1. CIBIS II Cardiac Insufficiency Bisoprolol Study
Biso 5 Korr
CIBIS II Cardiac 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)
Bisoprolol fumarate (2:1) is a racemate and as a derivative of phenoxyaminopropa-nol
it belongs to the class of therapeutic substances known as ß-blockers. Bisoprolol fumarate is very freely soluble in water and freely soluble in ethanol and chloroform. The molecular weight is , the white crystalline substance melts at 101°C.
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13

2. CIBIS II – Cardiac Insufficiency Bisoprolol Study Objectives
Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Objectives
Primary objective
All-cause mortality
Secondary objectives
Cardiovascular mortality
Hospital admissions
Cardiovascular mortality or cardiovascular hospital admissions
Permanent treatment withdrawal
Bisoprolol proved to be the compound with the highest ß1-selectivity in all in vitro and in vivo studies and in all animal species investigated. One measure of ß1-selectivity is the ratio of the constants of inhibition (ci) for the ß1- and ß2-receptor. The constants of inhibition of the ß-blockers bisoprolol, atenolol, betaxolol and propranolol were determined in ligand-binding studies using rat parotid gland (mainly occupied by ß1-receptors) and rat reticulocytes (mainly occupied by ß2-receptors) in human plasma: using a non-specific radiolabelled ligand, the ß1- and ß2-receptors of the rat parotid gland and reticulocytes were completely occupied. This cell suspension was then mixed with the plasma of volunteers pretreated with different ß-blockers. The non-specific radioligand was now displaced from the receptor by addition of this serum enriched with ß-blockers. Constants of inhibition of a characteristic magnitude for each ß-blocker and receptor type could be determined from these tests; the smaller the ci-value, the higher the affinity of the ß-blocker for the receptor type concerned.
The ratio of ci/ß1 to ci/ß2 was 1:75 for bisoprolol, 1:35 for atenolol and betaxolol, 1:20 for metoprolol, and 1.8:1 for propranolol.
Bisoprolol therefore proved to be the ß-blocker with the highest ß1-selectivity in this model as well.
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13

3. Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study 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%
Bisoprolol proved to be the compound with the highest ß1-selectivity in all in vitro and in vivo studies and in all animal species investigated. One measure of ß1-selectivity is the ratio of the constants of inhibition (ci) for the ß1- and ß2-receptor. The constants of inhibition of the ß-blockers bisoprolol, atenolol, betaxolol and propranolol were determined in ligand-binding studies using rat parotid gland (mainly occupied by ß1-receptors) and rat reticulocytes (mainly occupied by ß2-receptors) in human plasma: using a non-specific radiolabelled ligand, the ß1- and ß2-receptors of the rat parotid gland and reticulocytes were completely occupied. This cell suspension was then mixed with the plasma of volunteers pretreated with different ß-blockers. The non-specific radioligand was now displaced from the receptor by addition of this serum enriched with ß-blockers. Constants of inhibition of a characteristic magnitude for each ß-blocker and receptor type could be determined from these tests; the smaller the ci-value, the higher the affinity of the ß-blocker for the receptor type concerned.
The ratio of ci/ß1 to ci/ß2 was 1:75 for bisoprolol, 1:35 for atenolol and betaxolol, 1:20 for metoprolol, and 1.8:1 for propranolol.
Bisoprolol therefore proved to be the ß-blocker with the highest ß1-selectivity in this model as well.
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13

4. CIBIS II – Cardiac Insufficiency Bisoprolol Study Design
Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Design
Bisoprolol dose (mg)
10.00
Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man.
In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol – a dosage far beyond the therapeutic dose range – was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay.
24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions.
36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found.
At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well.
Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80 – 30% for the therapeutic dose range of 5 – 10 mg.
7.50
5.00
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13
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

5. CIBIS II – Cardiac Insufficiency Bisoprolol Study Characteristics (I)
Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Characteristics (I)
Placebo Bisoprolol (n=1320) (n=1327)
Demographic data
Mean (range) age (years) 61 (22–80) 61 (26–80)
Sex (M/F) 1062 (80%) 1070 (81%)
258 (20%) 257 (19%)
NYHA class
III 1096 (83%) 1106 (83%)
IV (17%) (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) left-ventricular ejection fraction (5.5%) 27.5 (6.0%)
*Coronary angiography unavailable or no history of myocardial infarction
Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man.
In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol – a dosage far beyond the therapeutic dose range – was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay.
24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions.
36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found.
At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well.
Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80 – 30% for the therapeutic dose range of 5 – 10 mg.
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13

6. CIBIS II – Cardiac Insufficiency Bisoprolol Study Characteristics (II)
Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Characteristics (II)
Placebo
Bisoprolol
(n=1320)
(n=1327)
Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man.
In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol – a dosage far beyond the therapeutic dose range – was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay.
24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions.
36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found.
At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well.
Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80 – 30% for the therapeutic dose range of 5 – 10 mg.
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: 9–13
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%)

7. CIBIS II – Cardiac Insufficiency Bisoprolol Study Survival
Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Survival
1.0
Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man.
In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol – a dosage far beyond the therapeutic dose range – was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay.
24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions.
36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found.
At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well.
Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80 – 30% for the therapeutic dose range of 5 – 10 mg.
0.8
Bisoprolol: 156 deaths (n = 1327)
Placebo: deaths (n = 1320)
log rank test, p <
Survival
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13
0.6
200
400
600
800
Time after inclusion (days)
34% reduction in all-cause mortality with bisoprolol

8. Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Analysis of time to death
Patients
100
p=0.0011 80 83 6%
Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man.
In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol – a dosage far beyond the therapeutic dose range – was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay.
24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions.
36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found.
At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well.
Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80 – 30% for the therapeutic dose range of 5 – 10 mg.
Bisoprolol (n = 1327) 60
Placebo (n = 1320)
p=0.0012
p=0.17 48 4% 49 4% 47 4%
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13 40
p=0.58 36 3% 28 2%
p=0.41 20 23 2% 23 2%
p=0.75 18 1% 14 1% 7 1% 8 1%
Sudden
Pump
Myocardial
Other cardio-
Non-cardio-
Unknown cause
death
failure
infarction
vascular deaths
vascular deaths
of death
Hazard ratio:
(95% CI)
0.56
0.74
0.85
1.17
0.75
0.45
(0.39 – 0.80)
(0.48 – 1.14)
(0.31 – 2.34)
(0.67 – 2.03)
(0.37 – 1.50)
(0.27 – 0.74)

9. CIBIS II – Cardiac Insufficiency Bisoprolol Study Secondary endpoints
Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Secondary endpoints
Placebo Bisoprolol Hazard ratio p
(log rank
(n = 1320) (n = 1327) (95% Cl) test)
All-cause hospital admissions 513 (39%) 440 (33%) (0.71–0.91)
All cardiovascular deaths 161 (12%) 119 (9%) (0.56–0.90)
Combined endpoint 463 (35%) 388 (29%) (0.69–0.90)
Permanent treatment 192 (15%) 194 (15%) (0.82–1.22) withdrawals
Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man.
In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol – a dosage far beyond the therapeutic dose range – was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay.
24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions.
36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found.
At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well.
Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80 – 30% for the therapeutic dose range of 5 – 10 mg.
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13

10. Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Mortality by baseline findings
Bisoprolol
Placebo
n/total
n/total
Ischaemia
75/662
121/654
Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man.
In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol – a dosage far beyond the therapeutic dose range – was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay.
24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions.
36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found.
At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well.
Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80 – 30% for the therapeutic dose range of 5 – 10 mg.
Primary DCM
13/160
15/157
Undefined
68/505
92/509
NYHA III
116/1106
173/1096
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13
NYHA IV
40/221
55/224
Total
Relative risk:
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Mortality did not differ significantly between groups whatever the aetiology or severity of heart failure

11. Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Main results at a glance
In the bisoprolol-treated group of patients there was a reduction in
All-cause mortality (independent of aetiology) by 34% (p<0.0001)
Sudden death by 44% (p<0.0011)
All-cause hospital admissions by 20% (p<0.0006)
Hospital admissions due to worsening heart failure by 36% (p<0.0001)
Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man.
In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol – a dosage far beyond the therapeutic dose range – was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay.
24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions.
36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found.
At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well.
Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80 – 30% for the therapeutic dose range of 5 – 10 mg.
CIBIS II Investigators and Committees, Lancet 1999, 353: 9–13

12. CIBIS II – Cardiac Insufficiency Bisoprolol Study Conclusions
Biso 5 Korr
CIBIS II – Cardiac Insufficiency Bisoprolol Study Conclusions
CIBIS II successfully demonstrated that ß1-selective bisoprolol – given in addition to standard therapy – reduces significantly all-cause mortality and all-cause hospitalisation in CHF patients.
Bisoprolol is the first ß-blocker which has proven its efficacy in a single large-scale CHF study with all-cause mortality as primary objective.
Bisoprolol was as well tolerated as placebo with a permanent treatment withdrawal rate of 15% in both groups.
Bisoprolol fumarate (2:1) is a racemate and as a derivative of phenoxyaminopropa-nol
it belongs to the class of therapeutic substances known as ß-blockers. Bisoprolol fumarate is very freely soluble in water and freely soluble in ethanol and chloroform. The molecular weight is , the white crystalline substance melts at 101°C.