on behalf of the charm programme investigators and committees candesartan in heart failure...

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


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


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


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


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


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


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


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



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



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


31

Baseline data: principal aetiology of heart failure


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


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


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


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


36

CHARM Programme

n=3025

LVEF >40% ACE inhibitor

treated/not treated

CHARM Added

CHARMPreserved

3 component trials comparingcandesartan to placebo

CHARMAlternative

n=2028


intolerant

n=2548


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


Lost to follow-upn=2

Lost to follow-up

n=1

2028 patients randomisedNYHA II-IV, LVEF 40%ACE inhibitor intolerant

39


Women (%) 32 21 40 32


Mean LVEF 30 28 54 39


Baseline characteristics


40







aspirin 58 52 58 56




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


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


treated/not treated

CHARM Added

CHARMPreserved

CHARM Programme

3 component trials comparingCandesartan to placebo

CHARMAlternative

n=2028

LVEF 40% ACE inhibitor

intolerant

n=2548


treated


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


Candesartann=1276

Placebon=1272




Lost to follow-up

n=1

2548 patients randomisedNYHA II-IV, LVEF 40%

ACE inhibitor treated

51


Women (%) 32 21 40 32


Mean LVEF 30 28 54 39




52







aspirin 58 52 58 56




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, 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


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


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


5 lost tofollow-up

2 lost tofollow-up

2284 completedstudy

2289 assigned toCandesartan

2285 completedstudy

2287 assigned toPlacebo

4576 patients randomised


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



CHARM - Low EF trials Baseline characteristics (1)

63


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



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


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



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



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



Number of episodes


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


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


71

CHARM Programme

n=3025


treated/not treated

CHARM Added

CHARMPreserved


CHARMAlternative

n=2028

LVEF 40% ACE inhibitor

intolerant

n=2548


treated


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


Candesartann=1514

Placebon=1509




Lost to follow-up

n=1

3025 patients randomisedNYHA II-IV

LVEF > 40%

2 patients with no data

74


Women (%) 32 21 40 32


Mean LVEF 30 28 54 39




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







aspirin 58 52 58 56




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


%

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, 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



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


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


CHARMAlternative

n=2028


intolerant

n=2548


treated

n=3025


treated/not treated

Primary outcome: All-cause death

85

CHARM-OverallPatient disposition


Candesartann=3803

Placebon=3796




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 %


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


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, 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



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


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:

on behalf of the charm programme investigators and committees candesartan in heart failure...

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