Cardiovascular and Renal Drugs Advisory Committee










                       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



                         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


       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.



                             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



                          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




                 DR. TEERLINK:  John Teerlink, heart


       failure specialist from University of California



       San Francisco and San Francisco VA.


                 LT. GROUPE:  Cathy Groupe, the executive


       secretary for the Cardiac and Renal Drugs Advisory




                 DR. KASKEL:  Rick Kaskel, pediatric


       nephrologist, Albert Einstein College of Medicine.


                 DR. SACKNER-BERNSTEIN:  Jonathan


       Sackner-Bernstein, cardiologist from North Shore


       University Hospital in New York.


                 DR. D'AGOSTINO:  Ralph D'Agostino,


       biostatistician from Boston University and the


       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.




                 DR. NISSEN:  Dr. Temple usually is awake


       by ten o'clock in the morning so I expect him


       later.  Lt. Cathy Groupe is going to read the


       conflict of interest statement.



                      Conflict of Interest Statement


                 LT. GROUPE:  The following announcement


       addresses the issue of conflict of interest with


       respect to this meeting, and is made part of the


       record to preclude even the appearance of such at


       this meeting.  Based on the submitted agenda and


       all financial interests reported by the committee


       participants, it has been determined that all


       interests in firms regulated by the Center for Drug


       Evaluation and Research present no potential for an


       appearance of a conflict of interest at this


       meeting, with the following exceptions:


                 In accordance with 18 USC Section


       208(b)(3), full waivers have been granted to the


       following participants, Dr. Ralph D'Agostino for


       consulting for two competitors on unrelated matters


       for which he receives less than $10,001 per year


       per firm; Dr. William Hiatt for consulting and


       speaking for a competitor on unrelated matters for


       which he receives between $10,001 to $50,000 per


       year per firm; Dr. Steven Nissen for consulting for


       the sponsor and for four competitors on unrelated



       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



       $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



       any current or previous financial involvement with


       any firm whose products they may wish to comment




                 DR. NISSEN:  Dr. Stockbridge, I believe


       you have some opening comments.


                           Welcome and Comments


                 DR. STOCKBRIDGE:  The first thing I wanted


       to say was sort of in the form of a public service


       announcement.  Last week someone, using the name of


       a Cardiorenal Advisory Committee member but


       claiming to be from the Division of Cardiorenal


       Drug Products, made calls to several parties, one


       on an investigator side and another a


       pharmaceutical company, clearly trying to get some


       kind of information.  If anyone else ever hears


       about a case like that I would like to suggest that


       you bring it to my attention so we can coordinate


       the investigation of any new case with the current




                 The other thing I wanted to say is that


       two days ago the division took an action to approve


       candesartan for use in heart failure and I have



       made sure that everybody, this morning at least,


       got the relevant parts of the labeling that


       resulted largely from the CHARM-Alternative trial.


       So, the question about whether candesartan works in


       heart failure is not what you have been invited to


       comment on.  Instead, there is a fairly simple


       question--it only takes three pages for me to ask






                 --about use of candesartan together with


       an ACE inhibitor.  Thank you.


                 DR. NISSEN:  Thanks, Norman.  Let's then


       just proceed to the sponsor presentation.  If it


       pleases the committee, I think what we would like


       to do is let the sponsor go ahead and go through


       their presentation and then maybe hold all the


       questions together because it is going to be, I


       think, easier to integrate everything.  However, if


       anybody has burning questions after any of the


       individual presentations, please let me know and we


       will try to make sure you get clarification.


                          Sponsor Presentation:



                           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



       CHARM U.S. national leaders.  Dr. McMurray served


       as he principal investigator for the CHARM-Added


       trial.  Dr. Granger served as the principal


       investigator for the CHARM-Alternative trial.  They


       also served as members of the CHARM executive




                 In addition, Dr. Lewis, Dr. McLaughlin,


       Dr. Kronmal and Dr. Hennekens are also available to


       assist today.  Dr. Hennekens is here in his role as


       the chair of the CHARM data and safety monitoring




                 To set the stage for the forthcoming


       presentations, here is a brief history as of 1996


       of the product's development and key previous


       interactions with the FDA in regard to the heart


       failure clinical program.  Three pilot studies were


       conducted to help identify the optimum dose and


       evaluate neurohormonal effects, LV systolic volume


       and tolerability of the 32 mg high dose under the


       U.S. IND, prior to the initiation of the CHARM




                 In 1998 AstraZeneca met with the Division



       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



       completed to date with this class of drugs for


       heart failure.  The CHARM program consists of three


       separate but complementary randomized,


       double-blind, placebo-controlled, parallel group


       studies including 7,601 patients.


                 Alternative was conducted in patients with


       ejection fraction less than or equal to 40 percent


       and not on an ACE inhibitor.  This Tuesday's


       approval was primarily based on this study.  Added,


       which is the focus of today's discussion, was


       conducted in patients with ejection fraction less


       than or equal to 40 percent and receiving an


       optimized dose of ACE inhibitor.  Preserved was


       conducted in patients with preserved left


       ventricular systolic function.


                 The primary endpoint for each trial was CV


       death and heart failure hospitalizations.  The data


       demonstrated a statistically significant and


       clinically important benefit for candesartan in the


       low ejection fraction studies, Added and


       Alternative.  The primary endpoint for Preserved


       was not statistically significant.  These results



       from Alternative, supported by the Added study,


       formed the basis of Tuesday's approval by FDA for


       candesartan in heart failure.  Additionally, to


       date candesartan has been approved in 18 countries


       for the treatment as add-on therapy based on


       CHARM-Added or without an ACE inhibitor based on




                 Specifically, in the United States the


       indication approved on Tuesday states Atacand is


       indicated for the treatment of heart failure (New


       York Heart Association class II-IV and ejection


       fraction less than or equal to 40 percent) to


       reduce the risk of death from cardiovascular causes


       and reduce hospitalization for heart failure.


                 In addition, the clinical trial section


       mentions CHARM-Added as a supportive study in the


       first sentence of the text you see on the screen.


       Also note there was a 15 percent lower risk of


       cardiovascular mortality based on both


       CHARM-Alternative and CHARM-Added together.


       Furthermore, symptoms of heart failure, as assessed


       by New York Heart Association functional class,



       were also improved.


                 Based on CHARM-Added, AstraZeneca requests


       approval for candesartan as add-on therapy when a


       patient is already receiving an ACE inhibitor.


       CHARM-Added was designed to allow an investigator


       to optimize the dose of ACE inhibitor treatment on


       an individual patient basis when either placebo or


       candesartan is used for the treatment of heart


       failure.  Treatment resulted in a statistically


       significant and clinically important benefit when


       candesartan was added to an evidence-based dose of


       an ACE inhibitor.


                 The FDA has posed the question does


       CHARM-Added provide compelling evidence that


       candesartan should under some circumstances be


       recommended for use in patients on an ACE




                 To help answer this and other questions


       posed today, we have conducted supplemental


       analyses, the results of which will be presented


       here to assist with these proceedings.  Next, Dr.


       Young will present the rationale for use of ARBs in



       heart failure.  The ARBs and ACE inhibitors have


       distinct and complementary mechanisms, and data


       from pilot studies are supportive of the beneficial


       effects demonstrated from treatment with


       candesartan added to an ACE inhibitor.


                 Following that, Dr. McMurray will present


       information on the selection of the recommended


       dose of an ACE inhibitor in CHARM-Added.  Dr.


       Pfeffer will then provide a summary of efficacy for


       CHARM-Added as well as the analyses for maximum ACE


       inhibitor doses defined by the FDA.  Dr. Hainer


       will present safety information.  Dr. Young will


       then present the benefit/risk profile.  That will


       conclude our formal presentation.  Now, Dr. Young?


                 DR. NISSEN:  Any clarification issues for


       anybody or can we go ahead and move on?  If not,


       let's do it.


                         Background and Rationale


                 DR. YOUNG:  Thank you, Cindy.  Dr. Nissen,


       ladies and gentlemen of the panel, the FDA and the


       audience, it is an honor for me to be here today so


       we can all reconsider an extraordinarily important



       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



       ARBs sufficiently different that CHARM-Added can


       support use of candesartan with ACE inhibitors?


                 To answer that question we need to


       consider the pathophysiology of heart failure and


       the relationship of ACE inhibitors and ARBs to the


       renin-angiotensin-aldosterone system.  It had been


       gratifying to see the insight gained over the last


       30 years into the pathophysiology of heart failure


       and this has helped us design better therapies.


       Particularly important is understanding


       implications of the renin-angiotensin-aldosterone




                 Indeed, the vast majority of drugs


       beneficial in this system, including beta-blockers,


       attenuate adverse effects of angiotensin-II.


       Emphasizing that point is this RAAS cascade.  I


       know everyone here has their own favorite RAAS


       cascade.  This happens to be mine.  Here we can see


       the potentially detrimental effects of


       angiotensin-II effected through the AT-I receptor,


       as well as some putative beneficial effects of


       angiotensin-II effected through the AT-II receptor,



       specifically increasing kinin and nitric oxide




                 These observations have significant


       implications when we consider ACE inhibitor and ARB


       use in heart failure, and particularly their


       combination.  First, angiotensin-converting enzyme


       is not the only molecule affecting production of


       angiotensin-II.  During long-term ACE inhibitor


       prescription chymase activity, for example, can


       increase levels of angiotensin-II even at doses of


       ACE inhibitors which completely inhibit this




                 ACE inhibitors have another important


       effect.  They are bradykinin potentiating factors.


       Indeed, when first isolated from the Brazilian pit


       viper venom, the molecule was labeled BPF.  It is


       also important to remember that candesartan, the


       agent of focus today, is a selective angiotensin-II


       type I receptor blocker that is tightly bound and


       long acting.


                 Again keeping in mind the last diagram, we


       can illustrate how ACE inhibitors mediate benefit



       in heart failure remembering the BPF and ACE escape


       issues.  Here we see the ARB effects which result


       in more specific and complete blockade of the


       angiotensin-II type I receptor.  Here, the


       rationale for combination ACE inhibitor and


       candesartan therapy is the fact that angiotensin-II


       produced by chymase activity will be attenuated


       without abrogation of ACE inhibitor BPF effects


       while allowing potentially beneficial effects of


       AT-II receptor activity.


                 There is robust basic scientific evidence


       that supports these concepts.  For example, in


       canine heart failure models ACE inhibitor and ARB


       combination improved hemodynamics, collagen volume


       fraction and mRNA for collagen 1 and 3 compared to


       either agent alone.


                 In Pfeffer model rats with heart failure


       the combination of valsartan and fosinopril was


       more effective in suppressing myocardial remodeling


       assessed by collagen production and decreased


       infarct size, while valsartan and benazopril


       improved more subsequent left ventricular



       hypertrophy and lusitropic properties noted in


       these pathophysiologic models.  In obese and


       hypertensive rats, blood pressure, left ventricular


       hypertrophy and renal function were improved more


       with the ACE inhibitor/ARB combination than with


       use of either agent alone.


                 We also see clinical evidence that a


       combination of an ACE inhibitor and an ARB could be


       beneficial.  For example, this now classic report


       of the ACE inhibitor escape phenomenon demonstrates


       the time-dependent increase of angiotensin-II


       despite almost complete reduction of plasma ACE


       activity over time.


                 This is one example of several very


       elegant demonstrations of a complicated interaction


       between ACE inhibition and AT-I receptor blockade


       in heart failure patients.  This experiment


       specifically focused on the contribution of


       bradykinin to vasodilation in patients on enalapril


       compared to losartan.  Specifically, all subjects


       received an infusion of a bradykinin receptor


       antagonist before an ACE inhibitor or ARB was





                 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



       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



       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



       we see a significant increase in peak exercise


       oxygen uptake and improvement in New York Heart


       Association symptomatic classification when 50 mg


       of losartan was added to either lisinopril and




                 Setting the stage for the CHARM program,


       and particularly the CHARM-Added study is this


       clear imperative to develop better strategies for


       heart failure treatment.  Certainly, attenuating


       the adverse effects of RAAS is important.  There is


       now substantial preclinical and clinical evidence


       that the combination of an ACE inhibitor and ARB


       will be effective interventions.  This is supported


       by clinical outcomes data in diabetes and chronic


       renal insufficiency patients, as well as


       hemodynamic, neurohormonal, cardiac remodeling,


       symptomatic and exercise changes in heart failure




                 To discuss in more detail the rationale


       for very important design characteristics of the


       CHARM-Added study is Prof. John McMurray of the


       University of Glasgow, in Scotland.  John is the



       global principal investigator for the CHARM-Added


       trial.  As we consider in more detail the


       CHARM-Added program design, Dr. McMurray will


       specifically address the issue of baseline ACE


       inhibitor choice, dose and utilization in our


       study.  This will address several additional


       questions posed by the FDA.  Then Dr. Pfeffer will


       subsequently present our outcomes data.  So, if


       there are no clarification questions, we can turn


       to John to deal with the ACE inhibitor issue.


                 DR. NISSEN:  Can we move on?  Okay.


             ACE Inhibitor Choice, Dose and Drug Utilization


                 DR. MCMURRAY:  Mr. Chairman, ladies and


       gentlemen, Dr. Young has explained to you that ARBs


       and ACE inhibitors have pharmacologically distinct


       mechanisms of action.  He has explain to you the


       scientific rationale for combining the two.  He has


       shown you the mechanistic data to show that there


       may be benefit from using the two different types


       of drugs together.  But to show that there is an


       important improvement in clinical outcome when you


       combine the two drugs you obviously have to conduct



       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



       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



       compared a very low dose of ACE inhibitor to a


       higher dose, that trial suggested that there is


       more morbidity benefit from using a higher dose of


       ACE inhibitors.  So, we were very strong.  We felt


       that to test the hypothesis it was very important


       that our investigators used the target doses, if


       possible, of the ACE inhibitors that had been shown


       to be of benefit in the large randomized trials.


       You can see here those trials and the target doses


       that were recommended.  These were what were put in


       the protocol.  These were what we spoke about at


       the investigator meetings.


                 So, that is what we planned.  What


       actually happened?  Well, in addition to those two


       things we also asked, once the investigators had


       individually optimized ACE inhibitor dosing in


       their patients, that the patients should be on a


       stable dose of an ACE inhibitor for at least 30


       days before randomization.


                 So, I want to now look at what our


       investigators actually did.  Well, if you remember,


       I said there were five ACE inhibitors proven to be



       of benefit in large-scale randomized trials.  We


       were pleased to find that, in fact, in 80 percent


       of the patients in CHARM-Added those five proven


       ACE inhibitors were the ones that were used.


                 The agency also recently asked us to look


       at all approved ACE inhibitors.  In fact, there are


       two additional ACE inhibitors.  There are seven


       FDA-approved ACE inhibitors for the treatment of


       heart failure.  In fact, it was 90 percent of


       patients in CHARM-Added who received an


       FDA-approved ACE inhibitor.  So, that is something


       about the drugs that were used.


                 What about the doses that were used by the


       CHARM-Added investigators?  Well, we asked our


       investigators to tell us that they actually felt


       that they had tried to individually optimize the


       dose of ACE inhibitor.  We did that by asking them


       to check a box before randomization on the CRF.  We


       wish we had collected more information about this


       but we didn't.


                 But I will show you what I believe is


       evidence to support the view that our investigators



       did a good job in trying to use evidence-based


       doses of ACE inhibitor.  On this slide you see the


       mean dose of ACE inhibitor used in those landmark


       trials.  You also see the mean dose of the same ACE


       inhibitors used in CHARM-Added.  For example, in


       the SOLVD treatment trial the mean dose achieved


       was 16.6 mg.  In CHARM-Added the mean dose of


       enalapril used was 17 mg.  Broadly, I think this


       slide shows that our investigators generally did


       achieve the sorts of doses of ACE inhibitor seen in


       the forced titration trials.


                 I am just going to focus on enalapril a


       little bit more, and the reason I am going to do


       that is two-fold.  Firstly, enalapril is by far the


       most evidence-based ACE inhibitor in heart failure


       and, secondly, it is the one where we have the most


       information about doses achieved during forced




                 You see on this slide all the trials that


       force titrated enalapril in heart failure.  You see


       the mean daily dose achieved which was generally


       between 15-18 mg, and in CHARM-Added our patients



       received 17 mg and enalapril was the most commonly


       used ACE inhibitor in CHARM-Added.


                 Perhaps an even more important slide I


       think is this one because it shows you the ACE


       inhibitor doses used in other recent important


       heart failure trials looking at treatments given in


       addition to an ACE inhibitor.  So, on this slide


       you see two of the recent key beta-blocker trials


       and you also see the RALES trial and you see the


       baseline dose of ACE inhibitor used in these


       trials.  In every case for these key ACE inhibitors


       the CHARM-Added investigators had their patients on


       a larger dose of ACE inhibitor than in these other


       trials.  We think that that tells us that our


       investigators did heed our advice; did follow the


       instructions in the protocol; did listen to what we


       said at the investigators meetings.


                 Here is another important slide and it


       really goes to the heart of what we were trying to


       do in CHARM-Added.  Here you see all the evidence


       that we can find about the use of ACE inhibitors in


       ordinary clinical practice in the community and in



       hospitals.  You can see again that the patients in


       CHARM-Added got much higher doses of ACE inhibitor


       than were used in ordinary clinical practice.


                 I want to now turn to the interesting


       question raised by the agency, what if we were to


       go to even higher doses of ACE inhibitors than


       those proven to be of benefit in the clinical


       trials?  That is actually quite a difficult thing


       to look at because though there are many


       dose-response study for ACE inhibitors, most of


       these haven't addressed that question.  What they


       have looked at is actually very small doses or


       medium doses compared to evidence-based doses.


       They haven't looked at the question that we were


       asked, which is what happens if you go above


       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



       people here who are, and we know that in our


       practice you can get some people to bigger doses


       than have been used in the key landmark trials, but


       I think individually it is very hard to get a


       handle on how many patients, what proportion of


       your patients can get above those doses.


                 It is interesting just to note that in the


       SOLVD treatment trial only about half the patients


       got 10 mg twice a day of enalapril.  In the


       CONSENSUS study it was only about a fifth of


       patients who actually got up to 20 mg twice a day.


       The one trial in the literature that has actually


       tested this question is shown on this slide.  That


       is a study that compared an evidence-based dose of


       enalapril, 20 mg a day, to a much larger dose, 60


       mg a day.  You can see the details of this trial


       here.  You can see that about a third of patients


       could get this larger dose of enalapril.  But what


       is of interest is that there was no statistically


       significant or clinically important difference in


       blood pressure, heart rate, ejection fraction or


       NYHA class in the group who got the larger dose of



       enalapril than in the group who got the


       evidence-based dose of enalapril.  There was also


       no significant difference in any of the clinical


       outcomes measured, though this was a relatively


       small trial but just so you can see what happened.


       Here is the endpoint of death or admission to


       hospital with worsening heart failure.  You can see


       the two treatment groups and I think you will agree


       that in this small study there is no difference


       between the two treatment groups.


                 To summarize, Mr. Chairman, ladies and


       gentlemen, in CHARM-Added we believe that our


       patients did receive an evidence-based ACE


       inhibitor; 80 percent of them got a proven ACE


       inhibitor.  We believe that they did get doses


       comparable to those obtained in the forced


       titration studies, for example 17 mg of enalapril.


       The doses patients in CHARM-Added got were much


       higher than doses used in other recent add-on


       trials, and clearly higher than doses used in


       ordinary clinical practice.  And, I have shown you


       what little evidence there is about whether going



       to higher dose of ACE inhibitor has any additional




                 So, to conclude, in our protocol and at


       our investigational meetings we advocated the use


       of evidence-based ACE inhibitor treatment, and we


       believe our investigators did do that.  In other


       words, we believe that CHARM-Added did test the


       hypothesis of whether adding an ARB to an


       evidence-based dose of ACE inhibitor would provide


       further clinical benefit, and my colleague, Dr.


       Pfeffer, will speak to the evidence that that is


       the case when he presents the efficacy findings


       from the CHARM-Added study.  Thank you very much.


                 DR. NISSEN:  Any clarification?  Yes,




                 DR. HIATT:  Just a quick question, when


       you presented the dose of ACE inhibitors how


       different was the median from the mean?


                 DR. MCMURRAY:  The medians were slightly


       smaller for one or two ACE inhibitors but they were


       generally similar.


                 DR. HIATT:  So, the mean data were



       representative of the distribution of use--


                 DR. MCMURRAY:  They were.


                 DR. NISSEN:  Before we go on, we have had


       two people join us a little bit late so perhaps


       they could introduce themselves.  Dr. Temple?


                 DR. TEMPLE:  Bob Temple, regularly late,


       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




                 DR. TEMPLE:  I have a question.


                 DR. NISSEN:  Yes, sir?


                 DR. TEMPLE:  The point was made that the


       doses used in CHARM-Added were similar to doses


       used in a variety of add-on studies.  But our view


       was that that isn't really relevant unless it is



       another drug that works the renin-angiotensin


       system.  The question here is whether it is sort of


       like giving another extra dose of your ACE


       inhibitor.  So, the fact that RALES used lower


       doses really doesn't matter particularly.


                 DR. MCMURRAY:  I understand that, Dr.


       Temple.  The dose of ACE inhibitor in CHARM-Added


       was larger than in any of the other add-on trials.


       We had the same view that you do.  I mean, we tried


       to design a study to test the question and I was


       only showing that slide to try to emphasize that I


       think our investigators did try and do better,


       certainly have done better than in ordinary


       clinical practice and actually did better than


       other investigators in other clinical trials.


                 DR. TEMPLE:  Yes, I take that point but


       the immediate question is whether you are just


       adding a little more of the same.  So, it really


       only matters in the ACE inhibitor trials.


                 DR. NISSEN:  Other clarifications?


                 [No response.]


                 Fortunately, I visited Scotland so I



       understood every word without English translation.


                 DR. MCMURRAY:  Thank you very much.






                 DR. PFEFFER:  Mr. Chairman, members of the


       panel, ladies and gentlemen, I am glad to be


       representing the CHARM investigators to present the


       efficacy data, and I will be concentrating on


       CHARM-Added.  But I would first like just to remind


       you that this was a program of research, and you


       met Dr. McMurray who led the CHARM-Added, which I


       will be talking about.  Dr. Granger is here.  He


       led CHARM-Alternative.  Dr. Slim Yusuf led the


       CHARM-Preserved, and I co-chaired this with Dr.


       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



       dose titration; same committees.  But one of the


       aspects of the protocol I call your attention to is


       that by definition the protocol stated that we


       would follow the last patient randomized for a


       minimum of two years.  That means the greatest


       exposure we have is in CHARM-Added for the longest


       observation of those on the experimental




                 For each of the projects--but we can


       concentrate on CHARM-Added--it is the same; the


       primary endpoint was cardiovascular mortality or


       hospitalization, unplanned hospitalization for


       management of heart failure, all adjudicated




                 The secondary endpoints for each of the


       projects was to look at all-cause mortality or


       hospitalization for heart failure, and another


       prespecified secondary endpoint was to add nonfatal


       MI to our primary endpoint of CV mortality or


       hospitalization for heart failure.


                 The dose titration regimen for all the


       protocols was the same.  The investigator had the



       option, after assessing patient status, of starting


       either at the first step or the second step.  So,


       effectively, they could have started either with 4


       mg or 8 mg of candesartan or matching placebo in a


       blinded fashion.  Investigators were asked to


       titrate at 2-week intervals according to clinical


       standards and whether or not they wanted to


       proceed.  As you can see, 71 percent of our placebo


       patients were able to be titrated to the full dose


       and 61 percent of the candesartan, which is quite


       comparable to other trials with forced titration.


                 The analyses that I will present within


       our analysis plan--and if I leave our analysis plan


       I will specify that--were all intention-to-treat.


       It is all time to first event for the primary and


       secondary endpoints.  We will be using log rank


       test for comparisons; the Cox proportional hazard


       models to estimate the effect size.  You will be


       seeing effects over time as a Kaplan-Meier.  For


       the secondary endpoints we are using a hierarchical


       closed test procedure.


                 Inclusion criteria for the whole program



       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



       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



       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



       individually.  Here is the Kaplan-Meier for CV


       death.  We are also showing the non-CV death but


       the impact on CV death over time--I have shown you


       that data.  Here is the impact on hospitalization


       and this, of course, is skewed by the survivor


       bias.  Obviously, there were more placebo patients


       at risk to have this but despite that fewer


       candesartan patients were hospitalization for heart


       failure, at least a first hospitalization.


                 Our secondary endpoints, prespecified,


       were to look at all-cause mortality, not the


       adjudicated but all-cause and add that to the


       hospitalization for heart failure.  As you can see,


       this secondary endpoint was also achieved and the


       components of this are also shown where both


       contribute to this important secondary endpoint.


                 Another prespecified secondary endpoint


       was to add nonfatal myocardial infarctions, and we


       add an equal number.  We add 13 and 19 to the


       primary endpoint--I may have this wrong; I can't do


       it from this one.  We add very few--





                 --equal numbers, but the point is how few


       it is relative to the primary endpoint.


                 Subgroups.  We do this with caution and I


       am showing 13.  I could show many more.  The


       analysis plan had several others.  These are the


       ones we thought would be of interest to the


       clinical audience.  Thirteen are on this.  There


       were no interactions, which allows me to say that


       the benefit we have been discussing was not


       modified by these subgroups.


                 There was really at the time, when we


       first analyzed our data and presented our data in


       the year 2003, clinically a very major issue


       addressed, and that was beta-blockade.  A study


       prior to ours had given an indication from a


       subgroup analysis of the potential safety issue.


       With that knowledge, our data monitoring board


       chaired by Dr. Hennekens, and our investigators and


       the world clearly wanted to know what was the


       exposure with beta-blockers.


                 I will remind you that in CHARM-Added


       everyone is on an ACE inhibitor, 100 percent.  So,



       when we talk about beta-blocker, it is ACE


       inhibitor, beta-blocker, plus candesartan or


       placebo.  Here is the experience.  There was no


       signal of loss of efficacy so the effectiveness was


       not modified by the presence or absence of a




                 This is a safety analysis--was there a


       mortality signal of using this now triple


       therapy--the so-called triple therapy, ACE


       inhibitor, beta-blocker, candesartan--and no signal


       of a safety issue.  So, this was an important group


       looked at, at the time.


                 Spironolactone was an opportunity for us


       to query potential issues, with 17 percent of


       patients on spironolactone.  We had 436 and there


       was no interaction here.  This is a


       non-prespecified sub-subgroup that I put here with


       trepidation, just to say everyone is on an ACE


       inhibitor, beta-blocker, spironolactone, placebo or


       candesartan, and it is only 237 patients but there


       is the data in that non-prespecified sub-subgroup.


       If we do that, we must look at safety and the best



       measure of safety would be all-cause mortality and


       we are showing that here with no signal but,


       certainly, the confidence is based on 237 people in


       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



       ejection fraction and symptomatic heart failure.


       One was a head-to-head comparison and in that the


       dose of the ARB was not found to provide clinical


       benefit or to be even comparable.


                 Here is the closest study to CHARM-Added.


       This is the ValHeFT experience which has been


       presented to this group.  In the ValHeFT it was


       conventional therapy and an ARB.  For the composite


       outcome, one of their co-primaries of morbidity and


       mortality, there was a significant reduction.  In


       the CHARM study there was a significant reduction.


       So, I think the external validation of adding an


       ARB, without looking at subgroups but looking at


       the total group, gave very similar information.


       The reason we have more events here is, again,


       because of the longer exposure and longer




                 The other questions from the agency which


       we will try to address the best we can--Dr.


       McMurray told you how the study was conducted and


       we did find that investigators were using a variety


       of ACE inhibitors.  So, if I look at those ACE



       inhibitors, as Dr. McMurray showed you, there were


       12 including enalapril and four of these did not


       have an FDA approval so we couldn't find the dose


       that would be used.


                 So, now just talking about the agents


       themselves with the different use of the agents, we


       used an analysis of was there a difference in the


       outcome of those who received an ACE inhibitor that


       had FDA approval or those that did not.  That


       analysis is a non-prespecified one that I am


       showing here.  Here are the patients that had the


       FDA approval using an ACE inhibitor, and here are


       agents that were not approved.  Again, the best


       estimate is the overall.  So, as far as the agent,


       we did not see any difference.


                 The real probing question that we have


       seen through your questions is the dose issue.  To


       get at that, I have to say the first analysis that


       the investigators and the sponsor did was the


       prespecified one.  Prior to unblinding, the


       academic group made a list of the evidence-based


       therapies and the doses.  We had made that



       definition called the recommended by the


       evidence-based.  When we did that, there were 1291


       patients who at baseline were receiving that dose.


                 I will talk about that dose in a moment


       but I think one of the questions about trial design


       and trial conduct that has to be addressed right up


       front was in order to test the addition of the new


       medication, candesartan, the study medication, did


       the investigators sustain the levels that Dr.


       McMurray was so proud of, or did they just reduce


       that to start the other inhibitor of the


       renin-angiotensin system--a very important and


       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



       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





                 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



       10 percent of our patients on enalapril at that


       dose.  So, overall now we are talking about 20


       percent of the patients, 529, who met the new




                 Here are the results of this new subgroup.


       The 529 and the remainder had the same efficacy so


       this candesartan benefit on reducing risk of


       cardiovascular death or hospitalization for heart


       failure was not modified by any definition of ACE


       inhibitor dose at baseline, our prespecified one


       and the two definitions that the agency requested.


                 Because we are a program of research, we


       can give one more, and that is the zero dose of an


       ACE inhibitor.  So, we have a whole trial that you


       have evaluated and that trial is zero,


       CHARM-Alternative, 2028 patients not receiving an


       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



       subsequently defined maximum levels at baseline.


                 That allows us to conclude that we really


       have an additional opportunity to help patients who


       are already on an ACE inhibitor and, more than 55


       percent, on a beta-blocker.  That really is the


       clinical question.  When CHARM was designed that


       was the issue, can we make an improvement in the


       practice of medicine?  We didn't know the answer.


       We now share that answer with you and we think we


       do.  We reduce the patient's risk of cardiovascular


       death or hospitalization for heart failure on top


       of other therapies, irrespective of the dose of the


       ACE inhibitor, and we offer that opportunity to


       reduce cardiovascular morbidity and mortality.


                 That opportunity does come with some


       responsibilities, and Dr. Hainer will discuss the


       risk of inhibiting the renin-angiotensin system in


       doses that improve morbidity and mortality, and


       then Dr. Young will come back and describe the


       risk/benefit.  Thank you.


                 DR. NISSEN:  Thank you, Mark.  Are there


       questions right now?  Yes?



                 DR. HIATT:  Just a quick one on slide 28.


       Is that a typo, the maximal FDA-revised for


       lisinopril?  Did the dose go down from 40 mg to 20


       mg?  Is that true?


                 DR. PFEFFER:  That is not a typo.  We were


       responding to definitions provided to us.


                 DR. PICKERING:  Could you give us a


       breakdown of which beta-blockers the patients in


       CHARM-Added were taking, in particular how many


       were on carvedilol?


                 DR. PFEFFER:  Yes, I could do that and I


       would like to do that.  I said 55 percent at the


       start and obviously that number increased to the


       mid-60s by the time it was over.  If I can show the


       beta-blockers that were used at baseline, the


       predominant beta-blockers were metoprolol and


       carvedilol, 81 percent.  These doses were sustained


       over time, but the number of patients alive on a


       beta-blocker increased over time.


                 DR. SACKNER-BERNSTEIN:  In light of that


       slide, you did a nice job of showing the effect of


       coronary heart disease on top of approved ACE



       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.




                 DR. NISSEN:  We have some very solid


       advice.  So, we are kind of going to finish the


       sponsor presentations and then we are going to have


       lots and lots of time for questions.




                 DR. HAINER:  Good morning, Dr. Nissen,


       members of the advisory panel, FDA, public guests. 



       I am Jim Hainer from AstraZeneca, and I would like


       to begin by stating that the candesartan safety


       profile in the CHARM program relative to


       placebo--the findings were really quite consistent


       across all three CHARM studies.  For the purposes


       of this presentation I will, like my other


       colleagues, review now the safety of candesartan in


       chronic heart failure when added to evidence-based


       doses of ACE inhibitors, the CHARM-Added trial.


                 Let's start then with two points that are


       really important to safety monitoring.  First, the


       CHARM provided explicit monitoring directives for


       the clinicians.  Second, the CHARM protocol was


       particularly specific about monitoring for


       hypotension, renal dysfunction and hyperkalemia,


       events expected for any drug which inhibits the


       renin-angiotensin system when added to an ACE




                 These directives included monitoring of


       blood pressure, creatinine and potassium at


       multiple intervals.  These were baseline, within 2


       weeks of dose adjustment, at the end of dose



       titration, annually and, of course, at any time in


       the judgment of the responsible clinician.  These


       monitoring directives are entirely consistent with


       usual clinical practice in caring for heart failure




                 With that said, let's look then at


       hypotension, renal dysfunction and hyperkalemia.


       Hypotension was reported as an adverse event in


       23.2 percent of the patients receiving candesartan


       and evidence-based doses of ACE inhibitors and 14.5


       percent among those receiving only ACE inhibitors.


       Hypotension was reported as one reason for


       treatment discontinuation for 5.4 versus 3.5; for


       hospitalization, 4.3 versus 1.7; and for serious


       fatal adverse events 0.2 versus 0.1 percent.


                 Note here, expressed as proportions of


       patients, that discontinuations due to hypotension


       in patients 75 years and older, those taking


       spironolactone or beta-blockers, were similar to


       the overall discontinuation rates.  The rate for


       candesartan was about 3.5 times higher though among


       patients entering the trial with a baseline



       systolic blood pressure less than 100 mmHg.


                 Renal dysfunction was reported for 15.4


       percent of the patients receiving candesartan and


       ACE inhibitors; 9.4 percent among those receiving


       only ACE inhibitors.  Renal dysfunction was


       reported as one reason for discontinuation in 8.2


       versus 4.2 percent; for hospitalization, 4.5 versus


       3.0 percent; dialysis, 1.6 and 1.6; and for a


       serious fatal adverse event, 0.9 versus 1.5




                 Discontinuations due to renal dysfunction


       in patients 75 years and older and diabetics taking


       spironolactone or with systolic blood pressure less


       than 100  were similar to the overall


       discontinuation rates in the trial.


                 For patients entering the trials with a


       creatinine already greater than 2, the rates were


       high in both groups but the rate for candesartan


       was really no higher than for placebo.


                 Next, hyperkalemia was reported in 9.6


       percent of the patients receiving candesartan and


       3.6 percent receiving placebo.  Hyperkalemia was



       reported as one reason for discontinuation in 3.8


       versus 0.9 percent; for hospitalization, 1.2 versus


       0.7 percent; and for a serious fatal adverse event,


       0.2 versus 0.0 percent.


                 Despite the potential for hyperkalemia to


       increase rates of sudden death and fatal


       ventricular fibrillation, both rates were somewhat


       lower in the candesartan group, specifically 11.2


       versus 13.7 and 0.7 versus 1.3 percent


       respectively.  Discontinuations due to hyperkalemia


       in diabetics and patients taking spironolactone was


       similar to the overall discontinuation rates in the


       trial.  The rates were higher in patients 75 years


       and older and those with potassium greater than 5.


       In patients entering the trial with a serum


       creatinine of 2 or greater, the rates were high but


       similar in both groups.


                 Now, having led with this data,


       highlighting these three specific areas of


       interest, let's examine whether they translate into


       global adverse consequences.  Any adverse event was


       reported in 80.4 percent of the patients receiving



       candesartan and evidence-based doses of ACE


       inhibitors and 78 percent among those receiving ACE


       inhibitors.  Of particular interest, serious


       adverse events were reported in 75.9 percent in


       both groups, of which serious fatal events were


       29.5 and 32.5 percent in the candesartan and


       placebo groups respectively.  Treatment


       discontinuations due to adverse events were 24.3


       and 17.6 percent.  Dose reduction due to adverse


       events were 17.2 and 9.7 percent respectively.


                 Listed here are the common serious fatal


       adverse events by treatment.  Sudden death occurred


       in 11.2 percent of the patients receiving


       candesartan and 13.7 percent amongst those


       receiving placebo.  For heart failure the


       corresponding figures were 5.8 and 8.8 percent


       respectively.  Other causes of death were far less


       common.  Of note, there was no trend toward a


       consistently higher risk in the candesartan group.


                 Now, safety concerns also surround the


       concomitant use of other heart failure treatment


       drugs, as already alluded to by Dr. Pfeffer.  To



       that end, Dr. Pfeffer presented this slide which


       demonstrates the benefits of candesartan on the


       primary prespecified endpoint of cardiovascular


       mortality or heart failure hospitalization, both


       overall as well as for subgroups of patients


       receiving spironolactone or spironolactone plus a




                 One logical concern is that the reduction


       in heart failure hospitalization may not be


       reflected in all-cause hospitalizations.  But, in


       fact, these data show no significant increases in


       all-cause hospitalizations either overall or in


       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



       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



       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



       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




                 Our CHARM program in its entirety, and


       specifically the CHARM-Added study, the broad


       patient population, comprehensively characterized



       the risks associated with treatment, particularly


       the combination of an ACE inhibitor and


       candesartan.  We believe that we have clearly


       delineated net benefits for this therapeutic


       strategy in CHF patients with depressed left


       ventricular ejection fraction.


                 Particularly important, CHARM-Added


       addressed the previously unresolved question of


       whether adding an ARB to an ACE inhibitor in


       patients with low EFV heart failure provided


       incremental benefit by reducing risk of


       cardiovascular death or heart failure


       hospitalization.  Interesting and also important is


       the fact that we have demonstrated added benefit in


       patients receiving evidence-based doses of ACE


       inhibitors proven effective in previous clinical


       trials, and we also believe we have demonstrated a


       favorable benefit/risk profile.


                 This benefit/risk profile is best


       summarized in this slide.  Overall there was a


       significant 15 percent relative risk reduction for


       the primary endpoint, cardiovascular death or heart



       failure hospitalization, over the 41-month median


       follow-up.  When analyzing the data per 1000


       patient-years, this translates into an absolute


       risk reduction of 25 patients having a primary


       endpoint event over that period of time, as


       summarized in the third column on this table.


                 Importantly, no increased risk for


       all-cause mortality or all-cause hospitalization or


       the combination was noted.  These observations were


       all less in the candesartan treatment group, again


       noted in this table.  This should assuage concern


       about adverse events precipitated by this


       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



       the use of this strategy are consistent with those


       provided to the CHARM investigators and good


       clinical management of any patient with heart




                 We will emphasize attention to volume


       status, blood pressure, renal function and


       potassium levels, and recommended monitoring of


       these measures will be with initiation of


       candesartan dose titration and periodically


       thereafter the same as we manage all of our


       patients with heart failure.


                 In conclusion, we believe that the


       addition of candesartan to an ACE inhibitor


       treatment of heart failure patients, as was done in


       the CHARM-Added trial, will result in substantial


       cardiovascular morbidity and mortality benefit.


       The positive risk/benefit profile is further


       supported by numerical reductions in both all-cause


       hospitalization and all-cause mortality.  We


       believe these findings support the use of


       candesartan with or without an ACE inhibitor at


       varying doses for the routine management of heart



       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



       we reconcile those two studies?


                 DR. PFEFFER:  Well, Dr. Carabello, I can't


       be definitive but I can give you my opinion on


       that.  I, like you and every clinician, wanted to


       be adding an ARB on top of other therapies to


       reduce adverse outcomes in patients and that


       beta-blocker subgroup gave us pause.  It really did


       because what we do know is that beta-blockers have


       a profound benefit and they do on top of an ACE


       inhibitor.  So, that was the conundrum in 1999.


                 Then, with the publication of our


       experience, I think it really showed that maybe


       that was a hazard of a subgroup.  It turns out, if


       we look at the numbers in our experience, there


       were even more patients having events.  if I could


       show that, because we had more patients on a


       beta-blocker and greater exposure time when we are


       giving you our subgroup, prespecified subgroup, it


       is based on more events.  Just to give you an idea


       of the two trials, the deaths, which is really what


       we are concerned about, the total deaths were 226


       in ValHeFT and really 370.  So, I think there is



       more confidence in our subgroup based on the


       increased number of events.


                 You then asked about the agent.  I think


       there is an excellent answer to that because there


       was a very large study, called VALIANT, which used


       that agent in a large number of people on triple


       therapy, actually more patients on triple therapy


       than here, and did not show an adverse safety


       interaction with beta-blocker, ACE inhibitor and


       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.



                 DR. PICKERING:  As a follow-up to that,


       you said 31 percent of the beta-blockers were


       carvedilol and I wasn't able to see what the


       proportion was in ValHeFT and, you know, there is


       the COMET study that suggests that there may be a


       difference between different beta-blockers in heart


       failure.  I wonder could that be one possible




                 DR. PFEFFER:  I am here for the CHARM


       data.  I really don't have detailed knowledge about


       ValHeFT and I would say, based on the small numbers


       we are talking about, if we start dividing that up


       by the agents it would be even more unreliable, but


       I don't have that information.


                 DR. NISSEN:  Ralph, you had a question?


                 DR. D'AGOSTINO:  In Table 59 of the recent


       material that you sent and our response to C-25 and


       C-29, I am trying to understand--I know this is all


       post hoc and I should not be excited about looking


       at post hoc analyses, but I am trying to understand


       what happens as you go from maximum dose no to yes.


       If I look at slide 25, what seems to happen is when



       you are dealing with the no--this is the


       recommended and you are dealing with the no you


       basically have the placebo and drug pretty much the


       same.  There is only something like a 12 events


       difference.  When you move to the yes you have a 43


       events difference, and the change is all basically


       in the candesartan.  Its events drop down.  The


       placebo, whether no or yes, 165 in terms of the


       events per 1000 follow-up years and the candesartan


       goes from 151 to 131.


                 Then when you move to the next slide,


       slide 29, here the no for analysis one has in terms


       of the placebo rate 172 versus 152, when you go to


       the yes where the candesartan has 145 to 133.


       Again, when you go from the no to the yes it is the


       candesartan that is showing the reduction.  The


       same with analysis two.  In analysis two if you


       look long enough you will find an analysis that


       will produce statistical significance.  So, my


       question is it seems to be the action in the


       candesartan.  Does that say anything about the


       added benefit to the ACE?



                 DR. PFEFFER:  Well, Dr. D'Agostino, I know


       enough not to discuss statistics with you on this--


                 DR. D'AGOSTINO:  Granted, we shouldn't


       have done this.


                 DR. PFEFFER:  I think you are asking me is


       there a pattern here, and I think there is no


       pattern here and I think the interpretation--may I


       have the slide, please?  You are asking is there a


       pattern in the no's.  Obviously, by every


       definition we are making a new definition of no.


       But I think the way to handle this is in any


       definition was there a hint of an interaction, and


       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



       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



       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.



                 DR. NISSEN:  Let me tell you why I am


       asking the question.  I want to understand if there


       is an early hazard.  That is where time to first is


       very helpful.  That is, when you are titrating up


       candesartan and you are getting these admissions,


       there is a fair number of admissions for


       hypotension and for hyperkalemia, and I want to see


       whether the pattern shows an early hazard within a


       more favorable effect later on because I think it


       is very important for clinicians.  I assume


       somebody has done that analysis.


                 DR. PFEFFER:  That is a very important


       point.  We can show early efficacy.  We were


       showing that.  And time to first hospitalization


       for any cause--let's see if I can get that for you.


                 DR. NISSEN:  That would be really helpful.


                 DR. D'AGOSTINO:  The graphs they do show


       seem to have a consistent hazard.  That is a good


       question if you go to all-cause hospitalizations.


                 DR. NISSEN:  I did a little Tom Fleming


       type back of the envelope calculation and I want to


       see if I am right about that, but there are a fair



       number of those hypotension hospitalizations and I


       am guessing that they are early, that when you are


       trying to titrate up the drug you run into some


       difficulty.  So, I think to inform clinicians about


       how to do this it is very important to understand


       whether there is in fact and early hazard.


                 DR. PFEFFER:  I totally agree.  I don't


       think that is the case and I would like--somebody


       is showing me CV hospitalizations but I need all


       hospitalizations to reassure.  CHF hospitalizations


       won't reassure you and I need all hospitalizations


       to reassure you.


                 DR. PORTMAN:  To turn from cardiorenal to


       renal for a second, based on DOQI guidelines and


       Framingham studies and so forth, we know that


       microalbumenuria is an important cardiovascular


       risk, independent risk.  Do you have data on the


       prevalence of microalbumenuria?  Was there


       improvement with the ACE/ARB or just the ACE alone


       in microalbumenuria?  In fact, did you even see


       resolution in a portion of the population in





                 DR. PFEFFER:  I have to say that that is a


       sub-study which is being run out of McMaster


       University and that as of this moment I don't have


       the results on the 600 people who were in what we


       call micro-CHARM.  My friend Dr. McMurray is closer


       to that data.  Do we have that?


                 DR. MCMURRAY:  No, we don't.


                 DR. PFEFFER:  We have yet to see that


       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



       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



       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. 



       Your specific question about discontinuation due to


       renal function and outcome, I am going to ask Dr.


       Lewis, our renal consultant.


                 DR. LEWIS:  I am Dr. Lewis, a Vanderbilt


       nephrologist.  I would first like to remind the


       panel that there is a great body of data in renal


       literature that inhibition of the renin-angiotensin


       system benefits people in terms of preserving renal


       function across a wide range of kidney disease and


       across a wide range of GFR, including CKD for the


       lowest GFR groups, which has now been reported from


       several of the major clinical trials.


                 There are two settings in which inhibition


       of the renin-angiotensin system can cause renal


       dysfunction.  One is that patients have ischemic


       renal disease or fixed renal artery stenosis.  The


       second, more relevant to the CHARM study, is if a


       patient has decreased effective arterial blood


       volume.  That occurs in two settings, decreased


       cardiac output which, of course, these patients


       were at risk for, and decreased intravascular


       volume, which they were at risk for because of the



       use of diuretics.


                 In both those settings the kidney becomes


       critically dependent on efferent arterial


       resistance to maintain GFR.  It is a hemodynamic


       effect.  One would predict when a patient has


       decreased effective arterial blood volume and


       develops renal dysfunction that the stopping of the


       agent, the inhibition of the renin-angiotensin


       system, would repair that renal hemodynamic and the


       patient should recover.  It should be a reversible




                 Evidence to support that--first I will


       remind you that Dr. Hainer showed you that the


       number of patients requiring dialysis was


       equivalent in the two groups, on his safety slide.


       Also, if I could have slide 48, looking at the


       ultimate outcomes for people who had renal




                 So, these are the patients who had any


       kind of renal dysfunction event during the course


       of the trial and what happened to them.  I have


       already told you that they had an equivalent amount



       of dialysis.  As you can see, 38 percent of the


       placebo group was alive at the end of the trial and


       55 percent of the candesartan group was alive at


       the end of the trial.  So, I think the signals we


       have from the CHARM-Added is what you would expect


       from the physiology, that this was a reversible




                 DR. SACKNER-BERNSTEIN:  Just to clarify,


       what was the definition of renal dysfunction in


       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.



                 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



       mg/dL during initiation of therapy.  Should


       clinicians be looking for that physiologic effect


       on efferent arterial as something that is a good


       sign or is it potentially a bad sign?


                 DR. LEWIS:  I think this is a great issue.


       I am actually giving cardiology grand rounds at


       Vanderbilt next week so I am going to address this




                 DR. SACKNER-BERNSTEIN:  What day?  What




                 DR. LEWIS:  I think this is so good


       because I think we really are learning more because


       I think what your paradox is--first let me say that


       in renal trials, as well as in cardiology


       literature, you are exactly right.  The patients


       who most benefit from inhibition of the


       renin-angiotensin system in the first three


       months--in terms of, you know, don't go into


       end-stage renal disease or hard outcome--in the


       first three months of exposure to the inhibition of


       the renin-angiotensin system do two things.  They


       drop their proteinuria and they drop their GFR by a



       hemodynamic mechanism because we have shown


       reversibility.  It is 3-5 mL.  It is not clinically


       significant but it is a signal, like you said, in


       heart failure patients that they are responding to


       the inhibition of the renin-angiotensin system.


                 I think the reason why you have the


       paradox is that the patient in the hospital who,


       despite you doing all you can do for them in a


       hospital setting has a very poor cardiac output, is


       the patient who has decreased effective arterial


       blood volume and you can't make it any better


       because they have reached a point where, short of a


       heart transplant, you can't make their cardiac


       output any better.  When you give that patient an


       ACE inhibitor or an ARB you can't get their heart


       to be better.  Nothing is going to get that heart


       to be better.  In that setting the kidney is giving


       you the message that the patient has reached an


       end-stage heart situation.


                 DR. MCMURRAY:  Jonathan, I can actually


       answer your question directly because we are all


       interested in this in heart failure at the moment. 



       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



       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



       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



       anything, we don't have enough African Americans to


       talk about but the point estimate goes the right


       way.  The other issue in the model, if you now


       force the U.S. into the model it does not come out


       as a predictor.


                 DR. TEMPLE:  We are sort of watching this.


       It keeps showing up or at least you notice it when


       it does show up, which is probably more to the


       point.  Sometimes there are oddities to it.  In


       both RENAL and IDNT the action was all in the Asian


       population, Asian including Israel and a variety of


       places you don't usually think of as Asian.  But


       when we actually looked at the end-stage renal


       disease endpoints it didn't look that way anymore.


       So, the long-term follow-up no longer was as


       conspicuous in the U.S. population.  So, I don't


       know what you make of something like that but these


       things are jarring when they show up.


                 DR. NISSEN:  Let me tell you why these


       things catch my attention and bother me.


       Obviously, the FDA is charged with regulating drugs


       in the United States and we are presented with a



       certain number of trials where the U.S.


       contribution was a minority of the population and


       where sometimes the point estimates like this are


       quite variable.  One of the things I always worry


       about is, you know, are these patients somehow


       different?  Is the underlying care, particularly if


       there are a lot of Eastern European and other


       countries involved different?  I am just trying to


       get an understanding of this because I know this


       must come up for you a lot.  It always gives us


       pause for thought considering the fact that this is


       a drug that we are considering for use in the


       United States.  So, any advice, Bob?


                 DR. TEMPLE:  No, it is just hard to know


       what to make of it.  My bias is that if people are


       treated badly they probably benefit more from a


       drug that they are actually getting.  So, maybe the


       U.S. is too well--you know, you could say, well, in


       the U.S. they really all got their ACE inhibitor


       and in the other places they all lied.


                 DR. PFEFFER:  That is a very U.S.-centric





                 DR. TEMPLE:  I am not alleging that it is


       true.  I am just saying what is the worst thing you


       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




                 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



       we all know most of all, if you look at the placebo


       groups, if you compare U.S. to non-U.S. the event


       rates are almost identical.  One is 41.7 percent,


       the other is about 42 percent.  So, the event rates


       in the conventional type of heart failure that we


       are all familiar with are virtually identical.


                 DR. NISSEN:  What are they in the




                 DR. MCMURRAY:  Someone is going to have to


       do the mathematics very rapidly for me.  I put the


       two low ejection together simply because it was


       large numbers but, again, you can see they are


       almost exactly the same.


                 DR. D'AGOSTINO:  Yes, they are almost


       identical.  It is a smaller group.  The confidence


       bands are large; lots of multiple comparisons.


                 DR. NISSEN:  And I do recognize that.  You


       know, this is not by any means definitive.  It is


       an observation that pops out and you want to try


       and understand it.  I mean, if we saw an event rate


       in the non-U.S. that was radically different from


       the U.S. that would be a signal to me that this is



       meaningful, and we don't see that here.


                 DR. MCMURRAY:  I was going to comment that


       on so many trials showing this with drugs and drugs


       being different--I mean, carvedilol was brought up


       earlier and that is an interesting example.  In the


       large trials done outside the U.S. the effect size


       of carvedilol was smaller than in the U.S.


       carvedilol trials.


                 DR. TEMPLE:  Well, you tend to notice it


       when the U.S. doesn't do well--




                 --so there is probably some selection.  We


       have actually done an internal analysis and there


       is some suggestion of it but it is mostly driven, I


       think and I don't know if Norm agrees, by the two


       studies that formed the hypothesis, RENAL and IDNT.


       Those didn't look so conspicuous.  You know, you


       are not supposed to use the ones that form the


       hypothesis, but it is certainly an interesting




                 I have one other question.  If you look at


       hyperkalemia can you show any relationship to what



       dose of diuretic people were on?  Should the dose


       of diuretic be higher in people who are getting


       both of these drugs?


                 DR. PFEFFER:  I was bragging about our


       case report forms.  We had doses of the ACE


       inhibitor, doses of the beta-blocker.  We did not


       have doses of diuretics which changes during time,


       so I could not tell you that.


                 DR. TEERLINK:  Mark, was there entry


       criteria for blood pressure in this trial?


                 DR. PFEFFER:  I mentioned that Dr. Yusuf


       was part of the executive committee so let's make


       this broad; let's make this inclusive; let's not


       have a blood pressure level as long as people are


       talking to you and are not symptomatically


       hypotensive.  So, we did not have a cut-off for a


       low blood pressure.


                 DR. TEERLINK: The reason I ask is because,


       obviously, given that we are only considering


       additive therapy here and clinicians only have so


       many millimeters of mercury to spend, and in slide


       CS-4 there is a conspicuous increase, as one would



       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.



                 So, everything I have been showing you is


       intent-to-treat but I will show you, John, in


       direct answer to your question that for


       hypotension, if you came into this trial with a


       blood pressure less than 100 systolic, and only 54


       of the placebo patients did and they not


       infrequently had to be discontinued, but then


       trying to add the active therapy, we discontinued


       their medication.  Now, that is not a demerit.


       Investigators tried.  This is a blinded study


       medication.  They discontinued and everything I


       have shown you has been intent-to-treat.


                 DR. NISSEN:  Another way to look at it is


       that in spite of allowing these patients in the


       trial it didn't undermine the results.  So, I


       presume those people didn't end up on much




                 DR. PFEFFER:  They didn't.  That is why I


       was bringing back the intent-to-treat not the per




                 DR. HIATT:  I have a slightly different


       question.  I tried to resolve the results of this



       development program with the other ones,


       particularly the valsartan.  I think a number of


       questions can be raised in that regard but I am


       struck by the interaction in ValHeFT between ACE


       inhibitors, beta-blockers and the addition of an


       ARB showing a worse outcome in contrast to your


       data.  Could you speak to that?


                 Then I have a follow-up question related


       to that, and that has more to do with the


       pharmacokinetics of these different agents.


       Valsartan has a very long half-life; candesartan


       has less.  I am worried about the receptor


       interactions and how they might differ because are


       all these ARBs created equal is sort of where I am


       going with this.


                 DR. PFEFFER:  These are key clinical


       questions and you can imagine the question in the


       year 2003 when we came up with these results.  I


       have no more insight than the distinguished panel


       but I will give you my personal views.  The


       question was of the agent, and I would have to say,


       no based on the VALIANT experience where a good



       number of patients were on so-called triple therapy


       and harm was not seen.


                 We are showing no harm and benefit.  I


       think that is the message.  If you look at overall


       the entire ValHeFT experience there is consistency.


       It is just when you get to that particular


       subgroup.  And that is where I gave you the


       numbers.  You have to look at the robustness of one


       subgroup and another.  We happen to have more


       events because we had a higher use of beta-blocker


       and longer follow-up.  But beyond that I would be




                 DR. HIATT:  Can anyone from the company


       sponsor distinguish some of the PK potential


       differences--dwell time on the receptor, those


       kinds of things, between these different agents?


                 DR. PFEFFER:  I am sure somebody from the


       company can tell you about the PK differences.


                 DR. NISSEN:  What do you say we do that


       after the break so you, guys, can kind of gather


       your thoughts together?  I am actually give you


       some thoughts; I was on that ValHeFT panel and also



       on a panel that reviewed candesartan compared to


       losartan, and I will give you some thoughts about


       that that might help you understand this.  Let's


       break for about 15 minutes.  We are doing very


       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



       so it was an exploratory analysis.  You know, I


       opine that you really couldn't--shouldn't make any


       regulatory decisions on that basis; that it was


       hypothesis generating at best and that, again, if


       you look at enough trials and enough people and


       enough subgroups you are going to see something


       like that happen once in a while.


                 I must say, it was very intense.  The


       final vote was 4-4, which meant that we actually


       had an even number so we didn't actually make a


       decision on the primary indication for valsartan.


       Even though the nominal p value looked very good


       and the data looked very good for the overall


       study, at the time I felt like people were being


       unduly influenced by the observational data on the


       subgroup.  I think now, in retrospect, that


       probably was spurious.  That is my own personal


       interpretation that it was just simply an unusual




                 DR. HIATT:  Where I was sort of going with


       this, is there really a difference in dosing


       between ARBs, or are there different pharmacologic



       differences that we should be recognizing between




                 DR. NISSEN:  There is some subtlety here.


       Again, there are obviously things that are class


       effects and there are things that are not class


       effects.  We looked at two trials comparing


       losartan and candesartan, and this committee voted


       I think unanimously that there was evidence that


       the blood pressure lowering effect was greater with


       candesartan than with losartan, both given in their


       full therapeutic doses.


                 DR. TEMPLE:  Well, the labeled full


       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



       blood pressure, bigger than the full doses of


       another ARB.  So, it is like any other therapeutic


       class, there are sometimes agents that are somewhat


       more potent than others, that perhaps have more


       affinity for the receptor.  So, if you want to test


       the hypothesis that blocking at the AT-I receptor


       produces an added benefit you want to probably do


       it where you are really blocking the receptor as


       well as you can block it, and I think that is one


       of the things that CHARM did.  They got to a really


       very robust dose of a very potent angiotensin


       receptor blocker so it really does test the




                 DR. TEMPLE:  Of course, our concern has


       been you can only test it if you really are on


       whatever the full dose is, but a full dose of the


       ACE inhibitor.  That is what has been addressed


       here.  In the case of ValHeFT, that was sort of a


       very Bayesian episode.  We actually approved the


       use on what was not a primary analysis at all.  I


       mean, that was just an accidental 7 percent of the


       people that weren't on any other drug.  That is



       what we approved, even though that was only


       300-some odd patients in a 5000 patient trial


       because the result was so conspicuously large.  The


       beta-blocker thing, we were skeptical about it too


       but it was the mortality outcome and we just didn't


       feel we could say anything about it.


                 DR. SACKNER-BERNSTEIN:  Also, in terms of


       the mortality in ValHeFT, I wasn't part of the


       committee but the randomization in that trial was


       stratified based on background beta-blocker therapy


       which does add some robustness to that analysis,


       just to clarify that.


                 DR. HIATT:  Before I leave this question,


       is there anyone from the sponsor who can talk about


       the differences in the pharmacokinetics and


       dynamics of these different ARBs?  I mean, I was


       struck that valsartan has a longer half-life.  It


       is certainly a less potent drug but then it is just


       a matter of milligrams.  If you can get them to the


       same equivalent dose you should overcome that but,


       if anything, candesartan maybe should be dosed more


       frequently. So, I am just questioning whether there



       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



       looking at it from a PK or a drug exclusionary


       phenomenon, but if it is still tightly bound to the


       receptor you won't have candesartan coming off the


       receptor and causing it to go back up.


                 DR. HIATT:  And that was my understanding.


       That is where I was going with this.  I wanted to


       say that because I think valsartan does not have


       that same kind of receptor affinity.  Am I correct?


                 DR. YOUNG:  It does not; you are correct.


                 DR. HIATT:  So, if it really is bound


       across the 24-hour dosing cycle and has a very high


       affinity there could be a pharmacologic basis for a


       slightly different clinical result.


                 DR. YOUNG:  And I stress the word "could




                 DR. NISSEN:  Yes, Tom?


                 DR. PICKERING:  I would like to discuss


       further the issue of hyperkalemia and


       spironolactone use.  I think the issue here is


       really one of labeling and whether it should


       specifically say anything about whether patients


       should be also taking spironolactone or not.  If



       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



       editorial that accompanied that New England Journal


       article.  So, let me ask Dr. McMurray to talk about




                 DR. MCMURRAY:  We share your concern.  In


       fact, I think the only reason I wrote that


       editorial was that we had already published our own


       experience with the misuse of spironolactone which


       became widespread after the publication of the


       RALES trial and I think that was a lesson from the


       Ontario experience and, indeed, from 13 other case


       series that have been published reporting the same


       thing in smaller numbers of individuals.  The


       striking thing about that was that essentially it


       boiled down to two problems, the use of the wrong


       dose of spironolactone, much higher than the small


       dose used in RALES which was 25 mg a day, and also


       misuse in the wrong patients.  So, RALES was a


       study targeted at a carefully defined group of


       patients and the Ontario experience with


       spironolactone was used in a completely different


       patient population, much older; many patients with


       preserved rather than low ejection fraction; more



       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



       producing one.




                 For fairly obvious reasons, it was




                 DR. PICKERING:  But if this gets approved


       there is going to be labeling that could or could


       not say something about concomitant spironolactone




                 DR. TEMPLE:  Indeed, it could.  Actually,


       my question from before goes.  I mean, everybody


       has moved down to low doses of diuretics because


       they are worried about hypokalemia.  Maybe they


       should make a comeback in the face of all this


       potassium retention.  Higher doses do work slightly


       better than 12.5.  That seems worth exploring too.


                 DR. NISSEN:  Actually, it does reflect a


       real problem for clinicians in managing heart


       failure.  The computer term for it is combinatorial


       explosion, which is you have four or five therapies


       and how do you combine, what kind of combinations


       and permutations of them can be used in individual


       patients.  It is not so easy.  I often don't know



       what to do so I am looking for guidance from FDA.


                 DR. TEMPLE:  So, you don't think anybody


       can just make a single pill that will just do it?


                 DR. NISSEN:  Yes, I don't think so.  I


       wanted to explore something else with you, guys.


       Obviously, one of the reasons we are here is


       because the agency reviewer and the agency has some


       concerns about has the hypothesis been proven that


       on top of maximal doses of ACE inhibitors


       candesartan produces an incremental benefit.  This


       all could have been resolved if you just picked


       enalapril, you know, pushed it to the heart failure


       doses and then everybody would have gotten the same


       ACE inhibitor and we would know exactly what they




                 I know what your answer is going to be.


       Your answer is going to be you wanted to make this


       a real-life trial with the real-life drugs that


       people use, but it does, in fact, undermine a


       little bit our ability to interpret the experiment.


       Did you, guys, consider actually just specifying


       the ACE inhibitor, pushing it up in the way they



       did in the ACE inhibitor trials and then, once you


       got to the maximum tolerated dose, randomize?


                 DR. PFEFFER:  Well, I gave you the names


       of the people involved in the planning so you can


       imagine we did consider it.  The other issue would


       be I could imagine if we came back here with the


       same findings on the most commonly used medication,


       which was enalapril, somebody--I am not saying






                 --would say what about the other ACE


       inhibitors, the other approved ACE inhibitors?


       Then we realized that to dictate the use of an ACE


       inhibitor, with the VA system telling us what ACE


       inhibitor you have to use, my healthcare system


       telling us what ACE inhibitor you have to use, we


       really did make the decision to optimize the


       individual dose and see if adding on improves




                 DR. NISSEN:  Although you did allow use of


       ACE inhibitors that were not approved for heart


       failure.  Was the assumption that everybody would



       feel okay about that, that even though the drug


       wasn't actually approved--


                 DR. PFEFFER:  Well, this was FDA approved.


       We are talking about 26 countries.  I was reminded


       in this international trial that the U.S. is one






                 DR. NISSEN:  Yes, we are getting reminded


       of that all the time now.  Other questions?  Yes,




                 DR. SACKNER-BERNSTEIN:  Just to get back


       to the U.S.-non-U.S. finding, there are a couple of


       different ways that I was trying to look at this to


       see if I could understand it.  Obviously, it could


       just be a statistical fluke, which my own bias says


       is the most likely.  But one issue that has come up


       before is the possibility of drug interactions.


       So, I am assuming that you looked and found that


       U.S. and non-U.S. subjects were treated similarly.


       A second one has to do with whether the statistical


       power was sufficient within the U.S. population,


       and I think we addressed that by the question



       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



       was nothing there.


                 But if you want to explore something where


       I don't believe it, I can tell you there are a lot


       of differences between U.S. patients and non-U.S.


       patients at baseline.  You heard that their


       outcomes are pretty much the same, and you heard


       that in the trial of 7599 in the program the effect


       of candesartan was pretty much the same.


                 But just to explore, in CHARM-Added, yes,


       there were some differences, fairly minor, in the


       medication use but here is medication use.  Now, I


       mentioned that being at the recommended dose, and I


       think Ralph pointed out that the arrow went in a


       good way so you can see the inconsistency, there


       are more people at the recommended dose.  So, there


       are a lot of inconsistencies here.


                 Let me show some more differences between


       U.S. and non-U.S.  We do more procedures.  That is


       no revelation.  Coronary procedures, we are very


       good at that.  That did not influence anyone's


       outcome.  We do more angioplasty.  We have ICDs and


       pacemakers.  So, procedures we do more of.  I am



       off the cuff going to ask Dr. McMurray, did we do


       any quality of life?  Did U.S. patients feel better


       with all this hardware?


                 DR. MCMURRAY:  Only in the U.S.


                 DR. PFEFFER:  Quality of life was only


       done in the U.S.  Now, for AEs we can give you this


       by North America.  Is that okay?  So, we can go


       across the border and I think it is important to


       look at placebo.  Placebo in the U.S. were more


       likely to tick a box, and we really asked these


       questions--renal function, 6.3 versus 2.9.  I am


       not going to make anything of it but numerically


       more.  Obviously, the agent increased that in both


       North America and the rest of the world.  Here is


       the hyperkalemia, increased in North America;


       increased by the same factorial in the rest of the




                 So, Jonathan, I don't see that there is a


       clue here that they are under-treated,


       over-treated; that the SAEs are helping us with


       this.  I go back to your first statement of fluke


       but I don't even say fluke because I don't make the





                 DR. NISSEN:  It is intriguing though,


       Mark.  I mean, some of the therapies like


       defibrillators do have an impact and, you know, the


       fact that there were more defibrillators used in


       the U.S..  You know, one of the mechanisms of


       death--you know probably better than I--in these


       patients is sudden death.  So, it is possible that


       there is a competition for benefit between


       defibrillators and more effective heart failure


       treatment.  If, in fact, there is more


       defibrillator use in the United States there may be


       less opportunity for benefit from candesartan.  So,


       some of these hypotheses, and they are just


       hypotheses--I basically agree with you but when you


       see an observation, it is our responsibility


       obviously to explore that and make sure we


       understand it, that there is some strong signal


       here and I think there is not a signal; I think


       there is an observation.  I think you can see how


       the defibrillator use could certainly drive some of





                 DR. PFEFFER:  And defibrillator use is


       something that in the year 2005 we are much smarter


       than in 1999.  I don't know what the balance would


       be around the world now but these are heart failure


       patients and I have some of my heart failure


       colleagues telling me to turn these things off


       sometimes too.  So, I don't have the answer for




                 DR. TEMPLE:  Of the U.S. differences you


       showed, one of them is sort of tempting.  More U.S.


       patients were on the full dose so maybe that would


       explain why the addition didn't work as well, but


       your overall data shows that people who were on a


       full dose on the whole did better.


                 DR. PFEFFER:  I mentioned that as an


       example of a confounder.  The point estimate for


       being on full dose moved in the right direction.


       More U.S. were on the full dose so it is a perfect




                 DR. TEMPLE:  Right.


                 DR. PFEFFER:  A fluke, and I just think it


       is a great example.  Dr. Granger has something to





                 DR. GRANGER:  We did look at this.  One of


       the obvious things is procedure use and prior


       re-vascularization.  When we looked at prior ICD or


       prior re-vascularization the point estimates were


       almost identical for the treatment effect of


       candesartan.  So, it doesn't appear to be that.


                 DR. NISSEN:  I would have guessed that


       having angioplasty would increase the event rate


       because we all know that angioplasty is bad for






                 --but I guess you didn't see that.


                 DR. PFEFFER:  We don't know how long ago


       the angioplasty was or where it was done.


                 DR. NISSEN:  Did you enroll any patients


       at the Cleveland Clinic?


                 DR. PFEFFER:  Cleveland Clinic was a


       vigorous proponent of conducting the CHARM trial


       and Jim was the U.S. lead investigator.  He


       probably asked you about some of your patients.


                 DR. PICKERING:  Could I raise the issue of



       African Americans?  I think you had 2.8 percent and


       the issue is if this gets approved what are we


       going to say about its use in black patients?


       Because there is evidence that blocking the


       renin-angiotensin system may not be so effective in


       African Americans.  At two meetings ago we reviewed


       a drug which was basically killed because of


       adverse effects, angioedema, which is commoner in


       African Americans, and there seems to be a total


       void here.  Should clinicians be using it in


       African Americans or not?  Or, what are we going to




                 DR. PFEFFER:  I think we have as much


       confidence in our data as any that have been


       presented here, and let me walk through that.


                 This is self-designated as


       black--self-designated.  In CHARM-Added, of the


       70-something patients there is the point estimate.


       I am not saying that it is this way or that way.


       That was Alternative.  That was not on an ACE


       inhibitor.  In CHARM-Added, in the few patients we


       had you can see the point estimate here.  But if



       you go through our whole program I think there is a


       consistent message here that designating yourself


       as black and then being enrolled in our study there


       is no loss of efficacy, and my interpretation would


       be we are offering an opportunity to reduce


       someone's risk regardless of this designation, and


       that is the best estimate even the point goes this


       way.  When we do the total, we are talking about


       over 300 patients.


                 DR. NISSEN:  While other people are


       thinking, Mark, let me tell you what triggered my


       request for the time to all-cause hospitalization.


       I did some sort of simple numerics and I see there


       were 56 fewer deaths or CHF hospitalizations in the


       primary endpoint.  So, you avoid 56 deaths in the


       primary analysis.  Then I looked at the hypotension


       and there are 33 more people hospitalized for


       hypotension.  So, at least in your mind, until you


       see an analysis you have to say, well, you kept 56


       out of the hospital and from dying but you had 33


       that had excess hospitalizations and you have 20


       excess hospitalizations for renal dysfunction and



       then you have another 10 in the hyperkalemia.


                 So, when you add all the numbers up, you


       know, you sort of see an analysis that says, well,


       you are keeping people out of the hospital for


       heart failure but you are admitting a lot more to


       the hospital for AEs, so isn't the hospitalization


       data kind of a wash?  I know it is not the correct


       analysis because once you have that first heart


       failure or hospitalization you may have more.  That


       is why I am so keen on seeing that.


                 DR. PFEFFER:  I think it is a key number


       to get you but we do have it without Kaplan-Meiers


       and Dr. McMurray would like to tell you about total




                 DR. MCMURRAY:  I am afraid I don't have a


       slide of this but I do have the numbers so you


       might want to write them down.  I was intrigued for


       my own interest to figure out how it balances up.


       On the benefit column what we actually have, and I


       will give it to you per 1000 patients treated over


       the duration of the study--on the benefit column


       there were 46 fewer patients hospitalized for heart



       failure.  There were 100 on ACE fewer heart failure


       hospitalizations and 35 fewer cardiovascular




                 On the risk side there were 26 more


       patients hospitalized with hypotension, but when I


       say with hypotension that means hypotension was


       just on the list of possible causes for that


       hospitalization.  For example, amongst those there


       were people with septicemia, people with GI


       bleeding, and this is true for all the AEs.  There


       were 16 extra hospital admissions for renal


       dysfunction and there were 8 extra hospital


       admissions with hyperkalemia.  Again, some of those


       groups overlap but we weren't able to quite tease


       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



       with worsening heart failure.  There were


       significantly fewer days in hospital for any reason


       whatsoever in the candesartan group.  So, yes, of


       course, there is a trade-off but it is


       substantially less on the benefit side in terms of


       morbidity and resource utilization.


                 DR. TEMPLE:  I just added up your numbers


       leaving deaths out of it for the moment, not that


       you necessarily want to.  There was a 46-patient


       benefit for heart failure hospitalizations.


                 DR. MCMURRAY:  Forty-six patients, yes.


                 DR. TEMPLE:  And 49 extra hospitalizations


       for hypotension, renal dysfunction and




                 DR. MCMURRAY:  Okay, the difference there


       is--well, there were several differences.  First of


       all, you have picked patients as opposed to


       admissions and, secondly, on the risk side when I


       said hypotension, when I said renal dysfunction,


       when I said hyperkalemia I really do mean that if


       those terms appeared anywhere on the long list of


       reasons for admission we counted that just in case



       it could be a risk.  Also, there was overlap.  The


       best estimate I can give you of overlap, and I


       really don't know the proper numbers but the best


       estimate of overlap is two-thirds of those patients


       were counted more than once.


                 DR. TEMPLE:  Okay, but those were extra


       hospitalizations in the treated group.


                 DR. MCMURRAY:  Extra hospitalizations,


       yes.  So, the contrabalancing number for that is




                 DR. NISSEN:  Bob, I understand what he is


       saying and I want to just see if I can rephrase it.


       You know, if you take the number of patients that


       had a hospitalization for either heart failure or a


       drug AE, it is fairly balanced.  But once you got


       admitted once for heart failure you are very much


       likely to be admitted again and again.  So, what


       they showed us was the Kaplan-Meier for cumulative


       incidence of all-cause hospitalization.  And I


       understand that.  And it is very important and I am


       not minimizing it at all.  But, you know, it did


       strike me that there was a cost for that, and the



       cost is that a fair number more patients--when you


       talk about AEs I look at hospitalized AEs rather


       than I do incidental AEs that are sort of


       discovered on a laboratory test.  If you have


       hyperkalemia sufficient to land yourself in the


       hospital, that is a pretty serious AE, and if you


       have hypotension that gets you in the hospital,


       that is a pretty serious AE.  So, that is why I am


       so keen on seeing that time to first event because


       that is an important objective.  Now, I know that


       over time the hospitalizations are clearly less in


       the candesartan arm.  But I am going to guess




                 DR. TEMPLE:  Yes, and the implications are


       different.  One is transient, you fix it and it is




                 DR. NISSEN:  Yes.


                 DR. TEMPLE:  But being hospitalized for


       heart failure means you are on the way to troubles.


                 DR. NISSEN:  You are on a downward spiral.


       Don't misunderstand me, I am not placing equal


       weight on them.



                 DR. MCMURRAY:  I was trying to give you


       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



       reason, 69 of the candesartan patients and 80 of


       the placebo.  At 6 months it is 297 and 304.  Then,


       as a function of time we get better, as you see.


       That doesn't mean we didn't hurt somebody early but


       in the overall, all-cause hospitalization for any


       reason numerically people were on the candesartan.


       Then you did see the curve of the cumulative




                 DR. NISSEN:  It actually does sort of


       support the hypothesis that you are really picking


       up the benefits once you get outside of that early


       sort of titration.  Once you have proven you can


       tolerate the agent, then you are starting to


       accumulate lots and lots of benefit.


                 DR. PFEFFER:  Well, I really have trouble


       with when was the benefit.  I know you spent some


       time on that last week--when is the benefit.  I


       don't know what statistical tool one uses to do


       that besides your eyeball.  So, why don't we look


       at our two low EFs combined?  You know, we did a


       lot of statin work, as you have, and for the most


       part, except for a few studies, you need a little



       time to see the benefit unless you are very, very


       aggressive with your statin use.  Treating heart


       failure, symptomatic heart failure, you tend to


       start to see things early.


                 So, Dr. Nissen, I don't know what to make


       of this, of when, but I do think we are starting to


       see the benefits that you would ask for in a


       medication for the treatment of people with


       symptomatic heart failure and, yes, there are other


       things that we must be vigilant to look for.  It


       happens in placebo too so I think we need to raise


       our standards of how to monitor patients whether


       they are on the triple therapy or not.


                 DR. SACKNER-BERNSTEIN:  In terms of the


       endpoint of heart failure hospitalization that was


       part of the primary endpoint, I am wondering if you


       might comment on how you can be confident that you


       captured all the heart failure hospitalization that


       occurred appropriately.  Literature, including the


       RESOLVe trial has shown that about as many as 11


       percent of heart failure hospitalizations are


       associated with pulmonary processes.  So, I am



       curious about how you made sure that the endpoint


       committee saw all the hospitalizations that an


       investigator may have thought were just bronchitis


       or pneumonia and may have actually been given IV


       diuretics.  Another issue is that of worsening


       renal function which certainly can be a sign of