# Presentation: 756001

## CHARM ProgramCandesartan in Heart Failure Assessment of Reduction in Mortality and MorbidityEfficacy

**Marc A. Pfeffer, MD, PhD**
**Interim Chair, Medicine****Brigham and Women’s Hospital****Boston, MA**

## Patients With Symptomatic CHFCHARM Program

**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**

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

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

## CHARM Program Recruitment

**0**

**2000**

**4000**

**6000**

**8000**

**Jan**

**June**

**Dec**

**June**

**1999**

**2000**

**Patients, n**

**First**
**patient**
**3/22/99**

**Total = 7599**

**Preserved**
**3023**

**Added**
**2548**

**Alternative**
**2028**

**Dec**

**2001**

**CHARM Program Recruitment**

**Mar**

**2003**

**Mar**

**Study close**

## Primary and Secondary Endpoints for Each CHARM Trial†

| Primaryendpoint | CV mortality or CHF hospitalization‡ |
| --- | --- |
| Secondary endpoints | All-cause mortality or CHF hospitalization
CV mortality or CHF hospitalization or nonfatal MI |

**† ****Protocol specified endpoints for the confirmatory analysis.**
**‡ ****Hospitalization for CHF defined as hospital admission primarily for worsening **
**   ****of CHF requiring IV diuretic and overnight stay, CEC adjudicated.**

**CSR SH-AHS-pooled P 3**

## Dose-Titration and Visit ScheduleCHARM Added

**0 w**

**2 w**

**4 w**

**6 w**

**6 m**

**Every 4 mo for ****minimum 24 mo**
**(maximum 48 mo)****Study close 31 March 2003**

**Visit**

**1**

**2**

**3**

**4**

**5**

**32 mg**

**Candesartan or****matching placebo**
**once daily**

**16 mg**

**8 mg**

**32 mg**

**4 mg**

**16 mg**

**8 mg**

**Dose-Titration and Visit Schedule****CHARM Added**

**Mean dose 24 mg candesartan and 27 mg placebo qd. **
**Target dose at 6 months - 61% on candesartan and 73% on placebo.**

**CSR SH-AHS-pooled F 1**

## Statistical Analysis PlanCHARM Program

**Intent-to-treat (ITT) population**
**Time to first event for 1° and 2° endpoints**
**Log rank test for comparisons**
**Cox proportional hazards models for ****effect size estimates**
**Kaplan Meier estimates of distribution function**
**Confirmatory strategy, primary and secondary analyses using a hierarchical closed test procedure**
**Each individual trial**
**Pooled analyses**

**CSR SH-AHS-pooled P 5**

## Patient Inclusion and Exclusion CriteriaCHARM Program

-  .

**Patient Inclusion and Exclusion Criteria****CHARM Program**

**Inclusion criteria**
**Age ≥ 18 years **
**Symptomatic HF for at least 4 weeks****(NYHA class II - IV)**
**CHARM Added: if NYHA class II, history of cardiac hospitalization in previous 6 months**
**CHARM Preserved: history of cardiac hospitalization**
**Key exclusion criteria**
**Serum ****creatinine ****≥**** 3 mg/dL (****≥**** 265 μmol/L)**
**Serum potassium ****≥**** 5.5 mmol/L**
**Bilateral renal artery stenosis**
**Symptomatic hypotension**
**ARB within 2 weeks**

**CSR SH-AHS-pooled P 61, 63**

## Baseline CharacteristicsCHARM Added

|  | Placebon = 1272 | Candesartann = 1276  |
| --- | --- | --- |
| Mean age ± SD, yr | 64.1 ± 11.3 | 64.0 ± 10.7 |
|    ≥ 75 yr, n (%)  |   245 (19.3) |   212 (16.6)  |
| Female |   272 (21.4) |   270 (21.2)  |
| NYHA class, n (%)  |  |  |
|    II  | 302 (23.7) | 312 (24.5)  |
|    III  | 925 (72.7) | 931 (73.0)  |
| 	IV | 45 (3.5) | 33 (2.6) |
| Mean heart rate ± SD, bpm |   73.7 ± 12.9 |   73.4 ± 13.3 |
| Mean blood pressure ± SD, mm Hg |  |  |
|    Systolic  | 125.6 ± 18.6 | 124.7 ± 18.6 |
|    Diastolic  |   75.2 ± 10.7 |   75.0 ± 10.8 |
| Diabetes mellitus  |   382 (30.0) |   376 (29.5)  |
| Hypertension  |   619 (48.7) |   609 (47.7)  |
| Atrial fibrillation  |   341 (26.8) |   346 (27.1)  |
| Myocardial infarction  |   703 (55.3) |   714 (56.0)  |

**1**

## Baseline Medical TreatmentCHARM Added

|  | Patients, n (%) |  |
| --- | --- | --- |
| Medical treatment | Placebon = 1272 | Candesartann = 1276  |
| β-blocker  |   711 (55.9) |   702 (55.0)  |
| Spironolactone  |   215 (16.9) |   222 (17.4)  |
| Digoxin/digitalis glycoside  |   753 (59.2) |   735 (57.6)  |
| Diuretic  | 1146 (90.1) | 1148 (90.0)  |
| Aspirin  |   659 (51.8) |   652 (51.1)  |
| Lipid-lowering drug  |   521 (41.0) |   528 (41.4)  |

**1**

**SH-AHS-0006 T20**

## Primary EndpointCV Death or CHF HospitalizationCHARM Added

**Primary Endpoint****CV Death or CHF Hospitalization****CHARM Added**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**45**

**50**

**0**

**6**

**12**

**18**

**24**

**30**

**36**

**42**

**48**

**Candesartan**
**(37.9%)**

**Placebo****(42.3%)**

**Relative risk reduction = 15%**
**HR = 0.85 (95% CI: 0.75, 0.96)**
***p***** = 0.011**

**Median follow-up 41.0 mo.**

**%**

**At risk, n**
**Placebo****	****1272****	****1017****	****852****	****735****	****338**
**Candesartan****	****1276****	****1074****	****914****	****793****	****395**

**Time, mo**

**CSR SH-AHS-0006 F 4**

## Primary Endpoint and Components CHARM Added

|  | Patients, n  |  |  |  |
| --- | --- | --- | --- | --- |
|  | PlaceboN = 1272 | CandesartanN = 1276 | Hazard ratio
(95% CI) | p value
(log-rank) |
| Primary endpoint |  |  |  |  |
| 	CV death or	CHF hospitalization | 538 | 483 | 0.85 (0.75, 0.96) | 0.011 |
| Components |  |  |  |  |
| 	CV death | 347 | 302 | 0.84 (0.72, 0.98) | 0.029 |
| 	CHF hospitalization | 356 | 309 | 0.83 (0.71, 0.96) | 0.013 |

**CSR SH-AHS-0006 T 24, 30**

**49**

**Candesartan****better**

**Placebo****better**

**0.5**

**1**

**1.5**

**Hazard ratio (95% CI)**

## CV and Non-CV DeathCHARM Added

**Placebo****	****1272****	****1136****	****1013****	****906****	****422**
**Candesartan****	****1276****	****1176****	****1063****	****948****	****458**

**CV and Non-CV Death****CHARM Added**

**Median follow-up 41.0 mo.**

**Time, mo**

**%**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**0**

**6**

**12**

**18**

**24**

**30**

**36**

**42**

**48**

**Placebo**

**Candesartan**

**Candesartan**

**Placebo**

**CV Death**
**Relative risk reduction = 16%**
**HR = 0.84 (95% CI: 0.72, 0.98)**
***p***** = 0.029**

**Non-CV Death**
**HR = 1.11 (95% CI: 0.80, 1.55)**

## CHF HospitalizationCHARM Added

**Median follow-up 41.0 months.**

**395**

**793**

**914**

**1074**

**1276**

**Candesartan**

**338**

**735**

**852**

**1017**

**1272**

**Placebo**

**Time, mo**

**%**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**0**

**6**

**12**

**18**

**24**

**30**

**36**

**42**

**48**

**Risk reduction = 17%**
**HR = 0.83 (95% CI: 0.71, 0.96)**
***p***** = 0.013**

**At risk, n**

**Placebo**

**Candesartan**

**CSR SH-AHS-0006 F 18**

## Secondary Endpoints and ComponentsCHARM Added (n = 2548) 

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**1.1**

**1.2**

**Hazard ratio (95% CI)**

**Secondary Endpoints and Components****CHARM Added (n = 2548) **

**Candesartan****better**

**Placebo****better**

|  | Patients, n |  |  |  |
| --- | --- | --- | --- | --- |
|  | Placebon = 1272 | Candesartann = 1276 | HR (95% CI) | p value |
| All-cause mortality or CHF hospitalization | 587 | 539 | 0.87 (0.78, 0.98) | 0.021 |
| 	All-cause mortality | 412 | 377 | 0.86 (0.77, 1.02) | 0.086 |
| 	CHF hospitalization | 356 | 309 | 0.83 (0.71, 0.96) | 0.013 |
| CV mortality orCHF hospitalization or nonfatal MI | 550 | 495 | 0.85 (0.76, 0.96) | 0.010 |

- CSR SH-AHS-0006 T S2, 27, 25, 26, 28, 12.1.9.4.43

**49**

## CV Mortality or CHF HospitalizationSubgroup Analysis CHARM Added

**CV Mortality or CHF Hospitalization****Subgroup Analysis ****CHARM Added**

|  |  | Patients, n/N |  |
| --- | --- | --- | --- |
|  |  | Placebo | Candesartan |
| Age | < 65 | 211/636 | 192/632 |
|  | ≥ 65 < 75 | 193/391 | 176/432 |
|  | ≥ 75 | 134/245 | 115/212 |
| Gender | Male | 427/1000 | 387/1006 |
|  | Female | 111/272 | 96/270 |
| NYHA | II | 104/302 | 93/312 |
|  | III / IV | 434/970 | 390/964 |
| LVEF | < 25 | 203/382 | 186/388 |
|  | ≥ 25 | 335/890 | 297/888 |
| Medical history |  |  |  |
| 	Diabetes | No | 334/890 | 291/900 |
|  | Yes | 204/382 | 192/376 |
| 	Hypertension | No | 261/653 | 248/667 |
|  | Yes | 277/619 | 235/609 |
| 	Previous MI | No | 224/569 | 188/562 |
|  | Yes | 314/703 | 295/714 |
| 	Atrial fibrillation | No | 375/931 | 335/929 |
|  | Yes | 163/341 | 148/346 |
| Diuretic | No | 27/126 | 26/128 |
|  | Yes | 511/1146 | 457/1148 |
| Digitalis | No | 185/519 | 172/541 |
|  | Yes | 353/753 | 311/735 |
| Aspirin | No | 264/613 | 240/624 |
|  | Yes | 274/659 | 243/652 |
| Lipid lowering | No | 336/751 | 294/748 |
|  | Yes | 202/521 | 189/528 |
| US | No | 410/970 | 355/981 |
|  | Yes | 128/302 | 128/295 |
| All patients (N = 2548) |  | 538/1272 | 483/1276 |

**DV CSR SH-AHS-0006 T 101, 102**

**20**

**Placebo better**

**Candesartan better**

**Hazard ratio (95% CI)**

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**1.1**

**1.2**

**1.3**

**1.4**

**1.5**

**1.6**

**All interaction*****p***** values****not****significant**

## Outcomes by Beta-Blocker TherapyCHARM Added

|  | Placebo | Candesartan |  |  | p value for
interaction |
| --- | --- | --- | --- | --- | --- |
| CV death or CHF hospitalization |  |  |  |  |  |
| ACEi + β-B |  |  |  |  |  |
| 	No | 264/563 | 260/574 |  |  | 0.13 |
| 	Yes | 274/709 | 223/702 |  |  |  |
| All patients | 538/1272 | 483/1276 |  |  |  |
| All-cause mortality |  |  |  |  |  |
| ACEi + β-B |  |  |  |  |  |
| 	No | 218/563 | 202/574 |  |  | 0.989 |
| 	Yes | 194/709 | 175/702 |  |  |  |
| All patients | 412/1272 | 377/1276 |  |  |  |

**Outcomes by Beta-Blocker Therapy****CHARM Added**

**Candesartan**
**better**

**Placebo**
**better**

**Briefing Document F7.**

- 52

## Outcomes by Spironolactone Use CHARM Added

| Group |  | N | Events 
placebo | Events 
candesartan |
| --- | --- | --- | --- | --- |
| CV mortality or CHF hospitalization |  |  |  |  |
| ACEi + spironolactone | No: 2112 |  | 441/1058 | 378/1054 |
|  | Yes: 436 |  | 97/214 | 105/222 |
| ACEi + β-B + spironolactone  | No: 2311 |  | 487/1144 | 444/1167 |
|  | Yes: 237 |  | 51/128 | 39/109 |
| All patients | 2548 |  | 538/1272 | 483/1276 |
| All-cause mortality |  |  |  |  |
| ACEi + spironolactone | No: 2112 |  | 324/1058 | 304/1054 |
|  | Yes: 436 |  | 88/214 | 73/222 |
| ACEi + β-B + spironolactone  | No: 2311 |  | 368/1144 | 350/1167 |
|  | Yes: 237 |  | 44/128 | 27/109 |
| All patients | 2548 |  | 412/1272 | 377/1276 |

- Table 102, App 12.1.9.4.73,74,77,78

**Candesartan****better**

**Placebo****better**

**Hazard ratio (95% CI)**

**0.5**

**1**

**1.5**

## SummaryCHARM Added

**	****In patients with symptomatic CHF and left ventricular systolic dysfunction on an ACE inhibitor, the addition of candesartan to standard therapy, including a beta-blocker, provides incremental benefit by:**
**Reducing CV mortality or ****CHF hospitalization**
**Reducing all-cause mortality or ****CHF hospitalization**

## CHARM Added and Val-HeFTMorbidity/Mortality

- 	**Placebo****	****Candesartan****	****Placebo****	****Valsartan**
**RRR =****	****                    15.0%****	****	****                       13.2%**
***p***** = ****	****                   0.011****	****	****                       0.009**

## Use of ACE Inhibitors CHARM Added

**Stable dose of ACEi for ≥ 30 days**
**Investigators were provided list of recommended doses of ACEi based on****target doses in positive trials**
**Individualized optimum doses of ACEi****at baseline**
**96% of patients were determined to be on ****an individualized optimum dose of ACEi ****at baseline**

## FDA-Approved ACE Inhibitors For Heart Failure

| ACE inhibitor |  | CHARM Added |  |
| --- | --- | --- | --- |
|  | Proportion of patientsat baseline, % | FDA labeled  HF dose | Baseline mean dose |
|  |  |  mg/d | mg/d |
| Enalapril | 27 | 5 - 20 (40) | 17 |
| Lisinopril | 19 | 5 - 40 (40) | 18 |
| Captopril | 17 | 150 - 300 (450) | 83 |
| Ramipril | 11 | 10 | 7 |
| Trandolapril | 6 | 4 | 2 |
| Perindopril | 6 | NA† | 4 |
| Quinapril | 5 | 20 - 40 | 25 |
| Fosinopril | 5 | 20 - 40 | 20 |
| Benazepril | 3 | NA† | 26 |
| Cilazapril, Moexipril | 1 | NA† | – |

**† ****NA = Not FDA approved for heart failure.**

## Outcomes in CHARM Added According to ACE Inhibitor Used at Baseline

|  | N |  | p value for interaction |
| --- | --- | --- | --- |
| FDA approved  |  |  |  |
| 	No | 258 |  |  |
| 	Yes | 2290 |  | 0.929 |
| All patients | 2548 |  |  |

**Hazard ratio (95% CI)**

**Candesartan**
**better**

**Placebo**
**better**

**0.4**

**0.6**

**0.8**

**1.0**

**1.2**

**1.4**

## Recommended and Actual Doses of ACEi

| ACE inhibitor |  | CHARM Added |  |
| --- | --- | --- | --- |
|  | Proportion of patientsat baseline, % | Recommended† HF  | Baseline mean |
|  |  | Dose, mg/d | Dose, mg/d |
| Enalapril | 27 | 20 | 17 |
| Lisinopril | 19 | 20 | 18 |
| Captopril | 17 | 150 | 83 |
| Ramipril | 11 | 10 | 7 |
| Trandolapril | 6 | 2 | 2 |
| Perindopril | 6 | 4 | 4 |
| Quinapril | 5 | 20 | 25 |
| Fosinopril | 5 | 20 | 20 |
| Benazepril | 3 | 20 | 26 |
| Other | 1 | – | – |

**† ****Adapted from ESC Guidelines.**

## Dosing and Visit ScheduleCHARM Added

**0 w**

**2 w**

**4 w**

**6 w**

**6 m**

**Visit**

**1**

**2**

**3**

**4**

**5**

**32 mg**

**Candesartan/****placebo **

**16 mg**

**8 mg**

**32 mg**

**4 mg**

**16 mg**

**8 mg**

**Dosing and Visit Schedule****CHARM Added**

**CSR SH-AHS-pooled F 1**

**ACEi mean daily dose, mg**
**Enalapril****	****17****	****17****	****17****	****17****	****17****	****16****	****17****	****17**
**Lisinopril****	****18 ****	****18****	****18****	****17****	****18****	****17****	****18****	****18**
**Captopril****	****83 ****	****82****	****82****	****81****	****80****	****79****	****78****	****78**
**Ramipril****	****7 ****	****7****	****7****	****7****	****7****	****7****	****8****	****7**
**Trandolapril****	****2.5****	****2.4****	****2.5****	****2.4****	****2.5****	****2.5****	****2.5****	****2.5**

**14 m**

**7**

**26 m**

**10**

**38 m**

**13**

## Prespecified SubgroupCV Death or CHF HospitalizationCHARM Added

**Candesartan ****better**

**Hazard ratio (95% CI)**

**Placebo ****better**

***p***** value for****interaction**

**0.26**

**37**

|  |  | Patients, n/N |  |
| --- | --- | --- | --- |
|  |  | Placebo | Candesartan |
| Recommendeddose of ACEi | No | 263/624 | 251/633 |
|  | Yes | 275/648 | 232/643 |
| All patients |  | 538/1272 | 483/1276 |

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**1.1**

**1.2**

**DV CSR SH-AHS-0006 T 101, 102**

## Proportion of Patients on Recommended Dose or FDA Defined Maximum Dose of ACEi at Baseline

|  | CHARM Added |  |  |  |
| --- | --- | --- | --- | --- |
| ACE inhibitor | ≥ Recommended (CHARM)n = 1291 |  | ≥ Maximum (FDA)†n = 721 |  |
|  | Dose, mg/d | Patients, % | Dose, mg/d | Patients, % |
| Enalapril | 20 | 52 | 20 | 52 |
| Lisinopril | 20 | 52 | 40 | 15 |
| Captopril | 150 | 21 | 150 | 21 |
| Ramipril | 10 | 39 | 10 | 39 |
| Trandolapril | 2 | 90 | 4 | 27 |
| Perindopril | 4 | 83 | 16 | 1 |
| Quinapril | 20 | 60 | 80 | 7 |
| Fosinopril | 20 | 59 | 40 | 20 |
| Benazepril | 20 | 62 | 80 | 5 |
| Other | – | 1 | – | 1 |
| All |  | 50.7 |  | 28.3 |

**† ****FDA communication 12-17-04.**

## CV Death or CHF Hospitalization— Recommended or Maximum ACEi Doses at BaselineCHARM Added

**Candesartan**
**better**

**Placebo**
**better**

**CV Death or CHF Hospitalization— Recommended or Maximum ACEi Doses at Baseline****CHARM Added**

|  |  | Patients, n |
| --- | --- | --- |
| Recommended dose of ACEi | No | 1257 |
| (CHARM) | Yes | 1291 |
| Maximum dose of ACEi | No | 1827 |
| (FDA)† | Yes | 721 |
|  |  |  |
| All patients  |  | 2548 |

**Follow-up to Dec 17 discussion with FDA T 3**

**36**

**CSR SH-AHS-0006 T 102**

**† ****FDA communication 12-17-04.**

***p***** value for****interaction**

**0.26**

**0.78**

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**1.1**

**1.2**

**1.3**

## Proportion of Patients on Recommended Dose or FDA Defined Maximum Dose of ACEi at Baseline

|  |  | CHARM Added |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| ACE inhibitor | % onRx | ≥ Recommended (CHARM)n = 1291 |  | ≥ Maximum (FDA)† n = 721 |  | ≥ Maximum (FDA)‡ revisedn = 529 |  |
|  |  | Dose, mg/d | Patients, % | Dose, mg/d | Patients, % | Dose, mg/d | Patients, % |
| Enalapril | 27 | 20 | 52 | 20 | 52 | 40 | 10 |
| Lisinopril | 19 | 20 | 52 | 40 | 15 | 20 | 52 |
| Captopril | 17 | 150 | 21 | 150 | 21 | 300 | 2 |
| Ramipril | 11 | 10 | 39 | 10 | 39 | 10 | 39 |
| Trandolapril | 6 | 2 | 90 | 4 | 27 | 4 | 27 |
| Perindopril | 6 | 4 | 83 | 16 | 1 | 16 | 1 |
| Quinapril | 5 | 20 | 60 | 80 | 7 | 80 | 7 |
| Fosinopril | 5 | 20 | 59 | 40 | 20 | 40 | 20 |
| Benazepril | 3 | 20 | 62 | 80 | 5 | 80 | 5 |
| Other | 1 |  |  |  |  |  |  |
| All | 100 |  | 50.7 |  | 28.3 |  | 20.8 |

**† ****FDA communication 12-17-04.**
**‡ ****FDA communication 01-24-05.**

## CV Death or CHF Hospitalization—Recommended or Maximum ACEi Doses at BaselineCHARM Added

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**1.1**

**1.2**

**1.3**

**Hazard ratio (95% CI)**

**Candesartan**
**better**

**Placebo**
**better**

**CV Death or CHF Hospitalization—Recommended or Maximum ACEi Doses at Baseline****CHARM Added**

|  |  | Patients, n |
| --- | --- | --- |
| Recommended dose of ACEi | No | 1257 |
| (CHARM) | Yes | 1291 |
| Maximum dose of ACEi | No | 1827 |
| (FDA)† | Yes | 721 |
| Maximum dose of ACEi | No | 2019 |
| (FDA)‡ revised | Yes | 529 |
| All patients  |  | 2548 |

**Follow-up to Dec 17 discussion with FDA T 3**

**36**

**CSR SH-AHS-0006 T 102**

***p***** value for ****interaction**

**0.26**

**0.78**

**0.29**

**† ****FDA communication 12-17-04.**
**‡ ****FDA communication 01-24-05.**

## CV Death or CHF Hospitalization—Maximum Range of ACEi Doses

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**1.1**

**1.2**

**1.3**

**Hazard ratio (95% CI)**

**Candesartan**
**better**

**Placebo**
**better**

**CV Death or CHF Hospitalization—Maximum Range of ACEi Doses**

|  |  | Patients, n |
| --- | --- | --- |
| Recommended dose of ACEi | No | 1257 |
| (CHARM) | Yes | 1291 |
| Maximum dose of ACEi | No | 1827 |
| (FDA)† | Yes | 721 |
| Maximum dose of ACEi | No | 2019 |
| (FDA)‡ revised | Yes | 529 |
| CHARM Added  |  | 2548 |
| CHARM Alternative |  | 2028 |
| 2 Pooled Low LVEF  |  | 4576 |

**Follow-up to Dec 17 discussion with FDA T 3**

**36**

**CSR SH-AHS-0006 T 102**

***p***** value for ****interaction**

**0.26**

**0.78**

**0.29**

**† ****FDA communication 12-17-04.**
**‡ ****FDA communication 01-24-05.**

## SummaryCHARM Added

**In patients with symptomatic CHF and left ventricular systolic dysfunction, the addition of candesartan to an ACE inhibitor provides incremental benefit. There was no evidence of modification of the beneficial effect of candesartan on CV death or CHF hospitalization based on ACE inhibitor dose or choice of****ACE inhibitor**