Results of the Longest and Largest EverResults of the Longest and Largest Ever-Blockade Study in CHF-Blockade Study in CHF

Mortality Reduction beyond ßMortality Reduction beyond ß11-Blockade-Blockade

Pub.: Results: Poole-Wilson et al. Lancet 2003;362:7-13Pub.: Results: Poole-Wilson et al. Lancet 2003;362:7-13 Design: Poole-Wilson et al. Eur J Heart Fail 2002;4:321-329Design: Poole-Wilson et al. Eur J Heart Fail 2002;4:321-329

Pharmacological Differences Within the Pharmacological Differences Within the Blocker Class Blocker Class

Agents currently evaluated for heart failureAgents currently evaluated for heart failure

11 22 11 Ancillary Ancillary

blockadeblockade blockadeblockade blockade ISA effects*blockade ISA effects*

CarvedilolCarvedilol ++++++ +++ ++++++ +++ - +++- +++

MetoprololMetoprolol ++++++ - - -- -- --

BisoprololBisoprolol ++++++ - - -- -- --

BucindololBucindolol ++++++ +++ -+++ - ++++ --

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

lack lack of of 11 receptor upregulationreceptor upregulation

The Normal Heart is a The Normal Heart is a 11-Organ that-Organ that

Functions in a Functions in a 11-Environment-Environment

11 1

Normal

1 11

11

11

1

2 2

Normal

1 11

11

11

1

2 2

11 1

Heart Failure Converts the Circulation Heart Failure Converts the Circulation From a From a 11 to a to a 11//22//11-Environment-Environment

Heart failure

1

2

22

2

1

1 1

1

1

11 2

21

1

Effects of Effects of 22-Receptors-Receptors Direct chronotropic, inotropic, lusitropic cAMP mediatedDirect chronotropic, inotropic, lusitropic cAMP mediated

– Coupling to the GS/cAMP pathway greater than via Coupling to the GS/cAMP pathway greater than via 1-adrenoceptor, further enhanced by selective 1-adrenoceptor, further enhanced by selective 1-blockade 1-blockade

– Newton et al. Circ 1999; Kaumann et al. Circ 1999Newton et al. Circ 1999; Kaumann et al. Circ 1999

– Hall et al. Circ Res 1990Hall et al. Circ Res 1990

Hypertrophy, fibrosis, remodellingHypertrophy, fibrosis, remodelling– Du et al. Circulation 2000Du et al. Circulation 2000

AntiapoptoticAntiapoptotic– Communal et al. Circulation 1999Communal et al. Circulation 1999

ArrhythmogenicArrhythmogenic– Billman et al. Circulation 1997Billman et al. Circulation 1997

Facilitation of norepinephrine release (presynaptic) Facilitation of norepinephrine release (presynaptic) – Boudreau et al. Am J Physiol 1993Boudreau et al. Am J Physiol 1993

Effects of Effects of 11 Receptors Receptors

Myocardial hypertrophy, fibrosis, remodelingMyocardial hypertrophy, fibrosis, remodeling– Simpson & McGrath, J Clin Invest 1983Simpson & McGrath, J Clin Invest 1983– Morgan & Baker, Circulation 1991Morgan & Baker, Circulation 1991

Cardiotoxicity (with Cardiotoxicity (with receptors) receptors) – Mann et al. Circulation 1992Mann et al. Circulation 1992

ArrhythmogenicArrhythmogenic– Molina-Viamonte et al. Circulation 1991Molina-Viamonte et al. Circulation 1991

Peripheral vasoconstrictionPeripheral vasoconstriction – Leier et al. Circulation 1990Leier et al. Circulation 1990

Renal hypoperfusion and sodium retentionRenal hypoperfusion and sodium retention– Smyth et al. Circ Res 1985Smyth et al. Circ Res 1985– Hesse et al. Br J Pharmacol 1985Hesse et al. Br J Pharmacol 1985

Effects of Different Effects of Different Blocking Agents Blocking Agents

Sympathetic activationSympathetic activation

Pharmacological differencesPharmacological differences

11

receptorsreceptors22

receptorsreceptors11

receptorsreceptors

CardiotoxicityCardiotoxicity

BisoprololBisoprolol

CarvedilolCarvedilol

MetoprololMetoprolol

Carvedilol, But Not Metoprolol, Reduces Carvedilol, But Not Metoprolol, Reduces Total Body and Cardiac Sympathetic DriveTotal Body and Cardiac Sympathetic Drive

Total BodyTotal BodyNorepinephrine Spillover Norepinephrine Spillover

-2.5-2.5

-1.5-1.5

-0.5-0.5

0.50.5

(nm

ol/m

in)

(nm

ol/m

in)

CardiacCardiacNorepinephrine SpilloverNorepinephrine Spillover

-150-150

-100-100

-50-50

00

5050

100100

(nm

ol/m

in)

(nm

ol/m

in)

** **

Azevedo et al. Circulation 2001 Azevedo et al. Circulation 2001

Carvedilol MetoprololCarvedilol Metoprolol Carvedilol MetoprololCarvedilol Metoprolol

00

* P < 0.05 vs. baseline and vs. metoprolol* P < 0.05 vs. baseline and vs. metoprolol

TrialTrial nn Hazard Ratio (95% Hazard Ratio (95% CI)CI)

MERIT-HF MERIT-HF 3,9913,991 0.66 (0.53-0.81) 0.66 (0.53-0.81)

US Carvedilol ProgUS Carvedilol Prog 1,0941,094 0.35 (0.20-0.61) 0.35 (0.20-0.61)

CIBIS II CIBIS II 2,6472,647 0.66 (0.54-0.81) 0.66 (0.54-0.81)

BESTBEST 2,7082,708 0.90 (0.78-1.02) 0.90 (0.78-1.02)

COPERNICUSCOPERNICUS 2,2892,289 0.65 (0.52-0.81) 0.65 (0.52-0.81)

Mortality Results of Mortality Results of Blockers Studies in CHF Blockers Studies in CHF

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

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

00 0.20.2 0.40.4 0.60.6 0.80.8 11

Mild

to

Mo

der

ate

Mild

to

Mo

der

ate

Sev

ere

Sev

ere

Carvedilol

Placebo

Survival

Days0 50 100 150 200 250300350400

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=0.0062

Risk reduction = 34%

MERIT-HF

COPERNICUSCOPERNICUS

MonthsMonths00

0033 66 99 1212 1515 1818 2121

100100

9090

8080

6060

7070

CarvedilolCarvedilol

PlaceboPlacebo

Risk reduction = 35%

p=0.00013

Survival

Packer et al (2001)

Herzinsuffizienz: NNT* - Herzinsuffizienz: NNT* - NNumber umber NNeeded to eeded to TTreat for one year to save one lifereat for one year to save one life

15 15

27

23

0

5

10

15

20

25

30

Carvedilol(COPERNICUS)

Carvedilol (US-Studienprg)

Metoprolol(MERIT-HF)

Bisoprolol (CIBIS-II)

*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

NYHA IVNYHA IV NYHA II-IIINYHA II-III NYHA II-IIINYHA II-III NYHA (II-) IIINYHA (II-) III

Veränderung LVEF: 4 direkte Vergleichsstudien

2

4

6

8

10

Carvedilol Metoprolol

D L

VE

F U

nits

Veränderung LVEF:15 Placebo-kontrollierte Studien

2

4

6

8

Carvedilol MetoprololD

LVE

F U

nits

Metaanalyse Betablockade bei Herzinsuffizienz:Verbesserung der Herzleistung

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

P=0,0002P=0,009

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

00

22

44

66

88

1010

1212

1414

1616

Ab

solu

te c

han

ge

fro

m b

asel

ine

Ab

solu

te c

han

ge

fro

m b

asel

ine

-40-40

-35-35

-30-30

-25-25

-20-20

-15-15

-10-10

-5-5

00

ml/

mm

l/m

22

LV Ejection FractionLV Ejection Fraction LV EDVLV EDV LV ESVLV ESV

LV

EF

(%

)L

VE

F (

%)

MetoprololMetoprolol CarvedilolCarvedilol

Metra M et al. Circ 2000Metra M et al. Circ 2000

****

******

******

******

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

******

******

P P = = 0.0380.038

Carvedilol Improves Cardiac Performance Carvedilol Improves Cardiac Performance to a Greater Extent than Metoprololto a Greater Extent than Metoprolol

Packer M et al. Am Heart J 2001Packer M et al. Am Heart J 2001

LV

Eje

ctio

nL

V E

ject

ion

Fra

ctio

n (

%)

Fra

ctio

n (

%)

00

+2+2

+4+4

+6+6

+8+8

+10+10

+12+12

MetoprololMetoprolol(n = 123)(n = 123)

CarvedilolCarvedilol(n = 125)(n = 125)

P = 0.009P = 0.009

Meta-analysis of Direct Comparison Trials Meta-analysis of Direct Comparison Trials with Metoprolol and Carvedilol in CHFwith Metoprolol and Carvedilol in CHF

Blocker Tolerability in Clinical TrialsBlocker Tolerability in Clinical Trials

Carvedilol (COPERNICUS)

00 2020 4040 6060 8080 100 %100 %

Bisoprolol (CIBIS II)

Metoprolol (MERIT-HF)

Carvedilol (US Carvedilol)

Percentage of patients achieving target dosePercentage of patients achieving target dose

COMET: Objectives and DesignCOMET: Objectives and Design To compare the effects of the combined To compare the effects of the combined

alpha/betablocker carvedilol with those of the alpha/betablocker carvedilol with those of the ß1-selective metoprolol on mortality and morbidity ß1-selective metoprolol on mortality and morbidity in patients with chronic heart failurein patients with chronic heart failure

No run-in periodNo run-in period

Mild, moderate or severe CHF Metoprolol (n = 1,518)

Carvedilol (n = 1,511)

Screening Titration Maintenance (estimated 4 - 6 yrs)

Randomisation

COMET TrialCOMET Trial

The COMET trial is not simply a comparison of The COMET trial is not simply a comparison of the survival effects of Metoprolol and Carvedilol the survival effects of Metoprolol and Carvedilol in patients with heart failure.in patients with heart failure.

The COMET trial is really a test of whether the The COMET trial is really a test of whether the properties of Carvedilol properties of Carvedilol beyond beyond 11-blockade-blockade

have favorable effects on survival.have favorable effects on survival.

To verify this theory, Metoprolol and Carvedilol To verify this theory, Metoprolol and Carvedilol were used in dosages, that produce equivalent were used in dosages, that produce equivalent degrees of degrees of 11-blockade (50 mg Metoprolol IR BID -blockade (50 mg Metoprolol IR BID

and 25 mg Carvedilol BID) and 25 mg Carvedilol BID)

4747717157.957.9

Minimum follow-up (months):Minimum follow-up (months):Maximum follow-up (months):Maximum follow-up (months):

Average follow-up (months):Average follow-up (months):

175447 (=14621 years)175447 (=14621 years)11121112

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

2002:2002:

01-Dec-199601-Dec-199615-Jan-199915-Jan-1999302930291511151115181518

First patient recruited:First patient recruited:Last patient recruited:Last patient recruited:

Total recruited:Total recruited:Carvedilol:Carvedilol:

Metoprolol:Metoprolol:

Dates, Timing and Follow-upDates, Timing and Follow-up

RandomisedRandomised30293029

CarvedilolCarvedilol15111511

MetoprololMetoprolol15181518

Assigned to drug Assigned to drug and received at least one tabletand received at least one tablet

Withdrew consent 10Withdrew consent 10Lost to follow-up Lost to follow-up 3 3

Withdrew consent 18Withdrew consent 18Lost to follow-up Lost to follow-up 2 2

Flow Chart of PatientsFlow Chart of Patients

Main Inclusion CriteriaMain Inclusion Criteria

Symptomatic CHF (NYHA II-IV) on standard treatmentSymptomatic CHF (NYHA II-IV) on standard treatment

Stable diuretic treatment Stable diuretic treatment 2 weeks 2 weeks

ACE inhibitor ACE inhibitor 4 weeks prior to study entry 4 weeks prior to study entry

– use of digitalis and/or vasodilators was discretionaryuse of digitalis and/or vasodilators was discretionary

LVEF LVEF 35% 35%

1 CVS hospitalisation in the previous 2 years1 CVS hospitalisation in the previous 2 years

Severity of Heart FailureSeverity of Heart Failure

COMETCOMET MERIT-MERIT-HFHF11

N=3,029N=3,029 N=3,991N=3,991

NYHA Class (%)NYHA Class (%)IIII 4848 4141IIIIII 4848 5555IVIV 44 44

  LVEF (%)LVEF (%) 2626 2828

1. Lancet 1999; 353: 2001-71. Lancet 1999; 353: 2001-7

Background TherapyBackground Therapy

COMETCOMET MERITMERIT-HF-HF

DiureticDiuretic 99%99% 90%90%

ACEiACEi 91%91% 90%90%

ARBARB 7% 7% 7%7%

SpironolactoneSpironolactone 11%11% 8%8%

DigoxinDigoxin 59%59% 64%64%

AspirinAspirin 37%37% 46%46%

WarfarinWarfarin 46%46% NANA

54545252Aetiology (IHD %)Aetiology (IHD %)42.2/2042.2/2042.6/2242.6/22Months of HF (mean/median)Months of HF (mean/median)

24.424.423.823.8DiabetesDiabetes19.219.220.520.5AF/flutter (%)AF/flutter (%)

81818181Heart rate (beats/min)Heart rate (beats/min)

49/47/449/47/448/48/348/48/3NYHA class (%) II/III/IVNYHA class (%) II/III/IV77777777Diastolic BP (mm Hg)Diastolic BP (mm Hg)

126126126126Systolic BP (mm Hg)Systolic BP (mm Hg)

80.280.279.479.4Male (%)Male (%)62.3 (11.4)62.3 (11.4)61.6 (11.3)61.6 (11.3)Age (y, mean/sd)Age (y, mean/sd)

Metoprolol Metoprolol (n=1518)(n=1518)

Carvedilol Carvedilol (n=1511)(n=1511)

COMET: Baseline Characteristics COMET: Baseline Characteristics

Time (years)Time (years)

Mo

rtal

ity

(%)

Mo

rtal

ity

(%)

00

1010

2020

3030

4040

00 11 22 33 44 55

MetoprololMetoprolol

CarvedilolCarvedilol

Hazard ratio 0.83, Hazard ratio 0.83, 95% CI 0.7495% CI 0.74 – – 0.93, P = 0.00170.93, P = 0.0017

Number at riskNumber at risk

CarvedilolCarvedilol 15111511 13671367 12591259 1155 1155 10021002 383383MetoprololMetoprolol 15181518 13591359 12341234 1105 1105 933933 352352

COMET: COMET: Primary Endpoint Total MortalityPrimary Endpoint Total Mortality

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

Time (years)Time (years)1,3591,359 1,2341,234 1,1051,105 933933 3523521,3661,366 1,2581,258 1,1551,155 1,0021,002 383383

Number at riskNumber at riskMetoprololMetoprololCarvedilolCarvedilol

1,5181,5181,5111,511

Mo

rta

lity

(%)

Mo

rta

lity

(%)

00

1010

2020

3030

4040

00 11 22 33 44 55

Survival benefit 20%,Survival benefit 20%,P = 0.0004P = 0.0004

MetoprololMetoprolol

CarvedilolCarvedilol

COMET: Cardiovascular MortalityCOMET: Cardiovascular Mortality

ESC 2003ESC 2003

COMET: COMET: Fatal or non-fatal myocardial infarctionFatal or non-fatal myocardial infarction

Time (years)

Hazard ratio 0.714 95% CI 0.523 - 0.974, p=0.0333

0

5

10

15

1 2 3 4 5

CarvedilolMetoprolol

Event %

K. Swedberg AHF 2003, Las Vegas

- 29%- 29%

COMET-Studie: Unterschiede in der COMET-Studie: Unterschiede in der Mortalität Carvedilol versus MetoprololMortalität Carvedilol versus Metoprolol

25%

27%

29%

31%

33%

35%

37%

39%

41%

43%

45%

Gesamtmortalität Kardiovaskuläre Mortalität

ab

so

lute

Mo

rta

litä

t in

%

Metoprolol

Dilatrend

-20%

-17%

P=0,0017

P=0,0004

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

-17%

-20%

-29%-30%

-25%

-20%

-15%

-10%

-5%

0%

Gesamt-Mortalitätkardiovaskuläre

Mortalitättödl. / nichttödl.

Herzinfarkte

% R

isik

ore

du

ktio

n

p=0,0333

p=0,0017

p=0,0004

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

COMET: Risikoreduktion gegenüber kardioselektiven Betablocker Metoprolol

COMET: Mode of DeathCOMET: Mode of Death

CarvedilolCarvedilol MetoprololMetoprololn=1511n=1511 n=1518n=1518

SuddenSudden 218 (42.6%)218 (42.6%) 262 (43.7%)262 (43.7%)

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

StrokeStroke 13 (2.5%)13 (2.5%) 38 (6.3%)38 (6.3%)

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

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

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

Time (years)Time (years)

Mo

rta

lity

(%)

Mo

rta

lity

(%) MetoprololMetoprolol

CarvedilolCarvedilol

00

11

22

33

00 11 22 33 44 55

Relative Risk Reduction 67% !!Relative Risk Reduction 67% !!P = 0.0006P = 0.0006

COMET: Death from StrokeCOMET: Death from Stroke

ESC 2003ESC 2003

0.500.50 0.750.75 1.001.00 1.251.25 1.501.50

SexSex Male Male (n = 2.417(n = 2.417))Female Female (n = 612!)(n = 612!)

AgeAge < 65< 65 6565

NYHANYHA IIIIIIIIIIIV IV (n = 115!)(n = 115!)

CauseCause OtherOtherIHDIHD

LVEFLVEF 25%25%> 25%> 25%

Heart rateHeart rate < 80< 80 8080

Systolic BPSystolic BP < 110< 110110 - 139110 - 139 140140

DiabetesDiabetes yesyesnono

OverallOverall

Carvedilol betterCarvedilol better Metoprolol betterMetoprolol better

COMET: COMET: Consistent Mortality Reduction in Sub-GroupsConsistent Mortality Reduction in Sub-Groups

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

0.01910.01910.807, 0.9810.807, 0.9810.890.89841/1518841/1518

55.4%55.4%

774/1511774/1511

51.2%51.2%

Death and Death and hospitalisation hospitalisation for worsening for worsening heart failureheart failure

0.01280.01280.798, 0.9740.798, 0.9740.8810.881815/1518815/1518

53.7%53.7%

745/1511745/1511

49.3%49.3%

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

0.09720.09720.85, 1.0140.85, 1.0140.9280.9281016/15181016/1518

66.9%66.9%

963/1511963/1511

63.7%63.7%

Death and Death and cardiovascular cardiovascular hospitalisationhospitalisation

P-P-valuevalue

95% CI95% CIHazard Hazard ratioratio

MetoprololMetoprololCarvedilolCarvedilolSecondarySecondary

endpointsendpoints

COMET: Secondary EndpointsCOMET: Secondary Endpoints

New

dia

bet

es (

%)

New

dia

bet

es (

%)

00

55

1010

00 11 22 33 44 55

991991 879879 764764 626626 2212211,0141,014 908908 827827 705705 254254

1515

Time (years)Time (years)MetoprololMetoprololCarvedilolCarvedilol

Number at riskNumber at risk1,1471,1471,1511,151

Relative Risk Reduction 22%,Relative Risk Reduction 22%,P = 0.04P = 0.04

MetoprololMetoprolol

CarvedilolCarvedilol

COMET: New Onset DiabetesCOMET: New Onset Diabetes

ESC 2003ESC 2003

COMET – ESC, Wien 2003: COMET – ESC, Wien 2003: Risikoreduktion Carvedilol im Vergleich zu Risikoreduktion Carvedilol im Vergleich zu

MetoprololMetoprolol

-67%

-22%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

Schlaganfall - Mortalität Diabetes Erstmanifestation

% R

isik

ore

du

ktio

n

P=0,006

P=0,04

Poole-Wilson P. ESC-Wien, 2.9.03

COMET: Events Related to COMET: Events Related to Blockade Blockade

CarvedilolCarvedilolMetoprololMetoprolol

n = n = 15111511 n = 1518n = 1518

Bradycardia as AEBradycardia as AE 9.5%9.5% 8.9%8.9%

Bradycardia as SAEBradycardia as SAE 2.6%2.6% 2.6%2.6%

Hypotension as AEHypotension as AE 14.2%14.2% 10.5%10.5%

Hypotension as SAEHypotension as SAE 3.2%3.2% 1.9%1.9%

SummarySummary

The COMET trial compared dosing The COMET trial compared dosing regimens of metoprolol and carvedilol regimens of metoprolol and carvedilol that produced similar degrees of that produced similar degrees of 11--

blockade, both at peak and at troughblockade, both at peak and at trough

The results of the COMET trial indicate The results of the COMET trial indicate that the actions of carvedilol beyond that the actions of carvedilol beyond 11--

blockade have favorable effects on blockade have favorable effects on survival survival

Summary and conclusion Summary and conclusion

First head-to-head mortality study comparing two First head-to-head mortality study comparing two beta-blocking agents in CHFbeta-blocking agents in CHF

Carvedilol saved significantly more lives than Carvedilol saved significantly more lives than metoprolol (by 17%, P = 0.0017) and reduced metoprolol (by 17%, P = 0.0017) and reduced cardiovascular mortality by 20%, p=0,0004cardiovascular mortality by 20%, p=0,0004

Carvedilol compared to metoprolol reduced Carvedilol compared to metoprolol reduced annual mortality from 10.0% to 8.3% and annual mortality from 10.0% to 8.3% and prolonged median survival by 1.4 yearsprolonged median survival by 1.4 years

Carvedilol is the preferred beta-blocker for the Carvedilol is the preferred beta-blocker for the treatment treatment of chronic heart failureof chronic heart failure

NYHA IINYHA III

NYHA I NYHA IV

US Carvedilol (Carvedilol vs Placebo): -65 %

CIBIS II (Bisoprolol vs Placebo): -34%

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

CAPRICORN(Carvedilol vs Placebo): -23 %

COPERNICUS(Carvedilol vs Placebo): -35%

Betablockade: Mortalitätsreduktion bei HI

COMET (Carvedilol vs Metoprolol: -17 %)

COMET: Fakten zur Metoprolol DosierungCOMET: Fakten zur Metoprolol Dosierung

In COMET wurde nicht retardiertes Metoprolol-Tartrat In COMET wurde nicht retardiertes Metoprolol-Tartrat eingesetzt, Zieldosis 100 mgeingesetzt, Zieldosis 100 mg

Retardiertes Metoprolol-Succinat war zu Beginn der Retardiertes Metoprolol-Succinat war zu Beginn der COMET (1996!) nicht verfügbar, die MERIT-HF Daten COMET (1996!) nicht verfügbar, die MERIT-HF Daten wurden erst 1999 publiziert wurden erst 1999 publiziert

Die Bioverfügbarkeit von retardiertem Metoprolol-Succinat Die Bioverfügbarkeit von retardiertem Metoprolol-Succinat ist um 30-35% niedriger ist um 30-35% niedriger (Poole-Wilson et al. Lancet 2003)(Poole-Wilson et al. Lancet 2003)

In MERIT-HF wurde retardiertes Metoprolol-Succinat In MERIT-HF wurde retardiertes Metoprolol-Succinat eingesetzt, Zieldosis 200 mg, dies entspricht ca. 130 mg eingesetzt, Zieldosis 200 mg, dies entspricht ca. 130 mg Metoprolol-Tartrat Metoprolol-Tartrat (Poole-Wilson et al. Lancet 2003)(Poole-Wilson et al. Lancet 2003)

In MERIT-In MERIT-HFHF war die Mortalitätsreduktion in der war die Mortalitätsreduktion in der Hochdosis-Gruppe (Hochdosis-Gruppe (øø192 mg) gleich wie in der 192 mg) gleich wie in der Niedrigdosis-Gruppe (Niedrigdosis-Gruppe (øø76 mg) 76 mg) (Wikstrand et al. JACC 2002)(Wikstrand et al. JACC 2002)

00

55

1010

1515

2020

2525

00 33 66 99 1212 1515

MonthsMonths

00

55

1010

1515

2020

2525

00 33 66 99 1212 1515

MonthsMonths

PlaceboPlacebon = 1845n = 1845

Metoprolol Succ.Metoprolol Succ.n = 604n = 604

38% 38% Risikored. Risikored.P = 0.P = 0.010010

MERIT-HF: Effekt der Dosis auf die MortalitätsrateMERIT-HF: Effekt der Dosis auf die Mortalitätsrate

Metoprolol-Succ.Metoprolol-Succ.192 mg/Tag192 mg/Tag

Metoprolol-Succ.Metoprolol-Succ.76 mg/Tag76 mg/Tag

PlaceboPlacebon = 1845n = 1845

38% 38% Risikored. Risikored.P = 0.P = 0.002002

Metoprolol Succ.Metoprolol Succ.n = 1202n = 1202

% M

ort

alit

ät%

Mo

rtal

ität

Wikstrand J et al. J Am Coll Cardiol 2002Wikstrand J et al. J Am Coll Cardiol 2002

MERIT-HF: Metoprolol-Dosisgruppen und MERIT-HF: Metoprolol-Dosisgruppen und Reduktion der MortalitätReduktion der Mortalität

EndpunktEndpunkt

< 100 mg < 100 mg Metoprolol (Metoprolol (ø 76 ø 76

mg )mg )

> 100 mg > 100 mg Metoprolol (Metoprolol (ø 192 ø 192

mg)mg)

MortalitätMortalität - 38 %- 38 % - 38 %- 38 %

Plötzl. Plötzl. HertodHertod - 50 %- 50 % - 41 %- 41 %

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

MERIT-HF: Reduktion der Mortalität in MERIT-HF: Reduktion der Mortalität in Abhängigkeit von der DosisAbhängigkeit von der Dosis

-60%

-50%

-40%

-30%

-20%

-10%

0%

< 100 mg Metoprolol (ø 76 mg ) > 100 mg Metoprolol (ø 192 mg)

%

Mortalität

Plötzl. Hertod

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

HI-Erhebung bei 96 Ärzten in Ö: HI-Erhebung bei 96 Ärzten in Ö: Betablocker Dosierung bei chron. HI in Betablocker Dosierung bei chron. HI in

der Praxisder Praxis

Anzahl Pat.

Ø Dosis (mg)

% Soll (ESC)

Atenolol 95 59,5 N.A.Bisoprolol 300 5,3 53,3Carvedilol 276 27,1 54,3Metoprolol-T 79 79,1 52,7Metoprolol-S 173 71,7 35,8

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