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Results of the Longest and Largest Ever b -Blockade Study in CHF Mortality Reduction beyond ß 1 -Blockade. Pub.: Results: Poole-Wilson et al. Lancet 2003;362:7-13 Design: Poole-Wilson et al. Eur J Heart Fail 2002;4:321-329.

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slide1

Results of the Longest and Largest Everb-Blockade Study in CHFMortality Reduction beyond ß1-Blockade

Pub.: Results: Poole-Wilson et al. Lancet 2003;362:7-13

Design: Poole-Wilson et al. Eur J Heart Fail 2002;4:321-329

slide2

Pharmacological Differences Within the b Blocker ClassAgents currently evaluated for heart failure

b1b2a1Ancillary blockadeblockadeblockade ISA effects*

Carvedilol +++ +++ +++ - +++

Metoprolol +++ - - - -

Bisoprolol +++ - - - -

Bucindolol +++ +++ -++ -

*anti-oxidant, anti-endothelin, anti-proliferative

lack of b1receptor upregulation

the normal heart is a b 1 organ that functions in a b 1 environment

b1

b1

b1

b1

b1

b1

b1

b1

b1

b1

b1

b2

b2

The Normal Heart is a b1-Organ thatFunctions in a b1-Environment

Normal

heart failure converts the circulation from a b 1 to a b 1 b 2 a 1 environment

b2

b1

b1

b2

b1

b1

b1

a1

b1

b1

b1

b1

b1

b1

b1

b1

b1

b2

b2

a1

b2

b1

b1

b1

b1

b1

b2

b2

b2

Heart Failure Converts the Circulation From a b1 to a b1/b2/a1-Environment

Normal

Heart failure

effects of 2 receptors
Effects of 2-Receptors
  • Direct chronotropic, inotropic, lusitropic cAMP mediated
    • Coupling to the GS/cAMP pathway greater than via 1-adrenoceptor, further enhanced by selective 1-blockade
      • Newton et al. Circ 1999; Kaumann et al. Circ 1999
      • Hall et al. Circ Res 1990
  • Hypertrophy, fibrosis, remodelling
      • Du et al. Circulation 2000
  • Antiapoptotic
      • Communal et al. Circulation 1999
  • Arrhythmogenic
      • Billman et al. Circulation 1997
  • Facilitation of norepinephrine release (presynaptic)
      • Boudreau et al. Am J Physiol 1993
effects of 1 receptors
Effects of 1 Receptors
  • Myocardial hypertrophy, fibrosis, remodeling
    • Simpson & McGrath, J Clin Invest 1983
    • Morgan & Baker, Circulation 1991
  • Cardiotoxicity (with  receptors)
    • Mann et al. Circulation 1992
  • Arrhythmogenic
    • Molina-Viamonte et al. Circulation 1991
  • Peripheral vasoconstriction
    • Leier et al. Circulation 1990
  • Renal hypoperfusion and sodium retention
    • Smyth et al. Circ Res 1985
    • Hesse et al. Br J Pharmacol 1985
effects of different b blocking agents

Bisoprolol

Metoprolol

Effects of Different b Blocking Agents

Pharmacological differences

Sympathetic activation

1

receptors

2

receptors

1

receptors

Carvedilol

Cardiotoxicity

carvedilol but not metoprolol reduces total body and cardiac sympathetic drive
Carvedilol, But Not Metoprolol, Reduces Total Body and Cardiac Sympathetic Drive

Total BodyNorepinephrine Spillover

CardiacNorepinephrine Spillover

100

0.5

50

0

0

-0.5

(nmol/min)

(nmol/min)

-50

-1.5

-100

*

*

-150

-2.5

Carvedilol Metoprolol

Carvedilol Metoprolol

Azevedo et al. Circulation 2001

* P < 0.05 vs. baseline and vs. metoprolol

mortality results of blockers studies in chf

0

0.2

0.4

0.6

0.8

1

Mortality Results of  Blockers Studies in CHF

Trial n Hazard Ratio (95% CI)

MERIT-HF 3,991 0.66 (0.53-0.81)

US Carvedilol Prog 1,094 0.35 (0.20-0.61)

CIBIS II 2,647 0.66 (0.54-0.81)

BEST 2,708 0.90 (0.78-1.02)

COPERNICUS 2,289 0.65 (0.52-0.81)

Mild to Moderate

Severe

Packer et al. NEJM 1996; CIBIS II Invest. Lancet 1999; MERIT-HF Study Gp. Lancet 1999

BEST Investigators. Lancet 1999; Packer et al. NEJM 2001

slide10

COPERNICUS

US Carvedilol Programme

Survival

Survival

1.0

0.9

0.8

0.7

0.6

0.5

Carvedilol

100

90

Carvedilol

Placebo

80

Placebo

70

Risk reduction = 65%

Risk reduction = 35%

p=0.00013

p<0.001

60

0

0

50

100

150

200

250

300

350

400

0

3

6

9

12

15

18

21

Days

Months

Packer et al (2001)

Packer et al (1996)

Survival

Mortality (%)

1.0

CIBIS-II

MERIT-HF

20

Placebo

Bisoprolol

15

0.8

Metoprolol CR/XL

10

Placebo

Risk reduction = 34%

Risk reduction = 34%

0.6

5

p=0.0062

p<0.0001

0

0

0 200 400 600 800

0

3

6

9

12

15

18

21

Time after inclusion (days)

Months of follow-up

The MERIT-HF Study Group (1999)

CIBIS-II Investigators (1999)

herzinsuffizienz nnt n umber n eeded to t reat for one year to save one life
Herzinsuffizienz: NNT* - Number Needed to Treat for one year to save one life

NYHA II-III

NYHA II-III

NYHA IV

NYHA (II-) III

*NNT= Wie viele Patienten muss man 1 Jahr lang behandeln, um einen Todesfall zu verhindern? Die NNT basiert auf der absoluten Mortalitätsreduktion gegenüber Placebo über eine Zeitperiode von genau 1 Jahr, nach Wehling M., J Kardiol 2003;10 (Suppl A) p 20-23

slide12

Metaanalyse Betablockade bei Herzinsuffizienz:

Verbesserung der Herzleistung

P=0,009

P=0,0002

Veränderung der LV-Auswurffraktion als Marker für die Herzfunktion unter der Therapie mit Carvedilol bzw. Metoprolol. Daten aus einer Metaanalyse von 4 direkten Vergleichsstudien bzw.

15 Placebo-kontrollierten Studien (Veränderung gegen Placebo) zwischen Carvedilol und Metoprolol

Nach M. Packer, Am Heart J 2001; 141:899-907

carvedilol improves cardiac performance to a greater extent than metoprolol

Metoprolol

Carvedilol

Carvedilol Improves Cardiac Performance to a Greater Extent than Metoprolol

LV Ejection Fraction

LV EDV

LV ESV

0

16

P = 0.038

-5

14

***

-10

12

-15

10

***

Absolute change from baseline

ml/m2

LVEF (%)

-20

8

**

-25

6

***

-30

4

***

2

-35

***

0

-40

**P < 0.01 ***P < 0.001vs baseline

Metra M et al. Circ 2000

meta analysis of direct comparison trials with metoprolol and carvedilol in chf
Meta-analysis of Direct Comparison Trials with Metoprolol and Carvedilol in CHF

+12

P = 0.009

+10

+8

LV Ejection

Fraction (%)

+6

+4

+2

0

Metoprolol

(n = 123)

Carvedilol

(n = 125)

Packer M et al. Am Heart J 2001

blocker tolerability in clinical trials
 Blocker Tolerability in Clinical Trials

Percentage of patients achieving target dose

Bisoprolol (CIBIS II)

Metoprolol (MERIT-HF)

Carvedilol (US Carvedilol)

Carvedilol (COPERNICUS)

0

20

40

60

80

100 %

comet objectives and design
COMET: Objectives and Design
  • To compare the effects of the combined alpha/betablocker carvedilol with those of the ß1-selective metoprolol on mortality and morbidity in patients with chronic heart failure
  • No run-in period

Randomisation

Carvedilol (n = 1,511)

Mild, moderate or severe CHF

Metoprolol (n = 1,518)

Screening Titration Maintenance (estimated 4 - 6 yrs)

comet trial
COMET Trial
  • The COMET trial is not simply a comparison of the survival effects of Metoprolol and Carvedilol in patients with heart failure.
  • The COMET trial is really a test of whether the properties of Carvedilol beyond 1-blockade have favorable effects on survival.
  • To verify this theory, Metoprolol and Carvedilol were used in dosages, that produce equivalent degrees of 1-blockade (50 mg Metoprolol IR BID and 25 mg Carvedilol BID)
dates timing and follow up
Dates, Timing and Follow-up

First patient recruited:

Last patient recruited:

Total recruited:

Carvedilol:

Metoprolol:

01-Dec-1996

15-Jan-1999

3029

1511

1518

Minimum follow-up (months):

Maximum follow-up (months):

Average follow-up (months):

47

71

57.9

Total patient months of follow-up: Total deaths prior to 15-Nov-2002:

175447 (=14621 years)

1112

flow chart of patients
Flow Chart of Patients

Randomised

3029

Carvedilol

1511

Metoprolol

1518

Assigned to drug

and received at least one tablet

Withdrew consent 10

Lost to follow-up 3

Withdrew consent 18

Lost to follow-up 2

main inclusion criteria
Main Inclusion Criteria
  • Symptomatic CHF (NYHA II-IV) on standard treatment
  • Stable diuretic treatment  2 weeks
  • ACE inhibitor  4 weeks prior to study entry
    • use of digitalis and/or vasodilators was discretionary
  • LVEF  35%
  •  1 CVS hospitalisation in the previous 2 years
severity of heart failure
Severity of Heart Failure

COMET MERIT-HF1 N=3,029 N=3,991

NYHA Class (%)II 48 41III 48 55IV 4 4

 LVEF (%) 26 28

1. Lancet 1999; 353: 2001-7

background therapy
Background Therapy

COMET MERIT-HF

Diuretic 99% 90%

ACEi 91% 90%

ARB 7% 7%

Spironolactone 11% 8%

Digoxin 59% 64%

Aspirin 37% 46%

Warfarin 46% NA

comet baseline characteristics
COMET: Baseline Characteristics

Carvedilol (n=1511)

Metoprolol

(n=1518)

Age (y, mean/sd)

61.6 (11.3)

62.3 (11.4)

Male (%)

79.4

80.2

Aetiology (IHD %)

52

54

Months of HF (mean/median)

42.6/22

42.2/20

Heart rate (beats/min)

81

81

Systolic BP (mm Hg)

126

126

Diastolic BP (mm Hg)

77

77

NYHA class (%) II/III/IV

48/48/3

49/47/4

AF/flutter (%)

20.5

19.2

Diabetes

23.8

24.4

comet primary endpoint total mortality
COMET: Primary Endpoint Total Mortality

40

Metoprolol

30

20

Carvedilol

Mortality (%)

Hazard ratio 0.83,

95% CI 0.74 – 0.93, P = 0.0017

10

0

0

1

2

3

4

5

Time (years)

Number at risk

Carvedilol 1511 1367 1259 1155 1002 383

Metoprolol 1518 1359 1234 1105 933 352

Poole-Wilson et al. Lancet 2003;362:7-13

comet cardiovascular mortality

40

Metoprolol

30

Mortality (%)

20

Carvedilol

10

Survival benefit 20%,

P = 0.0004

0

0

1

2

3

4

5

COMET: Cardiovascular Mortality

Time (years)

Number at risk

Metoprolol

Carvedilol

1,518

1,359

1,234

1,105

933

352

1,511

1,366

1,258

1,155

1,002

383

ESC 2003

comet fatal or non fatal myocardial infarction

Event %

15

Metoprolol

Carvedilol

10

5

0

1

2

3

4

5

COMET: Fatal or non-fatal myocardial infarction

Hazard ratio 0.714

95% CI 0.523 - 0.974,

p=0.0333

- 29%

Time (years)

K. Swedberg AHF 2003, Las Vegas

comet studie unterschiede in der mortalit t carvedilol versus metoprolol
COMET-Studie: Unterschiede in der Mortalität Carvedilol versus Metoprolol

-17%

-20%

P=0,0017

P=0,0004

Poole-Wilson P. et al. Lancer 2003; 362:7-13

slide28

COMET: Risikoreduktion gegenüber kardioselektiven Betablocker Metoprolol

p=0,0017

p=0,0004

p=0,0333

Nach P. Poole-Wilson, ESC 2003, Wien und K. Swedberg AHF 2003, Las Vegas

comet mode of death
COMET: Mode of Death

Carvedilol Metoprolol n=1511 n=1518

Sudden 218 (42.6%) 262 (43.7%)

Circulatory failure 168 (32.8%) 197 (32.9%)

Stroke 13 (2.5%) 38 (6.3%)

Other CV 19 (3.7%) 26 (4.3%)

Non-CV 74 (14.5%) 66 (11.0%)

Unable to classify 20 (3.9%) 11 (1.8%)

comet death from stroke
COMET: Death from Stroke

Relative Risk Reduction 67% !!

P = 0.0006

3

Metoprolol

2

Carvedilol

Mortality (%)

1

0

0

1

2

3

4

5

Time (years)

ESC 2003

comet consistent mortality reduction in sub groups
COMET: Consistent Mortality Reduction in Sub-Groups

Male (n = 2.417)

Sex

Female (n = 612!)

Age

< 65

 65

NYHA

II

III

IV (n = 115!)

Cause

Other

IHD

LVEF

 25%

> 25%

Heart rate

< 80

 80

Systolic BP

< 110

110 - 139

 140

Diabetes

yes

no

Overall

Metoprolol better

Carvedilol better

0.50

0.75

1.00

1.25

1.50

Poole-Wilson et al. Lancet 2003;362:7-13

comet secondary endpoints
COMET: Secondary Endpoints

Secondary

endpoints

Carvedilol

Metoprolol

Hazard ratio

95% CI

P-value

Death and cardiovascular hospitalisation

963/1511

63.7%

1016/1518

66.9%

0.928

0.85, 1.014

0.0972

Cardiovascular death, heart transplantation or hospitalisation for non-fatal AMI or worsening heart failure

745/1511

49.3%

815/1518

53.7%

0.881

0.798, 0.974

0.0128

Death and hospitalisation for worsening heart failure

774/1511

51.2%

841/1518

55.4%

0.89

0.807, 0.981

0.0191

comet new onset diabetes
COMET: New Onset Diabetes

Relative Risk Reduction 22%,

P = 0.04

15

10

Metoprolol

New diabetes (%)

5

Carvedilol

0

0

1

2

3

4

5

Time (years)

Number at risk

Metoprolol

1,147

991

879

764

626

221

Carvedilol

1,151

1,014

908

827

705

254

ESC 2003

comet esc wien 2003 risikoreduktion carvedilol im vergleich zu metoprolol
COMET – ESC, Wien 2003: Risikoreduktion Carvedilol im Vergleich zu Metoprolol

P=0,04

P=0,006

Poole-Wilson P. ESC-Wien, 2.9.03

comet events related to b blockade
COMET: Events Related to b Blockade

Carvedilol Metoprolol n = 1511 n = 1518

Bradycardia as AE 9.5% 8.9%

Bradycardia as SAE 2.6% 2.6%

Hypotension as AE 14.2% 10.5%

Hypotension as SAE 3.2% 1.9%

summary
Summary
  • The COMET trial compared dosing regimens of metoprolol and carvedilol that produced similar degrees of 1-blockade, both at peak and at trough
  • The results of the COMET trial indicate that the actions of carvedilol beyond 1-blockade have favorable effects on survival
summary and conclusion
Summary and conclusion
  • First head-to-head mortality study comparing two beta-blocking agents in CHF
  • Carvedilol saved significantly more lives than metoprolol (by 17%, P = 0.0017) and reduced cardiovascular mortality by 20%, p=0,0004
  • Carvedilol compared to metoprolol reduced annual mortality from 10.0% to 8.3% and prolonged median survival by 1.4 years
  • Carvedilol is the preferred beta-blocker for the treatment of chronic heart failure
slide38

Betablockade: Mortalitätsreduktion bei HI

NYHA I

NYHA II

NYHA IV

NYHA III

CAPRICORN

COPERNICUS

(Carvedilol vs Placebo): -23 %

(Carvedilol vs Placebo): -35%

US Carvedilol (Carvedilol vs Placebo):-65 %

CIBIS II (Bisoprolol vs Placebo): -34%

MERIT-HF (Metoprolol vs Placebo): -34%

COMET (Carvedilol vs Metoprolol: -17 %)

comet fakten zur metoprolol dosierung
COMET: Fakten zur Metoprolol Dosierung
  • In COMET wurde nicht retardiertes Metoprolol-Tartrat eingesetzt, Zieldosis 100 mg
  • Retardiertes Metoprolol-Succinat war zu Beginn der COMET (1996!) nicht verfügbar, die MERIT-HF Daten wurden erst 1999 publiziert
  • Die Bioverfügbarkeit von retardiertem Metoprolol-Succinat ist um 30-35% niedriger (Poole-Wilson et al. Lancet 2003)
  • In MERIT-HF wurde retardiertes Metoprolol-Succinat eingesetzt, Zieldosis 200 mg, dies entspricht ca. 130 mg Metoprolol-Tartrat (Poole-Wilson et al. Lancet 2003)
  • In MERIT-HF war die Mortalitätsreduktion in der Hochdosis-Gruppe (ø192 mg) gleich wie in der Niedrigdosis-Gruppe (ø76 mg) (Wikstrand et al. JACC 2002)
merit hf effekt der dosis auf die mortalit tsrate
MERIT-HF: Effekt der Dosis auf die Mortalitätsrate

Metoprolol-Succ.

76 mg/Tag

Metoprolol-Succ.

192 mg/Tag

25

25

38%  Risikored.

P = 0.010

38%  Risikored.

P = 0.002

20

20

15

15

Placebo

n = 1845

Placebo

n = 1845

% Mortalität

10

10

Metoprolol Succ.

n = 604

Metoprolol Succ.

n = 1202

5

5

0

0

0

3

6

9

12

15

0

3

6

9

12

15

Months

Months

Wikstrand J et al. J Am Coll Cardiol 2002

merit hf metoprolol dosisgruppen und reduktion der mortalit t
MERIT-HF: Metoprolol-Dosisgruppen und Reduktion der Mortalität

nach Wikstrand J. et al., JACC 2002;40:491-498

merit hf reduktion der mortalit t in abh ngigkeit von der dosis
MERIT-HF: Reduktion der Mortalität in Abhängigkeit von der Dosis

Nach Wikstrand J. et al., JACC 2002;40:491-498

hi erhebung bei 96 rzten in betablocker dosierung bei chron hi in der praxis
HI-Erhebung bei 96 Ärzten in Ö: Betablocker Dosierung bei chron. HI in der Praxis

Austrian Survey OF Treating Herat Failure, 2003, Prof. F. Fruhwald, Prof. P. Rehak, Graz