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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.

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