# Presentation: 337899

## Candesartan Support Slides

## Baseline Beta-BlockerCharm Added

| β-blocker | Of patients on β-blockers | Mean daily dose of β-blocker |  |
| --- | --- | --- | --- |
|  |  | Candesartan | Placebo |
| Metoprolol | 50% | 89 mg | 84 mg |
| Carvedilol | 31% | 29 mg | 28 mg |
| Atenolol | 8% | 44 mg | 47 mg |
| Bisoprolol | 5% | 6 mg | 5 mg |
| Other | 6% | – | – |

- 65

## Death and CV Death in Patients onACEi and β-blockerCHARM Added Compared to Val-HeFT

**37**

|  | Patients, n (%) |  |
| --- | --- | --- |
|  | Val-HeFTn = 5010 | CHARM Addedn = 2548 |
| All patients |  |  |
| 	Deaths | 979 (19.5) | 789 (26.2) |
| 	CV deaths | 846 (16.9) | 649 (25.5) |
| Patients on ACEiand β-blocker | n = 1610 | n = 1413 |
| 	Deaths | 226 (14.0) | 370 (26.2) |
| 	CV deaths | 201 (12.5) | 307 (21.7) |

**Death and CV Death in Patients on****ACEi and β-blocker****CHARM Added Compared to Val-HeFT**

**CHARM FDA questions.ppt**

## Discontinuation† byBaseline Estimated GFRCHARM Added

**AZ BD T 40 P 75**

|  | Placebon = 464 |  |  | Candesartann = 465 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | eGFR, mL/min/1.73 m2 |  |  | eGFR, mL/min/1.73 m2 |  |  |
|  | < 60 | 60 - < 90 | ≥ 90 | < 60 | 60 - < 90 | ≥ 90 |
| Patients in eachstratified group, n | 153 | 203 | 108 | 153 | 206 | 106 |
| Discontinuation ineach stratifiedgroup, n (%) | 46 (30.1) | 33 (16.3) | 13 (12.0) | 63 (41.2) | 60 (29.1) | 12 (11.3) |

**† ****Calculated by Modification of Diet in Renal Disease formula. North American sites.**

## Outcomes in Patients Discontinued for Renal DysfunctionCHARM Added

**62**

**Outcome_data.ppt**

|  | Patients, n/N (%) |  |
| --- | --- | --- |
| Alive at end of study | Placebo | Candesartan |
| Renal dysfunction | 20/53 (38) | 58/105 (55) |

## Estimated GFR† Over Study TimeCHARM Added

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**140**

**Baseline**

**Wk 6**

**Mo 14**

**Mo 38**

**LOCF**

**59**

**SAS pgm: box_wisher_gfr_006**

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**140**

**Baseline**

**Wk 6**

**Mo 14**

**Mo 38**

**LOCF**

**Placebo**

**Candesartan**

**n =**

**464**

**424**

**365**

**255**

**447**

**n =**

**465**

**412**

**359**

**234**

**436**

**LOCF = Last observation carried forward.**
**† ****Calculated by Modification of Diet and Renal Disease formula. North American sites. **

**eGFR, ml/min/1.73 m****2**

**eGFR, ml/min/1.73 m****2**

## 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**

**Interaction*****p***** value**

**0.115**

## CV Death or CHF Hospitalization by CountryCHARM Added

**CV Death or CHF Hospitalization by Country****CHARM Added**

|  | Patients, n |
| --- | --- |
| Sweden | 64 |
| Norway | 97 |
| Denmark | 207 |
| Finland | 14 |
| Iceland | 21 |
| Italy | 14 |
| Spain | 17 |
| Portugal | 19 |
| The Netherlands | 128 |
| France | 70 |
| Czech Republic | 71 |
| Poland | 79 |
| Hungary | 69 |
| Switzerland | 25 |
| Belgium/Luxembourg | 82 |
| Malaysia | 38 |
| Singapore | 21 |
| United Kingdom | 89 |
| Germany | 346 |
| Canada | 357 |
| US | 597 |
| Australia | 76 |
| South Africa | 32 |
| Russia | 15 |
| All patients | 2548 |

**Hazard ratio (95% CI)**

**>**

**>**

**>**

**>**

**>**

**0**

**1**

**2**

**3**

**4**

**5**

- 46

**US-**

**Interaction*****p***** value**

**0.557**

## US vs Non-US PatientsCV Death or CHF HospitalizationCHARM Program

|  | Patients, n/N |  |  | p value forinteraction |
| --- | --- | --- | --- | --- |
|  | Placebo | Candesartan |  |  |
| CHARM Added |  |  |  |  |
| 	US | 128/302 | 128/295 |  | 0.115 |
| 	Non-US | 410/970 | 355/981 |  |  |
| 	All patients | 538/1272 | 483/1276 |  |  |
| CHARM Alternative |  |  |  |  |
| 	US | 99/238 | 82/232 |  | 0.675 |
| 	Non-US | 307/777 | 252/781 |  |  |
| 	All patients | 406/1015 | 334/1013 |  |  |
| CHARM Preserved |  |  |  |  |
| 	US | 105/361 | 95/373 |  | 0.733 |
| 	Non-US | 261/1148 | 238/1141 |  |  |
| 	All patients | 366/1509 | 333/1514 |  |  |
| 2 Low LVEF trials pooled |  |  |  |  |
| 	US | 227/540 | 210/527 |  | 0.138 |
| 	Non-US | 717/1747 | 607/1762 |  |  |
| 	All patients | 944/2287 | 817/2289 |  |  |
| CHARM—3 trials pooled |  |  |  |  |
| 	US | 332/901 | 305/900 |  | 0.272 |
| 	Non-US | 978/2895 | 845/2903 |  |  |
| 	All patients | 1310/3796 | 1150/3803 |  |  |

**US vs Non-US Patients****CV Death or CHF Hospitalization****CHARM Program**

**Candesartan****better**

**Placebo****better**

- SH-AHS-0006 T101, 102, 12.1.9.11.1, 2, 3; SH-AHS-0003 T106, 107, 12.1.9.11.1, 2, 3; SH-AHS-0003, 0006 - 12.1.9.4.126, 87, 12.1.9.11.4, 5, 6; SH-AHS-pooled T 12.1.9.4.1; 12.1.9.11.1, 12.1.9.11.2,12.19.94.40,

- DV

## CV Death or CHF Hospitalization by US and Non-US PatientsCHARM Program

|  | Patients, n/N |  |  | p value forinteraction |
| --- | --- | --- | --- | --- |
|  | Placebo | Candesartan |  |  |
| CHARM Added |  |  |  |  |
| 	US | 128/302 | 128/295 |  | 0.115 |
| 	Non-US | 410/970 | 355/981 |  |  |
| 	All patients | 538/1272 | 483/1276 |  |  |
| CHARM Alternative |  |  |  |  |
| 	US | 99/238 | 82/232 |  | 0.675 |
| 	Non-US | 307/777 | 252/781 |  |  |
| 	All patients | 406/1015 | 334/1013 |  |  |
| 2 Low LVEF trials pooled |  |  |  |  |
| 	US | 227/540 | 210/527 |  | 0.138 |
| 	Non-US | 717/1747 | 607/1762 |  |  |
| 	All patients | 944/2287 | 817/2289 |  |  |
| CHARM Overall—3 trials pooled |  |  |  |  |
| 	US | 332/901 | 305/900 |  | 0.272 |
| 	Non-US | 978/2895 | 845/2903 |  |  |
| 	All patients | 1310/3796 | 1150/3803 |  |  |

**Candesartan****better**

**Placebo****better**

**Hazard ratio (95% CI)**

- DV

**0.6**

**0.8**

**1.0**

**1.2**

**1.4**

## Baseline MedicationsCHARM Added

|  | Patients, % |  |
| --- | --- | --- |
|  | USn = 597 | Non-USn = 1951 |
| Baseline therapy, % |  |  |
| 	ACE inhibitor | 100 | 100 |
| 		Recommended dose | 59.1 | 48.1 |
| 	β-blocker |   56.6 | 55.1 |
| 	Diuretic |   91.1 | 89.7 |
| 	Spironolactone | 15.2 | 17.7 |
| 	Digitalis |   75.0 | 53.3 |
| 	Aspirin |   51.8 | 51.4 |
| 	Lipid-lowering |   48.1 | 39.1 |

**CSR SH-AHS-0006 T 20; 12.1.9.3.1**

**50**

## Baseline Medical HistoryCHARM Added

|  | USn = 597 | Non-USn = 1951 |
| --- | --- | --- |
| Medical history, % |  |  |
| 	Myocardial infarction | 51.3 | 56.9 |
| 	Diabetes | 38.4 | 27.1 |
| 	Hypertension | 67.0 | 42.4 |
| 	Atrial fibrillation
   Coronary artery bypass graft
   PCI
   ICD
   Pacemaker | 25.8
32.2
19.4
8.5
13.9 | 27.3
22.1
13.3
2.5
7.6 |
|  |  |  |

**CSR SH-AHS-pooled T 81, S1; CSR SH-AHS-0007 T 80, S1; CSR SH-AHS-0003 T 85, S1; CSR SH-AHS-0006 T 80, S1**

## Most Common† Adverse Events Leadingto Treatment Discontinuation CHARM Added

|  | Patients, n (%) |  |  |  |
| --- | --- | --- | --- | --- |
|  | North America |  | Rest of world |  |
|  | Placebon = 477 | Candesartann = 477 | Placebon = 795 | Candesartann = 799 |
| Abnormal renal function‡ | 30 (6.3) | 46 (9.6) | 23 (2.9) | 59 (7.4) |
| Cardiac failure | 32 (6.7) | 28 (5.9) | 49 (6.2) | 41 (5.1) |
| Hypotension | 17 (3.6) | 28 (5.9) | 27 (3.4) | 41 (5.1) |
| Hyperkalemia |   8 (1.7) | 21 (4.4) |   3 (0.4) | 28 (3.5) |
| Acute renal failure |   8 (1.7) |   5 (1.0) |   6 (0.8) | 10 (1.3) |

**† ****Five leading reasons.**
**‡ ****Renal function abnormal/aggravated.**

## CV Death or CHF Hospitalization by Black and Non-Black PatientsCHARM Overall

|  |  | Patients, n/N |  |
| --- | --- | --- | --- |
| CHARM |  | Placebo | Candesartan |
| Alternative | Non-black | 387/970 | 328/985 |
|  | Black | 19/45 | 6/28 |
| Added | Non-black | 509/1210 | 459/1211 |
|  | Black | 29/62 | 24/65 |
| Preserved | Non-black | 355/1452 | 317/1445 |
|  | Black | 11/57 | 16/69 |
| 3 Pooled | Non-black | 1251/3632 | 1104/3641 |
|  | Black | 59/164 | 46/162 |
| All patients |  | 1310/3796 | 1150/3803 |

**CV Death or CHF Hospitalization by ****Black and Non-Black Patients****CHARM Overall**

**Candesartan****better**

**Placebo****better**

**0.4**

**0.6**

**0.8**

**1**

**1.2**

**1.4**

**1.6**

**0.2**

**Hazard ratio (95% CI)**

## Time to First  All-Cause Hospitalization

|  | 1 mo | 6 mo | 12 mo |  |
| --- | --- | --- | --- | --- |
| Candesartan | 69 | 297 | 458 |  |
| Placebo | 80 | 304 | 485 |  |
|  |  |  |  |  |
|  |  |  |  |  |

## Primary OutcomeCV Death or CHF Hospitalization CHARM Added 

**Placebo****	****1272****	****1017****	****852****	****736****	****338**
**Candesartan****	****1276****	****1074****	****914****	****793****	****395**

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

**1**

**2**

**3**

**Time, yr**

**0**

**10**

**20**

**30**

**40**

**50**

**Placebo**

**Candesartan**

**%**

**3.5**

**HR 0.85 (95% CI: 0.75, 0.96), *****p***** = 0.011****Adjusted HR = 0.85, *****p***** = 0.010**

**483 (37.9%)**

**538 (42.3%)**

**15% risk reduction**

**0**

**NNT = 23**

## Investigator-Reported HF Hospitalizationsfor the Individual CHARM Trials andOverall Program

**608**

**836**

**566**

**2010**

**445**

**607**

**402**

**1454**

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**Alternative**

**Added**

**Preserved**

**3 pooled**

**Total hospitalizations for CHF**

**Placebo**

**Candesartan**

***p***** < 0.001****†**

***p***** = 0.002****†**

***p***** = 0.013****†**

***p***** < 0.001****†**

**† ****Wilcoxon Rank Sum Test based on number of hospitalizations/follow up time.**

## Total Number of HospitalizationsCHARM Overall—3 Trials Pooled andCHARM Added

**7178**

**2798**

**6690**

**2462**

**0**

**1500**

**3000**

**4500**

**6000**

**7500**

**CHARM Overall**

**CHARM Added**

**Total number of hospitalizations**

## Doses of Most Common ACE Inhibitors at Selected Study VisitsCHARM Added

|  |  | Mean ACEi dose, mg/d |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | Patients at baseline, % | 1Baseline | 46 wk | 56 mo | 714 mo | 1026 mo | 1338 mo | 19Closing visit |
| Enalapril | 	26.7	P		C | 17.2 16.8 | 17.3 16.3 | 17.6 16.6 | 17.2 15.7 | 16.9 16.4 | 16.4 17.2 | 16.5 15.8 |
| Lisinopril | 	19.1	P		C | 17.717.7 | 17.3 17.6 | 17.7 17.5 | 17.6 17.1 | 17.9 17.6 | 17.5 17.5 | 19.4 18.1 |
| Captopril | 	16.8	P		C | 82.7 82.2 | 80.7 81.1 | 81.4 79.4 | 81.1 76.8 | 82.7 72.8 | 82.8 72.4 | 77.2 69.4 |
| Ramipril | 	11.0	P		C | 7.3 6.8 | 7.5 6.7 | 7.56.7 | 7.8 6.7 | 8.76.7 | 7.96.8 | 7.97.2 |

- Attachment A, 28 Jan Addendum to Jan Briefing Doc

## BD Table 48—Summary Table of Concomitant ACE Inhibitor Use(CHARM-Added)

## Endpoint Analyses Based on Recommended or Maximum† ACEi Doses During StudyCHARM Added

|  |  | Patients, n |  |
| --- | --- | --- | --- |
| CV death or CHF hospitalization |  |  |  |
| 	Recommended dose of ACEi | No | 1012 |  |
|  | Yes | 1535 |  |
| 	Maximum dose of ACEi | No | 1788 |  |
|  | Yes | 759 |  |
| All-cause mortality orCHF hospitalization |  |  |  |
| 	Recommended dose of ACEi | No | 1012 |  |
|  | Yes | 1535 |  |
| 	Maximum dose of ACEi | No | 1788 |  |
|  | Yes | 759 |  |
| CV death or CHF hospitalization or nonfatal MI |  |  |  |
| 	Recommended dose of ACEi | No | 1012 |  |
|  | Yes | 1535 |  |
| 	Maximum dose of ACEi | No | 1788 |  |
|  | Yes | 759 |  |
| All-cause mortality |  |  |  |
| 	Recommended dose of ACEi | No | 1012 |  |
|  | Yes | 1535 |  |
| 	Maximum dose of ACEi | No | 1788 |  |
|  | Yes | 759 |  |

**Endpoint Analyses Based on Recommended or Maximum****†**** ACEi Doses During Study****CHARM Added**

**36**

**Peter Johanson ACE analyses to US T 11 – T 20**

**Candesartan better**

**Placebo better**

**† ****FDA communication 12-17-04.**

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**1.1**

**1.2**

**1.3**

**Hazard ratio (95% CI)**

## Doses of Most Common ACEi at Selected Study VisitsCHARM Added

**Enalapril (27%)**

**Captopril (17%)**

**Lisinopril (19%)**

**Ramipril (11%)**

**Baseline**

**Closing**

**Baseline**

**Closing**

**Baseline**

**Closing**

**Baseline**

**Closing**

**6 wk**

**6 mo**

**14 mo**

**26 mo**

**38 mo**

**6 wk**

**6 mo**

**14 mo**

**26 mo**

**38 mo**