Heart failure randomized clinical trials: how we changed ... · • ” use of beta-blockers for the treatment of chronic heart failure remains investigational, but the official status

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

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

ESC HF Guidelines 2012

•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

••!!

ACC/AHA Guidelines for the management of CHF 1995

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.”

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)

Meta-analysis of 22 beta-blocker studies in CHF

Brophy et al Ann Int Med 2001


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

Classes of RAAS-inhibitors

Givertz, M Circ. 2001

Natriuretic peptides

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

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

Months

Worsening HFMean dose enalapril 16.6 mgRR 0.84; (CI 0.74-0.95) p=0.007

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

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



Natriuretic peptides

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

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

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

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• %

• %• %

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

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

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


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.”



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

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.

Primary Endpoint Cardiovascular Death or Hospitalization for HF -37%

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


McMurray et al EHJ 2012

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

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

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.

§ 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.

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.

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)


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


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


§ 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

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.


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.

Documents

Heart failure randomized clinical trials: how we changed ... · • ” use of beta-blockers for the treatment of chronic heart failure remains investigational, but the official status