CS-1

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

James W. Hainer, MD, MPH

AstraZeneca

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 theresponsible 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 S

um

m C

lin

saf

ety

T 2

2,

44;

SH

-AH

S-p

oo

led

T 1

50

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

0

5

10

15

20

Pa

tie

nts

dis

co

nti

nu

ed

, %

Placebo

C andesartan

59

All patients Age ≥ 75 BaselineSBP < 100

β-blockerSpiro

CS

R S

H-A

HS

-000

6 A

pp

12.

1.9.

5.22

; S

AS

pg

m:

rr_h

ypo

_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

Pa

tie

nts

dis

co

nti

nu

ed

, %

Placebo

C andesartan

59

† North American sites.

All patients Age ≥ 75 SCr ≥ 2.0†Spiro

SA

S p

gm

: rr

_ren

al_d

isc_

006;

Cli

ent

anal

ysis

SBP < 100

n =

Diabetes

382 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

Pa

tie

nts

dis

co

nti

nu

ed

, %

Placebo

C 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 S

um

m C

lin

saf

ety

T 2

1C

CS-10

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 Added

Group NEvents 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

Tab

le 1

02,

App

12.

1.9.

4.73

,74,

77,7

8

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 852/1276

All-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

ad

mis

sio

ns

Week

Candesartan

Placebo

CS-13

Rates of Hospital Admission by CauseCHARM Added

All CV HF Non-CV

Ad

mis

sio

ns

/pa

tien

t/y

r

0.4

0.8

1.0

1.2

1.4

1.6

0.6

0

0.2

Placebo Candesartan

CS-14

All-Cause MortalityCHARM Added

Time, mo

Cu

mu

lati

ve r

isk,

%

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)

CS-15

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

C

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