesn't count in this room, as we discussed yesterday.  But I find it ironic that the 12-month data was drawn from an ACS population.  The studies that are cited were kind of acute, sick, ACS, and so that 12-month recommendation that the three societies came up with was generally applied to a lower risk population, those at low risk of bleeding and generally a low risk for bad things in general, so we've come full circle.  So I would agree with 12 months for the off-label, and I'll pass the baton to Doug.
		CHAIRPERSON MAISEL: Dr. Morrison.
		DR. MORRISON: Well, in principle I really agree with Dr. Normand.  I think the issue is always compared to what, and I think that that was pretty clearly demonstrated by the patient who came in here and is not at all concerned about having three of three grafts occluded at one year but finds the concept that he has a stent a ticking time bomb, and that's, it seems to me, what we're getting stuck on.
		For purposes of not being here all night, I'll agree, but, you know, I just think we're off on the wrong tack trying to make a distinction between off-label and on-label.  That's not the issue for a patient with a left main stenosis, and the question is medical therapy, another CABG, or a stent, and should the stent be a drug-eluting one or not, and we don't -- 
		We've all acknowledged we don't have the data, except again I'm pleasantly surprised that in what I would have thought was the absolute worst group, acute STEMIs, there's one small set and two randomized trials that suggest drug-eluting stents are better.
		CHAIRPERSON MAISEL: Dr. Topol.
		DR. TOPOL: I'm concerned, Bill, because a number of the panelists have asked to get rid of drug-eluting and just make it stents, and I think that that's missing the target here.  We haven't recently brought back up BASKET-LATE, which Dr. Harrington wrote the editorial, and it was published JACC just last week, and that was a randomized trial, and it was indeed showing that there was excess of late stent thrombosis in the drug-eluting stent patients who had discontinued anti-platelets.
		I think that we should -- the statement should be pertaining to drug-eluting stents, and I think that the evidence, at least overall totality of it, suggests that there is an excess of late stent thrombosis for drug-eluting over bare metal stent patients in these complex lesion subsets or complex patient subsets.
		CHAIRPERSON MAISEL: Dr. Vetrovec.
		DR. VETROVEC: Yes, I would, first of all, acknowledge the uncertainty.  In general, I would agree with it. There's probably a middle ground between what some people have said and what Eric just said, and the middle ground would be to have in there the concept that more complex patients have higher risk, regardless of the therapy, be it drug-eluting or bare metal, but there is a concern potentially that there may be a higher signal in the drug-eluting, and I think if you modify it in that way, everybody will be heard.
		CHAIRPERSON MAISEL: Dr. Weinberger.
		DR. WEINBERGER: I agree with the thrust of what you've said, and I underline Dr. Page's assertion that if the patient cannot take plavix for a year, we should probably not be putting the drug-eluting stent  into the patient.
		CHAIRPERSON MAISEL: Dr. Nissen.
		DR. NISSEN: Let me add just one other wrinkle, and that is that before this meeting there was a lot of talk about the idea that long-term clopidogrel could mitigate the additional risk to drug-eluting stents.  
		I think it's important that we convey that up to 12 months we have a pretty good understanding that it very well may benefit patients but that we should not send the message that going beyond 12 months eliminates the residual risk from drug-eluting stents, which was being discussed by a lot of people prior to this panel.
		So the statement, I think, is very important, Bill, to say that we find no evidence that prolonged administration of clopidogrel eliminates the residual risk of drug-eluting stents.
		CHAIRPERSON MAISEL: Dr. Harrington.
		DR. HARRINGTON: Part of what we use the label for is to inform clinicians as to what to do, but part of what we use the label for is to ask the companies to fill in the evidence hole, because they can't promote if it's not in the label, and so I share Dr. Normand's concern that we truly have an inadequate evidence base on off-label use, looking at the comparative therapies, and I would also like to see that noted.
		I also agree with Eric that I think there is evidence that the drug-eluting stents are different than bare metal stent in the late period, and so I too would like the comments confined to drug-eluting.
		CHAIRPERSON MAISEL: Dr. Edmunds.
		DR. EDMUNDS: I agree that the drug-eluting stents in the off-label group is an increased hazard.  I also will point out that the hazard continues.  We do not know its rate, but it is a continuing hazard, and therefore I would support the 12-month clopidogrel treatment just as an empirical recommendation without the full data.
		CHAIRPERSON MAISEL: Dr. Domanski.
		DR. DOMANSKI: Well, I agree with -- I agree if 3A says stent, but not drug-eluting stent.  I agree with Dr. White, number one, and number two is I think you had said at least 12 months, and I agree if that's what you're going to put about clopidogrel.
		CHAIRPERSON MAISEL: Thank you.  I'd like to move on to question four, which is the actual labeling change given the -- I'll let Ashley Boam read it.
		MS. BOAM: "Given the currently available data and remaining areas of uncertainty, do the risks of stent thrombosis in the broad population of patients currently treated with drug-eluting stents in U.S. clinical practice potentially outweigh the benefits, in other words, reduce repeat revascularization procedures compared to the previous standards of care, for example, medical therapy, bare metal stent, and/or CABG such that the current drug-eluting stent labeling, which might include indications, contraindications, warnings, or precautions, should be modified?"
		CHAIRPERSON MAISEL: I'm going to make the following proposal in the interest of time that we make the following labeling change for both drug-eluting stents.  "Data outside these on-label indications" -- the word on-label wouldn't be there -- "Data outside these indications is limited.  Use of the stent outside these indications may be associated with an increased risk of stent thrombosis, MI, and death."  
		Dr. Topol.
		DR. TOPOL: I think there's a very important lesson we got by going around the panel on this, and that is yesterday we all concluded that with the three months of CYPHER anti-platelets and six months of TAXUS anti-platelets that the data were fine.  No one had a particular worry about excessive clinical events.
		And today, we just all agreed that anti-platelets should be extended, okay, in these patients, so that means that there is something different about these patients that we're talking about, even though there's not individual acknowledgment of that, or at least from many people in the group.  
		So I think that your point that you just made is indeed accurate, that the patients in the off-label compartment are at higher risk, and the sense of giving some increased duration of anti-platelets is a proxy for acknowledging that risk.
		CHAIRPERSON MAISEL: Does someone want to modify the statement I made or -- Dr. Domanski.
		DR. DOMANSKI: Yes, I don't -- actually, I don't think -- you know, we weren't talking about the duration.  I would have said the same thing yesterday about the on-label and the use of the anti-platelet agents being at least 12 months, so at least I for one --
		CHAIRPERSON MAISEL: Let's focus on the label, on-label use of this -- should we be adding something to the label to comment.
		DR. DOMANSKI: I was just responding to Eric.
		CHAIRPERSON MAISEL: Dr. Zuckerman.
		DR. ZUCKERMAN: I'd like to direct all the panel members.  I believe you have both the Cordis label and the Boston Scientific label, section 5.7, which already states that the safety and effectiveness, and this is where the TAXUS stent, the TAXUS Express stent, has not been established in the following patient populations, and then there are about ten off-label populations written.
		So in considering your point, Dr. Maisel, are you satisfied with the statement the safety and effectiveness has not been established, or are you stating that the point about death and MI needs to be also included?
		CHAIRPERSON MAISEL: I am proposing that we add a statement that -- suggesting that off-label use, that if you use the device off-label, you will not get the results that are demonstrated in the label, and I proposed the statement, and Dr. Nissen, you can comment.
		DR. NISSEN: Well, you know, for any label, be it a drug or a device, you know, it's inherent in the label that, you know, that off-label use is not recommended, so, I mean, that isn't saying anything new.  The question is do we have heightened concerns about the possibility of serious long-term adverse consequences, including death, if the device is used off-label in comparison to, in this case, bare metal stents.
		And again, I harken back to the Swedish data.  I cannot rule out the possibility that it's associated with a 20 percent or so increased risk of death, so I want to warn people in the label, you know, a little more strongly than maybe you put it.  The way it is now, it says, you know, we don't know.
		CHAIRPERSON MAISEL: I don't think the label is the place to comment on what happens if you use the device off-label compared to another product.  I think --
		DR. NISSEN: Well, we do put warnings in labels, though, Bill.  I mean, certainly in the drug world there are all kinds of warnings that are put into labels.  I'm -- what I'm -- I guess I'm not sure what the right mechanism is, but I don't want this to be passive.  
		I'm suggesting that we should be more active here in saying that there is enough of a concern here that we might actually be hurting people by putting drug-eluting stents in these populations, and make sure people understand that risk, and then if they decide they want to use off-label, well that's a physician judgement decision.
		CHAIRPERSON MAISEL: Dr. Kato.
		DR. KATO: Yes, I'd like to just strengthen that position, because I think that, you know, based on the package insert right now, this is how we got to this point.  I think to leave it alone means a tacit acknowledgment that we're not going to be changing anything and that this meeting was really a waste of time.  
		If you're going to -- well, if you're going to really say something about the uncertainties, and we have a lot of uncertainties here, then one, you know, one option, as I mentioned before, is a black box warning, which, you know, let me just quote.  It says, "Black box warnings are designed to highlight special problems, particularly those that are serious and that give health care professionals a clear understanding of a potential medical complication associated with a drug or device."
		CHAIRPERSON MAISEL: I think that --
		DR. KATO: And it sounds like it fits the definition.
		CHAIRPERSON MAISEL: I disagree. I think a black box warning is far too strong for a number of thoughtful physicians who choose to use this product off-label.  Dr. Somberg.
		DR. SOMBERG: I think our Chairman's wording was, and what I got immediately was, Bram, was to convey that there was more serious concern, so I think he covers Dr. Nissen's concerns, et cetera.  To have a black box warning, I think we need to have a more, a greater consensus and more information.  I think it's pouring in now. 
		This is just the beginning of the spigot on this area of hot interest that all you interventionists have, you know, registries and databases on and now organizing randomized trials, so the data's going to come in, and I think we should not go too far either way. Sorry to take too --
		CHAIRPERSON MAISEL: So we've heard from Dr. Zuckerman that there are already some comments in the current labeling, so the addition that we would put in would be something like, "Use of the stent outside of these indications may be associated with a higher risk of stent thrombosis, MI, and death."  Outside of these indications, outside of the label indications, if you use it outside the label's indications, you're going to have a higher risk of complications. 
		Dr. Edmunds.
		DR. EDMUNDS: Yes, I think you've got to put in here that then CABG or medical therapy -- you don't -- you say you have a comparison here, but you don't have a comparison.  I can't agree with this statement at all.  I think it has to be totally changed to be taken into consideration that CABG has better results than DES stents.
		CHAIRPERSON MAISEL: We're not comparing the --
		DR. EDMUNDS: At least there's evidence to bring this as a possibility. 
		CHAIRPERSON MAISEL: Okay.  Dr. Domanski.
		DR. DOMANSKI: Yes, I think there is -- you know, we've been listening to these, to surgery all day, and I think all of us should be concerned about the underuse of surgery and the overuse of angioplasty.  That said, there's substantially more equipoise in the community about whether or not surgery really is superior, and, in fact, that's -- that gains expression in the fact that we have two major trials going, one of three vessel disease and left main and one of diabetics and multi-vessel disease.  So I'm not at all bought into the fact that CABG is clearly better.
		CHAIRPERSON MAISEL: I think -- Dr. Zuckerman, do you have what you need with regard to the labeling at this point?
		DR. ZUCKERMAN: Yes.
		CHAIRPERSON MAISEL: Okay, let's move on.  We're going to move on to questions six and seven, which we'll do next.  We'll come back to question five.  Question six.
		MS. BOAM: Question six is, "What long-term data need to be collected to help further define the risk of thrombosis in drug-eluting stents?"  Part A is, "Should future pre-market studies conducted to support approval of new drug-eluting stents be modified to better assess thrombosis risk?"  And Part B is, "Should the long-term follow-up of the pivotal trial cohorts and post-approval studies currently mandated by FDA be modified?"
		CHAIRPERSON MAISEL: Can you do seven also, please?
		MS. BOAM: Question seven is, "The optimal duration of dual anti-platelet therapy in DES patients is undefined.  Indefinite clopidogrel use may not prevent very late stent thrombosis, may expose patients to an unacceptable increased risk of major bleeding, and may have important cost considerations for some patients.
		"Please comment specifically on the clinical study designs that would be most informative and yet feasible to evaluate this risk, given current patterns of drug-eluting stent use and uncertainty regarding the optimal duration of dual anti-platelet therapy."
		CHAIRPERSON MAISEL: Thank you. I'm going to invite Dr. Normand to propose -- let's focus first on the post-market type of information we need.  You had some thoughts yesterday and earlier today about that.  Could you give us your vision of what that would look like?
		DR. NORMAND: I think Dr. Mauri actually suggested some good ideas, as well as other people, so definitely we need a set of common definitions to define risk factors.  We do need some mechanism to collect information about patient compliance in the database as post-marketing, post-approval in terms of data collection.
	I am going to argue in terms of -- I'm not quite clear in terms of the guidance given to the sponsors, but we definitely need some information about a control group.  To go and just collect data on the -- let's see.  The DES arm is not going to be very helpful.  
		We're in a sticky situation today because of that, and while it might be very costly, one could come up with probably cheap, cost-effective ways to select patients on the control arm, and we can do that with propensity score designs.  There's a lot of innovative ways to do that on the cheap for the control arm, if that was possible, if that's going to happen, but I'll argue that we need something about the control, some control arm or arms. 
		We need information about the availability of types of stents and therapies that are available to the patients, and I'm saying that because of, well, the earlier comment regarding, at least with the earlier stents that it was really a supply issue.  It would be nice to know that supply issue, and it's a technical argument for doing something called instrumental variables, but you might have some way to help balance the unobservable.
		Information about -- again, I'm not sure about doing parallel naturalistic studies at the same time that you release something or even when you're doing a randomized trial.  We often do this in mental health studies.  We will enroll patients in mental health studies that want to participate in, let's say, bipolar or whatever, but those that refuse we can also look down the line and get some naturalistic information about those.
		So those parallel designs again, after things have been approved, even for ones that aren't approved, that's a natural way to collect information.  We want information from the same institutions for the control and treated arms, so there needs to be a real effort to collect information within the same institutions on, let's say, DES patients as well as bare metal stent patients or CABG patients or medical therapy patients, whatever that is, but we need to control for that.
		CHAIRPERSON MAISEL: How large should these trials be or these post-market studies?
		DR. NORMAND: Well, I started out -- my very first question was what size of a -- what's a clinically meaningful difference that you would worry about for stent thrombosis.  I can't tell you that.  No one can tell you the sample size unless the clinicians come up with a clinically meaningful event rate, and we need to define is it per patient, per year, whatever, but someone needs to decide that.
		CHAIRPERSON MAISEL: Dr. Topol.
		DR. TOPOL: Yes, I think we have to think about a different model for studying this entity.  The problem we have today is if we were to design -- and there's a registry centric thinking, which I think is wrong.  If we were to have more registries which have led to inconclusive uncertainty zone that we're in, it will take another three, four, or five years before we have some data out of that, which will lead to more uncertainty.
		So I think what another way to approach this is is to have a national registry of the patients who have had a late stent thrombosis.  Those would be skewed, because they are survivors, but nonetheless, they would be incredibly informative, because one could study the genomics of these patients as compared to those who have had a drug-eluting stent who have endured three or four years without any problem.  
		One could understand whether they have a predisposition to thrombosis, whether they have endothelial cell, progenerative cell issues as far as healing, and you might not be able to get to the issue of malapposition, but certainly the biologic issues that predispose to stent thrombosis could be ascertained by having a national registry of the patients who have suffered a very late stent thrombosis, and that would have immediate return in terms of informativeness.
		So I think the problem we have today is although there's a few good randomized trials that are pending, there are none with respect to the anti-platelet duration, which is a problem, but there is no concentration on the most important issue, which are the patients who suffer stent thrombosis and using the collaborative access to gain insights about these patients.
		CHAIRPERSON MAISEL: Dr. Laskey.
		DR. LASKEY: Just a quick one, Eric.  Just again the theme, compared to what?  Here you would take -- these are survivors.  This is like postmortem data.  The reason we don't believe autopsy data is because it's highly select, and you chose to look at that, but your data is comparing the genomics of those who survive ST versus nothing.
		DR. TOPOL: Versus those who have a duration of stent, a drug-eluting stent for multiple years and had no sequelae.
		DR. LASKEY: So it is -- you didn't say the comparative population.
		DR. TOPOL: I did mention that, yes.
		CHAIRPERSON MAISEL: Dr. Harrington.
		DR. HARRINGTON: So in terms of the pre-market study, I like the phrase that Eric used that there has been a registry-centric approach here in device development.  I too would like to see it move towards a randomized clinical trial focused area of -- paradigm of development, because we've sat here for two days and heard some good registry data, some terrible registry data, and we're going around the table and can't figure things out.
		I'm actually very much applauding -- I forget the name -- the ENDEAVOR program that Dr. Kuntz put forward.  There's an 8,000-patient randomized clinical trial comparing a new therapy against the current therapy.  You know, we didn't see the power calculations, but I'm going to guess it's pretty well powered for their primary end point.  That's the kind of work we need to see is large clinical trials.
		Now I would disagree with Eric in terms of the registry.  I do think there's usefulness to the registry, and I thought both ACC and STS made a plea for longitudinal databases.  Neither one of theirs is longitudinal, and that would be an enormously valuable service to have one or both of those follow patients over a prolonged period of time.
		CHAIRPERSON MAISEL: How long should pre-market studies be?  You said randomized trial.  I think we don't --
		DR. HARRINGTON: I'll go back to what Dr. -- I'll paraphrase Dr. Normand and say, "What's the question?"  If you're looking for incremental value beyond something that currently exists, you have to decide how much incremental value you're willing to accept as meaningful and then size your trial accordingly.
		CHAIRPERSON MAISEL: Are you comfortable approving a new stent with one-year data based on the data we're reviewed today about late stent thrombosis?
		DR. HARRINGTON: This is what -- I'll go to one of Clyde's comments to say that I'm glad I more typically sit on carpio-renal as opposed to this panel, because at least I look at the approval of things based on thousands of patients' worth of information.
		CHAIRPERSON MAISEL: Was that an answer?  I'd like someone to comment --
		DR. HARRINGTON: I think that most of what I've seen I would consider inadequate for approval.
		CHAIRPERSON MAISEL: Dr. Zuckerman.
		DR. ZUCKERMAN: Well, we're going to invite you to more cardiac device panels in the future, Dr. Harrington, but I think we want to respect what is the regulatory framework for the device approval process so that we can continue to move forward, and I'd like to press Dr. Topol and Dr. Harrington a bit.
		You heard about the -- I think we all recognize that one of the things that bedevils us today is the lack of randomized controlled clinical data to answer important health questions.  You heard about the Boston Scientific program where initially a limited approval based on randomized control trial data was granted.  
		The sponsor has subsequently almost completed very large trials in acute myocardial infarction, in three-vessel disease where the correct comparitor is CABG.  I mean, what else pre-approval are you looking for for the drug-eluting stent companies?  The usual paradigm here is different from drugs in that we're looking at more sequential development.
		Secondly, certainly Dr. Normand has raised an important point in that in our post-approval studies we should perhaps also concentrate on the important clinical end points of death and MI and be able to choose important comparitors, which may include CABG in appropriate circumstances, and we look forward to working with STS and ACC in getting appropriate control groups, et cetera.
		But aren't those the questions that the stent industry has to answer right now, as opposed to the genomic stuff is stuff that my colleague on the right, Dr. Domanski at NHLDI, is concerned with right now.  What are the fundamental issues that the stent industry is missing in their development, in their sequential development programs right now?
		DR. TOPOL: If I could respond first, I think that it's great that there are these trials that are pending.  SIRTAX and FREEDOM and the MI trials that you've mentioned, those are terrific.  Unfortunately, there was the promotion of these devices and the adoption without any evidence well beyond where the restrictive on-label criteria were first adopted, so there was a big gap in time, because these trials take multiple years to execute and get the requisite data, so that's been a problem, but hopefully we're getting close to the solution to that.
		But otherwise, unfortunately there has been unwillingness to do the appropriate trials of the conjunctive medical therapy, which is, as we've learned, is just as important.  There's no trials pending in that regard, and that's a real concern.
		And getting to the genomics, the problem is is that the incubation phase here -- the patients are calling after the tiny time bombs.  They're calling, "I want my stent taken out," to the cardiologists, and we need information now.  We can't wait four or five years.
		And actually, I think if we could quickly assemble hundreds of patients who have suffered a late stent thrombosis, we would be able to get that information very quickly with respect to the germ line DNA.  What are the genomic underpinnings for this serious adverse event?  
		That would help considerably, because today we use indiscriminate, long-term anti-platelet therapy.  We could target that.  We also use drug-eluting stents indiscriminately if we were to find out which patients are the ones who are most apt to get renarrowing.
		So those are sorts of things that could be done relatively quickly.  If we could assemble a few hundred patients with appropriate controls, we could have a study done within six months.
		CHAIRPERSON MAISEL: So I'd like specifically to address the pre-market question regarding stent thrombosis.  Do pre-market studies need to be designed and powered to demonstrate, let's say, non-inferiority to current DES stents on the market, and if so, at what time point?
		Dr. Somberg.
		DR. SOMBERG: I think -- after this controversy, I think the answer is to some extent yes.  We need longer, larger studies, randomized controlled, addressing more complexity, which increases the risk, and I think the sequential model, which works in some areas, may not work here at this moment, because the noise level would be high.  The signal would be low in the very simplest, and then you move along incrementally until you get to a problem.  
		So I think -- but with all that said, I was reassured by hearing at least one major developer is looking.  They're talking about eight to ten -- I thought 10,000 is the number I heard.  They're talking about, I thought, some complex situations, but also fundamentally to that is I think you have to start at the other end.
		And yes, I think Dr. Topol's idea of genomic studies is important.  When someone gets into it, does that stent need this?  How does it respond?  But also the drug that's put on the DES, what's the dose response?  Dr. Yancy made that statement, and I want to second that my concern is that I think too little thought is being given.
		But we're not going to get answers instantaneously to all these issues, so I think one is that future development is one thing.  Answering the current overall stent problem is another, and we have to separate them, and some of what Dr. Topol says is excellent, RO1s for the NIH, but I'm not sure is what's needed.
		I'm also say is that -- I just want to say one more thing, and that is the registries. Registries, I think, is to increase experience, always should have some comparator in it, and should never be short-term.  I mean, to close a registry at one year, I'm not sure it should be opened, so I think very long-term registries are very critical in this area.
		CHAIRPERSON MAISEL: Thank you.  Dr. Harrington, can you address the anti-platelet studies and what those should look like from this point forward so we can answer the important questions?
		DR. HARRINGTON: So it's clear that we don't -- we said today that we believe that at least 12 months of anti-platelet therapy is indicated.  What we don't know is going beyond that, and so what I would be -- there is, I think at last estimate, somewhere around six million patients who have had drug-eluting stents implanted, so this is a huge imperative to figure this out.
		I would recommend that we quickly get a group of investigators, and I suspect many would be interested, look at a group of patients who are still in the early days of having their stents put in and randomize a group of patients to various durations. 
		And I would somewhat arbitrarily for the strawman throw out 12, 18, and 24 months as the duration of follow-up and look at clinical outcomes, namely death, myocardial  infarction, with -- and I love a lot of Eric's ideas.  This would be fodder for sub-studies of looking at some of the issues of stent thrombosis.
		CHAIRPERSON MAISEL: So to summarize, should future pre-market studies be conducted to support approval of new DES be modified to better assess thrombosis risk?  I think we're saying yes, they need to be larger, longer, and give us some idea of the thrombosis risk for individual stents.
		Should the long-term follow-up of the pivotal trial cohorts and post-approval studies currently mandated by FDA be modified?  We heard proposals from the sponsors about making them, the ongoing studies, the cohorts being followed longer. I think we all feel that's appropriate.
		The post-market studies we've discussed.  It's important that we understand the patients.  We need similar definitions.  We need to assess compliance.  We need to understand the patient characteristics.  We need to understand the vessel characteristics. 
		There needs to be some control group.  I think there could be debate over what that control group would look like, but there needs to be a control group, and these studies need to be powered to detect a clinically meaningful difference in the critical end points that we have discussed.
		The optimal duration of dual anti-platelet therapy in DES patients is undefined.  Indefinite clopidogrel use may not prevent very late stent thrombosis, may expose patients to an unacceptable risk.  Please comment specifically on the clinical study designs.  
		We just heard certainly a randomized trial with varying durations of clopidogrel would answer that question.  We've heard 12, 18, 24, but that could be debated.  Perhaps you could also look at a cohort of patients who were on therapy already at 12 months and randomize those to discontinuation versus continuation.  That might save 12 months and get us to the end line or at least get some data sooner.
		Anyone have any major issues with what was said?  Dr. Nissen.
		DR. NISSEN: May I add one thing to what Bob Harrington suggested, and that is I think you need a third arm in that study, which is bare metal stent, because we really need to understand bare metal stent with relatively short-term clopidogrel compared to drug-eluting stent with conventional 12 months versus prolonged.  Otherwise, we don't really have the comparison that we need so we have to have all three arms.
		CHAIRPERSON MAISEL: Dr. Edmunds.
		DR. EDMUNDS: I really disagree with that statement.  I think that --
		CHAIRPERSON MAISEL: You had your microphone on before he made the statement.
		DR. EDMUNDS: It rambled on, and you sure covered a lot of territory, and what I think that any new drug-eluting stent has to be evaluated not against bare metal but against CABG.  I think that until somebody can show that the stented segment of coronary arteries are lined with functional endothelial cells, the patient should be informed of an ongoing thrombotic risk.  The magnitude is not know, but nevertheless the risk is there.  Those two things, I think, need to be in the informed consent part of any trial.
		CHAIRPERSON MAISEL: So as we spoke about, the post-market studies do need a control group, and new patient populations off-label will also obviously need to be studied.
		I'd like to move on to question five, which is, "In addition to current FDA efforts, what patient and/or physician education or other outreach measures, i.e. public health notifications, could potentially reduce the risk of stent thrombosis?"
		We spoke a little bit about this yesterday.  Certainly professional societies could help educate and have helped educate people regarding their current guidelines.  I'd be interested in knowing whether the panel felt that the FDA should specifically be doing something or sending out a letter or issuing a notification regarding any of the findings or statements made here today.
		Dr. Topol.
		DR. TOPOL: Yes, I think we could improve both at the patient and physician education level.  I think patients would benefit, those who are going to be undergoing  the stenting, to understand the three alternatives much better, that is of drug-eluting, bare metal stents, bypass surgery.  I don't know that they do get that education on the uncertainties attached to multiple vessel disease with drug-eluting stents and anti-platelet therapies and all the nuances that are attendant with that.
		The other point, though, is the physician -- I think this is the biggest problem is the cardiology community, because although we know that there is the interest in using drug-eluting stents to complex anatomical and complex patient subsets, because those patients have a higher risk of restenosis, the trade-off may not be favorable, and that's not been duly acknowledged.  
		So whether that comes from the FDA or it comes from other means, but education of the physician community to be more judicious, like for example the lesson --
		CHAIRPERSON MAISEL: So let's talk specifically about what the FDA should do.  Should there be any public health notification or any communication from the FDA other than this panel meeting and the publicity it will get?
		Dr. Nissen. 
		DR. NISSEN: I think a "Dear Doctor" letter would be very useful and that would summarize, you know, the take-home messages from this panel as interpreted by the FDA.  I know you guys always reserve the right to interpret, but we have to get the message out there of what we said here.
		CHAIRPERSON MAISEL: "Dear Doctor" letter sent by the FDA or sent by the manufacturer?
		DR. NISSEN: Well, you know, I'm not sure how the regulations work on the device side, but I would like to see it come from the FDA, in part because it would have a lot of impact if it did, if that's possible.
		CHAIRPERSON MAISEL: Pam.  Pam, why don't you go first?
		MS. ADAMS: Well, I have about six answers to several previous questions, so if you'll just bear with me one second.  Dr. Laskey, I have the same thing going on over here, so it's not just you.
		I like the fact that you made a comment about the regulatory process.  I think it's very important that the sponsor and FDA work together in accordance with what's typical and where the precedence is.  We've talked a lot about off-label use.
		It is -- there is not a precedent for companies including data and information in the label on off-label use.  That's just not -- it's not commonly done, and there's liability issues associated with that.  
		So I think we should encourage, speaking from an industry standpoint, that FDA and the sponsors work together to take the spirit of what has been said here and frame it from a regulatory standpoint in the appropriate manner.
		I heard someone mention contraindications and black boxes.  Those things all have very specific meanings.  Again, I think Dr. Page is -- the spirit of what you're saying regarding anti-platelet therapy and the continuation of it is an  important thing, but it's a very different thing to contraindicate something, so I'd like to be sure that we dial that in.
		And finally, the other thing that I think is key when we talk about pre-market and post-market studies is that we need to weigh the fact that there are a lot of companies that are already in the pipeline, have already conducted or finished studies pending approval, and that there is an impact  of some of what we're recommending so that we need to weigh that.
		And again I would ask -- I think FDA does a very good job of that -- that we all consider that what we're advising is that they take the spirit of what we're saying and the spirit of our concerns and frame that with respect to what the regulatory authority is.
		CHAIRPERSON MAISEL: Dr. Zuckerman.
		DR. ZUCKERMAN: Okay, Pam, I think those are very well phrased comments, and certainly the Agency recognizes the fact that it is a regulatory agency that works under the CFR, et cetera, but I think what's important for the stent industry, and also the FDA has heard today, the discomfort with the current lay of the land, and certainly we look forward to working with the industry investigators and professional societies in a legal framework to improve the lay of the land.  
		I would, you know, completely agree with you.  The notion of a black box isn't going to happen, but I think we have to understand, as you pointed out, the spirit of the discussion here.  Just like Dr. Nissen indicated a "Dear Doctor" letter, I think you're referring to an official statement from the Agency indicating what the scientific outcome here was today such that the public and physician community can be better informed.  Is that a better way of stating it?
		DR. NISSEN: Much better way, yes.  I also wanted to add to that one small thing.
		CHAIRPERSON MAISEL: Dr. Laskey's going to  speak first.
		DR. LASKEY: Maybe I'm going to say what you're going to say, but Bram, this one's on us.  I think it's our responsibility to step up, and I absolutely agree with Eric, and I hope Nissen was going to say this, but this is our responsibility.  We got into this mess in many respects.  We need to raise the level of awareness of our colleagues.  
		I think the professional societies and those whom we represent and work with need to be informed at a very substantive level. So it's nice for you to send out something on a letterhead within the constraints of what you can do, but this one is on us, and I think we all should rise to that challenge.
		CHAIRPERSON MAISEL: Dr. Nissen.
		DR. NISSEN: Yes, one other thing that we've done from time to time recently on the drug side is created materials, a patient guide, and I would recommend consideration be given to that.  And, you know, I think it has a lot of impact when it comes from the Agency, and so, you know, we have patient guides now for some high risk drugs, and the guide could emphasize, for example, the importance and the potential serious consequences of stopping dual anti-platelet therapy and so on.
		And the patient can't be left out of the equation here.  If a patient knows about this, the chances are that they are going to be more compliant, and let's be clear.  I mean, compliance is a problem across the field with drug administration, but if you don't comply with this therapy, you can get in a whole lot of trouble.
		And so I want the Agency to reach out to the patient, as well, with some communication.  Maybe when you get a stent, you ought to be given something from the Agency, which gives you some guidance about what does it mean to have a drug-eluting stent in your coronary.
		CHAIRPERSON MAISEL: Dr. Zuckerman, would you like the last word? 
		DR. ZUCKERMAN: Those --
		CHAIRPERSON MAISEL:  It's the last word before the last word.  It will be --
		DR. ZUCKERMAN: Regarding this question?
		CHAIRPERSON MAISEL: Yes, regarding the questions, because we're going to have to move on.
		DR. ZUCKERMAN: No, but I'd like to hear from Pam again to see if we've answered some of your concerns.
		MS. ADAMS: Thank you.  I appreciate that.  I think -- I just want to say that this has been an amazing process, and I thank you all for the input and the chance to work with you. 
		Dr. Zuckerman, yes, I think that my sense is that you're trying to do the right thing.  You're trying to work within the framework that you have.  Clearly the discussion today has been around the possibility of broadening the circle to solve some of these problems, to include societies and professionals, and I think that's very appropriate.
		CHAIRPERSON MAISEL: Thank you.  At this point, we will conclude the questions.  I am going to take a stab at summarizing 18 hours of meeting in about 15 seconds here, and then we're going to invite Dr. Dan Schultz to make some comments.
		We, over the last two days, have commented that there appears to be a numerical excess of very late stent thrombosis in drug-eluting stent patients.  The magnitude of the risk is uncertain based on the available data.  Importantly, there does not appear to be an increased rate of death or myocardial infarction when drug-eluting stents are used on-label and when compared to bare metal stents.
		Use of drug-eluting stents in off-label populations, like bare metal stents, is associated with an increased risk of stent thrombosis, death, and myocardial infarction.  I think we all agree we need more data, better data, more patients, longer studies, and hopefully this is the first step towards getting that information.
		At this point, I'd like to invite Dr. Dan Schultz, Director of FDA's CDRH, to make some comments.
		DR. SCHULTZ: Thank you, Bill.  Thanks you, Committee, and thank you to everybody who attended this meeting.  I'm going to try to make some comments that I would hope that everybody would agree with, but I guess I do that with some degree of trepidation given this audience.
		I think one thing that I would say that hopefully we would agree with is that this meeting needed to happen, and I think one of the things that I've certainly taken away is that it's important to bring these kinds of issues, some of these controversial issues, to this kind of an open public forum.  
		In the past, I think sometimes we've shied away from bringing these kinds of controversial issues, but to me what these last two days has demonstrated is that this is the best way, maybe the only way to get some, at least, some movement forward, if not some resolution of this kind of complicated issue.
		The second thing that I want to mention is that preparation is vital, and in that regard, I would like to pay particular attention to the work done by the FDA staff in putting this meeting together.  And when I say that, I mean both the scientific staff who prepared the materials, worked extremely hard to make sure that we had representation on this panel that was up to the task, and I think that they've done an excellent job in that regard, as well.
		And finally, I'd like to thank our panel management team for putting this kind of meeting together, again, fairly rapidly, and I think we recognize that this is something that not only needed to happen, but it needed to happen sooner rather than later.  And getting this kind of meeting together as quickly as they did, I think, was a real tour-de-force.
		Secondly, I'd like to thank the speakers.  I think we've had speakers not only from around this country but from around the world who have really added to our understanding of, again, what certainly is a very, very complicated issue.  And while we were presented with a lot of data, and I know part of your struggles was trying to make sense of all the different data, I think we would all agree that having had that data presented at this kind of meeting was extremely important.  And finally, I'd like to thank you for taking time out of your busy schedules to come here and helping us to move forward with this issue.
		But what did we learn?  I'm going to take a stab at it, and as Bill has done many times, but I get the last word, so I guess you guys can't comment on it.  I would say that what we learned was that the review process works.  
		Yesterday I think the discussion showed that there was unanimous agreement that for the on-label, and again, recognize that what we regulate is the on-label indications for these products, that the risk and benefit ratio, even given current new information, is still appropriate.  
		Second, I think it's important to understand that we need to update information, both to patients and physicians, based on new information, and it's our responsibility to make sure that the information that's out there is kept current. 
		Third, I think it's very clear to all of use, certainly to me, that we need to continue to monitor this particular issue, this particular safety issue, as well as additional issues that we may not even be aware of yet.  
		So having the time and the focus spent on post-market surveillance, again, in this case and in general to me is something that's of utmost importance and is a part of our responsibility that we can't afford to neglect.
		Fourth, I think we need to work closely with industry, academia, and other government agencies to encourage the design and performance of well designed studies to take a very diverse practice of medicine leading to considerable difference and convert those different practices to on-label indications when we have the data to do so.
		And fifth, I think that issue like this demonstrate the continued need for a strong and vital FDA with a commitment to a total product life cycle approach, both to the way we regulate devices as well as other medical products.  
		I was struck this morning in reading The Washington Post.  There were two articles related to FDA.  One talked about this meeting and the importance of this meeting.  The other talked about the fact that we now have a permanent commissioner.  I think both of those bode well for the future.
		Clearly, we all have a lot of work to do, but I would like again to thank you, because I think you've given us an incredibly valuable roadmap in terms of what we need to do in the days, weeks, months, and years to come.  Thank you very much.
		CHAIRPERSON MAISEL: Thank you very much, Dr. Schultz.  I'd like to thank the FDA for really putting together not only a comprehensive meeting but a comprehensive panel pack.  I'd like to thank Cordis and Boston Scientific for their excellent presentations and sharing of their data with us, all the speakers we had, and of course the panel members.  
		Our meeting is officially adjourned.  Oh, we need to clear out the room "immediately," so please, if you're going to have conversations, have them outside this room.
	(Whereupon, the above-entitled matter adjourned at 4:38 p.m.)