ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PERIPHERAL AND CENTRAL NERVOUS SYSTEM

ADVISORY COMMITTEE

ISSUE: SAFETY AND EFFICACY OF AGGRENOX

(DIPYRIDAMOLE/ASPIRIN CAPSULE (NDA 20‑884)

Wednesday, April 28, 1998

8:30 a.m.

Holiday Inn Gaithersburg
Two Montgomery Village
Gaithersburg, Maryland

Bethesda, Maryland

PARTICIPANTS

Sid Gilman, M.D., Chairperson
Sandra Titus, Ph.D., Executive Secretary

MEMBERS

Michael H. Brooke, M.D.
David A. Drachman, M.D.
James C. Grotta, M.D.
Claudia H. Kawas, M.D.

NEUROLOGICAL CONSULTANTS

Ella P. Lacey, Ph.D.
Richard D. Penn, M.D.
Gerald Van Belle, Ph.D.

SGE CONSULTANTS (CARDIOLOGY)

Robert Califf, M.D.
Marvin Konstam, M.D.

FDA 

Florence Houn, M.D.
Russell Katz, M.D.
Kathy Robie‑Suh, M.D.
Lilia Talarico, M.D.
Robert Temple, M.D.

C O N T E N T S
Page

Call to Order, Introductions
Sid Gilman, M.D.                        	  4

Conflict of Interest Statement
Sandra Titus, Ph.D.                     	  5

Introduction of Issues
Russell Katz, M.D.                       	 7

Presentation of Boehringer Ingelheim Pharmaceuticals

Introduction
Manfred Haehl, M.D.                     	 10

Clinical Overview
Gregory W. Albers, M.D.	47

Aggrenox Development Rationale
Thomas Muller, M.D., Ph.D.	79

Clinical Trial Efficacy
James Street, Ph.D.	94

Safety
Kenneth J. Rakowski, M.D.	179

Conclusion
Manfred Haehl, M.D.	191

Open Public Hearing

Dena Van Husen	194
Phillip B. Gorelick, M.D., MPH	196
Mark J. Alberts, M.D.	199

FDA Presentations

Overview of NDA
Kathy Robie‑Suh, M.D., Ph.D.	203

Efficacy Issues
Ann Farrell	209

Statistical Review of Aggrenox 
Mushfiqur Rashid, Ph.D.	215

Discussion by Advisory Committee 	252

P R O C E E D I N G S
Call to Order, Introductions
DR. GILMAN:  Good morning and welcome.  I would like to go around the table and have people introduce themselves.  I will start at the left here.
DR. VAN BELLE:  Gerald Van Belle, University of Washington, Seattle.
DR. GROTTA:  James Grotta, University of Texas Health Center, Houston.
DR. KONSTAM:  Marvin Konstam, New England Medical Center, Boston.
DR. LACEY:  I am Ella Lacey, Emerita Faculty, Southern Illinois University, Carbondale, Illinois.  Consumer Rep.
DR. PENN:  I am Richard Penn, Professor of Neurosurgery, Rush University in Chicago.
DR. DRACHMAN:  David Drachman, UMASS Memorial Health Care.
DR. CALIFF:  Bob Califf, Duke University.
DR. ROBIE‑SUH:  Kathy Robie‑Suh, Division of Gastrointestinal and Coagulation Products, FDA.
DR. TALARICO:  Lilia Talarico, Division of Gastrointestinal and Coagulation Products, FDA.
DR. KATZ:  Russ Katz, Division of Neuropharmacological Drug Products, FDA.
DR. GILMAN:  Thank you all.  Before we get started, let me just lay out a few ground rules.  At meetings like this, often two people will want to speak
simultaneously.  To avoid that, I ask that members of the committee at the table will raise your hand in some way to signal that you would like to speak.
For both the sponsor and the agency, I can assure you from previous experience on this committee that we have read the material thoroughly.  We are familiar with it.  We have a number of questions and we would like to have our questions addressed.
So when you are speaking, if we ask you a question, and we will‑‑we will interrupt from time to time‑‑please answer our question at that time.  Don't say you will get to it in a minute because sometimes those issues disappear and they we are left in our deliberation period not knowing the answer to the question.  So please allow us to interrupt and please answer the question as directly as you possibly can.
We have a conflict of interest statement by Sandra Titus, our Executive Secretary.
Conflict of Interest Statement
DR. TITUS:  The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of a conflict at this meeting.
Based on the submitted agenda for the meeting and all financial interests reported by the participants, it has been determined that all interests in firms regulated by the Center for Drug Evaluation and Research which have been reported by the participants present no potential for a conflict of interest of the committee with the following exceptions.
In accordance with 18 USC Section 208(b)(3), waivers have been granted to Drs. Richard Penn, Sid Gilman, Claudia Kawas and Marvin Konstam.  A copy of these waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A30 of the Parklawn Building.
We would also like to disclose that Dr. James Grotta was a local PI on a study of Syntex's Ticlid, a competing product to Aggrenox.  Further, we would like to disclose that Dr. Robert Califf is the Director of the Duke Clinical Research Institute at the Duke University Medical Center.  The Duke CRI is the coordinating center for numerous clinical trials and it has received funding from various pharmaceutical companies for a study of products unrelated to the product at issue or to the competing product.
Although these interests do not constitute a financial interest in the particular matter within the meaning of 18 USC, Section 208, they could create the appearance of the conflict.  The agency has determined, not withstanding these involvements, that the interests of the government in Dr. Califf's participation outweighs the concern that the integrity of the agency's programs and operations may be questioned.
Therefore, Dr. Califf may participate fully in the committee's deliberations concerning Aggrenox.  In the event the discussions involve any other product or firm not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.
With respect to all other participants, we ask, in the interest of fairness, that they address any current or previous involvement with any firm whose products they may wish to comment upon.
DR. GILMAN:  Thank you.
We will move right along to Dr. Katz' overview.
Introduction of Issues
DR. KATZ:  Thanks.  Actually, the agenda is somewhat misleading.  I am not going to give an overview.  I really just asked for a couple of minutes to welcome folks back.  In the Division of Neuropharmacological Drug Products, we have always considered this committee to be our committee, sort of an extension of the Division.  But technically I have been told that is not correct.
From time to time an issue will come before another division, other than ours, that needs to be brought before this committee.  That is the case this morning.  The NDA for Aggrenox, as Dr. Gilman pointed out, is the Gastrointestinal and Coagulation Drug Products Division.  But, because the issues are neurological, it is appropriate to bring it to this committee.
Having said that it is not "our" committee, I still think of it as our committee.  So I asked Dr. Talarico, as the Director of the division, if I could just give a welcome.  I am pleased to do that.
Dr. Talarico's division and staff have actually reviewed the data and they will be presenting the FDA's view of the results of the trial.  Dr. Feeney and I from the Neuropharm Division have consulted with that division and we are available to comment further if needed.
So I really just want to welcome you back, those of you who are coming back.  There have been many changes since our last meeting which, as Dr. Gilman reminds me, is quite a while ago. 
We have a number of new members.  And we have a number of members who are returning.  I want to welcome the new members, Dr. Grotta and Dr. Roy Penix, who, unfortunately, was ill and can't be here.  And Dr. Lacey.  Welcome.  I hope that your serve on the committee is interesting and stimulating.  I expect it will be.
Dr. Mike Brooke, Dr. Gerald Van Belle and Dr. Richard Penn are returning to this committee after a numbers of years off and are the inspirations we need to perform three or four more years of thankless, underpaid, government service.  So we want to thank them in advance.
There is one other major change in the committee that many of you have probably noticed and that is this is the first meeting of the PCNS Advisory Committee, in over twenty years, in which Dr. Paul Leber is not at the table.  As most of you know, Dr. Leber retired a couple of months ago, and this committee, and well as many of you know full well his extraordinary contribution.
Those of us in the division were fortunate to be able to experience his influence on a daily basis, some of us for many, many years.  I know that the committee will miss him and we at the division, of course, miss him very much.  I guess he is not here in the audience.
But, in any event, I just wanted to welcome you all back, those of you who have been on the committee.  And I hope that the discussion is interesting.  I expect it will be. 
I will go back to Dr. Gilman.  Thank you.
DR. GILMAN:  Thank you.  We have been joined by Dr. Claudia Kawas who is from Johns Hopkins University.
Boehringer is now going to begin with Dr. Manfred Haehl, Senior Vice President, Medical and Drug Regulatory Affairs.
Presentations by Boehringer Ingelheim Pharmaceuticals, Inc.
Introduction
DR. HAEHL:  Dr. Gilman, Dr. Talarico, Dr. Titus, members of the committee, good morning and thank you very much for giving us the opportunity to present to you this morning.
[Slide.]
My name is Manfred Haehl.  I am the Senior Vice President for Medical and Drug Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals.
[Slide.]
Boehringer Ingelheim seeks approval for Aggrenox and its extended‑release formulation product of dipyridamole and aspirin which reduces the combined risk of death and non‑fatal stroke in patients who have had transient ischemia of the brain or completed ischemic stroke.
Before we begin the detailed presentation of the data in support of this NDA, let me please read you the rationale for the development of Aggrenox and its potential for the presentation of stroke.
Ischemic stroke is a serious and devastating event in the larger group of ischemic vascular conditions.  Its incidence remains high at about 700,000 per year in this country in spite of risk management and pharmacologic approaches.  Therefore, the impact, not only on the patients but also their families and society, is enormous.
There is substantial prior information on the use of anti‑platelet agents both alone and in combination.  Safety and efficacy of those agents have been established in ischemic diseases in general and in the secondary prevention of stoke particularly.
Aspirin is the most widely studied anti‑platelet agent in the prevention of stroke.  The most recent FDA rulemaking for the professional labeling was published at the end of last year. 
[Slide.]
The indication in this final rule is as follows: to reduce the combined risk of death and non‑fatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin‑platelet emboli.  The dose in this rule is 50 to 325 mg/day.  It is important to note that this indication was granted on the basis of a relative risk reduction for the combined endpoint of stroke, TIA and death in the range of 13 to 18 percent.
The trial of aspirin alone in patients with prior TIA or occlusive stroke showed individually and in metaanalyses clear benefits on stroke.  However, the results on death were less conclusive.  The trials of dipyridamole alone were both fewer and underpowered and basic research suggested that the combination of aspirin and dipyridamole would yield greater benefits than either agent alone.
For these reasons, Boehringer Ingelheim sponsored two large‑scale trials.  First, the European Stroke Prevention Study No. 1 or, in short, ESPS‑1, which has been a combination of aspirin together with immediate‑release dipyridamole in one arm against placebo in the second arm.  And the second study was the European Stroke Prevention Study 2, or ESPS‑2 which was based, in part, on the results of ESPS‑1.
ESPS‑2 used a two‑times‑two factorial design of dipyridamole extended‑release and aspirin.  The combination dose and formulation were chosen to yield maximal and sustained inhibition of platelets together with minimal side effects, less frequent dosing, fewer pills, to enhance long‑term compliance.
[Slide.]
You will note that the pivotal trial, ESPS‑2, has contributed about 33 percent of the data to the world literature on aspirin and stroke, 3,400 to 5,050 and has more than doubled the world literature on dipyridamole in stroke.
[Slide.]
ESPS‑1 studied the efficacy of the combination of immediate‑release dipyridamole plus aspirin as compared to placebo in the prevention of secondary stroke.  This study confirms the highly significant benefit of the combination.  However, due to its design, it was not able to evaluate the contribution of dipyridamole or aspirin for the observed effects.
[Slide.]
A pivotal study for Aggrenox is ESPS‑2.  It was designed and it was powered to establish the efficacy of the Aggrenox combination product and of its components, and especially it studied the Aggrenox formulation which is under review today.
[Slide.]
The Aggrenox formulation was designed to combine doses of two active anti‑platelet agents with distinctly different modes of action.
[Slide.]
The product is formulated as a hard gelatin capsule containing an immediate‑release 25‑mg tablet of aspirin surrounded by approximately 700 extended‑release granules.  These granules amount to 200 mg of dipyridamole and have different coating to insure sustained release of dipyridamole over the entire dosing interval.
The Aggrenox formulation was desired to enhance compliance over immediate‑release dipyridamole formulations which require TID or QID dosing.  The 20 mg of aspirin was chosen to insure maximal cyclooxygenase inhibition in the platelet‑‑you know that this is a hit‑and‑run phenomenon for the lifetime of the platelet‑‑and, on the other hand, to minimize the potential for aspirin‑related adverse events.
The scientific hypothesis was that the two distinctly different mechanisms within a rational formulation with no power for kinetic interaction between the two components would actually translate into important benefits in the clinic, benefits which are additive and superior to the monotherapies.
ESPS‑2, in pivotal trial, did test for this hypothesis in a double‑blind, randomized, four‑armed parallel design in over 600 patients with preceding TIA or completed ischemic stroke.
The patients were recruited in 59 centers from 13 countries all over Europe.
[Slide.]
The study demonstrates the highly significant superiority of Aggrenox both over aspirin and dipyridamole in stroke prevention.  We will demonstrate to you that this superiority can be achieved without additional safety risk.
While the outcomes for the prevention of stroke are of powerful significance, the rate for deaths in the study was too low to establish a significantly signature reduction.  Nevertheless, the trends, both for Aggrenox and for aspirin, were positive.  They were comparable to each other and, even more important, and notably, they were consistent with prior experience and the recently published FDA‑approved labeling for aspirin.
[Slide.]
Finally, all significant results in ESPS‑2 are robust and reproducible independent and regardless of the statistical methods applied.  The powerful superiority results from ESPS for stroke prevention and with the consistent trend for combined death and stroke, we would like the committee to consider that the indication for Aggrenox should be harmonized with the approved indication for aspirin.
[Slide.]
In addition, we would like to ask you to consider how the label for Aggrenox can reflect the robust superiority of Aggrenox for the endpoint of stroke.
Finally, we will show you that ESPS‑2 meets the FDA requirements for a single trial to support the approvability of a product as shown on this slide.
[Slide.]
In addition, we will show that Aggrenox complies with the FDA guidance on combination products in which the sponsor must provide evidence of the contribution of each of the components.
[Slide.]
Before I now hand over to the next speaker, I would like to take a moment to mention the academic experts which are in attendance with us today.  They are Dr. Donald Easton, Professor and Chairman of Neurology, Brown University, Rhode Island Hospital; Dr. David Sherman, Professor and Chief of Neurology, The University of Texas Health Science Center; Dr. Charles Hennekens, Visiting Professor at Miami and Oxford, U.K.
[Slide.]
Dr. John Pathy, Director and Emeritus Professor, Health Care Research Unit, University of Wales.  Dr. Pathy also was the Chairman of the Independent Morbidity and Mortality Assessment Group of ESPS‑2.  
Ladies and gentlemen, unfortunately, I have to tell you that Dr. Diener from the University of Essen, who was one of the principle investigators of ESPS‑2, wanted to attend but could not come because his mother had to undergo acute surgery.
[Slide.]
Following this introduction, four additional speakers will now present to you.  Dr. Greg Albers of Stanford will present an overview of the current management of recurrent stroke and where Aggrenox will fit.  He will be followed by Dr. Thomas Muller from Oldenburg, Germany, who will review the pharmacological and the pharmacokinetic rationale for the formulation of Aggrenox.  The clinical efficacy and the clinical safety will be presented by Drs. Street and Rakowski from Boehringer Ingelheim Pharmaceuticals.  I will follow with concluding remarks.
Ladies and gentlemen, I would like to conclude my introduction with my sincere appreciation to the committee for their consideration and for their advice. 
Finally, I would like to introduce Dr. Greg Albers, Director of the Stanford Stroke Center, who was the lead author of the recently published American College of Chest Physicians Sixth Consensus Conference on Antithrombotic Agents in the Management of Stroke.
Dr. Albers will review the current treatment of stroke and place in perspective where Aggrenox might fit in the treatment armamentarium.
Thank you for your attention.
DR. GILMAN:  Dr. Haehl, please don't leave the podium just yet.  We have been joined by Drs. Houn and Temple.  Could you introduce yourselves.
DR. HOUN:  Florence Houn, Office of Drug Evaluation III.  Thank you.
DR. TEMPLE:  I am Bob Temple.  I am Associate Director for Medical Policy.  Thank you.
DR. GILMAN:  Dr. Haehl, you mentioned a number of issues that I think, perhaps, we should ask you about at this point unless you prefer to defer to some of your colleagues.  Question 1 concerns one of your slides where you described Aggrenox's proposed indication is to reduce the combined risk of death and non‑fatal stroke in patients who have had transient ischemia of the brain or completed ischemic stroke.
The original protocol, as I understand the situation, specified two endpoints.  One is stroke.  The second is all‑cause death.  Then, later, a third endpoint was added, apparently, which would be the composite endpoint stroke and/or death.
What you have shown is that there is an effect upon stroke that seems beneficial to your ingredient components.  But I don't believe that you have shown that, in fact, it is effective for the combined problem of stroke and/or death.
Could you address that question?  It had a couple of parts.  One is is this a reasonable request or reasonable indication in light of the findings, first.  And, second, can you explain the change in the endpoints?
DR. HAEHL:  Dr. Gilman, you find me in a conflict now.  The conflict is should I obey to your suggestion to immediately answer or should I tell you that we have prepared a presentation which will address that.
I will try to answer briefly and attend to it and then more extensively later.  Yes, the primary endpoints of the study ESPS‑2 were conducted in stroke endpoints and mortality.  This was a European study.  When we decided, because of the very, very significant and beneficial outcome of the study, that we would not want to hesitate to also propose this formulation for registration in the U.S., we had a pre‑NDA meeting with the FDA.
In the flavor of also looking at the effects of aspirin where ESPS‑2 has shown a major contribution of the data available for aspirin, it was agreed to also look at the endpoint combined stroke and death.  Dr. Street will address this in detail.
DR. GILMAN:  Is it your view that the results of this trial, ESPS‑2, in fact, did show that this medication is effective in patients for the combined risk of death and non‑fatal stroke?
DR. HAEHL:  Our assessment is that the results obtained for ESPS‑2 for this combined endpoint are absolutely consistent to prior experience which was in the aspirin label.  Therefore, we consider that as a confirmation of the database.
DR. GILMAN:  Questions from the rest of the committee?
DR. DRACHMAN:  I have one question.  Would you say something about the most frequent cause of death, meaning those with stroke, and the relation of aspirin to heart disease, the dosage levels?
DR. HAEHL:  Could you repeat precisely for me your question.  Are you talking about the results of ESPS‑2 and‑‑
DR. DRACHMAN:  That, or more generally, the reason for death in most people with stroke‑‑in other words, if this formulation was designed to prevent death, then one needs to think of why those with stroke die and, given that, how this medication would relate to those known causes of death.
DR. HAEHL:  I would like‑‑Dr. Street, could you show your slide on the mortality outcome in ESPS‑2?
[Slide.]
DR. HAEHL:  I am showing you a slide which will come up in the later presentation and maybe will somewhat disrupt the presentation and take it out of context.
DR. GILMAN:  Please answer the question, if you can, even briefly now.  You can get back to it later.
DR. STREET:  I believe I am not prepared with the slide here.  We have only the total mortality slide.  We examined that.  My presentation, that would be figure No. 24 of my slides.  The primary factorial analysis is where the supportive pairwise comparisons start at 26.  First maybe we should start with the slide to get a picture of the overall mortality.
[Slide.]
Here we see that there are very few little differences between the curves.  This is the aspirin curve on top in yellow.  The green is Aggrenox.  By the end of the two years, the planned endpoint of the study, most of the curves have converged.  Placebo in blue is slightly less.  These amount to very few patients' deaths saved per thousand treated.
I could look those up if you wish, but approximately 10 on aspirin‑‑13 on aspirin, 10 on Aggrenox‑‑but very moderate‑sized reductions.
DR. DRACHMAN:  The question was what did they die of?  What are the diagnoses leading to death?  What did they die of?
DR. HAEHL:  Since this is a clinical question, may I ask Dr. Hennekens to give us his perspective on that, if you permit.
DR. HENNEKENS:  First, by way of background, I chaired an aspirin strategy group that petitioned the FDA for indications for aspirin in this situation.  The same issue came up with the aspirin data which related to the fact that the trials are designed to test a particular outcome and all‑cause mortality is certainly not an outcome for which trials of the usual size will have adequate power, let alone cause specific mortality.
So, I think that with that as the caveat, there was no significant reduction from aspirin alone on death, but the combined endpoint of stroke plus death in patients with TIA and stroke did show a significant result, and the labeling indication was granted.  So, I think that is background.
Now, with regard to the causes of death, there is a variety of causes of death that basically are a major contributor here is death from stroke, and it shows the expected reduction, however, the numbers are just insufficient on which to make a firm judgment for death alone, let alone cause specific mortality, and I think that is an important methodologic point that has to be given, yet the data are consistent with reductions in stroke deaths.
DR. GILMAN:  Dr. Temple had a question.
DR. TEMPLE:  Actually, I have a comment.
In devising endpoints for these intervention trials, historically, people have tried to identify cause‑specific mortality, that is, the person died of a heart attack, the person died of sudden death, the person died of a stroke, and it is treacherous business, so the advice we often give‑‑not always accepted I should tell you‑‑is that you should look at total mortality, and not worry too much about your ability to separate the causes of death, because it is very difficult, it is after the fact, and you often can't do it.
So, it is not uncommon in a lot of the trials we give advice about for the endpoint to be total mortality plus the event of interest, such as stroke.  You know, one can even make a case for throwing MIs into that endpoint, too, because the populations get all of these things.
Overviews of aspirin data, for example, have consistently shown that people with stroke get heart attacks and stroke and die of what appear to be heart attack, stroke, and things like that, and people with heart attacks get stroke and die of heart attack, stroke, and all those things.
So, the causes of death in these atherosclerotic populations are pretty similar across the board, but the main thing I want to say is our experience has told us it is not easy to figure out the cause of death after the fact.  It is very difficult.  So, often total mortality is the endpoint chosen or the component chosen.
DR. GILMAN:  Since we are talking about this, that is a point, how, in fact, did the sponsor determine the cause of death.  Sometimes these would happen at home, sometimes in hospital, yet, you had regular follow‑up visits, how was it ascertained what the cause of death might have been in this trial.
Dr. Haehl.
DR. HAEHL:  We had a morbidity and mortality assessment committee, and Professor Pathy was the chairman of this committee, and I would invite Professor Pathy to comment how the cause of death was assessed.
DR. PATHY:  Thank you, Chairman.
Firstly, of course, the trialist reported back on the cause of death as he saw it, but the MMAG had to make certain clear‑cut definitions to ensure consistency of reporting.  Thus, anyone having an endpoint stroke is very likely to have other events, such as pneumonia, particularly aspiration pneumonia, equally somebody having a myocardial infarction is likely to have congestive heart failure.
Therefore, we made a very clear‑cut decision that a patient having a stroke, an endpoint stroke and dying within 30 days of that stroke would be classified, the death would be classified as stroke, though the trialist may have written down chest infection, but we would still label it as death from stroke if it occurred within 30 days.
Similarly, if a patient died within 30 days of a myocardial infarction, despite the fact that the trialist might label it as congestive heart failure, we would label the cause of death as a myocardial infarction.
So, we had to have long‑term consistency in the trial a certain specific criteria, diagnostic criteria.
DR. GILMAN:  Thank you.  That does help.
Dr. Katz, did you want to comment?
DR. KATZ:  I just was going to, before this last comment, reiterate that the comment that Dr. Temple gave, which is that it is true that it is difficult to ascribe any sort of a cause to mortality, and it is also true for stroke, because that is going to be an issue about stroke‑related death, and it is very difficult, and the comment we just heard suggested that there were some criteria, where there were some prospective criteria, I guess there were, about what was a stroke‑related death, that is arbitrary, as well, and doesn't necessarily mean that the deaths were actually related to stroke.
I think again, as Dr. Temple pointed out, I don't know how important this question is really in the overall schema.  I mean we are looking over a mortality which is probably a reasonable way to look at deaths.
DR. GILMAN:  Dr. Haehl, you commented when you were discussing the use of DP and aspirin in combination that you view these as mutually beneficial approaches drugs, but you haven't commented on the rationale for the dose.
Why did you choose 25 milligrams of aspirin, 200 of DP?  Did you do dose finding studies?
DR. HAEHL:  I explained that from the development point of view, we chose the 25 mg b.i.d. because we expected that, first of all, 50 mg daily would completely suffice to knock out cyclooxygenase in the platelet, and that is an effect which will last for the whole lifetime of the platelets or nine days roughly, and this is an important contribute to platelet aggregation.
Secondly, we were convinced that 25 mg b.i.d. are an effective dose of aspirin, however, would minimize the risk for the aspirin‑induced adverse events, and again I would like to ask Dr. Hennekens to comment and share with us his experience and his interpretation of the dose response of aspirin as to safety.
DR. HENNEKENS:  In the antiplatelet trialist collaboration, we found that the benefits of aspirin were present across a wide range of doses, from about 30 to 50 mg up to really several grams a day, but the most striking finding was the difference in the side effect profile.
In addition, working with Paul Ridker, we did plated aggregability and bleeding times for a dose of 50 mg a day for the Women's Health Study of aspirin in 40,000 women funded by the NIH, which is giving 50 mg of aspirin a day and placebo, and found that we got complete inhibition of platelet‑dependent cyclooxygenase for the life of the platelet.
These data in our small pilot are consistent with the prior seminal work of Garrett Fitzgerald of Carlo Patrono and Babette Wecksler confirming that this dose will give inhibition to platelets, and also from the antiplatelet trialist data at minimal side effects, so it is an optimal dose with regard to inhibiting platelet aggregation and minimizing side effects from aspirin.
DR. GILMAN:  Thank you.  And dipyridamole, how did you choose the dose of dipyridamole?
DR. HAEHL:  Dipyridamole, we choose with respect to its ability to inhibit adenosine uptake, and again here the rationale, where Dr. Muller will refer to and show you also slides to that, was that we wanted to obtain an 80 percent inhibition of adenosine uptake because we believed that 80 percent is a relevant inhibition which will translate into clinically important inhibition of platelet aggregation.  Just to tell you that we have determined IC50 values for this mechanism, and we translated that into concentrations which we would need in plasma.
DR. GILMAN:  So you did no dose finding studies then.
DR. HAEHL:  For outcome studies of this type, we did not feel the possibility to do Phase II‑A type dose finding studies.
DR. GILMAN:  Dr. Califf.
DR. CALIFF:  I guess we are covering a lot of background things, so I will just keep going here for a little bit.
There were two questions I had that are less‑‑well, that I would regard as background that I would like to hear a little discussion on.
One is the use of placebo.  How is the use of placebo justified in light of all the other data about the efficacy of aspirin for patients with vascular disease?
Secondly, in the population data at least that I saw, there is really a very homogeneous cultural ethnic background of the population, and would you propose that extend the findings to all races and ethnic backgrounds based on these data?
DR. HAEHL:  The ESPS‑2 was a study which was performed all over Europe, and coming from Europe, I would consider that Europe is a relatively large pool, genetic pool, and it covered all ethnic groups of Europe.
However, clearly, we don't have information on ethnic groups, especially specific to America or the United States, so we certainly do not have included African‑Americans in this study.
From the preclinical data, from pharmacokinetic data which we have, and from based on the pharmacologic mechanisms, we do not believe‑‑and I underline we do not believe‑‑that there is an important difference in the clinic between ethnic groups, but specifically for those in America, we have not investigated that.
Again, I would like to ask one of our clinician advisers, Dr. Albers maybe, whether he could comment on his interpretation of differences both in the treatment of stroke and also in the ethnic differences and the effects of Aggrenox between the two continents.
DR. ALBERS:  I don't think we have data from any of the antiplatelet stroke prevention trials to suggest that there is a different response between different ethnic populations.  One of the issues with ethnic compilations that some of them have more risk factors, and we have evidence from the ESPS‑2 trial that patients with risk factors, particularly hypertension, diabetes, did appear to respond in a similar manner.  I think that is as close as we are going to be able to come to extrapolating and saying that we don't have anything specific that would indicate that different populations would be expected to respond differently, although, as mentioned, there is no specific data in African‑Americans.
DR. HAEHL:  I didn't answer your first question as to placebo, the use of placebo.  May I have a slide.
[Slide.]
I think we have to separate between our today's point of view and the point of view when the study was initiated.  That holds true for the inclusion of placebo.  It also holds true for several other aspects of the methodology of clinical trials.
The placebo was included because of, at that time, conflicting results from previous stroke trials.  The placebo comparison was perceived to be necessary to assess the potential benefits of low‑dose aspirin at that time, and at the beginning of the trial, all 60 independent ethical review committees agreed that the use of placebo was appropriate, as did the Central Ethics Review Committee, and as did, of course, all the participating investigators.
It is clearly an issue from today's point of view and especially with the results of ESPS‑2 in hands, we would never suggest to do again a placebo‑controlled trial, but that is the development of knowledge and experience.
DR. GILMAN:  Thank you.
Dr. Katz.
DR. KATZ:  A couple of questions.  About the statement that there were no evidence that there were racial differences in response, has that been actually investigated, or has that question really not just been examined adequately?
DR. ALBERS:  It is extremely difficult to examine because of the sample sizes needed to show a benefit of an antiplatelet agent for stroke prevention.  You generally  need studies of several thousand patients in the trial minimum to show a benefit.
So, conceiving of doing a trial where you are going to have that appropriate power in individual racial groups, that hasn't been done, although currently there is an ongoing study that is looking just at African‑Americans with two different antiplatelet agents.
But the point that I was making is within the limitations of the study, which clearly are underpowered limitations, no obvious differences have been noted in terms of one racial group responding differently to an antiplatelet agent than another.
DR. KATZ:  Let me just ask you, I don't know those data, the representation, the degree of representation, let's say, of African‑American patients is presumably quite small.  I mean it is one thing to say within the limits of the data there is no obvious difference, but if the data are so limited, it's hard to say anything about it presumably, so I mean are they that limited?
DR. ALBERS:  In most of the stroke prevention trials, specifically African‑Americans have been very limited.  I think that was one of the rationale for the NIH to fund a specific trial looking just at African‑Americans.
DR. KATZ:  What about in‑vitro work and the effect on cyclooxygenase activity or whatever else you look at with these agents, using platelets from African‑Americans, has that been looked at?
DR. ALBERS:  I don't have any data on that.  I don't know if any of the other experts know of any specific studies that have looked at that issue.
DR. HAEHL:  We have information that pharmacokinetically, it behaves‑‑dipyridamole behaves in the same way in whites and in African‑Americans.
DR. KATZ:  Kinetically, but not necessarily mechanistically?
DR. HAEHL:  I am not aware that we have investigated platelets of different ethnic origin.
DR. KATZ:  I just had another question earlier about the dose response.
DR. HAEHL:  To the question under discussion, Dr. Gilman, Dr. Hennekens would want to comment.
DR. GILMAN:  Yes, please.
DR. HENNEKENS:  I wanted to emphasize Dr. Albers' important point.  It is true that there is a difference in the rates of these diseases that are occurring by ethnic group, but the question is do we have a priori any reason to suspect that there is a difference in the relationship of the agent to the disease, not the disease incidence itself.
My own view of this is I feel that a study that includes 5 percent or even 10 percent of African‑Americans is potentially more damaging than one that excludes them completely.  If you want to get the answer, you must have a sufficient number of people to answer that question definitively, and the inclusion of 5 percent or 10 percent is not going to answer that question.
I think it may be politically correct, but I think it is scientifically incorrect.  I think the way to do the study is the way the NIH is doing it in that population to get a reliable answer to that question.
DR. KATZ:  I don't disagree.  I am just trying to make, to sort of bring out the point that there really is not very much known about the effects in that population, and if the intention is to rely on one trial done not in this country, these are issues that I think are worth thinking about.
The question I had also, if I could, about dose response in aspirin and the choice of the dose, are there any trials that look directly, compare directly within one trial, various doses of aspirin, and has a dose response been shown in those?
Just the other half of that question is what about the side effect.  You say there is a dose response with side effect, but what does that look like?  I mean where does that start, where does the dose of aspirin start to be a problem?
DR. ALBERS:  In terms of the efficacy comparison, there are three trials that have given head‑to‑head comparisons of aspirin dose.  There was a Dutch TIA trial, which was a large study, looking at a 30‑mg dose versus about a 300‑mg dose, showing no difference.
There was a trial in the UK that looked at about a 300 mg dose versus a dose close to 1,000 mg, so medium versus high dose, and showed no difference in efficacy, and then I will show you some data in a few minutes about a more recent study that looked at carotid endarterectomy patients and compared low doses to high doses, and actually showed benefit of low doses over high doses.
Do you want to comment further about the side effect profile?
DR. HAEHL:  Dr. Albers, I would just put up a slide in support of your‑‑so that is the summary on a slide for the different doses in terms of efficacy for doses from 100 mg up to 900 mg.
DR. HENNEKENS:  With regard to the side effects issue, in the UK TIA trial, approximately 800 patients were randomized to placebo to 300 mg a day or 1,200 mg a day.  With regard to GI side effects, the rates were 24 percent in the placebo group, 29 percent in the low‑dose aspirin group of 300 a day, and 39 percent in the 1,000 mg a day.
Now, if one looks at those differences, they are statistically significantly different, not just between the high dose and placebo, but between the high dose and low dose, and the low dose was closer to the placebo in frequency than it is to the high dose.
With regard to GI bleeding, it was 1.6 percent in placebo, 2.6 percent in the low dose, and 4.9 percent in the high dose.  Furthermore, in the antiplatelet trial‑‑those are direct comparisons‑‑the indirect comparisons in the antiplatelet trial as collaborations show that the lower doses were associated with even fewer side effects, and also that 30 to 50 mg is enough to maximally inhibit platelet‑dependent cyclooxygenase for the life of the platelet.
So, I think there are compelling reasons for this dose with regard to efficacy and with regard to safety, as well.
DR. GILMAN:  Dr. Drachman and then Dr. Penn.
DR. DRACHMAN:  I am a little puzzled.  If 50 mg totally suppresses cyclooxygenase, what is the basis of more bleeding with larger doses?  What are the other effects of aspirin on bleeding tendency?
DR. HENNEKENS:  There is evidence there are direct toxic effects of the aspirin, for example, in the stomach, and that is also related to the dose, so that we have‑‑
DR. DRACHMAN:  On bleeding effects.
DR. HENNEKENS:  Yes, on bleeding, yes.
DR. GILMAN:  Do you want to address that question?  Go ahead, Bob.
DR. TEMPLE:  If you do endoscopy studies with NSAIDs and aspirin, you find local punctate ulcerations and things like that, so they have direct effects in addition to the effect on bleeding.  I doubt 300 mg once a day has a major effect of that kind, but at 1,200 or so, you definitely can get that.
DR. GILMAN:  Let's stay on this issue.  Dr. Califf.
DR. CALIFF:  I am buying the argument related to platelet function and cyclooxygenase, but I mean there are major questions about how aspirin works in the first place now with the evidence of the role of inflammation, and I don't know if we have similar kind of data about inflammation, so I am very skeptical of relying on some sort of biological measurement to tell us what the right dose of aspirin is in the first place.
DR. GILMAN:  Another issue.  Dr. Penn.
DR. PENN:  Yes, I just want to make sure that I understand the data on myocardial infarction and aspirin dose.  Is there a relationship between aspirin dose and myocardial infarction and death or is it just a trend as is indicated here?
DR. HAEHL:  In ESPS‑2, we have no significant result for the reduction of myocardial infarction, and we believe that that is also what you would not expect in a population with prior stroke or TIA.  That would not be the population where you would investigate the efficacy in preventing myocardial infarction.
DR. PENN:  My question is, is there going to be a different dose of aspirin recommended for myocardial infarction than the dose that we are now suggesting that you give for stroke.
DR. HAEHL:  On behalf of Aggrenox, I can only suggest the dose of 50 mg for stroke prevention.  I have to forward the question as to the most adequate dose for the prevention of myocardial infarction to the clinical experts.
DR. HENNEKENS:  Just as Dr. Albers participated with the American College of Chest Physicians, I, with Phal Fuster and Mark Cyken, wrote the AHA guidelines for aspirin and the citizens' petitions to the FDA.
Our view of the totality of evidence indicates that a dose of 50 mg a day is sufficient, and in the absence of any acute symptoms, whether or not you survived a prior heart attack, a prior occlusive stroke, a prior TIA, have chronic stable or unstable angina, a bypass or an angioplasty, that 50 mg of aspirin a day will suffice to maximally inhibit platelets, give the clinically beneficial effect, and minimize the side effects.
The place where the issue is different is if you are having an acute occlusive event, then, Fitzgerald has shown in healthy volunteers, as well as those with unstable angina, that while this dose is sufficient to get that effect, it takes about two days to occur from the time you start the first dose.
Therefore, you need a dose of at least 162.5, as was used in IC, 325 in GC, so for acute occlusive events, a dose of aspirin of about 325 in a regular aspirin is optimal to get a rapid clinical antithrombotic effect, whereas, for the prevention of occlusive events, the 50 mg dose, possibly with an enteric coat, might minimize the side effects even further.
So, for the vast majority of people who are treated with aspirin for the long term, 50 mg enteric is sufficient.  When you are having an occlusive event, regardless of the vascular bed, I think a 325 dose of regular aspirin is imperative, and if the patient can't swallow it, to at least dissolve it under the tongue.
DR. GILMAN:  Dr. Konstam.
DR. KONSTAM:  Dr. Hennekens, I am getting more confused, because I follow what you are saying, but I am having trouble following how much of it is on the basis of physiologic information and how much of it is on the basis of clinical data.
So, if I am not mistaken, the doses of aspirin approved are down to 75 mg a day.  Is that not right?
DR. TEMPLE:  They vary by indication.  I mean in the monograph, we are very empirical.  If 300 is what has been studied, that is sort of what the claim gets even though everybody believes, just the way Charley does, that 75 is probably enough.
Now, Rob just suggested, well, maybe you shouldn't believe that and you should stick with empiricism.
DR. KONSTAM:  I just want to know what the data are.  Can you just stick to the clinical trial data supporting the 50 mg dose?
DR. HENNEKENS:  Well, the data that have been studied go as low as 30 mg on clinical endpoints and show clinical benefits, and I think that‑‑you know, I take your point.  When we were designing the Women's Health Study and had it funded by NHLBI, Dr. Lenfant created another expert advisory committee that had us kick out the 325 every other day dose, because as Dr. Temple said, that was the dose we had shown in the Physician Study to be beneficial on acute MI.  We wanted to make sure to have that dose and frequency studied, and the expert committee was so convinced both on clinical data and on some of the biochemical correlates that they asked us to kick out the 325 every other day.
So, we are study 50 mg versus placebo in 40,000 women in prevention.  But the totality of evidence on this question includes not just basic research and clinical studies, but there are clinical trial suggesting that the lower doses will give net clinical benefits, as well.
The question in my mind, frankly, as a scientist, is whether higher doses, which might also potentially have antiatherogenic effects while having more side effects that we know might have greater benefits.  That has never been tested in direct head‑to‑head comparison.
DR. KONSTAM:  Just to follow up, I mean I think these points are all very well taken, we don't know what the ideal dose is.  There is a lot of reason to believe that lower doses may be beneficial, and you have made those points eloquently.
I guess this question arose‑‑and I think it is important‑‑is that what are we going to be recommending for the atherosclerotic population, and here, we are going to wind up focusing on patients with past TIAs and strokes, but there are broad questions here.
So, the question is what is the recommendation for aspirin going to be in that, and that is going to wind up being on the basis of clinical trial data.
DR. HENNEKENS:  Well, the FDA‑‑and I agree with their recommendations‑‑have recommended 50 to 325 based on the range of low doses that have shown clinical benefits in trials, and I agree with that.
What I am saying further is that especially when you are looking at a combined preparation with another mechanism of action, you want to minimize the side effects from this one component.
So, I think that from a purely scientific basis‑‑and I wasn't asked about this until a week ago‑‑but if I had been, I would have suggested 50 mg of aspirin as the component in Aggrenox.  I think it is the wisest scientifically with regard to maximizing benefits and minimizing side effects, and that is all I can say about it.
DR. GILMAN:  To go back to a comment that Dr. Haehl made, in fact, this would be the very population that you would be concerned about myocardial infarction, and these are people who have had stroke or TIA, and they are at risk for myocardial infarction.
DR. HENNEKENS:  Yes, I think that is an excellent point, and these are people that this dose of aspirin should from the totality of evidence, not from ESPS‑2, but from the totality of evidence from the antiplatelets trial is give benefits without side effects.
Furthermore, as has been asked by the other panelists, if this patient then, nonetheless, despite being on this prophylactic dose to prevent stroke and death, does exhibit symptoms of MI, that person should have a 325 mg of aspirin within 24 hours of onset of those symptoms.
DR. GILMAN:  Well, that still raises the question about the wisdom of 50 mg of aspirin in people who are at risk for myocardial infarction.
DR. HENNEKENS:  Well, perhaps I am not understanding the controversy here, because for the long term prophylaxis, you want to get the benefits with minimal side effects, and frankly, although we test at 325 every other day, 325 now, in 1999, is a dose that will show a benefit, but will also have a side effect profile that is higher than the 50 mg.
So, to keep this person for long‑term prophylaxis, both prevented with regard to occlusive complications with minimal side effects, I think the 50 mg dose is optimal.  If that person, despite this prevention, does develop acute symptoms, then, a high dose then would be necessary to get the maximal protection over that acute event, but for the chronic prophylaxis, it is the low dose that gives the benefits with minimal side effects in my view.
DR. GILMAN:  Thank you.
Yes, Dr. Lacey.
DR. LACEY:  I have a question which is on something that was presented a little bit earlier.  On addressing the issue of the percentage of African‑Americans in a study, the statement was made that 5 to 10 percent inclusion would be more damaging than exclusion, I would like to ask if that is without regard to the size of the study or did you mean related to this intended population of 7,000.
DR. HENNEKENS:  I will give you an example.  In the 1980s, the FDA prescription‑labeled aspirin for the treatment of TIAs in men, but not in women, and it was based on a totality of evidence that was driven by a Canadian study that had a number of women that, in my view, was inadequate to answer the question in women, let alone answer the question whether women were significantly different from men.
So, from 1980 to 1998, we said TIAs could be treated with aspirin in men, but not women.  Then, when a sufficient totality of evidence emerged from numerous trials that studied women, it was clear that the benefit in women was exactly the same as the benefit in men.
So, what I am saying generically is that I would favor a study in African‑Americans that can answer the question definitively in African‑Americans, and if I wanted to test whether African‑Americans were different from non‑African‑Americans, I would power my sample size overall to answer the overall question, and I would want 50 percent of that population to be African‑American compared with the comparison group to get the most powerful test.
When you have small numbers, I think there is so much variability in the numbers of endpoints and in the data that you might not get the right answer, and I am concerned that a lot of treatment decisions are being made based on the inclusion of 5, 10, 15 percent of a population in an overall study that simply can't with assurance answer that question.  It is a methodologic concern.
DR. LACEY:  But I am still not clear.  Are you saying that regardless of the study, 5 to 10 percent would always be unmeaningful and significant?
DR. HENNEKENS:  No.  What I am saying is that if a study is powered to get an overall result, and with 10 percent of that total sample can be shown to give not just a significant result in that subset, but a significantly different result if one exists between that subset and the rest of the population, then, I am satisfied.
In my experience, that hardly ever occurs by the inclusion of 10 percent of anything in a study the way they are designed.
DR. LACEY:  But conceivably if the study were large enough, 5 to 10 percent‑‑
DR. HENNEKENS:  If it were, but if I really wanted to answer the question about whether African‑Americans were different from non‑, I would do a 50‑50 split.
DR. GILMAN:  Dr. Califf.
DR. CALIFF:  I don't want to belabor this now, but I think it will be important to come back to this issue later because for those designing studies that will come before panels in the future, this is a very important question, and I share Dr. Hennekens' frustration with the way things have been done in the past, but I am not sure of what the guidance ought to be.  I think it will be worth discussing later.
DR. GILMAN:  Dr. Drachman.
DR. DRACHMAN:  Well, I don't really want to beat this to death, but‑‑but most of my patients with strokes and TIAs are hypertensive diabetics who have had one MI.  What are we to do?  And, furthermore, we learned, right or wrong, that the most common cause of death with stroke is MI.
Would you recommend that my patient with an MI, with an old MI and with a new TIA or stroke be put on this drug and aspirin, or what do we do?
DR. HAEHL:  If you allow, Dr. Easton would like to answer that question.
DR. EASTON:  Well, I am here today on behalf of stroke prevention.  I was here for ticlopidine, I was here for clopidogrel, I am here for this.
I think Dr. Drachman's question is germane and let me give you the numbers since we don't seem to have it on a slide, just so we know what it was in ESPS‑2.
It turns out that there were 757 deaths, and of those, 176 were due to stroke.  The next largest group was 143 due to infection, and we heard what the issues might be around that, how many of those were actually stroke.
The next largest group is sudden death, and there were 69 myocardial infarctions as compared to the 176 strokes.
DR. KONSTAM:  Sudden death?
DR. EASTON:  I am sorry, sudden death was 107.
DR. KONSTAM:  107 sudden deaths and 69 MIs.
DR. EASTON:  That is correct.  And then we have heard previously about how likely they are to reflect what actually happened to the patient, as I think Dr. Katz pointed out.
Those are the large ones, and then there are a smattering of other issues in the tables here, if you would like me to leave it with you just to look at in this trial.
DR. GILMAN:  Thank you.
Dr. Haehl, thank you for your forbearance.  You have answered a number of questions that were pressing us.
So, shall we move on to Dr. Albers?
DR. HAEHL:  Yes.  Thank you very much.
Clinical Overview
DR. ALBERS:  Good morning.
[Slide.]
Stroke occurs when there is an abrupt disruption of the blood flow to the brain that is severe enough to cause brain injury that will give lasting neurologic deficits.
Most strokes are due to blood vessel occlusions, but about 15 percent are due to ruptures of blood vessels, and this can either be within the parenchyma of the brain or in the subarachnoid space surrounding the brain.  We are going to ignore those and focus on the 85 percent of strokes are ischemic or due to blood occlusions.
These occlusions typically occur because of atherosclerosis involving either the cervical or the intracranial vessels, and atherosclerosis can cause embolic or thrombotic occlusion of the vessels because of aggregates of platelets, fibrin, and debris from these atherosclerotic plaques.
[Slide.]
Here is the diagram that shows the most common causes of ischemic stroke.  About 15 percent of ischemic strokes are due to emboli from the heart.  Cardiac emboli that typically occur because of atrial fibrillation, heart valve disease, or myocardial infarction can lead to clots that break loose and travel to the brain, but most strokes, as mentioned, are due to atherosclerosis either of the aorta, the cervical vessels, or the large or small intracranial vessels.
This atherosclerosis can cause flow‑limiting reductions, but more commonly it causes artery to artery emboli from the atherosclerotic plaques.
[Slide.]
A TIA has a very similar pathology to a stroke.  With a TIA there is a transient occlusion of an intracranial artery that is severe enough to cause focal neurologic symptoms, but these symptoms resolve rapidly because of fragmentation and dissolution of microemboli or thrombi.
TIAs typically last about 10 to 20 minutes.  It is very unusual for a TIA to last longer than an hour.
[Slide.]
Stroke, as you know, is a very devastating disease.  It is the leading cause of long‑term disability worldwide, and it is the third leading cause of death in the United States.  If you look on neurology wards, more than half of the beds are filled with stroke patients.
[Slide.]
Stroke is increasing in incidence.  The current estimates from the American Heart Association are that there are about 730,000 strokes occurring in the United States each year, but most patients from stroke, as we have already mentioned, don't die.
Only about 150,000 of those patients die, which leaves a large number of patients living with neurologic deficits due to stroke, and the current estimates are that there are 4 million Americans living with stroke‑related disabilities, and since the population is rapidly aging, the prediction is the incidence of stroke is going to go up considerably in the next couple of decades.
[Slide.]
The economic burden of stroke is also very frightening.  Current estimates are that the total cost of stroke in the United States is over $40 billion each year, and this breaks down to a per‑event cost of about $60,000 per stroke.  This can be divided into the direct costs, which involved the care and treatment of the patient, and that is about $40,000 a case, as well as the indirect costs including lost productivity of about $20,000 per stroke.  So, it is a phenomenally expensive disease.
[Slide.]
As we have been talking about, the major threat to the stroke patient, particularly in the short term, over the first few years, is not having a myocardial infarction or a vascular death.  The major threat, by far and away, is that they are going to have a recurrent stroke.
Some studies have shown that recurrent strokes are 10 times more likely than a myocardial infarction during the first few years after having a stroke.  Later on, they often die of a myocardial infarction or another vascular death, but the key early problem that a stroke patient faces is that they are going to have another stroke and be living with disability from two strokes.
Fortunately, there has been a lot of progress in stroke prevention for patients who have had a recent stroke or TIA.  Over the last decade, we have had a lot of progress specifically, carotid endarterectomy has shown to be highly beneficial for patients who have a stenosis of greater than 70 percent which has caused a stroke or a TIA, and recent data suggest that even patients in the 50 to 70 percent stenosis range can benefit if they are properly selected for surgery.
Also, patients with cardioemboli as the source of their stroke, such as atrial fibrillation, can have dramatic reductions in stroke risk with oral anticoagulation therapy, but unfortunately, these two categories, high‑grade carotid stenosis and cardiac emboli, only account for a minority of strokes.  Most strokes are due to atherosclerosis that is not appropriate for endarterectomy, and for these patients, antiplatelet agents are the treatment of choice, so we are going to focus on those.
[Slide.]
We now have four different antiplatelet agents that have been shown to be effective for preventing stroke in patients who have a TIA or an ischemic stroke.  These include aspirin, ticlopidine, clopidogrel, and dipyridamole particularly when it is combined with aspirin.
[Slide.]
Now, I want to look at a little bit of the data regarding the efficacy of antiplatelet agents for preventing the combined outcome of stroke, MI, and vascular death in patients of different types.  This data comes from the Antiplatelet Trialists Collaboration last published in 1994.
What this group did was they looked at a large number of studies, over 140 studies, that took patients with a wide variety of different vascular diseases ‑ myocardial infarction, stroke, peripheral arterial disease.  They combined these mixed vascular disease populations together and looked at the efficacy of all antiplatelet agents compared with placebo for preventing this combined vascular outcome.
What they reported was an odds reduction of a 27 percent, which translates to a relative risk reduction of 22 percent for preventing all these events in a mixed population with a mixed population of antiplatelet agents.
Now, what we are interested in are the stroke and TIA patients, and among these studies there were 18 studies that specifically looked at patients with stroke or TIA, and if you look at all antiplatelet agents in these patients, the benefit appears to be a little bit less, specifically, a 22 percent odds reduction or a 17 percent relative risk reduction.
A little more concerning is that when we look at the 10 trials that looked at stroke or TIA patients and evaluated aspirin versus placebo, the relative risk reductions are even more modest, 13 percent relative risk reduction or a 16 percent odds reduction.
DR. GILMAN:  What is the confidence interval of the odds reduction, is that 95 percent?
DR. ALBERS:  I don't have the confidence intervals on this study.  The confidence intervals for this 144 are really quite small.  I am going to show you the confidence intervals in just a moment for the specific stroke or TIA trials.
So, one of the questions is why are relative risk reductions lower than odds reductions, and that is because they are calculated differently, and we can talk about that later if there is interest.  But you can see that the interpretation of the data can be quite different if you are thinking of a 27 percent reduction versus a 13 percent reduction.
So, let's look now at the stroke and TIA patients specifically.
[Slide.]
Here are the patients with stroke or TIA who were randomized to an antiplatelet agent versus placebo, and as I reported for aspirin, there was a 13 percent relative risk reduction and for all antiplatelet agents combined there is a 17 percent relative risk reduction.
The reason for the difference is that there are two antiplatelet agents that appeared to be more effective, and that would be ticlopidine and a combination of dipyridamole and aspirin.  So, that is why we see the difference between the 13 and the 17.  Then, one of the concerns would be the dose which we have been discussing.
DR. GILMAN:  That is just the question.  So, aspirin, all doses.  How about specific doses though?
DR. ALBERS:  That is this slide.
[Slide.]
This is a meta‑analysis that was performed based on the data from the Antiplatelet Trialist, and here we have the relative risk reductions with the 95 percent confidence intervals, and it is broken into three groups:  studies that looked at low doses, less than 100 mg/day; medium dose 300 mg/day, and then the high doses 900 mg or more.  These are the placebo‑controlled studies.
Here you can see the point estimates for relative risk:  13, 9, and 14, and now you can see the 95 percent confidence intervals to get a feeling for what kind of differences we have, and then when you combine the all together, you have a 13 percent relative risk, obviously, with narrower confidence intervals.
So, there does not appear from the available data to be a relationship between aspirin dose and benefit for preventing this combined endpoint.
[Slide.]
Now, as I also mentioned earlier, there were three head‑to‑head comparisons.
DR. GILMAN:  What about the 9 percent for 300 mg?
DR. ALBERS:  Right.  That comes from one study, which was the UK TIA trial, and you can see that this one study in and of itself did not show a statistically significant benefit of 300 versus placebo.  That is the only study we have that compares 300 versus placebo.
Then, we have the Dutch TIA trial, a very large study that compared 300 versus 30, a head‑to‑head comparison there, which showed no difference in the efficacy between 300 and 30, and then there was the study, the UK TIA that compared this 300 to about 1,000 mg of aspirin.  Again, there was no difference in the efficacy of the head‑to‑head comparison.
[Slide.]
Now, there is one new study that has just come out recently which was a direct comparison of high‑dose aspirin versus low dose, and this is in a specific patient population.  These are patients who have had a carotid endarterectomy.  So, it is looking at preventing stroke, MI, and vascular death over the short term in a patient who has just undergone a carotid endarterectomy.  This data have just been presented recently.  It is called the ACE trial.
It is a large trial, you can see about 1,500 patients per group, and they were randomized to low‑dose aspirin which was either 81 or 325 mg of aspirin, or high dose, and the high dose was either 650 or 1,300 mg of aspirin.
Here you can see the results.  At three months, the rate of stroke, MI, or death was 6.2 percent in the low dose and 8.4 percent in the high dose, which was a statistically significant benefit favoring the efficacy of low dose over high dose.
So, the previous low dose/high dose comparisons had shown no difference.  In the special circumstance, carotid endarterectomy, short‑term follow‑up, we see a statistically significant difference favoring the low dose being more effective for preventing these vascular events.
DR. GILMAN:  These comments have not dealt with very low dose, such as 50 mg aspirin, though.
DR. ALBERS:  The 50 mg, the main effect here against placebo was the SALT trial, which was a 75 mg versus placebo.  The main data for the 50 mg against placebo will be the ESPS‑2 data, and the relative risk reduction seen with the 50 mg is certainly in the ballpark, if not greater, than the reductions that we are talking about here in the SALT trial, at 75, or these other trials at higher dose.
Then, we had the 30 versus 300 from the Dutch TIA.
DR. GILMAN:  Dr. Katz first.  Dr. Drachman next.
DR. KATZ:  Just a quick question about the Dutch study, the 300 versus the 30.  How big a trial was that, and were there numerical differences, you know, sort of a trend in favor of one dose or another?
DR. ALBERS:  It was a very large trial, it was over 3,000 patients.  Somebody might be able to help me.  There was not a trend.  It was very comparable.  If somebody has the exact numbers?
DR. EASTON:  Five percent better in the 30 mg as compared to the‑‑
DR. ALBERS:  So, we are hearing 5 percent better in the low dose.
DR. GILMAN:  Please use the microphone and repeat what you just said.
DR. EASTON:  I will check to confirm this, but with respect to the trend, I believe it was about 5 percent risk reduction favoring the 30 mg dose.
DR. GILMAN:  Dr. Drachman.
DR. DRACHMAN:  Would you go back one slide.  There, is it true that neither of the lower doses quite reached significance, since they overlap zero, is that right or not?
DR. ALBERS:  Yes, that is correct.  I suspect if you add in the ESPS‑2 to this‑‑this was a meta‑analysis performed before ESPS‑2 was available, and certainly the 50 mg versus placebo had a very statistically significant benefit in ESPS‑2, so I would be‑‑I don't know if somebody has done this already, but since it comes very close to meeting statistical significance without ESPS‑2, and ESPS‑2 being a very large trial, I think it is highly likely that this is now a statistically significant effect if you take all the low dose versus placebo data in stroke or TIA patients.
DR. GILMAN:  Dr. Kawas.
DR. KAWAS:  I would like some clarification on the next slide actually.
In the low‑dose group, can you separate out the two low doses?  I mean one of them is not so low, and is that really what is generating the effect of 325?
[Slide.]
DR. ALBERS:  There is a number of different analyses that have been done on this, and a study has not been published in full.  I understand that for some of the analyses, the 81 looked better, and that other of the analyses, the 325 may have looked a little bit better in terms of trends, but there was not a clear difference, there was not a clear difference saying that one dose was better than the other there.
DR. KAWAS:  What was the relative proportion of the two doses in that group that you pooled?
DR. ALBERS:  Fifty‑fifty.
[Slide.]
So, as already stated, based on the information that we have been discussing in detail, about six months ago the FDA revised the guidelines, and just quoting from the Federal Register, what they now say is that the "positive findings at lower dosages are sufficient reason to lower the dosage of aspirin for subjects with TIA and ischemic stroke."
For ischemic stroke and TIA, 50 to 325 mg aspirin once a day is currently the recommended dose.  The drug should be continued indefinitely.
[Slide.]
Other professional groups have also joined this low dose recommendation.  I was part of the American College of Chest Physicians group, and we put out a recommendation that was published essentially simultaneously with the FDA guidelines coming up with the same recommendation, 50 to 325 mg per day for stroke or TIA patients, and the American Heart Association is in the midst of revising their guidelines.  The proposed dose that is being finalized right now is the 50 to 325 mg dose, as well.
[Slide.]
Now, there are two other alternative antiplatelet agents that are approved for use in stroke or TIA patients for preventing stroke, and ticlopidine was the first one to be approved, and this drug has some advantages.
It was studied in two large trials.  The first was a trial against placebo, looking at patients with completed stroke, ticlopidine versus placebo, a study called CATS.  Ticlopidine was found to be statistically significantly more effective than placebo in preventing stroke or stroke and death.
It also was tested against aspirin, and this was the TASS study, another large study comparing patients who had had this time TIA or a recent stroke, ticlopidine versus aspirin, and it was a high dose aspirin that was chosen in the TASS study.  Again, ticlopidine was shown to be more effective than aspirin for preventing stroke or stroke and death.
The disadvantages of ticlopidine are the neutropenia.  There is about a 1 percent incidence of neutropenia, which can be very severe, but fortunately, reversible.  A little more concerning is the rare side effect which is not always predictable and not always reversible, which is TTP, thrombotic thrombocytopenic purpura, which carries a very high morbidity and mortality.
Because of these hemologic side effects, CBC monitoring is required with this drug, at least six CBCs during the first three months of therapy, and there is also some nuisance side effects that occur at relatively high frequencies, diarrhea and rash.  Five to 20 percent of patients will have these type of side effects from ticlopidine.
[Slide.]
Now, there is a related agent which is also approved, clopidogrel, similar to ticlopidine, but it has some substantial advantages in terms of the adverse effect profile.  It is much better tolerated than ticlopidine.  There has not been a placebo with neutropenia or TTP with this agent, so no hemologic monitoring is required.
The drug has proven efficacy.  It was compared in a huge trial against aspirin, the CAPRIE trial, which enrolled patients with stroke, myocardial infarction, or peripheral arterial disease, and in that combined group of patients, looking at the combined endpoint of stroke, MI, and vascular death, clopidogrel was more effective than aspirin.
Disadvantages of clopidogrel are that it has not yet been tested in a TIA population, so we have no data about clopidogrel in TIA patients, and then although the CAPRIE trial was not powered to look at the individual subgroups, stroke/MI, there were over 6,000 stroke patients and over 6,000 MI patients in the CAPRIE trial, and if you look at those patients as individual subgroups, there was not a statistically significant benefit of clopidogrel over aspirin in those 6,000 patient subgroups.
[Slide.]
Now, this is a slide that needs to be interpreted with great caution.  It is a figure that we put together when we made the ACCP guidelines for stroke prevention.  What it is an attempt to do is give a general feel for the efficacy data that have emerged from these three alternative antiplatelet agents, ticlopidine, clopidogrel, and dipyridamole‑aspirin combination.
It is important to note that there are no head‑to‑head comparisons.  We have no head‑to‑head comparison of any of these alternative agents one versus the other.  We only have comparisons with aspirin.  In fact, for each of these alternative agents, there is one single trial that had TIA and stroke patients and compared the alternative agent head to head with aspirin.
So, for clopidogrel, it is the CAPRIE trial, and here we are looking at just the subgroup of patients who got into CAPRIE because of a stroke.  So, that is 6,431 patients.  For ticlopidine, there was the TASS trial, and that was 3,000 patients, and then ESPS‑2, if we look at the combination versus the aspirin‑alone arm, that is about 3,299 patients.
DR. GILMAN:  Well, as you say, that really should not be shown here because you have not done head‑to‑head comparison with these other drugs.
DR. ALBERS:  Okay.  What this is just an attempt to do is show you what the risk reductions were in these trials.
DR. GILMAN:  But they are not comparable.
DR. ALBERS:  The trials‑‑and that is a very good point, that is why I said this needs to be interpreted with great caution because these are different trials, they had slightly different inclusion and exclusion criteria.  They had different doses of aspirin.  They are different studies.  So, this is not an attempt at all to say that these are direct comparisons.  This is just an attempt to summarize the data for common endpoints that were available from these trials.
So if you are looking at the endpoint of stroke from these three trials, then, what you can see is that in the stroke subgroup of CAPRIE, there was an 8 percent relative risk reduction over aspirin.  Clopidogrel over aspirin was 8 percent.
From the TASS study, ticlopidine over aspirin was 21 percent, the ESPS‑2 it was 23 percent.
The numbers for stroke, MI, and vascular death, just to show the results of the trials, are for clopidogrel 7 percent, ticlopidine 9 percent, and then the combination in the 22 percent range.
So, these are the available data, and unfortunately, it is unlikely that we will have head‑to‑head comparisons between these agents.  So, these are the numbers that we have available, but I certainly want to emphasize that these are not‑‑
DR. KONSTAM:  What was the dose of aspirin in the CAPRIE trial?
DR. ALBERS:  These all have different doses of aspirin.  The CAPRIE trial had 325 mg of aspirin.
DR. GILMAN:  The question was what was the dose of aspirin in the CAPRIE trial.
DR. ALBERS:  CAPRIE.  Ticlopidine was high dose aspirin, and then the dipyridamole/aspirin obviously was the low dose we have been discussing.
DR. KONSTAM:  So, in other words, these really are not comparable.
DR. GILMAN:  These are not comparable in any way.  I am not sure why you are showing these data.
DR. ALBERS:  Okay.  I am showing the data because these are the three agents that clinicians are faced with in terms of stroke prevention, and a very frequent question that neurologists ask is what were the efficacy of these agents in the trials that they were evaluated.  Of course, they have not been evaluated in head‑to‑head comparisons, so we have no way of comparing the efficacy between these agents.  We only have the comparator of aspirin in there different trials with three separate patient populations that were enrolled.
DR. GILMAN:  And different doses of aspirin.
DR. ALBERS:  And different doses of aspirin if you think that that is an important issue, yes.
DR. GILMAN:  Well, that is a question.
DR. CALIFF:  You have got me a little revved up here.  Just because some neurologists ask stupid questions is not a reason to show the data at a meeting like this, and we will come back to this later.
DR. ALBERS:  Whether it is a stupid question or not, I think is another issue.  You know, we have choices to make.
DR. CALIFF:  You are saying it is intelligent to do indirect comparisons and put things on a slide that lead people to create images in their mind that are not scientifically comparable.
DR. ALBERS:  I think the practical issue is that we have several antiplatelet agents that are available, and from the point of view of the clinician, one needs to try to balance what the perceived efficacy of these agents are, what the perceived side effects are, and what the cost of these agents are.
DR. GILMAN:  The clinicians can think for themselves, and by showing these data, it gives the impression of a direct comparison, which is false, it is just not valid.
DR. ALBERS:  Okay.  We will finish up with the ACCP guidelines.
[Slide.]
The guidelines that were currently agreed upon by the ACCP is that every patient who has had a non‑cardioembolic stroke or TIA should be taking an antiplatelet agent daily.  It was a very straightforward, high‑grade recommendation.
We also felt that aspirin, clopidogrel, ticlopidine, and the combination of aspirin and dipyridamole had all been shown to be effective for preventing stroke and that they were all acceptable options for initial therapy, and as we have clearly pointed out here, we have no direct comparisons to help determine the absolute efficacy differences.
However, we did have fairly clear safety, we felt, in looking at the ticlopidine side effect profile versus the clopidogrel side effect profile.  Even without head‑to‑head comparison, the incidence of adverse events were so dramatically different between those two agents that we made the recommendation that we would favor clopidogrel over ticlopidine because of that adverse event profile.
Finally, we mentioned‑‑and, again, no specific head‑to‑head comparison, so nothing that can draw any firm conclusion, but the combination of aspirin and dipyridamole may be more effective than clopidogrel and has a similar favorable adverse event profile.
[Slide.]
So, in summary, you can say that antiplatelet agents are effective in the secondary prevention of nonfatal stroke and death.
The currently approved antiplatelet regimens provide a relatively modest risk reduction.
The hope is that more effective and safer treatments to prevent stroke will be available on the immediate horizon.
DR. GILMAN:  Thank you.
Any other questions for Dr. Albers?  Dr. Grotta.
DR. GROTTA:  Dr. Albers, you sort of glossed a little bit over the previous dipyridamole data.  What about the early dipyridamole trials that were uniformly negative, how would you reconcile the later data with those?
DR. ALBERS:  I don't know if we have slides.  I am sure this is going to be covered in later presentations, but basically, prior to ESPS‑2, when you look at the dipyridamole/aspirin versus aspirin comparison, there were only three trials in cerebrovascular patients, and they all had very wide confidence intervals because of very small samples sizes.  When you sum them together, you see a trend in favor of the combination over aspirin, but it is not statistically significant, but the power of those studies to detect a difference is extremely small.  I am not sure if somebody has that slide available.
Then, in terms of the combination dipyridamole/aspirin versus placebo, the only large trial, of course, would be the ESPS‑1 that has already been shown.
[Slide.]
DR. HAEHL:  This slide shows you the patient numbers for the trials which included dipyridamole, to which we referred as being underpowered.
DR. ALBERS:  So, you can see that some of these trials were trials on the order of 300 patients.
DR. KONSTAM:  What about previous trials of dipyridamole alone, are there such trials?
DR. TEMPLE:  Well, there is PARIS.  I mean there were studies in the post‑infarction setting from a while ago.
[Slide.]
DR. HAEHL:  These are the randomized small‑scale studies of dipyridamole with or without placebo or aspirin control.
DR. ALBERS:  That last slide that had the "omit" written on it really addresses the earlier question.  I don't know if we can bring that up.
[Slide.]
It shows the confidence intervals of those trials.  Because the numbers were 300 to 400 patients, the confidence intervals are extremely wide.  With a 284‑patient trial, their chance of showing anything is extremely low.  You can see these huge confidence intervals.  That is the same with these other.
These are the comparison of dipyridamole and aspirin versus aspirin.  These are the previously available data which led to the conclusion before ESPS‑2 that there was no clear evidence of a benefit.
You can see if you sum these, you get a small trend in favor of the combination over aspirin, but ESPS‑2 overwhelms these because of the large number of patients, and when you have the totality of the evidence, then, you see a statistically significant benefit of the combination of dipyridamole and aspirin compared to aspirin alone.
DR. KONSTAM:  Dr. Gilman.
DR. GILMAN:  Please follow up, Dr. Konstam.
DR. KONSTAM:  You are saying not to look at these, and maybe we shouldn't, but I guess one of the things we are going to have to come back to is that we have a single trial to deal with.
So, I am going to be looking for some evidence elsewhere in the literature or in the data set or somewhere that confirms this.  I guess looking at what you just showed in the absence of ESPS‑2, it looks like you are right on unity for the comparison.  Is that not right?
DR. ALBERS:  There is a trend in favor of‑‑
DR. KONSTAM:  Do you want to put that up again?
DR. HAEHL:  Our interpretation as the company for these trials was that the wide range, which you have seen, actually allows for any conclusion from highly, and therefore, we decided to perform a very large‑scale trial.
DR. KONSTAM:  I understand that.  I will put the question this way.  Is there any evidence elsewhere outside of the ESPS‑2 data set that is supportive of the conclusions that you are trying to‑‑
DR. HAEHL:  Please put up Slide No. 5.  Dr. Hennekens.
DR. HENNEKENS:  First, dipyridamole, and then aspirin.  On dipyridamole, I think it is very important to understand the totality of evidence in the world literature on dipyridamole alone and dipyridamole plus aspirin had 120 total strokes as the outcome of all the studies in the world put together.
ESPS‑2 itself had about I believe 323 strokes in its own entirety, therefore, ESPS‑2 swamps the world literature on dipyridamole alone, because it contributes so much information, and I think we have to understand the difference between finding no association and an inability to find an association if one is there because we didn't have enough endpoints.  I think that is an important frame of reference for dipyridamole, I think, and for aspirin, I think an important frame of reference is to look at the‑‑
DR. GILMAN:  Please continue.
DR. HENNEKENS:  We have 3,406.  In the eight studies of aspirin in TIA or stroke patients, 3,406 randomized aspirin, 2,584 to placebo, an odds reduction of 18 percent with confidence intervals from 5 to 30.
Now, ESPS‑2 on its own has 1,649 randomized to aspirin and 1,649 to placebo, a 23 percent statistically significant reduction with confidence intervals from 4 to 37.
I believe that the FDA's recommendation to approve aspirin in this indication was based on the totality of evidence that combined the eight other studies with ESPS‑2, and this goes back to the dose issue.  The dose of ESPS‑2 of 50 mg a day is showing a highly significant, very reliable benefit of aspirin.
ESPS‑2 is also showing a significant reliable benefit of dipyridamole alone, and therefore, to me at least, what is going on with Aggrenox has to be looked upon in the context of this study showing a clear benefit on stroke of both 50 mg of aspirin and the extended release dipyridamole in this dose.
There are clear and conclusive benefits on stroke for both of these, and they represent‑‑you know, it is not just that it is just one study, it represents such a large contribution to the world literature on the treatment of TIA and stroke patients.  So, I think that has to be viewed as beyond the fact that it is just one study.
DR. GILMAN:  That is true, however, the benefit is upon stroke, and not stroke and/or all‑cause death.
DR. HENNEKENS:  Actually, if I remember the data correctly, there is a clear benefit of the combined preparation on stroke plus death.  However, it is not significantly superior to either of the components.  However, when looking at stroke, there is a clear and significant benefit of the combination that is not only robust, but it is significantly better than any of its components, and you will save double the number of lives from stroke by treating with the combined preparation, numbers of strokes, not death, but you are quite right, but the study wasn't powered to answer the death question, and in some ways I think it is a catch‑22 to ask it to find a benefit on something where it couldn't possibly do so.
DR. GILMAN:  But the primary endpoints originally designed were stroke, death, and now later modified to stroke and/or death.  That is the point I am making.
DR. HENNEKENS:  And I would just like to say on the stroke endpoint, there is not only a significant benefit of aspirin, there is a significant benefit of dipyridamole, and there is a much greater benefit of the combination that is significantly better than either component on the endpoint of stroke.
DR. GILMAN:  For stroke.
DR. HENNEKENS:  Yes.
DR. GILMAN:  Dr. Temple.
DR. TEMPLE:  Just a little bit of history.  We have major problems with this, as Marv and Rob will know.  We frequently look at combined endpoints, and our inclination is to label a drug that, one, on a combined endpoint with the benefit on the endpoint that was studied in the trial, but it is typical, for example, you don't want to leave deaths out of the combined endpoint, but it is very unusual to have a persuasive effect on death alone.
So, we dance around that.  We say the primary endpoint was death plus all stroke, and the study was successful, it reduced that, but you should not there was no significant effect on death alone.
We face this problem with aspirin claim.  Most of the individual studies we relied on do not have a significant effect of aspirin on death after MI, in fact, no single study does.  If you look at an overview, it sort of does.
But we still use the combined endpoint because, on the whole, that was what was studied, and if you were giving a full explanation, you would say but note there was no significant effect on death alone.
It is just very unclear about what to do.  It is sort of a matter of taste, but we face this every time.  All of the antiplatelet drugs being studied now are studied on a combined endpoint, and they never show an effect on death alone, but death is always in the endpoint because you can't really leave it out.
So, it is sort of a matter of taste about how you label it.  You don't want to mislead anybody into thinking there was an actual effect on death when there wasn't.  On the other hand, the combined endpoint may have been the endpoint that was the one of choice, so you feel funny not using it, and there is no perfect answer to this.
DR. GILMAN:  Dr. Penn.
DR. PENN:  Just from a policy standpoint, can I ask you, are we committed to the aspirin standard where you have added death, as you admit on not compelling data, in our approval here?  Do we have to be consistent?
DR. TEMPLE:  No.  That is sort of why I said it is a matter of taste.  I mean probably, in this case, since this is a prescription drug, we can provide a fuller explanation in the Clinical Trial Section if that were the outcome, and say, you know, the main endpoint was a combined endpoint, and the p‑values were for that, and on the other hand, almost all the action was on the stroke component.  You can give a lot of explanation, so that everybody knows what the truth is.
DR. PENN:  But we are going to ask the statisticians if you added some other endpoint other than death‑‑and one can think of lots of other endpoints to put in‑‑the effect was so strong on stroke, that might carry almost any endpoint that was neutral into it.
DR. TEMPLE:  Absolutely.
DR. PENN:  So, we could talk about dandruff, we could talk about, you know, something else, and that puts us in a difficult situation.  I think, knowing from years past, how the panel feels about these issues, we tried to stick to what the data really shows us, and it may be important for the company to tell us how they feel about this particular issue, whether they felt forced into adding death or whether it is something that it would save us a lot of trouble if we just take that indication out.
DR. TEMPLE:  Well, we often urge companies to at least include one endpoint that has death in it, and the reason isn't necessarily that you want to show a benefit, it is because when someone dies, I mean, for example, if you had a nice effect on stroke, but death went the wrong way, it would be kind of goofy to say you had done something good.
So, you put deaths in almost to prophylax against their going the wrong way, and yet you may not expect a beneficial effect on death.  The action may well all be or primarily be on stroke.
So, no, you are not bound by the way the aspirin thing was written.
DR. GILMAN:  Again, I have to point out that one of Dr. Haehl's slides said that this will reduce the combined risk of death and nonfatal stroke in patients, et cetera.
DR. TEMPLE:  That could be true, but irrelevant.  You know, you may reach the conclusion that that is not where the action was.  That is a possible conclusion to reach.
DR. GILMAN:  That is for this committee then to wrestle with.
Dr. Katz.
DR. KATZ:  I was basically just going to say the same thing that Bob just said.  The only point I want to make is that as I gather, it is not entirely clear that stroke and death was the primary outcome, so there is even that additional potential problem.
DR. GILMAN:  Dr. Califf.
DR. CALIFF:  Just to comment that it sounds like we are going to come back to this, but to me it is a bit of a time warp looking at stroke or myocardial infarction as in isolated endpoint.  I think it is fraught with so many difficulties that I would never advocate that now in a prospectively designed trial, because these sudden deaths that were mentioned, we have no idea how many of those were sudden deaths due to stroke and how many were sudden deaths due to heart disease.
So, it would be inconceivable to me in a large trial to design a trial looking at a nonfatal component of a frequently fatal pathophysiologic phenomenon without counting both components in the primary, but we are caught with what was done seven or eight years ago, in a previous time, and it is going to be something we have to come back and wrestle with.
DR. GILMAN:  Dr. Temple.
DR. TEMPLE:  But, Rob, let's say that is true and therefore you are urging that you use combined endpoints.  So, now you do the whole thing, you do the combined endpoint, and the deaths come out neutral.  Within the combined endpoint, the combined endpoint wins, let's say, but the deaths come out neutral and all the action seems to be in stroke, so you did the right study, but what do you put on the label?
DR. CALIFF:  Well, we got into this because we were doing studies trying to prevent nonfatal MI, and in the end, it actually was a little bit silly to try to prevent nonfatal MI, because people are most worried about the fatal MIs that they may have and we weren't counting those.
When people die, actually, from the statistical point of view, you are left with an odd situation where you are counting people who are dead as not having a endpoint, which is an odd thing.
DR. TEMPLE:  That is why you use combined endpoints.
DR. CALIFF:  What is why we used combined endpoints, and I would say that you sort of want to add up to the ultimate, preventing the combined endpoint where most of the effect was on the nonfatal component should just be noted.  As you say, most of the effect was on the nonfatal component.
DR. TEMPLE:  You have clearly heard other committee members wonder about that policy, and say, well, maybe you should only get the thing that you won on, and I do think it is a matter of taste.  There is no single right answer.
DR. CALIFF:  This study is raising a number of policy issues, I think.
DR. GILMAN:  Dr. Easton wanted to comment?
DR. EASTON:  That has resolved.
DR. GILMAN:  If there are any presenters for the open hearing, please talk with Sandra Titus.
Do you want to wrap this up?  I think we should take a break as soon as we are through with this segment.  Dr. Haehl, shall we stop here?
DR. HAEHL:  I think the proposal was to have a break and then we will continue with Dr. Muller for the next presentation.
DR. GILMAN:  Let's do that.  Let's take about a 10‑minute break.  We will start promptly in 10 minutes.
[Recess.]
DR. GILMAN:  We are missing Dr. Califf, but I expect he will be right back.
Please, Dr. Haehl, let's proceed.
DR. HAEHL:  Thank you, Mr. Chairman.
I would like now to call Dr. Thomas Muller from Oldenburg, Germany, and he will present the rationale from a pharmacological and from a pharmacokinetic point of view for the formulation of Aggrenox.
Please, Dr. Muller.
Aggrenox Development Rationale
DR. MULLER:  Ladies and gentlemen, I want to shortly summarize for you the pharmacologic background for the combination of low‑dose aspirin with an extended release preparation of dipyridamole to Aggrenox for the secondary prevention of stroke.
First, I want to demonstrate the superior inhibition of platelet thrombus formation by the combination of aspirin with dipyridamole in a model of plaque vessel wall interaction.
Then, I will shortly address the key mechanism of action of both aspirin and dipyridamole to finally, shortly address pharmacokinetic implications of these very different mechanisms of action.
Before we start, let us turn to the site where all the trouble starts in the patients with TIA and stroke.
[Slide.]
This is a cross‑section through a plaque vessel, a very schematic drawing, which demonstrates that the injury of the endothelial cell lining at the interface between the flowing plaque and the vessel wall, that this injury exposes pharmogenic elements of the vessel wall to the flowing plaque.  Platelets in the blood adhere to the collagen fibers, they get activated and they start to aggregate.  This very local and extremely rapid response to the injury ensures the hemostatic repair.  If, however, this process runs out of control, excessive thrombus formation may follow.
[Slide.]
Such a thrombotic occlusion of the blood vessel triggers a cascade of events which finally lead to the complex and diverse clinical manifestations of TIA and stroke.
The clinical evidence just discussed by Dr. Albers for the benefit of antiplatelet agents clearly supports this pathophysiologic concept.  Therefore, we have established a model which allows to directly assess the effects of antithrombotic agents on such plaque‑vessel wall interaction.
[Slide.]
Human anticoagulated whole blood is allowed to flow over thrombogenic surface and the thrombi attached and adherent to this matrix are measured by quantitative microscopy.
[Slide.]
This is shown in more detail in this slide.  The matrix is derived from cultured endothelial cells, and the cell‑free matrix is then exposed to the flowing human blood in order to allow for the thrombus formation, and each individual thrombus attached to the matrix is detected by automated fluorescein microscopy.
As you see, most of the platelets and thrombi adherent to this matrix are relatively small, however, there are about 5 percent of these thrombi which are extremely large and which might be biologically, especially important, and it is the unique advantage of this model to allow us to investigate the effects on these very large thrombi.
We have performed a double‑blind, randomized, placebo‑controlled group comparison with exactly the same medication used in ESPS‑2, that is, the combination of low‑ dose aspirin with extended release preparation of dipyridamole and the individual components.
Each subject was treated with five doses, and the blood was investigated just before the start of treatment and after the end of the treatment.
[Slide.]
This slide summarizes the results on the mean reduction of the size of all the thrombi detected on the extracellular matrix, and as you see, placebo treatment did not affect the mean size of the thrombi attached to the matrix.
Dipyridamole had an effect.  Aspirin showed about a 50 percent reduction, which means that, on average, each thrombus after treatment had only half of the size that it had before the treatment, and it is quite evident that the combination of this low dose of aspirin with extended release dipyridamole clearly shows an additive benefit with regard to the reduction of this mean area of all thrombi.
[Slide.]
I already addressed the issue that there are very large thrombi to be detected on the extracellular matrix in these flow experiments.  They represent about 5 percent of all the thrombi and as you see, placebo did not affect at all the proportion of the very large thrombi.
In contrast, the combination of aspirin with dipyridamole was very effect.  It reduced the proportion by an absolute number of 4 percent, which means by almost 80 percent, and it is quite evident that concerning the formation of the very large thrombi, the effect of the dipyridamole and the aspirin treatment is very similar in contrast to the effect on the total number of platelet thrombi.
DR. GILMAN:  Dr. Muller, can I ask a question here?
DR. MULLER:  Yes.
DR. GILMAN:  You are using 400 mg of DP there.
DR. MULLER:  Yes.
DR. GILMAN:  The formulation is with 200 mg.  Can you explain that?
DR. MULLER:  I am very sorry.  This means per day, so this was administered twice daily, so this refers to the   daily dose of dipyridamole.  It was exactly the same treatment which has been used in the ESPS‑2 study.
DR. DRACHMAN:  Would you explain the ordinate?  I don't really understand that.
DR. MULLER:  Right. The ordinate gives you the absolute reduction in the proportion of very large thrombi.  So, the proportion of very large thrombi in the control, in placebo, is normally 5 percent, and the reduction by the treatment was virtually zero.
So, the treatment did not affect the proportion of these very large thrombi, whereas, the combination of aspirin with dipyridamole was very efficient.  It reduced the proportion of these very large thrombi by about 4 percent, which means there were only still 1 percent, which represent 20 percent of these large thrombi remaining on the matrix.
DR. GILMAN:  This would be a nice model to test various doses, you tried different doses of aspirin or dipyridamole?
DR. MULLER:  You are addressing very intriguing point.  I have to emphasize these studies were performed in 1988, and at the time, nobody knew about the results of ESPS‑2, so when I tried to publish this, everybody was concerned about the positive outcome of dipyridamole in this model, and insofar I refrained from performing more detailed work in this model as I really had problems to get this published.
But now with the data from the ESPS‑2, I think it looks very persuasive.  That is my problem, I came too late, you are right.
[Slide.]
With this indication of a superior benefit of the combination of aspirin plus dipyridamole, on the mural thrombus formation, I wanted also to now look behind the scene and simply share with you the key biochemical mechanisms, and we already talked in quite some detail about this, so all of you are very much aware that the [exacerbation] of the platelets leads to the generation of this thromboxane.
Thromboxane is an activator of adjacent platelets, and thereby an almost explosive formation of thromboxane will occur in the close proximity of a growing thrombus.  This thromboxane not only activates platelets, it also triggers vasoconstriction.
[Slide.]
Thereby we are very happy that aspirin does a very efficient job with regard to the inhibition of the cyclooxygenase activity, and this has been already addressed in many details, so I need no longer to comment on this.
[Slide.]
But we have to keep in mind that thromboxane is not the only mediator of platelet activation and platelet aggregation.  There are quite a number of other ones, and I would like to focus your attention to adenosine diphosphate.  This is a molecule which is already stored in the granule of the platelets, and whenever a platelet is activated, it releases ADP from its internal store.
[Slide.]
This is depicted here in this slide, so in the proximity of a growing thrombus, the concentration of ADP, which was released from the granules of the activated platelets, will be converted rapidly to adenosine, and this adenosine is taken up by red blood cells and by platelets.
[Slide.]
Here, dipyridamole comes in.  It is a very efficient reversible inhibitor of the adenosine uptake.  It has an IC50 of only 0.25 microgram/mL in human plasma, and by inhibiting the elimination of the adenosine in the close proximity of the thrombus, it now can really bind to the platelet and inhibit further platelet activation.
This cycle triggers a very intelligent feedback mechanism, that is, the more platelets are activated, the  more ADP will be released and converted to adenosine, and the more adenosine will be accumulating in the presence of  dipyridamole to feedback inhibit then further platelet activation and thereby to allow for further growth of the thrombus, and this mechanism only works after some initial thrombus formation, and therefore it nicely explains the preferential inhibition of very large thrombi by dipyridamole.
The implications of the IC50 are that doubling this concentration of 0.25 microgram dipyridamole/mL of plasma, 0.5 microgram/mL, results in an approximately 80 percent inhibition of this mechanism.
[Slide.]
Therefore, it was the target of the development of an extended release preparation of dipyridamole to maintain a plasma level of 0.85 microgram/mL dipyridamole translating into an 80 percent inhibition of the adenosine uptake over the entire dosing interval, and Dr. Haehl already addressed the convenience of such an extended release preparation which has to be administered only twice daily.
In addition, all the data in the pharmacokinetic demonstrate that there is no interaction, no pharmacokinetic interaction between aspirin and the extended release formulation of dipyridamole in Aggrenox.
[Slide.]
In summary, I would like to emphasize that the suppression of thromboxane by aspirin and the reversible inhibition of the adenosine uptake by dipyridamole, and thus the increase in the local levels of adenosine combines two very independent and efficient mechanisms to express platelet thrombus formation.
The individual doses of the aspirin with its irreversible inactivation of the cyclooxygenase, and the extended release preparation of dipyridamole in order to maintain efficient plasma levels over the entire dosing interval have been selected.
There is no evidence for pharmacokinetic interactions.
[Slide.]
Finally, I have shown that the combination of aspirin with dipyridamole in Aggrenox combines with superior inhibition of platelet thrombus formation.
With these preclinical results, it is time to turn to the clinical benefits of Aggrenox, and therefore I would like to introduce Dr. James Street, biostatistician, of Boehringer‑Ingelheim.
I thank you very much for your attention.
DR. GILMAN:  Thank you.
Dr. Grotta, a question?
DR. GROTTA:  Yes, two questions.  Just coming back to my previous question about the fact that prior to ESPS‑1, there were at least two trials that, in aggregate, I thank gave no signal that the combination of aspirin and dipyridamole was superior to placebo or to aspirin alone.
Then, ESPS‑1, which I suppose you will show showed some efficacy, and now we have ESPS‑2, is there an explanation in your formulation of the drug that might explain this discrepancy and give us greater confidence, to understand this difference over time?
Then, how stable is this formulation that you are seeing in Aggrenox, was there a change in the formula since it seems to be that that might explain some of these discrepant results?  Was the formulation of the drug consistent throughout the trials?
DR. HAEHL:  The formulation of Aggrenox was consistent since ESPS‑2 when it was first used.
Dr. Sherman wanted to comment on your first question.
DR. SHERMAN:  One of the things that I have learned about dipyridamole is that it is a reversible inhibitor of platelets, and the effects on the platelets are dependent on the blood levels, which was something I didn't realize early on.
One could speculate that some of the earlier trials they were using immediately release with the sorts of plasma levels that you saw might have meant that a portion of the time the patients didn't have inhibition of their platelets.  It is a potential explanation.
I think maybe a better explanation is just the size of the studies, but from the understanding of the biological mechanism, you could also make that argument, I think.
DR. GILMAN:  Dr. Drachman.
DR. DRACHMAN:  Would you say a word about the PDE efficacy of dipyridamole?
DR. MULLER:  This is an important and interesting issue.  I think we all have read in our textbooks of pharmacology that indeed initially it was believed that dipyridamole preferentially inhibits the cyclic AMP dependent phosphodiesterase, however, these observations occur or this inhibition occurs only at plasma levels which are far above the therapeutic levels.
More recent advances have brought our attention to a different phosphodiesterase, which is the cyclic GMP dependent phosphodiesterase, which is usually busy to degrade cyclic GMP which is generated in the platelet in response to nitric oxide or EDIF, and whenever in the platelet there is an increase in cyclic GMP, dipyridamole does interfere with the degradation of this intraplatelet cyclic GMP, and indeed there is some experimental evidence that this mechanism might also contribute to the antithrombotic activity of dipyridamole, however, to keep the presentation focused, I have concentrated on the adenosine mechanism.
DR. DRACHMAN:  This mechanism, I believe is used in another recently accepted drug, namely, sildenafil, better known as Viagra.  What is the efficacy of this drug vis‑a‑vis the erectile dysfunction that is dealt with by sildenafil?
DR. HAEHL:  As you know, there are several subtypes of phosphodiesterases, and in addition, we have never investigated that.
DR. GILMAN:  Does Dr. Easton want to comment?
DR. EASTON:  Just one clarifying comment to Dr. Grotta's question, and that is, if you look at the three previous stroke trials for the endpoint stroke, which is the focus for the moment, there actually was an odds reduction of 17 percent favoring combination dipyridamole plus aspirin over aspirin alone.
It is clearly just a trend.  The confidence intervals do include unity.  Now, when you take that and add ‑‑and that turns out to be 120 events, and the difficulty now is when you add ESP to that, you have 443 events, and that number moves from 17 to 25, and is statistically significant.
So, the point I would only make is it wasn't negative data.  It was lack of data prior to this trial.  Similarly, if you do the same numbers for the 14 trials, not just now the three stroke included patients, but all of the patients in combined dipyridamole plus aspirin versus aspirin, again, you see this trend 12 percent reduction in favor of the combination for prevention of the endpoint stroke, and then that number also moves into the highly significant range when you add in the ESPS trial.
So, I think it is fair to say that it was a lack of data with a trend going in the right direction rather than negative data.
DR. GILMAN:  Thank you.
Dr. Califf.
DR. CALIFF:  I just want to take advantage of this one opportunity to maybe learn a little bit more about stroke since we are on the mechanisms of action.
You built the whole rationale on antithrombotic effect.  I guess it is a three‑part question.  What do we know about inflammation and risk of stroke?  Does dipyridamole add anything to aspirin in terms of antiinflammatory effects, and if so, what?
Thirdly, are you convinced that the only mechanism of action of aspirin is its antithrombotic mechanism in preventing recurrent stroke?
DR. MULLER:  We already discussed this issue this morning, that indeed there is current speculation that atherosclerosis may be an inflammatory process.  I completely agree on this.
My point was that however the acute reaction to this inflammation that is the rupture of a plaque or any other injury of the vessel wall triggers the instantaneous response of the platelets, and that is where the thromboxane inhibition and where the adenosine uptake inhibition really comes into play.
That, of course, does not rule out any other mechanism, but I think there is a rational basis for that, and as long we don't have any long‑term trials which clearly demonstrate a superiority of high doses of aspirin which are antiinflammatory active in the clinical endpoints, I think this remains pure speculation, don't you agree?
DR. CALIFF:  Yes, but like most pathophysiology, it is speculation.  In the end, we will come back to the clinical data, which I guess we are getting.
DR. HAEHL:  I would agree.  We made a hypothesis the basis for our formulation, and we tested it in the clinic, and it seems that there is a relation between the hypothesis and the result, but therefore it always is a jump from one side to the other, but it seems to be consistent.
I had the impression that Dr. Hennekens wanted to comment on the aspirin antiinflammatory efficacy.
DR. CALIFF:  It would be interesting to know if you have seen the same things that you saw with regard to cardiac events in the stroke events issue.
DR. HENNEKENS:  Well, our comparisons about aspirin in the presence of high levels of CRP are sort of post hoc, nonrandomized comparisons.  My own view is that I have serious doubts that a dose of 50 to 100 mg of aspirin is having a significant antiinflammatory effect.
I think the alternative hypothesis that at the time of an acute stroke or an acute MI, there is such increased platelet activation that it does go with the data from the antiplatelet trial, that people who were taking aspirin at the time of the event, who were given an acute amount of aspirin, tend to have lowered subsequent clinical outcome, suggesting that there must still be increased platelet activation and other mechanisms that are occurring around the time of the event that relate to these mechanisms described.
DR. CALIFF:  But people with high CRPs also have a high risk of stroke in addition to a high risk of MI.
DR. HENNEKENS:  Yes, they do, and we did find that people who were getting either 325 every other day in the physician study or 50 a day in the women's study, that there was some modification of the effect by aspirin, that is, that aspirin seemed to have its greatest benefit in the people with the highest levels, but as I say, they are not randomized comparisons and we need more data on that question.
DR. GILMAN:  I would just like to note that Dr. Michael Brooke has joined us.  He is from the University of Alberta, flew down this morning.  Welcome.
DR. GILMAN:  If there are no other questions, let's move on, Dr. Street.
Clinical Trial Efficacy
[Slide.]
DR. STREET:  Members of the committee, today, I will present an overview of the design, principal results, and reliability of the Second European Stroke Prevention Study.
This trial was designed to test the safety and efficacy of the two components of extended release dipyridamole and aspirin, alone and in combination, to prevent stroke and death in patients with prior TIA or ischemic stroke.
There were actually four specific clinical questions to be address by this trial.  First, does low‑dose aspirin, 50 mg a day, prevent stroke or death, which was not known at the time.
Does extended release dipyridamole prevent stroke or death?  That had also not been established.
Are the effects of the two drugs additive when administered in combination?
Finally, is Aggrenox well tolerated?
ESPS‑2 provides clear, positive answers to all of these questions.  I will address the first three, the efficacy questions, and Dr. Rakowski will follow with a discussion of the tolerability.
[Slide.]
Very briefly, I know you are all familiar with this trial, but just for the record we will briefly summarize.
This was a multicenter, randomized, double‑blind, placebo‑controlled trial, ranged in a 2 x 2 factorial design of four parallel treatment arms, each containing approximately the same number of patients.
[Slide.]
These patients were recruited from 13 countries, had 59 centers across Europe.  The randomization was performed by the European Organization for the Research and Treatment of Cancer, a group which is independent and highly experienced in centralized computer randomization.
This randomization was balanced with respect to four factors:  the gender, the age group, type of qualifying event, and the center.
Treatment and follow‑up were all to be two years and patients were to be followed for two years regardless of whether they ceased treatment. There were nine visits at one and three months, and then at three‑month intervals thereafter.
[Slide.]
This simply summarizes the numbers of patients in the four groups, roughly equal.
[Slide.]
As far as qualifying events which were to be within three months, and most of which occurred‑‑as a matter of fact, the mean time from the qualifying event to randomization was one month.  We see perfect balance between the treatment groups, roughly, one‑quarter having a TIA, and a little over three‑fourths a stroke as their qualifying event.
[Slide.]
The study was to include adult men and women, 58 percent were men, who had had, as I say, an ischemic stroke or TIA within three months.  They had to be stabilized from that stroke prior to entry.
Key exclusion criteria were they had had no history of gastric bleeding or other bleeding disturbances, active peptic ulcer, known hypersensitivity to either of the study medications, or any life‑threatening conditions.
[Slide.]
Sample size.  The protocol‑planned sample size was 5,000 patients, 1,250 per treatment arm, the same number as were present in the ESPS‑1 design.  In addition, this design contemplated one interim analysis in the protocol.
DR. GILMAN:  Could I ask about that?  Sorry to interrupt you.
DR. STREET:  Yes.
DR. GILMAN:  I thought you had planned interim analyses yearly.
DR. STREET:  No, there were interim safety reports to the ethics committee, but they were not the basis for decisions, nor were they analyzed with p‑values or anything like that, so there was only the one that was used as a decision point.
DR. KONSTAM:  I am not sure I understand that.  There were interim safety looks you are saying?  What were the purpose of these interim looks if you were not looking at the data?
DR. STREET:  Can someone actually comment on the nature of the review that was performed for safety?
DR. HAEHL:  Dr. Bertrand, would you please comment on the procedures to inform the ethics committee about the conduct of the trial in yearly intervals?  For your information, Dr. Bertrand is a co‑worker of Boehringer Ingelheim, and he was the responsible monitor for ESPS‑2 in Belgium.
DR. BERTRAND‑HARDY:  Data for the ethics committee, we prepare once a year and the statistician made a review of the main side effects as they were registered in the case report form, mainly headaches, bleeding, gastrointestinal diseases, and so on.
The results were presented to the ethics committee once a year and this committee had to decide whether the study could continue or not on the basis of those data.
DR. KONSTAM:  So deaths were reviewed as well, right?
DR. BERTRAND‑HARDY:  Yes, of course, yes.
DR. KONSTAM:  And strokes were not?
DR. BERTRAND‑HARDY:  And strokes also.
DR. KONSTAM:  Were reviewed.
DR. BERTRAND‑HARDY:  Yes, they were reviewed.  But the tables were randomly allocated so as to keep the blindness of the study, so it was not possible to identify the treatment groups.
DR. KONSTAM:  But if you had identified a major difference in the endpoint of stroke, let's say, between the two groups at an interim look, might not you have recommended stopping the study?
DR. BERTRAND‑HARDY:  No, because in the protocol, there would be only one interim analysis, and the rules for treatment cessation, of course, apart from the reason, and for seeing side effects or something which would be very important that the study would be stopped if the statistical significance would reach a value which was lower than p 1 for 1,000.  That was the only occasion, and also safety analysis, as far as I know, never the statistician did analyze the efficacy.
DR. GILMAN:  But you did compare placebo group, you know which was the placebo, you know which were the‑‑
DR. BERTRAND‑HARDY:  No.
DR. GILMAN:  No, you did not.
DR. BERTRAND‑HARDY:  Even the statistician did not know that.  He knew that there were three groups and named A, B, C, and D, but he could not identify them.
DR. GILMAN:  Then, explain how you would determine safety if you didn't know which was the placebo group.
DR. BERTRAND‑HARDY:  Just by difference between the groups.
DR. GILMAN:  And was there a trigger for stopping the trial?
DR. BERTRAND‑HARDY:  Yes, well, I mean regarding safety, there was no trigger, just a strong excess of death or something which would not be acceptable, and regarding the efficacy, I told you that was the p‑value.
DR. GILMAN:  How would you know, what would be your marker for excess, how would you know?
DR. BERTRAND‑HARDY:  Well, I can't specify exactly, I don't know exactly which was the rules which were applied by the statistician.
DR. GILMAN:  Does anybody in the company know what the rules were?
DR. HAEHL:  Dr. Pathy, as the Chairman of the Assessment Group, could you comment on that?
DR. PATHY:  Chairman, whereas we looked at deaths, we were totally blinded.  We didn't know whether the patient was on placebo or active medication.  Neither did we know the centers from which the reports were coming.  Everything was looked at totally blindly.  So, I can't give you an answer to that.
Also, of course, it was the ethical committee that would have made a decision to stop the trial on the basis of excess of adverse events.
DR. GILMAN:  But again, how would you determine what was excess?
DR. PATHY:  That really wasn't the role of the MMAG.
DR. HAEHL:  The definition of excess, in order to decide whether the trial should continue was limited to the interim analysis.  The safety information, the yearly safety information to the ethics committee was given in its totality to compare what was reasonable as an overall incidence, and then the ethics committees would intervene or not, and they did not.
DR. GILMAN:  But, again, how do they determine what was reasonable?
DR. HAEHL:  We, as the company, did not propose to them when they should intervene or not.
DR. GILMAN:  There are a number of questions.  So, Dr. Brooke had his hand up first, then, Dr. Califf, then, Dr. Grotta, then, Dr. Katz.
DR. BROOKE:  I want to be absolutely clear that I understand this.  A variable that was being used as an endpoint was also being used as a safety assessment?
DR. GILMAN:  Could we hear a response?
DR. HAEHL:  The incidence of the endpoint stroke at the predefined interim analysis was used in a randomly allocated treatment group design to decide whether the study could continue or not.
DR. BROOKE:  I don't want to be aggressive about this, but is it true, then, that a variable that you had planned on using as an endpoint was also used in an analysis of safety?  Is it yes or no?
DR. HAEHL:  The answer is yes.
DR. CALIFF:  I am not saying this is easy, and I am not actually sure how to deal with it, this is a common problem, but my understanding then of what happened was that you had an ethical committee that was reviewing for safety on a regular basis, looking at the primary endpoint, admittedly not knowing which group was which, but with the option if they were concerned about something for unblinding and doing something, and that is not being called an interim analysis every time they looked, is that correct?
DR. STREET:  That is correct, because there was the one decision point built into the protocol based‑‑
DR. CALIFF:  That was a built‑in decision point, but every year when they looked, if they had been concerned, I guess the question I would raise as a matter of policy is if there is only place to make a decision, why would you look at the other times if you are saying there is no way they could make a decision based on that data.
DR. HAEHL:  As we do in any of our large trials, that we inform the ethics committee about the conduct of the trial, and we would expect the ethics committees, both individually in the centers, but also if we have a central ethics committee, to interfere with the trial if they don't feel confident with the safety of the trial anymore.
It is I would say standard procedure, and as a matter of fact, in Europe, it is requested by the ethics committee that you inform them on a yearly basis.
DR. CALIFF:  That may be another point to come back to among the committee and maybe with Bob Temple's help, but this is a major issue of multiple looking and including the primary endpoint in the safety, and I don't know how to deal with that.
DR. GILMAN:  Dr. Grotta.
DR. GROTTA:  Well, I mean I could understand if your safety is looking at death, and death is combined in  your endpoint, and even strokes, that the safety committee needs to look at it.  I guess what is bothering me is whether the company was aware of these differences among the groups, as well.
So, maybe you could clarify a little bit about how much information about group differences on these important endpoints, namely, death and stroke, was known outside the ethics committee and by whom.
DR. HAEHL:  Dr. Bertrand, he has referred to the company and even not the statistician didn't know the treatment allocation for the safety updates.
DR. GILMAN:  That didn't answer the question.
DR. GROTTA:  Were you aware of the group differences?
DR. GILMAN:  In other words, were you notified about the number of deaths and the number of strokes in these groups?
DR. GROTTA:  In the different group, even though you didn't know the group identifications, the safety committee didn't know the identification of the groups either, they just knew that Groups A, B, C, and D had different rates of death or stroke.
So, my question is who besides the ethics committee or safety committee in the company knew that information?
DR. BERTRAND‑HARDY:  Yes.  The answer yes, we were informed about the number of events in a group.  I mean the person working in the study.
DR. GILMAN:  That still didn't answer the question.  The question was who in the company knew about the results of the ethics committees.
DR. BERTRAND‑HARDY:  Just the person involved in the studies, that means the little group working in Brussels, and the ethics committee, and that's it, no more persons.
DR. GILMAN:  Which little group in Brussels?
DR. BERTRAND‑HARDY:  I mean what we call the TSU, called the technical support.  That mean myself and three other physicians, and, of course, the statistician, and the members of the coordinating committee.
DR. GILMAN:  Dr. Katz, I think was next, then, Dr. Drachman.
DR. KATZ:  I guess maybe the fundamental question we are sort of dancing around is‑‑and we should ask the statisticians this question‑‑does the fact that they were looking periodically under the rubric of safety at an efficacy endpoint, even though there were no formal stopping rules, the way there was for the one formal interim analysis for death and stroke, should we be concerned that the testing at .05 at the end of the study inflates the Type I error, the sort of thing that we usually worry about?
I mean does this maneuver affect how we ought to think about the results?  I think this cuts right to the chase.
The concern is because the ethics committee on these safety analyses is blinded to the treatment group, and they are making assessments on death, on stroke, and on bleeding based on whether there appear to be extreme differences, they don't know what the nature of that difference is, for all they know it can be higher in the placebo group than in the active treatment group, so they don't know it.
But I think if I understand the issues correctly, it surrounds the fact that the study went on for three years, so there were like three safety looks and one efficacy look, and under the sort of if you follow the Peto Haybittle rules, which it appears they did, with a p‑value of .001 or more extreme for stopping, then, I think that my own view of this methodologically would be that there would be no necessity to adjust p‑values at the end for multiple looks.
If this had been like a 8 or 10‑year study, it would be a different story.  So, it may be a tempest in a teapot from the perspective of statistical adjustment, and it certainly seems, in terms of knowledge of the outcome because of the safety monitorings, nobody knew which treatment group was which.
DR. GILMAN:  Let's stick with the same point for a moment.
Dr. Grotta.
DR. GROTTA:  What we are going to hear about in a moment is that the sample size was increased during the study from the original number by over 1,000 or more additional patients, so decisions were made during the conduct of the study, and I guess the question then comes up is were those decisions influenced by the group differences and the magnitude of group differences that were being seen during the course of the study.
I suppose if no changes had been made in the study, it would be a little easier to accept the fact that group differences in the endpoints were known by the statisticians.
DR. STREET:  It is quite correct.  They did re‑estimate the sample size, and the group rates were used to rerun the simulation program that had been originally used to design the study, and instead of a 35 percent reduction between the best and the worst treatments, and with the assumption of the other treatments being halfway between, they found a 20 to 25 percent difference between the best and worst treatments at the interim analysis.
They plugged those rates into the computer program without knowledge of which treatment group was which, but simply on the overall test of homogeneity of these treatments, and that was the principle.
After this was done, and it was also done in another fashion, again still blind to the exact identity of the groups, the statistician concluded that 7,000 patients would be required or 1,750 per group.
His recommendation to the steering committee following the interim analysis in November of '91, the steering committee acted on that and said they agreed with it.
Later, in March of the next year, this was presented to the ethics committee, and the ethics committee reviewed the existing data on aspirin.  Again, from the meta‑analyses, they concluded that the efficacy of aspirin in stroke and TIA patients had not been adequately proven.  They agreed to continue the trial as originally constituted, and agreed at that time to increase the sample size to 7,000 patients per recommendation of the statistician.
DR. GILMAN:  Dr. Drachman had a question next.
DR. GROTTA:  This is just in response to that response.
So, therefore, this really turned out to be a demonstration more than an experiment, and that you found a difference, and then you adjusted your sample size to show that that difference really was true.
I guess I need to know is there precedent in clinical trial design, an accepted clinical trial design, to adjust your sample size mid‑trial, knowing that your differences weren't as great as you had initially hypothesized them to be as opposed to starting over again with a larger sample size.
DR. HAEHL:  When we initiated ESPS‑2, the situation was such that we had no information other than speculation what the contribution of dipyridamole in this four‑arm setting would be, what the contribution of low‑dose aspirin would be, and therefore, any assumption for sample size calculations were based on speculation.
And because this was the case, the statistician included in the protocol a planned interim analysis in order to prevent‑‑that we are performing a trial which involves a large number of patients and exposes them to medication, however, because based on wrong assumptions, non‑established assumptions, fails, just fails to show a true benefit.
I think that was the rationale for us how this trial was designed, and therefore, the interim analysis had to be in.  The other consequence would be that we would have potentially discontinued the trial just falling short of showing an existing benefit, and we would not have the results as we have them on the table today.
DR. GILMAN:  I think Dr. Grotta's question perhaps ought to be addressed by Dr. Katz, Dr. Temple, or both.
DR. KATZ:  No, I mean you have just said that the plan to reestimate the sample size was prospectively designated in your plan for the interim analysis.  That may be, and that is all well and good.
The question is, is it an appropriate thing to do. The fact that it is prospective doesn't automatically make it so.  So, I would ask the statistician, Dr. Van Belle, how you feel about what increasing the sample size on the basis of a look, which is blinded to some extent, but you do know A, B, C, D, and as Dr. Grotto suggests, that you could guess, for example, that the difference in Group C, if that had the largest difference compared to some other group, might have been the treatment you were interested in, the combination.
What does this maneuver do under these circumstances to the Type I error at the end?
DR. VAN BELLE:  Let me make several comments.  One is the issue of whether there was one interim analysis or more.  I think that is really one of the key issues here.
I get the impression, and this is the impression that the ethics committee had its own rules for looking at the data without any kind of an interim analysis.  I would think that if there had been an extreme imbalance, whatever that might mean, that they might have asked for an unblinding of the data, but as far as I can tell and from what I have heard today‑‑and maybe the company can also explicate that‑‑it seems that the ethics committee did not explicit rules for when to stop the trial or when to ask for unblinding, so that is one issue.
The other issue is the one that is raised now, what about the interim analysis affecting the sample size.  I think I have seen that done more than once, and it would affect the p‑value undoubtedly in some sense, but I would not know how to actually model that.  I think it is a very complicated question, and I don't think it is very fruitful either.
I think I would just take the added sample size as being reasonable and particularly in view of the results, I am not too concerned about that aspect.  I am more concerned about endpoints, whether they were prespecified or not, and also I am concerned about the number of interim analyses that were actually done, and I get the impression that there was only one.
DR. KATZ:  Can I have a follow‑up question?
DR. GILMAN:  All right, please.
DR. KATZ:  As far as the first point you addressed, what increasing the sample size on the basis of this interim analysis does to the p‑value, it might be fairly important in the analysis of this trial, because there is some question as to whether or not even the nominal p‑value for the comparison of the combination of the components is significant by the usual rules.
I mean obviously we will get to that, but the point is if it does do something to the p‑value, and we can't quantitate what it does, it might actually I think be fairly‑‑at least where they got the combined endpoint of mortality and stroke.
DR. VAN BELLE:  I don't know.  My impression would be that under any reasonable scenario, the effect on the p‑value would be reasonably small.
DR. GILMAN:  I would like to stick with this question for a moment.  Dr. Temple, can you comment?
DR. TEMPLE:  Well, it almost has to be relatively modest.  Even a full Bonferoni, which would be very conservative in this case, would only double it.
My impression is that Gordon Land actually has looked at this question fairly recently and has published on this very question, because there is naturally a desire to expand the population sometimes.
I don't know those data‑‑there may be people in the room who do‑‑but the conclusion was that the correction is real but modest, fairly small for expanding it.  Obviously, it isn't a whole separate study, most of the data are already locked in, so how much impact could it have.
We may need to look into that, but I believe it has been actually addressed, probably with modeling.
DR. GILMAN:  When you say real but small, can you give us an order of magnitude?
DR. TEMPLE:  Well, the most conservative thing you could do is say I have got two studies here, and if you did that, you would say the nominal p‑value has to be doubled.  That is a Bonferoni.  Well, that is obviously absurdly overconservative, because 80 percent of the data are already locked in, so they are not independent.  So, it has to be  considerably smaller than that, but I am well beyond my limits.
DR. HENNEKENS:  If I may make a comment, I agree with Bob that Gordon Land and Dave DeMets are publishing on the small corrections that one can make at the end, however, it is not uniformly agreed upon in clinical trials.  Peto's position is quite the opposite, that says that if you have an extreme enough p‑value to start with in terms of safety and efficacy monitoring with one look at year for several years, there is absolutely no need to make any correction.
Having said that, as a chair of several data monitoring boards, we routinely in the middle give advice to the investigators about whether to increase the sample size or not, and we have not taken the view that the p‑value needs to be corrected based on those interim looks, because then it becomes a catch‑22, because what is the net gain if, in fact, you are telling them they have to correct for something, they have to get an even result.
But there is a big philosophical debate between Land and DeMets and Peto on this issue, but I think Bob's point is the most important one, that even if you did it, the correction would be quite small.
DR. GILMAN:  Dr. Drachman.
DR. DRACHMAN:  I think you may have answered this, but maybe you would clarify.  The ethics committee knew membership in groups, but did not know which group was which or did not know who belonged in which group?
In other words, they were told that these patients are Group A, but we don't know what drug it is, or they were just given all the patients without any assignment by group, which was it?
DR. GILMAN:  I believe he said it was by group.
DR. BERTRAND‑HARDY:  By group.
DR. DRACHMAN:  They knew the groups, but they didn't know what the drug was?
DR. BERTRAND‑HARDY:  They knew the groups.  I mean they knew it was Group A, B, C, or D, they knew that.
DR. STREET:  It needs to be pointed out that those A, B, C, and D were not uniformly applied across each event.  They were randomly permuted in every table, so they were simply nominal levels, but you could not correlate from adverse events back to efficacy events using this.
In fact, I gave the study report to a statistician, I said can you decode this, and he said no.  I said can you tell from the adverse events what the efficacy groups are, he said no, so I tested it myself.
So, this random permutation preserved the blindness to that degree, but they were grouped with nominal levels.
DR. GILMAN:  The end results were stroke or death.  Why could that not be done?  If you have A, B, C, D groups, you know there are two deaths in A, three deaths in B, four deaths in C, five deaths in D, you can assume that you are looking at some endpoints, right?  And therefore, you are looking at efficacy, as well as adverse events.
DR. HAEHL:  In this respect, it is true.
DR. STREET:  That is, of course, true, but you don't know which of the treatment groups.  That's all we have.
DR. GILMAN:  I understand.  The point remains that the examination of safety also deals with the endpoint of the study.
DR. HAEHL:  In a study like this, it does.
DR. GILMAN:  Dr. Brooke.
DR. BROOKE:  When one is wrestling with a problem, I was once taught that you put it in language that your grandmother can understand, and I have a question here, because I work in a lab, as well as in a clinic, and sometimes I have an experiment which I know should come out the way I want it to come out, and then my lab tech comes to me and says it is not working the way you wanted it to work, and I say, well, put it back in the refrigerator until it does.
This change in number that is the result of an analysis, does that come under the same heading like the study isn't going quite the way we want it to, let's increase the numbers, because if that is in fact true, that is a bit of a problem.
DR. GILMAN:  Is there a grandmother in the room?  I mean can we hear a response from the company perhaps, the sponsor.
DR. HAEHL:  My answer would only be that is a hard endpoint which we would not have impact on just by, to stay in your picture, to put it back in the refrigerator, and as we have mentioned, the majority of the data was locked, so it was the extension in order to get the power for a true result, but I don't think that the study and the measures here are able to change direction and influence the direction.
Dr. Easton, you wanted to comment on that.
DR. GILMAN:  Stick with this point for a moment.
DR. EASTON:  I was struggling with what you are struggling with and thinking that in the Canadian and American ticlopidine study, the trial was extended by adding additional months on to the trial on the recommendation of the DSMB.  In the CAPRIE trial with clopidogrel recently, it started out at 15,000 patients, and it ended up at 19,000 patients based on a look at the blinded overall group event rate that was going on in the trial and adjusted upward.
So, certainly, those adjustments take place regularly.
DR. GILMAN:  Let's stick with this point.  Do you want to comment on this point, Dr. Califf?
DR. CALIFF:  Yes.  I mean Dr. Easton just made the point I was going to make.  I mean there is a methodology to do this that has been pretty well worked out based on either control group event rates or blended event rates prospectively planned.
I sort of agree and disagree with Dr. Hennekens, that the penalty, if there is one, and having sat through a number of debates about this meaning specifically devoted to this topic, the penalty is not huge for doing this, and probably will not have a major impact on the interpretation of this particular data set, but as a matter of policy, I think there is almost unanimous agreement that this is bad policy to continue your experiment having looked at the results part of the way and then adjusting the size of the experiment to confirm a result that you have already seen.  It is not good methodology.
DR. GILMAN:  Dr. Temple, will you address that question?
DR. TEMPLE:  I don't agree with that.  I don't think that is true any more than taking interim looks is true.  These changes can introduce some bias, and it is all about multiplicity.  These are all variations of having multiple endpoints, multiple looks, multiple subsets.  It is the same conceptual problem, and it is not that it is evil, it's that you may have to make some correction and adjust the alpha level.
As Rob says it is perfectly true if you do it without breaking the code in any way, so that you are just looking at total events, the correction is very small.  I used to think it was none, but I am told by statisticians that there is a very slight one, and that is the cleanest, but it is not as efficient.
So, if you want to make another one, you can do it, but you have to pay what the appropriate price is.
DR. CALIFF:  But since we don't know the price, this could be like a scud missile, you are getting closer and closer, and you keep redesigning and redesigning, and eventually, you have engineered the experiment to get the result you want.
DR. TEMPLE:  But you can't really do that.  I mean if you have 8,000 people, they don't go away when you add another 1,000.  You can't make it come out the way you want, but you do increase the possibility that you will have a favorable outcome when there shouldn't have been one, and you can correct for that.
I believe there is a recent‑‑I probably wouldn't understand it anyway‑‑but I believe there is a recent analysis of this by Gordon Land that suggests what the nature of the correction might be, and one would have to do that, I think.  I don't agree with Charley, I think you do have to consider the correction.
DR. GILMAN:  Can you address that point?
DR. HENNEKENS:  Yes, I would like to address that point.  You know, theoretical speculations are out there, but the p‑values here for the combination versus placebo is less than 0.001 on stroke.  For the combination versus aspirin it is 0.006.  For the combination versus dipyridamole it is 0.002.
So, while I take the point that there is this debate about whether or not to do so, with the robustness of these p‑values, I really think it would be unfortunate if this trial, we are giving the impression that, well, gee, I don't know about this because if you make a correction, you are going to get a qualitatively different answer.
You will not.  These are quite robust findings for the combination versus placebo, aspirin, or dipyridamole on stroke.
DR. GILMAN:  Dr. Grotta.
DR. GROTTA:  Just a question and then a comment.  So, the possible increase in sample size at the interim analysis was prespecified.  I mean when the study was designed, it was recognized that at the interim analysis, some increase in sample size might occur based on the data?
DR. HAEHL:  No.
DR. GROTTA:  It was not?
DR. HAEHL:  No, the sample, that the trial should be reassessed, that is the formulation.  At that time, in the protocol, there was no specification by what means the trial would be influenced.
The primary aspect was to discontinue should the results go to the extreme.  The other option that was seen by the statistician was to adopt a sample size for the outcome.
If I may, I would like to add an information which you will see later, is that because of this issue, the first 5,000 patients which were included in that have been analyzed separately, and just to anticipate, the result is the same as for the totality of the patients.  So, this is an additional step in addition to correcting for p‑values to ensure the homogeneity of the two populations.
DR. GROTTA:  Well, my comment is that, you know, I am a pragmatist, and so I think that we do need to make clinical trial execution somewhat flexible as long as we don't violate basic principles, so I mean this notion of increasing sample size doesn't really bother me that much, but I just think we need to be crystal‑clear and have it read it into the record that if this drug is approved, that the precedent has been set, that in the course of a trial, particularly if it is prespecified on the basis of an interim analysis that it is valid to increase the sample size to be more certain of the endpoint.
DR. GILMAN:  May I just ask you to clarify, prospectively, when did you plan to do your one interim analysis, and what did you plan to be the outcome of that analysis?
DR. HAEHL:  The interim analysis was planned with the protocol, and the outcome of the interim analysis was to consider the further conduct of the trial in both directions.
The primary idea was to discontinue the trial early should there be excessive or unexpected efficacy.
DR. GILMAN:  And if there were inadequate power, then?
DR. HAEHL:  And the statistician at that time‑‑and I think we have also to consider that this trial was not initiated today, and the protocol was not written today, under today's guidelines and rules‑‑and the statistician interpreted this, that he would also be requested to consider the power of the trial and the adequate sample size because when he did the sample size calculation at the beginning, he was left with assumptions which were not established in literature in the prior experience.
DR. GILMAN:  Was it planned for an interim analysis when you accumulated 5,000 patients?
DR. HAEHL:  What was the exact definition, when we accumulate 5,000 patients or was it after a certain time period?
DR. BERTRAND‑HARDY:  That was when we accumulate at least 1,600 patients followed for at least two years or 3,000 patients followed for any time.
DR. GILMAN:  Then, why did you, in fact, carry out this interim analysis with 5,000 patients?
DR. BERTRAND‑HARDY:  A little bit more.  There were 4,000 patients included in the interim analysis.
DR. GILMAN:  I thought it was 5,000.
DR. HAEHL:  I think we have to clarify.  When I mentioned the 5,000 patients, it was after the trial was concluded in order to see the impact of the increase of the sample size, an analysis was performed, not only on the total patient population, but also on the first 5,000 patients in order to reflect the original sample size.
DR. STREET:  In fact, the sample size‑‑
DR. GILMAN:  Wait a minute now.  Wait a minute now.  So, you did two interim analyses then.
DR. HAEHL:  No.
DR. GILMAN:  No, you did one.
DR. HAEHL:  Then the trial was concluded, and the complete analysis was done.  The question came up what is the impact of increasing the sample size, and above all the things that have been discussed here, we addressed this question by looking into the effects of the first 5,000 patients recruited into the trial as a subgroup.
So, that is an analysis for robustness if you want, and that was performed.
DR. KATZ:  The 5,000 comes in because that was the original protocol specified for the trial.
DR. HAEHL:  Yes, yes, we wanted to post hoc mimic the situation had we continued the trial as it was planned in the very beginning without interim analysis and without the consequence of the interim analysis.
DR. GILMAN:  Thank you.  That clarifies that situation.  It wasn't clear from the books.
Dr. Drachman.
DR. DRACHMAN:  Would you show us the data both at the time of the interim analysis right then and with the 5,000?  Let's see what you have got.
DR. STREET:  I don't know that we have the slides prepared for the interim analysis, which I want to remind you it was performed with 3,994 patients on an average of 12 months follow up, many who had not even reached two years, and so when the trial was continued, we found, as you have seen, increasing benefits over time between the two treatment groups.  So, I think that is why it appeared somewhat that the effects were smaller than they were in the final analysis.
So, I do not have that, but I was going through in the course of this, if we could jump ahead, please, to one of the robustness analysis slides.
DR. GILMAN:  If you can't show that, can you show a comparison between the 5,000 and the 7,000?
DR. STREET:  Yes, that is what I am getting here.
DR. KATZ:  Which outcome did you look at in the interim analysis as being primary, or was there one that was primary?
[Slide.]
DR. STREET:  In the interim analysis, they viewed the composite endpoint of stroke or death at the interim analysis.
DR. KATZ:  That was prospectively?
DR. STREET:  Well, to get the history of that, when you read the protocol‑‑let's go back to the original wording of protocol, because there seems to be a bit of confusion on this, and one needs to set the record straight.
The stopping rule was clearly specified.  That is the 0.001. That is for a global test of homogeneity between the four treatment groups, and that was going to be done by the statistician on the endpoint of stroke or death.
There was also a provision which was broadly worded, that said the interim analysis might be the basis for a new assessment of the rationale of the trial by the steering committee.
Now, that doesn't say anything specifically about an increase in sample size, however, the minutes to the steering committee meeting, which took place in 1990, I think in October of 1990 or thereabouts, a year before the interim analysis, do mention that this sample size would be increased‑‑I am sorry, not increased‑‑that it would reevaluated.  That is the first explicit mention of sample size increase, and that was one year prior to the actual analysis.
So, that is the record, and it is true what you are saying that adjustments are very difficult to provide when you don't have a clearly specified rule. In fact, in frequenter statistics, you really can't make that adjustment, but in making any reasonable assumptions, you know that the impact is small, and the bottom line is really over here in the first 5,002.
We were very fortunate that these results‑‑up here you see the planned primary efficacy analyses for stroke.  I am concentrating on stroke, which is where we have efficacy.
The primary analysis, the main effects which we had prespecified and were planned in the protocol, 0.001, less than 0.001 for aspirin.
When we come to the comparisons of Aggrenox versus its components and versus placebo, we will see a 0.002, a 0.008, and frankly, one, 10‑6, one in a million here for Aggrenox versus placebo.
We come down to the first 5,0002, and here we have the same level of significance, comparable anyway, across all the most important comparisons in the trial, so all I can say is it would have succeeded on the original plan.
It also succeeded even more on the final plan because many other endpoints could be investigated adequately.  So, I believe that is a direct pragmatic answer to a thorny technical question.
DR. GILMAN:  Dr. Robie‑Suh.
DR. ROBIE‑SUH:  I had wanted to ask about the interim analysis when the sample size was increased.  What were investigators told, if anything?  Did they know that the sample size had been increased or were they just continuing until someone told them to stop?
I guess sometimes one thing that I think about in increasing sample size is the penalty shouldn't be a whole lot if the patient population and all the other things sort of stay the same and we just go along, but, you know, people are kind of curious, investigators.
DR. STREET:  I have no knowledge of that.  I know that the basic decisions were taken by the steering committee and by the ethics committee.
DR. HAEHL:  I remember that the decision was taken, and the decision to increase the sample size was, of course, communicated to the participating investigators.
DR. GILMAN:  Did that answer your question?
DR. ROBIE‑SUH:  Was any reason given to them?
DR. HAEHL:  Yes, the reason was given that the sample size, as calculated, or that the previous sample size would not be adequate.
DR. GILMAN:  But it proved to be adequate.
DR. HAEHL:  It proved, but as Dr. Street has mentioned, the interim analysis, of course, didn't have the complete data as we have at the 5,000 patient level right now.
DR. STREET:  It has approximately 4,000 patient years of follow‑up at that time, and in totality, we ended up with 13,000.
DR. GILMAN:  Dr. Konstam had a question.
DR. KONSTAM:  I just wanted to make sure I understood something that you had said a moment ago, when you said that at the interim look it was prestated that the primary analysis would be stroke or death.
DR. STREET:  Number one, that is correct.
DR. KONSTAM:  Is it stroke or death, or stroke or death?  In other words, did the define the combined endpoint as the thing that they were looking at?
DR. STREET:  The statistician viewed it as the composite endpoint of stroke or death.
DR. KONSTAM:  This was defined in the protocol?
DR. STREET:  It is clearly indicated in the statistical appendix.
DR. HAEHL:  To be very clear, in the protocol, the endpoint, the primary endpoints are stroke firstoff, second primary endpoint, death.  In the analysis plan‑‑
DR. KONSTAM:  The primary endpoint was stroke, do I understand?
DR. HAEHL:  No, we had two primary endpoints.
DR. KONSTAM:  Two primary endpoints.
DR. HAEHL:  Yes, the two I mentioned.
DR. KONSTAM:  What are the two?
DR. HAEHL:  Stroke and death.
DR. KONSTAM:  Death.
DR. HAEHL:  And in the analysis plan, the statistician included the combined endpoint, and that is probably not up to date, but that is how‑‑
DR. KONSTAM:  Was it planned to share the alpha between these two primary endpoints?
DR. HAEHL:  I can't answer you about alpha, I have to get assistance.
DR. STREET:  No, it was not planned in the protocol to split the alpha, but when we took our proposal to FDA at a pre‑NDA meeting in August '97, we took our full analysis plans down there, and we proposed a Bonferoni home adjustment for the two planned primary endpoints of stroke and death, and we also adjusted per request of the statistician for the 0.001 interim analysis that was spent, the 0.001 that was spent.
So, no, the protocol did not specify, but we had, we felt, in our composite review of these data, we wanted to bring it up the standards as best we could of how it would be viewed today.
DR. GILMAN:  Dr. Drachman.
DR. DRACHMAN:  Had you looked at stroke alone at the interim, would it have made it then?  In other words, you now show us your stroke data for 5,000.  What was it like when you did the interim analysis?
DR. HAEHL:  I am sorry, we don't have the data right here.  If that is necessary, we have to get it.
DR. GILMAN:  Could you get that today or is that not possible?
DR. HAEHL:  I would have to consult and tell you later whether we can get it today.
DR. GILMAN:  Thank you.
Dr. Temple.
DR. TEMPLE:  If I remember the slide you showed, and if you applied sort of ordinary O'Brian‑Fleming rules, it probably would not be make it.  It was very encouraging, I imagine, but it wouldn't have made a 0.001 value.  That is for a three look, though, isn't it.
DR. HENNEKENS:  It is exactly right, it does not achieve a stopping boundary with 4,000 person years of observation, and even if the effect size, as large as it is at the end, it doesn't make a 3‑standard deviation.
DR. TEMPLE:  I should say as an aside, when anybody comes to us, we strongly urge that nobody stop trials for endpoints that can change.  Death doesn't change, that is a good endpoint, but stroke can be re‑evaluated, and endpoints committee can say something different, so we discourage doing that unless there is a perceived ethical compulsion to go ahead and do it, but it can lead to trouble.
DR. HENNEKENS:  And actually just speaking on the stopping rule, as chair of a number of data monitoring boards, we routinely review the data and give advice to the investigators about whether to keep the study going or not.
We don't expect that they need to adjust anything, but we are not giving them any information about what we are saying in the deltas.  We are talking about event rates in the placebo, either achieving or not achieving the expectations.
So, it is quite common to extend the trial and increase the sample size, and not have to spend anything at the end of the study about it.  I think the thorny issue comes when you are looking at the comparison at the time and then making that‑‑and it is not clear whether that was going on here given the fact that everyone was blinded.
As I understand it, if treatment A was the combination for stroke, it might not have been, treatment C might have been the combination for death.  So, it was very hard to unravel this.
DR. GILMAN:  Dr. Konstam.
DR. KONSTAM:  I understand this debate about how many looks there were and was there one, so let me just ask, in terms of the safety looks, how many of these safety looks were there that took place?
DR. GILMAN:  I think it was one a year, wasn't it?
DR. HAEHL:  How many safety, was it three or four?
DR. BERTRAND‑HARDY:  Four.
DR. HAEHL:  Four.
DR. KONSTAM:  I think one of the things that would be useful for us internally or among the statisticians to ask let's take the worst case, which is that these safety looks actually were interim looks of some sort, what would be the penalty and what would we wind up with.
My own suspicion is it won't kill it, but I think it would be worthwhile really asking that question.
DR. VAN BELLE:  If they had stuck to what was specified in the protocol that they would work at the 0.001 level of significance, so basically, the expenditure‑‑you are worried about the Type I error, namely, accepting effectiveness when there is none, that is really what we are looking and that is what we are worried about.
So, my judgment is that that would have been a minimal effect.
DR. GILMAN:  Any other questions?  Should we let Dr. Street continue?  Please, go ahead.
DR. STREET:  I will go on to the next concern, which you have already expressed, and that is what are the primary efficacy endpoints.
[Slide.]
Again, I think the best approach is to quote directly from the protocol where the record is unambiguous.  There will be two primary efficacy endpoints:  one, strokes; and two, total mortality.
These were to be the strokes confirmed by the MMAG, that is, the Morbidity and Mortality Assessment Group, and all‑cause mortality.  The MMAG, however, though blind to treatment, they did assess the cause of death as one of their functions, but still our analysis will be based on all‑cause mortality.
[Slide.]
In addition, there were four secondary efficacy endpoints.
DR. GROTTA:  Can I interrupt and ask a question?
DR. STREET:  Yes.
DR. GROTTA:  This is an important point to those neurologists among us who do clinical trials.  What information did the group, MMAG, have on which to base this judgment?  How much evaluation was done by a local neurologist?  How certain can we be of this primary endpoint stroke that you are resting your claim on?
DR. HAEHL:  That is an ideal question for Dr. Pathy, I think, as chairman of the MMAG.
Would you like to comment, and we have a slide for that on the basis of what?
DR. PATHY:  Yes, we have a slide.
[Slide.]
This just summarizes what the MMAG saw as its key areas of concern
Could I go to the next slide, please.
[Slide.]
These give the causes of death, but it is the next slide I need really.
[Slide.]
Yes. The MMAG, of course, was supplied with all the Trialist data, supplied with CT scan or MRI scan information if that were done, supplied with all the clinical background data, was supplied with all investigational data which would include ECGs and echocardiograms were they done.  ECGs were invariably done, of course.
We made certain definitions about stroke having come to the conclusion the patient had a stroke, so anyone dying, as I mentioned earlier, within 30 days following endpoint stroke, we wrote the cause of death as stroke in the same way as anyone dying of a myocardial infarction within 30 days of that infarction, we designated the cause of death as myocardial infarction whatever may have been a symptom, such as cardiac failure, and the same for stroke.  Even though the person may have developed an interim chest infection, we did not call the cause of death a chest infection, but a stroke if the patient died within 30 days.
DR. GROTTA:  I am sorry to belabor this point, but that just doesn't quite cut it for me.  I mean the main effect of the drug is on nonfatal stroke.
DR. PATHY:  Yes.
DR. GROTTA:  So, convince me that the nonfatal strokes that were called nonfatal strokes really were nonfatal strokes.
I realize the study was carried out in Europe, probably not all these patients were seen by a neurologist.  Was there a standard neurological examination at least that had to be carried out in everybody that was called a stroke, so that the central adjudicating committee had a neurological examination to go by?
What was required to call somebody a nonfatal stroke?
DR. PATHY:  Thank you.  Yes, we had to have the detailed neurological assessment of those patients before al members of the MMAG had to unanimously agree that this was a stroke.  There were three neurologists on the MMAG, and it required unanimity among them on the basis of the clinical data, the neurological data often amplified with, of course, a CT scan or an MRI.
DR. GROTTA:  Sometime before the end of the day, would it be possible to produce the case report form that had to be filled out on an endpoint stroke for me to look at?
DR. PATHY:  I think we could get hold of that.
DR. GILMAN:  Just to amplify one of Dr. Grotta's questions, was it a neurologist who saw the patient and collected the clinical data or what sort of physician would that have been?
DR. PATHY:  No, it would often be a general physician, by no means always a neurologist.
DR. KONSTAM:  Maybe this requires a cardiologist to ask this question.  Do you have set criteria?  In other words, you said unanimity of agreement among three neurologists, but were there prespecified criteria or some sort as to what defines a stroke?  Do we have them for MIs, for example?
DR. PATHY:  Yes.  Obviously, it depended.  We divided them between TIAs and strokes.  We wrote definitions much more precisely for TIAs because we found that this is where there was a greater degree of controversy, about strokes defined as an acute neurological deficit lasting for more than 24 hours.
DR. GILMAN:  Did you require that there be a physical sign of the deficit or would a symptom alone suffice?
DR. PATHY:  No.
DR. GILMAN:  For example, if numbness occurred on one side of the body, but no neurological abnormalities could be found on examination, would that qualify?
DR. PATHY:  If the person had an acute homonomous hemianopia, but then there would be physical signs, but that would qualify.
DR. GILMAN:  That's not my question.  That would be a physical sign.
DR. PATHY:  Yes.
DR. GILMAN:  My question is, if a patient had a symptom, but had a normal examination, and the symptom continued for days, would you consider that to be a stroke?
DR. PATHY:  No, they had to have positive clinical findings.
DR. GILMAN:  Thank you.
Dr. Katz.
DR KATZ:  When were these determinations made by the committee, after all the data were in at the end of the trial, or were they made in real time?
DR. PATHY:  Yes, the MMAG met about three times a year, therefore, there may be a longer or shorter interval between reviewing the Trialist data depending how near the death or the stroke, the endpoint was to the meeting, but we met regularly approximately three times a year.
DR. KONSTAM:  Did the committee principally have a confirmatory function?  I guess the question, would there be ever a circumstance where you would identify or define a stroke that was not categorized by the investigator as a stroke, would that ever happen?
DR. PATHY:  Yes, it would particularly in terms of TIAs.
DR. KONSTAM:  In other words, they were called TIA by the investigator, and you reclassified as a stroke?
DR. PATHY:  Yes, that's right.
DR. KONSTAM:  Can you give us an idea of what percentage of the total strokes might fall into that category?
DR. PATHY: I can't off the cuff I am afraid.
DR. KONSTAM:  Let me just follow then in that case.  Did you keep track of investigator‑defined strokes, was that something kept track of in the study, as well, or not?
DR. PATHY:  We, of course, didn't know the investigator at the time that we arrived at a decision.
DR. KONSTAM:  Maybe it's for the sponsor.  Was there a designation by the investigator that there was a stroke that had occurred?
DR. STREET:  Yes.
DR. KONSTAM:  Which then was confirmed by the endpoint committee?  If that is the case, I would just be curious to have a look at how the data look vis‑a‑vis the investigator‑defined endpoint as opposed to the endpoint, committee endpoint.  It would be worth looking at.
DR. STREET:  Yes, we have that data.
DR. GILMAN:  If you have those data, maybe you could show them to us.
DR. STREET:  If we go back to the summary of robustness slide, please, this is a bottom‑line look at it, but in addition to the MMAG‑confirmed strokes, there were a number of others which we can easily retrieve the numbers that were rejected by the MMAG.
[Slide.]
We put them into a separate category here and analyzed to see what the results were from including all of the strokes without regard to MMAG, and based on the clinical diagnosis of the neurologists, we found exactly the same results.
DR. KONSTAM:  I am curious the other way, too, in other words, strokes that were not considered strokes by the investigator, but were defined by the endpoint committee as  a stroke.  I would be interested in those events.
DR. STREET:  I am not aware of that data.
DR. KONSTAM:  The reason I bring it up is because I think there is the potential for those being softer events in my mind.
DR. STREET:  The ones that went from TIA to stroke, you say?
DR. KONSTAM:  Yes.
DR. STREET:  I was not aware of those.
DR. GILMAN:  Dr. Drachman.
DR. DRACHMAN:  Really, just a brief comment.  Whether or not the GPs were very reliable, this was blinded, wasn't it?  Bad as the diagnoses were, they were equivalent on all sides.
DR. GILMAN:  Dr. Katz.
DR. KATZ:  Just to sort of nail this down as much as possible, since it seems to be the endpoint of most interest, if a patient who died met that endpoint, and the death certificate arrives at the MMAG because you were also looking at cause of death, and it said patient had had a stroke, would that patient have been called a stroke with no other additional information for the patient?
DR. HAEHL:  Dr. Pathy.
DR. PATHY: We needed a good deal of information, for instance, if it was sudden death for which there was no cause known, and the Trialist had labeled it as stroke, we would disagree with that.  We would just label it sudden death, and all sudden deaths, that is, deaths occurring within 24 hours from unknown cause, and they would then be in the analysis, would be regarded as a vascular death.
So, merely to have a death certificate without any confirmatory evidence, that is, somebody had identified by examination the appropriate neurological deficits, no, that wasn't accepted.  It may also go under unknown if the was completely absent, just a diagnosis was not an acceptable piece of information to reach a conclusion.
DR. GILMAN:  Dr. Street, let's see if we can get through one more slide.
[Slide.]
DR. STREET:  Now we come to the controversial four secondary endpoints, which are transient ischemic attacks, which were clinical diagnoses by the investigator, and generally not reviewed by MMAG, MI, which was reviewed by MMAG, other vascular events.  All first other vascular events went to MMAG.
This was a composite of four endpoints.  All of these were prespecified in the protocol.  They consisted of pulmonary embolisms, deep vein thromboses, peripheral arterial occlusions, and retinal vascular accidents of which there were very few.
Finally, the protocol identified another composite endpoint called ischemic events, and this was stroke, MI, and sudden death.
[Slide.]
Now we come to the analyses, the types of analyses performed.  I think we have already mentioned numerous robustness tests, which I will describe in a moment.  These were designed to show that the efficacy results were not sensitive to various assumptions about the analysis or the subgroups.
We took these analysis plans to FDA at a pre‑NDA meeting, and confirmed these planned robustness tests, as well as our plans for exploratory subgroup analyses to check general consistency of results across numerous demographic and disease characteristics, some of which are listed here.
I just want to say generally, the subgroup analyses confirmed the primary efficacy of stroke, was consistent within limits of chance across most subgroups.
[Slide.]
The statistical analysis plans, I won't go into much detail here other than to say that these were conducted exactly as stated in the protocol.  The primary analyses were conducted exactly as stated in the protocol, that is, two‑year follow‑up, intent‑to‑treat population, Gehan‑Wilcox and survival analysis was chosen in the protocol in preference to log‑ran, but the results are consistent for the log rank, and also the plan was to have a factorial analysis of these effects.  I will say more about that in a minute, just so that we get the jargon straight.
I think I already said that last point.
[Slide.]
First, we have the factorial design.  Now, the principal advantage of this design is its ability to evaluate the effects both of the individual components and their combined effect in one experiment with fewer patients.
In statistical jargon, we have the main effects of each of the components, extended release dipyridamole and aspirin, and all this really means is you are going to be comparing the 3,300 patients who received dipyridamole with the 3,300 patients who didn't receive it.  That constitutes the main effect of dipyridamole.
Similarly, we compare half the patients on aspirin with the other half not on aspirin.  That doesn't complete the analysis, but it gives you, addresses two key questions that we had prespecified, do they each work, and finally, the interaction effect of the two drugs, and this is important because they may not be additive, they may be sub‑additives or super‑additive.
DR. GILMAN:  Can we interrupt for a second?  Dr. Van Belle has a question.
DR. STREET:  Yes.
DR. VAN BELLE:  The question I have is this, strictly speaking, a factorial design, and it is a little bit of a trick question because if I were a member of an HMO, I would say just give them dipyridamole plus aspirin, and you don't have to prescribe Aggrenox.  That would be the interpretation of a strictly factorial design.
So, what is your response to this issue?
DR. STREET:  Well, I would say extended release dipyridamole.  It proves that the effects are additive, and it is nothing but a combination of the two, a literal combination of the two ingredients, but you couldn't give them‑‑
DR. GILMAN:  I think the point is that extended release dipyridamole is not accepted or is not distributed here in this country.
DR. VAN BELLE:  No, no, my point is much more simple.  My point would be instead of giving people one drug, the Aggrenox, just give them dipyridamole plus a baby aspirin.  That would be the interpretation of a strict factorial design.
DR. HAEHL:  However, in the factorial design, it was not dipyridamole, but it was dipyridamole extended release.
DR. GILMAN:  Assuming extended release were available, then, your point remains.
DR. STREET:  It is truly the combination in one capsule.
DR. KONSTAM:  I would like to understand this a little bit, and just have Dr. Van Belle or others comment on it, because I am not sure I understand.
I guess the issue with regard to a factorial design or what's the design, really relates to what kind of correction has to be made, if any, I mean to me the question is what kind of correction is going to need to be made for the fact there are multiple cells.
Well, that is the question I am going to have.  I mean to me, if you are doing a factorial design to ask two discrete questions, and there is no anticipated interaction between the two drugs, and you are not actually looking at four individual cells, but you are simply asking two questions across the population, it is sort of like two trials that don't have anything to do with one another, you are just doing them together.
In that circumstance, it seems to me I don't have any problem making no correction.  This is a different scenario where there is interaction expected, and therefore what is going on in each of the individual cells is relevant, and in particular, you are looking at the combination and asking the specific question about the combination relative to the other cells.
So, I guess my question is, what, if anything, does all of that, how does all of that impact on your correction for multiple looks, multiple comparisons?
DR. VAN BELLE:  I don't think there is any issue there.  The test would be, first of all, a test of the overall effect, so basically, you would use it for the two main effects and the interaction, and that clearly was significant, so then you would go back and look at the individual main effects. 
That was not the point I was raising, I guess.  The point I was raising, and it is somewhat of a technical point, but should the extended dipyridamole become available in this country‑‑which it isn't I guess at this point‑‑then, what would be the advantage of prescribing Aggrenox over dipyridamole plus one baby aspirin.
DR. GILMAN:  Dr. Temple.
DR. TEMPLE:  There is never an advantage of using a fixed combination over the two components other than convenience.  That is the only advantage there could ever be, and all this study can show really is that the two components each contribute to the claimed effect, and a person who read this and said, oh, I am going to take dipyridamole and a baby aspirin would be within their rights.  As a company, they are hoping to gain something from marketing the combination, because it is convenient.
I do have one comment about what Marvin said.  This involves a little history of the combination policy.  The basic requirement to market a fixed combination is that you have to show that AB is better than A and AB is better than B, so that each of the two components has to contribute.
When you actually do that, not that we have ever allowed this, if you were making corrections, you would actually conclude that testing at 0.05 is too conservative, because there is a multiplication of beta error.  People have explained that to us, and we have said, well, that is interesting, but never mind.
So, we usually insist that each of those tests be positive at 0.05, but since you have to win on both, you don't really have to make a correction for multiple cells in the sense of preserving alpha, because you do have to win on both.  You have to show that each component wins.
DR. KONSTAM:  If that was the purpose of the study, I guess.
DR. TEMPLE:  Let me continue because you are raising a very interesting question.
A factorial study historically is designed to evaluate the effect to see what aspirin does and see what dipyridamole does, so a classic factorial analysis doesn't do pairwise comparisons, it does aspirin groups and dipyridamole groups, but we have generally said, well, that's nice, but that doesn't make a combination because we don't care whether aspirin works alone, in fact, we already know it does, you really have to show that aspirin works when you add it to dipyridamole.
So, we emphasize the pairwise comparisons, which of course are always less robust than the factorial analysis, and, you know, they are presenting both, and they have done both.
So, I am not sure what to make of the factorial analysis.  It isn't strictly designed or directed at the combination policy, which shows that you have to make a contribution when you add to the other drug.
It may, however, help you believe in the overall observation, in other words, as appeared on an earlier slide, we have identified as something that makes one study more persuasive the fact that something works when you use if alone and when you add it to a combination.  The example we gave was ISIS, but where aspirin and streptokinase worked alone against placebo, and also added to each other, and that was a kind of internal replication.  So, one might think that something like that is going on here.
But the factorial study, the factorial analysis strictly doesn't really address the combination question, because it could be driven by the aspirin alone component and the dipyridamole alone component.
DR. HENNEKENS:  Bob, but in the interest of sort of making an even playing field, they have got ESPS‑1 that shows that the combination reduces the risk of stroke in patients with TIA and stroke, and the rejoinder to that is yes, but we don't know which of the components works.
It may be just aspirin alone, the dipyridamole studies are too small, they haven't showed anything, we want to know that it is not only that both components work, but that the combination is better than both, and the only way to do this is a 2 x 2 factorial, and that was the state of knowledge.
DR. TEMPLE:  There is nothing wrong with the study, the study is fine.  The question is which analysis is the most telling, whether it is the factorial analysis, which draws from both, for example, dipyridamole versus placebo, and dipyridamole plus aspirin versus aspirin, and it gets part of its strength from something that is not relevant to the combination or not as relevant, namely, the comparison of dipyridamole with placebo.
So, it is the pairwise comparisons, that is, the combination versus A and the combination versus B, that is the most relevant to the combination policy.  We have had these conversations for 30 years.
DR. HAEHL:  And we will show you both.
DR. GILMAN:  Well, now, we have made it through one slide, Dr. Street.  Go ahead.
DR. STREET:  I want to move back a slide.  I haven't finished with this, no.  I wanted to also say, of course, the design allows six pairwise comparisons of which we made five.
We took Aggrenox versus each component, we took Aggrenox versus placebo, and then we took dipyridamole and aspirin versus placebo.  So, we present those.  They were designated in the protocol in a supportive role.
[Slide.]
I am going to present the results in a somewhat unusual order, but it is basically I think there is a certain logic to it, and that is, we are going to start with what we all know is the dominant result from this, the stroke results.
I will show you the planned primary analysis.  I will re‑review those robustness analyses I had put on the screen before.  We will take up the planned secondary endpoints.  We will come to the second primary endpoint of death, and then we will discuss the composite endpoint of nonfatal stroke or death.
Now, just a quick word about that endpoint.  This was not a primary or a secondary endpoint specified in the protocol, but it is clearly relevant to this application in view of the professional labeling of aspirin and, of course, our proposed labeling for Aggrenox.
This analysis of the stroke or death results, like all others, was confirmed at that same August 26th, '97, pre‑NDA meeting.
[Slide.]
I am going to just comment very briefly on treatment cessation.  What we see, these are the number of patients who ceased treatment.  Some continued treatment all the way through until month 24, some died while on treatment, and here are the percentages of patients in the aspirin/placebo groups, somewhat lower than the percentage who ceased treatment in the Aggrenox and extended release dipyridamole groups.  So, we see a little higher treatment cessation here.
Dr. Rakowski will give a further discussion of these data later, but what I want to emphasize at this point is that just because they ceased treatment doesn't mean they weren't followed to the end, nor were they excluded from the analysis.  Everything we did was intent‑to‑treat analysis, and we followed all patients to the best of our ability.
At the conclusion of the trial, there were 108 patients lost to follow‑up for stroke and 44 for death.  We then performed further follow‑up of these patients, and we were able to reduce the numbers down to 28 lost to follow‑up for stroke and 15 for death.  So, we do have complete follow‑up regardless of the treatment cessation rate.
[Slide.]
Now we come to the first result of the study and the primary result of the study, first graphically, and then analytically.  This depicts the stroke‑free survival over the two years, and we see that roughly 10 percent of patients had a stroke on the combination versus roughly 13 percent on the components.  On placebo, we are down to about 16 percent strokes.
If you translate that into the number of patients who were spared a stroke per 1,000 treated over a two‑year period, this comes out to be 59 spared on Aggrenox, 30 on aspirin, and 26 on dipyridamole.  These are comparisons with  placebo, so roughly 59 to 30, you are roughly sparing twice as many strokes on Aggrenox as on aspirin.  This is just a rough view of it.
[Slide.]
Let's take a look at the primary factorial analysis.  I call it primary because this is the per‑protocol analysis.  In the 3,300 on dipyridamole versus the 3,300 not, we have a 19 percent relative risk reduction, the p‑value 0.001.
With aspirin, 21.2 percent consistent with what we have heard earlier, also even more significant at less than 0.001.  For the interaction, we have virtually nothing, which is consistent with these being additive effects or each of the treatments makes an independent contribution to the combination, but let's look at that more specifically in terms of the pairwise comparisons on the next slide.
[Slide.]
Here, we have the ones that are clearly of greatest interest to this committee, and that is, Aggrenox versus aspirin, Aggrenox versus extended release  dipyridamole.  Both of these showed large relative risk reductions of around 22 and 24 percent respectively, and each was highly significant at 0.008 and 0.002 levels respectively.
Looking at Aggrenox versus placebo, we see approximately a 37 percent risk reduction, and as I quoted to you earlier, this 0.001 is quite misleading.  It is really 1 in 1 million, and we just chopped it off at 0.001.
Likewise, I am not going to pay much attention to these comparisons of dipyridamole versus placebo, and aspirin versus placebo, but both significant.  I will focus on the key points.
[Slide.]
To move on to the robustness analyses, and these have been of some concern also.  The primary analysis p‑values are summarized here.  When we did a Cox‑adjusted analysis for all significant predictors of stroke, we came up with the same results.  When log rank was done it was also the same stratified by center, when we studied investigator‑diagnosed strokes, ignoring MMAG, and so forth, and finally a worst‑case analysis where we imputed strokes to all the people who were lost to follow‑up, again totally consistent results.
[Slide.]
So, my conclusion is that we have answered three of the questions that were posed at the outset, that is, low‑dose aspirin effectively prevents stroke, extended release dipyridamole also prevents stroke and to a roughly comparable degree, and Aggrenox exhibits the additive benefits of its components, and these results are highly significant and robust.
DR. GROTTA:  On the Cox analysis, did it consider the concomitant use of anticoagulants, antiplatelet drugs, that were frequent in your population, although matched among the different groups?
DR. STREET:  No, it did not.  It was only based on baseline characteristics, baseline risk factors.
DR. GROTTA:  You will later show us that the concomitant use of antiplatelet drugs or anticoagulants among your population didn't contribute to these results?
DR. STREET:  No, I would have to construct such an analysis because we believe the ConMed data which only indicated whether or not it was used.  We had no information on dose duration or indication, were not sufficient to make a meaningful analysis.
DR. GILMAN:  This is of concern because more of the patients who received Aggrenox had carotid endarterectomy, some of them had added on aspirin, we don't know what dose, we don't know what percentage of these folks, so that is a question that has arisen in at least my analysis of this.
DR. STREET:  I think what we can do is we will‑‑  can we bring that back to you after the break because it would require a little work?
DR. GILMAN:  Please, yes.  We appreciate that, yes.
[Slide.]
DR. STREET:  Summarizing the secondary endpoints, this is a very important slide I believe to ESPS‑2.  I have got the four prespecified endpoints, I have stroke across the top.  Here, everything is put in terms of odds reductions just for consistency of presentation.  Results are similar to risk reductions.
What I want to note is that the effect on TIA was roughly the same size as one would hope as that on stroke, and it was also of comparable significance.  We see the effects of both components, their additivity, in the small group of 148 patients who had other vascular events, deep vein thromboses, and so forth, we see a similar effect, 40 percent on dipyridamole, 34 percent reduction aspirin, and fully 62 percent on the combination.
Ischemic events, which include stroke, MI, and sudden death, are naturally the mirrors of the stroke results because the stroke results dominate that endpoint, it is not just completely distinct information.
Finally, for MI, we see aspirin 21 percent risk reduction, not significant.  Similarly, 23 percent risk reduction on Aggrenox, also not significant as one might expect in a study like this, because these would be very low‑powered comparisons.
[Slide.]
In conclusion, I guess I have really stated the conclusions.  We have two very important endpoints which are distinct from the stroke endpoint, which internally confirm the reality of the efficacy on the stroke endpoint, and acute MI showed a positive trend on Aggrenox and on aspirin.
[Slide.]
Now, I turn to patient survival, the other primary endpoint, and we already looked at this curve, and I tried to tell you the numbers saved per 1,000 treated, and now I have them in front of me.  There were 11 per 1,000 on Aggrenox, 13 on aspirin, and 9 on dipyridamole, all closely comparable.
[Slide.]
The factorial analysis showed nothing of significance, small effects both of dipyridamole and aspirin, and no evidence of interaction.
[Slide.]
Pairwise comparisons, again, nothing statistically significant, but I would like to draw your attention to two lines, that is, Aggrenox, which is our drug, 9.2 percent relative risk reduction, comparable to that seen on aspirin in mortality with an 11 percent reduction, neither effect significant.
[Slide.]
So, for the death endpoint, to conclude, no statistically significant risk reductions, roughly 10 percent risk reduction on Aggrenox, is comparable to that of aspirin alone, and I say that these risk reductions are comparable to those that have been shown earlier today‑‑well, maybe they haven't been‑‑in meta‑analyses of placebo‑controlled studies of aspirin in this type of patient, stroke or TIA patients.
[Slide.]
Now we come to the nonfatal stroke or death results.  The lesser magnitude in statistical significance of this than the results for stroke, result from diluting the substantial additive effect which we saw on stroke with the modest equivalent effect on reduction on death between Aggrenox and aspirin.
So, what we see is the same general pattern of curves here with Aggrenox superior to the other curves, but not by as clean a line, all of them superior to placebo.  This is the dipyridamole in orange.  It takes a little longer to get into the act.
Now, I just want to caution you about the label.  When I call it a primary factorial analysis, it is a primary method of analysis, not a primary endpoint.  When we look at this, we do see some very strong effects on our composite endpoint.  We have a 14 percent relative risk reduction on dipyridamole, highly significant at 0.003; similarly, 12.2 on aspirin, 002, with again no evidence of interaction.
[Slide.]
Taking a look at the pairwise comparisons, we have Aggrenox versus aspirin, 12 percent reduction, not statistically significant, 0.084; Aggrenox versus dipyridamole, 10.3 percent. 0.079.
But I think the most impressive line of this table is for our compound, and that is Aggrenox versus placebo where we are seeing a full 24.4 percent on the combination, and this is statistically significant at the 2 in 100,000 level, 0.00002.
So, we do have, though not significant contributions, we do see a nice additive effect as earlier seen in the factorial analysis.
[Slide.]
So, for nonfatal stroke or death, I will just restate it because it is very important to the debates that are ongoing.  Highly significant efficacy of both dipyridamole and aspirin were shown in the factorial analysis, and we saw additive efficacy in Aggrenox.
The pairwise comparisons showed a 24 percent risk reduction on Aggrenox versus placebo, but only favorable trends on Aggrenox versus its components.
So, this brings me to my conclusions.
DR. GILMAN:  Just before you do that, Dr. Street, could I just ask, isn't it the effect on stroke that really carries the day for this?
DR. STREET:  Yes, definitely, no question.
DR. GILMAN:  So, you are showing essentially the same thing with effect on stroke as you are on nonfatal stroke or death, but it is all stroke.
DR. STREET:  But it is diluted, but it is diluted by the lesser effect.  You are combining a sensitive endpoint with an insensitive one, and one that normally requires meta‑analyses, such as Peto performs, to see effects.
DR. GILMAN:  Yes. So, the effect is on stroke, and not upon death, and when you combine the two, you still get highly significant effects because of the robustness of the effect on stroke.
DR. STREET:  Yes, you get highly significant effect in the primary factorial analysis, establishing they both work in that indication.  They also are completely consistent with additivity.
So, from that analysis, one would tend to draw the conclusion that yes, Aggrenox inherits the benefits of both components, but I just want to make it clear because it is very easy to get confused between all the various analyses I have presented today.
[Slide.]
Finally, just a word on the efficacy conclusions, and I will stop.  I have shown that Aggrenox is significantly more effective than aspirin alone and dipyridamole alone in reducing the risk of stroke in TIA and ischemic stroke patients.
Moreover, we believe that this conclusion is based on reliable, well‑controlled, and generalizable evidence, and satisfies the FDA requirements or guidelines for approval of single study NDAs.
First, it is a large multicenter trial, the largest single stroke prevention trial in TIA and stroke patients ever conducted, with 59 centers.  It had a factorial design which was able to demonstrate the effectiveness, not only of the monotherapies, but in view of the absence of interaction throughout the efficacy data, additive effectiveness of the combination.
Another requirement is the results, I think are very statistically persuasive in that they stand up to just about any reasonable test we throw at them, even a worst case analysis, and consistency is seen across subgroups, although not shown directly in my presentation, it is even longer than it is.
Finally, I want to reemphasize that we saw on distinct endpoints, OVE and TIA especially, very strong effects, which to me have an internal confirmation, if not an external confirmation.
I want to thank the committee for your attention.
DR. GILMAN:  Thank you for that clear presentation.
Dr. Brooke.
DR. BROOKE:  That is a very interesting result, and I wonder.  It's odd that you are having such a positive effect on stroke and yet death is not affected.  It would suggest that they are being killed by something else.
But I wonder, we always have a problem.  You would think that a neurologist could define death, but we always have a terrible trouble with defining death, and I wonder how you define death in your study.
The reason I ask is that neurologists sometimes take patients with strokes who would have died and put them on artificial life support in intensive care where they may survive for weeks or sometimes months.
I wonder how that figured into your endpoint definition.
DR. HAEHL:  I have to admit I was talking about administrative issues, so I cannot answer your question at the moment.  So, could you please‑‑I hear Dr. Pathy is willing to answer your question.
DR. PATHY:  There were no patients on life support machines that was reviewed by the MMAG.
DR. GILMAN:  Dr. Grotta.
DR. GROTTA:  Again, as a neurologist, I want to be reassured about the validity of the strokes as endpoints.  I also want to be reassured about the validity that the patients that were put into the study really did have TIAs or minor strokes, and maybe we could address that for a minute.
What percentage of your patients had CT scans to exclude other diagnoses, such as cerebral hemorrhage or other conditions that might mimic a stroke, and what were the time periods that those CT scans were carried out, and who made the diagnosis of stroke or TIA, and what were the criteria or definitions of TIA or stroke that a patient had to meet in order to get into the study, recognizing, as with the previous question, that this randomization should take care of this to some extent, but nevertheless, you know, junk in, junk out, you just want to be sure that these were stroke patients and that they, in fact, did have strokes.
DR. EASTON:  Speaking as a neurologist, it isn't junk in and junk out.  What came out is actually very positive.  It would strike me, though, Jim, wouldn't it, that if you are putting in migrainers, they are benefiting, too.  If you are putting in brain tumors, they are benefiting, too.
In other words, it would seem to me that that would take things in the other direction.  We can find out precisely sort of how that was done, but I would think this would be an especially germane question had it gone the other way, but here actually, whatever it is they are treating, it certainly works.
DR. HAEHL:  And there have been analyses done, and it doesn't quite answer your question as to how that was established, whether Rankin scale or other gradings of the qualifying stroke that influenced the result, and it did not.
I wanted to come back to your earlier question.  You were interested to see the case report form for the assessment of stroke as an endpoint, and I have overhead copies produced of that in the meantime.
DR. GROTTA:  Good, but I would still like the question answered about whether CT scans were done on these patients, when they were done, and what the definitions were of TIA and stroke for inclusion in the study.  I recognize what Dr. Easton said, and it is true.  I would be more concerned if it were a negative study, but nevertheless, I think it is still relevant to know who was put in the study.
DR. KATZ:  Just to sort of follow up on that, right, generally speaking, we would think that any heterogeneity of diagnosis would tend to obscure any drug effect if there was one, so I don't think it is that so much, but you have got to remember if the drug is approved, labeling has to be written.  I don't think this is really going to be a big problem, but if they are giving it to migrainers, and it is helping them, then, the drug would be labeled for preventing stroke and migrainers, so you want to know who you are dealing with, so I think Dr. Grotta's point is well taken.
DR. HAEHL:  We will come back if that is acceptable to you after the break and bring you the definitions of the entry criteria.  Are you interested in the case report forms issue?
DR. DRACHMAN:  The stroke or death, is the death merely bath water, in other words, was that merely thrown in?  Were there stroke or cancer, stroke or acne, would the data have been just as positive for both or those, or how do you remark that?  Do you regard that as being part of the real answer, should we view it that way, and just say stroke?
DR. HAEHL:  We have a significant result for stroke, and we have an endpoint which is very much related with the outcome of stroke, and that is death, and it has been established for aspirin, that aspirin does have an impact on death, and therefore in the situation where you have an approved dose of aspirin in your treatment regimen, we felt that it is consistent to investigate and to test whether the results of ESPS‑2 actually add up to this prior experience and are consistent with the prior experience, and as you have seen, it is, and we think that is different than just bath water.
DR. GILMAN:  But it is not different.  It is not true.  There was no change with respect to death.  There is no significant effect upon death.
DR. HAEHL:  There is no significant effect on death as opposed to stroke, however, the trend observed is consistent with the individual trends in aspirin trials, and is consistent with the summary, and we can show a slide to that.
DR. GILMAN:  We are seeking statistical evidence for the allegation that there is an effect upon death.
DR. HAEHL:  Yes, which is also true for aspirin.
DR. PENN:  The fact that we don't have good data for aspirin does not help us in this case.  I mean just because maybe a mistake was made in labeling aspirin does not help us say that we should make the same mistake in this labeling.
It seems to me your statistics, if anything, are diluted by adding death as was clearly outlined to us, so what is the compelling reason to this committee to include death?  We need a very strong reason other than somebody else included death in an aspirin study that there was only a trend in.
DR. HAEHL:  The question for us is if we were to administer aspirin 50 mg daily in patients after TIA or stroke, we would expect from the label a reduction or an impact on mortality.
Now, if we take that same tablet together with dipyridamole, and we have compelling evidence I think from the results presented that there is consistency between the aspirin in Aggrenox and the aspirin which you can buy individually, we would find it very strange and not to say confusing for both the patient and the treating physician that one formulation would reduce mortality and the other wouldn't.
DR. GILMAN:  We are not getting a clear answer to the question.  You are making presumptions not based upon the data.  The data do not show a beneficial effect upon death.
DR. HAEHL:  The data did not show a significant benefit, they showed a trend which is consistent what has shown for aspirin trials individually.
DR. GILMAN:  We have a lot of people that want to speak.  Bob Temple, Robert Califf, Marvin Konstam.
DR. TEMPLE:  The aspirin labeling at least partly reflects results of meta‑analyses of controlled trials that do show a small benefit of aspirin on survival.  So, when that labeling was written, that was taken into account.
It does seem an interesting dilemma that this product contains aspirin, and therefore one would imagine it would have the usual aspirin effect even though the study didn't show anything.  I don't have the answer to the dilemma I should tell you.
DR. CALIFF:  My reasoning and for feeling quite difficult than obviously most other people on the panel about this is for a different reason, which is that you cannot ascertain the effect of a drug on stroke if a large number of people died and you don't know why the died, because you have a lot of people who are likely to have had a stroke, who are dead, and therefore you can't assess whether they had a stroke or not.
So, the normal course of events in cardiovascular trials now is to prospectively declare the composite as the primary endpoint, because when you say we are assessing the effect of a drug on stroke, but we are going to ignore people who are dead, you can't do that.
DR. GILMAN:  You mean because they died, they didn't have an opportunity to have a stroke.
DR. CALIFF:  Well, they may have had a stroke and you don't know it.
DR. GILMAN:  But the committee did look at the cause of death and ascertained it as closely as possible.
DR. CALIFF:  But the cause of death is‑‑well, I don't want to say silly‑‑but what did all those people who had sudden death die of?
DR. GILMAN:  We have heard a variety of causes.
DR. CALIFF:  That's my point, you know, one of the main ones of which would be occlusion of an artery to the brain.
DR. KONSTAM:  To me there is two separate things going on.  One is I think at the end of the day, we are going to have to grapple with are we going to prove it and specifically for what, and so that is when this really is going to come up, and Bob spoke to this dilemma before, which is that you have a combined endpoint, and the combined endpoint is positive, but death is not, so we will have to deal with what the wording is, but I think Rob's point is that it is important to look at this combined endpoint, to look to see that the combined endpoint is, in fact, positive, because if it weren't, you would be worried that there is some fluky reason why the strokes were positive.  So, I think it is very important to look at that endpoint.
But I have to say I am confused about why deaths‑‑and maybe Bob said it‑‑why deaths is not positive.  This is where I think I would like the sponsor's help, because it isn't that the numbers of events were small because the number of death were actually substantial, so you can't say, well, okay, but the number of events was substantial.
I guess I share Rob's lack of interest in general in cause of death, but I actually would like to see it here, and I would like to see a table showing cause‑specific deaths across the different groups, because I am just wondering whether there is not some signal in there, that there is something negating the anticipated positive effect on death.
Several people have said it, and I guess I concur, I would like to see that.  Are we going to see it?
DR. EASTON:  I can make a copy of the table that I was reading before the panel, or just give them this.
DR. KONSTAM:  Does it show it across the different  treatment groups, because you mentioned the numbers?
DR. GILMAN:  Could you use the microphone, please, Don.
DR. HAEHL:  We don't have this provided.  We would have to take a copy.
DR. GILMAN:  It is really going to be important that all of us hear what you are saying and what you are reading, so could you just read it into the record.
DR. EASTON:  I would just say that if you would like copies of that, I would certainly see that that gets taken care of.  What it lists them is by the four groups, then, the summary.
DR. GILMAN:  We have something to show.  Good.
Let's look at the overhead.
[Slide.]
DR. FARRELL:  I am Dr. Farrell.  This is just a table produced from the clinical trials report showing mortality.  Qualified stroke are the individuals who died within the first 30 days.  The endpoint of stroke are those individuals who died of failed stroke, and then I continued on in the table those who died of myocardial infarction, cardiac failure, sudden death, vascular events, infection, bleeding, and other causes, just to show that there appears to be no difference for any form of mortality.
DR. KONSTAM:  I guess the striking thing is that there are a lot of noncardiac‑‑well, there aren't a lot of noncardiovascular deaths, are there?
DR. FARRELL:  No.
DR. KONSTAM:  So, if you added up all the cardiovascular deaths, there is still nothing, right, there is not even a hint of an effect in either of the treatment  groups on cardiovascular death.
DR. CALIFF:  Just a point here, if I may, on that issue.  You have two endpoints, one of which is much more common than the other in the population.  Even if the treatment had the same effect on both, you have got for the less common endpoint, a higher probability that you will see‑‑
DR. KONSTAM:  I am not sure that is true, Rob, though.
DR. CALIFF:  It is definitely true.
DR. KONSTAM:  No, no, the first statement that stroke is much more common than death.  I mean it isn't in this population.  It is just not true.
DR. CALIFF:  So, how many stroke endpoints were there?
DR. KONSTAM:  I mean the fatal and nonfatal stroke, it is running about, you know, a little over 200 per group, and the death is running a little 200 a group.  That is the point, it is not a major difference.
DR. CALIFF:  You are right.
DR. GILMAN:  Well, we settled that.
Dr. Temple.
DR. TEMPLE:  This is a good question, and I certainly don't have an explanation, but it is not unprecedented.  The aspirin trials, all of which were able to nicely show reduction in MIs, were uniformly unable to show improved survival for reasons that have never been quite clear.
The most striking example I know of is Charley Hennekens' study which reported‑‑of course, this is only one study, and there is a British study that sort of went the other way‑‑reported a 50 percent reduction, 50 percent reduction in nonfatal MIs and fatal MIs, but there are only a few, and survival was dead even, so to speak, which really makes just no‑‑it just makes no sense.
It could mean in his study there was at least a hint that there were more sudden deaths in the treated group, and maybe that was it, but you never could figure it out, but the aspirin history is if you take an overview, you find a smaller effect on deaths, but the individual studies, which are plenty large enough to show MIs, never show it and I don't think anybody knows why.
DR. HENNEKENS:  I think Dr. Temple makes an important methodologic issue in all the cardiovascular trials, and in the aspirin areas we see 30 to 40 percent reductions in the nonfatal events with aspirin and 10 to 15 percent reductions in deaths.
Furthermore, in the trials that accumulate a sufficient number of endpoints‑‑and our trial did not, our trial was stopped early, because of the MI finding we didn't have enough deaths.  We needed about five times the number of deaths to really find anything.  But they come later, as well, and I think this is a problem, and if we look at the aspirin data right now, now there are four primary prevention trials ‑ the HOT study, Tom Meade's thrombosis prevention trial, the British Doctors' trial, and the U.S. Physicians looked at an aggregate.
There is a p less than 1 in 100,000 benefit on MI of a third or more, and yet, there is still no significant effect on deaths in primary prevention.  In secondary prevention, 30 to 40 percent reductions in the nonfatal endpoints of MI and stroke, 10 to 15 percent reductions in death, which was significant, but they are not nearly as significant or extreme both in magnitude or statistical significance, and I think that this is not that surprising in that context in my view.
DR. GILMAN:  Dr. Grotta.
DR. GROTTA:  I guess I don't have as much trouble at least understanding why the drug doesn't have an effect on death that is all that obvious.  In stroke patients at least, the major determinant of whether a patient dies of the stroke is the severity of the stroke.  Patients who don't have very severe strokes generally have a much lower mortality rate.
I remember‑‑maybe you could clarify this‑‑but I remember in a presentation of these data at a meeting, although I have not seen this published, that the drug did not have an effect on the distribution of stroke severities, so that you are reducing the absolute number but not adjusting the severity of stroke.
So, maybe that is an explanation for why we don't see a major impact, that we can reduce the number of strokes, but not reduce mortality in this population.
DR. HAEHL:  There was a nonsignificant minor shift towards minor strokes over the treatment groups and away from major strokes, and that will be shown later.
DR. ALBERS:  I just want to say from the clinical point of view, I think that what the stroke patients are most concerned about is winding up with a disabling severe stroke, but death in general is thought to be less severe an outcome than winding up severely disabled in a nursing home, and when the severe strokes were looked at, there was a substantial benefit, and I think that may mediate a little bit of the death issue.
DR. GILMAN:  Dr. Konstam.
DR. KONSTAM:  I would like to just pose a hypothesis about what it is, which is that I guess it is only a percentage of cardiovascular events that are fatal, so you are collecting a number of cardiovascular events in the course of a study, and some minority of them I guess are going to be fatal, but then there are people dying, and I guess that they are dying in association with cardiovascular events that had occurred years ago.
So, somebody who has had an MI, you know, five years ago, before they entered the trial, is more likely to die during the course of the study than somebody who hasn't, and that is not going to be impacted by your drug, because you drug is not going to affect an MI that occurred before the trial started.
So, I think maybe the hypothesis is that deaths is harder to influence because there are events that have occurred before that you can't influence.
DR. DRACHMAN:  What about the dose of aspirin, the reduction of death was with much larger doses, was it not?
DR. GILMAN:  Dr. Temple.
DR. TEMPLE:  The original six trials that we used to approve the reduction in MI, probably reduction in MI plus death because we used the combined endpoint, mostly five out of six of them I think used doses of a gram per day, and had the same weak to none effect on survival.  There is no clear evidence that dose matters.
The disease matters though.  If you take people with unstable angina, you can show a nice effect on survival.
DR. GILMAN:  Dr. Haehl, did you want to show the form that you used for stroke?
DR. HAEHL:  The case report form you requested, yes.
DR. GILMAN:  Yes.
[Slide.]
DR. HAEHL:  This is a three‑page form photocopied out of the case report form to assess stroke as an endpoint during the course of the trial.
You can see the description of new stroke at onset, the description of motor power‑‑well, first of all, the date, the duration of symptoms, motor power, left, right, sensation.
[Slide.]
Other symptoms, etiology of stroke, location of the lesion, if performed, what neurological and other investigations supporting the diagnosis, CT scan, NMR, doppler, angiography or others, and comments, if necessary, and the last page.
DR. BROOKE:  These are descriptive features.  Was there a true inclusion form where, you know, you had to have four of the five features, or something like that, or was it just purely a description?
DR. HAEHL:  No, I am now talking on stroke as an outcome, as an event.  That is the assessment of the events, what was asked for, how did we assess if a patient had a stroke in the periphery.
DR. BROOKE:  I am sorry, I misunderstood.  I thought you were talking about the inclusion to the study.
DR. GILMAN:  This is purely descriptive.
DR. GROTTA:  So, how often were patients seen in the course of the study on a routine basis?
DR. HAEHL:  Every three months with the exception of the first month.  There was one after one month, and then every three months.
DR. GROTTA:  So, this form was filled out, then, by the local investigator, and each and every time a stroke was identified at a local site, then, it was adjudicated by the Central Committee.
DR. HAEHL:  Right, on the basis of this form and further data.
DR. GROTTA:  And other data, such as scans and things like that.
DR. GILMAN:  It is 1 o'clock.  We have successfully gotten ourself about three and a half hours behind schedule, but that's okay.  We are getting our questions answered.
So, let's take about an hour for lunch and resume here at 2 o'clock.  Let me caution the committee not to discuss anything related to this drug over lunch.  All discussion should be in public.  So, please don't talk about this drug, and there is a place in the restaurant next‑door for the committee members.
[Whereupon, at 1:00 p.m., the proceedings were recessed, to be resumed at 2:00 p.m.]

AFTERNOON PROCEEDINGS
[2:00 p.m.]
DR. GILMAN:  I think we should proceed.
Dr. Rakowski, would you start, please.
DR. RAKOWSKI:  Thank you.
Safety
DR. RAKOWSKI:  Good afternoon.
[Slide.]
My name is Ken Rakowski.  I am responsible for drug safety and information at Boehringer Ingelheim.
[Slide.]
Members of the committee, one safety question was posed to you by the FDA, and it is all‑encompassing:  Are there any particular safety concerns with the use of Aggrenox?
This portion of the presentation is intended to try to provide the pivotal information to allow you to assess that question.
[Slide.]
If we could summarize briefly what we do know about Aggrenox, three things would become evident.
One, there are no unexpected adverse events with Aggrenox.  This isn't really unexpected in the sense that you have a product with two components, dipyridamole and aspirin, that are well characterized compounds with well delineated safety profiles.
Two, the expected adverse events are established for the two compounds.  This truly is a phenomenon of what you are getting is what you have seen with the components.
I think you will notice that as I go through the subsequent slides with the data, I will show you the similarity of AE reporting patterns between Aggrenox and the appropriate component.
Three, I think the data will hopefully lead you to the conclusion that the benefit/risk assessment is favorable.
[Slide.]
If we start with a somewhat busy slide, but one that I think will put things in perspective, these are the on‑treatment adverse events with an incidence in the Aggrenox group exceeding that in the placebo group by 1 percent or more.
I think, cutting through all the data, focus in on the total number of patients with AEs and you will see a remarkable similarity and balance across the groups.  The highest number of total AEs occurred in the aspirin group, the lowest number actually occurred in the dipyridamole group.
If we look at headache, you will see some similarity between the experience with the dipyridamole component and the dipyridamole‑alone group and the Aggrenox group, and likewise, that holds true when you look at the gastrointestinal disorders as a whole with similarity between the dipyridamole group and Aggrenox.
If we focus in on the bleeding disorders, however, the parity seems to be between the aspirin group and the Aggrenox group, and likewise, with anemia, there is similarity between the aspirin group and the Aggrenox group.
DR. GILMAN:  Before you go on, I am struck that there is almost equal incidence of headache in the aspirin group as the placebo.
DR. RAKOWSKI:  Aspirin and placebo are very, very similar.
DR. GILMAN:  Pretty close, but‑‑
DR. RAKOWSKI:  And when I take you through a factorial analysis, which you can analyze for the contribution of a component to an AE, I will show you that the relationship with aspirin really appears to be a dipyridamole effect.
[Slide.]
If we look at the incidence of most common adverse events associated with treatment cessation, I think, relative to your point, you will find that there starts to be some differences between the groups.
The placebo group had a 21 percent discontinuation rate, the aspirin group discontinued at 19 percent, but there is remarkable similarity between the Aggrenox and the dipyridamole groups.
The most common events, headache, dizziness, and nausea again seem to be very compatible between the dipyridamole treatment and the Aggrenox treatment group.  If you really look at the slide and scan it quickly, you will find there is a consistent pattern that tends to emerge.
[Slide.]
We looked at potential interactions and we looked at drug to disease and drug‑demographics interactions, if the committee will bear with me, let me read this because I will be sure I get it right this way.
For the drug‑disease interactions, we basically analyzed for baseline TIA and stroke prior to the qualifying event, ischemic heart disease, peripheral vascular disease, previous cardiac failure or myocardial infarction, hypertension and baseline blood pressure, cardiovascular disease, hypercholesterolemia, diabetes, and arrhythmias.
Looking at the demographic interaction analyses that were performed, the areas were analyzed by geographic region, age bracket, gender, weight bracket, type of qualifying event, and the severity of the resulting handicap, and the consumption of coffee, alcohol, or cigarettes.
I think the slide clearly conveys that no clinically significant differences were evident in any of the interactions performed.
[Slide.]
Laboratory analyses were also performed.  Laboratory data was collected at baseline, one year, two years.  It was analyzed for hematology, indices of renal function, abnormalities of liver function, fasting glucose, cholesterol, and LDL cholesterol.
There were no clinically significant differences or effects demonstrated in any of the groups.
[Slide.]
Relevant to your question, if we look using the factorial analysis method to try to look at the contribution of a component to the occurrence of an adverse event, what you really see here is that, by a factorial analysis, the headaches, the gastrointestinal events as a whole, the nausea, diarrhea, and vomiting, appeared to be related to the presence of dipyridamole in the product.
The bleeding events obviously tend to be related to the presence of aspirin in the product.  Ulcers, although didn't show statistical significance, trended towards the expected association with the use of aspirin.
[Slide.]
I think if you ask the logical clinical question with the use of any antiplatelet agent, it is going to be what is the risk of bleeding with this compound.
This slide presents the incidence of on‑treatment events and focuses in on the bleeding events and the ulcers.  I think if you really look‑‑again, there is a lot of specific events provided‑‑but I think I would focus in on the overall occurrence of bleeding events, and notice the similarity between the placebo and the dipyridamole group in terms of the event rates for bleeding, and notice the similarity between the aspirin group and the Aggrenox group for the overall bleeding event rates.
Likewise, if we look at the ulcers, you will find the similarity again holds up between the aspirin‑alone group and the Aggrenox group.
[Slide.]
Focusing in on the serious adverse events, we start to see a little bit of difference that I think is fairly easily explainable.  I think the first thing you need to note is that the total number of serious adverse events actually occurred in the placebo group.  In an endpoint study as we discussed this morning, where you have a high probability that your endpoint stroke is going to be categorized and captured as a serious adverse event, I don't think that is unexpected to anybody.
The lowest actual raw number and the lowest percentage of total SAEs occurred in the Aggrenox group.
When we look at the total number of bleeding events, the numbers get small and we are now into the actual case‑specific numbers.  Placebo had 11 total bleeding events.  There were 17 in the aspirin group and there were 25 in the Aggrenox group.  The 25 comprises 1.5 percent as a total rate of the identified codes.
Although the contribution of each of the codes, the numbers are low and the contributions small, but the biggest contribution is made with melena and gastrointestinal bleeding.
Going down to the ulcer group, we see again numerical differences with the Aggrenox group having 7, 5 in the aspirin group.  Honestly, you know, when you don't power a study for safety endpoints, it is hard to put clinical significance to these findings in the sense that obviously, there is an uncommon, relatively low rate of overall bleeding events.  They are not statistically significant, but there is a numerical difference between the groups, and I think the clinical significance is still undetermined.
[Slide.]
If we look at the on‑treatment deaths, focusing just on the gastrointestinal bleeding and ulcers, we again see a numerical difference.  What is surprising to me at least in our table is zero for the aspirin group, 5 for Aggrenox group.
I think to put this finding into perspective and try to balance it, let's look at the total number of deaths across the group, and if you look at on‑treatment deaths, and here they were defined as a death that occurred on treatment or within 30 days of discontinuation of the treatment, the highest number of deaths occurred in the placebo group, the lowest number of deaths occurred in the Aggrenox group.
[Slide.]
In conclusion, we feel that ESPS‑2 clinical data supports the safety of Aggrenox.  There were no unexpected adverse events observed with the combined use of extended release dipyridamole and aspirin.
[Slide.]
The dipyridamole‑related adverse events are primarily headache and gastrointestinal and again as I think we all expect with that product, with that component, and the aspirin‑related groups are primarily bleeding events as expected.
[Slide.]
Serious adverse events of potential clinical significance other than stroke, as you can see from the GI analysis, are really relatively uncommon.
There were no demographic or disease‑related factors identified.  We believe that the data demonstrates the safety of Aggrenox when taken as directed, and I know a lot of contention about the endpoints, but given the benefits that were really explained this morning by Dr. Street, we do feel that it is reasonable to reach a conclusion that the benefit/risk assessment for Aggrenox is favorable.
Thank you very much.  I will turn it over to Dr. Haehl.
DR. GILMAN:  Let's see if there are any questions for you before you leave.
Any questions about safety?
[No response.]
DR. RAKOWSKI:  Thank you.
DR. GILMAN:  All right.  Thank you.
Dr. Haehl.
DR. HAEHL:  Mr. Chairman, we had some questions in the morning where we tried to collect answers.  One question was as to the diagnosis of the qualifying event.
A side remark to the qualifying event should be misdiagnosis between stroke and TIA in a randomized trial, placebo‑controlled and randomized, we would expect that this would work against the efficacy, showing efficacy, and underestimate a benefit should there be one.
So, we believe that in this trial, the possibly available or present degree of misdiagnosis like in any trial would not impact positively at least on the result and on the findings.
[Slide.]
This is a photocopy out of the report where it is described how the definitions for the qualifying events were.  I can read through that.
TIA, a focal disturbance of the cerebral circulation resulting in a clinical neurological deficit that completely resolved within 24 hours.  That was with functional sequelae.
Stroke, a focal disturbance of the cerebral circulation resulting in a clinical neurological deficit lasting more than 24 hours.
RIND defined in between.
These criteria were valid with no upper age limit or limitations in sex, number of previous neurological events, or the specific circumstances of the patient care after the qualifying event provided that neurological and general clinical condition was stable and not evolving.
The diagnosis of the qualifying event was made prior to inclusion by clinical neurological examination for neurological signs by the date of event, the evidence that the CVA had stabilized and by CT scan.
Also, optional disk examination was strongly recommended to confirm the ischemic origin of the CVA and to exclude other possible causes of the symptoms, such as tumor or intracranial hemorrhage.
The CT scan was performed in order to confirm to confirm the qualifying CVA.  An absence of CT scan abnormalities was not regarded as an exclusion criterion, and as an additional information, 80 percent of patients had such a CT scan.
The next question was did the qualifying event have impact on the outcome.
[Slide.]
Here, we have those patients with qualifying stroke, and you have the odds reduction in the factorial design for dipyridamole versus no, with 14 ASA with no, with 26, and then compares Aggrenox with placebo with 37, and if you take the group which had as a qualifying event TIA, then, these numbers are comparable, certainly not different.
[Slide.]
Just for your information, the composition of the Ethics Committee that accepted the changes or the increase of sample size.
[Slide.]
The next question is the interim analysis, and there I would like to ask Dr. Street to present that.
[Slide.]
DR. STREET:  This is from the ESPS‑2, November 1991 interim analysis report.  At the time, there were 3,994 patients followed for an average of 10.6 months, and here is the statistician's summary statement from the report.
For what concerns survival, no statistical test is presented as agreed upon by the protocol.  The signification level of 1 per 1,000 is never reached.  The overall impression that can be derived from the study of the survival functions for the endpoint is that the four groups are different, and no two groups seem to cluster as being identical.
Now, let me show you the data which he presented at that time.
These are the numbers of endpoints, and these endpoints mean here the composite of stroke or death, and it shows them both at 12 months and 24 months, and down below here you have some estimation of the size of the groups.
Now, the 4,190 versus the 3,994, that is a little hard to explain, but it is the survival analysis.  That is how it was taken into account.  Very few patients had reached the full duration of study, and this is the kind of presentation that was made on all the tables.  They were tr, 1, treat, 2, treat, 4, and so forth, and those were randomly permuted between each and every figure.
So, his conclusion was simply this group seems better than this, and none of them seemed to be clustering, so that is the conclusion he drew from the study.  Then, he re‑ran his sample size program and reestimated the same sample size.  That is nature of the information.
Conclusion
DR. HAEHL:  With this, I would like to come to our conclusion.
[Slide.]
Members of the committee, we have reviewed a lot of information and we have made an attempt to provide you with a broad understanding of both the science and our rationale for the development of Aggrenox.
We certainly do realize‑‑and that was reflected by the agenda this morning‑‑that an important NDA like this one necessarily also has to raise important and relevant questions, and we do hope that with the data presented we could show that there are clear answers to those questions.
Therefore, to complete the remarks I would like to propose to you our perspective relative to the data presented, and I would like to propose the following conclusions, and I would also like to have the pointer back.
[Slide.]
Aggrenox represents a therapeutic advance to the secondary prevention of stroke that builds on the vast clinical experience with its components.
The findings, both ex vivo and in the clinic, are consistent with additive beneficial effects of aspirin and dipyridamole.
[Slide.]
ESPS‑2 provides compelling evidence of the safety and efficacy of Aggrenox that can be generalize to general practice.
ESPS‑2 is robust and eliminates concerns regarding chance or bias as a basis for the findings.
ESPS‑2 meets the requirements for a single trial to support approvability of a product.
[Slide.]
The factorial and pairwise comparisons support the conclusion that in the second prevention of stroke, Aggrenox is significantly superior to aspirin or to extended release dipyridamole alone and has a favorable benefit‑risk ratio.
[Slide.]
This is reflected by the fact that with Aggrenox, 59 stroke events per 1,000 patients treated for two years versus 30 events prevented per 1,000 patients treated for two years with aspirin versus 26 events prevented per 1,000 patients treated for two years with dipyridamole.
[Slide.]
Mr. Chairman, after the discussion  of this morning, I take a big breath, and still I would like to propose to you the conclusion that based on the positive trend for a mortality benefit, which in our opinion is consistent with the aspirin label and on the basis of the inclusion of an FDA‑approved daily dose of aspirin, it is appropriate from a scientific and regulatory perspective to afford Aggrenox the same label indication as aspirin.
[Slide.]
And ESPS‑2 establishes Aggrenox as first line therapy for secondary prevention of stroke and its labeling should describe its superiority to aspirin.
[Slide.]
With this, I would like to thank the panel again for giving us the opportunity to present, for listening, and to give us your advice, and my colleagues and I continue to be happy to answer any questions.
Thank you very much.
DR. GILMAN:  Thank you, Dr. Haehl.
Any questions from the panel for the sponsor?
[No response.]
DR. GILMAN:  Is the sponsor content that you have presented all the data that you wish to present to us?
DR. HAEHL:  Yes.
DR. GILMAN:  Thank you.
I will break up the flow now by asking that we turn into a public hearing, an open public hearing, so that those people who had come here particularly to address the panel can have an opportunity to do so.
We will wait to hear the FDA's presentation and hear from the public.
Dena Van Husen, Senior Vice President of the National Stroke Association, Englewood, Colorado.
Open Public Hearing
MS. VAN HUSEN:  Thank you, Mr. Chairman, members of the committee.  My name is Dena Van Husen.  I am the Senior Vice President of the National Stroke Association.  On behalf of our entire organization, I thank you for the opportunity to talk to you today briefly about stroke.
The National Stroke Association devotes 100 percent of its resources to stroke.  We have been providing educational information to stroke survivors, caregivers, the general public, stroke at risk, and a broad variety of medical professionals since 1984.
Our mission is to reduce the incidence and impact of stroke by changing the way that a stroke is viewed and treated.  Our efforts cover stroke prevention, treatment, rehabilitation, and research.
I am here today to encourage you to accelerate the approval of all compounds that are found safe and effective for preventing strokes, treating strokes, helping in stroke recovery.
The National Stroke Association strongly supports the development of new medications because there are so few options available for treating stroke.
As you know, over 730,000 Americans experience a stroke each year in the United States.  That is one stroke every 45 seconds, and 160,000 people die from their strokes annually.  There are 4 million stroke survivors in the United States.  One‑third of stroke survivors are left with very serious impairments, and everyone who has a stroke is at greatly increased risk of having another stroke.
Stroke is devastating to the individuals and families both emotionally, financially, and strokes can affect anyone.  Strokes can no longer be written off as a disease of the elderly.  One‑third of strokes happen to people under age 65.  As the baby boomer population ages, stroke is expected to become even more prevalent.
May is National Stroke Awareness Month.  In three days, the National Stroke Association will launch one of its most significant public education efforts ever.  Former President George Bush, who has atrial fibrillation, which is the leading risk factor for stroke, will tell the nation through public service announcements to "Be Stroke Smart."
Research and identification of new drug therapies is pivotal in the management of stroke, and we honor the researchers who dedicate their days to finding new breakthroughs for stroke.
Should the Advisory Committee find any compound submitted for approval to be effective and safe, we encourage the committee to recommend its rapid approval, so that it can be made available for those at risk of stroke and to those who may experience or survive one.
Thank you.
Now I would like to turn the podium over to Dr. Phil Gorelick, who is the Chairman of the National Stroke Association's Prevention Advisory Board.
DR. GILMAN:  Dr. Gorelick.
DR. GORELICK:  Mr. Chairman, ladies and gentlemen, I am Dr. Phil Gorelick, Director of the Center for Stroke Research in Chicago.
My professional and research interests are the prevention of primary and secondary stroke.  I administer NIH funded research projects on stroke prevention and have particular expertise in the efficacy of antiplatelets in secondary stroke prevention in African‑Americans.
Today, I speak on behalf of the National Stroke Association, a not for profit agency whose mission is to reduce the incidence and impact of stroke by changing the way stroke is viewed and treated.  Through my comments today, I hope to lend support to the rapid approval of compounds which will enhance stroke treatment options.
I am affiliated with the National Stroke Association through its Stroke Center Network, its Professional Advisory Council, and I am Chair of its Stroke Prevention Advisory Board.  Over the past several months, I led the Stroke Prevention Advisory Board in the development of the National Stroke Association Consensus statement on primary stroke prevention.
I am here today to remind the committee of the devastating costs to patients and families from secondary stroke.  My commitment to stroke prevention stems from my professional experience with the staggering neurologic damage imposed by stroke.
Each year, more than 700,000 of our countrymen suffer stroke.  Approximately 160,000 of them die, the remaining 540,000 survive with varying levels of impairment.  Stroke is the third leading cause of death and the leading cause of adult disability in our nation.
There are a myriad of factors which place individuals at risk for stroke.  These factors range from those which are potentially modifiable, such as hypertension, to those which are potentially manageable, such as diabetes.
Through identification and management of risk factors for stroke, the incidence of this devastating condition can be diminished.  Given our understanding of the impact of stroke on our society, we face an imperative to develop and implement strategies for identification and management of all stroke risk factors.
A substantial risk factor for stroke is stroke itself.  Individuals with a personal history of stroke and transient ischemic attack are at extremely high risk for subsequent events.
Because this population is relatively well defined, we have the opportunity to offer aggressive intervention strategies for secondary stroke prevention.  Because this population is at risk for progressive neurologic damage resulting in progressive physical and cognitive dysfunction, we have a medical and ethical imperative to offer the most effective interventions available.
Research and identification of new and promising pharmaceutical agents is a critical part of our ability to offer patients effective treatments for stroke.  Based on my knowledge of the expanding population of stroke survivors and my understanding of the opportunity to offer medical interventions to preserve neurologic function, I am an advocate for the development and rapid approval of compounds to prevent recurrent stroke.
Thank you.
DR. GILMAN:  Thank you, Dr. Gorelick.
Mark J. Alberts, M.D., Associate Professor of Neurology, Director, Stroke Acute Care Unit, Duke University, Durham, North Carolina.
DR. ALBERTS:  Thank you, Dr. Gilman.
Good afternoon.  My name is Mark Alberts.  I am an Associate Professor of Neurology at Duke University Medical Center in Durham, North Carolina, and Director of the Stroke Acute Care Unit at Duke Hospital, however, I am here today representing The Stroke Belt Consortium.
The Consortium is a diverse, multidisciplinary group of people, organizations, and companies dedicated to improving public and professional education about stroke in the Stroke Belt area of our nation.
Let me disclose that I have not participated in research involving Aggrenox, nor do I have any financial ties with Boehringer Ingelheim.  However, I am a consultant to Boehringer Ingelheim, and the company has provided educational grants to the Consortium.
The Stroke Belt defines a region encompassing the Southeastern portion of the United States where stroke incidence and mortality has significantly exceeded the national average over the past 50 years.  The highest age‑adjusted stroke death rates for this region have been recorded in South Carolina, Georgia, and Mississippi.
The Consortium includes physicians, health care providers, pharmacists, representatives from the pharmaceutical industry, managed care groups, minority groups, legislators, NIH, CDC, and other interested parties.  The Consortium strongly believes that there is a need for concentrated efforts aimed at lowering the cerebrovascular disease health risks in this population.
The overall goal of this Consortium is to educate the public and the medical community about the risks of stroke for patients residing in the Stroke Belt region.  People in these states are at a greater risk of stroke in part due to higher incidences of hypertension, heart disease, and diabetes and higher rates of smoking and obesity.
In addition, these states have a higher than average population of African‑Americans and older patients, older adults, populations that are recognized to be at increased risk for stroke and for dying from a stroke.
The Consortium is committed to working with all groups in the Stroke Belt to improve methods for preventing, diagnosing, and treating stroke.  As such, the Consortium has led to the formation of several different state‑based programs and organizations to improve public and professional education about stroke.  These include the North Carolina Heart Disease and Stroke Prevention Task Force, as well as the Florida Stroke Partnership Council.
Also, the Consortium has funded dozens of pilot grants and demonstration projects aimed at furthering public and professional education about stroke and its prevention and treatment.  Examples of such projects include sponsorship of church‑based educational programs, including stroke warning signs in the mailing of utility bills, and conducting an education survey about stroke awareness in the Stroke Belt region.
The Stroke Belt Consortium applauds the efforts of the FDA Advisory Committee in considering the approval of Aggrenox for the secondary prevention of stroke.  As you know, each year, more than 700,000 Americans have a new or recurrent stroke and the risk of developing a subsequent stroke is in the range of 8 to 10 percent per year.
Despite educational efforts, most patients, even those with family members who have experienced a stroke, do not know the risk factors for stroke, and as such, they are unlikely to alter daily behaviors, such as smoking and poor diet, that increase their risk of having a stroke.  Therefore, it is even more imperative that new therapies for the prevention and treatment of stroke be made available in this country, especially in those regions of the country, like the Southeast, where the risk of stroke  is elevated significantly.
I believe that the development of new therapies, such as Aggrenox, is vital to our efforts in reducing stroke occurrence in patients at greatest risk, including those who have suffered a stroke or TIA.
As you know, Aggrenox combines two extensively studied antiplatelet agents.  Clinical studies of the combination have demonstrated its efficacy for the secondary prevention of stroke, with no additional risk of adverse events.
Such combination therapy may also enhance patient compliance by reducing the number of pills that a patient has to take in a given day.  Making this medical available to patients at risk for secondary stroke will add a valuable new option to our stroke prevention armamentarium and thereby decrease the number of Americans who suffer the consequences of a stroke. The ultimate result will be that fewer families will suffer the emotional as well as financial hardships that are commonly associated with stroke.
I urge you to recommend too the FDA that this new treatment be made available to patients and their physicians as rapidly as possible.
Thank you very much for your attention and for the opportunity to speak to you this afternoon.
DR. GILMAN:  Thank you, Dr. Alberts.
Does anybody else in the room from the public who wishes to make a presentation?
[No response.]
DR. GILMAN:  Thank you.  If not, we will go back into our regular mode and we will hear from the Food and Drug Administration now.
Dr. Robie‑Suh.
FDA Presentations
Overview of NDA
DR. ROBIE‑SUH:  Good afternoon.  I will try to be brief.
[Slide.]
This is the order of FDA presentation this afternoon on Aggrenox.  I am Kathy Robie‑Suh.  I am going to introduce to you issues that the Division has identified as being important and warranting some consideration in the committee's deliberations today.
Dr. Ann Farrell will then present the results of the medical review, and Dr. Rashid will present results of the statistical review of the application.
[Slide.]
These are issues that the Division has identified as being important.  First of all, the product Aggrenox is a combination product, and as we have talked about earlier today, that has some specific implications for the evidence for effectiveness.
There is, second, a single study presented for demonstration of effectiveness.
Third, there is the uncertainty somewhat about primary endpoints as specified in the protocol and what is appropriate, and so forth, as we have talked about earlier today.
Finally, there are considerations with regard to the study population.
[Slide.]
Aggrenox is a fixed combination of an extended release dipyridamole 200 mg and aspirin 25 mg to be dosed twice daily, providing a total of 50 mg of aspirin and 400 mg of dipyridamole.
We might ask what do we know about the individual components of this combination product.  The professional labeling for aspirin recommends once daily dosing with 50 to 325 mg for the purpose of reducing the combined risk of death and nonfatal stroke in ischemic stroke or TIA patients, and this is the indication being sought for the combination product today.
Dipyridamole is not approved for the desired indication.  The extended release formulation is not approved here in the U.S., and the immediate release product that is approved here, is approved only as an adjunct to coumadin therapy to prevent postoperative thromboembolic complications, cardiac valve replacement.
[Slide.]
In order to demonstrate effectiveness of a combination product, our regulations do allow combination of the product when each component makes a contribution to the claimed effects and the dosage of each component is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.
So, therefore, Aggrenox has to demonstrate superiority of the combination product over each of the individual components.
[Slide.]
For this purpose, we have submitted a single efficacy study.  Normally, in our approval process, the standard of evidence that is required is substantial evidence, and usually, this comes from substantial evidence that should come from adequate and well‑controlled investigations (plural), and the reason for the investigations has been the need for independent substantiation of the efficacy result, but sometimes we can find independent substantiation in a single study.
In May of 1998, a Guidance to Industry was published describing what is needed for demonstration of effectiveness, a demonstration of efficacy of drugs and biological products.
With regard to single studies, these are some of the criteria that were laid out as being highly desirable in a study presented for such purpose.  You probably recognize this slide from a prettier picture earlier this morning, so it is nice to know our guidances are getting out there.
I am going to say just a word about each one of these, but before I do that, all of this presupposes that that single study certainly is adequate and well controlled in the usual sense that we look for a clinical trial.
That means that it has to be well designed, adequate measures need to have been taken to minimize bias.  This includes minimizing baseline imbalances, being balanced with regard to risk factors, taking care to protect the blind, also with regard to having a predefined hypothesis that is being tested, and so forth.
So, all that being said, then, with the single study, look at these factors.  Large multicenter study.  Here, for each one of these factors, considering ESPS‑2 for this purpose.
[Slide.]
In this study, there were over 7,000 patients randomized.  One site was excluded because the data were felt to be unreliable, but you still have over 6,000 patients.
[Slide.]
Is there consistency across study subsets?  The effectiveness results were examined across centers, across gender, entry event, and a number of types of analyses.  Dr. Farrell will show you some more of these results.
[Slide.]
Other multiple studies?  Sometimes one study can be viewed as having two or more studies embedded within, and I know the example in the guidance talks about a factorial analysis, but I think for this combination product, we have talked about why pairwise is more appropriate for looking at effectiveness here, but certainly having the placebo group there and both of the component arms being shown superior to the placebo for an endpoint strengthens the trials.
You can also subdivide the trial and look for effectiveness in subdivisions, for instance, by geographic areas I think was one thing that was done for this trial.
[Slide.]
Are there multiple endpoints examined in this study, and endpoints that are independent, but still related to the indication we are interested in, and, yes, ESPS‑2 had a number of endpoints.  Again, Dr. Farrell is going to present a little bit more about some of these results.
[Slide.]
Finally, is the study statistically persuasive?  Again, a number of analyses were done, and looking at the efficacy analysis versus the components, I think we came up with p‑values of 0.002 for Aggrenox versus dipyridamole, and 0.008 for Aggrenox versus aspirin for the reduction of risk of stroke.
[Slide.]
Now, when you have a single study, you can either have a single study all by itself or usually there is some confirmatory evidence, as well, and two additional studies were submitted as additional information on this product.
ESPS‑1 was a study which tested combination of immediate release dipyridamole 75 mg plus aspirin 330 mg, given three times a day, versus placebo for 24 months.  There were some problems with the study, the protocol was not uniform, for instance.
Also, Study U88‑0473 tested that same combination versus dicumarol.  That was a small study with few events.
[Slide.]
With regard to primary endpoints, I don't think I need to say a whole lot.  The identification of primary endpoint, of course, has some impact on the statistical analyses, possible interpretations of what I saw in the protocol could have been either death alone or stroke alone, win with a benefit on both death and stroke when you analyze them individually, or win with benefit on the composite endpoint.
[Slide.]
Finally, with regard to the study population, ESPS‑2 was a European study.  There may be differences in th U.S. and European diagnosis of stroke and the practice of medicine.  Also, we have to consider the target population for whom Aggrenox would be indicated, you know, considering, for instance, that the daily dose is 50 of aspiring, would be 50 mg, whereas, in the aspirin monograph a dose of 75 mg is the lowest dose labeled for the cardiac indications basically, so these are things that I would like for you to consider and discuss.
[Slide.]
Again, this is just those issues again.
That concludes this part of the presentation.  Any questions?
DR. GILMAN:  Any questions from the panel?
[No response.]
DR. ROBIE‑SUH:  Then, Dr. Farrell will present the clinical efficacy data.
Efficacy Issues
DR. FARRELL:  Thank you very much.
ESPS‑2 was a single trial involving 7,040 patients in 60 centers in 13 countries.  One trial was excluded from the efficacy analysis, leaving 6,602 patients in the modified ITT population.
The trial was reasonable well balanced with respect to sex, age, qualifying event, risk factors for stroke and center among treatment groups.
[Slide.]
This is the table of carotid endarterectomies that occurred prior to or during the trial.  As you can see, there are a few more patients in the dipyridamole and aspirin group who underwent carotid endarterectomies and remained in the trial although this is a very small number and constitutes less than 1 percent of each treatment group.
[Slide.]
As the sponsor has already shown you, the benefit of the combination product on stroke.  What I wanted to show you was the subset analysis for nonfatal first stroke showing that the combination product gives you a statistically significant benefit over its components.  This was not true for fatal first stroke.  In fact, all of the categories were not significant.
[Slide.]
This is looking at stroke with respect to qualifying event, and you can see the numbers across.  For patients who entered the trial with a qualifying event of TIA, who experienced a stroke, there was not a significant difference between the combined product and aspirin.
Patients who entered the trial with a qualifying event of stroke did much better, did not reach statistical significance, but the trial was not sized to look at these separate endpoints, and it was sized for the European definition of stroke.
[Slide.]
This is basically going over the primary efficacy endpoint of death and just looking at the numbers, and there is no significant benefit here.
[Slide.]
This is a slide that I showed you earlier, looking at the cause of death as classified by the Morbidity and Mortality Assessment Group, and there was no real change for the combined product nor for the components over any of the categories of death.
[Slide.]
Looking at the efficacy endpoint of stroke and death, the combination product does not show a statistically significant benefit for the composite endpoint.
[Slide.]
This is a further analysis of the subcategory contributions to stroke and death, and it is only the subcategory of nonfatal first stroke and never died where there is a significant contribution.
There is virtually no change for fatal first stroke, nonfatal first stroke and later died due to stroke, nonfatal first stroke and later died to other causes or death due to other causes.
[Slide.]
The sponsor did a very interesting analysis looking at the first stroke handicap categories.  What your first stroke is, is the stroke you have on trial and during treatment.  This is how they classified minor stroke, major stroke, and fatal stroke.
[Slide.]
Looking at the first‑stroke handicap categories,  the combination product appears to show some benefit in terms of having an increased number of patients experiencing a minor stroke and a decreased percentage of patients experiencing a major stroke.  There appears to be no effect on fatal stroke.
[Slide.]
Here is the pairwise analysis for first stroke handicap categories based on this classification for minor and major stroke, and as you can see, the combination product produces a statistically significant benefit over dipyridamole for that endpoint.
[Slide.]
Another important category was transient ischemic attack.  This is how the number of patients who reported greater than 1 TIA during follow‑up did.  As you can see, the lowest percentage of patients is seen in the combined treatment group.
[Slide.]
Here is the pairwise analysis, which shows that the combined product produced a statistically significant benefit over dipyridamole alone.  This was not seen with aspirin.
[Slide.]
This is looking at TIA by qualifying event.  Certainly, the combined product was associated with the lowest frequency of TIA ‑ 64 for those who entered the trial with a qualifying event of TIA versus 102 for placebo, and those who entered the trial with a qualifying event of stroke, 108 for the combined product versus 165 for placebo.
[Slide.]
This is first ischemic event, and certainly there appears to be a significant benefit to the use of dipyridamole and aspirin for first ischemic event, and those are the numbers ‑ 206 for dipyridamole and aspirin versus 271 for dipyridamole, 266 for aspirin, and 307 for placebo.
[Slide.]
This is the pairwise analysis which shows a benefit for the combination product over its components.  One important thing to realize about first ischemic event, that stroke patients made up 78 percent of the data here.
[Slide.]
In terms of adverse events, there as a high incidence of adverse events for all treatment groups throughout the trial.  There was no significant difference between treatment groups for adverse events categories.
Some adverse events did lead to treatment cessation.
[Slide.]
Treatment cessation due to medication side effects.  For headache, there was approximately a 9 percent treatment cessation rate compared to 2 for placebo and aspirin.  Gastrointestinal contributed 8 percent.  That was nausea, vomiting, sometimes diarrhea.  Bleeding contributed 1.7.
It is interesting to note in the data that the patients who were on either the combined product or dipyridamole tended to go off study or have to stop their medication earlier than the patients on aspirin and placebo.
[Slide.]
There was no category of serious adverse events that were greater in the dipyridamole and aspirin treatment group than other treatment groups.
That's it.  Any questions?
DR. GILMAN:  Thank you.
Questions?  That was very clear and brief, appreciate that.
If there are no other questions, then, we will  move on to Dr. Rashid, mathematical statistician.
Statistical Review of Aggrenox
DR. RASHID:  I am going to summarize the statistical review, and since I am the last speaker, I had to cut down some of my transparencies.
[Slide.]
As Dr. Temple mentioned, that for combination drug, we looked for two combinations here, the combination versus the ingredients, in this case, Aggrenox versus DP alone, and DP was dipyridamole, and Aggrenox versus ASA, which is aspirin alone, and both test required statistical significance in favor of the combination drug.
[Slide.]
Now, this is for the stroke data.  We have seen this several times.  First, we look at the column, which is the p‑value of Gehan‑Wilcoxon test, which compares the survival curves over the two years.
The p‑value is 0.002 for Aggrenox versus DP, p‑value of 0.008 for Aggrenox versus aspirin, which is significant.
The next column gives information about Kaplan Meier stroke free rate, 89.9 percent for Aggrenox and 86.7 percent for the dipyridamole.
Similarly, for Aggrenox versus aspirin, 89.9 versus 87.1.
The risk reduction, the sponsor has shown it, which is 24.7 percent reduction for the Aggrenox versus DP and 23 percent for the Aggrenox versus aspirin.
Another measure which gives increased is stroke‑free rate increase, which is the last column, which is essentially the difference between the stroke‑free rate, 89.9 minus 86.7 divided by 86.7.  The stroke‑free rate increase of Aggrenox relative to dipyridamole, which is 3.7 percent, and the same measure for the other comparisons, for Aggrenox versus aspirin, we have 3.2 percent, and those numbers in the last column look consistent, over 3 percent, but if you look at the risk reduction, the fourth column.
The next one, for the death endpoint, we get the p‑value for Aggrenox versus dipyridamole, 0.79, so we don't have any evidence there.  If you look at the Kaplan‑Meier survival curve here, this is at the end of the two years, which is 88.7 percent versus 88.5 percent, only 0.2 percent increase.
The risk reduction is 1.3 percent, but if you look at Aggrenox versus aspirin, we see the p‑value of 0.74, so we have no evidence there, and if you look at the third column, which gives Kaplan‑Meier survival rate, for Aggrenox it is 88.7 and for the aspirin it was 88.9, and the risk reduction is minus 2.7 percent.
I would say the Aggrenox group has 2.7 percent death rate than aspirin group.  Survival increase we see the same thing, 0.2 percent increase and minus 0.2 point decrease.  So, that is important to look at, the second row.
[Slide.]
Now, stroke or death, we had a lot of discussion about this, but I thought I should give a transparency on this.  Let's look the p‑value for Aggrenox versus dipyridamole, which is 0.079.  I should say that is weak evidence.  If you look at the Kaplan‑Meier stroke and death free rate, which is 82.4 percent versus 80.3 percent, so if you go back to stroke, this is much less.
Now, risk reduction is 10 percent, for the stroke case we have seen it about 24 percent, and the survival rate increase in this case, 2.6 percent for again Aggrenox versus aspirin, which is second column, we have 0.084 p‑value for Gehan‑Wilcoxon test.  Again, we have weak evidence here.
If you look at the stroke or death free rate, we get 82.4 versus 79.9, the risk reduction 12 percent, and survival rate increase is 3.1 percent.
[Slide.]
So, in the protocol like we had two endpoints, stroke and death, and in the clinical summary report it said the other endpoint is death or stroke, so we need adjustment.  If you consider two primary endpoints, we need to adjust for the error rate, so I adjusted for the two endpoints for stroke or death, and I found that for unadjusted, Wilcoxon is 0.079, which you have seen before, and if you adjust it for the multiplicity, we get 0.1579, which is double the 0.079.  So, we have weaker evidence now if you adjust for multiplicity.
The same for DP/ASA vs aspirin group, we have 0.084 for the Wilcoxon, and if you adjust for multiplicity we have 0.167, again we have weak and weaker evidence.
[Slide.]
Now, Dr. Robie‑Suh discussed about the single study like you need some consistent result and substantial evidence, so I looked for composite endpoint, then region.  So, there are four regions in this study ‑ Scandinavia, Northern Europe, Southern Europe, and United Kingdom, can I compared four pairs here.
The first column gives you Aggrenox versus dipyridamole, and we see that only in Southern Europe Aggrenox beats dipyridamole.  Also, if you look at the second column we see that Aggrenox versus ASA, only Southern Europe Aggrenox beat aspirin.
But if you look at the other components here, like 0.51 for DP versus placebo for Southern Europe, so DP is not effective there, so that drives the significance here.
The same thing if you look at aspirin versus placebo for Southern Europe, we have 0.27, and again if you look at Aggrenox versus ASA we have 0.05.
DR. KONSTAM:  Can I stop you for a second?
DR. RASHID:  Yes.
DR. KONSTAM:  I mean so in these subsets, I mean I wouldn't expect any of these p‑values necessarily to reach significance, but is there any inconsistency across these different regions?
DR. RASHID:  I don't think so.
DR. KONSTAM:  I mean that would be the question I would think would be asked.
DR. RASHID:  I agree with you.
DR. KONSTAM:  More subgroups, you are not going to see a positive p‑value.
DR. RASHID:  I am going to say that, for a single study look at the internal consistency.  For example, suppose you had some centers in the United States, then, how would have been the results.
DR. TEMPLE:  Did you do the same thing for stroke?  Are we about to see that?
DR. RASHID:  I think we have similar answer.  I have that in the review, but not‑‑
DR. TEMPLE:  Okay, because I mean this wasn't strongly positive overall.  It has no chance of being positive by region, but stroke was positive overall, so that might be a more profitable place to look for consistency.
DR. GILMAN:  It is in his review.
DR. RASHID:  Now, the summary of issues.  Primary endpoints are not well defined in advance, as you know by now.
Adjustments to p‑values needed for multiple endpoints.
Two, sample size is increased at the interim analysis, so adjustment to p‑value is needed for the increase in sample size.
The internal consistency not well supported.
DR. DRACHMAN:  What was the third point there?  What do you mean by number 3?
DR. RASHID:  What I am saying like we have defined regions here, but we don't have the identical results here.
DR. PENN:  If I understood you, didn't you just say that the regional comparisons didn't reach any‑‑we wouldn't expect them to reach any statistical significance?
DR. RASHID:  You can reject the null hypothesis, but if you look at the components, you still have‑‑you can accept the null hypothesis, interaction there, but still you go by components, you can get significance.
DR. PENN:  Can you tell us one clean example of internal inconsistency in the study that makes you worry about the quality of the study?
DR. RASHID:  For example, Southern Europe, like patients here had less hypertension, and patients were younger, that may be the reason it was doing bad here.
[Slide.]
So, the study has shown that the combination drug product is effective only in stroke.  It is not clear that there is any added or any benefit for fatal stroke.  Dr. Farrell mentioned that.
Significant efficacy results are not demonstrated for either mortality or the composite endpoint.
DR. GILMAN:  Thank you.  Further questions from the panel?
DR. CALIFF:  Two things.  One is you said at the beginning there was a site excluded and it was written up in the booklet.  I just wanted to know how you arrived at the decision to exclude the data as opposed to including it.
DR. RASHID:  The company will answer better.
DR. CALIFF:  So, the company makes that decision?
DR. RASHID:  Yes, yes.
DR. PENN:  They listed all those reasons why they didn't include it.  I mean it sounded awful.
DR. TEMPLE:  It was sort of obviously made up.
DR. CALIFF:  So, it was made‑up data.
DR. TEMPLE:  It sure looked that way.
DR. GILMAN:  Other questions or comments from the panel?
DR. KONSTAM:  You know, I mean you showed different things, and I guess the way I interpret these remarks is that there are different ways within a single trial of potentially making the argument that it is equivalent or may be good enough that you don't have two trials.
So, you showed some ways in which you can't necessarily support it, but I guess, to me, the way that I will wind up trying to rationalize it to approve it if we do, is, first of all, it makes it or breaks it on the stroke endpoint.  That is the one that is really positive.
So, the question to me is going to be is that endpoint very statistically convincing, and I guess I didn't really get an analysis of that from what you showed, I mean with regard to the p‑values for stroke.
I noticed also the other thing I would thing I would say you avoided the factorial design‑‑
DR. RASHID:  Yes.
DR. KONSTAM:  ‑‑analysis, and I am not sure whether that is‑‑I mean I actually got attracted to the factorial design during the course of the day.  So, I guess I would ask are we going to be left at the end of the day with a strong p‑value for dipyridamole, that it is effective.  We believe aspirin is effective.
DR. GILMAN:  You mean Aggrenox or do you mean dipyridamole?
DR. KONSTAM:  Well, I guess, number one, is that we say that in order to have a combination product, the standard is each one is effective, so I guess the first question I have been asking myself is, is dipyridamole effective, and then, secondly, is dipyridamole plus aspirin better than aspirin alone.
I guess the question I have is I see very low p‑values for those analyses, and I guess the only question I have is should I be increasing those p‑values based on any of the corrections that you think we should do, like the fact that stroke wasn't the only endpoint that was measured, the fact that there were a questionable number of interim analyses.
I am struck with these very low p‑values for what I am looking at.
DR. RASHID:  The first thing like we are here for the combination drug, not for the components.  Okay.  We are looking at the effect of the combination drug.  Even we don't need placebo in the arm for the combination drug, and the literature said that.
DR. GILMAN:  Dr. Temple.
DR. TEMPLE:  There is no question that is true.  The crucial analysis for a combination is the two‑drug versus each of the one‑drug treatments.  There is no doubt about that.
But with respect to the question of what makes one study believable, we gave as a specific example‑‑I am not breaking any new ground here‑‑in our document that was referred to earlier, the evidence document, a case where you might choose to believe that a drug was effective from a single study, if it showed an effect, you might be more likely to accept a single study if it showed both an effect when you added it to something and when it showed an effect when it was used alone, not that the used alone is relevant to the combination, but it might add to the believability of the study.
So, that is a slightly subtle distinction that maybe we made more of than we should have, but I think that is the sense.  It doesn't contribute to the‑‑I mean aspirin is effective, but the question here is, is it effective when you add it to dipyridamole.  That is the crucial question.  We already know it is effective, but it might not add anything when you add it to dipyridamole.  So, that is a legitimate question.
The other thing, I am looking at the analysis of the factor analysis by region, looking only at stroke, and they are actually nominally significant values in the various regions, which considering that it's only half of a study, is not so shabby‑‑I am sorry‑‑I mean with the regions only each representing about a quarter of the study.
So, for stroke, which is obviously the more powerful endpoint, there was a certain consistency across regions, right, that is what you said?
DR. RASHID:  Yes.
DR. GILMAN:  Dr. Robie‑Suh.
DR. ROBIE‑SUH:  I also wanted to say also for stroke, that also with region, there was some variability in the risk factors that may have contributed toward the little imbalances that were seen in some geographic areas.
DR. GILMAN:  Dr. Grotta.
DR. GROTTA:  But wouldn't the Cox analysis have taken into consideration the baseline imbalances that existed in the population or among the different groups, and that apparently was done, and still the differences were there in the treatment groups.
I don't know.  I guess we heard this morning a very detailed analysis of the protocol, but I guess what I would sort of like to get is, is there something that we haven't already discussed that you have discovered in the data and in the analysis that you need to bring to our attention that would diminish the impact of these results, because I haven't heard anything.
DR. RASHID:  The first thing, that the sample size was based on the composite endpoint, and the sample size was not based on the death or stroke.  So, there is one problem there.
DR. GILMAN:  Dr. Kawas.
DR. KAWAS:  I just want clarification.  When you say the sample size was based on the composite endpoint, at what point in the study?
DR. RASHID:  In the protocol, it said there are two primary endpoints, stroke and death, but the in the clinical trial report, they said the sample size was based on the composite endpoint, death or statistical stroke.
DR. KAWAS:  So, was that at the interim time when they increased the sample size, that they said they were increasing it based on the composite endpoint?
DR. RASHID:  I think at both times they estimated the sample size based on the composite.
DR. KAWAS:  Both times.
DR. RASHID:  Both times.
DR. KAWAS:  So, even at the initiation of the study, they were generating their sample size based on the composite endpoint even though they didn't specify that initially.
DR. RASHID:  Yes.
DR. KAWAS:  Well, that sort of implies that maybe that was their endpoint at the beginning, which I didn't realize.
DR. RASHID:  I talked to the sponsor on telecon.  They said the statisticians identified the composite endpoint at the primary, but the clinicians identified death and stroke as two primary endpoints, so there is kind of a problem there.
DR. KAWAS:  At the beginning.
DR. RASHID:  Yes.
DR. GILMAN:  At the beginning, as I understand it, there were two primary endpoints, stroke, death, not a composite endpoint.
DR. KAWAS:  But what he just told us, I believe, Dr. Gilman, is that when they did the sample size calculation at exactly that point, somebody was calculating it based on a composite endpoint actually.
DR. GILMAN:  Exactly right.  They then changed and had three primary endpoints, as I understand the situation.
DR. RASHID:  Yes.
DR. GROTTA:  And why is that a problem?  Enlighten me, because I don't know these things, but tell me why is it important if they then changed and based their samples size on the composite endpoint.
DR. RASHID:  Like if they used only death, they had one sample size, right?  If they used only stroke, another sample size, and composite, another sample size.  So, it appears to me if they just used death, then, sample size would have been higher than 5,000.  That was a problem.
DR. TEMPLE:  It would have been 50,000.
DR. GILMAN:  Dr. Temple.
DR. TEMPLE:  It is perfectly possible for there to be more than one primary endpoint, but the sample size will be based on the one that you think you need the larger sample for.
So, if you had any hope of winning on the death plus stroke endpoint, and you thought the effect wasn't going to be as large, you would make the sample size larger and then you would be way overpowered for the stroke endpoint, and you would feel good about that.
So, we see lots of studies designed that way.  It doesn't really prove anything.  But what seems to be is that there was not crystal‑clear agreement on what the primary endpoint was, so there might be as many as three, they are not mutually independent, so there is going to be some correction, and you sort of have to struggle to figure out what that correction should be.
But as people have pointed out, you multiply these things by 3, and you are still there for the stroke, only for the stroke.
DR. GILMAN:  Dr. Katz.
DR. KATZ:  Dr. Grotta asked if there was anything that might make you question the p‑values for the stroke endpoint that you haven't heard, and there has been an issue that the statisticians have alerted me to, and I think we have sort of been very tangentially discussing it, but not explicitly, and it is probably worth just, at the risk of entering even more arcane territory, it is probably worth just airing it and sort of dealing with it, and I will ask Dr. O'Neill from our statistical group to talk about it in detail, but it has to do with the fact that the choice of stroke as an endpoint in a trial like this may be problematic because mortality is related to stroke, or at least they might be correlated at least theoretically, and that just looking at stroke without taking mortality into account might possibly give you a biased estimate of the treatment effect.
Therefore, under that theory, you would have to look first at the combined endpoint, and if it doesn't reach the usual standard for statistical significance on that endpoint, then, it may not really make any sense to go back and look at stroke independently, so that the p‑values, even though they appear to be quite small for stroke, might be difficult to interpret anyway.
He is here.  He can elaborate.
DR. O'NEILL:  I am Bob O'Neill.  I am in the Office of Biostatistics.
The discussion I had with Dr. Katz goes along the following lines, and this is in the spirit is there anything else that is sort of percolating around that you want to sort of think about.
The issue of how many primary endpoints you choose is important because you look at that in terms of at the end of the day, how many different ways do you agree clinically that you can win, and if you can win in more than one way, endpoint A or endpoint B or endpoint C, if any of those are positive, and you can win any one of those ways, then, some adjustment is needed.
So, the issue of whether one chose just death and stroke as the two endpoints, or whether one chose three endpoints, which was the union of both of those, essentially A or B, or both, is germane.
It is probably not crucial to the focused interpretation of stroke alone, but this isn't the only area, this medical area, that struggles with do you include mortality in a composite endpoint, and the reason you do that is because although you would like to clinically measure the incidence of stroke, you might not be able to do it because you have other things that get in the way, and mortality gets in the way, and the statistical analysis essentially has to estimate the incidence of stroke by making an assumption that if these folks had not‑‑because it is a denominator issue, who is in the denominator‑‑so, you have to make an assumption about had these people had not died, would they have gone on to have the same stroke occurrence as those who didn't die, so it is a competing risk issue.
So, what often happens in these trials is that folks union the composite endpoint, just as Bob Califf was talking about sort of earlier saying there was a fair amount of sudden deaths that were in this trial, how do we explain them, and there was a certain amount of probing of whether those events, those mortality events were really more related to stroke than not.
But the issue is to get out of that trying to find out what the true state of nature is, one unions the events, you say, stroke and/or mortality.  So, if you look at that as the primary endpoint, and then you go and look at the subcomponents of that primary endpoint, you get a different picture of this.
You essentially say that on the main comparison of the combo versus the single ingredients, on classical basic comparisons, there was not a significant difference, therefore, one can say there is really no reason to go into the components, and one of the reasons not to go into the component is that you really don't know if you have the right estimate of what the stroke incidence is, because in order to estimate it, you had to use statistical procedures that censored out mortality, and the censoring is informative, because mortality is related to stroke.
It is sort of a roundabout way, and this is not the only time this has been thought about.  This has been thought about in terms of defining endpoints in AIDS, progression to AIDS or mortality, or it has been thought about in other endpoints where you have mortality that gets in the way, and it is very related to the clinical endpoint.
Now, this may not be crucial to your overall thoughts, but in the spirit of what else is floating around, one could conceivably say that had you designed this study in the beginning, a priori, with the primary comparison being the union, meaning A or B, and then depending upon what you find there, you go further, you would have a different decision than you are now dealing with, essentially is I am looking at these two endpoints and possibly three endpoints on equal footing, which is not necessarily the way you might want to look at it had you planned it a little differently.
The other thing that I find somewhat retrospectively interesting‑‑and it is always easy to do this‑‑is to say, look, if this trial was sized with the union endpoint, as I understand it, not with that or stroke, but it was sized originally, 5,000 on the union argument, and it was sized to essentially detect with high power the difference between the combo and the placebo, not to size it to look at the difference between the combo and A, and the combo and B, but that is what we are dealing with right now.
That is the comparison we are dealing with.  So, this trial was resized halfway through on the basis of several things.  Taking a look at what the relative difference was, let's say, halfway through the trial, and upsizing the trial, not just to maintain the original power, but to maintain power against a reduced effect size, which originally was thought to be 33 percent, and is now somewhere on the order of 20 percent.
Anyway, these are just some other considerations around the interpretation.
DR. GILMAN:  Thank you.
Dr. Konstam.
DR. KONSTAM:  I actually am thinking about it a little bit differently.  You know, I mean I understand, I mean your point is very clear, and it is that if somebody dies, they can't get a stroke, and Rob made that point earlier, so that is the issue.
So, if you are going forward and starting a trial new, I think this is analogous in heart failure, for example, using a combined endpoint of hospitalization plus death, not hospitalization alone, so it is the same issue.
But I guess to me the real question is are you going to have this screwy positive endpoint because the drug is associated with some excess mortality, and therefore preventing the patients from developing stroke.
I guess that if you start out, as they did, saying that‑‑there are multiple issues, but let's just assume for the sake of argument there was one question, that is, the stroke question, we think that this thing is going to win on stroke, that is going to be our endpoint, and they went with that, and now here we are at the end of the day and saying, well, wait a minute, we have this problem.
Now, we go back and look at the combined endpoint, the p‑value goes up, but there certainly is no hint that the drug is associated with excess mortality.  So, in the absence of any hint that the drug is associated with excess mortality, I guess I don't concern myself too much that you wind up with a higher p‑value when you look at the combination given the fact that I take stroke as the predefined primary endpoint.
So, I am not sure, I mean I have to defer to you, but I am not sure that you have to revert to go to the combination endpoint that wasn't predefined in the absence of an excess mortality effect of the drug.
DR. O'NEILL:  I hear you, and intuitively I don't feel very much different than you do.  I don't know whether this is a big issue or not.  I am just saying that the reason it has been dealt with this way in all the other disease areas, just as you have just indicated, is because there is some concern about whether you are able to accurately estimate what you think you are estimating, which is the stroke incidence.
What makes it worth thinking about here is, as Bob pointed out, a third of all the endpoints are deaths that are unexplained due to stroke.  There is something else other than stroke.  If you look at the collection of total endpoints, a third of the whole show is being contributed by something that is not being classified as stroke related.
DR. KONSTAM:  Just this specific question.  Is it possible that you are spuriously making the stroke endpoint more significant here through this mortality interaction in the absence of the drug being associated with an excess mortality?
DR. O'NEILL:  That is a very good question, and I don't know.  I am just speculating, I don't know.  It would probably need a further look and at the end of the day may be able to say this is not the explanation for what is going on, so don't get too excited about it.
I am just pointing it out that there is a reason why other areas deal with the composite endpoint because this is a tough one to disentangle, and there has been research on trying to decouple the contribution of individual components in a composite endpoint, and the problem with it is, it is not all that simple because some of those components censor you for being able to observe the other ones.
The point you are making is does it overly censor you in a way that is contributing all what you are seeing, and I don't know the answer to that.
DR. GILMAN:  Dr. Temple.
DR. TEMPLE:  Let me throw something else into that mix.  I would be interested in what Bob thinks about it.
There is another set of analyses here other than the pairwise one, which in some sense goes to the larger question of whether there is some funny interaction between death and stroke, and that is the factorial analysis.
The factorial analyses, of course, have twice as many people in them, don't suffer from the lesion you described before.  They, in fact, are significant even for the combined endpoint.  I wonder if you think that is a partial mitigation, irrelevant, or what.
DR. O'NEILL:  I think I got the whole question.  I think there is two things here.  It is where the traditional factorial analysis weighs in, and certainly there is some convinceness there.  It is sort of the effect of each of the individual ingredients which is drawing strength from two out of the four treatment groups, and that is relatively strong, and there is no evidence for interactivity, negative, synergistic or antagonistic, so there is pretty good evidence for additivity here.
So, what Bob is saying that that counts for something.  But as I recall, the results don't change a whole lot for stroke whether you look at it that way or whether you look at it on the AB versus A, so something else is going on, on the mortality side of this that I don't fully understand, because I think if I understand the p‑values that were presented, there were strong p .001 or whatever, regardless of whether you did the factorial comparison or whether you did the pairwise AB versus A, AB versus B.
DR. TEMPLE:  They are stronger for the factorial.  They are just all pretty strong.
DR. O'NEILL:  Right, but that still doesn't get at the point I am making with regard to the contribution of the mortality, which I don't know.  Maybe Charley has got a view on this.
DR. HENNEKENS:  I want to agree in concept with the points you are making, but it is also true in going into the design of cardiovascular treatment trials, one is expecting a priori 20 to 30 percent plausible benefits on a nonfatal endpoint and 10 to 20 percent on death with the knowledge that the death one usually comes later than the nonfatal endpoint.
So, if I were designing ESPS‑2, and I were interested in finding an effect on stroke, I would study about 5‑ or 6,000 patients.  If I were interested in finding an effect on stroke plus death, I would study 15‑ to 20,000 patients, and if I really wanted to answer the death question, I would study 40‑ to 50,000 patients.
So, I think that the idea of increasing the sample size, implying that somehow that is moving the endpoint to making it more plausible that the death is assuming increasing importance, no, I think that what it is saying, and what I viewed that statistician on that ethics committee, who reported to the ethics committee, who looked at that combined endpoint, was basically saying, well, gee, you are going to have a much better chance to detect a 25 percent effect than a 33 percent effect, but I think that is fair to assume that the effect on fatal events is smaller and delayed, and if, in fact, fatal events were really the primary moving force in the design of this study, we would have to see 15‑ to 20,000 patients to really answer the question of superiority of Aggrenox over aspirin or dipyridamole alone on that combined endpoint.
DR. O'NEILL:  I hear you.  The only issue here is whether you are able to unbiasly estimate what you want to, and everybody wants to estimate, and that is stroke.  So, another caveat to what you said is you would design the trial where you would hope that no one would die before they either had a fatal or nonfatal stroke, or had the opportunity to experience that, and that is the issue here.
The issue is you can't guarantee that.  Other stuff gets in the way.  In order then to estimate the stroke incidence, you have to make some assumptions about the other competing events that occur, and that is the crucial issue.
DR. HENNEKENS:  Well, I agree with that and I think one way of doing that is to do this composite which has been done in other trials and other forms of vascular disease, and then one sees that the magnitude is smaller, as expected, the direction is in the direction of benefits as were the nonfatal, and it is not unexpected that they didn't achieve the same level of statistical significance.
So, I guess my own view is that I am comfortable with the fact that there is clear superiority on stroke, for what that is worth, and trends in the same direction on the combined endpoint, but though not achieving that level of significance because I know in advance that they wouldn't because I was adding a smaller effect size which I would have expected a priori in there.
DR. KONSTAM:  But that is not necessarily true, Charley.  I mean I think that, at least the trials that I have had experience with, in the majority of cases, a composite endpoint has been more convincing.
I mean your point about mortality is very well taken, that you need a lot more for that, but it isn't necessarily true that the composite endpoint would be associated with higher p‑values than any of the components.
DR. HENNEKENS:  It would depend on the relative numbers of both, but I think that, in general, one gets bigger effect sizes on nonfatal events, smaller effect sizes on fatal events, and the fact that the study had somewhat more depth than other studies like it, would lead to that conclusion.
If it had more nonfatal endpoints, as did the Physicians' Health Study, then, our composite endpoint remained statistically extreme and is driven totally by the MI result.  This, I thought was more reassuring than alarming in the sense of showing the same direction and a smaller magnitude, but that is on stroke.
I guess one of the things about the FDA's analyses is that they were all on the combined endpoint, so they looked less consistent than the stroke findings.  If one did the same analyses, which are expertly done, on stroke, one would come to the conclusion that they were quite consistent across a wide range of subgroups.
DR. GILMAN:  Dr. Drachman.
DR. DRACHMAN:  The number of deaths may be less than the number of strokes, but the number of strokes plus deaths is greater than the number of strokes.  Why, then, would you expect the significance to be less good?
I mean you have got a larger n, more event, even though it may not be as powerful.
DR. HENNEKENS:  The point I tried to make is that I believe that, in general, in trials of vascular disease that occur over a two‑ to three‑year follow‑up time, the most plausible effects on the nonfatal endpoints are usually 20 to 30 percent, but on death, they are more like 10 to 15 percent, so that the overall composite endpoint risk reduction is a weighted average of a larger effect on the nonfatal events and a smaller effect on the fatal events, and whether that composite endpoint is more or less significant than the individual components will depend on the relative contributions of the nonfatal and fatal events in a particular trial.
DR. DRACHMAN:  Give us some idea of the order of magnitude.
DR. HENNEKENS:  Well, I can tell you in the Physicians' Health Study, as Bob Temple pointed out, it was stopped early because of this extreme benefit on MI, a 44 percent p, less than 1 in 100,000 benefit on MI, but there is only about a 4 to 5 percent reduction in the death rate, in part because the numbers of deaths were so small.
We had prespecified a combined endpoint of nonfatal MI, nonfatal stroke, and deaths, and when one combines that, one gets a statistically still extreme, less than .01 benefit on the combined endpoint, because there were so many more nonfatal MIs than deaths.
If the case had been reversed, there were more deaths than, in fact, it might have been reduced even in theory to nonsignificance in the combined endpoint.
DR. CALIFF:  As we are finishing up the FDA analysis, I would just like a little guidance perhaps from the FDA about what‑‑I mean I think the exercise we are going through here now is to start out with a fairly dramatic result on the endpoint of stroke, and then we sort of ate away at it with all these things that are not quite right, you know, three endpoints, competing risk, a site thrown out, all these are relatively small individually.
Are we using a single trial, looking for sort of an estimated p‑value of less than .05 or less that 0.00125 or how are we viewing this in terms of after we add all these things up in our mind about our degree of uncertainty?
DR. GILMAN:  I think that is why we are here.  Our purpose if to take all of this into account, discuss the individual points, and answer the questions that are before us.
DR. CALIFF:  So, if we wanted to say 0.25 or 0.3 is okay with us, that would‑‑
DR. GILMAN:  No, I think we have to look at the data, discuss the data, speak about the caveats, and then answer the questions that are posed for us.
DR. CALIFF:  Is it okay for me to ask at least for a point of view from the FDA about level of statistical certainty in a single trial as compared with two?
DR. GILMAN:  Sure.
DR. CALIFF:  The reason I asked that again is that if you assume you need two trial, it is 0.05‑squared would be the approximate level of certainty that you would be looking for.
DR. GILMAN:  Dr. Temple.
DR. TEMPLE:  Well, we wrote a document trying to explain when we might rely on the results of a single study, and there were really two parts.  One situation is where you already know a lot of stuff from other studies.
You might, for example, find it easier to believe that aspirin does something because you know so much about aspirin, and in that sort of case, you might accept conventional p‑values.  But there isn't as much support for dipyridamole, so you probably want something stronger.
We listed the things that might make you feel good about relying on a single study.  Obviously, one of them is an extreme p‑value.  Now, you have to decide whether you think 0.003 is extreme or not, it's not 0.00125, but it is pretty low.
A specific other thing we gave was that you might find replication within a single study pertinent if you believed, for example, that what dipyridamole did alone was relevant to what it did when you added it to aspirin.  That is a judgment call.  You know, you might find highly relevant.  If you do, then, you might say, well, this is sort of two studies or you might think that is totally irrelevant because the only thing you want to know about it is its role as a combination, in which case you would say, well, I don't care at all.
We didn't try to settle those issues.  We just tried to indicate the kinds of things one might think about in reaching this, and then also regional consistency, it is very hard to put your finger on what that means.  If there had been an effect both on nonfatal stroke and overall death separately, you would say, well, those are two separate things, those are two separate findings, that is pretty convincing, but you don't have that here.
So, it is hard to go much beyond that, but there is lot of judgment in it, and that is why we call upon outside experts to help.
DR. TALARICO:  I think the clinical significance of the endpoint also is very important in dictating how low the p‑value should be.  Here, we are dealing with death and strokes.  It is quite different than having endpoints like heartburn or some other less clinically compelling endpoint.
DR. GILMAN:  That is very helpful.
Any other comments from the FDA?
[No response.]
DR. GILMAN:  Any thoughts from the sponsor that you have not communicated to us?
DR. HENNEKENS:  On this issue about this one particular study, I think it should be mentioned that it added 30 percent to the world's literature on the aspirin therapy of stroke and TIA, it added 300 percent to the world literature of dipyridamole to prevent stroke in patients with stroke and TIA, and provides a conclusive finding on stroke that the combination is better than either component alone.
So, it is not just some little single study out there.  I think it is making an important contribution to the totality of evidence.
DR. GILMAN:  Grotta.
DR. GROTTA:  It obviously has been said multiple times we are really making a decision based on the incidence of stroke, and you all have provided us with this information on how stroke was identified at each site, could you just finish up in answering my previous question, once a patient was identified by the site as a stroke, then, how was this deliberated and decided upon and adjudicated by the Central Committee, was there a definition, how often did they disagree with the local sites?
I think these are important in my mind. I am convinced that clinically, as has just been pointed out, stroke is an important endpoint.  I think any other stroke prevention drug that showed this magnitude of an effect on stroke, we wouldn't be arguing about, but I just need to know or feel a little more comfortable how the strokes were adjudicated.
DR. RAKOWSKI:  Hello.  I am Dr. Rakowski from Boehringer Ingelheim.  This is basically an overview where there were, as far as the entry of patients into the trial, as far as the adjudication by the Morbidity and Mortality Assessment Group, and it essentially provides a composite of understanding of a misinclusion where patients should not have been put into the trial versus misdiagnosis where the diagnosis by the investigator was initially wrong.
It gives you a basic understanding of all of the various types of misinclusions and misdiagnosis, but you can see a relative balance across the treatment groups as far as the entry of patients into the trial.
DR. GROTTA:  I am sorry, maybe I didn't make it clear.  The issue isn't really the entry, although that was a previous question, but the endpoint stroke, the nonfatal strokes that occurred in the trial upon which, you know, the real statistical difference between the groups rests.
DR. HAEHL:  Disagreement with the MMAG?
DR. GROTTA:  Yes, what I want to know is, is when the investigator filled out this form, a general practitioner in Southern Spain filled out this form and said the patient has had a stroke because their face is not normal on one side, and that was the only neurological focality that was identified, you know, I want to know how that was dealt with by the Central Adjudicating Committee and how often they disagreed with the diagnosis of stroke, and whether there were rules that they had a priori as to what had to be on this paper before they would call it a stroke.
I would think that when you designed a study there and set up this committee, that they established rules for what were going to be your primary endpoint.   After all, that was what the investigator identified as your primary endpoint was strokes.
DR. HAEHL:  As Dr. Pathy explained before, the procedure was based on this case report form plus the additional information available.  I do not have the number or the incidence of disagreement between the investigator and the MMAG at the moment at hand.
Do we have that?  No, not at the moment available, so I cannot give you a percentage or per‑treatment group a number for disagreements at the moment.
DR. PENN:  Can you at least give us a sense of the number of disagreements, was it half, was it a quarter, or was it rare?
DR. HAEHL:  Dr. Pathy, can you please comment on how often of rare this had happened?
DR. PATHY:  Thank you.  There were 179 cases of doubtful eligibility and 138 were actually ineligible, but that was due to a multitude of reasons, because of protocol violations or misdiagnosis, but we don't have a figure for the disagreements in the endpoint strokes unfortunately, at least I don't have one with me here.
DR. PENN:  Do you have a sense of what that figure is?  I mean was it a lot, were you debating constantly about whether the diagnosis was right, or was it very small?
DR. PATHY:  No, it was very small, it weighed no more than 10 percent.
DR. PENN:  Well, that is all we need to know.
DR. PATHY:  Where there was debate was most frequently in TIAs rather than established strokes.
DR. GILMAN:  Are we discussing now entry into the study or are we discussing the event that is counted as a stroke once a patient is on drug or placebo and in the study?  I think we are sort of at cross purposes here.
DR. HAEHL:  Our understanding was we are talking about the event, the outcome.
DR. GILMAN:  The outcome.
DR. HAEHL:  The outcome.
DR. GILMAN:  Is that what we just heard about?  Yes.  All right.
Dr. Drachman.
DR. DRACHMAN:  Although I certainly firmly agree with you, Jim, that everybody with a stroke should be diagnosed by a very good neurologist, I am more and more impressed whether if obstetricians were making the diagnosis, that would be even more impressive because there would be so much noise that defined a signal like this shows that it must be much better than we thought.
DR. HAEHL:  May call for the next slide?  Yes, that is what I was making reference to before that a misdiagnosis would certainly not support a positive outcome of a trial when it is randomized.
[Slide.]
This slide is a summary of the MMAG decisions between April 1990 and June 1995, and it gives you the number of agreements and disagreements for the different conditions, death, stroke.
DR. CALIFF:  How could you have 209 disagreements on death?  Oh, the cause of death.  Okay.
[Laughter.]
DR. HAEHL:  No, no, let me explain that.
DR. GILMAN:  Please, give him a chance.
DR. HAEHL:  What has also been mentioned before by Dr. Pathy, that is a change in the cause of death when, for example, the practitioner attributed the death to chest infection, and then they changed it to the primary event, which would have been myocardial infarction or could have been stroke, and therefore, the MMAG corrected it towards the primary diagnosis rather than to the final symptom.
That explains the numbers, and that is the complete information on this slide.
DR. GILMAN:  Dr. Brooke.
DR. BROOKE:  I think what we are seeing here, which is unspoken, is the inbred cynicism of neurologists.  We basically sit in a clinic and we become convinced that the only three diagnoses that general practitioners make are multiple sclerosis, stroke, and old polio, and I think that is at the basis of our skepticism about diagnoses, which are coming in from the periphery.
I don't entirely agree that the only thing that could happen, that would increase or decrease the p‑value, it depends a great deal on what kind of mishmash you have there, but it does make a huge difference on what the labeling instructions would be if, in fact‑‑and I am not saying it is‑‑but if, in fact, there are a lot of misdiagnoses, which neither the practitioner nor the MMAG were able to pick up, and that is the problem.
I mean it is not a solvable problem, and we can talk around it for a long time, but we do understand the predicament.  You have to understand our cynicism.
DR. GILMAN:  Dr. Kawas, did you have a comment?
DR. KAWAS:  I guess I just need to say I have been quite confused by this discussion.  I tend to agree mostly I think with Dr. Drachman.  I don't think it matters how these people got diagnosed as long as they were diagnosed the same way in each of the four groups, and nothing that I have seen here today has suggested to me that that had not occurred.
I mean there is no reason to believe that they are calling stroke something different in one of the treatment groups than they are in the placebo.  That being the case, whether it is done by an obstetrician or a neurologist or whatever, as long as the diagnosis is consistently applied, it seems to me the issue is irrelevant for the discussion.
DR. GILMAN:  Any other comments from the FDA, the sponsor?
[No response.]
Discussion by Advisory Committee
DR. GILMAN:  If not, then, you have all been given a couple of sheets that you already had in your packet.  They address the questions that we are supposed to come to grips with now.
There are five of them.  The first is the effectiveness of Aggrenox is being supported by a single European study.  Based on this single study, has the sponsor provided substantial evidence of effectiveness of Aggrenox for the desired indication?
If no to (1), has the sponsor provided substantial evidence of effectiveness of Aggrenox for any other indication?  If so, for what indication?
The third question.  Would you recommend approval for Aggrenox for the requested indication?
Fourth.  Would you recommend approval of Aggrenox for an indication other than the requested indication?  If so, for what indication?
Fifth.  Are there any particular safety concerns with use of Aggrenox?
Let's come to grips with Question No. 1 to begin.  If I may, I think I will just briefly summarize my own position in this to get a start maybe.
We have about a single large trial that had multiple concerns that we have been talking about all day today.  My own concern is that this medication was devised in a fixed dose combination without attempts to find clinically optimal doses for this indication.
There was a change in the primary endpoints over time with initially stroke, death as the two primary endpoints, and then later a third was added.  Yet, the randomization initially was based upon those two endpoints.
There is some question about the safety committee looking annually at the endpoints.  I think that is still somewhat of a question, but my feeling is that the committee was looking, blinded, to which case was in which group.
There is some question about the addition of the 2,000 cases to the originally prescribed number of 5,000, but I come away with the conclusion that there is convincing evidence Aggrenox is more effective than either of its components for stroke, but not for the composite of stroke or death.
So, I would be comfortable with the recommendation that it be utilized for stroke as the indication, but I am not very comfortable with the wish the company has expressed, that it be written up as indicated for stroke or death.
Let me see what my committee thinks.
DR. PENN:  I agree.
DR. DRACHMAN:  When it says for the desired indication, would you like to be very explicit‑‑
DR. GILMAN:  Yes.
DR. DRACHMAN:  I mean death is not an indication.  I mean that is a desired thing to avoid.  So, how does that read, what is it?
DR. GILMAN:  That is a good point.
DR. TEMPLE:  Stroke isn't a desired outcome either.
[Simultaneous comments.]
DR. GILMAN:  Stop.  One person at a time.
DR. TEMPLE:  It would be prevention or reduction of risk or some words like that.
DR. GILMAN:  So, the company wants it to be indicated to reduce the combined risk of death and nonfatal stroke in patients who have had transient ischemia of the brain or completed ischemic stroke.
My suggestion is that it be indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke because, to my mind, what the data tell us is that this medication works better than either of its components for that purpose, and I personally came away thinking that that is a reasonably robust p‑value, particularly for, as Dr. Talarico said, for such a serious problem.
DR. DRACHMAN:  Then, should it say, does it say somewhere thrombotic ischemic stroke?
DR. GILMAN:  I think that would be a very good idea, yes.  We don't want to use this for hemorrhagic stroke.
DR. DRACHMAN:  Right.  Does that include hemorrhagic ischemic stroke?
DR. GILMAN:  Well, that has not been defined in the trial, as I understand the trial.  There is no look with CT to determine whether blood was present consistently.
Is that correct?  Let me ask the company, the sponsor.
DR. HAEHL:  That is correct.
DR. GILMAN:  That is correct. Thank you.
DR. KONSTAM:  Can I just comment on that?  I mean I am thinking about this.  This is the first time we have talked about this.  I mean the endpoint defined was stroke.  What we are saying, at least some of us are agreeing that stroke was reduced, and I could justify that as the indication, that the total frequency of stroke was reduced.
Now, it is conceivable that there were a few more hemorrhagic strokes.  We don't know that.
DR. GILMAN:  We don't know that.
DR. KONSTAM:  But if they were, they were, you know, far outweighed by the number of thrombotic strokes.  So, I mean I personally would be comfortable just saying reduction in the frequency of stroke.
DR. DRACHMAN:  I wouldn't.  This is going to be the very first question my residents are going to ask me.  They will say should we do a scan, see whether there is hemorrhage in the stroke, and if there is, do we give it.
DR. KONSTAM:  That is something different, I guess.  That is I guess for which patients, what is the population for which it is indicated.  In other words, the indication will be to reduce subsequent stroke.  What is the population for which it is indicated?
There, I don't know.  I mean I assume that people with hemorrhagic strokes were not permitted into the trial, right?  They were not.
DR. HAEHL:  They were not.
DR. GILMAN:  Did they all have CT scans to ensure?  No.  They did not.
DR. TEMPLE:  It means no deliberate hemorrhagic stroke, but they don't know.
DR. HAEHL:  Patients with hemorrhagic stroke were not supposed to be included, and in 80 percent of the patients included a CT scan was there.
DR. GILMAN:  But in order to be sure you are not dealing with an initial hemorrhagic stroke, you need a CT scan in 100 percent, not 80.
DR. GILMAN:  Therefore, from the remaining 20 percent, we assume that they didn't have hemorrhagic stroke from the clinic, but we have not a CT scan.
DR. DRACHMAN:  But should that modify the wording of the indication?  Should we put that right in the indication and the labeling?
DR. GILMAN:  Dr. Talarico.
DR. TALARICO:  The labeling does call for reduction of combined risk of death and not for the stroke in patient or have transient ischemia of the brain or completed ischemic stroke.
DR. GILMAN:  That would be just fine.
DR. DRACHMAN:  That is all right, but ischemic stroke may be hemorrhagic.
DR. GILMAN:  What you mean is that sometimes an ischemic stroke will cause hemorrhage into the surrounding brain tissue because of damage to the blood vessels even though the basic mechanism is ischemic.
DR. DRACHMAN:  Right, emboli typically do that or may do that.
DR. GILMAN:  I think that what will happen is that if this drug is approved, the FDA will come to grips with the labeling with the company, taking in the light of what we have said, what we have deliberated about here.
DR. BROOKE:  Could we take a step backwards.  I hate to do that, but I am convinced that there has been interesting effect shown by the combination of aspirin and dipyridamole.  The question is whether it is a good thing to combine them in one drug.
Now, obviously, the advantage is convenience, but isn't there a severe disadvantage?  The dose of aspirin was argued about for a long time.  When you have a combination drug, you have set the ratio, so that it is inflexible, nobody can see whether you need less aspirin, more dipyridamole, and is that not a disadvantage?
I think that what I have been convinced of this afternoon is the combination of those two drugs is advantageous for the disease which has been tried.  I am not sure I have been convinced that combining them in one tablet has been shown to be a great advance to mankind.
DR. GILMAN:  I tend to agree with that position, which is why I think it is a pity that some dose finding studies were not carried out independently, looking at different doses of aspirin and of DP.
Dr. Grotta.
DR. GROTTA:  Well, I mean but the fact is, is that this combination is better, and somebody else can do a study of a different dose combination and find out if that is better than this one, but we do have a result that is positive, that seems to provide an advantage to our patients over what we have available now.
I mean I agree it would be nice if we had 10 different studies of different combinations and to choose the best one.  I also feel very uncomfortable with us changing the characteristics of the patient population and the study characteristics upon which we are basing any approval.
I would be very careful about doing that.  This was a study carried out in patients with suspected ischemic stroke or TIA, and I don't think we should be any more restrictive than that in deciding which patient population should be studied just because we have certain clinical assumptions.
The data indicate that when patients are included with TIAs or suspected ischemic stroke, that the combination reduces the incidence of stroke.  So, I really wouldn't change and be more restrictive than that.
As far as the death issue is concerned, to me, unless you are willing to take the indication of death away from aspirin 50 mg, I don't think that we should‑‑I would argue that we should include death because the drug contains aspirin 50 mg for which there is already an indication that it reduces the incidence of death, and the clinicians out there are going to be very confused when you approve a drug that has aspirin in it, at a dose that has already been approved to reduce death, and now you say that this drug doesn't.
I think we are being inconsistent and the study was not powered to look at the death endpoint really, and I don't have a problem‑‑I disagree‑‑I don't have a problem with the endpoint or the indication as stated.
DR. GILMAN:  Let me respond.  First, that this committee was not the committee that approved aspirin for the indication of death or stroke.
Second, the data that we have been presented showed no beneficial effect with respect to the endpoint of death.  That being the case, I think it would be rather illogical for us to approve it for benefit with respect to death.
Dr. Temple, do you want to comment?
DR. TEMPLE:  Well, we actually thought you would come to this, and we are agonizing about it ourselves.  It is very unclear whether to focus most on the individual study results which show no benefit on death or on the fact that it contains aspirin, which already has a claim, which I would say we probably still think is legitimate even though it wasn't shown in this study.
So, I don't have any advice for you except it is really hard, and we love to listen to what you say, and we will be undoubtedly agonizing about it more.
DR. GILMAN:  Dr. Califf.
DR. CALIFF:  Let me just try to summarize my feelings about this.  We start from a base of one out of three endpoints with a fairly dramatic result for that endpoint in terms of a p‑value, and then there are a list of things which raise the level of uncertainty from that fairly dramatic p‑value ‑ the three endpoints, the multiple looks, the resizing based on looking at the result, the elimination of some patients after randomization due to a problem with the site, the fact that there are no minority patients, which we are labeling this drug for use in a population which had not to some extent been studied, and I personally think that a nonfatal measure endpoint in a disease which is often fatal, looked at in isolation, is a fatally flawed endpoint.
Without any mathematical way of taking all these things into account, I guess that I have to agree with what everyone else has said, is that it looks like substantial evidence, but I would be also in favor of saying death or, because I am really stuck on the point that we can't look at a nonfatal endpoint in a disease which is often fatal.
The issue of dose ranging, if we think we have a problem with sample size looking at a single dose when we are looking at hard endpoints, if you want to do dose ranging for a drug like this, you are going to be talking about hundreds of thousands of patients.
I am just glad we actually have some combinations to look at now, because in most of the rest of medicine, we have got multiple drugs approved for indications with no knowledge at all about how to combine them.  At least this is a start.
DR. GILMAN:  Thank you.
We have heard from the sponsor.  Please, this is for the committee's deliberation now with all due respect, please.
Dr. Van Belle.
DR. VAN BELLE:  With respect to the mortality, I would be inclined to do two things.  One is pass the buck to the FDA ultimately because it is a policy issue, as well, but I would also say that from these studies, you would be able to argue that the results are not inconsistent with a mortality reduction.  I don't think that they contradict that.
So, then, the question comes up how seriously are you going to take the aspirin data by itself from other studies and imply the effectiveness to this particular study.
So, my inclination is let the FDA handle it, so that it can come up with a consistent labeling effort and that this committee would simply say that the results are not inconsistent with the effects of aspirin.
DR. GILMAN:  Dr. Konstam.
DR. KONSTAM:  I am just trying to think this through myself.  I guess I have a problem.  Well, let me just say that there must be some kind of imaginative language that needs to be used in combination products, because this is an issue that is specific for the fact that it is a combination product.
I have trouble saying that by definition because it contains aspirin‑‑you know, the labeling is going to be for this particular combination product‑‑and therefore to say, well, here is a combination product, and it reduces the incidence of death or stroke, when that has not been shown, boy, I guess you could market aspirin plus ginger root, you know, and say it is for reduction in death or stroke, because anything containing aspirin has shown that, so we didn't even have to do any of this.
We could have just said, well, as long as the dipyridamole is not having any adverse effect, we can market it for the combination of death and stroke if that is the logic.  So, I guess I am going to have trouble with that.  I mean I guess I am going to have to say that I can't get past saying that the specific combination is indicated for what we found in this study, and that is reduction in stroke in the population defined, and them some additional wording to say that, by the way, you know, we know aspirin is indicated for blah‑blah‑blah, and this thing contains aspirin.
You will have to work it out, but I think that is my feeling.
DR. GILMAN:  Dr. Katz.
DR. KATZ:  I don't know if this is terribly relevant, but you couldn't mark it ginger root and aspirin unless ginger root had an effect, as well, by the combination policy, so it doesn't necessarily address the aspirin issue, but you can't just add aspirin to anything.
DR. KONSTAM:  But then you have to ask then, okay, following that logically, well, then, what is this combination product approved for.
DR. KATZ:  No, I agree.  I agree.
DR. GILMAN:  Dr. Temple.
DR. TEMPLE:  If I understand your last suggestion, you were saying focus for the combination purposes on what was shown for the combination, and then perhaps somewhere else in the indications, remind people that aspirin is indicated for that.  That is not out of the question.  It doesn't have to be a one‑liner.  It can be longer than one line and explain more.
I forgot before, the matter of what the right dose is, that is a somewhat tricky question here.  For example, if the doses for people with coronary disease and MIs is larger than 50 mg a day, you have the problem suppose someone has both and the physician wants to use a somewhat larger dose along with dipyridamole because he is convinced that dipyridamole provides a benefit, well, I mean you could do it, you could do a baby aspirin to the combination, but my question was, is the controlled release product available or going to be available as a single entity or only in the form of this combination?
It is not available?  What is your plan?
DR. HAEHL:  It is now not available.  We have concentrated all our development on the combination product, however, if there is a population which is in need of that, then, we are certainly prepared to discuss that with the FDA.
DR. TEMPLE:  Obviously, that problem is complicated, too, because the only combination data we will have is with the 50.  Nonetheless, in response to what was said before, combinations pose that problem, and they always do.
The other thing is regrettably, we often don't see good dose finding when it takes 7‑ or 8,000 people per study to find even one dose works, so we are often devoid of good dose response data, although Rob is working on it in some of his studies.
DR. GILMAN:  I would like to have seen at least a couple of doses of aspirin with dipyridamole.
Are there any new points about this first question for us?
DR. PENN:  I was just going to go ahead procedurally and propose something to vote on.  Is that in order at this moment?
DR. GILMAN:  That is perfectly acceptable.
DR. PENN:  Since I agree basically with your position, I would vote no on Question 1 and tie that to a vote yes on Question 2, there is a specific indication which would be stroke.  I don't know whether procedurally we are allowed to combine those two.
DR. GILMAN:  Dr. Katz.
DR. KATZ:  Yes, I think procedurally you can pretty much do anything you want, I mean as long as it is clear what you are trying to tell us.
But I just want to make a gratuitous comment.  There has been considerable discussion about who should this be indicated in or what the actual effect is, is it stroke.  I just want to remind people‑‑and you may already be taking this into consideration in your votes‑‑but I just want to remind folks that there is another critical phrase in the question, which is substantial evidence, and that embodies the question of is one study enough.
So, even though you might be thinking about that, what I am hearing is a focus on what is the claim as opposed to is there substantial evidence.
DR. PENN:  I didn't mean to imply that because I think there is substantial evidence.
DR. GILMAN:  I thought there was substantial evidence also.
There is a motion on the floor which is that we say no to Question 1 and give some language for Question 2.
Is there a second?
DR. TEMPLE:  Can I just ask for a clarification?  A no could mean that there is no substantial evidence for anything or that there is no substantial evidence for including death.  So, however you phrase it, make sure we know what you are voting.
DR. GILMAN:  If you wish, we could discuss Question 1 and then go on to Question 2.  I think what is important is that we deliver the message that seems to have at least the majority of the committee 
DR. TALARICO:  Can you separate the two?
DR. GILMAN:  Separate the two?
DR. PENN:  Then, I can withdraw my motion and say that I do not think there is substantial evidence for the combined indication, and make that as a motion, well, we can vote that question, I guess.  We just vote the question, just call for the vote on the question.
DR. GILMAN:  Is there a second to the motion?
DR. DRACHMAN:  What motion?
DR. GILMAN:  The motion was that the answer to Question 1 will be no, there is not evidence that this single study supported the indication that the medication is useful in stroke and/or death.
Is that right, Dick?
DR. PENN:  Yes.  Yes, that is what I intended.
DR. BROOKE:  Stroke or death?
DR. GILMAN:  Stroke and/or death, the combined endpoint.
DR. BROOKE:  Isn't it stroke and death?  I think it may be effective in stroke.
DR. CALIFF:  In the composite of stroke.
DR. GILMAN:  Let's call it in the composite of stroke and death.
Was there a second?
[Second.]
DR. GILMAN:  There is a second.  All right.
Discussion?
[No response.]
DR. GILMAN:  All right.  All in favor of the motion, please so signify.
[Show of hands.]
DR. GILMAN:  Seven.
All opposed?
[Show of hands.]
DR. GILMAN:  Three.  Seven to three.
DR. TEMPLE:  So, yes means no, right?
DR. GILMAN:  Those in favor of the motion.  The motion was that the answer to Question 1 is no.
DR. TEMPLE:  Just making sure.
DR. GILMAN:  But we are going to modify that response by going to Question 2.
DR. PENN:  And the motion of Question 2 is the committee agrees that there is substantial evidence for the effect of the product on stroke.
DR. TEMPLE:  How should someone who thought there was evidence for both vote?
DR. PENN:  They have a choice.
DR. TEMPLE:  Well, no.
DR. PENN:  The people who voted, they already indicated, three people have indicated they think we are all wrong, you know, of the 7 that voted that way are wrong, but they have included their clear indications of why, and they do not want to confuse physicians about this.
DR. TEMPLE:  Let me suggest something different, that if you believe it should be approved for both stroke and death, you would want to support this, not vote against it  That will just confuse everything.
DR. GILMAN:  Dr. Grotta.
DR. GROTTA:  Well, you could amend your motion to reflect what Dr. Van Belle suggested, and that it doesn't exclude an effect on death, in other words, that the studies have shown that the drug reduces the incidence of stroke, and does not exclude an effect on death.
Then, I think that you would not have that dilemma for those three people who voted yes on No. 1.
DR. PENN:  I would be pleased to amend it in the way you have stated it.
DR. GILMAN:  Would you restate the motion then.
DR. PENN:  The motion, once again, is that there is substantial evidence to support the effectiveness of this product for stroke, and that there is not enough evidence to include in the indication death.
Isn't that what you were saying?
There is inconclusive be acceptable?
DR. VAN BELLE:  It is not inconsistent with.
DR. PENN:  It is not inconsistent, okay, I am sorry, I chose the wrong word.  Is that all agreeable, then, not inconsistent with the three people that voted the other way?
DR. LACEY:  Not inconsistent, I am not sure I understand.
DR. KONSTAM:  Can I restate it?  I think the motion would be that there is data supporting the prevention of stroke without regard to the death question is really I think what we are saying.  So, you would not prejudice your vote against this motion if you felt that there was a combined indication, there was sufficient data for a combined indication.
It is really focusing on the stroke indication independent of the combined question, right?
DR. GILMAN:  That is a little different from what Dr. Van Belle said now.
DR. CALIFF:  I think it is quite different because I can't accept‑‑I mean I will have to accept it if is a majority vote, but I would opposed vehemently‑‑I mean you just cannot ignore informative censoring.  O'Neill used the word, I couldn't think of the right word, but, you know, we will be rewriting the textbook of what we have learned about clinical trials in the last 10 years to say it that way.
I think the way it was stated before is fine.
DR. PENN:  Using inconsistent I think would‑‑
DR. GILMAN:  It is not inconsistent with an effect on death.
DR. BROOKE:  Do you feel you have to have death in the phraseology?
DR. GILMAN:  I don't think that Dick particularly cares, but we have three votes that may go the other way on this question unless that is included.
DR. PENN:  Yes, and I have no problem with stating what the fact is, at least I think what the facts are from what was presented to us.
DR. BROOKE:  It is like telling children not to stuff beans up their nose.  The first thing they do is they go and do it.  If you mention that it is not inconsistent with prolonging death, the person who reads the insert will think, oh, good, it prolongs life.
DR. KONSTAM:  Maybe we could ask the agency if we just went around the room and each of us said what we felt about this, would that not be sufficient information for them?  They are all nodding their head.
DR. PENN:  We have to vote, I thought.
DR. GILMAN:  We are supposed to give guidance.
DR. KATZ:  I think what is most critical is that we get clear, if you can give us clear guidance on what we should do, I think the vote is, you know, it is a tradition I guess.  I don't think there is anything in the law that says you have to vote.
But we would definitely like to get a clear picture of what you think the indication ought to be.
DR. TEMPLE:  Well, no, there is two things.  One, what do you think there is evidence for, and then there is a lot of nuances of exactly how to say it.
DR. KATZ:  When I say evidence, that is what I mean, what you think there is evidence for.
DR. GILMAN:  Well, folks, we have seen some evidence here that does not tell us that this medication will prevent death.  I am sorry, but no matter what any other trial says or what the FDA has said before, the data do not support that claim.
DR. TEMPLE:  Well, you actually voted on that.  Three people thought maybe it did, and the rest didn't, so that one you voted on, that is clear.  But the question here is we need a clear understanding of whether the committee thinks there was evidence for a different claim.
DR. PENN:  That is a misinterpretation of that vote.  I thought that the people who objected wanted consistency with other data, not just the data that was presented to us.
In other words, they thought that the aspirin labeling was all right, and that because we had aspirin that they would go along with that, and they didn't want to confuse physicians about it.
DR. TEMPLE:  You may be right, that isn't‑‑the question says whether there was substantial evidence supporting that claim, but you may be right about why people voted the way they did.
DR. BROOKE:  Just because aspirin used on its own has an effect on survival, doesn't mean that when it is used in combination with another drug that it has the same effect.  I mean there is numbers of examples of drugs that don't work well together.  I mean as far as death is concerned, I am not talking about stroke.
DR. GILMAN:  Claudia, do you want to comment?
DR. KAWAS:  There have been a lot of things said today, and I just thought I would run through the list of the ones I am not concerned with and end up with the one I am concerned with, which is exactly what we are debating.
I mean I know there were discussions about multiple looks with regards to safety, and that personally didn't concern me.  It looked to me like‑‑it was essentially as safety monitoring committee, and didn't affect the integrity of the study.
There was concern about the diagnosis of the events and the inclusion, and as I said before, I think that those were taken care of by the randomization process, and there doesn't seem to be any appearance of breaking the blind which would affect that.
So, as a trialist, I am not concerned about that, although as a neurologist, like many of the people here, I can say I am very concerned about accurately diagnosing strokes.
I was also taken with the discussion about the low dose of aspirin, but I think that the consensus of the scientific community supports that even if the data doesn't, and here is another place where the data doesn't support things, and that is the aspirin and the risk of death.  Most of the previous studies really haven't shown that aspirin has an effect on death even though we keep talking about it like it is clearer in the previous studies than it was in this one.
In regards to the questions that the FDA presented to us, I believe that this is a single study that meets a lot of their criteria.  I mean specifically, it is certainly large since we have heard repetitively it is significantly added to the number of patients exposed in clinical trials to both of the drugs.
It does have some consistency between groups, and I didn't find that a problem, as well as multiple studies or pairwise comparisons that were satisfactory in endpoints.
The issues about generalizing to other populations isn't any different from any other drug we have on the market since most of our studies have not been adequately studied in other racial groups, even the ones done in the United States, much less the ones done in Europe.
So, the things that do concern me come down to the primary endpoints.  In particular, the interim analysis wasn't prespecified, and increasing the sample size didn't bother me because I think that doesn't change the results, but I do have some concern about how the endpoints were decided, and I think that is the crux of the discussion we are having, because it makes it hard to know how many corrections or pairwise comparisons we should be making.
The data, to my mind, suggested that there was a role for this combination, better than placebo, to prevent stroke, and that there was a clear additive effect, and that is part of the consistency of the study where the estimates really looked very consistent to me.
The data does not show, however, to my mind, that there is an effect on death, and the problem is earlier in the day, you know, Dr. Temple told us that how we indicated this or interpreted this was to some extent are taste, and I don't know what my taste is in this because I understand both sides of the argument.
I mean death is very much embroiled in cerebrovascular disease.  Overall, despite the way I voted a minute ago, I do think probably death needs to be factored in, but there is not data that convinces me that this delays death.
That is why I don't know quite how to vote on all these convoluted suggestions that everybody is giving me with double negatives and triple, or whatever, but I do think that we just saw a factorial design that showed me that there was a role for this combination as compared to placebo in prevention of stroke.
I am glad that the FDA uses us as an advisory committee, and they get to figure out the real answer.
DR. GILMAN:  Dr. Talarico.
DR. TALARICO:  Probably it might be easier if we go back to the question as questions rather than making into making motions, because the first two questions address just whether you are convinced that this study has shown enough evidence of effectiveness of Aggrenox for the desired indication, which is the combined endpoint of death and stroke, and the answer can be yes or no.  Then, if not, then go to the next question because otherwise it becomes very difficult.
DR. GILMAN:  I understand.  We want to be as helpful as we can.
DR. TALARICO:  The discussion was very informative, but I think if we can come to the vote in terms of question, it might be easier for you.
DR. GILMAN:  We are getting a mixed signal now.  Would it be most helpful to the FDA if we were to vote or if we were to go around the table and just everybody respond to Question 1 and then Question 2, and so on?
DR. TALARICO:  The discussion is very informative, but eventually the vote has to come to the question as it is posed.
DR. TEMPLE:  But the question has to be clear.  For example, if there were someone‑‑Rob may not be such a person‑‑who thought that the stroke thing was well done and at least they ought to get that, then, you don't want a no answer on No. 2 just because they thought it also ought to get death.  That would be a confusing answer.
So, as long as you clarify those and say how people who think various things should vote, then, voting is fine or the recent discussion was very helpful, too.
DR. GILMAN:  Well, then, just to reiterate, in Question 1, the three no votes were based upon their view that death ought to be included as an indication for the reason that there was some evidence suggesting that it may be helpful even though the data were not significant.
Is that correct, the three no votes?
DR. VAN BELLE:  As one of the three, it just seemed to me that from the discussion earlier this morning, there was some degree of arbitrariness as to whether death is included in a labeling issue or not, and so I was just responding to Dr. Temple's comments earlier this morning that death is often included, and we have also heard some other aspects to that effect.
What I am saying is that when I look at the data, the data are not going to be inconsistent with that claim.  There clearly is no proof in these studies that death is delayed or reduced.  That is not the case.  But the results are not inconsistent, so it is really a question of power, and we have heard before that death as an endpoint requires much larger studies, and so you are just not going to get that.
So, I see it as somewhat more of a policy issue rather than a scientific issue.
DR. GILMAN:  Yet, the question is based on this single study, has the sponsor provided substantial evidence of effectiveness of Aggrenox for the desired indication, substantial evidence.
Dr. Drachman.
DR. DRACHMAN:  Just so we don't lose sight of Dr. Brooke's point, we will use aspirin for headache, yet, in this particular mode, the number of headaches in the mixed drug was greater than for placebo.
So, if we are thinking about something for which there is no evidence, meaning the alteration or elimination of death or reduction of death, the fact that aspirin sometimes works for a headache, sometimes may prevent death, may not provide substantial evidence here for either one.
Is that clear?
DR. TEMPLE:  No, I had a flash.
DR. DRACHMAN:  Let me say it again then, Sid.  We believe that aspirin by itself may reduce the amount of death in stroke.  We also do believe that aspirin in another setting is very useful for relieving headache.
Here, in this study, as I recall the data, there were more headaches in the combined drug than in the aspirin or placebo drug, meaning that the combination is not necessarily equivalent to the sum of its parts.
DR. GILMAN:  Well, that is because the headache came from the dipyridamole.
DR. DRACHMAN:  Well, we don't know that.
DR. TEMPLE:  This is 15 mg of aspirin.  It is not relevant to headache.
DR. GILMAN:  That is another point, small amount of aspirin.
DR. TEMPLE:  I had a flash.  See if this helps.  In Question 2, say, has the sponsor provided substantial evidence of effectiveness for either reduction of the risk of the stroke or the reduction of risk in stroke and/or death.  Then, you get both groups, one or the other.
Does that make sense?
DR. PENN:  No.  I think we should have a clear vote that we think that it works in stroke and get that over with.  The phrasing of how we indicate the situation on death, we are argued about and we have given you clear indication that‑‑not how confused we are‑‑but that we don't think that there is substantial evidence in this particular study.
DR. KONSTAM:  But you want people who voted yes to No. 1 to be able to vote yes for No. 2, as well, and I think that Bob's suggestion permits that.  So, I think it is just a tactic to do that, and I think it would work.
We already voted no, 7 to 3, on Question 1.  So, those three people have carved out their viewpoint.  What I think we want to say is we don't want to keep those three from voting no on 2, if we think that there is a stroke indication in there, and Bob's suggestion would do it.
DR. PENN:  Why would you vote no on 2?
DR. KONSTAM:  I think he doesn't want a 7 to 3 vote in favor of No. 2, and then in the end of the day, not being able to figure out what that 7 to 3 vote meant, when, in fact, the three people were convinced that this agent is worthy of an indication.  Right?
DR. BROOKE:  If you couple death and stroke, some of the people that voted for stroke will not vote for it.  You will lose the 7, as well as the 3.
DR. KONSTAM:  He is the one we are advising.
DR. PENN:  In fact, that is the case, I would not vote for something that couples it.
DR. DRACHMAN:  Why don't we just separate them?
DR. GILMAN:  One person at a time.  Dick?
DR. PENN:  I am sorry I interrupted that way, but I wouldn't unless somebody puts a very convincing argument it vote for a motion‑‑
DR. KONSTAM:  You are not being asked to.  You are being asked to vote yes for No. 2 if one of these is acceptable to you, and then in the discussion, you can tell which one.  We will go around the room, and we will be able to tell which one of the two, and we will give a yes vote, and it wind up with a clear message that there is an indication here, and give them the input about which one we think it is.  I think we are just trying to get over a hump  here, aren't we?
DR. TEMPLE:  This was really to do what you wanted to do, get a vote on stroke.
DR. KATZ:  Don't we already know that 7 folks want this to be approved as a treatment for prevention of stroke and that 3 people want it approved for stroke or death, don't we know that already?
DR. KONSTAM:  I think we have already voted on it.  I think we have done it.
DR. GILMAN:  We know that.
DR. TEMPLE:  No, the 7 who voted on the first one just said they didn't want it for stroke and death, and I am not sure where Rob is going to come out, for example.
DR. HOUN:  But then the 7 people, why don't we find out from them if they don't agree for stroke and/or death, what do they think there is substantial evidence for?  So, we just focus on the 7.  The 3, I think have voted‑‑is that true that they vote there is substantial evidence for the desired indication of decreased risk for death and nonfatal stroke?
DR. TEMPLE:  Which must include stroke.
DR. HOUN:  It is the 7 we want to know, if they don't believe, what do they feel there is substantial evidence for.
DR. GILMAN:  Rather than dealing slavishly with Question, let's just go around the table for the 7.
DR. DRACHMAN:  Stroke.
DR. CALIFF:  Stroke.
DR. GILMAN:  The evidence is substantial for reduction of stroke, yes, but not for any other indication.
DR. LACEY:  I echo that.
DR. KAWAS:  Stroke.
DR. KONSTAM:  Stroke, and I would just like to explain the vote a little bit.  I think that I would agree with stroke.  I take the argument around the concern about not having a combined endpoint and the possibility that by not including death in the combined endpoint, perhaps we are biasing it, but I don't believe that is going on here, because I don't think that there is any adverse effect on‑‑there is no adverse effect on mortality, and my guess is that at least components of this have a beneficial effect on mortality, so I am not concerned about that.
So, I am left saying that it does reduce the incidence of stroke, and I guess it would be worthwhile, I think, us spending a minute saying why it is that we believe this single trial provides sufficient evidence to support that, because I think the statistical reviewer are argued against that, so I don't know if enough of us have spoken to this specific question, what is it in the data set that really is driving us to say yes, so I will just speak for myself about it.
We have some very low p‑values.  I mean the specific p‑value that I focus in on is 0.008 for the combination compared to aspirin alone in the prevention of either fatal or nonfatal stroke, and I guess that would have to be corrected down for the fact that we have a couple of different endpoints at the beginning and there was more than one look, but I think given all we know about this, I am willing to accept that as very strongly positive signal that I will accept the one trial.
So, that is the summation of my feeling.  That was a yes for stroke.
DR. GROTTA:  I would like to say just one thing.  Again, it reiterates the point.  My understanding is, is that there are three drugs out there that are approved for the combination endpoint of stroke and death.  There are three drugs out there‑‑well, what is the indication for clopidogrel?  Is it just stroke?
DR. CALIFF:  Clopidogrel is stroke, death, MI, all three.
DR. TEMPLE:  And in a very mixed population, however.
DR. GROTTA:  Okay, and aspirin, as well.
DR. CALIFF:  But a very similar data set in terms of its actual effect on stroke.
DR. GROTTA:  And Ticlid is also a combined endpoint approval, it's not just stroke.
DR. TEMPLE:  That is true, and actually some of the data came from noncardiovascular deaths.
DR. GROTTA:  So, all I am saying is that the clinician has three drugs out there that are approved for more than stroke.  This drug comes out, and we have an indication for stroke.  The clinician is going to see that, when, in fact, the data shows that this drug is superior to aspirin for the prevention of stroke and in the combined endpoint of stroke and death, is at least as good.  There was a statistically significant effect of this combination on the endpoint of stroke and death.  It just wasn't statistically significantly better than aspirin or dipyridamole.
So, the fact of the matter is, is that this is why I have trouble with eliminating the death issue from this, that you are going to confuse clinicians by this, and not only that, it doesn't really reflect‑‑I mean we heard a very articulate summation of the data a minute ago by Dr. Kawas, and it seems to me that we just want to state what the data shows, what were the results.
Well, the results are that the drug is superior to aspirin or dipyridamole for prevention of stroke, and it is at least as good as aspirin for preventing the combined endpoint of stroke and death.  So, maybe that is what we should say, but that is why I have trouble just limiting it to stroke.  I don't know how I can say‑‑I have said it three times now, so I don't think I can say it any more than that.
DR. KONSTAM:  There is a really good point that is coming up here, which I don't think we have really touched on directly is the equivalence question.  I mean if we were able to derive from the data set that the combination is equivalent to aspirin, therefore, no worse than aspirin in preventing some larger endpoint such as mortality, then, I think that would be sufficient to warrant that indication, wouldn't it?
DR. GILMAN:  If you look at the data, there is no significant effect upon death as a marker.
DR. KONSTAM:  I understand.
DR. GROTTA:  Nobody is talking about death.  You are confusing the issue, no one is talking about death.  We are talking about the incidence of stroke or the incidence of the combined endpoint of stroke or death.
Nobody has suggested that there be a statement in there that says that the drug prevents death per se.  It is the combined endpoint of stroke or death over which there is an indication for all the other drugs.
DR. GILMAN:  But that has not been demonstrated in this study.
DR. TEMPLE:  Yes, it has.  Let me just make an observation.  I must say I am guilty of it.  We are so focused on the combination policy, which is what is the contribution of each component to it, that we have neglected the fact that the whole thing has the desired low p‑value effect on stroke and death.
DR. GILMAN:  But because it is a combination product, we are focusing on whether it is better than two other ingredients.
DR. TEMPLE:  Well, one could separate this conceptually by saying can you show that there is a contribution of a valid kind of each component of this thing to something, and one might conclude that that is shown by stroke.  A number of people have said that.
You then can sit back‑‑this is a labeling thing, I must say we have not dealt with something like this, so I am out on a limb here‑‑but one can think of what the whole drug is for without necessarily representing or requiring that each component be shown to do that.  Those are separable issues potentially which we would obviously need to think about.
DR. GILMAN:  Dr. Katz.
DR. KATZ:  The fact that the whole combination has shown an effect on the composite endpoint largely, if not entirely, is due to the fact of its effect on stroke.  So, I mean I think the question is, is it misleading‑‑I don't know about the data for the other drugs out there‑‑but is it misleading to tell people in labeling this has an effect on stroke or death, when, in fact, there is no evidence that is has an effect on death.
I mean I think we have to deal with the potential misleading nature of such a claim, and as Bob has said, it is very tough, it is hard to know what to do with this in the context of the fact that one of the components already has that indication, other drugs out there like this have that indication.  It is a very tough call, but I think the question of misleadingness is worthy of thought.
DR. TALARICO:  If people are concerned about misleading, the labeling can address the issue by showing exactly what were the results in strokes and what were the results in death.  So, it is not going to be just the indication for death and strokes.
DR. KATZ:  I should say we have regularly done that, where there was a triple component endpoint, we have given the actual results with each one.  Now, of course, we stick that in the clinical trial section that people may or may not read, but it could be in a more prominent place if that was thought important.
DR. GILMAN:  Dr. Califf.
DR. CALIFF:  Dr. Grotta couldn't have made his part of the argument as well.  I mean he really said it quite well, and I can't do it any better, but the other thing for me again is that I think you are seizing on a p‑value for an endpoint that you can't accurately measure, and that p‑value that you are looking at is counting a denominator which is not a real denominator.  It is influenced very much by the deaths which are unaccounted for, and that, combined with Dr. Grotta's reason, it is really both of those that are impacting the way I feel about this.
DR. GILMAN:  Again, I think Dr. Katz said it very well, the data on death or stroke in fact were carried by the very robust effect upon stroke.
DR. CALIFF:  The strokes that you think you are measuring being unable to account for all the patients that were randomized.  This is a well‑described phenomenon in composite endpoints where there is a significant mortality in the trial.
DR. BROOKE:  Censoring data is a problem, but we have to deal with the data that we have got.  We can't imagine what it would have been if we had the censored data.  Committees like this are accused of paternalism, and it is probably true.
I mean maybe the best way to do this is to say, look, this drug is safe, clients are the ones that decide whether they want it or not.  It will fall or stand in the marketplace, and if it is not a good drug, then, eventually, nobody will buy it.
But I still believe there is a last vestige of academic integrity around here, and the data that we have presented showed an effect of the combined treatment, which was additive, on stroke and, of course, the results on stroke was robust enough that it carried over into a combination.
But I think it would be a little dishonest‑‑I don't see what is wrong with voting one on stroke and one on death, and you were halfway around, and I thought that was a good idea.  I was one of the 7, and I would vote for stroke, but I wouldn't put death in the flyer.
DR. GILMAN:  Dr. Van Belle, you are the one person who has not spoken on that issue.
DR. VAN BELLE:  Well, I will certainly vote for stroke, and again, as I said, it is not a principial thing with me in spite of the academic concerns on my left here.  I think it is a matter of the FDA's setting up a labeling system that will not confuse practitioners, so I think it is a practical issue rather than a philosophical issue.
DR. GILMAN:  Dr. Penn.
DR. PENN:  I would just like to make one last point on this.  We are often in a situation where we have to deal with a scientific presentation and we are limited by what is presented to us in that scientific realm.
On the other hand, there is a fairness issue here, and that is that we are penalizing the company for getting an equal right to market its drug the way that other drugs have been marketed for the extra indication of death.
So, we have to indicate that to the FDA, that we think there is something wrong here.  The science is pretty clear to us, but there is a fairness issue to the company that has to be dealt with in a very positive and strong way, and to say maybe in the labeling, something to the effect that there is the same amount of information on this drug as the others for the indication, the combination indication, is a way of handling it at least in part.
It still penalizes the company because they can't advertise in the same exact same way, but this is not an uncommon problem that our hands are sort of tied by what has been happening in another realm, that death has been thrown in inappropriately when they didn't have the data because they didn't do large enough studies in any of these cases.
DR. GILMAN:  Let me ask the FDA now, have you heard enough?
DR. TEMPLE:  Can I say what I think I heard?  I didn't hear anybody who, despite the concerns about multiple endpoints and all that, didn't think that an effect on stroke had been shown.
The closest to a negative view of that would be from Rob Califf, who thinks that you really have to take the combined endpoint and look at that, but he seemed satisfied that that was okay anyway, but may want to clarify that, but I didn't hear any other reservation about the stroke endpoint.  There is a vigorous debate about what you should do about death, and we obviously have all heard that, and we will have to be imaginative, which since we are bureaucrats, is difficult, but we are going to work on it.
DR. GILMAN:  To summarize, it appears that 10 members agree that this drug has been shown to effective in stroke, and 3 believe that it should be labeled as helpful for preventing death or the combined stroke/death combination.  Only 3 believe that.
Do you want anything further on No. 2?  Have we done enough?  We have done 2.
No. 3.  Would you recommend approval for the requested indication?  I believe the answer is yes‑‑no, sorry.  It is late in the day.  The answer to that is no.
DR. KATZ:  I think the next two questions sort of complicate things.  I think they are basically equivalent to what you have already voted on, unless you thought there was a safety problem, which is the last question, but if you don't think there is a safety problem, I think you have given us your view on the matter of approvability.
DR. GILMAN:  Thank you.  Let's just skip down to 5, and I don't believe there are safety issues of particular concern, are there, members of the committee?
[No response.]
DR. GILMAN:  All right.  I believe we are done. I can't believe it, but we are done.
[Whereupon, at 4:50 p.m., the proceedings were adjourned.]
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