ACE-inhibitor trials in heart failure/LV-dysfunction-Mortality

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Classes of recommendations Classes of recommendations
I Condition for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective
II Condition for which there is conflicting evidence and /or a divergence of opinion about the usefulness / efficacy of a procedure or treatment
IIa Weight of evidence /opinion is in favour of usefulness / efficacy
IIb Usefulness/efficacy is less well established by evidence / opinion
III Evidence or general agreement that the treatment is not useful/effective and in some cases may be harmful
Levels of Evidence Levels of Evidence
A Data derived from multiple randomized clinical trials or meta-analyses
B Data derived from a single randomized trial or large non randomized studies
C Consensus of opinion of experts and/or small studies, retrospective studies , registries
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ACE-inhibitor trials in heart failure/LV-dysfuncti
on-Mortality

• Randomized large (gt1000 patients), long-term (1
  year) trials
• ACE-inhibitor vs placebo
• 12 763 patients in 4 trials

Flather et al Lancet 2000
0.74
SAVE, AIRE, TRACE
0.87
SOLVD
0.80
Total
0.5
1.0
0.75
ACE-inhibitor
Worse
Better
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ACE-inhibitors

• ACE-inhibitors are recommended as first-line
  therapy in patients with reduced LV systolic
  function (LVEF lt40-45) (Level of evidence A,
  class I)
• In the absence of fluid retention ACE-inhibitors
  should be given first, in the presence of fluid
  retention together with diuretics (Level of
  evidence B, class I)
• ACE-inhibitors should be up-titrated to the
  dosages shown to be effective in large trials
• They should not be titrated based on symptomatic
  improvement

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VAL-HeFT

• 5010 pts in NYHA class II (61.7), III (36.2) or
  IV (3.1)
• Mean EF 27 and mean age 62 years
• Randomized to placebo/valsartan
• Background ACE-I 92.3, Beta-blocker 35.5

Placebo Valsartan RR (C.I.) p n2511 n2499 Pri
mary endpoints All cause mortality 484
(19.4) 495 (19.7) 1.02 0.8 (0.9-1.15) Mort
ality and all cause hosp. 801 (32.1) 723
(28.8) 0.87 0.009 (0.79-0.96)
Cohn et al NEJM 2001
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Val-HeFT All-cause mortality or morbidity
Months
Cohn et al NEJM 2001
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Subgroups ACE-inhibitors and beta-blockers
Cohn et al NEJM 2001
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CHARM Programme

• 3 component trials (n7601) comparing candesartan
  to placebo in patients with symptomatic heart
  failure

CHARMAlternative
CHARM Added
CHARMPreserved
n2028 LVEF 40ACE-inhibitor intolerant
n2548 LVEF 40ACE-inhibitor treated
n3025 LVEF gt40ACE-inhibitor treated/not
treated
Primary outcome for each trial CV death or CHF
hospitalisation
Primary outcome for Overall Programme All-cause
death
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CHARM-Overall All-cause death
Death
Number at risk
Candesartan 3803 3563 3271 2215
Placebo 3796 3464 3170 2157
Pfeffer et al Lancet 2003
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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
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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 artery stenosis
• Symptomatic hypotension
• ARB within two weeks

• Inclusion criteria
• Age gt18 years
• Symptomatic heart failure for at least 4 weeks
  (New York Heart Association Class II-IV)

Young et al, Circulation 2004
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Study DesignDose-titration and visit schedule
Candesartan/matching placebo once daily
32 mg
16 mg
8 mg
32 mg
4 mg
16 mg
8 mg
Every 4 months until study end31 March 2003
Time
0 w
2 w
4 w
6 w
6 m
Visit
1
2
3
4
5
Young et al, Circulation 2004
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Baseline characteristics (1)
Candesartan Placebo n2289 n2287
Mean age (years) 65 65 Women () 26 26 NYHA
class () II 35 34 III 62 62 IV 3 4Mean LVEF
() 29 29 Medical history () myocardial
infarction 59 58 diabetes 29 29
hypertension 48 50 atrial fibrillation 26 26
Young et al, Circulation 2004
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Baseline characteristics (2)
Candesartan Placebo n2289 n2287
Baseline therapy () ACE inhibitor 56 56 beta-b
locker 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
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CHARM - Low EF (AlternativeAdded) All-cause
death
Young et al Circ 2004
40
Death
Placebo
30
One year HR 0.67 lt0.001
Candesartan
20
10
HR 0.88 (95 CI 0.79-0.98) p0.018
0
0
1
2
3
3.5
years
Number at risk Candesartan 2289 2105 1894 1382 Pl
acebo 2287 2023 1811 1333
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CHARM - Low EF trials CV death and non-CV death
CV deaths and Non CV deaths ()
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Placebo
CV death
Hazard ratio 0.84 (95 CI 0.75 0.95), p0.005
25
Candesartan
20
15
Non CV death
10
Candesartan
p0.60
5
Placebo
0
yrs
3.5
0
1
2
3
Number at risk Candesartan 2289 2105 1894 1382 580
Placebo 2287 2023 1811 1333 548
Young et al, Circulation 2004
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CHARM - Low EF (Alternative and Added) Primary
and secondary outcomes
p-value
Candesartan
Placebo
0.018
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
lt0.001
lt0.001
0.005
lt0.001
lt0.001
0.6
0.8
1.0
1.2
1.4
candesartan better
Hazard ratio
placebo better
Young et al, Circulation 2004
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CHARM - Low EF trials Investigator reported CHF
hospitalisations
Placebo
Candesartan
Proportion of patients ()
Number of episodes
HR 0.73 plt0.001
HR 0.80 plt0.001
35
1400
30
1200
25
1000
20
800
15
600
10
400
5
200
0
0
Patients hospitalised
Hospitalisations
Young et al, Circulation 2004
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CHARM - Low EF trials Permanent study drug
discontinuations
Percent of patients
Placebo
25
Candesartan
23.1
18.8
20
15
10
7.1
4.2
5
3.5
2.8
2.1
0.5
0
Hypo-tension
Increasedpotassium
AE/ lab. abnorm.
Increasedcreatinine
plt0.001
plt0.001
plt0.001
plt0.001
Young et al, Circulation 2004
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CHARM-Added Primary outcomeCV death or CHF
hospitalisation

50
538 (42.3)
Placebo
40
483 (37.9)
30
Candesartan
20
10
HR 0.85 (95 CI 0.75-0.96), p0.011Adjusted HR
0.85, p0.010
0
0
1
2
3
years
3.5
Number at risk Candesartan 1276 1176 1063 948 457
Placebo 1272 1136 1013 906 422
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CHARM-Added Secondary outcomes
p-value
Candesartan
Placebo
0.84
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, 548 596 MI, stroke, revasc
0.029
0.83
0.014
0.85
0.010
0.87
0.020
0.87
0.015
0.6
0.8
1.0
1.2
1.4
candesartan better
Hazard ratio
placebo better
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CHARM-Added Investigator reported CHF
hospitalisations
Placebo
Candesartan
Proportion of patients ()
Number of episodes
p0.008
p0.002
Hospitalisations
Patients hospitalised
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CHARM-Added Permanent study drug discontinuations
Percent of patients
Placebo
Candesartan
24.2
25
20
18.3
15
10
7.8
4.5
4.1
5
3.4
3.1
0.7
0
Hypo-tension
Increased creatinine
Increasedpotassium
AE/lab. abnorm.
p0.0003
p0.079
p0.0001
plt0.0001
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CHARM-Added Prespecified subgroups CV death or
CHF hospitalization
p-value for treatment interaction
Candesartan
Placebo
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
0.14
0.26
0.6
0.8
1.0
1.2
1.4
McMurray et al Lancet 2003
Candesartan better
Hazard ratio
Placebo better
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CHARM-Preserved Investigator Reported CHF
Hospitalizations
Yusuf et al Lancet 2003
Placebo
Number of episodes
Proportion of patients ()
Candesartan
RRR 29
HR 15
p0.014
p0.017
Hospitalizations
Patients hospitalized
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CHARM-OverallCHF hospitalizations
Pfeffer et al Lancet 2003
Placebo
Proportion of patients ( )
Number of episodes
Candesartan
RR 21
RR 28
plt0.0001
plt0.0001
Hospitalizations
Patients hospitalized
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All cause mortality and relative risk reduction
(RRR) at 12 months
Proportion of patients with events,
Placebo
18
16
Investigational drug
14
12
10
8
6
4
2
0
SOLVD
MERIT-HF
CHARM low EF
23 ACE-I diuretic, digoxin
33 Candesartan diuretic, digoxin ACE-I,
spironolactone, beta-blocker
34 beta-blocker diuretic, digoxinACE-I
RRR Investigational drug Baseline therapy
Young et al, Circulation 2004
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All cause mortality and relative risk reduction
(RRR) at 24 months
Proportion of patients with events,
Placebo
50
45
Investigational drug
40
35
30
25
20
15
10
5
0
SOLVD
RALES
CHARM low EF
23 ACE-I diuretic, digoxin
20 Candesartan diuretic, digoxin ACE-I,
spironolactone, beta-blocker
30 spironolactone diuretic, digoxinACE-I,
beta-blocker
RRR Investigational drug Baseline therapy
Young et al, Circulation 2004, Östergren et al,
JRAAS 2003
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ARBs and CHF Update 2005
In patients with systolic dysfunction

• ARBs are a good alternative to ACE-inhibition in
  symptomatic patients intolerant to ACE-inhibitors
  to improve morbidity and mortality (level of
  evidence B, class I)
• ARBs and ACE-inhibitors have similar efficacy in
  CHF (level of evidence B, class I)
• After acute myocardial infarction with signs of
  heart failure or left ventricular dysfunction,
  ARBs have similar efficacy to ACE-inhibitors
  (level of evidence B, class I)

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ARBs and CHF Update 2005

• ARBs can be considered in combination with
  ACE-inhibitors in patients who remain
  symptomatic, to reduce mortality
• (level of evidence B, class IIa)
• and hospital admissions for heart failure
• (level of evidence A, class I)

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Update 2005 and AA

• Aldosterone receptor antagonist
• is recommended in addition to ACE-inhibition,
  beta-blockers and diuretics in advanced heart
  failure (NYHA III-IV) to improve survival and
  morbidity (level of evidence B, class I)
• is recommended in addition to ACE-inhibition and
  beta-blockade in heart failure after myocardial
  infarction with left ventricular systolic
  dysfunction and signs of heart failure to reduce
  mortality and morbidity (level of evidence B,
  class I)

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Update 2005 and AA

• Whether an aldosterone antagonist is of proven
  benefit in patients with class II heart failure
  or asymptomatic left ventricular dysfunction
  remains to be established
• When symptoms increase, which neurohormonal
  antagonist to add is difficult to determine

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Pharmacological therapy of heart failure due to
Left Ventricular Systolic Dysfunction
For Survival/Morbiditymandatory therapy
For Symptoms
Cont. ACE-inhibitor/ARB if ACE-inhibitor
intolerant, continue aldosterone antagonist if
post-MI add beta-blocker if post-MI
reduce / stop diuretic
NYHA I
ACE-inhibitor as first-line treatment/ARB if
ACE-inhibitor intolerant add beta-blocker and
aldosterone antagonist if post MI

NYHA II
/- diuretic depending on fluid retention
ACE-inhibitor plus ARB or ARB alone if ACE
intolerant beta-blocker add aldosterone antagonist
NYHA III
diuretics digitalis If still symptomatic
NYHA IV
diuretics digitalis consider temporary
inotropic support
Continue ACE-inhibitor/ARB beta-blocker Aldosteron
e antagonist
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Approaches to the patient with heart failure
implication from recent trials
Fluid retention
Diuretics
Assessment of LV function
Low LVEF Ejection fraction lt40
Preserved LVEF Ejection fraction gt40
NYHA II/III
ACEI (ARB if intolerant)
Consider ARB
Beta Blocker
ARB
Treat comorbidities
Digoxin
NYHA III/IV
Spironolactone
European Heart Journal supplement (2004) 6 (Suppl
H), H55-H60
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European Heart failure indication

• AstraZeneca's Atacand garners MRP approval for
  use in chronic heart failure
• 11/29/2004
• AstraZeneca announced Monday the completion
  of the European Mutual Recognition Procedure for
  the use of Atacand (candesartan cilexetil) in the
  treatment of chronic heart failure, as reported
  in Morningstar.
• The selective angiotensin receptor blocker,
  already used for the treatment of hypertension,
  is now approved for the treatment of patients
  with heart failure and impaired left ventricle
  systolic function.
• The new indication states that Atacand can
  be used as add-on therapy for patients already
  taking a comprehensive range of drugs including
  ACE-inhibitors and beta-blockers, or given as an
  alternative therapy to an ACE-inhibitor in
  patients who have become intolerant to these
  drugs.
• The application to the EU regulatory body
  for Atacand's use in CHF was submitted in April
  2004 and the UK was the Reference Member State,
  as reported in Morningstar.

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Valsartan indication text
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