COPERNICUS and carvedilol Background and principal results slide kit December 2000.

COPERNICUSCOPERNICUSandand

carvedilolcarvedilol

Background and Background and principal results slide kitprincipal results slide kit

December 2000December 2000

NorepinephrineNorepinephrineAngiotensin IIAngiotensin II

Hypertrophy, apoptosis, ischaemia,Hypertrophy, apoptosis, ischaemia,arrhythmia, remodelling, fibrosisarrhythmia, remodelling, fibrosis

ACE inhibitors in heart failureACE inhibitors in heart failure

Approximately 7,000 patients evaluated in Approximately 7,000 patients evaluated in placebo-controlled clinical trialsplacebo-controlled clinical trials

Consistent improvement in cardiac function, Consistent improvement in cardiac function, symptoms and clinical statussymptoms and clinical status

Decrease in all-cause mortality by 20-25% Decrease in all-cause mortality by 20-25% (p<(p<0.001)0.001)

Decrease in combined risk of death and Decrease in combined risk of death and hospitalisation by 20-25% (hospitalisation by 20-25% (pp<0.001)<0.001)

US Consensus Recommendations (1996)US Consensus Recommendations (1996)

ACE inhibitors in heart failureACE inhibitors in heart failure

Consensus recommendationsConsensus recommendations

All patients with heart failure due to left ventricular All patients with heart failure due to left ventricular

systolic dysfunction should receive an ACE inhibitor systolic dysfunction should receive an ACE inhibitor

unless they have a contraindication to its use or unless they have a contraindication to its use or

cannot tolerate treatment with the drugcannot tolerate treatment with the drug

SOLVD PreventionSOLVD Prevention(enalapril)(enalapril)

Class IClass I Class IVClass IV

SOLVD Treatment (enalapril)SOLVD Treatment (enalapril)V-HeFT II (enalapril)V-HeFT II (enalapril)

CONSENSUSCONSENSUS(enalapril)(enalapril)

Class IIClass IIClass IIIClass III

blockersblockers

Over 13,000 patients evaluated in placebo-Over 13,000 patients evaluated in placebo-controlled clinical trialscontrolled clinical trials

Consistent improvement in cardiac function, Consistent improvement in cardiac function, symptoms and clinical statussymptoms and clinical status

Decrease in all-cause mortality by 30–35% Decrease in all-cause mortality by 30–35% ((p<p<0.0001)0.0001)

Decrease in combined risk of death and Decrease in combined risk of death and hospitalisation by 25–30% (hospitalisation by 25–30% (p<p<0.0001)0.0001)

Carvedilol(n=696)

Placebo(n=398)

Survival

Days

0 50 100 150 200 250 300 350 400

1.0

0.9

0.8

0.7

0.6

0.5

Risk reduction = 65%Risk reduction = 65%p<0.001

Packer et al (1996)

Lancet (1999)0 200 400 600 800

1.0

0.8

0.6

0

Bisoprolol

Placebo

Time after inclusion (days)

p<0.0001

Survival

Risk reduction = 34%Risk reduction = 34%

The MERIT-HF Study Group (1999)

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%Risk reduction = 34%

US Carvedilol StudyUS Carvedilol Study

blockers in blockers in heart failure -heart failure -

all-cause mortalityall-cause mortality

CIBIS-IICIBIS-II MERIT-HFMERIT-HF

blockers in heart failureblockers in heart failure

Consensus recommendationsConsensus recommendations

All patients with stable class II or III heart failure due All patients with stable class II or III heart failure due

to left ventricular systolic dysfunction should to left ventricular systolic dysfunction should

receive a receive a blocker (in addition to an ACE inhibitor) blocker (in addition to an ACE inhibitor)

unless they have a contraindication to its use or unless they have a contraindication to its use or

cannot tolerate treatment with the drugcannot tolerate treatment with the drug

Why are the recommendations more restrictive than Why are the recommendations more restrictive than for ACE inhibitors despite the available evidence?for ACE inhibitors despite the available evidence?



US Carvedilol Programme (carvedilol)US Carvedilol Programme (carvedilol)CIBIS II (bisoprolol)CIBIS II (bisoprolol)

MERIT-HF (metoprolol)MERIT-HF (metoprolol)

?? ??

Packer, AHA 2000Packer, AHA 2000

blockers in NYHA class IV heart failureblockers in NYHA class IV heart failure

Proportion of patientsProportion of patientswith class IV heart failurewith class IV heart failure

US Carvedilol Programme US Carvedilol Programme 3% 3%

MERIT-HFMERIT-HF 4% 4%

CIBIS-IICIBIS-II 17%17%

BESTBEST 8% 8%

MERIT-HFMERIT-HF

CIBIS IICIBIS II

BESTBEST

Favours treatmentFavours treatment Favours placeboFavours placebo0.50.50.250.25 0.750.75 1.51.5 2.02.01.01.0

Survival effects of Survival effects of blockers in blockers inclass IV heart failureclass IV heart failure


Effects of metoprolol inEffects of metoprolol inclass IV heart failureclass IV heart failure

0.50.50.250.25 0.750.75 1.51.5 2.02.01.01.0

Death or CHFDeath or CHFhospitalisationhospitalisation

Death or anyDeath or anyhospitalisationhospitalisation

Favours treatmentFavours treatment Favours placeboFavours placebo

Results of MERIT-HFResults of MERIT-HF


??


US Carvedilol (carvedilol)US Carvedilol (carvedilol)CIBIS II (bisoprolol)CIBIS II (bisoprolol)


COPERNICUSCOPERNICUS(carvedilol)(carvedilol)



CCarvedilarvedilool l PProsprospeective ctive RRaanndomdomiizedzedCCumumuulative lative SSurvival Trialurvival Trial

COPERNICUSCOPERNICUS

Objectives and designObjectives and design

To determine the effect of carvedilol compared To determine the effect of carvedilol compared with placebo on all-cause mortality in patients with placebo on all-cause mortality in patients with severe chronic heart failurewith severe chronic heart failure

Randomised, placebo-controlled, parallel-group Randomised, placebo-controlled, parallel-group multicenter study in patients with ischaemic or multicenter study in patients with ischaemic or non-ischaemic cardiomyopathynon-ischaemic cardiomyopathy


Patient CharacteristicsPatient Characteristics

Symptoms of heart failure at rest or minimal exertion Symptoms of heart failure at rest or minimal exertion for at least 2 monthsfor at least 2 months

LV ejection fraction <25%LV ejection fraction <25%

Receiving diuretics and an ACE inhibitor Receiving diuretics and an ACE inhibitor (+ digitalis) (+ digitalis) 2 months. Diuretics optimised to achieve 2 months. Diuretics optimised to achieve euvolaemiaeuvolaemia

No need for intensive care and no treatment with IV No need for intensive care and no treatment with IV inotropic or IV vasodilator therapy within 4 days of inotropic or IV vasodilator therapy within 4 days of screeningscreening


Patients not in COPERNICUSPatients not in COPERNICUS

Hospitalised patients were allowed in the trial but Hospitalised patients were allowed in the trial but not if they were in the CCU/ICUnot if they were in the CCU/ICU

Patients receiving IV diuretics were allowed in the Patients receiving IV diuretics were allowed in the trial but not if they had received IV vasodilator or trial but not if they had received IV vasodilator or IV positive inotropic drugs within 4 days of IV positive inotropic drugs within 4 days of screeningscreening

Diuretics were to be titrated until patients were Diuretics were to be titrated until patients were euvolaemic. Those with marked fluid retention or euvolaemic. Those with marked fluid retention or overload were not randomizedoverload were not randomized

RandomisationRandomisation

2289 patients were randomized 1:12289 patients were randomized 1:1

PlaceboPlacebo

CarvedilolCarvedilol

Initial dose 3.125 mg bid with doubling of dose Initial dose 3.125 mg bid with doubling of dose every 2 weeks until target dose of 25 mg bid was every 2 weeks until target dose of 25 mg bid was reached. Patients received highest tolerated dosereached. Patients received highest tolerated dose



Protocol-specified endpointsProtocol-specified endpoints

Primary endpointPrimary endpoint

– All-cause mortalityAll-cause mortality

Secondary endpoints Secondary endpoints

– All-cause mortality or hospitalisations for any All-cause mortality or hospitalisations for any reasonreason

– All-cause mortality or cardiovascular All-cause mortality or cardiovascular hospitalisations hospitalisations

– All-cause mortality or CHF hospitalisations All-cause mortality or CHF hospitalisations


COPERNICUS monitoring boundariesCOPERNICUS monitoring boundaries

Stop trial because highly Stop trial because highly positivepositive

Continue trialContinue trial

Z-scoreZ-score

Information fractionInformation fraction

0.20.2

00

22

44

-2-2

-4-4

0.40.4 0.60.6 0.80.8 1.01.000

Stop trial because highly Stop trial because highly negativenegative

Mar 00Mar 00

Aug 99Aug 99

Mar 99Mar 99

Nov 98Nov 98


DSMB recommendations (14 March 2000)DSMB recommendations (14 March 2000)

Highly significant effect on mortalityHighly significant effect on mortality

Exceeded predefined criteria for early terminationExceeded predefined criteria for early termination

Consistent across all predefined subgroupsConsistent across all predefined subgroups

Serious adverse events more common on placeboSerious adverse events more common on placebo

Unanimous recommendation for early terminationUnanimous recommendation for early termination

All patients should be offered open-label carvedilolAll patients should be offered open-label carvedilol

0000

% S

urv

ival

% S

urv

ival

33 66 99 1212 1515 1818 2121MonthsMonths

100100

9090

8080

6060

7070

pp=0.00013=0.0001335% risk reduction35% risk reduction


PlaceboPlacebo


All-cause mortalityAll-cause mortality


Mortality in Mortality in blocker heart failure trials blocker heart failure trials

Annual placeboAnnual placebomortality ratesmortality rates

MERIT-HFMERIT-HF 11.0%11.0%

US Carvedilol ProgrammeUS Carvedilol Programme 11.1%11.1%

CIBIS IICIBIS II 13.2%13.2%

BESTBEST 16.6%16.6%

COPERNICUSCOPERNICUS 19.7%19.7%

Class IV meta-analysisClass IV meta-analysis 20.7%20.7%


StabilisedStabilisedclass IVclass IV

UnstableUnstableclass IVclass IV

Annual Annual placeboplacebomortalitymortality

raterate

24-29%24-29% 30%30%18-23%18-23%

PRAISE-1PRAISE-1PROMISEPROMISE

CONSENSUSCONSENSUSFIRSTFIRST

COPERNICUSCOPERNICUSRALESRALES

Spectrum of trials in severe heart failureSpectrum of trials in severe heart failure


PlaceboPlacebo



2424

00

66

1212

1818

1-year Kaplan-1-year Kaplan-Meier ratesMeier rates

Annual mortalityAnnual mortalityrates (per pt-year)rates (per pt-year)

19.719.7

12.812.8

18.518.5

11.411.4



Treatment EffectTreatment Effect pp-Value-Value

Death or hospitalisationsDeath or hospitalisations 24%24% <0.0001<0.0001for any reasonfor any reason

Death or hospitalisationsDeath or hospitalisations 27%27% <0.0001<0.0001for cardiovascular reasonfor cardiovascular reason

Death or hospitalisationsDeath or hospitalisations 31%31% <0.0001<0.0001for heart failurefor heart failure




BESTBEST


Is the carvedilol benefit a class effect?Is the carvedilol benefit a class effect?

0.50.50.250.25 0.750.75 1.51.5 2.02.01.01.0

Effect in class IV patientsEffect in class IV patients



AllAllpatientspatients

Recent or recurrentRecent or recurrentdecompensationdecompensation

Annual placebo mortality rate Annual placebo mortality rate (per patient-year)(per patient-year)

19.7%19.7%

28.5%28.5%

0.50.50.250.25 0.750.75 1.251.251.01.000

Effect of carvedilol on mortalityEffect of carvedilol on mortality



All patientsAll patients

Recent or Recent or recurrentrecurrentdecompensationdecompensation

Death or anyDeath or anyhospitalisationshospitalisations

Death or Death or cardiovascularcardiovascularhospitalisationshospitalisations

Death or CHFDeath or CHFhospitalisationshospitalisations


Effect of carvedilol on morbidity and mortalityEffect of carvedilol on morbidity and mortality

0.50.50.250.25 0.750.75 1.251.251.01.000Favours treatmentFavours treatment Favours placeboFavours placebo



Effects on mortality in patient subgroupsEffects on mortality in patient subgroups

Consistent reductions in mortality across all patient Consistent reductions in mortality across all patient subgroups examined to date, e.g. in:subgroups examined to date, e.g. in:– patients <65 years and patients <65 years and 65 years65 years– men and womenmen and women– patients with ischaemic and non-ischaemic patients with ischaemic and non-ischaemic

cardiomyopathycardiomyopathy– patients with LVEF <0.20 and patients with LVEF <0.20 and 0.200.20

The benefits of carvedilol on mortality were apparent The benefits of carvedilol on mortality were apparent even in the highest-risk subgroups of the COPERNICUS even in the highest-risk subgroups of the COPERNICUS studystudy


Implications for public healthImplications for public health

Lives saved by treatingLives saved by treating1000 patients for 1 year1000 patients for 1 year

HOPE (ramipril)HOPE (ramipril) <1<1

SOLVD Prevention (enalapril)SOLVD Prevention (enalapril) 7 7

SOLVD Treatment (enalapril)SOLVD Treatment (enalapril) 17 17

MERIT-HF (metoprolol)MERIT-HF (metoprolol) 38 38

CIBIS-II (bisoprolol)CIBIS-II (bisoprolol) 42 42

RALES (spironolactone)RALES (spironolactone) 52 52

COPERNICUS (carvedilol)COPERNICUS (carvedilol) 70 70



SafetySafety

DizzinessDizziness

Bradycardia and heart blockBradycardia and heart block

FatigueFatigue

Worsening heart failureWorsening heart failure


CirculationCirculation 2000; 101:378-84 2000; 101:378-84

RESOLVDRESOLVD

426 patients with class II-III heart failure were 426 patients with class II-III heart failure were randomized to placebo or metoprolol CR/XL for 24 randomized to placebo or metoprolol CR/XL for 24 weeks, added to ACE inhibitor or AT antagonistweeks, added to ACE inhibitor or AT antagonist

PlaceboPlacebo MetoprololMetoprolol

Worsening CHF leading to:Worsening CHF leading to:

Decrease in doseDecrease in dose 44 1111

DiscontinuationDiscontinuation 33 66

HospitalisationHospitalisation 55 1515

pp=NS=NS

% P

atie

nts

per

man

entl

y%

Pat

ien

ts p

erm

anen

tly

wit

hd

raw

n w

ith

dra

wn

00 33 66 99 1212 1515 1818 2121

MetoprololMetoprolol

PlaceboPlacebo

MonthsMonths

4040

3030

1010

2020

00

MERIT-HFMERIT-HF

Permanent withdrawalsPermanent withdrawals


pp=0.02=0.02


4040

3030

1010

2020

0000 33 66 99 1212 1515 1818 2121


PlaceboPlacebo

MonthsMonths

% P

atie

nts

per

man

entl

y%

Pat

ien

ts p

erm

anen

tly

wit

hd

raw

n w

ith

dra

wn

Permanent withdrawalsPermanent withdrawals


COPERNICUS – Summary COPERNICUS – Summary

COPERNICUS establishes the efficacy of carvedilol COPERNICUS establishes the efficacy of carvedilol in severe heart failure and extends the benefits of in severe heart failure and extends the benefits of this drug first observed in patients with mild and this drug first observed in patients with mild and moderate symptoms to those with advanced diseasemoderate symptoms to those with advanced disease

COPERNICUS does not settle the question as to COPERNICUS does not settle the question as to whether all other whether all other blockers are effective in patients blockers are effective in patients with severe heart failure.with severe heart failure.

The effects of other The effects of other blockers in this patient blockers in this patient population remain to be determinedpopulation remain to be determined

CAPRICORNCAPRICORN(carvedilol)(carvedilol)







CAPRICORNCAPRICORN

Study characteristicsStudy characteristics 1958 patients with acute myocardial infarction within 1958 patients with acute myocardial infarction within

21 days21 days LV ejection fraction <40%, receiving an ACE inhibitorLV ejection fraction <40%, receiving an ACE inhibitor Randomized to placebo or carvedilol (target 25 mg Randomized to placebo or carvedilol (target 25 mg

BID)BID) Endpoints: combined risk of death or cardiovascular Endpoints: combined risk of death or cardiovascular

hospitalisations, all-cause mortalityhospitalisations, all-cause mortality Data analysis ongoingData analysis ongoing

Carvedilol Post Infarct Survival Controlin Left Ventricular Dysfunction


Why do we need another Why do we need another blocker trial in blocker trial in post-infarction patients?post-infarction patients?

Earlier post-MI trials with Earlier post-MI trials with blockers were performed blockers were performed in a different era and enrolled patients who generally in a different era and enrolled patients who generally were not receiving other agents that reduce mortality:were not receiving other agents that reduce mortality:

– No use of thrombolytic drugs No use of thrombolytic drugs

– Little use of aspirin or heparinLittle use of aspirin or heparin

– No use of ACE inhibitorsNo use of ACE inhibitors

– Did not have LV systolic dysfunctionDid not have LV systolic dysfunction

Are Are blockers still effective in the modern era? blockers still effective in the modern era?


Key messagesKey messages

Carvedilol is the only drug with Carvedilol is the only drug with -blocking activity that -blocking activity that provides comprehensive adrenergic blockadeprovides comprehensive adrenergic blockade

Carvedilol is more beneficial than conventional Carvedilol is more beneficial than conventional -blocking agents in mild-to-moderate heart failure-blocking agents in mild-to-moderate heart failure

Carvedilol is the only drug with Carvedilol is the only drug with -blocking activity -blocking activity proven to be effective at lower doses proven to be effective at lower doses

COPERNICUS enrolled the most severely affected heart COPERNICUS enrolled the most severely affected heart failure population of any trial of failure population of any trial of blockade blockade

Carvedilol significantly reduces mortality in severe heart Carvedilol significantly reduces mortality in severe heart failure patientsfailure patients

11 receptors receptors 22 receptors receptors

Myocyte hypertrophy & death,Myocyte hypertrophy & death,dilatation, ischaemia & arrhythmia'sdilatation, ischaemia & arrhythmia's

11 receptors receptors

CardiacCardiacsympathetic activitysympathetic activity

SympatheticSympatheticactivity to kidneysactivity to kidneys& blood vessels& blood vessels

VasoconstrictionVasoconstrictionSodium retentionSodium retention

CNS sympatheticCNS sympatheticoutflowoutflow

Adrenergic activationAdrenergic activation


11 receptors receptors 11 receptors receptors

CARDIOTOXICITYCARDIOTOXICITY

22 receptors receptors

Sympathetic activationSympathetic activation

BisoprololBisoprololMetoproloMetoprolollPropranololPropranolol


Antiadrenergic therapy by Antiadrenergic therapy by blockade blockade


MetoprololMetoprolol

CardiacCardiacnorepinephrinenorepinephrine

AntioxidantAntioxidanteffectseffects


CardiacCardiacnorepinephrinenorepinephrine

SympatheticSympatheticantagonismantagonism

11 receptor receptor

blockadeblockade

11 and and 22 receptor receptor

blockadeblockade

receptorreceptorupregulationupregulation

receptorreceptorsuppressionsuppression


Carvedilol provides comprehensive Carvedilol provides comprehensive adrenergic blockadeadrenergic blockade

Adapted from M PackerAdapted from M Packer

blockadeblockade

Cardiac Cardiac outputoutput

Renal Renal blood flowblood flow

Worsening Worsening heart failureheart failure

Sodium Sodium retentionretention

Carvedilol provides comprehensive Carvedilol provides comprehensive adrenergic blockadeadrenergic blockade

Adapted from M PackerAdapted from M Packer

blockadeblockade

blockadeblockade

blockadeblockade

Cardiac Cardiac outputoutput

Renal Renal blood flowblood flow

Worsening Worsening heart failureheart failure

Sodium Sodium retentionretention




Carvedilol is the only drug with Carvedilol is the only drug with -blocking activity -blocking activity proven to be effective at lower dosesproven to be effective at lower doses



Randomized trials directly comparing Randomized trials directly comparing metoprolol with carvedilolmetoprolol with carvedilol

DiLenarda et alDiLenarda et al J Am Coll Cardiol, 1999J Am Coll Cardiol, 1999– Open-label for 12 months (n=30)Open-label for 12 months (n=30)

Kukin et al Kukin et al Circulation, 1999Circulation, 1999– Open-label for 6 months (n=67)Open-label for 6 months (n=67)

Sanderson et alSanderson et al J Am Coll Cardiol, 1999J Am Coll Cardiol, 1999– Double-blind for 3 months (n=51)Double-blind for 3 months (n=51)

Metra et alMetra et al Circulation, 2000Circulation, 2000– Double-blind for 12–15 months (n=150)Double-blind for 12–15 months (n=150)


Udelson 2000Udelson 2000

LV ejectionLV ejectionfraction (%)fraction (%)

pp=0.009=0.009

00

22

44

66

88

1010

LV end diastolicLV end diastolicvolume (ml/mvolume (ml/m22))

pp=0.04=0.04-24-24

-18-18

-12-12

-6-6

00

CarvedilolCarvedilol MetoprololMetoprolol

Results of direct comparison trials with Results of direct comparison trials with metoprolol and carvedilol in HFmetoprolol and carvedilol in HF

Di Lenarda et al (1999)Di Lenarda et al (1999)

Change inChange inLV ejectionLV ejectionfraction (%)fraction (%)

Change inChange inend-diastolicend-diastolicvolume (ml)volume (ml)

Continued onContinued on

Switched toSwitched to

Metoprolol (n=16)Metoprolol (n=16)

Carvedilol (n=14)Carvedilol (n=14)

-20-20

-15-15

-10-10

-5-5

00

+5+5

+10+10

+15+15

**

**

pp=0.053=0.053

pp=0.045=0.045

Effect of switching patients from metoprolol Effect of switching patients from metoprolol to carvedilol for 12 monthsto carvedilol for 12 months

Metra et al (2000)Metra et al (2000)-20-20

-15-15

-10-10

-5-5

00

+6+6

+12+12

+18+18**

**

pp=0.002=0.002

pp<0.05<0.05

Double-blind comparison of effects of Double-blind comparison of effects of metoprolol and carvedilol for 13-15 monthsmetoprolol and carvedilol for 13-15 months

Change inChange inLV ejectionLV ejectionfraction (%)fraction (%)

Change inChange inpulmonary wedgepulmonary wedgepressure (mm Hg)pressure (mm Hg)

Metoprolol (n=75)Metoprolol (n=75)

Carvedilol (n=75)Carvedilol (n=75)



COMETCOMET(carvedilol vs metoprolol)(carvedilol vs metoprolol)




COMETCOMET

Objectives and designObjectives and design

To compare the effects of carvedilol with those of To compare the effects of carvedilol with those of metoprolol on the risk of death and hospitalisation metoprolol on the risk of death and hospitalisation in patients with chronic heart failurein patients with chronic heart failure

Randomised, double-blind, parallel-group, Randomised, double-blind, parallel-group, multicenter study of more than 3 years in durationmulticenter study of more than 3 years in duration

CCarvedilarvedilool l OOr r MMetoprolol etoprolol EEuropean uropean TTrialrial

COMETCOMET

>3000 patients with class II-IV heart failure due>3000 patients with class II-IV heart failure dueto ischaemic or non-ischaemic cardiomyopathyto ischaemic or non-ischaemic cardiomyopathy

Randomized to carvedilol or metoprolol (in addition to Randomized to carvedilol or metoprolol (in addition to usual therapy) for up to 3 yearsusual therapy) for up to 3 years

Pre-specified endpoints:Pre-specified endpoints:

– all-cause mortalityall-cause mortality

– death and hospitalisationdeath and hospitalisation

– all-cause mortality/all-cause hospitalisationall-cause mortality/all-cause hospitalisation


Target doseTarget dose Mortality effectMortality effect

MetoprololMetoprololMDCMDC 100-150 mg100-150 mg No No MERIT-HFMERIT-HF 200 mg200 mg 34% (sig) 34% (sig)

BisoprololBisoprololCIBISCIBIS 5 mg5 mg 20% (ns) 20% (ns)CIBIS-IICIBIS-II 10 mg10 mg 34% (sig) 34% (sig)

What should be the target dose?What should be the target dose?

What should the target What should the target dose of carvedilol be?dose of carvedilol be?

..

00

00..11

00..22

00..33

00..44


00

44

88

1122

1166

pp<0.05<0.05

pp=0.07=0.07

pp=0.01=0.01 pp=0.01=0.01

pp=0.01=0.01

Mortality %Mortality % Mean number per subjectMean number per subject

MortalityMortality Cardiovascular hospitalisationsCardiovascular hospitalisations

PlaceboPlacebo 6.25 mg bid6.25 mg bid 12.5 mg bid12.5 mg bid 25 mg bid25 mg bid PlaceboPlacebo 6.25 mg bid6.25 mg bid 12.5 mg bid12.5 mg bid 25 mg bid25 mg bid


pp<0.001<0.001

Dosing for Dosing for blockers in heart failure blockers in heart failure

DrugDrug Starting doseStarting dose Target Target dosedose

BisoprololBisoprolol 1.25 mg qd1.25 mg qd 10 mg qd10 mg qd

CarvedilolCarvedilol 3.125 mg bid3.125 mg bid 6.256.25––25 mg 25 mg bidbid

MetoprololMetoprolol 12.512.5––25 mg qd25 mg qd 200 mg qd200 mg qd(extended-release)(extended-release)

The Medical Letter, June 26, 2000The Medical Letter, June 26, 2000

Mortality in Mortality in blocker heart failure trials blocker heart failure trials

Annual placeboAnnual placebomortality ratesmortality rates

MERIT-HFMERIT-HF 11.0%11.0%

US Carvedilol ProgrammeUS Carvedilol Programme 11.1%11.1%

CIBIS IICIBIS II 13.2%13.2%

BESTBEST 16.6%16.6%

COPERNICUSCOPERNICUS 19.7%19.7%

Class IV meta-analysisClass IV meta-analysis 20.7%20.7%


0000

% S

urv

ival

% S

urv

ival

33 66 99 1212 1515 1818 2121MonthsMonths

100100

9090

8080

6060

7070

pp=0.00013=0.0001335% risk reduction35% risk reduction


PlaceboPlacebo






Lives saved by treatingLives saved by treating1000 patients for 1 year1000 patients for 1 year

HOPE (ramipril)HOPE (ramipril) <1<1

SOLVD Prevention (enalapril)SOLVD Prevention (enalapril) 7 7

SOLVD Treatment (enalapril)SOLVD Treatment (enalapril) 17 17

MERIT-HF (metoprolol)MERIT-HF (metoprolol) 38 38

CIBIS-II (bisoprolol)CIBIS-II (bisoprolol) 42 42

RALES (spironolactone)RALES (spironolactone) 52 52

COPERNICUS (carvedilol)COPERNICUS (carvedilol) 70 70



If 1000 patients are treated per year If 1000 patients are treated per year

approximately 70 lives would be savedapproximately 70 lives would be saved


COPERNICUS and carvedilol Background and principal results slide kit December 2000.

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Transcript of COPERNICUS and carvedilol Background and principal results slide kit December 2000.