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:
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:
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:
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 PAGE
CALL TO ORDER AND INTRODUCTIONS:
Jeffrey Borer 4
CONFLICT OF INTEREST STATEMENT:
Dornette Spell-LeSane 6
WELCOME AND INTRODUCTORY COMMENTS:
Douglas Throckmorton 8
SPONSOR PRESENTATIONS
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 185
PUBLIC STATEMENTS 186
FDA PRESENTATION:
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 301
COMMITTEE QUESTIONS/SUMMARY 396
ADJOURNMENT 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
(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. 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,
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.
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 if present.
There is a study, at least one, in the New England Journal 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 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., H. pylori. 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
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 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 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. 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 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 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.)