Bisoprolol

Cardioselective Beta-Blocker

Status: February 2001

2 Bisoprolol m 3

Contents

Pharmacokinetic data 8

Composition 8

1 Chemistry 9

2 Pharmacology and biochemistry 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

3 Toxicology 17

3.1 Acute toxicity 17

3.2 Short-term toxicity 17

3.3 Chronic toxicity 17

Merck KGaA 3.4 Specific toxicity studies 18

Darmstadt, Germany
www.bisoprolol.com
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4 Pharmacokinetics 19 6 Treatment of essential hypertension 52

4.1 Bioavailability 20 6.1 Blood pressure at rest – duration 52

of action
4.2 Distribution 20
6.2 Blood pressure during exercise – 56
4.3 Metabolism and excretion 20 duration of action

4.4 Elimination half-life 25 6.3 Normalisation rate 58

4.5 Interactions 25 6.4 Long-term treatment of arterial 61

hypertension with bisoprolol
4.6 Variability of plasma concentrations 28
6.5 Regression of left ventricular 63
5 Clinical profile 29 hypertrophy

5.1 Clinical pharmacology 29 6.6 Quality of life 64

5.1.1 Haemodynamics 29
6.7 Therapeutic comparison in 67
5.1.2 Electrophysiology 32
hypertensive patients
5.1.3 ␤1-selectivity 33
5.1.4 Receptor occupancy 33 6.7.1 Bisoprolol and atenolol 67
5.1.5 Lung function 35 6.7.2 Bisoprolol and metoprolol 70
5.1.6 Peripheral circulation 38 6.7.3 Bisoprolol and captopril 70
5.1.7 Metabolism 41 6.7.4 Bisoprolol and enalapril 71
5.1.8 ␤2-receptor density 48 6.7.5 Bisoprolol and lisinopril 71
5.1.9 Plasma renin activity 48 6.7.6 Bisoprolol and nifedipine retard 72
5.1.10 Fibrinolytic system 50 6.7.7 Bisoprolol and nitrendipine 72
5.1.11 Dose-response relationship 51 6.7.8 Bisoprolol and verapamil 74
6.7.9 Bisoprolol and a thiazide/potassium-sparing 74
diuretic combination
6.7.10 Bisoprolol and chlorthalidone 74
6.7.11 Bisoprolol and bendrofluazide 75
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6.8 Safety and efficacy in special populations 75 8.2 CIBIS II 95

6.8.1 Elderly hypertensives 75 8.2.1 Primary endpoint (all-cause mortality) 96
6.8.2 Diabetic hypertensives 76 8.2.2 Secondary endpoints 97
8.2.3 Additional analysis 98
7 Treatment of angina pectoris in 78 8.2.4 Pharmacoeconomic analyses 100
coronary heart disease
9 Further areas of research 101
7.1 Duration of action 78
9.1 Hyperthyreosis 101
7.2 Haemodynamics 80
9.2 Prophylaxis of migraine 101
7.3 Success rate 80
9.3 Perioperative risk reduction 102
7.4 Silent ischaemia 82
10 Psychophysiological functions 104
7.5 Cardioprotection 83
11 Tolerability 105
7.6 Therapeutic comparison in 84
coronary patients 12 References 109
7.6.1 Bisoprolol and atenolol 84
12.1 General 109
7.6.2 Bisoprolol and nifedipine 86
7.6.3 Bisoprolol and verapamil 89
12.2 Bisoprolol 111
7.6.4 Bisoprolol and isosorbide dinitrate 90

8 Treatment of chronic heart failure 91

8.1 CIBIS 91
8.1.1 Heart rate variability 95
8.1.2 Pharmacoeconomic analyses 95
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1 Chemistry

Pharmacokinetic data Bisoprolol fumarate (2:1) is the INN for (±) -1- [ [␣- (2-isopropoxy-
ethoxy)-p-tolyl ]oxy]-3- (isopropylamino)-2- propanol fumarate (2:1).
Absorption rate: > 90% It is a racemate and as a derivative of phenoxyaminopropanol it
belongs to the class of therapeutic substances which are known as
First-pass effect: <10%
the ␤-blockers. The structural formula is given in Fig.1.
Bioavailability: 90%
Cmax: ~50 ng /ml Fig. 1: Chemical structure of bisoprolol fumarate (2:1).

(10 mg bisoprolol /die; steady-state)

tmax: 2 –3 h
CH3
Elimination half-life: 10 –12 h
O N CH3
Clearance: 50% unchanged OH H HOOC
50% metabolised 1/2 CH
Excretion: approx. 95% renal HC
2% faecal COOH
O CH3
Renal clearance: 140 ml /min O
CH3
Distribution volume: 3.21 / kg
Plasma protein binding: ~30%
Placental patency: yes
The molecular weight is 383.48; the white crystalline substance
Passage into milk: yes
melts at 101°C. Bisoprolol fumarate (2:1) is very freely soluble in
water and methanol and freely soluble in ethanol and chloroform.
Composition The pKa of the bisoprolol base is 9.5. The partition coefficient (PC)
as a measure of lipophilicity has been determined in the two-
1 film-coated tablet contains
phase systems n-octanol /phosphate buffer and n-octanol / Davies
5 mg or 10 mg bisoprolol fumarate (2:1).
universal buffer (Tab.1) [113,191].
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2 Pharmacology and biochemistry

Thus, bisoprolol is less lipophilic than propranolol but more lipophilic 2.1 ␤1-selecivity
than atenolol [3]. This middle position is the determinant factor for
In comparison with other ␤1-selective ␤-blockers (atenolol,
the virtually ideal pharmacokinetic profile of bisoprolol.
metoprolol, betaxolol) bisoprolol proved to be the compound
with the highest ␤1-selectivity in all in vitro and in vivo
Tab. 1: Partition coefficients of bisoprolol at 37°C [113,190 ]. experiments and in all animal species investigated [85, 86,
98,105,127,156,157,160,163,187].
pH Partition log (PC)
coefficient (PC) metabolisation
The undesired bronchoconstrictory action component of ␤-blockers
was investigated in guinea pigs and compared with the ␤1-sympa-
n-Octanol/ 7.4 4.8 0.68 tholytic actions. Compared with the other ␤1-selective ␤-blockers,
phosphate buffer
bisoprolol exhibited the largest splitting between the dose-
n-Octanol/Davies 7.0 1.09 0.04 response curves for bronchoconstriction and reduction of heart
rate. The ratio of the heart-rate reducing action to the increase in
universal buffer 7.4 2.5 0.40 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 ther-
apeutically 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 ) The respective constants of inhibition (c i ) of bisoprolol, atenolol,
c i /␤1-receptors: c i /␤ 2-receptors determined in ligand-binding studies, betaxolol and the specific ␤2-blocker ICI 118.551 were determined
as a measure of the affinity of various ␤-blockers to ␤1 - and ␤2 - receptors, in ligand-binding studies performed on membrane preparations
respectively [according to 186,187]. of rat reticulocytes (␤2-receptors) and rat parotid glands (␤1-recep-
1 : 75 tors) 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 propran-
olol 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-recep-
1 : 35 1 : 35
tors in tissues [37].

increasing
The ␤1-selectivity of bisoprolol has also been demonstrated in
␤1- selectivity cloned human ␤-receptors [160,163]. In a study using membranes
prepared from recombinant cells selectively expressing human
300 : 1 1.8 : 1 ␤1- and ␤2-receptors [163], bisoprolol was found to have the
no selectivity
highest selectivity for the ␤1-receptor of all the ␤1-blockers studied.
Propranolol Atenolol Betaxolol Bisoprolol
Bisoprolol displayed a 19-fold affinity for the ␤1-receptor versus
increasing the ␤2-receptor. Atenolol, metoprolol and betaxolol displayed lower
␤2- selectivity 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,
ICI 118.551
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].
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2.3 Membrane -stabilising activity The cardioprotective effect of bisoprolol was further demonstrated
in anaesthetised pigs in which the coronary perfusion was reduced
Bisoprolol has no membrane-stabilising activity in the dose range
by about 60% due to stenosis of the left coronary artery. 50 µg /kg
relevant for ␤-receptor blockade.
bisoprolol increased the perfusion of the ischaemic myocardium,
Bisoprolol had a local anaesthetic action on the cornea of the rabbit and this effect was of particular benefit to the subendocardial
and the skin of the guinea pig. The concentrations of bisoprolol layers [152]. These cardioprotective effects of bisoprolol may help
required for this action were several times higher than the concen- to explain the reduction in perioperative mortality achieved with
trations required to induce ␤-blockade [85]. bisoprolol in the DECREASE study in high-risk patients undergoing
noncardiac surgery [142].

2.4 Antihypertensive effect

2.6 Renin-angiotensin system
Bisoprolol had an antihypertensive effect in all hypertension
models investigated. Bisoprolol reduced the blood pressure in Bisoprolol inhibits basal and stimulated renin secretion.
conscious dogs with renal hypertension, accompanied by only
In conscious dogs bisoprolol inhibited the secretion of renin stimu-
a slight decrease in heart rate. In comparison with bisoprolol,
lated by isoprenaline, and also reduced the basal activity of plasma
propranolol had a weaker antihypertensive effect even at a
renin. The release of renin was inhibited by about 65% and
considerably higher dose level [85]. Bisoprolol also reduced the
tachycardia by about 35% [85].
blood pressure in rats with renal hypertension. In rats with
spontaneous hypertension, the development of high blood pres-
sure could be clearly reduced by chronic treatment with
2.7 Duration of action
7.5 mg / kg bisoprolol [85].
Bisoprolol has a long duration of action.
The duration of action of bisoprolol was investigated in anaesthe-
2.5 Cardioprotection
tised guinea pigs after i.v. administration; the inhibition of
Bisoprolol protects the myocardium from ischaemia-related damage. isoprenaline-induced tachycardia was measured at various times
after the administration of the ␤-blocker. The drop in the action
Myocardial ischaemia was induced by coronary occlusion in anaesthe-
duration curve was flatter for bisoprolol than for propranolol [85].
tised open-chest dogs. The changes in the epicardial ECG typical
The results indicate a long duration of action for bisoprolol.
of myocardial hypoxia (ST segment elevation) were attenuated by
bisoprolol. A dose of 4 µg 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].
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3 Toxicology

2.8 Pharmacology of side-effects The toxicological studies revealed no irreversible organ damage
by bisoprolol. In animal experiments bisoprolol was not
The performed animal experimental investigations indicated for
cytotoxic nor mutagenic. Although it was embryotoxic at higher
bisoprolol no unexpected or serious side-effects.
doses it was not teratogenic nor was it carcinogenic in the
Even at high doses [30 and 100 mg / kg, single oral administration mouse or rat.
(rats)], the sedative effects ascribed to ␤-blockers are less marked
From the 30 mg per kg tolerated in the chronic study in dogs
with bisoprolol than, for instance, with propranolol [85].
a safety factor of 210 can be calculated for a daily dose of
Glucose tolerance was investigated in rats and was only slightly 10 mg /patient. On the basis of the 75 mg /kg tolerated in the
reduced at very high doses of bisoprolol, whereas it was considera- chronic study in rats the corresponding factor is 525 [92].
bly reduced with comparable doses of propranolol [114].
Bisoprolol did not influence the lipid metabolism of adult normoli-
3.1 Acute toxicity
pemic rats after repeated administration [85] nor was there any
quantitative change in the serum lipoprotein pattern in young On oral administration the LD 50 was 734 for the mouse and
hyperlipemic rats with increased plasma cholesterol and decreased 1116 mg /kg for the rat with a follow-up period of 14 days.
alpha-lipoprotein [85]. 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 m 19

4 Pharmacokinetics

3.4 Specific toxicity studies The pharmacokinetic properties of bisoprolol provide the prere-
quisite for a single daily dose and ensure an extremely low
Bisoprolol had no effect on the fertility or general reproductive
inter- and intra-individual variability of the plasma concentration
performance in rats.
profiles. The high therapeutic reliability of bisoprolol is based
At daily doses of 1.0, 2.5 and 6.25 mg /kg in rabbits as well as on these properties.
15.0 and 40.0 mg /kg in rats, bisoprolol had no embryotoxic or
Bisoprolol occupies a middle position as regards hydrophilia and
teratogenic effect. Higher doses have an embryolethal effect
lipophilia [191]. The favourable pharmacokinetic properties are
but not a teratogenic effect. When assessing the embryolethal
derived from this basic physicochemical feature. Thus, bisoprolol
effect it must be taken into consideration that this is a common
combines the advantages of both lipophilic ␤-blockers (e.g. high
finding with all ␤-blockers when sufficiently high doses are
absorption rate) and hydrophilic ␤-blockers (e.g. long plasma
administered to rats or rabbits.
elimination half-life, small first-pass effect) without any of the
Administered in daily doses of 15 and 50 mg /kg to pregnant respective pharmacokinetic disadvantages. With a 50% degree of
rats and rabbits, bisoprolol had no effect on either the late foetal metabolisation [45,111,113], bisoprolol occupies the middle
or postpartum development of the young or on parturition, the position between hydrophilic and lipophilic ␤-blockers (Tab. 2).
rearing instinct, lactation performance of the dams, physical
development or behaviour of the offspring. There was no influence
Tab. 2: The frequently observed influence of lipophilia and hydrophilia
on the reproductive performance of the F1-animals or the on the pharmacokinetic properties of ␤-blockers [3].
development of the F2-young animals up to their 28th day of life.
No signs of mutagenic potential were found either in bacterial Absorption Firstpass Bioavail- Plasma elimi- Degree of
rate effect ability nation half-life metabolisation
mutagenicity tests, the point mutation test and chromosome
aberration test in fibroblasts of the Chinese striped hamster or in Lipophilic ␤-blockers high high low short high
mutagenicity investigations in vivo (micronucleus test in the (90 -100%)
mouse, chromosome investigations in the Chinese striped hamster).
Hydrophilic ␤-blockers low low low long low
In long-term feeding studies, bisoprolol had no carcinogenic effect (0 -10%)
in mice at daily doses of 10, 50 and 250 mg /kg (20 months, Bisoprolol high low high long 50%
respectively) or in rats at daily doses of 5, 25 and 125 mg /kg
(26 months, respectively).
20 Bisoprolol m 21

4.1 Bioavailability 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
The bioavailability of bisoprolol from film-coated tablets is
of one of the clearance organs, the elimination half-life of biso-
about 90%.
prolol is in general only up to about double that of the half-life in
Bisoprolol is almost totally (> 90%) absorbed after administration. the healthy organism.
On its first passage through the liver (first-pass effect) a maximum
This was demonstrated for bisoprolol in pharmacokinetic studies in
of 10% of the dose is inactivated by metabolisation [111]. The high
patients with functional impairment of the kidney (Fig. 3) or of the
absorption rate and small first-pass effect result in an absolute
liver (Fig. 4) [81, 88,103,140]. Therefore, no dosage adjustment of
bioavailability of 88% [111]. Bisoprolol can be taken on an empty
bisoprolol is generally necessary in mild to moderate functional
stomach or with breakfast, without the pattern of absorption
impairment of the liver or kidney. A daily dose of 10 mg bisoprolol
being changed [111]. The bioavailability of bisoprolol is the same
should, however, not be exceeded in chronic terminal insufficiency
in either case.
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.
4.2 Distribution
Bisoprolol has a plasma protein binding of 30%. Fig. 3: Mean plasma concentrations of bisoprolol following repeated oral
administration of 10 mg bisoprolol once daily to healthy volunteers and
Only 30% of the bisoprolol in the blood is bound to plasma patients with moderate impairment (creatinine clearance 6 -21 ml /min )
proteins [45]. Therefore, interactions with other drugs in the sense or servere impairment (creatinine clearance 20-5 ml/min) of renal
of displacement from a plasma protein bond do not occur. The function [103].
pharmacokinetics of bisoprolol are not influenced by pathophysio- plasma concentration (ng / ml )
logical changes in the plasma proteins, e.g. when there are 100
increased acid ␣1- glycoproteins.
80
As a substance with only moderate lipophilia, bisoprolol exhibits
a medium volume of distribution with low plasma protein 60
binding. An exact determination following i.v. administration gave
( –x ± SEM) 226 ± 11 l [111]. 40

20
4.3 Metabolisation and excretion
0
Bisoprolol is removed from the plasma via two equally effective 0 24 48 72 96 120 144 168 192 h
routes of clearance – half of the dose is metabolised to inactive
metabolites in the liver and the other half is excreted as the Healthy volunteers (n = 8, t 1/2 = 10.0 h )
unchanged substance via the kidneys. 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 m 23

Fig. 4: Mean plasma concentrations of bisoprolol following repeated oral Fig. 5: Metabolism of bisoprolol in the human organism [113].
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].
R

plasma concentration (ng / ml)

100 O CH3
O
CH3
80
Bisoprolol
50 % of dose
60

40 R R R

20
OH O
OH O O OH
CH3
0 Metabolite M 4
0 24 48 72 96 120 144 168 192 h weakly active

R R R
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) O COOH
COOH O COOH O
CH3

In the human organism, half of a bisoprolol dose is transformed Metabolite M 3 Metabolite M 1 Metabolite M 2
into three metabolites (M1, M2, M3 in Fig. 5), none of which have a < 5 % of dose > 20 % of dose < 5 % of dose
inactive inactive inactive
␤-blocking effect. The weakly active metabolite M4 could not be
detected in the human organism and presumably occurs only in
CH3
traces as a metabolic intermediate stage [45, 113]. % of dose recovered in urine R = O N CH3
OH H
An accumulation factor of 1.2 was observed with a single daily [ ] = probable metabolic intermediate stage
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 body’s 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.
24 Bisoprolol m 25

Fig. 6: Degree of metabolisation with ␤1-selective ␤-blockers. Balanced Differences of genetic origin in the metabolisation of drugs (limited
clearance and no active metabolites with bisoprolol [according to 45,113], or extensive debrisoquine metabolism) are of no significance
small proportions of active metabolites with betaxolol and metoprolol.
for bisoprolol [113]. A slight difference has been observed in the
AUC and elimination half-life of bisoprolol enantiomers after
metabolisation of various ␤- blockers (%)
administration of the racemic drug in a study in four human sub-
100 jects [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].

50 4.4 Elimination half-life

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
0 69 - 80 years) [129]. Under steady-state conditions the plasma elimi-
0 Atenolol Bisoprolol Betaxolol Metoprolol nation half-life was always in the range of 10-12 hours.
This means that bisoprolol may be administered once daily, and
Balanced clearance this has a beneficial effect on the compliance of the patient.
50 % unchanged Maximum plasma levels are reached 1-3 hours after administra-
50 % metabolised tion (Fig. 7).
Excretion
approx. 95 % renal
2 % faecal 4.5 Interactions
The concomitant use of substances inducing the drug-metabolis-
Metabolites Unchanged substance
ing 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 Fig. 7: Plasma concentration time-curve and accumulative renal and faecal excretion
elimination half-life of bisoprolol [102]. Therefore, no interactions after oral administration of 1 x 20 mg 14 C- bisoprolol ( –x, SEM; n = 5 ) [45,113].
between drugs inhibiting liver enzymes and bisoprolol need to be
expected. The pharmacokinetic properties of theophylline were not plasma concentration (ng /ml )
affected by simultaneous therapy with bisoprolol [184]. Concurrent 150
treatment with bisoprolol and the anticoagulant warfarin had no
additional influence on the prothrombin time [184].
100
Simultaneous administration of bisoprolol and procainamide in
patients with ventricular tachyarrhythmia led to a therapeutically 50
desirable prolongation of the ventricular refractory period. Treat-
ment of ventricular arrhythmia with a combination of bisoprolol
and procainamide proved to be well tolerated in this study [175]. 0
0 4 8 12 16 20 24 28 32 36 40 44 48 h

Total radioactivity Unchanged bisoprolol

plasma concentration (ng /ml)

100

80

60

40

20

0
0 12 24 36 48 60 72 h

Total radioactivity in the urine Total radioactivity

Unchanged bisoprolol in the urine 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

5 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 admin-
istered 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 nega-
tively 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 Fig. 9: Changes in the left ventricular ejection fraction (EF) and pulmonary
coronary patient. The increase in peripheral arterial resistance fol- capillary pressure (PCP) before and 2 hours after oral administration of
5 and 20 mg bisoprolol to coronary patients ( –x, SEM)[164].
lowing acute administration of ␤-blockers without ISA is known and
must be regarded as a reflex phenomenon. The effects following before 2 h after before 2 h after
20 mg bisoprolol were quantitatively only slightly different from EF (%) bisoprolol bisoprolol bisoprolol bisoprolol
those following 5 mg (Fig. 8) [164]. 60

Neither of the two dosages of bisoprolol tested had a significant

effect on the ejection fraction (EF) or pulmonary capillary 50
pressure (PCP) either at rest or during ergometric exercise (Fig. 9).

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) PCP (mm Hg)
and during identical exercise (Ex). Measurements were carried out 30
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].
20
(%) HR RPP Cl TPR
200 10

180
before 2 h after before 2 h after
bisoprolol bisoprolol bisoprolol bisoprolol
160

140 at rest during exercise

120
5 mg; n = 6 20 mg; n = 10
100

80 In another study even the very high dose of 40 mg bisoprolol, which

60
is not used in therapy, led to only a slight rise in pulmonary
capillary pressure during ergometric exercise. Even this high dose
40 proved to be hemodynamically safe [33]. Thus bisoprolol shows
20 no negative inotropism of clinical relevance. Systolic time intervals
and echocardiographic data in hypertensive patients point in
0
the same direction [67].
R Ex R Ex R Ex R Ex

Pretreatment value 5 mg 20 mg
32 Bisoprolol m 33

5.1.2 Electrophysiology 5.1.3 ␤1-selectivity

␤-blockers inhibit the electrophysiological effects of adrenergic ␤-blockers with high ␤1 -selectivity have substantial clinical
stimulation. The frequency of primary and secondary pacemaker advantages over non-selective agents [68, 69,70,71] in terms
centres is reduced, AV conduction delayed and the refractory of their respiratory, haemodynamic and metabolic effects. Most
period of the AV node prolonged. of the desirable therapeutic actions of ␤-blockers result from
blocking the ␤1-receptor. Avoiding the inhibition of ␤2-receptor-
The effect of bisoprolol on the electrophysiological parameters
mediated actions helps to avoid undesirable side-effects on
corresponds to that of the known pattern of other ␤-blockers.
lung function, peripheral circulation, serum lipids and carbohy-
The influence of bisoprolol on electrophysiological processes in drate metabolism.
the heart was investigated in 10 patients with paroxysmal supra-
ventricular tachycardia [53, 136]. Potentials from the right atrium
and ventricle, from the coronary sinus if necessary, His-bundle 5.1.4 Receptor occupancy
potentials and a surface ECG were recorded before and after a
The respective degree of ␤1- and ␤2-receptor occupancy can
single i.v. dose of 10 mg bisoprolol. With bisoprolol there was
be determined by using the serum of volunteers /patients treated
a significant reduction in the sinus frequency and an increase in
with ␤-blockers in a ␤1 - and ␤2 -adrenoceptor-specific test. The
the sinus-node recovery time. The refractory parameters of the
relevance of these ex vivo/in vitro data is shown by the direct
AV node were prolonged (functional and effective refractory period,
correlation between the percentage occupancy of ␤1-receptors
advancement of Wenckebach point). As with other ␤-blockers
and the reduction of exercise -induced tachycardia [189].
as well, the refractory parameters on the atrial and ventricular
plane showed no clinically relevant change. A slight decrease in Plasma concentrations of bisoprolol occurring after adminis-
the frequency-corrected QT-time suggests a potentially positive tration of 5 mg or 10 mg bisoprolol did not lead to ␤2- receptor
antiarrhythmic effect in acute myocardial infarction (MI) [52]. blockade in this ex vivo /in vitro model [189].
In a further study 10 patients with an indication for electro- In a double-blind, placebo-controlled study groups of 6 volunteers
physiological examination (His-bundle ECG, programmed atrial received single oral doses of, among other things, 200 mg
and ventricular stimulation) received 5 mg or 10 mg bisoprolol atenolol and 100 mg bisoprolol, respectively; thus the doses by far
intravenously. Bisoprolol significantly prolonged the cycle length, exceeded therapeutic daily doses. In the course of 72 hours the
sinus-node recovery time, AH interval, and the functional and percentage of ␤1- and ␤2-receptor blockade was determined in an
effective refractory period of the AV node. The effects of 10 mg ex vivo /in vitro assay.
bisoprolol were only slightly more intense than those of 5 mg
Under 200 mg atenolol there was a maximum occupancy of
bisoprolol [150].
80% of ␤1-receptors and of 25% of ␤2-receptors whilst under
bisoprolol there was no occupancy of ␤2-receptors if occu-
pancy 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 5.1.5 Lung function
␤1-receptor occupancy by bisoprolol lies in the range of approx.
Bisoprolol is a ␤1-selective ␤-blocker with no clinically relevant
80 -30% for the dose range of 5 -10 mg (Fig.10).
affinity to the bronchial ␤2-receptors not even when plasma
levels are at their peak.
Fig. 10: Heart rate ␤-receptor occupancy and plasma concentrations over
72 hours after a single dose of 100 mg bisoprolol (left) and 200 mg
As the dilatation of the bronchial muscles is mainly induced via
atenolol (right). Shaded area: values observed in the dosage interval ␤2-receptors, non ␤1-selective ␤-blockade entails a risk for
of 24 hours after administration of 10 mg bisoprolol and 100 mg patients accordingly predisposed (asthma, chronic obstructive
atenolol [modified according to 188 ]. bronchitis). The pathologically increased airway resistance in
HR (beats /min) HR ( beats /min) these patients can be increased further and the forced expiratory
volume in one second (FEV1 ), can be reduced further. The risk
130 130
of bronchoconstriction decreases with increasing ␤1-selectivity.
120 120
110
The effect of bisoprolol on lung function was investigated in
110
4 controlled single-dose studies. A slight increase in the airway
100 100
resistance and a slight decrease in the FEV1 was measured in
90 90 patients with chronic obstructive bronchitis only after doses of
0 24 48 72 h 0 24 48 72 h
30 and 40 mg bisoprolol, i.e. at doses outside the therapeutic range
receptor receptor which already reduce the heart rate to an unduly large extent [65].
occupancy (%) occupancy (%)
The entire therapeutic dose range of 2.5 -20 mg bisoprolol proved
100 100 to be ␤1-selective. This was also the case when plasma levels
␤1 ␤1
75 75 were at their peak.
50 ␤2 50
The influence of single doses of placebo, 100 mg atenolol and
25 25 ␤2 20 mg bisoprolol on the airway resistance was investigated in
0 0 coronary patients suffering concomitantly from chronic obstructive
0 24 48 72 h 0 24 48 72 h
bronchitis [63]. Although the reduction in heart rate was in
plasma concen- plasma concen- some cases more pronounced with bisoprolol than with atenolol,
tration (ng /ml) tration (ng /ml)
the airway resistance remained unchanged with bisoprolol as
1000 1000 with placebo (Fig. 11). In contrast to this, with atenolol there was
100
a slight increase in the airway resistance.
100
In a study carried out in the cross-over design, 40 angina-pectoris
10
patients with chronic obstructive lung disease (COLD) were treated
0 10 with 50 mg atenolol or 5 mg bisoprolol over 6 months. The two
0 24 48 72 h 0 24 48 72 h substances were equally effective in the therapy of angina pectoris
Bisoprolol Atenolol 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) Fig. 12: Differences in the airway resistance (∆ AWR) in hypertensive patients
and after single oral administration of placebo, 20 mg bisoprolol and with bronchial asthma 2 hours after administration of single doses of
100 mg atenolol to 12 coronary patients suffering concomitantly from placebo, 10 and 20 mg bisoprolol and 100 mg atenolol compared to
chronic obstructive bronchitis ( –x ; SEM; n = 12, cross-over design) [63]. the initial value ( –x, SEM, cross-over design; n = 12) [49].

AWR (cm H2O/l/s) ⌬ AWR (cm H2O/l /s)

9 1.6

1.2
8

0.8
7
0.4
HR (beats/min)
90
0

70 0.4

0.8
50

b 2 4 8 24 b 2 4 8 24 b 2 4 8 24 h Placebo Bisoprolol Bisoprolol Atenolol

Placebo Bisoprolol Atenolol 10 mg 20 mg 100 mg

In a further study in 10 hypertensives with chronic obstructive air-

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

Fig. 13: Dose-response curve. The patients inhaled salbutamol 3 hours after acebutolol (␤1-selective ␤-blocker with ISA) and the non-selective
administration of placebo, 10 mg bisoprolol or 400 mg acebutolol. ␤-blockers penbutolol (with ISA) and propranolol in 16 healthy
The graph shows the mean increase in the specific airway conduc-
tance (∆ sGaw) at various salbutamol doses ( –x ± SEM) [123].
volunteers [107]. The selected dosages of the ␤-blockers reduced
the heart rate during exercise to an equal extent in a preliminary
⌬ sGaw (kPa 1 s 1 ) trial. A slighter shift to the right of the isoprenaline dose-response
0.8 curves under ␤-blockade signifies higher ␤1-selectivity. This can
be seen for bisoprolol, metoprolol and acebutolol in Fig.14.
Bisoprolol
0.6 The influence of a single oral dose of 20 mg bisoprolol and 100 mg
NS atenolol on the forearm circulation was investigated in 8 healthy
Placebo **
volunteers after short intra-arterial infusion of isoprenaline and
0.4 adrenaline [48]. The isoprenaline doseresponse curves were shifted
*
only slightly to the right as an expression of the ␤1-selectivity of
0.2
Acebutolol both ␤-blockers. The reduction in the adrenaline-induced vasodila-
tation was statistically significant (p < 0.05) only after atenolol
but not after 20 mg bisoprolol [47, 48].
0
0 100 200 400 800 inhaled salbutamol
Flow measurements in the brachial and femoral arteries by
dose (␮g) Doppler ultrasonic scanning in 9 volunteers revealed an increase in
* p < 0.05 ** p < 0.01 vascular resistance after 40 mg propranolol whereas the vascular
resistance was uninfluenced by 10 mg bisoprolol [28].
5.1.6 Peripheral circulation
Pulsed Doppler flowmetry and pulse wave velocity in 14 hyper-
The effect of ␤-blockers on the increase in blood flow induced tensive patients in a double-blind cross-over study with bisoprolol
by isoprenaline or the decrease in diastolic blood pressure (10 mg /day) confirmed the following results: no significant
caused by the substance can serve as a measure of ␤1-selectivity. changes occurred in diameter, blood flow or vascular resistance of
In the case of non-selective ␤-blockers, these effects of the carotid and brachial circulations after bisoprolol. Pulse wave
isoprenaline are considerably reduced and to achieve the same velocity significantly decreased whilst the brachial artery com-
effects much higher doses of isoprenaline are required. An pliance significantly increased. This indicates that the antihyperten-
impairment of the peripheral circulation is manifested by unde- sive effect of ␤1-blockade is associated with an improvement in
sirable side-effects, such as cold extremities, tingling and a the viscoelastic properties of the brachial artery wall [27].
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. adminis-
tration of bisoprolol and metoprolol (␤1-selective ␤-blocker),
40 Bisoprolol m 41

Fig. 14: Isoprenaline-(I-) induced decrease in the diastolic blood pressure (DBP) 5.1.7 Metabolism
before and 30 minutes after i.v. administration of placebo and various
␤-blockers to healthy volunteers ( –x, n =16) [107]. Serum lipids.

DBP (mm Hg) DBP (mm Hg) The lipid metabolism can be adversely affected by ␤-blocker
80 Placebo 80 Bisoprolol
therapy, in particular with non-␤1-selective ␤-blockers [14]. There
(saline) (0.07 mg /kg) is an increase in total cholesterol or LDL-cholesterol (atherogenic
60 60 risk factor) and a decrease in HDL-cholesterol (atherogenic
protective factor).
40 40
Bisoprolol generally induces no change in the cholesterol
20 20 fractions, including the cardioprotective HDL-cholesterol, in long-
term therapy.

0.25 1 4 16 64 ␮g I 0.25 1 4 16 64 ␮g I In a thirteen-months study hypertensive patients were treated with

the individual optimal dose of bisoprolol. Neither total cholesterol
80 Metoprolol 80 Acebutolol
(0.2 mg/kg) (0.8 mg /kg)
nor HDL- or LDL- cholesterol were changed to any significant or rele-
vant extent [72, 73].
60 60
The serum cholesterol and serum triglycerides were measured in a
40 40 placebo-controlled double-blind cross-over study in hypertensive
patients with type II diabetes [95]. In comparison with placebo there
20 20
were no significant changes in these lipid parameters with
10 mg bisoprolol.
0.25 1 4 16 64 ␮g I 0.25 1 4 16 64 ␮g I
In an open multicentre study in 2,012 outpatients, the lipids
80 80 were not affected by 5 and 10 mg bisoprolol/day administered for
a period of 8 weeks [91].
60 60
Prior to start After 8 weeks
40 40 of therapy of therapy
Propranolol Penbutolol Total cholesterol 237 ± 47 232 ± 42
(0.2 mg/kg) 20 (0.04 mg /kg)
20 (mg /dl)

Triglycerides 174 ± 75 171 ± 64

0.25 1 4 16 64 ␮g I 0.25 1 4 16 64 ␮g I (mg /dl)

Before administration 30 min after administration Results from open long-term studies with bisoprolol treatment for
of placebo or the ␤-blocker of placebo or the ␤-blocker up to 12 months showed no changes in the lipid parameters [148].
42 Bisoprolol m 43

In a randomised comparative study, 129 hypertensives received These results could be confirmed even over 5 years. 41 patients
propranolol (160 mg /day), atenolol (100 mg /day), mepindolol with essential hypertension were treated with bisoprolol in daily
(10 mg /day) or bisoprolol (10 mg /day) for 36 months following a doses up to 40 mg. No significant changes of the various lipid
one-month placebo phase. Bisoprolol affected the triglycerides less fractions were reported, which again reflects the high ␤1-selectivity
than propranolol or atenolol and during 36 months of therapy had of bisoprolol (Tab. 3) [74].
not led to any statistically significant change in HDL-cholesterol
(Fig.15). Total cholesterol and LDL-cholesterol were not affected Tab. 3: Changes in mean (SEM) triglycerides, total cholesterol, HDL-cholesterol,
either. This confirms the hypothesis that a higher ␤1-selectivity is and calculated LDL-cholesterol throughout the study (0-5 years) [74].
associated with a lesser effect on plasma lipids [69, 68].
Start 1 year 2 years 3 years 4 years 5 years
Also in studies measuring lipolysis after ␤2-stimulation with
terbutaline, the lack of influence of bisoprolol on free fatty acids Total cholesterol 5.98 6.14 6.21 5.98 6.23 6.15
again proved its high ␤1-selectivity. At doses of 5 mg virtually (mmol/l) (1.16) (1.11) (1.10) (0.98) (0.78) (0.68)
no ␤2-blocking activity could be measured for bisoprolol. Atenolol Triglycerides 1.29 1.57 1.64 1.71 1.75 1.53
did show an effect in either dosage (50 and 100 mg). (mmol/l) (0.69) (0.57) (0.60) (0.62) (0.62) (0.42)

HDL-cholesterol 1.45 1.53 1.66 1.54 1.60 1.58

Fig. 15: Percentage change in HDL-cholesterol after 36 months of therapy (mmol/l) (0.46) (0.52) (0.54) (0.52) (0.61) (0.49)
with propranolol (P), atenolol (A), bisoprolol (B) or mepindolol (M) [68].
LDL-cholesterol 3.87 3.87 3.85 3.57 3.95 3.87
⌬ % HDL-cholesterol (mmol/l) (1.14) (1.03) (1.06) (0.90) (0.86) (0.74)

+10
M A further 18-month double-blind randomised study in 152 hyperten-
0 B sive patients [70], studied the effects on plasma lipids of bisoprolol
–10 P 10 mg /day, atenolol 100 mg /day, propranolol 160 mg /day and
* A
** ** ** celiprolol 400 mg /day. Bisoprolol did not significantly change total
** **
–20 ** ** cholesterol, LDL-cholesterol, HDL-cholesterol or triglycerides. The
–30 **
** non-selective agent propranolol had negative effects on HDL-choles-
**
terol and triglycerides; the selective agent atenolol also negatively
–40 affected HDL-cholesterol and triglycerides, though to a lesser extent.

6 12 18 24 30 36 months
Carbohydrate metabolism.
Mepindolol * p < 0.05 vs. baseline
Bisoprolol ** p < 0.01 vs. baseline Owing to its high ␤1-selectivity, bisoprolol generally has no
Atenolol influence on the carbohydrate metabolism. In hypertensive
Propranolol
patients with type II diabetes requiring treatment, no additional
44 Bisoprolol m 45

monitoring is necessary during therapy with bisoprolol and 20 hypertensives with type II diabetes, 18 of whom were receiving
no adjustment is usually necessary in the dosage of oral anti- sulphonylurea therapy, were treated with 10 mg bisoprolol /day
diabetic preparations. for 14 days in a placebo-controlled study. The blood glucose was
not influenced by either 10 mg bisoprolol or placebo. Adjustment of
In an acute study, healthy volunteers received insulin 3 hours after
the sulphonylurea therapy was not necessary with bisoprolol
the oral administration of various ␤-blockers. The metabolic
[95, 96] (Fig.17).
reactions with 10 mg bisoprolol did not differ from those with
placebo, in particular the duration of the hypoglycaemic phase was Further studies measuring metabolic parameters in volunteers
not prolonged and there was no change in the course of serum confirmed the high ␤1-selectivity of bisoprolol. Hypokalaemia and
lactate concentration as compared with the control [112]. This must hyperglycaemia were stimulated by terbutaline, a ␤2-stimulating
be considered as a consequence of the high ␤1-selectivity of
bisoprolol (Fig.16). 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].
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 glucose (mg /dl) HbA 1 (%)
3 different ␤-blockers and placebo [112].
170
10
glucose (mmol /l)
5 160
4
9
3 150
2
140
1
8
0
130
0 30 45 60 90 120 min.

lactate (mmol /l)

120 7
1.7

1.5
110
1.3 6
1.1 100
0.9
0.7 0 0
A B C A B C
0 30 45 60 90 120 min.
( pC-B > 0.05) ( pC-B > 0.05)
Bisoprolol 10 mg Propranolol 40 mg A initial value B after 2 weeks C after 2 weeks
Metoprolol 50 mg Control with bisoprolol with placebo
46 Bisoprolol m 47

substance. All agents lowered the exercise heart rate significantly glucose availability or high demand (such as fasting, starving,
compared to placebo (p < 0.05). Bisoprolol 5 mg and 10 mg stress or hypoglycemia). As it is impossible to measure insulin
influenced the potassium concentration and the glucose concen- resistance, most tests measure overall glucose uptake as an
tration less than atenolol 50 mg and 100 mg, thus proving the index of insulin ”sensitivity”. With bisoprolol such tests were
higher ␤1-selectivity of bisoprolol. The effect of bisoprolol 5 mg performed, showing no negative effects on insulin sensitivity.
on glucose and potassium concentration was significantly less
In a double-blind cross-over study 22 healthy volunteers were
(p < 0.05) than that of both doses of atenolol and the two other
treated with either bisoprolol (5 mg /day for 4 weeks) or the ACE-
bisoprolol doses (10 mg and 20 mg) and not significantly different
inhibitor lisinopril (5 mg /day for 4 weeks). The insulin sensitivity
to placebo. The order of ␤1-selectivity was judged to be:
was evaluated by the glucose infusion rate and the serum insulin
bisoprolol 5 mg > bisoprolol 10 mg > atenolol 50 mg > bisoprolol
concentration (”glucose clamp”). The ratios before and after
20 mg > atenolol 100 mg [83].
treatment did not show any changes in either treatment groups:
In a crossover study in 12 hypertensive patients with untreated The insulin sensitivity index after intake of the ACE-inhibitor
type II diabetes mellitus [180], patients received bisoprolol amounted to 7.9 ± 2.4 (basic index 8.3 ± 1.9) and after treatment
10 mg / day or atenolol 100 mg /day for 4 weeks, with a 4-week with bisoprolol 7.5 ± 2.1 (basic index 8.2 ± 1.9). It may be con-
washout period between the active treatments. Neither drug had cluded that, when given in doses sufficient to significantly lower
any significant effect on glucose or insulin responses to intravenous the blood pressure, neither bisoprolol nor the ACE- inhibitor
glucose tolerance testing, nor caused any significant increase in exhibits any influence on the insulin sensitivity in normotensive
glucosuria. A study in 44 postinfarction patients with type IIa healthy volunteers [89].
diabetes mellitus [99] found that bisoprolol had no clinically sig-
In a double -blind parallel-group study in 12 patients with mild-to-
nificant negative effect on glucose metabolism during endurance
moderate essential hypertension [62], patients received bisoprolol
and maximal exercise.
5 mg /day or the ACE-inhibitor captopril 25 mg b.i.d. for 8 weeks.
In a study which included 21 elderly and 60 non- elderly hyperten- Specific insulin binding was not affected by either agent.
sives [84], bisoprolol (5 -10 mg /day for 12 weeks) had no signifi- Erythrocyte insulin binding and insulin-stimulated tyrosine kinase
cant effect on the response of plasma glucose and insulin to 75 mg (TK) activity were measured before and after therapy. Fasting
oral glucose in either age group. This demonstrates the lack of plasma glucose, insulin and insulin /glucose indices remained
adverse effects of bisoprolol on carbohydrate metabolism in elderly unchanged after both treatments. Maximal insulin-stimulated TK
as well as in younger patients. 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
Insulin sensitivity. measured by the half-maximal activity concentration. Thus, capto-
pril apparently increased the sensitivity of the insulin receptor,
␤-blockers are speculated to have a negative impact on certain
whereas bisoprolol increased its maximal activity. The authors of
parameters of glycemic control such as insulin resistance.
this study suggest that, far from having negative effects on insulin
This is an adaptive physiological phenomenon, when the cellular
sensitivity, bisoprolol might have potential beneficial effects in
requirement for glucose is jeopardised in conditions of low
some insulin resistance conditions [101].
48 Bisoprolol m 49

5.1.8 ␤2-receptor density Fig. 18: Course of the ␤2-receptor density measured as binding sites per cell for
iodocyanopindolol [(–)-ICYP], on lymphocytes volunteers before, during, and
Bisoprolol proved to be a highly ␤1-selective substance with no after the administration of bisoprolol, propranolol and pindolol ( –x) [38].
effect on ␤2-receptors in the human lymphocyte model.
( – )-ICYP-binding sites per cell
␤2-Agonists and ␤-blockers with ISA can reduce the density of the 1200
␤2-receptors on human lymphocytes whereas non-␤2-selective
␤-blockers without ISA increase the density of the ␤2-receptors [38].
1000
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 800

of the ␤2-receptors in this model in the sense of counter-regu-

lation and, on the other hand, from pindolol (␤-blocker with ISA), 600
which reduces the density of the ␤2-receptors (Fig. 18). In a similar
model atenolol increased the density of the ␤2-receptors on
400
leucocytes [16].
0 2 4 6 8 10 12 days
Bisoprolol 1x10 mg/d
5.1.9 Plasma renin activity
Propranolol 4 x 40 mg/d
Bisoprolol reduces the basal and stimulated renin activity. The Pindolol 2x 5 mg/d
renin released from the cells of the juxtaglomerular apparatus
of the kidney influences the initiation of a reaction chain (renin-
angiotensin-aldosterone system) which leads to the formation A population-based observational study in 728 middle -aged
of the vasoconstrictor angiotensin II. Renin release is stimulated subjects (treated and untreated ) [9] found that monotherapy with
via ␤1-receptors and can be inhibited by ␤-blockade. a ␤-blocker decreased mean renin concentrations compared
with untreated individuals. In contrast, treatment with an ACE-
A single dose of bisoprolol led to a marked reduction in both the
inhibitor and /or diuretic increased it. However, renin concentrations
basal and stimulated plasma renin activity [38, 77, 107]. Unlike
in individuals receiving a ␤-blocker with an ACE-inhibitor or a
␤-blockers with ISA, the renin-reducing effect of bisoprolol was
diuretic, or both, were significantly lower than in patients not
maintained even 7 days of administration [38]. Therefore bisoprolol
receiving ␤-blocker treatment. These data suggest that the upregu-
inhibits the renin-angiotensin system and consequently reduces
lation of renin by treatment with ACE-inhibitors, diuretics or both
the blood-pressure increasing effects of this regulatory system.
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 activation with potentially beneficial hemodynamic

consequences. These effects may help to account for the protective
Sympathetic activity and key components of the fibrinolytic system
effects of ␤-blockers against MI, particularly in the early morning
show circadian variability, which may help to explain for the well-
when the risk of infarction is greatest.
known 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
5.1.11 Dose-response relationship
in the morning, coinciding with the greatest risk of coronary occlu-
sion. Circadian variation in fibrinolytic activity may be related to Bisoprolol exhibits a close dose-response relationship. This favours
activation of the renin-angiotensin system. The circadian rhythm of simple dosage and reliable therapy.
MI is attenuated in patients taking ␤-blockers, and it has been sug-
The relationship between the ␤-blocking effect (as a reduction in
gested that this effect may be due to effects on circadian variation
exercise -induced tachycardia) and the plasma concentration
in sympathetic activity and /or the fibrinolytic system.
following 1x10 mg bisoprolol i.v. was investigated in a study in
Support for this theory is provided by a study in 20 patients with 10 healthy volunteers.The relationship between plasma concentration,
stable coronary artery disease [153], who were treated consecutively represented in a semilogarithmic scale, and the reduction in heart
for 4 weeks with placebo, 4 weeks with bisoprolol (10 mg /day, rate during exercise proved to be linear in the recorded plasma
in-creased to 20 mg /day if the resting heart rate remained > 60 beats concentration range of 10 -50 ng /ml [112]. Due to the high absolute
per minute), and 4 weeks with the ACE-inhibitor quinapril bioavailability of bisoprolol from film-coated tablets (88%), i.v.
(10 mg /day, increased to 20 mg /day if the resting heart rate remained and oral administration lead to comparable plasma concentrations.
> 60 beats per minute). At the end of each 4-week treatment Therefore, a therapeutic concentration range of 10 -50 ng /ml
period, 24 -hour ambulatory Holter monitoring and 6-hourly blood plasma may be given for 10 mg bisoprolol.
sampling was performed.
Bisoprolol is a ␤1-selective ␤-blocker with high potency, thus
Bisoprolol was found to significantly increase many of the requiring a low foreign substance intake per day.
nonspectral measures heart rate variability, while quinapril had no
The reduction in exercise-induced tachycardia in healthy volunteers
effect. Bisoprolol also tended to reduce the morning peak in
served to assess the potency of bisoprolol in direct comparison
PAI -1 activity and antigen, with a small increase in t PA activity.
with other ␤-blockers. On a molar basis, bisoprolol was 10 times
Although these differences failed to reach statistical significance
as effective as metoprolol, 5 times as effective as propranolol and
after correction for multiple comparisons, a clear trend was visible
7 times as effective as atenolol [112]. Clinical studies revealed
over the 24-hour monitoring period. In contrast, no effect on
a dose ratio of 1:10 between bisoprolol and atenolol [121, 126] as
circadian variation in fibrinolytic parameters was observed with
well as between bisoprolol and metoprolol [82].
quinapril. Quinapril did, however, produce a substantial rise in
plasma renin, which was not seen with bisoprolol. 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 hyper-
These data are consistent with the hypothesis that ␤-blockade
tension and angina pectoris, this results in a low intake of foreign
with bisoprolol tends to reduce the relatively prothrombotic state
substance per day.
that occurs in the early morning, and concomitantly reduces
52 Bisoprolol m 53

6 Treatment of essential hypertension

Systematic treatment of essential hypertension reduces cardio- Fig. 19: Reduction of supine systolic blood pressure ( ∆ SBP), diastolic blood
vascular morbidity and mortality [10]. Essential hypertension 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
is not usually associated with pronounced clinical symptoms. 20 mg bisoprolol as well as 7 days after withdrawal ( bisoprolol
Therefore, patients do not always take their medication on replaced by placebo) ( –x, SEM, n = 15 /group) [104].
a regular basis. Single daily administration and a treatment with
few side-effects favour patient compliance. ∆ SBP Bisoprolol Placebo
(mm Hg)
With one daily dose bisoprolol has a reliable 24-hour effect 28 56 84 91 days
0
on the blood pressure at rest and during exercise. The 24-hour
effect is ascribable in particular to the favourable –10
elimination half-life.
–20

6.1 Blood pressure at rest – duration of action –30

As a single daily dose, bisoprolol normalised the blood pressure

– 40
for 24 hours.
∆ DBP Bisoprolol Placebo
In two randomised double-blind studies it could be shown that in a (mm Hg)
28 56 84 91 days
dosage range of 5-20 mg once daily bisoprolol reduces the blood 0
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 –10

and heart rate in comparison to the initial status was determined

24 hours after the last single oral dose of 8 weeks of treatment –20
[185,186]. A comparable dose-proportional reduction in these
parameters, measured approx. 24 hours after the last dose of biso-
prolol in each case, was achieved in a second study (15 patients – 30

per dose group ) during 12 weeks of treatment with bisoprolol ∆HR Bisoprolol Placebo
(Fig. 19) [104]. (beats/min)
28 56 84 91 days
0
Further studies confirmed the dose-dependent efficacy of 5 to
20 mg bisoprolol in patients with mild to moderate hypertension
[32, 55].
–10
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].
– 20
5 mg 10 mg 20 mg Bisoprolol
54 Bisoprolol m 55

The effective lowering of the blood pressure over 24 hours after Fig. 21: 24-hour profiles of systolic blood pressure (SBP), diastolic blood
a single dose of bisoprolol was confirmed in a further study [100]. pressure (DBP), and heart rate (HR), determined by ambulatory, auto-
matic recordings, at the end of the placebo pretreatment phase as well
In 8 patients with mild to moderate hypertension, continuous as between hours 25 and 48 after withdrawal of bisoprolol following
ambulatory 24-hour measurements of blood pressure were carried 4 weeks of therapy with 10 mg bisoprolol /day ( –x, SEM; n = 11) [26].
out during treatment with 10 mg bisoprolol. The circadian rhythm
blood pressure (mm Hg)
was maintained while the blood pressure was effectively low-
ered for 24 hours; the blood pressure values were lowered more 150
strongly during the active day phase than in the resting phase at
night (Fig. 20). Similar results were achieved with 5 mg bisoprolol
130 SBP
after a treatment period of 2 weeks [134].

**

***
***

***
***
***
***
***

***

***

**
110
Fig. 20: 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].
90

**
mm Hg DBP

**
***
***

***
***
***
***
180

**
70

***
***
***
***

***

*
* **
160

**
* **
** *
140 50
SBP
120 10 12 14 16 18 20 22 24 2 4 6 8 h

100 HR (beats/min)

80 DBP 100

60 90

1 3 5 7 9 11 13 15 17 19 21 23 h 80

last day under placebo 70

**
**

** *
**
**

**
* **
***

*
* **
after 4 weeks with 10 mg bisoprolol

**
***

**
60

*
50
9 10 12 14 16 18 20 22 24 2 4 6 8 h
time of day

24 26 28 30 32 34 36 38 40 42 44 46 48 h
hours after
withdrawal of
after placebo * p < 0.05 bisoprolol
after 4 weeks of bisoprolol ** p < 0.01
*** p < 0.001
56 Bisoprolol m 57

Ambulatory, automatically recorded 24-hour measurements were Tab. 4: Residual 24-hour effects of bisoprolol (B) and metoprolol (M)
made of blood pressure and heart rate in 11 hypertensive (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
patients [26]. 24-hour profiles of blood pressure and heart rate curves (cf. Fig. 22) [82].
were recorded at the end of the placebo pretreatment phase as
well as 24 hours after completion of 4 weeks of therapy with B M p-value
10 mg bisoprolol /day (hours 25 to 48). Statistically significant B vs. M
reductions in blood pressure and heart rate in comparison with the SBP 100 W 86 63 0.02
initial status were observed up to 40 hours after withdrawal of area 90 66 < 0.02
bisoprolol. No rebound occurred up to the end of the observation
HR 100 W 90 53 0.001
period (Fig. 21) [26].
area 93 54 0.001
In open clinical studies with bisoprolol the full 24-hour effect
RPP 100 W 89 58 < 0.01
could be documented, related to a normalisation of the diastolic area 92 60 < 0.001
blood pressure to 90 mm Hg or below [29, 87,120,148].
24 hours after the last dose of bisoprolol the systolic bloodpres-
sure during exercise at 100 watts was still reduced by 86% of the
6.2 Blood pressure during exercise – duration of action
maximal effect after 3 hours. After 24 hours metoprolol had only
Bisoprolol controls exercise-induced blood pressure peaks over a residual effect of 63% (p = 0.02) (cf. Tab. 4, Fig. 22). Furthermore,
24 hours. The blood pressure peaks which occur under everyday with bisoprolol in contrast to metoprolol the effect on the heart
conditions and which may eventually result in cardiovascular rate during exercise as well as the rate-pressure product was
complications, are avoided. almost fully retained after 24 hours in comparison to the 3-hour
value (cf. Tab. 4) [82].
In previously mentioned double-blind comparative studies the
effect of 5 mg, 10 mg and 20 mg bisoprolol on blood pressure was 170 patients underwent standardised ergometry 24 hours after the
investigated in hypertensives under standardised ergometric last administration of bisoprolol at individual optimal doses. In
conditions. Bisoprolol was administered as a single daily dose over 133 patients with normalised diastolic blood pressure at rest, the
8 and 12 weeks [104, 185]. After already 4 weeks of treatment blood pressure during exercise was also reduced to a clinically
with only 5 mg bisoprolol, the blood pressure and heart rate during relevant degree. The blood pressure during exercise was also consid-
exercise were markedly reduced 24 hours after the last dose. erably reduced in 37 patients whose diastolic blood pressure at
rest could not be reduced to 90 mm Hg or below (Non responders
87 hypertensives were treated once daily with 10 mg bisoprolol
in Fig. 23) [148].
(n = 44) or 100 mg metoprolol (n = 43) in a double-blind rando-
mised 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).
58 Bisoprolol m 59

6.3 Normalisation rate Fig. 22: Effects of bisoprolol and metoprolol on systolic blood pressure (SBP),
and heart rate (HR) during and after ergometric exercise before (b) and
When used as monotherapy for essential hypertension, biso- 3 and 24 hours after the last dose of 4 weeks of therapy [( –x ± SEM;
prolol resulted in successful treatment for over 80% of the n = 44 ( bisoprolol ) and 43 (metoprolol)]. The dark shaded areas between
the exercise curves for 3 and 24 hours after administration are a
patients (normalisation of the diastolic blood pressure: reduction
measure of the loss of effect after 24 hours. The smaller the area, the
to 90 mm Hg or below, even 24 hours after administration) [13]. greater the residual effect after 24 hours (cf. Tab. 4) [82].
The almost full 24 -hour effect was guaranteed with a single
dose per day even under conditions of stress.
SBP HR
In an open prospective multicentre study [91] the antihypertensive (mm Hg) (beats/min)
effect of monotherapy with bisoprolol was investigated in 2,012 210 Metoprolol Metoprolol
patients. Aim of the treatment was to lower the sitting diastolic 120
blood pressure to values below 95 mm Hg or by at least 10 mm Hg. 190

The patients were first treated with 5 mg bisoprolol for 4 weeks, 100
170 b
b
and if blood pressure lowering was inadequate at this dose,
150 24 h 80 24 h
with 10 mg bisoprolol for a further 4 weeks. Out of the 1,067 fully 3h 3h
evaluable cases, 75.9% reached the therapeutic goal under 5 mg 60
bisoprolol. 210 Bisoprolol Bisoprolol
120
Increase of the dose to 10 mg bisoprolol in the nonresponders 190
resulted in a cumulative responder rate of 93.7%. The therapy 100
170 b
result was independent of the age of the patients treated b
(Figs. 24, 25). 150 80
24 h 24 h
3h 3h
In the double-blind dose finding study already mentioned [186] 130 60
the responder rate was 60%. 24 hours after drug adminis- 0 2 4 6 7 8 9 10 11 minutes 0 2 4 6 7 8 9 10 11 minutes
tration (defined as lowering of the diastolic blood pressure to 0 50 75 100 watts 0 50 75 100 watts
values ≤ 90 mm Hg) and 80% ( ^= lowering of the diastolic blood
pressure ≤ 95 mm Hg).
60 Bisoprolol m 61

Fig. 23: Mean values (SEM) for the systolic (SBP) and diastolic blood pressure (DBP), Fig. 24: Responder rates in the various age groups. No age dependence of the
and heart rate (HR) at rest (A), at maximum ergometric exercise (B) and responder rate is recognisable [90].
in the 5th recovery minute (C), according to dose groups with individualised
doses before and after 6 weeks of treatment with bisoprolol [148]. %
100
SBP 220
(mm Hg) 80

60
200
40
180 20

0
160 21–30 31– 40 41– 50 51– 60 61–70 > 70 age

140 week 4 week 8

DBP 120
(mm Hg) 6.4 Long-term treatment of arterial hypertension
100 with bisoprolol
Two studies [42,75] prove the long-term efficacy of bisoprolol
80 as a well-tolerated monotherapy of arterial hypertension.
A B C A B C A B C A B C Patients who had been successfully treated with bisoprolol already
HR for 1 year, were followed up for a further 1-2 years continuing
(beats/min)
120
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 biso-
100
prolol study over 2 years [42]. Long-term treatment with bisoprolol
did not cause any changes in the laboratory parameters deter-
80
mined (e.g. blood glucose, total cholesterol, triglycerides).

60
A rest A B C A B C A B C A B C
B max. exercise non-
5 mg 10 mg 20 mg responders
C 5 min recovery

before start n = 45 n = 71 n = 22 n = 40
6 wk n = 41 n = 70 n = 22 n = 37
62 Bisoprolol m 63

Fig. 25: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart Fig. 26: Course of the systolic and diastolic blood pressure (SBP and DBP)
rate (HR) prior to and during 8 weeks of therapy with bisoprolol and of the heart rate (HR) during the 2nd and 3rd year of treatment
( –x ± SD). Presented are values of patients who received 5 mg bisoprolol with bisoprolol [75].
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 mm Hg and
entire study period (n = 835). For 34 patients no dosage data are beats/min
available from week 4 on [91]. 180

mm Hg and
beats/min. 140 SBP

180 100
DBP
HR
60
160

0 12 15 18 21 24 27 30 33 36 months
SBP n = 102 102 97 102 101 102 102 102 100 102
140

120 6.5 Regression of left ventricular hypertrophy

Myocardial hypertrophy and coronary microangiopathy are
the two cardiac organ manifestations of essential hypertension.
100
Bisoprolol has been demonstrated to bring about not only a
DBP regression of left ventricular hypertrophy but also an improve-
ment of coronary reserve.
80
In a randomised single-blind study over 6 months with 10 mg
HR
bisoprolol vs. 20 mg enalapril echocardiography was performed in
60 addition to blood pressure measurements. The lowering effect on
0 4 8 weeks blood pressure and the significant reduction of left ventricular
hypertrophy as proven by echocardiography were similar in both
5 mg bisoprolol from week 0 to 4 and treatment groups [79].
10 mg bisoprolol from week 4 to 8 (n = 332)
5 mg bisoprolol from week 0 to 8 (n = 835) 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 161±18 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 Further studies have compared quality of life in patients receiving
hypertrophy. After 6 months a highly significant reduction of left bisoprolol with that in patients receiving calcium antagonists
ventricular mass and left ventricular mass index was proven [61]. or diuretics. In a double-blind, placebo-controlled study the anti-
hypertensive efficacy and tolerability of a single dose of either 10 mg
bisoprolol (n =26) or 20 mg nitrendipine (n =27) was investigated,
6.6 Quality of life also including sense of well-being parameters. After 4 weeks
of treatment bisoprolol was significantly more effective in the reduc-
Quality of life has become a relevant measure of efficacy in
tion of blood pressure than nitrendipine, which did not induce
clinical studies. Information on this parameter can be obtained
a significant reduction in the ambulatory night-time recordings.
by general health profiles or disease-specific measures. Quality
The sense of well-being scores improved significantly only with
of life remains unchanged under treatment with bisoprolol.
bisoprolol. It decreased to 15.7 in the bisoprolol group (p < 0.05)
Two studies were performed with bisoprolol in comparison to and to 17.8 in the nitrendipine group (not significant). (According
ACE-inhibitors measuring the quality of life besides blood pressure to the definition of this score for sense of well-being a decrease
reduction. means improvement) [132].
One study was done in 24 elderly hypertensive patients (> 65 years) In a double-blind double-dummy crossover study in 82 hyper-
with bisoprolol versus captopril. Parameters measured were tensive patients [57], patients received bisoprolol 5 mg once daily or
blood pressure, heart rate and the quality of life, expressed in nifedipine retard 10 mg twice daily for 8 weeks. The treatments
terms of psychophysical status in normal daily activities by a self- were of equal antihypertensive efficacy. Compared with baseline,
assessment questionnaire. Apart from a significant reduction of there was no significant change in quality of life variables with
blood pressure in both treatment groups no changes in quality of either drug. No significant differences were found between the treat-
life were seen. Bisoprolol also produced a marked but symptom- ments in quality of life variables such as the Health Status Index,
free reduction of heart rate compared with captopril [34]. somatic symptoms, anxiety, depression, total psychiatric morbidity,
cognitive symptoms and hostility score. There were no significant
In a double-blind cross-over study in 45 hypertensive patients
differences between the groups in the numbers of dropouts (2 on
treated either with bisoprolol 5 -10 mg or enalapril 10 -20 mg for
bisoprolol and 3 on nifedipine retard) or the percentage of patients
4 -8 weeks, the quality of life was one of the target parameters.
reporting adverse events (21% for bisoprolol and 16% for nife-
Both agents led to a comparable blood pressure reduction, while the
dipine retard, p = 0.64).
heart rate was significantly more decreased with bisoprolol.
At the end of the study 31 patients reported to have felt better A similar 8-week crossover study in 81 hypertensive patients [174]
during bisoprolol and 11 during enalapril treatment. The subjective compared bisoprolol, 5 mg daily, with the diuretic bendrofluazide,
well-being scores as measured by the "Inventory of Subjective 2.5 mg daily. The treatments were equally effective. No significant
Health” were comparable in both treatment groups and there was differences were found between the treatments in quality of life
no significant difference compared to the baseline score. During variables such as the Health Status Index, somatic symptoms, anxiety,
enalapril treatment more patients spontaneously mentioned depression, total psychiatric morbidity, cognitive symptoms and
adverse effects compared to bisoprolol [35, 168]. hostility score. Compared with baseline, the Health Status Index
66 Bisoprolol m 67

improved during bisoprolol treatment (p < 0.05). None of the other 6.7 Therapeutic comparison in hypertensive patients
quality of life variables changed in either group compared with
In comparison with other antihypertensive agents bisoprolol
baseline. No patients dropped out on either treatment.
frequently proved to be more effective or better tolerated.
An 8-week, double-blind crossover study in 154 patients [173],
half of whom were aged over 60 years, compared bisoprolol 6.7.1 Bisoprolol and atenolol
5 mg /day, bendrofluazide 2.5 mg /day and nifedipine retard 10 mg
Within the scope of a Europe- wide study in a randomised double-
twice daily. No significant difference was found in quality- of-life
blind cross- over design (Bisoprolol International Multicentre Study,
variables between treatments, or between older and younger
BIMS) the antihypertensive effect of bisoprolol was subjected to
patients.
intra-individual comparison with that of atenolol in hypertensives
A 24 -week double-blind study in elderly ( > 60 years ) hypertensive (initial diastolic blood pressure 100 -120 mm Hg) [44]. The aim of
patients [46] compared bisoprolol (5 mg daily) with nifedipine this study was the reduction of the diastolic blood pressure to
retard (40 mg daily). To achieve the target diastolic pressure 95 mm Hg or below, in each case 24 hours after administration of
of ≤ 90 mm Hg, the dose of bisoprolol or nifedipine retard could the last dose. After a 4 -week placebo phase the patients received
be doubled (10 mg bisoprolol, 80 mg nifedipine retard) or for 8 weeks either bisoprolol or atenolol, once daily. After 2 weeks
hydrochlorothiazide 25 mg added to the higher dose. In an inten- of treatment the daily dose was increased to 20 mg (bisoprolol)
tion-to-treat analysis, an excess of symptoms was observed in the or 100 mg (atenolol) in the case of diastolic blood pressures
nifedipine group for oedema of the legs, nocturia, constipation, exceeding 95 mm Hg. An intermediate washout phase was fol-
racing heart and heart thumping. Fewer patients reported wheeze lowed by the same therapeutic regimen with the other respective
in the nifedipine group. For quality of life, there were no statisti- ␤-blocker. Out of the 94 patients assessable for efficacy the number
cally significant differences between the two groups after 8 weeks. of those exhibiting diastolic blood pressure of 95 mm Hg or below
However, analysis of the last available assessment (usually at after 8 weeks was higher under bisoprolol than under atenolol.
24 weeks) showed significant (p < 0.05) improvements in tension / For bisoprolol there was a responder rate of 68% and for atenolol
anxiety, anger/hostility, vigour/activity, and confusion/ bewilder- one of 56%.
ment, assessed by the Profile of Mood States in patients receiving
Amongst these responders 5 patients responded to atenolol but
bisoprolol in comparison to those receiving nifedipine retard. The
not to bisoprolol, whilst 16 responded only to bisoprolol but not to
Sickness Impact Profile and objective tests of cognitive function
atenolol. This difference was statistically significant (p < 0.05) [44].
showed no significant differences between the two groups. It was
therefore concluded that quality of life was well maintained on A large multicentre double-blind study in 659 patients again
both treatments with advantages for bisoprolol in certain areas. 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 Fig. 27: Systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR)
produced significantly greater reductions in average 24-hour systolic 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
and diastolic blood pressure than showed atenolol (p < 0.005) 24 hours after administration of the last dose ( –x ± SD) [82].
and a longer duration of action [138].
mm Hg
A further study carried out in the same design as the BIMS [116] SBP
confirmed the stronger antihypertensive effect observed under
treatment with bisoprolol. 180

* n.s.
In another international multicentre double-blind study 249 hyper-
160
tensives received 5 mg bisoprolol, 10 mg bisoprolol or 50 mg
atenolol, respectively, as a single daily dose [121]. In all treatment SBP
groups there was a statistically significant reduction in blood 140
pressure and heart rate, measured 24 hours after the last adminis-
tration. The reduction in blood pressure was most pronounced 120
under 10 mg bisoprolol, the difference to atenolol being greater DBP
than to 5 mg bisoprolol. The responder rate (diastolic blood 100 ** **
pressure ≤ 90 mm Hg) as well as the reduction in blood pressure
DBP
were comparable in the 5 mg bisoprolol group and atenolol group,
80
corresponding to a dose ratio of 1:10 for bisoprolol : atenolol.
This dose ratio of bisoprolol and atenolol was also confirmed in beats/min
further studies [110]. 90 HR
* **
80
70 HR
60
50
2-4 weeks 0 +2 weeks +4 weeks

Placebo ␤-blocker

Bisoprolol (n = 44) ** p < 0.01 B vs. M

Metoprolol (n = 43) * 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 56 patients were enrolled in this randomised single-blind study over
100 mg metoprolol in 87 hypertensive patients who were treated for 6 months [79]. The patients received in randomised order 10 mg
4 weeks with a single daily dose [82]. At the end of the treat- bisoprolol once daily or 20 mg enalapril once daily. If the response
ment period, 3 hours after administration of the last dose, both of the blood pressure was inadequate with these doses they could
␤-blockers induced an equally effective reduction in blood pressure be doubled after 4 or 8 weeks. Both substances lowered the blood
and heart rate during exercise (100 watts), corresponding to a dose pressure effectively (office blood pressure as well as the 24-hour
ratio of 1:10 for bisoprolol : metoprolol. 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 meto- A double -blind cross-over study with bisoprolol versus enalapril
prolol on the diastolic blood pressure and heart rate at rest in 45 hypertensive patients again showed comparable blood pressure
(Fig. 27) as well as on the systolic blood pressure and heart rate reductions in both treatment groups after 4 to 8 weeks. The heart
during exercise. 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
6.7.5 Bisoprolol and lisinopril
double-blind, randomised cross-over study [34].
A 12-month study in 52 patients [151] compared the antihypertensive
After a 4-week placebo washout phase one patient group each
efficacy and effects on serum lipids of bisoprolol, 2.5 -10 mg /day,
received first 5 mg bisoprolol (1 x daily) or 50 mg captopril (2 x 25 mg
and lisinopril, 10-20 mg /day. There were no significant differences in
daily), for 6 weeks. If the blood pressure values remained high
antihypertensive efficacy between the two treatments, except for a
(>160 /95 mm Hg) the dosages could be increased to 10 mg biso-
significantly greater reduction in diastolic blood pressure with lisino-
prolol (1 x daily) or 100 mg captopril (2 x 50 mg daily). A further
pril at 6 months only (p < 0.05). Neither drug had any significant
4 week placebo washout phase was then followed by a second
effect on lipid parameters at 3, 6 or 12 months, and there were no
therapy phase in which the patients received the respective alterna-
significant differences between the treatments. As expected, bisopro-
tive antihypertensive drug. Systolic and diastolic blood pressure
lol significantly lowered heart rate, while lisinopril did not. Two
were lowered significantly with both therapy forms. As compared to
patients who received lisinopril experience presumed drug-related
the baseline values, the quality of life of the elderly hypertensive
adverse effects (dry cough and headache). None of the patients
patients investigated in this study remained unchanged under anti-
in the bisoprolol group experienced any drug-related adverse effects.
hypertensive therapy with captopril as well as with bisoprolol.
72 Bisoprolol m 73

An 8-week study in 105 patients with moderate hypertension [167] the daytime blood pressure effectively, whereas during the night
compared the antihypertensive efficacy of bisoprolol, 10 mg/day, only treatment with bisoprolol produced a significant greater blood
with that of lisinopril, 20 mg/day. No significant difference in antihy- pressure response than nitrendipine (Fig. 28). This study shows that,
pertensive efficacy was found between bisoprolol and lisinopril. in contrast to nitrendipine, a single dose of bisoprolol guarantees
effective lowering of the blood pressure over 24 hours [131,132].
A further 4-week single-blind crossover study in 29 patients [192]
The quality of life, which in these patients is reduced in the
with mild to moderate hypertension compared the antihypertensive
placebo phase as compared to the average population (assessed by
efficacy of bisoprolol, 5 -10 mg /day, lisinopril, 10-20 mg/day
means of a self-rating test) improved significantly under anti-
and lacidipine, 4 - 6 mg/day. No significant differences were found
hypertensive therapy with bisoprolol compared to treatment with
between the treatments in control of casually measured systolic
nitrendipine [132].
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 signifi- Fig. 28: Mean change ( –x ± SEM) in systolic and diastolic blood pressure after
cance. Bisoprolol and lacidipine were also better than lisinopril 4 weeks of treatment with either bisoprolol or nitrendipine as assessed
by ambulatory blood pressure measurement [131].
in controlling the rapid rise in blood pressure during the morning.
decrease in blood pressure
(mm Hg)
6.7.6 Bisoprolol and nifedipine retard 8am – 8 pm 8 pm – 8 am 8 am – 8 pm 8 pm – 8 am
0
In hypertensives over 60 years of age, a single daily dose of 10 mg
bisoprolol induced an equally effective reduction in blood 2
pressure as 20 mg nifedipine retard, administered as 2 daily doses.
4
Significantly fewer side-effects occurred with bisoprolol [25].
In a double-blind double-dummy 8-week crossover study in 6
82 hypertensive patients [57], there was no significant difference
in antihypertensive efficacy between bisoprolol 5 mg once daily 8
or nifedipine retard 10 mg twice daily.
10 *
n.s.

12 *
6.7.7 Bisoprolol and nitrendipine n.s.

In a double-blind placebo-controlled study (n = 51) two parallel 14

patient groups were treated with a single dose of 10 mg bisoprolol systolic diastolic
or 20 mg nitrendipine per day for 4 weeks. In order to check the 16

antihypertensive efficacy the casual blood pressure as well as the

24-hour blood pressure were measured. Both substances lowered 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 An 8-week crossover study in 81 hypertensive patients [174],
bisoprolol, 10 mg/day, and verapamil, 240 mg/day, on left ventricular described above, compared bisoprolol, 5 mg daily, with bendrofluazide,
filling in 54 hypertensive patients who had never previously 2.5 mg daily, and found both treatments to be equally effective.
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 6.8 Safety and efficacy in special populations
improved in the patients receiving bisoprolol. This effect was
6.8.1 Elderly hypertensives
observed immediately after the first administration and throughout
the 6-month treatment period, declining slowly during the Bisoprolol effectively reduces the blood pressure also in elderly
placebo wash-out. Improvement in left ventricular filling appeared patients.
to be independent from alterations in heart rate and was consi- The analysis of results from open long-term studies [29] in
dered to be a specific action of bisoprolol [80]. dependence on age shows that bisoprolol was equally effective
in all age groups.
A normalisation of the diastolic blood pressure (≤ 90 mm Hg)
6.7.9 Bisoprolol and a thiazide/potassium-sparing
could be achieved by means of monotherapy with bisoprolol in 80%
diuretic combination
of the hypertensive patients over 60 years of age in a multicentre
In a double-blind randomised study 34 hypertensive patients were study [148].
treated for 30 days with 10 mg bisoprolol or a fixed combination
A 12-week study in 40 patients aged < 65 years and 20 patients
consisting of 50 mg hydrochlorothiazide and 5 mg amiloride. A nor-
aged > 65 years [40] found no significant difference between older
malisation of the diastolic blood pressure could be achieved in
and younger patients in the antihypertensive efficacy of bisoprolol,
15 out of 17 patients in the bisoprolol group (88.2%) but in only
5 -10 mg/day. Bisoprolol also produced a similar reduction in heart
4 out of 17 patients in the diuretic group (23.5%) (p < 0.001) [93].
rate in the two groups. Bisoprolol was well-tolerated, with no
significant differences in adverse drug reactions between the groups.
6.7.10 Bisoprolol and chlorthalidone 59 hypertensive patients over 60 years of age participated in a
double-blind randomised comparative study of bisoprolol versus
In a double-blind randomised study, 21 patients were treated with
nifedipine retard [25]. For 4 weeks the patients received 10 mg biso-
10 mg bisoprolol or 50 mg chlorthalidone once daily for 4 weeks [43].
prolol once daily or 20 mg nifedipine retard twice daily. There was
Both substances lowered the systolic and the diastolic blood
no difference between the two treatment groups with regard
pressure effectively. The bisoprolol group showed less side-effects
to the normalisation rate of the diastolic blood pressure. However,
(13%) than the chlorthalidone group (37%). While under chlor-
the frequency of side-effects was statistically significantly lower in
thalidone treatment a significant reduction of the serum potassium
the bisoprolol group [25]. A further study carried out in the same
concentration and an increase in the serum urea level were
design confirmed this result in 40 patients aged over 65 years [128].
observed these laboratory parameters remained unaffected under
treatment with bisoprolol.
76 Bisoprolol m 77

An 8-week, double-blind crossover study in 154 patients [173], In a subgroup of 1,148 type II diabetic hypertensives, the
found that bisoprolol 5 mg/day, bendrofluazide, 2.5 mg/day and UK Prospective Diabetes Study (UKPDS) [19] has clearly shown
nifedipine retard 10 mg twice daily were all equally effective that tight blood pressure control (blood pressure target of
antihypertensive agents. Half the patients in this study were aged < 150/85 mm Hg) with either atenolol or captopril significantly
over 60 years; no difference was found between older and younger reduces the incidence of micro- or macro-vascular complications,
patients in the antihypertensive efficacy of any of the three drugs. compared with less tight control.
However, the overall response rate was significantly higher in the
Notably, the ␤1-selective blocker atenolol was at least as effective
elderly, as was the response to low dosages.
as the ACE-inhibitor captopril in reducing both microvascular and
With regard to the quality of life during antihypertensive therapy, macrovascular end points [20]. Indeed, there were trends favouring
a comparative study versus captopril [34] did not reveal any changes the ␤-blocker in all seven primary clinical endpoints, namely: any
in the quality of life occurring under bisoprolol in 24 hypertensive diabetes-related endpoint, deaths related to diabetes, all-cause
patients aged over 65 years. 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
6.8.2 Diabetic hypertensives in treatment of complications [21].
Diabetes, both type I and type II, is a major risk factor for In UKPDS [20], there was no significant difference in the rate of
coronary artery disease and MI [7, 24], and the risk of mortality hypoglycaemia with atenolol or captopril. In fact, even in elderly
is further increased by hypertension [17]. Effective control of patients [18], no clinically significant effect has been demonstrated
blood pressure has been shown to reduce mortality and to of ␤-blockade on the risk of hypoglycaemia.
preserve renal function [17, 24]. In the past, there has been
As described previously, specific studies on bisoprolol demonstrate
concern that ␤-blockers might have adverse metabolic effects in
that it has no significant adverse effects on lipid [95] or carbohy-
patients with diabetes, that might make them inappropriate
drate metabolism [95, 96, 99, 180] in diabetic hypertensives,
antihypertensive agents for diabetic patients. Today, however,
making it an appropriate agent for use also in this category of
there is clear evidence that ␤-blockers improve survival in
patients.
diabetic patients, whether with or without established coronary
artery disease [6,11,12,19, 20, 21]. The idea that ␤-blockers are contra-indicated as antihypertensive
agents in diabetic patients may be considered outdated [2]. The
A retrospective study [11] in 2,723 patients with type II diabetes
selection of a ␤1-selective agent such as atenolol or bisoprolol not
and coronary artery disease found a total 3- year mortality of 7.8%
only avoids deleterious effects on glucose and lipid metabolism,
in those receiving ␤-blockers, compared with 44% in those who
but also other side-effects related to non-selective ␤-blockade, such
were not (p = 0.0001). In post-MI patients with type I or II diabetes,
as bronchoconstriction and impaired exercise tolerance.
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.
78 Bisoprolol m 79

7 Treatment of angina pectoris in

coronary heart disease

The objective of anti-anginal therapy is to reduce the number of The reduction in ischaemic ST segment depression and the rate-pres-
angina pectoris attacks to a minimum, and to increase the sure product during ergometric exercise in comparison with the
patient’s exercise tolerance. This objective is achieved by therapy controls were used as assessment criteria. The effect 24 hours
with bisoprolol. after administration was not significantly less than the acute effect
4 hours after administration (Fig. 29) [147]. There were no signi-
Unlike the reduction in blood pressure, the anti-anginal effect of
ficant differences between 5 mg bisoprolol and 10 mg bisoprolol.
␤-blockers is more closely correlated to the plasma concentration
These results of single-dose studies were confirmed for 5 mg and
or to the body’s stock of the drug.
10 mg bisoprolol with chronic administration in a 2-week study [60].

7.1 Duration of action Fig. 29: Mean ST segment depression at rest and during identical exercise
before and after bisoprolol ( –x, SEM; n = 10) [145].
Bisoprolol still exhibits a full anti-anginal effect 24 hours after
administration. The long duration of action is a result of the ST (mV)
long plasma elimination half-life and does not have to be for- 0.5
cibly achieved by relative overdose in single administration,
a special pharmaceutical formulation or repeated daily adminis-
0.4
tration, as is the case with other anti-anginal drugs [30, 182].
The anti-ischaemic and anti-anginal effect of bisoprolol was inve-
0.3
stigated 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]. 0.2
during
As little as 5 mg bisoprolol was effective and with 10 mg almost exercise
maximal effects were achieved. With regard to the reduction in 0.1
ischaemic ST segment depression in the exercise ECG and the at rest
increase in exercise tolerance of coronary patients, these studies 0
showed no difference between 10 mg and 20 mg bisoprolol [117,
0 4 8 24 h
161,181]. Bisoprolol increases the exercise tolerance in patients
with varying degrees of impaired coronary reserve.
5 mg Bisoprolol
In randomised, double-blind, controlled studies in patients with 10 mg Bisoprolol
stable angina pectoris the 24- hour effect of bisoprolol in a dosage
range of 5-20 mg was demonstrated [60,145,147,181].
80 Bisoprolol m 81

7.2 Haemodynamics with bisoprolol was successful in 97.8% of patients. There was
a 37% increase in the exercise tolerance (watt-minute product) of
Bisoprolol increases the myocardial perfusion in coronary artery
patients of a multicentre study after 6 weeks of treatment with
disease. Myocardial perfusion defects are clearly reduced by
bisoprolol in comparison to the initial status, a 56% reduction in
10 mg bisoprolol. This makes the left ventricular function more
the ischaemic ST segment depression and a 17.4% reduction in
economical.
the rate-pressure product.
The effect of 5 and 10 mg bisoprolol on myocardial perfusion was
The success of treatment with the individual optimal dose was also
investigated in a double-blind study performed in 25 patients
maintained throughout the 12-month period of treatment [149].
with stable angina pectoris. 10 mg bisoprolol effected a significant
increase in myocardial perfusion in the thallium -201 scintigram
[124]. Fig. 30: 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
7.3 Success rate bisoprolol. Each symbol stands for one patient [149, 181].

Bisoprolol markedly improves the clinical symptoms in 97.8% Attacks Pretreatment 6 Weeks 12 Months
of angina pectoris patients. per week value (n = 64) (n = 62) (n = 51)

According to the results of controlled, double-blind studies lasting > 20

for 6 [126] and 24 weeks [182] as little as 5 mg bisoprolol was
a sufficiently effective dose for most patients, while 10 mg biso-
11 – 20
prolol 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 6 – 10
under chronic therapy [181].
In several open long-term studies, the treatment of stable angina 3–5
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
0
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
82 Bisoprolol m 83

Fig. 30 shows the number of patients per weekly frequency of ischaemia on ambulatory ECG monitoring. Bisoprolol in a single
attacks before and during a 12- month treatment with bisoprolol. It daily dose was an effective antianginal and anti-ischaemic treatment.
is clear that the exercise tolerance of the patients had improved In the reduction of the number and duration of ischaemic episodes
to a clinically relevant degree even after the first six weeks. Almost and total ischaemic burden bisoprolol proved superior to nifedipine s.r..
half of the patients were free from attacks after 6 weeks of Bisoprolol also was more effective concerning the responder rates,
treatment with bisoprolol [149,181]. the effect on angina and on the circadian variation of ischaemic epi-
sodes [176].
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 7.5 Cardioprotection
bisoprolol in 89% of the patients during a therapy period of
After MI, early administration of a ␤-blocker without ISA
4 weeks. 56% of the patients were free from attacks. The success
reduces the mortality. ␤-blockers are established in secondary
rate was equally high in patients over 60 and under 60 years of
prevention. The tolerability of bisoprolol after acute MI was
age, as well as in smokers and non-smokers [166].
documented in three studies.
In total three studies were performed with bisoprolol i.v. in patients
7.4 Silent ischaemia with acute myocardial infarction. Altogether 237 patients were
treated with bisoprolol i.v. followed by oral intake of 10 mg biso-
In patients with established coronary artery disease about 75%
prolol tablets once daily.
of all ischaemic episodes are asymptomatic.Bisoprolol significantly
decreases the incidence and duration of ischaemic episodes. 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
The incidence of ischaemic episodes in the 24- hour Holter ECG was
patients were treated with 10 mg bisoprolol orally for 3 weeks.
significantly reduced by 10 mg bisoprolol. The duration of the
The desired reduction of the heart rate and of the systolic blood
ischaemic episodes was shortened from 19 to 12 minutes (p ≤ 0.05).
pressure was already achieved with 2-3 mg i.v.The resulting decrease
This was shown in an open study in 13 patients with established
in the rate-pressure product indicated the intended reduction of
coronary artery disease. At the same time the incidence of ventricular
the myocardial oxygen consumption [58,119].
extrasystoles decreased by 80% in these patients [146].
In the second study, 35 patients received 1-2 times 2.5 mg biso-
10 hypertensives with anginal symptoms in the presence of
prolol i.v. within 6 hours after the infarction symptoms had started,
coronary microangiopathy were treated with 5 -10 mg bisoprolol for
and then 10 mg bisoprolol orally for 2 weeks. Bisoprolol was
4 weeks. The number of ST segment depressions in the 24-hour
well tolerated also under these conditions. The patients remained
Holter ECG was reduced by about 50% during the therapy [155].
haemodynamically stable [118].
A randomised multicentre double-blind study the "Total Ischaemic
A double-blind randomised study with acute MI was performed in
Burden Bisoprolol Study"(TIBBS), was performed with bisoprolol ver-
333 patients. 165 patients were treated with bisoprolol and
sus nifedipine slow release (s.r.) in 330 patients with stable angina
168 patients with atenolol for 7 days. The dosage regimen for
pectoris, a positive result on the exercise ECG and with transient
84 Bisoprolol m 85

bisoprolol was adapted from the pilot studies [119, 171] and the (10 mg daily) or atenolol (100 mg daily) for 12 weeks (subsequent
dosage regimen for atenolol corresponded to that used in the to a 2-week placebo phase). Both therapeutic regimens signifi-
ISIS I -study. The tolerability was similar for both substances and the cantly increased exercise tolerance and decreased the rate-pressure
adverse effects reported were rare and mainly well known for product. After 12 weeks of therapy, 29% of the patients treated
␤-blockers or due to the natural course of the disease. The reduc- with 10 mg bisoprolol and 18% of the patients treated with atenolol
tion of heart rate and blood pressure was similar in both groups, had no anginal complaints during exercise [59].
leading to a reduction of the myocardial oxygen consumption with
a positive influence on myocardial ischaemia. A cardioprotective
Fig. 31: Watt-minute product (W x min) and ST segment depression (mV) at
effect after MI can therefore be postulated for bisoprolol [119]. 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].
7.6 Therapeutic comparison in coronary patients
W x min
In single daily administration bisoprolol proved to be equally 400
effective as other anti-anginal agents, some of which require
repeated daily administration. 300

7.6.1 Bisoprolol and atenolol 200

In the randomised, double -blind, cross-over study already referred

100
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 biso-
0
prolol or 100 mg atenolol [126]. There was no significant difference
between the 3 therapies with regard to duration of exercise, time up ST (mV) 0 2 4 24 weeks
to the occurrence of an ST segment depression of 0.1 mV, frequency 0
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, – 0.10
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 – 0.20
a comparable improvement in exercise tolerance and ST segment
depression under both therapies (Fig. 31) [182].
In an international double-blind randomised study (MIRSA), – 0.30
157 patients with stable angina pectoris were treated with bisoprolol
Atenolol Bisoprolol
86 Bisoprolol m 87

7.6.2 Bisoprolol and nifedipine During phase 1 there was a significant reduction in the number
and duration of transient ischaemic episodes as well as in total
The total ischaemic burden – which includes both symptomatic and
ischaemic burden with both bisoprolol and nifedipine s.r.. Bisoprolol,
asymptomatic ischaemic episodes – as well as the number and
however, proved to be significantly more effective than nifedipine s.r.
duration of ischaemic episodes were investigated in a large double-
(Fig. 32). Additionally bisoprolol reduced the early-morning peak
blind multicentre study (TIBBS = Total Ischaemic Burden Bisoprolol
and lowered the afternoon peak of the transient ischaemic episodes
Study) which compared bisoprolol with nifedipine slow release (s.r.)
markedly. Nifedipine led only to a reduction of the second, late-
[176]. 330 patients with stable angina pectoris, positive exercise test
afternoon peak of transient ischaemic episodes (Fig. 33).
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 Fig. 33: Effects of bisoprolol and nifedipine s.r. on the distribution of
10 mg and nifedipine s.r. at 20 mg b.i.d.; for a further 4 weeks transient ischaemic episodes (sum of episodes / h on two consecutive
days as mean value / patient). From comparable baseline curves,
(phase 2) the dosages were doubled to bisoprolol 20 mg once daily bisoprolol effectively reduces the morning and afternoon peaks of
and nifedipine s.r. 40 mg b.i.d. A 48-hour Holter monitoring was transient ischaemic episodes but leaves the circadian distribution
performed at the end of each treatment phase. unchanged [176].

no. episodes/
patient/hour
Fig. 32: Effects of bisoprolol and nifedipine slow release (s.r.) on total
ischaemic burden. Reduction compared to baseline is significant with 0.45
both drugs and the difference in reduction between bisoprolol and
nifedipine is also significant ( p < 0.01), the reduction being greater
under bisoprolol [176].
0.30
min x mm /48 h
250
200 0.15
150
100
0
50 1 4 8 12 16 20 24 h
0
Baseline Bisoprolol Baseline Nifedipine s.r.
10 mg 20 mg 2 x 20 mg 2 x 40 mg Baseline Baseline
n = 133 n = 135
Bisoprolol Nifedipine s.r.
10 mg o.d. 20 mg b.i.d.
(s.r. = slow release)
88 Bisoprolol m 89

During Holter monitoring at the end of phase1, 54 patients (41%) The standard deviation of all 5 min mean cycle lengths and the
were free from ischaemic episodes in the bisoprolol group and standard deviation of the mean of all corrected RR intervals
only 20 patients (15%) in the nifedipine group (p < 0.0001). Only increased from low baseline values and declined from higher base-
slight additional effects were achieved by doubling the dosage, line values. The increase in heart rate variability on treatment with
and significant differences continued to exist between the two bisoprolol was accompanied by a tendency towards a better
treatment groups. prognosis. Patients in whom an increase in heart rate variability
was accompanied by complete suppression of ischaemia on therapy
The follow-up results of 520 patients were available at 1 year,
experienced no serious events during one year of follow-up.
comprising 317 patients randomised to the TIBBS study and 203
who had been screened but not randomised. Assessments of A UK economic analysis of the TIBBS study [139] showed that
cardiac events (cases of deaths, MI and unstable angina pectoris) therapy with bisoprolol resulted in lower costs per patient over
after 6 and 12 months proved that the number of events correlates 12 months (£ 1,372 vs £ 2,030 for nifedipine).
directly with the number of transient ischaemic episodes during
The effect of 10 mg bisoprolol and 20 mg nifedipine or of a combi-
TIBBS screening phase. Patients who responded to medical
nation of the two drugs on the resting and exercise haemodynamics
treatment by 100% (no further transient ischaemic episodes) in the
was compared in 21 patients enrolled in a double-blind study.
TIBBS study showed a significantly lower number of events than
The anti-ischaemic effect of bisoprolol was more pronounced than
the non-responders [177, 178]. The positive effect of bisoprolol in
that of nifedipine. The effect of the combination was not signifi-
TIBBS translated into an improved prognosis compared to
cantly stronger. The haemodynamic profiles of the two drugs were,
nifedipine s.r. during the 1- year follow-up. Patients randomised to
as expected, different [162].
bisoprolol during the TIBBS study had a reduced risk of events
(20.9%) in the follow-up compared to patients randomised to nife-
dipine s.r. (33.3%) (p < 0.05) [179].
7.6.3 Bisoprolol and verapamil
A retrospective analysis has been performed on data from the
A total of 21 CHD patients participated in an 8-week double-blind
TIBBS study [23], to analyse the effects of bisoprolol and nifedipine
study with parallel groups. After 4 weeks the dose of 10 mg biso-
on heart rate variability. An increase in heart rate variability can be
prolol, administered once daily, and 80 mg verapamil (3 times daily)
regarded as prognostically favourable. Analysis of 24-hour Holter
were increased (20 mg bisoprolol, 3 x 120 mg verapamil) [56].
monitoring data from 422 patients with stable angina found that
Under both therapies there was a comparable improvement in the
nifedipine reduced the mean values of all heart rate variability
symptoms of angina pectoris, and a prolongation of the duration
parameters tested (standard deviation of the mean of all corrected
of exercise and the time up to the occurrence of a ST segment
RR intervals, standard deviation of all 5 min mean cycle lengths,
depression of 0.1 mV. There was a significantly greater reduction in
square root of the mean of the squared differences of successive
heart rate and rate-pressure product at maximum exercise with
corrected RR intervals).
20 mg bisoprolol than with 360 mg verapamil, probably as a result
In contrast, the square root of the mean of the squared differences of the high dose of 20 mg bisoprolol, which was not required
of successive corrected RR intervals increased under bisoprolol. by all patients (fixed dosage increase for all patients after 4 weeks).
90 Bisoprolol m 91

8 Treatment of chronic heart failure

7.6.4 Bisoprolol and isosorbide dinitrate Although ␤-blockers have, in the past, been considered contra-
indicated in patients with chronic heart failure (CHF) due to
At a daily dose of 10 mg bisoprolol is superior in its effect on
their negative inotropic effects, the opinion is now changing in
transient ischaemia compared to isosorbide dinitrate (20 mg t.i.d.)
the light of some recent studies with ␤-blockers in heart failure
in patients with stable angina pectoris [143, 170]. While bisoprolol
and a better understanding of its pathophysiology. Over the past
and a combination of bisoprolol with isosorbide dinitrate led to
two decades, clinical trials in patients with CHF have demon-
a significant reduction of both early morning and late-afternoon
strated improvements in symptoms, exercise capacity, ventricular
peaks of ischaemic episodes, treatment with isosorbide dinitrate alone
function, functional status (NYHA class) and survival following
showed an effect only on the late-afternoon peak. A combination
␤-blockade on top of standard therapy when treatment was
of the two combounds did not achieve any additional effects in
carefully titrated. Recent mortality trials have provided clear
comparison to bisoprolol alone (Fig. 34) [143]
evidence that ␤-blockers without intrinsic sympathetic activity
are efficient in reducing mortality [1, 5,15, 22,55]. Recent
Fig. 34: Circadian distribution of ischaemic episodes under therapy with biso- meta-analyses of randomised trials also indicate a reduction in
prolol, isosorbide dinitrate, a combination of bisoprolol + isosorbide mortality in CHF in patients receiving ␤-blockers [4, 8, 13].
dinitrate, and placebo [143].
As a result, ␤-blockers are part of standard therapy for CHF treat-
number of ischaemic episodes ment today.
30 Two major clinical trials have been performed with bisoprolol in
CHF: the Cardiac Insufficiency Bisoprolol Study (CIBIS) [50] and the
25 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
20
primary outcome [51].

15
8.1 CIBIS
CIBIS was performed in 641 patients (NYHA III and IV) with chronic
10
heart failure of various aetiologies and left ventricular ejection
fraction of < 40%. In this double-blind multicentre study 320 patients
5 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
0 to 5 mg 1 month later. All patients received background diuretic
0 2 4 6 8 10 12 14 16 18 20 22 24 hours and vasodilator therapy, which was in 90% of cases an ACE-
inhibitor. Mean duration of follow-up was 1.9 ± 0.1 years. Although
Placebo Bisoprolol no significant reduction in mortality was observed under bisoprolol
ISDN Combination
92 Bisoprolol m 93

in the whole population, there were, however, fewer deaths in Fig. 36: Survival curves in CIBIS patients without a history of MI ( n = 338 ).
the bisoprolol group (53 patients or 16.6%) compared to placebo, 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
where 67 patients (20.9%) died (Fig. 35). rank test ) [50].
Furthermore subgroup analyses demonstrated additional benefits
survival (%)
for certain patient groups:
100
• a 47% reduction in mortality (p < 0.01) in patients without
history of MI (Fig. 36)
80
• a 53% reduction in mortality in patients with dilated cardio-
myopathy (Fig. 37)

• a 42% reduction in mortality (p = 0.05) in patients with a 60

ventricular rate > 80 bpm.

40
Fig. 35: Survival curves in CIBIS patients (n = 641). Within two years 0 200 400 600 800 1000 1200 1400
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 time (days)

survival (%)
Fig. 37: Survival curves in CIBIS patients with dilated cardiomyopathy
100 (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].
80
survival (%)

100
60

80
40
0 200 400 600 800 1000 1200 1400

survival time (days) 60

Bisoprolol
Placebo
40
0 200 400 600 800 1000 1200 1400

survival time (days)

Bisoprolol
Placebo
94 Bisoprolol m 95

Bisoprolol significantly improved the NYHA stages. Improvement 8.1.1 Heart rate variability
by one NYHA class was seen in 21% of the bisoprolol-treated
An increase in heart-rate variability is considered desirable in
patients compared to 15% in the placebo group ( p = 0.04) (Tab. 5a,
various cardiac conditions e.g. after a MI, in stable angina pectoris,
5b). Significantly less patients required hospitalisation for cardiac
and in cardiac insufficiency. The effects of bisoprolol on heart rate
decompensation (61 on bisoprolol vs. 90 on placebo, p < 0.01).
variability were investigated in 54 patients from the CIBIS study
[54, 144]. Bisoprolol produced a reduction in heart rate and an
Tab. 5a: NYHA class evolution between inclusion and last follow-up visit [50]. increase in heart-rate variability, whereas placebo had no such
effects. In particular, indicators of vagal activity were significantly
III IV Equal IV III IV II not
or III II or III I followed improved by bisoprolol.
Placebo 35 (11%) 226 (70%) 46 (14%) 2 (1%) 12 (4%)
Bisoprolol 41 (13%) 195 (61%) 66 (21%) 2 (1%) 16 (5%)
8.1.2 Pharmacoeconomic analyses
In analyses of economic data from the CIBIS trial, cost savings
Tab. 5b: Improvement by at least one functional class [50] associated with the use of bisoprolol in heart failure were demon-
strated for Germany [154] and France [115], and a UK study [125]
Placebo 48 (11%)
showed that the addition of bisoprolol to standard therapy was
Bisoprolol 68 (21%) p = 0.04
at least cost-neutral.

From a substudy in which echocardiographic assessment of left

8.2 CIBIS II
ventricular function (left ventricular diameter and left ventricular
fractional shortening) was performed, it could be demonstrated that The design of CIBIS II [109] was based on the background and
left ventricular fractional shortening was significantly improved results of the first CIBIS trial. It included 2,647 symptomatic ambu-
on bisoprolol (+ 4.6 ± 6.5%) at 5 months vs placebo (0.04 ± 5.5%; latory patients in NYHA class III or IV (ejection fraction ≤ 35%)
p < 0.001). This improvement was regardless of the aetiology of of various aetiologies. Men and women aged 18 - 80 years were
congestive heart failure and associated with a better prognosis for eligible for inclusion; women were only included if they were post-
patients with congestive heart failure: Survival in the entire popu- menopausal, surgically sterilised or using reliable contraceptive
lation after the initial 5 months period was significantly higher in the methods. Patients were required to be stable on standard treat-
bisoprolol group (8% of patients died compared to 15% in the ment with ACE-inhibitors and diuretics. They were assigned to
placebo group) [50]. 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 biso- Fig. 38: Survival in CIBIS II [51].
prolol 1.25 -10 mg daily (both given in addition to standard therapy)
survival (%)
on long-term all- cause mortality, in comparison to placebo.
Secondary endpoints included cardiovascular mortality (pump failure, 1.0

sudden death, fatal MI, other cardiovascular deaths, unknown

cause of death), hospital admissions, combined endpoints (cardio-
vascular mortality or hospitalisation for cardiovascular reasons)
and permanent treatment withdrawal. 0.8

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. 0.6

0
8.2.1 Primary endpoint (all-cause mortality) 0 200 400 500 800
Bisoprolol showed a highly significant beneficial effect on the time after inclusion (days)
primary endpoint all-cause mortality irrespective of aetiology or Bisoprolol
severity of the disease. 156 patients (11.8%) of patients died in the Placebo
bisoprolol group, compared with 228 (17.3%) in the placebo
group (p < 0.0001). The estimated annual mortality was 8.8% for
8.2.2 Secondary endpoints
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). The results for secondary endpoints are shown in Tab. 6. Signifi-
cantly fewer bisoprolol-treated patients were admitted to hospital
for any reason (33% vs 39%, p = 0.0006). Significantly fewer biso-
prolol-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 Bisoprolol Hazard ratio p Causes of death Placebo Bisoprolol Hazard ratio p
(n = 1,320) (n = 1,327) (95 % CI) (n = 1,320) (n = 1,327) (95 % CI)
All-cause hospital 513 440 0.80 0.0006 Sudden death 83 48 0.56 0.0011
admission (39 %) (33 %) (0.71- 0.91) (6 %) (4 %) (0.39 - 0.80)

All cardiovascular 161 119 0.71 0.0049 Pump failure 47 36 0.74 0.17
deaths (12 %) (9 %) (0.56 - 0.90) (4 %) (3 %) (0.48 -1.14)

Combined 463 388 0.79 0.0004 Myocardial 8 7 0.85 0.75

endpoint (35 %) (29 %) (0.69 - 0.90) infarction (1 %) (1 %) (0.31- 2.34)

Permanent 192 194 1.00 0.98 Other cardio- 23 28 1.17 0.58

treatment (15 %) (15%) (0.82 - 1.22) vascular deaths (2 %) (2 %) (0.67- 2.03)
withdrawals
Noncardio- 18 14 0.75 0.41
vascular deaths (1%) (1%) (0.37-1.50)
8.2.3 Additional analyses
Unknown cause 49 23 0.45 0.0012
Additional analyses demonstrated that the greatest effect of of death (4 %) (2 %) (0.27- 0.74)
bisoprolol on mortality was in the reduction of sudden death; there
was a 42% lower rate of sudden death among patients on Subgroup analyses (Fig. 39) showed no significant difference
bisoprolol (4% vs 6%, p = 0.011) (Tab. 7). There were also fewer between the groups for mortality or admission to hospital for any
deaths from pump failure in the bisoprolol group, though this subgroup of aetiology of heart failure or class of disease severity.
was not statistically significant (3% vs 4%, p = 0.17). However, many
Fig. 39: CIBIS II mortality by baseline findings [51].
deaths had to be classified for the purposes of the trial as being
of unknown cause (i.e. they were unwitnessed or insufficiently docu-
Relative risk Bisoprolol Placebo
mented). Significantly fewer deaths of unknown cause were recor- n/total n/total
ded in the bisoprolol group (2% vs 4%, p = 0.0012), which suggests
that many of these deaths were in fact from cardiac causes. Ischaemia 75/662 121/654

There were no significant differences between the groups in the Primary DCM 13/160 15/157
number of deaths from other cardiovascular causes, or non-
Undefined 68/505 92/509
cardiovascular causes. There were significantly fewer admissions
for worsening heart failure among bisoprolol-treated patients NYHA III 116/1,106 173/1, 096
(12% vs 18%, p = 0.0001).
NYHA IV 40/221 55/224

Total

Horizontal bars
Relative risk 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 represent 95% CIs.
100 Bisoprolol m 101

9 Further areas of research

8.2.4 Pharmacoeconomic analysis 9.1 Hyperthyreosis

A prospectively planned economic analysis was conducted based Three studies were performed with bisoprolol in patients with hyper-
resource utilisation data collected during the CIBIS II [130]. The thyreosis. In total 32 patients were investigated in these studies.
analysis was based on the comparison of conventional therapy for The main results were as follows: the subjective and objective
heart failure (diuretic, digoxin and ACE-inhibitor) to conventional clinical symptoms of hyperthyroidism were improved, heart rate and
therapy plus adjunctive bisoprolol and took the perspective of systolic as well as diastolic blood pressure were decreased.
a third party payer in France and Germany and the NHS in the UK. Changes in the serum levels of thyroid hormones were not observed
To take into account the additional costs related to bisoprolol [97,141]. The pharma cokinetics of bisoprolol remained unaltered,
treatment, it was assumed that all patients treated with bisoprolol only small variations in plasma concentrations of bisoprolol were
require 4 additional outpatient /office visits for initiation and observed [141].
up-titration of treatment.
One double-blind study compared the effects of bisoprolol with
The analysis found that the costs avoided by the reduced rate of the non-selective ␤-blocker propranolol. Bisoprolol was at least as
hospital admissions in the bisoprolol treated group more than effective as propranolol in ameliorating the clinical symptoms of
offset the extra costs of bisoprolol therapy. In all three countries hyperthyreosis [169].
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. 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 signifi-
cantly lower in patients receiving either dose of bisoprolol than
in those receiving placebo. One or more adverse events were repor-
ted 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 Two of 59 patients (3.4%) receiving bisoprolol died of cardiac
medication was rated as very good by 81- 82% of patients receiving causes, compared with 9 of 53 patients in the standard care group
bisoprolol and by 84% of patients receiving placebo. (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
A double-blind cross- over study [190] compared the prophylactic
care group (17%, p < 0.001). Overall, the primary study endpoint of
efficacy of bisoprolol, 5 mg /day, with that of metoprolol, 50 mg,
death from cardiac causes or non-fatal infarction occurred in
twice daily, in patients who had suffered from migraine with or with-
2 /59 patients in the bisoprolol group (3.4%) and 18/53 patients
out aura for at least two years. Patients were required to have
in the standard care group (34%, p < 0.001).
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.
104 Bisoprolol m 105

10 Psychological functions 11 Tolerability

The sleep quality and psychomotor performance capacity Tolerability data with bisoprolol confirm the excellent safety
were not impaired by bisoprolol. There was an improvement in profile. The number of undesirable side-effects was low and no
the driving abilities of infarction patients. new, unknown adverse reactions for ␤-blockers in general
occurred. Discontinuations of treatment were rare.
The effect of bisoprolol and pindolol on sleep quality was com-
pared with that of placebo in a group of 36 healthy volunteers. Undesirable side-effects could chiefly be attributed to intensified
With both bisoprolol and placebo, sleep quality was unchanged in pharmacodynamic effects. In open titration studies, patients
comparison with the initial status, whereas in the pindolol group suffering from hypertension and angina pectoris were treated with
it was below the initial level. Feeling refreshed after sleep was im- the individual optimal dose of bisoprolol after a 14- day placebo
paired with pindolol as compared with placebo whereas the effect pretreatment phase. In a group of 612 patients from long-term
of bisoprolol did not differ from that of placebo [78]. studies, reactions were reported by 136 patients (22.2%) in the
placebo pretreatment phase and by 167 patients (27.2%) during
In volunteers bisoprolol significantly reduced the blood pressure,
treatment with bisoprolol.
heart rate and rate-pressure product without any impairment
of psychomotor performance. In volunteers with cardiovascular The number of reports of the three most frequent undesirable side-
hyperreaction the rate-pressure product was reduced to a greater effects (giddiness, headache, fatigue) was comparable during the
extent than in volunteers with hyporeaction. The better psycho- placebo phase and during treatment with bisoprolol. The frequency
motor performance of the hyperreactive volunteers was, however, of reports decreased as the treatment proceeded.
not impaired by bisoprolol. The performance of the hyporeactive
Out of a total group of 1,396 patients and volunteers, 24 patients
volunteers was lowered by bisoprolol by only 9.6% [158].
(1.77%) discontinued the treatment with bisoprolol due to
The influence of 5 and 10 mg bisoprolol and 60 mg isosorbide undesirable side-effects. The drop-out rate was independent of the
dinitrate (ISDN) on driving performance under realistic conditions dose level (Tab. 8).
was investigated in 18 post-infarction patients. In contrast to
In an open multicentre study in 2,012 hypertensive patients the
ISDN, with 5 mg and 10 mg bisoprolol the orientation performance
tolerability of 5 and 10 mg bisoprolol /day was investigated
and driving technique in complicated traffic situations were im-
over 8 weeks. 96.3% of the patients assessed the tolerability
proved to an equal degree [159].
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 gastrointes-
tinal 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: Drop-outs due to undesirable side-effects from a total patient The study shows furthermore that undesirable side-effects are
population of n =1,396 [31]. not observed more frequently in elderly patients than in younger
patient groups [90].
Principal symptom Number of %
patients More than 15,000 patients were treated with bisoprolol in post
Bradycardia 8 0.59 marketing surveillance studies performed by Merck KGaA. Table 9
comprises the most important concomitant symptoms observed
Giddiness 3 0.22 and their incidence. Of 15,290 patients treated in post marketing
Gastrointestinal disorders 4 0.29
surveillance studies of Merck only 1,713 patients (11.2%) had
adverse events including 336 patients (2.2%) who discontinued
Malaise 3 0.22 treatment before the end of the study. The reported adverse events
were all already known for bisoprolol or for other ␤-blockers.
Dyspnoea 2 0.15
None of these can be rated as serious [41].
Asthmatic bronchites 1 0.07
This good tolerability of bisoprolol could be confirmed in over
Nightmares 1 0.07 50,000 patients controlled in total in clinical studies. Tolerability
also was independent of the indications treated with bisoprolol.
Feelings of anxiety 1 0.07

Hot flushes 1 0.07 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
Fig. 40: Rating of therapy with bisoprolol by doctor (a) and patient (b) [91]. effects on sexuality in newly diagnosed hypertensive patients were
found. In those patients already on antihypertensive medication
a b bisoprolol improved sexuality in some parameters [39].
good good

moderate
moderate
poor poor
no data no data
108 Bisoprolol

Tab. 9: Adverse events from post marketing surveillance studies in

15,290 patients [41].

Adverse reactions Number Incidence

of reports (%)

Nervous system
Tiredness 214 1.4
Dizziness 141 0.9
Headache 169 1.1
Sleep disturbances 143 0.9
Vivid dreams 2
Psychic disturbances (e.g. depressive mood) 31 0.2
Eyes
Visual disturbances 2
Conjunctivitis 6
Reduced lacrimation 1
Cardiovascular system
Paraesthesias 322 2.1
Bradycardia 69 0.5
Orthostatic hypotension 15 0.1
Intensification of Raynaud´s phenomenon 4
Airways
Dyspnoea in patients predisposed to 139 0.9
bronchospasm (e.g. in asthmatic bronchitis)
Gastrointestinal tract
Gastrointestinal complaints (e.g. diarrhoea, 187 1.2
constipation, nausea, abdominal pain)
Musculosceletal system
Muscle weakness 8
Skin
Skin reactions (e.g. itching/pruritus, flush, 39 0.3
sweating, skin rash)
Urogenital organs
Potency disorders 110 0.7
 m 109

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Notes

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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 thera-
peutic 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/ long-
term 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
m 070201