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
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 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
CS-14
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)
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