TAIWAN TANABE

1
??? Jimmy Chen ?? - ???? ??
??
TAIWAN TANABE
2
FOR CARDIOVASCULAR DISEASES
The Highest ß1-selectivity. The Best Quality of
Life

• CONCORTM 5mg/1.25mg
• Bisoprolol hemifumarate
• Indications Hypertension,Angina,CHF
• Dosage5 10mg QD ,1.25-QD

TANABE/MERCK KGaA
TAIWAN TANABE
3
First Choice of Antihypertensive Agent

• capacity for maximum exercise.
• Secondary protection well documented but primary
  protection less so.
• Small ? in stroke, angina, in ALLHAT, heart
  failure increased.
• JNCJoint National Committee VI, 1997
• WHO/ISHWorld Health Organization-International
  Society of Hypertension, 1999.

Taiwan Tanabe
4
Are the ß-blockers all the same?
5
Classification of ?-Blockers
?-Blockers
?1-Selective
Non-?1-Selective
Without ISA Bisoprolol Atenolol Betaxolol Metoprol
ol
With ISA Acebutolol
Without ISA Nadolol Propranolol Sotaolol Timolol C
arvedilol
With ISA Carteolol Pindolol Labetalol
ISAIntrinsic Sympathomimetic Activity
TAIWAN TANABE
Adapted from European Heart Journal (2004) 25,
1341-1362
6
Intrinsic Sympathomimetic Activity (ISA) or
Partial Agonist Effect
The most obvious pharmacological aspect of
Beta-blockers with ISA is that they produce less
of a decrease in resting heart rate than agents
without ISA
TAIWAN TANABE
7
ISA Is Controversially Discussed
TAIWAN TANABE
8
Secondary prevention of myocardial infarction
with different types of ß -blockers
Reduction of mortality
ß1-selective without ISA

Non-selective without ISA
-30
ß1-selective with ISA
Non-selective with ISA
-20
-10
ß-blockers without ISA
ß-blockers with ISA
TAIWAN TANABE
Adapted formProgress in Cardiovascular Diseases.
27(5)335-71, 1985 Mar-Apr
9
ß1 selectivity
10
Physiological effect of adrenergic receptor
Adapted fromEuropean Heart Journal.
21(5)354-64, 2000 Mar
11
Bisoprolol ß1-selectivity of various ß-blockers
Bisoprolol
175
Betaxolol
Atenolol
135
135
Metoprolol
increasing
120
ß
-selectivity
1
Wellstein A et al. J Cardiovasc Pharmacol 1986 8
(Suppl. 11) 36-40 Wellstein A et al. Eur Heart J
1987 8 (Suppl. M) 38
no
selectivity
1.81
Propranolol
increasing
ß
-selectivity
2
3001
ICI
118.551
Ratio of constants of inhibition
12
Bisoprolol ß1-selectivity and lung function in
coronary patients with chronic obstructive
bronchitis
AWR (cm H
O/I/s)
2
9
8
b before
7
n 12
SEM
x
HR (beats/min)
Dorow P. Eur J Clin Pharmacol 1986 31143147
90
70
50
b
2
4
8
24
Placebo
Bisoprolol(20mg)
Atenolol(100mg)
13
Bisoprolol ß1-selectivity and lung function in
asthmatichypertensives (2 h after administration)
AWR (cm H
O s/l)
2
1.6
n 12
SEM
x

1.2
0.8
Chatterjee SS. J Cardiovasc Pharmacol 1986 8
(Suppl. 11) 7477
0.4
0
0.4
0.8
10 mg
20 mg
100 mg
Placebo
Bisoprolol
Atenolol
14
Bisoprolol ß1-selectivity and lipid metabolism
in long-term therapy
lipids (mmol/l)
cholesterol (mmol/l)
5.0
7.0
total cholesterol
LDL-cholesterol
4.0
6.0
3.0
5.0
triglycerides
HDL-cholesterol
Frithz G et al. J Cardiovasc Pharmacol 1986 8
(Suppl. 11) 134138
2.0
2.0
1.0
1.0
0
3
5
7
9
11
13
0
3
5
7
9
11
13
months
months
n42
42
40
41
38
40
41
n42
42
40
39
35
40
41
( n36 for triglycerides)
x
SEM
15
Bisoprolol ß1-selectivity and lipid metabolism
in long-term therapy
Mepindolol 10 mg/day (n 16)
0
Bisoprolol 10 mg/day (n 17)
Propranolol 160 mg/day (n 15)
10
Atenolol 100 mg/day (n 22)
HDL-cholesterol

20
Fogari R et al. J Cardiovasc Pharmacol 1990 16
(Suppl 5) S 7680

30
?

40
6
12
18
24
30
36
months

plt0.05
vs. baseline
plt0.01
16
Bisoprolol ß1-selectivity and glucose metabolism
lactate
(mmol/l)
Leopold G et al. Br J Clin Pharmacol 1986
22293300
Bisoprolol 10 mg
Propranolol 40 mg
Metoprolol 50 mg
Control
17
Hydrophilic
Lipophilic
Propranolol Metoprolol Labetalol Carvedilol
Pindolol
Timolol
Atenolol Nadolol Sotalol
TAIWAN TANABE
18
Balance Clearance
Bisoprolol
TAIWAN TANABE
19
Bisoprolol Comparison to ß1-selective ß-blockers
Borchard U. ß-Rezeptorenblocker, Klinik und
Praxis, Aesopus Verlag 1996
dose-dependent
20
Bisoprolol Comparison to non-selective ß-blockers
Borchard U. ß-Rezeptorenblocker, Klinik und
Praxis, Aesopus Verlag 1996
21
Three indications of Bisoprolol

• Essential Hypertension
• Angina
• Stable Chronic Heart Failure (ModerateSevere)

22
Three Indications of Bisoprolol

• Essential Hypertension
• Angina
• Stable Chronic Heart Failure (ModerateSevere)

23
Bisoprolol Dose-dependent blood pressure
reductionin hypertensives
?
?

SBP

D
BP

Bisoprolol
Placebo
Bisoprolol
Placebo
28
56
84
91
days
28
56
84
91
days
0
0
10
10
(mm Hg)
(mm Hg)
20
Kirsten R et al. J Cardiovasc Pharmacol 1986 8
(Suppl. 11) 113121
20
30
40
30
Bisoprolol 5 mg
n 15/group
Bisoprolol 10 mg
SEM
x

Bisoprolol 20 mg
24
Bisoprolol Dose-dependent blood pressure
reduction3 and 24 hours after administration

• Davidov ME et al. Clin Cardiol 1994 17 263268

Bisoprolol dose
Placebo
5 mg
10 mg
20 mg
0
2
4
3.0
3.6
6
DBP sitting (mm Hg)
8
7.4
10
12
10.5
14
12.7
12.8
13.4
16
14.7


3 h p.a.
3 h p.a.
n 240


SEM
S
24 h p.a.
24 h p.a.
25
180
160
Bisoprolol Circadian rhythm
140
SBP
120
100
(mm Hg)
80
DBP
60
1
3
5
7
9
11
13
15
17
19
21
23
h

last day of placebo
after 4 weeks of bisoprolol(10mg)
Keim HJ. Therapiewoche 1988 4735073513
n 8

26
Bisoprolol Treatment of hypertensionin
comparison to atenolol

• Neutel JM et al. Am J Med 1993 94181187

DBP
0
Bisoprolol
(n 107)
Atenolol
(n 96)
night
5
)
10
mean change in diastolic blood pressure
(mm Hg
15
20
10 a.m.
4 p.m.
10 p.m.
4 a.m.
10 a.m.
time of day
dose
intake

27
Bisoprolol Long-term treatment of hypertension
180
140
SBP
(m
m Hg)
100
Giesecke HG et al. J Cardiovasc Pharmacol 1990
16 (Suppl 5) 175
DBP
(m
m Hg)
HR
(
beats/min)
60
0
12
15
18
21
24
27
30
33
36
months
102
102
97
102
101
102
102
102
100
102
n
28
Bisoprolol clinical study in Japan
Total patients81 Period12 weeks Dosage Bisopr
olol 5mg QD
TAIWAN TANABE
n80
n73
n71
Adapted from????????? 35? 1? (19981) P3338
29
Beta-Blockers Continue to surprise us


Diabetic Hypertension
30
JNC ? Clinical Trial and Guideline Basis for
Compelling Indications for Individual Drug Classes
Recommended Drugs Diuretic Beta-Blocker
ACE Inhibitor ARB CCB Aldosterone


Antagonist
High-Risk Conditions With Compelling
Indication Heart Failure Post-myocardial
infarction High coronary disease
risk Diabetes Chronic kidney
disease Recurrent stroke prevention
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. 20032892560-2572
31
Beta-blockersanother choice for HT with DM
therapy
32
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 - 1997
• 23 clinical centres
• patient population 5102 type 2 diabetic patients
• 53,000 patient years follow-up

33
UKPDS Blood Pressure Control Study tight vs.
less tight results

• Tight blood pressure control significantly
  reduces risks for
• any diabetes-related endpoint 24 (p0.0046)
• diabetes-related deaths 32 (p0.019)
• stroke 44 (p0.013)
• microvascular disease 37 (p0.0092)
• heart failure 56 (p0.0043)
• retinopathy progression 34 (p0.0038)
• deterioration of vision 47 (p0.0036)

34
Table 1Indications for initial treatment and
goals for adult hypertensive diabetic patients
 

• Adapted fromDIABETES CARE, VOLUME 25, NUMBER 1,
  JANUARY 2002

 
35
UKPDS Study
Adapted fromBMJ, Volume 317(7160).September 12,
1998.713-720
36
UKPDS Blood Pressure Control Study results
favour ß-blocker
Adapted fromBMJ, Volume 317(7160).September 12,
1998.713-720
37
UKPDS Study
Intermittent claudication or cold feet
0 15 (4)
lt0.0001 Bronchospasm
0
22(6) lt0.0001
Adapted fromBMJ, Volume 317(7160).September 12,
1998.713-720
38
UKPDS Blood Pressure Control Study implications
Before UKPDS
After UKPDS

• 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 diabetes
• first choice treatment
• ACE inhibitor or Beta-blocker

39
Treatment of Hypertensionin Adults With Diabetes

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

• Adapted fromDIABETES CARE, VOLUME 25, NUMBER 1,
  JANUARY 2002

40
Three Indications of Bisoprolol

• Essential Hypertension
• Angina
• Stable Chronic Heart Failure (ModerateSevere)

41
T I B B STotal Ischaemic Burden Bisoprolol Study
Randomised double-blind controlled study with two
parallel groups
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
patientswith stable angina pectoris
von Arnim Th et al. JACC 1995 1 231230
42
TIBBS Flow chart
20 mg o.d. Bisoprolol
Placebo
10 mg o.d. Bisoprolol
20 mg b.i.d. Nifedipine s.r.
40 mg b.i.d. Nifedipine s.r.
10 days
4 weeks
4 weeks
von Arnim Th et al. JACC 1995 1 231238
gt
History
If
2 ischaemic
ETT
episodes,
Inclusion
inclusion for
for
active
prephase
treatment
48 h Holter
48 h Holter
48 h Holter
43
TIBBS Number of ischaemic episodes at
baseline,on low dose and on high dose
No./48 h
10
8
6
4
von Arnim Th et al. JACC 1995 1 231238
2
0
Baseline
40 mg
20 mg
Baseline
20 mg
10 mg
Nifedipine s.r. b.i.d. (n 112)
Bisoprolol o.d. (n 111)
SEM
x

44
TIBBS Duration of ischaemic episodes at
baseline,on low dose and on high dose
minutes
120
90
60
von Arnim Th et al. JACC 1995 1 231238
30
0
Baseline
40 mg
20 mg
Baseline
20 mg
10 mg
Nifedipine s.r. b.i.d. (n 112)
Bisoprolol o.d. (n 111)
SEM
x

45
TIBBS Total ischaemic burden at baseline,on low
dose and on high dose
min. x mm
250
200
150
von Arnim Th et al. JACC 1995 1 231238
100
50
0
Baseline
40 mg
20 mg
Baseline
20 mg
10 mg
Nifedipine s.r. b.i.d. (n 112)
Bisoprolol o.d. (n 111)
SEM
x

46
Three Indications of Bisoprolol

• Essential Hypertension
• Angina
• Stable Chronic Heart Failure (ModerateSevere)

47
Beta-Blockers Continue to surprise us


From Contraindication to Indication
Heart Failure
48
Compensatory mechanisms in CHF

• The organism responds to the reduced cardiac
  output situation in CHF by a number of
  compensatory mechanisms to maintain cardiac
  output
• Frank-Starling mechanism (?CO)
• Raised sympathetic-nervous activity
• Renin-angiotensin-aldosterone system
• Enhanced exploitation of blood oxygen in the
  peripheral

TAIWAN TANABE
49
Chronically raised sympathetic tonus is
accompanied by a number of unfavourable
cadiovascular effects

• 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
50
?-blockers ?????CHF?????
51
?-blockers ?????CHF?????
52
CIBIS II
-beneficial concomitant therapy in
CHF PublicationThe Lancet 1999 3539-13
TAIWAN TANABE
53
CIBIS IICardiac Insufficiency Bisoprolol Study

• Double-blind, placebo-controlled, randomised
  trial
• 2,647 patients included (NYHA III IV)
• Bisoprolol administered on top of standard
  therapy(diuretic ACE inhibitor)

CIBIS II Investigators and Committees. Lancet
1999 353 913
54
CIBIS II Objectives

• Primary objective
• All-cause mortality
• Secondary objectives
• Cardiovascular mortality
• Hospital admissions
• Cardiovascular mortality orcardiovascular
  hospital admissions
• Permanent treatment withdrawal

CIBIS II Investigators and Committees. Lancet
1999 353 913
55
CIBIS II Main inclusion criteria

• Ambulatory patients with stable CHF of all
  aetiologies
• NYHA functional class III or IV
• Stable on ACE inhibitor and diuretic
• Aged 18 80 years
• Left ventricular ejection fraction - 35

CIBIS II Investigators and Committees. Lancet
1999 353 913
56
CIBIS IIDose titration
Bisoprolol dose (mg)
10.00


7.50
5.00
CIBIS II Investigators and Committees. Lancet
1999 353 913

3.75
2.50

1.25

W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
W14
W15
W16
Week

• No run-in period
• Dose increased according to tolerability

57
CIBIS IICharacteristics (I)
Placebo Bisoprolol (n1320) (n1327) Demographi
c data Mean (range) age (years) 61 (2280) 61
(2680) Sex (M/F) 1062 (80) 1070 (81) 258
(20) 257 (19) NYHA class III 1096 (83) 1106
(83) IV 224 (17) 221 (17) Heart failure
Documented ischaemic heart disease 654 (50) 662
(50) Primary dilated cardiomyopathy 157
(12) 160 (12) Others 509 (40) 505 (38) Mean
(SD) LV ejection fraction 27.6 (5.5) 27.5
(6.0) Coronary angiography unavailable or no
history of myocardial infarction
CIBIS II Investigators and Committees. Lancet
1999 353 913
58
CIBIS II Characteristics (II)
Placebo
Bisoprolol
(n1320)
(n1327)
Concomitant medication
Diuretic
1310
(99)
1305
(98)
ACE inhibitor
1274
(96)
1273
(96)
Dihydropyridine-type calcium antagonist
23
(2)
23
(2)
CIBIS II Investigators and Committees. Lancet
1999 353 913
Nitrate
762
(58)
773
(58)
Digoxin
670
(51)
697
(53)
Amiodarone
206
(16)
185
(14)
Anticoagulant
413
(31)
399
(30)
Antiplatelet agent
558
(42)
537
(40)
59
CIBIS II Survival
1.0
Bisoprolol 156 deaths(11.8) (n 1327)
Placebo 228 deaths(17.3) (n 1320) log rank
test, p lt 0.0001
0.8
Survival
CIBIS II Investigators and Committees. Lancet
1999 353 913
0.6
0
0
200
400
600
800
Time after inclusion (days)

• 34 reduction in all-cause mortality with
  bisoprolol

60
CIBIS II Causes of deaths
Patients
100
p0.0011
80
83 6
Bisoprolol (n 1327)
60
Placebo (n 1320)
p0.0012
p0.17
49 4
48 4
47 4
CIBIS II Investigators and Committees. Lancet
1999 353 913
40
p0.58
36 3
p0.41
28 2
23 2
23 2
20
p0.75
18 1
14 1
8 1
7 1
0
Unknown cause
Non-cardio-
Other cardio-
Myocardial
Pump
Sudden
of death
vascular deaths
vascular deaths
infarction
failure
death
Hazard ratio (95 CI)
0.45
0.75
1.17
0.85
0.56
0.74
(0.27 0.74)
(0.37 1.50)
(0.67 2.03)
(0.31 2.34)
(0.39 0.80)
(0.48 1.14)
61
CIBIS IIMain results at a glance

• In the bisoprolol-treated group of patients there
  was a reduction in
• All-cause mortality (independent of aetiology)
  by 34 (plt0.0001)
• Sudden death by 44 (plt0.0011)
• All-cause hospital admissions by 20 (plt0.0006)

CIBIS II Investigators and Committees. Lancet
1999 353 913
62

CIBIS II Conclusions

• CIBIS II successfully demonstrated that
  ß1-selective bisoprolol given in addition to
  standard therapy reduces significantly
  all-cause mortality andall-cause hospitalisation
  in CHF patients.
• Bisoprolol is the first ß-blocker which has
  provenits efficacy in a single large-scale CHF
  studywith all-cause mortality as primary
  objective.
• Bisoprolol was as well tolerated as placebowith
  a premature permanent treatment withdrawal rate
  of 15 in both groups.

CIBIS II Investigators and Committees. Lancet
1999 353 913
63
(No Transcript)
64
ACC/AHA Guidelines for the Evaluation and
Management of Chronic Heart Failure in the Adult
Drug Initial Dose
Maximum Dose
ß-receptor blockers Bisoprolol
1.25 mg once daily 10 mg once
daily Carvedilol 3.125 mg
twice daily 25 mg twice daily

50mg twice daily for

patients more than 85
kg Metoprolol tartrate 6.25 mg twice daily
75 mg twice daily Metoprolol
succinate Extended release 12.5 to 25 mg
daily
65
Major Trials of b-Blockade in Heart Failure

LVEF Target /Mean
dose Mortality Sudden Death
NYHA (mg/day) US
Carvedilol lt 35 50 - 100 /45 mg
?65 ?52 1094 7.5 mo II-IV
carvedilol (P.0001)
(Plt.05) CIBIS-II lt 35 10
/7.5 mg ?34 ?44 2647
1.3 y III-IV bisoprolol
(Plt.0001) (Plt.0011) MERIT-HF lt 40
200 /159 mg ?34 ?41
3991 1 y II-IV metoprolol
XL (P.0062) (P.002) BEST
lt 35 100-200/152 mg ?10
?12 2708 2 y III-IV
bucindolol NS NS


COPERNICUS lt 25 50/ 37
mg ?35 NA 2289 10.4
mo IV carvedilol
(P.0014)
Not a planned endpoint.
66
Effect of b-Blockade onAll-Cause Mortality
CIBIS-I 1.9 yearsplacebo 67/321 (20)
bisoprolol 53/320 (16)
P.22
US Carvedilol Trials 7.6 monthsplacebo 31/398
(8) carvedilol 22/696 (3)
P.001
0
0.25
0.5
0.75
1
1.25
1.5
1.75
2
Relative risk and 95 confidence intervals
Not a planned endpoint.
67
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)
68
CIBIS IIIBackground

• Chronic heart failure
• still a major clinical and public health problem
• current pharmacological therapy
• ACE-inhibitors
• Beta-blockers
• Diuretics
• Digitalis glycosides
• Aldosterone antagonists

Guidelines for the diagnosis and treatment of
chronic heart failure. Eur Heart J 2001 22
1527-60
69
Hypothesis

• Initiation of treatment in patients with CHF
• with the ß1-selective ß-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
70
CIBIS IIIDose titration
71
Primary objective

• 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).

DOI 10.1161/CIRCULATIONAHA.105.582320
72
CIBIS IIIPrimary objectives

• First primary objective
• Initiation of monotherapy with bisoprololol
  followed by the addition of enalapril
  (combination therapy) is comparable
  (non-inferior) to initiation with enalapril in
  CHF patients in preventing all-cause death and
  hospitalisation (combined endpoint) at end of
  study
• Second primary objective (if first primary
  objective is met)
• Initiation of monotherapy with bisoprolol is
  superior to initiation with enalapril in CHF
  patients (combined endpoint) at end of study

73
Combined primary endpoint
without endpoint
Per-protocol (PP) population
Bisoprolol-first significantly non-inferior to
enalapril-first if upper limit of 95 CI below
hazard ratio (HR) 1.17, Plt0.025. (RR 1.125, AR
5) In the PP population, bisoprolol- first
was not significantly non-inferior
to enalapril-first In the ITT population,
bisoprolol- first was significantly non-inferior
to enalapril-first
100
Bisoprolol-first
90
Enalapril-first
80
B/E vs E/B 163 vs 165 pts HR 0.97 (95 CI
0.78-1.21) non-inferiority P0.046
3 risk reduction
70
60
50
503 498
356 353
265 259
80 73
Numbers at risk
months
0
6
12
18
without endpoint
Intention-to-treat (ITT) population
100
90
6 risk reduction
80
B/E vs E/B 178 vs 186 pts HR 0.94 (95 CI
0.77-1.16) non-inferiority P0.019
70
60
50
505 505
389 388
291 277
87 76
Numbers at risk
DOI 10.1161/CIRCULATIONAHA.105.582320
months
0
6
12
18
74
All-cause hospitalization throughout study (ITT)
without hospitalization
Bisoprolol-first
Enalapril-first
100
90
80
B/E vs E/B 151 vs 157 pts hospitalized HR 0.95
(95 CI 0.76-1.19) P0.66 (difference)
70
60
5 risk reduction
50
months
0
6
12
18
Numbers at risk
289
85
386
505
277
76
387
505
DOI 10.1161/CIRCULATIONAHA.105.582320
75
All cause mortality throughout study (ITT)
survival
Bisoprolol-first
Enalapril-first
100
95
90
B/E vs E/B 65 vs 73 deaths HR 0.88 (95 CI
0.63-1.22) P0.44 (difference)
85
80
12 risk reduction
75
months
0
6
12
18
379
117
475
Numbers at risk
505
368
125
470
505
DOI 10.1161/CIRCULATIONAHA.105.582320
76
Primary endpoint at end of monotherapy (ITT)
(all cause mortality and all cause
hospitalization)
without endpoint

Bisoprolol-first
Enalapril-first
100
95
90
B/E vs E/B 109 vs 108 pts HR 1.02 (95 CI
0.78-1.33) P0.90 (difference)
85
2 risk increase
80
months
0
1
2
3
4
5
6
Numbers at risk
469
434
414
400
383
195
505
473
437
410
396
376
213
505
DOI 10.1161/CIRCULATIONAHA.105.582320
77
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

DOI 10.1161/CIRCULATIONAHA.105.582320
78
Conclusions (2)

• There was no difference in safety between the two
  strategies,
• showing that a bisoprolol-first strategy does not
  cause concerns

DOI 10.1161/CIRCULATIONAHA.105.582320
79
Thoughts for the future

• Bisoprolol-first might increase survival in the
  early phase of treatment, allowing a greater
  number of patients to subsequently benefit from
  combined ß-blocker ACEi.
• The bisoprolol-first strategy could be further
  improved with greater experience of up-titration
  of the ß-blocker-first, leading to less worsening
  of CHF.
• This should be further examined.

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80
Clinical implication
The CIBIS III result supports a free choice of
initial treatment for CHF - enalapril or
bisoprolol - based on the physicians individual
judgment in each patient
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81
Put into clinical practice
82
Hypertension Angina CHF
NHI price Concor 5 NT 7.6
ß1ß2 751
Bisoprolol
Balance Clearance
Non-ISA
CIBIS ? CIBISIII TIBBS DECREASE
TAIWAN TANABE
83
Thanks for your coming!
Concor wins your heart!!
TAIWAN TANABE