UNITED STATES OF AMERICA

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

8:31 a.m.

DR. BORER: We'll begin the Cardiovascular Renal Drugs Advisory Committee meeting. Why don't we introduce the committee members and the FDA Representatives, going around the table. John, we'll start at your end.

DR. NEYLAN: Yes, I'm John Neylan, I am the Acting Industry Representative to the Committee.

DR. CARABELLO: I'm Blase Carabello, a cardiologist from Houston.

DR. KNAPKA: I'm Joe Knapka. I'm a Patient Representative on the Committee.

DR. NISSEN: I'm Steve Nissen, I'm a cardiologist at the Cleveland Clinic.

DR. LORELL: Beverly Lorell, I'm a cardiologist, Harvard Medical School.

DR. PICKERING: Tom Pickering. Hypertension expert at Columbia Presbyterian in New York.

DR. HIRSCH: I'm Alan Hirsch, a Cardiologist and Vascular Medicine Specialist at the University of Minnesota in Minneapolis.

DR. FLEMING: Thomas Fleming, University of Washington, Seattle.

DR. BORER: Jeff Borer, Cardiologist at Cornell in New York City.

MS. SPELL-LESANE: Dornette Spell-LeSane, Executive Secretary for the Committee.

DR. CUNNINGHAM: Susanna Cunningham, University of Washington, Consumer Representative.

DR. ARMSTRONG: Paul Armstrong, cardiologist, University of Alberta.

DR. PORTMAN: Ron Portman, pediatric nephrologist, University of Texas in Houston.

DR. PRITCHETT: Ed Pritchett, Cardiology and Clinical Pharmacology at Duke University Medical Center in North Carolina.

DR. WOOD: I'm Alastair Wood, Clinical Pharmacology from Vanderbilt.

DR. HIATT: Bill Hiatt, vascular medicine, University of Colorado.

DR. ROSEBRAUGH: Curt Rosebraugh, Deputy Director, Division of Over-the-Counter Drug Products.

DR. THROCKMORTON: Doug Throckmorton. I'm the Division Director in the Division of Cardiorenal Drug Products.

DR. BORER: Okay, thank you very much. We'll begin with the Conflict of Interest Statement. Dornette Spell-LeSane, the Executive Secretary will read this.

MS. SPELL-LESANE: The following announcement addresses conflict of interest issues with respect to this meeting and is made a part of the record, to preclude even the appearance of impropriety at this meeting.

The topics to be discussed today, will not focus on any particular product or company, but rather may affect aspirin manufacturers.

The Conflict of Interest Statutes prohibit special government employees from participating in matters that could affect their own or their employer's financial interest.

All participants have been screened for interest in the products and companies that could be affected by today's discussion.

In accordance with 18 United States Code Section 208(b)(3), the Food and Drug Administration has granted waivers to the following individuals because it has determined that the need for their services outweighs the potential for a conflict of interest.

Thomas Fleming, Jeffery Borer, Edward Pritchett. A copy of the waiver statements may be obtained by submitting a written request to the Agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

We would also like to note that Dr. John Neylan is participating as a non-voting Industry Representative, acting on behalf of regulated industry.

Dr. Neylan is employed by Wyeth Research. In the event the discussions involve products or firms not 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 financial involvement with any firm whose products they may wish to comment upon. Thank you.

DR. BORER: We have some introductory comments and welcome from the FDA Representatives. Doug.

DR. THROCKMORTON: Thanks, Jeff. My comments will be quite brief. I'd just like to take this opportunity to thank the members of the Advisory Committee and the other participants in this meeting today, for coming together to discuss this highly important, highly relevant public health issue. I'm looking forward to a vigorous debate and I much appreciate everyone's participation. Thank you.

DR. BORER: Okay. As it says on the agenda, the committee will assess whether aspirin should be recommended for primary prevention of myocardial infarction in some defined population.

Professional labeling for aspirin currently recommends it's use for prevention of a second myocardial infarction. We'll begin the sponsor's presentation with Representatives from Bayer. Dr. Peitler.

MS. PEITLER: Mr. Chairman, members of the Advisory Committee, Drs. Rosebraugh, Throckmorton and Ganley, FDA Staff, good morning.

It is an honor to be here today to participate in this public health dialogue. My name is Erica Peitler and I am a Senior Vice President with Bayer Consumer Care, and acting Head of R&D.

Today, it is clear that we have consensus. Aspirin prevents MI. What we are here to consider is how to further expand the professional label for aspirin to include additional individuals.

Those at moderate to high risk for whom the benefits clearly outweigh the risk. Today, in spite of its widely-recognized benefits, aspirin, which costs only pennies per day, still remains underutilized.

There is a significant gap between the aspirin prevention recommendations of major scientific organizations and what happens in actual clinical practice.

Guidelines from the American Diabetes Association, and more recently from the American Heart Association and the United States Preventive Services Task Force, encourage the use of aspirin in moderate risk individuals.

These evidence-based guidelines represent the state of the science within the medical community. But they are not enough to effect the changes required.

Only with FDA approval of an expanded indication to prevent first heart attacks, can there be significant impact. Expanded professional labeling will, first, provide direction and increased clarity for health professionals in determining appropriate individuals for aspirin use.

Second, it will further increase patient awareness and education about cardiovascular risk and it will encourage them to discuss risk management strategies with their physician. In short, expanding the professional labeling for aspirin will help close the gap between the current medical evidence for aspirin and its optimal use.

Over the past two decades, our collective efforts have led to a number of important FDA approvals for the cardioprotective use of aspirin.

Including the prevention of a second heart attack in the 1980s and the prevention of death during an acute MI in the 1990s. And now we come together again.

This time to consider further expansion of aspirin use to prevent a first heart attack. At the center of this discussion, is the issue that we have a gap between the clinical evidence and the current labeling for aspirin.

Current guidelines suggest that patients with a ten year risk of coronary heart disease of at least ten percent, should be on an aspirin regimen, whether or not they have had a previous MI.

This recognizes that an event may be more likely to happen in someone with elevated risk factors than in someone who has already had a heart attack.

Yet, current professional labeling defines eligible candidates for aspirin therapy solely on the presence or absence of a previous event. A redefinition of patient selection criteria within the aspirin labeling is clearly needed.

To facilitate this change, we have filed a citizen's petition requesting that professional labeling be based on global rather than event-based risk.

In 1989, the Cardio Renal Advisory Committee voted six to two in favor of expanding the professional label to include first MI.

Since that time, three additional trials have been published. The patient database has doubled, from 27,000 to 55,000. The data that will be discussed today, from the five large studies, demonstrate a statistically significant reduction in non-fatal first MI.

Viewed in the context of the totality of the evidence, these five studies advance our understanding of the appropriate patient population who can benefit from an aspirin regimen.

The evidence is in, with respect to moderate and high risk patients; it is now time to take action. To help frame the discussion and dialogue, Bayer has taken the lead in assembling a group of Researchers and Clinicians.

With us today are the principle investigators from all five studies. We encourage you to take advantage of their expertise in having them further design, in having them further discuss the design features and the findings of their trials.

We also have the guideline authors from the AHA, the ADA, and the USPSTF. We have leading Cardiologists also with us, providing practice perspective. We have experts in GI safety and hemorrhagic stroke, as well as experts who can comment on epidemiology, labeling and utilization.

First this morning, Dr. Thomas Pearson, from the University of Rochester, will discuss the benefits of aspirin to a wider group of eligible patients.

Next, Dr. Colin Baigent, who leads the Antithrombotic Trialists' Collaboration, will comment on the totality of the evidence in both the primary and the secondary databases.

Dr. Noel Bairey Merz, of Cedars-Sinai Medical Center, will provide insight on what the labeling recommendations should be with respect to women.

Dr. Randall Stafford of Stanford University, will comment on the dramatic underutilization of aspirin in preventing cardiovascular events.

And then Dr. Eric Topol, of the Cleveland Clinic Foundation, will provide a clinical perspective on the proposed labeling change. Bayer is proud to have taken the lead today in building support for this public health partnership.

To more clearly determine appropriate candidates for aspirin therapy. We welcome today's dialogue and we share your sense of urgency about the role of aspirin in addressing this critical public health need. Thank you. Dr. Pearson.

DR. BORER: Does anyone have any overall questions for Dr. Peitler? I have just one, if I might. You made the point that FDA approval would have an impact on patient recognition of the potential role of aspirin. How would that happen?

MS. PEITLER: How would, how would the impact happen? Two things, two very important impacts. One is with the label approval, physicians in clinical practice would have specific clarity and assistance in helping to define and select appropriate patients.

Right now they don't have that specificity. Only an event determines whether aspirin is used or not. So the primary prevention labeling that we're requesting, which is risk-based, will help them decide which patients are at risk and who is appropriate for aspirin use. Second, the educational efforts that will then be rolled out through physicians, ultimately to patients, will raise awareness around risk factors, and engage the physician and the consumer and patients in appropriate dialogue around risk management strategies.

DR. BORER: If professional society guidelines suggest use of aspirin beyond the current label, how will this change cause that second effect. How will the labeling change cause that second effect.

That is that doctors will talk to patients about this, whereas before they wouldn't?

MS. PEITLER: Guidelines are one part of what we think is a collective and collaborative effort. To achieve a public health actionable outcome, it requires not only the guidelines from the leading scientific organizations, it requires FDA labeling.

It requires physician engagement, it requires patient education, to bring those forces together so that behaviors could be changed and appropriate dialogue can take place.

DR. BORER: Any other, yes.

DR. PRITCHETT: I think I heard you say that in 1989, the Committee considered this. And, in fact, I was on the Committee in `89, and I sort of remember this, and that they voted six to two in favor of additional labeling, which never happened, is that correct?

MS. PEITLER: That's correct.

DR. PRITCHETT: Can you or someone explain to us what happened? I remembered the vote as being five-four, but I'll take your word on it as being six-two.

What, what happened that it never happened?

MS. PEITLER: I think, the short answer, the six to two vote, at the time, the physician's health study and the British doctors trial, were the only two trials that were there.

And I believe that there was some discussion over the divergence of those findings. Today, we bring to the table now three additional published trials, the database which was 27,000 strong at that point, has now advanced to over 55,000.

DR. BORER: Okay.

MS. PEITLER: Thanks.

DR. PEARSON: Dr. Borer, Committee Members, Colleagues, it's my really distinct pleasure to have the opportunity to bring to you what we believe is a strong rationale for the expanded professional, professional labeling of aspirin to include moderate risk patients.

I'm Tom Pearson. I'm a Cardiovascular Epidemiologist. I run a preventive cardiology clinic at the University of Rochester Medical Center, and it's my opportunity to really describe our thinking on this matter in terms of supporting this labeling.

So we propose to adopt risk labeling for aspirin patient selection, and to include patients with ten year risk of coronary heart disease that exceeds ten percent, where we believe benefits outweigh the risks.

I'd like to outline the rationale that we'd like to bring to you today, and certainly the salient points that I want to make this morning.

First of all, coronary heart disease continues to be a major public health problem. Second is that many patients are at sufficient risk of coronary heart disease to warrant aspirin treatment.

Third is that global coronary heart disease risk and it's an appropriate way to determine the type and intensity of these interventions.

Professional labeling can define moderate and high risk populations where we believe the benefits outweigh the risks. And finally, and a point that will be made by Dr. Stafford in his studies, is that there is substantial underutilization of aspirin in high and moderate risk patients currently.

I think we all know that for the last, almost the last century, that coronary heart disease has been our leading cause of death. What, perhaps, we aren't quite as aware of is that the Epidemiology of this disease is changing.

Despite previous market reductions in the mortality, I think there is very good evidence to suggest that our incidence is no longer falling.

It's the incidence of coronary heart disease, since about 1990 in this country, as evidenced by community studies in Worcester, Massachusetts and Olmstead County, Minnesota has been flat.

In other words, no further reduction in incidence. With continued fall in case fatality rate, this leads to a rising prevalence of coronary heart disease. And as these patients are of increasing number in our communities, this carries huge implications to direct and indirect costs for our communities.

Finally, and as you all know in this committee, is that the first presentation of coronary heart disease is often times the last or often times a disabling one. Twenty percent of coronary heart disease initial cases present as sudden death.

And I think you're also aware that your hospitals are full of congestive heart failure patients, which is one of the few, if only, diseases whose incidence prevalence morbidity and mortality have increased every year for the last 25 years.

These are some data from Olmstead County, Minnesota in this paper by Veronique Roger, looking at incidence, not mortality, but incidence of coronary heart disease over the late 1970s through the mid 1990s.

But I think what you can appreciate, that certainly since 1990, you're very hard pressed to suggest any further decline in incidence in men. And, in fact, over this period of time, there's a 35 percent increase in incident coronary heart disease in women.

This is not a disease that is going away. It may be becoming less fatal, but it is certainly not becoming less common. And for the American College of Cardiology, I participated in a working group looking at the implications of the aging of the U.S. population, as well as some of these mortality trends.

Currently, with 12 and a half million Americans carrying the diagnosis of heart disease, that represents 12 percent of men above the age of 45.

And eight percent of women above the age of 45, hearing this diagnosis. We project, as you go through the first half of the 21st century, for a doubling of the prevalence.

Such that the prevalence of coronary disease in the United States will have more people, will number more people than a number of the countries of the world at that period in time.

And this is really a failure of the primary prevention of heart disease. Of turning off the pipeline in the first place and to reduce the number of people in our population with this disabling and costly disease.

The rationale for primary prevention also includes the fact that we know that heart disease is largely preventable. And it's preventable through relatively simple and inexpensive options, including lifestyle modification.

But I would include aspirin as one of these simple and inexpensive options. The use of safe and effective preventive interventions, will have a significant public health impact.

Anything we can do to turn off that pipeline of cases of coronary disease, I believe to be very worthwhile. Aspirin, we believe, is the most cost-effective pharmacologic option in coronary disease prevention and intervention for, literally, pennies a day.

And finally, we believe that patients at moderate to high risk, can be identified using clinical judgement and risk assessment tools to assist our health care providers in identifying those patients at the right, with the right risk benefit ratio for intervention.

Well, there's been several groups who have recommended guidelines for risk assessment. And the American Heart Association and the United States Preventive Services Task Force, have identified, have adopted guidelines which have encouraged risk assessment and, in those individuals at moderate to high risk intervention with aspirin.

The American Heart Association has recommend adults above the age of 40 should have an absolute coronary risk calculated. And in these individuals with moderate to high risk, there are guidelines for management based on that risk.

You see serum lipids are now, according to the National Cholesterol Education Program Adult Treatment Panel III guidelines are now risk-based. And also with the U.S. Preventive Services Task Force, and with the American Heart Association guidelines for aspirin are also based on these risk calculations.

Now global risk assessment, I believe, can be done easily in the health care provider's office. We believe it should be done at least every five years, or more often if more than two risk factors are present.

This uses the Framingham Risk Calculation, using age, sex, smoking status, systolic blood pressure, serum cholesterol and HDL cholesterol, to calculate a ten year risk of coronary heart disease, death or myocardial infarction.

I might point out that this is, diabetes is not in this equation, of course, because it is now considered a CHD equivalent, with all of those patients being at high risk.

The risk calculators are available in a variety of forms. They're on the Cholesterol Education Programs's web site, the American Heart Association's web site.

You can beam this on to your Palm Pilot. You can use scoring sheets or a variety of color-coded tables. At the University of Rochester, we have a little color-coded booklet.

Obviously easy to carry around in your coat pocket, and then literally, it takes about 11 seconds to identify, in a color-coded way, an individual to be at low, moderate or high risk.

This is not a difficult or time-consuming enterprise. We do believe it is a valuable enterprise, however, illustrated in this patient's, this next patient's scenario.

Now let's take a patient, and if you were in an internal medicine practice, would certainly not be a rare occurrence.

A middle-aged male who smokes, has moderate levels of systolic blood pressure, moderate elevations of systolic blood pressure and total cholesterol. Perhaps a little lower HDL than we would like.

Nothing extraordinarily extreme in any of those. But if, in fact, you put all of these factors together, you come up with a ten year risk of coronary heart disease of 30 percent.

A risk similar to those of our myocardial infarction survivors. So you can identify, either by clinical judgement or with these risk assessment tools, individuals at moderate to high risk, who have not yet had a coronary event.

Well, this then allows us the opportunities, as health care providers, to tailor individual treatment decisions based on this.

Both whether to treat and how intensively to treat. Rather than treating no one, or treating everyone to the fullest extent, we are able to stratify the intensity of therapy with the gradations of risk.

And by doing so, we will choose cost-effective therapies. My patients also like to participate in their care. And they like these little tables. They like to understand what their risk is and they like to participate in the selection of risk interventions.

And I think this motivates them to comply with non-pharmacologic and pharmacologic therapies. So I think this is also beneficial as a patient education tool.

We're talking about aspirin today. We're talking about a simple intervention. And we're going to show you a lot of data today, about what is the evidence for aspirin in the prevention of myocardial infarction.

Obviously, the place to start is with the secondary prevention data. Data that we all, including the American Heart Association's Secondary Prevention Guidelines, have agreed is a very important intervention in the prevention of heart disease.

So when you have a large database supporting the safety and efficacy of aspirin in secondary prevention, 150,000 patients from, literally, scores of studies.

And Dr. Colin Baigent today will briefly review some of those data for you. So the American Heart Association and the American College of Cardiology have used these data to recommend aspirin in the patients with established cardiovascular disease.

So one of the things we want to do is ask the question, can we take those data and move them down into other relatively high risk patients. Moderate and high risk patients who have not yet had that cardiac event.

Now obviously the Food and Drug Administration currently approves aspirin to reduce the risk of MI in patients with a variety of vascular presentations, MI, stroke, angina, revascularizations.

And all these patients have risk above 20 percent. Finally, the American Diabetes Association has also recognized the benefits of aspirin, way back in 1997, when they recommended the use of aspirin for the primary prevention of heart disease in a very high risk group of patients, that is diabetics. Now what we'd like to do is also then, move into the primary prevention issue.

The extrapolation of all we know from second in prevention, down into the moderate risk and high risk primary prevention patients.

And we feel we have a robust and clinically informative database with five trials involving 55,000 subjects. These are well-designed studies with high compliance and follow-up rates.

We think it is a great strength, it comes from a diverse patient population. There are a range of global risks with four studies being in the low risk category and one in the moderate risk group.

And they come from a geographically diverse group, literally, from all over the world. The number of doses, formulations and primary endpoints have been used.

And we feel, therefore, we have a rich evidence base for our recommendations. Let's talk a little bit about the individual studies that we have to look at.

There are five studies which provide clinically meaningful data on this issue of primary prevention and its safety and efficacy of the use of aspirin in primary prevention. It should be pointed out that at least two of these studies did not reach their predetermined endpoints, because they were stopped by their Data Safety and Monitoring Boards prematurely because of evidence for aspirin effectiveness.

This is the Physician's Health Study in the Primary Prevention Project. So I think it's very important to know that at least within their own studies, at least two, I felt that the data were already significant enough for the benefit of aspirin that they could not continue the trials.

The findings are also consistent with four of the other five studies and all five of these studies have been used in the meta-analysis that Dr. Baigent will be showing you, to more precisely estimate the risk and benefit of aspirin in primary prevention.

The findings, in terms of relative risk reduction of 25 percent are very consistent with those from the secondary prevention trials. Again, a database including 150,000 patients.

And, the American Heart Association, the U.S. Preventive Services Task Force, have used these data to encourage use in moderate risk patients of aspirin.

I chaired the writing group for the American Heart Association. We reviewed the data then. I've had an opportunity to review the data since then, and I am even more convinced now than when I chaired that writing group, that this is the right thing to do.

Let's provide then a little overview of the rationale for this strategy of extending these benefits into the moderate risk group.

And this is from the U.S. Preventative Services Task Force, which estimates the benefits and harm of aspirin for five years, treating 1,000 patients at various levels of baseline risk for coronary heart disease.

These are a bit modified from the, the Youth Preventative Services Task Force, in that we're using ten year risk here, rather than five year risk in the paper.

So you have two percent, six percent or ten percent, ten year risk. What you have is given a relative risk reduction across all of those risks, it looks like it's pretty stable.

You have increasing numbers of coronary disease events avoided with increasing baseline risk. What doesn't change over those groups, are the number of hemorrhagic strokes and the major gastrointestinal bleeding events, which appear to be stable across these risk strata.

Obviously, the strategy then and we would suggest ten percent and higher, both moderate and high risk primary prevention patients.

To provide aspirin for those individuals, in which we have a clear benefit, a clear excess of coronary heart disease events avoided, compared to this low baseline risk of GI hemorrhage and hemorrhagic stroke.

And we have experts on all of these areas, basically to comment on issues of both the risks and the benefits. I believe we can classify patients into three buckets.

Three groups of patients, which is what the risk calculator does. I think we tend to overestimate how precise these calculations are. What we're really doing is a risk stratification procedure.

Individuals into the low risk, moderate risk or high risk groups. And I believe these can be identified inexpensively and rapidly in the typical care provider's office.

Now the benefits of intervention, therefore, accrue to those with greatest underlying risk. If there is a stable, 25 percent relative risk reduction, across the risk groups, therefore the higher the risk you have, going from moderate to high risk, the larger the number of patients who will have MIs prevented per thousand patients treated for ten years.

That's the vertical axis here. Now it turns out, I think, that we have some empirical evidence to support this notion. And these are the secondary prevention trials. Again, 150,000 patients up here, in which, in these high risk patients we know that we prevent a large number of MIs per thousand patients treated per ten years.

We also have the five primary prevention trials. Four in the low risk group, and one in the moderate risk group, which I think support this notion, is that the higher the risk, the higher the numbers of myocardial infarctions potentially prevented.

And these are the data plotted, according to their CHD risk, of the placebo group, and the numbers of MI actually treated, actually prevented per thousand patients treated per ten years.

Now, we also have, and one of the complexities of this area, is this low underlying risk of hemorrhagic stroke and GI hemorrhage. Here estimated, according to the U.S. Preventative Services Task Force, and agreed by the Antiplatelet Trialists Group, of a four-to-12 range of adverse events, this threshold.

And so clearly what we want to do, and since this is constant, across the risk strata, what we want to do is identify those individuals who are at benefit, rather than at risk, for aspirin.

So basically, what we end up with then is here, with the data shown, superimposed, of the selection of high risk, greater than 20 percent, in primary prevention.

And there are a large number of these patients, obviously, in our practices, who have not yet had an infarction, or moderate risk, greater than ten percent, in which you have obviously a clear benefit, above the line, of the number of MIs prevented compared to their underlying risk of hemorrhagic stroke and GI hemorrhage.

And this is really the rationale for the recommendations that we're making. And we believe that you can extrapolate this to a broader population. There is a statistically significant benefit to preventing MIs in trials conducted both in primary and secondary prevention.

Even at the low risk, I might say, those four, those four studies, and in the low risk groups in which we're, in fact, not recommending because of the risk benefit ratio.

However, there is homogeneity of the relative risk reductions for coronary heart disease, as Dr. Baigent will show you, across the high and low risk population supporting the usefulness of aspirin therapy, across this continuum.

That in fact there is continued 25 percent risk reduction at all levels of risk. The benefit to risk ratio would be enhanced, therefore, by limiting the use of aspirin to those at least at moderate risk, ten percent or higher, including the high risk individuals in primary prevention.

And also to exclude those patients that we know may have a diathesis for bleeding. So in conclusion, I think we'd like to make several points very strongly.

One, is that there are robust findings supporting the utility of aspirin for preventing MI across the continuum, 150,000 patients in secondary prevention, 55,000 in primary prevention.

We can prevent this disease with aspirin taken on a regular basis. There is a favorable benefit to risk relationship at moderate risk and higher patients.

Approximately six to 20 MIs can be prevented. And these are MIs which lead to disability and possibly sudden death. And these six to 20 can be prevented for every two to four GI bleeds and zero to two hemorrhagic strokes caused.

A positive risk to benefit relationship. And we believe, that as you get into those higher risk patients, those greater than 20 percent, multiple risk factor patients that we see in our practice, the risk benefit ratio will be even greater.

We believe that there is a major public health benefit to be had here. And we could expect with the proposed label change, that we'll have increased numbers of patients having their risk assessed.

This continues to be an important opportunity that I think we often times miss in our primary care practices. Second, we'd like to reduce the underutilization of treatment.

In both primary and secondary, these treatment gaps continue. And Dr. Stafford is going to review these data with you.

And then finally, really, and in the end, our goal is to reduce long-term mortality, morbidity and costs from this most common disease, coronary heart disease. Thank you very much.

DR. BORER: Thank you very much, Dr. Pearson. Are there any specific issues? Steve.

DR. NISSEN: Tom, I wonder if you could put up your slide Number 30.

DR. PEARSON: Can we do it? Yes.

DR. NISSEN: Yeah. So, you know, usually, when we're asked to deliberate about, you know, a topic such as this, we want to look at the population that's going to be treated, and look at the risk benefits in that population.

And, you know, I wonder about your, if you would comment on this. One of the problems that I have here, is in that moderate risk category of ten to 20 percent, we have a single study.

And so, what you're really asking us to do, then, is to extrapolate from studies outside of the range of patients and whom we're really being asked to provide a label, and say, well based upon what happens at risk below and what happens at risk above, that we can then interpret what to do in that group that's in between.

Now really, arguably, there are really two trials. You know, BDT and TPT. Although, BDT doesn't quite make the ten percent risk. One of them looks pretty good, the other one looks pretty bad.

So how do we make this case, when we don't have trials in the range that we're really being asked to label.

DR. PEARSON: I have several responses to that. Number one, is that Dr. Baigent is going to show you individual study data as well as net analysis data of all of these five studies which basically show that even in this lower risk, there is an efficacy argument in support of aspirin therapy.

So, in all of these five studies, our contention is that we do, on an individual study basis, for two or more trials, have in fact efficacy shown for single.

They may not be in this group, but I don't think, our position here is that these are arbitrary cut points in terms of risk. What we have is a gradation of risk, and we're extrapolating the high risk individuals and the data we have, and the moderate risk into this other's, where the risk benefit ratio is positive.

Secondly is, is that what Dr. Baigent is going to show you, is in fact within all of these five studies including, and Dr. Meade is with us here, and the principle investigators for all of these studies, I might point out, are here today and provide a wonderful opportunity for us to discuss these data.

In addition to this one, I think, quite convincing, the TPT study, Dr. Meade is with us here from London. And, but in all of these patients there were moderate risk patients within the entire study set.

And these have been taken out in a net analysis and analyzed separately, as virtually a second piece of evidence within this group. And I'd like to not steal Dr. Baigent's thunder, but I think you'll be quite pleased to see that there is also very good evidence within the aggregated data from all five of these studies, that moderate risk patients do in fact benefit.

So, I think there are a considerable number of, there are positive studies in primary prevention. There's one positive study in the moderate risk individuals. And there's positive evidence in the moderate risk patients within the five studies.

DR. BORER: Tom Fleming, you wanted to make a comment about this?

DR. FLEMING: I think Steve's question was right on target. It was exactly my first question as well. And maybe just to add briefly, at least if we took literally your figure here, then essentially the essence that you would conclude is that where these five studies were performed, there isn't excess benefit relative to risk. In fact, three of them over a region where there would be expected by your own figure to be greater risk than benefit. Are we misinterpreting your figure?

DR. PEARSON: In these two studies, there would be greater risk than benefit. In these three studies there would be ?

DR. FLEMING: PHS, HOT and PPP, according to your ?

DR. PEARSON: Right, right.

DR. FLEMING: ? x-axis?

DR. PEARSON: Right. But this is, again, this is the number of MIs prevented per thousand patients treated. All five of these studies, in fact, show a benefit. The question is do they exceed a threshold of risk benefit?

And three of the five studies do. And again, as the risk of these individuals increase, the risk benefit ratio becomes increasingly small. Risk benefit ratio.

DR. FLEMING: But in essence, for the area that you're targeting here, which is the moderate risk, you're essentially needing to do an extrapolation with a key study, from the key study data.

DR. PEARSON: By individual study alone, but by looking at individual patients, I don't want to steal Dr. Baigent's thunder ?

DR. FLEMING: Okay, all right.

DR. PEARSON: ? because he has those data to show you and I think they're quite convincing.

DR. BORER: Okay, we had a number of other questions. I think, Bill Hiatt, you had one initially, and then we'll go to Tom and then Paul and Beverly.

DR. HIATT: My question is, is that we're trying to go from event-driven to global risk-driven assessment. Do you think that the event-driven populations are fundamentally the same as the patients that have this risk continuum?

I know, and so my question is, why is the label being probed just for prevention of first MI, whereas for secondary prevention it prevents MI and death?

DR. PEARSON: I think this is often times a natural history question. Dr. Baigent is going to address this issue looking at, comparing and contrasting the primary and secondary prevention studies for a number of end points, including death and stroke.

And you see a little bit different issues there. My own opinion on this is, of course, is we've converted coronary disease from a fatal disease to a chronic disease. Our case fatality rates for MI, although there is still a very high sudden death occurrence, the case fatality rates have continued to fall.

And therefore, in our powered trials is very much easier to get to an endpoint of reduction and non-fatal MI with relatively fewer of those actually becoming fatal.

So, but there are meta-analyses, again, bringing all of these data into, into play, in looking at those issues. But I think it's actually kind of a power natural history issue.

You're talking about individuals relatively earlier in the course of what is a disastrous natural history.

DR. HIATT: And qualitatively, you think that they actually look the same?

DR. PEARSON: Yes, and as you know, you've got patients with peripheral arterial disease who haven't had a myocardial infarction, you know what their risk is. It's horrendous.

DR. HIATT: But I also know aspirin doesn't work for those patients. Aspirin has not been approved or labeled or been shown to be effective for those patients.

And, that's a testable hypothesis. So, when you look at global risk as a way to make treatment decisions, that's still a testable hypothesis. And there is a primary prevention study going on in the UK right now, where ABI is being used as a risk stratification, much like Framingham risk is being done.

And that's a placebo-controlled trial to see if aspirin is effective in those moderate risk patients. So, I think in terms of the Framingham risk, can you tell us about any prospective trials based on that assessment that actually demonstrate aspirin benefit?

DR. PEARSON: Dr. Baigent is going to show you meta-analysis stratified by risk. I guess it doesn't really use the Framingham score, but rather more empiric data from that.

But he will show you the group kind of data of less than one, one to two, and greater than two percent per year risk, and show the relative risk reductions the same across those strata and increasing numbers then of potentially prevented MIs across them.

So the last thing is, the reason you think the label is different now, which is just to prevent non-fatal events, because you've hypothesized the disease has changed. That the mortality has gone down so much, that our goal now is to prevent non-fatal events, not MI, stroke and vascular death which is the common endpoint for all the other trials that are published.

DR. PEARSON: I believe we will prevent sudden deaths, coronary heart disease deaths in doing so. But I also believe that our primary goal should be to prevent this disease in the first place, given the disability and cost implications of even a non-fatal MI.

DR. BORER: Before we go on to Tom, did Doug or Bob Temple, did you have a clarification to make there?

DR. TEMPLE: I just wanted to add to the peripheral artery disease discussion, because it's of some interest. There's an invitation, not unreasonable in some sense, to extrapolate from data in a variety of populations.

And yet it's unbelievably striking that in the peripheral artery population, who, after all, have coronary heart disease and strokes sort of like everybody else, aspirin in the, in the aspirin trial submitted analysis shows absolutely nothing in about 2,000 patients.

And in trials of ticlopidine, oh, no, clopidogrel, it's very striking that all the benefit of clopidogrel is in the peripheral artery. All the advantage over aspirin is in the peripheral arterial group.

So, it just makes you wonder whether everybody is really as much the same as you'd at first think. And added to that, is that in the Physician's Health Study, which sort of drives a lot of the MI data here, strokes went the wrong way.

Which is really hard, not just hemorrhagic strokes, but what appeared to be, thrombotic strokes went the wrong way.

It just makes you wonder whether people are as much part of a continuum as they appear to be, even though it seems completely logical to say that they would be. I mean, I'd expect it too.

But the data doesn't always come out quite that way.

DR. BORER: Tom?

DR. PICKERING: I have a more general question. The focus of the presentation and also of the risk equations that we're being encouraged to use, although I suspect very few physicians are actually using them, are heavily focused on coronary heart disease and myocardial infarction.

But if you're a patient or a physician you don't know if the event that that patient is going to have is from coronary heart disease or a stroke.

So, should we not be using risk equations that tell you the overall risk of cardiovascular events as opposed to specifically focusing on MIs.

I mean, I know that the, for instance, blood pressure is more important a predictor of stroke, but again, you don't know, which event you're trying to prevent.

DR. PEARSON: My view of the use of these risk assessment tools is really a group designation. The identification of groups of patients at various risk.

I think the reading of this into a precise estimate of an individual chance of having any specific event, is probably beyond the use of these tools.

What we're really just stratifying a population by three groups to really allow a stratification of the use and intensity of therapies.

So, getting down to some of these other risks of subsets of disease, of other vascular systems of disease, I think should also in general work.

But I think a much more broad look at the way a practicing physician, on Monday morning, when he sees a patient and puts people into a low, moderate or high risk group in very broad a sense.

So that over his entire, his or her entire practice, they would have a better stratification of intensity of therapy by intensity of risk.

DR. BORER: Paul.

DR. ARMSTRONG: Dr. Pearson, you've been thinking about this for a long time and perhaps you have the best overview of any of us.

So, I'm going to ask you a couple of questions that I'm going to return to in relationship to some of the experts that we'll hear from later.

And it relates to the risk of the therapy, not the risk of the disease. What do we know about the patients who experience intracranial hemorrhage, GI bleeding? And what do we know, if anything, about transfusion requirement?

For example, are these small body weight, elderly ladies over the age of 80? When do they get these side effects in relationship to the exposure over the ten year period that you've elaborated in relationship to the risk of the disease?

And what can we or should we learn about balancing those risks against the benefit that you've elegantly presented?

DR. PEARSON: Would it be an opportunity to call some of our guest Consultants at this time? Is that ?

DR. ARMSTRONG: Up to the Chairman. We can defer those questions, if that's your pleasure. I just thought that you would have the best overview of anybody relative to all of these studies.

And it's a composite question related to the risk of the therapy. So, that's up to the Chairman.

DR. PEARSON: It's an important issue and we're ready and delighted to address that, because I agree with you. It's very important and makes this whole area a little bit more complicated than just all benefit, doesn't it?

DR. BORER: Yeah, perhaps we can wait until your planned presentation of the risk issues, and then we can come back to the composite question.

DR. PEARSON: Let me just, let me just make one overview comment. And that is, is that most of these GI hemorrhages are equated to those requiring transfusion.

So the ones we're talking about, in terms of a definition, is not perhaps a quiet positive stool, but rather a clinical event of meaning.

At the same time, we had a very lively discussion within our group of would you rather have a myocardial infarction or a GI bleed. Your gastric mucosa will heal.

You will have a transfusion requirement. But if you've had a myocardial infarction, as you know, you've lost part of your myocardium permanently and many of those individuals will not heal.

They'll have congestive heart failure and a variety of other sequelae. And that, that risk benefit for that more common adverse affect of GI hemorrhage, should be considered.

Hemorrhagic stroke is another issue. That's obviously a serious catastrophic event. Those are very uncommon. We would want to minimize them by individuals who have a bleeding diathesis and who, for some reason, would believe that they would have an adverse reaction to aspirin.

And we believe that people with a bleeding diathesis, or perhaps a previous history of hemorrhagic stroke, obviously should be excluded from aspirin therapy.

DR. BORER: Beverly.

DR. LORELL: I wonder if we could return to your Slide Number 20, that showed the patient profile. To me, one of the provocative things about the arguments today is not only the difficult dilemma of balancing risk benefit for those patients who sit right on the edge of low and moderate.

But you've alluded to the issue that current labeling, which is event-based, may also be driving failure to use aspirin in moderate-high and high risk individuals.

To give us a little better handle on that, with such a patient as you've described here, which is bread and butter general medicine and cardiology.

Can you give us any kind of estimate as to what percent of patients like this, may be using aspirin in the United States today and what percent are not?

DR. PEARSON: Yes, Dr. Randy Stafford is going to comment on that specific issue for us later. Let me just talk about the relative number of individuals in the low-moderate risk group.

And that, to some extent, differs by where you are. If you take an NHANES kind of data set, that looks like about 40 percent of individuals are at moderate or high risk pre-MI.

This is not a CHD group. About 40 percent of Americans are at moderate or high risk, adult Americans. If you look at an Internist's Clinic, and we did a survey of 3,200 medical records in 16 primary care clinics in New York.

It's about one-quarter low risk, one-half non-coronary high risk, and about 25 percent of a typical Internist's practice deals with coronary disease.

So, these are certainly not a minor issue for anyone's cardiovascular practice. Now Dr. Stafford has, and that's his major area of research is looking at the use of these preventive therapies.

And, if I could, I'd like to defer to his presentation.

DR. BORER: Alastair Wood and then Alan Hirsch.

DR. WOOD: I think you've addressed some of the stuff, what I was going to ask. But it does seem to me there's some risk in just adding up different adverse events and without giving them any differential value.

And, you know, without engaging in the vigorous discussion you described that your group had, it does seem to me that preventing an MI has some, has a different value, whether it's better or worse than a GI hemorrhage.

Do you want to comment on how one could get at that in terms of setting the ten percent level? Because the ten percent level comes essentially from adding up, without any qualitative input, the two different major adverse events.

DR. PEARSON: Right. The ten percent risk level is, according to the Framingham risk, and there have been a variety of Framingham equations, as you know. But the one used by the National Cholesterol Education Adult Treatment Panel III guideline is MI and CHD diff.

So those would be both risks of top end cardiovascular coronary manifestations. This is not angina, this is not positive electrocardiogram or whatever. This is CHD diff and MI.

I agree with you in the sense that we have taken these with virtually no value judgement other than the fact that the GI hemorrhage is usually a serious one requiring hospitalization and transfusion.

And, of course, hemorrhagic stroke is something we'd all like to prevent, particularly with hypertension control. So, these have been without value, I believe, as you, I think, are eluding to, is that this is conservative.

And, in fact, the U.S. Preventive Services Task Force used a six percent and higher threshold for the use of aspirin.

In our deliberations in the American Heart Association Working Group, we chose a more conservative ten percent, but I would acknowledge this issue of this definition of moderate risk and that at least one professional body has selected, I think, even a less conservative definition of moderate risk.

DR. BORER: Alan.

DR. HIRSCH: Tom, thanks very much. Can we also go back to Slide 20? Or, yes, Slide, excuse me, Slide 30, I believe. Which was a plot of relative risk and adverse event rates.

Like Paul, like the rest of the group, we're trying here today to look at the balance of risk and benefit. And one thing I've struggled with, going through the briefing document is that when we have our enthusiasm to prevent events we tend to look at relative risk deduction or number of MIs prevented as a laudable goal.

We look at GI bleeds and strokes. We look at annualized event rate. Not relative risk increase, sort of the same figure, or number of events caused.

And I want to again circle back to the same discussion. It seems as though we're asking physicians to do a global risk assessment, looking only again at the sort of risk of the benefit and not calculating it as the risk of the adverse event.

On these plots, is this truly a horizontal line and a stable adverse event rate, or is it a little more honest to plot the accruing risk, in association with the accruing benefit.

And do we truly know that that accruing risk is equal across these categories. There's really two lines that intersect in some different point.

DR. PEARSON: Right. Dr. Hirsch brings up several interesting issues. And let me see if I can tick them off in order. First of all is that Dr. Baigent is going to show you the relative risks, excess relative risks of hemorrhagic stroke and GI hemorrhage.

And so, by, again, our desire is to really give the Advisory Committee a full look at the data, but keep in mind, those relative risks are based on a low absolute risk rate. Okay?

So one per thousand, I believe, is the figure that Dr. Baigent's going to give you. And so the relative risk above that is a, you know, it's like a one to 1.6 increase in, say, GI hemorrhage.

And he's going to show you that for both primary and secondary prevention. If you've had an MI, you can still get a GI hemorrhage on aspirin, obviously. So he's going to show you that. And it does, in fact, I think, support this idea that this risk is stable across the way.

So in looking at this, and this is one of the reasons I'm pleased that these have stimulated a discussion and hopefully a conceptualization.

I would say the accruing risk is here. So it's this. So if you got out your ruler and, again, and this is the scale, this is four to 12 is what U.S. Preventive Services Task Force, the range of adverse events.

Again, not weighted by severity. We take that, but I think in a conservative sense. And so as you go above that, and this is why, again, we're into the moderate risk, is that this is the accrued benefit.

And that's why we've shown it this way. And obviously what we'd like to do is have a positive benefit to risk ratio.

DR. BORER: John and then Steve.

DR. NEYLAN: Actually, I'd like to revisit your first question, Jeff, to the previous speaker. And could you put up Slide 21.

And that is, Dr. Pearson, as an author of clinical practice guidelines and as one who incorporates this kind of global risk assessment into day-to-day practice, can you speak about the practical implications of what the difference would be in terms of having this kind of labeling as opposed to where we are today without that labeling?

DR. PEARSON: Thank you. I think it's very important for us all to be speaking the same language and all to be on the same page.

And I think currently this was an issue that we actually addressed when the U.S. Preventive Services Task Force came out while the American Heart Association guidelines were still being written.

And we felt that it was very important to look at these data and to have all of our recommendations on the same page. And our writing group basically agreed that there did appear to be a positive benefit to risk ratio, using the same risk cut points as we recommended as those of the National Cholesterol Education Program guidelines.

Again, a broader use of this risk stratification paradigm. And so I think it's very important that as our patients look at the labeling as our quality assurance agency's look at labeling using these four quality assurance measures, that we're all on the same page. The regulatory agencies, the professional societies and the scientific bodies are really all saying the same thing, based on the same evidence.

And our feeling is that the evidence in this instance, supports the use of aspirin in primary prevention in these individuals.

I think it is important.

DR. BORER: Steve.

DR. NISSEN: I wonder if we could see your Slide 25, and I had a couple of questions. Could you give me a relatively precise definition of what is meant in this slide by major gastrointestinal bleeding events? So, a definition.

DR. PEARSON: I believe the, and certainly Dr. Baigent is going to show you very similar data from their meta-analysis, is a GI hemorrhage requiring transfusion.

DR. NISSEN: Okay, I would like to see, before the day is out, more complete data, including those patients who are hospitalized for gastrointestinal hemorrhage, but maybe never get a transfusion.

So, in other words, there's obviously a health care cost around being admitted for a GI hemorrhage. And that is not just patients who bleed to the point of requiring a transfusion, that's everybody who has to go into the hospital for a gastrointestinal hemorrhage.

And so, I know you may not be the proper person, but I want to drill down a little bit further towards understanding the spectrum of adverse events that we're having to weigh here.

Including hospitalizations for a GI hemorrhage, even if they don't involve requiring a transfusion.

DR. PEARSON: Yes, thank you, Dr. Nissen, and I think we have the opportunity here, if I could defer this to the question and answer period.

We have Dr. Pignone from one of the leaders of the U.S. Preventive Services Task Force Writing Group, who can address this issue. And the Antiplatelet Trialists Group also looked at this issue in terms of adverse events so defined.

So, I believe we have the actual primary collectors of those data with us, and including the principle investigators. And I think this is an important issue.

Again, our feeling in terms of the magnitude of risk, the absolute magnitude of the risk, it's about one-tenth or so of that of the MI risk, in terms of serious medical reactions.

DR. BORER: All right, we'll probably have, we will have the opportunity to revisit this question after the data presented. And that may be more efficient. Susanna and then Dr. Knapka.

DR. CUNNINGHAM: Tom, is it true that if you have on GI event you don't have any increased risk for another, so you go back to zero, if they've had a GI bleed?

DR. PEARSON: There are some risk groups that, and several of them are treatable, like with H.pylori, in which I guess theoretically you would have a risk for, but those are usually at the time of a, one of these issues also treated for it.

We have three gastrointestinal consultants with us for the question and answer period in terms of the risk for recurrent GI bleed.

I think the other issue is if you had a GI hemorrhage, that may be a contraindication to further aspirin use. Unless there's some extraordinary, I think the other point is if there's an extraordinary benefit to be accrued to aspirin, there are also ways to minimize that GI hemorrhage recurrence through a variety of therapies that you could use to reduce the risk of ulcers.

But we have our GI consultants for that if we could, they could address that. If we could mark that as a question that we should come back to.

DR. BORER: Dr. Knapka, and then Bill Hiatt, again.

DR. KNAPKA: Just one quick question. We talk about risks, and I realize that these heart episodes are caused both genetic and environmental.

Now, is anybody, or are there any genetic markers that can really identify the people that are real high risk for these events?

Or are they looking for genetic markers and are there any?

DR. PEARSON: We should possibly defer that question to our colleagues from Cleveland Clinic, who have been in the media about this recently.

They are, and perhaps the person sitting next to you, as well. But the, there is obviously an avid search for genetic markers. And there clearly are some families, and we see them in the clinic, where everybody's had an early coronary death.

And these are obviously where the use of that is. I am a public health person, and I've been very struck with, such as the Nurses Study, that if you exercise, you don't smoke, you eat a good diet, you perhaps have moderate alcohol consumption and you have a normal body weight, that you have one-seventh of the risk of all those women that don't do that.

And so I think the evidence still is that our coronary epidemic in this country is not because we've had an in-migration of a lot of high risk families, but because our behaviors certainly aren't what they should be.

DR. HIATT: I'm still bothered by the concept that patients that have had events, are exactly the same as patients who haven't had events, but are high risk.

So that just a few days ago, there's a publication in Diabetes Care about a secondary analysis from the Primary Prevention Project, where they look at people with diabetes separately from the rest of the population.

And if you look at all the diabetes guidelines there's no coronary equivalent and they should all be on risk reduction therapies including aspirin.

But this subgroup analysis, which is just another post hoc thing, demonstrates absolutely no benefit of aspirin in those patients with diabetes.

And that bothered me. I mean I'm just, I'm just not convinced that you can identify these high risk groups that haven't had events, and think that they're going to respond exactly the same way as people who had events. And this is another example from just recent evidence, that that's not true. Can you help me with that?

DR. PEARSON: Yes, well, what I'd like to is maybe defer that, as well, to our group of experts. We have Dr. Colwell, who is representing the American Diabetes Association, and also has another larger study in diabetics from earlier, the 1980s, in fact, which influenced the American Diabetes recommendations for the use of aspirin in primary prevention.

And he can share with you, in fact, that strikingly positive study in individuals treated with 650 milligrams of aspirin versus placebo.

And so we would like to delve into the diabetic issue, it's an important issue. We also have the principle investigator for the Primary Prevention Project with us today.

And I think it would be most appropriate for him to comment on the, on the sub-analysis of that population, if we could.

DR. BORER: Tom.

DR. PICKERING: The patient that you showed with the 30 percent risk, had a systolic pressure of 148. So, by most definitions, he had uncontrolled hypertension, and I'm sure we're going to talk about this later, but whether or not these people should be included or excluded.

Can you say how many of the people in the moderate risk group you think are there because of some degree of hypertension?

DR. PEARSON: Hypertension, of course, in this country, as you have contributed to the literature, obviously is a very prevalent condition and therefore is a major determinant about getting into that moderate risk group.

In fact, it would be one of the ways to get into that group along with cigarette smoking, which is independent of your lipids and was one of the reasons why we recommended everyone above the age of 40.

Not just someone with hyperlipidemia, but everyone above the age of 40 should have an absolute risk score for primary prevention.

Let me also say that we have Professor Zanchetti with us from the HOT Trial. A trial that I'm sure you're familiar with, which of course, included aspirin in a largely hypertensive group in terms of the primary prevention opportunities there.

And I think this is relevant to that group. Clearly, that patient in my clinic, we have a lot of work to do. The point of that slide, however, and it's not just aspirin, it's many things.

But clearly the point of that slide, though, was that individuals with several modestly elevated risk factors, clearly, positively elevated, but modestly so, in fact contributes greatly to their overall risk for a cardiac event.

DR. BORER: Okay, thank you very much, Dr. Pearson, that was a wonderful overview and perhaps we can go on to Dr. Baigent.

As we get prepared to do that, I would observe that the questions that are being asked around the table are crucial questions. Very important, and they'll need to be answered before we can respond to the FDA's questions.

But, these aren't the kinds of questions we usually can ask and expect answers to, particularly with regard to safety, when we review NDAs on drugs.

Because the exposure isn't in large, well-controlled clinical trials. It isn't anything near what we're seeing here. So we have an extraordinary and relatively unique opportunity here and I think we'll hear more about it right now.

DR. BAIGENT: Dr. Borer, Committee Members, ladies and gentlemen, what I'd like to do today is to describe to you the work that's been conducted by the Antithrombotic Trialists' Collaboration, which has ultimately, I think, led to some insights on which types of patients might benefit from aspirin.

So I'm going to start off by describing to you the Antithrombotic Trialists Collaboration, which incidentally used to be called the Antiplatelet Trialists Collaboration, and I'm going to describe what we see in high risk patients and then explain to you why we then moved on to look at moderate risk patients.

In doing that, I'll be describing the balance of the benefits and the risks. And already we've had discussion about this very point. It's absolutely crucial to our deliberations that we understand that balance.

Now first of all, I need to tell you about how the Antithrombotic Trialists' Collaboration started. Right back in the mid `80s, we had a few studies of aspirin and other antiplatelet agents, and those studies were, on their own, too small to tell us about the detail of who to treat with aspirin.

And so the whole thrust of the Antithrombotic Trialists Collaboration, or the ATT for short, has been to try to put together all the randomized evidence in ways that are reliable. By going to the individual investigators. By getting their protocols, by getting their collaboration. By having individual patient data provided in a standard format, using uniform definitions.

By doing all that, we were able to put together a unique database that's uniquely able to answer particular questions about who to treat.

As Clinicians and as health professionals we really want to know who to treat. We can get information about the general impact of a drug, but we need to know who to treat.

So right back in the mid `80s, we defined outcomes that we would give most emphasis to. And the main outcome that we, right back in the early days, defined was this one, serious vascular event.

Which is a combined outcome of non-fatal MI, non-fatal stroke or vascular death. We did not include silent MI, nor have we ever since. So right at the very beginning we decided to stick to clinical outcomes that would be, thought to be clinically relevant.

We're also able to look, once we have large amounts of data, remember we're talking about, in the high risk studies, about 17,000 vascular events.

That means a hell of a lot of days in which we were able to explore events in particular. So we were able to look at myocardial infarction in particular. Stroke, in particular.

And subdivide stroke subtypes. So the large amount of data enables us to look in detail at the effects of aspirin on particular outcomes. We're able to look at mortality and we're able to look at major extracranial bleeding.

Right back in the beginning we defined major extracranial bleeding as bleeding due to hemorrhage. Over the years we have stuck to that definition. And so we're talking about a clinically significant adverse event.

So we're going to look at two sources of evidence today. The first of these is the evidence in high risk patients, by which we mean people with a definite history of occlusive arterial disease.

I'm going to describe the results in general terms, because we're mainly wanting to focus on moderate risk patients in this deliberation. Overall, in the most recent cycle of our analyses, remember we've done this over a number of years.

The first publication was in 1988. Subsequently in 1994, and most recently in 2002. And as Dr. Pearson has pointed out, there are about 135,000 patients in over 100 trials.

So, really large numbers of trials were able to contribute to this analysis. Overall, we saw one course of reduction in serious vascular events in a wide range of high risk patients.

Those benefits clearly outweighed the risks. And I think most clinicians now accept, that for a wide range of high risk patients, people with previous events, their benefit to risk ratio is very, very clear.

We're also able to demonstrate that if you are at high risk, it doesn't matter how you got to be high risk. So, in particular, if you're at high risk for some reason, it doesn't it matter if you're a woman. You're at high risk.

And we were able to show, among those 17,000 vascular events, by looking in great detail at individual patient data, we were able to show that the benefits were similar irrespective of age.

Irrespective of whether you're a man or a woman. Irrespective of blood pressure, at least within the range studied. And irrespective of the presence of diabetes.

So that database is really important when you start to think about the implications of lower level, moderate risk patients.

Most recently, when we published this paper, we pointed out that actually many patients, who haven't yet had an event, have already been studied within this high risk group.

We're talking about people with chronic stable angina. We're talking about people with intermittent claudication. These people are at high risk, and we already routinely treat them with aspirin as is appropriate.

But we also realized, there are many patients, many people out in the community, who, for various reasons, have an agglomeration of risk factors that also puts them at increased risk of vascular events.

We'd like to be able to prevent that. We can't get at that information by looking at the high risk studies, but we what we can do is look at the so-called primary prevention trials.

Many of which have actually targeted people at increased risk of a vascular event. So, again, I would emphasize we set out to do this a priori. We wanted, as a collaboration, among the five principle investigators already here today to answer questions, we pre-specified our outcomes. We put together a protocol. We met several times.

We most recently met in October. And what I'm showing you today is the results on behalf of that collaboration, based on individual patient data.

We are preparing a manuscript at the moment, but I'm going to show you the results as they currently are. Let's start with thinking about what the results tell us from high risk patients.

This is a summary of the absolute benefits of aspirin or antiplatelet therapy. About two-thirds of the trials were aspirin trials in the high risk group.

And what you see here, and you have these in front of you, so you're able to look at the detail. I realize you may not be able to read the numbers, but they're in your pack.

You see along here the absolute benefits per thousand patients treated with aspirin. And the yellow bar is the aspirin bar and the control bar is in red.

So over about 27 months, in a prior MI patient, patient with a previous MI, you get about 36 events avoided per thousand patients treated. And you get similar size benefits. The difference between the yellow and the red bar is similar in size in people with cerebrovascular disease. And also in a range of other conditions.

So what I want to emphasize from this slide, is that if you annualize this, then roughly speaking, you're talking about a benefit in vascular events of between ten and 20 events avoided per year.

And that is something that we need to bear in mind when thinking about the calculus in people at somewhat lower risk. Now I mentioned that we were able to demonstrate that if you are at high risk, then it doesn't matter how you got to be high risk.

Your particular demographic features don't appear to influence the benefit of aspirin. And here we see that for the split between men and women. In fact, women were at higher risk in this group here and we see that they have as much benefit as men do.

So it's a really important point that we need to keep coming back to throughout the day, I believe, that if you are at moderate or high risk, then it doesn't matter how you got to be that way.

After all, women do have platelets and we'd expect benefit in women in they are at high risk. Similarly in elderly people, the benefits seem to be as large as they are. In younger people, similar relationship for diastolic blood pressure.

Of course, people who are really hypertensive never get into these trials, at least not until they've had their blood pressure controlled.

But certainly within the range studied, we see similar benefits. And similarly for diabetes, if you are at high risk, it doesn't matter whether you are diabetic or not, you still benefit from antiplatelet therapy.

So these are really important points because they tell us that we can define the group of high risk patients a clear benefit from aspirin.

What about the negative side, and it's quite proper that we do consider the negative side. Actually, that is one of the key questions for this committee.

Well, in the meta-analysis that we did in high risk patients, we showed that there was a 1.6-fold increase in the risk of serious extracranial bleeding.

And that absolute excess risk translates to about one per thousand per year. It's very similar actually to what you see in the observational studies. About one per thousand per year is a good benchmark to have in mind. IF you compare that to the benefit of ten to 20 vascular events prevented per thousand per year, you can see that the benefit to risk ratio is actually extremely clear and favorable, and that is why it's appropriate to use aspirin so widely in people at high risk of vascular disease.

Now once we'd completed the most recent exercise, we felt that we'd actually not addressed a very important question. We showed, we thought, that for certain types of patients who already have clinical symptoms such as angina or intermittent claudication, that they would benefit from antiplatelet therapy.

But we felt that we should be trying to identify people who are at similar absolute risk, but who have not yet had an event and don't have any clinical symptoms.

After all, why would you not want to prevent an event in that type of person. It's obvious, from a public health standpoint, that you'd want to do that.

So, as I said, we brought together the principal investigators of those studies, the primary prevention studies, and these are the details of those studies that you're, no doubt, familiar with. You have all the details in your pack.

But just to remind you, The British Doctor Study and the Physician's Health Study, in the early days, looked at a relatively healthy group of patients, and more recently we've had studies, these three studies, the Thrombosis Prevention Trial, the HOT Study and the Primary Prevention Project, have all set out to identify people who have risk factors.

And therefore, they are specifically trying to do what we're all trying to do, identify people who might benefit from aspirin.

So, they generally studied a middle-aged group. They included some women and very few patients had a history of vascular disease. It's simply not the case that the results are driven by people who had vascular disease, who got included in these studies.

Most of the impact is in people who did not have recorded vascular disease at baseline. And we do have some people with diabetes.

We had individual patient data from all the investigators, and they spent a good amount of effort, actually working with us to make sure that data were absolutely straight.

So we've been liaising with them over the last couple of years to get the data straight. Extensive checking and validation of the data has gone on. And this is the knock out point.

Around one-fifth of these individuals were actually at moderate risk of a vascular event, a CHD event, rather. And that means that we have certainly got substantial amount of information that we're able to bring to bear on this problem.

We did not include silent MIs, I specifically mentioned earlier. But in doing this exercise, we also wanted to make a direct comparison, within the same project, of the effects of aspirin among post MI patients and post TIA patients.

So when I come on to my slides showing you the actual results, you will see secondary prevention as the second section of the figures. And that relates to the affects of aspirin in post MI and post TIA patients, just by way of comparison, so that you can see how the data shape up.

Now you may want to refer to your notes here, because the figures are quite tiny on the screen. Even standing here, I have difficulty seeing them.

This is the result on vascular events for the Primary Prevention Trials. In each of the five trials, what we have is an aspirin column here, a no aspirin column here. You're looking at events per patient-years, a follow-up and that enables you to look at an annualized event rate.

You can see that actually what's most striking is the similarity of these results. Overall, we get a 15 percent reduction. About four standard deviation, so statistically pretty clear.

And if you do a test for heterogeneity the similarity of results, it's clear that these results are completely compatible with each other.

So we're seeing something really striking. That there is similarity among these trials, they've looked at primary prevention patients.

But we want to go further than this. The whole point of this exercise is that if we have a large amount of data on vascular events with a similar comparison, aspirin versus control, we should be able to look at specific types of events.

We should be able to look at cardiac events, we should be able to look at strokes. And bring the data to bear on trying to understand why we see this result. Which, after all, is slightly less than the 25 percent reduction that we see in second prevention.

DR. HIATT: Sorry, what vascular events are you showing us here? MI, stroke and vascular death.

DR. BAIGENT: Exactly the same definition that we've used all along. Serious vascular events, non-fatal MI, non-fatal stroke or vascular death.

DR. HIATT: So those p-values, just aren't consistent with what's been published.

DR. BAIGENT: I'm sorry? This is the Primary Prevention Trial. These data have not been published before.

DR. HIATT: The MI, stroke and vascular death.

DR. BAIGENT: That's correct.

DR. HIATT: Hmm.

DR. BAIGENT: This is serious vascular events, non-fatal MI, non-fatal stroke or vascular death in prime prevention, 15 percent reduction. In secondary prevention, the high risk studies that I showed earlier, we see about a 25 percent reduction.

DR. HIATT: But you're saying that four out of those five trials were statistically significant across that competent endpoint.

DR. BAIGENT: I'm saying for each of these studies, what you see is a square, which is the point estimates, and the confidence interval. And 99 percent confidence interval is the line.

DR. HIATT: Well, the British Doctors was clearly negative. But the other four studies were negative on their primary endpoints. But you're making the composite endpoint and telling us, even though those composite intervals cross one, in all but the U.S. Physicians, that they are statistically significant.

DR. BAIGENT: I think what's important to recognize is that when, first of all these are 99 percent confidence intervals. So they, you would, if you had something that was completely clear of the line of no effect, then it would be significant at the one percent level.

As is appropriate, when you're looking at lots of analyses, you want to have a one percent alpha error rate, so that you can avoid concluding, inappropriately, the particular sub-root findings.

So that's why we've traditionally used a 99 percent confidence interval. So you can't say anything about whether these are significant at the five percent level, from this particular figure.

But what I think you can say and it's really important to look at the overall picture, is that you can see consistency of findings here.

There is no significant heterogeneity among these risk reductions. You see a very clear effect overall. And this is telling us something about aspirin working in people who are within the prime prevention population.

Now we move on to looking at the overall data subdivided by their predicted risk of coronary heart disease. So, just to take you through this figure, you're looking at the Primary Prevention Trials here, and we're look at affects on coronary heart disease events.

Remember, we're now subdividing the data because we understand that there is an affect on vascular events. We now want to look at specifically whether that affect is driven by coronary affects of by affects on stroke or both.

So now we're looking at coronary heart disease events. And what we've done, we've developed a model, prognostic model within the database, to look at patients who are at low risk, that is less than one percent per annum which I think there's a fairly strong conviction should not be treated.

The moderate risk patients that we're aiming to focus on and a small number of patients who actually were at high risk of a coronary heart disease event, this is the classification that's been used by the American Heart Association.

We wanted to be consistent with that to enable this committee to try to make a judgement based on similar data. Now we're looking at the second prevention trials, the post-TIA patients and the post-MI patients.

And you can see here, if you look at your figures within the pack, the absolute risks of an event are much higher. This is seven and a half percent per annum in the post-MI trials.

Remember, these are quite old now, so these rates would be lower now. And in the post-TIA patients, it's somewhat lower, about three percent per annum.

But if you look in these risk groups, then the risk in the placebo group of the high risk group is 2.4 percent. So that's clearly high risk. Moderate risk group, 1.3 percent, clearly a moderate risk. And low risk, only a half of a percent per annum.

So we successfully divided up the population into three different groups. And what's striking then, is when you look at this, it's absolutely straight, bang down the line, for all the risk groups we are getting a reduction in CHD events of a round about a quarter.

And that's very, very striking. And it's even more striking when you look at non-fatal MI. If we divide up the data and look at non-fatal MI, then what about that.

It's absolutely extraordinary. I think it is a very, very interesting figure. We see a one-quarter reduction in non-fatal MI, right across the different levels of risk.

And in the secondary prevention trials also. So this is telling us something very important about the affects of aspirin, I believe, among a wide range of different risk groups.

In stroke, things are a little bit different. In the secondary prevention context, we know, from previous analysis published in 2002, that roughly speaking, stroke is reduced by around about a sixth, around a quarter rather.

And in the context of primary prevention, we don't seem to have a significant effect on stroke. Is that because we have an increased risk of hemorrhagic stroke? The answer to that is no.

By the way, I should say that there was an error in your handout. So, if you try to look at the stroke result, I don't think you have the right figure. You need to go back, and we can put the slide up if there's any questions about that one.

If we look at stroke, then, it's clear that there's no significant effect because of hemorrhagic stroke. And as we expect, there's about a third increase in the risk of hemorrhagic stroke, an one-third proportional increase in the risk of hemorrhagic stroke.

But the absolute excess risk of hemorrhagic stroke, which is what matters in public health terms, is tiny. We're talking about 61 events here versus 49, it's less than .1 percent per annum.

So it's really a very small risk. It's not irrelevant, but in terms of weighing public health benefit, it is relatively less important.

If we look at vascular death, then similarly we say although we, in the high risk studies saw around about a one-sixth reduction in vascular death, there's no significant fate vascular death within the primary prevention studies.

Now, importantly, you also have to look at the risk of major extracranial bleeds. Again, defined in precisely the same way as we've defined it overall, transfusion-related bleeding.

You see around about a two-thirds increase. Obviously we're just looking at the aspirin studies here, we don't get very many bleeds.

We need to look at the high risk database overall to get a two-thirds increase in the risk of bleeding. Which is exactly similar to what we see in primary prevention.

So there's no concern that the proportional increase in the risk of bleeding might be different in primary prevention.

How does this all weigh up? Well, what we see here is particular outcomes. Non-fatal MI, stroke, vascular death and major bleeds.

In primary prevention, what is similar to secondary prevention is that we get a one-third reduction in non-fatal MI. And we get a two-thirds proportional increase in major bleeding, which translates to about one per thousand excess per year.

What's different is that we don't seem to have any significant effect. We can't really say for certain what the effects are, but it doesn't seem to be significant for stroke or vascular death.

Which is in contra-distinction to what we see in secondary prevention. Of course, it may well be that this is a quirk of the data, since we don't have that many events. But at the moment, there's no clear evidence of any benefit or harm on stroke or vascular death.

We now need to do some calculus to work out which types of patients who are at moderate risk, who, after all, we've demonstrated have clear benefit on non-fatal MI, which types of patients should be treated.

Well this figure shows you the risk groups. This is the coronary heart disease event rates. These should be percentage events up here.

You have one per thousand benefit here in low risk patients, so probably no clear argument for those patients being treated, since there's a one per thousand excess risk of major bleeding which balances that.

On moderate risk, however, we have three per thousand events prevented per year. And set against that one per thousand, you see there's a three-to-one ratio, which is quite clear.

If we also accept the major extracranial bleeding is perhaps of less importance in avoiding a non-fatal MI, then we can see that by setting three to one, we're actually being conservative, because we're weighing a major extracranial bleed as being similar to a non-fatal MI.

So this is actually a conservative estimate of the type of benefit you might see. And then in high risk patients, six per thousand benefit is really very clear.

So, I think this is probably the most important slide of all, the weighing of benefits and risk for high and low risk patients.

For high risk patients, that is either greater than 20 percent or people who've already had an event, then we're talking about avoiding 25 to 50 vascular events per thousand patients treated.

And also an additional effect on the ischemic stroke if patients have already had an event, but not if they haven't. And against that, we said over five years you will see one extra hemorrhagic stroke and five bleeds.

So this is clear. On the negative side, this is clearly outweighed by the benefits. In moderate risk, we see that we're preventing around about 14 coronary heart disease events, most of which are non-fatal MIs.

And against that, this is over five years. Against that we're weighing one hemorrhagic stroke and five major bleeds. And again, I reiterate what I say about being conservative by treating them as similar events.

We actually need to be conservative in making public health policy. And by doing it this way, we are doing that.

However, in low risk patients, it's quite clear that we should not be treating widely with aspirin, because the benefits are similar to the risks.

So to conclude, in the high risk patients, the benefits do clearly outweigh the risks. And I think most people are using aspirin widely in high risk patients.

In moderate risk, I believe that the Antithrombotic Trialists Collaboration analyses have helped us to see that there is a definite group of moderate risk patients that can be identified, not in a substantial group of patients in primary prevention, who could benefit from aspirin.

And that would be of substantial public health benefit. In low risk, however, we are not arguing that aspirin should be widely used, in fact we're arguing the opposite.

The balance is too fine and we would be potentially causing harm in this population. So, I'm going to close my talk there, thank you very much.

And pass over to Dr. Merz, from Cedars-Sinai Medical Center to talk about the issue in women.

DR. BORER: Doctor Baigent, I think we'll have several questions for you before the next speaker. And I'd like to begin with sort of, with an overarching question, and I'd be very interested in Tom's comment as well, when you're finished.

We have here studies, controlled clinical trials, involving thousands and thousands and thousands of patients. And that's very useful for us because we have a point estimate of risk for the entire group that's been treated that's a lot stronger than we usually see when we consider benefit to risk issues.

But this very large population was very important to have, because the rate of primary events, the outcome events is low. You know, populations with a two percent per year risk. A one percent per year risk or less than that.

And therefore, to obtain a large number of events, we need to study a large number of people. And one of the issues that everyone is grappling with, and I think it's implicit in the comments that Bob Temple made and the question that Bill raised about strokes and peripheral arterial disease, respectively, is that there, if you look at the individual trials, there is a variability in outcomes, in effect on outcomes in secondary analyses.

And presumably we gain greater clarity by pooling these data and doing meta-analyses, particularly when you use uniform criteria as you did, in the post hoc analysis.

So, I'd like a comment on the, from the point of view of a statistician, epidemiologist, etcetera, on the weight we should give in judging the variation we see among the individual trials for these relatively uncommon events that go one way or the other with treatment on secondary analysis versus the weight we should give to the pooled data.

I know that statisticians often argue about this, and I'd like to hear your opinion. That's one question, and while you're considering that, I have a second question that I'd like you to follow up on, follow up with.

Silent myocardial infarction was excluded as an endpoint here. And I can understand why that might have been. Some estimates suggest that as many as half the infarcs that occurred are silent.

If that's true, I think it's implausible to suggest aspirin would do anything bad to those people, but, although I can't say that rigorously, but if you assumed that aspirin had no effect, most conservative estimate, had no effect on those silent MIs and we had missed half the events, what impact would that have on the conclusions that you would draw about the benefits of aspirin for prevention of myocardial infarction.

So, two questions. Once you begin, then I'd like to hear what Tom has to say.

DR. BAIGENT: Okay, to deal with the issue about heterogeneity, that once these meta-analyses, I mean one would expect to see variability in the size of an affect on the treatment, on a particular outcome.

What is important to recognize is there will always be heterogeneity. It's whether that heterogeneity is striking in ways that help you understand the data that is really what we need to tease out.

So, if a set of trials are too small, when taken individually, to look at a particular outcome, then by putting them all together in a meta-analysis, one actually can pick out a true effect.

We have done that many times within the Antithrombotic Trials Collaboration. But we've also, specifically, always looked to see whether there is important heterogeneity that we can detect within that group of trials. And whether that leads us towards an important clinical message is something that we try to explore.

So I think we expect to see variation. Whether it's striking enough to warrant further attention is something that it behooves us to look at.

Your question about silent MI, it may well be the case that there are many silent MIs going on and their clinical relevance may well be worth debating.

But the fact is, that none of these trials, certainly none of the high risk trials, and only a few of the primary prevention trials, set out to record silent MI.

And they were only able to do so by taking ECGs at regular intervals. We cannot ascertain the date of the silent MI. Furthermore, many patients who have a silent MI, subsequently go on to have a clinical event.

And it's clinical events that we want to weigh as being important outcomes that affect patients. So I think that, actually, although there are things going on within our patients, that we can't record, we are getting into the nitty gritty, by looking at clinical outcomes.

And I don't think that in any way is detrimental to our analysis that we don't have information on silent MI available.

DR. BORER: Tom, do you have some comments about this, then we'll go on to Doug and Bob and Steve.

DR. FLEMING: Well, let me just make a few, brief, initial comments about your question, Jeff, and assume that a lot more detailed response will come during the day.

I think it's important when you have designed, large key studies, as these five studies have been designed. I think it's important to learn the very most you can from them and certainly analyzing them individually and looking carefully at what their primary intended outcomes were, is one critical feature of how we should be focusing in our interpretation.

Certainly, though, those studies may be under-power to address some very specific additional issues and meta-analyses can be extremely important in expanding our understanding.

Realizing, however, that you may be pooling different sources of information that are somewhat different. But, my own sense is, it is important to look at both the individual studies and what they were intending to address, and then also to look at meta-analyses.

One of the specific features that has been brought out, is these individual studies were all focusing in a primary sense on primary endpoints that had cardiovascular mortality as either the sole aspect of them or a major driving aspect.

And when you start looking at meta-analyses and then start looking at subcomponents, it's very important to realize you may have more statistical power but you also may be led down certain pathways to look at secondary measures.

One of the key issues here is if we're looking at non-fatal MIs, how important were non-fatal MIs in the overall view and the design of trials, in the context of the totality of the endpoints.

We have non-fatal MIs. We have non-fatal strokes. We have fatal events. I might have classified those in exactly that order in terms of their clinical relevance.

And so, as I look at these individual trials and the meta-analyses, one of the things that is important to my way of thinking is the meta-analysis has somewhat shifted the focus on what it was that these individual trials were intending to get at.

Let me just bring up one more feature. The silent MIs. And that's not a trivial issue, because one gets a very different picture in some analyses, in particular the one that the FDA has had a chance to go through in some depth. The HOT Trial, where you actually have an excess of events that are silent MIs, in the aspirin category, those may in fact be somewhat less clinically compelling than non-fatal MIs.

But non-fatal MIs, if you're only affecting non-fatal MIs, and not affecting fatal MIs or stroke or overall death, shouldn't that too, also be given somewhat less emphasis.

So it's a continuum here. And I think we'll discuss these issues in greater depth as the day goes on.

DR. BORER: Thank you. We'll go Doug, to Bob, to Steve, to Tom.

DR. THROCKMORTON: Thanks. I just had a little, a housekeeping issue. I wanted to ask you a little bit about the data presentation that you just made.

Do the analyses that you've shown us differ from the analyses you reported in the 2002 article? Do these come from that same analysis, or are these an extension of that?

DR. BAIGENT: The data we reported in 2002, did not look at time-to-event analyses. The data I've shown you today are limited for the post-TIA and post-MI trials, to trials of aspirin versus control, and they do have information on time-to-event.

So, they are from the same data search, but they, the results are likely to differ in only a few percentage points, because of that different method of answers.

DR. THROCKMORTON: Right, no, I was just curious. Were these submitted as a part of the package to the FDA? I don't remember if they were?

DR. BAIGENT: I'm sorry, I didn't hear that?

DR. THROCKMORTON: Were they submitted to the Agency. I don't remember seeing these particular analyses before. Do you know if they've been submitted to us?

DR. BAIGENT: What I provided from the Antithrombotic Trialists Collaboration for that package was a summary of the general findings. I obviously, in order to make it more informative for this committee, I'm showing you a little more detail now, so that you can flesh out that.

DR. THROCKMORTON: Right, sure. Okay, thanks. I just didn't want to think I'd missed something. Thank you. I have one other small thing. If you go to Slide 55, I'm sure it's just something I don't understand.

What are the two bars? What is the yellow and the red bar? Events preserved, what does that mean?

DR. BAIGENT: The left-hand axis shows you the percentage number of people who had a coronary heart disease event. And so what one sees is the yellow bar is aspirin therapy and the red bar is control therapy.

And that means that there's a difference of point one percent between aspirin, the proportion of CHD events. And so events prevented is actually a slightly misleading way of presenting it.

DR. THROCKMORTON: Okay, thanks, I was a little confused. Thank you. Bob.

DR. TEMPLE: There's information, at least in some settings, post-procedurally, anyway, that very small MIs that no one could detect, but that are detectable only by troponin excess, may have some implications for outcome and mortality in particular.

So, my assumption is that if you had good data on silent MIs, which you don't, you might well have used it. I understand how difficult it is if you don't have the data.

And it's particularly difficult if you're doing an analysis looking at events over time. But you were content in earlier analyses with analyses that weren't over time, but that were just total.

So, at least where the data were available, you actually could do that, I assume. And it seems not easy to argue that losing some myocardial tissue, but not having pain, isn't an event that matters. You'd think it would, usually.

But I guess the data aren't available for anybody, but the HOT Study.

DR. BAIGENT: We didn't seek information on silent MI from those studies that recorded it, because we felt a great strength around ours was that we had pre-specified, many years ago, when I was at medical school, asserted that we would only look at these types of events.

And I think that's been a great strength of the ATT over the years, that we've stuck to a consistent measure. And have brought all available studies together so that the public health community can see results in one chunk.

DR. TEMPLE: Did I understand that Slide 50 that was handed out, was just wrong and that you showed the correct slide?

DR. BAIGENT: Yeah, I'm sorry, that was a slip.

DR. TEMPLE: It seems to show a stroke affect, but there isn't. Do you have a slide for just thrombotic stroke?

DR. BAIGENT: We do have a slide.

DR. TEMPLE: This was total, and you showed hemorrhagic.

DR. BAIGENT: I believe it may be, I don't have my crib sheet here, but there is a back-up slide available to us on ischemic stroke. But I can tell you what it shows.

It shows no affect. Obviously, if you have no affect on any stroke, which is most of the strokes, and the ischemic stroke is most of those.

And you have a tiny, actually an excess risk of hemorrhagic stroke. And it implies that there cannot be any affect on ischemic stroke. Now the reason for that, we are exploring in more detail, as best we can, from the available data.

But at this point, it doesn't seem to be any obvious reason. For example, if you subdivide people by their baseline characteristics, you might want to try and identify people who are more likely to have a reduction in ischemic stroke.

We've not been able to find any such evidence that there is a particular group who do avoid ischemic stroke within that group. But I have to say, of course, that we have a limited number of strokes within the primary prevention database and so we're probably torturing the data more than we should in looking at that kind of level of detail.

DR. TEMPLE: One of the questions that will face the committee later, is the question, how much comfort should you take from the previous data in the sicker people, in the secondary prevention population.

And that's intended to be a question for discussion, but it does seem on its face that the failure to find what everybody knows is true and ask them if you've had stroke, in the primary prevention group, must shake one a little. So I just wondered what you would say about that.

DR. BAIGENT: I think it's an interesting finding. But we need to remember that we've got clear evidence on non-fatal MI, and that's a substantial protective effect.

We've got neutral results on stroke. There's no evidence that we're causing ischemic stroke. There's evidence that we might be causing a few, a very small number of hemorrhagic strokes.

And there's evidence that we might be causing some extracranial bleeds, which is obviously important to weigh. There's no evidence at this stage that we're preventing much death, although we would expect that to be an effect of aspirin, even in primary prevention. It may be we just don't have enough numbers.

One technical issue I think is worth considering, when we think about effects on death, and that is that many of the patients who had non-fatal events, non-fatal MI in particular, subsequently went on to die.

And so when we consider death on its own, we may well have the phenomenon whereby patients who have a non-fatal event then start active treatment.

And so the failure to find an effect on mortality, may in part be related to that technical issue. And so I think that what we're seeing is clear effects on MI. No concern that we might causing an excess risk of stroke or vascular death, and clear effects on bleeding.

And what we need to do is focus on those two things, where we have a clear signal and try to weigh those in ways that are sensible.

DR. TEMPLE: And so just, my last question. That's how we should take, I take it, the effect on vascular events slide, Number 47. Obviously the beneficial effects are driven mostly by effects on MI?

DR. BAIGENT: Yeah.

DR. TEMPLE: And you're saying well, the other events, mortality, don't take that benefit away, even if they don't add much to it.

So is that how one should look at Slide 47?

DR. BAIGENT: Have you got 47 there? Oh, no, you need to go to another presentation. Yeah, we're saying that most of this is driven by effects on coronary heart disease, that's important to understand we get that from this meta-analysis.

We can decided, from this meta-analysis, that this is a clear signal, that it's really important to emphasize that this comes from dominantly non-fatal MI.

DR. TEMPLE: You could add, I guess, I'll add it for you, that four out of the five studies, by that measure anyway, whatever one thinks of that measure, achieve nominal significance, you know whatever their other ?

DR. BAIGENT: That is certainly a true statement. But, I would argue that ?

DR. TEMPLE: It wasn't the primary, I know, I know.

DR. BAIGENT: Yeah, you know what my arguments are. I think that we're throwing out information if we just adhere to that kind of approach to interpreting data.

DR. BORER: Steve and then Tom Pickering, Blase, and Tom Fleming.

DR. NISSEN: From a regulatory policy point of view, one of the questions that we face here is when do you use a meta-analysis in deciding about regulatory policy.

And so I want to test a question on you. And the question is shouldn't we restrict such use to situations where there's not a testable hypothesis that can be answered with an appropriately designed prospective clinical trial.

And so the question I would ask is, is the question of whether there is a benefit over risk in the group with the ten to 20 percent risk? Is that a testable hypotheses? I mean could you design a trial?

I'm going to do some power calculations later myself, because I'm going to use your data and I'm going to go back and actually ask that question.

And so if it's a testable hypothesis, then I would ask you, why not test the hypothesis?

DR. BAIGENT: Well, I think there are trials going on at the moment that have identified this as being an important question and they were mentioned, I think, by Dr. Pearson earlier, that there is a trial--no, one of the speakers over there, mentioned that there was a trial in peripheral vascular disease going on Scotland. There's a trial in the elderly that's proposed, that will be looking at precisely that group.

You could think of other groups that would be interesting to have information. But I think that the principle that you might be able to ask physicians, identify particular patients within your practice who you consider to be at moderate risk, and that you feel might be able to benefit from aspirin, is a good one. And supported by the data.

DR. NISSEN: Sure, but it relates to whether that's something that might appear in a guideline written by an organization or something that would reach the level of evidence that a regulatory agency would want to provide a label for.

And I'm asking the question. I mean, most of the time what we're faced with here at this committee is, there's a hypothesis, the hypothesis is tested.

We have that data. We look at it, and we analyze it and we decide whether it meets the level of evidence required or not. And you know, you would agree here, that there is no trial that's tested the hypothesis that's being asked here.

Which is whether or not a group of people selected, for having a ten to 20 percent risk, have a benefit over the risk.

DR. BAIGENT: I think the objective of the trials that have been published most recently, the HOT Study, the Primary Prevention Projects and the Thrombosis Prevention Trial, was actually to identify such a group.

Their event rates were somewhat lower than they had hoped for, but that was the objective of those trials. And we can find a group, within those trials, you know, a randomized comparison within those trials, where those patients were studied.

So I think, you know, we already have randomized data within, looking at that very question.

DR. NISSEN: I guess the other question I wanted to ask is with the Thrombosis Prevention Trial, there are two p-values provided. One for coronary death and fatal and non-fatal MI. And that p is equal to 04.

And then there's a p of equal to 07 when you include silent MI. And I'd like to know which of those analyses was the primary pre-specified analysis of interest here? What did they pre-specify in the trial?

DR. BAIGENT: Well, we have Dr. Meade present in the audience, but I think I know what he will answer, so I can tell you the answer is that they did not plan to look at silent MI as their primary outcome. So it was specifically aimed, maybe Dr. Meade would want to come to the microphone and just affirm that that was the case. But it was not planned to look at silent MI.

PROFESSOR MEADE: Yes, I'm Professor Meade. It was not pre-specified. It was analysis that was actually carried out by your statistician, and which I actually think was inappropriate.

DR. NISSEN: Well, if it wasn't pre-specified, why would anybody have gotten all those EKGs and looked at it? I mean obviously somebody was interested enough in it to get a bunch of electrocardiograms.

PROFESSOR MEADE: We were carrying out serial ECGs throughout the follow-up of our trial participants, and it seemed to me an obvious question that people would ask about silent MIs.

The result we got was no effect at all. To me it doesn't actually follow, although we know about the significance of silent MIs that aspirin are necessarily going to influence silent MI.

But in any case, it was simply provided because people we discussed it with said, well, it would be interesting to show that.

It's not pre-specified. It was an analysis carried out by the FDA Statistician and which I take rather serious exception.

DR. BORER: Tom Pickering.

DR. PICKERING: I have a question about the blood pressure. In Slide 41, in the high risk patients, you said the benefit was the same whether or not the diastolic pressure was above or below 90.

Nowadays, as you know, we tend to focus on systolic pressure, in fact, some hypertension experts have said we don't even need to measure diastolic pressure.

So, can you tell us about systolic pressure, and also, you also said that if patients were really hypertensive, they didn't get into these studies.

So what sort of range of blood pressures are you talking about in this analysis?

DR. BAIGENT: Well, this particular analysis was done for the 1994 cycle analyses. In that stage we didn't analyze systolic blood pressure, although we could have done.

I haven't repeated these analyses specifically for this committee for looking at systolic blood pressure. I can't give you an answer to your question. However, we have looked in the primary prevention trials at whether systolic blood pressure is associated, no, raised systolic blood pressure is associated with any attenuation of benefit.

And we did not find that. We found similar benefits irrespective of blood pressure. That's to say within a particular risk level, the influence of blood pressure was not to attenuate benefit.

In terms of, so that answers, I hope answers your question about the effects of aspirin at different levels of blood pressure.

In terms of range of blood pressures that would typically be included in trials, you're as familiar as anyone with the types of patients who are excluded from aspirin or antiplatelet trials.

Generally speaking, people specify an upper limit. For example, 180 systolic, 200 systolic. It varies between trials. But generally speaking, we see an average of something like 140 over 80 in most trials.

And you might see systolic blood pressures going up to, you know, 160, 170, but not much higher than that. That's the range of values seen.

DR. BORER: Blase.

DR. CARABELLO: Out of these trials, the British Doctors Trial is the odd person out. And today it might be easier to blow it off because we have five trials and it's only one of those five.

But 14 years ago it was one of the two trials available. And at that time the committee still voted in favor of broader labeling.

I realize that a number of the physicians involved stopped taking their aspirin, and that might be one excuse. But as I read through that trial, I just found it hard to understand why it failed to come up with a difference.

And I was wondering if you or its PI could address that trial specifically, as it is the outlier here.

DR. BAIGENT: Okay, well I'm flattered that you say that I'm PI. I'm representing the British Doctors Study. Actually, I wasn't born when that was started.

(Laughter.)

DR. BAIGENT: Sir Richard Doll still comes into work every day and he has the office next to me. And still works longer hours than I do, so he is the principal investigator.

And I think what he would say is that there was an issue with compliance in the British Doctors Study. We really can't explain why this result is out of line with the others.

It may be to do with doctors starting treatment, you know how they are always the first to act on guidelines that have not yet been written.

And certainly I think that there was this phenomenon in the UK whereby some of the doctors accepted the evidence at an early stage.

We have actually gone to quite a lot of trouble to get the data from individual records out of the basement where they're still kept in Oxford.

And we, actually quite a lot of work went into trying to put the data together so that they could be analyzed as part of this work.

So I think if there was anything particularly striking, we would probably have discovered it during the course of doing that work. But nothing that we've analyzed has given us any clue at to why that study is a bit out of line.

DR. BORER: Tom Fleming.

DR. FLEMING: I have a couple of quick issues and then maybe one or two more detailed issues. Just very quickly, could you remind us the year in which you said you pre-specified your analysis plan for the analysis of these five primary prevention trials.

DR. BAIGENT: We did that and we met in 2000, I believe, January, 2000, February, 2000. But actually we've been, I mean that's really a bit misleading. Because I've been working on this for the last decade.

And after the high risk paper in 1994, we felt that we should be looking again at the high risk trials in a new cycle of analyses, and that was what we published in 2002.

But we also felt that in the 2002 paper, we should separate out the primary prevention trials. So, in some ways, we have been planning for some years, before that, to look at the primary prevention trials separately, knowing that particular new studies had been planned and were ongoing.

DR. FLEMING: And certainly we know from a scientific perspective, if we're looking at evidence to be interpreted as confirmatory, as opposed to exploratory, we like to have pre-specified hypotheses.

Usually we think of that pre-specification meaning before the data are unblinded, how we struggle when we're doing meta-analyses of studies that have been essentially completed.

The meta-analysis is pre-specified, but the data are out there, and so it's not rocket science to get a sense of what kinds of hypotheses are likely to be supported or not supported.

The second issue is as you did these analyses, some of these patients that came from these five primary prevention trials were in fact post-MI or secondary, in particular, PHS, that's true.

Did you exclude all of those patients when you did these meta-analyses?

DR. BAIGENT: We didn't exclude them. We had information about those patients or those individuals who had inadvertently been entered into the trials.

And what we have done is we've analyzed the data among those patients who had a history of vascular disease and among those patients who didn't have a history of vascular disease.

And we've been able to show, and I can make the data available to the committee. We've been able to show that the results were entirely similar in both groups.

And, moreover, the results are not explained by an effect only in those patients who had a history of vascular disease.

I note that Dr. Gaziano has come up to the microphone. I believe he probably wants to make a comment about the types of patients who were included in the U.S. Physicians Study. So, Mike, you might want to say a few things.

DR. GAZIANO: Yes, I represent the Physicians Health Study. I'm Mike Gaziano, the current PI of the study. And I take issue with the notion that there was a substantial number of individuals with prior MI in the Physicians Health Study.

It was a very low risk group of individuals. After very careful review of all records for any reported MI during the study, we've located one individual who's had a confirmed MI prior to the start of the study.

And there were no other clinical evidence of prior MI. In the study, in general, it was a very low risk group of people. We had about 15 percent of the overall anticipated mortality for an age-matched male group.

So it's a very low risk group. There were about 333 individuals with angina at baseline. But, in general, it was a very low risk primary prevention group.

DR. FLEMING: I'm not talking about the totality of the study distribution. I'm talking about whether there were a fraction of these patients in this study that, in fact, are in, what we would call secondary prevention categories for which we've already had approvals.

You're saying there are almost none, you're saying?

DR. GAZIANO: Almost none. Almost none. There were 333 who had pre-specified angina out of 22,000, and one MI. So it's a primary prevention trial, largely.

In those 333, there were 28 MIs.

DR. FLEMING: Could I have you go to Slide 50, actually I'm going to want to quickly scan through 50, 51, and 52. While you're going to that, one of the struggles here, and we alluded to this earlier on, is that we've got five studies in primary prevention and those primary prevention studies, as Dr. Pearson's slide previously showed, are heavily weighted toward what we would call low risk patients for whom we're not specifically advocating aspirin use.

I think you've indicated that as you've divided these patients up into low risk, moderate risk and high risk, in terms of person and years of follow up, I think only one-eighth of this population falls into the moderate risk group, and only three percent into the high risk group.

So certainly any conclusions particularly we would make about high risk, are extraordinarily fragile. And what we see about intermediate or moderate risk is, again, based on only one-eighth of these five.

But what's interesting is that at least for me, one of the issues that is very important here is that, in looking at a composite endpoint, not all components of the composite are of equal clinical relevance.

We've got, in your composite here, we're focusing on non-fatal MI. We're focusing on stroke and we're focusing on fatal events. And these data point out that when you do subdivide and take your seven-eighths of the population that you consider at less than one percent, and then your one-eighth of the population at one to two percent, which is your target group.

If we looked at the aggregate, one disconcerting element here is that we're not seeing even a positive trend for fatal MIs, for stroke and for overall cardiovascular death.

When you've done your meta-analysis here and you look at stroke, it looks even less favorable in your moderate group than in the low group. If we go to the next slide.

When you look at hemorrhagic stroke, it looks less favorable as well. Next slide. When you look at vascular death, it looks less favorable as well.

So, when we look at this entire data set, including the primaries, you see something very inconsistent with secondary. You don't see trends for beneficial effects on these very important elements.

And now when you subdivide it into primary, into low risk against moderate, on these critical features, moderate looks even worse. Am I misinterpreting or is that, in fact, a fair interpretation?

DR. BAIGENT: Well, I would interpret it a bit differently. If we could go back to the first one on stroke. If I'm understanding you correctly, you're concerned that the moderate risk patients are having a less favorable effect than the low risk patients, is that correct?

DR. FLEMING: What's your interpretation of it?

DR. BAIGENT: Well, I would say that this is likely to be the result of having subdivided the data in many ways. I mean we are looking at several hundred analyses here. We have to, I think, be careful about making errors by going into the data in too much detail.

I mean maybe one sign of that is that actually, although these moderate patients appear to be a little adverse, when you go to the higher risk patients they appear to be going back the other way.

Surely this is more likely to be due to random error, that we need to be careful that we don't make mistakes by looking at that kind of level of detail of the data.

DR. FLEMING: When we were talking to Dr. Pearson, we were, some of us were concerned that we're being asked here today to look at whether or not there is an adequately favorable benefit to risk profile in moderate risk patients, that an approval should be provided, this should be added the indication.

And we were concerned that the preponderance of evidence in these five studies comes from what you might call low risk. And we were told, well, wait for your presentation because you're going to pull out those moderate risks, and you're going to be able to show us the insights from that moderate risk.

So, I'm left on the one hand with my understanding that we are to look at these data in the moderate risk category and put some credibility as we make our assessment as to whether the label should be extended to this cohort.

And yet, when the results look more, look less favorable here, now you're telling me something that I understand. Which is gee don't overinterpret subgroups because this is going to be particularly unreliable, especially when it's such a small subgroup.

I understand that. But then I'm left with the thought that what little evidence is here, doesn't look good, how am I supposed to interpret this evidence then in some way as being the basis for an extension of the label?

DR. BAIGENT: Well, I believe I have shown you the moderate risk group in the context of the other risk groups. And that was my aim all along to, and the aim of the ATT, has been to try and present all of the available evidence to pick out the moderate risk group as being indicative of a general pattern.

Can we go back one or two slides, I think -- this one here. I never argued that this particular result should receive emphasis.

This particular one here, which happens to be three standard deviations in favor, a non-fatal MI. I didn't pick that out. But what I pointed out and I think is really important for this committee to understand, is that the results on non-fatal MI are similar across a wide range of risk levels.

And that is one piece of evidence we need to weigh. And then we need to think, well, what does that imply for the benefit to risk ratio?

We obviously need to consider stroke and vascular death as part of that overall evidence. But I would argue for looking at all the risk levels and trying to reach a synthesis of the data by looking at all the different risk levels and picking out how the benefit to risk ratio is favorable within particular risk groups.

And we're arguing that you should be conservative and say moderate risk seems to be about three to one. That seems to be a good level to pick.

If you go lower than that, then you may be causing significant harm.

DR. FLEMING: So essentially in Slides 50, 51 and 52, where these patterns look unfavorable, your overall sense is we should proceed with caution here because this subgroup is a fairly limited fraction of the total of this meta-analysis. Did I interpret you correctly?

DR. BAIGENT: I think they should be treated with caution, yes, because they are relatively small numbers of events.

DR. BORER: Paul.

DR. ARMSTRONG: Dr. Baigent, I've got two questions. Almost half of the population that you've presented were male doctors. And arguably, some would say that doctors are smarter than patients and some would say not.

(Laughter.)

DR. ARMSTRONG: And some would say that the applicability of treatments in doctors to the general population that we're considering is perhaps questionable.

And it leads to my second question. But the issue is surveillance as it relates to side effects, which I'm still trying to get a handle on, and the extent to which compliance and recognition of side effects, such as mylina or other things that might lead to more catastrophic events, might have been more sensitively surveyed by the receiver of the medicine.

So I'd like you to comment on that, and I'd like you to comment on the rigor with which surveillance, as it relates to these uncommon but important issues that we're grappling with, were actually detected or looked for in the broad cross-section of studies and patients which we're reviewing. So, if you could deal with that question first and then I have a second one.

DR. BAIGENT: Okay. We specifically asked people to give us information on serious bleeding, by which we meant typically transfusion.

There may occasionally be bleeds that don't need a transfusion that are serious, that are not cerebral, but we asked for serious bleeding and generally we got transfusion-related bleeding.

So that was the same for the U.S. Physicians and the British Doctors Study. We went to some length actually to ensure that numbers were transfusion-related.

So the absolute risks I've shown you are based on that specific outcome. And I don't believe surveillance would have accounted for much variation in the way in which people interpreted that.

DR. ARMSTRONG: And there was no heterogeneity across the doctor, non-doctor studies as it relates to the side effects? Because I couldn't get at that from your presentation.

DR. BAIGENT: Well, we could put up the slide on major bleeding. Actually, no, we don't have the individual studies available to look at.

But my recollection is, and I can get the data for you after the break, if you would permit that, is that there wasn't any heterogeneity between the studies.

DR. ARMSTRONG: My second question, in your 2002 BMJ work, you talk about the risk being similar across a wide category of patients, at least as it relates to extracranial bleeding.

And I'm still, and you mentioned in your presentation that you do have now time-to-event data. And so what I'm trying to get at is time-to-event as it relates to intercranial hemorrhage and GI bleeding, and bleeding requiring transfusion and the extent to which we can learn something from that relative to, for example, small, elderly females of low body weight for whom bleeding is of concern in relationship to other studies, as you well know.

So, do we have that information, sir?

DR. BAIGENT: We certainly have the information available that would enable us to do those analyses. We haven't done them as yet. But we've looked at the variation in the relative risk of hemorrhagic stroke and of extracranial bleeding according to baseline features, and we did not find any statistical heterogeneity among the different subgroups. So however, whatever type of person you are, the relative risk increase of each of those types of outcomes doesn't appear to be predicted by your particular baseline features.

However, the absolute risk of those events is modified by that, and that is something that we could look at. I should say that we have looked at time-to-event analyses of those adverse events and we find that they accrue uniformly over time.

So it's not as if we get a massive hit in the first year after starting treatment. They accrue over time.

DR. ARMSTRONG: That's helpful, thank you.

DR. BORER: Bob Temple.

DR. TEMPLE: I just wanted say, mention a couple of historical things. The idea that something like 500 of the patients in the Physicians Health Study had a prior MI was based on an onsite review by someone who is now dead, and who, therefore, cannot defend it anymore, but I can tell you she was a very careful reviewer. So, I can't say too much more about it than that. But that's what she thought when she did an on-site inspection of the records.

I guess I want to make the second observation that having one study go the wrong way is not unprecedented in the aspirin world. The largest secondary prevention study, AMIS, had mortality going adversely and didn't have a favorable effect overall.

So it's not so odd that that could happen, the rest of the studies looked much better. And I just want to say something about meta-analysis, really following up what Steve was saying.

As a general rule, I can't, I don't know enough to say that there's no exception. We have thought there ought to be some studies, how many to be debated, that actually show the effect of interest on their own.

And as Tom was saying before, that doesn't mean you can't learn a great deal from subsets and all kinds of other things that meta-analyses are done for.

But it would be unusual, I can't say never, to reach a conclusion based entirely on the meta-analysis of studies. Now, I don't, that's partly a reading of the law and it's partly nervousness about how meta-analyses come to be.

You usually know the results before you do them. It's worth noting, for example, that in secondary prevention there is no specific mortality claim in the current aspirin labeling. There is a claim for the sum of MI and mortality, because that endpoint is solid in many individual studies. But although the overall analysis clearly shows, I mean the meta-analyses clearly show a mortality effect, that is not in the label.

And the reason for that is the one I just gave you. No individual trials managed to show that. So you could describe that as an excess of caution or a lot of things, but there is some nervousness about not being able to see it in individual trials.

One last bit. The reason, when we saw only two studies, the British Doctors and the Physicians Health Study, we were not overimpressed was that, remember, the Physicians Health Study failed on its primary endpoint, because there weren't enough deaths.

We were too healthy. That's because we're too smart. I believe the first explanation is the best. I'm still in that study. When you actually, when you go to find an alternative endpoint, a good question is should you pick the one that knocks your eyes out, or should you have a broader endpoint which is stroke, hemorrhagic and non-hemorrhagic, death and MI.

Well, when you do that, you just saw the number, you get a .01. That doesn't necessarily overcome the British Doctor Study. That's not so powerful that it looks persuasive.

And I think that's why we were a little skeptical back then. Of course now there are three more studies and that's a lot more information.

DR. BORER: Before we go on to Bill, Tom, you wanted to comment on that?

DR. FLEMING: Just among the things that Bob Temple was just saying. Just to add a little bit to one point. You were talking about the Physicians Health Study and you were, I think what you had said was the mortality endpoint, the doctors are too healthy, there weren't enough deaths and so it wasn't positive because of that.

You're mic is not on.

DR. TEMPLE: Some of us think there were enough deaths.

DR. FLEMING: Well, I guess what I want to lead to is ?

DR. TEMPLE: I'm just kidding. It was good to have a healthy population.

DR. FLEMING: There's a difference between a non-significant result that's really trending and suggesting benefit, but you're underpowered, versus a study that's suggesting no difference.

And there were equal numbers of deaths in that study. So it is in fact true that that study needed to have more deaths to be able to be adequately powered to show differences it was targeted to be able to show.

On the other hand, it did show that in the substantial number of deaths that were there, they were balanced. And so that's, you know, it's important to say that a study that doesn't achieve statistical significance isn't the same as another one.

There is still information in there.

DR. PEARSON: I was wondering if I would invite Professor Meade to the microphone at this juncture. Because our point is, we have one moderate risk study which in fact, using predetermined endpoints, does show a significant effect.

And if we could perhaps have him give a couple of comments relative to Dr. Temple's point.

DR. BORER: We will want to hear that. Is that not part of any of your presentation later? No?

DR. PEARSON: No.

DR. BORER: Okay, let's hold off for one second and hear the other two questions which may relate to that same issue, and then we'll have Dr. Meade speak. Bill.

DR. HIATT: Just back to slide 47. I just want to understand your data analysis. Because when I look back at the trials themselves, on the composite endpoint, MI, stroke, vascular death, Physicians Health Study was positive.

HOT was positive if you exclude silent MIs. Looking at the Primary Prevention Project, Table 2 of the efficacy results, in the article itself, with the composite cardiovascular death, non-fatal infarction, non-fatal stroke, it's a non-significant with the confidence intervals up to 1.04. Your results show something different than that, which is why I asked the question when you presented it. I'm sorry I had to interrupt. And so that was confusing.

If you look at the TPT Study on Page 237 of that article, it says aspirin without warfarin reduced all ischemic heart disease. So that's fatal, non-fatal MI, excluding stroke, by 23 percent, but it's minus 42.

So that also crossed the one. So according to the actual primary articles, those two composite endpoints were statistically negative, but you're presenting them as positive. I didn't understand that.

DR. BORER: Before you answer the question, can I, you're referring back to the original article that presented the data on this trial.

If I'm not mistaken, in the ATT you pulled out segments of each of these trials, did you not? To look at the moderate risk patients, or do I misunderstand that?

DR. BAIGENT: This particular figure is showing all the available data. And I can't comment on individual numbers. I can certainly explore what you're saying, in more detail.

In the break, I can look at the numbers and try and explain why they differ. All I can say is that the principle investigators of these, of all the studies confirmed the data that we had presented were correct.

So, there maybe minor differences in definition that have accounted for those differences. We asked for particular outcomes to be provided and analyzed them de novo using our own definitions.

And that may account for some differences. But I would, I will look and see during the break.

DR. HIATT: Well, it might in fact, because the Primary Prevention Project was very close on that composite endpoint and the risk reduction was very close to what you present.

So maybe your analysis explains that. But it was just in contradistinction to the actual articles and FDA's statistical analysis were different from what you're presenting. And that's why I was just asking that question.

DR. BAIGENT: Naturally there will be, there will be minor differences. There shouldn't be major differences.

DR. HIATT: A related question is in the 2002 publication of the Antithrombotic Trialists Collaboration. The result of peripheral arterial disease is a 22 percent or 23 percent odds reduction. But that's when you include all the other antiplatelet drugs in addition to aspirin.

So, ticlopidine, dipryridamole, clopidogrel. If you continue to call off just the aspirin effect in those patients in your publication is that any different than it was in the earlier publication which was not significant?

DR. BAIGENT: The argument that we put in the 2002 publication was the same essentially as we argued all along. But what we're seeing is an antiplatelet effect of aspirin.

If we analyze all the, if we set out to analyze all the antiplatelet drugs together, get an estimate of the facts and then we examine in a separate analysis whether there was any evidence that aspirin working differently to other, had different effects to the other antiplatelet agents that are available.

We concluded from that analysis that the evidence among about two-thirds of the trial was using aspirin were similar to the other trials.

So that's been the basis for arguing that aspirin is an example of an antiplatelet effect. It's the most widely used example, it would be expected to produce results that are largely similar to the overall findings of the 2002 results.

DR. HIATT: So it wasn't driven by the same data from the CAPRI where clopidogrel was clearly superior to aspirin in that population? And ticlopidine had similar kinds of differences, but when they compare it with aspirin.

DR. BAIGENT: Yeah, the clopidogrel turned out to be very slightly more effective than aspirin in the range of patients they studied in CAPRI. It formed part of the evidence for the comparison of a different antiplatelet agent with aspirin.

But it was not, there was no evidence from the trials comparing an antiplatelet agent versus control. The effects varied according to the antiplatelet agent.

So overall, we had some limited evidence that could prove it might be more effective in particular types of patients. But generally speaking, the effect of antiplatelet drugs appeared similar across the board.

DR. BORER: Alastair.

DR. WOOD: Yeah, could you put up Slide 30, again. It seems to me that what the committee is struggling with is the lack of data in the pale yellow section.

And I guess what I expected and from the trailer for your talk was that you were going to fill that in by taking the data from all of the studies and give us some data on that.

Can you sort of verbally do that now and give us a sense of what that data would look like in the absence of a slide? And before you get to that, I guess the second thing it seems to me is you've all locked yourself into this ten percent as the cut point.

And at the same time you're offering all of the variables as a continuum. And which seems to me a mistake in some ways. But to go back to my point, I was expecting to see you fill this in.

DR. BAIGENT: If I could go back to the, if we bear that in mind, the light yellow section, the middle section is the second line on each of my figures.

So, if we go back to Slide 50, say, could you do that for me? Maybe one before that. Consistently throughout the talk, what I've been trying to do is show you, this is the section on the left-hand side, the low risk group.

This is the moderate risk group and this is the high risk group. As Dr. Pearson said, I was going to describe what happens in this group, but in fact what I've aimed to do through the talk is actually describe a continuum.

I tried to get the overall picture which is of consistency in non-fatal M, and then to argue that this has implications for considering this moderate risk group, and indeed for the high risk group, where some people would say that, you know, the issue is less, less contentious.

But for the moderate risk group, this is the relevant line. And I have a hope being able to show that the effects are similar throughout the board including this middle section for non-fatal MI.

It's not appropriate, in my view, to take this group here in isolation and start chopping it up. I think, I hope Dr. Fleming would agree that that would be inappropriate. We'd be looking in far too much detail at a relatively small number of events, when treated in isolation.

That actually would be over-analyzing a group of patients from within the overall context of the study.

DR. FLEMING: Indeed, I do share your caution when you point that when we take a meta-analysis and then we look at one-eighth of it, which is the moderate group, the middle group as you're pointing out, that we'd hoped to have filled in, and then the high risk which is three percent, you've got to be extremely cautious.

The issue, though, is this, to come back to Alastair's point, my understanding too was we were going to be led down a path that was going to show us how we could use these data which were predominantly in a low risk group, to try to have insight about risk benefit in this moderate risk group.

So the tension here is I share your concern about viewing this with great caution, but these are the data that we have to use, most importantly, to draw our conclusions.

And when you go beyond 49 and you look at Slide 50, if we could just, one more time, look at Slide 50, one of the issues here that is of concern to some of us, is that there seems to be an inconsistency between what we see in secondary prevention, which is, yes, you have a reduction in non-fatal MIs, but you correspondingly have a reduction in fatal MIs, in stroke, and in overall vascular death.

And that's not showing up in the meta-analysis of these five studies in primary prevention. So I was hoping to be led down a path here at least, granted, I have to view this with caution, that might suggest a continuum here.

And there isn't. It gets actually worse when you look at your moderate group on these measures that aren't showing benefit in the overall primary prevention meta-analysis.

Now I subdivide into the 13 percent that are the moderate target group, and I see even more concern. Granted, viewed with caution, that on this slide and the next two slides, the key most important endpoints seemingly are even more problematic.

DR. BORER: Steve, let's hold your issue until after a break, which I haven't called yet. But if we don't do it soon, we won't have one. Let's take a ten-minute break, we'll reconvene at 11:15 and we'll begin with Steve's question.

(Whereupon, the foregoing matter went off the record at 11:06 a.m., and went back on the record at 11:20 a.m.)

DR. BORER: So, if we can assemble, I will begin with Steve Nissen's question.

DR. NISSEN: We need a responder at the microphone, though.

DR. BORER: I think he's coming. Why don't you ask the question. A response will appear from somewhere.

DR. NISSEN: Okay. Well, I want to see Slide 50 again. This is a follow on to Tom Fleming's earlier question, which is what appears to be, I'll use the word signal, although it's obviously kind of a weak way to do it, that there is excessive stroke risk in that one to two percent category. And this is to some extent a rhetorical question, but there is a formal test for heterogeneity here.

And I know you did that for all of these, and I'd like you to maybe make sure everybody here understands what the results of that heterogeneity test is for this particular analysis.

In other words, is this, is there heterogeneity here or is there not?

DR. BAIGENT: Yes, there is. We tested between this result here and this result here. So the second prevention trial is a 90 percent reduction and the primary prevention trial is a five percent increase, non-significant increase.

If you test for heterogeneity between these two, that is to say is there any evidence that these differ. And you do get a p-value of .01. So it's clear evidence heterogeneity ?

DR. NISSEN: So clearly it is heterogeneity. I wanted to make sure everybody saw that, Tom.

DR. FLEMING: And it's even worse because that strength of evidence for heterogeneity is just looking at the five percent against the 19 percent.

And within the five percent, we see additional evidence that is, in fact, inconsistent with a linearity here. What you've got is the critical group of interest to us here is a subgroup within the group of five percent that looks even worse than the five percent.

DR. BAIGENT: I do think we need to, we must not lose sight of the fact, though, that we are arguing that we can prevent non-fatal MI. And that is worthwhile. We are also arguing that we have no clear evidence that we're causing ischemic stroke, and that is something that we'd like to have, but we don't have. So I do think there's been a little bit too much emphasis on this particular result and the result on vascular death.

Whereas we have something which is extremely striking in non-fatal MI, and we must not forget that.

DR. NISSEN: I have to follow up just a second on that and say you're getting pretty close there on that one to two percent category.

It's not quite significant, but it is really pretty close, isn't it?

DR. BAIGENT: Yeah, but we've looked at several hundred analyses. I mean, you know, you expect to see a little bit of garbage when you do that.

I mean if you torture the data enough, it will eventually confess. And, you know, I think we do need to bear in mind, I mean, you know, I think pretty much everyone agrees that there have been a lot of analyses here and, sure, we're going to see some apparently striking findings if we over analyze it.

DR. BORER: As a follow on to that, your Slide 55 where you look at CHD events, this presumably includes MI death and, non-fatal MI, non-fatal stroke and death.

And you've come up with a three, a benefit of three patients per thousand per year reduction. Is that correct for all events?

DR. BAIGENT: That is correct, yes. We did that because coronary heart disease event rates stratification is used by all the guidelines's bodies. So we wanted to make it easy for these data to be compared with other guidelines.

DR. BORER: Yeah, my only point was that this presumably is an integrator of all the good and bad things that happen.

DR. BAIGENT: This combines non-fatal MI and coronary heart disease death. It has a clear effect on non-fatal MI, there's no clear effect on coronary heart disease death.

Many patients who had a non-fatal MI go on to have a coronary heart disease death. So we're looking at the time to first of those events.

DR. BORER: I'm sorry, then I misunderstood. This is non-fatal MI and death.

DR. BAIGENT: Or coronary death, yes.

DR. BORER: Or coronary death, but does not include strokes.

DR. BAIGENT: No, it doesn't.

DR. BORER: Okay. Why don't we go on to the next, oh, I'm sorry, Bob.

DR. TEMPLE: Slide 47 shows study-by-study results for the combined endpoint of vascular events. Is there a similar table for just, a study-by-study now, not be risk, for the coronary events?

DR. BAIGENT: Yes, there is. If we, I mean I haven't got it available for you in this presentation, but I can tell you that it shows a similar pattern, a very similar pattern in fact.

As you'd expect because you're not getting much effects on stroke, you're not getting much effects on death, you're getting an effect on coronary heart disease.

And that's consistent throughout the study. So you see a similar sort of pattern with not much effect in British Doctors, and a clearer effect in the other studies.

And that reduction is around about a quarter.

DR. TEMPLE: Okay, and the other studies all achieve nominal significance, do they?

DR. BAIGENT: I couldn't tell you offhand. But they are very consistent and there's no heterogeneity among them, yeah.

DR. TEMPLE: Okay, I mean, that is the endpoint we're talking about here, so.

DR. BAIGENT: Coronary heart disease events is the one that we ?

DR. TEMPLE: Yeah, I don't feel embarrasses about asking. I mean, wouldn't, I guess I'm puzzled. Why wouldn't you show the results of each individual study for the endpoint that we're talking about, that we're hoping to get approval for?

DR. BAIGENT: Well, I said right at the start that we, right from the very beginning, had looked at vascular events as our primary outcome, as our main focus, right back to the early days when we started the ATT, APT.

And so I felt it was most appropriate, the least misleading, to show right up front what we saw in vascular events. We then planned to go into more detail with the data.

Obviously, in 15 minutes I can only show you a fraction of the several hundred or so analyses we've done. But I felt that by going straight to the issue, which is stratification by risk, we would actually, probably see more interesting information.

DR. TEMPLE: It's probably my hangup on individual studies, but, okay.

DR. BORER: On Page 35 of our background document, although p-values aren't in there, the absolute numbers are for all the trials for non-fatal MI are shown.

DR. BAIGENT: It should be pointed out that that is not the analyses you've seen today. This is a meta-analysis conducted by the Antithrombotic Trialists' Collaboration, I'm showing you.

You get very similar results when you look at the published data which is what previous authors have done. You know, qualitatively get similar results.

We've been able to look in a bit more detail because we have the individual data.

DR. BORER: I'm sorry, Tom, Tom Pickering.

DR. PICKERING: Yeah, could you show us the data on the overall vascular events divided into the three risk groups? I don't think we've seen that.

DR. BAIGENT: I think we have it as a backup slide. Can you access that? I mean, again, it's very similar to what you see on coronary heart disease events.

And won't add very much more to understanding because there's a neutral effect on strokes and a neutral effect on vascular deaths.

So, you see the same patterns, really. That's coronary heart disease events by risk. What we see is, so what we're looking for is vascular events in the same mode, okay.

Keep going, keep going, I think it might be the next one. No, not that one, not that one, not that one, keep going. Oh, I don't have it here.

It's very similar pattern to the coronary heart disease events, essentially similar. And, you know, I don't think there's anything more to say, really.

There is no qualitative difference between what we see for vascular events and coronary events. We just see a slightly smaller signal for vascular events, because we're mixing together something on which we have no effect and something on which we have a clear effect.

That's all that happens. It's not as if we're trying to hide anything. There's just a smaller effect, that's all.

DR. THROCKMORTON: The FDA analyses are in the statistical review, I think on Page 13.

DR. BAIGENT: I'm sorry, I didn't catch that? Was a point being made?

DR. TEMPLE: No, it's just those numbers are going to differ because they include silent MIs, where we knew them. So, I'm just explaining why it would look different.

DR. PEARSON: Mr. Chairman, just a point of clarification, should we go ahead with our core presentation, or would you like to have the individual addressings of specific questions.

DR. BORER: Why don't we try and complete the core presentation now, if we can before lunch, and then we'll, during the question and answer period we can have the individual PIs respond to specific issues that have come up.

DR. PEARSON: Excellent, thank you.

DR. MERZ: Hi, let me introduce myself. I'm Dr. Noel Berry Merz. I am a Clinical Cardiologist on faculty at Cedars-Sinai Medical Center.

I'm also a Scientific Investigative Cardiologist and Chair of the NHLBI-sponsored WISE Study, which is the Women's Ischemia Syndrome Evaluation Study, a prospective multi-center study of over 1,000 women.

I'm trying to understand better the different manifestations, if they are in women. So, with that expertise, I'll go ahead. One of my sort of introductory comments would be that this very good debate this morning basically is asking a basic question at a lot of different levels about lumping and splitting. And you're being asked to consider lumping for what is perceived as an important public health policy issue.

I'm going to talk to you about some of the hazards of splitting, specifically with the regard to how we have not adequately served women with their leading health care threat.

And also, why we really need to focus on aggregates because it's such an important public health problem.

Since 1984, more women than men have died annually of heart disease.

You can see from this figure where men are shown in the black bars and women in the gray hatched bars, that from an absolute number, women now comprise 52 percent annually of all heart disease deaths.

This is of course related to the aging of America, our obesity epidemic, our rising rates of diabetes as well as renewed interest in smoking. But this will worsen as this bolus in the python of baby boomers goes through.

And we've estimated in terms of man/women power, cardiovascular specialists, as well as hospital beds, we don't have enough to take care of this public health crisis that really has already started.

What do we know about the current status of primary prevention in women? Women are more likely now to die of sudden death prior to hospital arrival. These are new CDC statistics out analyzing data from 1999.

This is really for the first time. Men have always taken the prize for out-of-hospital sudden cardiac death, until this recent analyses.

Women historically, and this data goes back to the 1970s, have always taken the lion's share of cardiovascular health care costs. Now, because we are the dominant majority, but historically because we're so much more expensive to take care of when we do get a cardiovascular disease.

Fifty percent of women, from a primary care standpoint, greater than 55 years old, do have a high risk cholesterol level.

And within this age group as well, one-third of 55 years olds have a global CHD risk score that's greater than six percent. And this is why the American Heart Association and the American Preventive Services Task Force made these recommendations.

And they made them for men and women, they did not split. Women see primary care physicians more often than men for both routine and symptom related care. They're also actually quite a bit more compliant with preventive health care recommendations.

We now have something as simple as a screening annual mammography rates compliance up to 70 percent, where men are not as good with their prostates.

Women can also show that they're more compliant with more complex recommendations. For example, women are more compliant with these complex nutritional guidelines, which was really leading the charge for the cholesterol falls that we've seen, from a dietary standpoint, in the last decades.

Yet, women are less likely to receive appropriate care that is preventive, including aspirin, when indicated. And we have national survey data that when a women is at equal high risk, compared to a man, she is less likely to be given many different types of appropriate care, including aspirin.

Well, what are some of the issues to consider when we evaluate the data. Dr. Colin Baigent, showed us gender specific data.

Issues to consider when evaluating the data. Throughout a lot of investigation women have received what I call special population treatment, where women are considered a minority subgroup, and yet, we are the majority. We are the majority of the general population at 51 percent.

And we are now the strong majority at 52 percent of all cardiovascular disease. And upwards of 60 percent of our health care expenditure in terms of cardiovascular disease.

We also have had the pedestal treatment, where risk avoidance in women is factored relatively higher, shifting the perceived risk benefit ratio, such that effective treatments are less utilized.

And we can't tell you why physicians are not telling women to take their aspirin as much as men, but this would certainly be a concern.

Yet, when we examine the data, as we just did, there were no significant differences in either magnitude of risk or benefit between women and men in either the primary or secondary prevention aspirin trials, and indeed leading our authoritative bodies not to stratify by gender.

There's also no biological basis for a gender difference in aspirin benefit or risk. And again, it does not make sense that there should be.

So, in conclusion, the aging of America necessitates a focus on the majority, which is now women, and this will only become stronger. It is not just politically correct, and as my daughters say, with a smile on their face, girls rule.

And in a lot of ways we need to be very careful about how we lump and split now. Because our CCUs are going to be increasingly filled with women. And if we don't know what to do with them, we are not going to serve ourselves as well as them.

Risk stratification does exist. Women are amenable to preventive practices and yet therapies are underutilized.

There are similar favorable risk benefit ratios for women and men, for aspirin as primary prevention. We have the opportunity today to close what we consider is a very big evidenced-based practice gap, as well as to rectify special population and pedestal treatments, where the largest group afflicted by heart disease, which is women. I will close with that.

DR. BORER: Thank you very much, Dr. Merz. I think we'll hold any questions, because there will be some specifically about the data on which the similar, the conclusion of similar favorable risk benefit ratios is based.

But we'll hold that until the question and answer period later, only because we do have a published time of 1:00 at which we need to have public comments.

So why don't we move on to the next formal presentation and we'll hold the questions until later.

DR. MERZ: Which is Dr. Randall Stafford.

DR. STAFFORD: Dr. Borer, and other members of the Advisory Committee. My name is Dr. Randall Stafford. I serve as Director of the Program on Prevention Outcomes and Practices within the Stanford University Prevention Research Center.

I practice in the Stanford Preventive Cardiology Clinic as well. My presentation focuses on enhancing appropriate aspirin utilization with CHD risk-based therapy.

In brief, my presentation will address the following areas. Our study to examine national patterns of aspirin use, suggests a role for evidence-based labeling as a strategy for improving what is currently sub-optimal aspirin use.

What is the rationale for this study? The concept of global risk implies that a continuum of risk exists that can be used to tailor the intensity of clinical management.

More effective care results when patients at higher risk are treated more aggressively across multiple risk-reduction strategies. As you know, aspirin's role in secondary prevention for high risk patients is well-established.

Substantial benefits also exist for moderate risk patients, without known CVD events. There is a need to solidify physician recognition of risk stratification as a key tool in disease management.

Despite substantial efforts to develop the evidence concerning appropriate aspirin use, little is actually known about current physician aspirin utilization practices. Particularly for this moderate risk group.

This project's specific aims include first to evaluate 1992 through 2001, aspirin use in, by cardiovascular disease risk status.

We focus in particular on moderate risk patients. Second, to identify patient and physician characteristics associated with aspirin use.

Data sources for this study include the federally conducted National Care Surveys. These surveys are conducted in the settings of private physician offices, for NAMCS and hospital outpatient departments for the NHAMC study.

Patient visits are the unit of analysis. Annual samples of between 45 and 50,000 visits are available from these two surveys together. Visit specific information is included about patient demographics and diagnoses, physician activities and new or continuing medications.

While these surveys have been validated against other national data sources, there are inherent difficulties in assessing the use of over-the-counter medications.

Including uncertain reporting of aspirin use. Given the data elements that were available in these surveys, we define cardiovascular risk categories as follows.

High risk was defined as patients with existing coronary heart disease or other clinical forms of atherosclerosis. Moderate risk patients were defined as those with diabetes who had no coronary heart disease, or patients with two or more coronary heart disease risk factors among younger patients, and among older patients, one or more risk factors.

The remaining patients are low risk. Regarding the likelihood of aspirin use, by cardiovascular risk category, several conclusions can be drawn from the observed data on national practices.

There is dramatically lower than expected reported use of aspirin, both in high risk groups as well as moderate risk patients. For high risk patients, aspirin use was reported in only 25 percent of these patients.

For patients with diabetes and no CHD, six percent. For other patients in a moderate category on the basis of other risk factors, only seven percent were reported to be using aspirin.

We can see also that for low risk patients, less than one percent were reported to be using aspirin. We also see here, that over this ten year period there's been relatively modest increase in the use of aspirin.

We also examined aspirin use among patients taking statins. Use of these lipid-lowering drugs by these patients, indicates that they are not only at elevated risk, but that they are already receiving pharmacotherapy to modify their risk.

We see here that aspirin use in those patients with known CVD is around 30 percent. In those patients at moderate risk, here including those patients with diabetes, aspirin use was reported in only 16 percent in the most recent data. Although, you can see that there has been some increase over time.

We analyzed the independent impact of a range of factors on aspirin use. We found that aspirin use increased from moderate and high risk patients. It also increased with increasing patient age. Independent of all the other factors, aspirin use was less likely in women.

It was more likely in those patients with either private or public health insurance, and it was more likely in those patients who were visiting cardiologists as opposed to primary care physicians.

These patterns suggested that while overall aspirin use is sub-optimal, patterns for some sub-populations are even less optimal. As you've seen, aspirin is dramatically underused in the prevention of CHD in appropriate patients.

There's minimal inappropriate use in low risk patients and the extent of underutilization has improved only modestly over the past decade, in spite of accumulating evidence of benefit.

Greater aspirin use was independently associated with higher CVD risk, advanced age, male gender, health insurance coverage and cardiologist care.

Our study has limitations that are part and parcel of examining OTC drug use. There is possible under-reporting of aspirin use because of the over-the-counter status of this drug.

While the magnitude of under-reporting is unknown, it is telling that a physician would neglect reporting such an important therapy were it truly being used.

Even with this limitation, these are likely the best data we have available to assess aspirin use. They indicate that aspirin is under-used, particularly in moderate risk patients.

Well, what causes sub-optimal aspirin use. Possible contributors include lack of knowledge about existing evidence, lack of incentives and/or accountability for evidence-based practice.

It's true that both patients and physicians may unduly focus on acute issues. And the process of balancing costs, risks and benefits, may not always be straightforward.

Finally, aspirin is not labeled for primary prevention, despite available evidence of its benefits. How can we improve appropriate aspirin utilization?

Well, clearly only part of this puzzle, unambiguous labeling supporting the appropriate use of aspirin, will give both patients and physicians an unequivocal message regarding aspirin's role.

As you are considering today, it is vital to expand labeling to include moderate risk patients. Other strategies may include physician and patient education and engagement, including better incentives for attaining recommended practices.

We also may need to think about supplementing current mechanisms by which prevention services are delivered. For example, employing Nurse Case Managers to manage chronic issues and improve patient adherence.

With these and other strategies, I have no doubt that aspirin can come closer to fulfilling its promise as an effective an inexpensive therapy, capable of drastically reducing cardiovascular disease risk.

It's my pleasure to introduce Dr. Eric Topol of the Cleveland Clinic Foundation.

DR. TOPOL: Thanks very much, Randall. It's been difficult to sit through the morning, having much to say, but of course I'm trying to come to a point where we try to process a lot of this information.

I'm only going to make just a few remarks, but first to point out that we're all students of aspirin and antiplatelet therapy over, really, a couple of decades.

And I think the most important signal that we've seen, and of course a lot of that was the classic article that has been commented on of the Oxford Group in 2002 BMJ, is that the most important effect of aspirin, throughout all of its applications has been in the reduction of non-fatal MI.

And that is greatly overriding that of stroke or a vascular death. Which of that tripartite endpoint has been the one that the Oxford Group introduced many years ago.

So it's no surprise to me, to see that in the population under discussion today, and it's been a great discussion, very intellectually charged.

I knew it would be good, but it's even exceeded the dissection that I had anticipated. That non-fatal MI, is the signal that we're looking for. This is a much lower risk population.

So with that background, let me just try to sum up a few key points. The first is that we have a body of data that you've seen, with five trials.

It was the decision to present all the trials, although, for this particular extended label, it could have just been the thrombosis prevention trial.

And in retrospect, it might just be that trial. Because that is the one that directly addresses this moderate risk group. And the greater than one percent risk per year, ten percent risk per decade. So, in effect, if you just like to drill down on that trial, that will answer a lot of the comments that have been made throughout the course of the morning.

Particularly Tom Fleming's and Steve Nissen's and others. But in the totality, we have over 55,000 patients from five trials. And these five trials have been published in the, I think the most respected peer review journals.

And they include the New England Journal of Medicine, Lancet and British Medical Journal. Why they have not been reviewed by this supreme court, if you will, they certainly have undergone a strict peer review.

And no trial, and I've watched many clinical trials in the cardiovascular medicine space and medicine throughout the last couple of decades has been pristine, without any warts or glitches. I think you all would acknowledge that.

They are diverse populations, which is a great thing. It's a major strength of these trials, rather than a detractor as has been pointed out or at least suggested.

Now the most important point about these trials, which is the most salient aspect of the thrombosis prevention trial, which you'll hear separately from Professor Meade again, later today, is that this unequivocal, 30 percent reduction in non-fatal MI. Now this is so important because, as you've seen, this is the same proportionate reduction as is seen with secondary prevention, post-MI.

So this 30 percent reduction is important and it's a log order greater than the risk of a serious cataclysmic side effect that is of hemorrhagic stroke.

And the issue about the silent MI is somewhat disturbing to me. And that's because these trials did not use silent MI in their endpoint, their primary endpoint. And from the very outset, as Colin reviewed this morning, that has never been part of the endpoint, outcome data of these trials.

And we only have some data for two of the trials, and that data, of course, is compromised because of the lack of time to event and the lack of ability to define a silent infarction.

These are all clinically manifested non-fatal MIs, 30 percent reduction, and that's just right concordant with the overall effect of antiplatelet therapy and aspirin in particular.

And I also want to emphasize, I hope this is something we all have learned over the years about interpretation of clinic trials. That this subgroup issue is counterproductive and certainly can be quite misleading. And Noel emphasized that earlier with respect to the women, that applies to many other subgroups as well.

Now these data have been raked over considerably. They are five groups of individual societies or groups, clinical trial groups that have gone over the same data that you're going over, perhaps processed a little bit more up-to-date, a little more recent, but nonetheless, essentially the same data.

The American Heart Association, the American College of Cardiology, the American Diabetes Association, the U.S. Preventive Services Task Force and the Antithrombotic Trialists' Collaboration. And each of these groups have made specific recommendations regarding the use of primary prevention, suppression of infarcs with aspirin.

Now in the real world, interestingly, the medical community, and to a large extent the lay community, already accept primary prevention of aspirin.

So, although, not sanctioned by the regulatory authority here in the United States, the medical, and to a large proportion the lay public accept aspirin as a prevention tool.

Americans are, of course, empowered now and they have accepted this. So many are taking aspirin, more than 20 million Americans are taking aspirin on a daily basis to suppress events. And this, a large proportion of those are primary prevention by individuals.

But there is an inconsistent message. Because if you turn to any of the lay media, such as magazines like Good Housekeeping, the Reader?s Digest, the Consumer Reports on Health, Prevention Magazine, Ladies? Home Journal, you will see recommendations from physician advisors about taking aspirin.

Yet, this is all off label. This is all not sanctioned by the regulatory oversight. And so it's, of course, an inconsistent message which we'd like to get concordant, get on cue, get to be homologous.

That all of the responsible parties believe in the same thing. If that's possible. Now acute MI is something that we need to prevent much better, because recently, much work has gone in in clinical trials and little progress has been made.

So, here it is towards the end of `03, and as we look into the future, we know that platelet-thrombus is the proximate cause. So there is an obvious connection with the action of aspirin.

There has been no significant reduction in mortality in many recent trials, randomized clinical trials. And, in fact, over the last ten years, there was no incremental reduction of mortality through any new therapeutic intervention.

Once CMI has been initiated, bad outcomes are frequent and that's best exemplified by the recent VALIANT Trial which follow post-MI heart failure with a very high rate of death, quite alarming, over its extended follow up.

And then finally, as I think you would agree, the only meaningful way to deal with MI in the future, and much more effectively, is to prevent these events.

So which of the recommendations should we accept, assuming we're accepting one of them. That, of course, is not entirely clear from the discussion this morning, but at least we can consider three different strata or levels.

The U.S. Preventive Services Task Force, as you recall, recommended the threshold of .6 percent per year or six percent over a ten year period.

That was the most aggressive recommendation, that is published in the Annals of Internal Medicine in `02. Then there was the AHA and ACC recommendations, which, as Tom Pearson summarized, were less aggressive. That was a one percent per year.

And you've seen from Colin's review of the individualized data, and I would also add to the point, that having individualized data in this meta-analysis gives us a lot more to work with.

I think it makes the meta-analysis another credible tool to support the Thrombosis Prevention Trial, the primary body of data for this discussion.

But what you'll see is with this one percent threshold or ten percent over ten year anticipated event rate, there will be a 35 percent reduction of non-fatal MI.

That's three per thousand events reduced per year, with the average individual living a 20 year or longer life span. So this is a very large proportion of events over the course of that individual's lifetime.

And then two percent per year, which is perhaps the least aggressive, but certainly a supported threshold. This is not the one that is really been under discussion, but it would be the most conservative threshold. But it would yield an even higher proportionate reduction, as you noted in that analysis of non-fatal MI, is a 43 percent reduction.

That's six per thousand events per year accruing over many years as an individual's life goes on. Now, in addition to the benefit, which I would say in this population is solely related to the non-fatal MI protection, suppression of those events. The risks are that of bleeding, particularly the one that we are most concerned about, in terms of frequency, is that of GI bleeding.

Now it's important to recognize that since there is this relationship of a tradeoff, that the overriding myocardial infarcs are titrated in part by the incidents of GI bleeding. And these are GI bleeds that lead to hospitalization with or without transfusion.

But the point is that a GI bleed, and Alastair would have made this point earlier, is not necessarily as bad an outcome as an MI, even if they are equivalent, and they're not.

In fact, in this moderate or intermediate primary prevention risk group, there is a great excess of reduction of the events of MI, as compared to any type of GI bleeding.

The second point has to do with the lower doses of aspirin, and having been now in two recent trials, been shown to reduce the rate of bleeding as compared to 325. And I also would mention that the British Doctors Trial, used 500 milligrams.

That's an outlier and that also may have interfered with some of the efficacy in that trial. But nonetheless, the bleeding clearly does appear to have a relationship in the BRAVO and CURE Trials that were recently published back-to-back as far as the aspirin dose data output.

And that the preservation of aspirin does appear efficacy at doses as low as 75 to 81 milligrams. So to summarize, the most important direction in the future of medicine is primary prevention, without any question.

And this, of course, is really pushing the envelope and raising the bar in some respects. Because we're now, by definition, dealing with low event rate populations.

And there's only so long these clinical trials can go on in our lifetime. And as you can recognize, two of these trials of the five were stopped prematurely by their data and safety monitoring board and the steering committee because it had exceeded the expectations of their primary endpoint, or of a cardinal endpoint.

Secondly, that the ongoing large trials, such as CHARISMA, which several of you are involved in the CHARISMA trial, that's already accepted that aspirin is the backbone strategy for primary prevention.

In one arm of the CHARISM trial of over 15,000 patients is aspirin, and that's now being compared to aspirin plus a second antiplatelet, in this case clopidogrel. So we already have gone past aspirin. At least many of use, as Clinical Investigators in this field, thinking that this is a sure foundation strategy.

And so soon, if this is not recognized as a foundation strategy we'll have a runaway train, if you will, with respect to the new comparators.

And then finally, aspirin, I do believe, is a cornerstone of prevention of myocardial infarction. And that shouldn't be considered as secondary prevention, but also fully incorporated in our primary prevention strategies. Thank you for your attention.

DR. BORER: Okay, thank you very much, Dr. Topol. And also Dr. Stafford. There will be some questions about some aspects of these presentations. I think Dr. Stafford responded directly to Alan Hirsch's question earlier.

But it's noon and at 1:00 we have published the fact that we'll be having public comment. So, we're going to break now for lunch. We'll come back at 1:00, and after the public comments are concluded, we'll continue questions and hear from the PIs.

(Whereupon, the foregoing matter went off the record at 11:59 a.m., and went back on the record at 12:59 p.m.)

AFTERNOON SESSION

(12:59 p.m.)

CHAIRMAN BORER: We'll begin the afternoon portion of the meeting now. The meeting will be open for public hearing, for public statements. Several people have indicated their desire to make a statement for which three to five minutes per statement is available.

I'm going to read to you a guidance here regarding the public statements.

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

For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting.

For example, the financial information may include a company's or a group's payment of your travel, lodging or other expenses in connection with your attendance at the meeting. Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationships.

If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

The first of the speakers is Nathaniel G. Clark, National Vice President, Clinical Affairs and Community Programs of the American Diabetes Association.

Dr. Clark.

** DR. CLARK: Thank you very much for allowing me to speak on this important issue.

I just want to tell a bit about what my title means. Being the National Vice President for Clinical Affairs for the American Diabetes Association means that it is my responsibility to oversee our development and promotion of our clinical practice guidelines, one of which deals with the use of aspirin.

There are two comments I want to make briefly before beginning the remarks that I planned to make prior to the meeting beginning. The first is to urge the committee very carefully to consider the position of patients with diabetes who are in this very odd position, given the discussion this morning, of being at moderate or most would say high risk for the development of cardiovascular disease and yet have not had a documented event, and therefore, for those with diabetes, primary prevention, in fact, is secondary prevention.

And on behalf of the 18 million Americans with diabetes, what you will think about and decide today will have a great deal of importance in terms of their future health.

The second comment I wanted to make has to do with a question that came at the beginning in terms of what is the actual effect of what the FDA says on this topic if many of the professional bodies have already issued guidelines, and this is a case where I'd urge you to consider that there are two issues.

One is what did the FDA say, and the second is what did the FDA not say. If you had not recently reviewed the very same evidence that various bodies had looked at to make their guidelines, then the guideline issuing body, such as the American Diabetes Association, could say, "Well, I know there isn't actually an FDA indication for the use of aspirin as primary prevention, but we believe based on the evidence that this is reasonable.?

If you today decide to not grant primary prevention as an indication, that will be a significant detriment as we move forward, and I believe it will significantly contribute to the lack of compliance which already has been documented as poor to this guideline.

In terms of my previous remarks that I planned to make, I want to first say that the American Diabetes Association enthusiastically supports the proposed change, both as we believe it will benefit patients with diabetes, but also because if the FDA speaks, I believe this will help in regard to compliance to the guideline we have issued.

Second, that diabetes is a major risk factor for cardiovascular disease is well known to all of you and has been brought out. When NCEP ATP III defined diabetes as a coronary risk equivalent, thereby saying that those with diabetes based on that fact alone had a risk of cardiovascular disease of 20 percent or greater, this was tremendously important in regard to the need for patients with diabetes to understand the benefits of aspirin.

Cardiovascular disease is a major complication and the major complication for those with diabetes. We now talk about the treatment of diabetes to prevent cardiovascular disease as having many components. Currently the buzz word is to talk about the ABCs, A standing for A1C, a measure of blood sugar control; B being blood pressure; and C being cholesterol.

But equally important would be aspirin and smoking reduction.

Our current recommendation and guideline in regard to aspirin for those with diabetes is that all adults should be on aspirin essentially. We specifically state that those over the age of 40, regardless of any past cardiovascular history should receive an aspirin, and those younger than 40, those still adults, should be considered for aspirin if they have an additional cardiovascular risk factor in addition to their diabetes, and these are enumerated as a family history of cardiovascular disease, a history of dislipidemia, hypertension, microalbuminuria, or smoking.

So, in summary, I would urge you most strongly to consider the evidence that's been presented and to grant the proposal as stated and to enlarge the indication for aspirin to include primary prevention for cardiovascular disease.

Thank you very much.

CHAIRMAN BORER: Thank you, Dr. Clark.

The next statement is from Dr. Charles Curry of the Association of Black Cardiologists.

** DR. CURRY: Thank you very much.

Today I serve as a consultant for Bayer, and at this time, I represent the Association of Black Cardiologists.

I sit on the National Heart Attack Alert Program Committee for the National Medical Association, and on that committee we see all of the data that represents the millions of Americans who die of coronary artery disease annually, and one cannot help but be extremely concerned and hopeful, particularly when we've heard today that the mortality rate does not appear to be going down, as one would expect, with all of the great interventions that we have.

The African American community is a high risk community. As you all know, 50 percent of African Americans age 50 will have hypertension. Hypercholesterolemia is a major problem; cigarette smoking; all of the risk factors that we hear so much about and I truly believe in are in abundance in the African American population.

We also know that nine of ten patients with MI, with acute coronary syndrome will have at least one major risk factor.