Results of the Longest and Largest Ever -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: Design: Poole-Wilson et al. Eur J Heart Fail 2002;4:

Pharmacological Differences Within the Blocker Class Agents currently evaluated for heart failure Ancillary blockadeblockade blockade ISA effects* Ancillary blockadeblockade blockade ISA effects* Carvedilol Metoprolol Bisoprolol Bucindolol *anti-oxidant, anti-endothelin, anti-proliferative lack of 1 receptor upregulation

The Normal Heart is a 1 -Organ that Functions in a 1 -Environment Normal

Heart Failure Converts the Circulation From a 1 to a 1 / 2 / 1 -Environment Heart failure

Effects of 2 -Receptors nDirect 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 nHypertrophy, fibrosis, remodelling –Du et al. Circulation 2000 nAntiapoptotic –Communal et al. Circulation 1999 nArrhythmogenic –Billman et al. Circulation 1997 nFacilitation of norepinephrine release (presynaptic) –Boudreau et al. Am J Physiol 1993

Effects of 1 Receptors nMyocardial hypertrophy, fibrosis, remodeling –Simpson & McGrath, J Clin Invest 1983 –Morgan & Baker, Circulation 1991 nCardiotoxicity (with receptors) –Mann et al. Circulation 1992 nArrhythmogenic –Molina-Viamonte et al. Circulation 1991 nPeripheral vasoconstriction –Leier et al. Circulation 1990 nRenal hypoperfusion and sodium retention –Smyth et al. Circ Res 1985 –Hesse et al. Br J Pharmacol 1985

Effects of Different Blocking Agents Sympathetic activation Pharmacological differences 1receptors 2receptors 1receptors CardiotoxicityBisoprololCarvedilolMetoprolol

Carvedilol, But Not Metoprolol, Reduces Total Body and Cardiac Sympathetic Drive Total Body Norepinephrine Spillover (nmol/min) Cardiac Norepinephrine Spillover (nmol/min) * * Azevedo et al. Circulation 2001 Carvedilol Metoprolol 0 * P < 0.05 vs. baseline and vs. metoprolol

TrialnHazard Ratio (95% CI) MERIT-HF 3, ( ) US Carvedilol Prog1, ( ) CIBIS II 2, ( ) BEST2, ( ) COPERNICUS2, ( ) Mortality Results of Blockers Studies in CHF Packer et al. NEJM 1996; CIBIS II Invest. Lancet 1999; MERIT-HF Study Gp. Lancet 1999 BEST Investigators. Lancet 1999; Packer et al. NEJM Mild to Moderate Severe

Carvedil ol Placeb o Survival Days Risk reduction = 65% p<0.001 Packer et al (1996) CIBIS-II Investigators (1999) Bisoprolol Placebo Time after inclusion (days) p< Survival Risk reduction = 34% The MERIT-HF Study Group (1999) US Carvedilol Programme CIBIS-II Months of follow-up Mortality (%) Placebo Metoprolol CR/XL p= Risk reduction = 34% MERIT-HF COPERNICUS Months Carvedilol Placebo Risk reduction = 35% p= Survival Packer et al (2001)

Herzinsuffizienz: NNT* - Number Needed to Treat for one year to save one life *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 NYHA IV NYHA II-III NYHA (II-) III

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=0,0002 P=0,009 Nach M. Packer, Am Heart J 2001; 141:

Absolute change from baseline ml/m 2 LV Ejection Fraction LV EDV LV ESV LVEF (%) MetoprololCarvedilol Metra M et al. Circ 2000 ** *** *** *** **P < 0.01 ***P < vs baseline *** *** P = Carvedilol Improves Cardiac Performance to a Greater Extent than Metoprolol

Packer M et al. Am Heart J 2001 LV Ejection Fraction (%) Metoprolol (n = 123) Carvedilol (n = 125) P = P = Meta-analysis of Direct Comparison Trials with Metoprolol and Carvedilol in CHF

Blocker Tolerability in Clinical Trials Blocker Tolerability in Clinical Trials Carvedilol (COPERNICUS) % Bisoprolol (CIBIS II) Metoprolol (MERIT-HF) Carvedilol (US Carvedilol) Percentage of patients achieving target dose

COMET: Objectives and Design nTo 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 nNo run-in period Mild, moderate or severe CHF Metoprolol (n = 1,518) Carvedilol (n = 1,511) Screening Titration Maintenance (estimated yrs) Randomisation

COMET Trial nThe COMET trial is not simply a comparison of the survival effects of Metoprolol and Carvedilol in patients with heart failure. nThe COMET trial is really a test of whether the properties of Carvedilol beyond 1 -blockade have favorable effects on survival. nTo 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)

Minimum follow-up (months): Maximum follow-up (months): Average follow-up (months): (=14621 years) 1112 Total patient months of follow-up: Total deaths prior to 15-Nov-2002: 01-Dec Jan First patient recruited: Last patient recruited: Total recruited: Carvedilol:Metoprolol: Dates, Timing and Follow-up

Randomised3029 Carvedilol1511Metoprolol1518 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 Flow Chart of Patients

Main Inclusion Criteria nSymptomatic CHF (NYHA II-IV) on standard treatment nStable diuretic treatment 2 weeks nACE inhibitor 4 weeks prior to study entry –use of digitalis and/or vasodilators was discretionary nLVEF 35% n 1 CVS hospitalisation in the previous 2 years

Severity of Heart Failure COMETMERIT-HF 1 N=3,029N=3,991 NYHA Class (%) II4841 III4855 IV44 LVEF (%)2628 LVEF (%) Lancet 1999; 353:

Background Therapy COMETMERIT-HF Diuretic99%90% ACEi91%90% ARB 7%7% Spironolactone11%8% Digoxin59%64% Aspirin37%46% Warfarin46%NA

5452 Aetiology (IHD %) 42.2/2042.6/22 Months of HF (mean/median) Diabetes AF/flutter (%) 8181 Heart rate (beats/min) 49/47/448/48/3 NYHA class (%) II/III/IV 7777 Diastolic BP (mm Hg) Systolic BP (mm Hg) Male (%) 62.3 (11.4) 61.6 (11.3) Age (y, mean/sd) Metoprolol(n=1518) Carvedilol (n=1511) COMET: Baseline Characteristics

Time (years) Mortality (%) Metoprolol Carvedilol Hazard ratio 0.83, 95% CI 0.74 – 0.93, P = Number at risk Carvedilol Metoprolol COMET: Primary Endpoint Total Mortality Poole-Wilson et al. Lancet 2003;362:7-13

Time (years) 1,3591,2341, ,3661,2581,1551, Number at risk MetoprololCarvedilol 1,518 1,511 Mortality (%) Survival benefit 20%, P = Metoprolol Carvedilol COMET: Cardiovascular Mortality ESC 2003

COMET: Fatal or non-fatal myocardial infarction Time (years) Hazard ratio % CI , p= Carvedilol Metoprolol Event % K. Swedberg AHF 2003, Las Vegas - 29%

COMET-Studie: Unterschiede in der Mortalität Carvedilol versus Metoprolol -20% -17% P=0,0017 P=0,0004 Poole-Wilson P. et al. Lancer 2003; 362:7-13

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 Death CarvedilolMetoprolol n=1511n=1518 Sudden218 (42.6%)262 (43.7%) Circulatory failure168 (32.8%)197 (32.9%) Stroke13 (2.5%)38 (6.3%) Other CV19 (3.7%)26 (4.3%) Non-CV74 (14.5%)66 (11.0%) Unable to classify20 (3.9%)11 (1.8%)

Time (years) Mortality (%) Metoprolol Carvedilol Relative Risk Reduction 67% !! P = COMET: Death from Stroke ESC 2003

Sex Male (n = ) Female (n = 612!) Age < NYHAII III IV (n = 115!) CauseOther IHD LVEF 25% 25% > 25% Heart rate < Systolic BP < Diabetesyes no Overall Carvedilol better Metoprolol better COMET: Consistent Mortality Reduction in Sub-Groups Poole-Wilson et al. Lancet 2003;362:7-13

, / %774/ % Death and hospitalisation for worsening heart failure , / %745/ % Cardiovascular death, heart transplantation or hospitalisation for non-fatal AMI or worsening heart failure , / %963/ % Death and cardiovascular hospitalisation P- value 95% CI Hazard ratio MetoprololCarvedilolSecondaryendpoints COMET: Secondary Endpoints

New diabetes (%) , Time (years) Metoprolol Carvedilol Number at risk 1,147 1,151 Relative Risk Reduction 22%, P = 0.04 Metoprolol Carvedilol COMET: New Onset Diabetes ESC 2003

COMET – ESC, Wien 2003: Risikoreduktion Carvedilol im Vergleich zu Metoprolol P=0,006 P=0,04 Poole-Wilson P. ESC-Wien,

COMET: Events Related to Blockade CarvedilolMetoprolol n = 1511n = 1518 Bradycardia as AE9.5%8.9% Bradycardia as SAE2.6%2.6% Hypotension as AE14.2%10.5% Hypotension as SAE3.2%1.9%

Summary nThe COMET trial compared dosing regimens of metoprolol and carvedilol that produced similar degrees of 1 - blockade, both at peak and at trough nThe results of the COMET trial indicate that the actions of carvedilol beyond 1 - blockade have favorable effects on survival

Summary and conclusion nFirst head-to-head mortality study comparing two beta-blocking agents in CHF nCarvedilol saved significantly more lives than metoprolol (by 17%, P = ) and reduced cardiovascular mortality by 20%, p=0,0004 nCarvedilol compared to metoprolol reduced annual mortality from 10.0% to 8.3% and prolonged median survival by 1.4 years nCarvedilol is the preferred beta-blocker for the treatment of chronic heart failure

NYHA II NYHA III NYHA INYHA 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 Dosierung nIn COMET wurde nicht retardiertes Metoprolol-Tartrat eingesetzt, Zieldosis 100 mg nRetardiertes Metoprolol-Succinat war zu Beginn der COMET (1996!) nicht verfügbar, die MERIT-HF Daten wurden erst 1999 publiziert nDie Bioverfügbarkeit von retardiertem Metoprolol-Succinat ist um 30-35% niedriger (Poole-Wilson et al. Lancet 2003) nIn MERIT-HF wurde retardiertes Metoprolol-Succinat eingesetzt, Zieldosis 200 mg, dies entspricht ca. 130 mg Metoprolol-Tartrat (Poole-Wilson et al. Lancet 2003) nIn MERIT-HF war die Mortalitätsreduktion in der Hochdosis-Gruppe (ø192 mg) gleich wie in der Niedrigdosis-Gruppe (ø76 mg) (Wikstrand et al. JACC 2002)

Months Months Placebo n = 1845 Metoprolol Succ. n = % Risikored. P = MERIT-HF: Effekt der Dosis auf die Mortalitätsrate Metoprolol-Succ. 192 mg/Tag Metoprolol-Succ. 76 mg/Tag Placebo n = % Risikored. P = Metoprolol Succ. n = 1202 % Mortalität Wikstrand J et al. J Am Coll Cardiol 2002

MERIT-HF: Metoprolol-Dosisgruppen und Reduktion der Mortalität Endpunkt < 100 mg Metoprolol (ø 76 mg ) > 100 mg Metoprolol (ø 192 mg) Mortalität - 38 % Plötzl. Hertod - 50 % - 41 % nach Wikstrand J. et al., JACC 2002;40:

MERIT-HF: Reduktion der Mortalität in Abhängigkeit von der Dosis Nach Wikstrand J. et al., JACC 2002;40:

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