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Heart failure randomized clinical trials: how we changed standard of care.
Karl SwedbergSenior professor of Medicine
University of GothenburgProfessor of Cardiology
Imperial College, London
Disclosures:Honoraria/Consultancy: Amgen, Astrazeneca, Novartis,
Pfizer, Servier, ViforResearch grants: Amgen, Servier
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Treatment of heart failureFrom two textbooks 1929 and 1974
”…and for all this there is only digitalis and rest…”
Paul Dudley White: Textbook in Cardiology, 1929
Moderately severe heart failure Decrease physical activity Institute digitalis Give thiazide every day plus potassium If not enough use furosemide and
if insufficient, combine them
J W Hurst: The Heart 3rd edition, 1974
J Willis Hurst1920-2011
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ESC HF Guidelines 2012
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•First report (Waagstein et al)
•Indication improved survival (Swedberg et al)
•Confirmed in large clinical trials•carvedilol, bisoprolol and metoprolol
•
•1975•1979
•1993
•to
•1999
••??
Beta-blockade in heart failureBeta-blockade in heart failureSlow introduction of efficient therapySlow introduction of efficient therapy
••!!
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ACC/AHA Guidelines for the management of CHF 1995
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ACC/AHA Guidelines 1995
• ” use of beta-blockers for the treatment of chronic heart failure remains investigational, but the official status of beta-blockers may change as recent data are reviewed. Hence, physicians might consider the use of a beta-blocker in selected patients with chronic heart failure.”
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Carvedilol(n=696)
Placebo(n=398)
Survival
Days0 50 100 150 200 250 300 350 400
1.0
0.9
0.8
0.7
0.6
0.5
Risk reduction = 65%p<0.001
Packer et al (1996)Packer et al (1996)
CIBIS-II Investigators (1999)CIBIS-II Investigators (1999)
0 200 400 600 800
Bisoprolol
Placebo
Time after inclusion (days)
p<0.0001
Survival
Risk reduction = 34%
The MERIT-HF Study Group (1999)The MERIT-HF Study Group (1999)
US Carvedilol Programme
CIBIS-II
0.8
1.0
0.6
0
Months of follow-up
Mortality (%)
0 3 6 9 12 15 18 21
20
15
10
5
0
Placebo
Metoprolol CR/XL
p=0.0062Risk reduction = 34%
MERIT-HF
COPERNICUS:COPERNICUS:
MonthsMonths
0000
33 66 99 1212 1515 1818 2121
100100
9090
8080
6060
7070
CarvedilolCarvedilol
PlaceboPlacebo
Risk reduction = 35%
p = 0.00013p = 0.00013
Survival
Packer et al (2001)
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Meta-analysis of 22 beta-blocker studies in CHF
Brophy et al Ann Int Med 2001
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ESC HF Guidelines 2012
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Renin-angiotensin inaldosterone system
Angiotensinogen
renin Angiotensin I
Angiotensin IIACE
Cough,Angioedema
Benefits? Bradykinin Inactive
Fragments
· Vasodilation· Antiproliferation
(kinins)
Aldosterone AT2
AT1
· Vasoconstriction· Cell growth· Na/H2O retention· Sympathetic activation
McMurray et alMcMurray et al,, Circ 2004 Circ 2004
X
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Classes of RAAS-inhibitors
Givertz, M Circ. 2001
Natriuretic peptides
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CONSENSUS
0.2 0.4 0.6 0.8 1.0 1.2 1.40.00.10.20.30.40.50.60.70.80.91.0
PlaceboEnalapril
p=0.002
YearYear
MortalityMortality
Swedberg et al NEJM Swedberg et al NEJM 19871987
••253 patients in NYHA class IV 253 patients in NYHA class IV ••Randomized to placebo/enalaprilRandomized to placebo/enalapril••From first patient to end of study 20 monthFrom first patient to end of study 20 month••118 deaths118 deaths
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Neuroendocrine Activation and Mortality
%% P<0.01P<0.01
Six Month Mortality (%) by Plasma Levels of Hormones From CONSENSUS I Placebo Group N=120
Modified from Swedberg et al 1990Modified from Swedberg et al 1990
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Months
Worsening HFMean dose enalapril 16.6 mgRR 0.84; (CI 0.74-0.95) p=0.007
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ACE-inhibitor Trials in Heart Failure/LV-dysfunctionMortality
ACE-inhibitorACE-inhibitor
WorseWorseBetterBetter
1.01.00.50.5 0.750.75
SAVE, AIRE, SAVE, AIRE, TRACETRACE
SOLVD
TotalTotal
0.870.87
0.740.74
0.80
Flather et al Lancet 2000Flather et al Lancet 2000
••Randomized large (>1000 patients), long-term (1 year) trialsRandomized large (>1000 patients), long-term (1 year) trials••ACEI vs. placeboACEI vs. placebo••12763 patients in 4 trials12763 patients in 4 trials
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CONSENSUS 10-Year Follow-UpAll Randomized Patients, Original and Follow-Up
1 2 3 4 5 6 7 8 9 10 110.00.10.20.30.40.50.60.70.80.91.0
PlaceboEnalapril
p=0.008
YearYear
MortalityMortality
Swedberg et al EHJ 1999Swedberg et al EHJ 1999
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Classes of RAAS-inhibitors
Givertz, M Circ. 2001
Natriuretic peptides
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VAL-Heft
5010 pts in NYHA class II (61.7%), III (36.2%) or IV (3.1%). 5010 pts in NYHA class II (61.7%), III (36.2%) or IV (3.1%). Mean EF 27% and mean age 62 yearsMean EF 27% and mean age 62 yearsBackground: ACEI 92.3%, Beta-blocker 35.5%Background: ACEI 92.3%, Beta-blocker 35.5%
PlaceboPlacebo ValsartanValsartan RR (C.I.)RR (C.I.) PP
Primary endpointsPrimary endpoints N=2511N=2511 N=2499N=2499
All cause mortalityAll cause mortality 484 (19.4%)484 (19.4%) (495(19.7%)(495(19.7%) 1.021.02 0.80.8(0.9-1.15)(0.9-1.15)
Mortality Mortality and all cause hosp.and all cause hosp. 801 (32.1%)801 (32.1%) 723(28.8%)723(28.8%) 0.87 0.87 0.0090.009
(0.79-0.96)(0.79-0.96)
Cohn et al NEJM 2002Cohn et al NEJM 2002
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1.0
0.9
0 3 6 9 12 15 18 21 24 27Time after randomization (months)
0.7
0.8
P = 0.8
Valsartan Placebo
•All Cause Mortality in the Val-HeFT Trial•P
roba
bilit
y of
Sur
viva
l
•n=5010
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20
CHARM Added
CHARMPreserved
CHARM Programme
3 component trials (N=7601) comparing candesartan to placebo in patients with symptomatic heart failure
CHARMAlternative
n=2548LVEF 40%
ACE inhibitor treated
n=3025LVEF >40%
ACE inhibitor treated/not treated
Primary outcome for Overall Programme: All-cause deathPrimary outcome for each trial: CV death or CHF hospitalization
n=2028 LVEF 40%
ACE inhibitor intolerant
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21
CHARM: Primary endpoint
•0 •1 •2 •3 •anni•3.5•0
•10
•20
•30
•Placebo
•Candesartan
•5
•15
•25
•35
•HR 0.91 (CI 95 % 0.83-1.00), p=0.055
• adjusted HR 0.90 (CI 95 % 0.82–0.99), p=0•032
•945 (24.9%)•886 (23.3%)
•Overall
•0 •1 •2 •3 •anni•0
•10
•20
•30
•40
•50
•Placebo
•Candesartan
•3.5
HR 0.85 (95% CI 0.75-0.96), p=0.011 adjusted HR 0·85 (CI 95 % 0.75–0.96), p=0.010
•483 (37.9%)
•538 (42.3%)•Added
•0 •1 •2 •3 •anni•0
•10
•20
•30
•40
•50
•Placebo
•Candesartan
•HR 0.77 (CI 95 % 0.67-0.89), p=0.0004 adjustedHR 0.70 (CI 95 % 0·60–0·81),
p<0.0001
•3.5
•406 (40.0%)
•334 (33.0%)
•Alternative
•0 •1 •2 •3 •anni•3.5•0
•10
•20
•30
•Placebo
•Candesartan
•5
•15
•25
HR 0.89 (CI 95 % 0.77-1.03), p=0.118adjusted HR 0·86 (CI 95 % 0.74–1.0) p=0·051
• %
•366 (24.3%)•333 (22.0%)
•Preserved• %
• %• %
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22
CHARM-Overall: All-cause death
0 1 2 3 yearsNumber at riskCandesartan 3803 3563 3271 2215 761Placebo 3796 3464 3170 2157 743
3.50
10
20
30Placebo
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%)
HR 0.70P<0.001
HR 0.82P<0.001
Pfeffer et al Lancet 2003Pfeffer et al Lancet 2003
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23CHARM Result meeting Hennekens 030827
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
Young et al Circ 2004Young et al Circ 2004
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diuretic
digoxin
diuretic
digoxin
ACE-I
diuretic
digoxin
ACE-I
diuretic
digoxin
ACE-I
blocker
diuretic
digoxin
ACE-I
blocker
diuretic
digoxin
ACE-I
blocker
ARB
SOLVD-T (1991)
RRR 21%
CIBIS-2 (1999)
RRR 33%
CHARM-Added (2003) ( blocker subgroup)
RRR 30%
Improving survival in CHF 1 year mortality
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ESC HF Guidelines 2012
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ACC/AHA Guidelines 1995
• ” trials support the use of ACE inhibitors in all patients with symptomatic heart failure, unless the inhibitors are contraindicated or not tolerated.”
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Classes of RAAS-inhibitors
Givertz, M Circ. 2001
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RALESRandomized ALdactone Evaluation Study
• 1663 pts HF (NYHA III or IV, EF <35%)
• spironolactone vs. placebo
• Endpoint:– Total mortality
NEJM 1999
30% risk reduction
N Engl J Med., 341(10):709-17, 1999 Pitt et al NEJM 1999
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Inclusion Criteria
• Inclusion– > 55 years of age– NYHA functional class II– Ejection fraction < 30% (or, if between 30% and 35%, QRS >130 msec)– Treated with the recommended or maximally tolerated dose of ACE inhibitor
(or an ARB or both) and a beta-blocker (unless contraindicated).– within 6 months of hospitalization for a cardiovascular reason [or, if no such
hospitalization, BNP > 250 pg/ml or Nt-pro-BNP >500 pg/ml (males) or 750 pg/ml (females).]
• Exclusion– Serum potassium > 5.0 mmol/L– eGFR < 30 ml/min/1.73 m2
– Need for a potassium-sparing diuretic– Any other significant comorbid condition.
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Primary Endpoint Cardiovascular Death or Hospitalization for HF -37%
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Safety (Investigator reported events)
Patients with an adverse event— no. (%)
Outcome Eplerenone (N=1360)
Placebo (N=1373) P Value
All 979 (72) 1007 (73.6) 0.37
Hyperkalemia – n (%) 109 (8) 50 (3.7) <0.001
Hypokalemia – n (%) 16 (1.2) 30 (2.2) 0.05Renal failure – n (%) 39 (2.9) 42 (3.1) 0.82Hypotension – n (%) 46 (3.4) 37 (2.7) 0.32Gynecomastia and other breast disorders – n (%) 10 (0.7) 14 (1.0) 0.54
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ESC HF Guidelines 2012
McMurray et al EHJ 2012
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Relative risk of primary composite endpoint in the placebo group divided by quintiles of heart rate
Böhm et al Lancet 2010
1.0 2.0 3.00.5 1.5 2.5 3.5
70 - <72 1.00
72 - <75 1.15
75 - <80 1.33
80 - <87 1.80
≥ 87 2.34
Heart rate atbaseline (bpm) HR
1.0 2.0 3.00.5 1.5 2.5 3.5
70 - <72 1.00
72 - <75 1.55
75 - <80 1.85
80 - <87 2.20
≥ 87 2.99
Heart rate atbaseline (bpm)
HR
4.0 4.5
1.0 2.0 3.00.5 1.5 2.5
1.00
0.87
1.03
1.64
1.85
HR
1.0
1.00
1.29
2.29
3.40
3.56
HR
2.0 3.0 4.0 5.0 6.0 7.0 8.0
Primary composite endpoint
HF hospitalisation
CV death
Death from HF
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23 trials in 19 209 HF patients with beta23 trials in 19 209 HF patients with beta--blocker (mean EF=17%-36%)blocker (mean EF=17%-36%)
McAlister et al. Ann Intern Med. 2009;150:784-794.
BetaBeta-blocker dose and heart rate reduction -blocker dose and heart rate reduction in chronic HF patientsin chronic HF patients
Results of 13 univariable meta-regressions evaluating the effect of individual covariates on mortality benefits of beta-blockers in heart failure
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Ivabradine: pure heart rate reduction
If inhibition reduces the diastolic depolarization slope, thereby lowering heart rate
RR
Pureheart ratereduction
0 mV
-40 mV
-70 mV
closedopen
closed
Ivabradine
Thollon et al. Br J Pharmacol. 1994;112:37-42.
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§ 18 years
§ Class II to IV NYHA heart failure
§ Ischaemic/non-ischaemic aetiology
§ LV systolic dysfunction (EF 35%)
§ Heart rate 70 bpm
§ Sinus rhythm
§ Documented hospital admission for worsening heart failure 12 months
Inclusion criteriaInclusion criteria
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
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Chronic HF background treatment
89 9184
61
22
3
90 9183
59
22
40
10
20
30
40
50
60
70
80
90
100
Beta-blockers ACEIs and/orARBs
Diuretics Aldosterone antagonists
Digitalis ICD/CRT
IvabradinePlacebo
Patients (%)Patients (%)
Swedberg K, et al. Lancet. 2010.
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Mean heart rate reduction
Mean ivabradine dose: 6.4 mg bid at 1 monthMean ivabradine dose: 6.4 mg bid at 1 month 6.5 mg bid at 1 year 6.5 mg bid at 1 year
0 2 weeks 1 4 8 12 16 20 24 28 32Months
90
80
70
60
50
67
7575
80
64
IvabradinePlacebo
Heart rate (bpm)Heart rate (bpm)
Swedberg K, et al. Lancet. 2010.
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0 6 12 18 24 30Months
40
30
20
10
0
Primary composite endpoint (CV death or hospital admission for worsening HF)
- 18%
Cumulative frequency (%)Cumulative frequency (%)
Placebo
Ivabradine
HR (95% CI), 0.82 (0.75–0.90),
p<0.0001
Swedberg K, et al. Lancet. 2010.
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Age <65 years ≥65 years Sex Male Female Beta-blockers No YesAetiology of heart failure Non-ischaemic IschaemicNYHA class NYHA class II NYHA class III or IVDiabetes No YesHypertension No YesBaseline heart rate <77 bpm ≥77 bpm
Test for interaction
p=0.029
1.51.00.5Hazard ratio
Favours ivabradine Favours placebo
Effect of ivabradine in prespecified subgroups
Swedberg K, et al. Lancet. 2010.
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§ A cut-off of ≥75 bpm was chosen by the EMA for the
approval of ivabradine in chronic heart failure
§ 64% of the patients enrolled in SHIFT had a heart
rate ≥ 75 bpm
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1.00
Primary composite end point
Cardiovascular mortality
Hospitalization for worsening HF
Death from HF
All-cause mortality
All-cause hospitalization
Any cardiovascular hospitalization
0.76 0.68-0.85
0.83 0.71-0.97
0.70 0.61-0.80
0.61 0.46-0.81
0.83 0.72-0.96
0.82 0.75-0.90
0.79 0.71-0.88
0.20
<0.0001
0.0166
<0.0001
0.0006
0.0109
<0.0001
<0.0001
PHazard ratio
1.200.40 0.60 0.80
Effect of ivabradine on major outcomes in patients with HR 75 bpm
Favors ivabradine Favors placebo
95% CI
Böhm M, et al. Clin Res Cardiol. 2012.
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ESC HF Guidelines 2012
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Summary
· Over the last 40 years, treatment of chronic heart failure has improved dramatically
· A series of randomized, controlled trials have led to a change in standard of care
· Further improvements should hopefully replace old by new therapies more than adding them.