CHARM

Candesartan in Heart failure

Assessment of Reduction
in Mortality and morbidity

On behalf of the CHARM Programme

Investigators and Committees
 Background

• CHF patients with optimal treatment

(ACE inhibitors, beta-blockers and
spironolactone) still remain at high risk for
death and readmissions

• ARBs offer the potential to produce further

clinical improvements above and beyond
ACE inhibition through a distinct mechanism
CHARM participants
618 centers in 26 countries
 CHARM Program

3 component trials comparing candesartan

to placebo in patients with symptomatic heart failure

CHARM CHARM CHARM

Alternative Added Preserved
n=2028 n=2548 n=3025
LVEF ≤40% LVEF ≤40% LVEF >40%
ACE inhibitor ACE inhibitor ACE inhibitor
intolerant treated treated/not treated

Primary outcome for each trial: CV death or CHF hospitalization

Primary outcome for Overall Program: All-cause death
 CHARM - Low EF trials

• A prespecified and important analysis was

performed of the two trials defined by EF≤40%
(CHARM Alternative and CHARM Added)

• This was carefully considered because earlier

studies with ACE inhibitors, beta-blockers,
aldosterone antagonists, and ARBs in CHF
were done specifically in this population

Young et al, Circulation 2004

 Inclusion and Exclusion Criteria

Inclusion criteria Key exclusion criteria

• Age >18 years • S-creatinine ≥ 265 µmol/L
(≥3mg/dL)
• Symptomatic heart
failure for at least • S-potassium ≥ 5.5mmol/L
4 weeks (New York • Bilateral renal artery
Heart Association stenosis
Class II-IV)
• Symptomatic hypotension
• ARB within two weeks
Young et al, Circulation 2004
 Study Design
Dose-titration and visit schedule

Candesartan/
32 mg matching placebo
16 mg once daily
8 mg 32 mg
4 mg 16 mg
8 mg

Every 4 months
Time 0 w 2w 4w 6w 6 m until study end
31 March 2003
Visit 1 2 3 4 5

Young et al, Circulation 2004

 CHARM - Low EF trials
Patient disposition

4576 patients randomised

2289 assigned to 2287 assigned to

Candesartan Placebo

5 lost to 2 lost to
follow-up follow-up

2284 completed 2285 completed

study study

Median follow-up of 40 months

Young et al, Circulation 2004
 Baseline characteristics (1)

Candesartan Placebo
n=2289 n=2287
Mean age (years) 65 65
Women (%) 26 26
NYHA class (%)
II 35 34
III 62 62
IV 3 4
Mean LVEF (%) 29 29
Medical history (%)
myocardial infarction 59 58
diabetes 29 29
hypertension 48 50
atrial fibrillation 26 26
Young et al, Circulation 2004
 Baseline characteristics (2)

Candesartan Placebo
n=2289 n=2287
Baseline therapy (%)
ACE inhibitor 56 56
beta-blocker* 55 55
diuretic 88 88
spironolactone* 21 20
digitalis 52 53
ASA 54 55
lipid lowering 42 41
*At end of study usage of beta-blockade was 64% and 67%
and of spironolactone 22% and 27%, for candesartan and
placebo respectively
Young et al, Circulation 2004
 CHARM - Low EF trials
All-cause death
All cause death (%)
40 Placebo
708 (31.0%)
35
30 Two year HR 0.80
p=0.001 Candesartan
25
642 (28.0%)
One year HR 0.67
20
p<0.001
15
10
Hazard ratio 0.88 (95% CI 0.79 – 0.98),
5
p=0.018
0
Number at risk 0 1 2 3 3.5 yrs
Candesartan 2289 2105 1894 1382 580
Placebo 2287 2023 1811 1333 548
Young et al, Circulation 2004
 CHARM - Low EF trials
CV death and non-CV death

CV deaths and Non CV deaths (%)

30
CV death Placebo
25 Hazard ratio 0.84 Candesartan
(95% CI 0.75 – 0.95),
20 p=0.005
15

10 Non CV death
Candesartan
p=0.60
5
Placebo
0
Number at risk 0 1 2 3 3.5 yrs
Candesartan 2289 2105 1894 1382 580
Placebo 2287 2023 1811 1333 548
Young et al, Circulation 2004
 CHARM - Low EF trials
CV death or CHF hospitalisations

CV death or CHF hosp (%) Placebo

50 944 (41.3%)
Two year HR 0.77
40
p<0.001
One year HR 0.70 Candesartan
30
p<0.001 817 (35.7%)

20

10 Hazard ratio 0.82 (95% CI 0.74 – 0.90),

p<0.001
0
Number at risk 0 1 2 3 3.5 yrs
Candesartan 2289 2105 1894 1382 580
Placebo 2287 2023 1811 1333 548
Young et al, Circulation 2004
 CHARM - Low EF (Alternative and Added)
Primary and secondary outcomes

Candesartan Placebo p-value

All cause death 642 708 0.018

All cause/CHF hosp 910 1020 <0.001
CV death, CHF hosp. 817 944 <0.001
- CV death 521 599 0.005
- CHF hosp. 516 642 <0.001
CV death, CHF hosp, 848 970 <0.001
MI

0.6 0.8 1.0 1.2 1.4

candesartan Hazard placebo
better ratio better

Young et al, Circulation 2004

 CHARM - Low EF trials
CV death or CHF hospitalisations

Cande- Placebo Test for

sartan interaction
Age ≤65 312/1044 327/1028
(yrs) >65 <75 299/ 800 358/ 775 p=0.23
≥75 206/ 445 259/ 484
Gender Male 618/1697 712/1691 p=0.95
Female 199/ 592 232/ 596
EF <25 296/ 627 321/ 596 p=0.93
≥25 521/1661 623/1691
NYHA II 208/ 799 251/ 781
p=0.46
III/IV 609/1490 693/1506
Overall 817/2289 944/2287

0.60.70.80.91.01.11.21.3
Candesartan Hazard Placebo
better ratio better
Young et al, Circulation 2004
 CHARM - Low EF trials
CV death or CHF hospitalisation

Cande- Placebo Test for

sartan interaction
Diabetes No 499/1635 605/1635 p=0.12
Yes 318/ 654 339/ 652
Hyper- No 397/1180 455/1153 p=0.79
tension Yes 420/1109 489/1134
ACE No 333/1012 405/1015 p=0.26
inhibitors Yes 484/1277 539/1272
Beta- No 432/1034 496/1023 p=0.75
blocker Yes 385/1255 448/1264
Spirono- No 602/1817 730/1839 p=0.26
lactone Yes 215/ 472 214/ 448
Overall 817/2289 944/2287
0.60.70.80.91.01.11.21.3
Candesartan Hazard Placebo
better ratio better
Young et al, Circulation 2004
 CHARM - Low EF trials
CV death or CHF hospitalisation

Cande- Placebo Test for

sartan interaction
ACEi+Bb+ No 778/2180 893/2159 p=0.93
Spiro Yes 39/ 109 51/ 128
Other No 43/ 277 58/ 272 p=0.51
diuretics Yes 774/2012 886/2015
Digitalis No 321/1099 368/1065 p=0.90
Yes 496/1190 576/1222
Aspirin No 399/1059 451/1033 p=0.79
Yes 418/1230 493/1254
Lipid No 504/1328 607/1357 p=0.27
lowering Yes 313/ 961 337/ 930
Overall 817/2289 944/2287
0.60.70.80.91.01.11.21.3
Candesartan Hazard Placebo
better ratio better
Young et al, Circulation 2004
 CHARM - Low EF trials
Investigator reported CHF hospitalisations

Placebo
Candesartan
Proportion of Number of
patients (%) episodes HR 0.73
HR 0.80 p<0.001
35
p<0.001 1400
30
1200
25
1000
20
800
15 600
10 400
5 200
0 0
Patients hospitalised Hospitalisations
Young et al, Circulation 2004
 CV death or CHF hospitalisation and relative
risk reduction (RRR) at 12 and 24 months and
end of study

Placebo
Proportion of patients with events, %
45 Candesartan

40
35
30
25
20
15
10
5
0
Months 12 24 End of study
RRR 30% 23% 18%
p-value <0.001 <0.001 <0.001
Young et al, Circulation 2004
 CHARM - Low EF trials
Permanent study drug discontinuations

Percent of patients Placebo

25 23.1 Candesartan

20 18.8

15

10
7.1
5 4.2 3.5
2.1 2.8
0.5
0
AE/ Hypo- Increased Increased
lab. abnorm. tension creatinine potassium
p<0.001 p<0.001 p<0.001 p<0.001
Young et al, Circulation 2004
 All cause mortality and relative risk
reduction (RRR) at 12 months
Proportion of patients with events, %
18 Placebo

16 Investigational
14 drug

12
10
8
6
4
2
0
SOLVD MERIT-HF CHARM low EF
RRR 23% 34% 33%
Investigational drug ACE-I beta-blocker Candesartan
Baseline therapy diuretic, digoxin diuretic, digoxin diuretic, digoxin ACE-I,
ACE-I spironolactone, beta-blocker
Young et al, Circulation 2004
 All cause mortality and relative risk
reduction (RRR) at 24 months
Proportion of patients with events, %
50 Placebo
45 Investigational
40 drug
35
30
25
20
15
10
5
0
SOLVD RALES CHARM low EF
RRR 23% 30% 20%
Investigational drug ACE-I spironolactone Candesartan
Baseline therapy diuretic, digoxin diuretic, digoxin diuretic, digoxin ACE-I,
ACE-I, beta-blocker spironolactone, beta-blocker
Young et al, Circulation 2004, Östergren et al, JRAAS 2003
 CHARM - Low EF trials
Conclusions

Treatment of heart failure patients and left

ventricular systolic dysfunction with
candesartan resulted in a:
• 12% reduction in all cause deaths
(p=0.018)
• 16% reduction in CV mortality (p=0.005)
• 24% reduction in CHF hosp. (p<0.001)
• 18% reduction in CV deaths or CHF hosp.
(p<0.001)
Young et al, Circulation 2004
 CHARM-Low EF
Implications

• Candesartan significantly reduces cardiovascular

death, hospital admission for heart failure, and
all-cause mortality in patients with CHF and
LVEF ≤40% when added to standard therapies
including ACE inhibitors, beta-blockers, and an
aldosterone antagonist

• This approach offers the clinician an opportunity

to make additional improvements in the poor
prognosis of CHF patients when left ventricular
systolic dysfunction is present

Young et al, Circulation 2004