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

CS-1

Safety of Candesartan in CHFWhen Added to Evidence-based Doses of ACE Inhibitors

James W. Hainer, MD, MPHAstraZeneca

C

CS-2

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

CS-3

HypotensionCHARM Added

C

Patients, n (%)PlaceboN = 1272

CandesartanN = 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 Su

mm

Clin

saf

ety

T 22

, 44;

SH-A

HS-

pool

ed T

150

CS-4Discontinuation Due to Hypotension in Important Baseline SubgroupsCHARM Added

0

5

10

15

20

Pat

ien

ts d

isco

nti

nu

ed, %

PlaceboC andesartan

59

All patients Age ≥ 75 BaselineSBP < 100

β-blockerSpiro

CSR

SH

-AH

S-00

06 A

pp 1

2.1.

9.5.

22;

SAS

pgm

: rr_

hypo

_dis

c_00

6

n = 1272 1276 245 212 215 222 711 702 54 77

CS-5CSR SH-AHS-pooled; data from section 11.3.6.1, T 175;August 11 pmD2454 Briefing Document T22; T_disk_6mos_eos.doc T99

Renal DysfunctionCHARM Added

C

Patients, n (%)PlaceboN = 1272

CandesartanN = 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.

CS-6Discontinuation Due to Renal Dysfunction in Important Baseline SubgroupsCHARM Added

0

10

20

30

40

Pat

ien

ts d

isco

nti

nu

ed, %

PlaceboC andesartan

59

† North American sites.

All patients Age ≥ 75 SCr ≥ 2.0†Spiro

SAS

pgm

: rr_

rena

l_di

sc_0

06; C

lient

ana

lysi

s

SBP < 100n =

Diabetes382 3761272 1276 245 212 54 77 215 222 20 26

CS-7

HyperkalemiaCHARM Added

C

All patients, n (%)PlaceboN = 1272

CandesartanN = 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.

CS-8Discontinuation Due to Hyperkalemia in Important Baseline SubgroupsCHARM Added

0

5

10

15

20

Pat

ien

ts d

isco

nti

nu

ed, %

PlaceboC andesartan

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

CS-9

Summary of Adverse EventsCHARM Added

Patients, n (%)PlaceboN = 1272

CandesartanN = 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 discontinuationdue to AE

224 (17.6) 310 (24.3)

Dose reductiondue to AE

123 (9.7) 220 (17.2)

2.7.

4 Su

mm

Clin

saf

ety

T 21

C

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Common Serious Fatal Adverse EventsCHARM Added

Patients, n (%)PlaceboN = 1272

CandesartanN = 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

CS-11Outcomes by β-blocker and Spironolactone Use CHARM AddedGroup N

Events placebo

Events candesartan

CV mortality or CHF hospitalizationACEi + spironolactone No: 2112

Yes: 436441/105897/214

378/1054105/222

ACEi + β-B + spironolactone No: 2311Yes: 237

487/114451/128

444/116739/109

All patients 2548 538/1272 483/1276

Tabl

e 10

2, A

pp 1

2.1.

9.4.

73,7

4,77

,78

Candesartanbetter

Placebobetter

Hazard ratio (95% CI)0.5 1 1.5

All-cause hospitalizationACEi + spironolactone No: 2112

Yes:436714/1058144/214

696/1054156/222

ACEi + β-B + spironolactone No: 2311Yes: 237

775/114483/128

776/116776/109

All patients 2548 858/1272 852/1276All-cause mortalityACEi + spironolactone No: 2112

Yes: 436324/105888/214

304/105473/222

ACEi + β-B + spironolactone No: 2311Yes: 237

368/114444/128

350/116727/109

All patients 2548 412/1272 377/1276

CS-12Cumulative Number of Hospital Admissions for Any CauseCHARM Added

0

500

1000

1500

2000

2500

3000

0 50 100 150 200

No.

of a

dmis

sion

s

Week

Candesartan

Placebo

CS-13

Rates of Hospital Admission by CauseCHARM Added

All CV HF Non-CV

Adm

issi

ons/

patie

nt/y

r

0.4

0.8

1.0

1.2

1.4

1.6

0.6

0

0.2

Placebo Candesartan

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All-Cause MortalityCHARM Added

Time, mo

Cum

ulat

ive

risk,

%

0

5

10

15

20

25

30

35

0 6 12 18 24 30 36 42 48

PlaceboCandesartan

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

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Safety Findings and ConclusionsCHARM 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

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CS-16

Risk MinimizationCHARM 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