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