DEPARTMENT OF HEALTH AND HUMAN SERVICES
UNITED STATES FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
Cardiovascular and Renal Drugs Advisory Committee
THURSDAY, FEBRUARY 24, 2005
Food and Drug Administration
CDER Advisory Committee Conference Room
5630 Fishers Lane
P A R T I C I P A N T S
Steven E. Nissen, M.D., F.A.C.C., Chair
Lt. Cathy Groupe, RN, BSN, Executive Secretary
Blase A. Carabello, M.D.
Susanna L. Cunningham, Ph.D., Consumer
William R. Hiatt, M.D.
Frederick J. Kaskel, M.D., Ph.D.
John F. Neylan, M.D., Industry Representative
Thomas Pickering, M.D., D.Phil.
Ronald Portman, M.D.
John R. Teerlink, M.D.
Special Government Employee Consultants (Voting):
Jonathan Sackner-Bernstein, M.D.
Ralph B. D'Agostino, Ph.D.
Robert Temple, M.D.
Norman Stockbridge, M.D.
C O N T E N T S
Call to Order and Introductions,
Steven E. Nissen, M.D., Chair 4
Conflict of Interest Statement,
Lt. Cathy Groupe, BSN, Executive Secretary 6
Welcome and Comments, Norman Stockbridge, M.D.,
Acting Director, Division of Cardiac and
Renal Drug Products 9
Regulatory Overview, Cindy Lancaster, M.S.,
M.B.A., J.D., AstraZeneca, L.P. 10
Background and Rationale, James B. Young,
M.D., Cleveland Clinic Foundation 17
ACE Inhibitor Choice, Dose and Drug Utilization,
John J.V. McMurray, M.D.,
Glasgow University, Scotland 27
Efficacy, Mark A. Pfeffer, M.D., Ph.D.,
Brigham and Women's Hospital, Boston 40
Safety, James Hainer, M.D., M.P.H.,
AstraZeneca, LP 58
Benefit/Risk Summary, James B. Young, M.D.
Cleveland Clinic Foundation 67
Discussion, Marc A. Pfeffer, M.D., Ph.D.,
Brigham and Women's Hospital, Boston
Questions from the Committee 71
Committee Discussion and Questions 151
P R O C E E D I N G S
Call to Order and Introductions
DR. NISSEN: I think we have all our
committee members. My name is Steve Nissen. I am
a cardiologist in the Cleveland Clinic, and we are
going to do some introductions first so that you
all know who is on the committee. Let's start with
John, over there.
DR. NEYLAN: Yes, I am John Neylan. I am
the industry representative on the committee, from
DR. CARABELLO: Blase Carabello, a
cardiologist from Houston.
DR. HIATT: Bill Hiatt, University of
Colorado, vascular medicine.
DR. PICKERING: Tom Pickering,
hypertension, Columbia University Medical School.
DR. PORTMAN: Ron Portman, pediatric
nephrologist from the University of Texas in
DR. TEERLINK: John Teerlink, heart
failure specialist from University of
San Francisco and San Francisco VA.
LT. GROUPE: Cathy Groupe, the executive
secretary for the Cardiac and Renal Drugs Advisory
DR. KASKEL: Rick Kaskel, pediatric
nephrologist, Albert Einstein College of Medicine.
DR. SACKNER-BERNSTEIN: Jonathan
Sackner-Bernstein, cardiologist from North Shore
University Hospital in New York.
DR. D'AGOSTINO: Ralph D'Agostino,
biostatistician from Boston University and the
DR. STOCKBRIDGE: I am Norman Stockbridge.
I am the Acting Director of the Division of
Cardiorenal Drug Products. To my right would be
Dr. Temple, but it is completely unreasonable for
us to start on time and expect him to be here.
DR. NISSEN: Dr. Temple usually is awake
by ten o'clock in the morning so I expect him
later. Lt. Cathy Groupe is going to read the
conflict of interest statement.
Conflict of Interest Statement
LT. GROUPE: 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 at
this meeting. Based on the submitted agenda and
all financial interests reported by the committee
participants, it has been determined that all
interests in firms regulated by the Center for Drug
Evaluation and Research present no potential for an
appearance of a conflict of interest at this
meeting, with the following exceptions:
In accordance with 18 USC Section
208(b)(3), full waivers have been granted to the
following participants, Dr. Ralph D'Agostino for
consulting for two competitors on unrelated matters
for which he receives less than $10,001 per year
per firm; Dr. William Hiatt for consulting and
speaking for a competitor on unrelated matters for
which he receives between $10,001 to $50,000 per
year per firm; Dr. Steven Nissen for consulting for
the sponsor and for four competitors on
matters for which he receives less than $10,001 per
year per firm; Dr. Thomas Pickering for consulting
and speaking for two competitors on unrelated
issues for which he receives less than $10,001 per
year per firm; Dr. Ronald Portman for consulting
for two competitors on unrelated issues for which
he receives less than $10,001 per year from one
firm and between $10,001 to $50,000 per year from
the other firm; Dr. Sackner-Bernstein for
consulting for a competitor on a related matter
which was general in nature for which he receives
less than $10,001 per year.
In accordance with 18 USC Section
208(b)(1) a full waiver has been granted to Dr.
John Teerlink for his role as an independent and
blinded adjudicator, consulting and steering
committee member on unrelated matters for two
competitors. He receives from $10,001 to $50,000
per year from one firm and less than $10,001 per
year from the other; for his role as an endpoint
committee member on a related matter for a
competitor for which he receives from
$50,000 per year; for his role as a
sub-investigator on a related matter for a
competitor for which the contract was less than
$100,000 per year.
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.
In the event that the discussions involve
any other products or firms not already on the
agenda for which an FDA participants has a
financial interest, the participants are aware of
the need to exclude themselves from such
involvement and their exclusion will be noted for
We would also like to note that Dr. John
Neylan has been invited to participate as an
industry representative acting on behalf of
regulated industry. Dr. Neylan is employed by
With respect to all other participants, we
ask in the interest of fairness that
any current or previous financial involvement with
any firm whose products they may wish to comment
DR. NISSEN: Dr. Stockbridge, I believe
you have some opening comments.
Welcome and Comments
DR. STOCKBRIDGE: The first thing I wanted
to say was sort of in the form of a public service
announcement. Last week someone, using the name of
a Cardiorenal Advisory Committee member but
claiming to be from the Division of Cardiorenal
Drug Products, made calls to several parties, one
on an investigator side and another a
pharmaceutical company, clearly trying to get some
kind of information. If anyone else ever hears
about a case like that I would like to suggest that
you bring it to my attention so we can coordinate
the investigation of any new case with the current
The other thing I wanted to say is that
two days ago the division took an action to approve
candesartan for use in heart failure and
made sure that everybody, this morning at least,
got the relevant parts of the labeling that
resulted largely from the CHARM-Alternative trial.
So, the question about whether candesartan works in
heart failure is not what you have been invited to
comment on. Instead, there is a fairly simple
question--it only takes three pages for me to ask
--about use of candesartan together with
an ACE inhibitor. Thank you.
DR. NISSEN: Thanks, Norman. Let's then
just proceed to the sponsor presentation. If it
pleases the committee, I think what we would like
to do is let the sponsor go ahead and go through
their presentation and then maybe hold all the
questions together because it is going to be, I
think, easier to integrate everything. However, if
anybody has burning questions after any of the
individual presentations, please let me know and we
will try to make sure you get clarification.
MS. LANCASTER: Good morning, Mr.
Chairman, members of the committee, members of FDA
and ladies and gentlemen. I am Cindy Lancaster,
and on behalf of AstraZeneca I would like to thank
the division and the committee for giving us the
opportunity to present the results of our clinical
program for candesartan cilexetil in heart failure.
Atacand has been approved since 1997 for
the treatment of hypertension and, more
specifically, approved in the United States in
1998. Atacand is currently marketed in 92
countries and to date we have 20 million
patient-years of exposure available.
Let me begin by sharing a list of
individuals who are here today to participate in
these proceedings. These are the sponsor
representatives. We have also invited our expert
external advisers to share their experiences with
the heart failure clinical program. Dr. Pfeffer
served as a co-chair on the CHARM executive
committee. Dr. Young and Dr. Dunlap served as
CHARM U.S. national leaders. Dr. McMurray served
as he principal investigator for the CHARM-Added
trial. Dr. Granger served as the principal
investigator for the CHARM-Alternative trial. They
also served as members of the CHARM executive
In addition, Dr. Lewis, Dr. McLaughlin,
Dr. Kronmal and Dr. Hennekens are also available to
assist today. Dr. Hennekens is here in his role as
the chair of the CHARM data and safety monitoring
To set the stage for the forthcoming
presentations, here is a brief history as of 1996
of the product's development and key previous
interactions with the FDA in regard to the heart
failure clinical program. Three pilot studies were
conducted to help identify the optimum dose and
evaluate neurohormonal effects, LV systolic volume
and tolerability of the 32 mg high dose under the
U.S. IND, prior to the initiation of the CHARM
In 1998 AstraZeneca met with
of Cardiorenal Drug Products to discuss the design
of the CHARM program, and gained agreement that the
program would support a claim for heart failure.
The CHARM program was initiated in 1999, and in
March, 2003 we completed the program. Later in
2003 a pre-sNDA conference was held with FDA to
discuss the content and format of the application.
The heart failure supplement was then submitted to
the FDA in June, 2004 and a priority review was
assigned for CHARM-Added.
An approvable letter was issue by the FDA
at the end of December for the CHARM-Added study.
As Dr. Stockbridge stated this morning, on Tuesday
of this week the division granted approval for the
use of candesartan in heart failure primarily based
on CHARM-Alternative. As such, today we are here
to specifically discuss CHARM-Added and approval
based on the results from this particular study.
To that point, let me first provide a little
background on the CHARM program.
CHARM-Alternative and CHARM-Added were
part of the most comprehensive trial
completed to date with this class of drugs for
heart failure. The CHARM program consists of three
separate but complementary randomized,
double-blind, placebo-controlled, parallel group
studies including 7,601 patients.
Alternative was conducted in patients with
ejection fraction less than or equal to 40 percent
and not on an ACE inhibitor. This Tuesday's
approval was primarily based on this study. Added,
which is the focus of today's discussion, was
conducted in patients with ejection fraction less
than or equal to 40 percent and receiving an
optimized dose of ACE inhibitor. Preserved was
conducted in patients with preserved left
ventricular systolic function.
The primary endpoint for each trial was CV
death and heart failure hospitalizations. The data
demonstrated a statistically significant and
clinically important benefit for candesartan in the
low ejection fraction studies, Added and
Alternative. The primary endpoint for Preserved
was not statistically significant. These results
from Alternative, supported by the Added study,
formed the basis of Tuesday's approval by FDA for
candesartan in heart failure. Additionally, to
date candesartan has been approved in 18 countries
for the treatment as add-on therapy based on
CHARM-Added or without an ACE inhibitor based on
Specifically, in the United States the
indication approved on Tuesday states Atacand is
indicated for the treatment of heart failure (New
York Heart Association class II-IV and ejection
fraction less than or equal to 40 percent) to
reduce the risk of death from cardiovascular causes
and reduce hospitalization for heart failure.
In addition, the clinical trial section
mentions CHARM-Added as a supportive study in the
first sentence of the text you see on the screen.
Also note there was a 15 percent lower risk of
cardiovascular mortality based on both
CHARM-Alternative and CHARM-Added together.
Furthermore, symptoms of heart failure, as assessed
by New York Heart Association functional
were also improved.
Based on CHARM-Added, AstraZeneca requests
approval for candesartan as add-on therapy when a
patient is already receiving an ACE inhibitor.
CHARM-Added was designed to allow an investigator
to optimize the dose of ACE inhibitor treatment on
an individual patient basis when either placebo or
candesartan is used for the treatment of heart
failure. Treatment resulted in a statistically
significant and clinically important benefit when
candesartan was added to an evidence-based dose of
an ACE inhibitor.
The FDA has posed the question does
CHARM-Added provide compelling evidence that
candesartan should under some circumstances be
recommended for use in patients on an ACE
To help answer this and other questions
posed today, we have conducted supplemental
analyses, the results of which will be presented
here to assist with these proceedings. Next, Dr.
Young will present the rationale for use
of ARBs in
heart failure. The ARBs and ACE inhibitors have
distinct and complementary mechanisms, and data
from pilot studies are supportive of the beneficial
effects demonstrated from treatment with
candesartan added to an ACE inhibitor.
Following that, Dr. McMurray will present
information on the selection of the recommended
dose of an ACE inhibitor in CHARM-Added. Dr.
Pfeffer will then provide a summary of efficacy for
CHARM-Added as well as the analyses for maximum ACE
inhibitor doses defined by the FDA. Dr. Hainer
will present safety information. Dr. Young will
then present the benefit/risk profile. That will
conclude our formal presentation. Now, Dr. Young?
DR. NISSEN: Any clarification issues for
anybody or can we go ahead and move on? If not,
let's do it.
Background and Rationale
DR. YOUNG: Thank you, Cindy. Dr. Nissen,
ladies and gentlemen of the panel, the FDA and the
audience, it is an honor for me to be here today so
we can all reconsider an extraordinarily
healthcare challenge and review data which supports
a new pharmacotherapeutic strategy for chronic
I need not detail the devastating impact
of chronic heart failure's morbidity and mortality.
Particularly concerning is the high prevalence of
this syndrome and the number of hospitalizations
precipitated annually which is increasing, and in
those patients associated with even higher
mortality rates during follow-up.
This survival data from the Framingham
cohort study is important as it demonstrates that
though some progress has been made over time heart
failure mortality is still great. Even in the
so-called modern era of heart failure, the last
decade, which would have included ACE inhibitors
and to a lesser extent beta-blockers, the 5-year
survival rate for men with CHF is still only about
40 percent and women fare only slightly better.
Germane to today's CHARM program
presentation is question 1 from the FDA, and
specifically question 1.4, are ACE
ARBs sufficiently different that CHARM-Added can
support use of candesartan with ACE inhibitors?
To answer that question we need to
consider the pathophysiology of heart failure and
the relationship of ACE inhibitors and ARBs to the
renin-angiotensin-aldosterone system. It had been
gratifying to see the insight gained over the last
30 years into the pathophysiology of heart failure
and this has helped us design better therapies.
Particularly important is understanding
implications of the renin-angiotensin-aldosterone
Indeed, the vast majority of drugs
beneficial in this system, including beta-blockers,
attenuate adverse effects of angiotensin-II.
Emphasizing that point is this RAAS cascade. I
know everyone here has their own favorite RAAS
cascade. This happens to be mine. Here we can see
the potentially detrimental effects of
angiotensin-II effected through the AT-I receptor,
as well as some putative beneficial effects of
angiotensin-II effected through the
specifically increasing kinin and nitric oxide
These observations have significant
implications when we consider ACE inhibitor and ARB
use in heart failure, and particularly their
combination. First, angiotensin-converting enzyme
is not the only molecule affecting production of
angiotensin-II. During long-term ACE inhibitor
prescription chymase activity, for example, can
increase levels of angiotensin-II even at doses of
ACE inhibitors which completely inhibit this
ACE inhibitors have another important
effect. They are bradykinin potentiating factors.
Indeed, when first isolated from the Brazilian pit
viper venom, the molecule was labeled BPF. It is
also important to remember that candesartan, the
agent of focus today, is a selective angiotensin-II
type I receptor blocker that is tightly bound and
Again keeping in mind the last diagram, we
can illustrate how ACE inhibitors
in heart failure remembering the BPF and ACE escape
issues. Here we see the ARB effects which result
in more specific and complete blockade of the
angiotensin-II type I receptor. Here, the
rationale for combination ACE inhibitor and
candesartan therapy is the fact that angiotensin-II
produced by chymase activity will be attenuated
without abrogation of ACE inhibitor BPF effects
while allowing potentially beneficial effects of
AT-II receptor activity.
There is robust basic scientific evidence
that supports these concepts. For example, in
canine heart failure models ACE inhibitor and ARB
combination improved hemodynamics, collagen volume
fraction and mRNA for collagen 1 and 3 compared to
either agent alone.
In Pfeffer model rats with heart failure
the combination of valsartan and fosinopril was
more effective in suppressing myocardial remodeling
assessed by collagen production and decreased
infarct size, while valsartan and benazopril
improved more subsequent left ventricular
hypertrophy and lusitropic properties noted in
these pathophysiologic models. In obese and
hypertensive rats, blood pressure, left ventricular
hypertrophy and renal function were improved more
with the ACE inhibitor/ARB combination than with
use of either agent alone.
We also see clinical evidence that a
combination of an ACE inhibitor and an ARB could be
beneficial. For example, this now classic report
of the ACE inhibitor escape phenomenon demonstrates
the time-dependent increase of angiotensin-II
despite almost complete reduction of plasma ACE
activity over time.
This is one example of several very
elegant demonstrations of a complicated interaction
between ACE inhibition and AT-I receptor blockade
in heart failure patients. This experiment
specifically focused on the contribution of
bradykinin to vasodilation in patients on enalapril
compared to losartan. Specifically, all subjects
received an infusion of a bradykinin receptor
antagonist before an ACE inhibitor or
This is a complicated diagram but focus on
the change in mean arterial pressure and change in
systemic vascular resistance. The top line is the
ACE inhibitor; the middle line the ARB. What this
study shows is that in patients with chronic heart
failure infusion of a bradykinin receptor
antagonist attenuates the blood pressure lowering
effects of long-term enalapril therapy when
compared with losartan treatment indicating loss of
the BPF activity of the ACE inhibitor.
Additional information has also become
available supporting the hypothesis that an ACE
inhibitor/ARB combination will produce incremental
benefit with respect to significant clinical
outcomes, albeit in a non-cardiac vascular bed.
The first three small clinical studies listed on
this slide explored in type 1 and 2 diabetics the
value of adding valsartan, candesartan or
irbesartan to substantive doses of an ACE inhibitor
and consistently demonstrated, when a crossover
trial design was used, significantly
reduction in proteinuria with the contribution of
an ACE inhibitor and ARB.
The COOPERATE trial was a small but
significant clinical outcome study in nondiabetic
renal insufficiency patients when a maximally
effective dose of trandolapril, and this was
determined as the dose above which there was no
further reduction in proteinuria, was combined with
100 mg of losartan. There was significantly
greater reduction in proteinuria with the drugs
combined, but most important, with the combination
there were significantly fewer primary endpoints of
combination of developing end-stage renal disease
or a doubling of creatinine.
With respect to clinical effects of
combination of ACE inhibitors and ARB in heart
failure, a ValHeFT pilot study demonstrated that
adding valsartan to 20 mg of lisinopril effected
more reduction in some hemodynamic parameters.
RSOLVe was a very important pilot study of
candesartan in heart failure patients. Its primary
purpose was to determine if this ARB in
doses could be added safely to 20 mg of enalapril
and then if long-acting metoprolol could be added
to the ACE inhibitor/ARB combination.
Exploratory efficacy endpoints were
included and this slide demonstrates the important
finding that BNP dropped significantly in the
combination group at the 43-week follow-up point.
The combination of candesartan and enalapril also
more favorably affected aldosterone and
angiotensin-II levels, not shown on this slide.
The combination ACE inhibitor/ARB
pharmacologic effects seemingly translated into
greater beneficial cardiac remodeling, demonstrated
by this data also from the RESOLVe pilot study.
Candesartan alone and enalapril alone had about the
same effect on left ventricular end diastolic and
end systolic volumes during the course of this
trial, whereas, a more substantial effect was
apparent with the combination.
Another small clinical study demonstrated
the additive effects of ACE inhibitor and ARB on
heart failure symptoms and exercise
we see a significant increase in peak exercise
oxygen uptake and improvement in New York Heart
Association symptomatic classification when 50 mg
of losartan was added to either lisinopril and
Setting the stage for the CHARM program,
and particularly the CHARM-Added study is this
clear imperative to develop better strategies for
heart failure treatment. Certainly, attenuating
the adverse effects of RAAS is important. There is
now substantial preclinical and clinical evidence
that the combination of an ACE inhibitor and ARB
will be effective interventions. This is supported
by clinical outcomes data in diabetes and chronic
renal insufficiency patients, as well as
hemodynamic, neurohormonal, cardiac remodeling,
symptomatic and exercise changes in heart failure
To discuss in more detail the rationale
for very important design characteristics of the
CHARM-Added study is Prof. John McMurray of the
University of Glasgow, in Scotland. John is the
global principal investigator for the CHARM-Added
trial. As we consider in more detail the
CHARM-Added program design, Dr. McMurray will
specifically address the issue of baseline ACE
inhibitor choice, dose and utilization in our
study. This will address several additional
questions posed by the FDA. Then Dr. Pfeffer will
subsequently present our outcomes data. So, if
there are no clarification questions, we can turn
to John to deal with the ACE inhibitor issue.
DR. NISSEN: Can we move on? Okay.
ACE Inhibitor Choice, Dose and Drug Utilization
DR. MCMURRAY: Mr. Chairman, ladies and
gentlemen, Dr. Young has explained to you that ARBs
and ACE inhibitors have pharmacologically distinct
mechanisms of action. He has explain to you the
scientific rationale for combining the two. He has
shown you the mechanistic data to show that there
may be benefit from using the two different types
of drugs together. But to show that there is an
important improvement in clinical outcome when you
combine the two drugs you obviously have
a trial like CHARM-Added, and what I want to
consider is the way we approached this question
when we designed CHARM-Added. In particular, I
want to show you the approach we took to ensuring
that the background dose of ACE inhibitor was
optimized because to test this hypothesis in an
outcomes study it was important that candesartan
was added to a good dose of an ACE inhibitor, to
optimum background ACE inhibitor therapy.
So, in line with the questions that we
received from the agency, I am going to speak to
how we did this in the CHARM protocol, and I am
going to tell you how we tried to optimize
background ACE inhibitor dose, and I am going to
show you what our investigators actually did. So,
I am going to talk about which drug and what dose.
I am going to show you the evidence-based trials on
which we based our recommendations and then also
address a question raised by the agency which is
about higher than evidence-based doses. I will
come back to that at the end of my presentation.
So, what did we do when we
CHARM-Added? What did we write in the protocol?
What did we tell our investigators at all the
meetings that we spoke at? Well, at the time that
we were designing the study there were five ACE
inhibitors that you could call evidence-based. In
other words, five ACE inhibitors that have been
used in large-scale clinical outcomes
studies--captopril, ramipril, trandolapril,
lisinopril and enalapril. These are the five ACE
inhibitors that we recommended to our investigators
that ideally they should use in their patients.
What about dose? What did we say about
dose? Well, here are some words from the protocol.
I am sorry, this is quite a long slide to read but
I will just draw your attention to the last
sentence. We say here the investigators are
reminded that these trials--so we referred to the
trials I just mentioned--had target ACE inhibitor
doses higher than those commonly used in clinical
practice. We have an appendix, which I will come
to, which showed the doses. We also said at that
time that the recently reported ATLAS
compared a very low dose of ACE inhibitor to a
higher dose, that trial suggested that there is
more morbidity benefit from using a higher dose of
ACE inhibitors. So, we were very strong. We felt
that to test the hypothesis it was very important
that our investigators used the target doses, if
possible, of the ACE inhibitors that had been shown
to be of benefit in the large randomized trials.
You can see here those trials and the target doses
that were recommended. These were what were put in
the protocol. These were what we spoke about at
the investigator meetings.
So, that is what we planned. What
actually happened? Well, in addition to those two
things we also asked, once the investigators had
individually optimized ACE inhibitor dosing in
their patients, that the patients should be on a
stable dose of an ACE inhibitor for at least 30
days before randomization.
So, I want to now look at what our
investigators actually did. Well, if you remember,
I said there were five ACE inhibitors
proven to be
of benefit in large-scale randomized trials. We
were pleased to find that, in fact, in 80 percent
of the patients in CHARM-Added those five proven
ACE inhibitors were the ones that were used.
The agency also recently asked us to look
at all approved ACE inhibitors. In fact, there are
two additional ACE inhibitors. There are seven
FDA-approved ACE inhibitors for the treatment of
heart failure. In fact, it was 90 percent of
patients in CHARM-Added who received an
FDA-approved ACE inhibitor. So, that is something
about the drugs that were used.
What about the doses that were used by the
CHARM-Added investigators? Well, we asked our
investigators to tell us that they actually felt
that they had tried to individually optimize the
dose of ACE inhibitor. We did that by asking them
to check a box before randomization on the CRF. We
wish we had collected more information about this
but we didn't.
But I will show you what I believe is
evidence to support the view that our
did a good job in trying to use evidence-based
doses of ACE inhibitor. On this slide you see the
mean dose of ACE inhibitor used in those landmark
trials. You also see the mean dose of the same ACE
inhibitors used in CHARM-Added. For example, in
the SOLVD treatment trial the mean dose achieved
was 16.6 mg. In CHARM-Added the mean dose of
enalapril used was 17 mg. Broadly, I think this
slide shows that our investigators generally did
achieve the sorts of doses of ACE inhibitor seen in
the forced titration trials.
I am just going to focus on enalapril a
little bit more, and the reason I am going to do
that is two-fold. Firstly, enalapril is by far the
most evidence-based ACE inhibitor in heart failure
and, secondly, it is the one where we have the most
information about doses achieved during forced
You see on this slide all the trials that
force titrated enalapril in heart failure. You see
the mean daily dose achieved which was generally
between 15-18 mg, and in CHARM-Added our
received 17 mg and enalapril was the most commonly
used ACE inhibitor in CHARM-Added.
Perhaps an even more important slide I
think is this one because it shows you the ACE
inhibitor doses used in other recent important
heart failure trials looking at treatments given in
addition to an ACE inhibitor. So, on this slide
you see two of the recent key beta-blocker trials
and you also see the RALES trial and you see the
baseline dose of ACE inhibitor used in these
trials. In every case for these key ACE inhibitors
the CHARM-Added investigators had their patients on
a larger dose of ACE inhibitor than in these other
trials. We think that that tells us that our
investigators did heed our advice; did follow the
instructions in the protocol; did listen to what we
said at the investigators meetings.
Here is another important slide and it
really goes to the heart of what we were trying to
do in CHARM-Added. Here you see all the evidence
that we can find about the use of ACE inhibitors in
ordinary clinical practice in the
community and in
hospitals. You can see again that the patients in
CHARM-Added got much higher doses of ACE inhibitor
than were used in ordinary clinical practice.
I want to now turn to the interesting
question raised by the agency, what if we were to
go to even higher doses of ACE inhibitors than
those proven to be of benefit in the clinical
trials? That is actually quite a difficult thing
to look at because though there are many
dose-response study for ACE inhibitors, most of
these haven't addressed that question. What they
have looked at is actually very small doses or
medium doses compared to evidence-based doses.
They haven't looked at the question that we were
asked, which is what happens if you go above
It is interesting to think about that
question because the first part of it is really is
it possible to do that? Can patients get to these
much higher doses? Secondly, even if they do, is
there additional benefit? Well, I am a heart
failure specialist and I know there are
people here who are, and we know that in our
practice you can get some people to bigger doses
than have been used in the key landmark trials, but
I think individually it is very hard to get a
handle on how many patients, what proportion of
your patients can get above those doses.
It is interesting just to note that in the
SOLVD treatment trial only about half the patients
got 10 mg twice a day of enalapril. In the
CONSENSUS study it was only about a fifth of
patients who actually got up to 20 mg twice a day.
The one trial in the literature that has actually
tested this question is shown on this slide. That
is a study that compared an evidence-based dose of
enalapril, 20 mg a day, to a much larger dose, 60
mg a day. You can see the details of this trial
here. You can see that about a third of patients
could get this larger dose of enalapril. But what
is of interest is that there was no statistically
significant or clinically important difference in
blood pressure, heart rate, ejection fraction or
NYHA class in the group who got the
larger dose of
enalapril than in the group who got the
evidence-based dose of enalapril. There was also
no significant difference in any of the clinical
outcomes measured, though this was a relatively
small trial but just so you can see what happened.
Here is the endpoint of death or admission to
hospital with worsening heart failure. You can see
the two treatment groups and I think you will agree
that in this small study there is no difference
between the two treatment groups.
To summarize, Mr. Chairman, ladies and
gentlemen, in CHARM-Added we believe that our
patients did receive an evidence-based ACE
inhibitor; 80 percent of them got a proven ACE
inhibitor. We believe that they did get doses
comparable to those obtained in the forced
titration studies, for example 17 mg of enalapril.
The doses patients in CHARM-Added got were much
higher than doses used in other recent add-on
trials, and clearly higher than doses used in
ordinary clinical practice. And, I have shown you
what little evidence there is about
to higher dose of ACE inhibitor has any additional
So, to conclude, in our protocol and at
our investigational meetings we advocated the use
of evidence-based ACE inhibitor treatment, and we
believe our investigators did do that. In other
words, we believe that CHARM-Added did test the
hypothesis of whether adding an ARB to an
evidence-based dose of ACE inhibitor would provide
further clinical benefit, and my colleague, Dr.
Pfeffer, will speak to the evidence that that is
the case when he presents the efficacy findings
from the CHARM-Added study. Thank you very much.
DR. NISSEN: Any clarification? Yes,
DR. HIATT: Just a quick question, when
you presented the dose of ACE inhibitors how
different was the median from the mean?
DR. MCMURRAY: The medians were slightly
smaller for one or two ACE inhibitors but they were
DR. HIATT: So, the mean data were
representative of the distribution of use--
DR. MCMURRAY: They were.
DR. NISSEN: Before we go on, we have had
two people join us a little bit late so perhaps
they could introduce themselves. Dr. Temple?
DR. TEMPLE: Bob Temple, regularly late,
DR. CUNNINGHAM: Susanna Cunningham,
University of Washington.
DR. NISSEN: And you might tell them what
your role is here.
DR. CUNNINGHAM: I am the consumer
representative on the committee.
DR. NISSEN: Thank you very much. Let's
move on unless there are other questions of
DR. TEMPLE: I have a question.
DR. NISSEN: Yes, sir?
DR. TEMPLE: The point was made that the
doses used in CHARM-Added were similar to doses
used in a variety of add-on studies. But our view
was that that isn't really relevant
unless it is
another drug that works the renin-angiotensin
system. The question here is whether it is sort of
like giving another extra dose of your ACE
inhibitor. So, the fact that RALES used lower
doses really doesn't matter particularly.
DR. MCMURRAY: I understand that, Dr.
Temple. The dose of ACE inhibitor in CHARM-Added
was larger than in any of the other add-on trials.
We had the same view that you do. I mean, we tried
to design a study to test the question and I was
only showing that slide to try to emphasize that I
think our investigators did try and do better,
certainly have done better than in ordinary
clinical practice and actually did better than
other investigators in other clinical trials.
DR. TEMPLE: Yes, I take that point but
the immediate question is whether you are just
adding a little more of the same. So, it really
only matters in the ACE inhibitor trials.
DR. NISSEN: Other clarifications?
Fortunately, I visited
Scotland so I
understood every word without English translation.
DR. MCMURRAY: Thank you very much.
DR. PFEFFER: Mr. Chairman, members of the
panel, ladies and gentlemen, I am glad to be
representing the CHARM investigators to present the
efficacy data, and I will be concentrating on
CHARM-Added. But I would first like just to remind
you that this was a program of research, and you
met Dr. McMurray who led the CHARM-Added, which I
will be talking about. Dr. Granger is here. He
led CHARM-Alternative. Dr. Slim Yusuf led the
CHARM-Preserved, and I co-chaired this with Dr.
The program of research had some
interesting aspects which relate to CHARM-Added
particularly. By definition, by protocol the
program was three individual projects, each asking
its own question in its own population; each with
its own sample size; and each was united under the
banner of the same investigator, same
dose titration; same committees. But one of the
aspects of the protocol I call your attention to is
that by definition the protocol stated that we
would follow the last patient randomized for a
minimum of two years. That means the greatest
exposure we have is in CHARM-Added for the longest
observation of those on the experimental
For each of the projects--but we can
concentrate on CHARM-Added--it is the same; the
primary endpoint was cardiovascular mortality or
hospitalization, unplanned hospitalization for
management of heart failure, all adjudicated
The secondary endpoints for each of the
projects was to look at all-cause mortality or
hospitalization for heart failure, and another
prespecified secondary endpoint was to add nonfatal
MI to our primary endpoint of CV mortality or
hospitalization for heart failure.
The dose titration regimen for all the
protocols was the same. The investigator had the
option, after assessing patient status, of starting
either at the first step or the second step. So,
effectively, they could have started either with 4
mg or 8 mg of candesartan or matching placebo in a
blinded fashion. Investigators were asked to
titrate at 2-week intervals according to clinical
standards and whether or not they wanted to
proceed. As you can see, 71 percent of our placebo
patients were able to be titrated to the full dose
and 61 percent of the candesartan, which is quite
comparable to other trials with forced titration.
The analyses that I will present within
our analysis plan--and if I leave our analysis plan
I will specify that--were all intention-to-treat.
It is all time to first event for the primary and
secondary endpoints. We will be using log rank
test for comparisons; the Cox proportional hazard
models to estimate the effect size. You will be
seeing effects over time as a Kaplan-Meier. For
the secondary endpoints we are using a hierarchical
closed test procedure.
Inclusion criteria for the
were symptomatic heart failure patients above the
age of 18, and they had to be stable for at least 4
weeks, and II-IV. For the CHARM-Added we had the
additional criteria that if a patient was class II
they could be admitted but they had to have a
history of a cardiac hospitalization in the
previous 6 months.
For the program, patients were to be
excluded if their creatinine was greater than 3;
potassium greater than or equal to 5.5; and known
contraindications to inhibitors of the
renin-angiotensin system or use of an ARB.
I think Dr. U's report demonstrates that
we did achieve balance in the randomization process
so I just want to highlight that approximately 17,
18 percent of our patients were over 75 years of
age and 21 percent were female. The predominant
New York Heart Association class was III. The
background of co-morbid diseases is well-known to
this group, with about a third known diabetics;
hypertension in about a half; and atrial
fibrillation in just over a quarter; and
myocardial infarction in about 55 percent.
Concomitant medications is an important
point for any study. Our enrollment started in
1999 and ended in 1999 for this trial. Around 1990
were very exciting times with the proof of
beta-blockers continuing to mount. As I mentioned,
Dr. Swedberg was one of the co-chairmen and he has
been on the vanguard of beta-blocker use. So, our
investigators were well on top of the wave at the
time so for a study randomizing in 1999 I think we
have the highest use of a beta-blocker at 55
percent. We did allow the use of spironolactone at
the physician's discretion, and our exposure will
be on 17 percent on patients.
Here are the results of the primary
endpoint. CV death or hospitalization for heart
failure is reduced by 15 percent, showing the
confidence interval here. This is a significant
reduction. This relative risk really represents
44/1000 events reduced, and that event is either a
CV death or a hospitalization for heart failure.
The number needed to treat over the time
would be 23 to prevent either a CV death or first
hospitalization for heart failure.
I will just use this opportunity to say
that this is the first hospitalization for heart
failure and, as this group knows, this is a
revolving door. Once a person has that, they are
much more likely to come back again. Subsequent
total hospitalizations will be discussed.
Well, here are the components of the
endpoint. The endpoint was a composite of CV death
or hospitalization for heart failure. This is
basically what I was showing on the Kaplan-Meiers
but if we look at the contribution of both
components, they are a 16 percent reduction in risk
of CV death and a 17 percent reduction in the risk
of a hospitalization for heart failure. As
everyone knows, if you add the components, it
exceeds that because a person can have a
hospitalization for heart failure and subsequently
die, and that was a common finding more often in
the placebo group.
Here are the components looked
individually. Here is the Kaplan-Meier for CV
death. We are also showing the non-CV death but
the impact on CV death over time--I have shown you
that data. Here is the impact on hospitalization
and this, of course, is skewed by the survivor
bias. Obviously, there were more placebo patients
at risk to have this but despite that fewer
candesartan patients were hospitalization for heart
failure, at least a first hospitalization.
Our secondary endpoints, prespecified,
were to look at all-cause mortality, not the
adjudicated but all-cause and add that to the
hospitalization for heart failure. As you can see,
this secondary endpoint was also achieved and the
components of this are also shown where both
contribute to this important secondary endpoint.
Another prespecified secondary endpoint
was to add nonfatal myocardial infarctions, and we
add an equal number. We add 13 and 19 to the
primary endpoint--I may have this wrong; I can't do
it from this one. We add very few--
--equal numbers, but the point is how few
it is relative to the primary endpoint.
Subgroups. We do this with caution and I
am showing 13. I could show many more. The
analysis plan had several others. These are the
ones we thought would be of interest to the
clinical audience. Thirteen are on this. There
were no interactions, which allows me to say that
the benefit we have been discussing was not
modified by these subgroups.
There was really at the time, when we
first analyzed our data and presented our data in
the year 2003, clinically a very major issue
addressed, and that was beta-blockade. A study
prior to ours had given an indication from a
subgroup analysis of the potential safety issue.
With that knowledge, our data monitoring board
chaired by Dr. Hennekens, and our investigators and
the world clearly wanted to know what was the
exposure with beta-blockers.
I will remind you that in CHARM-Added
everyone is on an ACE inhibitor, 100
when we talk about beta-blocker, it is ACE
inhibitor, beta-blocker, plus candesartan or
placebo. Here is the experience. There was no
signal of loss of efficacy so the effectiveness was
not modified by the presence or absence of a
This is a safety analysis--was there a
mortality signal of using this now triple
therapy--the so-called triple therapy, ACE
inhibitor, beta-blocker, candesartan--and no signal
of a safety issue. So, this was an important group
looked at, at the time.
Spironolactone was an opportunity for us
to query potential issues, with 17 percent of
patients on spironolactone. We had 436 and there
was no interaction here. This is a
non-prespecified sub-subgroup that I put here with
trepidation, just to say everyone is on an ACE
inhibitor, beta-blocker, spironolactone, placebo or
candesartan, and it is only 237 patients but there
is the data in that non-prespecified sub-subgroup.
If we do that, we must look at safety
and the best
measure of safety would be all-cause mortality and
we are showing that here with no signal but,
certainly, the confidence is based on 237 people in
So, this part of my presentation is really
the standard CHARM-Added and we believe we have
addressed the hypothesis that we set out to test,
that for patients with symptomatic heart failure
already being treated with an ACE inhibitor and
other conventional therapies the addition of
candesartan improved clinical outcome, and
improving clinical outcome by our definition was
reducing the risk of CV death or a hospitalization
for heart failure, and we can confirm that with our
secondary endpoint of reducing all-cause mortality
and hospitalization for heart failure which was
In response to the agency's very pointed
and very stimulating questions, I will present some
other data. One is to put CHARM in external
perspective. There have been three major outcomes
trials with ARBs in patients with
ejection fraction and symptomatic heart failure.
One was a head-to-head comparison and in that the
dose of the ARB was not found to provide clinical
benefit or to be even comparable.
Here is the closest study to CHARM-Added.
This is the ValHeFT experience which has been
presented to this group. In the ValHeFT it was
conventional therapy and an ARB. For the composite
outcome, one of their co-primaries of morbidity and
mortality, there was a significant reduction. In
the CHARM study there was a significant reduction.
So, I think the external validation of adding an
ARB, without looking at subgroups but looking at
the total group, gave very similar information.
The reason we have more events here is, again,
because of the longer exposure and longer
The other questions from the agency which
we will try to address the best we can--Dr.
McMurray told you how the study was conducted and
we did find that investigators were using a variety
of ACE inhibitors. So, if I look at those ACE
inhibitors, as Dr. McMurray showed you, there were
12 including enalapril and four of these did not
have an FDA approval so we couldn't find the dose
that would be used.
So, now just talking about the agents
themselves with the different use of the agents, we
used an analysis of was there a difference in the
outcome of those who received an ACE inhibitor that
had FDA approval or those that did not. That
analysis is a non-prespecified one that I am
showing here. Here are the patients that had the
FDA approval using an ACE inhibitor, and here are
agents that were not approved. Again, the best
estimate is the overall. So, as far as the agent,
we did not see any difference.
The real probing question that we have
seen through your questions is the dose issue. To
get at that, I have to say the first analysis that
the investigators and the sponsor did was the
prespecified one. Prior to unblinding, the
academic group made a list of the evidence-based
therapies and the doses. We had made that
definition called the recommended by the
evidence-based. When we did that, there were 1291
patients who at baseline were receiving that dose.
I will talk about that dose in a moment
but I think one of the questions about trial design
and trial conduct that has to be addressed right up
front was in order to test the addition of the new
medication, candesartan, the study medication, did
the investigators sustain the levels that Dr.
McMurray was so proud of, or did they just reduce
that to start the other inhibitor of the
renin-angiotensin system--a very important and
To do that, I will just be talking about
the five most commonly used, which is approximately
80 percent of our patients and is representative,
and the dose, and look at the titration time
period. While patients were being titrated to
either placebo or candesartan there was no
down-titration of the ACE inhibitor. That was
something that was conveyed to investigators. If
your patient is stable on these doses of
inhibitor, that is what you should be sustaining.
If you have issues you should be down-titrating the
I also have some additional data here on
the use of the ACE inhibitors over time, and I
think it is quite reflective of our baseline
numbers, that there was no attrition of the use of
ACE inhibitors. So, we are looking at the added
value of candesartan. It is on top of holding good
doses of ACE inhibitor over the time frame.
So, what was the analysis? This is the
prespecified one from the investigators. These are
the 1291 patients who at baseline were receiving
doses equivalent to those in the evidence-based
trials, and these are the patients who were not.
That does not mean these patients weren't receiving
optimal dose for them; it is individualized care.
But just making this definition, there was no
interaction here. The observation of the overall
benefit means that this benefit was not modified by
the baseline dose of the ACE inhibitor using this
In subsequent communication with the
agency, there were requests to create additional
subgroups. Since our forms were designed to know
the ACE inhibitor and the dose, we are able to
comply with those requirements. The agency asked
for different doses, a definition of maximum where
now the lisinopril dose is increased and some of
the other agents are increased. So, we go from
having 1291 who met our definition to now 721 who
met the new subgroup criteria.
If we look at the results of that, I think
you can see the consistency that there was no
modification of this benefit of candesartan that I
have been describing based on the ACE inhibitor
dose at baseline with these two definitions of ACE
In subsequent communications with the
agency another subgroup was defined, and we were
pleased to be able to comply. This one raises the
captopril to 300 mg and we did have 2 percent of
our patients at baseline. More importantly, it
raised the enalapril dose to 40 mg and
we did have
10 percent of our patients on enalapril at that
dose. So, overall now we are talking about 20
percent of the patients, 529, who met the new
Here are the results of this new subgroup.
The 529 and the remainder had the same efficacy so
this candesartan benefit on reducing risk of
cardiovascular death or hospitalization for heart
failure was not modified by any definition of ACE
inhibitor dose at baseline, our prespecified one
and the two definitions that the agency requested.
Because we are a program of research, we
can give one more, and that is the zero dose of an
ACE inhibitor. So, we have a whole trial that you
have evaluated and that trial is zero,
CHARM-Alternative, 2028 patients not receiving an
So, I think we have run the whole spectrum
here and you can see the results. Now if we pool
the two, the benefits that we are describing of
candesartan were not modified by the dose of the
ACE inhibitor from zero to predefined
subsequently defined maximum levels at baseline.
That allows us to conclude that we really
have an additional opportunity to help patients who
are already on an ACE inhibitor and, more than 55
percent, on a beta-blocker. That really is the
clinical question. When CHARM was designed that
was the issue, can we make an improvement in the
practice of medicine? We didn't know the answer.
We now share that answer with you and we think we
do. We reduce the patient's risk of cardiovascular
death or hospitalization for heart failure on top
of other therapies, irrespective of the dose of the
ACE inhibitor, and we offer that opportunity to
reduce cardiovascular morbidity and mortality.
That opportunity does come with some
responsibilities, and Dr. Hainer will discuss the
risk of inhibiting the renin-angiotensin system in
doses that improve morbidity and mortality, and
then Dr. Young will come back and describe the
risk/benefit. Thank you.
DR. NISSEN: Thank you, Mark. Are there
questions right now? Yes?
DR. HIATT: Just a quick one on slide 28.
Is that a typo, the maximal FDA-revised for
lisinopril? Did the dose go down from 40 mg to 20
mg? Is that true?
DR. PFEFFER: That is not a typo. We were
responding to definitions provided to us.
DR. PICKERING: Could you give us a
breakdown of which beta-blockers the patients in
CHARM-Added were taking, in particular how many
were on carvedilol?
DR. PFEFFER: Yes, I could do that and I
would like to do that. I said 55 percent at the
start and obviously that number increased to the
mid-60s by the time it was over. If I can show the
beta-blockers that were used at baseline, the
predominant beta-blockers were metoprolol and
carvedilol, 81 percent. These doses were sustained
over time, but the number of patients alive on a
beta-blocker increased over time.
DR. SACKNER-BERNSTEIN: In light of that
slide, you did a nice job of showing the effect of
coronary heart disease on top of
inhibitors, trying to make sure that we really were
evidence-based. Can you show us a similar analysis
for approved beta-blockers as background therapy?
DR. PFEFFER: I don't think I can,
Jonathan, but with 80 percent of the people on the
approved, I would think the numbers would be the
same--if I have this information, and I don't think
DR. NISSEN: We are going to have lots of
time for questions. If there ar clarifications,
let's do that.
DR. TEMPLE: Just one thought, I just
wanted to say that with all these after the fact
analyses, don't try these in your own home.
DR. NISSEN: We have some very solid
advice. So, we are kind of going to finish the
sponsor presentations and then we are going to have
lots and lots of time for questions.
DR. HAINER: Good morning, Dr. Nissen,
members of the advisory panel, FDA,
I am Jim Hainer from AstraZeneca, and I would like
to begin by stating that the candesartan safety
profile in the CHARM program relative to
placebo--the findings were really quite consistent
across all three CHARM studies. For the purposes
of this presentation I will, like my other
colleagues, review now the safety of candesartan in
chronic heart failure when added to evidence-based
doses of ACE inhibitors, the CHARM-Added trial.
Let's start then with two points that are
really important to safety monitoring. First, the
CHARM provided explicit monitoring directives for
the clinicians. Second, the CHARM protocol was
particularly specific about monitoring for
hypotension, renal dysfunction and hyperkalemia,
events expected for any drug which inhibits the
renin-angiotensin system when added to an ACE
These directives included monitoring of
blood pressure, creatinine and potassium at
multiple intervals. These were baseline, within 2
weeks of dose adjustment, at the end of
titration, annually and, of course, at any time in
the judgment of the responsible clinician. These
monitoring directives are entirely consistent with
usual clinical practice in caring for heart failure
With that said, let's look then at
hypotension, renal dysfunction and hyperkalemia.
Hypotension was reported as an adverse event in
23.2 percent of the patients receiving candesartan
and evidence-based doses of ACE inhibitors and 14.5
percent among those receiving only ACE inhibitors.
Hypotension was reported as one reason for
treatment discontinuation for 5.4 versus 3.5; for
hospitalization, 4.3 versus 1.7; and for serious
fatal adverse events 0.2 versus 0.1 percent.
Note here, expressed as proportions of
patients, that discontinuations due to hypotension
in patients 75 years and older, those taking
spironolactone or beta-blockers, were similar to
the overall discontinuation rates. The rate for
candesartan was about 3.5 times higher though among
patients entering the trial with a
systolic blood pressure less than 100 mmHg.
Renal dysfunction was reported for 15.4
percent of the patients receiving candesartan and
ACE inhibitors; 9.4 percent among those receiving
only ACE inhibitors. Renal dysfunction was
reported as one reason for discontinuation in 8.2
versus 4.2 percent; for hospitalization, 4.5 versus
3.0 percent; dialysis, 1.6 and 1.6; and for a
serious fatal adverse event, 0.9 versus 1.5
Discontinuations due to renal dysfunction
in patients 75 years and older and diabetics taking
spironolactone or with systolic blood pressure less
than 100 were similar to the overall
discontinuation rates in the trial.
For patients entering the trials with a
creatinine already greater than 2, the rates were
high in both groups but the rate for candesartan
was really no higher than for placebo.
Next, hyperkalemia was reported in 9.6
percent of the patients receiving candesartan and
3.6 percent receiving placebo. Hyperkalemia was
reported as one reason for discontinuation in 3.8
versus 0.9 percent; for hospitalization, 1.2 versus
0.7 percent; and for a serious fatal adverse event,
0.2 versus 0.0 percent.
Despite the potential for hyperkalemia to
increase rates of sudden death and fatal
ventricular fibrillation, both rates were somewhat
lower in the candesartan group, specifically 11.2
versus 13.7 and 0.7 versus 1.3 percent
respectively. Discontinuations due to hyperkalemia
in diabetics and patients taking spironolactone was
similar to the overall discontinuation rates in the
trial. The rates were higher in patients 75 years
and older and those with potassium greater than 5.
In patients entering the trial with a serum
creatinine of 2 or greater, the rates were high but
similar in both groups.
Now, having led with this data,
highlighting these three specific areas of
interest, let's examine whether they translate into
global adverse consequences. Any adverse event was
reported in 80.4 percent of the patients
candesartan and evidence-based doses of ACE
inhibitors and 78 percent among those receiving ACE
inhibitors. Of particular interest, serious
adverse events were reported in 75.9 percent in
both groups, of which serious fatal events were
29.5 and 32.5 percent in the candesartan and
placebo groups respectively. Treatment
discontinuations due to adverse events were 24.3
and 17.6 percent. Dose reduction due to adverse
events were 17.2 and 9.7 percent respectively.
Listed here are the common serious fatal
adverse events by treatment. Sudden death occurred
in 11.2 percent of the patients receiving
candesartan and 13.7 percent amongst those
receiving placebo. For heart failure the
corresponding figures were 5.8 and 8.8 percent
respectively. Other causes of death were far less
common. Of note, there was no trend toward a
consistently higher risk in the candesartan group.
Now, safety concerns also surround the
concomitant use of other heart failure treatment
drugs, as already alluded to by Dr. Pfeffer. To
that end, Dr. Pfeffer presented this slide which
demonstrates the benefits of candesartan on the
primary prespecified endpoint of cardiovascular
mortality or heart failure hospitalization, both
overall as well as for subgroups of patients
receiving spironolactone or spironolactone plus a
One logical concern is that the reduction
in heart failure hospitalization may not be
reflected in all-cause hospitalizations. But, in
fact, these data show no significant increases in
all-cause hospitalizations either overall or in
A second logical concern is that the
reduction in cardiovascular mortality might not be
reflected in all-cause mortality. But here, again,
these data show no significant increases in
all-cause mortality either overall or in any of
These trends in hospitalizations are
further reinforced by the cumulative number of
hospital admissions for any cause shown
here in the
candesartan and placebo groups and, as Dr. Pfeffer
pointed out, even though the risk remains larger
for the candesartan group. Importantly, there is
no increase in the non-cardiovascular rate for
hospitalization in the candesartan group.
Next, if you can recall the all-cause
mortality data for CHARM-Added, note how they are
reinforced by the cumulative number of deaths from
any cause in the candesartan compared to the
Having now examined the safety of
candesartan in chronic heart failure when added to
evidence-based doses of ACE inhibitors, I want to
conclude with two final slides. First, let me
summarize the safety findings and conclusions. As
expected, due to greater renin-angiotensin
inhibition, rates of hypotension, abnormal renal
function and hyperkalemia were greater with
candesartan. But these predictable adverse events
did not translate into any increase in all-cause
hospitalization or mortality, sudden death, renal
failure or ventricular
fibrillation. These data
show that candesartan is safe and generally well
tolerated by patients with heart failure receiving
evidence-based doses of ACE inhibitors.
Second, understand that AstraZeneca is
firmly committed to risk minimization. We also
wish to maximize opportunities for benefits. In
order to ensure proper use of candesartan with
heart failure receiving ACE inhibitors, AstraZeneca
will implement all of the following risk
minimization activities: Administration and dosing
instructions which are consistent with those that
guided the CHARM-Added investigators; labeling
which includes precautions and warnings regarding
these adverse events; collaboration with major
societies involved in the treatment of heart
failure patients; and educational activities to
ensure that healthcare providers understand the
risks as well as the benefits of using candesartan
in heart failure. This includes focused training
of sales force; and expert scientific liaison
groups; continuing medical education activities;
and prominently displaying information
promotional materials regarding the risk of using
candesartan in heart failure.
With these measures in place, candesartan
can be safely used as another important treatment
option to reduce cardiovascular events in patients
with heart failure who are receiving ACE
inhibitors. I will turn now to Dr. Young once
again who will elaborate on the issues of benefits
and risks of candesartan in the treatment of
chronic heart failure.
DR. NISSEN: If there are any burning
questions on this presentation let's have them,
otherwise I think we are ready to launch into full
questions after Dr. Young.
DR. YOUNG: Thank you, Jim. It is now to
overview our data and quickly consider the impact
we can make on ill patients with significant heart
Our CHARM program in its entirety, and
specifically the CHARM-Added study, the broad
patient population, comprehensively
the risks associated with treatment, particularly
the combination of an ACE inhibitor and
candesartan. We believe that we have clearly
delineated net benefits for this therapeutic
strategy in CHF patients with depressed left
ventricular ejection fraction.
Particularly important, CHARM-Added
addressed the previously unresolved question of
whether adding an ARB to an ACE inhibitor in
patients with low EFV heart failure provided
incremental benefit by reducing risk of
cardiovascular death or heart failure
hospitalization. Interesting and also important is
the fact that we have demonstrated added benefit in
patients receiving evidence-based doses of ACE
inhibitors proven effective in previous clinical
trials, and we also believe we have demonstrated a
favorable benefit/risk profile.
This benefit/risk profile is best
summarized in this slide. Overall there was a
significant 15 percent relative risk reduction for
the primary endpoint, cardiovascular
death or heart
failure hospitalization, over the 41-month median
follow-up. When analyzing the data per 1000
patient-years, this translates into an absolute
risk reduction of 25 patients having a primary
endpoint event over that period of time, as
summarized in the third column on this table.
Importantly, no increased risk for
all-cause mortality or all-cause hospitalization or
the combination was noted. These observations were
all less in the candesartan treatment group, again
noted in this table. This should assuage concern
about adverse events precipitated by this
Thus, candesartan, at a target dose of 32
mg daily, significantly reduces the risk of
cardiovascular death or heart failure
hospitalization when added to an ACE inhibitor,
irrespective of agent and irrespective of dose.
Given our understanding of heart failure, it is
prudent to look at the most common adverse events
in this population--hypotension, hyperkalemia,
abnormal renal function. Proposed instructions for
the use of this strategy are consistent with those
provided to the CHARM investigators and good
clinical management of any patient with heart
We will emphasize attention to volume
status, blood pressure, renal function and
potassium levels, and recommended monitoring of
these measures will be with initiation of
candesartan dose titration and periodically
thereafter the same as we manage all of our
patients with heart failure.
In conclusion, we believe that the
addition of candesartan to an ACE inhibitor
treatment of heart failure patients, as was done in
the CHARM-Added trial, will result in substantial
cardiovascular morbidity and mortality benefit.
The positive risk/benefit profile is further
supported by numerical reductions in both all-cause
hospitalization and all-cause mortality. We
believe these findings support the use of
candesartan with or without an ACE inhibitor at
varying doses for the routine management
failure so that candesartan can be prescribed for
managing these patients with left ventricular
Dr. Nissen, ladies and gentlemen of the
panel, thank you very much. I will ask Dr. Mark
Pfeffer to come back to the podium so that we can
direct any questions to the group.
DR. NISSEN: Thank you very much. I must
compliment the sponsor. It is rare that we finish
ahead of time. We don't have a break scheduled
until ten o'clock so I think we can maybe start
taking some questions and we will take our break a
little bit later. Blase?
Questions from the Committee
DR. CARABELLO: Mark, based on ValHeFT I
have routinely avoided the use of an ARB in
patients already receiving a beta-blocker and an
ACE inhibitor. Now CHARM-Added seems to ameliorate
that. So, what is the difference? Is this the two
agents? Is this the kind of beta-blockers that
were used in the two different studies? Is this a
statistical glitch among the two
studies? How can
we reconcile those two studies?
DR. PFEFFER: Well, Dr. Carabello, I can't
be definitive but I can give you my opinion on
that. I, like you and every clinician, wanted to
be adding an ARB on top of other therapies to
reduce adverse outcomes in patients and that
beta-blocker subgroup gave us pause. It really did
because what we do know is that beta-blockers have
a profound benefit and they do on top of an ACE
inhibitor. So, that was the conundrum in 1999.
Then, with the publication of our
experience, I think it really showed that maybe
that was a hazard of a subgroup. It turns out, if
we look at the numbers in our experience, there
were even more patients having events. if I could
show that, because we had more patients on a
beta-blocker and greater exposure time when we are
giving you our subgroup, prespecified subgroup, it
is based on more events. Just to give you an idea
of the two trials, the deaths, which is really what
we are concerned about, the total deaths were 226
in ValHeFT and really 370. So, I think there is
more confidence in our subgroup based on the
increased number of events.
You then asked about the agent. I think
there is an excellent answer to that because there
was a very large study, called VALIANT, which used
that agent in a large number of people on triple
therapy, actually more patients on triple therapy
than here, and did not show an adverse safety
interaction with beta-blocker, ACE inhibitor and
So, I think there was a pause because
safety doesn't require the same boundaries of
statistics that efficacy does, and that pause I
think is now erased by what we showed you for
candesartan and that other study. So, I do think
the message for clinicians--and this is really the
important thing, the message for clinicians should
be ACE inhibitors at the optimized dose,
beta-blockers and then this addition of candesartan
in the strategy we have shown can reduce morbidity
DR. NISSEN: Go ahead, Tom.
DR. PICKERING: As a follow-up to that,
you said 31 percent of the beta-blockers were
carvedilol and I wasn't able to see what the
proportion was in ValHeFT and, you know, there is
the COMET study that suggests that there may be a
difference between different beta-blockers in heart
failure. I wonder could that be one possible
DR. PFEFFER: I am here for the CHARM
data. I really don't have detailed knowledge about
ValHeFT and I would say, based on the small numbers
we are talking about, if we start dividing that up
by the agents it would be even more unreliable, but
I don't have that information.
DR. NISSEN: Ralph, you had a question?
DR. D'AGOSTINO: In Table 59 of the recent
material that you sent and our response to C-25 and
C-29, I am trying to understand--I know this is all
post hoc and I should not be excited about looking
at post hoc analyses, but I am trying to understand
what happens as you go from maximum dose no to yes.
If I look at slide 25, what seems to
happen is when
you are dealing with the no--this is the
recommended and you are dealing with the no you
basically have the placebo and drug pretty much the
same. There is only something like a 12 events
difference. When you move to the yes you have a 43
events difference, and the change is all basically
in the candesartan. Its events drop down. The
placebo, whether no or yes, 165 in terms of the
events per 1000 follow-up years and the candesartan
goes from 151 to 131.
Then when you move to the next slide,
slide 29, here the no for analysis one has in terms
of the placebo rate 172 versus 152, when you go to
the yes where the candesartan has 145 to 133.
Again, when you go from the no to the yes it is the
candesartan that is showing the reduction. The
same with analysis two. In analysis two if you
look long enough you will find an analysis that
will produce statistical significance. So, my
question is it seems to be the action in the
candesartan. Does that say anything about the
added benefit to the ACE?
DR. PFEFFER: Well, Dr. D'Agostino, I know
enough not to discuss statistics with you on this--
DR. D'AGOSTINO: Granted, we shouldn't
have done this.
DR. PFEFFER: I think you are asking me is
there a pattern here, and I think there is no
pattern here and I think the interpretation--may I
have the slide, please? You are asking is there a
pattern in the no's. Obviously, by every
definition we are making a new definition of no.
But I think the way to handle this is in any
definition was there a hint of an interaction, and
DR. D'AGOSTINO: The interaction test is
notoriously lacking in power, which is the problem.
DR. PFEFFER: But let's look for
consistency here, is there a consistent message?
If anything, we are not making the message that we
are even better on top of an ACE because we also
have this 2000 experience here of zero. That is
the definite no. So, I think we run the range of
no's from low doses, from zero doses to
we go here we have a higher and higher dose of no
really, the no group, because of the higher dose of
ACE inhibitor. So, I personally don't see any
consistency here and I don't see any pattern. But
if you do, then I would be worried--
DR. D'AGOSTINO: Well, I am just trying to
sort out why you would say that candesartan adds to
the ACE inhibitor. What is the revelation in the
data that would say that?
DR. PFEFFER: I think it is this point
right here that candesartan adds to an ACE
inhibitor. A 100 percent of these patients are on
ACE inhibitor. I will remind you that from the
clinician's perspective--I will go back to what Dr.
McMurray was saying, from the clinician's
perspective, 96 percent of our clinicians checked
the box that says I believe I have optimized their
care. Now, that is a box. We then upped the ante.
We made the evidence-based medicine definition.
The FDA made these definitions. So, really the
best way to look at our data is overall and I don't
see a pattern here with the different
DR. NISSEN: I wanted to ask a question
related to CS-12. You may not have this but I sure
would like to see it. This is a little unusual
Kaplan-Meier plot. It is cumulative number of
hospital admissions and I would like to see time to
first hospital admission for any cause because that
is a more traditional analysis.
DR. PFEFFER: Yes, and Dr. McMurray has
done a lot of analyses of pharmacoeconomics so for
that we needed cumulative numbers. For safety, and
this was presented in our safety presentation, we
think the burden is the cumulative. That is
something I was alluding to also although our
analysis plan didn't let me show you that because
we were timed to first. I think in the clinical
scenario we are really trying to keep the revolving
door. And, this is showing all admissions for any
cause and we thought this was the strongest safety
statement we could make about the population. I
don't know if I have hospitalization as time to
first event. I don't know that I have that.
DR. NISSEN: Let me tell you why I am
asking the question. I want to understand if there
is an early hazard. That is where time to first is
very helpful. That is, when you are titrating up
candesartan and you are getting these admissions,
there is a fair number of admissions for
hypotension and for hyperkalemia, and I want to see
whether the pattern shows an early hazard within a
more favorable effect later on because I think it
is very important for clinicians. I assume
somebody has done that analysis.
DR. PFEFFER: That is a very important
point. We can show early efficacy. We were
showing that. And time to first hospitalization
for any cause--let's see if I can get that for you.
DR. NISSEN: That would be really helpful.
DR. D'AGOSTINO: The graphs they do show
seem to have a consistent hazard. That is a good
question if you go to all-cause hospitalizations.
DR. NISSEN: I did a little Tom Fleming
type back of the envelope calculation and I want to
see if I am right about that, but there
are a fair
number of those hypotension hospitalizations and I
am guessing that they are early, that when you are
trying to titrate up the drug you run into some
difficulty. So, I think to inform clinicians about
how to do this it is very important to understand
whether there is in fact and early hazard.
DR. PFEFFER: I totally agree. I don't
think that is the case and I would like--somebody
is showing me CV hospitalizations but I need all
hospitalizations to reassure. CHF hospitalizations
won't reassure you and I need all hospitalizations
to reassure you.
DR. PORTMAN: To turn from cardiorenal to
renal for a second, based on DOQI guidelines and
Framingham studies and so forth, we know that
microalbumenuria is an important cardiovascular
risk, independent risk. Do you have data on the
prevalence of microalbumenuria? Was there
improvement with the ACE/ARB or just the ACE alone
in microalbumenuria? In fact, did you even see
resolution in a portion of the population in
DR. PFEFFER: I have to say that that is a
sub-study which is being run out of McMaster
University and that as of this moment I don't have
the results on the 600 people who were in what we
call micro-CHARM. My friend Dr. McMurray is closer
to that data. Do we have that?
DR. MCMURRAY: No, we don't.
DR. PFEFFER: We have yet to see that
DR. KASKEL: With regard to kidney, those
patients with creatinines less than 3 and maybe
above 1.5 are still at risk for dysfunction and you
had hyperkalemia as one of the early changes. I am
just wondering if there are any other guidelines
that might be helpful to prevent hyperkalmeic
episode in patients with diminished renal function.
DR. PFEFFER: Definitely, the patients
with impaired renal function are much more
vulnerable. They are also the patients at highest
CV risk. Here is where cardiorenal really should
be cardiorenal; we should be getting together more.
So, we identified the same risk and now
have learned how to use the MDRD equation we are
suddenly realizing we have more patients at risk.
But that was true for placebo as well as for
candesartan. All the augmentations are related to
baseline renal function, more so on candesartan,
but you need the same monitoring for someone with
impaired renal function whether or not you add
candesartan because they are at high risk also.
Let me see if I can show you something
like that. I would like to show you the EGFR and
just to show the adverse experience, just to share
that with you. I believe I have a better
opportunity to show you that than all-cause
hospitalizations as a function of time. May I have
the EGFR? We do have that information and it is
concerning for both placebo and candesartan. I
think the message we have to get out there for
education is that we should be looking at renal
function and we should be alerting ourselves to
vulnerable patients. I will have that for you a
DR. SACKNER-BERNSTEIN: Getting back to
Steve's point about how we can create a way for
clinicians to understand how to utilize the drug
and manage the patients who are getting the drug,
as well as the point you just made about renal
function, I am wondering if you could provide us
with some insight as to what happens to patients
who develop worsening renal function specifically
during the titration. I look back to the SAVE
trial where you did such a nice job of talking
about the prognostic importance of heart failure
hospitalization and subsequent course. What can
you tell us about worsening renal function?
DR. PFEFFER: I am going to ask Dr. Lewis
but I do want to show the slide that I was just
alluding to. Let me just show this first. I will
get back to the EGFR and then we will continue the
thread of what happens to people.
So, here cardiologists have learned how to
do EGFR, and it is a risk for discontinuation of
any causes and candesartan augments that risk. But
this also tells us how carefully we have to monitor
the placebo patients with impaired renal
Your specific question about discontinuation due to
renal function and outcome, I am going to ask Dr.
Lewis, our renal consultant.
DR. LEWIS: I am Dr. Lewis, a Vanderbilt
nephrologist. I would first like to remind the
panel that there is a great body of data in renal
literature that inhibition of the renin-angiotensin
system benefits people in terms of preserving renal
function across a wide range of kidney disease and
across a wide range of GFR, including CKD for the
lowest GFR groups, which has now been reported from
several of the major clinical trials.
There are two settings in which inhibition
of the renin-angiotensin system can cause renal
dysfunction. One is that patients have ischemic
renal disease or fixed renal artery stenosis. The
second, more relevant to the CHARM study, is if a
patient has decreased effective arterial blood
volume. That occurs in two settings, decreased
cardiac output which, of course, these patients
were at risk for, and decreased intravascular
volume, which they were at risk for
because of the
use of diuretics.
In both those settings the kidney becomes
critically dependent on efferent arterial
resistance to maintain GFR. It is a hemodynamic
effect. One would predict when a patient has
decreased effective arterial blood volume and
develops renal dysfunction that the stopping of the
agent, the inhibition of the renin-angiotensin
system, would repair that renal hemodynamic and the
patient should recover. It should be a reversible
Evidence to support that--first I will
remind you that Dr. Hainer showed you that the
number of patients requiring dialysis was
equivalent in the two groups, on his safety slide.
Also, if I could have slide 48, looking at the
ultimate outcomes for people who had renal
So, these are the patients who had any
kind of renal dysfunction event during the course
of the trial and what happened to them. I have
already told you that they had an
of dialysis. As you can see, 38 percent of the
placebo group was alive at the end of the trial and
55 percent of the candesartan group was alive at
the end of the trial. So, I think the signals we
have from the CHARM-Added is what you would expect
from the physiology, that this was a reversible
DR. SACKNER-BERNSTEIN: Just to clarify,
what was the definition of renal dysfunction in
DR. LEWIS: The definition of renal
dysfunction in this analysis was if an investigator
indicated in a narrative form that the patient had
renal dysfunction of any sort. The narratives were
scanned very closely. There was an appendix about
renal dysfunction attached to the protocol that had
precise instructions for a given change in renal
function. So, for more than 1 mg/dL increase to a
level greater than 2, the investigator was
instructed to respond to that. But for the
purposes of the safety analysis we used any change
of renal dysfunction that the investigators
DR. SACKNER-BERNSTEIN: Part of the reason
I am bringing this up is because of a little bit of
discomfort that I have about how to know the
optimal way to interpret changes in creatinine.
Certainly, if you take a heart failure patient and
you treat them with an inhibitor of the
renin-angiotensin system you would almost hope to
see an increase in creatinine, consistent with the
hemodynamic mechanism you defined, as reflecting
the fact that you are achieving a pharmacologically
relevant level of inhibition. That is the way most
people, I believe most people think about the use
of these agents in a chronic setting such as this
trial. In the acute setting there is a growing
body of literature that increases in creatinine
during treatment of acutely decompensated heart
failure in a hospitalized setting portends a worse
In trying to bring those two observations
together I found a relative paucity of data to look
at what happens to people in a chronic setting
where serum creatinine goes up by 0.3
mg/dL during initiation of therapy. Should
clinicians be looking for that physiologic effect
on efferent arterial as something that is a good
sign or is it potentially a bad sign?
DR. LEWIS: I think this is a great issue.
I am actually giving cardiology grand rounds at
Vanderbilt next week so I am going to address this
DR. SACKNER-BERNSTEIN: What day? What
DR. LEWIS: I think this is so good
because I think we really are learning more because
I think what your paradox is--first let me say that
in renal trials, as well as in cardiology
literature, you are exactly right. The patients
who most benefit from inhibition of the
renin-angiotensin system in the first three
months--in terms of, you know, don't go into
end-stage renal disease or hard outcome--in the
first three months of exposure to the inhibition of
the renin-angiotensin system do two things. They
drop their proteinuria and they drop
their GFR by a
hemodynamic mechanism because we have shown
reversibility. It is 3-5 mL. It is not clinically
significant but it is a signal, like you said, in
heart failure patients that they are responding to
the inhibition of the renin-angiotensin system.
I think the reason why you have the
paradox is that the patient in the hospital who,
despite you doing all you can do for them in a
hospital setting has a very poor cardiac output, is
the patient who has decreased effective arterial
blood volume and you can't make it any better
because they have reached a point where, short of a
heart transplant, you can't make their cardiac
output any better. When you give that patient an
ACE inhibitor or an ARB you can't get their heart
to be better. Nothing is going to get that heart
to be better. In that setting the kidney is giving
you the message that the patient has reached an
end-stage heart situation.
DR. MCMURRAY: Jonathan, I can actually
answer your question directly because we are all
interested in this in heart failure at
I will show you a slide that shows you the change
in GFR over time, but it is in a slightly different
way than my own personal slide of this issue in
CHARM-Added because what you see in CHARM-Added is
you see a sort of steady decline in GFR over the
three and a half years of follow-up. The placebo
group and the candesartan group run in parallel.
But if you plot those two lines together what you
see is this initial little drop in the candesartan
group and thereafter they run parallel with the
So, it is interesting to me because I
think, unlike the nephrology issue, we don't see
protection or preservation of GFR over time with an
ACE inhibitor or with an ARB or with the
combination. We see this initial little decline in
GFR but then the two lines run absolutely parallel.
It intrigues me why the kidney in heart failure
seems to be a bit different than the kidney in,
say, diabetic nephropathy.
DR. NISSEN: I would be very interested in
seeing the U.S.-non-U.S. analysis. There are some
obvious differences there. I presume you have a
slide that drills down on that, or maybe by region
if that would be possible. Do we have that?
DR. PFEFFER: Yes, I think this is the
observation that you are discussing. This is one
of multiple subgroups.
DR. NISSEN: Of course, and obviously I
recognize the hazards of this but, to me, it is a
rather striking difference. We have seen this now
in a fair number of drug development programs where
the effect is seen outside the U.S. but not in the
U.S. and I want to understand it.
DR. PFEFFER: Well, first you would have
to believe that that is a truism. So, if you just
take the countries it bounces around like crazy.
You would expect that. One of the real strengths
of CHARM is that we have 7599 patients with
long-term follow-up, and if there is something
about carrying a U.S. passport you would expect to
see a consistent message. So, we really are coming
to you with three trials.
I would like to show you this
is the point, and it was just over the line at
1.019. On this scale it looks like it is on line,
just over. But there was no inconsistency here.
But let's look at the total program. If
there is something about being a U.S. citizen that
means you are not going to see the benefit of
candesartan, let's look at all patients. When we
get down to the 7,500 patients U.S.-non-U.S., I
think you would agree with me there is nothing
here. More importantly, I think when you look at
studies was the U.S. represented? The U.S. was the
major contributor to the CHARM program.
DR. NISSEN: Were the overall event rates
different in the U.S. and other countries?
DR. PFEFFER: I am going to represent Dr.
Granger because he has done a complex analysis that
only the Duke group can do of the CHARM data,
looking for the modifiers and predictors of
outcome. Despite hundreds of man and women hours,
the things you know about--ejection fraction,
diabetes, age--I asked Chris what else have you
done; put in re-vascularization? No.
anything, we don't have enough African Americans to
talk about but the point estimate goes the right
way. The other issue in the model, if you now
force the U.S. into the model it does not come out
as a predictor.
DR. TEMPLE: We are sort of watching this.
It keeps showing up or at least you notice it when
it does show up, which is probably more to the
point. Sometimes there are oddities to it. In
both RENAL and IDNT the action was all in the Asian
population, Asian including Israel and a variety of
places you don't usually think of as Asian. But
when we actually looked at the end-stage renal
disease endpoints it didn't look that way anymore.
So, the long-term follow-up no longer was as
conspicuous in the U.S. population. So, I don't
know what you make of something like that but these
things are jarring when they show up.
DR. NISSEN: Let me tell you why these
things catch my attention and bother me.
Obviously, the FDA is charged with regulating drugs
in the United States and we are
presented with a
certain number of trials where the U.S.
contribution was a minority of the population and
where sometimes the point estimates like this are
quite variable. One of the things I always worry
about is, you know, are these patients somehow
different? Is the underlying care, particularly if
there are a lot of Eastern European and other
countries involved different? I am just trying to
get an understanding of this because I know this
must come up for you a lot. It always gives us
pause for thought considering the fact that this is
a drug that we are considering for use in the
United States. So, any advice, Bob?
DR. TEMPLE: No, it is just hard to know
what to make of it. My bias is that if people are
treated badly they probably benefit more from a
drug that they are actually getting. So, maybe the
U.S. is too well--you know, you could say, well, in
the U.S. they really all got their ACE inhibitor
and in the other places they all lied.
DR. PFEFFER: That is a very U.S.-centric
DR. TEMPLE: I am not alleging that it is
true. I am just saying what is the worst thing you
DR. PFEFFER: I am not speaking about
CHARM now but in almost every database the
presumption was that U.S. are better treated,
better outcomes. I have many friends in Canada and
every time we have sliced it Canadians do a little
bit better, so less procedures and do a little bit
better so it is hard to even support the
DR. TEMPLE: I am in no way saying it is
true. I am just saying, you know, what is the
worst thing you can imagine?
DR. NISSEN: One way to test this which
would be very helpful to me just to get comfortable
here is what the actual event rate was in the U.S.
versus the non-U.S.
DR. MCMURRAY: To answer your question
directly, if you look at the two low ejection
fraction groups pooled, and I am only saying that
because I think that is the type of heart
we all know most of all, if you look at the placebo
groups, if you compare U.S. to non-U.S. the event
rates are almost identical. One is 41.7 percent,
the other is about 42 percent. So, the event rates
in the conventional type of heart failure that we
are all familiar with are virtually identical.
DR. NISSEN: What are they in the
DR. MCMURRAY: Someone is going to have to
do the mathematics very rapidly for me. I put the
two low ejection together simply because it was
large numbers but, again, you can see they are
almost exactly the same.
DR. D'AGOSTINO: Yes, they are almost
identical. It is a smaller group. The confidence
bands are large; lots of multiple comparisons.
DR. NISSEN: And I do recognize that. You
know, this is not by any means definitive. It is
an observation that pops out and you want to try
and understand it. I mean, if we saw an event rate
in the non-U.S. that was radically different from
the U.S. that would be a signal to me
that this is
meaningful, and we don't see that here.
DR. MCMURRAY: I was going to comment that
on so many trials showing this with drugs and drugs
being different--I mean, carvedilol was brought up
earlier and that is an interesting example. In the
large trials done outside the U.S. the effect size
of carvedilol was smaller than in the U.S.
DR. TEMPLE: Well, you tend to notice it
when the U.S. doesn't do well--
--so there is probably some selection. We
have actually done an internal analysis and there
is some suggestion of it but it is mostly driven, I
think and I don't know if Norm agrees, by the two
studies that formed the hypothesis, RENAL and IDNT.
Those didn't look so conspicuous. You know, you
are not supposed to use the ones that form the
hypothesis, but it is certainly an interesting
I have one other question. If you look at
hyperkalemia can you show any
relationship to what
dose of diuretic people were on? Should the dose
of diuretic be higher in people who are getting
both of these drugs?
DR. PFEFFER: I was bragging about our
case report forms. We had doses of the ACE
inhibitor, doses of the beta-blocker. We did not
have doses of diuretics which changes during time,
so I could not tell you that.
DR. TEERLINK: Mark, was there entry
criteria for blood pressure in this trial?
DR. PFEFFER: I mentioned that Dr. Yusuf
was part of the executive committee so let's make
this broad; let's make this inclusive; let's not
have a blood pressure level as long as people are
talking to you and are not symptomatically
hypotensive. So, we did not have a cut-off for a
low blood pressure.
DR. TEERLINK: The reason I ask is because,
obviously, given that we are only considering
additive therapy here and clinicians only have so
many millimeters of mercury to spend, and in slide
CS-4 there is a conspicuous increase, as
expect, in terms of the increase in hypotension in
patients who start out with a blood pressure that
is already borderline low. Then we also recognize
that many adverse events can spin off that
hypotension so you can have hypotension that then
leads to renal failure and then leads to other
aspects. Is there a blood pressure--and we can
choose 100--at which the risk to benefit of
candesartan in addition to other therapies is no
DR. PFEFFER: John, it is a tough question
because one person's blood pressure of 98 and
another person's blood pressure of 98 are totally
different, as you know. So, by opening the door
and allowing these patients in we have a total
experience of about 120 patients. They are
vulnerable patients. A patient who walks around
with symptomatic heart failure and blood pressure
less than 100 is more likely to have an adverse
event, and more likely to discontinue due to
hypotension. So, it is the person you want to put
on the medications and are unable to.
So, everything I have been showing you is
intent-to-treat but I will show you, John, in
direct answer to your question that for
hypotension, if you came into this trial with a
blood pressure less than 100 systolic, and only 54
of the placebo patients did and they not
infrequently had to be discontinued, but then
trying to add the active therapy, we discontinued
their medication. Now, that is not a demerit.
Investigators tried. This is a blinded study
medication. They discontinued and everything I
have shown you has been intent-to-treat.
DR. NISSEN: Another way to look at it is
that in spite of allowing these patients in the
trial it didn't undermine the results. So, I
presume those people didn't end up on much
DR. PFEFFER: They didn't. That is why I
was bringing back the intent-to-treat not the per
DR. HIATT: I have a slightly different
question. I tried to resolve the results of this
development program with the other ones,
particularly the valsartan. I think a number of
questions can be raised in that regard but I am
struck by the interaction in ValHeFT between ACE
inhibitors, beta-blockers and the addition of an
ARB showing a worse outcome in contrast to your
data. Could you speak to that?
Then I have a follow-up question related
to that, and that has more to do with the
pharmacokinetics of these different agents.
Valsartan has a very long half-life; candesartan
has less. I am worried about the receptor
interactions and how they might differ because are
all these ARBs created equal is sort of where I am
going with this.
DR. PFEFFER: These are key clinical
questions and you can imagine the question in the
year 2003 when we came up with these results. I
have no more insight than the distinguished panel
but I will give you my personal views. The
question was of the agent, and I would have to say,
no based on the VALIANT experience where
number of patients were on so-called triple therapy
and harm was not seen.
We are showing no harm and benefit. I
think that is the message. If you look at overall
the entire ValHeFT experience there is consistency.
It is just when you get to that particular
subgroup. And that is where I gave you the
numbers. You have to look at the robustness of one
subgroup and another. We happen to have more
events because we had a higher use of beta-blocker
and longer follow-up. But beyond that I would be
DR. HIATT: Can anyone from the company
sponsor distinguish some of the PK potential
differences--dwell time on the receptor, those
kinds of things, between these different agents?
DR. PFEFFER: I am sure somebody from the
company can tell you about the PK differences.
DR. NISSEN: What do you say we do that
after the break so you, guys, can kind of gather
your thoughts together? I am actually give you
some thoughts; I was on that ValHeFT
panel and also
on a panel that reviewed candesartan compared to
losartan, and I will give you some thoughts about
that that might help you understand this. Let's
break for about 15 minutes. We are doing very
DR. NISSEN: If everybody can take their
seats we will try to get started again.
Bill, before the break you asked about
differences in any ARBs, and I can offer a little
bit of perspective. Sometimes there is a little
institutional memory around here and I served on
the advisory panel for ValHeFT and we also looked
for comparative data between losartan and
candesartan. I think both were helpful to me in
understanding some of this. At the time the
ValHeFT data were presented there were a number of
us on the committee that were very suspicious that
the result, the beta-blocker hazard--you know, the
triple therapy hazard observation was spurious.
One of the reasons is that that particular
analysis, as I recall, was not really
so it was an exploratory analysis. You know, I
opine that you really couldn't--shouldn't make any
regulatory decisions on that basis; that it was
hypothesis generating at best and that, again, if
you look at enough trials and enough people and
enough subgroups you are going to see something
like that happen once in a while.
I must say, it was very intense. The
final vote was 4-4, which meant that we actually
had an even number so we didn't actually make a
decision on the primary indication for valsartan.
Even though the nominal p value looked very good
and the data looked very good for the overall
study, at the time I felt like people were being
unduly influenced by the observational data on the
subgroup. I think now, in retrospect, that
probably was spurious. That is my own personal
interpretation that it was just simply an unusual
DR. HIATT: Where I was sort of going with
this, is there really a difference in dosing
between ARBs, or are there different
differences that we should be recognizing between
DR. NISSEN: There is some subtlety here.
Again, there are obviously things that are class
effects and there are things that are not class
effects. We looked at two trials comparing
losartan and candesartan, and this committee voted
I think unanimously that there was evidence that
the blood pressure lowering effect was greater with
candesartan than with losartan, both given in their
full therapeutic doses.
DR. TEMPLE: Well, the labeled full
DR. NISSEN: Yes.
DR. TEMPLE: I think we all had the
impression that losartan probably should be higher
but wasn't pushed.
DR. NISSEN: Yes.
DR. TEMPLE: Whatever the reason, they
DR. NISSEN: Yes. But what we can say is
that 32 mg of candesartan had a very big
blood pressure, bigger than the full doses of
another ARB. So, it is like any other therapeutic
class, there are sometimes agents that are somewhat
more potent than others, that perhaps have more
affinity for the receptor. So, if you want to test
the hypothesis that blocking at the AT-I receptor
produces an added benefit you want to probably do
it where you are really blocking the receptor as
well as you can block it, and I think that is one
of the things that CHARM did. They got to a really
very robust dose of a very potent angiotensin
receptor blocker so it really does test the
DR. TEMPLE: Of course, our concern has
been you can only test it if you really are on
whatever the full dose is, but a full dose of the
ACE inhibitor. That is what has been addressed
here. In the case of ValHeFT, that was sort of a
very Bayesian episode. We actually approved the
use on what was not a primary analysis at all. I
mean, that was just an accidental 7 percent of the
people that weren't on any other
drug. That is
what we approved, even though that was only
300-some odd patients in a 5000 patient trial
because the result was so conspicuously large. The
beta-blocker thing, we were skeptical about it too
but it was the mortality outcome and we just didn't
feel we could say anything about it.
DR. SACKNER-BERNSTEIN: Also, in terms of
the mortality in ValHeFT, I wasn't part of the
committee but the randomization in that trial was
stratified based on background beta-blocker therapy
which does add some robustness to that analysis,
just to clarify that.
DR. HIATT: Before I leave this question,
is there anyone from the sponsor who can talk about
the differences in the pharmacokinetics and
dynamics of these different ARBs? I mean, I was
struck that valsartan has a longer half-life. It
is certainly a less potent drug but then it is just
a matter of milligrams. If you can get them to the
same equivalent dose you should overcome that but,
if anything, candesartan maybe should be dosed more
frequently. So, I am just questioning
are any other pharmacologic properties between
these agents we should be discussing today.
DR. NISSEN: That is a fair question so
can somebody just tell us about PK and PD data?
DR. YOUNG: I can give you a clinician's
perspective because this is important when we are
setting up a lot of these clinical trials and we
are looking at this, and all these are different
molecules and it gets at this issue of variability
from an ACE inhibitor to an ACE inhibitor, from a
beta-blocker to a beta-blocker, an ARB to an ARB,
and there are differences, some of them subtle and
some of them may translate into outcomes data that
But with respect to the ARBs, candesartan
is the most tightly bound of the ARBs. It has an
insurmountable binding property, sort of a
non-competitive type of binding property that lasts
well over 24 hours. You can detect effects in
binding activity after 24 hours, and what happens
is that the PK levels will go up and drop and the
half-life will appear to be less when
looking at it from a PK or a drug exclusionary
phenomenon, but if it is still tightly bound to the
receptor you won't have candesartan coming off the
receptor and causing it to go back up.
DR. HIATT: And that was my understanding.
That is where I was going with this. I wanted to
say that because I think valsartan does not have
that same kind of receptor affinity. Am I correct?
DR. YOUNG: It does not; you are correct.
DR. HIATT: So, if it really is bound
across the 24-hour dosing cycle and has a very high
affinity there could be a pharmacologic basis for a
slightly different clinical result.
DR. YOUNG: And I stress the word "could
DR. NISSEN: Yes, Tom?
DR. PICKERING: I would like to discuss
further the issue of hyperkalemia and
spironolactone use. I think the issue here is
really one of labeling and whether it should
specifically say anything about whether patients
should be also taking spironolactone or
you look at slide CE-17, there doesn't seem to be
any advantage of being on spironolactone in terms
of the primary outcome variables. Although there
is a trend in the lower panels for improved
mortality, I guess it is not significant.
The other one was CS-8 which shows that
the hyperkalemia occurrence is increased in
patients taking spironolactone in diabetics, and so
forth. I guess the reason for the concern was the
publication in The New England Journal about what
happened after the RALES trial was published, that
the hospitalization rate for hyperkalemia rose from
2.4 per 1000 to 11 per 1000 with an increase in
mortality. You know, obviously, in this trial
everything was very nicely controlled and people
were doing what they were supposed to be doing, but
what will the consequences be when it sort of gets
out into the real world? So, perhaps we could
DR. PFEFFER: Certainly, inhibiting
renin-angiotensin system does have its issues and,
fortunately, one of my colleagues wrote
editorial that accompanied that New England Journal
article. So, let me ask Dr. McMurray to talk about
DR. MCMURRAY: We share your concern. In
fact, I think the only reason I wrote that
editorial was that we had already published our own
experience with the misuse of spironolactone which
became widespread after the publication of the
RALES trial and I think that was a lesson from the
Ontario experience and, indeed, from 13 other case
series that have been published reporting the same
thing in smaller numbers of individuals. The
striking thing about that was that essentially it
boiled down to two problems, the use of the wrong
dose of spironolactone, much higher than the small
dose used in RALES which was 25 mg a day, and also
misuse in the wrong patients. So, RALES was a
study targeted at a carefully defined group of
patients and the Ontario experience with
spironolactone was used in a completely different
patient population, much older; many patients with
preserved rather than low ejection
diabetics, and so on.
So, one of the points I tried to make in
that editorial was that RALES was a very unusual
trial in one respect, and that was that it was a
trial done with a generic drug that had no sponsor
and the usual care in terms of risk management, in
terms of educational programs, in terms of meetings
and so on, to emphasize how you must use the drug;
you must monitor what happens to patients. I think
perhaps I would look more to the experience with
ACE inhibitors where they were used in a more
responsible way because there was a sponsor acting
behind them to ensure that the program education
was carried out. Unfortunately, that didn't happen
after RALES. Certainly my personal interpretation
would be that the reason there have been major
problems is because people didn't go through the
usual process of introducing a new treatment and
ensuring it was used as carefully as possible.
DR. TEMPLE: There is, of course, no
labeling of any spironolactone product reflected in
RALES despite my attempts to embarrass
For fairly obvious reasons, it was
DR. PICKERING: But if this gets approved
there is going to be labeling that could or could
not say something about concomitant spironolactone
DR. TEMPLE: Indeed, it could. Actually,
my question from before goes. I mean, everybody
has moved down to low doses of diuretics because
they are worried about hypokalemia. Maybe they
should make a comeback in the face of all this
potassium retention. Higher doses do work slightly
better than 12.5. That seems worth exploring too.
DR. NISSEN: Actually, it does reflect a
real problem for clinicians in managing heart
failure. The computer term for it is combinatorial
explosion, which is you have four or five therapies
and how do you combine, what kind of combinations
and permutations of them can be used in individual
patients. It is not so easy. I often don't know
what to do so I am looking for guidance from FDA.
DR. TEMPLE: So, you don't think anybody
can just make a single pill that will just do it?
DR. NISSEN: Yes, I don't think so. I
wanted to explore something else with you, guys.
Obviously, one of the reasons we are here is
because the agency reviewer and the agency has some
concerns about has the hypothesis been proven that
on top of maximal doses of ACE inhibitors
candesartan produces an incremental benefit. This
all could have been resolved if you just picked
enalapril, you know, pushed it to the heart failure
doses and then everybody would have gotten the same
ACE inhibitor and we would know exactly what they
I know what your answer is going to be.
Your answer is going to be you wanted to make this
a real-life trial with the real-life drugs that
people use, but it does, in fact, undermine a
little bit our ability to interpret the experiment.
Did you, guys, consider actually just specifying
the ACE inhibitor, pushing it up in the
did in the ACE inhibitor trials and then, once you
got to the maximum tolerated dose, randomize?
DR. PFEFFER: Well, I gave you the names
of the people involved in the planning so you can
imagine we did consider it. The other issue would
be I could imagine if we came back here with the
same findings on the most commonly used medication,
which was enalapril, somebody--I am not saying
--would say what about the other ACE
inhibitors, the other approved ACE inhibitors?
Then we realized that to dictate the use of an ACE
inhibitor, with the VA system telling us what ACE
inhibitor you have to use, my healthcare system
telling us what ACE inhibitor you have to use, we
really did make the decision to optimize the
individual dose and see if adding on improves
DR. NISSEN: Although you did allow use of
ACE inhibitors that were not approved for heart
Was the assumption that everybody would
feel okay about that, that even though the drug
wasn't actually approved--
DR. PFEFFER: Well, this was FDA approved.
We are talking about 26 countries. I was reminded
in this international trial that the U.S. is one
DR. NISSEN: Yes, we are getting reminded
of that all the time now. Other questions? Yes,
DR. SACKNER-BERNSTEIN: Just to get back
to the U.S.-non-U.S. finding, there are a couple of
different ways that I was trying to look at this to
see if I could understand it. Obviously, it could
just be a statistical fluke, which my own bias says
is the most likely. But one issue that has come up
before is the possibility of drug interactions.
So, I am assuming that you looked and found that
U.S. and non-U.S. subjects were treated similarly.
A second one has to do with whether the statistical
power was sufficient within the U.S. population,
and I think we addressed that by the
earlier. The third question has to do with what is
unlikely but possible, that perhaps the people in
American who have systolic dysfunction are already
treated with an ACE inhibitor. There is a potency
issue about the way candesartan works compared to
the way it works in similarly described patients
outside of the U.S.
One of the ways I would like to get a
handle on that is by seeing what the AE effects
were. If you were to tell me that by region the
North Americans had a very low rate of renal
insufficiency, a very low rate of hypotension, then
I would have the bias that perhaps we are looking
at a differential potency in a population. I
wouldn't understand why. Perhaps I am putting
myself at risk of attack from pharmacologists but
that is the way I have thought about this and I am
wondering if you looked at that data.
DR. PFEFFER: Let me first start by what
it is. I reject that there is anything here
personally. So, if you are asking me to defend
what it is, I can't do that because I
was nothing there.
But if you want to explore something where
I don't believe it, I can tell you there are a lot
of differences between U.S. patients and non-U.S.
patients at baseline. You heard that their
outcomes are pretty much the same, and you heard
that in the trial of 7599 in the program the effect
of candesartan was pretty much the same.
But just to explore, in CHARM-Added, yes,
there were some differences, fairly minor, in the
medication use but here is medication use. Now, I
mentioned that being at the recommended dose, and I
think Ralph pointed out that the arrow went in a
good way so you can see the inconsistency, there
are more people at the recommended dose. So, there
are a lot of inconsistencies here.
Let me show some more differences between
U.S. and non-U.S. We do more procedures. That is
no revelation. Coronary procedures, we are very
good at that. That did not influence anyone's
outcome. We do more angioplasty. We have ICDs and
pacemakers. So, procedures we do more of. I am
off the cuff going to ask Dr. McMurray, did we do
any quality of life? Did U.S. patients feel better
with all this hardware?
DR. MCMURRAY: Only in the U.S.
DR. PFEFFER: Quality of life was only
done in the U.S. Now, for AEs we can give you this
by North America. Is that okay? So, we can go
across the border and I think it is important to
look at placebo. Placebo in the U.S. were more
likely to tick a box, and we really asked these
questions--renal function, 6.3 versus 2.9. I am
not going to make anything of it but numerically
more. Obviously, the agent increased that in both
North America and the rest of the world. Here is
the hyperkalemia, increased in North America;
increased by the same factorial in the rest of the
So, Jonathan, I don't see that there is a
clue here that they are under-treated,
over-treated; that the SAEs are helping us with
this. I go back to your first statement of fluke
but I don't even say fluke because I don't
DR. NISSEN: It is intriguing though,
Mark. I mean, some of the therapies like
defibrillators do have an impact and, you know, the
fact that there were more defibrillators used in
the U.S.. You know, one of the mechanisms of
death--you know probably better than I--in these
patients is sudden death. So, it is possible that
there is a competition for benefit between
defibrillators and more effective heart failure
treatment. If, in fact, there is more
defibrillator use in the United States there may be
less opportunity for benefit from candesartan. So,
some of these hypotheses, and they are just
hypotheses--I basically agree with you but when you
see an observation, it is our responsibility
obviously to explore that and make sure we
understand it, that there is some strong signal
here and I think there is not a signal; I think
there is an observation. I think you can see how
the defibrillator use could certainly drive some of
DR. PFEFFER: And defibrillator use is
something that in the year 2005 we are much smarter
than in 1999. I don't know what the balance would
be around the world now but these are heart failure
patients and I have some of my heart failure
colleagues telling me to turn these things off
sometimes too. So, I don't have the answer for
DR. TEMPLE: Of the U.S. differences you
showed, one of them is sort of tempting. More U.S.
patients were on the full dose so maybe that would
explain why the addition didn't work as well, but
your overall data shows that people who were on a
full dose on the whole did better.
DR. PFEFFER: I mentioned that as an
example of a confounder. The point estimate for
being on full dose moved in the right direction.
More U.S. were on the full dose so it is a perfect
DR. TEMPLE: Right.
DR. PFEFFER: A fluke, and I just think it
is a great example. Dr. Granger has something to
DR. GRANGER: We did look at this. One of
the obvious things is procedure use and prior
re-vascularization. When we looked at prior ICD or
prior re-vascularization the point estimates were
almost identical for the treatment effect of
candesartan. So, it doesn't appear to be that.
DR. NISSEN: I would have guessed that
having angioplasty would increase the event rate
because we all know that angioplasty is bad for
--but I guess you didn't see that.
DR. PFEFFER: We don't know how long ago
the angioplasty was or where it was done.
DR. NISSEN: Did you enroll any patients
at the Cleveland Clinic?
DR. PFEFFER: Cleveland Clinic was a
vigorous proponent of conducting the CHARM trial
and Jim was the U.S. lead investigator. He
probably asked you about some of your patients.
DR. PICKERING: Could I raise the issue of
African Americans? I think you had 2.8 percent and
the issue is if this gets approved what are we
going to say about its use in black patients?
Because there is evidence that blocking the
renin-angiotensin system may not be so effective in
African Americans. At two meetings ago we reviewed
a drug which was basically killed because of
adverse effects, angioedema, which is commoner in
African Americans, and there seems to be a total
void here. Should clinicians be using it in
African Americans or not? Or, what are we going to
DR. PFEFFER: I think we have as much
confidence in our data as any that have been
presented here, and let me walk through that.
This is self-designated as
black--self-designated. In CHARM-Added, of the
70-something patients there is the point estimate.
I am not saying that it is this way or that way.
That was Alternative. That was not on an ACE
inhibitor. In CHARM-Added, in the few patients we
had you can see the point estimate
here. But if
you go through our whole program I think there is a
consistent message here that designating yourself
as black and then being enrolled in our study there
is no loss of efficacy, and my interpretation would
be we are offering an opportunity to reduce
someone's risk regardless of this designation, and
that is the best estimate even the point goes this
way. When we do the total, we are talking about
over 300 patients.
DR. NISSEN: While other people are
thinking, Mark, let me tell you what triggered my
request for the time to all-cause hospitalization.
I did some sort of simple numerics and I see there
were 56 fewer deaths or CHF hospitalizations in the
primary endpoint. So, you avoid 56 deaths in the
primary analysis. Then I looked at the hypotension
and there are 33 more people hospitalized for
hypotension. So, at least in your mind, until you
see an analysis you have to say, well, you kept 56
out of the hospital and from dying but you had 33
that had excess hospitalizations and you have 20
excess hospitalizations for renal
then you have another 10 in the hyperkalemia.
So, when you add all the numbers up, you
know, you sort of see an analysis that says, well,
you are keeping people out of the hospital for
heart failure but you are admitting a lot more to
the hospital for AEs, so isn't the hospitalization
data kind of a wash? I know it is not the correct
analysis because once you have that first heart
failure or hospitalization you may have more. That
is why I am so keen on seeing that.
DR. PFEFFER: I think it is a key number
to get you but we do have it without Kaplan-Meiers
and Dr. McMurray would like to tell you about total
DR. MCMURRAY: I am afraid I don't have a
slide of this but I do have the numbers so you
might want to write them down. I was intrigued for
my own interest to figure out how it balances up.
On the benefit column what we actually have, and I
will give it to you per 1000 patients treated over
the duration of the study--on the benefit column
there were 46 fewer patients
hospitalized for heart
failure. There were 100 on ACE fewer heart failure
hospitalizations and 35 fewer cardiovascular
On the risk side there were 26 more
patients hospitalized with hypotension, but when I
say with hypotension that means hypotension was
just on the list of possible causes for that
hospitalization. For example, amongst those there
were people with septicemia, people with GI
bleeding, and this is true for all the AEs. There
were 16 extra hospital admissions for renal
dysfunction and there were 8 extra hospital
admissions with hyperkalemia. Again, some of those
groups overlap but we weren't able to quite tease
In summary, the balance was substantially
in favor of candesartan and, in fact, I can give
you sort of a handle on that because we have done
an economic analysis in Europe and a resource
utilization economic analysis, and over the course
of the study for every 1000 patients treated with
candesartan there were 1900 fewer days
with worsening heart failure. There were
significantly fewer days in hospital for any reason
whatsoever in the candesartan group. So, yes, of
course, there is a trade-off but it is
substantially less on the benefit side in terms of
morbidity and resource utilization.
DR. TEMPLE: I just added up your numbers
leaving deaths out of it for the moment, not that
you necessarily want to. There was a 46-patient
benefit for heart failure hospitalizations.
DR. MCMURRAY: Forty-six patients, yes.
DR. TEMPLE: And 49 extra hospitalizations
for hypotension, renal dysfunction and
DR. MCMURRAY: Okay, the difference there
is--well, there were several differences. First of
all, you have picked patients as opposed to
admissions and, secondly, on the risk side when I
said hypotension, when I said renal dysfunction,
when I said hyperkalemia I really do mean that if
those terms appeared anywhere on the long list of
reasons for admission we counted that
just in case
it could be a risk. Also, there was overlap. The
best estimate I can give you of overlap, and I
really don't know the proper numbers but the best
estimate of overlap is two-thirds of those patients
were counted more than once.
DR. TEMPLE: Okay, but those were extra
hospitalizations in the treated group.
DR. MCMURRAY: Extra hospitalizations,
yes. So, the contrabalancing number for that is
DR. NISSEN: Bob, I understand what he is
saying and I want to just see if I can rephrase it.
You know, if you take the number of patients that
had a hospitalization for either heart failure or a
drug AE, it is fairly balanced. But once you got
admitted once for heart failure you are very much
likely to be admitted again and again. So, what
they showed us was the Kaplan-Meier for cumulative
incidence of all-cause hospitalization. And I
understand that. And it is very important and I am
not minimizing it at all. But, you know, it did
strike me that there was a cost for
that, and the
cost is that a fair number more patients--when you
talk about AEs I look at hospitalized AEs rather
than I do incidental AEs that are sort of
discovered on a laboratory test. If you have
hyperkalemia sufficient to land yourself in the
hospital, that is a pretty serious AE, and if you
have hypotension that gets you in the hospital,
that is a pretty serious AE. So, that is why I am
so keen on seeing that time to first event because
that is an important objective. Now, I know that
over time the hospitalizations are clearly less in
the candesartan arm. But I am going to guess
DR. TEMPLE: Yes, and the implications are
different. One is transient, you fix it and it is
DR. NISSEN: Yes.
DR. TEMPLE: But being hospitalized for
heart failure means you are on the way to troubles.
DR. NISSEN: You are on a downward spiral.
Don't misunderstand me, I am not placing equal
weight on them.
DR. MCMURRAY: I was trying to give you
DR. NISSEN: Yes. Obviously, FDA is going
to have to write a label and we have to understand
this as well as we can in order to help them
DR. PFEFFER: Dr. McMurray was looking at
pharmacoeconomics and multiple admissions. I think
what he was explaining is that for hyperkalemia and
hypotension, we can count both of those for the
same admission just to be on the safe side. But I
have also learned something--when I go over there
and sit down I become a little smarter, and people
have now fed me the numbers for the total
hospitalizations as a function of time with your
question about the early hazard. I didn't know
this answer so it is new for me too, and it was a
very appropriate question, what happens in the
first month. May I share that slide or do I read
numbers--I don't have a slide; I read numbers.
So, at the first month, which is that
up-titration phase, for hospitalization
reason, 69 of the candesartan patients and 80 of
the placebo. At 6 months it is 297 and 304. Then,
as a function of time we get better, as you see.
That doesn't mean we didn't hurt somebody early but
in the overall, all-cause hospitalization for any
reason numerically people were on the candesartan.
Then you did see the curve of the cumulative
DR. NISSEN: It actually does sort of
support the hypothesis that you are really picking
up the benefits once you get outside of that early
sort of titration. Once you have proven you can
tolerate the agent, then you are starting to
accumulate lots and lots of benefit.
DR. PFEFFER: Well, I really have trouble
with when was the benefit. I know you spent some
time on that last week--when is the benefit. I
don't know what statistical tool one uses to do
that besides your eyeball. So, why don't we look
at our two low EFs combined? You know, we did a
lot of statin work, as you have, and for the most
part, except for a few studies, you need
time to see the benefit unless you are very, very
aggressive with your statin use. Treating heart
failure, symptomatic heart failure, you tend to
start to see things early.
So, Dr. Nissen, I don't know what to make
of this, of when, but I do think we are starting to
see the benefits that you would ask for in a
medication for the treatment of people with
symptomatic heart failure and, yes, there are other
things that we must be vigilant to look for. It
happens in placebo too so I think we need to raise
our standards of how to monitor patients whether
they are on the triple therapy or not.
DR. SACKNER-BERNSTEIN: In terms of the
endpoint of heart failure hospitalization that was
part of the primary endpoint, I am wondering if you
might comment on how you can be confident that you
captured all the heart failure hospitalization that
occurred appropriately. Literature, including the
RESOLVe trial has shown that about as many as 11
percent of heart failure hospitalizations are
associated with pulmonary
processes. So, I am
curious about how you made sure that the endpoint
committee saw all the hospitalizations that an
investigator may have thought were just bronchitis
or pneumonia and may have actually been given IV
diuretics. Another issue is that of worsening
renal function which certainly can be a sign of