UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

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CARDIOVASCULAR AND RENAL DRUGS ADVISORY COMMITTEE

MEETING

MONDAY, DECEMBER 8, 2003

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The Advisory Committee met at 8:30 a.m. in the Ballroom of the
Gaithersburg Hilton, 620 Perry Parkway, Gaithersburg, Maryland, Dr.
Jeffrey Borer, Chairman, presiding.

[PRESENT]{.underline}:

JEFFREY S. BORER, M.D., Chairman

PAUL W. ARMSTRONG, M.D., Member

BLASE A. CARABELLO, M.D., Member

SUSANNA L. CUNNINGHAM, Ph.D., Consumer Representative

THOMAS FLEMING, Ph.D., Consultant (Voting)

WILLIAM R. HIATT, M.D., Member

ALAN T. HIRSCH, M.D., Member

JOSEPH KNAPKA, Ph.D, Patient Representative

BEVERLY H. LORELL, M.D., Member

JOHN NEYLAN, M.D., Acting Industry Representative

(Non-voting)

STEVEN E. NISSEN, M.D., F.A.C.C., Member

THOMAS PICKERING,, M.D., Member

EDWARD PRITCHETT, M.D., Consultant (Voting)

RONALD PORTMAN, M.D., Member

ALASTAIR WOOD, M.D., Consultant (Voting)

[SPONSOR REPRESENTATIVES]{.underline}:

COLIN BAIGENT, M.D.

JOHN A. COLWELL, M.D., Ph.D.

C. NOEL BAIREY MERZ, M.D.

J. MICHAEL GAZIANO, M.D.

LOREN LAINE, M.D.

THOMAS W. MEADE, D.M., F.R.S.

THOMAS A. PEARSON, M.D., M.P.H., Ph.D.

ERICA PEITLER, Rph

RANDALL STAFFORD, M.D., Ph.D.

GIANNI TOGNONI, M.D.

ERIC J. TOPOL, M.D.

[FDA REPRESENTATIVES]{.underline}:

MICHELLE M. JACKSON, Ph.D.

CHENXIONG (CHARLES) LE, Ph.D.

CURTIS ROSEBRAUGH, M.D., M.P.H.

ROBERT TEMPLE, M.D.

DOUGLAS THROCKMORTON, M.D.

[AGENDA ITEM]{.underline} [PAGE]{.underline}

[CALL TO ORDER AND INTRODUCTIONS:]{.underline}

Jeffrey Borer 4

CONFLICT OF INTEREST STATEMENT:

Dornette Spell-LeSane 6

WELCOME AND INTRODUCTORY COMMENTS:

Douglas Throckmorton 8

[SPONSOR PRESENTATIONS]{.underline}

INTRODUCTION

Erica Peitler 9

ASPIRIN BENEFIT/RISK IN PRIMARY PREVENTION

Thomas Pearson 17

SAFE/EFFICACY IN MODERATE RISK POPULATION

Colin Baigent 69

ASPIRIN USE IN WOMEN

C. Noel Bairey Merz 159

ASPIRIN UTILIZATION

Randall Stafford 165

ASPIRIN IN CLINICAL PRACTICE

Eric Topol 173

[BREAK]{.underline} 185

[PUBLIC STATEMENTS]{.underline} 186

[FDA PRESENTATION:]{.underline}

REGULATORY HISTORY OF ASPIRIN

Michelle M. Jackson 271

STATISTICAL ANALYSES OF THE BAYER\'S CITIZENS PETITION

Chenxiong (Charles) Le 283

[COMMITTEE DISCUSSION/QUESTIONS TO THE FDA]{.underline} 301

[COMMITTEE QUESTIONS/SUMMARY]{.underline} 396

[ADJOURNMENT]{.underline} 443

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]{.underline}

(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. So it seems
reasonable that somewhere in the spectrum of coronary artery disease and
sudden death and myocardial infarction and angina there must be a pool
of people who simply have a lot of risk factors and they\'re waiting to
develop an acute coronary syndrome.

And it seems to me that this committee today has an opportunity to
approve a form of primary prevention that has been used in millions of
people, and it\'s clearly not malignant.

I know how much the FDA likes studies. I heard Dr. Temple say once he
liked to see two studies better than .05 P values, but we have studies,
and I don\'t think that we\'re likely to get any additional major
studies because I don\'t believe you\'ll find a control group in the
United States.

So I think we would like to endorse the recommendations of the American
Heart Association and hope that you can find enough evidence to convince
you to help further reduce the incidence of coronary artery disease in
the American population.

Thank you.

CHAIRMAN BORER: Thank you very much, Dr. Curry.

The next speaker is Dr. W. Fred Miser of Ohio State University.

\*\* DR. MISER: Dr. Borer, members of the Advisory Committee and FDA
staff, good afternoon. It\'s an honor to be here today, even if it\'s
just after lunch, to urge you to approve aspirin therapy as primary
prevention of myocardial infarction.

My name is Dr. Fred Miser. I\'m a Board certified family physician, a
Diplomat and Fellow of the American Academy of Family Practice, and an
associate professor of family medicine at the Ohio State University
College of Medicine and Public Health.

I was invited here today by the Bayer Corporation, who assisted in my
travel and lodging here because of an editorial that I wrote last year
for the [American Family Physician]{.underline}. This peer reviewed
journal, published by the American Academy of Family Physicians, is
distributed to over 192,000 physicians and health care providers.

In its editorial entitled \"An Aspirin a Day Keeps the MI Away for
Some,\" I reviewed the latest recommendations by the third U.S.
Preventative Services Task Force which found good evidence that the
potential benefit of daily aspirin therapy in persons of moderate to
high risk for a cardiovascular event outweigh the potential harm.

I then went on to review other studies including the ATT and summarized
by acknowledging that aspirin is not a panacea, and as with all
therapies, we as physicians are obligated to spend time with our
patients discussing the advantages and disadvantages of this treatment
and assist them in making wise decisions.

As you know, the 90,135 family physicians here in the United States
provide the vast majority of primary care. Our focus is on the care of
the whole person. Not only do we provide for acute care needs and
managed chronic disease. We also provide advice in promoting health and
hopefully attempt to prevent disease.

In terms of coronary heart disease, which despite modern medical
technology continues to be the most common cause of death and disability
in the U.S., our goal is to keep our patients away from you, the
cardiologist, nothing personal, by attempting to modify these known
cardiac risk factors to prevent their first MI.

On a daily basis we care for our individuals, just like the one
described earlier today by Dr. Pearson. We encourage our patients to
stop smoking, to get off the sofa and get some moderate exercise, and to
eat wisely. We also make therapeutic decisions about controlling their
blood pressure and their lipids.

The decision to treat these conditions with medicines comes as we assess
their overall risk with the potential benefit of the therapy. As
physicians, we can easily identify those for whom the MI clock is
ticking, which leads me to aspirin therapy.

As with all therapies, we understand that aspirin has its benefits and
its risks, and as with all therapies, we are obligated to use aspirin
wisely. Daily we use clinical guidelines and decision rules to guide our
therapy for a myriad of conditions.

Likewise, we are capable of deciding who is at moderate and high risk
for coronary artery disease using the coronary risk assessment tools,
whether it be in paper format or on our PDAs or on the Internet.

Our patients, likewise, are smart and often use these tools on their
own. Using this tool allows us to sift through the 30 to 40 patients
that we see daily to stratify and identify those at cardiac risk and to
tailor our treatment based on that risk, which brings me finally to the
labeling issue for aspirin as primary prevention.

As you know, there\'s a dramatic lag between when research shows a
benefit and when that science is actually put into practice. Many of our
patients who would benefit from aspirin therapy are not on aspirin, and
many are taking aspirin inappropriately who may not benefit.

This change in labeling, I believe, would dramatically raise the
awareness of appropriate use of aspirin both for the physician and the
patient. As noted by the patient education handout developed by the
American Academy of Family Physicians called \"Coronary Heart Disease,
Reducing your Risk\" one of the recommendations is ask your doctor about
taking a low dose of aspirin each day. Aspirin helps prevent coronary
heart disease, but taking it also has some risks.

This open dialogue between a physician and patient is crucial. This
alliance, combined with the wise use of clinical judgment, can identify
those who will benefit from aspirin as primary prevention or preventing
those who are not at risk for harm.

I am convinced as a family physician that this change in labeling is
crucial, and I urge you to approve this change, and, yes, I do take my
daily baby aspirin.

Thank you.

CHAIRMAN BORER: Thank you, Dr. Miser.

The next speaker is Eric Topol of the Cleveland Clinic, who has spoken
with us a little earlier.

\*\* DR. TOPOL: Thanks very much, Dr. Borer.

I want to first acknowledge that I have worked as a consultant to both
Bayer and to McNeil and my time is reimbursed. I also at this juncture
am speaking not only in behalf of McNeil\'s view, but also of mine as to
build on some comments earlier regarding selection of patients, that is,
the clinical criteria apart from such things as a Framingham score, and
also the improved risk-benefit ratio in recent times.

So first I just want to talk about the charisma trial very briefly. This
is a large-scale trial that has been conducted. The enrollment phase has
been complete. It\'s one of the most rapid enrollment trials that has
ever been performed. Nine hundred hospitals across six continents in 32
countries, and it is comparing aspirin plus placebo as compared to
aspirin plus clopidogrel.

Now, instead of using any kind of Framingham risk score or other risk
scores, we actually use a combination of major and minor criteria, and
so in going along with the American Diabetes Association
recommendations, diabetes as a major criteria; also an abnormal
ankle-brachial index, asymptomatic carotid stenosis, or abnormal carotid
plaque by ultrasound. Those are major. One of those plus two minor or
two major would constitute sufficient enrollment criteria.

And the minor criteria include systolic blood pressure abnormality,
hypercholesterolemia, smoking, current smoking, and age by gender.

So these criteria, that is, three minor or combinations of major and
minor, were the enrolling population. What I wanted to tell you is that
we had a chance to look at this population now which just completed its
enrollment in November, just a few weeks ago, and there were over 15,600
patients enrolled. Of these patients, the population, 21 percent
constituted a primary prevention cohort never having had any type of
vascular event.

And the main event rate for the trial is death of any cause, MI or
stroke, and interestingly, despite the use of evidence based medicines
that included statins in 67 percent, ACE inhibitors or angiotensin
receptor blockers in 67 percent, and beta blockers in 48 percent, we
still see a very high event rate.

So the point is that even in 2003 with all of the other evidence based
medicines, things that might go into the \"polypill\" some day, which
include low dose aspirin, we see a very high event rate.

Now, the other thing I wanted to just build on was a comment I made
earlier regarding tradeoff, and I want to just review the two studies
that have shown what I believe are the best evidence we have today: that
aspirin at lower doses within the 75 to 325 range is associated with
even less bleeding hazard.

And what you can see, these are data from the BRAVO trial, which was
another large trial over 9,000 patients conducted worldwide in which we
were looking at an oral 2B3 inhibitor, lotrafiban plus aspirin, versus
aspirin and placebo. These are the aspirin only patients, and it was at
the discretion of the treating physician investigator to use a lower
dose or the dose that was over the 162 threshold, which was largely 300
or 325.

And it turned out by multivariate analysis, by propensity analysis there
was no difference between these patients with respect to the aspirin
compartment, and what you can see is that there was a significant
gradient of bleeding: serious bleeding requiring a hospitalization;
transfusion; and any bleeding, favoring the lowest dose aspirin.

In addition, the CURE trial the week after we published BRAVO in
[Circulation]{.underline}, the CURE trial investigators published their
experience with aspirin, and what you can see, again, is a very
important relationship between aspirin dose and bleeding.

But also I call your attention to the relationship to the major events
of death, MI, stroke, because at the low dose of less than 100
milligrams, again, the patient is not being demographically different at
all at the lowest dose. This is obviously not a randomized trial, but
it\'s the best data that we have today. It\'s in a cumulative 20,000
patients.

You can see the event rates were not compromised, but on the other hand,
major bleeding was substantially less at the lowest dose of aspirin.

And as you can see, in summary, the actual data for the dose of aspirin
and major bleeding, you see the gradient goes up very sharply from 1.9
to 3.7 for aspirin alone, and then the combination also follows that
same trend.

So just to summarize the important points is that apart from using risk
scores, very straightforward, simple, clinical criteria can
distinguished patients at increased risk and also to emphasize it, the
current use of evidence based medicine does not appear to preempt or
reduce that risk to any significant degree. That is, it\'s very easy
still today to find a population of primary prevention with high hazard.

And secondly, that the efficacy of aspirin does appear to be well
preserved at doses less than 162 and even doses of 75 or 81 milligrams,
and that bleeding complications, particularly gastrointestinal bleeding,
serious bleeding, is markedly reduced associated with this less dose of
aspirin.

Thank you.

CHAIRMAN BORER: Thank you, Eric.

The next speaker is Suzanne Hughes of the Preventive Cardiovascular
Nurses Association.

DR. HIATT: Is it possible to comment on these or not?

CHAIRMAN BORER: I\'m sorry?

DR. HIATT: Is it possible to ask questions or do you want to wait until
the end?

CHAIRMAN BORER: Why don\'t we wait until the statements are made and
then we can raise the questions generically?

\*\* MS. HUGHES: Good afternoon. I\'m Suzanne Hughes, and I\'m a
registered nurse at Akron General Medical Center in Akron, Ohio, and
today I represent the Board of Directors of the Preventive
Cardiovascular Nurses Association.

Our group does not have a financial relationship with Bayer, and the
expenses related to my attendance here today are the responsibility of
the Preventive Cardiovascular Nurses group.

We are pleased to have the opportunity to address this committee on the
use of aspirin for primary prevention of acute myocardial infarction.
Heart disease and stroke affect over 61 million Americans and cost more
than \$350 billion annually. In order to change the tide of this
epidemic, we must develop and implement safe, efficacious, and cost
effective primary interventions.

Our organization\'s mission is to improve the health of all Americans
through the reduction of cardiovascular disease risk factors. We achieve
our mission through professional and public education, dissemination of
national guidelines, and public awareness campaigns.

We fully support the American Hearth Association\'s 2002 guidelines for
primary prevention of cardiovascular disease and stroke 2002 update. A
key feature of this guideline is the identification of persons who are
at substantial risk for a primary cardiovascular event in the next ten
years. This is defined as a risk of greater than or equal to ten percent
based on age, gender and various coronary risk factors. The
recommendations for this group include the use of low dose aspirin.

Eidelman and colleagues recently published a meta analysis of five
large, randomized trials of aspirin in the primary prevention of
cardiovascular disease. Fifty-five thousand five hundred and eighty men
and women were included in this analysis. Aspirin users were found to
have a 32 percent reduction in nonfatal myocardial infarction. Their
recommendations are similar to those of the American Heart Association.

In summary, we support the use of low dose aspirin in the primary
prevention for persons at moderate to high risk of acute MI. This is, of
course, with full recognition that there are persons in this risk group
in whom aspirin even at low dose could be associated with
gastrointestinal bleeding or even hemorrhagic stroke.

We feel that the net benefit in the group described above has been
clearly demonstrated. The challenge that we face as health care
professionals is the dissemination of this information to the public and
to our colleagues in a way that they fully understand both the risks and
the benefits of this therapy.

We are prepared to be an active partner in educating nurses and other
health care providers about the measurement of global risk and the
potential benefit of aspirin in moderate to high risk persons.

In addition, we will seek ways to educate the public about aspirin and
to encourage those at risk to seek the advice of their health care
provider regarding aspirin use.

Thank you.

CHAIRMAN BORER: Thank you, Ms. Hughes.

Our next speaker is Dr. Michael Pignone from the University of North
Carolina at Chapel Hill, Division of General Internal Medicine.

\*\* DR. PIGNONE: Thank you, Dr. Borer.

I\'m Mike Pignone from the University of North Carolina. I\'m a general
internist and clinical epidemiologist, and I was the lead author on the
evidence report for the U.S. Preventative Services Task Force, which
you\'ve seen some of the results today, and was posted in [Annals of
Internal Medicine]{.underline}.

I just wanted to reinforce really three points from the Preventive
Services Task Force Process. Number one, they considered three main
questions: is there benefit in the prevention of cardiovascular or CHD
events with aspirin? Are there known harms associated with aspirin? And,
third, what\'s the benefit-to-harm ratio?

As part of that process, they considered the same evidence as being
considered here today. The Preventative Services Task Force felt
strongly that there was good evidence supporting the benefits of aspirin
in reducing nonfatal myocardial infarction. They also agreed with the
results presented earlier today, suggesting that there were known harms,
including a relative risk of approximately 1.6 for GI bleeding and
approximately 1.3 for hemorrhagic strokes, leading to in excess of one
per 1,000 per year for GI bleeding and one per 1,000 over five years for
hemorrhagic strokes.

I believe that really all of the evidence you heard today has been
consistent with those findings and consistent with good scientific and
epidemiologic principles. The difficult issue is to consider where the
benefit-to-harm ratio should be drawn for a recommendation of aspirin to
the general public, particularly in adults who might be at increased
risk of cardiovascular disease.

The U.S. Preventive Services Task Force did not want to define a strict
criteria below or above which people would receive aspirin. Instead they
recommended that at high risk people be counseled that aspirin is
potentially beneficial. At very low risk, they should be counseled that
aspirin probably is not beneficial and that there is an area in between
for which shared decision making would be appropriate.

For that reason, the risk threshold use for the discussion of the
benefits and harms of aspirin is slightly lower, 0.6 percent over ten
years, than that considered by the American Heart Association. This
should in no way be interpreted as being differential interpretation of
the data or different findings, but rather answering slightly different
questions that are actually quite compatible with one another.

So I hope that additional information is helpful to the deliberation of
the FDA committee. The Preventive Services Task Force for those of you
who are not aware is an independent, government sponsored body,
sponsored under HHS and the Agency for Health Care Research and Quality
that has been tasked with evaluating preventive care for a variety of
different preventive services, including aspirin as well as several
screening tests, and is made up of mostly physicians, nurses, and other
public health experts who consider preventive care strategies.

Thank you.

CHAIRMAN BORER: Thank you, Dr. Pignone.

The next speaker is Dr. Noel Bairey Merz who we heard from a little
while ago.

\*\* DR. MERZ: I\'m here now representing the American College of
Cardiology and do need to declare a conflict that Bayer assisted with my
travel to this meeting.

I am pleased to speak on behalf of the American College of Cardiology. I
am a Fellow in the ACC and have served as the past chair of its
Prevention of Cardiovascular Disease Committee.

I also serve as a member of the board of trustees. I am the current
American College of Cardiology representative to the National
Cholesterol Education Program, chaired the 33rd Bethesda Conference
entitled \"Preventive Cardiology: How Can We Do Better?\" and was a
participant author in the 27th Bethesda conference matching the
intensity of risk factor management to the level of risk.

I was a recent reviewer on the soon to be published American Heart
Association primary prevention of coronary heart disease in women
guidelines and participated as the ACC representative in the 1997
aspirin for primary prevention hearings.

The American College of Cardiology appreciates the opportunity to offer
its comments regarding this Food and Drug Administration\'s
consideration for the labeling of low dose aspirin, 81 to 325 milligrams
daily, for the primary prevention of a first myocardial infarction in
moderate risk subjects. The ACC is a 25,000 member, nonprofit,
professional medical society and teaching institution whose mission is
to foster optimal cardiovascular care and disease prevention through
professional education, promotion of research, leadership in the
development of standards and guidelines, and formulation of health care
policy.

The ACC represents more than 90 percent of the cardiologists practicing
in the United States. Our interest and concern about the FDA\'s labeling
of low dose aspirin grows out of our primary responsibility as
cardiovascular specialists to insure the patients have the best care
available to them, care that is safe, effective, appropriate and
comprehensive, and our testimony today is with that responsibility
clearly in mind. We are advocates of good drug therapy because we know
that when appropriately utilized they can substantially improve patient
outcomes.

Within that framework, we testify here regarding support for the
labeling of low dose aspirin for the prevention of first myocardial
infarction in these moderate risk subjects. We in the cardiovascular
community work each day to close the gap between evidence based
guidelines for CHD prevention and the hard realities of practice. Today
we have the opportunity to help close that gap.

We believe that the FDA\'s current approach to regulating
over-the-counter drug products works to insure that such products are
safe, effective, and offer safeguards to insure that consumers receive
care that is appropriate and comprehensive. We agree that it\'s
appropriate for the FDA to examine its overall philosophy and approach
to regulating these drug products in the light of continuous changing
health care environment and including the growing self-care movement.

Furthermore, we find that the FDA\'s current approach insures that
consumers have easy access to certain drugs that can be used safely for
conditions that consumers can self-treat without the help of a health
care practitioner and that this is the correct approach to regulating
drug products that are over the counter.

The American College of Cardiology joins other authoritative
organizations, such as the American Heart Association and the U.S.
Preventive Services Task Force, in supporting the labeling of low dose
aspirin for the prevention of first myocardial infarction in moderate
risk subjects. The following reasons outline the rationale for this
support.

Number one, coronary heart disease is the leading cause of death and
disability in this country. Rates of coronary heart disease are rising
again in this country due to aging, the obesity epidemic, and a
resurgence of cigarette smoking. Strategies to reduce CHD must be taken
undertaken urgently to counteract this growing epidemic.

Number two, aspirin is effective in reducing first myocardial infarction
in subjects at an appropriate level of risk. Eight randomized controlled
trials demonstrate absolute benefits that outweigh risks for subject at
high, as well as moderate and low global risk of coronary heart disease.

Number three, current authoritative organizations, including the
American Heart Association, the American Diabetes Association, and the
U.S. Preventive Services Task Force, using expert consensus, evidence
based review, currently recommend low dose aspirin for both the high,
above 20 percent, ten-year risk, as well as the moderately low, six to
20 percent ten-year CHD risk subjects.

Number four, current use of low dose aspirin in appropriate risk
subjects is poor with national surveys indicating less than 50 percent
of the eligible high risk subjects using low dose aspirin. Aspirin use
is even lower in the moderate-low risk subjects, as low as under eight
to ten percent.

Number five, health care professional and consumer global CHD risk
assessment is available in print media and internet formulations. Women
over 60 and men over 50 years of age with at least one risk factor often
typically fit within this moderate risk level and should be considered
for low dose aspirin therapy.

Six, and finally, alignment of aspirin labeling with current scientific
knowledge and evidence based clinical practice guidelines would
strengthen both physician and consumer knowledge in the appropriate use
of aspirin. Significant public health benefit in terms of reductions in
coronary heart disease, as well as coronary heart disease related health
care costs could be expected.

We look forward at the American College of Cardiology to working further
with the FDA as it continues to review its labeling of aspirin, and I\'m
happy to take any questions when appropriate, Chairman.

CHAIRMAN BORER: Thank you very much, Dr. Merz.

We have a final scheduled speaker, Dr. Udho Thadani, who is a professor
of medicine at the University of Oklahoma.

\*\* DR. THADANI: Mr. Chairman, ladies and gentlemen, you heard from
other speakers today\'s conflict of interest. I am on the Speakers
Bureau for several companies. I\'ve acted as advisor to several
companies, including Bayer in the past. I\'ve been on the FDA committee
1995 and \'99, and special government agent.

But today I\'m not a hired gun from any of the companies. I paid my own
way to be here.

I think you have already heard a very positive note from a lot of
speakers, and I really come here to say what my view is and what my
patients ask me. There is no doubt this data on aspirin was presented in
1997 to the committee on secondary prevention, and there was no doubt
that the drug was definitely effective when it was approved.

Here we\'re talking about primary prevention, and the data from the five
studies, what you\'re seeing, shows that it does reduce the clinical
infarcts, but not the silent infarct at this point, one, and the patient
might pay a little bit higher price that he might get a stroke or may go
to hospital with a GI bleed.

And if I ask my patient, give them option of taking aspirin when he
doesn?t for primary prevention, and if I tell him, \"Look. You may not
get a heart attack and go to hospital, but you might get a heart attack
on your electrocardiogram which you may not know,\" and we know a lot of
diabetic patients have no symptoms or they get short of breath and they
don\'t go to hospital, and you do an ECG and they\'ve got a QA
infarction.

And then I tell him, \"Look. You know, there\'s a chance that you get a
stroke,\" and the answer usually is, \"Forget about the infarct. I do
not want to get a stroke,\" because stroke is devastating. Patients are
incapacitated, and a lot of patients with a big hemorrhagic stroke would
rather die than get an infarct.

So I think you have to keep that in perspective, although the data here
has shown there\'s 30 percent reduction in clinical infarcts, but when
you look at the silent infarct, the data is not so overwhelming, and yet
when you look at the stroke, that\'s going in the wrong direction.

So I think the committee has to put a balance before they certainly
recommend on the basis of these trials, and then we have heard that
subgroup analysis, stroke is going in the wrong direction, that we
should ignore it as all garbage, and Dr. Eric Topol, who is a very
important committee cardiologist has said that perhaps infarction is
worse than bleeding. I\'m not sure that one could accept that because if
you have a GI bleed and get a transfusion, there are risks involved with
that.

So I think one has to be balanced. Obviously the benefit is greater.

Then if infarctions are so important, why they do not transmit into
saving lives? We have heard and we have read the literature that slight
bump in troponin translates into saving lives, and yet despite a
reduction in infarcts of 30 percent, there is no improvement in
survival, and you might have a negative impact on stroke.

So I think there are different issues. I\'m a fellow of the Canadian
Cardiovascular Society as well as American Heart Association, ACC. I\'m
sure I?ll be kicked out. So these are my views.

(Laughter.)

DR. THADANI: Have nothing, nothing to do with the society views, but I
think if I look at it, clearly I think one has to be very careful
because the guidelines are written by very prominent, important people.
I have done research in ischemic heart disease for 34 years, and if the
guidelines are not driven by the solid evidence of data, then it\'s
expert opinion.

So I think committee members here have to make a judgment which is
driven by the data and not by suggestions by different people.

Thank you for your time.

CHAIRMAN BORER: Thank you very much, Udho.

That concludes the list of speakers who have applied to make comments.
Is there anyone else who has a comment to make, a member of the public?

(No response.)

CHAIRMAN BORER: If not, we\'ll move ahead. Dr. Pearson, you indicated
that the PIs of the five relevant trials are here. We don\'t need a
presentation of the data, although it would have been interesting to
hear that in the primary presentation, but I\'m sure we\'ll talk a
little bit more about it after the FDA presentation.

But there were specific issues that came up, and I think we would
benefit from hearing a response to those issues from the PIs of their
specific studies.

\*\* DR. PEARSON: Thank you, Mr. Chairman.

And I just wanted just to put this into the context again about what the
issues are and where our principal investigators will be commenting on
specific questions.

Our feeling is that we have proof of efficacy in the high risk
individuals. We have proof of efficacy from a moderate risk trial, the
TPT trial that you\'re going to hear from in a moment from Dr. Meade. We
have evidence of efficacy from those individuals in the low risk studies
which, in fact, are at moderate risk, and in fact, we have efficacy from
several of the low risk studies.

So the issue is not efficacy. The issue is risk-benefit, with this
underlying risk of hemorrhagic stroke and GI hemorrhage, and obviously
it\'s arbitrary where you cut the line. The American Heart Association
writing group cut it at ten percent, the U.S. Preventive Services at six
percent.

So what we want to do is now frame this discussion and solidify these
issues of efficacy, and I\'d like to invite Professor Tom Meade to talk
about the TPT trial at the microphone in terms of some of the issues
related to this being a moderate risk trial with predetermined
endpoints.

Dr. Meade.

DR. MEADE: Thank you very much.

I am, as you\'ve heard, Tom Meade. I\'m emeritus professor of
epidemiology now in London University. I was the principal investigator
of the Medical Research Council, the British Medical Research Council\'s
thrombosis prevention trial at the time that I was Director of the
council\'s epidemiology and medical care unit. And thank you very much
for allowing me to say a few words about the trial which I will outline
very briefly because of the time question, but in view of the importance
that I think is being attached to it I obviously need to say a few
words.

As you know, this was a trial carried out in moderate risk patients, and
the events that would be prevented, as you\'ve seen on this slide which
was just up, are approximately equal to those in secondary prevention,
although none of the people in our trial had previously had an event.

It was carried out in general practice, and it had a 50 percent take-up
of those who are eligible to take part, which is a very high proportion
for a trial making the demands on the participants that this did.

Ninety-five percent of the or 98 percent of the population in the U.K.
are registered, and we conducted this trial in 108 practices throughout
the whole of the United Kingdom. So it is a very representative result
in the U.K., and as you know, we use 70 milligrams of aspirin a day.

Now, I will briefly show the main results in a moment, but I believe
that saying a word or two about this trial does fulfill what I
understand to be one of the FDA\'s requirements for at least one trial
in the relevant category that meets the criteria and satisfies the
endpoints.

But I think I should say a little first about some of the concerns about
the trial which are in the documentation that you\'ve had, and I hope
that this will help to allow the committee to view our results without
misapprehensions about some of the points that have been made.

There is a statement that neither the protocol nor the data were
available. I wasn\'t actually asked for either of those, and the data,
of course, have now gone to Colin Baigent at CTSU, and I think that that
is actually an overriding way of looking at the question that we\'re
talking about.

The protocol and the paper both say that we would look at fatal and
nonfatal MI, and we do that on the same footing as all events, in other
words, the combination of the two, and there\'s a very good reason for
that which was that there was already evidence from the 1994 ATT paper
and now from the 2002 that the effects on fatal events are considerably
less than nonfatal.

So it would seem inappropriate for us to look at the results for all
coronary events without looking at those two contributory subgroups.

So the trial, in fact, did have a primary endpoint of myocardial
infarction which answers, I think, your question in 2.1.3 of the
questions that you\'ve sent us.

Now, silent MI was not mentioned in the protocol, and it was not
included in our results, our main results, which was made quite clear in
the paper. So I think that the .07 significance value which is being
mentioned in the FDA\'s questions is actually inappropriate.

We looked at the data on silent MIs because we had got serially ECGs
throughout the seven-year follow-up, and it was pretty clear that I
think if we hadn\'t shown those data somebody would have asked us to do
so.

And if I may say in a friendly but firm context of a scientific
discussion with people who I can hope are called colleagues, we did, in
fact, put in the results about silent MI really almost as a footnote
about the main coronary heart disease results, and given the emphasis
that there has been from members of the questioning group about
pre-specification, I could have dealt with that, but in the absence of
the protocol, you weren\'t able to see what we said, and so I really
don\'t think it was correct for the .07 result to have been shown, and I
hope you\'ll disregard it.

There are some inaccuracies following that in the footnotes to Tables 9
and 10 in your statistical review. We did also, incidentally show the
results for fatal and nonfatal strokes combined which arises in your
questions and is shown in our trial not to have been done.

In the memorandum, it\'s stated that aspirin caused more bleeding
independent of site and severity, and that also is not correct. For
example, hematuria occurred slightly more frequently in those on aspirin
than those who are not, although it wasn\'t a significant or very big
difference, and it was only the bleeding events which we call minor
events which differed significantly between aspirin and not aspirin.

The differences between the major and the intermediate bleeding results
are not significant, although a case of major result of bleeding
episodes, fortunately we had very few events.

And then finally, I think at this stage there is the slightly downbeat
comment at the end of one of your documents that gives a quote from our
paper. Results give limited, if any, agreement for the general use of
aspirin regardless of risk. In other words, in those who are not at
increased risk where the benefit and the harm might be more equal.

That sentence doesn\'t mean obviously that aspirin shouldn\'t be used in
those who are at high risk. It obviously should be.

Now, if I could have Slide 158, please, I have four slides to show
quickly. As you know, the trial was a factorial trial involving warfarin
as well, and there were four treatment groups, and I only want to say
that the letters in the right hand of each line there describe the four
groups which I\'ll show in a moment.

WA refers to those who are on both warfarin and aspirin. W are to those
who are on warfarin only, A to those who are on aspirin only, and P to
those who were on placebo.

And if I could have the next slide, 159, please, there\'s a summary of
what was our main statistical analysis, which was according to the main
effects, and so for aspirin we compared everybody who was on aspirin,
WA, and warfarin \-- I beg your pardon \-- WA and W against A plus P.
Whereas for aspirin, it was WA and A against W plus P, having
demonstrated that the effect of one agent does not influence the other.
In other words, there\'s no interaction.

The point that was made earlier about the A versus P in the separate
group\'s comparison not being significant, I think, is actually not
appropriate. We simply describe that to show that the effect \-- I think
it\'s a 23 percent reduction in all events \-- was very much the same as
what we had when we looked at the main effects, but it\'s the main
effects which are the principal approach to our analysis.

Well, so for the results. First of all, if I could have Slide 172,
please. You can see \-- I\'m sorry \-- I hope you can see that down at
the bottom there is the effect in the log rank presentation of aspirin
on nonfatal events, significant at the .004 level.

Next above that is the to me unexpected but nevertheless real absence of
any effect of aspirin on fatal events, and at the top is the sum of
those two which in my view is actually perhaps no longer a very
appropriate analysis to do, but nevertheless is significant according to
all our criteria and specifications at the .04 level.

I have got results on stroke and major bleeds. We\'ve showed no
significant reduction in stroke attributable to aspirin, and there was
no significant difference in major bleeds between aspirin and placebo,
although the number of events were fortunately very small.

So in conclusion, I think there\'s no doubt about the value of aspirin
in reducing nonfatal myocardial infarction in those who are at moderate
risk, according to our trial. It would be nice if it also reduced fatal
events, but if it doesn\'t I don\'t know the explanation for that, and I
think the reduction in nonfatal events is certainly a worthwhile
achievement.

Thank you very much.

CHAIRMAN BORER: Thank you, Dr. Meade.

Let\'s limit any questions we have to clarifications of what Dr. Meade
has said instead of value issue.

Tom?

DR. FLEMING: Well, just on this last issue where you were referring to
the fact that there isn\'t an adverse or a positive effect on fatal
events and you showed that second figure there, well, globally if I\'m
following it in your Lancet publication in 1998, if I count up in your
table the listing of all deaths that are cardiovascular deaths, there\'s
a 101 versus 81 excess. So there\'s a substantial excess of deaths in
the aspirin group in cardiovascular deaths.

DR. MEADE: Well, if I could have slide 169, please.

This shows the results in the previous slide, the log rank
demonstrations, but in fact, yes, there was in our data a nonsignificant
adverse effect of aspirin on fatal events. That\'s absolutely true.

DR. FLEMING: There you\'re only giving the MI, fatal MIs.

DR. MEADE: Yes.

DR. FLEMING: The total, however \-- and that\'s 60 versus 53 \-- the
total, however, for all fatal cardiovascular events is 101 versus 81.

DR. MEADE: Could you just refer? Which table are you looking at?

DR. FLEMING: I\'m looking at page 238 in your Lancet publication. It\'s
Table 3, Table 3, Lancet.

DR. MEADE: Yes, I have that.

DR. FLEMING: 1998, under deaths.

DR. MEADE: Yes.

DR. FLEMING: I\'m summing the one, two, three, four columns that relate
to various subcategories of cardiovascular death, and when you sum them
up, it\'s 101 against 81.

(Pause in proceedings.)

DR. MEADE: Yes. You\'ve done a calculation which is not actually shown
in the paper, and you\'ve included the noncardiovascular events.

DR. FLEMING: Correct.

DR. MEADE: And some other categories. That\'s not talking about coronary
events specifically, which is what I\'ve been addressing.

DR. FLEMING: It\'s IHD or stroke, stroke, or other cardiovascular.

DR. MEADE: Yes. Well, I would want to check those figures myself, but I
think already answered the question in that you\'ve included several
categories there. I\'ve just been talking about the MI question.

DR. FLEMING: That is correct, and that\'s why I wanted to clarify,
because you\'re only talking MI, but if we look at all cardiovascular
deaths, it\'s 101/81.

DR. MEADE: Well, again, that was not a specified endpoint in our trial,
and I think it points up the importance of contributing these data to
Colin Baigent\'s overview.

CHAIRMAN BORER: May I ask for a clarification? As you said, Dr. Meade,
we don\'t have the protocol, but if I understood correctly the
prespecified primary endpoint was combined events.

DR. MEADE: No. We made it clear in the protocol and the paper that we
would put all coronary events, fatal events and nonfatal events, on the
same footing, and I\'ve explained why that was, because in the secondary
prevention \--

DR. THROCKMORTON: The endpoints are specified in the first part, the
endpoints part of the paper. If you want to read that out loud, it does
\-- I mean, the paper says the primary endpoint was all IHD deaths
defined as the sum of fatal and nonfatal events, i.e., coronary death
and fatal and nonfatal MI.

Now, that seems to differ from some of the things you\'ve said.

DR. MEADE: No, but it also goes on to say that fatal and nonfatal events
separately were also to be examined.

I think that absolutely rigid adherence to rules like prespecification
and definition and so on are a good servant but a bad master, and I have
explained, I think, a very reasonable reason why we separated out fatal
and nonfatal, because we had an indication already that the effect of
aspirin might be different.

DR. TEMPLE: Were the fatalities just what appeared to be fatal
infarctions or all cardiovascular ‑-

DR. MEADE: No, fatal infarctions.

DR. TEMPLE: Okay. So if someone dies suddenly, that doesn\'t get
counted?

DR. MEADE: No, that does get counted because we thought that most sudden
deaths were coronary events, and the ones that the adjudicators thought
weren\'t were omitted.

DR. TEMPLE: Okay. So all seven of unobserved deaths were counted.

DR. MEADE: Yeah, yeah, yeah.

DR. TEMPLE: Okay. So that could include some strokes or as long as you
don\'t \--

DR. MEADE: But not in the coronary events.

DR. TEMPLE: Well, no, that\'s what I\'m asking. The primary endpoint
included heart attacks, okay? Coronary events that you survived.

DR. MEADE: Yeah.

DR. TEMPLE: And which fatal events?

DR. MEADE: Fatal events that are attributed to coronary disease.

DR. TEMPLE: Well, that turns out to be a huge problem in knowing how to
attribute it. I can give you documentation for that, but what did you
count?

DR. MEADE: We got all of the information that we could from coroners and
hospitals, submitted them to an independent adjudicator, and if he
decided they were due to coronary disease, they went in. If he decided
on the few cases that they weren\'t, they didn\'t.

DR. TEMPLE: Did you do an analysis that included all fatal events or all
fatal cardiovascular events plus nonfatal coronary events?

DR. MEADE: No, we didn\'t.

CHAIRMAN BORER: Okay. Well, we\'ll get back to this after a bit, but
let\'s go through the other issues that were raised if we can.

DR. PEARSON: Yes. I\'d like to introduce Dr. Michael Gaziano who is the
principal investigator for the physicians health study currently and
particularly deal with issues of why they stopped this trial early and
this issue of the disagreement about the prevalent coronary patients.

Dr. Gaziano.

\*\* DR. GAZIANO: Thank you very much. This has been a very stimulating
discussion.

The first point I\'d like to make is that the physiology of myocardial
infarction and other major important events is the same in physicians as
it is in anyone else.

(Laughter.)

DR. GAZIANO: I would like to respectfully disagree with the assertion
that there were 500 prerandomized MIs. That can unequivocally not be the
case. We had a total of 139 events in one group, 239 in the other group,
a total of 378 incident myocardial infarctions. All of the physicians
reported these events. They were confirmed at a rate of about 80
percent. None of the physicians on their initial questionnaires either
at randomization or at run-in reported a prior myocardial infarction.

I don\'t know how the number of 500 could have been achieved. We get
records only on the reported cases, which would have been some 400-odd
reported myocardial infarctions and some 250 reported strokes, of which
about 70, 80-plus percent were confirmed.

So I have no idea where that number could have come from, but it
absolutely could not have been 500. We have identified one myocardial
infarction that was reported after randomization, that the date was
confirmed prior to randomization.

The second point is with respect to the endpoints. The information on
vascular death does not provide informative results from this study. The
data monitoring board voted six to two, with all six members who were
present voting for termination and the two absent members voting for
continuation based on the 44 percent reduction that we see in the
previous slide on myocardial infarction.

The power for fatal events was not what was anticipated in the original
trial, and I don\'t think that this data can be interpreted in this
study or in PPP that was also terminated early as indicating proof of a
lack of benefit.

Here you see the fatal events in the physicians health study. Total
cardiovascular events, 81 versus 83. All the way down at the bottom,
total deaths, 217 and 227.

These findings are consistent with an effect of the 44 percent reduction
in fatal and nonfatal myocardial infarction translated to a low risk
population, which would be quite consistent with the data that we\'ve
seen in secondary prevention.

So I don\'t think that the lack of statistically significant difference
on cardiovascular death or total death provides an informative
information, and the most informative information that we get here is on
myocardial infarction.

The third point is that in my opinion the physicians health study and
the other trials must be interpreted not in isolation as if this were a
new drug, but in the context of the wealth of over 300 secondary
prevention trials, the basic science data suggesting that there is a
consistent effect of each of the individual trials and the pooled
analysis.

And the utility of the pooled analysis in my mind is not that it
provides new and unique information overall. It\'s that it provides the
best quantitative estimates for the reduction in the risk for myocardial
infarction in primary prevention, which is very consistent with the
secondary prevention data. The trials like the physicians health study
were not well powered for risk. So, therefore, the pooled analyses are
also better estimates.

But I also think you take that information that we get from the primary
prevention trials with the secondary prevention trials on a risk to come
up with the best estimate so that we could come to a conclusion about
whether or not there would be a risk versus a benefit and where that
break point might be in primary prevention.

I think that these trials individually provide very important
information and its pooled data.

Lastly, were we asked to do a similar trial in an intermediate risk
population, the feasibility of that trial logistically and also
ethically would be questioned, and we have recommendations from the ACC
?- from the AACHA and from the U.S. Preventive Task Force. I think it
would be very difficult for us to take a moderate risk population and
randomize them not only because there would be a lot of drop-in in that
group, but also because I think it would be difficult for us to get it
behind, to get backing of our institutional review boards.

In primary prevention, I think that this series of five trials alone and
collectively in the pooled analysis represent very good primary
prevention data suggesting that the physiology is the same in primary
prevention. They provide useful information, but not the totality of
information on risk, and it\'s my opinion that there is a point at which
we can find a benefit-to-risk ratio based on the existing primary
prevention data, which is very difficult to achieve and which has been
done in five trials and in which we\'ll get more information in the
coming years with a couple of ongoing trials.

Thank you.

CHAIRMAN BORER: Thank you.

Doug?

DR. THROCKMORTON: Yeah. I\'ll just make a couple of general comments to
sort of clear up some of the small things because I think the committee
probably has important things to talk about later on here.

First, as regards the individuals that were thought to have had prior
MIs, as best as can be made out, again, Dr. Temple pointed out that the
reviewer is no longer with us. That was based on the use of PTCA or
CABG, the individuals that had been enrolled in the trial. That\'s not
the same thing, I grant you, as knowing that those individuals had had
MIs as the basis for either of those interventions, but that accounts
for the 40 individuals that Dr. Triantas \-- sorry \-- 38 of the 40 that
Dr. Triantas identified as having had a prior MI. I take the point that
that\'s not quite the evidence for that that you might like unless
there\'s other data that we don\'t have access to at this point.

And then the second issue, this issue of the .07 P value. I think this
was the TPT comment that was made previously. I\'d agree that without
access to the primary data, it\'s hard for us to be precise on that
value, and other than saying in general the value was higher than .04,
it\'s probably best to leave it there.

Thanks.

DR. GAZIANO: Well, we collect information on revascularization
procedures. We certainly don\'t consider those myocardial infarctions
although they are important events, and there would likely have been a
small number of P randomization vascular interventions.

DR. THROCKMORTON: Yeah, I think we\'re probably asking that a trial of
this age to bear up more than maybe we would be able to recover at this
point.

DR. GAZIANO: Absolutely. I think our definition of MI has changed over
the years. There are smaller events that we might have called unstable
coronary syndromes historically which now with troponin we might call a
myocardial infarction. The numbers would have been different, but I
don\'t think the answer would have been any different.

CHAIRMAN BORER: Bob.

DR. TEMPLE: There was a lot of discussion and publication about the new
analysis of the physicians health study when it was terminated. There\'s
no question that there was no possibility of reaching the primary
endpoint.

The choice of the secondary endpoint, however, as nonfatal MIs is of
some interest. I mean, the primary endpoint had failed. So that was out,
and then you have some choices as to the secondary endpoint or the new
primary endpoint.

It could have been fatal and nonfatal MI, fatal and nonfatal stroke plus
other cardiovascular events. It could have been any of those things. We
know that if you do the latter and be more inclusive, the P value comes
out .01. So it\'s not a negative study even in those terms.

But can you say any more about how it happened to be the choice of the
one thing that turned out absolutely best instead of something that
seems a little more logical?

DR. GAZIANO: It was not as you point out the one thing that turns out to
be the best. It was not nonfatal myocardial infarction. It was total
myocardial infarction.

DR. TEMPLE: Actually the fatal MIs come out very well.

DR. GAZIANO: The fatal ones do come out very well, ten versus 28, but
the endpoint that we showed \-- could I have Slide 71? \-- the endpoint
that we showed, 139 versus 239, is totally myocardial infarction
including both fatal and nonfatal myocardial infarction.

DR. TEMPLE: Right, but those come out really great. I mean, those are
the best flexible numbers that \--

DR. GAZIANO: The choice of that endpoint, the choice of that endpoint,
that was a prespecified secondary endpoint, and it was actually the data
monitoring board\'s emphasis on that particular event.

DR. TEMPLE: Yeah, I know. There was discussion about it though at the
time.

DR. GAZIANO: For which the investigators had little control, and then if
you look at important vascular events, which was also a prespecified
endpoint and an endpoint that Colin Baigent talked much about, this
includes not only nonfatal myocardial infarction, but nonfatal stroke
where we\'re anticipating seeing perhaps some benefit as well as some
risk. So I think it\'s a very valuable and important.

Composite risk shows also a clinically relevant 18 percent reduction in
risk with a P value of .01.

DR. TEMPLE: Yeah, I don\'t disagree with that, and the reviewer actually
thought that .01 was the right P value for this trial because she
thought why wouldn\'t you count fatal and nonfatal MIs and other
cardiovascular fatalities and strokes since we don\'t know what we\'re
doing here and we\'re off the primary effort.

DR. GAZIANO: Now, you mentioned subsequent other analyses that are
relevant, and I wish Nancy Cook were here to address those, but if you
look at compliance adjustment, obviously the effects get much stronger,
although this was an intention to treat analysis and none of those
analyses were included, and then if you look at the combination of the
first five years plus the seven years of follow-up that obviously it\'s
observational data, you get a statistically significant reduction in
cardiovascular mortality as well.

So we get a very consistent story from the physicians health study.

CHAIRMAN BORER: Tom Fleming.

DR. FLEMING: It might be useful though for a little bit of a statistical
clarification on this. I thought where you were headed in your
questions, Bob, were certainly consistent with my own thought.

It\'s interesting that the domain that was chosen when the primary
endpoint was lurking around at 81 against 83, was the endpoint for which
we had the most positive signal, and indeed, yes, the team included the
fatal MIs that were in the right direction at ten against 26, but
interestingly everything else looked pretty unimpressive if you look at
deaths due to sudden death, stroke, or other cardiovascular. They were
just as strong in the other direction, the 47 against 30, so that
overall mortality showed no difference, and stroke was in the wrong
direction.

And if you pool together the endpoint of 307 against 370, the positive
is entirely driven by what they chose as the endpoint for positivity.
This level of difference wouldn\'t have justified early termination by a
group sequential monitoring procedure, i.e., if you had gone with this
endpoint, with a P of .01, .01 is not impressive statistically, an
interim monitoring aspect for group sequential.

So you were right, I believe. They went in the only direction they could
have that would have given this the evidence needed to say it\'s
conclusive on that specific endpoint.

You talked about 81-86, and you\'re right. This study in not
conclusively ruling out benefit on mortality or on cardiovascular
mortality. It\'s certainly though suggestive of no difference, and it
contributes 160 events. You would need fivefold that though basically to
rule out a 15 percent reduction, which is close to what you might see in
a secondary prevention setting, but, oh, by the way, you do have
fivefold that many when you do the meta analysis, and it shows the same
thing that the 81 against 83 shows.

DR. GAZIANO: I would say that, again, the choice of myocardial
infarction, total myocardial infarction being the dominant particularly
in a male population, the dominant cardiovascular event driving this
analysis was one that was prespecified, and it was the data monitoring
board that felt it was unethical to continue a trial with such a
dramatic reduction in one of the important prespecified secondary
endpoints when the primary endpoint was not likely to provide meaningful
information within the context of the duration of the trial.

But I would argue that the 81 versus 83 should not in any way be
interpreted as proof of lack of benefit is very analogous to the early
cholesterol reduction trials where we saw clear reduction in CHD risk,
and we saw no benefit in total mortality, and there were those that
interpreted that as proof of lack of efficacy on total mortality.
Therefore, there must be excess vascular risk, and it wasn\'t until we
got large enough trials with big enough agents that proved that those
original interpretations were not correct, that the data for the early
primary intervention clusteral (phonetic) trials were consistent with
the secondary prevention trials and did not disapprove the benefit on
total mortality. They were just not designed to show that.

This study was designed \--

DR. FLEMING: The monitoring committee did not have access to the
totality of what we have access to today in terms of total numbers of
cardiovascular events, which is 900. They only had access to 160. Those
data certainly do not rule out benefit. They don\'t conclusively
establish no effect. They suggest no difference in this context, and the
monitoring committee made a judgment based on what they had at the time.

We know much more at this point in time, including the fact that we now
have 900 events showing the same pattern of no effect which now does
have a confidence interval that could rule out about a 15 percent
reduction, which is on the range of what you could get in secondary
prevention.

So now you do have the kind of evidence that you were saying you didn\'t
have at the time that the monitoring committee had to make this
judgment.

DR. GAZIANO: I would just have to disagree that that taken out of
context of what we know about the effect of aspirin in secondary
prevention, that still these effects are not inconsistent with an
overall effect in MI and an overall effect in cardiovascular events.

CHAIRMAN BORER: Dr. Pearson, do we have some additional comments?

DR. PEARSON: In addition, we\'d like to move on to another principal
investigator, Dr. Dianni Tognoni from Milan, and the PPP trial, again,
another trial that was stopped early. I\'d also like him to comment on
the subanalysis published recently on the issue of the diabetics.

DR. TOGNONI: Thanks.

As you say, the group I am representing here, the PPP, is the general
practice oriented group of the GC group who has been working for trials
in myocardial infarction. We applied to the testing of this primary
prevention, the same methodology we had applied for.

Myocardial trials, they are very pragmatic trials in a real condition of
care. So I think that I would like just to underline some of these
points because of the definition of the population and because that is
relevant for the reason why we were requesting them to stop.

General practitioners, as you have seen passing in the publication,
would ask to include patients who they believed to be at the
sufficiently high risk despite the background treatment for background
condition for which statins and antihypertensive therapy, to be exposed
to aspirin against no treatment.

The trial was a self-tutorial (phonetic) of whether those general
practitioners randomized those patients, and at the occasion of an
interim analysis the request was made to the same committee to consider
stopping the trial because of what we could call something between
ethical or futility reasons.

On one side there was a strong internal consistency of results pointing
to positive effects in the primary endpoint, which was associated with
increasing external evidence of recommending aspirin for primary
prevention. The TPT results were published. There were already some
recommendations and guidelines, and the general practitioners were
asking whether it was still ethical to go on with a trial if the trial
could add any new, important information based on that.

The final decision was to stop the trial before the planned number of
events, and as you have seen the results, the collection of all the
events which were foreseen in the primary endpoint confirmed the
internal consistency of results both for the combined endpoint and for
the separate endpoint of cardiovascular death.

On the other side, there was no evidence posed with the opposite of risk
associated with aspirin therapy with respect to the stroke, which was
obviously the risk. The HOT results were already published.

Also we had for the stroke in our population difference in favor of
aspirin both in overall stroke and hemorrhagic stroke.

Within the population just for information, and I have to confirm what
Dr. Meade said before, our database also is perfectly available
obviously for whatever inspection that has been done for other occasions
for FDA for the trial.

We had made also some evaluation on the attributability of the
benefit-to-different risk integrity. We have also prepared risk chart
with the database of the study showing that the benefit is there across
the different categories and obviously the absolute benefit is better
with what could be called here moderate categories.

The second observation for the recent publication in this group of
diabetes patients, I think that here as it\'s said clearly in our paper
and in the accompanying editorial, there are general caveats about
subgroup analysis.

As you have seen for general presentation, the diabetes patient
represents approximately 20 percent, one-fifth of the population. So
that\'s a subpopulation for which there was no preplanned analysis.

The general analysis was suggested first because there was a specific
interest of adding something on diabetes because we are working on
diabetes and then I think as the editorial points out in our comments,
we see that as kind of a research issue in the framework of the
formulation of the what is called now the aspirin resistance and whether
or not the background diabetes condition could be seen as a situation
where to investigate, but our interpretation is in general \-- that\'s
the subgroup analysis \-- is not against the general classical
interpretation of main trial result because that has been proposed is
after the main analysis.

CHAIRMAN BORER: Thank you.

Dr. Pearson, do we have any other comments? Can we focus them
specifically on the issues that were raised rather than a summary?

DR. PEARSON: Yes. The issue raised there was this diabetes issue, and I
did want to ask Dr. Colwell, if I might, to just comment on another
issue relative to diabetics if we could quickly show his one slide.

DR. COLWELL: Well, thank you.

I\'m John Colwell. I\'m professor of medicine at the Medical University
of South Carolina, and I was the lead author on the initial position
paper that the ADA put out in 1997 about primary prevention for
cardiovascular events in people with diabetes at high risk.

The deliberations at that time were, of course, the recognition which
you\'ve heard over and over again today that people with diabetes are at
tremendously high risk for cardiovascular events, perhaps two to
fivefold above control groups, and that we needed to look at every
possible way to prevent cardiovascular events that we could.

At that time we were impressed by the analysis that Dr. Baigent showed
from the antiplatelet trialists and secondary prevention trials where
the diabetics seemed to do better with aspirin therapy.

And there was one trial specifically in diabetes. If we could see one
slide, it\'s Slide 262. It may have escaped people\'s notice. This was
the early treatment diabetic retinopathy study. This is a large study
done by the ophthalmologists, the National Eye Institute, and of course,
they were interested in whether aspirin would prevent progression of
retinopathy. So this was the primary reason for an aspirin versus
placebo study in this group.

They were also studying various forms of laser therapy and
pre-proliferative diabetic retinopathy, but they agreed to monitor
cardiovascular events because of the prediction that aspirin might be
protective in terms of cardiovascular event in this high risk group as a
secondary analysis, of course.

But there were 3,711 patients. About 30 percent of them had Type I
diabetes. The rest had Type II. They had pre-proliferative retinopathy.
So they\'re fairly advanced. About half of them had hypertension. A fair
number had lipid disturbances, hemoglobin A1Cs, and about half of them
were above ten percent, and so forth.

So this was a high risk diabetes group, but only ten percent of them had
a previous history of cardiovascular event. So in a sense it\'s mixed
primary and secondary prevention trial in a high risk group.

A large dose of aspirin was used, 650 milligrams a day versus placebo,
and the five-year follow-up.

In terms of myocardial infarction, the aspirin group, 9.1 percent had
MIs, fatal and nonfatal. In the placebo it was 12.3 percent. Relative
risk was .83, and the confidence limits just went past one in this
particular study.

We were impressed that this went along with previous studies. There\'s
one other subgroup study, if I could have the next slide, which is in
the primary prevention trial, the U.S. physicians health study. The
diabetics in that group are shown in this slide.

There were 533 people with diabetes in that slide, and we know about the
design. In terms of myocardial infarction within the people with
diabetes, it was four percent on aspirin and ten percent in the placebo
group with a relative risk of .39. Obviously this is a very small
subgroup study, but it did influence the committee at the time. So this,
along with the ETDRS and the meta analysis from the antiplatelet
trialists, were really the reasons why the ADA came up with their
position statement that high risk diabetics should be put on aspirin
therapy.

Thank you.

CHAIRMAN BORER: Steve, clarification question?

DR. NISSEN: Yes, clarification on those last two slides. Could you tell
us about the P values and the other events?

I mean, obviously, again we\'ve gotten a very clear focus on myocardial
infarction, but we\'re trying to make a decision here on the basis of a
totality of evidence, and so if you go back one slide, I\'d like to know
what the P value was for that comparison, and I\'d also like to know
what happened with the other events like stroke, hemorrhagic stroke, et
cetera.

DR. GAZIANO: The P value in that comparison was about .0038, and the
other comparisons were not significant, but there was no \--

DR. NISSEN: So if you look at the totality of cardiovascular events,
including stroke, was it significant or not?

DR. GAZIANO: Not significant.

DR. NISSEN: Okay, and how about the next study? Can we see that?

DR. GAZIANO: That is the study you just heard about.

DR. NISSEN: Yes.

DR. GAZIANO: I don\'t know what happened to the diabetic subgroup in
this particular study. It has not been published, and we didn\'t analyze
that.

DR. NISSEN: Okay. Because I think obviously when we see numbers like
this, we have to understand what the confidence intervals are around
those numbers, and I think, you know, I\'m concerned that we not look
just at one type of event, myocardial infarction. We\'re really trying
to balance here in this committee a balance of risk and benefit for all
kinds of events and not just myocardial infarction.

So you know, if you\'re going to show us this, then show us everything.
Don\'t show us a piece of the data.

CHAIRMAN BORER: Okay. Thank you very much.

Dr. Crawford, Dr. Pearson, are there any other focused comments?

DR. PEARSON: Yes. Professor Zanchetti, also from Milan and principal
investigator of the HOT study, has to give a talk tomorrow morning in
Rome and had to leave early. He was here earlier. I\'d just like to, at
his urging, I\'d like to just show you two slides.

One, oh, two, and this gets at the question from the panel about this
inclusion of or this discussion of whether or not silent MIs should be
considered separately.

And prior to unblinding of results, they had \-- their statistical
analysis group had made the decision not to include silent MI, and the
reason for this was their inability to include this in meta analysis
because no other antihypertensive or antiplatelet therapy trials had
included silent MI among the endpoint.

Particularly, this point has not been covered by the group yet, and they
considered silent MI a soft endpoint because nonfatal MI was defined by
the usual two or three criteria, chest pain, elevated enzymes and ECG
changes, whereas silent MI was only one, and they considered this a soft
endpoint.

Silent MI, again, you heard about the time dependent issue, and of
course, they had 14 percent of ECGs could not be obtained.

With that, if I could have slide 101, please, that trial obviously
showed then a 15 percent reduction in major cardiovascular event and a
36 percent reduction in all MI. Again, this lack of certainly no
evidence of detriment, but certainly not any cardiovascular mortality
findings.

But I did want to point this out, that this is the fourth trial, again,
with evidence suggestive of the ability to prevent MI.

I had one other group that I wanted to address relative to questions
from the panel, and I\'d like to call Dr. Laine to talk really about
some of the questions I believe Dr. Cunningham had raised about the
issues related to GI toxicity.

DR. LAINE: Very briefly, I promise.

I\'m a gastroenterologist from USC. That\'s known for being cheated by
the BCS. In any event \--

(Laughter.)

DR. LAINE: And with a clinical research interest in ulcer disease and
upper GI bleeding.

And Dr. Nissen asked a question about what were the levels of, quote,
hospitalized bleeding, serious bleeding. The data that you were shown
was actually the investigators gave their numbers for serious bleeding,
such as transfusion requiring, but frankly, it\'s not clear how many of
them were transfusion, how many events were called serious.

If we look at the literature, one of the best epidemiologic groups is
Garcia Rodriguez. They have recently published a meta analysis with the
endpoint of hospitalization for upper GI bleeding. They suggest about a
twofold increased risk. That\'s 2.2 relative risk, and they also have
about a baseline in the normal population of about .1 percent.

So given those data, the suggestion is about .1, just over .1 percent
per year, though admittedly within that analysis there\'s a range up to
as much as a third of a percent in a Denmark study, a large cohort study
from Denmark.

If we want to just look at any mention of GI bleeding, maybe the best is
to look at a meta analysis in the BMJ by Derry and Loke, and they
suggest perhaps as much as, again, a one-third of one percent any GI
bleeding increase.

I think it was Dr. Cunningham who asked about the long-term risk and
what we do with people who come in with GI bleeding. Based on the latest
data from HCUP project of the Agency for Health Care Research and
Quality, it says the mortality for upper GI bleeding due to ulcers has
really dropped below five percent now. So that we always read about ten
percent in textbooks. It\'s probably somewhat lower in the United States
now.

The other important thing is although I would never trivialize upper GI
bleeding \-- it\'s one of my favorite things \-- once people get out of
the hospital and their ulcers heal, there is no residual damage there.
There is no doubt there\'s marked increased recurrence rate, but the way
we handle that is we go at the three pathophysiologic mechanisms, if you
will.

One, get rid of [H. pylori]{.underline} if present. There is a study, at
least one, in the [New England Journal]{.underline} that says you can
decrease risk by doing that.

Two, avoid NSAIDs, which increase the risk of aspirin bleeding by two to
fourfold.

And, three, give potent antiacid treatment with things like proton pump
inhibitors, again, at least one study in the [New England
Journal]{.underline} showing a significant decrease.

So I wouldn\'t trivialize it. I would just say that we can at least
decrease the risk, although not get rid of it.

CHAIRMAN BORER: Thank you very much.

Okay. Paul.

DR. ARMSTRONG: Is this the time to pursue to GI bleeding issue or not
with the expert?

CHAIRMAN BORER: Yes, I think this may be our only time. So you go ahead.

DR. ARMSTRONG: In the trials that we\'re reviewing, there are a variety
of exclusion criteria, some of which have been published and some not.
I\'m trying to understand the patient population that we\'re asked to
make a judgment on relative to the patient population for the proposed
label, and I\'d appreciate your comments on the homogeneity versus the
heterogeneity of the exclusion criteria in the five trials. That\'s the
first question.

The second is we are looking at two other trials that Dr. Topol showed
us: one, the CURE trial and the other the BRAVO trial in which the
frequency of serious bleeding, most of which was GI substantially in
excess of the bleeding in the prevention trials.

There are exclusion criteria and patient populations described in those
studies, but the bleeding rates, for example, in BRAVO are 2.4 to 3.3
percent in a population studied for about a year; 1.9 to 3.7 percent in
CURE for a population studied about nine months.

Can you help me understand these issues because I\'m struggling, and I
really need to understand the issue of the frequency of GI bleeding,
cure, for example. You need two units to be declared as a transfusion.

DR. LAINE: I think of it some come \-- I think we have to be careful \--

DR. ARMSTRONG: Of course.

DR. LAINE: \-- of on these studies. The real problem is there are so
many other risk factors for GI bleeding just in a background population,
[H.]{.underline}, [H. pylori]{.underline}. These patients get a number
of other anticoagulants, and I also was struck by the high rates.
Without a placebo group it\'s hard to say.

For instance, the placebo bleeding rate in some of these studies can be
over half a percent and, you know, in the .5 to one percent range. So
I\'ll let Dr. Topol talk about those.

DR. TOPOL: No, that\'s a very important point. Of course, those trials
were not primary prevention trials, CURE and BRAVO. Most of that
bleeding was up front in the hospitalization and included bypass surgery
bleeding, bleeding related to other procedures. So it\'s a different
patient population, but nonetheless, it was the gradient of a bleeding
relationship as a function of aspirin dose.

But totally different incidence levels as compared to the patients in
the primary prevention trials.

CHAIRMAN BORER: Blase.

DR. CARABELLO: Are we asked to approve all aspirin or enteric coated
versus not enteric coated aspirin in terms of our risk-benefit analysis?
And what is the difference in risk of enteric versus not enteric coated
aspirin?

DR. LAINE: That\'s actually a fairly easy one in the sense that
virtually all of the studies do suggest that at least in terms of
clinically important events like bleeding, that there is no significant
difference between low dose plain, buffered, or enteric coated aspirin.

DR. PEARSON: I believe Dr. Meade has also comments from his experience
with both warfarin and aspirin study.

DR. MEADE: Professor Meade again.

I just have had a chance now to look at the figures which Dr. Fleming
raised just now, which I hadn\'t had a chance to check over, and I
thought it might be helpful just to explain those in a bit more detail.

First of all, there were, as you can see, 13 more deaths from MI in the
aspirin than the placebo group, and I\'ve referred to that already,
although it\'s a far from significant excess. So that\'s part of the
reason.

Now, the other point is that Table 3, which is the one you were looking
at, is one where it is rather important to look at the separate
treatment effects because the WA group there or at least the aspirin
group includes the WA group, and there were certain fatal cerebral
hemorrhages in the WA group which were attributable to warfarin.

So to that extent the figure where it says IHD or stroke, first event,
should allow for those.

Now, if you want to take those figures to one side, it makes the balance
much more even, and the other point is that I don\'t think the other
cardiovascular deaths should really be rolled into this because they
were nearly all due to ruptured aortic abdominal aneurism, and you know,
I don\'t think that they\'re really part of the story that we\'re trying
to unravel.

DR. FLEMING: But those other cardiovascular weren\'t contributing to
this excess of 20. There are actually two fewer other cardiovascular on
the aspirin. So if we take out that ten and 12, the 101 against 81
becomes 91 against 69, which is slightly a little worse now.

DR. MEADE: No, I think you should also then take out the seven fatal
cerebral hemorrhages because they were definitely due to warfarin.

DR. FLEMING: Well, but this is a factorial design. So you have the same
fraction of people in the aspirin group on warfarin as in the controls.
So if it\'s only happening warfarin when they\'re on aspirin, then that
is, in fact, partly causal to aspirin as well.

Your analysis is very appropriate here. Your analysis in this paper
captures the power of a factorial design, and it allows you to
understand what the effect is of warfarin and what the effect is of
aspirin. So this analysis is very appropriate, and it is already
balanced for warfarin use.

DR. MEADE: Yes. As I said, I thought I would just \-- since this is a
calculation which you\'ve done, which I haven\'t seen and have only had
a chance to think about would comment on, and a lot of it is due to the
excess of fatal MI events, which I\'ve already referred to.

Why that happened, I don\'t know, but it was far from statistically
significant, and I think that if one is going to start going into
aspects of this sort, you should really look at the deaths from all
causes, and of course, they were very equally balanced.

CHAIRMAN BORER: Okay. Thank you very much, Dr. Meade.

I think we\'re going to have to move on to the FDA presentation. Dr.
Jackson and Dr. Le.

DR. JACKSON: Good afternoon. I\'m Michelle Jackson with the FDA\'s
division of over-the-counter drug products and the Center for Drug
Evaluation and Research.

I\'d like to briefly describe the OTC drug review and provide some
background on the regulatory history of aspirin. I\'ll describe the
events leading up to this Advisory Committee meeting to discuss the
citizens\' petition submitted by Bayer Health Care.

What I\'m going to discuss includes, first, an overview of the OTC drug
monograph process, which will include a general concept of professional
labeling for an OTC drug product; then the regulatory history for
aspirin leading up to this Advisory Committee meeting; and I\'ll also
mention some highlights from the 1989 and 1997 Advisory Committee
meetings and also briefly discuss the final rule on the professional
labeling of aspirin.

The OTC drug review began in 1972 as a four-phase review of the safety
and effectiveness of OTC drugs on the market. This is referred to as the
OTC drug monograph process.

The first stage of the review involves the advisory review panels made
up of independent experts. The panel then submits a report to the FDA
with their recommendations.

In the second stage, FDA publishes the panel\'s report in the [Federal
Register]{.underline} as the advanced notice of the proposed rulemaking
or the ANPR. A public comment period follows, allowing interested
persons to submit comments and additional data.

Based on the panel\'s recommendations and comments received in response
to the panel\'s recommendations, a third stage of the review is that
FDA\'s proposed rule published in the [Federal Register]{.underline} as
a tentative final monograph are referred to as the TFM or the proposed
rule.

This is then followed by a public comment period.

In the fourth stage of the review, FDA considers additional comments,
new information submitted in response to the TFM. The agency then
develops a final monograph or a final rule which is the final regulation
for that particular drug class.

At this point in time, FDA has developed a final monograph with the
professional labeling for aspirin, and so today\'s discussion will be
considering an amendment to the current regulation.

Once the comment period for the particular rulemaking is closed,
interested parties may still provide comments and additional data to the
OTC drug review through the citizens\' petition process. The Code of
Federal Regulations, the CFR, in Section 10.30 describes in detail how
to submit a citizens\' petition. Anyone from the public can submit a
petition to the agency. Essentially it\'s the right of citizens to
petition the government.

Through this process someone may request that the agency issue, amend,
revoke a regulation or take or refrain from taking certain actions.

Petitions are placed on public display in the Division of Dockets
Management. The agency has received a number of petitions to the
internal analgesics monograph requesting cardiovascular indication for
aspirin.

During the OTC drug review, labeling of the drug product is included in
the review. There are two types of labeling: OTC labeling and
professional labeling. The difference between the two is that OTC
labeling is provided for consumers, and consumers are able to safely
self-medicate themselves with the product.

Professional drug labeling is provided for health care professionals
only and is not intended for the general public, and advice from a
health care professional is needed for the safe and effective use of the
drug product.

By the way of introduction, in the next two slides outline the key
chronological events leading up to the issues for this Advisory
Committee meeting. The regulatory history of aspirin for today\'s
discussion will mainly focus on cardiovascular issues. I\'ll briefly run
through the key events and then discuss each event in greater detail.

In July 1972, we had the formation of the advisory panel review to the
OTC internal analgesic ingredients. In July 1977, we had the publication
of the OTC internal analgesics panel\'s report and the ANPR. This is
then followed by a public comment period.

In November 1988, we had the publication of the TFM, also followed by a
public comment period. In May 1989, the agency received a comment from
the Sterling Drug Company requesting a claim for aspirin for the
prevention of primary heart attack.

In October 1989, the Advisory Committee met to discuss the claim for
aspirin for the prevention of primary heart attack.

In October 1992, the Aspirin Foundation submitted a citizens petition
requesting an aspirin claims for treating acute MI.

In December 1992, the Aspirin Strategy Group also submitted a citizens
petition requesting an aspirin claim for treating acute MI.

In June 1994, the aspirin strategy group submitted another citizens
petition, and this time requesting a claim for aspirin for anyone at
risk for MI and stroke.

In June 1996, the agency published an amendment to the TFM to include
two citizens petition requests to include an aspirin claim for treating
acute MI. In January 1997, the Advisory Committee met to discuss an
aspirin study group\'s petition claim for aspirin for treating acute MI.

In January 1997, the Advisory Committee met to discuss an Aspirin
Strategy Group\'s petition claim for aspirin for anybody at risk for MI
and stroke. This then led to the October 1998 final monograph for the
professional labeling of aspirin.

Now that I\'ve given you a brief overview of what\'s to come, we\'ll
move on to some regulatory history beginning with the 1977
recommendations of the advisory review panel for the OTC internal
analgesics and antirheumatic drug products.

The Advisory Review Panel is responsible for the evaluation of the
safety and effectiveness of OTC internal analgesic drug products
containing aspirin. In the [Federal Register]{.underline} of July 8th,
1977, the agency published the panel\'s recommendation in the ANPR to
establish a monograph for OTC internal analgesics, anti-pyretic and
anti-rheumatic drug products. In its report, the panel extensively
discussed antiplatelet effects of aspirin, increased bleeding time,
warnings against use in people with GI or bleeding problems or during
pregnancy, and there was also no mention of cardiovascular claims and
the panel\'s report at that time.

After reviewing the comments and new data submitted in response to the
ANPR, the agency published a TFM in 1988. This document described the
agency\'s position concerning the condition under which OTC internal
analgesic drug products are generally recognized as safe and effective.

Some of the highlights included in the TFM is that the agency propose
professional labeling for the use of aspirin for reducing the risk of
recurrent TIAs or stroke in men, for reducing the risk of death and/or
nonfatal MI in patients with previous infarction or unstable angina, and
for rheumatologic diseases.

In response to the TFM, the agency received the following comments that
professional labeling be approved for the use of primary prevention of
MI under a doctor\'s supervision, reduce a dose for TIA and stroke from
1,300 milligrams to 300 milligrams per day; and to also include labeling
for both men and women.

On October 5th, 1989, the Advisory Committee met to consider data from
the physician health study to support the use of aspirin for primary
prevention of MI. Some of the highlights and concerns from the committee
was that aspirin had no effect on total cardiovascular mortality, and
there was no data on aspirin used routinely in men without risk factors
and in women, and the committee was concerned that aspirin would be used
in healthy people or inappropriate patient population and would, in
addition, be advertised for said use.

On June 13th, 1996, the agency proposed to amend the TFM to include an
indication for the use of aspirin in treating acute MI, an initial dose
of 160 milligrams to 162.5 milligrams continue daily for at least 30
days.

This proposal was in response to two citizens\' petitions submitted by
the Aspen Strategy Group and the Aspirin Foundation of American.

On January 23rd, 1997, the Advisory Committee met to consider another
citizens petition\'s request. The citizens petition requested an
amendment to the professional labeling for aspirin and secondary
prevention of cardiovascular events in patients undergoing coronary,
cerebral, peripheral, arterial revascularization procedures with chronic
non-valvular atrial fibrillation, and requiring hemodialysis access with
fistula or shunt and with elevated risk due to some form of vascular
disease.

At the 1997 Advisory Committee meeting, the committee recommended the
use of low dose aspirin in patients with stable angina. The committee
recommended the use of low dose aspirin in patients with arterial or
vascularization procedures, and the committee also recommended the
professional labeling not indicate use in patients with peripheral
vascular disease.

The federal notice of 1998 final rule contained the agency\'s reasons
why the claim for a primary prevention of MI was not included in the
final monograph. After reviewing the committee\'s decision on the
physicians health study, FDA concluded that some subjects had prior MI
and aspirin is already known to reduce the risk of recurrent MI in such
patients.

FDA\'s evaluation showed that eight percent of the subjects who suffered
from nonfatal MI during the study also had evidence of a previous MI,
and there was no statistically significant effects of aspirin when fatal
and nonfatal MI and strokes were combined.

FDA\'s evaluation of the physician health study show the reduction of
the incidence of fatal and nonfatal MI was accompanied by an increase in
hemorrhagic stroke, sudden death, and other cardiovascular deaths, and
the British doctors trial, despite its similarities to the physician
health study, does not support the use of aspirin to prevent an initial
MI. The study revealed no effect on total cardiovascular mortality.

Aspirin as an OTC product is somewhat unique in that the professional
labeling information does not appear on the OTC label. The regulation
constitutes that labeling be provided to health care professionals by
manufacturers. It has a comprehensive prescribing information similar to
that found on prescription labels. The professional labeling for the use
of aspirin is used for vascular indication and patients that have
undergone certain revascularization procedures and rheumatologic
diseases.

The professional labeling is similar in structure to the prescription
label by providing information on studies supporting efficacy
indications, dosage recommendations, and warnings. Listed here are some
of the components that go into the professional labeling of aspirin. You
have adverse reactions such as hearing loss, dizziness, GI bleeding and
upset stomach; warnings such as de-alcohol and Reye\'s Syndrome warning,
indications such as the vascular and revascularization procedures and
arthritis, dosage administration describing the dosage for the indicated
use, and dosage describing what actions to be taken, and precautions
such as patients with renal failure, patients on strict sodium diets and
drug interactions and contraindications that include the allergy and
Reye\'s Syndrome.

This table shows the indication and the recommended daily dose for the
use of aspirin in patients who have vascular problems, and listed here
are just some of the examples of the vascular indications.

This table shows the indication and the recommended daily dose for
aspirin used in patients who have undergone revascularization
procedures, and listed here are some of the examples of the procedures.

So in today\'s meeting, the Division of OTC Drug Products is seeking the
committee\'s perspective and recommendation concerning Bayer Health
Care\'s request to expand the cardiovascular indications for
professional labeling of aspirin for the use of a regime dose of 75 to
325 milligrams for primary prevention of MI in patients at risk for
coronary heart disease.

The agency\'s primary concern is an assessment of the overall data.

Thank you for your attention.

CHAIRMAN BORER: Thank you, Dr. Jackson.

Now we\'ll have the review by the FDA statistician.

DR. LE: Good afternoon. My name is Charles Le. I\'m a statistician at
the FDA.

I\'m going to talk about the issues with the statistical analysis in
this citizens petition. This is the outline of my talk.

First, I will talk about background. Then I will introduce the
sponsor\'s meta analysis peripherally. Next I will talk about the HOT
study issues and the pooled analysis issues which are corresponding to
the sponsor\'s meta analysis issues, and then I will talk about the
exploratory benefit-to-risk analysis family summary.

The background. The sponsor requested amendment to the professional
labeling for aspirin. The new indication is that low dose aspirin
reduces the risk of the first MRI in patients with a coronary heart
disease risk of ten percent or greater over ten years or there is a
positive benefit risk as assessed by the health care provider.

Five studies were selected to support the petition. Here are the five
studies: the BDT, the British Doctors Trial; and the PHS, the U.S.
Physicians Health Study; the TPT, the thrombosis prevention trial; the
HOT, the hypertension optimal trend study; the PPP, the primary
prevention project.

Over the five studies, PHS and HOT are two of the larger ones. Each has
approximately 20,000 subjects. Under the other three studies, each has
around 5,000 subjects. Combining the five studies, the total number of
subjects is more than 55,000.

FDA only has data for HOT. For the other three or four studies, the
reviews were based on the published literature.

The agency considered aspirin for this indication before and did not
approve it. Dr. Jackson already did a summary listing some of the
reasons. At that time, only two studies were available, the BDT and the
PHS. The reasons were PHS showed that some patients had a prior MI, and
the aspirin is already known to reduce the risk of recurring MI. The PHS
did not achieve statistical significance when combined with nonfatal MI
and the nonfatal stroke. The BDT, which was very similar to the PHS, was
neutral on the effect of \-- I\'m sorry The BDT was neutral on the
effect of aspirin on MI.

So what\'s new in this petition? Three new studies were included, the
TPT, HOT, and PPP. Among the three studies, HOT is the largest one.
Under the sponsor\'s meta analysis of the five studies was submitted to
support the petition.

So in the following, I\'m going to introduce in the sponsor\'s meta
analysis peripherally, and then I will talk about HOT study issues and
come back to the meta analysis issues.

This is the sponsor\'s meta analysis for a nonfatal MI. The data from
the published literature for HOT under the information for nonfatal MI
is not available. So combining the other four studies, the relative risk
is .68 and then the 95 percent confidence interval is from \-- I\'m
sorry \-- the 95 percent confidence interval is from .59 to .79.

For the composite of MI, stroke, and the cardiovascular death, combining
the five studies and the relative risk is .85, and the 95 percent
confidence interval is from .79 to .93.

For cardiovascular death, combining five studies the relative risk is
.98 and the 95 percent confidence interval is from .85 to 1.12.

Now we talk about HOT study issues. The main issue is the silent MI. In
the heart, the primary endpoint was major cardiovascular events. It was
the composite of nonfatal and silent MI, nonfatal stroke and
cardiovascular death, and the silent MIs were obtained by comparing the
ECGs at the baseline with the final visit. The randomization was a
one-to-one ratio. Each group had approximately 9,400 subjects.

Here is a silent MI, and the total MI by treatment group. There were 48
percent and 31 percent sudden MIs in aspirin group and placebo group
respectively.

These are the efficacy results for the HOT study. If we look at the
first column, the difference between the first row and second row is
whether we include or exclude sudden MIs. The same thing for the third
row and fourth row, and now we have a worst stroke, cardiovascular
mortality and total mortality. If we look at the number of P values,
this column, only two rows with not enough P values, and that\'s .05,
that\'s one way to exclude silent MIs.

When we include silent MIs in the lines above, the nominal P values are
more than .05. So whether to include or exclude silent MIs is crucial.

The published paper reported that statistical significance was achieved
for the composite of nonfatal MI, nonfatal stroke, and the
cardiovascular death, and for MI alone and the silent MIs should be
included in both efficacy endpoints according to the study protocol.
When silent MIs are included both in the primary endpoint and the MI
unknown and not statistically significant.

Now we talk about the meta analysis issues. I called it a pooled
analysis. This is the summary for the five studies.

If we look at the patient population for PHS and the BDT, the patient
population was apparently healthy male physicians. For TPT, it was mail
subjects at high risk of cardiovascular disease, for heart and PPP. The
patient population, the patients were at some risk of cardiovascular
disease.

The master row is the aspirin dose. It ranges from 75 milligrams per day
to 500 milligrams per day, including 325 milligrams every other day. So
the patient populations were quite different among five studies, and the
aspirin doses varied.

Now if we look at the primary endpoint for each individual study, for
PHS and the BDT the primary endpoint was cardiovascular death. For TPT
it was fatal and nonfatal ischemic heart disease. For HOT and the PPP,
it was the composite of cardiovascular mortality, nonfatal MI, and the
nonfatal stroke for heart. As mentioned before, sudden MIs were
included.

Now, the five studies is positive in the sense that the statistical
significance is not achieved for the primary endpoint.

Now we look at the MI. MI is one of the secondary endpoints in the five
studies. If you look that the five studies individually, all the
relative risks are less than one and the PHS has the smallest relative
risk at the .58, and the BDT has the largest relative risk at the .96,
and if you look at the nominal P values, PHS has a very small nominal P
value, less than .0001, and the TPT has a nominal P value at a .04. For
the other three studies the nominal values are more than .05.

Now we combine the studies. The first line in yellow is combining the
five studies. The relative risk is .77. The nominal P value is less than
.0001, and the 95 percent confidence interval is from .69 to .85, and
the yellow line in the middle here where you excluded the PHS because
PHS has a very small nominal P value; so when you exclude it and
combining the other four studies, and then the nominal P value becomes
.011.

And in the last row here, we exclude two studies, PHS and TPT, because
the two studies, both have a nominal P value less than .05, and then
combining the other three studies, the nominal P value is .096.

There were some issues with the pooled analysis, why and how the five
studies were selected. The patient populations were very different and
aspirin doses are different.

So what\'s the evidence for MI? MI is only a second random point in all
the five studies, and the silent MI is an issue. If we look at the five
studies individually, PHS suggested potential benefit. TPT had a nominal
P value at .04. Heart is not clear. BDT and TPT failed to show
statistical significance, and then the pooled analysis did not provide
any additional information beyond the individual studies.

Finally, we talk about the exploratory rate, benefit-risk analysis. The
new indication where you expanded the risk population and the bleeding
is one of the known adverse events for aspirin. The benefit and risk
ratios should be considered.

We only have data for HOT. So here is the MI and the major bleeding by
treatment group, provided overall for male low and for female low. In
each case aspirin has a lower rate for MI and a high rate for bleeding.

So we\'re trying to quantify the benefit-risk ratios. This method was
developed by Andrew Willan and others, published in [Controlled Clinical
Trials]{.underline}. I listed a reference at the bottom.

That Pt and Ps, the probability of MI free in aspirin and placebo group,
respectively, that Qt and Qs is the probability of major bleeding in
aspirin and placebo group, respectively. Then a possible measure of
benefit-to-risk ratios are \-- which is defined as Pt minus Ps over Qt
minus QS are defined this way.

Then are measures. How many MIs can be prevented and the cost of one
major bleeding by using aspirin, and the confidence interval can be
obtained. From the HOT study we got the estimates for all, and the
confidence intervals are wide. So they\'re not provided here.

For the definition of major bleeding, you can look at the final report
for the HOT study. What does this mean?

It means for male and female combined, it is estimated 54 MIs can be
prevented and the cost of 100 major bleeds by using aspirin. For male
alone, 85 MIs may be prevented at the cost of 100 major bleeds by using
aspirin, and for female alone, 14 MIs may be prevented and the cost of
100 major bleeds by using aspirin.

In summary, MI is only a secondary endpoint, and in all of the five
studies silent MI is an issue. For primary prevention of MI, PHS
suggested the potential benefit. TPT had a nominal P value at the .04.
Hot failed to share statistical significance when sudden MIs were
included. BDT and the PPP failed to show statistical significance.

The two studies in yellow were considered by the agency before, and
there were some issues with the pooled analysis, why and how the five
studies were selected, the risk factor of the patient population, and
the aspirin doses, and the pooled analysis does not provide additional
information beyond the individual studies.

And finally, the benefit and the risk should be considered.

Thank you.

CHAIRMAN BORER: Thank you very much, Dr. Le.

Yes, Alastair.

DR. WOOD: I have a question. One of the strengths of meta analysis is to
take the totality of the data. How do you justify excluding two of the
major studies which by my sort of back-of-the-envelope calculation cut
by 50 percent the number of patients you had in the study?

DR. LE: The idea is if you\'ve already cut the number of people less
than .05, we\'re trying to get the information from the other three
studies, and combining the other studies, the sample size is increased.
Hopefully we can get the statistics in significant results to obtain the
nominal P values still, .096.

That\'s the idea, but you\'ve already got that PHS has a very small,
nominal P value, and the TPT had a nominal P value at .04.

DR. WOOD: I\'m not sure I understood your answer.

DR. TOPOL: Alastair, I think it\'s an attempt to find a confirmatory
meta analysis after you accept the physicians health study. A done deal,
and then you see if the rest of it looks like the confirmation.

I think a lot of people \--

DR. LE: Right. That\'s the idea.

DR. FLEMING: I guess I would say in understanding the nature of your
question, the estimate is \-- the best estimate is the totality of the
data. The physicians health study gave a very strong signal. The
totality of the data gives a strong signal. It\'s relevant to get a
sense of whether or not there\'s robustness. If that physicians health
study was out, would the remainder of the study still basically
themselves be providing a strong signal?

It\'s in that context, but clearly the best estimate, as I think your
intuition is saying is going to be the one based on using all of the
data.

CHAIRMAN BORER: Okay. There were \-- I\'m sorry. Beverly?

DR. LORELL: I think one of the things that I\'d like to make a point of
in regard to your otherwise excellent analysis is that for the totality
of the risk-benefit experience around cardiovascular events, must
coronary and MI include subsequent development of heart failure, which
confers both morbidity as well as followed out longer than these studies
a secondary risk of mortality, as well as stroke?

So I think unfortunately \-- and I don\'t think we can squeeze these
trials to get this data \-- but it would have been of interest to have
actually had some kind of an estimate of prevention of risk of heart
failure, morbidity and mortality over both a shorter and a longer range?

So my comment is I think in this risk-benefit equation, this is a
component of risk that we\'re not able to look at today.

CHAIRMAN BORER: Steve.

DR. NISSEN: Yes. There\'s sort of an issue on the table that we haven\'t
really talked about, and maybe I can frame it. It is a question really
for the FDA and for the OTC group.

And that relates to direct to consumer advertising. I assume that
what\'s really at issue today, which we haven\'t talked about is what
you can do with direct-to-consumer advertising, which I suspect is why
this application is here.

And so the question is: if we give this label, are we likely to see
direct-to-consumer advertising promoting the use of aspirin in primary
prevention, or is that simply not an issue? Is it an issue?

This is professional labeling versus \-- I mean I don\'t understand what
the implications of a decision here would be on how this would likely
play out.

DR. TEMPLE: Charlie may want to answer more. This was once an issue when
there wasn\'t much direct to consumer advertising of prescription drugs,
but now there\'s direct to consumer advertising of prescription drugs.
There would be direct to consumer promotion of a so-called professional
claim in advertising, and I think nothing would stop that any more than
direct to consumer advertising of prescription drugs.

So I think the issue here is what\'s the right statement of what the
indications are, which will limit promotion and affect promotion of all
kinds to all people, but the DTC thing is really not such a \-- I mean,
it\'s not an important question. It will happen, guaranteed.

DR. NISSEN: Well, assuming we give the label it would happen.

DR. TEMPLE: Yeah, yeah. Not unless.

DR. NISSEN: Okay. I just wanted to make sure we understand that, yeah.

DR. TEMPLE: Maybe not unless.

DR. NISSEN: What I\'m trying to weigh here as a \-- you know, trying to
do what I think is in the public interest here and what I\'m trying to
understand is what the risks are that people at such low risk that
aspirin would increase their risk of harm will get the drug versus more
people who would benefit getting the drug, and so this is playing into
my thinking here.

DR. TEMPLE: Can I make an observation about that? I mean, to my surprise
to some extent almost the entire presentation about this has been who to
give the drug to. Usually the first thing you do is you find out whether
it works in the population like people who haven\'t had an MI yet.

And I guess I would urge you to think a lot about that question, and
then it\'s very important who to direct the drug to, and really the
presenters have talked a lot about that and who is at great enough risk
to do that, and you can advise us on how much emphasis we should put on
that, but it\'s really important to us to know whether you think
they\'ve got the data that supports the effectiveness in primary
prevention, and I hope you\'ll concentrate on that and not worry too
much about promotion because we\'ll worry about that.

CHAIRMAN BORER: I promise we\'ll concentrate on that.

DR. NISSEN: Okay. I just thought that we ought to say something.

DR. TEMPLE: It\'s not uninteresting. It\'s very interesting, but where
we need help is what to make of the data.

DR. NISSEN: I understand completely, but I just thought it was not being
said and it probably ought to be said.

CHAIRMAN BORER: Okay. With that issue having been put on the table,
let\'s move along here. We have some unanswered questions. Bill Hiatt
had one, and I think Susanna had one, but what I\'m going to propose
that we do is to begin discussion of these issues in the context of the
FDA\'s questions. If we require clarification of any points by any of
the committee members from the sponsor and its representatives, then
we\'ll do that, but otherwise the sponsor\'s comments are concluded at
this point.

Alastair.

DR. WOOD: I\'m sorry. Just before we leave the sponsor, the
presentations were so different. It does seem to me there ought to be a
chance from the sponsor to respond to the comments from the FDA.

CHAIRMAN BORER: To which comments?

DR. WOOD: Well, some of the specific comments in the last presentation
seem to me to beg for a response, and I think it would be appropriate to
hear why they see such a disparity between the two presentations.

CHAIRMAN BORER: Okay. We\'re not going to do that right now only because
I think the discussion will get a little convoluted. The FDA statistical
review was available a while ago, and the sponsor gave its views of how
the data look. It can respond to the FDA, could have responded to the
FDA\'s statistical review, but I think our discussion will take both of
these sets of analyses into consideration, that is, what we\'ve been
presented by the sponsor and what we\'ve been presented by the FDA
reviewer.

So I think we\'ll hold off on a specific response right now. As we go
along, it may be necessary to do it.

Okay. Again, if you need clarification from the sponsor about anything,
then we can certainly get into that in the context of our consideration.

I\'m not going to call for a break right now. If anybody needs to come
in and go out, you can certainly do that.

The questions put to the committee are as follows. The Cardiorenal
Advisory Committee is asked to give an opinion on the use of aspirin for
the primary prevention of myocardial infarction in response to a
citizens petition. That petition cites five studies. We\'ve heard a
great deal about the five studies. They\'re summarized on the first page
of questions.

The specific characteristics of these studies are presented here on page
4 of the questions, and with these characteristics in mind and with the
data that we\'ve heard in mind, are there any other studies that should
have been considered?

Is there anyone on the committee who believes that there are studies
that should have been considered that weren\'t for this purpose?

DR. HIATT: I don\'t believe so, but I just would point out that there is
this subgroup analysis the Primary Prevention Project published in
[Diabetes Care]{.underline} this month. It maybe has limited value, but
it\'s new.

CHAIRMAN BORER: Okay. Are there any other studies of which anyone is
aware that should have been considered in drawing conclusions here?

(No response.)

CHAIRMAN BORER: I will take that as a no.

Number two, in considering how to interpret these trials with respect to
primary prevention of MI, whether by formal or informal meta analysis,
what is the significance of each of the following?

And I\'m going to ask Tom to take the lead in providing a response to
these questions and then each of the other committee members can follow
up if she or he chooses.

Two, point, one, one, the study protocol is unavailable for BDT, TPT,
and PPP. Tom?

DR. FLEMING: Should I group my answers and maybe give a global answer to
Question 2 in the efficient use of time here or do you want me to go ‑-

CHAIRMAN BORER: No, you go ahead and group your answers.

DR. FLEMING: Okay.

CHAIRMAN BORER: If you think that\'s appropriate.

DR. FLEMING: All right. I might try to answer Question 2 by grouping
these seven elements into four parts in responding to them in these four
part. The first two parts I\'ll put together. The study protocol was
unavailable and the source data are unavailable. What is the
significance?

Certainly there is some non-trivial significance. Having been involved
in many advisory committees, I\'ve been convinced that what comes
forward in a detailed FDA presentation often is substantive additional
insight beyond what I might have gotten by reading the published
literature presentation of the results.

And an example of this certainly is the HOT trial is the one that the
FDA did give a careful analysis for, and the insights about silent MI
that I want to refer back to in subsequent questions as to why I
consider it to be of relevance is certainly something that was much
clearer when we were seeing the FDA presentation compared to the
literature publication of these results.

So I do believe that literature publications are very informative, but
from experience, I think there is a substantive added insight that we
get when the protocol and source data have been reviewed in depth by the
FDA and presented to the advisory committee.

The second and third and fourth components, no study had a primary
prevention of MI as the primary endpoint and only one study showed an
effect on its prespecified primary endpoint.

My sense about this is these certainly are also relevant facts, as I\'ll
allude to in some subsequent questions. I think the clinical community
used considerable judgment in identifying what would be the most
appropriate endpoint in each of these five trials, and those endpoints
typically were focusing very much on cardiovascular morality, as well as
nonfatal MI and nonfatal stroke, and the fact that none of these were
significant, or the way I might put it is the fact that the results on
those measures were far less favorable than the result on MI certainly
indicates the fact that the more global measures that we were looking at
were not nearly as persuasive as the specific subcomponent, which was
nonfatal MI.

And this is an issue of considerable significance when we put in the
context benefit to risk and the fact that there is increased bleeding
and hemorrhagic stroke. So the nature of this significance, I think,
will come clear as we also answer subsequent questions.

Part number 215, the studies varied with respect to what MIs were
captured, and certainly that is of some significance. In an example of
this, the HOT trial did provide us an analysis of the silent MIs as well
as other MIs, and that did, in fact, have some relevance or does have
some relevance in interpretation.

The final two elements, the dose regimen and biopharmaceutical
properties of aspirin varied. The baseline risk factors varied. What is
the significance of this?

In fact, I think there\'s a tradeoff. I think there are some beneficial
aspects to this variability. I think it gives us the opportunity to
assess at some level how generalizable our results are by looking at the
assessments over a range of different regimens and characteristics of
participants.

However, this generalizability comes at the risk of greater clarity for
any specific setting. So we have less certainty about any specific
indication and specific regimen by virtue of the fact that there was
this heterogeneity.

I\'ll stop. Those are the 2.1.

CHAIRMAN BORER: Great. Okay. Does anybody on the committee have any
additional comments with regard to 2.1? Remember we will come to these
issues again, I think, in Question 6, but specifically I\'d like to hear
if anyone would like to comment on 2.13 and 2.1.4. \"No study had
primary prevention of MI as a primary endpoint, and only one study
appears to have shown an effect on its prespecified primary endpoint.\"

How does that impact on your thinking about the evaluation of what was
found? Steve.

DR. NISSEN: Well, like I think Tom, I\'m much less comfortable in
analyzing data in a clinical trial when the primary endpoint is not met,
and I think it should be said that, you know, there are lots of risks of
looking at even prespecified subgroups, let along non-prespecified
subgroups, but those risks go up, it seems to me, when the primary trial
fails to meet its prespecified endpoint.

And so this tends to weaken the overall case, and it\'s unfortunate that
it\'s true for virtually the entirety of the data, that none of these
studies really were a slam dunk for their primary endpoint, and that
makes me not want to go into those subgroups with the same level of
confidence that I would in a study that actually met its endpoint.

CHAIRMAN BORER: What about the presence or absence of consistency among
the various endpoints, primary or secondary, given the fact that the
primary was not met in any of the trials? Does anybody have any thoughts
about that, the impact of the consistency or lack of consistency among
the various outcome events?

Beverly.

DR. LORELL: Well, I\'m not sure if this is precisely what you\'re
getting at, but I did want to comment about the issue of consistency of
defining myocardial infarction and to put a little bit of my perspective
on the FDA comments here.

I am not troubled by the inclusion or lack thereof of silent MI. It\'s a
whole different issue as to whether or not there was any awkwardness in
what was defined in the protocol versus the final assessment, but I\'m
talking about linking of the clinical totality of our judgment today.

I think it\'s worth emphasizing that we know a huge amount from many
studies and large evidence based trials beyond the studies here about
the outcome short and long term of the clinical event of myocardial
infarction.

In contrast, we know remarkably little and the data is conflicting about
the long-term clinical outcome of so-called silent infarction and
probably could not even reach consensus around this table except in the
narrow setting of post PCI experience of how to even define that.

So in responding to query number 2.1.5, I think my own view is I\'m not
troubled by this issue of silent versus clinical event, and I personally
would urge this group to think predominantly about the clinical MI event
database.

DR. TEMPLE: I just want to be sure one distinction is made. You may not
\-- some of the studies don\'t have any information on silent MIs. So I
think you\'re saying don\'t discard the studies for that.

What about the studies that do have information about it, but didn\'t
include it? How do you feel about that? I just want to separate those
two issues.

DR. LORELL: I think I would say the same thing, that I think in making a
clinically sound decision we have very little data, and it\'s discrepant
about the implications of a silent MI in this kind of prospective
primary prevention setting.

DR. TEMPLE: Okay. So you\'re saying that you think the right endpoint is
the clinically manifest MI.

DR. LORELL: In the database that we have today, I do.

DR. TEMPLE: Okay. I\'d be interested in being sure how other people feel
about that, too.

CHAIRMAN BORER: Paul.

DR. ARMSTRONG: I wanted to respond to 2.1.3, but before doing that,
silent MI, of course, expresses itself as sudden death, which is the
first manifestation of the disease, and if it uniformly defined as new
Q, then it has prognostically meaningful implications that are clear
cut.

The complications of myocardial infarction, if they\'re meaningful,
should express themselves in death downstream, and so the consistency
issue is potentially troublesome. The point I wanted to make relative to
2.1.3 was one that I thought Tom would address and I\'ll ask him
directly through you, which is: if you terminate a trial early because
of an efficacy endpoint that\'s not your primary, then there\'s another
layer to this discussion relative to the confidence in the estimate
which Steve spoke about, and that, of course, is that you overestimate
the extent of the efficacy.

Could you give us some sense based on your experience of the proportion
of the estimate of efficacy that\'s likely overestimated because the
trial terminated based on that judgment?

DR. FLEMING: Well, Paul, you\'re right. If you\'re monitoring a trial
and at an interim analysis you see a result that looks extreme and that
triggers a recommendation to terminate, then essentially it\'s a bit of
what you might call a regression in the mean phenomenon.

Essentially your estimate undoubtedly reflects the fact that there\'s
benefit, but probably at a time period where you might be getting a
particularly favorable estimate of that benefit. So you\'re tending to
overestimate the true benefit.

A seat of the pants adjustment is about a ten percent difference. I had
mentioned in the PHS trial though that if we\'re looking \-- and I
don\'t think we\'re going to look at these data purely from the
perspective of statistical significance, yes versus no in individual
trials, but one has to recognize as well that what you call
statistically significant also has to be assessed in a more conservative
way, that you need much stronger evidence for you to judge something as
statistically significant.

Could I go back though? I thought you raised a really important issue on
the silent MIs, and I was wanting to wait until Question 6 to give a
basis for why I would view it to be of some relevance, but maybe that\'s
artificially too long.

My own sense is that there\'s a continuum in the clinical relevance of
outcome measures, and I would tend to think most of use would put
mortality at the highest, and we may specifically here put
cardiovascular mortality there because we\'re trying to achieve greater
sensitivity by not diluting our mortality on point by those non-cost
specific measures.

My sense is we might well put nonfatal strokes then at next in line and
that I might be putting nonfatal MIs next in line to that. I would be
readily persuaded that silent MIs would then go below the nonfatal MIs
in this continuum.

Where I\'m struggling is there is a paradox here because when we talk
about \-- and the sponsor in their documentation says we\'re trying to
deal with morbidity and mortality, and I think if you reduce MIs and
even if you\'re reducing nonfatal MIs, I\'m believing we\'re inclined to
think that should translate into some overall mortality trend, and when
it doesn\'t I want to try to probe and find out why.

And in one trial where we\'re giving evidence, which is the HOT trial,
the silent MIs go 75/57 in the wrong direction, and when we look at the
PHS trial and we see some positive trends in MI deaths, we\'re seeing an
equal number of excess sudden death and other cardiovascular deaths that
are occurring in the other types.

And so I\'m saying: is there a clue here that it may be that silent MIs
are, in fact, not as favorably affected, but they too have some effect
on subsequent mortality? And so if we\'re only looking at MIs and
nonfatal MIs, and we\'re getting the impression of benefit, but our
mortality data and stroke data say, no, you\'re not getting benefit,
then do the silent MIs help us to address that paradox?

DR. ARMSTRONG: Could I respond to that?

We\'ve heard from some of the PIs that the data is available, but the
FDA has not had it, which is a paradox in relationship to discussing
this important issue because in that data one would be able to address
the robustness and the symmetry with which the silent MI question was,
in fact, evaluated, would be, I think, a key issue here.

So I would just make that point in relationship to where we are with
this issue.

CHAIRMAN BORER: Yeah, Tom, your response actually got to what I was
trying to ask about consistency of the endpoints. The fact that there
was not consistency is a little troubling perhaps.

Tom Pickering.

DR. PICKERING: I just wanted to say I would be somewhat concerned if the
way the recommendation went depended on this issue of silent MI since
most of the studies didn\'t evaluate it as far as we know, and in those
that did, it was just a single ECG analysis, and I don\'t know how
reliable that is.

CHAIRMAN BORER: Steve.

DR. NISSEN: I wanted to respond to Bob\'s question about silent MI. I
mean, the way I would view this is I would look at the data as it was
prespecified, and so in those trials, it\'s that we\'re going to include
silent MI. Then I would hold them to that, and in trials that said we
are not going to include silent MI, I would hold them to that.

You know, I think to me that\'s the only appropriate standard we can
come up with, and I guess my second comment is that we really don\'t
have enough information to know whether silent MI does or does not carry
with it the same precise implications as a non-silent MI, and so in the
absence of any data, then you just simply look at what was
pre-specified, and you classify them the same.

I don\'t think we have any basis for making any other judgment, and so
let\'s look at the prespecified endpoints, and it sounds like in HOT
clearly they did prespecify that those silent MIs would be included, and
I think we should hold them to that.

CHAIRMAN BORER: Bob.

DR. TEMPLE: I have a comment about something else, but I must say given
how often an unusual thing occurs in an MI or angina and is confused
with esophageal things, it seems odd not to count them just as much, but
I\'ll leave that aside. You know more about that than I do.

I have a question. Even though the endpoints were different in all of
the trials, as we saw, most of the trials, but I\'ll express a
reservation about that, do have an endpoint that consists of nonfatal MI
and nonfatal stroke and fatal cardiovascular. They all have that, and
four of them were presented as showing at least border line statistical
significance.

So I guess my question is maybe that\'s all just after the fact stuff on
my part, but is that somewhat reassuring in that you can find a common,
not unreasonable endpoint in all of them, and I just do have to observe
that I\'m concerned about the thrombosis prevention trial because I
don\'t think we have total cardiovascular mortality data there, and we
would surely want to get that, especially if the data become available
to us.

But leaving that question aside, if that endpoint were reasonably common
to all of the trials, would that help in this discussion, even though it
wasn\'t prospective and even though we\'re just being wise guys after
the fact because it sounds plausible?

Does that help at all?

CHAIRMAN BORER: Alan, do you want to respond to that?

DR. HIRSCH: Well, I have a profound response. Certainly that would help.
Let me take the first aspect.

Yes, I think the post hoc recognitional signals for the nonfatal MI is
somewhat reassuring. All of us look with our blinders on after the fact,
but a secondary endpoint prespecified they had some consistency would be
reassuring, I think, to most members of the panel, certainly to me.

CHAIRMAN BORER: Any other responses?

(No response.)

CHAIRMAN BORER: Well, let\'s move on to number three. Aspirin has a
claim for secondary prevention of myocardial infarction. How much, if at
all, does this lower the evidentiary burden for primary prevention of
myocardial infarction?

Bill, do you want to talk about that?

DR. HIATT: I don\'t think it changes at all. In fact, the population is
so much bigger for primary prevention the burden of evidence should be
every bit as strong.

I asked this question early on. It makes intuitive sense that it\'s a
continuum and there are all the same patients, but there may be some
qualitative differences from patients who have had an event, whose
plaque has ruptured versus those who have not.

So I was just struggling to look at whether the signals were consistent
from those form whom there is approval versus those for whom we\'re
trying to gain approval today, and my questions remain. In women, in
people with diabetes, in people with other manifestations of
athrothrombosis like peripheral arterial disease, are these populations
when they\'re lumped into the primary prevention cohort really
equivalent to just an overall risk score assessment and treatment?

And those questions haven\'t really been answered.

CHAIRMAN BORER: Yeah. Hold that because we\'re going to get back to that
in Question No. 5, which may be an important issue for us. So we will
get back to that.

Does anybody else have any comment on 3.1?

Yes, Alastair.

DR. WOOD: I guess my comment relates to the following. This is not
really a primary prevention in the usual way we think about it. It seems
to me that what\'s being asked for here is moving from an event based
prescription strategy to a risk based prescription strategy, which is a
little different from just viewing this as primary prevention in itself.

And so it seems to me the real issue we have to debate is whether a
risk-based and prescription strategy is appropriate, and if it is
appropriate, at what level do you set the risk and for your
prescription?

And the problem with setting the risk is that we need to have some
value, that we need to have some measure of that risk that takes some
value weighted measure of risk, value weighted meaning, you know, that I
don\'t accept an MI the same as a GI bleed, frankly, and equally I
don\'t accept that a GI bleed is the same as a hemorrhagic stroke. I
mean, I think I\'d value these differently and greater obviously.

And so the primary question is do we move from an event based strategy
to a risk based strategy, and if we do, then at what level do you set
the risk?

The whole problem here is and what we\'re being asked to debate is this
finite cut point between ten and 20 percent where the data are all
largely below that cut point, but that doesn\'t bother me so much
because if you come in with a lower cut point I might be even more
comfortable with that than I would be with a higher end cut point given
the data.

And in addition, I\'m not sure that the ten percent cut point has much
rationale anyway.

CHAIRMAN BORER: Bob.

DR. TEMPLE: Alastair, maybe that\'s what we should have asked you. We do
ask you that in the seventh question, but that question comes only after
you are satisfied that the drug works and you haven\'t had an event yet.
Now, maybe that\'s all stupid of us and the whole question is already
answered already because it\'s really all the same and it doesn\'t make
any difference. That\'s certainly the presentation we heard, I think.

Don\'t worry about this particular population. Just try to direct the
drug to the right people in whom the benefits outweigh the risks.

But we really want to know, for reasons Dr. Hiatt suggested, whether
these people really do have a benefit of some kind, that is, people who
haven\'t had an identified event yet. Then you can talk about who to
direct the drug to.

So we did not ask those questions. We did not ask the question the way
Alastair put it. We really want to know whether you think in people who
haven\'t had an identified event yet these drugs prevent events.

And it\'s not just who to direct it to. That comes only after you answer
that first question.

CHAIRMAN BORER: Alan.

DR. WOOD: But that\'s confusing. I think the albatross in the room, in a
sense, was something that Steve mentioned earlier. I think we\'ve all
gotten past this idea that it\'s pure primary prevention or a continuum
of risk or secondary prevention.

And I find the word, again, to be distracting here because it really is,
going back to what Bill said, a question of how an OTC medication which
will be delivered by the public to itself in a primary prevention motif
will be applied in a whole slew of individual, some with diabetes, some
with PAD, some with risk factors.

And it is the ability to think we have evidence for primary prevention
in those groups consistently that I think confuses this question.

DR. WARD: But there\'s no suggestion that this would be delivered by
patients to themselves without professional intervention.

DR. HIRSCH: Ah, the albatross in the room. I understand that. That is
the challenge.

DR. WARD: No, I agree. I don\'t think we should worry about that at all.

DR. HIRSCH: We need \-- look. It may turn out you think this was silly,
but the original approval here was for people who had had an event, and
it\'s not completely obvious that those people are just like the other
people for reasons Dr. Hiatt has been trying to get everybody to pay
attention to. The mortality effect is different. The effect on stroke is
different. Maybe they\'re not the same and we\'re not smart enough to
figure out why.

In any event what we\'re really asking is is there evidence for use of
the drug in some or all? We\'ll get to that. That\'s question seven of
the people who have not had an event yet.

Now, I suppose you could tell us that\'s a stupid question. Of course
aspirin works. These people aren\'t any different from anybody else. If
that\'s what you think, tell us that and we don\'t have to spend a lot
of time worrying about the data because that would not be a data
dependent conclusion. So that\'s all right, too.

But I just want to focus the first six questions are about whether
there\'s evidence that it works in people who haven\'t had an event yet.
Feel free to tell us that\'s a stupid question, but be specific about
it.

CHAIRMAN BORER: Bill and then Paul.

DR. HIATT: Okay. So just to follow up on that, I\'ll go to 3.2 because
it appears to me from the data that if you just focus on nonfatal MI,
those are all prespecified events at some level, and it does appear to
be effective.

But I\'m not convinced that it doesn\'t adversely affect mortality or
strokes. So if it was really convincing that the effect on those two
endpoints was absolutely neutral and all you care about is the bleeding
risk and that you\'re convinced that it doesn\'t reduce MIs, I\'m okay
with that.

The question is how far those confidence intervals shift in the adverse
direction for the other cardiovascular endpoints that I \--

DR. TEMPLE: That\'s actually why I asked you whether you were impressed
by the fact that at least with one exception that I\'m not sure of, when
you look at fatal and nonfatal MIs and strokes and total cardiovascular
mortality, all of them seem to show, except the British doctors study,
which doesn\'t show anything, all of the others seem to show a favorable
effect.

Now, one could know, well, they were presented as Ps less than .05. You
can debate each one. I guess I offer the proposition that if you believe
there\'s a persuasive effect on MIs, even though it wasn\'t the primary
endpoint, one might take as reassurance that nothing bad is happening
the fact that those things all end up really being driven by the MI.
They\'re not reversed.

That\'s really what I was asking about, the commonality of that endpoint
which I guess I must, you can probably figure out, fine at least
somewhat reassuring against what you\'re worried about maybe, that
certain people are disadvantaged badly.

DR. HIATT: So in trying to answer this question on efficacy, not just
look at the bleeding risk but look at the stroke risk and the mortality
risk, and if those things are convincingly acceptable, then the MI
reduction is probably clinically relevant.

CHAIRMAN BORER: Okay. Before we go on to Paul, you wanted to make a
clarification, Tom?

PARTICIPANT: No further comment.

CHAIRMAN BORER: Oh, okay. Sorry.

Paul.

DR. ARMSTRONG: The conversation today has been predicated on aspirin\'s
mechanism being clear-cut, which is an antiplatelet agent. There has
been some data from some of these trials suggesting the
anti-inflammatory effect is important. It would be helpful in
relationship to primary prevention for someone, if there is data, clear
data supporting an anti-inflammatory effect that\'s translated into a
vascular benefit to state it, but it hasn\'t been stated today, and I
would just be in terms of extending the indications into an area where
there\'s not much data, it would be helpful to know the answer to that.

CHAIRMAN BORER: That\'s a very important point, but I think that we have
to look first at the data and only after that begin to talk about how it
got that way on a pathophysiological basis because I don\'t think we\'re
going to come to a conclusion about the latter.

DR. CUNNINGHAM: Jeff.

CHAIRMAN BORER: Yes, Susanna.

DR. CUNNINGHAM: This may belong to Question 5, but I\'m a little
disturbed that we\'re talking about efficacy for prevention of MI when
there\'s no data necessarily for efficacy prevention of MI in women. I
have yet to see that and the discussion goes on and on, and yet, you
know, for 50 percent of the population here, we don\'t have data that I
can tell and only 20 percent of the population that was studied were
women. Those were in the last two trials, and there is a published study
in sort of a minor journal, a journal of gender specific medicine
reporting on the HOT data and saying that there was no benefit for MIs
in women, no significant benefit.

So I\'m a little concerned that we keep talking about the benefit on MIs
when that may not exist in women.

CHAIRMAN BORER: The analyses we were given showed no significant benefit
in women, but as I read them, there was at least a nominal reduction in
events in women in the analysis that was done. Is that different from
the way you viewed it?

DR. CUNNINGHAM: Well, the report that was in this small journal is kind
of a minor report, but it says that the reduction in women was .4 MIs
per person-years for women, and it was 2.1 per men, and it was a 19
percent reduction, but it doesn\'t differentiate in this little report
about whether it was all MIs, fatal MIs or exactly what it was. So it\'s
kind of hard to interpret.

I\'m just concerned that I haven\'t yet heard. I heard terminology about
women. I heard about women being special population or whatever else. I
think in some cases I think they may be second hand rose.

CHAIRMAN BORER: Ron and then Doug.

DR. PORTMAN: Being a pediatrician, prevention is what we\'re about in
large part, and my concern is how long do you treat with aspirin.
Forever?

We have a lot of children now that are becoming very high risk. That
slide we saw this morning of the 52 year old I could put about 10,000 15
year olds into that same slide with hypercholesterolemia and
hypertension and insulin resistance, and so on.

And so do we treat children? And if so, when? At what age? And what
marker are we going to use?

If I treat hypertension, I know what happens to blood pressure. If I
treat cholesterol, I know what happens to that. If I use aspirin, I\'m
looking for the absence of something.

And so I\'m waiting for how many years to see that absence. Is there no
other marker that we can use for that?

CHAIRMAN BORER: Doug.

DR. THROCKMORTON: Sorry. It was just a comment that Dr. Le had included
a subgroup analysis in females from the HOT study on page 15 of his
review. I think the sponsor had some materials. I don\'t remember for
sure what those are.

CHAIRMAN BORER: Tom.

DR. FLEMING: Just to respond in general to Question 3.2, it is as we\'re
looking at what influences the evidentiary burden for evidence of
primary prevention of MI, as we go from secondary prevention to this
primary prevention setting, we\'re dealing with a situation where the
disease rates are lower, and yet where by all indications the safety
risks remain constant, and so to establish favorable benefit to risk,
those observations in their own right provide an increased or enhanced
burden of establishing efficacy because there has to be an impressive
level of efficacy when you\'re looking at a more rare disease endpoint
to offset a constant level of risk.

In that context, when we look at the results or the inconsistency of
results on stroke and overall cardiovascular mortality between the
secondary and the primary settings, this is very important. In the
secondary setting, what we\'re looking at is about a one third reduction
in nonfatal MI and strokes by 20 to 25 percent and cardiovascular
mortality by ten to 15 percent. There\'s a very nice positive
reinforcement there.

In this setting, we\'re looking at suggestions, data that suggest that
there isn\'t a benefit on stroke. In fact, there might be a slightly
adverse relative risk, and that overall cardiovascular mortality has a
relative risk that\'s near unit.

And in the meta analysis, it\'s not that there\'s just a trivial amount
of information here. We have in nonfatal MIs a thousand events, but in
nonfatal strokes, there are 650, and in an overall total cardiovascular
mortality, there\'s 900 events.

These data taken in totality give us confidence intervals that are
ruling out the level of benefit that we\'re seeing in the secondary
prevention setting for effects on stroke and overall cardiovascular
mortality.

So these observations have a profound effect, I would argue, on what
strength of evidence you would need to establish adequate efficacy by
just showing what the effects are on primary prevention of MI.

DR. HIATT: Sorry, but just to interpret that comment, so do you believe
then that the evidence is very strong that aspirin is neutral on
cardiovascular mortality in the primary setting?

DR. FLEMING: We\'re going to jump ahead, but let me just comment right
now. The essence is, in my words, I think these data suggest lack of
benefit over the time period that participants were followed in this
study.

And whether we call it compelling is something that could be
controversial, but there\'s sufficient evidence here that we can rule
out the level of benefit that at least was seen in the secondary
prevention setting.

So it\'s a considerably strong suggestion for lack of benefit. Now, one
of the issues that I struggle with is is it that we followed people an
average of five years. What if we follow them an average of seven years
or ten years? Might there be some evolving benefit that would occur that
we haven\'t yet weighted to see?

I don\'t know the answer to that.

DR. HIATT: My question is: have you excluded harm? I think this does do
that, right?

Lack of benefit, yes. Have you excluded any adverse effect on CV
mortality?

DR. FLEMING: Well, we can certainly exclude just off the top of my head
\-- and I would have to go back and look at this in a bit more detail
\-- but you would exclude harm at the level of saying you\'re going to
double the rate of strokes, and you could actually exclude probably much
lesser excesses than that, but you could still have moderate excesses.

And now if there are moderate excesses and there\'s no positive effect
by indication on cardiovascular mortality and you have the bleeding
episodes, then what does an effect on nonfatal MI do to offset all of
those concerns?

CHAIRMAN BORER: Alastair?

DR. WOOD: Well, while I agree with Tom, I think we have to be careful
about carrying that too far. I mean really what you\'re saying is is
prevention of MI an approvable indication, and I think it is. We\'ve
approved lots of drugs for indications like prevention for
hospitalization for heart failure and in the absence of at that time
mortality data, and so on.

So I don\'t think the absence of positive mortality data and
particularly where it\'s reasonable to say that you were studying a
disease an earlier stage in its life cycle should preclude it being
approved. We approve drugs every day for non-mortality driven endpoints.

And then to turn the thing around I\'d just echo what Bill I think was
saying, that the absence of a mortality signal in the opposite direction
certainly provides you with some reassurance that you\'ve not selected
some specific indication out here, and that is masking some other
encompassed endpoint that would have actually picked up something bad
happening.

So I think the question is: is this an approvable indication? My view is
it is, the indication of prevention of MI.

And if that\'s the case, you don\'t need a mortality endpoint.

DR. FLEMING: Well, let me clarify what I was saying. I was answering the
question specifically do the results on stroke and overall
cardiovascular mortality raise the burden absolutely?

Because if, in fact, we say is an effect on MI an adequate efficacy
measure upon which an approval could be based, is it possible, of
course, but that\'s not sufficient in answering the question. One has to
look at the totality of the efficacy information. One has to look at the
totality of the safety information.

If there weren\'t evidence here of major bleeds and hemorrhagic stroke,
that\'s going to substantially lower the bar for how much efficacy
information or what the level of efficacy benefit we have to see.

Furthermore, if you just told me we saw an effect on MI and that\'s all
you told me, and in fact, when I read the sponsor\'s document, the
suggestion is this is, in fact, evidence of benefit on morbidity and
mortality, and you would tend to think it\'s evidence of benefit on
morbidity and mortality, but if I then tell you, \"But, oh, by the way,
there isn\'t a mortality benefit,\" then does that somewhat reduce the
overall clinical relevance of an effect on nonfatal MI when there\'s no
overall effect on mortality, particularly in the context where I didn\'t
get it for free. I got it in the context of bleeding and hemorrhagic
stroke.

DR. WOOD: Well, not necessarily,. I might make the judgement that
preventing me having an MI was a worthwhile endpoint in itself, provided
my risk of mortality wasn\'t increased, which it is not.

CHAIRMAN BORER: Okay. We\'ll go on. Steve and Susanna had comments. Can
I ask you, Steve, in the context of your comment, can you begin to
answer Question No. 4?

DR. NISSEN: Yeah, I was actually going to do that, and, Alastair, I
agree with you. Prevention of MI is absolutely an approvable indication,
but I would ask you a question, and that is: how often has this
committee or any committee granted such an indication when there\'s not
a single trial in which it was the primary prespecified endpoint?

DR. WOOD: Well, carvedilol was approved where the endpoint was not the
prespecified endpoint. Isn\'t that right, Paul? I remember that from my
days on the committee.

DR. THROCKMORTON: Yeah, for mortality. The original approval of
carvedilol was a mortality endpoint. I think that was not prespecified.
Typically in other settings we have sort of said mortality is more or
less always primary, but that is exactly \--

DR. WOOD: Right. I remember the discussion then about having spent your
P value and so on. There was a non-primary endpoint, which resulted in
approval.

DR. NISSEN: But I\'m just wanting to point out to you that obviously,
while it may be an approvable indication, usually that\'s supported by
testing that question in a prospective way in a clinical trial where
that is a prespecified primary endpoint. We aren\'t given any data here
in which that was a primary prespecified endpoint. So we\'re now being
asked to render that opinion based upon analysis of secondary endpoints,
not primary endpoints.

CHAIRMAN BORER: How about Question No. 4 here? Do you want to?

DR. NISSEN: You know, it\'s interesting because I do think there
probably is an effect here, but I think it\'s very difficult to say so
from a rigorous statistical vantage point and, again, for the reasons
that all of you have said, that, in fact, it was never the primary
endpoint for any of these studies. The messages are kind of mixed.

There\'s an issue of women versus men. I mean, to me to say that the
available data support that, I would sure like to see at least one trial
where that was the tested hypothesis of the trial. That to me would be a
tremendous boon to making that ‑- to answering that question.

And you know, I don\'t know if Tom is going to offer it up, but I mean,
I\'ve made some mental calculations over whether that is, in fact, a
testable hypothesis, and it is a testable hypothesis in a clinical
trial.

CHAIRMAN BORER: Susanna.

DR. CUNNINGHAM: Actually I\'m not sure if I had a new comment, but I
just want to reiterate the issue that every time someone says preventing
MI, that we ought to say preventing MI in men because we don\'t have
that data for women.

CHAIRMAN BORER: Yeah. The data that exists from HOT are on page 15,
Table 15 where there\'s a nominal reduction in events with aspirin, but
not anywhere close to a significant change, statistically significant
change.

I\'m sorry? Still on four, yeah.

DR. FLEMING: I mean, what I\'ve found very helpful here was to go back
to the statisticians, the FDA statistician\'s review, and thinking
through the first three parts of Question 4, the Tables 9, 10, and 11,
looking at basically relative risks across all of the studies, and I was
answering Question 4 in two subelements, looking at what we know about
the effects on nonfatal MI and looking at what we know about the effects
on fatal MI, page 13 of 18 and 14 of 18 in the statistical review at the
end of our document.

So in Table 10, Table 10 is looking at nonfatal MI. The overall relative
risk that the statistical review achieved was 27 percent reduction,
somewhat smaller than the estimate of the sponsor, in part, through the
inclusion of the silent MIs in the HOT trial.

Certainly the PHS study is a huge, driving power to the strength of
statistical evidence, but what this analysis shows is that there still
is marginally significant evidence of effects on nonfatal MI, even
eliminating the HOT trial.

But in Table 11, looking at fatal MIs, the relative risk in the totality
of the data is .91, and that benefit is entirely due to the PHS trial.
If you remove that, the overall relative risk is 1.01. So in the absence
of the PHS trial, the overall effect on fatal MI is estimated to be
neutral.

Now, that doesn\'t mean it\'s appropriate to leave it out. The PHS study
is certainly one of the relevant contributors of information, but
what\'s interesting is this positive trend, the positive influence of
the PHS study is based on ten versus 26 fatal MIs. That\'s a reduction
of 16, but in that same trial if you\'re looking at the combination of
death due to sudden death, stroke, or other cardiovascular, it\'s 47/30
in the wrong direction.

So the only study that\'s contributing to a positive trend on fatal MIs
is overall not contributing to any positive net benefit. It\'s just a
cost specific benefit on one type that\'s offset by another.

So my overall sense here is the answer to this question is it\'s
certainly appropriate to look at the two components, that there is
evidence; there is evidence, I believe, that there is an effect on
nonfatal MIs. The strength of that evidence is heavily carried by the
PHS trial, but the overall nonfatal MI is very interestingly not
affected, and that is what I referred to earlier as part of a paradox
that I think is very relevant.

If you just tell me nonfatal MIs are benefitted, that\'s a different
story than if you tell me nonfatal MIs are benefitted, but it\'s not
translating into any kind of mortality benefit.

CHAIRMAN BORER: Okay. Doug, you\'ve asked us how to explain differences
in outcome among these studies. Is that a critical question for you to
have an answer to?

DR. THROCKMORTON: I think it probably is in sort of a larger context,
and maybe in the interest of time and things, I could \-- there\'s
another part to some of these questions that I haven\'t heard a lot of
discussion about.

One aspect of several of the questions, maybe not defined clearly
enough, was the thinking that\'s going behind the answers you\'ll be
asked to give in Question 6 and Question 7. How are you looking at these
five trials?

So sort of the first step was just are you going to put them together in
some aggregate fashion in a meta-analytic sort of way or is there
another way that you\'re going to think about them in terms of their
contribution to efficacy and safety? And just sort of ask everyone to
sort of comment on their own thinking.

Can you look at the trials and say, \"Nope. They\'re too heterogeneous.
Formal meta analytical approaches don\'t seem appropriate here, but
I\'ve got other ways that with large data sets I feel comfortable
understanding their outcomes, and here it is.\"

Just a little more conversation and I think that would capture what we
were at in the question as well.

CHAIRMAN BORER: Okay. I\'ll start off if you like, and then anybody can
jump in.

I would look at the totality of the data, but I\'d hope that there was
some reasonable consistency at least at the top level among the studies.
There is some consistency. There is some consistency. It\'s not the
consistency necessarily that the investigators expected when they began
the trials, but there is some consistency.

So I don\'t feel overwhelmingly concerned about combining them in a
meta-analysis. There are some rough edges though. There are some
differences. There are some heterogeneity. We\'re going to be asked
about subpopulations where in situations where there wasn\'t much data
to allow us to answer.

But in general, there was some consistency. I am concerned about
becoming too detailed in subanalyses. Now, having said that, it appears
that each of these studies did subanalyses to come to a positive outcome
since the primary analysis wasn\'t positive in most of the studies.

Nonetheless, there was a consistency in the subanalysis that turned out
to be positive. So I don\'t have an overwhelming problem with combining,
and even in doing a formal meta-analysis the strength of my confidence
in the outcome, however, is something that we\'re going to have to
define as we go through these questions.

So I don\'t have a problem with combining.

DR. THROCKMORTON: Okay. So sorry. Just to press a little more, your
consistency you\'re referring to there is in the results.

CHAIRMAN BORER: In the results, yeah.

DR. THROCKMORTON: And not \-- I mean there are sort of two parts to
consistency that you might think about for meta-analytic things. You
start out saying the trials themselves enrolled populations that were
similar enough to be poolable, and then after that you might in some
meta-analytic approaches say, \"And the results, in fact, give
consistent results.\"

Now, you gave me an answer to that last one. You think that the results
at least for some chosen endpoints were consistent enough to be
poolable. You\'re saying then \-- I\'m inferring the same thing about
the trial populations.

CHAIRMAN BORER: Right. You would be inferring correctly. The fact is
that these were heterogeneous populations, but in my view the
heterogeneity within these populations was not sufficient to negate the
capacity to look at them together.

DR. KNAPKA: But what about the difference in dose rate? I mean, I think
one of the things I remember in Statistics 101 is that when you\'re
planning your study, that\'s when you decide what statistics you do, and
now they\'re saying, \"Well, we\'ve got some data here. Let\'s go around
and find some statistics and make it look good.\"

Now, every single \-- most of these have different dosages, and that
could have some effect. It definitely would; different populations, too.

CHAIRMAN BORER: What do you think about the doses? What conclusions
would you draw, if any?

DR. KNAPKA: I don\'t know, but I think I haven\'t seen actual
statistics, but surely the dose rate was a major difference between
these, among them. You know, anything from 75 to 500, and surely that
has to be accounted for in the statistics, does it not?

CHAIRMAN BORER: I would think so, but as I recall the analyses that we
were presented, even though there appeared to be a gradient in terms of
response depending upon dose, in other words, it looked like maybe there
was a dose-response curve and that response was inversely related to
dose.

Nonetheless, if you looked at all of the subgroups based on dose, there
was a consistency qualitatively in the results. So I mean, it\'s still a
factor, but I\'m not as overwhelmingly concerned as I might be, given
that consistency.

Steve.

DR. NISSEN: I wanted to directly address Dr. Throckmorton\'s first part
of the question, and that is the populations, and I would point out that
if you look at, you k now, Slide 30 from the presentation, the range of
risk in the populations varies over a fivefold range from about a two or
three percent ten-year risk in HOT to about a 12 percent or so ten-year
risk in TPT.

So if you say you want to combine them, well, you\'re now talking about
a sixfold difference across the range of what the actual risk
characteristics of the patients were. That suggests that they were
pretty heterogeneous.

CHAIRMAN BORER: Just to play the devil\'s advocate, I would accept that,
but I think we have to remember what we\'re using to define risk. We\'re
using epidemiological data that are inherently somewhat limited, applied
to study populations. There\'s a difference, and, yes, it\'s fivefold.
Is that enough so that you would negate the similarities among these
populations?

I would say no, but you could certainly say yes.

DR. NISSEN: Well, no, I\'m not talking about estimated risk. I\'m
talking about actual risk. So \--

CHAIRMAN BORER: You mean event number, the incidence of events that we
saw?

DR. NISSEN: Yeah, I think. Isn\'t that right? Isn\'t there about a
fivefold or sixfold difference in the actual event rates in the patient
populations?

I think that\'s right, and somebody correct me if I\'m wrong, but I
think we\'re being asked to put together trials where there is a five X
difference in the actual event rates between the least risky trial and
the most risky trial, and to me it\'s not an estimate. That\'s an actual
fact.

CHAIRMAN BORER: Paul.

DR. ARMSTRONG: I think these populations \-- I mean, we\'ve heard that
the strength of these analyses is the diversity of the population. So if
we go back to the question can you group them vis-a-vis meta analysis on
a population basis, we have nearly half physicians, and I continue to
believe those physicians responded differently as it relates to
adherence and complained of side effects.

We don\'t have many ladies, as my colleague to the right has said. We
have a trial of hypertensive patients with concomitant calcium
antagonists which have sometimes been reported to exacerbate GI
bleeding. So I would think that these populations are heterogenous.

So that there\'s a strength in that, and we should explore the
diversity, but I\'m concerned about grouping them.

DR. THROCKMORTON: Do you have an alternative strategy to a sort of
standard grouping thing? We\'ve made it till almost four o\'clock
without saying \"Bayesian.\" But I mean, is this a time to start
thinking of, you know, four out of five sorts of things?

Are there other ways that, Paul, you\'d suggest that in the face of,
say, we concluded \-- say that it was concluded, in fact, that these
trials were so heterogeneous that formal pooling strategies weren\'t
appropriate. I\'m just saying that. Are there other strategies that the
committee might suggest?

DR. ARMSTRONG: I think there are, and that\'s when I\'d go and talk to
Dr. Fleming.

DR. HIRSCH: But before we talk to Dr. Fleming, taking the point brought
up by Steven again, yes. I mean, one way is to say that we have allowed
PHS to sort of drive this as the salient trial that initiated this
discussion, but in that risk continuum, it really is TPT that is germane
to the indication we\'re being asked to look at.

So first I think it\'s fine to pool and say overall the populations that
we\'re looking at are somewhat similar or diverse, and there\'s a
spectrum. Is the dose ranging acceptable within the range where the
clinical effect is known and reasonable?

Is there some signal across all of the trials of nonfatal MIs? Thomas
said yes, and then you subdivide out TPT, which is a medium risk
population, and you say, \"Is it still there?\"

And I think we can go around and ask that question, but I think it is.

CHAIRMAN BORER: Tom?

DR. FLEMING: Well, I was commenting earlier that with the heterogeneity
that exists between these two trials it\'s a plus and a minus. The plus
is that it does give you an opportunity to generalize or at least have a
sense as to whether or not the conclusions or the results generalize to
a broader population.

The negative or the minus is that you have much less insight about any
specific indication, and my biggest concern here is that you\'re right,
Steve. There is heterogeneity in the baseline rates. I computed them in
the control arm, and there\'s about a fourfold difference from the
lowest to the highest.

My biggest concern is the highest, which kind of stands alone, which is
TPT, is just barely into the range of what indication that we\'re being
asked to consider.

So there is some heterogeneity here, but a limitation here is that the
vast majority of that heterogeneity is covering a region that is low
risk, and so we\'re left with, by the Oxford analysis\' own indication,
one-eighth of the data in the region that we\'re being asked to really
consider here as moderate risk.

DR. HIATT: Just to clarify heterogeneity, is there any statistical
heterogeneity in the results from the FDA analysis? I don\'t recall
hearing that.

DR. FLEMING: I think the answer is no.

DR. THROCKMORTON: Dr. Le could comment.

DR. LE: For all MI, there is a statistical heterogeneity for all MI. For
nonfatal MI, there is not.

DR. FLEMING: And certainly one of the areas of heterogeneity is one that
Jeff had referred to at the very beginning of the discussion of
heterogeneity, which is heterogeneity in the nature of the effect that
we\'re seeing on various endpoints and specifically heterogeneity
between how that effect differs from the way the effect was seen in
secondary prevention, which is to my view the most important type of
heterogeneity. It\'s an inconsistency in the nature in the nature of
intervention effect that we\'re seeing in the primary prevention setting
versus the secondary prevention setting.

And when we do the subgroup analysis, even though we only have 12
percent of the data to do it in the moderate category, we are not
reassured. The problems are exacerbated by the fact that where we\'re
seeing lack of benefit, which is on the most important endpoints, I
would say, cardiovascular mortality and stroke, the results tend to be
even worse in the moderate risk group compared to the totality of the
primary prevention setting.

CHAIRMAN BORER: Go ahead.

DR. HIRSCH: Well, just heterogeneity has benefit if it allows the
incremental risk to be linked to sort of an appropriate dose response
benefit, and I think what we\'re not seeing here is heterogeneity
helping form us in that direction.

CHAIRMAN BORER: Okay. Let\'s move on to Question No. 5.

DR. FLEMING: One quick second.

CHAIRMAN BORER: Yes.

DR. FLEMING: Just because Susanna raised an important point and I was
waiting to respond until we got to it, which was Question 4.4, which was
looking at effect in relevant demographic subgroups. She raised the
issue, what about gender, and I would think it\'s worth at least briefly
looking at the FDA medical officer review, page 18, Table D5, where
essentially, as you know, we have unfortunately not nearly the evidence
we should have in females to be able to answer the question as to
whether the results that we\'re seeing apply equally to females and to
males.

And the largest portion of the data in the females does come from the
HOT trial, and so this is an extremely important analysis looking at the
relative risk estimate in the females compared to males for the all MI
endpoint where there is in this analysis a 20 percent reduction in males
and a five percent reduction in females.

I\'m going to jump ahead just because you\'re looking in the right
place. On the next page is some information relative to Question 5.1,
which is now saying what about safety in subgroups, and the safety
evidence in females on fatal bleeds and nonfatal major bleeds is on the
bottom of page 19 in Table D8 compared to that in males, and basically
from the risk perspective, it looks like there is a substantial risk in
both groups.

So the evidence that we have here is suggesting that females endure the
same risk that males endure, but are achieving much less benefit. Is
that proven? No, it\'s not proven, but if the only evidence that we have
is suggesting less benefit, it\'s certainly saying to me we\'re paying a
big price by virtue of the price that many of these studies didn\'t
collect information in females, and we\'re left with a disturbing
position here, which is maybe benefit to risk is the same in females as
in males.

The little information that we have at least raises a question as to
whether it might be less favorable.

DR. LORELL: Tom, may I ask a question while you are on this point?

Are you helped in any way or not helped in thinking about the analysis
you\'ve just done by pulling in the larger experience in the high risk
population that was done earlier this morning?

DR. PICKERING: A very good point. To what extent can we be reassured by
the high risk? My biggest concern is that the high risk is very
inconsistent with the primary prevention data that we have on many key
measures, and if in the data that I have I\'m seeing a lot of
consistencies, then I\'m willing to extrapolate in those settings where
I don\'t have data.

But where I have data, where I have data in the primary prevention
setting, there are some very inconsistent results compared to the
secondary prevention setting. So that makes me then much less willing to
extrapolate in settings where I don\'t have data in the primary
prevention setting using evidence from the secondary prevention setting.

CHAIRMAN BORER: Tom.

DR. PICKERING: On this issue of demographic subgroups, I want to bring
up the issue of hypertension again because I think in TPT, it was stated
that if the blood pressure was above 145, there was no evidence of
benefit, and in one of the subgroup analyses of the HOT trial, the
patients who had diastolics between 85 and 90 didn\'t benefit. It was
only the ones who are really very well controlled.

So I think this is a sort of murky issue, and we really don\'t know what
level of blood pressure if we\'re going to recommend this at all it\'s
safe to recommend aspirin.

CHAIRMAN BORER: Ron.

DR. PORTMAN: We also haven\'t talked all day about the issue of race,
and in the HOT trial, I mean, one of the only significant P values on
major cardiovascular events was in the African American, you know,
group.

DR. THROCKMORTON: But that\'s D4 in Dr. Polaya\'s (phonetic) review
also, page 18.

CHAIRMAN BORER: Is that sufficient for us to draw conclusions about the
effect of therapy in different racial groups?

DR. PORTMAN: Well, I\'m only pointing at the HOT trial. I haven\'t
really seen much analysis if you look at all of the other trials. You
know, at least in this booklet there\'s not much on African Americans
there. So I don\'t think you can.

CHAIRMAN BORER: There won\'t be either. Most of the trials were done in
Europe.

DR. PORTMAN: Right.

CHAIRMAN BORER: Okay. How about H?

DR. ARMSTRONG: Well, exactly. The elderly Oriental or Asian individual
who is worried about ICH, I was looking for stratification of that
information according to risk. I see it relative to efficacy, but not
safety, and it\'s critically important, I think.

Where is that data?

CHAIRMAN BORER: So, Paul, could you say what you\'re worried about
there?

DR. THROCKMORTON: Sorry, Paul. Many of us are concerned about the \--

DR. ARMSTRONG: Many of us who care for the Asian population where the
ICH frequency is much higher and the mode of exit from life more common,
there\'s a special concern in relationship to their management around a
host of agents, especially those that reduce the potential for clotting.

So I\'m keen to know what the risk of the things we\'ve been talking
about is relative to that population.

DR. THROCKMORTON: I confess I was thinking of the international
conference on harmonization when you said that instead of intracranial
hemorrhage. Thank you. Sorry about that.

CHAIRMAN BORER: Okay. Let\'s move on to Question No. 5. What do the
available data say about the safety of aspirin in primary prevention?
What do you know about?

Well, we\'ve just discussed this to some extent. Risks in demographic
subgroups, I think we\'ve discussed that.

Interactions with underlying disease, does anyone have any comment about
our knowledge or lack thereof?

DR. WOOD: Well, I think that was the point Tom was making, that there
may be an interaction with hypertension. is that right, Tom? I think
that was collected from \--

CHAIRMAN BORER: Any other important potential diseases that might
interact in a way that we want to know about and don\'t know about?

DR. THROCKMORTON: Yeah, actually that\'s pretty much a particular thing
we were interested in here, and it goes back to previous discussions
where we\'ve come before the committee and the committee has said, \"You
guys haven\'t even thought to worry about leading risk perioperatively,
for instance.\"

So if there are drug or disease interactions or other demographic
interactions that you believe risk to the level beyond those that were
sort of statutorily obligated to be concerned about gender, race, and
ethnicity, please, it would be very useful to identify those for us.

Well, I mean, there are 20 million people in this country with chronic
kidney disease, a CKD, and they are considered in the highest, you know,
cardiovascular risk group, and obviously we\'re going to have to worry
about GFR when we talk about aspirin as to what level we can safely give
aspirin, but I think that issue needs to be addressed.

And just since I have the microphone, in concomitant drug issues, I\'m
concerned, again, as a pediatrician, kind of a naive question, but when
we talk about risk and moderate risk, is a patient who is on an
antihypertensive and normotensive, on a statin and normocholesterolemic
at a moderate risk? Obviously he had it initially, but now he\'s
treated, and so does he warrant aspirin or not?

CHAIRMAN BORER: Good question.

Blase.

DR. CARABELLO: It\'s not clear to me whether diabetes is simply off the
table by virtue of being high risk to begin with, and do those patients
automatically constitute a high risk group that \--

CHAIRMAN BORER: Not according to current labeling.

DR. CARABELLO: Well, then I think that\'s a pretty clear area to think
about.

CHAIRMAN BORER: Steve.

DR. NISSEN: Just to be aware of it, there has been some data presented
that suggests that giving ibuprofen with aspirin may neutralize its
benefit. So there would be some issues there since both agents are
available over the counter, and I don\'t know the extent to which others
think that that is convincing or compelling evidence, but I know there
is some evidence about mixing and matching over-the-counter analgesics
that may take away the benefit of aspirin, and we have to be careful
about that.

CHAIRMAN BORER: Yes. Correct me if I\'m wrong, Doug, but you know,
several issues have been raised: kidney disease, concomitant
medications, et cetera, et cetera, about which clearly we don\'t have
sufficient data to make statements. We can only raise concerns.

Unless we think it does, that by itself wouldn\'t preclude us from
determining that in some population that we could define it would be
appropriate to use this drug and the labeling could talk about all of
the things we don\'t know if we came to that conclusion; is that
correct?

DR. THROCKMORTON: I think in general that is correct. You might say, for
reasons that I\'m not saying we\'re in this situation; you might say
this demographic is so critical it\'s going to be entirely used in women
and all of the studies have been conducted in men. You know that really
has to be addressed before you can think about approving it for this
particular indication or something like that.

Short of that, there have been analyses in a lot of these subgroups. We
haven\'t talked about them today. I don\'t think the FDA conducted any
formal analyses of several of them.

What I\'m hearing is concern, interest in information, examination, not
that so critical aspect to it. If I\'m wrong, it might be worth
clarifying, but that is about right.

CHAIRMAN BORER: Okay. We\'re up to Question No. 6, and for this one, we
need specific responses from each committee member. We will start with
Tom and go around that way and come back up.

Question No. 6: should professional labeling for aspirin recommend its
use for primary prevention of MI? And if so, et cetera, et cetera.

Tom.

DR. FLEMING: Well, in trying to provide some of the logic for the
response I\'d provide, let me just quickly run through a few issues that
we\'ve already discussed in the previous questions that have led up to
this.

Starting from the secondary prevention setting, using, for example, the
Oxford presentation that we saw today, there is a strong and I would
call consistent signal that\'s coming across the key traditional
measures that we would look at, nonfatal MI reduced by 33 percent,
stroke by 20 to 25 percent, cardiovascular mortality by ten to 15
percent. Event mortality in some of the settings is significant, and all
of these other measures are significant.

So there is, in fact, a clear message of benefit in the setting of
secondary prevention. Not surprisingly to me, in secondary prevention,
in secondary prevention, which isn\'t what we\'re talking about today,
but I\'m leading up to where we\'re going to be, in the five trials on
primary prevention it\'s not surprising to me that these studies had
targeted the same global endpoint, two of them essentially focusing on
CV mortality and the others basically look at CV mortality and nonfatal
MI, nonfatal stroke.

These studies predominantly, certainly those that looked at CV
mortality, the BDT and the PHS study, fell well short of showing benefit
on that. In fact, suggested lack of benefit on that measure.

The other three that we\'re looking at, the aggregate all vascular event
showed positive trends. We\'ve talked a lot about the fact that it\'s
important to look at these individual studies being true to how they
were designed as we focus on what we can say, but in any clinical
setting obviously it is important to learn everything that we can, and
so we do appropriately look at some level at aggregate analyses, and the
meta analyses in that context do provide us some additional insights,
although one has to be extremely careful when the primary endpoints
aren\'t positive and then we can look in some domains and see benefit.

One has to be cautious about the overall interpretation, particularly
when those other domains are less clinically compelling than what the
primary endpoint was, which is very different from the carvedilol
example.

Back on January 7th, at the Cardiorenal Advisory Committee we had a very
long discussion about what strength of evidence can we put on secondary
measures, and my recollection of that long discussion was, well, if the
secondary measure is survival, that is so unique in terms of its overall
clinical relevance that you still pay a price, maybe an order of
magnitude greater strength of evidence you would need, but survival is
something that can still be persuasive in a secondary endpoint.

My concern is that we\'re going a bit in the other direction. We\'re
going from an endpoint that certainly had important mortality elements
to it, and we\'re moving away from that to an endpoint that is nonfatal
MI.

Well, what do we know? What we know, I believe there is substantial
evidence within the context of these five trials to indicate a level of
benefit on nonfatal MI, some estimates 32 percent, some estimates 23
percent. By my calculation that translates in the context of these five
trials, if you look at these five trials which are predominantly in a
lower risk group than what we\'re asked to focus on as a moderate risk
group; by my calculation we get about five events prevented over a
five-year period. That\'s what the meta analysis of these five data
would tell us about nonfatal MI.

What about fatal MI? Does nonfatal MI in some sense correlate or
translate into some benefit? Probably at a level that can vary, but we
surely hope it does, and I believe part of the overall clinical
relevance of a reduction in nonfatal MI is a subtle imputation we make
in our mind about what that means about death and fatal MIs.

Well, in these data in the PHS study we have the most encouraging
evidence, ten against 26, but for the other five studies, the evidence
is there\'s no reduction in fatal MIs, and as I had mentioned earlier,
what\'s concerning to me is in the one study PHS that did show a fatal
MI positive trend where there were 16 less fatal MIs, there are 17 more
fatal sudden death strokes or other cardiovascular events.

So even that trial that was sort of the one we hold out shows no net
benefit in the evidence in hand in overall fatal cardiovascular events.

Well, globally what about overall cardiovascular death and what about
stroke? The evidence that we have in hand is very informative. It may
not be conclusive, but it\'s very informative. While we have about 1,000
nonfatal MIs in these five trials, we have 650 nonfatal strokes, and we
have 1,000 total cardiovascular deaths.

So those latter two measures show relative risk estimates that are just
about unity, slightly positive on mortality, somewhat negative on
stroke, with however a substantial amount of evidence when you look at
the totality of these studies. A lot more than was known to the PHS data
monitoring committee at the time that they looked at their data where
they only had 160 cardiovascular deaths to look at, we have nearly
fivefold that many.

And essentially with this amount of evidence in hand, what we can say is
there\'s fairly substantial evidence that we have (a) lack of benefit on
these measures and (b) at a level that\'s inconsistent with the
corresponding level of benefit that we saw on those measures in the
secondary prevention setting, and looking in the other setting, we can
rule out a 25 to 50 percent harm, but we can\'t rule out a 20 percent
harm. There is, in fact, still some modest harmful effect that these
data remain consistent with on cardiovascular mortality and on overall
stroke.

So as I look at all of this and kind of put it together, what do we
know? Well, from these five trials that are focusing on an early or low
risk primary prevention setting, by my best estimate we\'re preventing
for 1,000 people over five years, we\'re preventing five nonfatal MIs in
this setting.

In turn, it\'s not translating into any beneficial effect on stroke or
any beneficial effect on cardiovascular mortality. That in its own right
is of some clinical relevance. Five prevented nonfatal MIs is of some
relevance. It is, however, to my way of thinking concerning when there
isn\'t any suggestion that that\'s translating into any beneficial
effect on stroke or on overall mortality.

And there is a price. Hemorrhagic stroke is estimated at one excess
event and major bleeds at two to four excess events, and so in the
context of this particular set of five trials, I wonder why that is a
clear benefit.

Now, the issue is can we extrapolate. Can we take these data, however,
and extrapolate to the setting that we\'re really asked to focus on,
which is moderate risk.

Well, the first issue is the moderate risk group is only 12 and a half
percent of the totality of these data. On the one hand, we\'re asked to
use this as a basis of providing extrapolation to the extent that we can
argue \-- and it has been argued \-- that there will be a prevention not
only of five events in five years for 1,000 people, but this could be as
much as 14.

But this is an extrapolation on a limited amount of data, and this same
evidence if we look at stroke and we look at cardiovascular death is
suggesting in the moderate group that results are worse than what I was
talking about when I said it didn\'t look like there was harm. Numbers
are small, but there\'s an estimate of a 78 percent increase in
hemorrhagic stroke, a 33 percent increase in stroke, and in vascular
deaths, whereas it\'s six percent benefit in the complement, in the low
risk group, it\'s four percent harm in the group that we\'re targeting.

Now, we\'re asked, however, look at these data with extreme caution
because this is a small subgroup. I acknowledge that, but wait a minute.
We have to be consistent. This is the same small subgroup upon which we
have to base our extrapolation that this five prevented events if you
looked at it in a moderate setting would be 14 prevented events.

And so one of the issues here that I struggle with is do we consider
silent MIs. Well, I\'m not a surrogate endpoint person. Any of you who
have known me on this committee would know that well, and in a certain
sense, I would consider silent MIs to be a level of a surrogate less
clinically relevant in this continuum.

But when I see nonfatal MI trends that aren\'t translating into other
domains of benefit and then I see the single study that looks at the
domain of silent MIs, and it goes 75/57 in the wrong direction, then I
begin to wonder whether technically speaking even our measurement of who
had an MI or nonfatal MI or not is not capturing the essence of the
overall cardiovascular influence that we\'re having on these
individuals.

And it leaves me in the end with a sense that it just well may be that
there\'s a positive benefit to risk if I can target the right
population.

Actually I do think the question today isn\'t does aspirin work. We know
it works, and we certainly know it works in a net benefit to risk
positive sense in the secondary prevention setting.

The question is: can we go back now to a primary prevention setting and
target a high enough risk group where the effect that we have is going
to offset the known and constant negative effects, and what we\'re left
with here is evidence that suggests that the effect that it has is
clearly not at all parallel to what the effect is in the secondary
prevention setting, in those elements that are most important to the
patient.

Oh, I didn\'t vote.

CHAIRMAN BORER: Right.

(Laughter.)

DR. FLEMING: So my vote is going to be to Question 6, it\'s going to be
no, and I\'ll have a comment in 6.2 as to what additional evidence we
could get to answer the unknown questions.

CHAIRMAN BORER: Why don\'t you go ahead and give that answer now?

DR. FLEMING: In 6.2?

CHAIRMAN BORER: Six, point, two.

DR. FLEMING: Well, as I said, my vote of no is not a vote that is based
on my conclusion that we\'ve established lack of favorable benefit to
risk in this setting. It\'s rather based on the fact that there is a
paucity of data in truth in the setting in which we\'re really being
asked to make a judgment, and what we have to extrapolate is from a
primary prevention setting where the overall benefit to risk is five
prevented cases for one additional hemorrhagic stroke and two to four
additional major bleeds, and that doesn\'t translate into positivity to
me.

And yet my own sense is if we did a trial that would, in fact, truly
target these people who were at moderate levels of risk and we, in fact,
had sufficient duration of follow-up that we would, in fact, be able to
see whether we just didn\'t look long enough.

And if we build in an even distribution of males and females so that we
can actually understand what\'s happening in the females, this is, in
fact, I think, a doable study, and just very quickly from some crude
calculations, if we were doing a study that would have seven years of
follow-up \-- and I say, in part, seven years of follow-up to give
aspirin its best shot, to give it an opportunity to see whether or not
these early, nonfatal MIs are going to translate into something that is,
in fact, favorable in some of these other domains, such as other
cardiovascular or vascular mortality events.

Essentially it?s a study that would require 1,500 events, and so
approximately 15,000, and so, in fact, a study that\'s of the size of
what we\'ve heard reported today both in terms of these five and what
we\'ve heard from other investigators that under contemplation, and
essentially what that would do is it would relieve us from having to do
as the Oxford analysis indicated an extrapolation of the data using a
fairly small subgroup into being able to actually have the direct
population that we care about and to have them followed for an adequate
duration of time; that if there is benefit beyond a nonfatal MI, we\'ll
have greater sensitivity to detect it.

CHAIRMAN BORER: Alan.

DR. HIRSCH: I want to go on record and say we\'ll never sit to Tom\'s
right again when you call a vote.

It\'s hard to follow that, Tom.

First, I want to answer backwards. Actually that\'s very much the study
that actually needs to be done. Otherwise I feel like we\'re dealing a
vote in the absence of unambitious data, and this is so important. I
believe that one could go that way and perform that ethically.

I expected to come to the room and be overwhelmed by the positivity of
the data, by consistency of effects, by subgroups that clarified the
relative risk reduction, and that could be applied to this medium risk
population for which the application was made, and I\'m impressed by the
relative paucity of data that actually helps me feel strong in the vote
I\'m going to give you in three more sentences.

But I do believe that there is enough signal that is sort of generated
iteratively across the studies in the benefit of nonfatal MI. I think we
see that. I think we have spoken to it across the panel today.

One word. I actually am troubled by the nonfatal, silent MI Q-wave
infarctions. To me that\'s no surrogate endpoint, and from what I know
of cardiology, there should be clinical impact down the road if we
followed patients long enough.

I think that\'s the one trial that was designed correctly and for which
we actually gain the greatest amount of information, and I would caution
us and those who interpret our panel vote to think clearly about that.

I think there is adequate information to recommend aspirin to prevent
nonfatal MI in, I guess, primary prevention, but again, riddled with
caution, and maybe if I can jump to 6.1.2 with that caution or 1.1 and
1.2, I can\'t quite answer the patient population question, and I\'m
looking for more discussion because I still don\'t really know what
population achieves that benefit.

So I\'m going to dodge that and look for more erudite answers from my
counterparts.

The dosing I think was no issue at all really. I think we have from 70
milligrams to 150 to 325, adequate information across the trials to
suggest benefit on the nonfatal MI outcome.

So there.

CHAIRMAN BORER: Tom.

DR. PICKERING: I guess if the question was \-- the way the question is
phrased, primarily prevention of MI, I guess I would say yes, but in
this particular population I think the issue is not just the prevention
of MI, but we have to look at all vascular events because that also is
at high risk for stroke.

And overall I would say the net benefit, not just looking at MI, is so
small that I would not support it. I\'m still particularly concerned
about the patients with uncontrolled hypertension who have not really
been addressed in these studies. I mean what evidence we have is that
they don\'t derive benefit, and whether we like it or not, most of the
hypertensives who are in this medium risk group are not adequately
controlled.

DR. THROCKMORTON: Sorry, Tom. I don\'t want to put words into your
mouth, but so you\'re saying that you are unable to define the
population that you believe an effect on nonfatal MIs is adequately
demonstrated? I\'m just trying to understand.

DR. PICKERING: My vote would be no because I don\'t think, you know,
just nonfatal MI is really the right question.

CHAIRMAN BORER: Do you want to talk about the studies that might be done
to provide compelling evidence?

DR. PICKERING: Well, I think I would like to see more evidence in
patients who have systolic blood pressures that are, say, above 145,
which is a large proportion of the hypertensives.

CHAIRMAN BORER: Beverly.

DR. LORELL: I do think the evidence in its totality supports the use of
aspirin for primary prevention of nonfatal MI, and that\'s how I would
modify that question. I think Tom has eloquently addressed the fact that
the data is ambiguous to neutral on prevention of fatal MI and all cause
mortality.

I guess I am more persuaded than I think Tom was. I couldn\'t quite tell
about Alan\'s thoughts, that there is a continuum at risk. I think that
Tom\'s estimate of benefit is probably and maybe appropriately on the
conservative end because the trials we have to look at looked at low
risk patients for the large part.

And I guess that was not quite a question that you asked, but I do buy
the notion of a continuum of cardiac risk and the ability to get some
handle on that with the measures that we talked about this morning.

With regard to a study, I think it would be profoundly difficult in the
United States in 2004 to do any study except revisit low risk in those
patients who sit right on the border of low and moderate risk. I think
the thing that is driving me in part to make my vote the way it is is my
concern that in the United States not only are we not treating these
patients on the border of low and moderate, but that we\'re failing to
treat moderate and high risk patients who have not yet had an event.

We have to wait for something that is life threatening to occur to the
individual patient before we can treat them.

In terms of defining the population to whom one might target this, I
think that here one does have to be conservative and to go back to the
characteristics of the patients included in these trials, and including
what their exclusionary criteria were for systolic hypertension and for
GI bleeding risk.

But I think we do have some data from these low risk population about
what levels of patients with hypertension we might want to caution
inclusion or not inclusion.

And finally, like Susanna, I am troubled about the issue of women. I
think this becomes a matter of philosophy rather than science. My vote
would be to be a lumper rather than a splitter.

My suspicion is that \-- and I\'m not 100 percent sure about this \--
that with further data analysis of the enormous Women\'s Health
Initiative, there may, in fact, come some additional informative data
about aspirin/no aspirin with regard to cardiovascular events from that
huge database.

But I think that summarizes my answer to that question.

CHAIRMAN BORER: Doug, can I ask for a clarification? Your question
specifically says recommend its use for primary prevention of MI.
Beverly has modified that to say nonfatal MI. Do you need \--

DR. THROCKMORTON: Yeah, I think what Beverly did was modify an answer
for both fatal and nonfatal, and that seemed an appropriate
modification. If people felt all types of MI, then that\'s certainly one
answer you could give us: a blanket yes.

If you think it\'s nonfatal, then like Beverly did, I think that would
be useful.

DR. LORELL: Yeah, let me even be clearer. I would say no for all MI
because I think the answer Tom eloquently described what we know about
fatal MI, and I think we also clearly saw today we don\'t know enough
about silent MI. So I think, you know, I would say no for all MI, but
yes for nonfatal MI.

DR. THROCKMORTON: Alan, do you need to clarify your remarks? You were
the other person that\'s voted yes to now.

DR. HIRSCH: If the question were on all MIs or fatal MIs, I would vote
no, and it\'s yes to nonfatal MIs.

CHAIRMAN BORER: Steve.

DR. NISSEN: Well, I\'m going to choose not to cherry pick the data for a
specific endpoint. You know, for a patient it doesn\'t matter how you
get dead. You\'re either dead or you\'re alive, and so I, like Tom, want
to look at this as a totality. I don\'t like the way the question is
worded because it really is a question for me of whether this label
ought to be extended.

And once you extend it, you\'ve got to take everything that comes with
it. It means benefit on MI but maybe some hazard on stroke, and I\'m not
so sure about total mortality.

So, you know, to me it\'s really a question of the totality of benefit.

Now, let me just point out something to the rest of the committee. We
are being asked to opine on the basis of a group of trials that were
largely negative on their primary endpoint. The minute you start to go
there, you know, we\'re in some trouble. I mean, it\'s a very slippery
slope when you try to interpret data from trials where they were
negative on their primary endpoints.

So we\'re going to pick some things out from the trials that look pretty
good for a drug, and we\'re going to choose to emphasize the benefits
from those secondary analyses, and that in and of itself is potentially
hazardous. The next thing we\'re going to be asked to do is we\'re going
to be asked to extend that information to the moderate risk group for
which the data from those five trials only contains about 12 and a half
percent patients in that group.

And so now in addition to taking trials that were largely negative on
their primary endpoint, you want us now to take and extrapolate that to
a group that they weren\'t even intended to study, a group with a
different risk category, and so that has huge statistical risks
associated with it.

And then there\'s the question of potential for harm. Now, I\'m more
familiar with the statin world since I tend to operate in that area, and
I can tell you we have all been struck by the fact that over the last
few years there seem to be a rising number of patients in such trials
with stroke as an endpoint compared to MI. The ratio of MI to stroke as
patient populations get older, you know, stroke is an increasingly
important endpoint and particularly among older patients and among
hypertensive patients I worry about hemorrhagic stroke because I know
what the consequences of that are, and it is a far worse outcome than a
myocardial infarction for most patients. Most MI patients we can get
through it. If they have a little heart failure usually it\'s treatable.
We\'ve got very good drugs now for that, but once you\'ve had a stroke
and you can\'t speak and you can\'t walk, your life is never the same
again.

And I\'m not so sure we\'ve excluded the possibility in this population
of a moderate harm in that population. So that influences my thinking.

The fourth point is, you know, I\'ve spent a lot of years thinking about
silent MI and I went through this gritting of teeth over whether MIs
after PCI were important or not, and I looked at the totality of data,
and I\'m convinced that a myocardial infarction is probably a myocardial
infarction.

If you lose myocardium it\'s not a good thing, and so when a trial
prespecifies silent MI, then that\'s the endpoint I\'m going to hold
that trial to, and one of the key trials here did, and it certainly did
go in the wrong direction.

Finally, does it make sense? Are primary prevention patients different
from secondary? Is there a pathophysiological reason why we might expect
this to be different?

And the answer is you bet there is, that once you rupture plaque in the
coronary, the underlying pathophysiology of what\'s happening may well
be entirely different from a patient who has never ruptured a plaque in
a coronary or in a middle cerebral artery.

And so there is a pathophysiological reason to expect these patients are
different.

Number six, could I wrote a label? Do I have enough information here to
write a label that would describe how one should use these drugs?

Well, given all of the extrapolation one has to do, I have no idea what
to say about women, the elderly, people with concomitant hypertension.
How do I write a reasonable or meaningful label for such a use?

And so what I finally come down to is that if in a 55,000 patient meta
analysis you can\'t come to a definitive conclusion, if there is a
benefit it\'s got to be pretty small, and therefore, in order to prove
it to my satisfaction, I want a prospective randomized trial because
that\'s the level of evidence that this committee is usually asked to
opine about, and in the absence of data I do not agree with Beverly. I
usually do, but I don\'t here, that I think that when we can\'t come to
a solid conclusion from a 55,000 patient meta analysis, we need a
prospective trial, and the NIH or other organizations, as they did in
the ALLHAT study involving some 42,000 patients over seven years, we
could answer this question. We should answer this question, and if it
were a positive study, I would be the first one to line up and give my
vote to giving the label.

So I vote no.

CHAIRMAN BORER: Dr. Knapka.

DR. KNAPKA: Okay. I guess I\'m in a little strange position here because
I am a scientist, a nutritionist, and I\'m also a heart patient. I am
one who had a silent MI at some point. That\'s why I don\'t know when it
was.

And I think in those days I know I had hypertension. My father died at
age 34 with heart disease. So I was really at high risk, and I think I
would have welcomed it if someone would have told me, \"Look. If you
take aspirin, it will probably really help you.\"

So as a scientist I would vote no because I agree that the data is
really pretty weak. I think the analysis is bad, although, you know,
lumping all of this together I still maintain there\'s a lot of
differences.

And as a scientist I\'d probably vote no, but as a heart patient and
I\'m supposed to be representing the patients, I would probably say yes,
vote yes with some stipulations.

Number one, only high risk patients should be \-- for people at high
risk as defined this morning, high risk, and also that there be some
follow-up, that people are not just told to take aspirin and never
followed. Maybe quarterly they have a blood clot, draw a blood clot in
time to try to at least help to prevent some of these others, the
bleeding, the stroke, et cetera.

So I think it probably isn\'t clear. As a scientist, I say no. As a
patient, I say yes with these stipulations.

DR. NISSEN: Does he get two votes or one?

DR. THROCKMORTON: Unfortunately we\'ll ask you to integrate your.

DR. KNAPKA: Give me one half.

DR. THROCKMORTON: I think we really do need to ask for a yes or a no,
and your other comments are taken into account. But a yes or a no.

DR. KNAPKA: I would say no.

CHAIRMAN BORER: Blase.

DR. CARABELLO: Well, I certainly agree with Steve that there are plenty
of reasons to suppose that primary and secondary prevention could be
quite different, and after you\'ve had an MI you begin the cascade of
inflammation that leads to yet further disruption of caps and more
disease down the road. So I could see why the two things would be
different.

My biggest concern and the reason I think I want to vote today yes is I
don\'t believe we can do the trial that Steve thinks we can do. Every
guideline organization has come on line is saying that you should give
this drug. I have never heard so much public comment in the brief two
years I have been on the committee as we had today for incredibly
influential people speaking for the drug\'s use, and I think in that
background it would be very difficult to ever do the trial that we\'re
talking about doing to prove whether or not this stuff works.

I would say yes for nonfatal MIs in men. I don\'t see any way of
labeling it for women where it appears that the risk of hemorrhagic
stroke is increased and there\'s very little evidence of benefit. We
just don\'t have those data.

DR. THROCKMORTON: Sorry. I need to ask you to fill it out. So primary
prevention for MI, which was the thing the sponsor was seeking for,
which would be total MI, fatal and nonfatal. I need to ask you to
comment on that as well.

DR. CARABELLO: I would say yes, but in men.

DR. THROCKMORTON: Yes to fatal and nonfatal MI.

DR. CARABELLO: Yes.

DR. THROCKMORTON: And then populational comment?

DR. CARABELLO: Would be men, and I don\'t think you can do the study to
hack it out.

CHAIRMAN BORER: John, you cannot vote, but you can comment. So let\'s
hear what you have to say.

DR. NEYLAN: Great. Thanks, Jeff.

It strikes me how voracious we are when it comes to data, and I think
about this drug and there\'s some, I guess, quarter million patients in
which it has been studied now low these many decades, and still I have
to agree as I sat through this day\'s session that there is much we
still don\'t know, and so I certainly listened very intently to Tom
Fleming\'s overall exigencies of the status of the statistical knowledge
and lack thereof.

That said, I think looking at this new cohort of some 55,000 patients,
it strikes me that it would be impossible to see this cohort not
included within the professional labeling of this drug within the
clinical studies section to speak to the in general trend of direction
in which the composite endpoints, at least four of these five studies,
have brought us.

There is, I think, good reason why professional societies have taken
these data and although they are not ironclad and absolutely foolproof,
nor can they ever be, have made the good faith efforts to drive the
clinical practice forward with the intent, of course, of reducing
cardiovascular morbidity and mortality.

And that\'s something I think that even as we adhere to the rigors of
our science we still have to keep in mind. There is a public health
safety issue here. Sure, we can sit back and say the definitive trial
has not yet been done and we can say, all right, let\'s prospectively
devise one, but I am in complete agreement with several who have opined
so far that actually in today\'s society and today\'s world that that is
not really a practicality at least for most patients with moderate risk.

While we could design a theoretical trial that would satisfy statistical
number and so forth, I don\'t believe that many IRBs nor many patients
would actually agree to that kind of a study.

As we look to where therapies are moving now, so many of them are now
including aspirin as part of the baseline strategy. That train has left
the station. So my answer is that although we don\'t have all the
answers, I do believe there is a way to craft a label inclusive of the
data coming out of these very important clinical trials that could guide
clinicians in the treatment of both fatal and nonfatal myocardial
infarction.

CHAIRMAN BORER: Bill.

DR. HIATT: It\'s my first meeting. Do I have to vote?

(Laughter.)

CHAIRMAN BORER: You\'ve got to vote.

DR. HIATT: As I look at this data coming in, I think Dr. Fleming
summarized my impressions before all of the discussion. Although I would
differ slightly and think you might have presented the worst case
scenario for the limited component of the data, which is the nonfatal
events, and it may be preventing five; it may be preventing 14. So I
think the point estimate there may be somewhat variable.

I\'m convinced it doesn\'t prevent fatal events, and I\'m uneasy about
its effect on safety, and it\'s not just bleeding, but also strokes.

So my struggle is trying to get what was actually in the label which is
defining this intermediate risk group using Framingham to match the
data, which I think is fairly consistent in terms of the nonfatal MIs in
the population study, which don\'t exactly match the label that\'s being
proposed; that in these relatively lower risk patients ironically it
appears to consistently reduce the risk of nonfatal MI.

And so in that context and in the caveat that it only applies to men
that match the inclusion/exclusion criteria that define those trials,
can the label actually match the data? If it can\'t, then I would vote
no, and if it can, that it\'s really clearly disclosed, that there\'s
really very limited value of aspirin in the totality of treating
cardiovascular disease prevention limited to a subgroup of people with
certain risk characteristics that are defined by a largely male gender,
et cetera; that in that context the signal, I think, is robust enough to
support it.

CHAIRMAN BORER: So give us a summary.

DR. THROCKMORTON: So, again, without trying to put words into your
mouth, what I\'m hearing is that you can \-- I\'ll change it around a
little bit \-- you can define that a treatment effect exists as regards
nonfatal MI. The precise population is sort of another issue, but you
believe a population could be defined as relates to the trials that make
up this database.

DR. HIATT: Yeah, I think the data support a treatment effect narrowly
defined by the population on that one particular endpoint called out in
isolation from everything else.

DR. THROCKMORTON: And just to be clear then, so nonfatal MI, you believe
that those evidence exist. Fatal MI?

DR. HIATT: No.

DR. THROCKMORTON: Okay. Again, I don\'t know. I would interpret that as
for the question. The question specifically is for all MIs, which is
what the sponsor was seeking prevention.

DR. HIATT: Oh, I\'d vote no for that.

DR. THROCKMORTON: You would be saying no, but that nonfatal MI was
something you thought the data existed for.

DR. HIATT: Correct.

DR. THROCKMORTON: Okay. Thanks.

CHAIRMAN BORER: Alastair.

DR. WOOD: Well, I think it\'s worth thinking about why we even think
about labeling, and you know, as you sit here sometimes it\'s easy to
imagine that this is something that comes down from the mountain on
stone tablets. Presumably the purpose of amending a label is to better
inform physicians about how to use a drug, and so one question to ask is
is there an opportunity here to better inform physicians about how to
use aspirin, and I think the answer to that is unequivocally yes.

And I think that obligates us to change the label, therefore, and make
changes in a number of directions.

The first one and the place I\'m going to start, which is sort of
ass-backwards in some ways, is that it\'s certainly important to change
the label to inform physicians about the kinds of patients you ought not
to be treating with aspirin. In other words, given the potential for
risk, it\'s certainly worth informing physicians better as to whom it is
improbable that the benefit will exceed the risk, and we can define that
however you want, but it\'s certainly somewhere between five and six
percent, I guess, or somewhere around that number.

The second thing is in the same light. I was working here on my Palm
Pilot just a minute or two ago just running through the Framingham
algorithm that everybody has now, I guess, on their Palm Pilots or
whatever. It\'s worth remembering you get a big hit in risk for having
your blood pressure over 140. So you don\'t necessarily want to put
yourself into the high risk group by having your blood pressure over 140
because, like Tom, I\'m not persuaded that that\'s a group I would
necessarily want to be treating first.

So I think there\'s a clear reason to improve the information that\'s in
the current professional labeling for aspirin, and do I believe that the
current data support and indication for a nonfatal MI? Yes, I do
actually, and I think there are more patients in these studies than in
any study that we\'ve ever seen presented at an advisory committee that
I\'ve been on, and these studies also include more women and more of
every other group than any study we\'ve ever seen presented.

You know, we can bemoan the fact that there aren\'t enough women or
there are not the same number of women as men, but, God, you know, when
we see studies for NDAs that have 2,000 people in them, they don\'t have
this number of women. They don\'t have this number of people.

And so I think that the data do exist to suggest it should be approved
for nonfatal MI, and I also think that I don\'t agree with the way the
question is phrased. Should professional labeling for aspirin recommend
its use for primary prevention of MI? Well, there are two ways to
approach that. You can tell people what the data as they exist say. That
doesn\'t mean to say you have to recommend it. You can that meta
analysis of the 55,000 people or whatever it is show a benefit in the
treatment of nonfatal MI, and I think that\'s worth informing physicians
about.

That\'s not necessarily the same as a recommendation, and we\'ve done
that lots of times before where there are didactic statements made and
labels that talk about subgroup analysis that appear to show risk or
benefit or whatever that wouldn\'t stand up to rigorous analysis because
they were not primary endpoints.

So I would vote in favor of an approval for a limited indication, and
I\'d strongly recommend amendment of the label that allows physicians to
be informed of the current state of the data.

CHAIRMAN BORER: So that\'s a yes for nonfatal MI. How about all MI?

DR. WOOD: No.

CHAIRMAN BORER: No for all MI with clear information in the label about
what actually is found.

DR. WOOD: And some caution about just using \-- that\'s not been
discussed actually in the meeting at all, but these scoring systems all
include blood pressure as a heavy weighter for the risk, and I\'m not
sure that I necessarily agree that these risks can be uniformly
assessed.

CHAIRMAN BORER: Ed?

DR. THROCKMORTON: We\'ll come back to that. I very much want to hear
comments around that. That was part of what we were looking for in the
next question.

CHAIRMAN BORER: Ed.

DR. PRITCHETT: Well, this is kind of a remarkable situation for me to be
in because I was here at the October 6th, 1989 meeting when we
considered this question with far less data available to us, and at that
meeting I voted \-- I answered this question yes, and today I\'m going
to answer it no.

And I think before you all run back to Duke and say that Ed has lost his
mind, let me try and explain where I\'m coming from. One is I think that
it\'s not something that has happened to the data. It\'s probably
something that has happened to me.

One is that I\'ve developed a health skepticism about the sort of
exploration of data sets after the primary outcomes fail or even when
they\'re positive. So I\'ve become much more skeptical of the
interpretation of data within clinical trials.

And the other thing is that I\'ve developed almost a reverence for the
FDA standard for approval. Frankly, I\'m a cardiologist, and I take an
aspirin every day, and I have since I was 40 years old. I recommend that
my patients do this. I applaud the recommendations of the American Heart
Association and the American College and Preventive Health Services Task
Force. I support all of them.

I do not think that the evidence presented to us meets the standard that
the FDA has required of us in the past or still requires of us. I don\'t
think it\'s there.

So the answer \-- if the question is do I think that aspirin may be
valuable in primary prevention of myocardial infarction, I think it is.
Do I believe that the regulatory standard has been met? I think it has
not, and my vote is no.

DR. WOOD: Ed, can I just challenge you a little bit on that or at least
start a conversation?

It seems to me that there is a difference here between approving a drug
for the first time to be used, to be marketed, and one in which we\'re
trying to inform physicians about how they should use the drug, and it
disturbs me a lot to hear you say that you would take a drug for an
indication, but you wouldn\'t want to inform other physicians about how
appropriate to use that.

So let me niggle you a bit on that.

DR. PRITCHETT: Well, it\'s just I have no problem with the notion that
there are a lot of drugs used; maybe most of the drugs used today are
used for what I referred to as off label indications, and in some cases
those uses are very well established by many multi-center clinical
trials, and in some cases they\'re established only by hearsay, and
that\'s the way we practice medicine, and I see no conflict there.

I think the question is: are we practicing medicine by, you know, just
by what\'s written in the FDA label? And the answer is, no, we\'re not.

And so I think if you want someone to say, \"This is the way we think we
ought to practice medicine,\" the Heart Association has done that. The
college has done that. The Preventive Health Services Task Force has
done that. The FDA standard hasn\'t been met, and I don\'t think the FDA
standard is different.

If the drug is already on the market and labeled for another indication,
we might feel good about it. There are certain even classes of drugs
that we feel good about. We feel good about beta blockers. We feel good
about statins because those are classes of drugs that have been shown to
reduce mortality. So we might smile more kindly or be less concerned
about those drugs if they come forward with another indication.

But they\'re still a standard that has to be met. I don\'t think it has
been met here.

CHAIRMAN BORER: Ron.

DR. PORTMAN: You walk into the doctor\'s office and after they say,
\"What brought you here today?\" the next question will be, \"Now, are
you planing on a fatal or a nonfatal MI?\"

(Laughter.)

DR. PORTMAN: You know, for those who say, \"I\'m going to have a
nonfatal one,\" I mean, here\'s your aspirin. Fine, and for those of you
who are going to have a fatal one, well, you don\'t need an aspirin.

So, I mean, I don\'t think you can separate it like that. I mean, you
either recommend it for the prevention of cardiovascular disease or you
don\'t, and you know, the data that has been presented to me today that
I have seen would suggest that there\'s not enough evidence there to
recommend it. I think we really need a study that specifically addresses
this question.

And so my vote is no.

CHAIRMAN BORER: Paul.

DR. ARMSTRONG: Not all MIs are the same, Mr. Chairman. I\'ve been caring
for them for over 30 years and investigating them, and I don\'t know
what the MIs in this data set consisted of. So I\'m troubled by that.

I do know that silent myocardial infarctions are important, and I do
know that half of them are misinterpreted and they\'re not clinically
silent at all. They just don\'t get to the hospital, and those that
survive you learn about later.

I think the definition of MI is changing dramatically, and we are, as
you know, working in a consensus group with Europe which will increase
the frequency of MI by 30 percent based on new diagnostic criteria, and
the MIs that we\'re looking at, many of which were studied and acquired
15 or 20 years ago were in an environment where prevention and milieu
pharmacologically when they occurred was different and, indeed, what we
can do now relative to the occurrence of MI is far different than it was
then.

I think there is data and gold in these trials that we have not been
able to access, and so in relationship to what other information might
be germane to the question on the table, I think we\'ve heard from two
of the PIs at least that it\'s there for the FDA to look at, and it
might well be revealing on some of these issues, and I would be the
first one to want to get down and wrestle with it.

I think Steve Nissan said something that I believe very strongly, having
been in the position of prescribing something that produced a disabling,
nonfatal intracranial hemorrhage and stroke, and that is that it\'s a
very devastating, complication of a treatment. It\'s not valued the same
way as a myocardial infarction or a GI bleed, and the transfusions
associated with a GI bleed likely have different implications now than
they did 20 years ago.

So I have enough doubt and enough uncertainty relative to the likelihood
of harm that the small benefit that I think is probably there is not in
my view justification to approve this, and if I were, it would certainly
be at a dose of 100 milligrams or less.

So I vote no.

CHAIRMAN BORER: Susanna.

DR. CUNNINGHAM: I think the public looks to the FDA for safety as well
as efficacy, and I think when the public gets a recommendation from the
FDA, they anticipate and they assume that the medication is going to be
safe. So if the public knew that the medication that was recommended had
a high probability or some probability, it may not be that high, but
some probability of causing them a stroke, which is a devastating event,
for some small possibility of maybe preventing an MI, they wouldn\'t be
willing to make that tradeoff.

So I would like to see data that was convincing because I would like
there to be a medication that was as useful as aspirin looks to be. I
think it\'s something that the public needs. The public has a hard time
with diets and exercise and weight loss, and they would like a
medication that worked.

But they wouldn\'t, I don\'t think, be willing to take the tradeoff of
having a stroke. So I\'m unfortunately not convinced by the data. I
think that I\'d like to be. I\'d like there to be more analysis. I hope
the Women\'s Health Initiative has more data. I think women are not
served by this data because there\'s no benefit in the 20 percent of the
population who were women. There\'s no benefit shown.

I\'d like there to be benefit for women. So I\'d like there to be
something there for them. So my vote has to be no.

The other interesting thing I was thinking about is somewhere it was
said, I\'ve heard, there was no such thing as a silent MI just, a
caretaker who was unable to hear. So maybe we need to look further at
those silent MIs.

DR. THROCKMORTON: Jeff, I\'m sorry. We\'ve lost track with the nonfatal
and fatal. You said?

DR. CUNNINGHAM: I said I agree with Ron. If the patient walked in the
door and I knew what they were \--

DR. THROCKMORTON: No, I heard that, and actually that was well put, but
we were asking the other members. I guess I\'d just invite the last
people since Ron said that if their vote was any different for a claim
for nonfatal MI.

DR. CUNNINGHAM: I\'m going to be no all around until I have better data.

DR. THROCKMORTON: Okay, and Paul and Ed, I guess.

DR. ARMSTRONG: No.

DR. THROCKMORTON: Okay. I just wanted to make sure that I understand.
Thank you.

CHAIRMAN BORER: Okay. I\'m in a situation a little bit different from
Ed\'s in that I wasn\'t here during the 1989 meeting, but I was at the
earlier one that wasn\'t mentioned in any of the reviews when we
considered aspirin for secondary prevention after myocardial infarction,
which I believe was in 1982, so long ago that everybody has forgotten
about it.

DR. NISSEN: I wasn\'t even born then.

(Laughter.)

CHAIRMAN BORER: Well, I take that under advisement.

Before I give my vote, and I\'ll go through the reasoning, I want to
make a few preliminary statements. First of all, the reason that we have
guidelines committees is primarily to obtain a consensus about the best
thing to do generally in the absence of dispositive data.

Ultimately a patient comes in to be seen and you have to make a
decision: do this, do that. And in the absence of the kinds of data that
we\'d all like, we make the best decision we can, and in the current
era, guidelines committees are formed to help inform those decisions,
and that\'s fine, and that\'s good.

Drug approval, however, as Ed said, I think, carries with it the, or
always has carried with it and, I think, will continue to carry with it,
a sense of adequacy of data to draw a firm conclusion. So I don\'t think
the fact that guidelines committees have come to a conclusion causes the
FDA to need to jump on board.

And the fact that a study perhaps cannot be done anymore because of the
milieu in which we find ourselves is not an argument. It\'s not an
acceptable argument in favor of granting an approval. We might just say
we don\'t know but, you know, do the best we can with the data we\'ve
got.

So I think we have to judge these data as they are, not because of
circumscribing situations.

Having said that, I\'ll go a little bit further. I think nonfatal MI
reduction, if that\'s what has happened here, is a real benefit, and if
nothing else happened, everything else was neutral but nonfatal MI was
decreased by treatment, then I would say that\'s a good thing, and
that\'s an approvable indication.

I think that CVAs are bad things, that strokes are bad things, are very
bad things. I think nonfatal strokes are very bad things. Fatal strokes
in parallel with what Ron said, if a patient walks into your office
dead, I don\'t think he or she cares how he got there, whether it\'s a
stroke, an MI, or a car accident.

But nonfatal strokes are very bad for all of the reasons that have been
said. I don\'t know what to make of silent MIs, and I don\'t want to get
into a discussion of putative mechanisms because I don\'t think that we
have sufficient data, as I\'ve said so many times about any drug to
determine how specific pharmacological effects track with clinical
effects. We know they track; we don\'t know why.

However, I would point out only that the data would be consistent with,
not suggestive of, but consistent with some effect of aspirin that
reduces the perception of the symptom that\'s associated with an MI. You
know, aspirin does do that. You know, it\'s an anti-inflammatory drug
that reduces pain.

I\'m not suggesting that\'s what happens here, but you know, we ought to
keep it in mind if the silent MI data seem to be discordant, those few
data that we have seem to be discordant with the other data.

And I\'m very concerned that we don\'t have sufficient information about
women to make a strong statement, although the data we have are at least
not inconsistent with there being similar benefit, if there is benefit,
in women as in men, but you know, if this drug were to be approved for a
new indication, I would certainly make it very clear what we don\'t know
in labeling.

Now, having said all of that, we come down to what the data tell us, and
you know, I\'m concerned about the fact that the primary endpoints
generally weren\'t met, and I\'m concerned about all of these things,
but I think that there is a plausible interrelation between the outcome
events of greatest interest: cardiovascular death, MI, fatal or
nonfatal, what have you.

So I\'m not necessarily a priori opposed to voting for approval of a
drug for an indication for use of a drug because it didn\'t meet the
primary endpoint in the various trials. I\'m concerned about it, but
I\'m not a priori against it.

And I look at the numbers that we have here, and I\'m going to go
through them specifically so I can make a point. The data indicate that
for all five trials there was a 27 percent reduction in nonfatal MI. We
don\'t know about silent MI, but the data we have, 27 percent reduction.

For the TPT study, which was the one study perhaps in the population for
whom the sponsor would have us aim this drug, the reduction was 32
percent. That\'s the same.

For all MI, fatal or nonfatal, the entire data set shows a 23 percent
reduction in relative risk. The TPT study, 19 percent, I\'m going to say
that\'s the same.

For all stroke, the totality of the data shows an increase in all
stroke. That\'s fatal and nonfatal, a tremendous increase in fatal
strokes, but for fatal and nonfatal, five percent. TPT decreased by two
percent all stroke. You know, that sounds pretty similar, although it
disturbs me that strokes are increased, particularly if they\'re not
fatal.

And then look at all vascular deaths. For the totality of the group, the
RR is .98 in favor of aspirin, which is no change at all, but that\'s
where the disturbing point is because TPT increased by 20 percent all
vascular death. That would be disturbing to me.

How disturbing? Well, not as disturbing as it might be. The numbers are
relatively small, and then we have this confound with the warfarin that,
you know, I don\'t even want to get into that. I don\'t know how to make
any sense of that.

So I\'m willing to back off on that concern for the moment. Given all of
those numbers that I\'ve given you that seem to be consistent, I would
draw from those numbers the conclusion that all MIs are reduced by some
proportion. I would say maybe 20 percent, maybe a little bit more, for
some population that\'s been defined here; that vascular deaths probably
aren\'t changed much for that same population, and that strokes probably
aren\'t changed much. They may increase a little bit, and that\'s
disturbing. That\'s a real disturbing point.

But when you put it all together as concerned as I am, I would have to
say that I think the bulk of the evidence favors benefit over risk for
some population. Now, what\'s the population?

Well, the sponsor would tell us that if we use an algorithm that defines
people who have a ten percent, ten-year risk of some CHD event or
greater than that, that that\'s a high risk population, and I\'m willing
to buy that.

Now, you know, we\'re going to get into another question here, which is
very important, which has to do with how we define that group, whether
anybody can use a label indication to define that group, whether anybody
will use label indications, but let\'s say they could.

I would say that that case has been made. So I would vote yes for the
question of recommend its use for primary prevention of MI in a
population as I\'ve defined it greater than ten percent ten-year risk,
which puts me in the distinct minority because the majority said no.

Now, having said that, Doug, do you want us to move on sine the vote is
no? Do you want us to move on?

DR. THROCKMORTON: Let\'s move on \--

DR. CUNNINGHAM: Can I add something?

CHAIRMAN BORER: Yes, sir. Susanna.

DR. CUNNINGHAM: I just want to make one comment that no one else has
commented on, and that is that we don\'t have adequate data for
different ethnic groups. Do we have a positive signal for African
Americans? But we only have 650 people in that group. We have very few
group \-- any other data about any other ethnic group.

So I think as the consumer representative, I really want to encourage
that we have data for other populations and that we explore further the
data in the African American population because if it\'s a benefit
there, that\'s critically important.

And the elderly, yes.

MS. SPELL-LeSANE: Yes, can Dr. Hirsch and Dr. Fleming vote again for
nonfatal MI, please?

DR. THROCKMORTON: Yeah. By my count there were four individuals that
voted yes on the question for all MIs: Alan; Dr. Hirsch, you\'re one;
Dr. Lorell, you\'re one; Dr. Carabello, you\'re one; and Dr. Borer,
you\'re one.

Several of you voted yes for nonfatal MIs, and I\'ve tried to capture
those as well, but just on the strict this was the proposal. I just want
to make sure we have the right numbers. Is that a correct understanding
of everyone\'s votes for the question of recommending inclusion of
language for fatal and nonfatal, all MIs?

MS. SPELL-LeSANE: Dr. Lorell, you had?

DR. LORELL: I had originally voted no on the totality, but I will change
my vote on that to a yes. So yes and yes.

DR. THROCKMORTON: Dr. Carabello?

Okay. Dr. Hirsch?

I\'m not putting on anyone else that wants to change \-- clarify their
votes should certainly do so as well. I\'m just going down the people
that I had identified.

DR. HIRSCH: I believe my vote was yes for prevention of nonfatal MI, no
for the totality of MI.

DR. THROCKMORTON: Okay. Thank you for clarifying that.

Does anyone else need to clarify their vote? I as well need to make sure
that we understand this.

Yours, Dr. Wood was also the same way, no on the total, yes on the
nonfatal. Dr. Knapka, I also have you for a no and a yes. Okay.

DR. KNAPKA: Actually overall it\'s probably no.

DR. THROCKMORTON: You came down on the no at the end of the day.

DR. KNAPKA: But yes if there are stipulations.

DR. THROCKMORTON: Yes.

DR. KNAPKA: The population being well defined and there is some
follow-up, and they just don\'t say take aspirin and do nothing.

DR. THROCKMORTON: Okay. As I counted then there are three individuals
who are saying yes to the proposed labeling. I just want to make sure.
Is that everybody\'s count so that then we can move forward to some more
discussion? Because there are at least two other things I really would
like to get some input on.

MS. SPELL-LeSANE: I have ten noes and four yeses for the all MIs.

DR. THROCKMORTON: You\'re going to have to give a list of the names. I
have \--

MS. SPELL-LeSANE: I have Hirsch, Lorell, Carabello and Borer.

DR. THROCKMORTON: Right, and Dr. Hirsch just clarified that his was a no
for all MIs, but was a yes for the nonfatal MIs. So that would reduce
that count to three individuals. Okay?

Two things that I wanted to ask, one thing sort of very separately, and
we\'ll come to that at the end, which was to revisit what Dr. Hiatt had
raised this morning, the use of our secondary prevention people differ
fundamentally from the primary prevention, but first I want to come back
to what Dr. Wood raised and what Dr. Pickering talked about was were an
indication to be crafted, how to define risk, how to sort of decide what
population would benefit.

Are these instruments that have been proposed by the sponsor \-- is that
an appropriate way to do that or is it more appropriate, well, along the
lines of the Question 7? Are there other tools that may be the more
usual way of describing populations that would benefit men, women, that
sort of thing, another way to go?

CHAIRMAN BORER: Okay. Bill, why don\'t you go ahead and then we\'ll ask
for comments if anybody differs with what you say.

DR. HIATT: In contrast to my thinking about the data showing a reduction
in nonfatal events, I think the use of a risk stratifying device,
whether it\'s Framingham, whether it\'s other surrogates of risk,
coronary calcium scores, ankle-brachial indices, other risk factors,
CRP, for example, these are all testable hypotheses, and I guess for
Question No. 7, I think if the label sticks to the evidence that has
actually been studied, that I would have comfort with.

But if it goes to the next level saying you can use this risk score and
define the population that really wasn\'t represented in the trial, I
don\'t think there\'s any evidence to support that. So I would vote no
for using Framingham risk to define the responsive group of people who
should take aspirin and haven\'t had an event.

That is a testable hypothesis. That should be studied.

DR. THROCKMORTON: Are there other ways that you would define \-- well,
you sort of intimated in your comments on the last question that you\'d
use I guess I\'ll call it a more traditional approach of the population
studied in the trials. Again, without putting words into your mouth or
\--

DR. HIATT: If you\'d just stick with the data and stick with the
efficacy signal in those cohorts and you\'re careful to define who they
are by inclusion and exclusion and demographics, then you\'re as close
to the data as you can get.

But if you use then that to say that in this small minority who were, in
fact moderate risk by Framingham, we should apply that to all people in
the United States who should take aspirin to prevent a nonfatal event, I
don\'t think that\'s supported by any of the evidence.

And I do think that there are a number of things, simple things, and I
think Al would agree if you did the ankle-brachial index as a way to
risk stratify in conjunction with these other risk scores or other kinds
of things like that, you could define intermediate populations, and they
would be very responsive to a variety of therapies including aspirin or
statins or other risk modifying agents.

But that really needs to be prospectively tested.

CHAIRMAN BORER: Let me ask you to answer two additional questions then.
So am I understanding that if this drug were to be approved now, and
obviously the majority thinks it should not be for this new indication;
that if it were to be in the current setting, you would want to see the
inclusion and exclusion criteria for the TPT used as the definition of
population since that was the only moderate risk group and showed the
biggest \--

DR. HIATT: No, I think that that would also be a risk because then
you\'re dropping down to just one trial. So it ought to really reflect
the totality of the demographic actually reported, which is mostly the
very low risk people.

DR. WOOD: So you\'d use just physicians?

(Laughter.)

DR. HIATT: Well, must male physicians. Well, I think that\'s the bind
we\'re in because I think the evidence looks okay in that cohort. I
would not extrapolate.

CHAIRMAN BORER: Okay. Then we won\'t go on to the next issue, which is
can physicians use this, but we\'ll get to that again and can patients
understand it.

Does anyone else have any? Steve.

DR. NISSEN: Yeah. Doug, there\'s something you\'ve got to be really
careful about here. The NCEP guidelines, and I have some knowledge about
how these were framed, the questions that were being addressed were
different. We had a class of drugs, statins, which produced pretty
uniform benefits, had very, very low risk, I mean, myopathy
notwithstanding, and the risks are in the few per million.

And so the question that NCEP was dealing with with the Framingham risk
score was cost effectiveness. You know, at what level of risk do you
rise to where it\'s worth spending the amount of money you have to spend
on a drug in order to achieve a benefit?

We\'re asking a different question here. We have a drug which can cause
harm and can also do good, and so now we\'re trying to weigh harm versus
benefit, and it\'s a very different equation. So if you want to take the
NCEP Framingham and extrapolate that to a very, very different situation
of risk versus benefit where there\'s harm that could be done, I would
have to say that that would be a very dicey proposition to do that
because there is a different balance in the potential risks of the drugs
involved, between statins and, say, aspirin.

DR. THROCKMORTON: Yeah, you might also argue that those guidelines are
actually based on prospectively designed outcome trials that have sort
of tested those strategies, if I understand.

DR. NISSEN: Oh, I have already made that argument. That\'s why I voted
no. I mean, I think that if you\'re going to use some strategy, the
strategy ought to have been a tested strategy that there\'s been some
testing of and proof that, in fact, it works.

And we don\'t know whether a Framingham risk score works as a means to
select patients for therapy, which is why I voted no. I don\'t see how
you\'re going to do this.

DR. THROCKMORTON: Yeah, although probably to be fair, you could have
managed \-- I mean, the sponsor\'s argument is that, in fact, a scoring
system like this might promote a more appropriate use. That is, a
physician that was looking at the data, if you were convinced that, in
fact, it was extrapolatable from the identified data and all of those
things, you might \-- it might be a thing that physicians might more
readily apply and the sort of general practice population might be more
likely to have, you know, full use.

I\'m not hearing a lot of enthusiasm for that extrapolation, I guess.

DR. NISSEN: I\'ll shut up in just a minute, but just keep in mind that
this is an over-the-counter drug, not one that you have to write a
prescription for.

So what\'s really a question is who\'s making the decision.

CHAIRMAN BORER: Beverly, then Alastair and then Blase.

DR. LORELL: Yeah, I actually think it is feasible and it\'s the
direction of cardiology in primary care practice today to think about
gradations of benefit and risk, and a term was used earlier today, \"the
intensity of therapy.\" So I think it would be possible to write a label
that were as vague as moderate to high risk and to refer to assorted
scoring systems.

I don\'t think it\'s in the FDA\'s business to put its imprimatur on any
single system. To me part of defining the population in which this might
be used is defining what we know about safety, and for that being a
different issue is we do have safety data, the analysis that Tom did
here, in a large number of patients and trials that had exclusion
criteria.

So to me a part of writing a label, if one were to do so, would be to
look very carefully at this very large database regarding the
exclusionary criteria for upper limits of severe, uncontrolled
hypertension. These trials did not exclude people with some
hypertension, a risk of GI bleeding, et cetera.

So I think there\'s a very different issue of defining the exclusionary
population based on what were used as exclusionary data in these trials
versus whom you would include.

And I don\'t think it is at all out of the question to identify a target
population of moderate or moderately high risk.

DR. THROCKMORTON: Sorry. I\'ve got to press on that. What I heard you
say was you should use the exclusion; you should look to the exclusion
criteria used in the trials to sort of describe the population that
would potentially benefit, but then you turned it around and said, no, I
think you should use some sort of scoring or that a scoring system \--

DR. LORELL: No. I would use the exclusionary criteria as a way of
defining safety boundaries. So you know what happened in terms of
adverse events in these trials based on whom was excluded. So among a
population who, in other words, did not have exclusionary criteria, you
can say something about safety or more specifically what the risks are
of hemorrhagic stroke and major bleeding, including GI bleeding.

In terms of the inclusionary criteria, I think it is feasible in 2004 to
make a recommendation for use in moderate to high risk patients who have
not yet had an event.

DR. THROCKMORTON: Right. So just again to paraphrase, you might say we
know a lot about the safety of aspirin in terms of outcomes from a lot
of different places, obviously not just these trials, but you might be
able to draw on such a database to inform the kinds of safety in
different kinds of populations \-- I don\'t know \-- women or people
over the page of 75 or whatever.

Help me out now how to move from that to decide who would be receiving
the therapy and how to describe that population efficacy-wise.

DR. LORELL: Yeah, I think efficacy-wise you would consider writing
recommendation or a labeling trying to get across the notion of
balancing potential benefit and risk and targeting from moderate to high
risk patients.

And I think primary care physicians, as we heard earlier today in some
of the public commentary and cardiologists are becoming increasingly
comfortable with doing that in their own practice, and there\'s several
different pathways for doing that.

I think you\'d have to have an efficacy statement saying that very
clearly the level of confidence of benefit \-- there are ways one could
word this that are already done in labels \-- is much less certain for
women and certain other subgroups.

DR. WOOD: Yeah, I think there\'s a number of points, Doug. The first is
that you can use the scoring system presumably to define futility. It
seems to me highly unlikely that you\'re going to see benefits in a
group for whom the risk is less than that of the risk of hemorrhagic
stroke and some measure of a GI hemorrhage, and I wouldn\'t count these,
as I said before, equal, but at least, yo know, as you reduce your risk
you\'re certainly not going to get to a point where you could be
confident you would exceed in the risk-benefit ratio.

The same question, which I think is what Steve was trying to say as
well, does the Framingham algorithm define the group that\'s going to
benefit from aspirin, and I suspect it doesn\'t although it may be
useful to do just what I said a second ago.

And I think we could actually get data particularly from the Oxford
group that would help with that. For example, you get a big hit from
having a blood pressure greater than 140 on the Framingham data, and yet
intuitively one would think that that\'s a group that would be at
particular risk from hemorrhagic stroke.

Now, that\'s an answerable question, I guess, from your data, and you
could go back and look at that fairly easily.

So I would recommend that that was done, and that we look and see if the
group who had a blood pressure greater than 140 or some number were at
particular risk for hemorrhagic strokes during aspirin administration.

But that doesn\'t mean that the scoring system would be valueless
because I think it does define groups in whom there\'s unlikely to be
any benefit just because of the sheer futility, and it certainly assists
you in defining groups who are at great risk from cardiovascular
disease, and physicians tend not to do a very good job of that, I think.
They tend to work on specifics. You know, they\'re treating blood
pressure or they\'re treating cholesterol. They don\'t sum it all
together and put it into a composite score very well, although they
could.

DR. THROCKMORTON: So would that be predictive value or operating
characteristics? I mean are those the sorts of words that \-- I mean,
you define the operating characteristics of this screen whether it\'s
the Framingham study or \-- I\'ll turn my off in a minute and you can
have \-- I mean, is that sort of what you\'re saying?

Because I want to hear Dr. Pickering as well. I mean, this is really
important because this is a really fairly new thing. Other than NCPT and
things like that where they have been prospectively applied to the
database, actually taking a population based analysis, you know, set of
data like this and saying, \"Now I can use a scoring system,\" is
relatively novel and it\'s really important for us to understand, you
know, how you think we should go about doing that.

DR. WOOD: Well, I guess what I\'m saying is that the scoring system has
potentially two or three benefits. The first benefit is that by looking
at the group that\'s at very low risk and you can probably within a fair
degree of certainty say that that group is unlikely to benefit from
aspirin, given the horizontal lines shown on these multiple copies of
that slide, that is, they\'re at constant risk and they\'re unlikely,
therefore, to benefit if the absolute risk is less than the risk of the
adverse events.

Does the scoring system define the group that will benefit? I don\'t
think we know that, and all we know is \-- and Bill said this earlier
\-- is the data that were used as the entry criteria for the studies.

That may be okay, but we don\'t know it with any level of certainty.
However, the scoring system by definition is a composite, and we have
prima facie reasons, I think, to believe that some of the contributors
to that scoring system may actually increase your risk of aspirin rather
than decrease it, and I think that\'s something that needs to be
carefully explored before we just blindly go into the scoring system.

CHAIRMAN BORER: We have Blase, Tom, Alan and then I have a comment that
I think may end us.

Blase.

DR. CARABELLO: I think it\'s fine to define or suggest that we use it in
moderate or high risk populations, but I wouldn\'t want to see us go
with one scoring system. We all have different ways of risk stratifying.

In the [New England Journal]{.underline} article that was included in
the packet by Michael Laragh, the 45 year old guy with a densely high
positive family history, an LDL of 160, and an HDL of 35, I\'d have
given him aspirin, and they concluded not to.

So, I mean, I think that I would be very careful about how we define
these, or I would leave it broad and not limit it to one system or
another.

CHAIRMAN BORER: Tom.

DR. PICKERING: Yeah, we\'ve only been talking about scoring systems for
MI, but there have also been algorithms developed for risk of stroke. I
haven\'t seen any that give you overall risk. It would be interesting.
There may be some.

But it seems to me there may be patients who on the MI score would be
moderate risk and, therefore, according to what we\'ve heard today would
benefit in terms of nonfatal MI, but that patient might also score high
on the stroke risk, particularly if their blood pressure is a little
high because blood pressure is a more important to stroke than MI.

And in those patients, it may be that aspirin is particularly harmful
since we really don\'t know. So I think, you know, this may depend on
which scoring system you happen to prefer for your particular patient.

CHAIRMAN BORER: Alan.

DR. HIRSCH: The fact that we\'re all having our lights on here pushing
six o\'clock shows how important this question is to us.

You know, I\'ve been in favor of the use of Framingham risk or as other
risk indicators because to me their use is primarily as the sponsor and
many of the advocates stated; they\'re a call to action for complacent
physicians to do good things for people at risk.

That said, I wanted to go on record as we\'re asked to opine that \-- I
was really troubled by the creative use of the risk or to apply a
population in which it was not pre-hoc defined in any of these trials.

And I just want to echo again there\'s good reasons to believe that the
pathophysiology of effective aspirin would be quite distinct from that
from NCP, great reasons to believe it, and these data actually suggest,
in fact, that it doesn\'t work. There was less risk reduction in the
population in the medium risk group.

So here\'s a suggestion. It\'s a nice hypothesis. You test it in future
trials or, you know, there\'s enough data here in 55,000 individuals
probably whom have some blood pressures and some cholesterols. One could
actually test this post hoc by an appropriate analysis and come back and
inform us in some subsequent publication.

CHAIRMAN BORER: Yes. I will begin with Alan\'s statement because it was
part of my conclusion here.

Let me say at the outset I suggested that there was benefit here and
that the benefit outweighed the risk, but I didn\'t say for whom and I
don\'t know how to write a label.

I don\'t think we have the data. I would have to agree with Steve that I
don\'t know who to say should get the drug because I don\'t know what
drove the benefit.

Now, having said that, I think that one rational place to start would
be, since the suggestion has been made to use the Framingham score, to
go back and apply the Framingham score in the populations that were
studied and see what comes out. Maybe it works; maybe it doesn\'t, but I
wouldn\'t know how to write the label.

And I agree with Blase that I am very worried about a very prescriptive
set of criteria in a legal document. I probably wouldn\'t agree with
whatever you wrote, but I don\'t know what to write, and so even though
I voted that there\'s something here to be approved, I don\'t know who
to approve it for.

So we need more data.

Now, next point because you asked these questions. Let\'s say we had a
scoring system. Let\'s say it was the Framingham scoring system. Let\'s
say post hoc you do the analysis and it works beautifully. Can
physicians use this?

Well, sort of, maybe. I want to remind you of Dr. Stafford\'s data.
There is a label for aspirin. it says that people who have had an event,
people who are at high risk, et cetera, et cetera, that they should get
aspirin.

And what we learned was that maybe 20 percent of them do. Maybe 30
percent of them do. So can doctors use it? I mean, people with an event,
what could be simpler?

It\'s a lot simpler than the scoring system, but only 20 to maybe 30
percent of doctors tell patients to use aspirin. So I think it\'s tough
to expect doctors to use a scoring system. That doesn\'t that, you know,
if it works we shouldn\'t put in the label and prescribe it and
whatever.

And can patients understand it? Forget it. I mean it\'s just not going
to happen.

So if the goal of writing guidelines and if the drug were to be
approved, one of the benefits that\'s inferred to occur from having had
the drug get the imprimatur of the FDA for a specific indication is
that, you know, a lot more people are going to use it. Well, in absolute
terms, a lot more may, but in percentage terms, I think that the
response is going to be relatively small at first, and it\'s going to
take a major educational effort for it to be better than that, and I
worry a little bit about educational efforts because the principals that
they espouse tend to be carved in stone and every patient is an
individual, and you have to make individual decisions in the clinical
arena.

So having said that, I don\'t know how to write the label. I think some
more work has to be done to determine how to write the label, and once
you do, I don\'t know if it\'s going to be practical for physicians to
apply it or for patients to use it.

I don\'t see any other lights on. Are there any other comments?

Because if not \--

DR. THROCKMORTON: Sorry. One more comment and then I\'ll let you go, and
this comes up just from something that Dr. Hiatt said this morning. He
was expressing concern that looking at the secondary data, you know,
there was an obvious continuum as far as secondary prevention down to
primary prevention. I was just wondering whether there was some reason
to be concerned about that.

And I believe he was expressing some concern about that, and I wondered
whether anyone else had any comments about that. Because at least a
portion of the argument here has been look at all of the secondary
prevention data that is obviously robust and quite impressive, and
should we be discounting that in some sense because it\'s not \-- has a
different physiology, something like that.

CHAIRMAN BORER: You know, I\'ll tell you. There may be some
pathophysiological differences between the patients who are
beneficiaries of aspirin for second prevention and those that we\'re
talking about now. There may well be. I don\'t doubt that there are.

You know, in general, however, I think that we make a final decision
about whether a drug is appropriate for an indication or whether it\'s
not based on a body count because we don\'t really know the
pathophysiology, I mean, or if we do know it today, we\'ll know it
differently a year from now.

So I would look at the body counts, and to me there is a consistency,
albeit there\'s some noise; there is some consistency across the trials
if you go from the high risk to the low risk. So I have a concern, but
it doesn\'t reach the level of concern where I would change my vote that
was in the minority.

Steve.

DR. NISSEN: Yeah, I have to try to get the last word in here. You know,
the idea that we will go back and now apply some criteria to determine
who in that ten to 20 percent group ought to get the drug, I want to
point out to everybody that we have very few patients from these five
trials in that group, and so now we\'re going to try to apply a tool to
a group of people that perhaps includes maybe 12 percent of that 55,000
patients, and I would guess, just guessing, that it will be very
difficult to apply any tool post facto to the data when so little of the
data we were presented with actually occurs in the range that we\'re
most interested in.

And so I\'m not very optimistic, Doug, that you\'re going to be able to
go back and figure out some scale to apply here.

CHAIRMAN BORER: Okay, Doug. Any other issues? Have we solved this one
for you?

DR. THROCKMORTON: Thanks to everyone very much.

CHAIRMAN BORER: Okay. We\'ll conclude this session and we\'ll meet again
tomorrow morning.

(Whereupon, at 5:49 p.m., the meeting was adjourned.)