Bisoprolol PDF

Bisoprolol
Cardioselective Beta-Blocker
Status: February 2001
2 Bisoprolol
m 3
Contents
www.bisoprolol.com
Composition
Chemistry
Pharmacology and biochemistry
Merck KGaA
Darmstadt, Germany
Pharmacokinetic data
9
11
2.1 1-selectivity
11
2.2 Intrinsic sympathomimetic activity (ISA)
13
2.3 Membrane-stabilising activity
14
2.4 Antihypertensive effect
14
2.5 Cardioprotection
14
2.6 Renin-angiotensin system
15
2.7 Duration of action
15
2.8 Pharmacology of side-effects
16
Toxicology
17
3.1 Acute toxicity
17
3.2 Short-term toxicity
17
3.3 Chronic toxicity
17
3.4 Specific toxicity studies
18
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Pharmacokinetics
19
Treatment of essential hypertension
52
6.1 Blood pressure at rest duration

of action
52
6.2 Blood pressure during exercise

duration of action
56
20
4.4 Elimination half-life
25
6.3 Normalisation rate
58
4.5 Interactions
25
6.4 Long-term treatment of arterial

hypertension with bisoprolol
61
4.6 Variability of plasma concentrations
28
4.1 Bioavailability
20
4.2 Distribution
20
4.3 Metabolism and excretion
29
6.5 Regression of left ventricular

hypertrophy
63
Clinical profile
5.1 Clinical pharmacology
29
6.6 Quality of life
64
5.1.1
5.1.2
5.1.3
5.1.4
5.1.5
5.1.6
5.1.7
5.1.8
5.1.9
5.1.10
5.1.11
29
32
33
33
35
38
41
48
48
50
51
6.7 Therapeutic comparison in

hypertensive patients
67
6.7.1
6.7.2
6.7.3
6.7.4
6.7.5
6.7.6
6.7.7
6.7.8
6.7.9
67
70
70
71
71
72
72
74
74
Haemodynamics
Electrophysiology
1-selectivity
Receptor occupancy
Lung function
Peripheral circulation
Metabolism
2-receptor density
Plasma renin activity
Fibrinolytic system
Dose-response relationship
Bisoprolol and atenolol

Bisoprolol and metoprolol
Bisoprolol and captopril
Bisoprolol and enalapril
Bisoprolol and lisinopril
Bisoprolol and nifedipine retard
Bisoprolol and nitrendipine
Bisoprolol and verapamil
Bisoprolol and a thiazide/potassium-sparing
diuretic combination
6.7.10 Bisoprolol and chlorthalidone
6.7.11 Bisoprolol and bendrofluazide
74
75
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6.8 Safety and efficacy in special populations
75
8.2 CIBIS II
6.8.1 Elderly hypertensives

6.8.2 Diabetic hypertensives
75
76
8.2.1
8.2.2
8.2.3
8.2.4
Treatment of angina pectoris in

coronary heart disease
78
78
7.2 Haemodynamics
80
7.3 Success rate
80
7.4 Silent ischaemia
82
83
7.6 Therapeutic comparison in

coronary patients
84
7.6.1
7.6.2
7.6.3
7.6.4
Bisoprolol and atenolol

Bisoprolol and nifedipine
Bisoprolol and verapamil
Bisoprolol and isosorbide dinitrate
84
86
89
90
Treatment of chronic heart failure
91
8.1 CIBIS
91
8.1.1 Heart rate variability

8.1.2 Pharmacoeconomic analyses
95
95
95
Primary endpoint (all-cause mortality)

Secondary endpoints
Additional analysis
Pharmacoeconomic analyses
96
97
98
100
Further areas of research
101
9.1 Hyperthyreosis
101
9.2 Prophylaxis of migraine
101
9.3 Perioperative risk reduction
102
10
Psychophysiological functions
104
11
Tolerability
105
12
References
109
12.1 General
109
12.2 Bisoprolol
111
8 Bisoprolol
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Pharmacokinetic data
Absorption rate:
> 90%
First-pass effect:
<10%
Bioavailability:
90%
Cmax:
~50 ng /ml
(10 mg bisoprolol /die; steady-state)
tmax:
2 3 h
Elimination half-life:
10 12 h
Clearance:
50% unchanged
50% metabolised
approx. 95% renal
2% faecal
Excretion:
Renal clearance:
140 ml /min
Distribution volume:
3.21 / kg
Plasma protein binding:
~30%
Placental patency:
yes
Passage into milk:
yes
Composition
1 film-coated tablet contains
5 mg or 10 mg bisoprolol fumarate (2:1).
Chemistry
Bisoprolol fumarate (2:1) is the INN for () -1- [ [- (2-isopropoxyethoxy)-p-tolyl ]oxy]-3- (isopropylamino)-2- propanol fumarate (2:1).
It is a racemate and as a derivative of phenoxyaminopropanol it
belongs to the class of therapeutic substances which are known as
the -blockers. The structural formula is given in Fig.1.
Fig. 1:
Chemical structure of bisoprolol fumarate (2:1).
CH3
O
OH
N
H
CH3
HOOC
1/2
CH
HC
CH3
COOH
CH3
The molecular weight is 383.48; the white crystalline substance

melts at 101C. Bisoprolol fumarate (2:1) is very freely soluble in
water and methanol and freely soluble in ethanol and chloroform.
The pKa of the bisoprolol base is 9.5. The partition coefficient (PC)
as a measure of lipophilicity has been determined in the twophase systems n-octanol /phosphate buffer and n-octanol / Davies
universal buffer (Tab.1) [113,191].
10 Bisoprolol
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Thus, bisoprolol is less lipophilic than propranolol but more lipophilic

than atenolol [3]. This middle position is the determinant factor for
the virtually ideal pharmacokinetic profile of bisoprolol.
Tab. 1:
Partition coefficients of bisoprolol at 37C [113,190 ].

pH
Partition
coefficient (PC)
log (PC)
metabolisation
n-Octanol/
phosphate buffer
7.4
4.8
0.68
n-Octanol/Davies
7.0
1.09
0.04
universal buffer
7.4
2.5
0.40
Pharmacology and biochemistry
2.1 1-selecivity
In comparison with other 1-selective -blockers (atenolol,
metoprolol, betaxolol) bisoprolol proved to be the compound
with the highest 1-selectivity in all in vitro and in vivo
experiments and in all animal species investigated [85, 86,
98,105,127,156,157,160,163,187].
The undesired bronchoconstrictory action component of -blockers
was investigated in guinea pigs and compared with the 1-sympatholytic actions. Compared with the other 1-selective -blockers,
bisoprolol exhibited the largest splitting between the doseresponse curves for bronchoconstriction and reduction of heart
rate. The ratio of the heart-rate reducing action to the increase in
tracheal lateral pressure as a measure of the airway resistance gave
a splitting factor of over 100 for bisoprolol, 15-35 for atenolol,
metoprolol and betaxolol and a factor of 1 for the non-selective
-blocker propranolol [157]. This was also confirmed in isolated
human bronchi. On incubation of the bronchial tissue with therapeutically effective 1-blocker concentrations, the bronchodilatory
effective isoprenaline dose had to be increased by a factor of
2.82 as compared to the control in the experiments with atenolol,
and by a factor of only 1.95 in the experiments with bisoprolol.
This shows the high 1-selectivity of bisoprolol also in the
human bronchus [135].
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Fig. 2:
Ratio of constants of inhibition (c i )

c i /1-receptors: c i / 2-receptors determined in ligand-binding studies,
as a measure of the affinity of various -blockers to 1 - and 2 - receptors,
respectively [according to 186,187].
1 : 75
1 : 35
1 : 35
increasing
1- selectivity
no selectivity
300 : 1
1.8 : 1
Propranolol Atenolol
increasing
2- selectivity
ICI 118.551
Betaxolol
Bisoprolol
The respective constants of inhibition (c i ) of bisoprolol, atenolol,

betaxolol and the specific 2-blocker ICI 118.551 were determined
in ligand-binding studies performed on membrane preparations
of rat reticulocytes (2-receptors) and rat parotid glands (1-receptors) in human plasma. The ratio of c i /1 to c i /2 was 1:75 for
bisoprolol, 1:35 for betaxolol, 1:35 for atenolol, 1.8:1 for propranolol and 300:1 for ICI 118.551 [187,188] (Fig. 2). Therefore
bisoprolol proved to be the -blocker with the highest affinity to
1-receptors in this model as well. It is due to this that bisoprolol
is a tool substance, e.g. in studies on the proportion of 1-receptors in tissues [37].
The 1-selectivity of bisoprolol has also been demonstrated in
cloned human -receptors [160,163]. In a study using membranes
prepared from recombinant cells selectively expressing human
1- and 2-receptors [163], bisoprolol was found to have the
highest selectivity for the 1-receptor of all the 1-blockers studied.
Bisoprolol displayed a 19-fold affinity for the 1-receptor versus
the 2-receptor. Atenolol, metoprolol and betaxolol displayed lower
selectivity for the 1-receptor than bisoprolol, whereas propranolol
and carvedilol were not 1-selective.
In another study using cloned human receptors [160], bisoprolol
displayed 15-fold selectivity for 1-receptors versus 2-receptors,
and 31-fold selectivity for 1-receptors versus 3-receptors. In
contrast, atenolol and metoprolol exhibited only 5-fold selectivity
for 1-receptors versus 2- and 3-receptors. Carvediolol was
non-selective for any -receptor.
2.2 Intrinsic sympathomimetic activity (ISA)

Bisoprolol has no intrinsic -sympathomimetic activity.
Contractility measurements on the electrically stimulated left
atrium of the heart of guinea pigs pretreated with reserpine gave
no evidence of ISA. Investigations in rats confirmed the absence
of ISA [85].
14 Bisoprolol
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2.3 Membrane -stabilising activity

Bisoprolol has no membrane-stabilising activity in the dose range
relevant for -receptor blockade.
Bisoprolol had a local anaesthetic action on the cornea of the rabbit
and the skin of the guinea pig. The concentrations of bisoprolol
required for this action were several times higher than the concentrations required to induce -blockade [85].
The cardioprotective effect of bisoprolol was further demonstrated

in anaesthetised pigs in which the coronary perfusion was reduced
by about 60% due to stenosis of the left coronary artery. 50 g /kg
bisoprolol increased the perfusion of the ischaemic myocardium,
and this effect was of particular benefit to the subendocardial
layers [152]. These cardioprotective effects of bisoprolol may help
to explain the reduction in perioperative mortality achieved with
bisoprolol in the DECREASE study in high-risk patients undergoing
noncardiac surgery [142].
2.4 Antihypertensive effect

Bisoprolol had an antihypertensive effect in all hypertension
models investigated. Bisoprolol reduced the blood pressure in
conscious dogs with renal hypertension, accompanied by only
a slight decrease in heart rate. In comparison with bisoprolol,
propranolol had a weaker antihypertensive effect even at a
considerably higher dose level [85]. Bisoprolol also reduced the
blood pressure in rats with renal hypertension. In rats with
spontaneous hypertension, the development of high blood pressure could be clearly reduced by chronic treatment with
7.5 mg / kg bisoprolol [85].
2.6 Renin-angiotensin system

Bisoprolol inhibits basal and stimulated renin secretion.
In conscious dogs bisoprolol inhibited the secretion of renin stimulated by isoprenaline, and also reduced the basal activity of plasma
renin. The release of renin was inhibited by about 65% and
tachycardia by about 35% [85].

Bisoprolol has a long duration of action.
Bisoprolol protects the myocardium from ischaemia-related damage.
Myocardial ischaemia was induced by coronary occlusion in anaesthetised open-chest dogs. The changes in the epicardial ECG typical
of myocardial hypoxia (ST segment elevation) were attenuated by
bisoprolol. A dose of 4 g bisoprolol per kg i.v. inhibited the
ST segment elevation, induced by coronary occlusion, by 60%. This
cardioprotective effect of bisoprolol was still present 40 minutes
after injection [85].
The duration of action of bisoprolol was investigated in anaesthetised guinea pigs after i.v. administration; the inhibition of
isoprenaline-induced tachycardia was measured at various times
after the administration of the -blocker. The drop in the action
duration curve was flatter for bisoprolol than for propranolol [85].
The results indicate a long duration of action for bisoprolol.
16 Bisoprolol
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2.8 Pharmacology of side-effects
The toxicological studies revealed no irreversible organ damage

by bisoprolol. In animal experiments bisoprolol was not
cytotoxic nor mutagenic. Although it was embryotoxic at higher
doses it was not teratogenic nor was it carcinogenic in the
mouse or rat.
The performed animal experimental investigations indicated for

bisoprolol no unexpected or serious side-effects.
Even at high doses [30 and 100 mg / kg, single oral administration
(rats)], the sedative effects ascribed to -blockers are less marked
with bisoprolol than, for instance, with propranolol [85].
From the 30 mg per kg tolerated in the chronic study in dogs

a safety factor of 210 can be calculated for a daily dose of
10 mg /patient. On the basis of the 75 mg /kg tolerated in the
chronic study in rats the corresponding factor is 525 [92].
Glucose tolerance was investigated in rats and was only slightly

reduced at very high doses of bisoprolol, whereas it was considerably reduced with comparable doses of propranolol [114].
Bisoprolol did not influence the lipid metabolism of adult normolipemic rats after repeated administration [85] nor was there any
quantitative change in the serum lipoprotein pattern in young
hyperlipemic rats with increased plasma cholesterol and decreased
alpha-lipoprotein [85].
Toxicology
3.1 Acute toxicity

On oral administration the LD 50 was 734 for the mouse and
1116 mg /kg for the rat with a follow-up period of 14 days.
On intravenous administration values of 127 (mouse), 53 (rat)
and 24 (dog) mg /kg were found.
3.2 Short-term toxicity

Daily i.v. administration of 0.2, 1 and 5 mg /kg in rats and 1, 3
and 10 mg /kg in dogs was tolerated for four weeks with no sign
of significant toxicological changes.
3.3 Chronic toxicity

No toxic effects were detected in rats after oral administration for
6 months at daily doses of 15, 50 and 150 mg /kg. 10 mg/kg was
not toxic for beagles after daily administration for 6 months.
Rats tolerated daily treatment with 25 mg /kg for 12 months with
no toxic damage. 75 mg /kg was also tolerated, with the exception
of a slight reduction in body weight gain. In a 12-month study in
beagles daily doses of 3, 10 and 30 mg /kg were tolerated.
18 Bisoprolol
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3.4 Specific toxicity studies
The pharmacokinetic properties of bisoprolol provide the prerequisite for a single daily dose and ensure an extremely low
inter- and intra-individual variability of the plasma concentration
profiles. The high therapeutic reliability of bisoprolol is based
on these properties.
Bisoprolol had no effect on the fertility or general reproductive

performance in rats.
At daily doses of 1.0, 2.5 and 6.25 mg /kg in rabbits as well as
15.0 and 40.0 mg /kg in rats, bisoprolol had no embryotoxic or
teratogenic effect. Higher doses have an embryolethal effect
but not a teratogenic effect. When assessing the embryolethal
effect it must be taken into consideration that this is a common
finding with all -blockers when sufficiently high doses are
administered to rats or rabbits.
Bisoprolol occupies a middle position as regards hydrophilia and

lipophilia [191]. The favourable pharmacokinetic properties are
derived from this basic physicochemical feature. Thus, bisoprolol
combines the advantages of both lipophilic -blockers (e.g. high
absorption rate) and hydrophilic -blockers (e.g. long plasma
elimination half-life, small first-pass effect) without any of the
respective pharmacokinetic disadvantages. With a 50% degree of
metabolisation [45,111,113], bisoprolol occupies the middle
position between hydrophilic and lipophilic -blockers (Tab. 2).
Administered in daily doses of 15 and 50 mg /kg to pregnant

rats and rabbits, bisoprolol had no effect on either the late foetal
or postpartum development of the young or on parturition, the
rearing instinct, lactation performance of the dams, physical
development or behaviour of the offspring. There was no influence
on the reproductive performance of the F1-animals or the
development of the F2-young animals up to their 28th day of life.
No signs of mutagenic potential were found either in bacterial
mutagenicity tests, the point mutation test and chromosome
aberration test in fibroblasts of the Chinese striped hamster or in
mutagenicity investigations in vivo (micronucleus test in the
mouse, chromosome investigations in the Chinese striped hamster).
In long-term feeding studies, bisoprolol had no carcinogenic effect
in mice at daily doses of 10, 50 and 250 mg /kg (20 months,
respectively) or in rats at daily doses of 5, 25 and 125 mg /kg
(26 months, respectively).
Pharmacokinetics
Tab. 2:
The frequently observed influence of lipophilia and hydrophilia

on the pharmacokinetic properties of -blockers [3].
Absorption
rate
Firstpass
effect
Bioavailability
Plasma elimination half-life
Degree of
metabolisation
Lipophilic -blockers
high
high
low
short
high
(90 -100%)
Hydrophilic -blockers
low
low
low
long
low
(0 -10%)
Bisoprolol
high
low
high
long
50%
20 Bisoprolol
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4.1 Bioavailability
The bioavailability of bisoprolol from film-coated tablets is
about 90%.
Bisoprolol is almost totally (> 90%) absorbed after administration.
On its first passage through the liver (first-pass effect) a maximum
of 10% of the dose is inactivated by metabolisation [111]. The high
absorption rate and small first-pass effect result in an absolute
bioavailability of 88% [111]. Bisoprolol can be taken on an empty
stomach or with breakfast, without the pattern of absorption
being changed [111]. The bioavailability of bisoprolol is the same
in either case.
4.2 Distribution
Bisoprolol has a plasma protein binding of 30%.
Only 30% of the bisoprolol in the blood is bound to plasma
proteins [45]. Therefore, interactions with other drugs in the sense
of displacement from a plasma protein bond do not occur. The
pharmacokinetics of bisoprolol are not influenced by pathophysiological changes in the plasma proteins, e.g. when there are
increased acid 1- glycoproteins.
As a substance with only moderate lipophilia, bisoprolol exhibits
a medium volume of distribution with low plasma protein
binding. An exact determination following i.v. administration gave
( x SEM) 226 11 l [111].
The result of this special feature, which is known as balanced

clearance (Fig. 6, cf. Fig. 7), is that even in cases of complete failure
of one of the clearance organs, the elimination half-life of bisoprolol is in general only up to about double that of the half-life in
the healthy organism.
This was demonstrated for bisoprolol in pharmacokinetic studies in
patients with functional impairment of the kidney (Fig. 3) or of the
liver (Fig. 4) [81, 88,103,140]. Therefore, no dosage adjustment of
bisoprolol is generally necessary in mild to moderate functional
impairment of the liver or kidney. A daily dose of 10 mg bisoprolol
should, however, not be exceeded in chronic terminal insufficiency
of one of these two organs. In any case, the dosage should be
determined individually, chiefly in accordance with the pulse rate
and therapeutic success.
Fig. 3:
Mean plasma concentrations of bisoprolol following repeated oral

administration of 10 mg bisoprolol once daily to healthy volunteers and
patients with moderate impairment (creatinine clearance 6 -21 ml /min )
or servere impairment (creatinine clearance 20-5 ml/min) of renal
function [103].
plasma concentration (ng / ml )

100
80
60
40
20
4.3 Metabolisation and excretion

Bisoprolol is removed from the plasma via two equally effective
routes of clearance half of the dose is metabolised to inactive
metabolites in the liver and the other half is excreted as the
unchanged substance via the kidneys.
0
0
24
48
72
96
120
144
168
192
Healthy volunteers (n = 8, t 1/2 = 10.0 h )

Patients with slightly impaired renal function (n = 6, t 1/2 = 16.2 h)
Patients with severely impaired renal function (n = 4, t 1/2 = 19.7 h)
22 Bisoprolol
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Fig. 4:
Mean plasma concentrations of bisoprolol following repeated oral

administration of 10 mg bisoprolol once daily healthy volunteers,
patients with cirrhosis of the liver and patients with cirrhosis of the
liver and ascites [103].
Fig. 5:
Metabolism of bisoprolol in the human organism [113].
plasma concentration (ng / ml)

100
CH3
CH3
80
Bisoprolol
50 % of dose
60
R
40
20
OH
24
48
72
96
120
144
168
192
Healthy volunteers (n = 8, t 1/2 = 10.0 h )

Patients with cirrhosis of the liver (n = 8, t 1/2 = 11.8 h)
Patients with cirrhosis of the liver and ascites (n = 5, t 1/2 = 15.3 h)
OH
COOH
OH
CH3
Metabolite M 4
weakly active
0
0
COOH
COOH
CH3
In the human organism, half of a bisoprolol dose is transformed

into three metabolites (M1, M2, M3 in Fig. 5), none of which have a
-blocking effect. The weakly active metabolite M4 could not be
detected in the human organism and presumably occurs only in
traces as a metabolic intermediate stage [45, 113].
An accumulation factor of 1.2 was observed with a single daily
dose of bisoprolol for one week [113]. Together with the maximum
first-pass effect of 10%, this means that with a single daily dose
the first-pass effect and accumulation counteract each other.
Therefore, during maintenance therapy the bodys stock of the drug
is at exactly the same level as the administered dose in each dose
interval. This applies to all the therapeutic dose levels on account
of the linearity of the kinetics.
Metabolite M 3
< 5 % of dose
inactive
Metabolite M 1
> 20 % of dose
inactive
% of dose recovered in urine
Metabolite M 2
< 5 % of dose
inactive
CH3
R =
O
OH
[ ] = probable metabolic intermediate stage
N
H
CH3
24 Bisoprolol
m 25
Fig. 6:
Differences of genetic origin in the metabolisation of drugs (limited

or extensive debrisoquine metabolism) are of no significance
for bisoprolol [113]. A slight difference has been observed in the
AUC and elimination half-life of bisoprolol enantiomers after
administration of the racemic drug in a study in four human subjects [94]. However, this difference is so small that it is unlikely
to be of any clinical significance [45, 94]. The kinetics of
bisoprolol are not dependent on age or sex [113,129], nor is the
biotransformation of bisoprolol accelerated even in patients
with hyperthyroidism [141].
Degree of metabolisation with 1-selective -blockers. Balanced

clearance and no active metabolites with bisoprolol [according to 45,113],
small proportions of active metabolites with betaxolol and metoprolol.
metabolisation of various - blockers (%)

100
4.4 Elimination half-life
50
Bisoprolol is removed from the plasma with a half-life of

10 -12 hours [113].
The plasma elimination half-life of bisoprolol was investigated
both in volunteers [113] and in younger (mean age 49, age range
26 - 63 years) and elderly hypertensive patients (age range
69 - 80 years) [129]. Under steady-state conditions the plasma elimination half-life was always in the range of 10-12 hours.
0
0
Atenolol
Bisoprolol
Betaxolol
Metoprolol
This means that bisoprolol may be administered once daily, and

this has a beneficial effect on the compliance of the patient.
Maximum plasma levels are reached 1-3 hours after administration (Fig. 7).
Balanced clearance
50 % unchanged
50 % metabolised
Excretion
approx. 95 % renal
2 % faecal
Metabolites
Unchanged substance
4.5 Interactions
The concomitant use of substances inducing the drug-metabolising enzymes in the liver shortens the half-life of bisoprolol to
only a negligible extent. The half-life of bisoprolol is shortened by
only 35% during simultaneous administration of rifampicin, a
potent liver enzyme inducer; as a rule, an adjustment of the dose is
not required [102]. This is particularly the case when enzyme
inducers weaker than rifampicin are administered simultaneously.
26 Bisoprolol
m 27
Cimetidine, a potent liver enzyme inhibitor, does not influence the

elimination half-life of bisoprolol [102]. Therefore, no interactions
between drugs inhibiting liver enzymes and bisoprolol need to be
expected. The pharmacokinetic properties of theophylline were not
affected by simultaneous therapy with bisoprolol [184]. Concurrent
treatment with bisoprolol and the anticoagulant warfarin had no
additional influence on the prothrombin time [184].
Simultaneous administration of bisoprolol and procainamide in
patients with ventricular tachyarrhythmia led to a therapeutically
desirable prolongation of the ventricular refractory period. Treatment of ventricular arrhythmia with a combination of bisoprolol
and procainamide proved to be well tolerated in this study [175].
Fig. 7:
Plasma concentration time-curve and accumulative renal and faecal excretion

after oral administration of 1 x 20 mg 14 C- bisoprolol ( x, SEM; n = 5 ) [45,113].
plasma concentration (ng /ml )

150
100
50
0
0
16
12
20
24
Total radioactivity
28
32
36
40
44
48 h
Unchanged bisoprolol
plasma concentration (ng /ml)

100
80
60
40
20
0
0
12
24
36
Total radioactivity in the urine

Unchanged bisoprolol in the urine
48
60
72 h
Total radioactivity
in the faeces
28 Bisoprolol
4.6 Variability of plasma concentration

The pharmacokinetics of bisoprolol are stable.
Bisoprolol exhibits a low inter- and intra-individual variability of
plasma levels on account of its high bioavailability and the
minimum sensitivity of its kinetics to disturbing factors, as also
shown in a study in 8 coronary patients [113, 114]. The plasma
concentrations measured 2 hours after administration of
10 mg or 20 mg bisoprolol were 49.0 5.07 ng /ml ( x SD)
and 100.9 11.3 ng / ml ( x SD). The inter-individual scatter of
plasma concentrations was remarkably low (coefficient of
variation 10.3% and 11.2%). As to be expected on the basis of
its linearity of kinetics, a doubling of the dose also led to a
doubling of plasma concentrations [114]. Moreover, even
above the therapeutic dosage range the kinetics of bisoprolol
are independent of the dose [113]. These characteristics
find expression in the therapeutic reliability of bisoprolol in the
indications angina pectoris and essential hypertension.
m 29
Clinical profile
-blockers are established drugs for the treatment of essential

hypertension and angina pectoris.
A beneficial effect in the prophylaxis of recurrent infarction has
been proved for -blockers.
Bisoprolol, a highly 1-selective -blocker, has a reliable
24-hour action in hypertension and angina pectoris when administered once daily. The success rates for both indications are
about 80%.
Recently, it has been established that some -blockers reduce
mortality and morbidity in patients with congestive heart failure
(CHF).
In ambulatory patients with New York Heart Association
Class III and IV CHF, bisoprolol reduced total mortality by 34%
and sudden death by 44%.
5.1 Clinical pharmacology

5.1.1 Haemodynamics
-blockers generally have a heart-rate reducing effect and
a negatively inotropic effect. With regard to patients with latent
cardiac insufficiency, the negatively inotropic active component
should be small so as to prevent as far as possible the cardiac
insufficiency from becoming manifest.
In haemodynamic studies bisoprolol showed only a small negatively inotropic effect.
The influence of 5 and 20 mg bisoprolol on the haemodynamics in
coronary patients was investigated 2 hours after oral administration,
using flow-directed catheters in the right ventricle and radionuclide
ventriculography [164]. After only 5 mg bisoprolol, there was
a distinct decrease in heart rate, rate-pressure product and cardiac
index both at rest and also during exercise. These haemodynamic
30 Bisoprolol
m 31
changes are oxygensparing mechanisms and desirable for the

coronary patient. The increase in peripheral arterial resistance following acute administration of -blockers without ISA is known and
must be regarded as a reflex phenomenon. The effects following
20 mg bisoprolol were quantitatively only slightly different from
those following 5 mg (Fig. 8) [164].
Neither of the two dosages of bisoprolol tested had a significant
effect on the ejection fraction (EF) or pulmonary capillary
pressure (PCP) either at rest or during ergometric exercise (Fig. 9).
Fig. 9:
Changes in the left ventricular ejection fraction (EF) and pulmonary

capillary pressure (PCP) before and 2 hours after oral administration of
5 and 20 mg bisoprolol to coronary patients ( x, SEM)[164].
EF (%)
before
bisoprolol
2 h after
bisoprolol
before
bisoprolol
2 h after
bisoprolol
before
bisoprolol
2 h after
bisoprolol
before
bisoprolol
2 h after
bisoprolol
60
50
40
Fig. 8:
Mean relative changes in heart rate (HR), rate-pressure product (RPP),

cardiac index (CI) and total peripheral resistance (TPR) at rest (R)
and during identical exercise (Ex). Measurements were carried out
before and 2 hours after oral administration of 5 mg (n = 6) and 20 mg
bisoprolol (n =10) to coronary patients (conditions at rest before
-blockade = 100%) [according to 164].
HR
(%)
RPP
Cl
PCP (mm Hg)

30
20
TPR
200
10
180
160
at rest
140
120
5 mg; n = 6
during exercise
20 mg; n = 10
100
80
60
40
20
0
R
Ex
Ex
Pretreatment value
R
5 mg
Ex
20 mg
Ex
In another study even the very high dose of 40 mg bisoprolol, which

is not used in therapy, led to only a slight rise in pulmonary
capillary pressure during ergometric exercise. Even this high dose
proved to be hemodynamically safe [33]. Thus bisoprolol shows
no negative inotropism of clinical relevance. Systolic time intervals
and echocardiographic data in hypertensive patients point in
the same direction [67].
32 Bisoprolol
m 33
5.1.2 Electrophysiology
5.1.3 1-selectivity
-blockers inhibit the electrophysiological effects of adrenergic

stimulation. The frequency of primary and secondary pacemaker
centres is reduced, AV conduction delayed and the refractory
period of the AV node prolonged.
-blockers with high 1 -selectivity have substantial clinical

advantages over non-selective agents [68, 69,70,71] in terms
of their respiratory, haemodynamic and metabolic effects. Most
of the desirable therapeutic actions of -blockers result from
blocking the 1-receptor. Avoiding the inhibition of 2-receptormediated actions helps to avoid undesirable side-effects on
lung function, peripheral circulation, serum lipids and carbohydrate metabolism.
The effect of bisoprolol on the electrophysiological parameters

corresponds to that of the known pattern of other -blockers.
The influence of bisoprolol on electrophysiological processes in
the heart was investigated in 10 patients with paroxysmal supraventricular tachycardia [53, 136]. Potentials from the right atrium
and ventricle, from the coronary sinus if necessary, His-bundle
potentials and a surface ECG were recorded before and after a
single i.v. dose of 10 mg bisoprolol. With bisoprolol there was
a significant reduction in the sinus frequency and an increase in
the sinus-node recovery time. The refractory parameters of the
AV node were prolonged (functional and effective refractory period,
advancement of Wenckebach point). As with other -blockers
as well, the refractory parameters on the atrial and ventricular
plane showed no clinically relevant change. A slight decrease in
the frequency-corrected QT-time suggests a potentially positive
antiarrhythmic effect in acute myocardial infarction (MI) [52].
In a further study 10 patients with an indication for electrophysiological examination (His-bundle ECG, programmed atrial
and ventricular stimulation) received 5 mg or 10 mg bisoprolol
intravenously. Bisoprolol significantly prolonged the cycle length,
sinus-node recovery time, AH interval, and the functional and
effective refractory period of the AV node. The effects of 10 mg
bisoprolol were only slightly more intense than those of 5 mg
bisoprolol [150].
5.1.4 Receptor occupancy

The respective degree of 1- and 2-receptor occupancy can
be determined by using the serum of volunteers /patients treated
with -blockers in a 1 - and 2 -adrenoceptor-specific test. The
relevance of these ex vivo/in vitro data is shown by the direct
correlation between the percentage occupancy of 1-receptors
and the reduction of exercise -induced tachycardia [189].
Plasma concentrations of bisoprolol occurring after administration of 5 mg or 10 mg bisoprolol did not lead to 2- receptor
blockade in this ex vivo /in vitro model [189].
In a double-blind, placebo-controlled study groups of 6 volunteers
received single oral doses of, among other things, 200 mg
atenolol and 100 mg bisoprolol, respectively; thus the doses by far
exceeded therapeutic daily doses. In the course of 72 hours the
percentage of 1- and 2-receptor blockade was determined in an
ex vivo /in vitro assay.
Under 200 mg atenolol there was a maximum occupancy of
80% of 1-receptors and of 25% of 2-receptors whilst under
bisoprolol there was no occupancy of 2-receptors if occupancy of 1-receptors was 80%. This demonstrates the higher
1-selectivity of bisoprolol. About 30 hours after 100 mg bisoprolol,
plasma concentrations are corresponding to those following
34 Bisoprolol
m 35
10 mg bisoprolol [187]. In the 24- hour dosage interval the

1-receptor occupancy by bisoprolol lies in the range of approx.
80 -30% for the dose range of 5 -10 mg (Fig.10).
Fig. 10:
5.1.5 Lung function

Bisoprolol is a 1-selective -blocker with no clinically relevant
affinity to the bronchial 2-receptors not even when plasma
levels are at their peak.
Heart rate -receptor occupancy and plasma concentrations over

72 hours after a single dose of 100 mg bisoprolol (left) and 200 mg
atenolol (right). Shaded area: values observed in the dosage interval
of 24 hours after administration of 10 mg bisoprolol and 100 mg
atenolol [modified according to 188 ].
HR (beats /min)
As the dilatation of the bronchial muscles is mainly induced via

2-receptors, non 1-selective -blockade entails a risk for
patients accordingly predisposed (asthma, chronic obstructive
bronchitis). The pathologically increased airway resistance in
these patients can be increased further and the forced expiratory
volume in one second (FEV1 ), can be reduced further. The risk
of bronchoconstriction decreases with increasing 1-selectivity.
HR ( beats /min)
130
130
120
120
110
110
100
100
90
90
0
24
48
72
24
48
72
receptor
occupancy (%)
receptor
occupancy (%)
100
100
1
75
50
75
50
25
25
0
0
24
48
72
1000
1000
24
48
72
100
100
10
10
0
0
24
48
Bisoprolol
72
24
48
Atenolol
72
The effect of bisoprolol on lung function was investigated in

4 controlled single-dose studies. A slight increase in the airway
resistance and a slight decrease in the FEV1 was measured in
patients with chronic obstructive bronchitis only after doses of
30 and 40 mg bisoprolol, i.e. at doses outside the therapeutic range
which already reduce the heart rate to an unduly large extent [65].
The entire therapeutic dose range of 2.5 -20 mg bisoprolol proved
to be 1-selective. This was also the case when plasma levels
were at their peak.
The influence of single doses of placebo, 100 mg atenolol and
20 mg bisoprolol on the airway resistance was investigated in
coronary patients suffering concomitantly from chronic obstructive
bronchitis [63]. Although the reduction in heart rate was in
some cases more pronounced with bisoprolol than with atenolol,
the airway resistance remained unchanged with bisoprolol as
with placebo (Fig. 11). In contrast to this, with atenolol there was
a slight increase in the airway resistance.
In a study carried out in the cross-over design, 40 angina-pectoris
patients with chronic obstructive lung disease (COLD) were treated
with 50 mg atenolol or 5 mg bisoprolol over 6 months. The two
substances were equally effective in the therapy of angina pectoris
and affected lung function (AWR, FEV1) only to a slight extent.
36 Bisoprolol
m 37
Fig. 11:
Course of the airway resistance (AWR) and heart rate (HR) before (b)
and after single oral administration of placebo, 20 mg bisoprolol and
100 mg atenolol to 12 coronary patients suffering concomitantly from
chronic obstructive bronchitis ( x ; SEM; n = 12, cross-over design) [63].
Fig. 12:
Differences in the airway resistance ( AWR) in hypertensive patients

with bronchial asthma 2 hours after administration of single doses of
placebo, 10 and 20 mg bisoprolol and 100 mg atenolol compared to
the initial value ( x, SEM, cross-over design; n = 12) [49].
AWR (cm H2O/l /s)
AWR (cm H2O/l/s)
1.6
1.2
8
0.8
7
0.4
HR (beats/min)
90
0.4
70
0.8
50
b
4
Placebo
24
Bisoprolol
24
Atenolol
No clinically relevant deterioration of the lung function was

observed. In the presence of COLD, however, in particular seasonal
fluctuations in lung function became evident [64].
In a randomised 4-fold cross-over single-dose study in 12 hypertensive patients suffering concomitantly from bronchial
asthma, there was a significant increase in the airway resistance
with 100 mg atenolol as compared with placebo, whereas
after 10 and 20 mg bisoprolol no changes were measured as
compared with placebo (Fig. 12). As opposed to 100 mg atenolol,
1-selectivity was maintained at 10 and 20 mg bisoprolol.
The effects on the cardiovascular parameters were, however,
comparable with both 1-blockers [49].
24 h
Placebo
Bisoprolol
10 mg
Bisoprolol
20 mg
Atenolol
100 mg
In a further study in 10 hypertensives with chronic obstructive airway disease, bisoprolol proved to be more 1-selective by a factor
of 2 than the reference substances atenolol and metoprolol [122].
In healthy volunteers the bronchodilatory effect of the -mimetic
isoprenaline was not inhibited by bisoprolol even at a dosage of
40 mg [165]. In asthmatic patients bisoprolol had no influence on
the bronchodilatory effect of the 2-agonist terbutaline [108].
In both studies bisoprolol proved to be a 1-selective -blocker.
In contrast to 400 mg acebutolol (1-receptor blocker with ISA),
10 mg bisoprolol had no influence on the bronchodilatory effect of
the 2 -agonist salbutamol (Fig. 13) in patients with mild obstructive disorders of lung function [123].
38 Bisoprolol
m 39
Fig. 13:
Dose-response curve. The patients inhaled salbutamol 3 hours after

administration of placebo, 10 mg bisoprolol or 400 mg acebutolol.
The graph shows the mean increase in the specific airway conductance ( sGaw) at various salbutamol doses ( x SEM) [123].
sGaw (kPa 1 s 1 )
0.8
Bisoprolol
0.6
NS
Placebo
0.4
**
Acebutolol
0.2
0
0
100
* p < 0.05
200
400
800 inhaled salbutamol

dose (g)
** p < 0.01
5.1.6 Peripheral circulation

The effect of -blockers on the increase in blood flow induced
by isoprenaline or the decrease in diastolic blood pressure
caused by the substance can serve as a measure of 1-selectivity.
In the case of non-selective -blockers, these effects of
isoprenaline are considerably reduced and to achieve the same
effects much higher doses of isoprenaline are required. An
impairment of the peripheral circulation is manifested by undesirable side-effects, such as cold extremities, tingling and a
feeling of heaviness in the legs. These side-effects are rare in
the case of bisoprolol and if they occur, are attributable to
a reduction in cardiac output.
Isoprenaline dose-response curves were determined for the
decrease in diastolic blood pressure before and after i. v. administration of bisoprolol and metoprolol (1-selective -blocker),
acebutolol (1-selective -blocker with ISA) and the non-selective

-blockers penbutolol (with ISA) and propranolol in 16 healthy
volunteers [107]. The selected dosages of the -blockers reduced
the heart rate during exercise to an equal extent in a preliminary
trial. A slighter shift to the right of the isoprenaline dose-response
curves under -blockade signifies higher 1-selectivity. This can
be seen for bisoprolol, metoprolol and acebutolol in Fig.14.
The influence of a single oral dose of 20 mg bisoprolol and 100 mg
atenolol on the forearm circulation was investigated in 8 healthy
volunteers after short intra-arterial infusion of isoprenaline and
adrenaline [48]. The isoprenaline doseresponse curves were shifted
only slightly to the right as an expression of the 1-selectivity of
both -blockers. The reduction in the adrenaline-induced vasodilatation was statistically significant (p < 0.05) only after atenolol
but not after 20 mg bisoprolol [47, 48].
Flow measurements in the brachial and femoral arteries by
Doppler ultrasonic scanning in 9 volunteers revealed an increase in
vascular resistance after 40 mg propranolol whereas the vascular
resistance was uninfluenced by 10 mg bisoprolol [28].
Pulsed Doppler flowmetry and pulse wave velocity in 14 hypertensive patients in a double-blind cross-over study with bisoprolol
(10 mg /day) confirmed the following results: no significant
changes occurred in diameter, blood flow or vascular resistance of
the carotid and brachial circulations after bisoprolol. Pulse wave
velocity significantly decreased whilst the brachial artery compliance significantly increased. This indicates that the antihypertensive effect of 1-blockade is associated with an improvement in
the viscoelastic properties of the brachial artery wall [27].
40 Bisoprolol
m 41
Fig. 14:
Isoprenaline-(I-) induced decrease in the diastolic blood pressure (DBP)

before and 30 minutes after i.v. administration of placebo and various
-blockers to healthy volunteers ( x, n =16) [107].
DBP (mm Hg)
DBP (mm Hg)

80
Placebo
(saline)
80
60
60
40
40
20
20
0.25
80
16
64 g I
Metoprolol
(0.2 mg/kg)
40
40
20
20
16
64 g I
80
60
60
40
40
Propranolol
(0.2 mg/kg)
0.25
16
64 g I
Before administration
of placebo or the -blocker
16
64 g I
Acebutolol
(0.8 mg /kg)
The lipid metabolism can be adversely affected by -blocker

therapy, in particular with non-1-selective -blockers [14]. There
is an increase in total cholesterol or LDL-cholesterol (atherogenic
risk factor) and a decrease in HDL-cholesterol (atherogenic
protective factor).
In a thirteen-months study hypertensive patients were treated with

the individual optimal dose of bisoprolol. Neither total cholesterol
nor HDL- or LDL- cholesterol were changed to any significant or relevant extent [72, 73].
The serum cholesterol and serum triglycerides were measured in a
placebo-controlled double-blind cross-over study in hypertensive
patients with type II diabetes [95]. In comparison with placebo there
were no significant changes in these lipid parameters with
10 mg bisoprolol.
0.25
80
20
80
60
Serum lipids.
Bisoprolol generally induces no change in the cholesterol

fractions, including the cardioprotective HDL-cholesterol, in longterm therapy.
0.25
60
0.25
Bisoprolol
(0.07 mg /kg)
5.1.7 Metabolism
16
64 g I
Penbutolol
(0.04 mg /kg)
20
0.25
16
64 g I
30 min after administration

of placebo or the -blocker
In an open multicentre study in 2,012 outpatients, the lipids

were not affected by 5 and 10 mg bisoprolol/day administered for
a period of 8 weeks [91].
Prior to start
of therapy
After 8 weeks
of therapy
Total cholesterol
(mg /dl)
237 47
232 42
Triglycerides
(mg /dl)
174 75
171 64
Results from open long-term studies with bisoprolol treatment for

up to 12 months showed no changes in the lipid parameters [148].
42 Bisoprolol
m 43
In a randomised comparative study, 129 hypertensives received

propranolol (160 mg /day), atenolol (100 mg /day), mepindolol
(10 mg /day) or bisoprolol (10 mg /day) for 36 months following a
one-month placebo phase. Bisoprolol affected the triglycerides less
than propranolol or atenolol and during 36 months of therapy had
not led to any statistically significant change in HDL-cholesterol
(Fig.15). Total cholesterol and LDL-cholesterol were not affected
either. This confirms the hypothesis that a higher 1-selectivity is
associated with a lesser effect on plasma lipids [69, 68].
Also in studies measuring lipolysis after 2-stimulation with
terbutaline, the lack of influence of bisoprolol on free fatty acids
again proved its high 1-selectivity. At doses of 5 mg virtually
no 2-blocking activity could be measured for bisoprolol. Atenolol
did show an effect in either dosage (50 and 100 mg).
Fig. 15:
Percentage change in HDL-cholesterol after 36 months of therapy

with propranolol (P), atenolol (A), bisoprolol (B) or mepindolol (M) [68].
% HDL-cholesterol
These results could be confirmed even over 5 years. 41 patients

with essential hypertension were treated with bisoprolol in daily
doses up to 40 mg. No significant changes of the various lipid
fractions were reported, which again reflects the high 1-selectivity
of bisoprolol (Tab. 3) [74].
Tab. 3:
Changes in mean (SEM) triglycerides, total cholesterol, HDL-cholesterol,

and calculated LDL-cholesterol throughout the study (0-5 years) [74].
Start
1 year
2 years 3 years 4 years 5 years
Total cholesterol
(mmol/l)
5.98
(1.16)
6.14
(1.11)
6.21
(1.10)
5.98
(0.98)
6.23
(0.78)
6.15
(0.68)
Triglycerides
(mmol/l)
1.29
(0.69)
1.57
(0.57)
1.64
(0.60)
1.71
(0.62)
1.75
(0.62)
1.53
(0.42)
HDL-cholesterol
(mmol/l)
1.45
(0.46)
1.53
(0.52)
1.66
(0.54)
1.54
(0.52)
1.60
(0.61)
1.58
(0.49)
LDL-cholesterol
(mmol/l)
3.87
(1.14)
3.87
(1.03)
3.85
(1.06)
3.57
(0.90)
3.95
(0.86)
3.87
(0.74)
+10
M
B
0
10
20
**
**
**
**
P
A
**
**
30
**
**
**
12
18
**
40
6
24
30
A further 18-month double-blind randomised study in 152 hypertensive patients [70], studied the effects on plasma lipids of bisoprolol
10 mg /day, atenolol 100 mg /day, propranolol 160 mg /day and
celiprolol 400 mg /day. Bisoprolol did not significantly change total
cholesterol, LDL-cholesterol, HDL-cholesterol or triglycerides. The
non-selective agent propranolol had negative effects on HDL-cholesterol and triglycerides; the selective agent atenolol also negatively
affected HDL-cholesterol and triglycerides, though to a lesser extent.
36 months
Carbohydrate metabolism.
Mepindolol
Bisoprolol
Atenolol
Propranolol
* p < 0.05 vs. baseline

** p < 0.01 vs. baseline
Owing to its high 1-selectivity, bisoprolol generally has no

influence on the carbohydrate metabolism. In hypertensive
patients with type II diabetes requiring treatment, no additional
44 Bisoprolol
m 45
monitoring is necessary during therapy with bisoprolol and

no adjustment is usually necessary in the dosage of oral antidiabetic preparations.
In an acute study, healthy volunteers received insulin 3 hours after
the oral administration of various -blockers. The metabolic
reactions with 10 mg bisoprolol did not differ from those with
placebo, in particular the duration of the hypoglycaemic phase was
not prolonged and there was no change in the course of serum
lactate concentration as compared with the control [112]. This must
be considered as a consequence of the high 1-selectivity of
bisoprolol (Fig.16).
Fig. 16:
Serum concentrations of glucose and lactate for 2 hours after 0.1 I.U.
insulin /kg body weight i.v., 3 hours after the oral administration of
3 different -blockers and placebo [112].
20 hypertensives with type II diabetes, 18 of whom were receiving

sulphonylurea therapy, were treated with 10 mg bisoprolol /day
for 14 days in a placebo-controlled study. The blood glucose was
not influenced by either 10 mg bisoprolol or placebo. Adjustment of
the sulphonylurea therapy was not necessary with bisoprolol
[95, 96] (Fig.17).
Further studies measuring metabolic parameters in volunteers
confirmed the high 1-selectivity of bisoprolol. Hypokalaemia and
hyperglycaemia were stimulated by terbutaline, a 2-stimulating
Fig. 17:
Mean values of glucose and HbA1 in 20 or 18 hypertensive

patients with type II diabetes mellitus (fasting values, x, SEM;
cross-over design) [95].
glucose (mg /dl)
HbA 1 (%)
170
10
glucose (mmol /l)

5
160
4
9
150
2
140
0
0
30
45
60
90
120 min.
130
lactate (mmol /l)
120
1.7
1.5
110
1.3
1.1
100
0.9
0
0.7
0
30
45
Bisoprolol 10 mg
Metoprolol 50 mg
60
90
Propranolol 40 mg
Control
120 min.
0
A
C
B
( pC-B > 0.05)
A initial value
B after 2 weeks
with bisoprolol
C
B
( pC-B > 0.05)
C after 2 weeks
with placebo
46 Bisoprolol
m 47
substance. All agents lowered the exercise heart rate significantly

compared to placebo (p < 0.05). Bisoprolol 5 mg and 10 mg
influenced the potassium concentration and the glucose concentration less than atenolol 50 mg and 100 mg, thus proving the
higher 1-selectivity of bisoprolol. The effect of bisoprolol 5 mg
on glucose and potassium concentration was significantly less
(p < 0.05) than that of both doses of atenolol and the two other
bisoprolol doses (10 mg and 20 mg) and not significantly different
to placebo. The order of 1-selectivity was judged to be:
bisoprolol 5 mg > bisoprolol 10 mg > atenolol 50 mg > bisoprolol
20 mg > atenolol 100 mg [83].
In a crossover study in 12 hypertensive patients with untreated
type II diabetes mellitus [180], patients received bisoprolol
10 mg / day or atenolol 100 mg /day for 4 weeks, with a 4-week
washout period between the active treatments. Neither drug had
any significant effect on glucose or insulin responses to intravenous
glucose tolerance testing, nor caused any significant increase in
glucosuria. A study in 44 postinfarction patients with type IIa
diabetes mellitus [99] found that bisoprolol had no clinically significant negative effect on glucose metabolism during endurance
and maximal exercise.
In a study which included 21 elderly and 60 non- elderly hypertensives [84], bisoprolol (5 -10 mg /day for 12 weeks) had no significant effect on the response of plasma glucose and insulin to 75 mg
oral glucose in either age group. This demonstrates the lack of
adverse effects of bisoprolol on carbohydrate metabolism in elderly
as well as in younger patients.
Insulin sensitivity.
-blockers are speculated to have a negative impact on certain
parameters of glycemic control such as insulin resistance.
This is an adaptive physiological phenomenon, when the cellular
requirement for glucose is jeopardised in conditions of low
glucose availability or high demand (such as fasting, starving,

stress or hypoglycemia). As it is impossible to measure insulin
resistance, most tests measure overall glucose uptake as an
index of insulin sensitivity. With bisoprolol such tests were
performed, showing no negative effects on insulin sensitivity.
In a double-blind cross-over study 22 healthy volunteers were
treated with either bisoprolol (5 mg /day for 4 weeks) or the ACEinhibitor lisinopril (5 mg /day for 4 weeks). The insulin sensitivity
was evaluated by the glucose infusion rate and the serum insulin
concentration (glucose clamp). The ratios before and after
treatment did not show any changes in either treatment groups:
The insulin sensitivity index after intake of the ACE-inhibitor
amounted to 7.9 2.4 (basic index 8.3 1.9) and after treatment
with bisoprolol 7.5 2.1 (basic index 8.2 1.9). It may be concluded that, when given in doses sufficient to significantly lower
the blood pressure, neither bisoprolol nor the ACE- inhibitor
exhibits any influence on the insulin sensitivity in normotensive
healthy volunteers [89].
In a double -blind parallel-group study in 12 patients with mild-tomoderate essential hypertension [62], patients received bisoprolol
5 mg /day or the ACE-inhibitor captopril 25 mg b.i.d. for 8 weeks.
Specific insulin binding was not affected by either agent.
Erythrocyte insulin binding and insulin-stimulated tyrosine kinase
(TK) activity were measured before and after therapy. Fasting
plasma glucose, insulin and insulin /glucose indices remained
unchanged after both treatments. Maximal insulin-stimulated TK
activity was significantly higher (p < 0.05) after bisoprolol
treatment, but not after captopril treatment. Captopril, but not
bisoprolol, increased the sensitivity of the receptor TK activity, as
measured by the half-maximal activity concentration. Thus, captopril apparently increased the sensitivity of the insulin receptor,
whereas bisoprolol increased its maximal activity. The authors of
this study suggest that, far from having negative effects on insulin
sensitivity, bisoprolol might have potential beneficial effects in
some insulin resistance conditions [101].
48 Bisoprolol
m 49
5.1.8 2-receptor density

Bisoprolol proved to be a highly 1-selective substance with no
effect on 2-receptors in the human lymphocyte model.
2-Agonists and -blockers with ISA can reduce the density of the
2-receptors on human lymphocytes whereas non-2-selective
-blockers without ISA increase the density of the 2-receptors [38].
Bisoprolol does not influence the density of the 2-receptors on
human lymphocytes [36, 38]. This property distinguishes bisoprolol
from, on the one hand, propranolol which increases the density
of the 2-receptors in this model in the sense of counter-regulation and, on the other hand, from pindolol (-blocker with ISA),
which reduces the density of the 2-receptors (Fig. 18). In a similar
model atenolol increased the density of the 2-receptors on
leucocytes [16].
Fig. 18:
Course of the 2-receptor density measured as binding sites per cell for
iodocyanopindolol [()-ICYP], on lymphocytes volunteers before, during, and
after the administration of bisoprolol, propranolol and pindolol ( x) [38].
( )-ICYP-binding sites per cell

1200
1000
800
600
400
0
5.1.9 Plasma renin activity

Bisoprolol reduces the basal and stimulated renin activity. The
renin released from the cells of the juxtaglomerular apparatus
of the kidney influences the initiation of a reaction chain (reninangiotensin-aldosterone system) which leads to the formation
of the vasoconstrictor angiotensin II. Renin release is stimulated
via 1-receptors and can be inhibited by -blockade.
A single dose of bisoprolol led to a marked reduction in both the
basal and stimulated plasma renin activity [38, 77, 107]. Unlike
-blockers with ISA, the renin-reducing effect of bisoprolol was
maintained even 7 days of administration [38]. Therefore bisoprolol
inhibits the renin-angiotensin system and consequently reduces
the blood-pressure increasing effects of this regulatory system.
10
12
days
Bisoprolol 1x10 mg/d

Propranolol 4 x 40 mg/d
Pindolol 2x 5 mg/d
A population-based observational study in 728 middle -aged

subjects (treated and untreated ) [9] found that monotherapy with
a -blocker decreased mean renin concentrations compared
with untreated individuals. In contrast, treatment with an ACEinhibitor and /or diuretic increased it. However, renin concentrations
in individuals receiving a -blocker with an ACE-inhibitor or a
diuretic, or both, were significantly lower than in patients not
receiving -blocker treatment. These data suggest that the upregulation of renin by treatment with ACE-inhibitors, diuretics or both
can be largely prevented by concomitant -blocker treatment.
-blockade appears to have a sufficiently large effect to completely
prevent the threefold renin reduction observed in patients who
receive the combination of ACE-inhibitors and diuretics.
50 Bisoprolol
m 51
5.1.10 Fibrinolytic system

Sympathetic activity and key components of the fibrinolytic system
show circadian variability, which may help to explain for the wellknown circadian variability in acute MI. Peak activity of plasminogen
activator inhibitor-1 (PAI-1) and trough activity of tissue plasminogen
activator (tPA) combine to produce a relatively prothrombotic state
in the morning, coinciding with the greatest risk of coronary occlusion. Circadian variation in fibrinolytic activity may be related to
activation of the renin-angiotensin system. The circadian rhythm of
MI is attenuated in patients taking -blockers, and it has been suggested that this effect may be due to effects on circadian variation
in sympathetic activity and /or the fibrinolytic system.
Support for this theory is provided by a study in 20 patients with
stable coronary artery disease [153], who were treated consecutively
for 4 weeks with placebo, 4 weeks with bisoprolol (10 mg /day,
in-creased to 20 mg /day if the resting heart rate remained > 60 beats
per minute), and 4 weeks with the ACE-inhibitor quinapril
(10 mg /day, increased to 20 mg /day if the resting heart rate remained
> 60 beats per minute). At the end of each 4-week treatment
period, 24 -hour ambulatory Holter monitoring and 6-hourly blood
sampling was performed.
Bisoprolol was found to significantly increase many of the
nonspectral measures heart rate variability, while quinapril had no
effect. Bisoprolol also tended to reduce the morning peak in
PAI -1 activity and antigen, with a small increase in t PA activity.
Although these differences failed to reach statistical significance
after correction for multiple comparisons, a clear trend was visible
over the 24-hour monitoring period. In contrast, no effect on
circadian variation in fibrinolytic parameters was observed with
quinapril. Quinapril did, however, produce a substantial rise in
plasma renin, which was not seen with bisoprolol.
These data are consistent with the hypothesis that -blockade
with bisoprolol tends to reduce the relatively prothrombotic state
that occurs in the early morning, and concomitantly reduces
sympathetic activation with potentially beneficial hemodynamic

consequences. These effects may help to account for the protective
effects of -blockers against MI, particularly in the early morning
when the risk of infarction is greatest.
5.1.11 Dose-response relationship

Bisoprolol exhibits a close dose-response relationship. This favours
simple dosage and reliable therapy.
The relationship between the -blocking effect (as a reduction in
exercise -induced tachycardia) and the plasma concentration
following 1x10 mg bisoprolol i.v. was investigated in a study in
10 healthy volunteers.The relationship between plasma concentration,
represented in a semilogarithmic scale, and the reduction in heart
rate during exercise proved to be linear in the recorded plasma
concentration range of 10 -50 ng /ml [112]. Due to the high absolute
bioavailability of bisoprolol from film-coated tablets (88%), i.v.
and oral administration lead to comparable plasma concentrations.
Therefore, a therapeutic concentration range of 10 -50 ng /ml
plasma may be given for 10 mg bisoprolol.
Bisoprolol is a 1-selective -blocker with high potency, thus
requiring a low foreign substance intake per day.
The reduction in exercise-induced tachycardia in healthy volunteers
served to assess the potency of bisoprolol in direct comparison
with other -blockers. On a molar basis, bisoprolol was 10 times
as effective as metoprolol, 5 times as effective as propranolol and
7 times as effective as atenolol [112]. Clinical studies revealed
a dose ratio of 1:10 between bisoprolol and atenolol [121, 126] as
well as between bisoprolol and metoprolol [82].
As bisoprolol is therapeutically effective in most cases at a single
daily dosage of 1 x 5 mg or 1 x 1 mg in the indications hypertension and angina pectoris, this results in a low intake of foreign
substance per day.
52 Bisoprolol
m 53
Treatment of essential hypertension
Systematic treatment of essential hypertension reduces cardiovascular morbidity and mortality [10]. Essential hypertension
is not usually associated with pronounced clinical symptoms.
Therefore, patients do not always take their medication on
a regular basis. Single daily administration and a treatment with
few side-effects favour patient compliance.
With one daily dose bisoprolol has a reliable 24-hour effect
on the blood pressure at rest and during exercise. The 24-hour
effect is ascribable in particular to the favourable
elimination half-life.
Fig. 19:
Reduction of supine systolic blood pressure ( SBP), diastolic blood

pressure ( DBP), and heart rate ( HR) compared to baseline after
28, 56 and 84 days of treatment with daily doses of 5 mg, 10 mg and
20 mg bisoprolol as well as 7 days after withdrawal ( bisoprolol
replaced by placebo) ( x, SEM, n = 15 /group) [104].
SBP
(mm Hg)
Bisoprolol
28
56
Placebo
84
91
days
91
days
91
days
10
20
6.1 Blood pressure at rest duration of action

As a single daily dose, bisoprolol normalised the blood pressure
for 24 hours.
In two randomised double-blind studies it could be shown that in a
dosage range of 5-20 mg once daily bisoprolol reduces the blood
pressure almost in proportion to the dose in patients with essential
hypertension (initial diastolic blood pressure 95 -120 mm Hg )
[104,185,186]. In the first study the reduction in blood pressure
and heart rate in comparison to the initial status was determined
24 hours after the last single oral dose of 8 weeks of treatment
[185,186]. A comparable dose-proportional reduction in these
parameters, measured approx. 24 hours after the last dose of bisoprolol in each case, was achieved in a second study (15 patients
per dose group ) during 12 weeks of treatment with bisoprolol
(Fig. 19) [104].
Further studies confirmed the dose-dependent efficacy of 5 to
20 mg bisoprolol in patients with mild to moderate hypertension
[32, 55].
In the course of a 7- day placebo phase after withdrawal of
bisoprolol there was a slow re-increase in blood pressure and
heart rate [104].
30
40
DBP
(mm Hg)
0
Bisoprolol
28
56
Placebo
84
10
20
30
HR
(beats/min)
Bisoprolol
28
56
Placebo
84
10
20
5 mg
10 mg
20 mg Bisoprolol
54 Bisoprolol
m 55
24-hour profiles of systolic blood pressure (SBP), diastolic blood

pressure (DBP), and heart rate (HR), determined by ambulatory, automatic recordings, at the end of the placebo pretreatment phase as well
as between hours 25 and 48 after withdrawal of bisoprolol following
4 weeks of therapy with 10 mg bisoprolol /day ( x, SEM; n = 11) [26].
blood pressure (mm Hg)

150
SBP
130
**
110
Hourly mean values of systolic blood pressure (SBP) and diastolic

blood pressure (DBP) on the last day under placebo and after
4 weeks of treatment with 10 mg bisoprolol [100].
**
*
**
70
160
140
SBP
**
***
***
***
***
***
***
***
***
***
***
**
***
* **
*
**
* **
180
**
90
mm Hg
50
12
10
120
14
18
16
20
22
24
DBP
** *
Fig. 20:
Fig. 21:
**
***
***
***
***
***
***
***
***
***
**
The effective lowering of the blood pressure over 24 hours after

a single dose of bisoprolol was confirmed in a further study [100].
In 8 patients with mild to moderate hypertension, continuous
ambulatory 24-hour measurements of blood pressure were carried
out during treatment with 10 mg bisoprolol. The circadian rhythm
was maintained while the blood pressure was effectively lowered for 24 hours; the blood pressure values were lowered more
strongly during the active day phase than in the resting phase at
night (Fig. 20). Similar results were achieved with 5 mg bisoprolol
after a treatment period of 2 weeks [134].
HR (beats/min)
100
DBP
80
100
90
11
13
15
last day under placebo

after 4 weeks with 10 mg bisoprolol
17
19
21
23
80
70
60
**
** *
**
***
***
* **
*
**
**
**
**
* **
**
60
50
12
9 10
14
18
16
20
22
24
time of day
24
26
28
30
32
34
36
after placebo
after 4 weeks of bisoprolol
38
40
42
44
* p < 0.05
** p < 0.01
*** p < 0.001
46
48 h
hours after
withdrawal of
bisoprolol
56 Bisoprolol
m 57
Ambulatory, automatically recorded 24-hour measurements were

made of blood pressure and heart rate in 11 hypertensive
patients [26]. 24-hour profiles of blood pressure and heart rate
were recorded at the end of the placebo pretreatment phase as
well as 24 hours after completion of 4 weeks of therapy with
10 mg bisoprolol /day (hours 25 to 48). Statistically significant
reductions in blood pressure and heart rate in comparison with the
initial status were observed up to 40 hours after withdrawal of
bisoprolol. No rebound occurred up to the end of the observation
period (Fig. 21) [26].
In open clinical studies with bisoprolol the full 24-hour effect
could be documented, related to a normalisation of the diastolic
blood pressure to 90 mm Hg or below [29, 87,120,148].
6.2 Blood pressure during exercise duration of action

Bisoprolol controls exercise-induced blood pressure peaks over
24 hours. The blood pressure peaks which occur under everyday
conditions and which may eventually result in cardiovascular
complications, are avoided.
In previously mentioned double-blind comparative studies the
effect of 5 mg, 10 mg and 20 mg bisoprolol on blood pressure was
investigated in hypertensives under standardised ergometric
conditions. Bisoprolol was administered as a single daily dose over
8 and 12 weeks [104, 185]. After already 4 weeks of treatment
with only 5 mg bisoprolol, the blood pressure and heart rate during
exercise were markedly reduced 24 hours after the last dose.
87 hypertensives were treated once daily with 10 mg bisoprolol
(n = 44) or 100 mg metoprolol (n = 43) in a double-blind randomised study (BISOMET study) [82]. Standardised ergometry was
performed before and at the end of 4 weeks of treatment, in
each case 3 and 24 hours after the last dose (50, 75, 100 watts,
2 minutes per workload).
Tab. 4:
Residual 24-hour effects of bisoprolol (B) and metoprolol (M)

(as a percentage of the 3-hour effects) at a workload of 100 watts
and calculated from the area between the 24-hour and 3-hour
curves (cf. Fig. 22) [82].
B
p-value
B vs. M
SBP
100 W
area
86
90
63
66
0.02
< 0.02
HR
100 W
area
90
93
53
54
0.001
0.001
RPP
100 W
area
89
92
58
60
< 0.01
< 0.001
24 hours after the last dose of bisoprolol the systolic bloodpressure during exercise at 100 watts was still reduced by 86% of the
maximal effect after 3 hours. After 24 hours metoprolol had only
a residual effect of 63% (p = 0.02) (cf. Tab. 4, Fig. 22). Furthermore,
with bisoprolol in contrast to metoprolol the effect on the heart
rate during exercise as well as the rate-pressure product was
almost fully retained after 24 hours in comparison to the 3-hour
value (cf. Tab. 4) [82].
170 patients underwent standardised ergometry 24 hours after the
last administration of bisoprolol at individual optimal doses. In
133 patients with normalised diastolic blood pressure at rest, the
blood pressure during exercise was also reduced to a clinically
relevant degree. The blood pressure during exercise was also considerably reduced in 37 patients whose diastolic blood pressure at
rest could not be reduced to 90 mm Hg or below (Non responders
in Fig. 23) [148].
58 Bisoprolol
m 59
6.3 Normalisation rate
Fig. 22:
When used as monotherapy for essential hypertension, bisoprolol resulted in successful treatment for over 80% of the
patients (normalisation of the diastolic blood pressure: reduction
to 90 mm Hg or below, even 24 hours after administration) [13].
The almost full 24 -hour effect was guaranteed with a single
dose per day even under conditions of stress.
In an open prospective multicentre study [91] the antihypertensive
effect of monotherapy with bisoprolol was investigated in 2,012
patients. Aim of the treatment was to lower the sitting diastolic
blood pressure to values below 95 mm Hg or by at least 10 mm Hg.
The patients were first treated with 5 mg bisoprolol for 4 weeks,
and if blood pressure lowering was inadequate at this dose,
with 10 mg bisoprolol for a further 4 weeks. Out of the 1,067 fully
evaluable cases, 75.9% reached the therapeutic goal under 5 mg
bisoprolol.
Increase of the dose to 10 mg bisoprolol in the nonresponders
resulted in a cumulative responder rate of 93.7%. The therapy
result was independent of the age of the patients treated
(Figs. 24, 25).
In the double-blind dose finding study already mentioned [186]
the responder rate was 60%. 24 hours after drug administration (defined as lowering of the diastolic blood pressure to
values 90 mm Hg) and 80% ( ^= lowering of the diastolic blood
pressure 95 mm Hg).
Effects of bisoprolol and metoprolol on systolic blood pressure (SBP),

and heart rate (HR) during and after ergometric exercise before (b) and
3 and 24 hours after the last dose of 4 weeks of therapy [( x SEM;
n = 44 ( bisoprolol ) and 43 (metoprolol)]. The dark shaded areas between
the exercise curves for 3 and 24 hours after administration are a
measure of the loss of effect after 24 hours. The smaller the area, the
greater the residual effect after 24 hours (cf. Tab. 4) [82].
SBP
(mm Hg)
210
HR
(beats/min)
Metoprolol
Metoprolol
120
190
170
150
24 h
3h
100
b
80
24 h
3h
60
210
Bisoprolol
Bisoprolol
120
190
b
170
150
24 h
3h
130
0
50
75
6 7 8 9 10 11 minutes
100 watts
100
b
80
24 h
3h
60
0
50
75
6 7 8 9 10 11 minutes
100 watts
60 Bisoprolol
m 61
Fig. 23:
Mean values (SEM) for the systolic (SBP) and diastolic blood pressure (DBP),
and heart rate (HR) at rest (A), at maximum ergometric exercise (B) and
in the 5th recovery minute (C), according to dose groups with individualised
doses before and after 6 weeks of treatment with bisoprolol [148].
Fig. 24:
Responder rates in the various age groups. No age dependence of the

responder rate is recognisable [90].
%
100
SBP
(mm Hg)
220
80
60
200
40
180
20
0
160
2130
week 4
140
DBP
(mm Hg)
120
51 60
6170
> 70
age
week 8
Two studies [42,75] prove the long-term efficacy of bisoprolol

as a well-tolerated monotherapy of arterial hypertension.
80
A
HR
(beats/min)
120
100
80
60
before start
6 wk
41 50
6.4 Long-term treatment of arterial hypertension

with bisoprolol
100
A rest
B max. exercise
C 5 min recovery
31 40
5 mg
10 mg
20 mg
nonresponders
n = 45
n = 41
n = 71
n = 70
n = 22
n = 22
n = 40
n = 37
Patients who had been successfully treated with bisoprolol already

for 1 year, were followed up for a further 1-2 years continuing
the dosage which had proved to be effective. 102 patients had been
adequately treated with a bisoprolol dose of 5 mg or 10 mg
(Fig. 26). An analogous distribution was found in a further bisoprolol study over 2 years [42]. Long-term treatment with bisoprolol
did not cause any changes in the laboratory parameters determined (e.g. blood glucose, total cholesterol, triglycerides).
62 Bisoprolol
m 63
Fig. 25:
Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart
rate (HR) prior to and during 8 weeks of therapy with bisoprolol
( x SD). Presented are values of patients who received 5 mg bisoprolol
from week 0 to 4 and 10 mg bisoprolol from week 4 to 8 (n = 332)
as well as of patients who were given 5 mg bisoprolol throughout the
entire study period (n = 835). For 34 patients no dosage data are
available from week 4 on [91].
Fig. 26:
Course of the systolic and diastolic blood pressure (SBP and DBP)
and of the heart rate (HR) during the 2nd and 3rd year of treatment
with bisoprolol [75].
mm Hg and
beats/min
180
mm Hg and
beats/min.
140
180
100
SBP
DBP
HR
60
160
SBP
140
0
n = 102
12
15
18
21
24
27
30
33
36 months
102
97
102
101
102
102
102
100
102
6.5 Regression of left ventricular hypertrophy
120
100
DBP
80
HR
60
0
4
5 mg bisoprolol from week 0 to 4 and
10 mg bisoprolol from week 4 to 8 (n = 332)
5 mg bisoprolol from week 0 to 8 (n = 835)
8 weeks
Myocardial hypertrophy and coronary microangiopathy are

the two cardiac organ manifestations of essential hypertension.
Bisoprolol has been demonstrated to bring about not only a
regression of left ventricular hypertrophy but also an improvement of coronary reserve.
In a randomised single-blind study over 6 months with 10 mg
bisoprolol vs. 20 mg enalapril echocardiography was performed in
addition to blood pressure measurements. The lowering effect on
blood pressure and the significant reduction of left ventricular
hypertrophy as proven by echocardiography were similar in both
treatment groups [79].
In a further long-term study (9 -18 months treatment) bisoprolol
increased both maximal coronary perfusion and coronary reserve by
22%. Left ventricular muscle mass decreased from 16118 to
146 21 g/m 2 [133]. These results were confirmed by a further
64 Bisoprolol
m 65
study in 27 patients with essential hypertension and left ventricular

hypertrophy. After 6 months a highly significant reduction of left
ventricular mass and left ventricular mass index was proven [61].
6.6 Quality of life

Quality of life has become a relevant measure of efficacy in
clinical studies. Information on this parameter can be obtained
by general health profiles or disease-specific measures. Quality
of life remains unchanged under treatment with bisoprolol.
Two studies were performed with bisoprolol in comparison to
ACE-inhibitors measuring the quality of life besides blood pressure
reduction.
One study was done in 24 elderly hypertensive patients (> 65 years)
with bisoprolol versus captopril. Parameters measured were
blood pressure, heart rate and the quality of life, expressed in
terms of psychophysical status in normal daily activities by a selfassessment questionnaire. Apart from a significant reduction of
blood pressure in both treatment groups no changes in quality of
life were seen. Bisoprolol also produced a marked but symptomfree reduction of heart rate compared with captopril [34].
In a double-blind cross-over study in 45 hypertensive patients
treated either with bisoprolol 5 -10 mg or enalapril 10 -20 mg for
4 -8 weeks, the quality of life was one of the target parameters.
Both agents led to a comparable blood pressure reduction, while the
heart rate was significantly more decreased with bisoprolol.
At the end of the study 31 patients reported to have felt better
during bisoprolol and 11 during enalapril treatment. The subjective
well-being scores as measured by the "Inventory of Subjective
Health were comparable in both treatment groups and there was
no significant difference compared to the baseline score. During
enalapril treatment more patients spontaneously mentioned
adverse effects compared to bisoprolol [35, 168].
Further studies have compared quality of life in patients receiving

bisoprolol with that in patients receiving calcium antagonists
or diuretics. In a double-blind, placebo-controlled study the antihypertensive efficacy and tolerability of a single dose of either 10 mg
bisoprolol (n =26) or 20 mg nitrendipine (n =27) was investigated,
also including sense of well-being parameters. After 4 weeks
of treatment bisoprolol was significantly more effective in the reduction of blood pressure than nitrendipine, which did not induce
a significant reduction in the ambulatory night-time recordings.
The sense of well-being scores improved significantly only with
bisoprolol. It decreased to 15.7 in the bisoprolol group (p < 0.05)
and to 17.8 in the nitrendipine group (not significant). (According
to the definition of this score for sense of well-being a decrease
means improvement) [132].
In a double-blind double-dummy crossover study in 82 hypertensive patients [57], patients received bisoprolol 5 mg once daily or
nifedipine retard 10 mg twice daily for 8 weeks. The treatments
were of equal antihypertensive efficacy. Compared with baseline,
there was no significant change in quality of life variables with
either drug. No significant differences were found between the treatments in quality of life variables such as the Health Status Index,
somatic symptoms, anxiety, depression, total psychiatric morbidity,
cognitive symptoms and hostility score. There were no significant
differences between the groups in the numbers of dropouts (2 on
bisoprolol and 3 on nifedipine retard) or the percentage of patients
reporting adverse events (21% for bisoprolol and 16% for nifedipine retard, p = 0.64).
A similar 8-week crossover study in 81 hypertensive patients [174]
compared bisoprolol, 5 mg daily, with the diuretic bendrofluazide,
2.5 mg daily. The treatments were equally effective. No significant
differences were found between the treatments in quality of life
variables such as the Health Status Index, somatic symptoms, anxiety,
depression, total psychiatric morbidity, cognitive symptoms and
hostility score. Compared with baseline, the Health Status Index
66 Bisoprolol
m 67
improved during bisoprolol treatment (p < 0.05). None of the other

quality of life variables changed in either group compared with
baseline. No patients dropped out on either treatment.
An 8-week, double-blind crossover study in 154 patients [173],
half of whom were aged over 60 years, compared bisoprolol
5 mg /day, bendrofluazide 2.5 mg /day and nifedipine retard 10 mg
twice daily. No significant difference was found in quality- of-life
variables between treatments, or between older and younger
patients.
A 24 -week double-blind study in elderly ( > 60 years ) hypertensive
patients [46] compared bisoprolol (5 mg daily) with nifedipine
retard (40 mg daily). To achieve the target diastolic pressure
of 90 mm Hg, the dose of bisoprolol or nifedipine retard could
be doubled (10 mg bisoprolol, 80 mg nifedipine retard) or
hydrochlorothiazide 25 mg added to the higher dose. In an intention-to-treat analysis, an excess of symptoms was observed in the
nifedipine group for oedema of the legs, nocturia, constipation,
racing heart and heart thumping. Fewer patients reported wheeze
in the nifedipine group. For quality of life, there were no statistically significant differences between the two groups after 8 weeks.
However, analysis of the last available assessment (usually at
24 weeks) showed significant (p < 0.05) improvements in tension /
anxiety, anger/hostility, vigour/activity, and confusion/ bewilderment, assessed by the Profile of Mood States in patients receiving
bisoprolol in comparison to those receiving nifedipine retard. The
Sickness Impact Profile and objective tests of cognitive function
showed no significant differences between the two groups. It was
therefore concluded that quality of life was well maintained on
both treatments with advantages for bisoprolol in certain areas.
6.7 Therapeutic comparison in hypertensive patients

In comparison with other antihypertensive agents bisoprolol
frequently proved to be more effective or better tolerated.
6.7.1 Bisoprolol and atenolol
Within the scope of a Europe- wide study in a randomised doubleblind cross- over design (Bisoprolol International Multicentre Study,
BIMS) the antihypertensive effect of bisoprolol was subjected to
intra-individual comparison with that of atenolol in hypertensives
(initial diastolic blood pressure 100 -120 mm Hg) [44]. The aim of
this study was the reduction of the diastolic blood pressure to
95 mm Hg or below, in each case 24 hours after administration of
the last dose. After a 4 -week placebo phase the patients received
for 8 weeks either bisoprolol or atenolol, once daily. After 2 weeks
of treatment the daily dose was increased to 20 mg (bisoprolol)
or 100 mg (atenolol) in the case of diastolic blood pressures
exceeding 95 mm Hg. An intermediate washout phase was followed by the same therapeutic regimen with the other respective
-blocker. Out of the 94 patients assessable for efficacy the number
of those exhibiting diastolic blood pressure of 95 mm Hg or below
after 8 weeks was higher under bisoprolol than under atenolol.
For bisoprolol there was a responder rate of 68% and for atenolol
one of 56%.
Amongst these responders 5 patients responded to atenolol but
not to bisoprolol, whilst 16 responded only to bisoprolol but not to
atenolol. This difference was statistically significant (p < 0.05) [44].
A large multicentre double-blind study in 659 patients again
proved that bisoprolol in doses of 10 -20 mg is more effective than
atenolol 50 -100 mg with regard to blood pressure reduction
and response rates. The side effect profile was comparable in both
treatment groups [137]. In the elderly patients (> 60 years),
68 Bisoprolol
m 69
despite a similar reduction in heart rate for both agents bisoprolol

produced significantly greater reductions in average 24-hour systolic
and diastolic blood pressure than showed atenolol (p < 0.005)
and a longer duration of action [138].
A further study carried out in the same design as the BIMS [116]
confirmed the stronger antihypertensive effect observed under
treatment with bisoprolol.
In another international multicentre double-blind study 249 hypertensives received 5 mg bisoprolol, 10 mg bisoprolol or 50 mg
atenolol, respectively, as a single daily dose [121]. In all treatment
groups there was a statistically significant reduction in blood
pressure and heart rate, measured 24 hours after the last administration. The reduction in blood pressure was most pronounced
under 10 mg bisoprolol, the difference to atenolol being greater
than to 5 mg bisoprolol. The responder rate (diastolic blood
pressure 90 mm Hg) as well as the reduction in blood pressure
were comparable in the 5 mg bisoprolol group and atenolol group,
corresponding to a dose ratio of 1:10 for bisoprolol : atenolol.
This dose ratio of bisoprolol and atenolol was also confirmed in
further studies [110].
Fig. 27:
Systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR)
at rest before and in the course of 4 weeks of therapy with single daily
doses of 10 mg bisoprolol and 100 mg metoprolol, measured in each case
24 hours after administration of the last dose ( x SD) [82].
mm Hg
SBP
180
n.s.
160
SBP
140
120
DBP
**
**
100
DBP
80
beats/min
90
HR
**
80
70
HR
60
50
2-4 weeks
Placebo
Bisoprolol (n = 44)
Metoprolol (n = 43)
+2 weeks
+4 weeks
-blocker
** p < 0.01
B vs. M
* p < 0.05
n.s. not significant
70 Bisoprolol
m 71
6.7.2 Bisoprolol and metoprolol
6.7.4 Bisoprolol and enalapril
The BISOMET study (see above) compared 10 mg bisoprolol with

100 mg metoprolol in 87 hypertensive patients who were treated for
4 weeks with a single daily dose [82]. At the end of the treatment period, 3 hours after administration of the last dose, both
-blockers induced an equally effective reduction in blood pressure
and heart rate during exercise (100 watts), corresponding to a dose
ratio of 1:10 for bisoprolol : metoprolol.
56 patients were enrolled in this randomised single-blind study over

6 months [79]. The patients received in randomised order 10 mg
bisoprolol once daily or 20 mg enalapril once daily. If the response
of the blood pressure was inadequate with these doses they could
be doubled after 4 or 8 weeks. Both substances lowered the blood
pressure effectively (office blood pressure as well as the 24-hour
blood pressure). Echocardiography showed a significant reduction
of left ventricular hypertrophy by bisoprolol and enalapril.
After 4 weeks of treatment, 24 hours after administration of the last

dose, bisoprolol exhibited significantly stronger effects than metoprolol on the diastolic blood pressure and heart rate at rest
(Fig. 27) as well as on the systolic blood pressure and heart rate
during exercise.
A double -blind cross-over study with bisoprolol versus enalapril

in 45 hypertensive patients again showed comparable blood pressure
reductions in both treatment groups after 4 to 8 weeks. The heart
rate was, as expected, significantly more decreased with bisoprolol
and the spontaneously mentioned adverse effects were more
frequent during enalapril than during bisoprolol treatment [35].
6.7.3 Bisoprolol and captopril

24 hypertensive patients aged over 65 years were enrolled in a
double-blind, randomised cross-over study [34].
After a 4-week placebo washout phase one patient group each
received first 5 mg bisoprolol (1 x daily) or 50 mg captopril (2 x 25 mg
daily), for 6 weeks. If the blood pressure values remained high
(>160 /95 mm Hg) the dosages could be increased to 10 mg bisoprolol (1 x daily) or 100 mg captopril (2 x 50 mg daily). A further
4 week placebo washout phase was then followed by a second
therapy phase in which the patients received the respective alternative antihypertensive drug. Systolic and diastolic blood pressure
were lowered significantly with both therapy forms. As compared to
the baseline values, the quality of life of the elderly hypertensive
patients investigated in this study remained unchanged under antihypertensive therapy with captopril as well as with bisoprolol.
6.7.5 Bisoprolol and lisinopril

A 12-month study in 52 patients [151] compared the antihypertensive
efficacy and effects on serum lipids of bisoprolol, 2.5 -10 mg /day,
and lisinopril, 10-20 mg /day. There were no significant differences in
antihypertensive efficacy between the two treatments, except for a
significantly greater reduction in diastolic blood pressure with lisinopril at 6 months only (p < 0.05). Neither drug had any significant
effect on lipid parameters at 3, 6 or 12 months, and there were no
significant differences between the treatments. As expected, bisoprolol significantly lowered heart rate, while lisinopril did not. Two
patients who received lisinopril experience presumed drug-related
adverse effects (dry cough and headache). None of the patients
in the bisoprolol group experienced any drug-related adverse effects.
72 Bisoprolol
m 73
An 8-week study in 105 patients with moderate hypertension [167]

compared the antihypertensive efficacy of bisoprolol, 10 mg/day,
with that of lisinopril, 20 mg/day. No significant difference in antihypertensive efficacy was found between bisoprolol and lisinopril.
A further 4-week single-blind crossover study in 29 patients [192]
with mild to moderate hypertension compared the antihypertensive
efficacy of bisoprolol, 5 -10 mg /day, lisinopril, 10-20 mg/day
and lacidipine, 4 - 6 mg/day. No significant differences were found
between the treatments in control of casually measured systolic
or diastolic blood pressure. Bisoprolol and lacidipine tended to show
greater reduction in 24-hour and mean daytime blood pressure
than lisinopril, but these differences did not reach statistical significance. Bisoprolol and lacidipine were also better than lisinopril
in controlling the rapid rise in blood pressure during the morning.
the daytime blood pressure effectively, whereas during the night

only treatment with bisoprolol produced a significant greater blood
pressure response than nitrendipine (Fig. 28). This study shows that,
in contrast to nitrendipine, a single dose of bisoprolol guarantees
effective lowering of the blood pressure over 24 hours [131,132].
The quality of life, which in these patients is reduced in the
placebo phase as compared to the average population (assessed by
means of a self-rating test) improved significantly under antihypertensive therapy with bisoprolol compared to treatment with
nitrendipine [132].
Fig. 28:
Mean change ( x SEM) in systolic and diastolic blood pressure after

4 weeks of treatment with either bisoprolol or nitrendipine as assessed
by ambulatory blood pressure measurement [131].
decrease in blood pressure

(mm Hg)
6.7.6 Bisoprolol and nifedipine retard

In hypertensives over 60 years of age, a single daily dose of 10 mg
bisoprolol induced an equally effective reduction in blood
pressure as 20 mg nifedipine retard, administered as 2 daily doses.
Significantly fewer side-effects occurred with bisoprolol [25].
In a double-blind double-dummy 8-week crossover study in
82 hypertensive patients [57], there was no significant difference
in antihypertensive efficacy between bisoprolol 5 mg once daily
or nifedipine retard 10 mg twice daily.
8am 8 pm
8 pm 8 am
8 am 8 pm
8 pm 8 am
2
4
6
8
*
10
n.s.
6.7.7 Bisoprolol and nitrendipine

In a double-blind placebo-controlled study (n = 51) two parallel
patient groups were treated with a single dose of 10 mg bisoprolol
or 20 mg nitrendipine per day for 4 weeks. In order to check the
antihypertensive efficacy the casual blood pressure as well as the
24-hour blood pressure were measured. Both substances lowered
12
*
n.s.
14
16
diastolic
systolic
Bisoprolol
Nitrendipine
* p < 0.05
74 Bisoprolol
m 75
6.7.8 Bisoprolol and verapamil
6.7.11 Bisoprolol and bendrofluazide
A 6-month double-blind randomised trial compared the effects of

bisoprolol, 10 mg/day, and verapamil, 240 mg/day, on left ventricular
filling in 54 hypertensive patients who had never previously
received the same class of drug. The reduction in blood pressure
was similar in the two groups. There was no significant reduction
in left ventricular mass, but left ventricular filling was significantly
improved in the patients receiving bisoprolol. This effect was
observed immediately after the first administration and throughout
the 6-month treatment period, declining slowly during the
placebo wash-out. Improvement in left ventricular filling appeared
to be independent from alterations in heart rate and was considered to be a specific action of bisoprolol [80].
An 8-week crossover study in 81 hypertensive patients [174],

described above, compared bisoprolol, 5 mg daily, with bendrofluazide,
2.5 mg daily, and found both treatments to be equally effective.
6.7.9 Bisoprolol and a thiazide/potassium-sparing

diuretic combination
In a double-blind randomised study 34 hypertensive patients were
treated for 30 days with 10 mg bisoprolol or a fixed combination
consisting of 50 mg hydrochlorothiazide and 5 mg amiloride. A normalisation of the diastolic blood pressure could be achieved in
15 out of 17 patients in the bisoprolol group (88.2%) but in only
4 out of 17 patients in the diuretic group (23.5%) (p < 0.001) [93].
6.7.10 Bisoprolol and chlorthalidone

In a double-blind randomised study, 21 patients were treated with
10 mg bisoprolol or 50 mg chlorthalidone once daily for 4 weeks [43].
Both substances lowered the systolic and the diastolic blood
pressure effectively. The bisoprolol group showed less side-effects
(13%) than the chlorthalidone group (37%). While under chlorthalidone treatment a significant reduction of the serum potassium
concentration and an increase in the serum urea level were
observed these laboratory parameters remained unaffected under
6.8 Safety and efficacy in special populations

6.8.1 Elderly hypertensives
Bisoprolol effectively reduces the blood pressure also in elderly
patients.
The analysis of results from open long-term studies [29] in
dependence on age shows that bisoprolol was equally effective
in all age groups.
A normalisation of the diastolic blood pressure ( 90 mm Hg)
could be achieved by means of monotherapy with bisoprolol in 80%
of the hypertensive patients over 60 years of age in a multicentre
study [148].
A 12-week study in 40 patients aged < 65 years and 20 patients
aged > 65 years [40] found no significant difference between older
and younger patients in the antihypertensive efficacy of bisoprolol,
5 -10 mg/day. Bisoprolol also produced a similar reduction in heart
rate in the two groups. Bisoprolol was well-tolerated, with no
significant differences in adverse drug reactions between the groups.
59 hypertensive patients over 60 years of age participated in a
double-blind randomised comparative study of bisoprolol versus
nifedipine retard [25]. For 4 weeks the patients received 10 mg bisoprolol once daily or 20 mg nifedipine retard twice daily. There was
no difference between the two treatment groups with regard
to the normalisation rate of the diastolic blood pressure. However,
the frequency of side-effects was statistically significantly lower in
the bisoprolol group [25]. A further study carried out in the same
design confirmed this result in 40 patients aged over 65 years [128].
76 Bisoprolol
m 77
An 8-week, double-blind crossover study in 154 patients [173],

found that bisoprolol 5 mg/day, bendrofluazide, 2.5 mg/day and
nifedipine retard 10 mg twice daily were all equally effective
antihypertensive agents. Half the patients in this study were aged
over 60 years; no difference was found between older and younger
patients in the antihypertensive efficacy of any of the three drugs.
However, the overall response rate was significantly higher in the
elderly, as was the response to low dosages.
With regard to the quality of life during antihypertensive therapy,
a comparative study versus captopril [34] did not reveal any changes
in the quality of life occurring under bisoprolol in 24 hypertensive
patients aged over 65 years.
6.8.2 Diabetic hypertensives

Diabetes, both type I and type II, is a major risk factor for
coronary artery disease and MI [7, 24], and the risk of mortality
is further increased by hypertension [17]. Effective control of
blood pressure has been shown to reduce mortality and to
preserve renal function [17, 24]. In the past, there has been
concern that -blockers might have adverse metabolic effects in
patients with diabetes, that might make them inappropriate
antihypertensive agents for diabetic patients. Today, however,
there is clear evidence that -blockers improve survival in
diabetic patients, whether with or without established coronary
artery disease [6,11,12,19, 20, 21].
A retrospective study [11] in 2,723 patients with type II diabetes
and coronary artery disease found a total 3- year mortality of 7.8%
in those receiving -blockers, compared with 44% in those who
were not (p = 0.0001). In post-MI patients with type I or II diabetes,
two studies have also shown a substantial significant reduction
on mortality over one [12] or two years [6] in patients who received
-blockers, compared with those who did not.
In a subgroup of 1,148 type II diabetic hypertensives, the

UK Prospective Diabetes Study (UKPDS) [19] has clearly shown
that tight blood pressure control (blood pressure target of
< 150/85 mm Hg) with either atenolol or captopril significantly
reduces the incidence of micro- or macro-vascular complications,
compared with less tight control.
Notably, the 1-selective blocker atenolol was at least as effective
as the ACE-inhibitor captopril in reducing both microvascular and
macrovascular end points [20]. Indeed, there were trends favouring
the -blocker in all seven primary clinical endpoints, namely: any
diabetes-related endpoint, deaths related to diabetes, all-cause
mortality, MI, stroke, peripheral vascular disease and micro-vascular
disease. Notably, the additional drug costs incurred with tight
blood pressure control were more than offset by the savings made
in treatment of complications [21].
In UKPDS [20], there was no significant difference in the rate of
hypoglycaemia with atenolol or captopril. In fact, even in elderly
patients [18], no clinically significant effect has been demonstrated
of -blockade on the risk of hypoglycaemia.
As described previously, specific studies on bisoprolol demonstrate
that it has no significant adverse effects on lipid [95] or carbohydrate metabolism [95, 96, 99, 180] in diabetic hypertensives,
making it an appropriate agent for use also in this category of
patients.
The idea that -blockers are contra-indicated as antihypertensive
agents in diabetic patients may be considered outdated [2]. The
selection of a 1-selective agent such as atenolol or bisoprolol not
only avoids deleterious effects on glucose and lipid metabolism,
but also other side-effects related to non-selective -blockade, such
as bronchoconstriction and impaired exercise tolerance.
78 Bisoprolol
m 79
Treatment of angina pectoris in

coronary heart disease
The objective of anti-anginal therapy is to reduce the number of

angina pectoris attacks to a minimum, and to increase the
patients exercise tolerance. This objective is achieved by therapy
with bisoprolol.
Unlike the reduction in blood pressure, the anti-anginal effect of
-blockers is more closely correlated to the plasma concentration
or to the bodys stock of the drug.

Bisoprolol still exhibits a full anti-anginal effect 24 hours after
administration. The long duration of action is a result of the
long plasma elimination half-life and does not have to be forcibly achieved by relative overdose in single administration,
a special pharmaceutical formulation or repeated daily administration, as is the case with other anti-anginal drugs [30, 182].
The anti-ischaemic and anti-anginal effect of bisoprolol was investigated in numerous controlled, randomised, double-blind studies
following single oral doses or with periods of treatment lasting
up to 8 weeks [60, 65,117,124,147,161,164,183].
As little as 5 mg bisoprolol was effective and with 10 mg almost
maximal effects were achieved. With regard to the reduction in
ischaemic ST segment depression in the exercise ECG and the
increase in exercise tolerance of coronary patients, these studies
showed no difference between 10 mg and 20 mg bisoprolol [117,
161,181]. Bisoprolol increases the exercise tolerance in patients
with varying degrees of impaired coronary reserve.
In randomised, double-blind, controlled studies in patients with
stable angina pectoris the 24- hour effect of bisoprolol in a dosage
range of 5-20 mg was demonstrated [60,145,147,181].
The reduction in ischaemic ST segment depression and the rate-pressure product during ergometric exercise in comparison with the
controls were used as assessment criteria. The effect 24 hours
after administration was not significantly less than the acute effect
4 hours after administration (Fig. 29) [147]. There were no significant differences between 5 mg bisoprolol and 10 mg bisoprolol.
These results of single-dose studies were confirmed for 5 mg and
10 mg bisoprolol with chronic administration in a 2-week study [60].
Fig. 29:
Mean ST segment depression at rest and during identical exercise

before and after bisoprolol ( x, SEM; n = 10) [145].
ST (mV)
0.5
0.4
0.3
0.2
during
exercise
0.1
at rest
0
0
5 mg Bisoprolol
10 mg Bisoprolol
24 h
80 Bisoprolol
m 81
7.2 Haemodynamics
Bisoprolol increases the myocardial perfusion in coronary artery
disease. Myocardial perfusion defects are clearly reduced by
10 mg bisoprolol. This makes the left ventricular function more
economical.
The effect of 5 and 10 mg bisoprolol on myocardial perfusion was
investigated in a double-blind study performed in 25 patients
with stable angina pectoris. 10 mg bisoprolol effected a significant
increase in myocardial perfusion in the thallium -201 scintigram
[124].
with bisoprolol was successful in 97.8% of patients. There was

a 37% increase in the exercise tolerance (watt-minute product) of
patients of a multicentre study after 6 weeks of treatment with
bisoprolol in comparison to the initial status, a 56% reduction in
the ischaemic ST segment depression and a 17.4% reduction in
the rate-pressure product.
The success of treatment with the individual optimal dose was also
maintained throughout the 12-month period of treatment [149].
Fig. 30:
7.3 Success rate

Bisoprolol markedly improves the clinical symptoms in 97.8%
of angina pectoris patients.
Angina pectoris patients from a multicentre long-term study, classified

according to the frequency of weekly angina pectoris attacks before
treatment with bisoprolol, after a 6-week dose titration phase and at
the end of 12 months of treatment with individual optimal doses of
bisoprolol. Each symbol stands for one patient [149, 181].
Attacks
per week
According to the results of controlled, double-blind studies lasting

for 6 [126] and 24 weeks [182] as little as 5 mg bisoprolol was
a sufficiently effective dose for most patients, while 10 mg bisoprolol had only a slightly stronger effect on exercise tolerance and
frequency of attacks. The dose-response relationship found after
single administration was therefore confirmed in CHD patients
under chronic therapy [181].
> 20
In several open long-term studies, the treatment of stable angina

pectoris was tested in 135 coronary patients [30]. The long-term
treatment was preceded by a titration phase with 5 mg bisoprolol
per day as the initial dose. The dose could be increased as required
to 10 or 20 mg if the exercise tolerance and the clinical symptoms
(frequency of attacks, use of nitrates) were not clearly improved.
The treatment was continued with the individual optimal dose for
up to one year [66]. At the end of the 8-week titration phase
26.7% of the patients received 5 mg bisoprolol and 58.5% 10 mg
bisoprolol [30]. The highest dose of 20 mg was needed in only a
very low percentage of cases. At this point of time monotherapy
35
11 20
6 10
Pretreatment
value (n = 64)
6 Weeks
(n = 62)
12 Months
(n = 51)
82 Bisoprolol
m 83
Fig. 30 shows the number of patients per weekly frequency of

attacks before and during a 12- month treatment with bisoprolol. It
is clear that the exercise tolerance of the patients had improved
to a clinically relevant degree even after the first six weeks. Almost
half of the patients were free from attacks after 6 weeks of
treatment with bisoprolol [149,181].
More than 80% of the patients were successfully treated with 5 or
10 mg bisoprolol once daily as monotherapy.
In a further study, the incidence of attacks was clearly reduced by
bisoprolol in 89% of the patients during a therapy period of
4 weeks. 56% of the patients were free from attacks. The success
rate was equally high in patients over 60 and under 60 years of
age, as well as in smokers and non-smokers [166].
7.4 Silent ischaemia

In patients with established coronary artery disease about 75%
of all ischaemic episodes are asymptomatic.Bisoprolol significantly
decreases the incidence and duration of ischaemic episodes.
The incidence of ischaemic episodes in the 24- hour Holter ECG was
significantly reduced by 10 mg bisoprolol. The duration of the
ischaemic episodes was shortened from 19 to 12 minutes (p 0.05).
This was shown in an open study in 13 patients with established
coronary artery disease. At the same time the incidence of ventricular
extrasystoles decreased by 80% in these patients [146].
ischaemia on ambulatory ECG monitoring. Bisoprolol in a single

daily dose was an effective antianginal and anti-ischaemic treatment.
In the reduction of the number and duration of ischaemic episodes
and total ischaemic burden bisoprolol proved superior to nifedipine s.r..
Bisoprolol also was more effective concerning the responder rates,
the effect on angina and on the circadian variation of ischaemic episodes [176].
After MI, early administration of a -blocker without ISA
reduces the mortality. -blockers are established in secondary
prevention. The tolerability of bisoprolol after acute MI was
documented in three studies.
In total three studies were performed with bisoprolol i.v. in patients
with acute myocardial infarction. Altogether 237 patients were
treated with bisoprolol i.v. followed by oral intake of 10 mg bisoprolol tablets once daily.
In a first study, 37 patients received up to 5 mg bisoprolol i.v.
(titration with 1 mg) on the 3rd day after a MI. Subsequently, the
patients were treated with 10 mg bisoprolol orally for 3 weeks.
The desired reduction of the heart rate and of the systolic blood
pressure was already achieved with 2-3 mg i.v.The resulting decrease
in the rate-pressure product indicated the intended reduction of
the myocardial oxygen consumption [58,119].
10 hypertensives with anginal symptoms in the presence of

coronary microangiopathy were treated with 5 -10 mg bisoprolol for
4 weeks. The number of ST segment depressions in the 24-hour
Holter ECG was reduced by about 50% during the therapy [155].
In the second study, 35 patients received 1-2 times 2.5 mg bisoprolol i.v. within 6 hours after the infarction symptoms had started,
and then 10 mg bisoprolol orally for 2 weeks. Bisoprolol was
well tolerated also under these conditions. The patients remained
haemodynamically stable [118].
A randomised multicentre double-blind study the "Total Ischaemic

Burden Bisoprolol Study"(TIBBS), was performed with bisoprolol versus nifedipine slow release (s.r.) in 330 patients with stable angina
pectoris, a positive result on the exercise ECG and with transient
A double-blind randomised study with acute MI was performed in

333 patients. 165 patients were treated with bisoprolol and
168 patients with atenolol for 7 days. The dosage regimen for
84 Bisoprolol
m 85
bisoprolol was adapted from the pilot studies [119, 171] and the
dosage regimen for atenolol corresponded to that used in the
ISIS I -study. The tolerability was similar for both substances and the
adverse effects reported were rare and mainly well known for
-blockers or due to the natural course of the disease. The reduction of heart rate and blood pressure was similar in both groups,
leading to a reduction of the myocardial oxygen consumption with
a positive influence on myocardial ischaemia. A cardioprotective
effect after MI can therefore be postulated for bisoprolol [119].
7.6 Therapeutic comparison in coronary patients
(10 mg daily) or atenolol (100 mg daily) for 12 weeks (subsequent

to a 2-week placebo phase). Both therapeutic regimens significantly increased exercise tolerance and decreased the rate-pressure
product. After 12 weeks of therapy, 29% of the patients treated
with 10 mg bisoprolol and 18% of the patients treated with atenolol
had no anginal complaints during exercise [59].
Fig. 31:
W x min
In single daily administration bisoprolol proved to be equally

effective as other anti-anginal agents, some of which require
repeated daily administration.
400
7.6.1 Bisoprolol and atenolol
200
In the randomised, double -blind, cross-over study already referred

to on p. 80, 19 coronary patients were treated for 6 weeks in
each case with single daily doses of 5 mg bisoprolol, 10 mg bisoprolol or 100 mg atenolol [126]. There was no significant difference
between the 3 therapies with regard to duration of exercise, time up
to the occurrence of an ST segment depression of 0.1 mV, frequency
of attacks and nitroglycerin consumption. Only the rate-pressure
product at maximum exercise was reduced to a lesser extent under
5 mg bisoprolol than under 10 mg bisoprolol and 100 mg atenolol,
the doses which are to be described as equivalent [126].
In 40 coronary patients, who received 5 mg bisoprolol (see above)
or 50 mg atenolol for 6 months (cross-over study), there was
a comparable improvement in exercise tolerance and ST segment
depression under both therapies (Fig. 31) [182].
In an international double-blind randomised study (MIRSA),
157 patients with stable angina pectoris were treated with bisoprolol
Watt-minute product (W x min) and ST segment depression (mV) at

maximum exercise after 2 weeks of placebo (week 0) and after 2, 4 and
24 weeks of treatment with 5 mg bisoprolol or 50 mg atenolol
( x SEM; n = 40) [182].
300
100
0
ST (mV)
0.10
0.20
0.30
Atenolol
Bisoprolol
24
weeks
86 Bisoprolol
m 87
7.6.2 Bisoprolol and nifedipine

The total ischaemic burden which includes both symptomatic and
asymptomatic ischaemic episodes as well as the number and
duration of ischaemic episodes were investigated in a large doubleblind multicentre study (TIBBS = Total Ischaemic Burden Bisoprolol
Study) which compared bisoprolol with nifedipine slow release (s.r.)
[176]. 330 patients with stable angina pectoris, positive exercise test
and at least two transient ischaemic episodes during a 48 -hour
Holter monitoring were included in the study. During the first
4 weeks (phase 1) bisoprolol was administered at a daily dose of
10 mg and nifedipine s.r. at 20 mg b.i.d.; for a further 4 weeks
(phase 2) the dosages were doubled to bisoprolol 20 mg once daily
and nifedipine s.r. 40 mg b.i.d. A 48-hour Holter monitoring was
performed at the end of each treatment phase.
Fig. 32:
Effects of bisoprolol and nifedipine slow release (s.r.) on total

ischaemic burden. Reduction compared to baseline is significant with
both drugs and the difference in reduction between bisoprolol and
nifedipine is also significant ( p < 0.01), the reduction being greater
under bisoprolol [176].
During phase 1 there was a significant reduction in the number

and duration of transient ischaemic episodes as well as in total
ischaemic burden with both bisoprolol and nifedipine s.r.. Bisoprolol,
however, proved to be significantly more effective than nifedipine s.r.
(Fig. 32). Additionally bisoprolol reduced the early-morning peak
and lowered the afternoon peak of the transient ischaemic episodes
markedly. Nifedipine led only to a reduction of the second, lateafternoon peak of transient ischaemic episodes (Fig. 33).
Fig. 33:
Effects of bisoprolol and nifedipine s.r. on the distribution of

transient ischaemic episodes (sum of episodes / h on two consecutive
days as mean value / patient). From comparable baseline curves,
bisoprolol effectively reduces the morning and afternoon peaks of
transient ischaemic episodes but leaves the circadian distribution
unchanged [176].
no. episodes/
patient/hour
0.45
0.30
min x mm /48 h
250
200
0.15
150
100
0
50
12
16
20
24 h
0
Baseline
Bisoprolol
20 mg
10 mg
Baseline
Nifedipine s.r.
2 x 20 mg 2 x 40 mg
Baseline
Bisoprolol
10 mg o.d.
n = 133
Baseline
n = 135
Nifedipine s.r.
20 mg b.i.d.
(s.r. = slow release)
88 Bisoprolol
m 89
During Holter monitoring at the end of phase1, 54 patients (41%)

were free from ischaemic episodes in the bisoprolol group and
only 20 patients (15%) in the nifedipine group (p < 0.0001). Only
slight additional effects were achieved by doubling the dosage,
and significant differences continued to exist between the two
treatment groups.
The follow-up results of 520 patients were available at 1 year,
comprising 317 patients randomised to the TIBBS study and 203
who had been screened but not randomised. Assessments of
cardiac events (cases of deaths, MI and unstable angina pectoris)
after 6 and 12 months proved that the number of events correlates
directly with the number of transient ischaemic episodes during
TIBBS screening phase. Patients who responded to medical
treatment by 100% (no further transient ischaemic episodes) in the
TIBBS study showed a significantly lower number of events than
the non-responders [177, 178]. The positive effect of bisoprolol in
TIBBS translated into an improved prognosis compared to
nifedipine s.r. during the 1- year follow-up. Patients randomised to
bisoprolol during the TIBBS study had a reduced risk of events
(20.9%) in the follow-up compared to patients randomised to nifedipine s.r. (33.3%) (p < 0.05) [179].
A retrospective analysis has been performed on data from the
TIBBS study [23], to analyse the effects of bisoprolol and nifedipine
on heart rate variability. An increase in heart rate variability can be
regarded as prognostically favourable. Analysis of 24-hour Holter
monitoring data from 422 patients with stable angina found that
nifedipine reduced the mean values of all heart rate variability
parameters tested (standard deviation of the mean of all corrected
RR intervals, standard deviation of all 5 min mean cycle lengths,
square root of the mean of the squared differences of successive
corrected RR intervals).
In contrast, the square root of the mean of the squared differences
of successive corrected RR intervals increased under bisoprolol.
The standard deviation of all 5 min mean cycle lengths and the
standard deviation of the mean of all corrected RR intervals
increased from low baseline values and declined from higher baseline values. The increase in heart rate variability on treatment with
bisoprolol was accompanied by a tendency towards a better
prognosis. Patients in whom an increase in heart rate variability
was accompanied by complete suppression of ischaemia on therapy
experienced no serious events during one year of follow-up.
A UK economic analysis of the TIBBS study [139] showed that
therapy with bisoprolol resulted in lower costs per patient over
12 months ( 1,372 vs 2,030 for nifedipine).
The effect of 10 mg bisoprolol and 20 mg nifedipine or of a combination of the two drugs on the resting and exercise haemodynamics
was compared in 21 patients enrolled in a double-blind study.
The anti-ischaemic effect of bisoprolol was more pronounced than
that of nifedipine. The effect of the combination was not significantly stronger. The haemodynamic profiles of the two drugs were,
as expected, different [162].
7.6.3 Bisoprolol and verapamil

A total of 21 CHD patients participated in an 8-week double-blind
study with parallel groups. After 4 weeks the dose of 10 mg bisoprolol, administered once daily, and 80 mg verapamil (3 times daily)
were increased (20 mg bisoprolol, 3 x 120 mg verapamil) [56].
Under both therapies there was a comparable improvement in the
symptoms of angina pectoris, and a prolongation of the duration
of exercise and the time up to the occurrence of a ST segment
depression of 0.1 mV. There was a significantly greater reduction in
heart rate and rate-pressure product at maximum exercise with
20 mg bisoprolol than with 360 mg verapamil, probably as a result
of the high dose of 20 mg bisoprolol, which was not required
by all patients (fixed dosage increase for all patients after 4 weeks).
90 Bisoprolol
m 91
Although -blockers have, in the past, been considered contraindicated in patients with chronic heart failure (CHF) due to
their negative inotropic effects, the opinion is now changing in
the light of some recent studies with -blockers in heart failure
and a better understanding of its pathophysiology. Over the past
two decades, clinical trials in patients with CHF have demonstrated improvements in symptoms, exercise capacity, ventricular
function, functional status (NYHA class) and survival following
-blockade on top of standard therapy when treatment was
carefully titrated. Recent mortality trials have provided clear
evidence that -blockers without intrinsic sympathetic activity
are efficient in reducing mortality [1, 5,15, 22,55]. Recent
meta-analyses of randomised trials also indicate a reduction in
mortality in CHF in patients receiving -blockers [4, 8, 13].
As a result, -blockers are part of standard therapy for CHF treatment today.
7.6.4 Bisoprolol and isosorbide dinitrate

At a daily dose of 10 mg bisoprolol is superior in its effect on
transient ischaemia compared to isosorbide dinitrate (20 mg t.i.d.)
in patients with stable angina pectoris [143, 170]. While bisoprolol
and a combination of bisoprolol with isosorbide dinitrate led to
a significant reduction of both early morning and late-afternoon
peaks of ischaemic episodes, treatment with isosorbide dinitrate alone
showed an effect only on the late-afternoon peak. A combination
of the two combounds did not achieve any additional effects in
comparison to bisoprolol alone (Fig. 34) [143]
Fig. 34:
Treatment of chronic heart failure
Circadian distribution of ischaemic episodes under therapy with bisoprolol, isosorbide dinitrate, a combination of bisoprolol + isosorbide
dinitrate, and placebo [143].
number of ischaemic episodes

30
Two major clinical trials have been performed with bisoprolol in

CHF: the Cardiac Insufficiency Bisoprolol Study (CIBIS) [50] and the
Cardiac Insufficiency Bisoprolol Study II (CIBIS II) [51]. Bisoprolol
is the first -blocker to have proven its efficacy in reducing mortality
in a single large -scale CHF study with all-cause mortality as the
primary outcome [51].
25
20
15
8.1 CIBIS
10
0
0
4
Placebo
ISDN
10
12
14
Bisoprolol
Combination
16
18
20
22
24 hours
CIBIS was performed in 641 patients (NYHA III and IV) with chronic
heart failure of various aetiologies and left ventricular ejection
fraction of < 40%. In this double-blind multicentre study 320 patients
were treated with bisoprolol and 321 received placebo. The initial
dose of 1.25 mg/d was increased to 2.5 mg/d after 48 hours and
to 5 mg 1 month later. All patients received background diuretic
and vasodilator therapy, which was in 90% of cases an ACEinhibitor. Mean duration of follow-up was 1.9 0.1 years. Although
no significant reduction in mortality was observed under bisoprolol
92 Bisoprolol
m 93
in the whole population, there were, however, fewer deaths in

the bisoprolol group (53 patients or 16.6%) compared to placebo,
where 67 patients (20.9%) died (Fig. 35).
Furthermore subgroup analyses demonstrated additional benefits
for certain patient groups:
a 47% reduction in mortality (p < 0.01) in patients without
history of MI (Fig. 36)
Fig. 36:
survival (%)
100
a 53% reduction in mortality in patients with dilated cardiomyopathy (Fig. 37)
80
a 42% reduction in mortality (p = 0.05) in patients with a

ventricular rate > 80 bpm.
60
Fig. 35:
Survival curves in CIBIS patients (n = 641). Within two years

67 patients (20.9%) died in the placebo group and 53 (16.6%) in the
bisoprolol group (p = 0.22 log rank test) [50].
Survival curves in CIBIS patients without a history of MI ( n = 338 ).

Within two years 42 patients (22.5%) died in the placebo group
and 18 patients (11.9%) died in the bisoprolol group ( p = 0.01 log
rank test ) [50].
40
0
200
400
600
800
1000
1200
1400
survival time (days)
survival (%)
Fig. 37:
100
80
Survival curves in CIBIS patients with dilated cardiomyopathy

(n =232). Within two years 23 patients (20%) died in the placebo
group and 11 patients (9.4%) died in the bisoprolol group
( p = 0.01 log rank test ) [50].
survival (%)
100
60
80
40
0
200
400
600
800
1000
1200
1400
60
Bisoprolol
Placebo
40
0
200
400
600
800
1000
1200
1400

Bisoprolol
Placebo
94 Bisoprolol
m 95
8.1.1 Heart rate variability
Bisoprolol significantly improved the NYHA stages. Improvement

by one NYHA class was seen in 21% of the bisoprolol-treated
patients compared to 15% in the placebo group ( p = 0.04) (Tab. 5a,
5b). Significantly less patients required hospitalisation for cardiac
decompensation (61 on bisoprolol vs. 90 on placebo, p < 0.01).
An increase in heart-rate variability is considered desirable in

various cardiac conditions e.g. after a MI, in stable angina pectoris,
and in cardiac insufficiency. The effects of bisoprolol on heart rate
variability were investigated in 54 patients from the CIBIS study
[54, 144]. Bisoprolol produced a reduction in heart rate and an
increase in heart-rate variability, whereas placebo had no such
effects. In particular, indicators of vagal activity were significantly
improved by bisoprolol.
Tab. 5a: NYHA class evolution between inclusion and last follow-up visit [50].
Placebo
Bisoprolol
III IV
Equal
IV III
or III II
IV II
or III I
not
followed
35 (11%)
41 (13%)
226 (70%)
195 (61%)
46 (14%)
66 (21%)
2 (1%)
2 (1%)
12 (4%)
16 (5%)
8.1.2 Pharmacoeconomic analyses

In analyses of economic data from the CIBIS trial, cost savings
associated with the use of bisoprolol in heart failure were demonstrated for Germany [154] and France [115], and a UK study [125]
showed that the addition of bisoprolol to standard therapy was
at least cost-neutral.
Tab. 5b: Improvement by at least one functional class [50]

Placebo
Bisoprolol
48 (11%)
68 (21%) p = 0.04
From a substudy in which echocardiographic assessment of left

ventricular function (left ventricular diameter and left ventricular
fractional shortening) was performed, it could be demonstrated that
left ventricular fractional shortening was significantly improved
on bisoprolol (+ 4.6 6.5%) at 5 months vs placebo (0.04 5.5%;
p < 0.001). This improvement was regardless of the aetiology of
congestive heart failure and associated with a better prognosis for
patients with congestive heart failure: Survival in the entire population after the initial 5 months period was significantly higher in the
bisoprolol group (8% of patients died compared to 15% in the
placebo group) [50].
8.2 CIBIS II
The design of CIBIS II [109] was based on the background and
results of the first CIBIS trial. It included 2,647 symptomatic ambulatory patients in NYHA class III or IV (ejection fraction 35%)
of various aetiologies. Men and women aged 18 - 80 years were
eligible for inclusion; women were only included if they were postmenopausal, surgically sterilised or using reliable contraceptive
methods. Patients were required to be stable on standard treatment with ACE-inhibitors and diuretics. They were assigned to
treatment with bisoprolol (n =1,327), progressively increased from
1.25 mg via 2.5, 3.75, 5 and 7.5 mg to a maximum of 10 mg /day, or
to placebo (n = 1,320). There was no run-in period in this study.
96 Bisoprolol
m 97
The primary objective of CIBIS II was to evaluate the effect of bisoprolol 1.25 -10 mg daily (both given in addition to standard therapy)
on long-term all- cause mortality, in comparison to placebo.
Secondary endpoints included cardiovascular mortality (pump failure,
sudden death, fatal MI, other cardiovascular deaths, unknown
cause of death), hospital admissions, combined endpoints (cardiovascular mortality or hospitalisation for cardiovascular reasons)
and permanent treatment withdrawal.
The study was stopped early, after the second interim analysis
showed a significant mortality benefit in favour of bisoprolol. Mean
follow -up was 1.3 years.
8.2.1 Primary endpoint (all-cause mortality)

Bisoprolol showed a highly significant beneficial effect on the
primary endpoint all-cause mortality irrespective of aetiology or
severity of the disease. 156 patients (11.8%) of patients died in the
bisoprolol group, compared with 228 (17.3%) in the placebo
group (p < 0.0001). The estimated annual mortality was 8.8% for
bisoprolol and 13.2% for placebo. Thus, bisoprolol reduced mortality
by 34%; the hazard ratio was 0.66 (95% CI 0.54 - 0.81) (Fig. 38).
Fig. 38:
Survival in CIBIS II [51].
survival (%)
1.0
0.8
0.6
0
0
200
400
500
800
time after inclusion (days)

Bisoprolol
Placebo
8.2.2 Secondary endpoints

The results for secondary endpoints are shown in Tab. 6. Significantly fewer bisoprolol-treated patients were admitted to hospital
for any reason (33% vs 39%, p = 0.0006). Significantly fewer bisoprolol-treated patients died of cardiovascular causes (9% vs 12%,
p = 0.0049), and significantly fewer bisoprolol-treated patients
experienced the combined endpoint of cardiovascular death
or admission to hospital for a cardiovascular event (29% vs 35%,
p = 0.0004). The percentage of permanent treatment withdrawals
was identical (15%) in each group, suggesting good tolerability
for bisoprolol in this study.
98 Bisoprolol
m 99
Tab. 6:
CIBIS II secondary endpoints [51] .
Tab. 7:
CIBIS II causes of death [51].
Placebo
(n = 1,320)
Bisoprolol
(n = 1,327)
Hazard ratio
(95 % CI)
Causes of death
Placebo
(n = 1,320)
Bisoprolol
(n = 1,327)
Hazard ratio
(95 % CI)
All-cause hospital
admission
513
(39 %)
440
(33 %)
0.80
(0.71- 0.91)
0.0006
Sudden death
83
(6 %)
48
(4 %)
0.56
(0.39 - 0.80)
0.0011
All cardiovascular
deaths
161
(12 %)
119
(9 %)
0.71
(0.56 - 0.90)
0.0049
Pump failure
47
(4 %)
36
(3 %)
0.74
(0.48 -1.14)
0.17
Combined
endpoint
463
(35 %)
388
(29 %)
0.79
(0.69 - 0.90)
0.0004
Myocardial
infarction
8
(1 %)
7
(1 %)
0.85
(0.31- 2.34)
0.75
Permanent
treatment
withdrawals
192
(15 %)
194
(15%)
1.00
(0.82 - 1.22)
0.98
Other cardiovascular deaths
23
(2 %)
28
(2 %)
1.17
(0.67- 2.03)
0.58
Noncardiovascular deaths
18
(1%)
14
(1%)
0.75
(0.37-1.50)
0.41
Unknown cause
of death
49
(4 %)
23
(2 %)
0.45
(0.27- 0.74)
0.0012
8.2.3 Additional analyses

Additional analyses demonstrated that the greatest effect of
bisoprolol on mortality was in the reduction of sudden death; there
was a 42% lower rate of sudden death among patients on
bisoprolol (4% vs 6%, p = 0.011) (Tab. 7). There were also fewer
deaths from pump failure in the bisoprolol group, though this
was not statistically significant (3% vs 4%, p = 0.17). However, many
deaths had to be classified for the purposes of the trial as being
of unknown cause (i.e. they were unwitnessed or insufficiently documented). Significantly fewer deaths of unknown cause were recorded in the bisoprolol group (2% vs 4%, p = 0.0012), which suggests
that many of these deaths were in fact from cardiac causes.
There were no significant differences between the groups in the
number of deaths from other cardiovascular causes, or noncardiovascular causes. There were significantly fewer admissions
for worsening heart failure among bisoprolol-treated patients
(12% vs 18%, p = 0.0001).
Subgroup analyses (Fig. 39) showed no significant difference

between the groups for mortality or admission to hospital for any
subgroup of aetiology of heart failure or class of disease severity.
Fig. 39: CIBIS II mortality by baseline findings [51].
Relative risk
Bisoprolol
n/total
Placebo
n/total
Ischaemia
75/662
121/654
Primary DCM
13/160
15/157
Undefined
68/505
92/509
NYHA III
116/1,106
173/1, 096
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
Horizontal bars
represent 95% CIs.
100 Bisoprolol
m 101
8.2.4 Pharmacoeconomic analysis

A prospectively planned economic analysis was conducted based
resource utilisation data collected during the CIBIS II [130]. The
analysis was based on the comparison of conventional therapy for
heart failure (diuretic, digoxin and ACE-inhibitor) to conventional
therapy plus adjunctive bisoprolol and took the perspective of
a third party payer in France and Germany and the NHS in the UK.
To take into account the additional costs related to bisoprolol
treatment, it was assumed that all patients treated with bisoprolol
require 4 additional outpatient /office visits for initiation and
up-titration of treatment.
The analysis found that the costs avoided by the reduced rate of
hospital admissions in the bisoprolol treated group more than
offset the extra costs of bisoprolol therapy. In all three countries
the cost of care in the bisoprolol group was 5 to 10 per cent less
than in the conventionally treated group. This was despite adding
the cost of bisoprolol and extra initiation /up -titration visits.
Further areas of research
9.1 Hyperthyreosis
Three studies were performed with bisoprolol in patients with hyperthyreosis. In total 32 patients were investigated in these studies.
The main results were as follows: the subjective and objective
clinical symptoms of hyperthyroidism were improved, heart rate and
systolic as well as diastolic blood pressure were decreased.
Changes in the serum levels of thyroid hormones were not observed
[97,141]. The pharma cokinetics of bisoprolol remained unaltered,
only small variations in plasma concentrations of bisoprolol were
observed [141].
One double-blind study compared the effects of bisoprolol with
the non-selective -blocker propranolol. Bisoprolol was at least as
effective as propranolol in ameliorating the clinical symptoms of
hyperthyreosis [169].
9.2 Prophylaxis of migraine

Bisoprolol is of demonstrated efficacy in the prophylaxis
of migraine.
A double-blind placebo-controlled study [172] was conducted in
226 patients who had suffered from migraine with or without aura
for at least two years and who had experienced at least three
migraine attacks during a four-week run-in period. Patients received
bisoprolol, 5 or 10 mg /day, or placebo, for 12 weeks. As expected,
there was a substantial placebo effect (22% reduction in attack
frequency in the placebo group), but bisoprolol was significantly
more effective than placebo (39% reduction in attacks for both
doses, p < 0.05 vs placebo). There was no significant reduction in
the duration or severity of headaches.
As would be expected, heart rate and blood pressure were significantly lower in patients receiving either dose of bisoprolol than
in those receiving placebo. One or more adverse events were reported by 35% of patients on bisoprolol 5 mg, 43% of patients on
102 Bisoprolol
m 103
bisoprolol 10 mg, and 33% on placebo. The tolerability of study

medication was rated as very good by 81- 82% of patients receiving
bisoprolol and by 84% of patients receiving placebo.
A double-blind cross- over study [190] compared the prophylactic
efficacy of bisoprolol, 5 mg /day, with that of metoprolol, 50 mg,
twice daily, in patients who had suffered from migraine with or without aura for at least two years. Patients were required to have
suffered at least 3 migraine attacks during a four-week run in-phase.
Treatment with each agent lasted 12 weeks. In 78 patients for
whom efficacy data could be compared, both -blockers reduced
the mean frequency of migraine by about 50%, compared with
the run in-phase. No differences in tolerability were observed
between the two drugs.
9.3 Perioperative risk reduction

Patients undergoing major vascular surgery are at risk for serious
perioperative cardiac complications such as MI and cardiac
death. Bisoprolol reduces the incidence of death from cardiac
causes and non-fatal MI in high-risk patients undergoing
major vascular surgery.
The Dutch Echocardiographic Cardiac Risk Evaluation Applying
Stress Echocardiography (DECREASE) study [142] was carried out
in 112 patients undergoing major vascular surgery who had
one or more cardiac risk factors, but who were not already taking
a -blocker or did not have extensive wall motion abnormalities
(demonstrated by dobutamine echocardiography either at rest or
during stress testing). Patients were randomised to bisoprolol
(started at least one week before surgery and continued for 30 days
postoperatively) or standard care. The starting dose of bisoprolol
was 5 mg /day, increased to 10 mg /day if the heart rate remained
above 60 beats per minute.
Two of 59 patients (3.4%) receiving bisoprolol died of cardiac

causes, compared with 9 of 53 patients in the standard care group
(17%, p = 0.02). None of the patients in the bisoprolol group
suffered a non-fatal MI, compared with 9 of those in the standard
care group (17%, p < 0.001). Overall, the primary study endpoint of
death from cardiac causes or non-fatal infarction occurred in
2 /59 patients in the bisoprolol group (3.4%) and 18/53 patients
in the standard care group (34%, p < 0.001).
104 Bisoprolol
m 105
10 Psychological functions
11 Tolerability
The sleep quality and psychomotor performance capacity

were not impaired by bisoprolol. There was an improvement in
the driving abilities of infarction patients.
Tolerability data with bisoprolol confirm the excellent safety

profile. The number of undesirable side-effects was low and no
new, unknown adverse reactions for -blockers in general
occurred. Discontinuations of treatment were rare.
The effect of bisoprolol and pindolol on sleep quality was compared with that of placebo in a group of 36 healthy volunteers.
With both bisoprolol and placebo, sleep quality was unchanged in
comparison with the initial status, whereas in the pindolol group
it was below the initial level. Feeling refreshed after sleep was impaired with pindolol as compared with placebo whereas the effect
of bisoprolol did not differ from that of placebo [78].
In volunteers bisoprolol significantly reduced the blood pressure,
heart rate and rate-pressure product without any impairment
of psychomotor performance. In volunteers with cardiovascular
hyperreaction the rate-pressure product was reduced to a greater
extent than in volunteers with hyporeaction. The better psychomotor performance of the hyperreactive volunteers was, however,
not impaired by bisoprolol. The performance of the hyporeactive
volunteers was lowered by bisoprolol by only 9.6% [158].
The influence of 5 and 10 mg bisoprolol and 60 mg isosorbide
dinitrate (ISDN) on driving performance under realistic conditions
was investigated in 18 post-infarction patients. In contrast to
ISDN, with 5 mg and 10 mg bisoprolol the orientation performance
and driving technique in complicated traffic situations were improved to an equal degree [159].
Undesirable side-effects could chiefly be attributed to intensified

pharmacodynamic effects. In open titration studies, patients
suffering from hypertension and angina pectoris were treated with
the individual optimal dose of bisoprolol after a 14- day placebo
pretreatment phase. In a group of 612 patients from long-term
studies, reactions were reported by 136 patients (22.2%) in the
placebo pretreatment phase and by 167 patients (27.2%) during
The number of reports of the three most frequent undesirable sideeffects (giddiness, headache, fatigue) was comparable during the
placebo phase and during treatment with bisoprolol. The frequency
of reports decreased as the treatment proceeded.
Out of a total group of 1,396 patients and volunteers, 24 patients
(1.77%) discontinued the treatment with bisoprolol due to
undesirable side-effects. The drop-out rate was independent of the
dose level (Tab. 8).
In an open multicentre study in 2,012 hypertensive patients the
tolerability of 5 and 10 mg bisoprolol /day was investigated
over 8 weeks. 96.3% of the patients assessed the tolerability
to be good (Fig. 42). Altogether, 234 out of 2,012 (11.6%) of
the patients enrolled in the study reported undesirable effects.
The symptoms giddiness and fatigue typical of -blockers were
reported by 3.2% and 2.6% respectively and were thus the most
frequent symptoms reported. They were followed by gastrointestinal disorders (1.9%), headaches (1.8%) or cold extremities
(1.0%). Bradycardia (0.7%) or potency disorders (0.5%) were
rare events [91].
106 Bisoprolol
m 107
Tab. 8:
Principal symptom
Number of
patients
Bradycardia
0.59
Giddiness
0.22
Gastrointestinal disorders
0.29
Malaise
0.22
Dyspnoea
0.15
Asthmatic bronchites
0.07
Nightmares
0.07
Feelings of anxiety
0.07
Hot flushes
0.07
Fig. 40:
a
The study shows furthermore that undesirable side-effects are

not observed more frequently in elderly patients than in younger
patient groups [90].
Drop-outs due to undesirable side-effects from a total patient

population of n =1,396 [31].
More than 15,000 patients were treated with bisoprolol in post

marketing surveillance studies performed by Merck KGaA. Table 9
comprises the most important concomitant symptoms observed
and their incidence. Of 15,290 patients treated in post marketing
surveillance studies of Merck only 1,713 patients (11.2%) had
adverse events including 336 patients (2.2%) who discontinued
treatment before the end of the study. The reported adverse events
were all already known for bisoprolol or for other -blockers.
None of these can be rated as serious [41].
This good tolerability of bisoprolol could be confirmed in over
50,000 patients controlled in total in clinical studies. Tolerability
also was independent of the indications treated with bisoprolol.
Rating of therapy with bisoprolol by doctor (a) and patient (b) [91].
good
moderate
poor
no data
good
moderate
poor
no data
As potency disorders are sometimes discussed in connection with

nonselective -blockers, a study was performed with the highly
selective 1-blocker bisoprolol in 26 hypertensive males. Various
parameters on sexual functioning were assessed. No detrimental
effects on sexuality in newly diagnosed hypertensive patients were
found. In those patients already on antihypertensive medication
bisoprolol improved sexuality in some parameters [39].
108 Bisoprolol
Tab. 9:
Adverse events from post marketing surveillance studies in

15,290 patients [41].
Adverse reactions
Number
of reports
Incidence
(%)
Tiredness
214
1.4
Dizziness
141
0.9
Headache
169
1.1
Sleep disturbances
143
0.9
Vivid dreams
Psychic disturbances (e.g. depressive mood)
31
Visual disturbances
Conjunctivitis
Reduced lacrimation
Nervous system
0.2
Eyes
Cardiovascular system
Paraesthesias
322
2.1
Bradycardia
69
0.5
Orthostatic hypotension
15
0.1
Intensification of Raynauds phenomenon
Dyspnoea in patients predisposed to

bronchospasm (e.g. in asthmatic bronchitis)
139
0.9
187
1.2
Airways
Gastrointestinal tract
Gastrointestinal complaints (e.g. diarrhoea,
constipation, nausea, abdominal pain)
Musculosceletal system
Muscle weakness
Skin reactions (e.g. itching/pruritus, flush,

sweating, skin rash)
39
0.3
110
0.7
Skin
Urogenital organs
Potency disorders
m 109
12 References
12.1 General
1
Australia / New Zealand Heart Failure Research

Collaborative Group. Randomized, placebo-controlled trial
of carvedilol in patients with congestive heart failure due
to ischemic heart disease. Lancet 1997; 349: 375.
Cruickshank JM. Beta-blockers continue to surprise us.

Eur Heart J 2000; 21: 354.
Cruickshank JM. The clinical importance of cardioselectivity

and lipophilicity in beta-blockers. Am Heart J 1980; 100: 160.
Doughty RN et al. Effects of beta-blocker therapy on

mortality in patients with heart failure: a systematic overview
of randomized trials. Eur Heart J 1997; 18: 560 .
Fagerberg B et al. Effect of metoprolol CR/XL in chronic

heart failure: Metoprolol CR/XL Randomized Intervention Trial
in Heart Failure (MERIT-HF). Lancet 1999; 353: 2001.
Gottlieb SS et al. Effect of beta-blockade on mortality

among high-risk and low-risk patients after myocardial
infarction. N Engl J Med 1998; 339: 489.
Haffner SM et al. Mortality from coronary heart disease in

subjects with type 2 diabetes and in nondiabetic subjects
with and without prior myocardial infarction. N Engl J Med
1998; 339: 229.
Heidenreich PA et al. Effect of beta-blockade on mortality

in patients with heart failure: A meta-analysis of randomized
clinical trials. J Am Coll Cardiol 1997; 30: 27.
Holmer SR et al. -adrenergic blockers lower renin in

patients treated with ACE-inhibitors and diuretics. Heart
1998; 80: 45.
110 Bisoprolol
m 111
10
Hypertension Detection and Follow-up-Program

Cooperative Group. Five year findings of the hypertension
detection and follow-up-program. I. Reduction in mortality of
persons with high blood pressure, including mild hypertension.
JAMA 1979; 242: 2562.
11
Jonas M et al. Usefulness of beta-blocker therapy in patients

with non-insulin dependent diabetes mellitus and coronary
artery disease. Am J Cardiol 1996; 77: 1273.
12
Kjekshus J et al. Diabetic patients and beta-blockers after

acute myocardial infarction. European Heart J 1990; 11: 43.
13
Lechat P et al. Clinical effects of beta-adrenergic blockade in

chronic heart failure: a meta-analysis of double-blind, placebocontrolled, randomized trials. Circulation 1998; 98: 1184.
14
Lohmann FW. Die Beeinflussung des Stoffwechsels durch

Beta-Rezeptoren-Blocker. Klin Wschr 1981; 59: 49.
15
Packer M et al. The effect of carvedilol on morbidity and

mortality in patients with chronic heart failure. N Engl J Med
1996; 334: 1349.
16
Piantanelli L et al. Atenolol-induced regulation of leukocyte

2-adrenoceptors in hypertension. Pharmacol 1984; 29: 210.
17
Sawicki PT et al. Antihypertensive treatment and mortality

in diabetic patients. Diabetologica 1997; 40 : 134.
18
SHORR RI et al. Antihypertensives and the risk of serious

hypoglycemia in older persons using insulin or sulfonylureas.
JAMA 1997; 278: 40.
19
UK Prospective Diabetes Study Group.

Tight blood pressure control and risk of macrovascular and
microvascular complications in type 2 diabetes: UKPDS 38.
Br Med J 1998; 317: 703.
20

Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes:
UKPDS 39. Br Med J 1998; 317: 713.
21

Cost effectiveness analysis of improved blood pressure control
in hypertensive patients with type 2 diabetes: UKPDS 40.
Br Med J 1998; 317: 720.
22
Waagstein F et al for the Metroprolol in

dilated Cardiomyopathie (MDC) Trial Study Group.
Beneficial effects of metoprolol in idiopathic dilated
cardiomyopathy. Lancet 1993; 342: 1441.
23
Weber F et al. Heart rate variability and ischaemia in

patients with coronary heart disease and stable angina
pectoris. Eur Heart J 1999; 20: 38.
24
Webster MWI, Scott RS. What cardiologists need to know

about diabetes. Lancet 1997; 350 (Suppl I): 23.
25
Amabile G, Serradimigni A. Comparison of bisoprolol with

nifedipine for treatment of essential hypertension in the
elderly: Comparative double-blind trial. Eur Heart J 1987;
8 (Suppl M): 65.
26
Asmar R et al. Duration of action of bisoprolol after cessation

of a 4 week treatment and its influence on pulse wave velocity
and aortic diameter: A pilot study in hypertensive patients.
Eur Heart J 1987; 8 (Suppl M): 115.
27
Asmar R et al. Effect of bisoprolol on blood pressure and

arterial hemodynamics in systemic hypertension. Am J Cardiol
1991; 68: 61.
28
Bailliart O et al. Effects of bisoprolol on local vascular

resistance. Eur Heart J 1987; 8 (Suppl M): 87.
12.2 Bisoprolol
112 Bisoprolol
m 113
39
Bethge H et al. Bisoprolol in angina pectoris. Cardiovasc

Drug Reviews 1991; 2: 110.
Broekmann CPM et al. Bisoprolol and hypertension:

effects on sexual functioning in men. J Sex Marital Ther
1992; 4: 325.
40
Bethge H. Bewertende Zusammenfassung Klinik. Merck KGaA,

Darmstadt, 1985.
Broncel M et al. Bisoprolol in the treatment of hypertension

in the elderly. J Hum Hypertens 1998; 12: 643.
41
Buchner-Mll D et al. Safety update on bisoprolol.

Merck KGaA, Darmstadt, 1995.
42
Buchner-Mll D et al. Wirksamkeit und Vertrglichkeit

von Bisoprolol bei der Langzeittherapie der essentiellen
Hypertonie. Hochdruck 1989; 9: 33.
43
Bueno J et al. Bisoprolol vs. chlorthalidone: A randomized,

double-blind comparative study in arterial hypertension.
J Cardiovasc Pharmacol 1990; 16 (Suppl 5): 189.
44
Bhler FR et al. Double-blind comparison of the cardioselective -blockers bisoprolol and atenolol in hypertension:
The Bisoprolol International Multicenter Study (BIMS).
45
Bhring KU et al. Pharmacokinetics and metabolism

of bisoprolol-C14 in three animal species and in humans.
46
Bulpitt CJ et al. Bisoprolol and nifedipine retard in

elderly hypertensive patients: effect on quality of life.
J Hum Hypertens 2000; 14: 205.
47
Chang PC et al. 1-Adrenoceptor selectivity of single oral

doses of bisoprolol and atenolol. J Cardiovasc Pharmacol
1988; 12: 317.
48
Chang PC et al. Double-blind comparison of the

1-selectivity of single doses of bisoprolol and atenolol.
29
Bethge H et al. 24-Stunden-Wirkung von Bisoprolol auf

Ruhe- und Belastungsblutdruck. Fortschr Med 1989; 107: 153.
30
31
32
33
Boejinga JK et al. A dose-finding study with bisoprolol

in the treatment of mild to moderate essential hypertension.
Curr Ther Res 1990; 6: 1036.
Bonelli J, Staribacher H. Hemodynamic effects of bisoprolol
in patients with coronary heart disease: Influence of various
bisoprolol plasma concentration. J Cardiovasc Pharmacol
1986; 8 (Suppl 11): 83.
34
Bracchetti D et al. A double-blind comparison of bisoprolol

and captopril for treatment of essential hypertension in the
elderly. Cardiovasc Drugs Ther 1990; 4: 261.
35
Breed JGS et al. Quality of life perception during antihypertensive treatment: a comparative study of bisoprolol
and enalapril. J Cardiovasc Pharmacol 1992; 20: 750.
36
37
38
Brodde O-E et al. Differentiation of 1- and 2- adrenoceptor

mediated effects in humans. Am J Physiol 1988; 254: II 199.
Brodde O-E. 1 - und 2 - Adrenozeptoren sind funktionell an
der Kontraktionskraft im rechten Vorhof des Menschenherzens beteiligt. In: Schlmerich P and Holtmeier H-J (Hg.):
Kardiovaskulre Rezeptoren. Thieme Verlag, Stuttgart
1986: 86.
Brodde O-E. Bisoprolol (EMD 33 512), a highly selective
1-adrenoceptor antagonist: in vitro and in vivo studies.
114 Bisoprolol
m 115
49
Chatterje SS. The cardioselective and hypotensive effects

of bisoprolol in hypertensive asthmatics.
50
CIBIS Investigators and Committees: Lechat Ph et al.

A randomized trial of -blockade in heart failure.
The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation
1994; 90: 1765.
59
De Muinck E et al. Comparative study on the

antianginal efficacy and safety of bisoprolol and atenolol
a multicenter international randomized study in angina
pectoris (MIRSA). J Cardiovasc Pharm 1992; 19: 870.
60
De Muinck E et al. Comparison of the effects of two

doses of bisoprolol on exercise tolerance in exercise-induced
stable angina pectoris. Eur Heart J 1987; 8 (Suppl M): 31.
51
CIBIS II Investigators and Committees.

The Cardiac Insufficiency Bisoprolol Study II (CIBIS II):
a randomized trial. Lancet 1999; 353: 9.
61
De Teresa E et al. Effects of Bisoprolol on Left Ventricular

Hypertrophy in Essential Hypertension. Cardiovasc Drugs
Ther 1994; 6: 837.
52
Clmenty J et al. Study of the electrophysiological properties

of intravenous bisoprolol in patients with and without
coronary artery disease by programmed stimulation.
62
Dominguez LJ et al. Bisoprolol and captopril effects

on insulin receptor kinase activity in essential hypertension.
Am J Hypertens 1997; 10: 1349.
63
53
Conrad A et al. Elektrophysiologische Befunde von

Bisoprolol bei Patienten mit supraventrikulren Tachykardien.
Klin Wschr 1986; 64 (Suppl V): 135.
Dorow P et al. Effects of single oral doses of bisoprolol

and atenolol on airway function in nonasthmatic
chronic obstructive lung disease and angina pectoris.
Eur J Clin Pharmacol 1986; 31: 143.
54
Copie X et al. Effects of -blockade with bisoprolol

on heart rate variability in advanced heart failure: Analysis
of scatterplots of R-R intervals at selected heart rates.
Am Heart J 1996; 132: 369.
64
Dorow P et al. Long-term treatment of angina pectoris

with bisoprolol or atenolol in patients with chronic
obstructive bronchitis: A randomized, double-blind crossover
study. J Cardiovasc Pharmacol 1990; 16 (Suppl 5): 36.
55
Davidov ME et al. Bisoprolol, a once-a-day beta-blocking

agent for patients with mild to moderate hypertension.
Clin Cardiol 1994; 17: 263.
65
56
De Divitiis O et al. Bisoprolol in the treatment of angina

pectoris: a double blind comparison with verapamil.
Dorow P and Tnnesmann U. Dose-response relationship

of the -adrenoceptor antagonist bisoprolol in patients with
coronary heart disease and chronic obstructive bronchitis.
66
De Hoon JNJM et al. Quality of life comparison

between bisoprolol and nifedipine retard in hypertension.
Cardiovasc Drugs Therapy 1997; 11: 465.
Englert RG and Dring G. Leistungssteigerung bei

Angina-Pectoris-Patienten whrend Langzeittherapie mit
Bisoprolol. Mnch med Wschr 1987; 129: 117.
67
Esper RJ et al. Non invasive assessment of left

ventricular performance after administration of bisoprolol.
57
58
De Muinck E et al. Bisoprolol pilot studies in myocardial

infarction. J Cardiovasc Pharmacol 1990; 16 (Suppl 5): 196.
116 Bisoprolol
m 117
68
Fogari R et al. -blocker effects on plasma lipids in

antihypertensive therapy: importance of the duration of
treatment and the lipid status before treatment.
78
Grtelmeyer R and Klingmann I.

Vergleichende Untersuchungen zur zentralnervsen
Wirkung der Beta-Rezeptorenblocker Pindolol und Bisoprolol.
Arzneimittel-Forsch 1985; 35: 1707.
69
Fogari R et al. Effects of different beta-blockers

on lipid metabolism in chronic therapy of hypertension.
Int J Clin Pharm Ther Tox 1988; 26: 597.
79
Gosse P et al. Betablockers vs. angiotensin-converting

enzyme inhibitors in hypertension: effects on left ventricular
hypertrophy. J Cardiovasc Pharmacol 1990; 16 (Suppl 5): 145.
70
Fogari R et al. -blocker effects on plasma lipids during

prolonged treatment of hypertensive patients with
hypercholesteremia. J Cardiovasc Pharmacol 1999; 33: 534.
80
Gosse P et al. Comparison of bisoprolol and verapamil in

hypertension: influence on left ventricular mass and function
a pilot study. Thrapie 1999; 54: 217.
71
Fogari R, Zoppi A. The clinical benefits of 1-selectivity.

Rev Contemp Pharmacother 1997; 8: 45.
81
Grevel J et al. Population pharmacokinetic analysis of

bisoprolol. Clin Pharmacokinet 1989; 17: 53.
72
Frithz G and Weiner L. Effects of bisoprolol, dosed once

daily, on blood pressure and serum lipids and HDL- cholesterol
in patients with mild to moderate hypertension.
82
73
Frithz G and Weiner L. Long-term effects of bisoprolol on

blood pressure, serum lipids and HDL-cholesterol in patients
with essential hypertension. J Cardiovasc Pharmacol 1986;
8 (Suppl 11): 134.
Haasis R and Bethge H. Exercise blood pressure and heart

rate reduction 24 and 3 hours after drug intake in hypertensive patients following 4 weeks of treatment with
bisoprolol and metoprolol: A randomized multicenter doubleblind study (BISOMET). Eur Heart J 1987; 8 (Suppl M): 103.
83
Haffner CA, Horton RC et al. A metabolic assessment

of the beta1-selectivity of bisoprolol. J Human Hypertension
1992; 6: 397- 400.
84
Haneda T et al. Effect of bisoprolol, a 1-selective

-blocker, on lipid and glucose metabolism and quality
of life in elderly patients with essential hypertension.
Jpn J Geriat 1998; 35: 33.
85
Harting J et al. Pharmacodynamic profile of

the selective 1-adrenoceptor antagonist bisoprolol.
86
Husler G et al. High 1-selectivity and favourable

pharmacokinetics as the outstanding properties of bisoprolol.
74
Frithz G. 5th International Symposium on Cardiovascular

Pharmacotherapy, Minneapolis, August 1993.
75
Giesecke HG et al. Three years experience with bisoprolol

in the treatment of mild to moderate hypertension.
76
77
Giesecke H-J and Englert R.

Langzeitbehandlung der essentiellen Hypertonie mit
Bisoprolol.Therapiewoche 1986; 36: 1378.
Glck Z and Reubi FC. Acute changes in renal function
induced by bisoprolol, a new cardioselective betablocking
agent. Eur J Clin Pharmacol 1986; 31: 107.
118 Bisoprolol
m 119
87
Haustein KO et al. Zur blutdrucksenkenden Wirkung

von Bisoprolol, einem 1-selektiven Rezeptorenblocker
eine multizentrische Studie unter Praxisbedingungen.
Inn Med 1993; 48: 476.
88
Hayes PC et al. Single oral dose pharmacokinetics

of bisoprolol 10 mg in liver disease. Eur Heart J 1987;
8 (Suppl M): 23.
89
Heinemann L et al. Four week administration of an

ACE-inhibitor and a cardioselective -blocker in healthy
volunteers: no influence on insulin sensitivity.
Eur J Clin Invest 1995; 25 (8): 595 - 600.
90
Hffler D et al. Age dependence of therapy result and

risk in the treatment of arterial hypertension?
91
Hffler D et al. Zur Monotherapie der Hypertonie mit einem

lang wirksamen Betablocker, Therapiewoche 1988; 38: 391.
92
Hofmann A. EMD 33 512 (Bisoprolol): Bewertende

Zusammenfassung Toxikologie. Merck KGaA,
Darmstadt, 1984.
93
Honor P. Bisoprolol versus hydrochlorothiazide

plus amiloride in essential hypertension, a randomized
double-blind study. Eur Heart J 1987; 8 (Suppl M): 95.
94
Horikiri Y et al. Pharmacokinetics and

metabolism of bisoprolol enantiomers in humans.
J Pharm Sciences 1998; 87 (3): 289.
95
Janka HU et al. Einflu von Bisoprolol auf

den Kohlenhydratstoffwechsel von Typ-II-Diabetikern.
Mnch med Wschr 1986; 128: 582.
96
Janka HU et al. Influence of bisoprolol on blood glucose,

glucosuria and hemoglobin A1 in non-insulin-dependent
diabetics. J Cardiovasc Pharmacol 1986; 8 (Suppl 11): 110.
97
Jungmann E et al. Kardioselektiver Betablocker Bisoprolol.

Stellenwert in der Therapie der floriden Hyperthyreose.
Fortschr Med 1986; 104: 661.
98
Kaumann A J et al. Direct labelling of myocardial

1-adrenoceptors. Comparison of binding
affinity of 3H - () - bisoprolol with its blocking potency.
Naunyn Schmiedebergs Arch Pharmacol 1985; 331: 27.
99
Keck M. Einflu einer selektiven vs. nicht-selektiven

Beta-rezeptorblockade auf das Stoffwechselverhalten bei
Ausdauer- bzw. symptomlimitierter Belastung von Patienten
mit stabiler Belastungskoronarinsuffizienz und Diabetes
mellitus Typ IIa. Herz/Kreislauf 1995; 27: 256.
100 Keim HJ et al. Behandlung der leichten bis

mittelschweren essentiellen Hypertonie mit Bisoprolol.
Therapiewoche 1988; 38: 3507.
101 Kendall MJ et al. Assessment of 1-selectivity of
bisoprolol and atenolol by means of their influence on the
lipolytic response to an infusion of terbutaline.
J Clin Pharm Ther 1991; 16: 25 -29.
102 Kirch W et al. Interaction of bisoprolol with cimetidin and
rifampicin. Eur J Clin Pharmacol 1986; 31: 59.
103 Kirch W et al. Pharmacokinetics of bisoprolol during
repeated administration to normal subjects and patients with
kidney or liver disease. Clin Pharmacokin 1987; 13 : 110
and: Kirch W quoted after Leopold G. Discussion session 2.
104 Kirsten R et al. Influence of different bisoprolol doses on
hemodynamics, plasma catecholamines, platelet aggregaton,
and 2 - and -receptors in hypertensive patients.
105 Klockow M et al. Studies on the receptor profile of bisoprolol.
120 Bisoprolol
m 121
106 Kohli RS et al. Efficacy of once daily bisoprolol in stable

angina pectoris: An objective comparison with atenolol and
a long term follow up. Eur Heart J 1985; 6: 845.
116 Lewis R et al. Comparison of bisoprolol and atenolol in

the treatment of mild to moderate hypertension.
Br J Clin Pharmacol 1988; 26: 53.
107 Krmer B et al. Comparison of bisoprolol with other

beta adrenoceptor blocking drugs. J Cardiovasc Pharmacol
1986; 8 (Suppl 11): 46.
117 Lichtlen P et al. Evaluation of the effects of oral bisoprolol

(EMD 33 512) on exercise tolerance in patients suffering
from stable angina pectoris due to coronary heart disease.
108 Lammers JWJ et al. Ventilatory effects of beta1-receptorselective blockade with bisoprolol and metoprolol in asthmatic
patients. Eur J Clin Pharmacol 1984; 27: 141.
109 Lechat P for The CIBIS II Scientific Committee.
Design of the Cardiac Insufficiency Bisoprolol Study II (CIBISII).
Fundam Clin Pharmacol 1997; 11: 138.
110 Leeman M et al. Bisoprolol and atenolol in essential
hypertension: effects on systemic and renal
hemodynamics and on ambulatory blood pressure.
J Cardiovasc Pharmacol 1993; 22: 785.
111 Leopold G et al. Basic pharmacokinetics of bisoprolol,
a new highly beta1-selective adrenoceptor antagonist.
J Clin Pharmacol 1986; 26: 616.
112 Leopold G et al. Pharmacodynamic profile of
bisoprolol, a new 1 -selective adrenoceptor antagonist.
113 Leopold G. Balanced pharmacokinetics and metabolism
of bisoprolol. J Cardiovasc Pharmacol 1986; 8 ( Suppl 11): 16.
114 Lettenbaur H. EMD 33 512 (Bisoprolol): Prfung der
Wirkung auf die Serumglukosekonzentration an Ratten im
Vergleich zu Propranolol. Merck KGaA, Darmstadt, 1979.
115 Levy P et al. A cost-minimization of heart failure therapy
with bisoprolol in the French setting: an analysis from CIBIS
trial data. Cardiovasc Drugs Ther 1998; 12: 301.
118 Lie K et al. Efficacy and safety of bisoprolol in the early

phase of myocardial infarction with special regard to central
hemodynamics and ventricular arrhythmias. Merck KGaA,
Darmstadt, 1990.
119 Lie K et al. Efficacy and safety of i.v. and subsequently
oral bisoprolol in post-infarction patients. Merck KGaA,
Darmstadt, 1989.
120 Liebau H. Monotherapie der essentiellen Hypertonie
mit Bisoprolol eine Multizenter-Langzeitstudie.
121 Lithell J et al. Efficacy and safety of bisoprolol and
atenolol in patients with mild to moderate hypertension:
A double-blind parallel group international multicenter study.
Eur Heart J 1987; 8 (Suppl M) (1987): 55.
122 Lohmller G et al. Klinische Untersuchungen
zur 1-Selektivitt von Bisoprolol unter Dauertherapie.
Mnch med Wschr 1988; 130: 595.
123 Macquin-Mavier I et al. Comparative effects of
bisoprolol and acebutolol in smokers with airway obstruction.
124 Maisch B et al. Effects of bisoprolol on cardiac
performance in coronary heart disease. Eur J Clin Pharmacol
1989; 36: 217.
122 Bisoprolol
m 123
125 Malek M et al. A cost minimisation analysis of

cardiac failure treatment in the UK using CIBIS trial data.
Int J Clin Pract 1999; 53 (1): 19.
126 Maltz MB et al. A comparison of once daily bisoprolol,
5 and 10 mg, and atenolol 100 mg in the treatment of angina
pectoris. Eur Heart J 1987; 8 (Suppl M): 37.
127 Manalan AS et al. Characterization of [3H] () carazolol
binding to -adrenergic receptors; Circ Res 1981; 49: 326.
128 Martinez O et al. Bisoprolol and nifedipine s.r. in the treatment
of hypertension in the elderly. J Cardiovasc Pharmacol 1990;
16 ( Suppl 5): 95.
129 Mc Devitt DG quoted after Leopold G.
Discussion session 2. Eur Heart J 1987; 8 (Suppl M): 147.
130 Mc Murray J. CIBIS II and health economics. Presentation at
the ESC congress, Barcelona 1999.
131 Mengden T et al. An evaluation of self-measured blood
pressure in a study with a calcium-channel antagonist versus
a -blocker. Am J Hypertens 1992; 5: 154.
132 Mengden T et al. Comparison of casual, ambulatory
and self-measured blood pressure in a study of nitrendipine vs
bisoprolol. Eur J Clin Pharmacol 1992, 42: 569.
133 Motz W et al. Verbesserung der Koronarreserve nach Hypertrophieregression durch blutdrucksenkende Therapie mit
einem -Rezeptorenblocker. Dtsch Med Wschr 1993; 15: 535.
134 Nakanishi T et al. Effect of bisoprolol hemifumarate on the
diurnal variation of blood pressure in patients with essential
hypertension. Current Ther Res 1992; 5: 779.
135 Naline E et al. Comparative -adrenoceptor blocking
effects to propranolol, bisoprolol, atenolol, acebutolol and
diacetolol on the human isolated bronchus.
136 Neuss H et al. Electrophysiologic effects of an acute

-blockade induced by bisoprolol in patients with supraventricular tachycardia as assessed by his-bundle
electrograms. J Cardiovasc Pharmacol 1986; 8 (Suppl 11): 167.
137 Neutel JM et al. Application of ambulatory blood pressure
monitoring in differentiating between antihypertensive agents.
Am J Med 1993; 94: 181.
138 Neutel JM et al. Comparison of bisoprolol with atenolol for
systemic hypertension in four population groups (young,
old, black and nonblack) using ambulatory blood pressure
monitoring. Am J Cardiol 1993; 72: 41.
139 Palmer AJ et al. Economic implications of the total ischemic
burden bisoprolol study (TIBBS) follow-up. J Med Economics
1998; 1: 263 -280.
140 Payton CD et al. The single dose pharmacokinetics of bisoprolol (10 mg) in renal insufficiency: The clinical significance
of balanced clearance. Eur Heart J 1987; 8 (Suppl 11): 15.
141 Pfannenstiel P et al. Pharmacokinetics of bisoprolol and
influence on serum thyroid hormones in hyperthyroid patients.
J Cardiovasc Pharmacol 1986: 8 (Suppl 11): 100.
142 Poldermans D et al. The effect of bisoprolol on perioperative
mortality and myocardial infarction in high-risk patients
undergoing vascular surgery. N Engl J Med 1999; 341: 1789.
143 Portegies MCM et al. Effects of bisoprolol and isosorbide
dinitrate on the circadian distribution of myocardial ischaemia.
Curr Ther Res 1995; 56 : 1225 -1236.
144 Pousset F et al. Effects of bisoprolol on heart rate variability
in heart failure. Am J Cardiol 1996; 77: 612.
145 Prager G et al. Wirkung von Bisoprolol bei koronarer
Herzkrankheit. DMW 1984; 109: 1914.
124 Bisoprolol
m 125
146 Prager G et al. Effect of -adrenergic blockade on circadian

rhythm of myocardial ischaemia in ambulatory patients
with stable angina. J Cardiovasc Pharmacol 1989; 13: 638.
156 Schliep H-J et al. Antagonistic effects of bisoprolol on

several -adrenoceptor-mediated actions in anaesthetised cats.
Eur J Pharmacol 1986; 123: 253.
147 Prager G et al. Ergometrischer Vergleich von Wirkungsstrke

und Wirkungsdauer zweier Bisoprololdosen bei
Angina-pectoris-Patienten. Therapiewoche 1987; 37: 2116.
157 Schliep H-J et al. 1-Selectivity of bisoprolol, a new

-adrenoceptor antagonist in anesthetised dogs and guinea
gigs. J Cardiovasc Pharmacol 1984; 6: 1156.
148 Prager G et al. Langzeitbehandlung der essentiellen Hypertonie mit Bisoprolol : Eine multizentrische Monotherapiestudie
unter Bercksichtigung des Belastungshochdrucks.
158 Schmidt TH et al. Wirkung von Bisoprolol auf Blutdruck und

Herzfrequenz unter Labor- und Alltagsbedingungen bei
gesunden zirkulatorisch hyper- und hyporeaktiven Probanden.
149 Prager G et al. Therapeutischer Dosisbereich von Bisoprolol

whrend einer Langzeitstudie bei Angina-pectoris-Patienten.
Herz / Kreisl 1988; 20: 505.
159 Schmidt U et al. Einflu von Bisoprolol auf die Fahrleistung

und das Kreislaufverhalten von Autofahrern mit koronarer
Herzkrankheit. Herz / Kreislauf 1987; 19: 273.
150 Proclemer A et al. Electrophysiological effects of bisoprolol.

160 Schnabel P et al. Binding properties of -adrenoceptor

antagonists used in heart failure at recombinant 1, 2 and
3-adrenoceptors. Eur Heart J 1999; 20 (Suppl): A 28.
151 Saku K et al. Effects of lisinopril and bisoprolol on

lipoprotein metabolism in patients with mild-to-moderate
essential hypertension. Clin Therapeutics 1995; 17: 1136.
152 Sassen LMA et al. Bisoprolol improves perfusion
of ischemic myocardium in anesthesized pigs. Br J Pharmacol
1988; 95: 361.
153 Sayer JW et al. Circadian activity of the endogenous
fibrinolytic system in stable coronary artery disease: effects
of beta-adrenoceptor blockers and angiotensin-converting
enzyme inhibitors. JACC 1998; 32: 1962.
154 Schdlich PK et al. Economic evaluation of the cardiac
insufficiency bisoprolol study for the Federal Republic
of Germany. Pharmacoeconomics 1998; 13 (1 Pt 2): 147.
155 Scheler S et al. Reduction of ST segment depression in hypertensive microvascular angina. Circulation 1990; 82: III. 164.
161 Schnellbacher K et al. Effect of bisoprolol on exercise

tolerance in patients with coronary heart disease: placebocontrolled double-blind cross-over study. J Cardiovasc
Pharmacol 1986; 8 (Suppl 11): 143.
162 Schnellbacher K et al. Hemodynamics and exercise
tolerance after bisoprolol, nifedipine, and their combination in
patients with angina pectoris. J Cardiovasc Pharmacol 1990;
16 (Suppl 5): 201.
163 Smith C, Teitler M. Beta-blocker selectivity at cloned human
beta1 and beta 2-adrenergic receptors. Cardiovasc Drugs
and Ther 1999; 13: 123.
164 Steinmann E et al. Acute hemodynamic effects of bisoprolol,
a new 1-selective adrenoceptor blocking agent, in
patients with coronary artery disease. J Cardiovasc Pharmacol
1986; 8: 1044.
126 Bisoprolol
m 127
165 Tattersfield AE et al. Assessment of -adrenoceptor

selectivity of a new -adrenoceptor antagonist, bisoprolol,
in man. Br J Clin Pharmacol 1984; 18: 343.
175 Verrostte JM et al. Interaction of bisoprolol and procainamid in human cardiac impulse generation and conduction.
166 Terol I et al. Bisoprolol in the treatment of chronic stable angina

pectoris. J Cardiovasc Pharmacol 1990; 16 (Suppl 5): 208.
176 Von Arnim T et al. Medical treatment to reduce total

ischemic burden: Total Ischemic Burden Bisoprolol Study (TIBBS),
a multicenter trial comparing bisoprolol and nifedipine.
JACC 1995; 1: 231.
167 Vaisse B et al. Assessment of antihypertensive effect by

blood pressure monitoring: Applications to bisoprolol and
lisinopril in a double-blind study. J Cardiovasc Pharmacol
1997; 29: 612.
168 Van Bortel LMAB et al. Bisoprolol versus enalapril; een
dubbelblind vergelijkend onderzoek naar de invloed op de
kwaliteit van het leven. 18 th Ann J Drug Ther Res 1993; 151.
169 Van de Ven LLM et al. The effects of bisoprolol and propranolol on symptoms and thyroid function in hyperthyroidism.
Acta Therapeut 1995; 21: 65.
170 Van de Ven LLM et al. Which drug to choose for stable angina
pectoris: a comparative study between bisoprolol and nitrates.
Internat J Cardiol 1995; 47: 217.
171 Van de Ven LLM et al. Safety of beta-blocker therapy with and
without thrombolysis: a comparison of bisoprolol and atenolol
in acute myocardial infarction. Curr Ther Res 1996; 57: 313.
172 Van de Ven LLM et al. Prophylactic treatment of
migraine with bisoprolol: a placebo-controlled study.
Cephalalgia 1997; 17: 596.
173 Van de Ven LLM. Age-dependent differences in the efficacy
and tolerability of different classes of antihypertensive drugs.
Clin Drug Invest 1997; 14: 16.
174 Van Molkot FHM et al. Impact of antihypertensive
treatment on quality of life: comparison between bisoprolol
and bendrofluazide. J Hum Hypertens 1999; 13: 559.
177 Von Arnim T et al. Prognostische Einflsse bei stummer

Myokardischmie. Ein-Jahres-Nachbeobachtung von TIBBS.
Kardiologie 1995; 84 (Suppl 1): A 628.
178 Von Arnim T. Prognostic significance of transient ischemic
episodes; response to treatment shows improved prognosis.
Results of the TIBBS-follow-up. J Am Coll Cardiol 1996; 28: 20 - 4.
179 Von Arnim T. Transient ischemic episodes on ambulatory electrocardiogram: influence on prognosis and improved prognosis
following response to medical treatment. Results of the
TIBBS- follow -up. Eur Heart J 1995; 16 (Abstract Suppl): 178.
180 Vulpis V et al.: Effeti di bisoprololo e atenololo sul metabolismo glicidico in pazienti ipertesi con diabete mellito non
insulino-dipendente. Minerva Med 1991; 82: 189.
181 Wagner G. Summary of short- and long-term studies with
bisoprolol in coronary heart disease. J Cardiovasc Pharmacol
1986; 8 (Suppl 11): 160.
182 Wagner G. The treatment of patients with angina pectoris
with bisoprolol, a new highly selective 1-adrenoceptorantagonist. In: Birkenhger WH et al. (Hg.): -blockade
agonist hypertension. Focus on bisoprolol. Proc of a Symp,
Scheveningen-Excerpta med Amsterdam 1988: 57.
183 Walther H et al. Effects of oral bisoprolol (EMD 33 512) once
daily on exercise capacity in patients with angina pectoris due
to coronary heart disease. Merck KGaA, Darmstadt, 1984.
128 Bisoprolol
m 129
Notes
184 Warrington SJ et al. Bisoprolol: Studies on potential interactions with theophylline and warfarin in healthy volunteers.
185 Weiner L et al. Antihypertensive effects of bisoprolol
during once daily administration in patients with essential
hypertension. A dose-ranging study with parallel groups.
186 Weiner L et al. Dose-effect relationship and longterm
effects of bisoprolol in mild to moderate hypertension.
187 Wellstein A et al. Affinity and selectivity of -adrenoceptor
antagonists in vitro. J Cardiovasc Pharmacol 1986;
8 (Suppl 11): 36.
188 Wellstein A et al. Concentration kinetics of propranolol,
bisoprolol and atenolol in humans assessed with
chemical detection and a subtype selective adrenoceptor.
189 Wellstein A et al. Reduction of exercise tachycardia in man
after propranolol, atenolol and bisoprolol in comparison to
beta-adrenoceptor occupancy. Eur Heart J 1987; 8 (Suppl M): 3.
190 Wrz R et al. Migraine prophylaxis with bisoprolol. (Headache
Quarterly, Current Treatment and Research 1992; 3: 64 -72).
Translated from R. Wrz et al. Migrneprophylaxe durch
Bisoprolol. Fortschr. Med 1992; 110: 268 -272.
191 Wotschokowsky M. Pharmakologisch relevante physikochemische Eigenschaften von Bisoprolol-hemifumarat
(EMD 33 512). Merck KGaA, Darmstadt, 1985.
192 ZHU LM et al. The efficacy of once-daily bisoprolol,
lacidipine and lisinopril on the 24-hour blood pressure in
patients with essential hypertension. J Hypertension 1997;
15 (Suppl 4 ): 212
130 Bisoprolol
m 131
Notes
Notes
Bisoprolol
Bisoprolol at a glance
Bisoprolol is reliably effective for 24 hours in hypertension
and coronary artery disease (angina pectoris) with a single
dose per day.
Bisoprolol has demonstrated significant survival benefit in
CHF patients whatever the aetiology of the disease.
Bisoprolol is well tolerated in all three indications.
Bisoprolol has a high 1-selectivity over the entire therapeutic dosage range and at all times.
Bisoprolol is the most potent 1-selective -blocker thus
requiring the lowest substance intake.
Bisoprolol is in general metabolically neutral (lipids/ longterm therapy, glucose).
Bisoprolol has a bioavailability of about 90%.
Bisoprolol is removed from the plasma via 2 equally
effective routes of clearance (balanced clearance):
50% metabolisation to inactive metabolite
50% renal excretion of the unchanged substance.
No dosage adjustment of bisoprolol is necessary in patients
with mild to moderate renal or hepatic dysfunction.
A maximum dose of 10 mg /day is called for only in terminal
stages of insufficiency.
W 811195
070201

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Bisoprolol

Status: February 2001

Pharmacology and biochemistry

2.2 Intrinsic sympathomimetic activity (ISA)

2.3 Membrane-stabilising activity

2.4 Antihypertensive effect

2.6 Renin-angiotensin system

2.7 Duration of action

2.8 Pharmacology of side-effects

3.1 Acute toxicity

3.2 Short-term toxicity

3.3 Chronic toxicity

3.4 Specific toxicity studies

Treatment of essential hypertension

6.1 Blood pressure at rest duration

6.2 Blood pressure during exercise

4.4 Elimination half-life

6.3 Normalisation rate

6.4 Long-term treatment of arterial

4.6 Variability of plasma concentrations

4.3 Metabolism and excretion

6.5 Regression of left ventricular

6.6 Quality of life

6.7 Therapeutic comparison in

Bisoprolol and atenolol

6.8 Safety and efficacy in special populations

6.8.1 Elderly hypertensives

Treatment of angina pectoris in

7.1 Duration of action

7.3 Success rate

7.4 Silent ischaemia

7.6 Therapeutic comparison in

Bisoprolol and atenolol

Treatment of chronic heart failure

8.1.1 Heart rate variability

Primary endpoint (all-cause mortality)

Further areas of research

9.2 Prophylaxis of migraine

9.3 Perioperative risk reduction

Plasma protein binding:

Passage into milk:

Chemical structure of bisoprolol fumarate (2:1).

The molecular weight is 383.48; the white crystalline substance

Thus, bisoprolol is less lipophilic than propranolol but more lipophilic

Partition coefficients of bisoprolol at 37C [113,190 ].

Pharmacology and biochemistry

Ratio of constants of inhibition (c i )

The respective constants of inhibition (c i ) of bisoprolol, atenolol,

2.2 Intrinsic sympathomimetic activity (ISA)

2.3 Membrane -stabilising activity

The cardioprotective effect of bisoprolol was further demonstrated

2.4 Antihypertensive effect

2.6 Renin-angiotensin system

2.7 Duration of action

2.8 Pharmacology of side-effects

The toxicological studies revealed no irreversible organ damage

The performed animal experimental investigations indicated for

From the 30 mg per kg tolerated in the chronic study in dogs

Glucose tolerance was investigated in rats and was only slightly

3.1 Acute toxicity

3.2 Short-term toxicity

3.3 Chronic toxicity

3.4 Specific toxicity studies