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On behalf of the CHARM Programme Investigators and Committees
Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity
CHARM
2
Background (1)
ACE inhibitors, beta-blockers and spironolactone have been demonstrated to be life-saving in patients with CHF
However, these patients still remain at high risk for cardiovascular death and recurrent hospital admissions for heart failure
3
Burden of chronic heart failure (CHF)
CHF is an increasing burden to health care [1] Pharmacological treatments improve survival and
reduce hospitalisations in patients with low LVEF [2–5]
Despite these treatments, morbidity and mortality remain high
30–50% of CHF patients have preserved LVEF [6] Not known what treatments benefit CHF patients
with preserved LVEF
1. Cowie et al. Eur Heart J 1997; 18(2): 208–252. Garg et al. Lancet 1999; 353: 9–133. CIBIS-II Investigators and Committees. Lancet 1999; 353: 9–134. Hjalmarson et al. JAMA 2000; 283(10): 1295–3025. Pitt et al. N Engl J Med 1999; 341(10): 709–176. Senni et al. Circulation 1998; 98: 2282–89
4
Background (2)
Angiotensin II type 1 (AT1) receptor blockers (ARBs) provide a pharmacologically distinct mechanism of inhibiting the renin-angiotensin-aldosterone system
ARBs offer the potential to produce further clinical improvements above and beyond ACE inhibitors as well as an alternative for those previously intolerant to an ACE inhibitor
5
AT1-receptor blockers: mechanism of action
Angiotensin II type 1 (AT1) receptor blockers – pharmacologically distinct mechanism of inhibiting RAAS
AT1-receptor inhibition – more complete blockade of angiotensin II action
Existence of alternative, non-ACE enzymatic pathways – angiotensin II can be generated from angiotensin I even in presence of ACE inhibitor [1]
Reflex increase in angiotensin I induced by ACE inhibition may overcome competitive blockade of ACE enabling angiotensin II (and aldosterone) ‘escape’
Blockade of AT1-receptor, rather than ACE, could be better at inhibiting adverse effects of RAAS
1. Wolny et al. Circ Res 1997; 80(2): 219–27
6
AT1-receptor blockers: improving heart function
Reducing hypertension [1] Reducing LV hypertrophy/improving LV
relaxation Antagonising adverse effects of elevated
neurohormones Reducing aldosterone levels Maintaining renal function
1. Goodfriend et al. N Engl J Med 1996; 334: 1649–542. Swedberg et al. J Card Failure 1999; 5: 276–82
7
AT1-receptor blockers reduce left ventricular hypertrophy: CATCH
study
50
40
30
20
10
0Pa
tient
s w
ith r
egre
ssio
n o
fve
ntr
icu
lar
ma
ss (
%) Enalapril
Candesartan
Week 24 Week 48
3025
3630
Cuspidi et al. J Hypertens 2002; 20: 2293–300
8
Trials with AT1-receptor blockers in CHF: ELITE II and Val-HeFT
ELITE-IIELITE-II: losartan vs captopril [1] Losartan similar in efficacy compared to captopril in patients with CHF and an impaired left ventricular function, and losartan better tolerated
Val-HeFTVal-HeFT: valsartan vs placebo in addition to standard heart failure therapy [2] Modest but significant reduction in one of the primary endpoints, but no effect on all-cause mortality
1. Pitt et al. Lancet 2000; 355: 1582–72. Cohn et al. N Engl J Med 2001; 345: 1667–75
9
Candesartan: potent and long-acting
AT1-receptor blocker Highly potent [1] Long-acting [1]
10,000 greater affinity for AT1-receptor than AT2-receptor [1]
‘Insurmountable’ antagonist [1] Antihypertensive agent [2] Well tolerated [3–6] Effect on morbidity and mortality?
1. Ojima et al. Eur J Pharmacol 1997; 319: 137–46. 2. Andersson et al. J Hum Hypertens 1997; 11(Supp2): S63–4.3. McKelvie et al. Circulation 1999; 100: 1056–64. 4. Granger et al. Am Heart J 2000 139(4): 609–17. 5. Riegger et al. Circulation 1999; 100: 2224–30. 6. Mitrovic et al. Am Heart J 2003; 145: E14.
10
Clinical experience with candesartan
in CHF RESOLVD pilot studyRESOLVD pilot study: candesartan combined with enalapril
improved LV function more than either of agents alone, and suppressed aldosterone levels to a greater extent [1]
SPICE pilot studySPICE pilot study: in patients with history of ACE inhibitor intolerance, similar percentage of patients completed 12-week treatment period on candesartan vs placebo [2]
STRETCH studySTRETCH study: maximal exercise capacity increased dose-dependently with candesartan compared to placebo [3]
Mitrovic et al. studyMitrovic et al. study: candesartan demonstrated significant short- and long-term improvements in haemodynamic, neurohormonal and symptomatic status [4]
1. McKelvie et al. Circulation 1999; 100: 1056–642. Granger et al. Am Heart J 2000 139(4): 609–173. Riegger et al. Circulation 1999; 100: 2224–304. Mitrovic et al. Am Heart J 2003; 145: E14
11
CHARM design rationale
An international, multicentre programme comprising of three double-blind studies
To provide definitive and quantitative clinical information on the role of candesartan in a broad spectrum of symptomatic heart failure
To allow uniform procedures across the three independent studies
To provide adequate power for study objectives
Swedberg et al. J Card Failure 1999; 5(3): 276–82
12
CHARM programme studies
CHARM-AlternativeCHARM-Alternative: patients with depressed LV systolic function (LVEF 40%) and not treated with an ACE inhibitor (due to intolerance)
CHARM-AddedCHARM-Added: patients with depressed LV systolic function (LVEF 40%) and treated with an ACE inhibitor
CHARM-PreservedCHARM-Preserved: patients with preserved LV systolic function (LVEF > 40%) treated or not treated with an ACE inhibitor
Swedberg et al. J Card Failure 1999; 5(3): 276–82
13
Design of CHARM programme
CHF: NYHA class II–IV
EF 40% EF > 40%
ACE-intolerance ACE-I treated
Randomisation‘Alternative’
Randomisation‘Added’
Randomisation‘Preserved’
Candesartan 4/8 32 mg Placebo
Titration period
Visit every 4 months up toat least 24 months
Mortality/morbidity endpoints
Swedberg et al. J Card Failure 1999; 5(3): 276–82
14
Aims: CHARM Programme
Effects of Candesartan on Each trial: Cardiovascular death or CHF
hospitalisation Overall programme: All-cause death
Key secondary outcomes Other major CV-outcomes Mortality in patients with LVEF 40%
Other prespecified outcomes Development of diabetes mellitus Investigator reported outcomes
15
CHARM Added
CHARMPreserved
CHARM Programme
3 component trials comparing candesartan to placebo in patients with symptomatic heart failure
CHARMAlternative
n=2028
LVEF 40%ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
n=3025
LVEF >40%ACE inhibitor
treated/not treated
Primary outcome for Overall Programme: All-cause death
Primary outcome for each trial: CV death or CHF hospitalisation
16
CHARM secondary objectives for each study
To determine if candesartan, compared with placebo, reduces the combined endpoint of: cardiovascular mortality, hospitalisation for the
management of CHF, or nonfatal myocardial infarction
cardiovascular mortality, or hospitalisation for the management of CHF, or nonfatal myocardial infarction, or coronary revascularisation procedures
all-cause mortality and all-cause hospitalisation
Swedberg et al. J Card Failure 1999; 5(3): 276–82
17
CHARM other objectives for each study
To determine if candesartan, compared with placebo:
influences of assignment to candesartan on each of the individual components of the composite endpoints
effects the functional state and symptoms according to the NYHA classification, as well as the safety and tolerability
influences the use of candesartan on health care costs
Swedberg et al. J Card Failure 1999; 5(3): 276–82
18
Countries and national leaders
Country Co-ordinator Patients
Australia P. Aylward 227
Belg/Lux J. Vanhaecke 249
Canada R. S. McKelvieJ-L. Rouleau 943
Czech Rep M. J. Hradec 194
Denmark P. Thayssen 487
Finland M. Niemelä 102
France A. Cohen Solal 225
Germany R. Dietz 803
Hungary I. Edes 204
Iceland A. Kristinson 82
Italy A. Maggioni 151
Malaysia C. C. Lang 140
Netherlands D.J. van Veldhuisen 420
Norway T. Gundersen 217
Poland J. Kuch 215
Portugal R. Seabra Gomes 93
Russia A. Yurenev 200
Singapore D. Zee Pin 62
South Africa A. J. Dalby 120
Spain J. Soler Soler 125
Sweden H. Persson 192
Switzerland O. Hess 68
UK/Ireland A. J. S. Coats 281
USA J. Young 1.801M. Dunlap
Total number of patients 7,601
Country Co-ordinator Patients
19
Recruitment in the three component CHARM-trials
0
2000
4000
6000
8000
Jan June Dec June
1999 2000
Number of patients
Firstpatient
March 221999
Overall7601
Preserved3025Added
2548
Alternative2028
Dec2001
20
Inclusion and exclusion criteria
Inclusion Aged 18 years Symptomatic CHF NYHA class II–IV 4 weeks
pre-randomisation LVEF documentation 6 months
Exclusion Heart transplant recipients Hypertension, stroke, acute MI, recent open
heart surgery Life expectancy < 2 years due to noncardiac disease
Swedberg et al. J Card Failure 1999; 5(3): 276–82
21
Inclusion and exclusion criteria
Key exclusion criteria
S-creatinine 265 mol/L (3mg/dL)
S-potassium 5.5mmol/L
Bilateral renal artery stenosis
Symptomatic hypotension
ARB within two weeks
Inclusion criteria
Age >18 years
Symptomatic heart failure for at least 4 weeks (New York Heart Association Class II-IV)
22
Study designDose-titration and visit schedule
Time 0 w 2 w 4 w 6 w 6 mEvery 4 monthsuntil study end31 March 2003
Visit 1 2 3 4 5
32 mgCandesartan/matching placeboonce daily16 mg
8 mg 32 mg4 mg 16 mg8 mg
23
Statistical methods (1)
In each component trial, sample size was independently estimated for the composite outcome of cardiovascular death or hospitalisation for heart failure
All-cause mortality was evaluated in the Overall programme
24
Statistical methods (2)
Main analysis for each trial: CV death and hospitalisation for CHF based on adjudicated events
Supportive analysis: Cox regression model with 33 prespecified baseline covariates to improve precision
Other analyses: investigor reported outcomes and prespecified subgroups
25
Baseline data: number of patients randomised per country and study
CountryCountry CHARM- CHARM- CHARM-CHARM- CHARM-CHARM- TotalTotal AlternativeAlternative Added Added Preserved Preserved
Australia 54 76 97 227Belgium 60 82 106 248Canada 208 357 378 943Czech Republic 66 71 57 194Denmark 92 207 188 487Finland 29 14 59 102France 55 70 100 225Germany 154 346 303 803Hungary 66 69 69 204Iceland 25 21 36 82Italy 20 14 91 151Luxembourg 0 0 1 1Malaysia 53 38 49 140The Netherlands 173 128 118 419Norway 47 97 73 217Poland 66 79 70 215Portugal 21 19 53 93Russia 53 15 132 200Singapore 20 21 21 62South Africa 48 32 40 120Spain 50 17 58 125Sweden 53 64 75 192Switzerland 15 25 28 68United Kingdom 104 89 87 280USA 470 597 734 1801
Total 2028 2548 3023 7599
McMurray et al. Eur J Heart Fail; 5(3): 261–70
26
Baseline data: characteristics of patients
VariableVariable CHARM-AlternativeCHARM-Alternative CHARM-Added CHARM-Added CHARM-Preserved CHARM-Preserved (n=2028)(n=2028) (n=2548)(n=2548) (n=3025)(n=3025)
Mean age (years) 67 64 67Males (%) 68 79 60LVEF 0.30 0.28 0.54Diabetes mellitus (%) 27 30 28Hypertension (%) 50 48 64Atrial fibrillation (%) 25 26 29Previous MI (%) 62 56 44Angina pectoris (%) 58 53 60Previous stroke (%) 9 9 9NYHA II (%) 48 24 61NYHA III (%) 49 73 38NYHA IV (%) 4 3 2Current smoker (%) 14 17 14
McMurray et al. Eur J Heart Fail; 5(3): 261–70
27
Mean age (years) 67 64 67 66
Women (%) 32 21 40 32
NYHA class (%)II 48 24 60 45III 49 73 38 52IV 3 3 2 3
Mean LVEF 30 28 54 39
Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27
Baseline characteristics (1)
Alternative Added Preserved Overalln=2028 n=2548 n=3023 n=7599
28
LVEF (%)
- Mean 30 28 54 39
- Proportion <0.40 100 100 0 60
SBP/DBP (mmHg) 130/77 125/75 136/78 131/77
Heart rate (beats/min) 74 74 71 73
Baseline characteristics (2)
Alternative Added Preserved Overalln=2028 n=2548 n=3023 n=7599
29
Baseline therapy (%)
ACE inhibitor 0 100 19 41
beta-blocker 55 56 56 55
diuretic 86 90 75 83
spironolactone 24 17 12 17
digitalis 46 58 28 43
aspirin 58 52 58 56
lipid lowering 41 41 42 42
Baseline characteristics (3)
Alternative Added Preserved Overalln=2028 n=2548 n=3023 n=7599
30
Baseline data: background medication
VariableVariable CHARM-CHARM- CHARM- CHARM- CHARM- CHARM- Alternative Alternative Added Added PreservedPreserved
Digoxin (%) 46 59 28
Diuretics (%) 86 90 75
Loop diuretics (%) 78 84 63
Spironolactone (%) 24 17 12
Beta blocker (%) 55 56 56
Calcium antagonist (%) 16 10 31
Long acting nitrates (%) 37 33 33
Amiodarone (%) 12 11 8
Lipid lowering agent (%) 42 42 42
Oral anticoagulant (%) 31 38 25
Aspirin (%) 58 52 58
McMurray et al. Eur J Heart Fail; 5(3): 261–70
31
Baseline data: principal aetiology of heart failure
McMurray et al. Eur J Heart Fail; 5(3): 261–70
0
20
40
60
80
%
Ischaemic Idiopathic Hypertensive AF
CHARM alternative
CHARM added
CHARM preserved
32
Baseline data: reason for ACE-intolerance for patients in CHARM-
Alternative
ACE-inhibitor intolerance due to:ACE-inhibitor intolerance due to: CHARM-CHARM-AlternativeAlternative
AllAll MenMen WomenWomen
Angioedema, anaphylaxis (%) 4 4 5
Cough (%) 72 69 77
Symptomatic hypotension (%) 13 1410
Renal dysfunction (%) 12 13 8
Other adverse events (%) 11 11 10
McMurray et al. Eur J Heart Fail; 5(3): 261–70
33
Baseline data: physical examination and ECG
VariableVariable CHARM-AlternativeCHARM-Alternative CHARM-Added CHARM-Added CHARM-Preserved CHARM-Preserved
BMI (kg/m2) 27 28 29
Heart rate (bpm) 74 74 71
Mean DBP (mm Hg) 77 75 78
Mean SBP (mm Hg) 130 125 136
Atrial fib/flutter (%) 14 16 16
Bundle branch block (%) 30 31 14
Pathological Q waves (%) 30 27 20
LVH (%) 15 17 15
BMI=body mass index; bpm=beats per minute; DBP=diastolic blood pressure; SBP=systolic blood pressure
McMurray et al. Eur J Heart Fail; 5(3): 261–70
34
Baseline data: ELITE-II vs CHARM-Alternative and Val-HeFT vs CHARM-
Added
ELITE-II ELITE-II CHARM-CHARM- Val-HeFT Val-HeFT CHARM- CHARM- [1] [1] Alternative [4]Alternative [4] [2,3] [2,3] Added [4]Added [4]
Number 3152 2028 5010 2548
Mean age (years) 71 67 63 64
Men (%) 70 68 80 79
LVEF (%) 31 30 27 28
NYHA II (%) 49 48 62 24
NYHA III (%) 45 49 36 73
Digoxin (%) 50 46 68 58
Beta blocker 24 55 36 55
Spironolactone (%) — 24 2 17
ACEI=ACE inhibitors
Variable Alternative to ACEI Addition to ACEIVariable Alternative to ACEI Addition to ACEI
1. Pitt et al. Lancet 2000; 355:1582–72. Cohn et al. N Engl J Med 2001; 345:1667–753. Cohn et al. Eur J Heart Failure 2000; 2: 439–464. McMurray et al. Eur J Heart Fail; 5(3): 261–70
35
Conclusions from baseline characteristics
CHARM patient population represents broad spectrum of heart failure patients
Patients have a modern background pharmacological heart failure treatment
CHARM results will answer many questions unresolved by previous large trials on AT1-receptor blockers in CHF
McMurray et al. Eur J Heart Fail; 5(3): 261–70
36
CHARM Programme
n=3025
LVEF >40% ACE inhibitor
treated/not treated
CHARM Added
CHARMPreserved
3 component trials comparingcandesartan to placebo
CHARMAlternative
n=2028
LVEF 40%ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
Primary outcome:CV death or CHF hosp
37
CHARM-AlternativeBackground
At least 20% of patients with CHF are not receiving ACE inhibitors, about half (10%) due to ACE inhibitor intolerance. Aim
To evaluate effects of candesartan in patients with symptomatic CHF and intolerance to ACE-I
38
CHARM-AlternativePatient disposition
Median follow-up of 34 months
Candesartann=1013
Placebon=1015
Completed Studyn=1011
Completed Studyn=1014
Lost to follow-upn=2
Lost to follow-up
n=1
2028 patients randomisedNYHA II-IV, LVEF 40%ACE inhibitor intolerant
39
Mean age (years) 67 64 67 66
Women (%) 32 21 40 32
NYHA class (%)II 48 24 60 45III 49 73 38 52IV 3 3 2 3
Mean LVEF 30 28 54 39
Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27
Baseline characteristics
Alternative Added Preserved Overalln=2028 n=2548 n=3023 n=7599
40
Baseline therapy (%)
ACE inhibitor 0 100 19 41
beta-blocker 55 56 56 55
diuretic 86 90 75 83
spironolactone 24 17 12 17
digitalis 46 58 28 43
aspirin 58 52 58 56
lipid lowering 41 41 42 42
Baseline characteristics
Alternative Added Preserved Overalln=2028 n=2548 n=3023 n=7599
41
Reason for ACE-I intolerance (%)
cough 70 74
hypotension 14 12
renal dysfunction 13 10
angioedema/anaphylaxis 4 4
other 10 11
CHARM-AlternativeBaseline characteristics
Candesartan Placebon=1013 n=1015
42
CHARM-Alternative: Primary outcome CV death or CHF hospitalisation
0 1 2 3 years0
10
20
30
40
50
Placebo
Candesartan
%
HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001
Number at risk
Candesartan 1013 929 831 434 122
Placebo 1015 887 798 427 126
3.5
406 (40.0%)
334 (33.0%)
43
CHARM-Alternative Secondary outcomes
CV death 219 252
CHF hosp. 207 286
CV death, CHF hosp, 353 420 MI
CV death, CHF hosp, 369 432 MI, stroke
CV death, CHF hosp, 396 456 MI, stroke, revasc
Candesartan Placebo
candesartan better
Hazard ratio
placebo better
0.6 0.8 1.0 1.2 1.4
p-value
0.072
<0.0001
0.0007
0.001
0.002
0.85
0.68
0.78
0.80
0.81
44
CHARM-Alternative Investigator reported CHF hospitalisations
0
5
10
15
20
25
30
35
0
100
200
300
400
500
600
700
PlaceboCandesartanProportion of
patients (%)
Patients hospitalised Hospitalisations
p<0.0001 p=0.0001
Number of episodes
45
CHARM-Alternative Permanent study drug discontinuations
0
5
10
15
20
25Percent of patients
PlaceboCandesartan
19.3
0.92.7
0.3 0.4
21.5
3.76.1
1.90.2
p=0.23 p<0.0001 p<0.0001 p=0.0005 p=0.69
Hypo-tension
Increased creatinine
Increasedpotassium
CoughAE/lab. abnorm.
0 0.1
p=0.50
Angio-edema
Among all patients
46
CHARM-Alternative Permanent study drug discontinuations
4.2
12.0
1.0 0.5
9.1
23.1
13.6
0.3
According to prior ACE-I intolerance
Percent of patients
0
5
10
15
20
25
Hypo-tension
Increased creatinine
Cough
PlaceboCandesartan
Increasedpotassium
02.6
(1/39)
Angioedema
47
CHARM-AlternativeConclusions
Despite prior intolerance to another inhibitor of the renin-angiotensin-aldosterone system, candesartan was well tolerated
In patients with symptomatic chronic heart failure and ACE-inhibitor intolerance, candesartan reduces cardiovascular mortality and morbidity
48
n=3025
LVEF >40%ACE inhibitor
treated/not treated
CHARM Added
CHARMPreserved
CHARM Programme
3 component trials comparingCandesartan to placebo
CHARMAlternative
n=2028
LVEF 40% ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
Primary outcome:CV death or CHF hosp
49
Despite full conventional treatment, patients with CHF have a poor prognosis - new treatments are needed
Non-ACE pathways produce angiotensin II
ACE (kininase II) inhibition increases bradykinin
CHARM-AddedBackground
Aim
To evaluate the effects of adding candesartan to a ACE-inhibitor in patients with symptomatic CHF
50
CHARM-AddedPatient disposition
Median follow-up of 41 months
Candesartann=1276
Placebon=1272
Completed Studyn=1273
Completed Studyn=1271
Lost to follow-upn=3
Lost to follow-up
n=1
2548 patients randomisedNYHA II-IV, LVEF 40%
ACE inhibitor treated
51
Mean age (years) 67 64 67 66
Women (%) 32 21 40 32
NYHA class (%)II 48 24 60 45III 49 73 38 52IV 3 3 2 3
Mean LVEF 30 28 54 39
Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27
Baseline characteristics
Alternative Added Preserved Overalln=2028 n=2548 n=3023 n=7599
52
Baseline therapy (%)
ACE inhibitor 0 100 19 41
beta-blocker 55 56 56 55
diuretic 86 90 75 83
spironolactone 24 17 12 17
digitalis 46 58 28 43
aspirin 58 52 58 56
lipid lowering 41 41 42 42
Baseline characteristics
Alternative Added Preserved Overalln=2028 n=2548 n=3023 n=7599
53
CHARM-AddedBaseline ACE inhibitor
enalapril 27% 17 17
lisinopril 19% 17 17
captopril 17% 82 83
ramipril 11% 7 7
Mean daily dose of ACE inhibitor (mg)
Candesartan Placebo
Proportion taking
ACE inhibitor
54
CHARM-Added: Primary outcomeCV death or CHF hospitalisation
0 1 2 3 years0
10
20
30
40
50
Placebo
Candesartan
Number at risk
Candesartan 1276 1176 1063 948 457
Placebo 1272 1136 1013 906 422
3.5
HR 0.85 (95% CI 0.75-0.96), p=0.011Adjusted HR 0.85, p=0.010
483 (37.9%)538 (42.3%)
%
55
CHARM-Added Secondary outcomes
CV death 302 347
CHF hosp. 309 356
CV death, CHF hosp, 495 550 MI
CV death,CHF hosp, 512 559 MI, stroke
CV death,CHF hosp, 548 596MI, stroke, revasc
candesartan better
Hazard ratio
placebo better
0.6 0.8 1.0 1.2 1.4
p-value
0.029
0.014
0.010
0.020
0.015
Candesartan Placebo0.84
0.83
0.85
0.87
0.87
56
CHARM-AddedPrespecified subgroups, CV death
or CHF hosp.
Beta- Yes 223/702 274/711blocker No 260/574 264/561
Recom. Yes 232/643 275/648dose of No 251/633 263/624ACE inhib.
All patients 483/1276 538/1272
Candesartan Placebo
candesartan better
Hazard ratio
placebo better
0.6 0.8 1.0 1.2 1.4
p-value fortreatment interaction
0.14
0.26
57
CHARM-Added Investigator reported CHF hospitalisations
0
5
10
15
20
25
30
35
0
200
400
600
800
1000
PlaceboCandesartan
p=0.002p=0.008
Patients hospitalised Hospitalisations
Proportion of patients (%)
Number of episodes
58
CHARM-Added Permanent study drug discontinuations
PlaceboCandesartan
0
5
10
15
20
25
Percent of patients
p=0.0003 p=0.079 p=0.0001 p<0.0001
Hypo-tension
Increased creatinine
Increasedpotassium
AE/lab. abnorm.
18.3
3.1 4.1
0.7
24.2
4.5
7.8
3.4
59
CHARM-AddedConclusions
Addition of candesartan to an ACE inhibitor (and beta-blocker) leads to a further and clinically important reduction in CV mortality and morbidity in patients with CHF
This benefit is obtained with relatively few adverse effects, although there is an increased risk of hypotension, hyperkalaemia and renal dysfunction
60
CHARM - Low EF trials
A prespecified and important analysis was performed of the two trials defined by EF40% (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
61
CHARM - Low EF trialsPatient disposition
Median follow-up of 40 months
5 lost tofollow-up
2 lost tofollow-up
2284 completedstudy
2289 assigned toCandesartan
2285 completedstudy
2287 assigned toPlacebo
4576 patients randomised
Young et al, Circulation 2004
62
Mean age (years) 65 65
Women (%) 26 26
NYHA class (%)II 35 34III 62 62IV 3 4
Mean LVEF (%) 29 29
Medical history (%) myocardial infarction 59 58 diabetes 29 29 hypertension 48 50 atrial fibrillation 26 26
Candesartan Placebon=2289 n=2287
Young et al, Circulation 2004
CHARM - Low EF trials Baseline characteristics (1)
63
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
CHARM - Low EF trials Baseline characteristics (2)
*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
Candesartan Placebon=2289 n=2287
64
CHARM - Low EF trialsAll-cause death
Number at riskCandesartan 2289 2105 1894 1382 580Placebo 2287 2023 1811 1333 548
Placebo708 (31.0%)
Candesartan642 (28.0%)
yrs3.50 1 2 30
10
20
30
All cause death (%)
5
35
25
15
40
Hazard ratio 0.88 (95% CI 0.79 – 0.98), p=0.018
One year HR 0.67p<0.001
Two year HR 0.80p=0.001
Young et al, Circulation 2004
65
yrs3.50 1 2 30
10
20
30CV deaths and Non CV deaths (%)
5
25
15
CHARM - Low EF trials CV death and non-CV death
Non CV death
Placebo
Candesartan
Candesartan
Placebo
Hazard ratio 0.84(95% CI 0.75 – 0.95),p=0.005
p=0.60
CV death
Number at riskCandesartan 2289 2105 1894 1382 580Placebo 2287 2023 1811 1333 548
Young et al, Circulation 2004
66
CHARM LVEF 40% (Alternative and Added)
All-cause death 0.88 0.79-0.98 0.018
CV death 0.84 0.75-0.95 0.005
HR CI p-value
67
CHARM - Low EF trials CV death or CHF hospitalisations
Placebo944 (41.3%)
Candesartan817 (35.7%)
yrs3.50 1 2 30
10
20
30
CV death or CHF hosp (%)
40
Hazard ratio 0.82 (95% CI 0.74 – 0.90), p<0.001
50
One year HR 0.70p<0.001
Two year HR 0.77p<0.001
Number at riskCandesartan 2289 2105 1894 1382 580Placebo 2287 2023 1811 1333 548
Young et al, Circulation 2004
68
CHARM - Low EF trials Investigator reported CHF
hospitalisations
0
5
10
15
20
25
30
35
0
200
400
600
800
1000
1200
1400
HR 0.73p<0.001HR 0.80
p<0.001
Patients hospitalised Hospitalisations
Proportion of patients (%)
Number of episodes
Young et al, Circulation 2004
Placebo
Candesartan
69
CHARM - Low EF trials Permanent study drug discontinuations
0
5
10
15
20
25
Percent of patients
p<0.001 p<0.001 p<0.001 p<0.001
Hypo-tension
Increasedpotassium
AE/lab. abnorm.
18.8
2.13.5
0.5
23.1
4.27.1
2.8
Young et al, Circulation 2004
Increasedcreatinine
PlaceboCandesartan
70
CHARM-Low EFImplications
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
71
CHARM Programme
n=3025
LVEF >40%ACE inhibitor
treated/not treated
CHARM Added
CHARMPreserved
3 component trials comparingcandesartan to placebo
CHARMAlternative
n=2028
LVEF 40% ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
Primary outcome:CV death or CHF hosp
72
CHARM-Preserved Background
Although half of patients with CHF have preserved ejection fractions (>40%), few treatments have specifically been evaluated in such patients
Aim
To evaluate effects of candesartan in patients with symptomatic CHF and LVEF >40%
73
CHARM-PreservedPatient disposition
Median follow-up of 37 months
Candesartann=1514
Placebon=1509
Completed Studyn=1512
Completed Studyn=1508
Lost to follow-upn=2
Lost to follow-up
n=1
3025 patients randomisedNYHA II-IV
LVEF > 40%
2 patients with no data
74
Mean age (years) 67 64 67 66
Women (%) 32 21 40 32
NYHA class (%)II 48 24 60 45III 49 73 38 52IV 3 3 2 3
Mean LVEF 30 28 54 39
Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27
Baseline characteristics
Alternative Added Preserved Overalln=2028 n=2548 n=3023 n=7599
75
Baseline signs, symptoms and radiographic findings
PreservedAddedAlternative35
30
25
20
15
10
5
0
%
Oedema Orthop-noea
PND Restdyspnoea
S3 Crackles JVP>6 cm
Cardio-megaly
76
Baseline therapy (%)
ACE inhibitor 0 100 19 41
beta-blocker 55 56 56 55
diuretic 86 90 75 83
spironolactone 24 17 12 17
digitalis 46 58 28 43
aspirin 58 52 58 56
lipid lowering 41 41 42 42
Baseline characteristics
Alternative Added Preserved Overalln=2028 n=2548 n=3023 n=7599
77
CHARM-Preserved: Primary outcome CV death or CHF hospitalisation
0 1 2 3 yearsNumber at risk
Candesartan 1514 1458 1377 833 182
Placebo 1509 1441 1359 824 195
3.50
10
20
30Placebo
Candesartan
5
15
25
HR 0.89 (95% CI 0.77-1.03), p=0.118Adjusted HR 0.86, p=0.051
%
366 (24.3%)333 (22.0%)
78
CHARM-Preserved Primary and secondary outcomes
CV death, CHF hosp. 333 366
- CV death 170 170
- CHF hosp. 241 276
CV death, CHF hosp, 365 399 MI
CV death,CHF hosp, 388 429 MI, stroke
CV death,CHF hosp, 460 497 MI, stroke, revasc
candesartan better
Hazard ratio
placebo better
0.8 1.0 1.2
p-value
0.9180.072
0.118
0.126
0.078
0.123
Covariateadjusted
p-value
0.6350.047
0.051
0.051
0.037
0.13
Candesartan Placebo0.89
0.99
0.85
0.90
0.88
0.91
79
CHARM-Preserved Investigator reported CHF hospitalisations
0
5
10
15
20
25
0
100
200
300
400
500
600
700
PlaceboCandesartan
p=0.014p=0.017
Patients hospitalised Hospitalisations
Proportion of patients (%)
Number of episodes
80
CHARM-Preserved Development of new diabetes
47 77 0.60 0.005 (0.41-0.86)
Number of cases HR p-value
Candesartan Placebo (CI)
81
CHARM-Preserved Permanent study drug discontinuations
Hypo-tension
Increased creatinine
Increasedpotassium
Any adverseevent
0
5
10
15
20
25
30 PlaceboCandesartan
Percent of patients
p=0.001 p=0.006 p<0.001 p=0.019
13.5
1.1 2.40.6
17.8
2.44.8
1.5
82
CHARM-PreservedConclusions
The CHARM Preserved trial provides supportive evidence that the ARB,
candesartan can prevent CHF hospitalisations and can prevent the development of diabetes mellitus.
83
CHARM-Preserved
This trial provides information on the poorly studied, but large, group of CHF patients with LVEF >40%
Data on their own are suggestive of benefit
When taken in the context of the results of the two parallel CHARM trials in patients with low LVEF, physicians may consider candesartan in patients with CHF irrespective of EF
84
CHARM Programme
CHARM Added
CHARMPreserved
3 component trials comparingcandesartan to placebo
CHARMAlternative
n=2028
LVEF 40%ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
n=3025
LVEF >40%ACE inhibitor
treated/not treated
Primary outcome: All-cause death
85
CHARM-OverallPatient disposition
Median follow-up of 38 months
Candesartann=3803
Placebon=3796
Completed Studyn=3796
Completed Studyn=3793
Lost to follow-upn=7
Lost to follow-up
n=3
7601 patients randomisedNYHA II-IV
2 patients with no data
86
CHARM-Overall All-cause death
0 1 2 3 yearsNumber at risk
Candesartan 3803 3563 3271 2215 761
Placebo 3796 3464 3170 2157 743
3.50
10
20
30
Placebo
Candesartan
5
15
25
35 %
HR 0.91 (95% CI 0.83-1.00), p=0.055Adjusted HR 0.90, p=0.032
945 (24.9%)886 (23.3%)
87
CHARM-Overall CV death and non-CV death
0 1 2 3 years
5
10
15
20
25
30%
0
CV death
Non-CV death
Placebo
Candesartan
Placebo
Candesartan
HR 0.88 (95% CI 0.79-0.97), p=0.012Adjusted HR 0.87, p=0.006
p=0.45
3.5Number at risk
Candesartan 3803 3563 3271 2215 761
Placebo 3796 3464 3170 2157 743
88
CHARM-OverallCV death or CHF hosp.
0 1 2 3 years0
10
20
30
40
50%
Placebo
Candesartan
HR 0.84 (95% CI 0.77-0.91), p<0.0001Adjusted HR 0.82, p<0.0001
3.5Number at risk
Candesartan 3803 3563 3271 2215 761
Placebo 3796 3464 3170 2157 743
1310 (34.5%)1150 (30.2%)
89
CHARM Programme Mortality and morbidity
0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2
All Cause MortalityCV Death or
CHF Hospitalisation
Hazard ratio Hazard ratio
p heterogeneity=0.43
Alternative
Added
Preserved
Overall
p heterogeneity=0.37
p=0.0004
p=0.055
p=0.011
p=0.118
p<0.0001
0.77
0.85
0.89
0.840.91
90
CHARM-OverallSecondary composite outcomes
CV death 691 769
CHF hosp. 757 918
CV death, CHF hosp. 1150 1310
CV death, CHF hosp, 1213 1369 MI
CV death, CHF hosp, 1269 1420 MI, stroke
CV death, CHF hosp, 1404 1549 MI, stroke, revasc
candesartan better
Hazard ratio
placebo better
0.6 0.8 1.0 1.2 1.4
p-value
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.0120.88
0.79
0.84
0.85
0.86
0.84
Candesartan Placebo
91
CV death or hospitalisation for CHF
candesartan better
Hazard ratio
placebo better
0.6 0.8 1.0 1.2 1.4
Age <65 384/1614 413/1642(yrs) >65 <75 416/1337 476/1270
>75 350/852 421/884
LVEF <40 817/2287 944/2292>40 333/1516 366/1504
Gender Male 813/2617 917/2582Female 337/1186 393/1214
NYHA II 359/1730 415/1686III/IV 791/2073 895/2110
Overall 1150/3803 1310/3796
Candesartanevent/n
Placeboevent/n
p=0.26
p=0.93
p=0.63
p=0.40
Test for interaction
92
CV death or hospitalisation for CHF
Diabetes No 680/2715 815/2721Yes 470/1088 495/1075
Hyper- No 484/1710 579/1703tension Yes 666/2093 731/2093
ACE No 586/2230688/2244 inhibitors Yes 564/1573 622/1552
Beta- No 611/1701 710/1695blocker Yes 539/2102 600/2101
Spirono- No 880/3160 1041/3167lactone Yes 270/643 269/629
Overall 1150/3803 1310/3796
Test for interaction
p=0.09
p=0.51
p=0.32
p=0.19
p=0.17
candesartan better
Hazard ratio
placebo better
0.6 0.8 1.0 1.2 1.4
Candesartanevent/n
Placeboevent/n
93
0
5
10
15
20
25
30
CHARM-OverallCHF hospitalisations
0
400
800
1200
1600
2000
2400
PlaceboCandesartan
p<0.0001
Patients hospitalised Hospitalisations
Proportion of patients (%)
Number of episodes
p<0.0001
94
CHARM-Overall Development of new diabetes
163 (6) 202 (7) 0.78 0.020 (0.64-0.96)
Number of cases (%) HR p-value
Candesartan Placebo (CI)n=2715 n=2721
95
CHARM-OverallPermanent study drug discontinuations
PlaceboCandesartan
0
5
10
15
20
25Percent of patients
p<0.0001 p<0.0001 p<0.0001 p<0.0001
Hypo-tension
Increased creatinine
Increasedpotassium
AE/ lab. abnorm.
16.7
1.73.0
0.6
21.0
3.56.2
2.2
96
CHARM-Overall Conclusions
9% reduction in all cause deaths (p=0.055, covariate adj. p=0.032)
12% reduction in CV mortality (p=0.012)
21% reduction in CHF hosp. (p<0.0001)
16% reduction in CV deaths or CHF hosp. (p<0.0001)
Treatment of a broad spectrum of patients with symptomatic heart failure with candesartan resulted in a:
97
CHARM-OverallImplications
The addition of the ARB, candesartan, can be considered in all patients with chronic heart failure irrespective of ejection fraction, age and sex
Benefits were achieved on top of other effective concomitant therapies including ACE inhibitors and beta-blockers
The consistent effects of candesartan across the three CHARM trials suggest that: