DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
JOINT MEETING OF
THE ARTHRITIS ADVISORY COMMITTEE AND
THE DRUG SAFETY AND RISK MANAGEMENT
Wednesday, February 16, 2005
620 Perry Parkway
P A R T I C I P A N T S
Alastair J.J. Wood, M.D., Chair
Arthritis Advisory Committee:
Allan Gibofsky, M.D., J.D.
Joan M. Bathon, M.D.
Dennis W. Boulware, M.D.
John J. Cush, M.D.
Gary Stuart Hoffman, M.D.
Norman T. Ilowite, M.D.
Susan M. Manzi, M.D., M.P.H.
Drug Safety and Risk Management Advisory Committee:
Peter A. Gross, M.D.
Stephanie Y. Crawford, Ph.D., M.P.H.
Ruth S. Day, Ph.D.
Curt D. Furberg, M.D., Ph.D.
Jacqueline S. Gardner, Ph.D., M.P.H.
Eric S. Holmboe, M.D.
Arthur A. Levin, M.P.H., Consumer Representative
Louis A. Morris, Ph.D.
Richard Platt, M.D., M.Sc.
Robyn S. Shapiro, J.D.
Annette Stemhagen, Dr.PH. Industry Representative
FDA Consultants (Voting):
Steven Abramson, M.D.
Ralph B. D'Agostino, Ph.D.
Robert H. Dworkin, Ph.D.
Janet Elashoff, Ph.D.
John T. Farrar, M.D.
Leona M. Malone, L.C.S.W., Patient Representative
Thomas Fleming, Ph.D.
Charles H. Hennekens, M.D.
Steven Nissen, M.D.
Emil Paganini, M.D., FACP, FRCP
Steven L. Shafer, M.D.
Alastair J.J. Wood, M.D., Chair
P A R T I C I P A N T S (Continued)
National Institutes of Health Participants
Richard O. Cannon, III, M.D.
Michael J. Domanski, M.D.
Lawrence Friedman, M.D.
FDA Consultants (Non-Voting):
Byron Cryer, M.D. (Speaker and Discussant)
Milton Packer, M.D. (Speaker only)
Guest Speakers (Non-Voting):
Garret A. FitzGerald, M.D.
Ernest Hawk, M.D., M.P.H.
Bernard Levin, M.D.
Constantine Lyketsos, M.D., M.H.S.
Jonca Bull, M.D.
David Graham, M.D., M.P.H.
Brian Harvey, M.D.
Sharon Hertz, M.D.
John Jenkins, M.D., F.C.C.P.
Sandy Kweder, M.D.
Robert O'Neill, Ph.D.
Joel Schiffenbauer, M.D.
Paul Seligman, M.D.
Robert Temple, M.D.
Anne Trontell, M.D., M.P.H.
Lourdes Villalba, M.D.
James Witter, M.D., Ph.D.
Steven Galson, M.D.
Kimberly Littleton Topper, M.S., Executive
C O N T E N T S
Call to Order:
Alastair J. Wood, M.D., Chair 6
Conflict of Interest Statement:
Kimberly Littleton Topper, M.S., 13
Steven Galson, M.D., MPH 16
Jonca Bull, M.D. 24
Gastrointestinal Effects of NSAIDs and COX-2
Byron Cryer, M.D., 30
Mechanism Based Adverse Cardiovascular Events and
Specific Inhibitors of COX-2
Garret FitzGerald, 80
Committe Questions to Speakers 112
Sponsor Presentation: Vioxx (Rofecoxib),
Peter S. Kim, M.D. 130
Ned S. Braunstein, M.D. 131
FDA Presentation: Vioxx (Rofecoxib),
Lourdes Villalba, M.D., 227
Committee Questions to the Speakers 263
Sponsor Presentation: Celebrex (Celecoxib),
Joseph M. Feczko, M.D. 293
Cardiac Safety and Risk/Benefit Assessment of
Kenneth M. Verburg, Ph.D. 295
FDA Presentation: COX-2 CV Safety: Celecoxib,
James Witter, M.D., Ph.D., 373
NIH and Investigator Presentation: Celecoxib in
Adenoma Prevention Trials: The APC Trial
(Prevention of Sporadic Colorectal Adenomas with
Ernest Hawk, M.D. 402
C O N T E N T S (Continued)
NIH Investigator Presentation: The PreSAP Trial
(Prevention of Colorectal Sporadic Adenomatous
Bernard Levin, M.D. 422
Committee Questions to Speakers 427
Sponsor Presentation: Cardiovascular Safety and
Risk/Benefit Assessment of Valdecoxib and
Kenneth M. Verburg, Ph.D. 443
Joseph M. Feczko, M.D. 465
FDA Presentation: COX-2 CV Safety:
James Witter, M.D., Ph.D. 493
Bayer and Roche Joint Presentation on Naproxen,
Leonard M. Baum, R.Ph. 509
Martin H. Huber, M.D. 517
Committee Questions to Speakers 527
P R O C E E D I N G S
Call to Order
DR. WOOD: Let's get started. For those
of you who missed the memo, this is the committee
to discuss the safety and efficacy of COX-2
inhibitors. It is worth perhaps just giving some
thought to why we are here. We are here to
evaluate the relative efficacy and risk of these
drugs, and to decide whether the benefits from
these drugs outweigh the risk, in contrast to
whether the risks outweigh the benefits.
It is probably also worth just saying what
we are not here for. We are not here to delegate
blame or revisit the past. We are here to look
into the future and determine what we should do in
the future. It is important I think for everybody
to remember that as we move through the
I guess the first thing to do is let
people at this enormous table introduce themselves.
Let's start down in this corner with John.
DR. JENKINS: Good morning.
I am John
Jenkins. I am Director of the Office of New Drugs
in the Center for Drug Evaluation at FDA.
DR. O'NEILL: I am Bob O'Neill. I am the
Director of the Office of Biostatistics in CDER.
DR. BULL: Good morning. I am Jonca Bull,
the Director of the Office of Drug Evaluation V, in
the Office of New Drugs.
DR. GALSON: I am Steven Galson, the
Acting Director of CDER.
DR. TRONTELL: Anne Trontell, Deputy
Director of the Office of Drug Safety.
DR. SHAFER: Steve Shafer. I am not the
director of anything. I am a Professor of
Anesthesia at Stanford and Biopharmaceutical
Science at UCSF.
DR. HENNEKENS: Charlie Hennekens at the
University of Miami School of Medicine and Florida
DR. FRIEDMAN: Larry Friedman, from the
National Heart, Lung and Blood Institute.
DR. PAGANINI: Emil Paganini, a
nephrologist out of the Cleveland Clinic.
MS. SHAPIRO: Robyn Shapiro, I direct the
Center for of Bioethics of the Medical College of
Wisconsin. I am a Professor of Bioethics there and
I chair the Health Law Practice Group at Michael,
Best and Friedreich.
DR. CANNON: I am Richard Cannon. I am
Clinical Director of the Division of Intramural
Research, NHBLI, National Institutes of Health.
DR. MORRIS: Lou Morris, President, Lou
Morris and Associates.
DR. D'AGOSTINO: Ralph D'Agostino,
biostatistician from Boston University and the
DR. ILOWITE: Norm Ilowite, Schneider
Children's Hospital and Rheumatology at Albert
Einstein College of Medicine.
MR. LEVIN: Arthur Levin, Director of the
Center for Clinical Consumers and consumer
representative on the Drug Safety Committee.
MS. MALONE: I am Leona Malone. I am a
licensed clinical social worker and I am here as a
patient representative for the Arthritis
and I have struggled with rheumatoid arthritis and
osteoarthritis for 35 years.
DR. BATHON: Joan Bathon, Johns Hopkins
University, Department of Medicine, Division of
DR. CUSH: I am Jack Cush. I am a
rheumatologist from Presbyterian Hospital, Dallas.
DR. GIBOFSKY: Allan Gibofsky, Professor
of Medicine and Public Health, Cornell University;
Adjunct Professor of Law at Fordham University; and
I am Chair of the Arthritis Advisory Committee.
MS. TOPPER: Kimberly Topper, with the
FDA. I am the Executive Secretary for the
DR. GROSS: I am Peter Gross. I am
Professor of Medicine and Community Health in New
Jersey Medical School; Chair of Medicine,
Hackensack University Medical Center; and I chair
the Drug Safety and Risk Management Advisory
DR. HOLMBOE: I am Eric Holmboe, Vice
President for Evaluation Research at the
Board of Internal Medicine.
DR. FARRAR: I am John Farrar. I am a
neurologist and epidemiologist at the Center for
Clinical Epidemiology and Biostatistics at the
University of Pennsylvania.
DR. MANZI: I am Susan Manzi. I am a
rheumatologist from the University of Pittsburgh
Medical Center, and with an appointment in
epidemiology at the Graduate School of Public
DR. HOFFMAN: I am Gary Hoffman. I am
Professor and Chairman of Rheumatic and Immunologic
Diseases at the Cleveland Clinic.
DR. DWORKIN: Hi. I am Bob Dworkin. I am
Professor of Anesthesiology and Neurology at the
University of Rochester School of Medicine.
DR. BOULWARE: I am Dennis Boulware,
Professor of Medicine, and rheumatologist at the
University of Alabama at Birmingham, and member of
the Arthritis Advisory Committee.
DR. DOMANSKI: I am Mike Domanski. I am a
cardiologist. I head the Clinical Trials Group at
the National Heart, Lung and Blood Institute.
DR. FLEMING: Thomas Fleming, Chair of
Biostatistics, University of Washington.
DR. FURBERG: Curt Furberg, Professor of
Public Health Sciences, Wake Forest University. I
am a member of the Drug Safety and Risk Management
DR. DAY: Ruth Day, Duke University,
Director of the Medical Cognition Lab, and a member
of the Drug Safety Committee.
DR. PLATT: I am Richard Platt. I am
Professor and Chair of the Harvard Medical School,
Harvard Pilgrim Healthcare Department, Ambulatory
Care and Prevention. I am principal investigator
of one of the HHRQ centers for education and
research in therapeutics. I am a member of the
Drug Safety Committee.
DR. GARDNER: I am Jacqueline Gardner,
University of Washington School of Pharmacy and
Pharmaceutical Outcomes Research Program. I am on
the Drug Safety and Risk Management Committee.
DR. ELASHOFF: Janet Elashoff,
Biostatistics, Cedars-Sinai and UCLA.
DR. NISSEN: I am Steve Nissen. I am the
Medical Director of Cleveland Clinic Cardiovascular
Coordinating Center. I am a cardiologist, and I am
the Chair of the Cardiorenal Advisory Panel for the
DR. ABRAMSON: Steve Abramson, I am
Chairman of Rheumatology at NYU and the Hospital
for Joint Diseases.
DR. CRYER: I am Byron Cryer. I am a
gastroenterologist from the University of Texas
Southwestern Medical School in Dallas, and the
Dallas VA Medical Center. My role here today is as
an FDA consultant to this group and as a member of
the Gastrointestinal Drugs Advisory Committee.
DR. STEMHAGEN: I am Annette Stemhagen. I
am an epidemiologist with Covance and I am the
industry representative to the Drug Safety and Risk
DR. WOOD: I am Alastair Wood. I am the
Associate Dean at Vanderbilt and Professor of
Medicine and Professor of Pharmacology.
Now we will have the "reading of the
lesson" from Kimberly Topper.
Conflict of Interest
MS. TOPPER: The following announcement
addresses the issue of conflict of interest with
respect to this meeting, and is made part of the
record to preclude even the appearance of such.
Based on the agenda, it has been determined that
the topics of today's meeting are issues of broad
applicability and there are no products being
approved. Unlike issues before a committee in
which a particular product is discussed, issues of
broader applicability include many industrial
sponsors and academic institutions.
All special government employees have been
screened for their financial interests as they may
apply to the general topics at hand. To determine
if any conflict of interests existed, the agency
has reviewed the agenda and all relevant financial
interests reported by the meeting participants.
The Food and Drug Administration has granted
general matters waivers to the special
employees participating in the meeting who require
a waiver under Title 18 United States Code, Section
208. 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.
Because general topics impact so many
entities, it is not practical to recite all
potential conflicts of interest as they apply to
each member, consultant and guest speaker. FDA
acknowledges that there may be potential conflicts
of interest but, because of the general nature of
the discussions before the committee, these
potential conflicts are mitigated.
Further, during today's session Dr.
Bernard Levin will be presenting data on the
prevention of colorectal sporadic adenomatous
polyps trial, the PreSAP trial, a Pfizer-sponsored
clinical trial. We would like to note for the
record that Dr. Levin is attending this meeting as
a consultant to Pfizer.
With respect to FDA's invited
representative, we would also like to disclose that
Dr. Annette Stemhagen is participating in this
meeting as a non-voting industry representative,
acting on behalf of regulated industry. Dr.
Stemhagen's role on this committee is to represent
industry interests in general and not one
particular company. Dr. Stemhagen is the Vice
President of Strategic Development Services for
Covance Periapproval Services, Inc.
In the event that the discussions involve
any other products or firms not already on the
agenda for which FDA participants have a financial
interest, the participant's 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 product they may wish to comment
upon. Thank you.
DR. WOOD: For those of you still
standing, there are apparently seats in the
overflow room. Let's go right on to the first
speaker, who is Steve Galson. Steve?
DR. GALSON: Thank you. I want to welcome
everyone and thanks in particular to our Chair, Dr.
Alastair Wood, committee members, special guests,
members of the public and FDA staff who have really
done a tremendous job in putting together a
particularly and unusually complex meeting.
We have some special guests today that I
want to point out. We have representatives from
the drug regulatory authorities of the member
countries of the European Union and six separate
countries--Canada, Japan, Singapore, Australia,
Switzerland and Mexico, and I really want to
welcome them. Thank you for being with us. We
also have several guests from congressional staff
offices and we are very pleased that they are with
us as well to learn about this important issue.
There is really an unprecedented level of
international attention to one of our advisory
committees today, and we are very proud that this
is taking place and we think it
represents a new
level of collaboration and discussion around the
world about an emerging public health issue.
Many millions of people all over the world
are taking the products that we are discussing.
Indeed, they depend on them for a range of
conditions from the mild to the severe and
life-threatening. We must keep the interests and
health of these patients front and center in these
I wouldn't be complete in this
introduction if I didn't acknowledge the
controversy surrounding these products,
particularly over the last year. I want to
emphasize that we are anxious to hear all points of
views from the advisory committee and, of course,
from agency staff. It goes without saying that all
FDA staff are free to make any presentation without
fear of any retaliation. I don't want anyone
sitting around this table to be shy.
Also, we look forward to hearing a wide
range of views from the more than 50 members of the
public who are going to be making brief
later in the meeting. I want to remind the public
that all members of this committee have been
carefully screened for conflicts of interest and we
have used the same standards in this process that
we have used for other committees and similar
A few comments about the challenging
risk/benefit balance that the agency must achieve
in making its regulatory decisions: Although you
have all heard strong opinions in the media and
medical literature about safety issues related to
the drugs we are discussing, our job and, indeed,
your job is to assess any safety concerns when
balanced by the benefit of these products. We
cannot lose sight of the reduced morbidity, pain
and suffering achieved by the products that are
under discussion and the real impact on people that
changes in the regulatory status may entail.
You will be assessing the risk/benefit
balance of these products this week in the midst of
a changing information environment and this
represents a particular challenge. We are aware of
at least a half dozen ongoing meta-analyses and
huge population-based studies, in addition to
several of the studies you will hear about this
week for which data analysis continues as we speak.
Although we have a full three days, the time really
isn't long enough to hear details about every
single ongoing, or incomplete, or unreviewed study
of which we are aware. Leaving them out of the
agenda has absolutely nothing to do with wanting to
keep information from you and everything to do with
allowing you to focus so that you have time to get
to our critical advisory questions.
We must be very cautious about
interpreting data for regulatory decision-making
that has not been thoroughly vetted and peer
reviewed, and even more cautious about interpreting
data of preliminary studies that are not even
complete. You will be hearing about some data in
these categories and I would remind you to exercise
caution in their interpretation.
As scientists, we have all seen examples
of ongoing studies whose findings have
analysis is in the final stages, or examples where
inadvertent errors have led to misclassification in
epidemiologic studies, or when data that comes in
at the end of the data gathering stage influences
results. In today's 24-hour news environment, it
is difficult to not react to these incomplete
reports but we must go back to the basics of
relying on sound science and use the peer review
system to strengthen findings before utilizing them
to make regulatory decisions.
Lastly on the risk/benefit balance, as you
members know but it is sometimes difficult for us
to convey to the public, our job at FDA and your
job in the advisory group is to balance risks and
benefits on a population basis for the nation as a
whole. This is very different from the
risk/benefit assessment physicians do with
individual patients where specific risks of the
medications, family history, a patient's risk
tolerance and other factors must be taken into
consideration. A drug may, based on the weight of
evidence, have a positive benefit/risk
the population leading to approval, yet, cause
grievous harm in a specific subset of individuals.
We say over and over again that all drugs have
risks, but when a person you know suffers an
adverse event the faulty assumption is sometimes
made that we must have made a mistake in the
I would also like to mention an unusual
feature of many of the data from the trials you
will be hearing over the next few days. The data
on safety of these drugs is, as I have mentioned,
unusually complex and represents the fact that
clinical trial methodology to look at
cardiovascular effects as adverse events has
changed dramatically. When discussions began about
cardiovascular safety of NSAIDs there was no
standard methodology by which cardiovascular
adverse events were confirmed or categorized.
Analyses vary by trial. Confirmatory processes
vary by trial. Only after the VIGOR trial did the
methods of establishing confirmatory processes and
standardization become better
course, in population-based cohorts and case
control studies case reporting and confirmation is
both rudimentary and completely inconsistent
In addition, as you know already, unlike
drugs designed to treat cardiovascular disease,
these trials have not been designed to do a full
cardiovascular assessment. So, major pieces of
information that you might like to have are simply
not available. So, in many ways we are forced to
compare apples to oranges in these trials and
studies, and when you are not doing that you are
trying to draw conclusions based on insufficient
information, making your task even harder.
In spite of all the ambiguity, work in
progress, changing standards and questions, we ask
you for the miraculous job of crystal clarity in
your responses to our questions. We know this is
tough on such challenging scientific and
controversial issues, and we are enormously
grateful to you because we know that you all are up
to this challenge. The agency will act rapidly
within the next few weeks to act on the
recommendations you communicate to us over the next
I would like to quickly go to the agenda.
Today through midday tomorrow you will hear from
sponsor companies, FDA staff and NIH researchers
about data on both approved and unapproved COX-2
selective and non-selective products. Tomorrow
afternoon we have 54 members of the public
registered to speak. On Friday you will hear about
important methodological issues in interpretation
of these studies, and then we will move on to the
Again, thank you and on behalf of the FDA
I wish you the very best of luck on this important
endeavor. Thanks, Dr. Wood.
DR. WOOD: Thanks a lot. Two additional
people have joined the cast of thousands that we
have at the table, and perhaps it would be worth
having them introduce themselves. Bob, you go
DR. TEMPLE: I am Bob Temple. I am
Director of the Office of Medical Policy.
DR. WOOD: Stephanie?
DR. CRAWFORD: Thank you, Mr. Chair.
Stephanie Crawford--good morning--University of
Illinois at Chicago, College of Pharmacy; member of
the Drug Safety and Risk Management Advisory
DR. SELIGMAN: Good morning. This is Paul
Seligman. I am the Director of the Office of
Pharmacoepidemiology and Statistical Science.
DR. WOOD: Is there anyone else I didn't
notice arrive? No? Then, let's move on to the
next speaker. Jonca?
DR. BULL: Good morning. Again, I would
like to extend a warm welcome to the members of the
committee and to extend and acknowledge a
particular thanks to our staff at FDA, specifically
Dr. Villalba, Dr. Witter, Dr. Schiffenbauer from
our team, our statistical staff, and colleagues in
the Office of Drug Safety who have put in countless
hours in preparation for this meeting.
The NSAID class is one that probably
everybody in this room has a product in their
medicine cabinet that is a member. It is a large
class of marketed products for both OTC and
prescription indication use. It is a wide range of
products with varying risk/benefit profiles. Their
approved indications are for short-term use such as
dysmenorrhea and acute pain; chronic use for
osteoarthritis, rheumatoid arthritis, familial
adenomatous polyposis in the example of Celebrex.
So, clearly, we have drugs that for everyone, from
the young female with cramps to the senior citizen
with arthritic pain, have importance and clearly
there is a need for them in the marketplace. There
are other proposed uses that are known to be under
investigation, and you will hear about studies in
the setting of Alzheimer's disease, as well as
sporadic polyp prevention.
I would like to briefly review some of the
regulatory history for these products, going back
to December of 1986 when there was a public
advisory committee meeting that discussed the
paragraph and databases were discussed at that
This was followed in 1995 where revisions
for the NSAID class label were discussed, as well
as a subsequent advisory committee in 1998 when the
new science of the COX-2s were discussed and their
potential enhanced safety for GI benefit.
In December of 1998 an advisory committee
was held to discuss the data for Celebrex, followed
in December of 1998 when that drug was approved
first in this new class of products. In April of
1999 an advisory committee was held for Vioxx,
followed by its approval in May of 1999. We held
another advisory committee meeting in 2001 which
discussed the large outcome studies which sponsors
had undertaken to further evaluate how clinically
meaningful the data from endoscopic studies was in
order to further evaluate the enhanced GI safety
This time line has several points I would
like to bring to your attention. The first IND for
these products came in 1994 so we are
a relatively short time line, given that this is
year 2005, in drug development, marketing and an
evolving picture for safety.
The products below the time line are the
ones that have been approved, and I would like to
bring your attention to those above the line,
Arcoxia, Prexige, the IV formulation of Bextra
which have not been approved in the United States
due to insufficient safety data.
The COX-2 agents--are they different? In
what way? When we look at risk to benefit, how do
these agents differ from the traditional NSAIDs?
Can a clinically meaningful benefit for GI safety
and less risk, that is for CV risk, renal risk,
hepatic risk, allergy--can that be characterized?
What additional study is needed to better
understand the science of COX-2 inhibition?
When we think in terms of labeling risk
management, what risk management options are
appropriate in this settings, ranging from
potential withdrawal of the product to labeling
Certainly there are lessons learned for
drug development. I cite a quote at the end of an
article by Dr. Temple and Marty Himmel,
in JAMA in
May, 2002, and I think the statement is quite a
relevant one to our deliberation, that no
improvements in drug development can completely
eliminate the risk of unexpected events.
Looking at large NDA databases is helpful
but continued monitoring is essential to assess
evolving risk profiles for new products.
Certainly, the impact of aggressive marketing must
be taken into account for these unknowns of drug
Dr. Galson has already gone through the
schedule for the meeting. I will just briefly
allude to our framework for this deliberation.
Following me, Dr. Byron Cryer will be discussing
the gastrointestinal effects of the NSAIDs and
COX-2 specific inhibitors; followed by Dr. Garret
FitzGerald on mechanisms for cardiovascular risk
from inhibition of COX-2s. This will be followed
by a presentation by Merck and the FDA
by Dr. Lourdes Villalba.
This afternoon you will hear from Pfizer
and their review of cardiovascular safety and
risk/benefit assessment of celecoxib, followed by
the FDA presentation by Dr. James Witter. There
will be a presentation then on the NIH-sponsored
colon polyp prevention trials, with subsequent
presentations by Pfizer on valdecoxib and
parecoxib, and an FDA presentation on valdecoxib.
This will be followed by Bayer and Roche discussing
Tomorrow you will hear about the
epidemiologic studies, followed in the afternoon by
the open public hearing and committee discussion.
Day three in the morning will focus on the
Alzheimer's prevention trials. The ADAPT trial
will be discussed that morning by Dr. Constantine
Lyketsos; followed by a presentation by Dr. Milton
Packer on interpretation of cardiovascular events;
a presentation by Dr. Robert Temple on clinical
trial design and patient safety, future directions
for COX-2 selective agents; and a
Dr. Robert O'Neill on issues in projecting
increased risk of cardiovascular events to the
exposed population. Dr. Sharon Hertz will then
present a summary of the meeting presentations
prior to the afternoon discussion of our questions.
Again, our thanks to the committee members
for taking time from their extraordinarily busy
schedules for this important meeting as we reach
another milestone in the regulatory history of
DR. WOOD: Thanks very much. Let's just
go straight on to the next speaker, who is Dr.
Byron Cryer who is going to talk on the GI effects.
Gastrointestinal Effects of NSAIDs
and COX-2 Specific Inhibitors
DR. CRYER: Thank you. For the purposes
of full disclosure, I would first like it to be
noted that I have been invited to give this
presentation by the Analgesic and Anti-Inflammatory
Division of the FDA. I do have relationships with
sponsors of products being mentioned in
presentation, however, I am not being paid for my
participation in this meeting nor for my
For those of you not familiar with me, I
am a gastroenterologist and I am thrilled that the
FDA has been begun this meeting with the focus on
this subject because many of us have forgotten that
the initial reason for the development of the class
of the COX-2 specific inhibitors was entirely
because of the gastrointestinal effects of the
non-steroidal anti-inflammatory drugs and, for that
reason, I think it is very appropriate that we have
this review of the gastrointestinal effects of
NSAIDs and what the data say from the GI
perspective about the gastrointestinal effects of
COX-2 specific inhibitors.
From the perspective of the NSAIDs risk,
listed here are several of the known risks
associated with the non-steroidal anti-inflammatory
drugs, the gastrointestinal risks, the cardiorenal
risks and the anti-platelet concerns. Among these,
as the group knows, the adverse concerns
greatest risk historically were the
gastrointestinal effects that present with features
such as ulcers, perforations, bleeding, obstruction
strictures and many other interesting
manifestations. Over the last several years, added
to this list and a focus of this meeting are
cardiovascular concerns of the non-steroidal
anti-inflammatory drugs but my perspective are the
issues listed at the top, the gastrointestinal
When looking more extensively at what the
specific gastrointestinal effects of NSAIDs are, we
have learned that NSAIDs have effects throughout
the GI tract. The upper gastrointestinal effects
are the most pronounced but there are some very
interesting effects that we see throughout the GI
tract, such as in the small intestine and colon.
In recent years we have had an increasing focus on
lower gastrointestinal effects of NSAIDs, a very
interesting phenomenon. Several have been assessed
by endoscopic means but there has been a lot of
discussion as to what are the clinically
untoward major events that might happen in the
lower gastrointestinal tract. While this is
debated with respect to the prevalence of lower GI
effects, these effects are likely somewhere in the
range of 10-20 percent of total gastrointestinal
effects that happen within the GI tract
attributable to NSAIDs. Clearly, the major effects
of NSAIDs in the GI tract are in the upper
gastrointestinal tract, such as ulcers more
commonly in the stomach and the duodenum, and
concerns such as gastrointestinal bleeding,
perforations and obstructions. So, that is really
the focus upon which the strategies were developed
to increase NSAID safety within the
With respect to the epidemiology of ulcer
disease in general, some very interesting phenomena
have been observed which have persisted into recent
years. But the overall summary of the phenomenon
that I would like to focus your attention to is
that while in recent years the overall incidence of
uncomplicated ulcers, both gastric and
has been markedly declining in the U.S. and
worldwide, very interestingly, the incidence of
complications, specifically gastrointestinal
bleeding, has not declined in similar proportions
and, in fact, has persisted or increased. This
phenomenon, in particular the bleeding, has been
felt to be a manifestation of the effects of the
non-steroidal anti-inflammatory drugs within the GI
This problem presents itself clearly with
respect to morbidity and, unfortunately, mortality
and several hundreds of thousands of
hospitalizations. The costs have been debated.
The actual quantified amount of mortality in the
U.S. is also a number that is debated. The 16,500
estimate is probably an overestimate. But the
bottom line is that NSAIDs are clearly associated
with morbidity, mortality and costs in this country
as well as worldwide, and this is has been the
issue that has led to the discussions of the need
for increasing gastrointestinal safety for NSAIDs.
So, the various ways in which
assessments have been done has ranged from studies
which we have seen over the years that have been
short-term evaluations of physiologic or
pharmacologic effects on healthy volunteers to the
more relevant studies of the gastrointestinal
effects of these drugs in arthritis patients.
These studies have ranged from long-term endoscopy
studies to a fewer number but very important
studies that have assessed clinical events such as
symptomatic ulcers, GI bleeding, perforation and
Over the years there has been extensive
discussion as to the relevance of the endoscopy
studies and how the endoscopic observations with
NSAIDs might relate to the outcome studies. One of
the criticisms of the endoscopic studies is that
the endoscopic lesions are numerous. They are
mostly only known from endoscopies that are done as
a part of a scheduled study and they are
asymptomatic. However, what we have learned from
comparing the numerous endoscopic studies to
observations that have been seen in the
studies is that the relative proportions in terms
of outcomes seen in endoscopic studies tend to be
predictive of what one would expect to see in an
outcome study. So, we have come full circle then
in our understanding of the role of endoscopic
studies and, at least in the gastroenterology
community, we now feel that there is some
substantial value in endoscopic studies and that
they are predictive of what one might expect to see
in outcome trials.
Now, with respect to what we see in these
types of trials, when one looks endoscopically
there is a range of findings in people who are
taking high doses of NSAIDs. In greater than 90
percent, if one were to look, we would see this
phenomenon of NSAID gastropathy, which is this
constellation of erosions and hemorrhages but it is
mostly asymptomatic, mostly not clinically
With respect to incidences of asymptomatic
endoscopic ulcers, gastric ulcers happen two to
three times more commonly than the
with the ranges that are shown on the slide.
Again, these lesions are mostly asymptomatic and
don't progress in the majority of individuals to
clinically untoward gastrointestinal events.
What these things look like--this is an
endoscopic photograph of gastropathy demonstrating
the constellation of hemorrhages and erosions that,
again, are going to be mostly asymptomatic, ranging
to a picture, shown here, of an endoscopic ulcer
seen in the antrum of the stomach of an NSAID user.
The more clinically concerning endpoint,
that being clinically significant ulcers, occurs
with the non-selective NSAIDs on average about 2
percent, with a range of about 1-4 percent. This
range and this mean are important numbers as
benchmarks to remember because they will become
relevant as we discuss some of the outcome studies
that have been conducted with the COX-2 specific
Having reviewed what the risks are, I
would now like to move the discussion to what our
strategies have been to reduce the risk
gastrointestinal complications with NSAIDs. It is
a simple strategy and most experts will recommend
identifying the patient population who might be at
risk and this is based upon identification of risk
factors. Then, once having identified susceptible
populations for risk, one employs strategies that
would reduce risk, such as either the use of
gastroprotective drugs or the use of safer NSAIDs,
and the category of safer NSAIDs clearly involves
the subclass of the COX-2 specific inhibitors.
With regard to identification of risk
factors, a risk factor not commonly mentioned is
the NSAIDs themselves. NSAIDs clearly provide risk
for gastrointestinal effects. Shown here are
various NSAIDs available by class and by
prescription in the United States. As you can see,
they have been divided into traditional NSAIDs,
non-salicylates; aspirin related, salicylate-based
compounds; and then COX-2 inhibitors which are
currently available, in development or previously
available in the U.S.
With regard to identifying
characteristics which may suggest risk, these have
been extensively studied and they are listed here,
things such as increasing age and the threshold age
is widely debated but one category that has been
suggested would be those greater than 65, let's
say. Clearly history of GI ulceration; having had
a complication; concomitant drugs such as
corticosteroids or anticoagulants; cardiovascular
disease, interestingly, such as CHF; and this issue
of multiple NSAIDs all increase the risk.
Of this list that the group is very
familiar with, the one that has probably not been
as widely appreciated and one which has been
highlighted from some of the outcome trials of the
COX-2 specific inhibitors is this issue of multiple
NSAIDs, and it is a risk factor that presents
itself in the context of a patient profile, a
patient who takes prescribed NSAIDs along with
either low doses of aspirin of over-the-counter
NSAIDs. Since we know that the risk for
NSAID-related gastrointestinal events is related to
dose, what one accomplishes in this group
multiple NSAIDs is essentially to increase the
overall dose of NSAIDs delivered.
With regard to the strategies after having
identified the susceptible population, the first
category essentially is that of co-therapeutic
gastroprotection. As alluded to a minute ago, it
would be desirable to use the lowest effective dose
of an NSAID. Then really the two prevailing
gastroprotective or co-therapy strategies that we
have are the use of either misoprostol or proton
Several studies have been done in either
of these categories. I will just highlight for
purposes of discussion two outcome trials that I
think nicely demonstrate the effectiveness of these
strategies. With regard to misoprostol, the most
widely quoted study was the outcome trial, the
MUCOSA trial in which misoprostol was given to
patients who were chronically taking NSAIDs over 6
months and were demonstrated to be associated with
a 40 percent or less reduction in gastrointestinal
From the perspective of the PPI outcome
trials, there have been fewer evaluations but there
have been, in fact, some evaluations for
relevant outcomes for PPIs, this being one example
of a trial which was actually not intended in its
design to evaluate outcomes of a proton pump
inhibitor in patients taking NSAIDs but,
nevertheless, provided us with some insight into
the potential effects from the perspective of
This was a trial that was designed with
the question in mind of whether or not H. pylori
eradication prior to starting an NSAID would be an
effective therapy or not for the reduction
potentially of NSAID-related bleeds. So, in this
group of H. pylori infected NSAID users, half of
them were treated for their H. pylori infections
prior to being started on an NSAID and acted as a
control. The other half were given a proton pump
inhibitor. In this specific instance omeprazole.
What was observed, very interestingly, at
the end of 6 months is that in this
was a 76 percent reduction in the subsequent
incidence of upper gastrointestinal bleeding in the
group that had received the proton pump inhibitor
From the perspective of the safer NSAIDs,
this is a story that is also well known. Its focus
today is really to look at specifically the COX-2
specific inhibitors shown on the far right. The
concept has been widely discussed and is arguably
somewhat simplistic, but for the sake of today's
discussion, as the group knows, it is highlighted
by the observation that there are 2 COX isoforms
available, COX-2 and COX-1, and that COX-1 is the
isoform which is primarily responsible for the
protective prostaglandins in the stomach which
typically protect against injury. Once inhibited
by non-selective NSAIDs, the prostaglandin products
produced by COX-1 lead to an increased
susceptibility for injury. The concept at least
for COX-2 specific NSAIDs in that they have limited
inhibitory effects on COX-1 is that they would
likely not inhibit prostaglandins, likely
associated with ulcers, and likely be associated
with a reduction in clinically significant
gastrointestinal untoward events with NSAIDs.
Having said that, there have been a few
gastrointestinal outcome trials that have been
designed to evaluation whether or not the COX-2
inhibitors would meet this objective or not. Shown
here are two of the outcome trials with rofecoxib
As the group knows, there has also
recently been another completed outcome trial with
lumiracoxib. In general, the outcome trials have
compared COX-2 specific inhibitors at higher than
usual therapeutic doses for osteoarthritis to
non-selective NSAIDs and evaluated the clinically
significant events on average over a year. The
major difference of importance between the outcome
trials with celecoxib and rofecoxib was the
inclusion or exclusion of low doses of aspirin. We
know that low doses of aspirin are ulcerogenic. In
the CLASS trial 21 percent of patients took low
doses of aspirin, 325 mg/day or less, and
the patients in the rofecoxib experience were
taking low doses of aspirin.
The principal gastrointestinal
observations from the CLASS trial are, as shown
here in this figure, taken from the publication in
the JAMA, which represents the 6-month data point
from this year-long trial. In the top panel are
all the patients who were evaluated in the trial
who were taking either celecoxib or one of the
non-selective NSAIDs, ibuprofen or diclofenac. As
you note, there was a numeric but not statistically
significant reduction in ulcer complications in the
overall group, remembering that 21 percent of the
patients in the CLASS trial were taking low doses
of aspirin and that some of the ulcer effects were
related to the effects of aspirin.
So, to get a better concept of the effects
of a COX inhibitor compared to non-selective
NSAIDs, the middle panel looks exclusively at the
patients in this 6-month evaluation of the CLASS
trial who were not taking aspirin, just celecoxib,
ibuprofen or diclofenac. As you observe in this
middle panel, there were statistically significant
reductions associated for GI outcomes with
celecoxib when compared to traditional NSAIDs in
the absence of aspirin at 6 months.
However, for those of you who were here
four years ago this month at the long-term safety
evaluations of the FDA, the entire CLASS trial data
set was evaluated with respect to gastrointestinal
complications. When compared to either ibuprofen
or diclofenac alone or combined, with respect to
complications there were not statistically
significant gastrointestinal reductions in events
associated, as you can see, with celecoxib.
With regard to the VIGOR trial, just to
refresh the group's memory, this was clearly
exclusively an evaluation of rofecoxib versus
naproxen. There was no low dose aspirin. Their
observations were straightforward in with respect
to either primary or secondary event being
confirmed upper GI events or complicated events.
There was a statistically significant reduction
associated with rofecoxib compared to naproxen.
As I have mentioned, there has also been a
similar in design outcome study with lumiracoxib.
The variable observations between these
trials have led to extensive debate in the medical
and scientific communities as to why one might have
observed differences with respect to
gastrointestinal endpoints between the outcome
trials of COX-2 specific inhibitors.
While I don't have time to get into the
nuances and specifics of that debate, one point
that I would like to bring to the group's attention
that I do think is worthwhile reviewing is that, to
the extent that there were differences between the
observations in the outcome trials, these
differences may have had more to do with
differences in ulcerogenic effects with the
traditional NSAID comparators such as naproxen,
ibuprofen and diclofenac than they may have had to
do with differences with respect to ulcerogenic
effects between rofecoxib and celecoxib.
The point to be highlighted is that the
non-selective NSAIDs differ with regard
ulcerogenic effects and that the delta, the
difference observed between a COX-2 inhibitor and a
non-selective NSAID will matter, and it will be
based upon the choice of comparator being used. I
am not here to speak about cardiovascular effects.
Dr. Garret FitzGerald will talk about
cardiovascular issues in the talk to follow. But I
would like to point out that this concept of
differences in COX-1 effects of non-selective
NSAIDs is also applicable when we turn to a
discussion of considerations of potential
differences in cardiovascular observations between
the trials of COX-2 inhibitors.
Having pointed out the data with the COX-2
specific inhibitors, I would like to mention that
there are other potential approaches, and I would
like to turn the discussion to a consideration, as
shown on the bottom, of potentially older, safer
NSAIDs that may be associated with gastrointestinal
safety, agents such as the non-acetylated
salicylates, nabumetone, diclofenac and etodolac.
I mention this because--these
gastrointestinal events, this is a reflection of in
vitro evaluations of COX-1 versus COX-2 selectivity
of various NSAIDs. On the left, in the green, are
NSAIDs which have increasing in vitro COX-1
selectivity and are going in the negative
direction; on the right, is increasing COX-2
selectivity. When one evaluates COX-2 selectivity
in vitro, there is a group of NSAIDs which fall
within this mid-range category of what I would call
moderately COX-2 selective, and this COX-2
selectivity of agents such as meloxicam or etodolac
may be predictive of what one might see in outcome
Taking etodolac as an example, when it was
evaluated with respect to gastrointestinal outcomes
compared to a non-selective NSAID such as naproxen,
shown in the upper panel, there was a statistically
significant, greater than 50 percent, reduction in
gastrointestinal outcomes associated with an agent
such as etodolac. So, this leads me to conclude,
over here in this group of category for COX-2
specific inhibitors, that there are
have COX-2 selective activity which had not been
widely appreciated historically.
Since aspirin was such and important
phenomenon in outcome trials, I think it is
relevant to review the gastrointestinal effects of
low doses of aspirin. This has been looked at
mostly from an epidemiologic perspective, and
trials such as this have tended to show a
dose-response relationship. Although not
statistically significant in this case, clearly
lower doses, at least numerically, of aspirin such
as 75 mg were associated with a lower rate of
clinically relevant gastrointestinal bleeding than
higher doses such as 300 mg. In this instance, at
least numerically from 75 to 300 mg, the odds ratio
of clinically relevant upper gastrointestinal bleed
Because of the risk associated with very
low doses of aspirin such as 75 mg, doses of
aspirin that have been quite low, such as 10 mg,
have been evaluated in human studies to assess the
question of whether or not there would be
orally administered dose of aspirin which would be
without gastrointestinal effects.
When measured by use of an intermediate
marker that would be of COX inhibition or
measurement of gastrointestinal prostaglandins,
daily doses of aspirin given out to 3 months, as
low as 10 mg, were associated with as great of a
reduction of gastrointestinal COX as seen with 320,
and gastric ulcerations were observed with a dose
of aspirin that was as low as 10 mg, suggesting
that there is likely not a dose of aspirin that
would be effective that would be daily administered
that would be without gastrointestinal risk.
Another commonly asked question would be
the potential benefit of an enteric coating or
buffered preparation of aspirin. When assessed in
this cohort from the Framingham trial of patients
who were taking various formulations of low dose
aspirin, as one sees that there was no appreciable
reduction in gastrointestinal bleeding associated
with either enteric coating of aspirin or buffered
aspirin when compared to plain,
non-buffered aspirin preparations.
Coming back to the risk factor which I
mentioned had been not widely appreciated, the risk
factor of multiple NSAID use, that is, combining
low dose aspirin with a non-selective NSAID or
COX-2 specific inhibitor, I think it is valuable to
appreciate for a moment the actual risk, numerical
risk, contributed by the addition of aspirin to
another prescribed NSAID.
From this population study in Denmark, it
was apparent that when one combines the use of low
dose aspirin and a non-selective NSAID the risk of
having a clinically significant bleed, upper
gastrointestinal bleed, more than doubled, such
that several people would feel that the risk of a
6-fold increase in the combination of a
non-selective NSAID plus aspirin is sufficiently
high that this population of users would need to be
further risk reduced.
These are data with non-selective NSAIDs.
The data with respect to COX-2 specific inhibitors
have come primarily from a few
sources. In this
previous figure in which we saw earlier the 6-month
data from the CLASS trial we stopped with the
middle panel and had events in individuals taking
celecoxib or non-selective NSAIDs in the absence of
But when one looks at the bottom panel,
rates of events, complications or symptomatic
ulcers and ulcer complications in individuals who
were taking one of these agents in the face of low
doses of aspirin, it is clear that the use of low
dose aspirin in the face of a COX-2 specific
inhibitor markedly increased the rates of
But a point that I would like you to focus
your attention on is the actual incidence of events
in the patients who were taking either aspirin in
combination with a COX inhibitor or non-selective
NSAID. You will remember that the problem that led
to really the focus and development of classes of
safer NSAIDs is an incidence of ulcer complications
of 1-4 percent in the population that takes
non-selective NSAIDs. When one looks at the
incidence of events that occurs annualized in
patients who take aspirin, at least derived from
the data in the CLASS trial, it is clear that the
incidence that was observed of 2-6 percent is
higher than the original problem.
So, I would like to summarize with respect
to the effects of low dose aspirin that low dose
aspirin clearly increases the risk and mitigates
the potential gastrointestinal beneficial effects
of a COX-2 specific inhibitor. These observations
have been seen in other experiences with regard to
the total lack of outcome data which I previously
showed you, where we stopped on the top panel.
When looking at the observations in patients taking
low doses of aspirin, the beneficial effects of
total lack disappear.
In endoscopic trials recently we have also
seen this effect of aspirin in this trial over 12
weeks in which either aspirin was given alone or in
combination with rofecoxib and compared to
ibuprofen. Focusing on the rofecoxib plus aspirin
comparison, rofecoxib plus aspirin users
similar, equivalent incidence of endoscopic
ulcerations to non-selective NSAIDs such as
ibuprofen. So, the short conceptual way of
summarizing this is a COX-2 specific inhibitor plus
aspirin equals the effects of a non-selective
The gastrointestinal discussion that we
have had so far has pointed out some of the
potential gastrointestinal effect benefits of a
safer class of agents such as a COX-2 specific
inhibitor. Clearly, the gastrointestinal benefit
does not exist in the face of aspirin and what we
have recently learned is that the gastrointestinal
benefit derived from a class of safer agents in the
GI tract might be mitigated by adverse events in
other areas, and other areas for consideration for
this week's meeting are potential cardiovascular
Given the limitations of COX-2 specific
inhibitors and low dose aspirin users or when there
may be potential cardiovascular concerns, one
question that we have been asked to
be in a potential world of no COX-2 specific
inhibitors would we return to the problem of
several gastrointestinal bleeds, hospitalizations
Well, this brings us back to the question
of what might be the other approaches to accomplish
the objective of reductions in GI events. We have
discussed some of the older, safer NSAIDs. There
are NSAIDs in development such as nitric oxide
NSAIDs or phosphatidylcholine NSAIDs, the effects
of which we are unsure of now and they are
currently being evaluated. But the other
prevailing strategy to accomplish this objective
would be the consideration of a non-selective NSAID
plus co-therapy with either a proton pump inhibitor
Data in support of the proton inhibitor
approach have been looked at in several trials, one
example of which is shown here, endoscopic
ulceration in NSAID users receiving co-therapy with
either placebo, a proton pump inhibitor or
misoprostol. What the data pretty consistently say
is that proton pump inhibitors have similar ability
to misoprostol to prevent recurrent ulceration in
Given that there are two prevailing
approaches to accomplishing GI safety, either COX-2
specific inhibitor alone or a non-selective NSAID
plus a PPI, an important question which has
presented itself for evaluation has been how might
these two approaches compare directly and this is
an important question to consider when considering
the alternatives to having a world potentially in
which there might not be COX-2 specific inhibitors
available. Could GI safety be accomplished?
Well, this question has been asked at
least in two trials or similar design in which high
risk NSAID users--high risk being defined as people
who previously had a history of bleeding ulcers.
Once the ulcers were healed, they were then placed
on either of the combination of non-selective NSAID
plus a proton pump inhibitor or a COX-2 specific
inhibitor, and then were followed for 6 months for
rates of recurrent gastrointestinal
results of one of these trials has been fully
published in a peer reviewed journals, shown here.
The two endpoints being looked at--on the
right are outcomes such as upper gastrointestinal
bleeding; on the left are the results of endoscopic
ulceration. Either of these endpoints tells us
that the approach of a non-selective NSAID plus a
PPI appears comparable to the COX-2 specific
inhibitor approach for achieving the objective of
reductions in GI safety. However, two important
points that I would like to point out to the group
are, one, we have endoscopy on the left and
outcomes, GI bleeding, on the right. Again, the
endoscopic ulcerations that are seen in the trials
generally predict what one would see in an outcomes
study but, more importantly, if one looks at the
actual rates of events which occurred, on the
right, 5 percent and 6 percent with either approach
in a group of individuals at high risk, meaning
they previously had a history of gastrointestinal
bleed, it is clear that either approach, either
NSAID plus PPI or COX-2 specific
sufficiently adequate to reduce the rates of events
back to a comfortable range. The rates of events
seen here in a high risk population are similar to
the initial problem for which these approaches were
In conclusion I have several observations.
The untoward gastrointestinal effects of NSAIDs, as
we know, cause considerable morbidity, mortality
and cost. Secondly, COX-2 specific inhibitors were
developed principally to achieve a reduction in
NSAID gastrointestinal toxicity. That was a very
desirable objective to be reached. But very
interestingly, as we just reviewed, this objective
has been partially reached. It seems that the risk
reduction may not be achieved to the extent that we
would have liked in patients who are at high risk
for gastrointestinal bleeding, and the reason this
is important is that that is clinically the target
group of interest for risk reduction.
Paradoxically, I did not mention that if
one looks at subgroup analyses of outcome studies
it appears that people who are at lower
gastrointestinal risk do have a benefit from
receiving a COX-2 specific inhibitor. However, the
low risk group has a low prevalence of this problem
of NSAID-related gastrointestinal events in the
So COX-2 inhibitors, it appears, have been
widely used by patients who are not at high risk
for GI effects, and we have reviewed over the last
several minutes that there are some limitations
with COX inhibitors. In my opinion, there is no
great clinical need for COX-2 specific inhibitors
in patients who are at baseline at low GI risk. It
is also clear that there is no GI benefit in
patients who are concurrently taking aspirin. We
are here to discuss the possibility that
cardiovascular concerns may exist for some groups
So, the strategies to reduce the
gastrointestinal effects of NSAIDs should focus on
patients at greatest risk. Just to reiterate, the
patients at greatest risk may not be sufficiently
risk reduced by either of the prevailing
which we currently have available clinically. For
such patients, COX-2 specific inhibitors may be an
attractive option but it looks like the target
group of interest may not have the anticipated
For patients who are taking low dose
aspirin or, if cardiovascular concerns were to
exist, we have been asked to consider that if there
were a world without COX-2 specific inhibitors how
might we accomplish this objective, and it is clear
that there are other strategies available that may
lead to a reduction in NSAID GI effects. Thank you
DR. WOOD: Thank you very much. Byron,
could you just stay there in case there are
specific questions for you while the slides are up?
I have one. Could you put up slide 4 again? That
shows data through 1990.
DR. CRYER: Yes.
DR. WOOD: What surprised me is Jim Freis
has updated that data through 2000, and that
dramatically changes what that slide
In fact, he found a 67 percent decline since 1990
in complicated ulcers, the vast majority of which
occurred actually before COX-2 specific inhibitors
went on the market. So, I am interested, first of
all, in why you chose to present 15-year old data
when there is new data out there that contradicts
that, and whether you would like to comment on his
publications from which this data came as well.
DR. CRYER: Sure. It is correct that
there are newer data available that have
demonstrated a reduction in gastrointestinal bleeds
on a population basis. On the other hand, it is
also very true that this problem of
gastrointestinal bleeding with NSAIDs continues to
be a significant problem despite its more recent
decline. But, more importantly, he also
highlighted a very important observation which is
that the declines in gastrointestinal bleeding that
have been seen in populations preceded the
introduction of COX-2 specific inhibitors, and
there are some data sets to suggest, at least in
the U.S., that hospitalizations for
gastrointestinal bleeding since the introduction of
COX-2 specific inhibitors have not markedly
declined compared to hospitalizations prior to
DR. WOOD: Right. So, most of the 67
percent decline occurred before these drugs went to
the market, and that 67 percent occurs from the
points on your slide here.
DR. CRYER: Point well taken.
DR. WOOD: And one other point of
clarification I guess, the data you showed from
CLASS, was that data from the predefined endpoint
of the study at 18 months or the 6-month analysis
that was published?
DR. CRYER: Just for sake of review, I
have pointed out both time-dependent endpoints.
The endpoint that was published and shown here, in
the JAMA, was the predefined 6-month data and the
endpoints that are shown here represent an
evaluation of the entire data set. There are
clearly differences in the conclusions about the
effects of celecoxib which varied by time
varied by whether one evaluates the data at 6
months or evaluates the entire data set.
DR. WOOD: Just remind us, at 18 months
what did the data set show?
DR. CRYER: At 13 months the data, with
respect to complications, indicate that there was
no statistically significant reduction in upper
gastrointestinal complications associated with
celecoxib, at a dose of 400 twice daily, when
compared to either diclofenac or ibuprofen
individually or when compared to both of them
together. I will point out for the sake of fair
balance that this data does include the 21 percent
of individuals who were taking low doses of
DR. WOOD: Other questions from the
committee? Dr. Nissen?
DR. NISSEN: Yes, this 1-4 percent rate, I
am interested in understanding the time-dependent
hazard. If a patient is put on a non-selective
NSAID and, let's say, for the first year has no GI
events, is the risk in the second and
fourth years the same as it is in the first year?
In other words, once you know that a patient is
tolerating an NSAID are they no longer at high
DR. CRYER: There are a few answers,
sub-answers to that question. It is a complicated
discussion. What is clear that risk persists, that
even in the individual who did not develop a
complication in year one, that individual continues
to have risk in subsequent years--two, three, four,
etc. There are data sets that suggest that the
period of highest susceptibility, highest risk is
within the first three months of administration.
Having said that, there are other data sets to the
contrary. This incidence of gastrointestinal
events that are time-dependent in individuals has
been difficult to assess primarily based upon a
concept of selection of susceptible individuals.
People drop out because of other reasons such as
dyspepsia. So, it is difficult to get a firm
estimate on that. But it is clear, in summary,
that the risk after one year or after any
time is always persistent as long as the NSAID
exposure is present.
DR. NISSEN: Two more quick questions. I
didn't see any analysis of COX-2 plus low dose
aspirin versus a non-selective NSAID plus low dose
aspirin. The reason I am asking that is that, as a
cardiologist, in my patients who are taking
conventional NSAIDs, if they need aspirin for
cardiovascular prophylaxis I give them aspirin.
So, the question is are there any studies looking
at NSAID plus aspirin versus COX-2 specific
inhibitor plus aspirin?
DR. CRYER: Well, the CLASS trial
addressed that question in a subpopulation of
individuals which was under-powered statistically
to give a definitive answer to that question. That
is an ongoing debate within the medical
communities. I will say, however, that while the
debate continues what is clear is that with either
approach COX-2 specific inhibitor plus aspirin or
non-selective inhibitor plus aspirin the ensuing
rates of gastrointestinal events are too
us to feel comfortable that we have risk-reduced
those patients sufficiently.
DR. NISSEN: And a final question,
symptoms of dyspepsia are obviously one of the
issues as well, and I want to make sure I
understand what fraction of the population, let's
say an osteoarthritis population, simply cannot
tolerate NSAIDs because of GI discomfort. Do we
have data on that?
DR. CRYER: Sure. A couple of comments
about dyspepsia which I didn't mention, NSAID
dyspepsia is common. Its prevalence varies
depending on how dyspepsia has been defined in
trials, and because there have been variable
definitions of dyspepsia, its reported rates have
varied anywhere from 10-30 percent of NSAID users,
but it is clearly more common than complications.
In the patient who has dyspepsia, the
presence of dyspepsia is not predictive of the
patient who might have risk. In most of these
studies dyspepsia, in my way of thinking, is
considered more of a nuisance issue that
controlled symptomatically with acid reduction
rather than something that presents significant
DR. WOOD: Dr. Gibofsky?
DR. GIBOFSKY: You commented extensively
on the upper GI risk but in your second slide you
correctly pointed out that there are problems with
traditional medications affecting the structures of
the GI tract below the ligament of triads. Could
you comment somewhat on the data comparing the
effect of COX-2 specific inhibitors versus
traditional non-steroidals with or without proton
pump inhibitor protection on the lower GI tract?
DR. CRYER: There have been fewer data
sets which have assessed the lower gastrointestinal
events with NSAIDs. A few comments on the types of
studies that have been done, there have been
studies using pill endoscopy which have indicated
that lesions, endoscopic ulcers and erosions occur
in the lower gastrointestinal tract contributed to
by non-selective NSAIDs, an effect which can be
reduced by a COX-2 specific inhibitor, an
which is not reduced by the co-therapy approach of
adding a PPI to a non-selective NSAID. I am
speaking of the lower gastrointestinal effects.
Having said that, again similar to the
endoscopic ulcer story, these endoscopically
detected lesions in the lower gastrointestinal
tract probably have very limited clinical
relevance. When lower gastrointestinal clinically
significant events have been assessed from the
prospective trials, the one noted most commonly in
the literature is an assessment of the VIGOR trial
looking at the effects of rofecoxib compared to
naproxen, in which case a 40-50 percent reduction
was seen in lower gastrointestinal events with
rofecoxib compared to naproxen, again to reiterate,
a reduction which would not be expected to be
observed with the proton pump inhibitor approach.
Having said that, in that assessment of
the rofecoxib experience there was an inclusion in
the definition of lower GI events of individuals
who had had reductions in hemoglobin and hematocrit
and who did not otherwise have clinically
Probably the best assessment in terms of
the risk of lower gastrointestinal events on NSAIDs
comes from population-based observational studies.
While there is variance in that estimate, it looks
like the lower gastrointestinal events probably
contribute 10-20 percent of clinically relevant
events when compared to all GI events that might
happen on NSAIDs.
DR. GIBOFSKY: One last quick point, would
your recognize that there might well be a
population of patients whom you would stratify as
low GI risk who, nevertheless because of either
intolerance, as the last speaker asked, or lack of
efficacy to traditional non-steroidals, would be
candidates for another class of agents?
DR. CRYER: Sure. Their NSAID dyspepsia
is a common phenomenon. I will say that when
dyspepsia has been carefully evaluated in the
prospective trials of COX-2 specific inhibitors in
general there tends to be a reduction in the rates
of dyspepsia associated with the COX-2
inhibitors. However, when one evaluates the
absolute reduction in rates of dyspepsia in the
trials it generally tends to be a few percentage
points. Finally, some of the other strategies that
were mentioned to accomplish risk reduction, for
reduction in GI events in patients on NSAIDs, also
accomplished reductions in dyspepsia in patients
who might experience NSAID-related dyspepsia.
DR. WOOD: Dr. Cush?
DR. CUSH: Byron, two time questions.
One, is there a time point at which peptic
ulcerations and bleeds plateau over time in NSAID
users or COX-2 users? Second, what is the longest
data set that we have as far as the use of a COX-2
agent in a clinical trial where observation is
carried out? Do we have two-year data; five-year
DR. CRYER: Right. There does appear to
be some plateau-ing of the effect. The data sets
do suggest that after long-term exposure the rates
of events with longer-term exposure are not as
great as rates of events with initial
NSAIDs but, again, that may be attributable to the
phenomenon of dropping out of susceptibles. The
second portion of your question, Jack, was?
DR. CUSH: What is the longest data set we
have on COX-2 agents?
DR. CRYER: Well, when one looks at the
trials, the prospectively defined outcome
trials--we have CLASS, TARGET, VIGOR--there are
periods of observation out to 13 months. Having
said that, we certainly have longer periods of
observations of COX-2 specific inhibitors for
trials in which the specific outcome of interest
was defined for an endpoint that was other than
upper GI bleeding, so specific polyp reduction,
Alzheimer's disease, other trials that we certainly
will hear about over the course of the next few
days, many of which have gone out to periods as
much as 3 years.
DR. WOOD: Is there anyone else who has a
question that specifically addresses something on a
slide that the speaker could show again? If not,
we will come back to these questions and
Byron, if you would, to be available this
DR. CRYER: Yes.
DR. WOOD: Are there any questions that
somebody has specifically? Tom?
DR. FLEMING: Yes, could we go back to the
slide that showed the CLASS trial with the time to
DR. CRYER: There were two. You can tell
me which one you are referring to, this or the
DR. FLEMING: Both, this and the next.
Basically, here what you are showing us is that in
the presence of aspirin there doesn't seem to be a
reduction in the complicated ulcers although in
those that are not taking aspirin there is this
reduction of about two-thirds. If you go to the
next slide, that is at 6 months. Hence, we see at
6 months this reduction in the rate in the
celecoxib group that is driven by those patients
who are not on aspirin. But that effect, as you
noted, has disappeared out at a year.
I know that is making a lot of a single
data set but is this suggestive of the possibility
that, in response to Steve Nissen's
could be a group that is more susceptible and what
you are doing, in the presence of aspirin, is
achieving not effect; in the absence of aspirin you
are achieving a delayed effect but, in essence, you
are going to have the same overall incidence by a
year even with the COX-2 specific inhibitor?
DR. CRYER: Sure, your point is that there
are likely subgroups of susceptibility for GI risk
on NSAIDs or on COX-2 specific inhibitors. But I
would say also that underlying that argument, which
I think is accurate, is the observation which
confounds the whole discussion, which I have
mentioned previously, which is that early on in any
of these trials you are going to remove the most
susceptible of the individuals and those who
actually persist in the trial tend to be the least
DR. FLEMING: Indeed, but that is the
essence of what I am saying, and this
consistent then with the theory that if there is a
particular susceptible group, that group is going
to have a higher risk and it is, in fact, going to
have complicated ulcers. They just occur somewhat
sooner with the non-specific NSAIDs. The COX-2s
are not preventing that, they are just delaying the
time to the occurrence.
DR. CRYER: I think we are in agreement
DR. WOOD: Richard?
DR. PLATT: To extend that, on slide 13
you list some risk factors for NSAID-associated GI
toxicity. Can you tell us how well those
discriminate low risk individuals from high risk
individuals? And, if they do, what fraction of the
population falls into low risk, medium risk, high
risk? And, quantitatively what are those risks?
DR. CRYER: That is a complicated question
but it is an important one. When people like
myself have shown these risks we commonly lead to
the assumption that these risk are numerically
equivalent, which they are not. There are certain
risk factors which clearly place one individual at
higher risk than others. The highest risk most
consistently seen in trials would be that of having
had a previous history of a gastrointestinal
bleeding ulcer. But not far behind that would be
the risk of taking an anticoagulant, such as
Coumadin, in association with a non-selective
NSAID. Age as a risk factor is a variable one.
Although we suggest in our discussions of this that
there may be a threshold of age below which one may
be not at risk and above which at risk for having
it. In fact, it is a continuum. In fact, the risk
contributed by age is about a 2 percent increase in
risk per decade of life, such that people who are
in their 80s are at very high risk, much higher
risk than people who are in their 40s.
With respect to your question of
quantifying the risk in a population, that is a
difficult issue because all of these risk factors
do not individually present themselves in any one
patient. The more risk factors one has--two risk
factors present greater risk than one;
greater than two. I would say, having said that
and trying to give you a reasonable estimate, in my
opinion the percentage of NSAID users who would
likely be candidates for this is probably somewhere
on the order of 20-25 percent, depending on how one
assesses that. If one looks at an OA or RA
population and concludes that age in and of itself
is a risk factor, then you are close to 80 or 90
percent of the population that might be at risk
based upon that risk factor of age. So, it really
depends on which risk factor, and it really depends
on the quantitative contribution of the risk factor
being described. But, certainly, I would say the
one that most clearly and consistently has
presented itself as highest risk in the various
trials has been the risk factor of having had a
previous bleeding ulcer, and it is the one that I
would like to underscore which does not appear to
be sufficiently risk-reduced by either of the
strategies which we have available.
DR. WOOD: Any other questions that are so
burning that they have to be asked now
and not in
the discussion? Ralph? Burning? And let's try
and make the answers as brief as we can.
DR. D'AGOSTINO: What are the consequences
of complicated ulcers in, say, the CLASS trial
where you do see this differential and this
catching up? Do they follow to see the
consequences of these ulcers? Were they different
over the time period?
DR. CRYER: I am sorry, I don't
DR. D'AGOSTINO: What are the
consequences? What happened to these subjects
after? Were they reversible, the ulcer? Does it
lead to mortality?
DR. CRYER: Right, what I assume is
driving your question is whether there are
differences in mortality--
DR. D'AGOSTINO: Well, morbidity,
mortality, what happens.
DR. CRYER: Well, clearly, morbid effects
are hospitalization and the complications of them
having a massive gastrointestinal bleed,
be several. The ultimate complication or
consequence of these morbid effects is mortality
and in these outcome trials there were no
differences in the level of mortality. With regard
to the various other consequences, most of them are
clearly going to be reversible after having
suffered a significant hospitalization.
DR. WOOD: Any other smoking questions?
DR. GROSS: A question on the third to
last slide, on recurrent ulcer bleeding in high
risk patients, the so-called non-selective NSAIDs
selected diclofenac to compare with celecoxib.
DR. CRYER: Yes.
DR. GROSS: Diclofenac is roughly
comparable in COX-2 selectivity. Is that the right
drug to test with PPI to show that the PPI plus a
non-selective NSAID is comparable to a COX-2
inhibitor like celecoxib? Should they have picked
a non-selective NSAID that was less selective for
DR. CRYER: Sure.
Your point is very well
taken and it is one which I tried to underscore
throughout the talk, which is that there are
clearly differences in the COX-1, i.e.,
ulcerogenic, effects of non-selective NSAIDs.
Diclofenac clearly is an agent which is associated
with a lower rate of gastrointestinal ulceration
and complications than non-selective NSAIDs. So,
in this evaluation of the comparison of diclofenac
plus omeprazole compared to celecoxib there is a
valid discussion that the results may have been
biased in favor of the diclofenac plus omeprazole
The reason I showed that is that that was
a fully published paper. There are, however, other
trials not yet fully peer reviewed, which have been
presented in the gastrointestinal community,
looking at other NSAIDs, such as naproxen plus a
proton pump inhibitor compared to the COX-2
specific inhibitor approach, and the results of
those observations again are comparable endpoints
between the two strategies.
DR. WOOD: I am going to move us on now
and we will come back after the next talk. Dr.
Cryer, we would like you to come back up if there
are questions at that time as well. The next
speaker is Dr. Garret FitzGerald. Garret?
Mechanism Based Adverse Cardiovascular Events
and Specific Inhibitors of COX-2
DR. FITZGERALD: Thank you, Dr. Wood. You
are, please, going to have to forgive me, I feel
quite nauseated; I have a touch of the flu and I
took a medicine to reduce my temperature, but I am
not prepared to tell you what it is!
I would like to thank Dr. Wood and the FDA
and the committee for the opportunity to visit
Gaithersburg at this time of the year.
When I boarded the Metro last night at
Union Station and began the apparently interminable
trip to the sylvan embrace of Shady Grove I thought
to myself it might be useful to try and summarize
for you a message that will derive from my talk.
The message is that, just as low dose
affords cardioprotection and a small but absolute
risk of serious GI bleeds, as you heard from Byron
just now, through inhibition of COX-1, so specific
inhibitors of cyclooxygenase-2 afford
gastroprotection and a small but absolute risk of
cardiovascular events. So, I have titled my talk
mechanism-based adverse cardiovascular events and
specific inhibitors of COX-2.
Well, as every lawyer and broker and
journalist knows, this is the cyclooxygenase
catalyzed pathway of arachidonic acid metabolism.
Arachidonic acid is mobilized for release from cell
membranes by activation of phospholipases and it is
subject to metabolism by two enzymes which we call
prostaglandin JH synthases 1 and 2 but which are
known more commonly as cyclooxygenases 1 and 2.
They give rise to a series of lipid products called
prostaglandins which activate receptors and have
very diverse biological effects.
One of the reasons we are here is that
this, although depicted in a very simplistic way,
is actually a quite complex system. To illustrate
that, I will just mention two of these lipid
products, prostaglandin E-2 and prostacyclin or
prostaglandin I-2. When formed by
cyclooxygenase-1, these two lipid products afford
gastroprotection, and our thinking is that the
common GI adverse events of typical non-steroidal
anti-inflammatory drugs reflect the inhibition of
COX-1-derived PGI-2 and PGE-2, thereby, exposing
people to gastroduodenal liability.
But it turns out that when the very same
lipids, prostacyclin and prostaglandin E-2, are
formed by cyclooxygenase-2 as opposed to
cyclooxygenase-1 they mediate pain and
inflammation. Indeed, it is the suppression of the
formation of these two prostaglandins by COX-2
inhibitors that retains the anti-inflammatory and
analgesic efficacy of traditional non-steroidal
anti-inflammatory drugs which inhibit the two
But it turns out that these two
prostaglandins, prostaglandin I-2 and prostaglandin
E-2, formed by cyclooxygenase-2 also
cardioprotection which can manifest itself in
various ways, and suppression of that capability is
the cogent mechanism which explains the
cardiovascular hazard which has emerged.
Well, I am sure this audience well knows
that cyclooxygenase-2 inhibitors do not inhibit
platelet aggregation, a way that we look at
platelet activation in people that have been
administered drugs. This just illustrates the
absence of an effect at several doses of celecoxib
in healthy volunteers compared to the inhibition of
this signal by a mixed inhibitor at the time of
peak drug action. Of course, that reflects the
absence of cyclooxygenase-2. There should be a big
shade here on this Western Blot if it was present
but, unlike cyclooxygenase-1, which is there in
abundance, cyclooxygenase-2 is not present in
mature human platelets.
The wrinkle in all of this is that if you
look at two structurally distinct members of the
class of COX-2 inhibitors, the depression of the
formation of that protective lipid,
as reflected by urinary excretion of its major
metabolite which, believe it or not, is the gold
standard of how you look at prostaglandin formation
in people--this depression is comparable on
specific inhibitors of COX-2 with the depression we
see with structurally distinct mixed inhibitors
like ibuprofen and indomethacin.
So, one might logically deduce from this
that even under physiological conditions, never
mind under conditions of pathology, a COX-2 might
be induced by cytokines for example. It is a
dominant source of prostacyclin. We hypothesized
at the time that that reflected a mechanism which
had been described in vitro by Topper and Jim
Broney and which is illustrated here, which is when
you subject endothelial cells to laminar shear
force, which mimics the effect of the blood stream
on the lining of blood vessels, you up-regulate the
Well, that raised a question rather than
answered a question even though it anteceded the
approval of the first of these
drugs. The first
proof of principle that prostacyclin did actually
modulate cardiovascular function in vivo stems from
this study where we used mice lacking the
prostacyclin receptor, known as the IP, or the
thromboxane receptor, known as the TP, or both
together. Thromboxane is the lipid which is formed
by COX-1 in platelets and has harmful effects on
the heart and cardiovascular system, and
suppression of thromboxane reflects the
cardioprotection of low dose aspirin.
In these studies we looked at the response
to vascular injury in mice and we found that there
was a signal of increased proliferation in response
to vascular injury in the mice lacking the
prostacyclin receptor which accorded with its in
Furthermore, when you injure the lining of
a blood vessels in a mouse, just as if you do it in
humans by performing an angioplasty, you get an
attendant increase in platelet activation which is
reflected by a time-dependent increase in excretion
of a major thromboxane metabolite. We were
interested to see that this signal was grossly
augmented in the absence of the prostacyclin
receptor, and that all of these reflections of the
phenotype could be rescued by co-incidental
deletion of the thromboxane receptor along with the
Now, these studies were criticized as to
their relevance to the COX-2 inhibitor story mainly
because people said, well, you have taken away the
prostacyclin receptor but when we give the drugs,
although we suppress prostacyclin, we do it to a
substantial but incomplete degree, maybe 60-80
percent on average.
So, we performed these studies in another
model of induced thrombogenesis in mice where we
injured the vasculature in a free radical catalyzed
fashion. In these studies we looked at the effect
of a biochemically selective regimen of a COX-2
inhibitor, and we found that the response time to
the thrombogenic stimulus was significantly
accelerated. Furthermore, as opposed to looking at
the absence of both copies of the
receptor, we looked at the effect of deletion of
just one copy and we found a significant and
More recently we have devised a technique
which permits us to remove cyclooxygenase-2 from
particular cells. What I am showing here is the
removal of only one copy of cyclooxygenase-2 from
endothelial cells. As you can see, that also
accelerates the response to a thrombogenic
stimulus. So, these new studies are proof of
concept of precisely the mechanism that we
Well, I think this is a point that we will
come back to. We have some scientific evidence
that there is a very non-linear relationship
between inhibition of the capacity of platelets to
make COX-1 derived thromboxane and inhibition of
thromboxane-dependent function, that is,
To get into the red zone for inhibition of
platelet function you certainly have to be in
excess of 95 percent inhibition of
like up in the 98 percent range. Where we have
actually almost no experimental evidence is whether
there is a discordance between that and the
relationship between inhibition of prostacyclin and
inhibition of its protective cardiovascular
function. Perhaps the intermediate phenotype of
the prostacyclin receptor deleted mice losing one
copy of the gene may suggest that that is so.
So, we are back in the mouse model of
induced thrombosis. The reason I am showing you
this slide is that a theme that will recur and is
relevant to the clinical consideration is whether
inhibition of COX-1, along with inhibition of
COX-2, modulates the implications of inhibiting
So, in these studies we have looked at the
rescue from thrombosis induced by intravenously
administering arachidonic acid to mice at two
different doses in mice that either lack completely
COX-1 or in mice that lack 98 percent of the
capacity to make COX-1 derived thromboxane by
platelets. As you can see, these two genetically
modified mice behaved very similarly in terms of
the rescue from arachidonic acid induced thrombosis
or, indeed, the time to complete occlusion induced
by the thrombogenic stimulus I showed you in the
earlier slide. This accords with that
non-linearity of the relationship for COX-1 that I
showed you. You would expect that to be suppressed
in the 98 percent inhibited mice.
Now, that is all very well because it is
in mice. So, you would way, well, how would we
address this in terms of seeking a proof of concept
in people? Well, if you delete the prostacyclin
receptor mice don't fall over dead with thrombosis.
They are more responsive to thrombogenic stimuli.
So, if you wish to seek proof of concept in people,
you would move to a population that had hemostatic
activation and you would postulate that in such a
population you would detect a signal faster and in
a smaller study than might otherwise be the case.
Indeed, given the widespread recognition
that patients undergoing coronary-artery bypass
grafting exhibit hemostatic activation,
suggestion also that they may be a model of aspirin
resistance, it is perhaps unsurprising that we are
able to detect a clear signal of cardiovascular
hazard in two placebo-controlled trials in this
Now, when I think of people at risk of
thrombosis when one is considering where one goes
with these drugs, I tend to think of middle-aged or
elderly people who have suffered a myocardial
infarction or stroke. But I think it is important
to remember that risk of thrombosis can manifest
itself in susceptibility to this cardiovascular
hazard of these drugs in other populations.
This is a ventilation perfusion scan of a
23 year-old athlete who had been on the pill for 3
years, who went on a 6-hour car journey, having
been put on valdecoxib for the antecedent 8 days
and, at the end of the trip, developed left-sided
chest pain; was misdiagnosed and continued on
valdecoxib for another 10 days; had right-sided
pleuritic chest pain that led to this VQ scan.
This is purely an anecdote but
to mind that individuals who have environmental
predisposition to thrombosis, with a relatively
small absolute risk such as being on the pill or
prolonged stasis or genetic predispositions like
Factor V Leiden, might be susceptible to a
geometric interaction of relatively low risk from
this class of drugs.
So, as far as thrombosis is concerned,
where does this take us? Well, first of all, we
have evidence that at least in vitro COX-2 can be
induced in endothelial cells and produce
prostacyclin. We have evidence that it constrains
platelet activation and thrombogenesis in vivo.
Suppression of prostacyclin does not cause
spontaneous thrombosis but augments the response to
thrombogenic stimuli in vivo. So, the hazard from
coxibs would be expected to be particularly evident
in those otherwise predisposed to thrombosis, and
we have evidence that this hazard is modulated by
inhibition of COX-1 in the appropriate zone.
Well, there has been a lot of talk, as we
all know, about mechanisms and one of the
have found really curious is the notion that
hypertension is a distinct mechanism. People get
hypertension on traditional non-steroidal
anti-inflammatory drugs as well as COX-2 inhibitors
for a reason. The reason is the same mechanism.
Illustrated here from studies in mice by Matt
Breyer and his colleagues is how inhibition of
COX-2, shown in red, will augment the pressor
response to an infused pressor like angiotensin-II.
Again, as in the setting of thrombosis, COX-1 is
not neutral. As you can see, if he uses a
selective inhibitor of COX-1 he attenuates the
response to angiotensin-II.
Now, these studies have been complemented
by congruent data with gene-deleted mice. They
raise the prospect that the incidence of
hypertension would reflect not only the degree of
inhibition of COX-2 but the selectivity with which
it is attained. Indeed, in this week's Archives we
have the first epidemiological evidence consistent
with that concept.
Now, the products of COX-2 that
response to pressor agents include prostacyclin and
PGE-2. Here we are looking at the effect on blood
pressure, of deletion of the prostacyclin receptor
and, as you can see, blood pressure is elevated and
the response to salt loading is increased. One
sees exactly the same phenotype deleting one of the
receptors for PGE-2.
So, as far as blood pressure is concerned,
suppression of COX-2 derived PGI-2 and PGE-2
increases blood pressure and augments the response
to hypertensive stimuli in mice. Deletion or
inhibition of COX-1 depresses the response to
vasoconstrictors in vivo so again we see COX-1
modulating the hazard from COX-2 inhibition.
Hypertension on NSAIDs would be expected to relate
to the inhibition of COX-2 and the selectivity with
which it is attained.
Let's think of a more chronically
unfolding cardiovascular hazard. These data
arbitration taken from Narumiya. They are looking
at the development of atherosclerosis in a
genetically prone mouse, and you can see
deletion of the prostacyclin receptor accelerates
atherogenesis in male ApoeE-deficient mice. In
fact, the impact was most particularly marked at
initiation and early development of
By contrast, deletion of the thromboxane
receptor does the complete reverse, and other
studies conducted by us and others have shown that
inhibition of COX-1 selectively or antagonism of
the thromboxane receptor will have the same effect
as deleting the thromboxane receptor, as shown
So, as far as atherosclerosis is
concerned, we see this buffering capacity between
COX-1 and COX-2. Furthermore, we have shown
recently that in a different genetically proned
mouse model deletion of the prostacyclin receptor
and inhibition of COX-2 dependent formation of
prostacyclin is important in affording the
atheroprotection conferred by estrogen in female
So, here we see the
terms of reduction of lesion development with
estrogen treatment in vasectomized mice being
dramatically reduced by deletion of the
prostacyclin receptor, which raises a whole new set
of questions about the use of these drugs in
So, as far as this other manifestation of
a cardiovascular hazard is concerned, initiation
and acceleration of early atherogenesis occurs in
response to deletion of the prostacyclin receptor.
I haven't gotten into mechanism but it fosters
platelet and neutrophil activation and vascular
interactions of these cells, and removes the
constraint on attendant oxidant stress.
Now, we know that hypertension, which is
also a consequence of inhibition of this pathway,
itself accelerates atherogenesis. So, one could
imagine that the direct and indirect effect could
converge to transform cardiovascular risk.
Finally, again COX-1 is playing a modulatory role.
There is a lot of speculation, which will
no doubt be addressed in this meeting, as
whether in the APPROVe study we actually saw a
delayed appearance of augmented cardiovascular
risk. I think, for me, the answer is we are not so
sure but, if we did, this mechanism would explain
not only early events but also the delayed
emergence of cardiovascular phenotype.
The other thing that is often trotted out
is, well, but people on aspirin have had some of
these events. Well, of course, people on aspirin
also have myocardial infarctions. But I think it
is worthwhile remembering as we consider that
prostacyclin will buffer effects of thromboxane on
blood pressure, atherogenesis, hemostasis and,
indeed, cardiac damage, which I haven't gotten into
today. It acts as a general constraint on any
agonist that acts harmfully on these systems. So,
one would expect aspirin, in a perfect world, to
damp rather than abolish the signal.
So, I think, if you will pardon me just
for a moment to muse, one could relate the ability
to detect a signal, expressed here as maybe numbers
needed to treat or trial duration, as a
the underlying cardiovascular risk of the patients
involved. The higher the risk, the more you would
be able to detect it easily. The lower the risk,
it may require that you either perform a very large
study or go on for a very long time because we are
all mindful of the fact that clinical trials, even
randomized clinical trials, are very crude detector
systems for uncommon risk.
Additionally, other elements will impact
on this, including elements related to drug
exposure and the degree of selectivity that is
actually attained in vivo. So, I think in some of
the efforts to dismiss this idea of a class-based
effect some have lost sight of the fact that one
would expect not only the underlying substrate to
be relevant, but elements of drug exposure like
dose, duration of dosing, duration of drug action
and, indeed, concomitant therapy to be relevant to
the ability to detect a risk. So, one is looking
for a needle in the haystack and, to some extent,
when one finds the needle it doesn't really matter
how long it has been in the haystack.
So, let's consider the extreme phenotypes
of cardiovascular benefit and hazard in this
First of all, let's consider aspirin.
Here we have a sustained mechanism of action that
leads to complete and sustained inhibition of
COX-1. Even low dose aspirin inhibits prostacyclin
to a minor degree. But one would expect, and one
sees, a cardiovascular benefit from aspirin, at
least in the secondary prevention of stroke and
In the case of COX-2 inhibitors one sees a
reversible inhibition of COX-2. One also sees
variable degrees of inhibition of COX-1 but,
because of that non-linearity that I mentioned to
you in the relationship, effectively this makes
these drugs selective for COX-2 because you have no
inhibition of COX-1 dependent platelet function.
That brings me to the last topic that I
would like to address, and that is what about the
traditional NSAIDs? Well, here is one way of
comparing aspirin to a prototypic NSAID, ibuprofen.
You take healthy volunteers, you
low dose aspirin to stead-state efficacy, or
ibuprofen 3 times a day to a steady-state effect,
and you look at the offset of effect on enzyme
inhibition and inhibition of function.
With aspirin you see sustained inhibition
over the 24 hours after stopping the drug. As you
would expect, with stopping ibuprofen you see
offset of this reversible inhibitor on the enzyme.
From whatever I have told you about that
non-linearity in the relationship, you are not
surprised to see a steeper offset of inhibition of
Well, of course, we have no randomized,
placebo-controlled trials of traditional NSAIDs.
We have various overviews of the epidemiological
experience, with all the limitations of that
approach and we can see that ibuprofen looks like
it is not really altering cardiovascular hazard.
There seems to be a sort of 10 percent or so
reduction with naproxen, particularly 500 mg twice
a day which was the most commonly used dosage in
Now, this would be like a dilute aspirin
effect and, obviously, has relevance to the
interpretation of studies like VIGOR and
the experience with the etoricoxib that you will
hear about as to whether naproxen is actually
behaving like aspirin.
Well, I think actually the epidemiology is
entirely consistent with the clinical pharmacology
of naproxen. This elegant study was performed by
Patrignani. Again we are looking at the offset
action of aspirin and naproxen 500 mg per day
administered to steady state. We are looking at
inhibition of enzyme function, and we see with
aspirin exactly what we would have expected,
sustained inhibition. However, at the end of a
typical dosing interval for naproxen we see
heterogeneity of response. In fact, everybody is
at 95 percent or lower, suggesting that within the
dosing interval there is a variable degree of
cardioprotection afforded through this mechanism,
which would be consistent with the dilute aspirin
effect from the epidemiology.
This is a plot of the IC-50 for inhibition
of COX-2. This is inhibition of COX-1 in whole
human blood. As we move in this direction we are
getting more selective for COX-2. It brings us
back to a point that arose in Byron's study, and
that is that although there is a
potency, celecoxib and diclofenac look remarkably
I would also remind you that naproxen,
bearing in mind the Aleve study fiasco, is on the
other side of the line, just like ibuprofen is, and
exhibits preference for inhibition of COX-1.
Well, you have had a nice job giving you a
full data set, demonstrating that actually in whole
human blood diclofenac and celecoxib are
superimposable. So, I would contend that through
various lines of evidence diclofenac is probably a
selective COX-2 inhibitor like Celebrex.
Consistent with that is a pharmacodynamic
interaction where we showed that prior occupancy of
the COX-1 site by a typical mixed inhibitor like
ibuprofen would block access of aspirin
target acetylation site. If we give aspirin and
ibuprofen chronically we actually see a pattern
that looks just like giving ibuprofen alone, an
onset of action and a steep offset of function.
However, if we substitute diclofenac for aspirin it
looks like giving aspirin alone, which is
consistent with the type of information you get
with a selective COX-2 inhibitor like rofecoxib or
celecoxib in this assay.
So, I think we can start thinking of
diclofenac as Celebrex with hepatic side effects.
It has the same selectivity in whole blood in
vitro. It has no pharmacodynamic interaction with
aspirin. It has no clinical interaction with
aspirin in the one epidemiological study which has
addressed this interaction with the two drugs.
Also, it is consistent with the superimposition of
the GI and cardiovascular events in the
retrospective look at CLASS in non-aspirin users.
So, I would suggest the two trials that
you will hear about, EDGE and the ongoing MEDAL,
are actually the first trials that are a
within the class.
Well, let's come back to this
relationship. I would remind you that while we
have very strong evidence for this being true, we
have almost no evidence that this is true. The
conjecture of this discordance underlies the
argument for the fact that we have a problem with
selective COX-2 inhibitors but, you know something,
we have a problem with all of these drugs which
clearly obscures the message. We have no evidence
for that and you will hear people parsing in
meta-analyses naproxen versus non-naproxen NSAIDs.
Well, I don't think that is a legitimate
lumping of non-naproxen NSAIDs, which is really
diclofenac plus ibuprofen in most instances. I
think it is as legitimate to consider them all
individually as it is to consider naproxen
So, could there be a hazard from a
non-naproxen NSAID like ibuprofen where there is
coincident inhibition of COX-1 and COX-2 over
typical multiple dosing interval? If there is a
discordance in the relationship between inhibition
of enzyme function and inhibition of enzyme
product, then there might be a narrow part of the
dosing interval where there could be a potential
exposure to risk. But the likelihood of detecting
this notional risk would be much less than the
likelihood of detecting the clear evidence-based
risk of selective inhibitors of COX-2.
So, there is some suggestion that naproxen
achieves sustained platelet inhibition in some
individuals. I like to think of it as a dilute
aspirin. There is evidence that diclofenac is
Celebrex. There is evidence that ibuprofen may
undermine the benefit from aspirin, although that
is not yet answered one way or the other with a
controlled trial. And, I would say quite
forcefully there is no rationale for lumping
diclofenac and ibuprofen as non-naproxen NSAIDs in
meta-analyses and the like.
I am not sure when a canard becomes a dead
--so I decided to dismiss some of the
things that I think are worth dismissing and call
them dead dragons. First of all, naproxen clearly
is not the full explanation of VIGOR.
Here is another one that needs to be
chopped down, hypertension is not a different
There are a lot of off-target fantasies
being touted around at the moment, strange chemical
interactions that haven't actually been shown to
occur in vivo yet but are postulated as the
explanation for a drug-related rather than a
Oddly, we never heard any of this
conjecture when we were considering how all the
drugs in this class afforded relief from pain and
Here is another nice notion that makes
clinical pharmacologists squirm in their seat, it
is just a matter of reducing the dose. Well, there
is a lot of interindividual variability in response
to COX-2 inhibitors and we all have our
dose-response curves. It has been an approach in
the past when a hazard emerges to suggest that in a
population sense one just cuts the dose--perhaps in
a population sense but it certainly does not
obviate the possibility of individual hazard.
Finally, if there ever was one, I think we
have certainly moved beyond the need for a trial of
a COX-2 inhibitor in patients with acute coronary
syndrome. Indeed, I feel that the evidence that
supports a trial in patients at high cardiovascular
risk to detect protection is scientific quite weak,
and in the face of an emergent hazard is ethically
Indeed, in the case of mice if one
combines a thromboxane antagonist as a surrogate
for the suppression of thromboxane by low dose
aspirin with a COX-2 inhibitor, one doesn't see any
benefit in terms of atheroprotection, but what one
does see is the loss of the fibrous cap in the
combination and necrosis of the atherosclerotic
core, consistent with destabilization of the
Finally, and you will be glad to know it
is finally, I would just like to mention a couple
of things relating to where we might go
Well, I think clearly an easy thing to write down
and perhaps a more tricky thing to do is to exclude
patients at high intrinsic risk of thrombosis, and
you have heard my views on that. Dose reduction
alone is a simple message. It has a political and
legal appeal but in pharmacological terms it is
I think we are likely to subject new drugs
that might be approved from this class to
significant hurdles before they are approved. It
seems logical to me that existing drugs in this
class should be subject to the same hurdles to
retain approval, particularly for extended dosing.
And, I think that frankly one should logically
restrict the duration of dosing until the
parameters of safety for extended dosing have been
I mentioned interindividual variability,
and these are log scales but they
looking at inhibition of COX-2 either in the
typical ex vivo assay or by excretion of
prostacyclin metabolite or inhibition of COX-1,
that with this sort of display of the data to
highlight it, there is considerable interindividual
variability of response. This is no surprise. It
is true of all drugs.
But perhaps we can exploit the biochemical
variability, the physiological response variability
and, indeed, perhaps some genetic markers such as
these polymorphisms associated with metabolism of
drug or these polymorphisms in cyclooxygenase-1 to
try and identify those patients at emerging
cardiovascular risk before they culminate in
events. So, you might say that the future of these
drugs or the challenge to the future of these drugs
is that if their value--and I believe they have
value as a class--is to be harvested, then to
manage the risk we have to actually move to an
example of personalized medicine.
One would want to obviously restrict these
drugs in some way to people who really
for GI reasons. We need to determine whether risk
transformation actually occurs during chronic
dosing and, if so, whether we can detect it. And,
it is likely, because we have so few events in any
one trial, we can only do this by a combined
analysis across the class in relevant trials.
Then, obviously, we would have to validate
prospectively such an index of emergent risk in a
So, I really thank you for your patience
and I would like to conclude. Selective inhibitors
of COX-2 depress prostacyclin without a concomitant
thromboxane-A2. This can result in an augmented
response to thrombotic and hypertensive stimuli and
acceleration of atherogenesis in mice. Indeed, the
terrible beauty of this unfolding drama is how
faithfully the emerging clinical information has
fitted the predictable science, and that should
reassure us in terms of the likelihood that the
science can predict a way to conserve the value of
these drugs while managing the risk.
An increase in MI and/or stroke has been
seen at last count, as of yesterday, in 5
placebo-controlled trials with 3
distinct COX-2 inhibitors. Given the bulk of
evidence, the mechanism-based evidence from mice
and people, the pharmacopeidemiology and this, it
seems to be that most rational people would accept
a class-based mechanism as they did for efficacy.
Finally, hazard would be expected to
relate at the individual level to the drug
selectivity attained in vivo, dose and duration of
exposure and to interindividual differences in drug
response. Thank you.
DR. WOOD: Thank you. Just before you sit
down, one thing you seemed to be saying is that we
should exclude patients at high risk. The point
estimate in the APPROVe trial for people with no
symptomatic history of heart disease is 1.6 so that
would be one way you would exclude people, I guess,
but the point estimate remains 1.6. Does that
DR. FITZGERALD: No, as I alluded to, I
think the nature of the information we have in the
APPROVe trial so far remains to be played out.
Clearly, there was an attempt to exclude people at
high cardiovascular risk but we all know that
people who are at risk slip through any exclusion
criteria. So, one question is, is all that we are
seeing people who, for one reason or another, are
predisposed to thrombosis and they are the people
that are having events? Or, are we seeing people
who through atherogenesis transform their risk?
Or, are we seeing some combination of the two? I
don't think we know the answer to that.
DR. WOOD: We are running behind time so
we will call a break right now and give everybody a
moment or two to get out. Before we do that, Dr.
Galson wants to say some things and then, whenever
he is finished, we will take a break and we will
reconvene at 10:15. So, those of you who don't
want to hear what Dr. Galson has to say can get out
now and the rest--
DR. GALSON: No, no, just a very brief
announcement, and that is we have a space
in this facility. There are more people than we
have seats for. So, we have established a live
video feed in our advisors and consultants
conference room on the FDA campus at 5630 Fishers
Lane, designed for FDA employees only. So, FDA
employees who may be sitting in the public section,
I strongly urge you to please move to that area to
make more room for the public and, of course, you
will need your FDA ID badge to get into that space.
But it is ready now and if you could move at the
break, it would be great. Thanks.
DR. WOOD: Okay, we start promptly at
Committee Questions to Speakers
DR. WOOD: Let's get started and get the
two previous speakers up for questions, Dr. Cryer
and Dr. FitzGerald. Yes, Susan?
DR. MANZI: I have a question for Dr.
FitzGerald. This is really in reference to your
suggestion that we exclude people with high
thrombotic potential. I think there is clearly
evidence that the natural aging process is
associated with less effective fibrinolytic system,
really increased thrombogenic potential with high
levels of fibrinogen, PI-1 platelet aggregation,
and considering that the elderly population is a
huge target for non-steroidals, would you consider
age as a risk?
DR. FITZGERALD: Well, I think, as you
indicate, lots of things happen as we get older
including the complexity of administering drugs and
it ultimately culminates in death. But I think the
issue of determining cardiovascular risk is
actually a very challenging one because it includes
continuous and discontinuous variables. It is easy
to say if you have had a heart attack or a stroke
you are statistically at greater risk of having
another one. It is harder to say that at an
individual level, somebody who hasn't had a heart
attack or a stroke has a cluster of variables that,
in the eyes of their physician, determines their
With some of the discontinuous
like some of the genetic mutations we can have an
attributable risk that we can measure but, again,
that can play geometrically into other small but
absolute risks. So, unfortunately, I think it is
where the art and science of medicine intersect.
DR. WOOD: Richard Cannon?
DR. CANNON: You asked my question.
DR. WOOD: Joan Bathon?
DR. BATHON: We know that patients with
rheumatoid arthritis and other inflammatory
conditions are at higher risk for developing acute
MIs and strokes, and these are the very patients
who are taking NSAIDs chronically. This is a big,
confounding problem in interpreting some of the
data and I am wondering if you have any thoughts.
The reigning theory is that there is more
atherosclerosis and RA due to vascular inflammation
but I am wondering if you have any thoughts about
whether the NSAIDs might be the sole contributor to
increased events in these folks.
DR. FITZGERALD: Right. As I indicated,
through a COX-2 inhibitory mechanism one
anticipate that the clinical substrate of
underlying cardiovascular risk would be one of the
modulators of either individual hazard or the ease
of detecting hazard with this crude detector system
we call clinical trials.
As you know, the relative risk of heart
attack or stroke and RA is increased by about 50
percent on average compared to RA or no arthritis.
As a population that would be one of the
ingredients predisposing towards emergence of a
hazard. Of course, within that population there is
a very substantial interindividual variability
conditioned by many other factors that impinge on
cardiovascular risk. So, at the time when we were
naval gazing, looking at the contrast between CLASS
and VIGOR, amongst the many things that were
discussed was whether the preponderance of RA
patients in VIGOR versus the preponderance of OA
patients in CLASS may have been a factor. I think
it is reasonable to say it may have been a factor
but I don't think we can really take it beyond
conjecture in light of any current
evidence that I
am aware of.
DR. WOOD: Garret, let's cut to the chase.
Is what you are saying--that was such a long
answer, I am not sure what it meant!
Is what you are saying that you think that
COX-2 inhibitors have an effect here that the most
selective, so-called non-selective like diclofenac
and naproxen may also have an effect, and the
non-selective, non-steroidals do not have an
effect, or at least have not been shown to have an
effect? Is that your position? If it is not,
DR. FITZGERALD: No, I think that is
DR. WOOD: So, that is what you wanted us
to take away from all the mice and stuff, is it?
DR. FITZGERALD: You have such a way with
DR. WOOD: Because I am a Scot.
DR. FITZGERALD: You are very economical
DR. WOOD: Exactly.
DR. FITZGERALD: Unfortunately, reality is
conditioned by a lot of different factors. I think
one of the things, both in terms of benefit and
hazard, we have paid insufficient attention to is
variability in drug response between individuals,
and I think actually one of the things that has got
us to today is not paying enough attention to that.
But I think one of the ways out of the challenge
that faces us today if we are to conserve the value
is to exploit that variability in imaginative ways.
So, I think that that is a tractable issue.
DR. WOOD: Okay. Dr. Abramson?
DR. ABRAMSON: Yes, Garret, even though
you are under the weather I wanted to follow-up
with Dr. Wood's question and put you on the spot a
little bit. It is partly definitions because we
use the word NSAIDs which we elect by inhibiting
COX-2s. Based on your presentation, it is clearly
a continuum and there are highly
There is a cluster of five or six drugs, like
diclofenac, that are in vitro at least comparably
COX-2 selected. Then you have these very complex
stories of what one might call functional COX-2
selectivity, which is based on the fact that the
COX-1 inhibition may be more transient effectively
than a more prolonged COX-2, which would give you
imbalance. So, I guess the "put on the spot"
question is what do you define as the class? How
do you propose we should think about this continuum
and personalize medicine?
DR. FITZGERALD: I think you are right. I
would remind all of us that COX-2 inhibitors are
NSAIDs; they were never anything else. They are
NSAIDs that are selective for COX-2 and, as you are
rightly pointing out, this is a continuous variable
and within each drug, as I tried to point out,
there is the same continuous variable between
individuals. So, my 800 mg of Celebrex may be your
200 mg of Celebrex for example.
So, I think all I am trying to raise is
that there is clearly a mechanism which
the selective inhibition of COX-2. That selective
inhibition of COX-2, in terms of hazard, is
modulated by COX-1 inhibition that occurs at the
same time if it is sufficient to inhibit platelet
activation for example. So, I can't simplify that
because I believe there is that complexity, but
within the class--and I am referring to the class
as the mechanism by which selective inhibition of
COX-2 is attained--I think there is clearly a
mechanism that explains everything that we have
At the individual level this issue of a
continuum comes into play because not only is there
a continuum in terms of drug action and the degree
of selectivity attained in an individual, but also
many other factors impinging on cardiovascular risk
that condition the emergence of that hazard at the
DR. WOOD: Steve?
DR. NISSEN: Yes, I have two quick
questions. You know, I want to talk with you a
little bit more about this issue of dose
dependency. I want to make sure we didn't
misunderstand you. What you are saying I believe
is that there is sufficient overlap in the
biological effects that a low dose in one patient
may be equivalent to a high dose in another. But
you didn't mean to suggest that we don't see
evidence, as I think we do see from the trials,
that the higher the dose of the drug on a
population basis, the more we see--
DR. FITZGERALD: No, no, clearly there is
evidence of a dose-related effect in populations.
I am talking more at the individual level, that the
assurance to a population based on population type
evidence that all you need to do is reduce the dose
and you, as an individual, will be protected from
hazard is a false one.
DR. NISSEN: Yes, but it is quite relevant
obviously to our discussions on Friday because one
of the strategies to limit risk with this class of
drugs is to limit dose--
DR. FITZGERALD: Sure.
DR. NISSEN: --and it may not make the
hazard go away but it may make it smaller, and we
are going to have to explore that in some detail
before we finish.
DR. FITZGERALD: Well, I think that
distinction between reducing it as opposed to
making it go away and the distinction between
population hazard and individual hazard is an
important one. It is the reason that I raised that
particular point because I think that had not
received sufficient attention.
DR. NISSEN: The second question I have
is, you know, we have very few direct head-to-head
trials amongst the so-called COX-2 inhibitors, but
we do have for hypertension and there seemed to be
really pretty striking differences in the
hypertensive response between rofecoxib and
celecoxib. Would your point of view be that those
differences are strictly a matter of COX-2
selectivity of the two drugs, or do you think that
it is possible that there is some dissociation in
the hypertension response?
DR. FITZGERALD: I would make two points.
I would say, first of all, that in that particular
comparison, again on average, we would anticipate
that selectivity and duration of action would be
confounded and it would be impossible to really
segregate the two.
The second is that, in a sense you pressed
my button, I believe we have not performed the
studies in hypertension that let us address the key
questions that are on the table, and that is
standardizing for the degree of selectivity
attained or the degree of COX-2 inhibition attained
do drugs come apart? That question has been on the
table since the mouse studies of Breyer and
Kaufman, and perhaps the first signal of that is
the epidemiological overview analysis from
Australia. But, in fact, we have never performed a
study to address the hypothesis and I think it is
timely that we do.
DR. WOOD: I see Dr. Cryer. Did you want
to say something?
DR. CRYER: Dr. Cryer has a question.
DR. WOOD: Go ahead.
DR. CRYER: Garret, you clearly made the
point that diclofenac appears to have some COX-2
selectivity. In fact, I think you called it
celecoxib with hepatic side effects. You also made
the point that we should subject drugs already
approved to the same requirements. So, the
specific question I have for you is are you
suggesting that we should evaluate diclofenac as
well for its potential cardiac effects?
DR. FITZGERALD: Yes, I think there are
quite a few unanswered questions on the table. I
think clearly the diclofenac question is one of
them. I think there are other drugs that fall into
potentially the same situation, like meloxicam and
nimesulide which, again, based on the IC-50
comparisons look awfully similar to diclofenac and
Celebrex but we just don't have the information
even at a more fundamental level than outcome
studies. So, I think those questions are on the
The reason I made the comparison between
retention of approval and gaining approval
to me, if we do actually have to address some
questions to determine the parameters within which
drugs in this class can be administered safely and
that would be a hurdle that any new drug would be
required to overcome, in logic to me, it would be
sensible to apply the sam standard to the extended
dosing of drugs that already are on the market as a
condition of their retention of approval.
DR. WOOD: Dr. Shafer?
DR. SHAFER: Yes, this is the question we
just talked about briefly at the break, but as you
pointed out, low dose aspirin gives you 100 percent
inhibition of COX-1. One might think then that low
dose aspirin plus a COX-2 selective antagonist
might give you the same risks as a non-selective
NSAID. Yet, in all the studies where they had
aspirin present and they showed a CV risk, when
they stratified by aspirin, among aspirin users the
hazard didn't go away. Now, what did happen is
that some statistically significant hazards became
non-statistically significant hazards but the
actual magnitude of the hazard, at least
as far as
I can tell in all the studies that I looked at,
didn't change. I am having trouble understanding
how that is consistent with the whole thing being
the COX-2 imbalance.
DR. FITZGERALD: Right. So, one important
missing dimension in your question is time. One of
the key ingredients of aspirin's ability to afford
cardioprotection is that while it inhibits COX-1
like a ibuprofen does, it does it molecularly in a
quite distinct fashion. This results in sustained
maximal inhibition throughout the dosing interval.
By contrast, in the typical non-steroidal you are
in the red zone for platelet inhibition transiently
in the dosing interval. Therefore, one would not
expect the combination of, say, ibuprofen with a
COX-2 inhibitor to be similar to aspirin with a
COX-2 inhibitor in terms of cardiac protection.
DR. SHAFER: Doesn't that head in the
DR. FITZGERALD: In terms of which?
DR. SHAFER: The fact that the aspirin's
effect is sustained because, you know, it
covalently bonded there--the fact that you are
having a sustained aspirin effect means that you
should absolutely--I mean, it would seem to me that
that would really try to make the COX-2s look--
DR. FITZGERALD: Well, I will come back to
what I said during my talk, and that is that I
think a real mistake is to think of this as a yin
and yang type of seesaw arrangement between
thromboxane and prostacyclin. We know that
prostacyclin acts as a general biological
constraint on anything that will activate
platelets, elevate blood pressure, accelerate
atherogenesis, and so on. So, a priori we would
expect that aspirin would damp rather than abolish
Now, I would contend that, first of all,
we have never formally addressed this and, in terms
of the trials that have events, although we have
attempted to look at the relationship to aspirin
the numbers are so vanishingly small that it is
really conjecture. But one would expect a signal
to be damped. Indeed, from some of the
epidemiology that is sort of what we are seeing,
you know, a signal goes away at 25 mg of rofecoxib
if they are on aspirin but not at 50, that sort of
stuff. But I would be the first to agree that this
is really a crude stab at the issue that you are
trying to get at.
DR. WOOD: Yes, and these studies did not
stratify by aspirin use. They were post hoc
analyses in the majority of cases. Dr. D'Agostino?
DR. D'AGOSTINO: I would like to go back
to the question that was asked right after the
break about the age. If you tried to say, well,
the perfect way of doing this is to make sure that
people at high cardiovascular risk aren't going to
take the drug, then males over 60, for example, are
almost certain to be excluded. How realistic--
DR. FITZGERALD: Certainly I am not trying
to be dictatorial--
DR. D'AGOSTINO: No, no, your suggestion
is fine, it is just how do you implement it?
DR. FITZGERALD: Yes, so I think all one
can really hope to do is set the bar at
level and then signal it in a way that is explicit
and leave it to the patient-doctor relationship to
divine the individual behavior. I would love to
say there is a different way of doing it but, yes,
as we get older our cardiovascular risk goes up and
multiple other things. But that is where the
balance against value comes into play. As we get
older with get arthritis; as we get older we get
more GI bleeds on non-steroidals.
DR. WOOD: Okay, we got it. Let's not go
too far there. One more question from Dr.
DR. GIBOFSKY: Dr. FitzGerald, in response
to Dr. Nissen, I believe, you raised the notion and
asked us to think about population variation as a
factor in addition to individual variation. One of
the things that I am struggling with is exactly
that, and one of the concerns I have is to what
extent then can one extrapolate observations in
populations of patients who may have Alzheimer's
disease or who may have taken a drug for polyp
prevention to the population of patients
taking the drug for their arthritis?
DR. FITZGERALD: Well, I think in a way
this whole cathartic experience is a cardinal point
in the way that we look at drug development. You
know, we have talked about individualized medicine
for a long time and never really had to care, and
here is a situation where we actually do have to
care and it is at the forefront of how we may or
may not be able to find a way out of this. You are
absolutely right, there may be factors associated
with an incident disease which is under study which
modulates the importance or non-importance of the
signal; modulates the way that drugs are
metabolized; may be associated with genetic
variance that influence outcome as well.
DR. WOOD: Any other questions for the
last two speakers?
In that case, let's move on to the
sponsor's presentation. I understand Dr. Kim is
going to present first.
Sponsor Presentation: Vioxx (Rofecoxib)
DR. KIM: Mr. Chairman, members of the
advisory committee and FDA and ladies and
gentlemen, my name is Peter Kim and I am
of Merck Research Laboratories. My colleagues and
I welcome the opportunity to present information at
this advisory committee meeting, and I would like
to begin with just a few introductory comments.
As you will hear, to determine both its
risks and its benefits, Merck extensively studied
Vioxx before seeking regulatory approval to market
it, and we continued to conduct clinical trials
after the FDA approved Vioxx.
As Merck continued to monitor the
cardiovascular safety of Vioxx, we recognized the
value and interest in obtaining additional
cardiovascular safety data on this medicine. After
deliberations with numerous outside advisors, Merck
developed and discussed with FDA a plan to
prospectively analyze cardiovascular event rates
from 3 large placebo-controlled trials.
It was preliminary information from one of
these long-term trials, the APPROVe
trial, that led
to Merck's decision to voluntarily withdraw Vioxx.
When Merck made the decision to voluntarily
withdraw Vioxx from the market, we stated that we
believed that it would have been possible to
continue to market Vioxx with labeling that would
incorporate the data from the APPROVe trial. We
concluded, however, based on the science available
at that time, that a voluntary withdrawal of the
medicine was the responsible course to take given
the availability of alternative therapies and the
questions raised by the data.
Since that time new cardiovascular safety
data for other COX-2 inhibitors have become
available and were reported on just this week in
the New England Journal of Medicine. We look
forward to hearing and seeing presentations of
these data and to hearing discussions and
interpretation of them during this advisory
committee meeting. Thank you, and now I would like
to turn the podium over to Dr. Ned Braunstein.
DR. BRAUNSTEIN: Good morning, Dr.
Chairman, members of the availability
FDA, I am Dr. Ned Braunstein, Senior Director of
Merck Research Labs.
Millions of patients suffer with painful
arthritis and need effective therapies. The recent
data that have come to light on NSAIDs and
selective COX-2 inhibitors raise many questions.
Patients and physicians need information and
guidance on the use of these effective medicines
that we know are not without risk. We recognize
that the cardiovascular safety of the NSAID and
coxib classes is an important public health issue
and we welcome the opportunity to present this
advisory committee information that we believe will
help the FDA and the committee in their work in
developing recommendations in the best interest of
patients. To assist us today, we have
brought along as consultants Dr. Marc Hochberg from
the University of Maryland School of Medicine, Dr.
Marvin Konstam from Tufts University School of
Medicine, and Dr. Loren Laine from the University
of Southern California School of Medicine. They
are here to help answer your questions
otherwise assist the committee.
Merck's objective today is to provide you
with data on rofecoxib and review how those data
affected our assessment of risk/benefit over time.
The presentation will focus on GI and
cardiovascular data or rofecoxib, starting with the
data in the original NDA and proceeding through the
voluntary withdrawal of Vioxx and the APPROVe data.
In talking about the data, I will try to
highlight some of the methodology we used to
obtain, adjudicate and analyze cardiovascular data,
and I will spend some time discussing the
considerations that went into designing a study of
cardiovascular outcomes with rofecoxib as the
information may be useful in considering similar
The presentation of data will end with a
presentation of new exploratory analyses that we
have performed and I will follow with a
risk/benefit assessment, the review the major
outstanding questions of the day, and the next
steps we are taking and/or propose.
I will start with an overview of the
issues we face today. Starting with the GI tract,
as you have already heard, NSAID
been the most common cause of drug-related
morbidity and mortality in industrialized nations.
The development of rofecoxib was based on the
desire to limit and reduce this problem.
You have also heard already about the
COX-2 hypothesis. I just want to emphasize two
points. First, all NSAIDs inhibit COX-2 in a
dose-dependent manner and selective COX-2
inhibitors do not inhibit COX-1 at clinical doses.
The rofecoxib develop program confirmed
the COX-2 hypothesis and demonstrated a reduction
in clinical upper GI events, that is, actual GI
outcomes with rofecoxib versus non-selective
NSAIDs. This was shown for rofecoxib in the VIGOR
study and, based on that, rofecoxib was the only
selective COX-2 inhibitor with a modified GI
warning. Since that time we have accrued
additional information that extend the GI benefit
of rofecoxib and have shown that the
clinical upper GI events is consistently seen with
rofecoxib versus diclofenac, ibuprofen and
Although rofecoxib is associated with a
reduced rate of upper GI events compared to these
NSAIDs, rofecoxib is not placebo. In addition to
the upper GI findings, we have also observed a
reduced incidence of lower GI events compared to
naproxen in VIGOR, So, although there remain some
unanswered questions, for example for aspirin
users, the GI benefit for rofecoxib is clear.
As we have also learned, there are
important cardiovascular findings with these drugs
and perhaps with the larger class of NSAIDs. In
1998 Merck had implemented an adjudication standard
operating procedure to methodically study the
cardiovascular effects of its COX-2 selective
inhibitor drugs in clinical trials. Clinical data
on thrombotic cardiovascular events with rofecoxib
show an increased risk of events relative to
placebo. This was seen in APPROVe with
In contrast to the difference seen from
placebo, we have not observed a difference in
cardiovascular event rates between
NSAIDs other than naproxen. Long-term data,
however, are limited. In contrast to what had been
observed versus the placebo, the increased risk
compared to naproxen appears after short-term use.
I think it is worth noting that similar
observations have now been made with other
selective COX-2 inhibitors. We believe that these
new data on rofecoxib and COX-2 inhibitors raise
several questions about these drugs important to
the public health.
First, based on the data available, how do
we currently assess the relative risks or benefits
of selective COX-2 agents? I cannot speak to the
data on all of these drugs but I can talk about
rofecoxib. Clearly, there are risks versus
placebo, and not just cardiovascular risks.
however, placebo is not a choice for patients with
chronic arthritis and pain who require chronic
NSAID therapy. For these patients the question is
the risk and benefit of selective COX-2 agents
versus non-selective NSAIDs. I will present data
on this question related to the GI and
cardiovascular safety of these drugs.
Second, can we identify factors associated
with the observed increased risk for thrombotic
cardiovascular events with these drugs? Although
we do not have definitive answers, I will present
the data that we have.
Finally, is the increased thrombotic
cardiovascular risk that we have observed with
rofecoxib indicative of a larger class effect of
COX-2 inhibitor? If so, how big is the class?
That is perhaps the central question of this
meeting. At present we do not know the long-term
cardiovascular effects of traditional NSAIDs.
Other than aspirin, these agents have not been
studied long term versus placebo. We believe that
long-term studies are needed and, in particular,
comparator studies between selective COX-2 agents
and non-selective agents to better understand the
relative risk/benefit profiles.
I will now turn to a presentation of the
data, and will do so chronologically as it
highlights the magnitude of data that
ultimately needed to dine the long-term
cardiovascular risks of selective inhibitors. This
information may be useful regarding the development
of future COX-2 inhibitors and in informing this
committee on its decisions.
I would like to start by reviewing the
initial GI and cardiovascular data that were in the
new drug application. There were two main clinical
components of the GI safety program in the original
rofecoxib NDA, the GI endoscopy studies, which are
described in your background package, and a pooled
analysis of clinical upper GI events, shown here.
Investigator reports of suspected upper GI
perforations, ulcers or bleeds or PUBs were
adjudicated by an external committee of blinded
adjudicators, and the confirmed events formed the
basis of this prespecified analysis.
The Kaplan-Meier plot of the data is shown
on this slide. Throughout my presentation I will
be showing several of these so I would like to take
some time to walk through this first one. Time is
shown on the X axis, and below that the number of
patients remaining in the studies at the different
time points. Cumulative incidence is shown on the
Y axis and also shown are summary statistics,
relative risk confidence interval and a p value.
At the time of the original NDA a
significant difference was demonstrated between
rofecoxib and the combined NSAID comparators,
mostly data on ibuprofen and diclofenac. The
relative risk of 0.45 corresponded to a 55 percent
risk reduction with rofecoxib and, thus, we believe
that we had established a GI safety advantage over
these older NSAIDs.
These are the cardiovascular safety data
from the OA development program. Rates per 100
patient years of investigator reports or cardiac,
cerebrovascular and peripheral arterial and venous
serious thrombotic events were examined both in
aggregate, as shown on this slide, and also in
individually, as shown in your background
As you can see, then rates were similar for
rofecoxib compared to the NSAIDs diclofenac,
ibuprofen and nabumetone and for rofecoxib compared
These cardiovascular and GI data, along
with our other data, were submitted to FDA in 1998
as part of the new drug application for rofecoxib.
They were discussed at the April, 1999 Arthritis
Advisory Committee and the FDA concluded that there
was a favorable risk/benefit profile for rofecoxib,
and rofecoxib was approved in May of 1999.
Around that time we were completing our
Phase III osteoarthritis studies. The results of
studies that we were doing in collaboration with
Dr. Garret FitzGerald became available, and he has
already told you about those and the hypothesis
that selective COX-2 inhibitors could be
prothrombotic by inhibiting systemic prostacyclin
production without inhibiting thromboxane
In addition to that hypothesis, there were
other hypotheses being discussed in the
literature and in the basic science literature at
that time, including the possibility that NSAIDs,
through their effects on COX-1, might decrease the
risk of cardiovascular events. Another was that
perhaps by inhibiting COX-2 there may be a
beneficial effect by inhibiting the enzyme in
Merck recognized that it would be
important to continue to acquire cardiovascular
data with its selective COX-2 inhibitors. To
address these hypotheses, in 1998 Merck initiated a
vascular event adjudication standard operating
procedure to standardize the evaluation of
cardiovascular events in all of its COX-2 inhibitor
studies. Adjudication of events was based on
predefined criteria. Under the standard operating
procedure all source documentation on events was
collected and the data were then reviewed by
blinded, external adjudication committees. With
this procedure, over 92 percent of cases had
sufficient data for definitive determination and
adjudication. Thus, we can be confident in the
quality of the data. By eliminating questionable
events, we would amplify and improve the clarity of
any signal if present. The standard operating
procedure called for a pooled analysis of events
across all studies to improve the precision of what
would be obtained from individual studies.
In order to obtain more data on the effect
of rofecoxib on GI outcomes Merck initiated the
Vioxx GI Outcomes Research, or VIGOR, study in
January, 1999. GI events would be adjudicated
using the same approach as had been done for the
osteoarthritis studies. The cardiovascular events
in VIGOR fell under the new standard operating
VIGOR was designed to definitely assess
the GI components of the COX-2 hypothesis. It was
conducted exclusively in rheumatoid arthritis
patients because Merck believed that a GI benefit
had already been established in osteoarthritis
patients. Rofecoxib of 50 mg, 2-4 times the
recommended chronic dose, was chosen to provide a
rigorous assessment of safety. We chose as a
comparator naproxen 500 mg twice a day to extend
the GI findings to an additional NSAID and because
that was the most commonly prescribed NSAID regimen
in rheumatoid arthritis. Patients using aspirin
were excluded to avoid COX-1 inhibition as this
could confound the ability to rigorously assess the
The primary endpoint was reduction
confirmed clinical upper GI events. There were 56
events on rofecoxib and 121 on naproxen. The time
to event curve separated early and they continued
to separate, and the relative risk of 0.46
corresponds to a 54 percent risk reduction with
rofecoxib. The p value, as you can see, was highly
significant. A similar GI benefit was seen with
confirmed complicated events, and in a post hoc
analysis for lower GI events.
A second finding in VIGOR was the
difference in the rates of thrombotic
cardiovascular events between the two treatment
groups. There was a relative risk of 2.4 for the
confirmed events, as shown here. The p value,
again, was highly significant.
Examination of the individual types of
events broken down by vascular bed, cardia,
cerebrovascular and peripheral shows that the
difference between treatment groups was largely
driven by the difference in myocardial infarction,
20 on rofecoxib and 4 on naproxen. Of note, there
were similar numbers of patients with strokes in
the two groups.
Additional exploratory analyses were
undertaken to better understand these
cardiovascular findings. I will focus on the types
of analyses that I will show later for APPROVe. In
VIGOR the use of 50 mg, a dose 2-4 times the
recommended approved chronic doses, was associated
with a higher incidence of hypertension adverse
experiences than with naproxen. In analyses
described in the background package the relative
risk of events was similar in patients with or
without increases in blood pressure during the
study. The relative risk of events was also
similar in patients with or without
factors for cardiovascular risk.
Finally, multiple analyses were performed
to examine the patterns of risk and relative risk
over time, both by Merck and the FDA. Merck's
interpretation was that there was no significant
increase in relative risk over time for rofecoxib
versus naproxen. However, the FDA felt that a
change in relative risk over time could not be
Because VIGOR did not have a placebo
control, we turned to other data from other studies
to better understand these results. Merck had
initiated a program to assess the ability of
rofecoxib to delay the onset of Alzheimer's disease
in patients with minimal cognitive impairment or to