taiwan tanabe 陳榮明 jimmy chen 藥師 - 地區經理嘉南 – 藥學 for cardiovascular...

TAIWAN TANABE

陳榮明 Jimmy Chen 藥師 - 地區經理

嘉南 –藥學

FOR CARDIOVASCULAR DISEASES

CONCORTM 5mg/1.25mg

Bisoprolol hemifumarate

Indications: Hypertension,Angina,CHFDosage:5 ~ 10mg QD ,1.25-QD

TANABE/MERCK KGaA

The Highest ß1-selectivity. The Best Quality of Life

TAIWAN TANABE

Are the β-blockers all the same?

TAIWAN TANABE

Classification of -Blockers

-Blockers

1-Selective Non-1-Selective

Without ISA

Bisoprolol

Atenolol

Betaxolol

Metoprolol

With ISA

Acebutolol

Without ISA

Nadolol

Propranolol

Sotaolol

Timolol

Carvedilol

With ISA

Carteolol

Pindolol

Labetalol

ISA:Intrinsic Sympathomimetic ActivityAdapted from: European Heart Journal (2004) 25, 1341-1362

Secondary prevention of myocardial infarction with different types of β -blockers

-30

-20

-10

%

Reduction of mortality β1-selective without ISA

Non-selective without ISA

β1-selective with ISA

Non-selective with ISA

Adapted form:Progress in Cardiovascular Diseases. 27(5):335-71, 1985 Mar-Apr

β-blockers without ISA β-blockers with ISA

TAIWAN TANABE

β1 selectivity:

β 2

Kidney β 1 Renin release

Smooth muscle of bronchi β 2 Bronchodilatation

α 1 Vasoconstriction

β 2 Vasodilatation

β 1 Vasodilatation(cononary)

α 2 Inhibition of lipolysis

β 2>β 1 Stimulation oflipolysis

α 1 Glycogenolysis

α 2 Inhibition of insulinrelease

β 2 Stimulation of insulinrelease

Pancreas

Fat tissue

Liver

β 2 Glycogenolysis ,Gluconeogenesis

Myocardium β 1 Stimulation ofcontractility and HR

Blood vessel smooth muscle

Adapted from:European Heart Journal. 21(5):354-64, 2000 Mar

Physiological effect of adrenergic receptor

300:1

1:35 1:35

1:75

increasing ß1-selectivity

increasing ß2-selectivity

ICI 118.551

1.8:1 Propranolol

Atenolol Betaxolol

Bisoprolol

no selectivity

Ratio of constants of inhibition

1:20

Metoprolol

Bisoprolol: ß1-selectivity of various ß-blockersBisoprolol: ß1-selectivity of various ß-blockers

Wel

lste

in A

et a

l. J

Car

diov

asc

Pha

rmac

ol 1

986;

8 (

Sup

pl. 1

1): 3

6-40

Wel

lste

in A

et a

l. E

ur H

eart

J 1

987;

8 (

Sup

pl. M

): 3

–8

b 21 h3 6 12 1 3 6 12 1 3 6 12

4 8 24 b 2 4 8 24 b 2 4 8 24

Placebo Bisoprolol(20mg) Atenolol(100mg)

50

70

90

7

8

9

AWR (cm H2 O/I/s)

HR (beats/min)

b = beforen = 12

± SEM

Bisoprolol: ß1-selectivity and lung function in coronary patients with chronic obstructive bronchitis

Bisoprolol: ß1-selectivity and lung function in coronary patients with chronic obstructive bronchitis

Dor

ow P

. Eur

J C

lin P

harm

acol

198

6; 3

1:14

3–14

7

x

Propranolol

Metoprolol

Labetalol

Carvedilol

Atenolol

Nadolol

Sotalol

PindololTimolol

Lipophilic Hydrophilic

TAIWAN TANABE

Balance Clearance

Bisoprolol

TAIWAN TANABE

*dose-dependent

Criteria Bisoprolol Atenolol Metoprolol Acebutolol Celiprolol

Plasma eliminationhalf-life (h)

10 – 12 6 – 9 3 – 4 7 – 13 5

Absorption (%) > 90 50 > 95 70 50

First-pass effect – – + + –

Bioavailability (%) 88 50 50 40 – 60 50*

Protein binding (%) 30 3 12 11 – 25 25

Active metabolites – – – + –

Balanced clearance + – – – –

Bisoprolol: Comparison to ß1-selective ß-blockersBisoprolol: Comparison to ß1-selective ß-blockers

Bor

char

d U

. ß-R

ezep

tore

nblo

cker

, Klin

ik u

nd P

raxi

s, A

esop

us V

erla

g 19

96

Three indications of BisoprololThree indications of Bisoprolol

Essential Hypertension

Angina

Stable Chronic Heart Failure (Moderate~Severe)

Three Indications of BisoprololThree Indications of Bisoprolol


Angina


28 56 84 91 days

Bisoprolol

Bisoprolol 5 mg n = 15/group

Bisoprolol 10 mg

Bisoprolol 20 mg

Placebo Bisoprolol PlaceboΔ SBP

0

– 10

– 20

– 30

– 40

(mm

Hg

)

28 56 84 91 days0

Δ DBP

– 10

– 20

– 30

(mm

Hg

)

Bisoprolol: Dose-dependent blood pressure reductionin hypertensives

Bisoprolol: Dose-dependent blood pressure reductionin hypertensives

Kirs

ten

R e

t al.

J C

ardi

ovas

c P

harm

acol

198

6; 8

(S

uppl

. 11)

: 113

–121

± SEMx

Bisoprolol: Dose-dependent blood pressure reduction3 and 24 hours after administration

Bisoprolol: Dose-dependent blood pressure reduction3 and 24 hours after administration

Da

vid

ov

ME

et

al.

Clin

Ca

rdio

l 19

94

; 1

7: 2

63

–2

680

– 2

– 4

– 6

– 8

– 10

– 12

– 14

– 16

DB

P s

itti

ng

(m

m H

g)

Bisoprolol dose

Placebo 5 mg 10 mg 20 mg

–3.6 –3.0

–10.5

–7.4

–12.7 –12.8

–14.7

–13.4

3 h p.a.

24 h p.a.

3 h p.a.

24 h p.a.

n = 240

S ± SEM

SBP

DBP

180

160

140

120

100

80

60

1 3 5 7 9 11 13 15 17 19 21 23 h

(mm

Hg

)

last day of placebo

after 4 weeks of bisoprolol(10mg)

n = 8

Bisoprolol: Circadian rhythmBisoprolol: Circadian rhythm

Kei

m H

J. T

hera

piew

oche

198

8; 4

7:35

07–3

513

Bisoprolol: Treatment of hypertensionin comparison to atenolol

Bisoprolol: Treatment of hypertensionin comparison to atenolol

Ne

ute

l JM

et

al.

Am

J M

ed

19

93

; 9

4:1

81

–1

87

0

–5

–10

–15

–2010 a.m. 4 p.m. 10 p.m. 4 a.m. 10 a.m.

time of day

me

an

ch

an

ge

in d

iast

olic

blo

od

pre

ssu

re

(mm

Hg )

DBPBisoprolol (n = 107)

night

Atenolol (n = 96)

doseintake

BisoDIAS Endgültig 27

180

140

100

60

0 12 15 18 21 24 27 30 33 36

102 102 97 102 101 102 102 102 100 102

months

SBP (mm Hg)

DBP (mm Hg)

HR (beats/min)

n =

Bisoprolol: Long-term treatment of hypertensionBisoprolol: Long-term treatment of hypertension

Gie

seck

e H

G e

t al.

J C

ardi

ovas

c P

harm

acol

199

0; 1

6 (S

uppl

5):

175

Diabetic Hypertension

Beta-Blockers:Continue to surprise us

JNC ⅦClinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes

JNC ⅦClinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes

High-Risk Conditions With Compelling Indication*

Heart Failure

Post-myocardial infarction

High coronary disease risk

Diabetes

Chronic kidney disease

Recurrent stroke prevention

Recommended Drugs

Diuretic Beta-Blocker ACE Inhibitor ARB CCB Aldosterone Antagonist

Clinical Trial Basis

ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHERT, RALES

ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE

NKF-ADA Guidelin, UKPKS, ALLHAT

NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

PROGRESS

• • • • •

• • • • •

• • • •

• • •

• •

• •

Adapted from: JAMA. 2003 ； 289 ： 2560-2572

UK Prospective Diabetes Study

largest multi-centre randomised controlled trial of different therapies of Type 2 diabeteslargest study ever conducted in the prevention of diabetic complications in type II diabetics:study duration: 1977 - 199723 clinical centrespatient population: 5102 type 2 diabetic patients53,000 patient years follow-up

UKPDS Blood Pressure Control Study tight vs. less tight: results

Tight blood pressure control significantly reduces risks for

any diabetes-related endpoint 24% (p=0.0046)diabetes-related deaths 32% (p=0.019)stroke 44% (p=0.013)microvascular disease 37% (p=0.0092)heart failure 56% (p=0.0043)retinopathy progression 34% (p=0.0038)deterioration of vision 47% (p=0.0036)

UKPDS Study

Adapted from:BMJ, Volume 317(7160).September 12, 1998.713-720

UKPDS Blood Pressure Control Study results favour ß-blocker:

Adapted from:BMJ, Volume 317(7160).September 12, 1998.713-720

After UKPDS

management of blood pressure was not a high priority for type 2 diabetics

first choice treatment

ACE inhibitors

management of blood pressure was not a high priority for type 2 diabetics

first choice treatment

ACE inhibitors

management of blood pressure should have high priority in the treatment of type 2 diabetesfirst choice treatment

ACE inhibitor or or Beta-blockerBeta-blocker

management of blood pressure should have high priority in the treatment of type 2 diabetesfirst choice treatment

ACE inhibitor or or Beta-blockerBeta-blocker

Before UKPDS

UKPDS Blood Pressure Control Study implications

Treatment of Hypertensionin Adults With Diabetes

A-level evidence: Initial drug therapy may be with ACE inhibitors, ARBs, β-blockers, or diuretics. Additional drugs may be chosen from these classes or another drug class. In patients with a recent myocardial infarction, β-blockers, in addition,should be considered to reduce mortality.

•Adapted from:DIABETES CARE, VOLUME 25, NUMBER 1, JANUARY 2002



Angina


Objectives:

To evaluate the effects of Bisoprolol o.d.

and Nifedipine slow release b.i.d.on the occurrence and circadian

distributionof ischaemic episodes in patients

with stable angina pectoris

Randomised double-blind controlled studywith two parallel groups

T I B B STotal Ischaemic Burden Bisoprolol Study

T I B B STotal Ischaemic Burden Bisoprolol Study

von

Arn

im T

h et

al.

JAC

C 1

995;

1: 2

31–2

30

10 days 4 weeks 4 weeks

48 h Holter 48 h Holter

History ETT Inclusion for prephase

If > 2 ischaemicepisodes,inclusion for active treatment

20 mg o.d. Bisoprolol

10 mg o.d. Bisoprolol

40 mg b.i.d. Nifedipine s.r.20 mg b.i.d. Nifedipine s.r.

Placebo

48 h Holter

TIBBS: Flow chartTIBBS: Flow chart

von

Arn

im T

h et

al.

JAC

C 1

995;

1: 2

31–2

38


No./48 h

Baseline 40 mg20 mgBaseline 20 mg10 mg

Nifedipine s.r. b.i.d. (n = 112)Bisoprolol o.d. (n = 111)

2

4

6

8

10

0

TIBBS: Number of ischaemic episodes at baseline,on low dose and on high dose

TIBBS: Number of ischaemic episodes at baseline,on low dose and on high dose

von

Arn

im T

h et

al.

JAC

C 1

995;

1: 2

31–2

38

±SEMx


minutes120

90

60

30

0Baseline 40 mg20 mgBaseline 20 mg10 mg


TIBBS: Duration of ischaemic episodes at baseline,on low dose and on high dose

TIBBS: Duration of ischaemic episodes at baseline,on low dose and on high dose

von

Arn

im T

h et

al.

JAC

C 1

995;

1: 2

31–2

38

±SEMx


min. x mm

50

100

150

200

250

0Baseline 40 mg20 mgBaseline 20 mg10 mg


TIBBS: Total ischaemic burden at baseline,on low dose and on high dose

TIBBS: Total ischaemic burden at baseline,on low dose and on high dose

von

Arn

im T

h et

al.

JAC

C 1

995;

1: 2

31–2

38

±SEMx



Angina


Heart Failure

From Contraindication to Indication

Beta-Blockers:Continue to surprise us

Rise in oxygen consumption

Arrhythmogenicity

Diminished diastolic filling

Systolic function impairment

Cardiotoxic effect of endogenous catecholamines

Down-regulation of the -receptors

Metabolic disorders

TAIWAN TANABE

Chronically raised sympathetic tonus is accompanied by a number of unfavourable cadiovascular effects

Chronically raised sympathetic tonus is accompanied by a number of unfavourable cadiovascular effects

交感神經系統的活化 -blockers 的作用

心跳心跳 1. 心舒張期(Diastole duration) 心舒張期注血時間回心血流量心搏出量

2. 心內膜灌流(Subendocardial perfusion) 3. 心肌工作量氧氣消耗(Oxygen

consumption)

心律不整性(Arrhymogenicity) 抗心律不整(Antiarrhythmia) 1. 心肌保護作用預後

-blockers 應用於治療 CHF 的理論基礎-blockers 應用於治療 CHF 的理論基礎

-blockers 應用於治療 CHF 的理論基礎-blockers 應用於治療 CHF 的理論基礎

交感神經系統的活化 -blocker 的作用

心肌細胞-受體的down-regulation (心肌細胞-受體的密度 )

阻止心肌細胞-受體的 down- regulation,恢復-受體的密度 1.心肌細胞對交感神經刺激的反應性

2.心收縮力 3.運動耐受度

心毒性具有心臟保護作用

-beneficial concomitant therapy in CHF

Publication:The Lancet 1999; 353:9-13

TAIWAN TANABE

• Double-blind, placebo-controlled, randomised trial

• 2,647 patients included (NYHA III + IV)

• Bisoprolol administered on top of standard therapy(diuretic + ACE inhibitor)

CIBIS IICardiac Insufficiency Bisoprolol Study

CIBIS IICardiac Insufficiency Bisoprolol Study

CIB

IS II

Inve

stig

ator

s an

d C

omm

ittee

s. L

ance

t 199

9; 3

53: 9

–13

• Primary objective– All-cause mortality

• Secondary objectives– Cardiovascular mortality

– Hospital admissions

– Cardiovascular mortality orcardiovascular hospital admissions

– Permanent treatment withdrawal

CIBIS IIObjectivesCIBIS II

Objectives

CIB

IS II

Inve

stig

ator

s an

d C

omm

ittee

s. L

ance

t 199

9; 3

53: 9

–13

7.50

10.00

5.00

3.75

2.50

1.25

W1 W2 W3 W4 W5 W6 W7 W8 W9 W10W11W12 W13W14W15W16 Week

Bisoprolol dose (mg)

No run-in period Dose increased according to tolerability

CIBIS IIDose titration

CIBIS IIDose titration

CIB

IS II

Inve

stig

ator

s an

d C

omm

ittee

s. L

ance

t 199

9; 3

53: 9

–13

34% reduction in all-cause mortality with bisoprolol

1.0

0.8

0.6

0

0 200 400 600 800Time after inclusion (days)

Su

rviv

al

Bisoprolol: 156 deaths(11.8%) (n = 1327)

Placebo: 228 deaths(17.3%) (n = 1320)

log rank test, p < 0.0001

CIBIS IISurvivalCIBIS IISurvival

CIB

IS II

Inve

stig

ator

s an

d C

omm

ittee

s. L

ance

t 199

9; 3

53: 9

–13

Patients

Unknown causeof death

Non-cardio-vascular deaths

Other cardio-vascular deaths

Myocardialinfarction

Pumpfailure

Suddendeath

0.45(0.27 – 0.74)

0.75(0.37 – 1.50)

1.17(0.67 – 2.03)

0.85(0.31 – 2.34)

836%

p=0.0011

484%

363%

0.56(0.39 – 0.80)

0.74(0.48 – 1.14)

Hazard ratio:(95% CI)

p=0.17

p=0.75

p=0.58

p=0.41

p=0.0012

Bisoprolol (n = 1327)

Placebo (n = 1320)

0

20

40

60

80

100

474%

71%

81%

282% 23

2%

141%

181%

232%

494%

CIBIS II Causes of deaths

CIBIS II Causes of deaths

CIB

IS II

Inve

stig

ator

s an

d C

omm

ittee

s. L

ance

t 199

9; 3

53: 9

–13

In the bisoprolol-treated group of patients there was a reduction in

• All-cause mortality (independent of aetiology) by34% (p<0.0001)

• Sudden death by44% (p<0.0011)

• All-cause hospital admissions by20% (p<0.0006)

CIBIS IIMain results at a glance

CIBIS IIMain results at a glance

CIB

IS II

Inve

stig

ator

s an

d C

omm

ittee

s. L

ance

t 199

9; 3

53: 9

–13

CIBIS IIICardiac Insufficiency Bisoprolol Study

CIBIS IIICardiac Insufficiency Bisoprolol Study

CIBIS III

Comparison of the efficacy and safety of initiation of

treatment

with bisoprolol or enalapril as monotherapy followed by their

combination in patients with chronic heart failure (CHF)

Initiation of treatment in patients with CHF

with the β1-selective β-blocker bisoprolol

(to which enalapril is subsequently added)

is as effective and safe as a regimen

beginning with the ACEi enalapril

(to which bisoprolol is subsequently added).

DOI: 10.1161/CIRCULATIONAHA.105.582320

Hypothesis

6 months 6 to 18 months

week week week week week week week week week week week week0 10 12 ... 28 30 32 34 36 ...

6 months

bisoprolol(mg/d)

enalapril(mg/d)

bisoprolol(mg/d)

Monotherapy Combination therapy

Randomisation

24months

1.25 2.5 3.75 57.5

10

1.25 2.5 3.75 57.5

10

510

20

510

20

enalapril(mg/d)

2 4 6 8

CIBIS IIIDose titration

CIBIS IIIDose titration

To show that initial mono-therapy with bisoprolol

followed by combination therapy with enalapril

is comparable (non-inferior) to the reverse order

in preventing death and hospitalization for all causes (combined endpoint).


Primary objective

Intention-to-treat (ITT) population

50

60

70

80

90

100

0 6 12 18

Bisoprolol-firstEnalapril-first

Per-protocol (PP) population

50

60

70

80

90

100

0 6 12 18

Combined primary endpoint

% withoutendpoint

% withoutendpoint

B/E vs E/B163 vs 165 ptsHR 0.97 (95% CI 0.78-1.21)non-inferiority P=0.046

B/E vs E/B178 vs 186 ptsHR 0.94 (95% CI 0.77-1.16)non-inferiority P=0.019

503498

356353

265259

8073

505505

389388

291277

8776

months

months

Bisoprolol-first significantly non-inferior to enalapril-first if upper limit of 95% CIbelow hazard ratio (HR) 1.17, P<0.025.(=RR 1.125, AR +5%)

In the PP population, bisoprolol-first was not significantly non-inferior toenalapril-first

In the ITT population, bisoprolol-first was significantly non-inferior toenalapril-first

Numbers at risk

Numbers at risk

3%risk reduction

6%risk reduction


Conclusions (1)

In terms of combined mortality / hospitalization

Bisoprolol-first was non-inferior to enalapril-first

in the ITT sample

Bisoprolol-first was close to non-inferior to enalapril-

first

in the PP sample


There was no difference in safety

between the two strategies,

showing that a bisoprolol-first strategy

does not cause concerns

Conclusions (2)


Clinical implication

The CIBIS III result supports a free choice

of initial treatment for CHF - enalapril or bisoprolol -

based on the physician’s individual judgment in each patient


Put into clinical practiceCHF specific

logo

dosage easyto identify from

all sides

dose specificcolor code

CHF specific color code

β1:β2= 75:1β1:β2= 75:1

BisoprololBisoprolol

Non-ISANon-ISA

CIBIS ⅡCIBISIIITIBBS

DECREASE

CIBIS ⅡCIBISIIITIBBS

DECREASEBalance ClearanceBalance Clearance

NHI price: Concor 5= NT 7.6

NHI price: Concor 5= NT 7.6

TAIWAN TANABE

HypertensionAngina

CHF

HypertensionAngina

CHF

Thanks for your coming!

TAIWAN TANABEConcor wins your heart!!

taiwan tanabe 陳榮明 jimmy chen 藥師 - 地區經理 嘉南 – 藥學 for cardiovascular...

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taiwan tanabe 陳榮明 jimmy chen 藥師 - 地區經理嘉南 – 藥學 for cardiovascular...