# Presentation: 691090

## Safety of Candesartan in CHFWhen Added to Evidence-based Doses of ACE Inhibitors

**James W. Hainer, MD, MPH**
**AstraZeneca**

**C**

## CHARM Protocol—Monitoring Directives for Blood Pressure, Creatinine, and Potassium

**At baseline**
**Within 2 wks of dose adjustment**
**At end of dose titration**
**Annually**
**At any time in the judgment of the****responsible clinician**

**59**

**Client fax 2-7-05**

## HypotensionCHARM Added  

**C**

|  | Patients, n (%) |  |
| --- | --- | --- |
|  | PlaceboN = 1272 | CandesartanN = 1276 |
| Adverse event | 184 (14.5) | 296 (23.2) |
| Discontinuation | 44 (3.5) | 69 (5.4) |
| Hospitalization | 22 (1.7) | 55 (4.3) |
| Serious fatal† |   1 (0.1) |   3 (0.2) |

**† ****One of the reported causes of death.**

**2.7.4 Summ Clin safety T 22, 44;**
**SH-AHS-pooled T 150**

## Discontinuation Due to Hypotension in Important Baseline SubgroupsCHARM Added

**59**

**All patients**

**Age ≥ 75**

**Baseline****SBP < 100**

**β-blocker**

**Spiro**

**CSR SH-AHS-0006 App 12.1.9.5.22; **
**SAS pgm: rr_hypo_disc_006**

**n = **

**1272**

**1276**

**245**

**212**

**215**

**222**

**711**

**702**

**54**

**77**

## Renal DysfunctionCHARM Added

**August 11 pmD2454 Briefing Document T22; T_disk_6mos_eos.doc T99**

**Renal Dysfunction****CHARM Added**

**C**

|  | Patients, n (%) |  |
| --- | --- | --- |
|  | PlaceboN = 1272 | CandesartanN = 1276 |
| Adverse event | 119	 (9.4) |   196 (15.4) |
| Discontinuation |   53 (4.2) | 105 (8.2) |
| Hospitalization |   38 (3.0) | 	  58 (4.5) |
| Dialysis |   20 (1.6) |   20 (1.6) |
| Serious fatal†‡ |   19 (1.5) |   12 (0.9) |

**† ****Renal function abnormal/aggravated, renal failure acute/aggravated, or renal failure NOS.**
**‡ ****One of the reported causes of death.**

## Discontinuation Due to Renal Dysfunction in Important Baseline SubgroupsCHARM Added

**59**

**† ****North American sites.**

**All patients**

**Age ≥ 75**

**SCr ≥ 2.0****†**

**Spiro**

**SAS pgm: rr_renal_disc_006; Client analysis**

**SBP < 100**

**n =**

**Diabetes**

**382**

**376**

**1272**

**1276**

**245**

**212**

**54**

**77**

**215**

**222**

**20**

**26**

## HyperkalemiaCHARM Added

**C**

|  | All patients, n (%) |  |
| --- | --- | --- |
|  | PlaceboN = 1272 | CandesartanN = 1276 |
| Adverse event | 46 (3.6) | 123 (9.6) |
| Discontinuation | 11 (0.9) |   49 (3.8) |
| Hospitalization |   9 (0.7) |  19 (1.2) |
| Serious, fatal† | 0 |    2 (0.2) |
|  |  |  |
|  |  |  |
| Sudden death | 174 (13.7) |  	143 (11.2) |
| Fatal ventricular fibrillation | 16 (1.3) |    9 (0.7) |

**2.7.4 Summ Clin Safety T22, 44; Clin Study Rpt T 150**

**† ****One of the reported causes of death.**

## Discontinuation Due to Hyperkalemia in Important Baseline SubgroupsCHARM Added

**CSR SH-AHS-Pooled T 66; T68; 12.1.9.5.22; AZ BD T 22 **

**59**

**† ****North American sites.**

**All patients**

**Age ≥ 75**

**Diabetes**

**Spiro**

**SCr ≥ 2.0****†**

**K+ ≥ 5.0****†**

**n =**

**1272**

**1276**

**245**

**212**

**382**

**376**

**215**

**222**

**50**

**64**

**20**

**26**

## Summary of Adverse EventsCHARM Added

|  | Patients, n (%) |  |
| --- | --- | --- |
|  | PlaceboN = 1272 | CandesartanN = 1276 |
| Any AE |  992 (78.0) | 1026 (80.4) |
| Serious AE |  966 (75.9) |   969 (75.9) |
| 	Serious fatal |  413 (32.5) |   377 (29.5) |
| Treatment discontinuationdue to AE |  224 (17.6) |   310 (24.3) |
| Dose reductiondue to AE | 123 (9.7) |   220 (17.2) |

**2.7.4 Summ Clin safety T 21**

**C**

## Common Serious Fatal Adverse EventsCHARM Added

|  | Patients, n (%) |  |
| --- | --- | --- |
|  | PlaceboN = 1272 | CandesartanN = 1276 |
| Sudden death |   174 (13.7) | 143 (11.2) |
| Cardiac failure | 112 (8.8) | 74 (5.8) |
| Myocardial infarction |   20 (1.6) | 21 (1.6) |
| Pneumonia |   19 (1.5) | 10 (0.8) |
| Cerebrovascular disorder |   11 (0.9) | 12 (0.9) |
| Death |   13 (1.0) | 19 (1.5) |
| Cardiac arrest |   13 (1.0) | 13 (1.0) |
| Sepsis |   10 (0.8) | 11 (0.9) |
| Ventricular fibrillation |   16 (1.3) | 9 (0.7) |
| Cardiomyopathy |     8 (0.6) | 8 (0.6) |

**10-6**

**2.7.4 Summ Clin safety T 33**

## Outcomes by β-blocker and Spironolactone Use CHARM Added

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

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

**Candesartan****better**

**Placebo****better**

**Hazard ratio (95% CI)**

**0.5**

**1**

**1.5**

| All-cause hospitalization |  |  |  |
| --- | --- | --- | --- |
| ACEi + spironolactone | No: 2112
Yes:436 | 714/1058
144/214 | 696/1054
156/222 |
| ACEi + β-B + spironolactone  | No: 2311
Yes: 237 | 775/1144
83/128 | 776/1167
76/109 |
| All patients | 2548 | 858/1272 | 852/1276 |

| All-cause mortality |  |  |  |
| --- | --- | --- | --- |
| ACEi + spironolactone | No: 2112
Yes: 436 | 324/1058
88/214 | 304/1054
73/222 |
| ACEi + β-B + spironolactone  | No: 2311
Yes: 237 | 368/1144
44/128 | 350/1167
27/109 |
| All patients | 2548 | 412/1272 | 377/1276 |

## Cumulative Number of Hospital Admissions for Any CauseCHARM Added

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**3000**

**0**

**50**

**100**

**150**

**200**

**No. of admissions**

**Week**

**Candesartan**

**Placebo**

## Rates of Hospital Admission by CauseCHARM Added

**All**

**CV**

**HF**

**Non-CV**

**Admissions/patient/yr**

**0.4**

**0.8**

**1.0**

**1.2**

**1.4**

**1.6**

**0.6**

**0**

**0.2**

**Placebo**

**Candesartan**

## All-Cause MortalityCHARM Added

**Time, mo**

**Cumulative risk, %**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**0**

**6**

**12**

**18**

**24**

**30**

**36**

**42**

**48**

**Placebo**

**Candesartan**

**HR = 0.88 (95% CI: 0.77, 1.02)**

## Safety Findings and ConclusionsCHARM Added

**As expected, due to the greater RAAS inhibition, rates of hypotension, abnormal renal function, and hyperkalemia were greater with candesartan**
**These predictable adverse events did not translate into any increases in all-cause hospitalization and/or mortality as well as sudden death, renal failure, or ventricular fibrillation**
**Candesartan is safe and generally well-tolerated by patients with CHF receiving evidence-based doses of ACE inhibitors**

**C**

## Risk MinimizationCHARM Added

**Warnings/precautions**
**Hypotension, renal dysfunction, hyperkalemia**
**Patients/populations at risk**
**Recommendations for monitoring and reducing risk**
**Interactions with major societies/treatment guideline committees**
**Sales force/scientific liaison training**
**Physician, pharmacists continuing medical****education programs**
**Risks displayed in promotional materials**
**Patient information brochures and updated websites**