# Presentation: 867033

## ATACAND® (candesartan cilexetil)

**Cardiovascular and Renal **
**Drugs Advisory Committee**
**Rockville, Maryland**
**February 24, 2005**

**C**

## ATACAND® (candesartan cilexetil)Introduction

**Cindy M. Lancaster, MS, MBA, JD**
**Director, Regulatory Affairs**
**AstraZeneca LP**

**C**

## Sponsor Representatives

**Cindy M. Lancaster, MS, MBA, JD*****Director, Regulatory Affairs***
**James Hainer, MD, MPH*****Senior Director, Clinical Research***
**Eric Michelson, MD*****Senior Director, Clinical Research***
**Howard Hutchinson, MD*****Vice President, Clinical Research***
**Richard Caplan, PhD*****Senior Statistical Scientist***
**Bertil Olofsson, PhD*****Senior Statistical Scientist***

## External Advisors

| Marc A. Pfeffer, MD, PhD | Brigham and Women’s HospitalInterim Chairman of Medicine Co-Chair CHARM Executive Committee |
| --- | --- |
| James B. Young, MD | Cleveland Clinic FoundationChairman of MedicineCHARM US National Leader |
| John J.V. McMurray, MD | Professor of Medical CardiologyUniversity of Glasgow Member, CHARM Executive CommitteePrincipal Investigator, CHARM Added Trial |
| Christopher B. Granger, MD

 | Director, Cardiac Care UnitDuke University Medical CenterMember, CHARM Executive CommitteePrincipal Investigator, CHARM Alternative Trial |
| Mark E. Dunlap, MD         | Director, Cardiology ResearchDepartment of MedicineLouis Stokes VA Medical Center,Case Western Reserve UniversityCHARM US National Leader  |

## External Advisors

| Julia Lewis, MD | Professor in the Division of NephrologyDepartment of MedicineVanderbilt University |
| --- | --- |
| Joseph McLaughlin, PhD | International Epidemiology InstitutePresidentEpidemiology Consultant |
| Richard Kronmal, PhD | Professor of BiostatisticsUniversity of Washington |
| Charles Hennekens, MD | University of Miami School of MedicineChair, CHARM Data and Safety Monitoring Board |

## ATACAND® (candesartan cilexetil)Heart Failure Regulatory History

**1998**

**1999**

**2000**

**2001**

**2004**

**2002**

**2003**

**1996**

**1997**

**2005**

## Patients With Symptomatic CHFCHARM Program

**CHARM****Added**

**n = 2548**
**LVEF ****≤** **40%****ACE inhibitor ****treated**

**CHARM**** Alternative**

**n = 2028**
**LVEF ****≤**** 40%****ACE inhibitor ****intolerant**

**CHARM****Preserved**

**Patients With Symptomatic CHF****CHARM Program**

**n = 3023**
**LVEF > 40%****ACE inhibitor ****treated/not treated**

**3 component trials comparing candesartan to placebo**

- Pooled CSR S 5.1 P 58, S 5.4.5 P 69-70, S 8.2 P 160

**Primary endpoint for each trial: CV death or CHF hospitalization**

## Primary Endpoint CV Death or CHF HospitalizationCHARM Program

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**1.1**

**1.2**

| CHARM | Patients, n/N |  |
| --- | --- | --- |
| Alternative | 406/1015 | 334/1013 |
| Added | 538/1272 | 483/1276 |
| Preserved | 366/1509 | 333/1514 |
|  |  |  |

**Hazard ratio (95% CI)**

**Candesartan****better**

**Placebo****better**

## Approval for Add-on Therapy or for Use Without an ACE Inhibitor

**Austria**
**Belgium**
**Denmark**
**Finland**
**Germany**
**Greece**
**Ireland**
**Italy**
**Latvia **

**Luxemburg **
**Mexico **
**The Netherlands**
**New Zealand**
**Portugal**
**Slovakia **
**Spain**
**Sweden**
**UK**

## Approved Labeling for Heart FailureIndications and Usage Section

**ATACAND****®**** is indicated for the treatment of heart failure (NYHA class II-IV and ejection fraction****≤ 40%) to reduce the risk of death from cardiovascular causes and reduce hospitalizations for heart failure **

**C**

## Approved Labeling for Heart FailureClinical Trials Section

**The use of candesartan was supported by a second study (CHARM Added) of 2548 subjects with NYHA Class II-IV heart failure and ejection fraction ≤ 40% in which subjects were mostly on submaximal doses of ACE inhibitors.  Together, in these studies, subjects on Atacand****®**** had a 15% lower risk of cardiovascular mortality (*****p***** = 0.005). In these studies, symptoms of heart failure as assessed by NYHA functional class were also improved (*****p***** < 0.001).**

**C**

## Current Regulatory Question

**CHARM Added **
**Designed to allow investigators to optimize ACE inhibitor dose**
**Demonstrated statistically significant and clinically important benefits when candesartan was added to evidence-based doses of ACE inhibitors**
**FDA’s central question**
**Does “CHARM Added provide compelling evidence that candesartan should, under some circumstances, be recommended for use in patients on an ACE inhibitor?”**

## Presentation Overview

| Background |  |
| --- | --- |
| James B. Young, MD
Cleveland Clinic Foundation | Rationale for use of an ARB in heart failure
ARBs and ACE inhibitors have distinct and complementary mechanisms
Candesartan has potentially beneficial effects when added to an ACE inhibitor |
| John J.V. McMurray, MD
University of Glasgow | Evidence-based dose of ACE inhibitor |
| Efficacy |  |
| Marc A. Pfeffer, MD, PhDBrigham and Women’s Hospital Boston | CHARM Added
FDA requested supplemental analyses—maximum ACE inhibitor dose |
| Safety |  |
| James W. Hainer, MD, MPHAstraZeneca LP | CHARM Added |
| Benefit/Risk |  |
| James B. Young, MD
Cleveland Clinic Foundation | CHARM Added |