CHARM Low EF Slides

8/14/2019 CHARM Low EF Slides

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On behalf of the CHARM ProgrammeInvestigators and Committees

CandesartaninHeart failure

Assessment ofReductioninMortalityand morbidity

CHARM


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Background

CHF patients with optimal treatment(ACE inhibitors, beta-blockers andspironolactone) still remain at high risk for

death and readmissions

ARBs offer the potential to produce further

clinical improvements above and beyondACE inhibition through a distinct mechanism


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CHARM participants618 centers in 26 countries


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CHARMAdded CHARMPreserved

3 component trials comparing candesartanto 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 inhibitortreated/not treated

Primary outcome for Overall Program: All-cause death

Primary outcome for each trial: CV death or CHF hospitalization

CHARM Program


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CHARM - Low EF trials

A prespecified and important analysis wasperformed of the two trials defined by EF40%(CHARM Alternative and CHARM Added)

This was carefully considered because earlierstudies with ACE inhibitors, beta-blockers,aldosterone antagonists, and ARBs in CHFwere done specifically in this population

Young et al, Circulation 2004


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Inclusion and Exclusion Criteria

Key exclusion criteria

S-creatinine 265 mol/L(3mg/dL)

S-potassium 5.5mmol/L

Bilateral renal arterystenosis

Symptomatic hypotension

ARB within two weeks

Inclusion criteria

Age >18 years

Symptomatic heartfailure for at least4 weeks (New YorkHeart Association

Class II-IV)



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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



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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



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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 58diabetes 29 29hypertension 48 50atrial fibrillation 26 26

Candesartan Placebon=2289 n=2287

Baseline characteristics (1)



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Baseline therapy (%)

ACE inhibitor 56 56

beta-blocker* 55 55diuretic 88 88

spironolactone* 21 20

digitalis 52 53

ASA 54 55

lipid lowering 42 41

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 respectivelyYoung et al, Circulation 2004

Candesartan Placebon=2289 n=2287


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CHARM - Low EF trialsAll-cause death

Number at riskCandesartan 2289 2105 1894 1382 580Placebo 2287 2023 1811 1333 548

Placebo708 (31.0%)

Candesartan

642 (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


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yrs3.50 1 2 30

10

20

30CV deaths and Non CV deaths (%)

5

25

15

CHARM - Low EF trialsCV 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



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CHARM - Low EF trialsCV 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


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CHARM - Low EF (Alternative and Added)Primary and secondary outcomes

All cause death 642 708

All cause/CHF hosp 910 1020

CV death, CHF hosp. 817 944- CV death 521 599

- CHF hosp. 516 642

CV death, CHF hosp, 848 970

MI

candesartanbetter

Hazardratio

placebobetter

0.6 0.8 1.0 1.2 1.4

p-value

0.018


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CHARM - Low EF trialsCV death or CHF hospitalisations

Age 65 312/1044 327/1028(yrs) >65


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CHARM - Low EF trialsCV death or CHF hospitalisation

Diabetes No 499/1635 605/1635Yes 318/ 654 339/ 652

Hyper- No 397/1180 455/1153tension Yes 420/1109 489/1134

ACE No 333/1012 405/1015inhibitors Yes 484/1277 539/1272

Beta- No 432/1034 496/1023blocker Yes 385/1255 448/1264

Spirono- No 602/1817 730/1839lactone Yes 215/ 472 214/ 448

Overall 817/2289 944/2287

Test forinteraction

Candesartan

better

Placebo

better

Hazard

ratio

0.60.70.80.91.01.11.21.3

p=0.12

p=0.79

p=0.26

p=0.75

p=0.26

Cande-sartan

Placebo


C


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CHARM - Low EF trialsCV death or CHF hospitalisation

ACEi+Bb+No 778/2180 893/2159Spiro Yes 39/ 109 51/ 128

Other No 43/ 277 58/ 272diuretics Yes 774/2012 886/2015

Digitalis No 321/1099 368/1065Yes 496/1190 576/1222

Aspirin No 399/1059 451/1033Yes 418/1230 493/1254

Lipid No 504/1328 607/1357lowering Yes 313/ 961 337/ 930

Overall 817/2289 944/2287

Test forinteraction

Candesartan

better

Placebo

better

Hazard

ratio

p=0.93

p=0.51

p=0.90

p=0.79

p=0.27

0.60.70.80.91.01.11.21.3

Cande-sartan

Placebo


CHARM L EF i l


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CHARM - Low EF trialsInvestigator reported CHF hospitalisations

0

5

10

15

20

25

30

35

0

200

400600

800

1000

1200

1400

HR 0.73p


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CV death or CHF hospitalisation and relativerisk reduction (RRR) at 12 and 24 months and

end of study

0

510

15

20

25

30

35

40

45

012 24 End of studyMonths

30% 18%23%RRR


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CHARM - Low EF trialsPermanent study drug discontinuations

0

5

10

15

20

25

Percent of patients

p


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02

4

6

810

12

14

16

18

All cause mortality and relative riskreduction (RRR) at 12 months

SOLVD MERIT-HF CHARM low EF23%

ACE-I

diuretic, digoxin

33%Candesartan

diuretic, digoxin ACE-I,spironolactone, beta-blocker

34%beta-blocker

diuretic, digoxinACE-I

RRRInvestigational drug

Baseline therapy

Proportion of patients with events, % Placebo

Investigationaldrug


All t lit d l ti i k


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05

10

1520

2530

3540

45

50

All cause mortality and relative riskreduction (RRR) at 24 months

SOLVD RALES CHARM low EF

Proportion of patients with events, % Placebo

Investigationaldrug

Young et al, Circulation 2004, stergren et al, JRAAS 2003

23%ACE-I

diuretic, digoxin

20%Candesartan

diuretic, digoxin ACE-I,spironolactone, beta-blocker

30%spironolactone

diuretic, digoxinACE-I, beta-blocker

RRRInvestigational drug

Baseline therapy


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CHARM L EF


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CHARM-Low EFImplications

Candesartan significantly reduces cardiovasculardeath, hospital admission for heart failure, andall-cause mortality in patients with CHF andLVEF 40% when added to standard therapies

including ACE inhibitors, beta-blockers, and analdosterone antagonist

This approach offers the clinician an opportunity

to make additional improvements in the poorprognosis of CHF patients when left ventricularsystolic dysfunction is present

Young et al Circulation 2004

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