1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
UNITED STATES FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
Cardiovascular and Renal Drugs
Advisory Committee
Meeting
THURSDAY, FEBRUARY 24,
2005
8:00 a.m.
Food and Drug
Administration
CDER Advisory Committee
Conference Room
Room 1066
5630 Fishers Lane
Rockville,
Maryland 20005
2
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
Committee Members:
Blase A. Carabello, M.D.
Susanna L. Cunningham, Ph.D., Consumer
Representative
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.
FDA Participants:
Robert Temple, M.D.
Norman Stockbridge, M.D.
3
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
Sponsor Presentations:
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
4
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
Wyeth Pharmaceuticals.
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
Houston.
DR. TEERLINK: John Teerlink, heart
failure specialist from University of
California
5
San Francisco and San Francisco VA.
LT. GROUPE: Cathy Groupe, the executive
secretary for the Cardiac and Renal
Drugs Advisory
Committee.
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
Framingham study.
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.
[Laughter.]
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.
6
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
unrelated
7
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
$10,001 to
8
$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
the record.
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
Wyeth Research.
With respect to all other
participants, we
ask in the interest of fairness that
they address
9
any current or previous financial
involvement with
any firm whose products they may wish to
comment
upon.
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
one.
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
I have
10
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
it--
[Laughter.]
--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.
Sponsor Presentation:
11
Regulatory Overview
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
12
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
committee.
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
board.
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
program.
In 1998 AstraZeneca met with
the Division
13
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
program
14
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
15
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
CHARM-Alternative.
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
class,
16
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
inhibitor.
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
17
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
important
18
healthcare challenge and review data
which supports
a new pharmacotherapeutic strategy for
chronic
heart failure.
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
inhibitors and
19
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
system.
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
AT-II receptor,
20
specifically increasing kinin and nitric
oxide
activity.
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
enzyme.
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
long acting.
Again keeping in mind the last
diagram, we
can illustrate how ACE inhibitors
mediate benefit
21
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
22
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
ARB was
23
given.
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
greater
24
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
varying
25
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
capacity. Here
26
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
enalapril.
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
patients.
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
27
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
to conduct
28
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
designed
29
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
trial, which
30
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
31
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
investigators
32
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
titration.
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
patients
33
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
34
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
evidence-based doses?
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
other
35
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
36
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
whether going
37
to higher dose of ACE inhibitor has any
additional
benefit.
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,
Bill?
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
generally similar.
DR. HIATT: So, the mean data were
38
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,
Office Director.
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
clarification.
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
39
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?
[No response.]
Fortunately, I visited
Scotland so I
40
understood every word without English
translation.
DR. MCMURRAY: Thank you very much.
[Laughter.]
Efficacy
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.
Carl Swedberg.
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
form, same
41
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
medication.
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
centrally.
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
42
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
whole program
43
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
a prior
44
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
course
45
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
at
46
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--
[Laughter.]
47
--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
percent. So,
48
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
beta-blocker.
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
49
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
the sub-subgroup.
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
also reduced.
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
depressed
50
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
follow-up.
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
51
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
52
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
valid question.
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
an ACE
53
inhibitor, that is what you should be
sustaining.
If you have issues you should be
down-titrating the
experimental medication.
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
definition.
54
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
inhibitor dose.
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
55
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
definition.
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
ACE inhibitor.
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
levels to
56
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?
57
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
approved ACE
58
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
I have.
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.
[Laughter.]
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.
Safety
DR. HAINER: Good morning, Dr. Nissen,
members of the advisory panel, FDA,
public guests.
59
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
inhibitor.
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
dose
60
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
patients.
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
baseline
61
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
percent.
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
62
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
receiving
63
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
64
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
beta-blocker.
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
these subgroups.
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 subgroups.
These trends in
hospitalizations are
further reinforced by the cumulative
number of
hospital admissions for any cause shown
here in the
65
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
placebo groups.
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
66
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
on all
67
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.
Risk/Benefit Summary
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
failure.
Our CHARM program in its
entirety, and
specifically the CHARM-Added study, the
broad
patient population, comprehensively
characterized
68
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
69
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
therapeutic strategy.
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
70
the use of this strategy are consistent
with those
provided to the CHARM investigators and
good
clinical management of any patient with
heart
failure.
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
of heart
71
failure so that candesartan can be
prescribed for
managing these patients with left
ventricular
systolic dysfunction.
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
72
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
73
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
that agent.
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
and mortality.
DR. NISSEN: Go ahead, Tom.
74
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
explanation.
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
75
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?
76
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
the answer--
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
higher--as
77
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
definitions
78
of doses.
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.
79
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
80
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
microalbumenuria?
81
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
data, sorry.
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
that we
82
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
little later.
DR. SACKNER-BERNSTEIN: Getting back to
83
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
function.
84
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
85
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
event.
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
dysfunction?
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
equivalent amount
86
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
event.
DR. SACKNER-BERNSTEIN: Just to clarify,
what was the definition of renal dysfunction in
that analysis?
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
noted.
87
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
long-term prognosis.
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, 0.5
88
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
issue.
DR. SACKNER-BERNSTEIN: What day?
What
time?
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
89
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
the moment.
90
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
placebo group.
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
91
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
slide. This
92
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.
Race? If
93
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
94
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
view--
95
DR. TEMPLE: I am not alleging that it is
true.
I am just saying what is the worst thing you
could imagine.
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
hypothesis.
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
failure
96
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
CHARM-Added?
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
97
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.
carvedilol trials.
DR. TEMPLE: Well, you tend to notice it
when the U.S. doesn't do well--
[Laughter.]
--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
question.
I have one other
question. If you look at
hyperkalemia can you show any
relationship to what
98
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
one would
99
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
longer favorable?
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.
100
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
candesartan.
DR. PFEFFER: They didn't.
That is why I
was bringing back the intent-to-treat
not the per
protocol.
DR. HIATT: I have a slightly different
question. I tried to resolve the results of this
101
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
a good
102
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
speculating.
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
103
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
well, everybody.
[Brief recess.]
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
prespecified
104
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
result.
DR. HIATT: Where I was sort of going with
this, is there really a difference in
dosing
between ARBs, or are there different
pharmacologic
105
differences that we should be
recognizing between
ARBs?
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
therapeutic dose.
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
beat them.
DR. NISSEN: Yes.
But what we can say is
that 32 mg of candesartan had a very big
effect on
106
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
hypothesis.
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
107
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
whether there
108
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
are important.
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
you are
109
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
be."
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
not. If
110
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
discuss that.
DR. PFEFFER: Certainly, inhibiting
renin-angiotensin system does have its
issues and,
fortunately, one of my colleagues wrote
the
111
editorial that accompanied that New
England Journal
article.
So, let me ask Dr. McMurray to talk about
that.
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
fraction; more
112
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
people into
113
producing one.
[Laughter.]
For fairly obvious reasons, it
was
unsuccessful.
DR. PICKERING: But if this gets approved
there is going to be labeling that could
or could
not say something about concomitant
spironolactone
use.
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
114
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
got.
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
way they
115
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
who--
[Laughter.]
--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
outcome.
DR. NISSEN: Although you did allow use of
ACE inhibitors that were not approved
for heart
failure.
Was the assumption that everybody would
116
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
country.
[Laughter.]
DR. NISSEN: Yes, we are getting reminded
of that all the time now. Other questions? Yes,
Jonathan?
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
question
117
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
think there
118
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
119
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
world.
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
make the
120
observation.
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
this.
121
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
that.
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
confounder--
DR. TEMPLE: Right.
DR. PFEFFER: A fluke, and I just think it
is a great example. Dr. Granger has something to
122
add.
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
you--
[Laughter.]
--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
123
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
say?
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
124
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
dysfunction and
125
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
hospitalizations.
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
126
failure.
There were 100 on ACE fewer heart failure
hospitalizations and 35 fewer
cardiovascular
deaths.
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
that out.
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
in hospital
127
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
hyperkalemia.
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
128
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
188.
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
129
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
that--
DR. TEMPLE: Yes, and the implications are
different. One is transient, you fix it and it is
over--
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.
130
DR. MCMURRAY: I was trying to give you
actual numbers.
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
understand it.
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
for any
131
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
hospitalizations.
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
a little
132
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
133
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
worsening heart failure, and in many of
those cases
patients aren't treated with IV
diuretics, which I
understand was part of the definition
for heart
failure hospitalization. So, I am curious about
those two and, with respect to the first
one, it
would also be interesting to know if
there were
baseline imbalances in underlying
pulmonary disease
between the two groups that may play
into the
potential risk there.
DR. PFEFFER: Thank you, Jonathan. Yes,
you are right. We set the bar high so that as we
stand here we can feel that when we are
talking
about hospitalizations for heart failure
they all
reach a certain level, which means there
are other
admissions which probably were for heart
failure
but didn't reach our predefined
definition, just so
134
that we could have some common
definitions around
the world. As you know, it required
overnight and
it required intravenous use.
Now, around the world we were
told before
we even started the project by some
investigators
that in my country I might admit
somebody who has
an unplanned deterioration and I might
just double
the diuretic dose orally. So, we knew this and our
steering committee made that decision to
raise the
bar at that level just so that we could
take out
some of those less severe.
Now, we have, of course,
analyzed our data
in both ways, investigator reported
versus the
core.
I would like to be able to show that but I
can't.
But I can tell you the results are the
same.
As a matter of fact, Dr. Yusuf was beside
himself because CHARM-Preserve looks a
lot better
on investigator reported. So, if you open the
window a little bit more you will get
more
admissions and it did not change our
results.
DR. SACKNER-BERNSTEIN: But that addresses
only part of my concern. The other part is that
135
people who come in, or have a discharge
diagnosis,
however you want to label it, say, with
pneumonia
but in fact they were treated with
intravenous
diuretics and they did have some lower
extremity
edema, are we sure that all of those
cases were
reviewed by a committee? Because there the
investigator may not have considered
heart failure
so it wouldn't fall into the
investigator
designated, and it didn't get to the
committee and
didn't form part of the primary analysis
either.
DR. PFEFFER: No, the net to catch these,
these would have gone to our committee. As a
matter of fact, there were swings both
ways and it
was the flavor of this such that the
white count
was elevated and, even though they got a
diuretic,
what was the flavor? I had a very interesting
chuckle over this because Dr. Swedberg
who was my
co--this was all done by fax
machine--one of the
first we said no to was a person just
like you are
describing, who got antibiotics and got pneumonia
and had a diuretic, and we sent for more
information from the site. It happened to be his
136
site and it happened to be one we
rejected.
Could I have the slide I was just
looking
at, the investigator reported? So, that is a
bigger window. This is the information from the
investigator reported for all the
studies. So,
this is this definition we are not
using. Now, if
we use this definition, that allows Dr.
McMurray to
do his pharmacoeconomic analysis because
his
pharmacoeconomic analysis does not care
what Scott
Solomon, in Boston, says, and there it
becomes even
more impressive and you can see the
multiple
admissions. So, the window is even larger if you
use the broader category.
DR. MCMURRAY: I can tell you the
difference in the numbers, Jonathan. If you look
at the investigator reported admissions,
in the
placebo group the adjudicated admissions
were 356;
the investigator reported were 437. In the
candesartan group the adjudicated number
was 309
and the investigator reported was
381. That is
just in CHARM-Added that I am talking
about.
We also saw--and I can't quite
remember
137
but I can get it for you if you want--a
very strong
trend, if not a statistically
significant
difference to a lower number of
admissions for
pneumonia as well, reminiscent of the
SOLVED trial.
I can dig those numbers out.
DR. D'AGOSTINO: Just a comment, we don't
want to make too much of this discussion
because
the adjudication process was to remove
all of this
uncertainty.
DR. NISSEN: Oh, I completely agree but,
you know, since we are sort of exploring
risk and
benefit, I mean, in many ways it sort of
doesn't
matter why you are in the hospital, you
know, I
mean, from a patient perspective.
DR. D'AGOSTINO: I think in the cost
benefit, and so forth, and if we did
quality of
life you would focus on this very much
but in terms
of the endpoint analysis, we don't want
to say
there is even a better result.
DR. NISSEN: No, I completely agree with
that but, you know, my view of this in
part is that
you stand in the patient's shoes and,
you know,
138
being in the hospital is not a desirable
outcome;
it is not pleasant for patients; they
don't like
the idea. So, I would like in a study, even though
it is not a prespecified endpoint, to
understand
all-cause hospitalization because these
are, in
fact, very meaningful to patients in
terms of what
they put up with and it is not the
primary analysis
by any means.
DR. PFEFFER: In our endpoint committee we
commonly say that we are doing this for
the trial,
the patients in the hospital, the
patients
admitted. If we say it is not for heart failure
but something else, the patient is
admitted, I
think that is why the best analysis
would then be
the hospitalizations for any reason.
DR. HIATT: A slightly definition question
is that a central issue before the
committee is
whether adding candesartan to background
ACE
inhibitor provides some unique benefit
or is it
simply that you should push the dose of
the ACE
inhibitor and that would erase the
benefit of
candesartan? Clearly, you have shown those
139
different analyses and at different levels of
heart failure doses of ACE, and the FDA
briefing
document, Table 37, shows this sort of
counter-intuitive
dose-response curve that candesartan
plus
high dose ACE beats high dose ACE with a
relative
risk reduction of 20.6 percent. For candesartan
plus low dose ACE versus low dose ACE
the relative
risk reduction is only 8.5 percent. I am assuming
that is a statistical fluke of multiple
subgroup
kinds of analyses, but it does kind of
go in the
wrong direction.
So, I guess I would like you
to comment on
that.
Then that begs the second question which is
if then you extrapolate this, perhaps
somewhat
illogically, into a community setting
and not every
patient is taking an appropriate dose of
an ACE
inhibitor they more match the low dose
ACE, and
would that then suggest that the addition
to
candesartan for those patients really
wouldn't be
beneficial, begging a third question, is
the
sponsor going to do anything about
optimizing ACE
inhibitor dosing post-approval?
140
DR. PFEFFER: We think to stand here in
2005 and say we have advanced the
practice of
medicine you have to stand on the
shoulders of
those before you who have advanced the
practice of
medicine, and that is ACE inhibitors and
beta-blockers.
I think the group you are
describing--I
would like to add CHARM-Alternative to
this, if I
could have the slide that I have been
using,
because I think it does make a point
looking for
consistency in subgroups, and I would
call each of
these new definitions of somebody else's
definition
of what an ACE inhibitor is and what the
right dose
for their patient is. You talk about me, being in
Boston, telling somebody whether they
had an
infarct or not in Poland, this is us
telling the
doctor what dose of ACE inhibitor they
should use
for their patient. So, here are the three
definitions. I think what you are talking about
is--
DR. HIATT: Well, this clearly plays into
your hand. Obviously, all this suggests is that if
141
you push the ACE inhibitor dose the
candesartan
benefit is even more robust.
DR. PFEFFER: But let me add again that
our 2028 patients who had zero ACE
inhibitors and
they had a profound benefit, that the agency
has
already agreed with us about.
DR. CARABELLO: It would seem very hard to
say that ARB and no ACE is great and ARB
and lots
of ACE is great, but ARB and a little
bit of ACE
isn't so good. I can't logically see how that
could come out.
DR. HIATT: Me neither, but that is what
we are here for. So, thank you, Dr. Carabello.
[Laughter.]
DR. NISSEN: I was going to say that is
why it is quite relevant. Even though the agency
has made a decision already on the
Alternative, it
is quite germane to our discussions and
why it is
appropriate that you should be reviewing
that
because, you know, I do think this was a
package of
trials designed together that should be
considered
as contributing to our understanding
together. So,
142
even though you have already made your
minds up
about this, it is quite relevant and I
am glad you
asked about it.
DR. PFEFFER: Dr. Nissen, I don't have the
slide you asked for but you brought up
the point
about multiple hospitalizations and that
the
patient doesn't care what they are in
the hospital
for so I just want to show that again,
if I may--
DR. NISSEN: We saw that once I think.
DR. PFEFFER: But to me that is a
risk/benefit analysis too and you have
to realize
this is in the context of more people
available to
be hospitalized. This you haven't seen so I will
do
this one. It is a slide you have not
seen.
Here are to total
hospitalizations for the
whole program and, yes, there is a
counter but that
counter ends up with numerically
fewer. We are
here for CHARM-Added but in the whole
program but
we are double and triple counting people
coming in
for hypotension and renal dysfunction
that would be
double counting. But it is real and we are the
first to say it is real. As a matter of fact, Dr.
143
McMurray has taught me that when you use
an
inhibitor of the renin-angiotensin
system in doses
that save lives there is a responsibility,
and we
are prepared to use that in a
responsible fashion.
DR. SACKNER-BERNSTEIN: In terms of the
analyses that were alluded to about the
low dose
versus high dose ACE background and
throughout the
briefing document I think those are most
convincing
to me, that patients who could only
tolerate a low
dose of ACE inhibitor were probably
sicker. I
think if you look at all of the
analyses--remember,
the patients weren't randomized but
based on low or
high dose, it is most logically
explained and most
internally consistent if you look at
it--
DR. HIATT: The rates were the same. I am
looking at it right here.
DR. SACKNER-BERNSTEIN: You are looking at
one table. There are subsequent analyses that have
to do with risk of AEs, that have to do
with risk
of the other endpoints. I think when you look at
the totality of those, post hoc
analyses, it looks
like the low dose ACE patients are just
a sicker
144
bunch, which would make sense as to why
the doctors
couldn't get them to high dose because
they are
more brittle. I mean, that is my interpretation
and I think it is worth looking at the
tables in
that respect.
DR. D'AGOSTINO: I don't think that is the
case with the data though. I think the ones who
are not on recommended dose, and so
forth, the two
groups look very much alike. It is when you start
doing the right thing that you see the
candesartan
looking better, and I am not sure we
should make
much out of that for reasons that we
talked about
before, but it is there.
DR. PFEFFER: I have to take objection to
the low dose because this is our doctor
in the
field saying this is the dose for that
patient.
DR. D'AGOSTINO: Well, it is the
recommended dose.
DR. PFEFFER: Yes, and we didn't find a
distinction. I think Dr. McMurray really shared
with you all the information we have on
could I go
even higher on an ACE inhibitor, and if
somebody
145
can and had improved clinical outcome,
let's do
that.
But until we have that, we now have in our
hands a way to reduce CHF
hospitalizations and CV
deaths.
DR. NISSEN: I have a question for you
about the hospitalization. I don't know what you
do in Boston, but it is common at our
place--we
have an emergency room, sort of a little
short stay
area where people can get admitted--not
admitted,
they are actually there for about 12
hours and they
can get IV diuretics and so on. Were you able to
capture those non-admission admissions,
and how did
you treat them?
DR. PFEFFER: In 1997-8, when this was
being designed we heard a lot about my
clinic
infuses dobutamine as an outpatient and
you would
miss these patients, and we heard a lot
about we
have a special place for these patients
and they
are not admitted. We would not have captured that.
So, if that is such an abundant part of
the heart
failure scene, we would not have
captured that
because, again, we set this bar for
something
146
across the globe that we could come here
and
defend.
DR. SACKNER-BERNSTEIN: In terms of the
background ACE inhibitor dose that you
showed in
the CHARM-Added study in one of your
slide
presentations--I guess it is slide
number CE-24
where you show the mean daily doses of
five
different ACE inhibitors over time in
the Added
trial, I look at that and then I look at
Table 48
in the sponsor's briefing document, page
96 through
98, and I see some evidence that maybe the
mean
dose doesn't tell the whole story about
the level
of ACE inhibitor use over time. In Table 48 it
appears that as you look at each visit
up until the
last visit where, obviously, not
everybody had the
full 42-month follow-up since the median was
only
41 months, but if you look out to month
38 you see
that there is some consistent trend at
each visit
for a slight bit of disparity between
the
maintenance of that same level of ACE
inhibitor
dose over time. So, I am hoping you can put these
two pieces of data, these two analyses
together to
147
reassure me that the patients really
were receiving
continued appropriate doses of ACE
inhibitor with
the addition of candesartan.
DR. PFEFFER: I would like to put this
table up. This is the data from CHARM-Added. We
have been talking about baseline use
because that
is not confounded. I particularly went into the
time during the titration phase because
that is
really an issue. Anything post randomization
really is totally confounded by somebody
being
admitted for hyperkalemia; somebody
having an MI;
somebody saying I don't like you
anymore, I'm not
taking any medications; somebody having
cancer and
saying, you know, I am done with these
medications.
So, that is totally confounded. But I can show you
the numbers here. I take some comfort that we are
not taking a nosedive in the use of the
ACE
inhibitor over time but, Jonathan, I
don't know how
best to do that. These people at 36 months are
very different than people at the other
times.
Now, I do have a slide of the
daily doses
of the top four. This is as a table and I do have
148
a graph of this. So, yes, there are some people
who stopped; stopped all their
medications. Some
people stopped our study
medication. But this is
trends over time for the use of the four
most
commonly used ones in our study.
DR. MCMURRAY: We did an analysis that I
suppose we shouldn't have done but, like
you, I was
intrigued by that very question so here
you see the
sort of analysis you saw before looking
at ACE
inhibitor doses but no longer at
baseline but for
people who were maintained on big doses
of an ACE
inhibitor for the duration of the
study. We have
done that analysis also by looking at
people who
stayed on the dose until just before the
events.
Whatever way you look at it, I think you
see the
same thing that you saw when you looked
at baseline
dose.
So, I think looking at baseline dose is
probably the important dose to look at
because of
all the things that Mark said.
DR. NISSEN: Other questions from the
committee?
[No response.]
149
This is good; this is
unprecedented. I
have a procedural question. Are we obligated to
answer the questions to the committee
after the
public hearing or could we begin that
now?
DR. TEMPLE: I don't know.
I suppose if
public input is going to be meaningful
you should
probably have it.
DR. NISSEN: Yes, I think so too. Since
we told people it is at one o'clock, since
no one
has actually signed up to offer an
opinion, could
we do that now? Would that be acceptable
procedurally? I don't want to break any rules. I
never break rules.
DR. TEMPLE: I don't know.
Is there
actually anyone in the room planning to
get up?
DR. NISSEN: Anybody?
DR. TEMPLE: Of course, it is not one
o'clock so they wouldn't all be
here. Why don't
you check? I don't know the answer.
DR. NISSEN: We are going to check.
DR. TEMPLE: We don't want to violate
anything.
150
DR. NISSEN: This may be the first time in
five years of doing this that I actually
make the
flight that I originally intended to fly
out on,
which is extraordinary. Of course, we could get
bogged down on the questions. One never knows.
DR. TEMPLE: It could snow.
DR. NISSEN: Yes, we do have a little bit
of weather to contend with. So, while we check, if
anybody does pop up with an additional
question?
The sponsor did a great job. I must also comment
to Dr. U that that was perhaps the most
comprehensive review that I have read in
five years
of doing this. There wasn't anything in there that
I wanted to find that I couldn't find. So, that
actually I think in part contributes to
the fact
that there are not as many questions
here. And I
thought your presentations also were
very complete.
It makes it easier.
Let's take a coffee break for
about ten
minutes and we will get the answer to
our questions
and we will move on if we can.
[Brief recess.]
151
Committee Discussion and Questions
DR. NISSEN: We have an answer to our
question so we would like to get started
again. We
will abandon our unscheduled break and
we will get
moving.
What we are going to do is we are going to
allow anyone who wants to speak at the
open public
hearing to speak now. We are going to then make
another announcement at one o'clock so
that if
anybody has come in especially to speak
at one
o'clock they will have that
opportunity. If I may,
let me announce if there is anyone in
the audience
that would like to address the
committee, please
step up.
Seeing none, we are going to go ahead and
do the questions to the committee, and
we will try
to get done what we can before lunch and
we will
pick up after lunch.
Let's begin with the
background statement.
This states that we are asked to opine
on the
candesartan development program for
heart failure
in a series of three studies, enrolling
a total of
7601 subjects.
The division expects to
approve the use of
152
candesartan in patients with heart
failure who are
not, for whatever reason, taking an ACE
inhibitor.
And we have already heard that that has
been done.
CHARM-Alternative shows that candesartan
is
effective in patients intolerant of ACE
inhibitors
and at least CHARM-Added is supportive
of this use.
The question for the advisory committee
is whether
CHARM-Added provides compelling evidence
that
candesartan should, under some
circumstances, be
recommended for use in patients on an
ACE
inhibitor.
The questions address three
possible bases
for approval. Once there is general agreement on a
possible basis for approval, the
committee is
invited to skip directly to question 7
and address
the strength of evidence for this claim.
Here is our first question,
when two drugs
are presumed to operate by sufficiently
distinct
mechanisms, one generally does not worry
whether
therapy with the older one has been
optimized
before testing the addition of the newer
one.
Should one, in fact, test a new drug
against
153
optimized background therapy? Let's take that 1.1
first.
We are not going to vote on all of these.
This is one for discussion. So, comments?
DR. HIATT: Based on the dose-response
curve, and so if it is flat, then it
optimizes any
dose, and if it is not, then you have to
consider
optimizing the dose. Here, when I was reading this
literature I wasn't convinced. I mean, it wasn't
compelling that there was a huge dose
response for
background ACE.
DR. TEMPLE: I think this is a tricky
question, a different question. If, for example,
you were adding an ACE inhibitor to a
diuretic what
this question says is we don't actually
care
whether you are imperfect on the
diuretic as long
as it is a reasonably effective dose
because the
mechanisms are totally different and
adding an ACE
inhibitor to a diuretic isn't like
adding more
diuretic. But, for example, take the most obvious
case, if you are already on an ACE
inhibitor and
you were testing whether another ACE
inhibitor
would be beneficial, I mean, there might
be
154
theoretical reasons why that would be
sensible but
you would want to be sure that you are
on a maximum
dose otherwise it is just like giving
more of the
same drug and that is not very
informative. So,
that is what this is about. But I guess you were
asking, Norm, whether we think you
should always
optimize the other therapy.
DR. STOCKBRIDGE: Right.
DR. NISSEN: Well, it is a little
complicated because, in fact, there are
some
examples where a strategic approach to
management
of a disease might, in fact, dictate a
different
strategy. Let me opine about that. I happen to be
a believer that in management of
hypertension it is
often desirable to use modest doses of
several
medications rather than push doses to
the highest
level because we have generally observed
that in a
lot of classes you really do get a lot
more AEs
when you push the dose. Tom might want to comment
about that more than me. So, there are a lot of
reasons why you might want to explore
the value of
an added therapy. The problem you get into is the
155
one that you stated. I mean, adding a second ACE
inhibitor on top of submaximal doses of
another ACE
inhibitor, that is a no-brainer. You don't want to
do that.
Obviously, the reason that this whole
question is germane here is that there
was some
discomfort in the agency about whether
ARBs and
ACEs are really different. We are going to get to
that.
We are going to drill down to that in a
little bit. But I do think that you don't always
have to insist on the maximally
effective dose in
one class before you test the efficacy
of adding
another class because there are other
reasons why
you might want to added it.
DR. TEMPLE: The other part of our
reasoning though is, apart from what the
best
practice is and I think everyone would
probably
agree with what you said, you don't push
till
people are sick, the inferential quality
isn't
impaired, or at least that is the
thinking. If you
are testing an ACE inhibitor in heart
failure if it
adds, in the presence of a modest dose
of a
diuretic or a large dose of a diuretic,
you have
156
evidence of an added effect and we have
never
thought it mattered that much whether
you were on
the maximum dose. It is a different theory because
of the non-relationship of the
pharmacology.
DR. HIATT: I do think I get the question
and, you know, the problem here is I
think that it
gets a little bit into
pharmacodynamics. In other
words, is the dose-response linear or do
you reach
an asymtope? I mean did you push the dose of
enalapril from 20 mg to 40 mg or 40 mg
to 80 mg?
Are you gaining a 0.1 percent
incremental increase
for every doubling of the dose? In that case you
may be clinically at an effective dose
at 20 and
going to 40 and 80 doesn't really matter. So, I
think even in this situation you can't
just ask
that sort of like, well, of course you
need to
optimize the ACE dose, or whatever. It has a lot
to do with how the drug is actually
operating
clinically.
DR. TEMPLE: Okay, but we are focusing
here on the dose of the thing that you
are adding
to.
Yes, you should test the dose response for the
157
drug you are interested in. We get that with 6000-patient
studies, you wish you did. But this is
about what the dose of the baseline
should be. You
can think of reasons that aren't
necessarily noble
ones why someone might want to us a
suboptimal dose
if you have completely obliterated the
problem and
there is no room for improvement. That is one
reason people might use--
DR. HIATT: Also you double the cost of
therapy if you add another drug that
could sort of
have been maximized by a modest increase
in the
dose of the background therapy.
DR. TEMPLE: Well, our presumption has
been that if the baseline therapy
doesn't wipe out
the disease, if it was an antibiotic or
something,
it doesn't matter that much whether you
add a
perfect dose of that or a modest dose as
long as it
is an effective dose. You wouldn't want a
non-effective dose.
DR. NISSEN: Blase?
DR. CARABELLO: Surely we wouldn't even be
discussing this if the average dose of
enalapril
158
had been 2.5 mg. I mean, we would have said, well,
of course the addition of another drug
affecting
the same system worked and it wouldn't
prove
anything. I mean, in order to prove effectiveness
here there had to be some reasonable
dose of the
baseline medication. Whether that was maximum or
not I don't know but it had to be a
reasonable dose
or we wouldn't believe it.
DR. TEMPLE: Yes, but that is the case
where they are pharmacologically related
and we
totally agree that is why we are
here. But we have
thought that if it is something
completely
different--diuretic is the most
obvious--it doesn't
matter that much whether you have
optimized,
whereas, with an ACE inhibitor it really
does seem
to matter. So, we have made that distinction. The
question is to find out whether you
think that is a
good idea.
DR. D'AGOSTINO: I was going to pick up on
Bill's comment. If you are talking about a
dose-response where that flattens out, I
mean, you
could interpret optimal to be at the
beginning of
159
that flattening out though it is hard to
avoid the
context of the study, even though it is
question 2.
I mean, this study did try to get an
optimal type
of dose for the ACE inhibitor and then
move on, and
I think that is a very sensible thing to
do if you
are worried about the same mechanism,
and so forth,
that you bring it up to reasonable
optimization,
and it doesn't necessarily mean the
optimal point
but something that is a reasonably good
level that
the patient can tolerate, then I think
the answer
is yes.
DR. HIATT: And my interpretation in fact,
even though I posed the question differently
earlier, is that it doesn't look like a
strong
dose-response curve so usual care, as
you were
pointing out, or maximal care certainly
is in the
same range of dose response versus a 2.5
mg
enalapril dose where you really may be
below a
threshold of clinical benefit.
DR. D'AGOSTINO: If you are deliberately
below the optimal, and so forth, then
you are in
the bind that Bob is raising. You are not going to
160
be able to sort it out.
DR. HIATT: I was just saying I think you
probably are in the flat part of the
dose-response
curve, and the data here actually
support retained,
if not better, efficacy of the higher
dose of
background ACE.
DR. NISSEN: The difference here, of
course--having sat through a number of
these where
we looked at comparative trials--when
you are
comparing two therapies then we are
talking about
an entirely different animal. You know, I think it
is very important that we make that
distinction.
We can smell a rat very quickly when
somebody does
a comparative trial and the drug they
are comparing
to is being used in suboptimal
doses. That is not
a fair comparison. You, guys, have many times said
no, you don't get a superiority claim by
beating a
suboptimal dose.
DR. TEMPLE: But you do get a claim. It
did work.
DR. NISSEN: Yes, it worked.
DR. TEMPLE: You don't get superiority.
161
DR. NISSEN: You don't get superiority.
DR. TEMPLE: If there is good evidence of
effectiveness--
DR. NISSEN: Yes, if you can beat placebo,
and so on.
DR. TEMPLE: Right.
It is easier to
interpret than a non-inferiority study
by a lot.
DR. NISSEN: Yes, absolutely. But one of
the things that obviously this sort of
an analysis
has to do is it has to survive a sniff
test. If
you look at the doses and if you say,
hey, are
these doses in the realm of what
clinicians
commonly use and what clinical trials
have commonly
used to treat this disorder, then it is
probably a
reasonable analysis. If it is clearly below that,
then you have a real problem.
DR. TEMPLE: The distinction we were
trying to make, and I don't think we did
it so
well, is that if you think the drugs are
pharmacologically close then to show an
added
effect you absolutely have to have what
appears to
be as good an effect from the thing you
are adding
162
to--
DR. NISSEN: Yes.
DR. TEMPLE: --as you can get. So, it
really has to be the maximum dose, the
dose beyond
which there is no point in treating,
otherwise
adding to it could be just adding more of
the same.
We don't have the same feeling about
pharmacologically different drugs.
DR. NISSEN: No, I think you probably
heard what we had to say. The reason everybody is
struggling with this one a little bit is
that these
two classes of drugs, ACEs and ARBs, are
similar in
some respects and different in others
and now the
real big question is are they more
similar or more
different? And, this one is that
oddball case
where you are interrupting the same
pathophysiological mechanism but by two
different
pathways. So, it creates this problem for you and
I see why have a problem here and I
understand it.
There are not a lot of examples of this
but this is
a very good one.
DR. TEMPLE: But if you think they are
163
pretty similar or can't say that they
are not, then
it becomes important to know that you
have maxed
out the dose of the ACE inhibitor.
DR. NISSEN: Does that answer?
DR. TEMPLE: I think it does.
DR. NISSEN: What are the implications if
such optimization is not done? I think we have
heard that; we have said that. We have all said I
think very clearly that you are way
under what we
believe to be a reasonable dose and
obviously that
is one thing.
DR. TEMPLE: Right, but reasonable
dose--if you think they might be the
same,
reasonable dose is not good enough. It really has
to be a dose beyond which there is not
much more
point, as far as we know, in pushing
it. Otherwise
it would be like adding another ACE
inhibitor to an
ACE inhibitor. As you said, it is the no-brainer
case.
DR. NISSEN: I wouldn't really necessarily
say that I guess. And, part of the problem is
that, you know, I wouldn't say as a
standard here
164
that one would have to push the
background therapy
just to the level of tolerance, I mean,
the idea
that you have to literally go to the
point where
you are getting into trouble and then
back off
before you add a second therapy. That is why I
used the word reasonable. You know, they could
have tried to really force titrate these
folks up
to the highest tolerable dose and they
would have
probably got a lot of AEs if they had
done that and
there would have been issues with that,
and that
wouldn't have been a practical study
design so I
wouldn't set the standard that high.
DR. TEMPLE: I don't think we are
suggesting that. The distinction is we care much
more about the dose of the ACE inhibitor
than we do
about the dose of the diuretic.
DR. NISSEN: Tom?
DR. PICKERING: Yes, I think we are
talking about three doses here for the
ACE
inhibitors. There are inadequate doses, adequate
doses and then mega doses and you have
been talking
about the difference between adequate
doses and
165
mega doses.
The only study that showed a dose
response was I think ATLAS where you
went from
inadequate to adequate. When captopril first came
into use for hypertension in the '80s we
were using
doses of 300 mg and 400 mg and I
remember there
were a lot of reports of neutropenia and
proteinuria, and it was said that this
was because
captopril had a hydril group and the
other ACE
inhibitors didn't. But I don't think we know what
the long-term effects are of mega doses
of ACE
inhibitors and there could be adverse
effects that
we just don't know about.
DR. TEMPLE: We also know that those high
doses didn't add to the hypotensive
effect.
DR. PICKERING: Right.
I am in favor of
combinations of moderate, more adequate
doses
rather than trying to push to the
absolute maximum.
DR. STOCKBRIDGE: But, again, that is not
really the question. The question is if you want
to assert that the mechanisms are
different, that
ARBs or this particular one has some
property that
you can't get out of an ACE inhibitor,
the only way
166
to do that is with the ACE inhibitor
maximized.
DR. HIATT: Optimized.
But I think the
other concern I have with this
conversation is that
we are talking about this in terms of
milligrams,
not in terms of patient
optimization. We have
heard earlier today that for some
patients a "low
dose" by milligram may be a maximal
dose tolerated
in a patient who is sicker. So, I would like to be
a little careful. I don't necessarily believe that
the box that they checked really defines
that they
were on optimal ACE dose. On the other hand, if
the patient populations are somewhat
heterogeneous,
then we can't necessarily assume that
they were all
on optimal doses of ACE inhibitors and
then the
difference in milligrams is a reflection
of the
demographic of the population.
DR. TEMPLE: But imagine for the moment
that someone had a theory that his ACE
inhibitor
had an effect that somebody else's ACE
inhibitor
didn't have. Now we know they are both ACE
inhibitors so the bias that they are the
same is
stronger than here. If they took, I don't know, 25
167
mg of captopril and showed that you get
a better
effect by adding this drug to it, that
wouldn't
really prove a whole lot. That is just getting the
dose of ACE inhibitor up to where it
should be.
So, for them to make that case I think
you would
say, well, we should be at the top of
whatever the
thing you are adding to is or close to
it--you
know, you don't have to make everybody
ill. And, I
think the point of this question is how
close are
we to that situation where it is obvious
you have
to get the dose up otherwise you are
just showing
something entirely trivial.
DR. HIATT: But they showed that. If you
look at that subgroup analysis at the
"highest
dose" defined a couple of different
ways the risk
reductions were even bigger.
DR. TEMPLE: Yes, well, we are just asking
what the principle should be.
DR. HIATT: Well, I think that the drugs
are different enough.
DR. NISSEN: Well, we are going to get to
that.
We will get to that; that is coming up.
168
DR. TEMPLE: I just want to make sure you
know why we are asking the question.
DR. NISSEN: No, I think it is a really
interesting, highly relevant
question. It is not
the last time it is going to come up, I
am sure.
DR. TEMPLE: Right.
I should mention that
when we analyzed--and maybe this was a
mistake, who
knows--when we analyzed ValHeFT it
appeared clear
that the drug worked when there was no
ACE
inhibitor, valsartan did, but the effect
of the
drug seemed to be better and better as
you went
further and further away from having the
proper
dose of the ACE inhibitor.
DR. NISSEN: Right.
DR. TEMPLE: So, it sort of looked like if
you had the proper dose of an ACE inhibitor
you
didn't have any effect. Given these data, maybe
that was all wrong but that is how that
looked.
DR. NISSEN: Yes, and again we are going
to come to that later, but the ValHeFT
data, how
relevant is it to our current
considerations? I
think you are going to ask us that
later. Now, we
169
have a question that says did
CHARM-Added have
adequate optimization of background
therapy with
respect to ACE inhibitor use? I would like people
to discuss that. Ralph?
DR. D'AGOSTINO: The protocol implied that
they were after some optimal use and
this question
becomes do we believe the results that
they are
reporting to us but they were aware of
that
question.
DR. NISSEN: Yes.
Blase, go ahead.
DR. CARABELLO: But even if they didn't,
the subset analysis of the mega doses is very
assuring.
DR. NISSEN: Yes, but that is not what we
are being asked. I am going to answer it. My view
is that, you know, everything I saw this
morning
tells me that they made their very best
effort.
Now, you know, could you quibble about
it? You
know, could you find some expert that
would say it
wasn't enough? But, you know, the enalapril doses
in the high teens look about like you
see in other
heart failure trials. The other ACE inhibitors are
170
being used in what I would consider full
therapeutic doses. The instructions to the
investigators clearly emphasized what
they were
trying to do. So, I have to give the study points
for making a very good effort at this
and I don't
see any compelling evidence that there
was an
effort not to optimize; every efforts seems
to have
been to optimize and I think they got to
optimal or
near optimal doses.
DR. STOCKBRIDGE: What do you mean every
effort was made? They checked the box and then
what did they do, press people to get
them up as
high as possible on their ACE?
DR. NISSEN: Well, we got a statement that
was given to investigators which
basically told
them to push the ACE inhibitor and,
again, they got
to doses, Norman, that were pretty
similar to the
doses used in the classical ACE
inhibitor trials.
Presumably, in those trials the sponsor
was very,
very eager to get to the optimal dose. So, if you
look at SOLVD versus this study you get
about the
same numbers, don't you? So, if the people doing
171
the SOLVD trial were under-treating,
okay, but they
were clearly not motivated to
under-treat in SOLVD.
DR. TEERLINK: I think actually the
efforts that the CHARM program made to
optimize
were quite considerable, and I think
they are to be
congratulated on at least looking on that as
an
issue.
For future trials, obviously, it might be
interesting to have them fill out a
little more
information on what is limiting the dose
in this
particular patient and have a CFR that
says, you
know, we can't go any further because of
renal
function, hypotension, hyperkalemia, and
list some
of the limiting things. You are still left with
having to trust the investigator that
they tried
and they pushed as hard as they could,
and that is
true in all cases.
DR. TEMPLE: You can also see the doses
they achieved and the various subsets of
analyses.
DR. NISSEN: I may be missing something
here, Norman, but do you not agree that
the doses
that they achieved were very similar to
what were
used in the classical heart failure
trials?
172
DR. STOCKBRIDGE: Oh, I think that is
true.
What I think is missing is a protocol-driven
effort to make sure that the doses were
as high as
they could be. You can take some comfort if you
think the populations in this trial were
similar
enough to populations in the other
trials that you
are using as references for what looks
like it, but
you are stuck having to make the
decision based on
comparing mean doses across trials and
there is
nothing in the protocol about pushing
the dose of
the ACE inhibitor.
DR. D'AGOSTINO: This is exactly what I
was trying to say earlier, that there is
a protocol
statement that they are going to
optimize but there
is no real indication about how they got
it so we
can believe or not believe what the
investigators
are telling us and then also the actual
doses that
were achieved.
DR. TEMPLE: Which is a separate
question
from whether the doses they got to
were--
DR. NISSEN: Yes.
Again, you know, I
understand your argument and it is
actually a very
173
relevant argument. I mean, what you are
really
arguing for is almost, you know, maybe
there needed
to be more of a forced titration
strategy here to
really, really push and I can understand
why that
wasn't done. You know, these are very fragile
patients and, you know, I see some of
these folks
myself and I suspect that a lot of the
patients
that had blood pressures that were
tolerated would
have been pushed and those that were not
able to
tolerate higher doses of ACE are
dominating why you
get to these similar average doses in
SOLVD and in
CHARM.
DR. TEMPLE: It could even be that if
people pushed the dose of the ACE
inhibitor to
where it should be you would decide that
certain
people weren't suitable for the trial
because their
blood pressure was already too low. That is okay
too.
DR. HIATT: There could be an
inherent
bias.
If you are going to put a patient in a trial
like this, you may not really want to
push the dose
of the ACE because you want to get them
in the
174
trial and you know that the ARB is going
to lower
blood pressure, raise potassium and this
kind of
thing.
So, there could be an underlying bias to
not optimize ACE, which gets really to
the heart of
this question.
DR. STOCKBRIDGE: You have other
opportunities in the questions to
address whether
or not there is a claim that that
related to--you
know, I have worked this system as well
as I can
with an ACE inhibitor and now I am going
to work it
from a different angle. You get another
opportunity to do that. This question was
different. This question was about establishing
that an ARB is so different in mechanism
that you
clearly get something on top of ACE
inhibition. It
doesn't matter what you do with the ACE
inhibitor.
You know, you could give it at high
doses and you
still couldn't possibly get the effect
you get out
of candesartan.
DR. NISSEN: Let me tell you one of the
pieces of evidence that suggests to me
that the
system wasn't getting gamed here, the
fact that
175
patients were enrolled with virtually
any blood
pressure. You know, if you really wanted to
exclude people who might not have
benefited,
basically all those low blood pressure
people where
you might have had trouble adding
candesartan, you
would have just kept them out of the
trial, and
they didn't do that. So, it means that they were
including people who might have been more
vulnerable to the candesartan add-on as
opposed to
just sort of getting an ACE inhibitor.
DR. HIATT: I wouldn't have called that
gaming at all. In fact, I don't think if they had
done that, if they had in fact driven
people up to
maximum labeled doses or maximum ACE
inhibition or
something like that everybody in the
trial and then
established the benefit there--I
wouldn't have said
that that was the only way to use the
drug. I
wouldn't have said you had to have blood
pressure
that was high enough to start with that
this
didn't, you know, cause tolerance
problems. But it
really would have established that as a
class you
could get something out of it that you
can't get
176
out of an ACE inhibitor. We all think we have
really answered that question so my
comment on the
data is that there is enough preclinical and
clinical data to suggest that they are
more
different than similar.
DR. NISSEN: Well, we are going to get to
that.
DR. HIATT: Then we have answered the
question.
DR. NISSEN: Any more comment on 1.3.1,
the question of whether there was
adequate
optimization of ACE inhibitor use? Any more
comment?
Have you heard enough discussion?
We
don't all necessarily completely agree
here but,
you know, I think that there is some
sense from the
committee.
What about other treatments
for heart
failure?
I will take comments about that.
DR. TEERLINK: I think this was a very
interesting portion of the question
because there
are those that believe that actually
beta-blockers
work via suppression; that one of the
major effects
177
of beta-blockers is that they suppress
the
renin-angiotensin system. So, does that actually
count as a related drug or a non-related
drug? If
it is a related drug, well, then should
we have
really said that they had to
optimize? I think
this is not pertinent to the CHARM. It doesn't
influence my thinking on the CHARM trial
but in
terms of future trials, which we are all
trying to
design, are we going to now require or
would we
want to suggest that those doses need to
be
optimized as well? And, what direction are we
going to give those trialists to decide
how to
optimize those? My personal opinion is that a
similar approach to what was done in
this trial,
with the addition of a clinical report
form or
something else that says, look, did you
really push
it as best you could, would be a
reasonable
approach in my opinion.
DR. TEMPLE: So, since there is at least
some overlap of the pharmacology you are
also
interested in being sure that that has
been
reasonably well optimized so you know whether
you
178
are just giving more beta-blocker or
actually doing
something different.
DR. NISSEN: There is a real problem here
with contemporary therapy, not just in
this area
but in other areas as well, and that is
as therapy
gets better and better you get to
diminishing
returns and we always want to know when
we get to
that point. You know, in coronary disease if you
look at trial after trial the event
rates year by
year seem to get lower and lower. So, companies
that are designing programs to lower the
risk of
death and MI with lipid-modulating
therapies are
estimating lower event rates as we are adding on
multiple agents.
DR. TEMPLE: The event rates get lower;
the hazard ratios don't always get
lower.
DR. NISSEN: No, they don't necessarily
but we like to know that in evaluating an agent
that given on a background of what we
know to be
effective customary therapy. Now this trial has
the problem, of course, that it was at a
transition
point.
Beta-blockers were coming on very rapidly
179
but they weren't fully penetrating the
heart
failure area. So, my answer to this is if you look
at the time frame when this was done,
having at the
beginning of the trial 55 percent on
beta-blockers,
going up into the 60s during the course
of the
trial is pretty reasonable given the
time frame
when this was taking place, there was
certainly
more beta-blocker use than in ValHeFT
which was an
earlier trial. So, it does reflect that the
background therapy looks pretty
contemporary but I
would be interested in other people's
comments.
DR. PICKERING: I would like to bring up
the issue of spironolactone again
because I would
be interested to hear what other people
think.
There didn't seem to be any clear
benefit of
patients in CHARM-Added being on
spironolactone as
well, and there is clearly the
possibility for harm
there.
So, perhaps the concomitant use should be
discouraged.
DR. TEMPLE: How can you tell that? They
weren't randomized to spironolactone.
DR. PICKERING: I know but from what we
180
have heard--
DR. TEMPLE: They might have been sicker.
I think that is really hard to know from
this
design.
DR. NISSEN: It is an unanswered question.
DR. TEMPLE: But also, for what it is
worth, in mind with the other question,
you want a
reasonable dose I guess but it is not as
important
because you don't think it might be the
same
pharmacology as the drug you are
testing.
DR. NISSEN: Bob, you know, there are
clinicians that are going to look at the
results of
whatever we do today and they are going
to have to
answer the question for a patient with,
you know,
class IV heart failure. I think everybody is going
to get an ACE inhibitor and a
beta-blocker. Now we
are being asked to opine whether adding
ARB is
good.
Should you also add spironolactone?
That is
an everyday practical, important
question on what
is the benefit and what is the risk of
quadruple
therapy rather than triple therapy. What I see
here is that we can't answer that
question. We
181
don't have enough information.
DR. TEMPLE: You do know that RALES was
done in a population that mostly got ACE
inhibitors, diuretics and a fair amount
of
beta-blockade I think--
DR. NISSEN: Yes, but not ARBs.
DR. TEMPLE: But definitely not ARBs. So,
we
presume everybody is going to get ACE inhibitors
before ARBs because, as Norm told you,
we are all
set to approve ARBs as a substitute for
an ACE
inhibitor as the initial therapy. Of course, none
of these data tell you that you still
need the ACE
inhibitor. These trials never do. They always add
on but they never subtract, or hardly
ever
subtract.
DR. CARABELLO: The answer to 1.3.2 is we
just don't know. We don't know what the diuretic
doses are. If you believe carvedilol is a superior
beta-blocker, you know, we just don't
know.
DR. STOCKBRIDGE: Well, the question was
whether or not it was adequate, and we
have
asserted in the preamble to this
question that if
182
it is an unrelated mechanism it sort of
doesn't
matter to us. So, you tell us that it does matter
to you and that you don't have enough
information.
Is that right?
DR. CARABELLO: I don't know what adequate
in terms of diuretics for instance would
mean in
this trial. We don't know. But that is not the
question. The question is does it matter. That is
the question you are asking.
DR. NISSEN: Actually, I am going to
interpret the question a little bit
differently.
What you are saying is given what we
know about
therapies for heart failure, are we
satisfied here
that the background therapy used, you
know, was
evidence-based contemporary
therapies. Now, we
don't have any evidence on diuretic
dose, Blase.
We don't know what the optimal diuretic
dose is for
patients with heart failure. So, there are a lot
of things we don't know here so within
the realm of
what we have evidence for, did this
trial achieve
reasonable optimization--adequate was the
word you
used; I will use the word reasonable but
adequate
183
is fine--of background therapy? It looks like the
background therapy there was at least as
good as
any trial done during this era, maybe
even a little
bit better and so I would deem it
adequate. Now,
maybe other people have a different view
but I
think--
DR. TEMPLE: Especially for the ones that
aren't as critical.
DR. NISSEN: Yes.
DR. TEMPLE: I mean ACE inhibitors are a
special problem.
DR. NISSEN: Yes.
DR. TEMPLE: Maybe beta-blockers are a
special problem. But for the others you just need
to know they are reasonable.
DR. NISSEN: Yes.
You know, there doesn't
seem to me to be any evidence that there
was some
under-utilization of an important
concomitant
therapy that might have benefited these
patients
and, therefore, reduced the benefits of
this
add-on.
I don't see any evidence of that.
DR. SACKNER-BERNSTEIN: I also think it is
184
interesting to look at the wording of
the question.
Maybe you could just help me understand
it better
because putting adequate and optimized
together is
a little bit confusing to me. I have been
interpreting the goal as being one where
we are
saying were the patients in the
CHARM-Added trial
were treated well with an ACE inhibitor,
the way
contemporary medicine says they should
be.
DR. TEMPLE: No--
DR. SACKNER-BERNSTEIN: I don't mean well
compared to clinical practice; I mean
well compared
to clinical trials.
DR. TEMPLE: No, that is not the question.
This is not about virtue or whether
somebody
tried--
[Laughter.]
--it is whether somebody
thinks another
ACE inhibitor is going to have an
additive effect
to an appropriate dose of the first ACE
inhibitor
and for some reason they think it does
something
else.
What would you want that first ACE inhibitor
to be dosed at to be convinced that you
are not
185
just giving 10 mg instead of 5 mg of the
first ACE
inhibitor, which would be a completely
trivial
thing.
So, if the drugs are the same in their
pharmacology, what we are hinting at here,
asking
you about is, is it much more important
to know
that you have pretty much gotten all you
can out of
that drug so that you know you are not
just giving
enough of the same old thing? So, for example,
nobody would think that an A2B is like a
diuretic
so you don't care if you are on the
absolute
maximum dose of the diuretic. When you have an
effect when you add it to a reasonable dose
of the
diuretic, it must be the drug that is
doing it; it
must be doing something different.
Our thought has always been we
are not
sure about that when it comes to ACE
inhibitors.
There are a lot of theories about how
they are
different and we saw them up there, and
it is not
implausible but we have been more
concerned that
people be on full dose of the ACE
inhibitor,
whatever that means, so that you know you
are
actually adding something and you don't
know that
186
if they are not on the full dose of the
ACE
inhibitor.
Now, what full dose means is
tricky. We
haven't talked about this but if you get
a 20-or so
percent reduction in this outcome, do
you believe
that increasing the dose of the ACE
inhibitor a
little bit will give you a 20 percent
reduction?
No, I don't. I mean, we have some idea of what the
dose response is; it is not that
big. So, that
also argues that finally getting the
dose of
renin-angiotensin inhibition right is a
good
explanation. The effect is too large for that, you
could say. That is where we are trying to make the
distinction.
DR. NISSEN: Let me give everybody an
analogy that I think is really extremely
relevant
here.
The relevant analogy is the HOPE trial and
the PEACE trial. In the HOPE trial there was very
little in the way of contemporary
background
therapy given very little use of
lipid-lowering
therapy, low use of other beneficial concomitant
therapies, and ACE inhibitors produced a
rather
187
robust benefit. The experiment was repeated with
what we have reason to believe is every
bit as good
an ACE inhibitor but the therapy was
contemporary
and, lo and behold, when you added the
ACE
inhibitor on top of contemporary therapy
there
wasn't a whit of benefit. Some of us predicted
that outcome as a matter of fact. So, why it is so
relevant is that we do really want to
know that a
new therapy, regardless of mechanism of
action, is
incremental.
DR. TEMPLE: That is an interesting
question.
DR. NISSEN: Yes.
DR. TEMPLE: It is not what we are trying
to get at--
[Laughter.]
--but really going back to
adding one ACE
inhibitor to another, you wouldn't
expect that to
work if the dose of the first ACE
inhibitor weren't
appropriate and optimized because you
would just be
adding more of the same and it shouldn't
work. It
is like, you know, adding three
antibiotics where
188
one is an adequate dose. You wouldn't expect any
benefit unless it does something
different.
DR. NISSEN: Yes.
DR TEMPLE: And it might.
That is really
what we are trying to get at.
DR. SACKNER-BERNSTEIN: So, as I was
talking about before, I think that
adequate and
optimization is confusing. I am going to try and
start again with the same thing. I think the
question is are these patients in
CHARM-Added well
treated with ACE inhibitors? When I say well
treated I look at that in two ways. One is are
they following the evidence, the
investigators, and
using the doses that are used in
clinical trials,
and then look at that in combination
with the
little we know about the dose-related
impact of ACE
inhibitors in clinical outcomes. So, you put all
those together, because there is not
much dose
response as you go up to higher doses,
and you are
at the doses that are used in clinical
trials and I
think you could say adequate
optimization, yes,
they probably were with ACE inhibitors.
189
DR. TEMPLE: Meaning that they probably
got as much out of an ACE inhibitor as
you can get
out of an ACE inhibitor.
DR. SACKNER-BERNSTEIN: I thought that is
what you meant by adequate optimization.
DR. CARABELLO: Yes, that is 1.3.1 but
what about 1.3.2?
DR. TEMPLE: Well, we are asking how you
feel about the other drugs, how
important it is to
optimize those. But we start with less strong
feelings about that because it is not
the same
mechanism. We know it is not the same mechanism.
DR. PICKERING: I don't think we can
answer your question about huge doses of
ACE
inhibitors because it has never been
done and what
we heard conforms to general clinical
practice and
we basically have to deal with the data
we have.
So, I mean, I think it is a hypothetical
question.
DR. NISSEN: Yes.
DR. HIATT: Except that when I first tried
to answer this question it was the
concept that you
were at an asymptote and I still believe
that. So,
190
20 mg of enalapril versus 40 mg--like
you just
said, going from 40 to 80 is not going
to give you
15 percent risk reduction in
events. Therefore,
they are optimized.
DR. TEMPLE: That is an entirely pertinent
and perfectly plausible answer.
DR. NISSEN: It is a little tougher to
answer 1.3.2. Let me tell you why, personally, it
is a little tougher to answer it. You know, the
effect of agents like carvadilol, as we
all know,
is very robust. Some people have suggested it is
more robust than metoprolol. I don't think that
that has been demonstrated beyond a
shadow of a
doubt in my mind. But, you know, we don't know for
sure here that if you redid this study
in 2005 and
gave an ACE inhibitor to these doses,
gave
carvadilol and pushed it all the way up to the
maximum tolerated dose that then adding
candesartan
would produce the same benefit. Like every
experiment that is done, you have a
background that
involves a moving target and, given that
moving
target here, it leaves just enough
uncertainty
191
about what might happen. So, I can't guaranty that
that experiment done again with
everybody possible
on background beta-blockers--but the
subgroup
analysis from the beta-blocker group
would suggest
that that is not a problem. But it is not proven.
DR. TEMPLE: What I hear is a general
statement, not because you are worried
about the
similar pharmacology, but you want to be
sure there
is still something left to treat after
you have
treated all these things. It is not a bad idea to
have a pretty good dose of the other
appropriate
therapies.
DR. NISSEN: Now, given the fact that 1.4
will involve a fair amount of discussion
and we are
going to have to vote on this, it might
be a really
good time to take a lunch break. There is an
alternative approach if we think we are
moving
really fast, which would be to defer
lunch but we
have to have a one o'clock public
hearing anyway.
So, any comments or thoughts about how
you might
want to proceed? What do you want to do, Ralph?
DR. D'AGOSTINO: I would like to just
192
continue.
DR. NISSEN: Continue?
Okay. Any other
folks?
Again, this is precedent setting efficiency
of this meeting and we are going to keep
going.
So, we have our ACE inhibitors
and ARBs
sufficiently different that CHARM-Added
can support
use of candesartan with ACE
inhibitors. What
clinical data support your view?
This kind of gets to the heart
of what is
being asked. So, I want some discussion and we
will take a formal vote on this.
DR. TEMPLE: Steve, I think the question
actually needs to say are they
sufficiently
different that it would support use of
candesartan
even if the dose of ACE inhibitor wasn't
optimized?
DR. STOCKBRIDGE: No, I think that is
really not what I intended.
DR. NISSEN: Bob is re-interpreting you.
DR. STOCKBRIDGE: Later questions invite
the committee to say it doesn't matter
whether or
not the mechanisms overlap. There is a way to get
the thing approved for use with an ACE
193
inhibitor--there are other ways to do
this. This
question was really intended to get at
do you know
from some other data or perhaps from
this that ACE
inhibitors and ARBs are so different in
terms of
their clinical outcomes that--
DR. TEMPLE: You should treat it like a
diuretic.
DR. STOCKBRIDGE--that you
should treat it
like it was a diuretic. If the mechanism is
different, then the dose doesn't matter.
DR. TEMPLE: Right.
DR. NISSEN: Blase?
DR. CARABELLO: I just want to be clear
that throughout these discussions we are
talking
about CHARM-Added. I mean, we are not proposing
that any of our deliberations extend to
the person
with preserved systolic function.
DR. NISSEN: That is right.
DR. CARABELLO: That hasn't been spelled
out and that should be clear.
DR. NISSEN: So, this is a pretty tough
and pretty important question and let's
see whether
194
people want to talk about it. I have my own
thoughts. Blase?
DR. CARABELLO: I am convinced. I would
say yes and the clinical data to support
it are--
DR. TEMPLE: That is not the question--
[Laughter.]
--that is why I tried to add
this. If you
believe the dose is optimized and it showed
an
effect, it really doesn't matter whether
they are
different drugs or not. You don't have to answer
this question. This question only goes to the
point if this is just like a diuretic
and the two
drugs are totally different, then you
didn't have
to optimize it. So, the question here is are they
so different you would like to treat it
as if it is
a diuretic. I think that is the only way the
question makes sense.
DR. NISSEN: Okay, I think I understand
the spirit of what both of you are
saying. It is a
very touchy and difficult area.
DR. TEMPLE: Clearly.
DR. NISSEN: And that is why it is being
195
asked of us.
DR. TEMPLE: Right.
DR. NISSEN: So, you know, we are being
asked to opine about this. Maybe I can help the
discussion a little bit by making a
couple of
comments. There is a principle involved that comes
up in medicine not infrequently. The principle
involves the sequential block of a
metabolic
pathway.
I will give you an example from the
infectious disease literature.
Trimethoprim-sulfamethoxazole blocks the
same
pathway at two different places and
there is very
good evidence that when you do that you
end up with
an antibacterial that is more effective
than either
agent is alone, and I can think of other
examples
of that.
So, that is why this one is tricky.
It
is because it is a pathway and you are
asking if
you block that pathway at two points
yielding the
same final common denominator,
particularly if
those pathways involve some slight
differences--
DR. TEMPLE: And some similarities.
DR. NISSEN: --and some similarities, are
196
the similarities more prevalent here or
are the
differences more prevalent? So, it is really is
the glass half full or is the glass half
empty? I
would say that because the principle of
sequential
block is a very important one and has
been
reaffirmed in some other models, and
particularly
when you consider things like bradykinin
and I
happen to think bradykinin actually does
have an
important role to play, and because of
the evidence
of escape, and I think there has been
some
reasonable evidence that escape occurs
when you
give an ACE inhibitor, now you are talking
about
something that is beginning to come
apart as a
common mechanism. So, you know, I personally lean
toward the view that in this particular
application
these drugs are somewhat different. They are
certainly not as different as a diuretic
is from an
ACE inhibitor but they are somewhat
different.
DR. TEMPLE: But if you believe that then
any dose of the ACE inhibitor, even if
it was half
the doses here, could be perfectly good
enough.
DR. NISSEN: Yes, and I wouldn't go that
197
far, Bob. You know, if we were sitting here today
and the average dose was 2.5 mg of
enalapril I
would be having a whole lot more
trouble.
DR. TEMPLE: How about half the dose that
they achieved?
DR. NISSEN: Okay, 10 mg.
I mean, I think
that this does speak to whether we
really do think
they were in an appropriate range for
having the
full biological effect or most of the
full
biological effect.
DR. TEMPLE: But if you think they need
full biological effect, then the answer
to this
question is no.
DR. NISSEN: I said most of the biological
effect.
DR. TEMPLE: That is what it turns on. If
you really think they are different,
then you don't
have to optimize. You don't have to have the full
effect of the ACE inhibitor. That is only if you
think they are or might be sort of the
same drug,
and you might not know the answer to
that.
DR. NISSEN: Again, what we have is a
198
partial overlap situation here and that
is where
the rubber hits the road.
DR. TEMPLE: Right.
DR. CARABELLO: But that is what I said
before.
I mean, I think the answer is yes they are
sufficiently different and the proof of
that is
that when you have maximized the dose of
one you
still get benefit from the other. If they were
working exactly the same way how could
that be
true?
DR. TEMPLE: Well, that is fair but that
is because you think they did maximize
it and you
not only think they did but you think
they needed
to so as to convince you, as you have
just become
convinced. That is fine.
We have no trouble with
that.
That is a different theory though.
That is
a theory that says because they might be
more or
less the same, to make a convincing case
that one
adds you have to use the full dose of
the first
one.
Whereas, if it was just a diuretic you
wouldn't need to do that. So, answering this isn't
whether they make it or not. That is not the
199
question.
DR. NISSEN: So, answering the question in
the spirit in which it was intended, I
don't think
they are sufficiently different. That is, if we
were talking here about what was clearly
a
non-adequate dose of ACE inhibitors,
then the
mechanism is not sufficiently different.
In other
words, if we are being asked to approve
an add-on
like an ARB in a situation where we
really thought
inadequate doses of ACE inhibitors had
been used I
think this would be very difficult to
justify. So,
my
answer to this is no. Well, we will vote
eventually.
DR. PICKERING: Also, it is not just a
single pathway. I mean, I think there is fairly
good evidence that however big a dose of
ACE
inhibitor you use you still don't really
knock that
angiotensin-II level so, as we heard
earlier, there
are the bradykinin effects and the
chymase effects.
So, I think there is very good evidence
that for
the complete blockade of the
renin-angiotensin
system you need multiple sites of action
and this
200
is what this does.
DR. HIATT: I agree with Tom completely on
that.
And, I think, Steve, your example of those
2.5 mg--I would say you just wouldn't
know or you
could conclude either way. In this situation I
think we do have enough evidence at
higher doses.
So, I would vote for different enough.
DR. TEMPLE: Remember, the question is
asking whether you even need the
evidence at higher
doses.
See, if you are satisfied that it works and
they are different because they used the
higher
dose, that is not answering the
question.
DR. NISSEN: Yes.
DR. TEMPLE: That is a different question,
a perfectly good basis for saying I
think it works
but it doesn't answer the question did
we even need
to bother.
DR. NISSEN: Can I shift the thinking a
little bit? I am going to shift this, and let's
suppose we had the same two drugs--
DR. TEMPLE: Mind you, we are hearing a
lot about what everyone thinks.
201
DR. NISSEN: Yes.
Let's say we have the
same two drugs and the endpoint you are
interested
in
is not heart failure but blood pressure.
Okay?
And, suppose somebody came in and said
we want a
label to add our ARB to an ACE inhibitor
to produce
incremental antihypertensive
effect. And, suppose
some submaximal doses of ACE inhibitors
were used
and they got a blood pressure back and
they added
in an ARB and they got a couple
millimeters more
blood pressure effect. Okay?
Would you decide in
that case that the mechanisms
sufficiently
overlapped that that would not be
approvable
because what should have happened is
that the ACE
inhibitor should have been pushed up to
a higher
dose?
I mean, take it out of the context for the
moment of heart failure. Have you given a label to
anybody for adding an ARB to an ACE to
further
lower blood pressure?
DR. TEMPLE: No.
DR. NISSEN: You haven't done that? Okay.
So, we are talking about something that
has some
relevance here. So, what do you think? What would
202
you, guys, think about that?
DR. HIATT: So, if you had three doses of
ACE, low, medium and high, and ARB
lowered blood
pressure in all three scenarios I think
that kind
of answers the question.
DR. NISSEN: Would it have to be
prespecified and would you have to--
DR. TEMPLE: No, that is the same
distinction. If you added an ARB to a diuretic you
wouldn't worry about whether it was
12.5, 25 or 50
because the mechanisms are totally
different and
you would say, oh, additive effect. But if you
added 25 mg to a very low dose of an ACE
inhibitor
and showed that you could improve the
blood
pressure control by adding an ARB to it,
that
wouldn't tell you anything. You just finally got
around to blocking the renin-angiotensin
system.
DR. HIATT: At the low dose but what if
you added it to the high dose?
DR. TEMPLE: That would be convincing.
They would have to do that because you
think the
mechanisms are similar enough that you
want
203
evidence that they actually add.
DR. STOCKBRIDGE: That is key.
If you
need the answer to that question, the
business
about what happens at the high dose of
the ACE
inhibitor, then you have to answer no to
1.4.
DR. TEERLINK: So, this becomes in some
ways a burden of proof question.
DR. TEMPLE: Right.
DR. TEERLINK: All of us around the table
I think acknowledge that there is ACE
escape, that
bradykinins are probably important to
some
different degree and so there are
differences
between ARBs and ACE inhibitors that are
probably
significant. My personal opinion though is that
the overlap between them is sufficient
enough that
the burden of proof needs to be that
they do need
to do the trial in the context of
adequate,
optimized--
DR. TEMPLE: That is the exact point.
DR. TEERLINK: --so my answer to that
would be I guess no.
DR. NISSEN: And, John, I think you
204
articulated that very well. Again, in the context
of a hypertension study I guaranty that
a sponsor
would have a whole lot of trouble
getting from a
committee like this an added label for
ARB on top
of ACE without doing a forced titration
of the ACE
to maximal dose, and showing that even
when you do
that there is incremental blood pressure
lowering
by adding the ARB. So, if it is good for the
goose, it is good for the gander. I mean, if the
hypertension story says you have to
prove that, I
think we really do have to be convinced
that the
ACE was optimized before we can be
comfortable.
DR. PICKERING: This has been done in
hypertension. Jules Manard, from Paris, has
studied I think maximum doses of ACE
inhibitors and
shown that you can still get an
incremental effect
on blood pressure by adding an ARB. I mean, it may
not be as big as if you add a diuretic
but it is
there.
DR. TEMPLE: Well, that is okay. The
point is whether you have to do that or
not.
DR. KASKEL: Can I say something from the
205
kidney standpoint? There are some trials looking
at ACE and ARB in progression of renal
disease and
treating the proteinuria, and the
recommendations
are to maximize the ACE and then start
your ARB.
DR. CARABELLO: I would say that before
this trial was done the answer to 1.4
was no. Now
that the trial has been done, the answer
is yes.
DR. TEMPLE: Well, you have to pretend you
don't have the trial yet for this
question.
DR. CARABELLO: But I am reading the
question and it says that CHARM-Added
has been
done.
DR. NISSEN: We want you to be a bit more
ignorant! Would you do that, please?
DR. CARABELLO: Change the question.
CHARM-Added is included in the question;
I am
reading it. Now that CHARM-Added has been done,
the answer to the question is yes. Before
CHARM-Added was done the answer to the
question was
no.
DR. TEMPLE: Well, that is fair. That is
fair.
206
DR. NISSEN: Blase, to really have
answered the question here is what
CHARM-Added
would have had to have done: They would have had
to force titrate the ACE inhibitor up to
the
maximum tolerated dose and then drop on
the ARB.
That would have ended this discussion
once and for
all.
And, the reason that the agency is asking us
about this and why there is some discomfort
here is
that that wasn't exactly the
design. We understand
why it wasn't the design and we are not
criticizing
it, but on a theoretical basis I
understand better
why you are asking this and I think that
the design
would have answered that question
forever--it might
have been done for hypertension but it
hasn't been
done for heart failure.
DR. CARABELLO: But I think the rescue is
that there is enough data from the
sponsor that at
the very, very highest doses of ACE the
stuff still
works.
DR. NISSEN: We are going to get a chance
to opine about all of that, you know, when
we
decide whether or not they have made
their case.
207
DR. TEMPLE: These are going into it
questions.
DR. NISSEN: Are you, guys, ready to vote?
Let's start with Blase.
DR. CARABELLO: I think I have made it
clear.
I mean, a priori the answer is no.
DR. CUNINGHAM: I agree with Blase.
DR. HIATT: Yes, same a priori, it is no.
DR. PICKERING: Can you repeat the
question? I am now totally confused.
DR. NISSEN: Are ACE inhibitors and ARBs
sufficiently different that CHARM-Added
can support
use of candesartan with ACE inhibitors,
with the
implication what clinical data support
your view?
DR. TEMPLE: It is could have supported
even if you didn't think the dose was
reasonable.
DR. NISSEN: Even if you thought the dose
was inadequate. I really do think that is the
spirit of the question. So, if you thought the
dose of ACE was inadequate, would this
have been
sufficient data to support use of candesartan
with
ACE inhibitors?
208
DR. PICKERING: I didn't think the dose of
ACE inhibitor was inadequate.
DR. NISSEN: I know, but if you did? If
you did hypothetically?
DR. PICKERING: Well, if I did think that
then I guess I would say no.
DR. PORTMAN: Based on those last
conditions, no.
DR. TEERLINK: No.
DR. NISSEN: No.
DR. KASKEL: No.
DR. D'AGOSTINO: No.
DR. SACKNER-BERNSTEIN: No.
DR. NISSEN: So that was, indeed,
unanimous.
DR. STOCKBRIDGE: Then you can't skip to
7.
DR. NISSEN: If you conclude that ACE
inhibitors and ARBs are sufficiently
different,
skip to question 7. If the mechanisms overlap,
then optimization of ACE inhibitors
matters more.
The protocol for CHARM-Added
required
209
subjects to be on an ACE inhibitor and
possible
choices were not limited to ones with
established
claims for heart failure. In designing a trial for
an add-on claim, should the ACE
inhibitors all be
ones with an established claim in heart
failure?
Comments?
DR. TEERLINK: Is that intended solely for
United States being one country or being
the
country?
[Laughter.]
DR. TEMPLE: That is interesting. I mean,
if there were good evidence I might say
that might
be a half-way thing. I don't know whether there
are data for the other ones or not. We only know
what we have seen.
DR. TEERLINK: It would have been
interesting actually if someone could
have asked
the sponsor in the question session, you
know, in
the United States what was the percent
of
FDA-approved ACE inhibitors and maybe
that would
have addressed the U.S.--
DR. TEMPLE: Well, the percentages
210
overall--
DR. TEERLINK: That is what I am saying,
it is already 80-90 percent of the
patients anyway,
and I would anticipate it is even higher
in the
U.S.
So, I do think I would ideally like them to
be ones with established claims but it
doesn't
detract from my interpretation of the
CHARM-Added
trial that they weren't.
DR. NISSEN: Anybody else?
Yes, Jonathan?
DR. SACKNER-BERNSTEIN: I wonder if anyone
else is of the mind set of wondering
whether it
matters if the ACE inhibitor is proven
to work for
chronic heart failure versus heart
failure post
myocardial infarction. Obviously, the FDA-approved
ACE inhibitors in all these analyses
were those two
indications lumped together.
DR. TEMPLE: That is correct.
DR. NISSEN: You know, this is difficult.
Obviously, this is one of those examples
where
there are very few people that doubt
that there is
class effect here. Having said that, I think this
trial was very well run. There are a few things
211
that I would have done differently and I
would have
given investigators a list of approved
ACE
inhibitors that would include those ACE
inhibitors
for which there was some reasonable data
to support
their use in chronic heart failure. That would
have given plenty of choices so we
wouldn't be
strong-arming people, you know, beyond
any
reasonable belief. Having said that, they really
mostly used ACE inhibitors that are
approved. It
doesn't detract hugely from the
trial. But if I
were somebody sitting here, listening to
this,
designing a trial I would take that out
of the
equation. I would try to take it out so nobody
could criticize me for using an
unapproved ACE
inhibitor. And, there are enough ACE inhibitors
out there that have some trial
evidence--have trial
evidence that they work in heart failure
that you
probably could have easily limited to
that. It is
not, in my view, an issue of
approvability but it
is an issue in terms of what is an
optimal design.
Anybody else?
The next question is how does
one pick the
212
target regimen for the ACE
inhibitors? You always
ask tough questions, you know.
DR. TEMPLE: It is all Norman's doing!
DR. NISSEN: Since nobody else is
speaking--you know, my motto is
frequently wrong;
never in doubt! But the cleanest possible design
of a study like this which, in fact was
not
impossible--we heard all the reasons why
it wasn't
done but it would have been to take an
ACE
inhibitor--if you were doing a study
like this
tomorrow, right, enalapril is generic;
you can get
it
very easily; you can over-encapsulate it and you
can come up with a strategy where
everybody gets
enalapril, a drug we know a lot about;
gets it
titrated up to effective
"adequate" therapy and
then gets randomized, and it is just a
whole lot
cleaner.
In my view, the perfect design here is to
take a drug in a class that is approved
for that
indication, for which there is lots of
data on what
an effective dose is, and use that agent
and
demonstrate that you are using it at
doses that we
know to be fully effective. That would be ideal.
213
DR. TEERLINK: And given that you had
already said that in future trials you
would also
do the same, would you do the same for
beta-blockers so that now we have a
two-phase
run-in up-titration trial?
DR. NISSEN: I would sure try. That is
the cleanest experiment you can possibly
run. The
real life is tougher. As somebody who does
clinical trials, I mean, I know that you
can't
always achieve the optimal but if I were
a
regulator and I wanted to see a perfect
application
that would just leave me no questions,
that is what
I would expect to see.
DR. TEMPLE: Of course, it presumes that
they are all the same, which they
probably are--
DR. NISSEN: They probably are, yes.
DR. TEMPLE: --but you don't really
necessarily always know that.
DR. NISSEN: Other people?
[No response.]
Number three, the CHARM-Added
protocol
recommended that subjects be treated on
214
individualized optimum doses of ACE
inhibitor based
on tolerability and "recommended target
doses."
What is known about the relationship
between dose
of ACE inhibitor and clinical benefits
and risks in
heart failure?
DR. TEMPLE: Well, there is one high/low
study that barely maybe showed a
difference at the
borderline. That was sort of high/medium versus
really, really low. So, I think everyone agreed
that we don't know much about pushing
it, although
we saw the results of a trial where I
guess the
pushed dose did work.
DR. PICKERING: The enalapril 20 versus 60
but there was no difference. It was the ATLAS
trial where you had an inadequate dose
of
lisinopril of 2.5-5 versus--what was
it?--32.5
where there was a difference.
DR. TEMPLE: The 20 versus 60 showed no
difference--
DR. PICKERING: Right.
DR. TEMPLE: --but my dim recollection is
that the higher dose was slightly
worse. So, it
215
doesn't encourage you to think there is
a real
benefit.
DR. CARABELLO: Right, but within some
brackets of dose what is high for one
patient may
be low for another, and vice versa. If you say you
have to push everybody to a given number
of
milligrams you will have some people
falling over
from hypotension. Obviously, 1.25 mg of enalapril
is probably not an effective dose. That is why I
think that you can't get away from
titration on a
case-by-case basis. I don't think that you could
ever come up with a recommended number
of
milligrams.
DR. TEERLINK: That being said, the ATLAS
trial, which is the one that really
compared the
low dose to actually a pretty high dose,
was a
3000-plus patient trial and it ended up
getting
patients at the end of dose titration to
33.2 mg of
lisinopril. So, they were able to get 1500-plus
patients on a mean dose of 33.2. I think they have
shown that you can actually titrate it
up to that
point, and the low dose ended up being
4.5 mg. So,
216
you know, it is a lower dose than we
have talked
about before.
DR. TEMPLE: But even that didn't show a
huge difference.
DR. TEERLINK: Yes, I guess it was an 8
percent decrease in all-cause mortality
with a p
value of 0.13.
DR. NISSEN: This is a weakness of what is
known about an awful lot of drugs. It is a really
interesting problem for us because if
you look at
some of the clinical trials that are
done with
fixed doses of drugs, and you have some
massive
clinical trial with, you know, metoprolol
in post
myocardial infarction and you pick a
fixed dose and
you give everybody the same dose, and
you know that
dose works but you don't know that more
wouldn't
work better or less wouldn't work as
well. This is
another example where we don't know as
much as we
would like to know about the
dose-response curve.
I would argue that Blase is probably
right here,
that with an enzyme inhibitor--
DR. CARABELLO: Gee, thanks a lot!
217
DR. NISSEN: It has to happen once!
DR. TEMPLE: We should break for lunch
after that!
DR. NISSEN: We should break for lunch,
but with an enzyme inhibitor, when you
know that
the background of activity of that
enzyme system
varies over an extraordinary range--you
know, the
amount of activation of the renin-angiotensin
system in heart failure has been studied
and I am
sure there are probably people out there
in the
audience who know a hundred times more
about this
than I do but, in fact, the more geared
up the
system is, usually the sicker the
patient is. So,
when you have a biological system that
is deranged
and that can be real deranged or can be
only
moderately deranged, it is not
surprising that the
optimal dose of an inhibitor of that
system might
vary over a fairly broad range.
So, I would like to believe
that there are
people in whom a 2.5 mg or 5 mg dose of
enalapril
is all they will tolerate and all that
they will
need, and that there are other people that you
218
really want to get to 40 mg or maybe
more to get
the same kind of benefit. So, if you say, well, we
tried to do an individualized and
optimal dose and
if an effort was made to do that, that
seems
reasonable and that is not an irrational
approach,
to the background therapy. Am I making any sense?
DR. TEMPLE: Well, you know, we have quite
good data on blood pressure responses--
DR. NISSEN: Yes.
DR. TEMPLE: --you know, in hypertension
studies the curves tend to be, over the
range you
are looking at--you know, we are not
going up by
orders of magnitude like Ray would have
asked, but
within the limits of the doses that are
used the
curves tend to be fairly flat toward the
upper part
of the dose so you don't really think
you are
getting much.
I guess the other pitch I
would make is
there actually are ways of looking at
individual
dose-response curves. A method developed by Lou
Shiner actually can be used that way,
and they
never are. So, I just want to make my usual pitch.
219
Proper analysis of titration designs can
actually
identify people who are much more responsive
and
much less responsive, and those methods
are just
never used. You have to give more than one dose to
people to do that.
DR. NISSEN: Yes.
You know, one of the
problems that exists in a program like
this is you
have this global trial going on in a
whole bunch of
countries and, you know, these very
elegant dose
titration sorts of effects are very hard
to explore
in this kind of a large, multi-country,
multi-center trial. So, I don't think you are
going to see a lot of examples where
people are
going to do this in real life. It is just hard to
pull off; hard to pull off in a big
study, for
sure.
Other comments?
[No response.]
Were the choices of ACE
inhibitor in
CHARM-Added reasonable? Anybody?
[A chorus of yeses.]
Is there anybody who disagrees
with that?
No disagreement.
220
Were the target regimens in
CHARM-Added
reasonable? I am not sure what the difference is
here.
DR. D'AGOSTINO: The answer is yes though.
[Laughter.]
DR. TEMPLE: Well, one is about which
drugs, the other is about the regimens.
DR. NISSEN: I see.
Okay. So, one is
about the regimens. Were they reasonable?
[A chorus of yeses.]
Anybody think they weren't?
[No response.]
What features of the
CHARM-Added ensured
ACE inhibitor optimization? That speaks to
Norman's challenge earlier.
DR. TEERLINK: I think this is kind of
like shipping packages with FedEx or
something like
that where it is insured but not
necessarily
guarantied.
[Laughter.]
So, I think they did very
reasonable
techniques to try to ensure that they
were in terms
221
of giving specific guidance in the
protocol and
having the investigators--
DR. STOCKBRIDGE: What specific guidance
are you talking about?
DR. TEERLINK: The specific guidance in
terms of the slide, whatever it is,
saying these
patients have to be on these things, and I
didn't
get to finish--
DR. STOCKBRIDGE: That sentence says you
should try really hard.
DR. TEERLINK: Yes.
DR. STOCKBRIDGE: That is it.
DR. TEERLINK: And that is the same
thing--
DR. STOCKBRIDGE: There are no
procedures--
DR. TEERLINK: Well, if you would have let
me finish--
[Laughter.]
--in addition, the
investigator had to put
their nickel down and say yes, I really
tried. So,
there you are going to be impugning the
virtue of
222
the investigator, saying they are lying
if they
don't do that, which is possible. Then, in
addition, the thing that adds additional
kind of
comfort to me is that, in fact, post hoc
it turned
out that they actually did get what we
believe to
be reasonable doses.
DR. NISSEN: That wasn't the question.
DR. TEERLINK: Then, the other thing that
I had added earlier in terms of having a
clinical
response form saying, you know, this is
why we
couldn't get any higher would also have
been
reasonable.
DR. NISSEN: You know, I think that we
have all said we thought they got
adequate doses,
but they got there in spite of the fact
that they
didn't necessarily build it into the
protocol in
the way you are suggesting. So, I would opine that
additional assurances could have been
provided.
Let me talk about reality
here. Who do
you think checks off the box? The research nurse
or the investigator? Somebody there says, you
know, we did our best. In fact, to be able to have
223
a document and have data that says why
didn't you
go higher on the ACE inhibitor, because,
(a), the
patient's blood pressure was too low or,
(b), they
were coughing or, (c), whatever the reason
might
be, would have amplified our ability to
be
comfortable here and would have enhanced
the
submission.
So, part of what we always do
here, we try
to tell people who are out there, who
are maybe
planning follow-on trials what can you
learn from
CHARM that somebody else might be able
to do just a
little bit better. I think, Norman, there are some
things that could have been done. Not everything
that could have been done was done. Now,
gratefully, for the study, you know,
they got to
very reasonable doses but not every
possible thing.
I personally would have liked the forced
titration
design.
I would have liked a design that really
was a forced titration design on the
background ACE
inhibitor. That would have been incredibly
compelling, if that had been done and
that could
have been done. It wasn't the design that was
224
chosen and we have to live with what
they did but
more could have been done. Anybody else?
[No response.]
3.5, was optimized usage of
ACE inhibitors
realized? How do you know?
DR. SACKNER-BERNSTEIN: I don't think
there is a way to know because we don't
have the
kind of information gathered that we
would like to
and so we are forced to go back to the
data that we
do have about the doses that were
employed and how
those doses compared to other trials
which,
fortunately for the sake of the
applicant, really
fell within the range that I think we
all believe
are appropriate doses, or adequately
optimized or
whatever, but we don't actually know
that.
DR. TEMPLE: Norman is going to become
famous for that phrase.
DR. NISSEN: Adequately optimized, yes.
We call this FDA double-talk!
DR. D'AGOSTINO: I think the response to
4, 5 and 6--we are very uncomfortable
with it, but
they did start off and had in the
protocol that
225
they were going to attempt to sort of
have the
optimal--adequate optimal dose and we
don't really
have any verification of it.
DR. NISSEN: Yes. I
mean, what we have is
what we have and we know what the mean
doses were.
We don't have a lot of individualized
data on what
happened. For example, you know, how often was the
ACE inhibitor down-titrated temporarily
or
permanently? You know, when you look at exposure
data and you have some snapshots in time
it doesn't
always tell you actually what was going
on in the
meantime. There may have been some people who, for
example, temporarily had lower doses of ACE
inhibitors in order to tolerate the
candesartan and
then later they got up-titrated
again. I mean,
that is always possible. And, that degree of
transparency in a trial, a big trial, is
really
hard to achieve. The more you can achieve it, the
more you can actually look at the area
under the
curve, if you will, for exposure the
more robust
information you have.
The reason it is not so
germane here is
226
that we just don't have a huge amount of
information that suggests that the
endpoint is that
sensitive to it. You know, a few milligrams more
or less of the ACE inhibitor, is it
really likely
to make a big difference? The clinical data
suggests that it is probably not. But if this were
a lipid-lowering trial, if you were
going to use an
add-on therapy and as you added on
therapy you were
down-titrating or up-titrating the
background
therapy, there might be a lot of
discomfort. You
know, we have a lot of information that
suggests
that it really does matter a lot exactly
how much
LDL reduction you get. Here we don't have that
background information.
DR. SACKNER-BERNSTEIN: I think we
actually do have a pretty good sense of
what
happened to ACE inhibitor therapy and
the
background over time. The sponsor's document on
page 96 gives us a very nice
snapshot. I think
that we discussed that. There are issues in trying
to figure out how to interpret that as a
post
randomization phenomenon. Intuitively, as I look
227
at the numbers it looks like they are a
little bit
different but it doesn't seem like there
is a whole
heck of a lot of difference. I don't think there
is a statistical test you can use. But I think you
do see that there is some difference and
they do
provide that data at each visit for the
percent of
patients at the recommended doses, the
maximal
doses, the means normalized to the
maximum doses.
They really do a very nice job of
presenting all
this data. So, it is there. I think it is pretty
transparent.
DR. PORTMAN: In summary, it was
inadequately optimized because the
methods were
inadequate to get there but they
actually did get
there.
DR. NISSEN: What is really interesting to
ask ourselves theoretically is how would
we feel
about this application if between the
start of the
trial and the end of the trial the ACE
inhibitor
dose fell by 30 percent, or if you went
from an
average of 17 mg of enalapril to 12 mg
of
enalapril? What would we think if that had
228
happened? And the answer is there would be some
trouble here today if that had
happened. So, the
fact that we have enough information to
be
comfortable is good, and it is germane,
very
germane to this question that we are
asking.
DR. TEMPLE: Some of the subanalyses
though of people who were on high doses
would also
contribute.
DR. SACKNER-BERNSTEIN: So, another point
here that could be used for future
trials is that a
protocol like this where there is
overlap in
mechanism perhaps should spell out very
explicitly
the first three things you do when you
have an
increase in creatinine, cut back the
study
medication in half, then cut it back to
a quarter,
then cut it back and then worry about
the
background therapy. Maybe things like that,
perhaps not that extreme, should be
considered as
part of future protocols to make sure
there is not
too much dropout. But here it doesn't seem like it
makes much of a difference.
DR. NISSEN: You know, when I was
229
answering 3.7.1, is this a potential
problem, the
answer is absolutely yes I think. Was it an actual
problem?
The answer is no. Any more
discussion on
number 3? Have you, guys, got what you need there?
A second possible claim would
be that
candesartan has effects one could not
achieve with
ACE inhibitors, regardless of dose. What evidence
does CHARM-Added provide that
candesartan has
benefits in patients with full ACE
inhibition?
4.1, in analyses of
CHARM-Added that
factored into ACE inhibitor dose, does
it matter
that subjects were not randomized to ACE
inhibitor
dose?
I am not sure I completely understand what
you are asking.
DR. TEMPLE: Well, what dose you were on
is the baseline characteristic.
DR. NISSEN: I see.
DR. TEMPLE: People were randomized to
where they got the sartan or not but
they weren't
randomized to the ACE inhibitor dose.
DR. NISSEN: I see.
DR. TEMPLE: The question is does that
230
matter.
It is not easy to think of how the study
would be done if you did want to
randomize the ACE
inhibitor dose. I guess you could do a full
factorial which would be very
interesting for next
time.
DR. NISSEN: And
unethical.
DR. TEMPLE: Why would it be unethical?
DR. NISSEN:
Full factorial? You would
have to have--
DR. TEMPLE: Combination versus each
single.
DR. NISSEN: Oh, but nobody would get
placebo?
DR. TEMPLE: No, that would be unethical.
DR. NISSEN: You said full factorial. I
interpret that one way, Bob.
DR. TEMPLE: You don't always have to have
a placebo.
DR. NISSEN: It actually would be a very
interesting design.
DR. HIATT: The problem with an ACE
inhibitor, as we talked a lot about
earlier, is
231
that I am not sure the same milligrams
means the
same thing in every patient. So, I would have a
hard time knowing what to do with that
because I
think it is the clinical pharmacodynamic
effect in
that patient that matters, so you would
sort of
have to randomize then to hypotension or
just
before hypotension, hyperkalemia or not.
DR. TEMPLE: Or a dose and then you pull
back.
DR. NISSEN: The approach that I was
suggesting earlier to me makes a whole
lot more
sense, which is to pick an agent that we
know works
and do a forced titration with certain
parameters
to guide, you know, when you stop, and
then add.
That is I think fine in terms of design.
DR. TEMPLE: It still doesn't tell you
whether the ACE inhibitor helps.
DR. NISSEN: Do you have any doubts about
that?
DR. TEMPLE: Sure.
If you put someone on
an A2B, do they still need the ACE
inhibitor? How
would one know that?
232
DR. NISSEN: I see.
DR. TEMPLE: You don't know that for any
therapy you add to.
DR. NISSEN: I see.
DR. TEMPLE: We are stuck with it. I
don't know of anything to do if they are
not toxic.
If they were toxic you would test their
elimination
but you are just not going to know that.
DR. NISSEN: Fair enough.
Any other
discussion of 4.1?
[No response.]
Compared with full ACE
inhibition, what
loss of effect with candesartan has been
excluded
by these analyses?
DR. STOCKBRIDGE: What you saw was a
series of comparisons of the effect of
candesartan
depending on sort of how close to target
you were
by various measures. The question is those things
didn't appear to be alarming and, in
fact, they
don't appear to have any consistent
relationship in
terms of sort of the background ACE
level. But
there are wide confidence limits around
all of
233
those things and so the question was how
reassuring
was that?
DR. NISSEN: Comments?
DR. TEERLINK: I think to directly answer
the question that is here, since 4.1,
for me, is
that yes, it does matter that they
weren't
randomized and weren't pushed to full
dose, then
the question in number 4.2 which is
saying, you
know, how can we interpret it, I don't
know because
we don't have the data to actually look
at the
effect of candesartan on top of full
dose ACE
inhibitor. I think we have data to look at perhaps
an inadequately optimized dose of ACE
inhibitor.
DR. D'AGOSTINO: When you look at the
subgroup analysis, and there is a big
danger in
doing so, I think sort of the legitimate
subgroup
analysis that you want to do is recommended
dose,
yes and no. They did that analysis and when it is
yes you actually see a better effect for
candesartan. This is on Table 59. When you look
at the maximum dose with the two
different
analyses, again, when they are yes you
see a better
234
effect.
Now, I don't know how much we should make
of it but, certainly, it doesn't destroy
the
effect.
If it went the other way and sort of lost
the effect it would be very disturbing.
DR. TEERLINK: The only challenge with
that is that the patients in the lower
dose, you
don't know what would have happened to
them had--
DR. D'AGOSTINO: Absolutely, yes. I agree
100 percent. It is very uncomfortable. My stomach
is jumping, talking about these analyses
given that
they are so after the fact, and
what-have-you but
they aren't disturbing in terms of their
results
and I think it is, you know, sort of a
very
sensible analysis to look at.
DR. NISSEN: As reassuring as it is, you
know, you asked the question what loss
of effect
has been excluded and the answer is we
don't know.
I mean, we really can't answer
that. We can tell
you that we are not worried about it;
that all of
us saw exactly the same thing Ralph
saw. Again,
you know, we might ask ourselves what
kind of votes
we would be taking today if those
patients who had
235
gotten the highest doses of ACE
inhibitors had no
benefit.
If that had happened, if that had been
the result of CHARM, then you and I and
all of us
would be having a really big battle here
around
this table.
DR. TEMPLE: You wouldn't have seen it.
[Laughter.]
DR. NISSEN: You would have flushed it
before we ever got to it. Let me tell you why that
is a really important issue. If you are out there
and you are going to design another
trial, maybe
you don't make yourself vulnerable and
maybe you
would do the forced titration so you can
absolutely
assure the agency and the committee that
you got to
the maximum tolerated dose before you
added the
other therapy and you protect
yourself. If we
think there is no effect, then the way
to guaranty
trouble is not to make this analysis,
you know,
that subgroup which could have really
caused a lot
of trouble if there was a lower effect
size or no
effect size.
Do the results of CHARM-Added
support a
236
claim that candesartan has clinical
benefits
unachievable with ACE inhibitors?
You asked this question ten
different ways
to us, which is good.
DR. TEMPLE: But this is the real one.
DR. NISSEN: And we are going to have to
vote on this one, by the way. This is a voting
question. So, discussion first.
DR. SACKNER-BERNSTEIN: I will start out
by looking at the word
unachievable. I would put
forth that that is quite a
selection. Unachieved
might be something that is more relevant
to the way
clinical guidelines are written and
clinical
practice evolves and clinical trials are
performed.
If you are asking unachievable by saying
is it
possible in any scenario ever that we
could add
more ACE inhibitor to get this effect,
well, yes,
it is possible but we have no data to
say that that
is a clinical likelihood.
DR. TEMPLE: But if somebody asks you that
question about can you get effects with
an ACE
inhibitor that you couldn't get with a
diuretic
237
alone, you would have no problem
answering that
question. There are dozens of studies that have
shown that a diuretic takes you up to a
certain
point and then you need a different
modality.
Probably a lot of people would find the
same
argument convincing on beta-blockers
where people
were on pretty good doses. So, we are just asking
the question here. It is the same question we have
been asking over and over again. If these people
have pretty much had it with ACE
inhibitors, have
you now added something to it?
DR. STOCKBRIDGE: But the unachieved
question is number 5. We are not there yet. This
is the unachievable.
DR. SACKNER-BERNSTEIN: So, can we say it
is unachievable based on a
population? Because
anybody who sees patients knows there
are
occasionally patient responders.
DR. TEMPLE: I must say, I think it is the
same question. If you think people were on pretty
much optimal--you know, details to be
discussed--pretty much optimal ACE
inhibition, then
238
you would say, well, this added
something so ACE
inhibitors didn't achieve that. As Norm says,
there is another one. Maybe for practical reasons
they couldn't get to the optimal ACE
inhibitor.
That is a different argument but what
everybody has
said repeatedly is they think they got
pretty close
to the optimal. So, if you believe that, if you
do--
DR. TEERLINK: Given my previous answers
to 4.1 and 4.2 when I said I don't know
in terms of
what the effects are on full dose ACE
inhibitor
because that wasn't tested in this
study, and given
that I my sense is that you are asking
should we
have a claim that candesartan adds
something to
full dose ACE inhibition on the basis of
this
study, I would have to say no, the
results don't
support it because it wasn't a
hypothesis that was
tested by this trial design or any other
trial
design, for that matter.
DR. TEMPLE: And the subanalyses in which
they looked at people who pretty much
were on high
doses--
239
DR. TEERLINK: Those help in addressing
question 5 but, given that I don't know
what
happened to the patients who were on low
dose, whom
they didn't force to go up to higher
dose--maybe
those patients on low dose when they got
into high
dose would have diluted any beneficial
effect of
the candesartan. Since they didn't force titrate
the low dose people up they are now
removed from
that group of high dose ACE
inhibitors. If they
had been moved up to a high dose group
and treated
and now were included in the high dose
group,
perhaps candesartan would have had no
beneficial
effect in that overall group of full
titration
patients. I think it probably would have--
DR. TEMPLE: But no drug has to work in
everybody.
DR. TEERLINK: I know, but they weren't
forced to go up to high.
DR. HIATT: I agree with you, John. There
is a margin of uncertainty here with this
question.
I think the population achieved adequate
doses; the
individuals may not have and I think
that is what
240
we are wrestling with a little bit so I think
there
remains some uncertainty here about
individual
cases.
Truly, they could have achieved all the
benefit from just pushing their ACE dose
and for
some reason they hadn't. But the question in my
mind is really whether that is really an
individual
patient kind of question or if it is a
population
question. Population-wise, they got close enough.
DR. NISSEN: Yes, I am willing to be a
little more generous here than I guess
some of my
colleagues are. You know, as you point out you
never know about an individual
patient. That is
just too difficult to know because the
optimal dose
of an ACE inhibitor for Bob Temple might
be 80 mg
of lisinopril, for all I know. That is something
one can never know. So, I think that if you weigh
all of the evidence here, particularly
when you
look at the subgroup that did get high
doses, and
you see, if anything, the result is a
little more
robust, you know, my comfort level that
these
results could not have been achieved by
up-titrating the ACE inhibitor is very
high.
241
Now, you know, it is all a
matter of your
comfort level. Is it 100 percent certainty? Would
I bet my life that another trial
couldn't show
this?
No, but I think it is very, very probable
that these are unachievable by
increasing ACE
inhibitor.
DR. SACKNER-BERNSTEIN: You said that you
were persuaded by the point estimate of
the effect
at the best treated--
DR. NISSEN:
Influenced by, yes.
DR. TEMPLE: Well, then it doesn't go
away.
DR. NISSEN: Yes.
DR. SACKNER-BERNSTEIN: So, that sort of
gets back to the 4.2 question of how convincing
was
that really. It has now taken more import in your
interpretation than just being fairly
reassuring.
You are banking quite a bit on that
point estimate.
DR. NISSEN: Yes, I guess there is more
involved here than this. I mean, I guess I am also
recognizing that we know a fair amount
about the
dose-response curve to ACE
inhibitors. I think
242
that Bob has pointed out, and others have
pointed
out, that it does tend to flatten out at
the higher
doses.
You know, we have a body of evidence here
that suggests that you are unlikely to
get a lot
more bang by increasing the ACE
inhibitor dose.
The hypotension stuff seems to show
it. There is
not really any secure evidence from the
heart
failure literature. You have the data from this
trial that at high doses of ACE inhibitors
there
was still a benefit when you added
candesartan.
So, I am trying to weigh the body of
evidence here
that suggests that there is much of a
chance that
pushing up the ACE inhibitor would have
achieved
the same results, and I just don't think there
is.
DR. TEERLINK: To try to clarify this
issue, if you had a choice between
saying that you
would recommend this for approval as
additional
therapy on top of full dose ACE
inhibitor, that it
has been shown to have benefit on top of
full dose
ACE inhibition versus approvable on the
basis of
having beneficial effects on top of
optimized ACE
inhibition, which of those would you
pick? Isn't
243
that the question you are getting at?
DR. NISSEN: Yes, and I think we all agree
that what was used here was optimized or
adequately
optimized.
DR. CARABELLO: But what is full dose? If
the guy can't stand up or his creatinine
is 7, that
is not full dose for him.
DR. TEERLINK: But that wasn't ever tested
in this trial. The hypothesis of whether
candesartan can add beneficial effect to
full dose
force-titrated ACE inhibitor was not
tested in
this.
If you are asking my belief system, I have
certain beliefs but in terms of what
actually has
been proven and what should go into
labeling and
those kind of things from a regulatory
standpoint,
I would have to say I don't know based
on this
data.
DR. TEMPLE: And you don't find the subset
analyses convincing on that point?
DR. TEERLINK: No, because as actually in
every point of the subset analyses Dr. U
mentioned,
he says, you know, of all the caveats of
subset
244
analyses the number one is that these
were not
randomized, not force-titrated
doses. So, we just
don't know.
DR. TEMPLE: But some of them were at the
largest approved doses of those drugs.
DR. TEERLINK: Some of them were, but we
are splitting up populations so this is
a self-selected
population of those who could tolerate.
Maybe the people who could tolerate high
doses of
ACE inhibitors really have no effect
from ACE
inhibitors because they are getting more
ACE
escape.
Therefore, they would get better benefit
for the A2. So, I think there are too many
confounders and I can come up with all
sorts of
interesting scenarios for how you could
explain a
balanced effect in the groups but that
is pure
conjecture based on some interesting
hypotheses.
So, on the basis of this data--and just
so nobody
over there is concerned, obviously
number 5 will
look much better from my standpoint but,
for number
4, I have a hard time saying that it
really adds to
full dose ACE inhibitor therapy because
we don't
245
know.
DR. D'AGOSTINO: I was going to support
that.
I think the way we looked at the high dose
previously, because it showed an effect
and seemed
to be consistent we were very comforted
by that,
but do we then take the other flip that,
therefore,
we don't worry about the randomization
and all
these other matters that should go into
a
randomized clinical trial? I think that is a big
jump.
DR. NISSEN: Let's vote on this. Let's
this time start with Ralph.
DR. D'AGOSTINO: No.
DR. SACKNER-BERNSTEIN: No.
DR. KASKEL: No.
DR. NISSEN: You, guys, have convinced me.
No.
DR. TEERLINK: No.
DR. PORTMAN: No.
DR. PICKERING: No.
DR. HIATT: No.
DR. CUNNINGHAM: No.
246
DR. CARABELLO: No.
DR. NISSEN: It is unanimous. If
CHARM-Added supports use of candesartan
by virtue
of effects unachievable with an ACE
inhibitor, skip
to question 7. We are not there yet.
A third possible claim might
result if one
could not achieve a full effect on a
system by one
drug, perhaps because of
system-independent
tolerance problems, but one could
achieve a larger
effect with the addition of a second
agent, does
one need to establish that the original,
poorly
tolerated therapy is still needed in
such a trial?
A really interesting question. This speaks to what
Bob really wants to see somebody
do. Reminds me of
your Cox ALLHAT study.
DR. TEMPLE: I don't know, people are
lining up.
DR. NISSEN: You know, it really cannot be
answered. I mean, I just don't think we have
sufficient data, and it would be
wonderful to know
that.
I mean, what you are really suggesting by
this question is that in those people that
either
247
didn't tolerate very well the ACE
inhibitors and,
therefore, maybe were suboptimally
treated, you
could have put them on candesartan and
taken away
the ACE inhibitor and gotten the same
event
reduction. I guess the only way you find that out
is by doing your non-full factorial
design where
some people get started with one and get
the other
added.
So, you would start with ARB and add ACE in
some people. Is that what you are looking for?
DR. TEMPLE: I am not sure, but I do want
to point out one nuance here. If you are talking
about blood pressure lowering, you could
assess
whether a person was getting full
desired effect or
not.
In this case we are talking about something
different. You have no idea whether they are
getting the full effect. So, it may or may not be
the full dose of an ACE inhibitor but it
is sort of
the best dose you can manage. That is what this
question is about.
DR. TEERLINK: So, in that perspective, I
think CHARM-Added really does address
this
hypothesis. The hypothesis was, okay, we told the
248
investigators to push as best they
could. They did
their best. They checked the box and said they
did, or the study coordinator did. And, in that
context then, candesartan did
demonstrate
beneficial effects on top of that. So, if that is
the question that you are asking, then
it seems
reasonable.
DR. SACKNER-BERNSTEIN: The only thing
about this question, since it is
starting out as a
hypothetical and then moving into this
particular
application, is that we just need to be
clear. I
mean, I don't think the background
therapy is one
that should be labeled or considered
poorly
tolerated in this particular case. ACE inhibitors
are not poorly tolerated therapies.
DR. CARABELLO: Not only are they not
poorly tolerated, but they are the
foundation of
the therapy for heart failure.
DR. NISSEN: But there is a study design
that would be possible here. I am not saying that
it should be done and I am not even sure
that IRBs
would agree to do it, but what could
happen is you
249
could take people, you know, optimize
them on an
ACE inhibitor and then you could add in
candesartan, and if you got to the full
dose of
candesartan then you could randomize
them to have
the ACE inhibitor withdrawn, and you
could then
compare outcomes in a group. In other words, you
are really asking the question a
different way.
DR. TEMPLE: You could take the study as
it was planned and as it was done and
after six
months randomly take the ACE inhibitor
away.
DR. NISSEN: Yes.
DR. CARABELLO: You could do it now
because candesartan was just approved
for the
therapy of heart failure but three days
ago you
couldn't have done that.
DR. TEMPLE: Well, I think it would be a
very had study to do now. You are taking a drug
that isn't very toxic and taking it away
to see if
people are going to die, and I think
very few
IRBs--
DR. NISSEN: That is why I said I don't
think any IRBs--
250
DR. TEMPLE: --it is not like stopping
tamoxifen after five years because
tamoxifen has
toxicity.
DR. NISSEN: Yes, I think we are not going
to know the answer to that.
What would be required to
obtain such a
claim?
I think we have sort of discussed that.
Does CHARM-Added have these design
features? Does anybody think that they do? No?
Okay.
This is now a voting question,
5.4, did
the results of CHARM-Added support a
claim that
candesartan should be used in patients
unable to
take a full dose of ACE inhibitor?
DR. HIATT: We just don't know that. We
don't know that so how can we vote on
that?
DR. NISSEN: Well, if you don't know the
answer, then the answer is no, the study
does not
support such a claim. I think the spirit of this
is that this would be something that one
could
discern if you did a forced titration
study and you
took those people in whom you were
simply unable to
251
up-titrate to a full dose of ACE
inhibitor and you
asked the question in advance,
prespecified,
whether those people got additional
benefits. That
would be the design that would answer
that question
and that was not the design that was
used here.
DR. CARABELLO: Yes, but the physicians
involved in taking care of these patients
pushed
the ACE inhibitor to the maximum dose
that they
thought they could. They have said that.
DR. NISSEN: Yes, Blase, I think it is
different though from a forced titration
study. I
mean, I think there is a design element
here that
the FDA's question is really asking us
to comment
on, and that is, this was not a forced
titration
study.
DR. STOCKBRIDGE: Well, this is your
invitation to say I think people got the
highest
dose they could reasonably be expected
to get to on
their ACE inhibitor, and the drug
clearly has an
effect in that setting.
DR. TEMPLE: And in many cases that dose
was the highest labeled dose.
252
DR. STOCKBRIDGE: Right, it was sometimes
that.
DR. TEMPLE: But those are not people
unable to take a full dose of ACE
inhibitor.
DR. NISSEN: That is right.
DR. STOCKBRIDGE. Right, fine.
That is
true.
DR. NISSEN: I am reading this question
very literally, which is do we know that
those
people who simply couldn't tolerate a
full dose of
ACE inhibitor--
DR. STOCKBRIDGE: No, that is not really
the intent here. This really is poorly worded in
that respect.
DR. NISSEN: I mean, we have all said we
think they got to very reasonable
clinically
important, generally accepted
doses. We have all
said that many times here. So, that answer is
obviously somewhat different.
DR. HIATT: I also think that this whole
dose question makes me wonder if the
forced
titration experiment, which we are not
going to
253
see, versus the data we are seeing
now--the margin
of uncertainty here, I mean
quantitatively, has got
to be small, not large. So, it would be, you know,
a 100,000-patient trial to really prove
that there
was some meaningful clinical difference
between
forced titrated, can't take anymore, and
then we
add candesartan versus what we are
getting today.
I mean, that margin of uncertainty I
just don't
think is big enough to matter.
DR. NISSEN: And what you are doing in
answering that question is you are
integrating
everything we know about the
dose-response curve of
a patient's ACE inhibitor and how well
tolerated--
DR. HIATT: With the flat dose-response
curve individuals don't exactly give you
the
information you need.
DR. NISSEN: So, you are integrating
everything we know and saying, you know,
I just
don't think that we would learn very much by
doing
a forced titration because I don't think
you are
going to get very much more out of it,
and I think
that may be the spirit of what you are
asking.
254
DR. TEMPLE: The real question is--I mean,
from what I hear everybody saying they
all think
that the study showed something.
DR. NISSEN: Yes.
DR. TEMPLE: Though there is a general
feeing that people got a pretty
reasonable dose,
even if it wasn't the optimal dose in
every case.
So, the question sort of is if you think
all that
how would you describe the population
the stuff
should be used in? Who are they?
The question
here is unable to take full dose of ACE
inhibitor.
I don't think that is right so there
must be
something else that can characterize
this
population.
DR. NISSEN: I think that would be a real
important discussion to have because it
does speak
to what the label ought to look
like. So, how
would the committee advise the agency to
describe
the population in which this therapy
would be
beneficial?
DR. SACKNER-BERNSTEIN: Not to pick on the
diction before but I think it basically
falls into
255
this idea of adequately optimized
background
therapy with ACE inhibitors in patients
with low
ejection fraction.
DR. TEMPLE: So would it be recommended
for addition in people on adequately
optimized
therapy?
[Laughter.]
We will find another word--on
an
appropriate, or whatever, dose of ACE
inhibitor.
That is who it would be for?
DR. NISSEN: Yes.
DR. SACKNER-BERNSTEIN: You could say
maximally tolerated.
DR. NISSEN: But that is not what was
studied.
DR. TEMPLE: We will obviously have to
think about it but you could use words
like
recommended dose of an ACE inhibitor.
DR. HIATT: Yes, heart failure doses.
DR. NISSEN: I like the idea of saying on
recommended or usual or typical--
DR. TEMPLE: Usual is often well below
256
what is recommended.
DR. NISSEN: All right, let's say of
effective doses.
DR. TEMPLE: Okay, we will think about
that.
DR. NISSEN: Words like that, to me, imply
that the agent has been proven to work
on top of
what are considered clinically
meaningful
therapeutic doses of the agent that they
are being
added onto.
DR. HIATT: I don't know if you want to go
this far but you could actually use the
doses they
achieved here and actually put in that
mean or some
range around what you all think really
is a heart
failure dose for each of these drugs.
DR. NISSEN: The problem is there are so
many ACE inhibitors.
DR. TEERLINK: And I wouldn't necessarily
say what dose they were on, but I would
include--you know, basically you live
and die by
the protocol you write and you get the
label for
what you did. So, what they did was they suggested
257
that physicians optimize the dose of ACE
inhibitor
according to a table that is shown here,
with the
blurb that was shown. I would be tempted to put in
that table and say these were the doses
of ACE
inhibitors that were the target doses,
and in
patients who achieved those target doses
candesartan showed blah, blah, blah.
DR. TEMPLE: And the description could
even say what fraction of patients
achieved those
doses.
DR. NISSEN: I guess what we are really
saying, and we said this several times,
is that we
think that they achieved the doses that
are used in
the treatment of heart failure, commonly
used,
known to be effective doses. I mean, there are
lots of ways to say it. But we do not think that
they used inadequate doses; we think
they used
adequate doses. I think the spirit of that should
come through.
DR. KASKEL: We currently have an NIH
trial for treatment of focal segmental
glomerulosclerosis in patients up to 35
years of
258
age, and there is a template in that
trial that
just began in January with a chart
showing how to
titrate these patients that are
randomized, with
enalapril over a course of six weeks,
getting their
blood pressure under control, checking
for
hyperkalemia. If they can't tolerate the drug,
they can then take losartan. So, there is a
template that is going on in a
500-patient trial
now that was well thought out over the
course of
about two years. So, that can be used as
recommendations for this.
DR. NISSEN: Blase?
DR. CARABELLO: So we don't vitiate the
entire proceedings here, haven't we
delayed this
till one o'clock for the opportunity for
the public
to speak?
DR. NISSEN: Oh, my goodness, thank you.
Yes.
DR. CARABELLO: We don't want to vote on
question 8 and then find out that there
is
difficulty--
DR. NISSEN: Yes, I have been very remiss
259
here.
If there is anyone that would like to speak
at the open public hearing, now is the
time. Oh, I
have to read the statement. Of course.
I don't
want to miss that.
Both the Food and Drug
Administration and
the public believe in a transparent
process for
information gathering and
decision-making. To
ensure such transparency at the open
public hearing
session of the advisory committee
meeting, FDA
believes it is important to understand
the context
of an individual's presentation.
For this reason, FDA encourages you,
the
open public appearing speaker, whoever
you might
be, at the beginning of your written or
oral
statement to advise the committee of any
financial
relationship that you may have with the
sponsor,
its product and, if known, its direct
competitors.
For example, this financial information
may include
the sponsor's payment of your travel,
lodging or
other expenses in connection with your attendance
at the meeting. Likewise, FDA encourages you at
the beginning of your statement to
advise the
260
committee if you do not have any such
financial
relationships. If you choose not to address this
issue of financial relationships at the
beginning
of your statement, it will not preclude
you from
speaking.
[No response.]
DR. NISSEN: Great.
You wanted to vote on
5.4 so we really are going to vote, but
you really
changed the question. Would you rephrase it for
the committee?
DR. STOCKBRIDGE: The real problem is the
full dose part of that. That seems to be where
people have a problem. And, 5.4 really was
intended to establish whether or not
people thought
whether it supported a claim. You may be ready to
vote on whether or not it alone is
adequate to
support a claim, which is 8.
DR. NISSEN: I think we can go on. You
have heard a lot of discussion about
this.
DR. TEMPLE: Well, we will listen and
figure out what you think who it is for.
DR. NISSEN: So, we are not going to vote.
261
Is there another possible claim
resulting from
CHARM-Added? Anybody want to offer up any other
claims?
DR. TEERLINK: There is one issue that is
of concern to me. It is actually not so much what
other claim results from it but I want
to ensure
against a certain claim being made, and
that is,
having heard that candesartan was
approved for
heart failure, I actually am
concerned--and I know
the FDA mandate is not to tell
physicians what to
use, when and to look mostly to efficacy
and
safety--but I would want to urge caution in
writing
a label that suggests that candesartan
should be
substituted for ACE inhibitors in
patients who are
tolerating ACE inhibitors. I don't know if that is
even germane to this, but this seemed to
be the
forum to at least bring that up.
DR. NISSEN: Is that label already
written?
DR. TEMPLE: Well, we are not telling
anybody to take somebody off something
they are
doing well on. But CHARM-Alternative has been
262
taken as making the case that if you are
going to
pick a drug you could pick candesartan
as well as
one of the ACE inhibitors. We didn't do that for
valsartan because it was based on a
300-patient
subanalysis and we didn't feel that was
quite the
level of data that was needed. So, it is labeled
only for people who can't tolerate an
ACE
inhibitor. But we have several thousand patients
studied; it is about as good as the
other studies,
so we didn't make that distinction.
DR. TEERLINK: The only distinction that I
am concerned about here is that you are
leaving the
door open for potential marketing and
other forces
to have people withdrawn from ACE
inhibitors and
switched to ARBs. That, to me, on the basis of
problematic trials but even the RESOLVe
trial and
OPTIMAL have troubles with them. I admit those.
But certainly there is no evidence to
say that they
are better than, and there is some trend
towards
saying they may be worse in terms of
survival. If
this were a blood pressure thing
purely--I mean,
this is not just a symptom
endpoint. You are
263
potentially withdrawing people from a
life-saving
therapy, a therapy that has been
demonstrated to
save lives in multiple tens of thousands
patient
trials, and substituting on the basis of
one trial
an agent that we think does have
benefit, but I am
not sure that it preserves all of the
survival
advantage of an ACE inhibitor. And, I am just a
bit concerned by the proposed labeling
that I have
seen.
It seems to leave that door open, and once a
door like that is opened it is going to
be their
job to walk through it and encourage
people.
DR. TEMPLE: Do you have suggested
language?
DR. TEERLINK: I would continue it to be
in intolerant patients.
DR. NISSEN: The difficulty, of course, is
the distinction between practice
guidelines and
regulatory--
DR. TEERLINK: And I understand that.
DR. NISSEN: I think there will be a need
for the practice guidelines that we
write for the
management of heart failure to address
the issue of
264
is candesartan a first-line alternative
to starting
an ACE inhibitor? I mean, that is a very
interesting practice question.
DR. TEMPLE: There is now a trial more or
less equivalent to the individual trials
of ACE
inhibitors, many of which are supported
by just a
single trial in heart failure.
DR. TEERLINK: And if we didn't have
ELETE-II and if we didn't have OPTIMAl
and if we
didn't have RESOLVe, then I might feel
more
sanguine about that. But these other trials do
show, if anything, a turn in the wrong
direction in
terms of mortality. I guess there are things that
the FDA can do and these are things
that, okay, if
we are going to say that we don't want
to have the
sponsor walk through that door, then
through
educational activities and postmarketing
requirements of the sponsor and certain
prohibitions in terms of marketing in
certain
manners, are in the purview of the FDA,
or you can
tell them to do a trial, a head-to-head
comparison
and show that it is better.
265
DR. SACKNER-BERNSTEIN: Even before a
trial, I think a point that you made
about there
being a slight trend, an apparent signal
that an
ARB, or at least the ones tested,
compared to some
ACEs are probably not quite as good are
of a
magnitude that is going to be difficult
to detect
comparing the result in the
CHARM-Alternative trial
to the historical ACE inhibitor trials,
and the
CHARM-Alternative trial was an
alternative in
patients who were intolerant, or at
least should be
thought of as CHARM-intolerant, that
should be the
name of it not CHARM-Alternative because
it wasn't
an alternative; it was an intolerant.
DR. TEMPLE: No, I know.
We thought being
intolerant to an ACE inhibitor doesn't
predict how
you are going to respond to another
drug. It does
mean you need another drug but we
concluded that it
represents essentially a regular
population,
indistinguishable from any other
population and now
in a trial of substantial size, that was
about as
big as trials of individual ACE
inhibitors at
least.
266
DR. TEERLINK: As long as you are
comfortable potentially recommending to
the
physicians to substitute a drug that
hasn't been
shown to preserve all the survival
advantage of an
ACE inhibitor--
DR. TEMPLE: And vice versa.
DR. TEERLINK: --then that sounds right,
and vice versa.
DR. NISSEN: See, the problem, John, we
don't know.
DR. TEERLINK: And the group that was
studied in the CHARM-Alternative study
is a select
subset.
If you open up that subset by the
labeling, saying anybody with or without
an ACE
inhibitor--
DR. TEMPLE: Right, we did not think it
was a subset. I mean, the fact that you have an
adverse effect on a particular drug
doesn't usually
say anything to whether the drug is
going to work
in you.
Why would it? There are people
who
coughed or who had angioedema. That doesn't really
go--or at least we didn't think it
did--to whether
267
the drug works or not. So, we thought the
conclusion that it works is more
generalizable.
DR. NISSEN: The other thing about this
just to be very, very careful about is
that if you
want to look at this with historical
vision, a lot
of the ACE inhibitor trials are before
beta-blockers. So, it is a completely different
experiment.
DR. TEMPLE: Right, and everybody was on a
lipid-lowering drug.
DR. NISSEN: Exactly.
So, the experiment
is completely different and if you look
at this
from a regulatory point of view, you had
to answer
the question did they make the case that
candesartan reduced morbidity and
mortality in
heart failure in people not on an ACE inhibitor?
And, you concluded that it did, and that
you didn't
need our advice to conclude that. Would I hope
that somebody would do a candesartan
versus full
dose of ACE inhibitor comparative trial,
that would
now be justified. Such a trial would be very, very
easily justified and would be
potentially useful.
268
It would be, however, very large.
DR. TEMPLE: So, you don't think most
people are going to read these results
by saying
you should probably be on both?
DR. NISSEN: Yes, they will, and if you
can't take an ACE candesartan is a great
alternative.
DR. TEERLINK: But I think direct to
marketing, which is going to be allowed,
to the
consumer is going to say candesartan is
a great
drug for you for heart failure. Ask your doctor
why aren't you on candesartan.
DR. TEMPLE: No doubt.
No, I think we
contemplated that that would
happen. As far as we
were concerned, the data looked
similar. Obviously
the data for each ACE inhibitor isn't
exactly the
same either.
DR. NISSEN: Yes.
You really have
difficulty in this situation when your
trials of
the other class of agents are completely
different
era.
It is very, very hard to know.
And that is
where I think people writing guidelines
for heart
269
failure will have to really chew on this
pretty
hard.
DR. TEMPLE: We also don't know how the
beta-blockers compare and there are
concerns that
they might not be comparable. I mean, it is very
hard to know when drugs work and the
differences
are small. You have to tease those out. That is
what ALLHAT sort of tells you. It
is very hard to
sort out differences.
DR. NISSEN: Yes.
Obviously, your
concerns are on the record.
DR. TEMPLE: That is helpful.
DR. NISSEN: Can we go to 7?
DR. STOCKBRIDGE: For question 7 you have
to think about whether you want to ask
it at all.
It walks through the strength of
evidence, you
know, components, if you believe you
already know
what you want to do with 8.
DR. NISSEN: I think we probably do. I
did want to make a couple of comments
here that I
do think are relevant. This has come up several
times on the committee. That is, you know, do we
270
place any weight on ValHeFT? The answer is yes.
When there is prior evidence of another
drug in
this class that has some similarities,
producing
similar benefits, to me, it has an
effect on my
thinking. It suggests to me that from a
mechanistic point of view the hypothesis
that a
dual inhibition of the renin-angiotensin
system
might be better than inhibiting only the
ACE
mechanism.
DR. TEMPLE: Of course, we found ValHeFT
unpersuasive on that point.
DR. NISSEN: Yes, but if you remember--
DR. TEMPLE: We could debate that.
DR. NISSEN: If you remember, I happen to
be one of the four people that voted in
favor, for
what it is worth. I didn't win that argument but I
thought that they made a good case
because I
thought that the beta-blocker data was
likely
spurious and it didn't influence me as
much as it
influenced other people.
DR. TEMPLE: But even leaving that aside,
what we mostly found was that the dose
was really
271
not adequate of the ACE inhibitor, and
that there
appeared to be improved response the
lower the dose
got.
DR. NISSEN: Yes.
DR. TEMPLE: Which itself is not
so
surprising.
DR. NISSEN: Yes.
Having said that, if
the result of ValHeFT had gone the other
way--I am
trying to say is that it is relevant and
the fact
that it went in the right direction, to
me,
allows--this hypothesis has been tested
before. We
know something about that, and it tends
to lower
the bar.
Now, it turns out that the CHARM trial
did very, very well, but what if the p
values had
been somewhat more marginal? We did this once
before, if you remember, with RENAL and
IDNT and we
ultimately said, well, we got these two
trials with
two different ARBs and neither of them
was
necessarily a slam-dunk but if you take
the two of
them together it probably means
something. I guess
I am saying we are not rejecting that as
irrelevant; it is relevant and I do
think it is
272
supportive. I don't know if anybody else has any
other comments about that.
DR. CARABELLO: No, in those trials we
even allowed the fact that ACE inhibitors
were
helpful in reducing the progression to
renal
failure.
So, we took the totality of the
information.
DR. NISSEN: Yes.
You know, every time
you get more information it adds to a
database of
what you know and, you know, we know
something from
ValHeFT and we know more now from CHARM.
DR. TEMPLE: So, we should probably see if
we want to have you take another look at
ValHeFT.
DR. NISSEN:
Maybe.
DR. TEMPLE: I see mixed reactions.
DR. NISSEN: People want more work.
DR. TEMPLE: We will think about it.
DR. NISSEN: All right.
Anybody else want
to
comment on anything that is in 7? Any of
this
that has any impact?
[No response.]
So, we come to a question that
may be of
273
some importance to the sponsor.
[Laughter.]
Should candesartan be approved
for use
with an ACE inhibitor in the treatment
of heart
failure?
Discussion and then voting.
DR. CUNNINGHAM: I want to make one
comment, and that is, if this gets
approved, one of
the things that we really don't have is
data on
African Americans in the percentage in
which they
are represented in the American population. I know
we are only one of many countries but I
would like
to encourage the sponsor, if they want
approval in
this country, to think about having
representation
of major ethnic groups in the same
population as
exists in the country.
DR. TEMPLE: Could they do it?
DR. CUNNINGHAM: It would be a good goal.
DR. TEMPLE: How would somebody feel about
doing, say, the same trial with the results
you now
have?
Would that be okay?
DR. CUNNINGHAM: I wasn't talking about
going backwards; I was talking about
going
274
forwards.
DR. TEERLINK: Are you talking about a
CHARM?
DR. TEMPLE: Yes, something like that. I
mean, it is perfectly true that the
participation
of blacks was very modest, sort of
leaning the
right way, but now that you have a survival
plus
hospitalization effect in the overall
population
convincing enough--well, we will see,
you haven't
voted yet but I am just guessing--how
would you
feel about a placebo-controlled trial in
a black
population in this setting? I guess I think that
would be a very difficult thing to
support.
DR. CUNNINGHAM: I am trying to push going
forwards. So, I am trying to make a point so that
people in the future, when they are
thinking about
designing their trials, think about
having a
representative population.
DR. TEMPLE: Oh, I totally agree.
DR. TEERLINK: I think your point is well
taken. The challenge is they are going
to get--also
using foresight--probably approval for
this now not
275
having done that. So, there is no stick here. We
continually mention these things; we say
they have
to have better representation of
minorities.
DR. TEMPLE: The other part of the
problem, as I just read about in today's
paper, is
that offshore is in and it is very hard
for us to
stop when you are talking about large
trials. All
the trials we have seen recently are
multinational
and most nationals don't have a large
black
population. That doesn't mean people couldn't go
out of their way to try to find people
even in
those countries, and they should.
DR. NISSEN: What Susanna is saying is it
is a very desirable thing to have
information that
tells us about how minority populations
respond
since we know that in this class of
drugs there may
be differences, so it is very
relevant. I thought
that in ALLHAT it was very helpful to
have that
information and, to me, it actually
changed my
practice to some extent.
DR. STOCKBRIDGE: The only thing I would
add to or amend what she suggested is
that if you
276
really cared about that as a fundamental
issue you
wouldn't target having representation
that was
consistent with the U.S.
population. You would, in
fact, try to get more.
DR. PICKERING: Maybe I could comment. To
do an NIH study you wouldn't be allowed
to do a
study like this with
under-representation of
minorities, and I don't see any reason
why the FDA
shouldn't make similar type of
requirements of
studies.
DR. NISSEN: Well, they can't do that.
DR. TEMPLE: Well, it is not clear we can.
In a limited way we can. The labeling has to
provide adequate directions for us for
the people
who are going to use it. The difficulty for us is
we are seeing large numbers of very
desirable
international trials and it is a real
problem to
have them be representative of the U.S.
population.
What I can answer for you is
whether if
people made a major effort in Europe and
elsewhere
where there are minorities, after all,
they could
actually succeed in doing that if they
really
277
tried.
These are helpful comments.
DR. PORTMAN: Just remember in pediatric
studies we have a burden that 40-60
percent of the
population have to be African Americans.
DR. TEMPLE: In cooperative studies in the
U.S.
DR. PORTMAN: Right.
DR. TEMPLE: Well, NIH clearly has
requirements for funding that are--
DR. PORTMAN: That is the FDA's
requirement. That is your requirement.
DR. TEMPLE: Oh, for the pediatric
exclusivity, yes, there we can be bossy.
DR. PICKERING: But the design of this
study, I think we heard, was reviewed
with FDA and
I don't know whether anything was said
about
minority representation in the original
study
design.
DR. TEMPLE: Well, we will look further.
We have accepted the inevitability, maybe
too
quickly, that if you do--I don't know
what it
was--75, 80 percent of your trial
outside the U.S.
278
you are going to have a population that
is not
going to be typical of the U.S. Maybe we have been
insufficiently attentive to that.
DR. NISSEN: Bob, what would you do if you
got a study which was done 100 percent
outside of
the U.S. for a regulatory claim?
DR. TEMPLE: Which happened. That is not
uncommon.
DR. NISSEN: What do you do with it? You
just treat it exactly the same way?
DR. TEMPLE: Yes.
We inspect various
sites.
We have to make a decision whether we think
it is relevant to our population. So, it depends
on whether the condition is one that you
think is
similarly treated, all of those
things. This is
all discussed actually in an ICH
guideline called
E5.
If we are nervous enough about it, we might
ask for a domestic study. There are certain
categories where we might. We are very nervous
about depression. We have seen some examples of
entirely foreign studies with the
impression that
they were successful and they utterly
failed when
279
they came to the U.S.--one case, not making
more
out of it than it deserves. So, it is on
everybody's mind but the reality is that
a lot of
studies are being carried out abroad.
DR. NISSEN: All right.
DR. SACKNER-BERNSTEIN: At the risk of
getting into a political aspect of this
as opposed
to where we are headed, if the
discussion is going
to go into the direction of trying to
get sponsors
to do studies where minorities are
recruited, as an
important part it also needs to be done
with
genetic analysis at the same time. There is a fair
amount of literature that shows that
African
Americans and African blacks, blacks
from various
parts of the globe, have a tremendous
amount of
differences in terms of the ACE gene
polymorphisms,
with some areas of Africa being more
akin to white
Norwegians than other parts of
Africa. So, to
merely create a document or a set of
guidelines
based on skin color would be an
inappropriate
application of the science that we have
at hand
currently.
280
DR. TEMPLE: This has come up in
discussions. We don't know what genetics to look
for.
If we did, ho-ho! But at the
moment we
don't.
If there were a characteristic that was a
good predictor everybody would be
beating a path to
it, but so far there are relatively few
characteristics that are well
characterized that
way.
DR. KASKEL: There are two clinical trials
now that involve taking bloods, urines
and other
specimens at particular time points and
having them
stored in the NIH biorepositories
because no one in
those trials knows what genes to study
right now
either.
DR. TEMPLE: Well, we know that drug
companies keep lots of samples around
and there
will be things to look for. There is a lot of
thinking. We are working with somebody to try to
look at serum in people who have torsade
to see if
you can characterize them. The NIDDK is looking at
people who have adverse reactions to
hepatotoxins.
Why do some people have it and others
not? So,
281
there is tremendous interest in this, as
you can
imagine, but it would be hard to say we
would know
what to look for yet.
DR. NISSEN: Yes, the era of
pharmacogenomics is not yet fully
developed.
DR. TEMPLE: Yes, but there is a lot of
interesting stuff.
DR. NISSEN: Interesting stuff, yes. I
think this is perhaps a little bit of a
tangent so
let's come back. I want more discussion on 8, if
there is any, and if we are ready to
vote, we are
ready to vote. So, let's start with Blase.
DR. CARABELLO: I vote yes.
I am
convinced that the investigators did
their best to
up-titrate the drugs. The final doses of ACE
inhibitor achieved were quite substantial
and in
line with other trials of ACE
inhibitors, and the
subset analysis of patients on very,
very high dose
ACE inhibitors all go in the same
direction.
DR. CUNNINGHAM: Yes, I am convinced by
the investigators' data.
DR. HIATT: I vote yes too, and I think we
282
have emphasized the need to provide data
on what
those doses mean that were achieved so
that we
don't fall off that target.
DR. PICKERING: Yes.
DR. PORTMAN: Yes.
DR. TEERLINK: Yes, with the definition of
the optimal therapy as per protocol,
which is given
on page 26.
DR. CARABELLO: Excuse me, just to add to
my answer, yes, with the obvious caveat
we are
talking about, patients with low
ejection fraction.
That is not in the question.
DR. NISSEN: My answer is yes as well.
With all the nit-picking aside about
optimal
strategies, I have to say I think it was
a very
professionally run trial. You know, you can pick
apart any trial and find things you
might want to
see done differently but I think they
executed this
trial well and I think the idea of
having three
trials together that would actually
answer
questions, separating out the Preserve,
the low EF
Added and the Alternative was very
informative. It
283
gave us a lot of information in a single
trial,
much more than we would ever hope for,
and it gave
the investigators a lot of manuscripts,
which they
really liked--
[Laughter.]
--but in all seriousness, I do
think this
was a very well done study, which doesn't
mean we
can't learn something from it about how
to do the
next one even a little bit better. But I think the
case is convincing and I think this
does, in fact,
add to the opportunity for patients to
benefit with
heart failure, and I think it is going
to be good
for patients and I vote yes.
DR. KASKEL: Yes.
DR. SACKNER-BERNSTEIN: Yes.
DR. D'AGOSTINO: Yes.
DR. NISSEN: If there are no further
comments, I think we can declare the
meeting
closed.
Thank you.
[Whereupon, at 1:32 p.m., the
meeting
concluded.]