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.\]