The current treatment for chronic heart

failure a CHARM of therapy

Bambang Herwanto
 Key issues in heart failure

Chronic heart failure is

Common 2% of the population
Dangerous high mortality
Disabling high morbidity
Costly 2% of health care budget
Treatable very successful
pharmacological therapy developed
 Barriers to optimal treatment

Any factors (insufficient knowledge, attitudes,

business practices, policies or regulations) with the
potential to lead to suboptimal treatment
Six sources of barriers

1. Patients
2. Physicians
3. Payers/Institutions
4. Professional societies
5. Industry
6. Regulatory agencies
Adherence (>80 v <80) and Adjusted Outcomes

Endpoint Odds ratio (95% CI)

Death
.52
Candesartan
.54
Placebo
CHF Hosp
.58
Candesartan
.58
Placebo
0.50 0.75 1.0
Adherent better worse
Granger B et al, ESC 2005
 Kaplan-Meier estimates for cardiovascular
hospitalisation according to GAI3
Estimated probability
1.00
0.95
0.90
0.85
0.80
0.75
0.70 Log-rank test: p-value = 0.002
0.65 Low adherence
0.60 Middle adherence
0.55 High adherence
0.50
0 20 40 60 80 100 120 140 160 180
Time (days)

Komajda M et al, Eur Heart J Aug 2005

 Euroheart Failure Survey
% of patients with CHF on beta-blockers
11019 patients in 116 hospitals in 25 countries
%
100

80

60

40

20

Komajda et al, EHJ 2003

 Overcoming the barriers

Promotion of patient adherence

Physician education
Disease management programs
Audit and feedback
(Antimineralocorticoid)
(Hydralazine + Isosorbid Dinitrate)
 NICE Guideline (2011)

Consider an ARB
If the patient is intolerant
To ACE inhibitors

Ann Intern Med. 2011;155(4):252-259

 Renin-angiotensin
aldosterone system
Non-ACE Pathways Vasoconstriction
(e.g., chymase)
Cell growth
Na/H2O retention
Sympathetic activation
Angiotensinogen

renin Angiotensin I AT1

Angiotensin II ARB
ACEi

Aldosterone AT2

Cough, Vasodilation
Angioedema Bradykinin
Inactive Antiproliferation
Benefits? Fragments (kinins)

McMurray et al, Circ 2004

 CHARM Programme

3 component trials (N=7601) 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 Programme: All-cause death
16
 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

17
 CHARM Programme
3 component trials comparing
candesartan to placebo

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:
CV death or CHF hosp
18
 CHARM-Alternative: Primary outcome CV
death or CHF hospitalization
%
50
406 (40%)
Placebo
40
1 year HR 0.64 334 (33%)
P<0.0001
30
Candesartan
20

10 HR 0.77 (95% CI 0.67-0.89), p=0.0004

Adjusted HR 0.70, p<0.0001
0
0 1 2 3 3.5 years
Number at risk
Candesartan 1013 929 831 434 122
Placebo 1015 887 798 427 126
19
 CHARM-Alternative:
Investigator reported CHF hospitalizations
Placebo
Proportion of Number of Candesartan
patients (% ) episodes
RRR 32% RRR 27%
35 700 p=0.0001
p<0.0001
30 600
25 500
20 400
15 300
10 200
5 100
0 0
Patients hospitalized Hospitalizations
20
 CHARM Programme
3 component trials comparing
Candesartan to placebo

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:
CV death or CHF hosp
21
 CHARM-Added: Primary outcome
CV death or CHF hospitalization
%
50
Placebo 538 (42.3%)
40 483 (37.9%)
1 year HR 0.76
P<0.001
30
Candesartan
20

10 HR 0.85 (95% CI 0.75-0.96), p=0.011

Adjusted HR 0.85, p=0.010
0
0 1 2 3 3.5 years
Number at risk
Candesartan 1276 1176 1063 948 457
Placebo 1272 1136 1013 906 422 NNT = 23
22
 CHARM-Added:
Investigator reported CHF hospitalizations
Placebo
Proportion of Number of Candesartan
patients (% ) episodes
HR 17% RRR 27%
35 1000
p=0.008 p=0.002
30
800
25
20 600
15 400
10
200
5
0 0
Patients hospitalized hospitalizations
23
Was there really an additional benefit from
adding candesartan?

Was the dose of ACE inhibitor too low?

Is candesartan beneficial even when added to

full dose ACE inhibitor?

24
 CHARM Added
CV and Non-CV Death
30 CV Death Placebo
Relative risk reduction = 16%
Candesartan
25 HR = 0.84 (95% CI: 0.72, 0.98)
p = 0.029
20
%
15
Non-CV Death
HR = 1.11 (95% CI: 0.80, 1.55)
10
Candesartan
5 Placebo

0
0 6 12 18 24 30 36 42 48
Time, mo
At risk, n
Placebo 1272 1136 1013 906 422
Candesartan 1276 1176 1063 948 458
Median follow-up 41.0 mo. 25
 Dose of ACE inhibitor achieved in
CHARM-Added compared to randomised
outcome trials using forced titration
ACE-inhibitor Mean dose in Mean dose in
Trial (% in CHARM outcome trial CHARM-Added
Added) (mg) (mg)
SOLVD Enalapril (27%) 16.6 17.0
GISSI 3 Lisinopril (19%) 17 17.7
SAVE Captopril (17%) 121 82.5
AIRE Ramipril (11%) 8.7 7.1
TRACE Trandolapril (6%) 3.0 2.5

26
 CHARM Added
CV Death or HF HospitalisationRecommended
or maximum ACE inhibitor doses at baseline
Candesartan Placebo
better better p value for
Patients, n interaction
Recommended dose of ACEi No 1257
0.26
(CHARM) Yes 1291

Maximum dose of ACEi No 1827

0.78
(FDA) Yes 721

Maximum dose of ACEi No 2019

(FDA) revised Yes 529 0.29

All patients 2548

0.6 0.7 0.8 0.9 1 1.1 1.2 1.3

FDA communication 12-17-04. Hazard ratio (95% CI)
FDA communication 01-24-05.
 Improving survival in CHF
1 year mortality
SOLVD-T (1991) CIBIS-2 (1999) CHARM-Added (2003)
20 ( blocker subgroup)
RRR 21% RRR 33% RRR 30%

15
%

10

0
diuretic diuretic diuretic diuretic diuretic diuretic

digoxin digoxin digoxin digoxin digoxin digoxin

ACE-I ACE-I ACE-I ACE-I ACE-I
blocker blocker blocker
28
ARB
Take Home Messages

Chronic heart Failure is manageable. There is a choice for a

very successful pharmacological therapy.
ACEi/ARB is recommended as a first line treatment for chronic
heart failure as suggested by the current guidelines (ESC 2012;
NICE 2011).
Candesartan can be used as an alternative for ACEi in
intolerant chronic heart failure patients as suggested by
CHARM Alternative trial.
Candesartan can also be used as an add-on therapy to ACEi to
achieve better outcomes for chronic heart failure patients as
suggested by CHARM Added trial.
THANK YOU