Download Bisoprolol dose–response relationship in patients with congestive

European Heart Journal (2003) 24, 552–559
Bisoprolol dose–response relationship in patients
with congestive heart failure: a subgroup analysis
in the cardiac insufficiency bisoprolol study
(CIBIS II)
T. Simon a*, M. Mary-Krause b, C. Funck-Brentano a, Ph. Lechat c,
P. Jaillon a, on behalf of CIBIS II investigators
a
Department of Pharmacology, Saint Antoine University Hospital AP-HP, 27, Rue Chaligny, 75012, Paris,
France
b
INSERM EMI0214, 56 Bvd V. Auriol, 75013, France
c
Department of Pharmacology, Pitié-Salpétrière University Hospital AP-HP, 83, Bcd de l’hopital, 75013, France
Received 17 August 2002; revised 8 October 2002; accepted 9 October 2002
KEYWORDS
Congestive heart
failure;
Adrenergic
beta-antagonists;
Dose–response
relationship;
Mortality
Aims Whether all patients with congestive heart failure (CHF) need to reach the target
dose of beta-blocker to obtain a benefit in terms of survival remains uncertain.
Methods and results We classified by tertile the 2647 patients enrolled in CIBIS II
according to the last tolerated dose: low dose (LD: 1.25, 2.5 or 3.75 mg/day, n⫽434),
moderate dose (MD: 5 or 7.5 mg/day, n⫽328) and high dose (HD: 10 mg/day, n⫽565)
of bisoprolol or placebo (LD=234, MD=278 and HD=808). In both groups, patients
tolerating only low doses were significantly older with more severe New York Heart
Association (NYHA) functional class and higher frequency of co-morbidities. Treatment withdrawal was associated with a significant increase of mortality in the
bisoprolol group (relative hazard (RH)=2.13, 95% confidence interval (CI)=1.43–3.17,
p⫽0.0002). After adjustment, all-cause mortality was significantly reduced in the
bisoprolol group compared to placebo regardless of the dose level considered: LD
(RH=0.66, 95% CI=0.48–0.92), MD (RH=0.33, 95% CI=0.21–0.51) or HD (RH=0.59, 95%
CI=0.40–0.89).
Conclusions Bisoprolol reduces mortality in CHF patients at all tolerated dose levels
and its withdrawal increases the risk of mortality. Efforts should be made to maintain
bisoprolol therapy based on the individual patient's tolerability.
© 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All
rights reserved.
Introduction
The rationale for using -adrenoceptor blockers in
the treatment of congestive heart failure (CHF) is
This work was presented at the Annual Scientific Sessions of the
American Heart Association, Circulation 2000; 102(18): II-629,
3051.
* Corresponding author. Tel.: +33-1-40-01-14-57; fax: +33-140-01-14-04
E-mail address: tabassome.simon@chusa.jussieu.fr (T. Simon).
well described and established.1,2 The degree of
sympathetic activation correlates with the severity
and clinical outcome of the disease.3 The Cardiac
Insufficiency Bisoprolol Study (CIBIS II), a randomized double-blind placebo-controlled trial,4
showed a 34% reduction in all-cause mortality with
bisoprolol, a 1-selective adrenergic antagonist,
added to standard treatment with ACE inhibitors
and diuretics in class III and IV CHF patients.
0195-668X/03/$ - see front matter © 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0195-668X(02)00743-1
Bisoprolol dose–response relationship
Because blockade has been shown to produce a
dose-dependent improvement in ventricular function5,6 which may result in a dose-related decrease
in mortality,6 all effort is made in order to achieve
the highest tolerated dosage.1,2 Thus the strategy
for administering a blocker in each of the major
clinical trials has been based on a very slow gradual
tolerance-limited up-titration7 over the course of
several weeks until the target dose is achieved
(10 mg daily for bisoprolol,4 200 mg/day for
metoprolol succinate CR8 and 50 mg daily for
Carvedilol9–11). Despite this slow dose-titration,
some patients do not tolerate the target dose
and/or experience various degrees of decompensated CHF which may lead to blocker withdrawal.
Previous studies have shown the risk of deterioration with the beta-blockade withdrawal in CHF
patients.12,13
An important challenge for physicians in charge
of the management of beta-blocker therapy in CHF
patients is therefore to find the relevant and
optimal dose for each individual patient in order to
obtain the best benefit/risk ratio for the treatment. The purpose of the current study was to
examine whether patient's survival in CIBIS II was
related to the tolerated dose of the bisoprolol.
Methods
Patients
We analyzed the data in CIBIS II by classifying the
patients enrolled into tertile groups according to
the last tolerated dose before event or last
follow-up visit14: low dose (1.25, 2.5 or 3.75 mg/
day, n⫽434 (33%)), moderate dose (5 or 7.5 mg/
day, n⫽328 (25%)) and high dose (10 mg/day,
n⫽565 (43%)) of bisoprolol or placebo (low dose
(n⫽234 (18%)), moderate (n⫽278 (21%)) and high
dose (n⫽808 (61%)).
Details on the study design and results of CIBIS II
trial have been reported previously.4 Briefly, a
total of 2647 patients with New York Heart Association (NYHA) class III and IV heart failure treated by
diuretic and ACE inhibitor for at least 2 weeks were
randomized in the study. Other vasodilator was
allowed in case of intolerance to an ACE inhibitor
(4%), whereas the use of digoxin was optional.
Additional entry criteria included clinical stability
for at least 6 weeks for heart failure (3 months in
case of heart failure due to myocardial infarction),
a left ventricular ejection fraction (LVEF) of 35% or
less obtained either from echocardiography or ventriculography. The titration of the randomized
study medication was performed without a run in
553
period. The initial dose of bisoprolol was administered for a week and was increased according to
clinical response towards the target dose; patients
received the first three dose levels (1.25, 2.5 and
3.75 mg) for 1 week, and the higher levels (5 and
7.50 mg) for 4 weeks before the final step of 10 mg
daily. It was recommended to maintain the target
dose if possible throughout the study.
Outcome events
The primary endpoint in CIBIS II was all-cause mortality. Classification of deaths has been reported
elsewhere.4 Secondary endpoints were cardiovascular mortality, non-cardiovascular mortality,
all-cause hospital admissions, cardiovascular
hospital admissions and permanent treatment withdrawal (PTW). Temporary treatment withdrawals
were authorized in the trial.
All medical events, including treatment withdrawals, were blindly reviewed and classified by
members of an independent Critical Event Committee according to standardized definitions established before inclusions started. Medical events
considered in CIBIS II were worsening of heart
failure, cardiogenic shock, documented ventricular tachycardia/fibrillation, symptomatic supraventricular tachycardia, symptomatic bradycardia,
symptomatic hypotension, myocardial infarction,
revascularization, cardiac transplantation, other
cardiac surgery, angina pectoris requiring hospital
admission, stroke, other cardiovascular hospitalizations and non-cardiovascular events. The reasons
for PTW were classified by the Critical Event
Committee as personal decision of patient or
investigator (i.e. not a medical event considered by
the Committee as justifying withdrawal), contraindication to beta-blocker therapy or mandatory
indication for beta-blocker therapy (intractable
angina, high ventricular rate despite authorized
bradycardiac treatments and severe ventricular
arrhythmias which did not respond to amiodarone
alone).
Statistical analysis
Statistical analysis was performed by using SAS®
computer software version 8.2. Follow-up data
for outcome events were available for all
patients. Survival curves were estimated by the
Kaplan–Meier method and compared by log–rank
test.
Chi square and non-parametric tests were used
to assess the relationship between baseline characteristics and dose groups. Each significant predictor
554
identified by this analysis was tested for time to
death in a multivariate Cox proportional hazards
model stratified on PTW. Other variables considered likely to have an important prognostic
factor, and variables with a p value up to 0.20,
were also forced into the model. Adjustment was
performed with the following variables: age,
gender, body mass index, NYHA class, duration of
heart failure, etiology of CHF, smoking status,
history of diabetes, atrial fibrillation, heart rate at
inclusion, systolic and diastolic blood pressure,
presence of left and right bundle branch block,
presence of atrio-ventricular block, abnormal ST
segment interval, LVEF, concomitant and randomized treatment, and the last tolerated dose
group. Results are expressed as relative hazard
(RH) and 95% confidence intervals (CI). Presence of
interaction between dose groups and randomized
treatment, and between PTW and randomized
treatment were also tested by Cox analysis.
Results
Baseline patients characteristics
Patients characteristics at baseline in each tolerated dose group of bisoprolol and placebo are
shown in Table 1 (a) and (b), respectively. No
difference was observed across the three bisoprolol
groups of dose with regard to factors such as
gender, race, LVEF, abnormal ST segment, diabetes
and atrial fibrillation. However, compared with
patients treated with moderate and high doses of
bisoprolol (25 and 43% of patients), those receiving
low doses (33%) were significantly older with more
severe NYHA functional class and had a lower systolic and diastolic blood pressure (Table 1 (a)).
They were more likely to have a previous history of
hypotension, severe arrhythmia and a higher frequency of left bundle branch block and atrioventricular block. Patients tolerating low doses of
beta-blocker were also those who had a higher
prevalence of documented ischemia as the underlying cause of CHF, whereas an undefined etiology
was more frequent among moderate and high dose
groups (Table 1 (a)). A similar proportion were
receiving ACE inhibitors, diuretics, digitalis and
aspirin whereas the use of nitrates and amiodarone
were significantly more frequent in patients receiving low dose of bisoprolol. In the same way there
was a consistent pattern of a more severe disease
among patients in whom placebo was maintained at
low doses (Table 1 (b)).
Patients tolerating low doses of bisoprolol
or placebo did not differ regarding their baseline
Simon et al.
clinical characteristics with the exception of heart
rate at rest, lower in the bisoprolol group
(77±14 bpm vs. 81±14 bpm, p⫽0.003). The use of
nitrates was the single variable that differed among
patients tolerating moderate doses (67 vs. 57% in
the placebo and bisoprolol groups, respectively,
p⫽0.01). Among patients tolerating high dose,
those in the bisoprolol group had a lower frequency
of previous history of hypotension (1 vs. 3%,
p⫽0.016), severe arrythmia (19 vs. 27%, p⫽0.001),
concomitant use of amiodarone (10 vs. 14%,
p⫽0.038) and diuretics (98 vs. 100%, p⫽0.021)
compared to placebo.
Permanent treatment withdrawal during
follow-up
PTW was required in 381 patients, 191 treated with
placebo and 190 with bisoprolol groups (14% of
patients in each group). No difference was
observed in the two treatment groups regarding the
main cause of PTW (the patient's or investigator's
personal decision in 81% of cases, i.e. not a medical
event considered by the Critical Event Committee
as justifying withdrawal) or the cause of death after
PTW.
The distribution of the PTW was significantly
related to the tolerated dose in both placebo and
bisoprolol groups: 125 patients (9%) and 87 patients
(7%) stopped bisoprolol or placebo at low doses, 45
patients (3%) and 47 patients (4%) at moderate
doses, and 20 (2%) and 57 patients (4%) at high
doses of bisoprolol and placebo, respectively,
(p⫽0.001). PTW occurred earlier in patients receiving low doses of placebo and bisoprolol. Time
between the start of the dose in which PTW
occurred and PTW was significantly dosedependent in both bisoprolol (61±114 days,
123±143 and 171±131 days in LD, MD and HD,
respectively, p<0.0001) and placebo groups
(76±139 days, 101±120 and 254±176 days in LD, MD
and HD, respectively, p<0.0001).
PTW was associated with an increased risk of
mortality (RH=2.13, 95% CI=1.43–3.17, p⫽0.0002)
in the bisoprolol group. A non-significant increase
was also observed in the placebo group (RH=1.44,
95% CI=0.99–2.08) but the impact of PTW on the
risk of mortality was significantly more pronounced
in the bisoprolol group compared to placebo
(p⫽0.02). Time from withdrawal to death and
causes of deaths did not differ significantly in the
bisoprolol and the placebo groups.
The deleterious impact of bisoprolol withdrawal
on survival was related to the dose. Compared to
patients in whom bisoprolol was continued, the
Bisoprolol dose–response relationship
Table 1
555
Baseline characteristics
(a) Patients in bisoprolol group (n=1327)
Lowa dose (n=434)
Moderateb dose (n=328)
Highc dose (n=565)
p
Age (years)
Male/female (%)
White
Body mass index (kg/m2)
LVEF (%)
Heart rate (bpm)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
NYHA classification (III/IV) (%)
Diabetes, n (%)
Atrial fibrillation, n (%)
Etiology of heart failure
Documented ischemia, n (%)
Primary cardiomyopathy, n (%)
Undefined etiology, n (%)
History of hypotension, n (%)
History of severe arrythmia, n (%)
Left BBB, n (%)
Right BBB, n (%)
Abnomal ST-segment, n (%)
AV block, n (%)
Digitalis, n (%)
Amiodarone, n (%)
ACE inhibitors, n (%)
Aspirin, n (%)
Diuretics, n (%)
Nitrates, n (%)
62±11
79/21
99%
26±4
27±6
77±14
126±19
78±11
77/23
49 (11%)
76 (18%)
60±10
82/18
99%
27±4
27±6
79±14
130±19
80±11
86/14
47 (14%)
71 (22%)
60±11
81/19
99%
27±4
27±6
82±15
132±19
80±11
87/13
61 (11%)
110 (20%)
0.045
0.66
0.69
0.007
0.98
0.0001
0.0001
0.001
0.001
0.26
0.35
0.007
245
54
135
17
142
132
30
241
52
217
80
412
183
424
285
151
39
138
9
70
73
17
262
23
163
46
320
131
326
186
266
67
232
6
107
127
21
323
33
317
59
541
223
555
302
(b) Patients in placebo group (n=1320)
Lowa dose (n=234)
Moderateb dose (n=278)
Highc dose (n=808)
p
Age (years)
Male/female (%)
White
Body mass index (kg/m2)
LVEF (%)
Heart rate (bpm)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
NYHA classification (III/IV) (%)
Diabetes, n (%)
Atrial fibrillation, n (%)
Etiology of heart failure
Documented ischemia, n (%)
Primary cardiomyopathy, n (%)
Undefined etiology, n (%)
History of hypotension, n (%)
History of severe arrythmia, n (%)
Left BBB, n (%)
Right BBB, n (%)
Abnomal ST-segment, n (%)
AV block, n (%)
Digitalis, n (%)
Amiodarone, n (%)
ACE inhibitors, n (%)
Aspirin, n (%)
Diuretics, n(%)
Nitrates, n (%)
62±10
80/20
100%
26±4
27±6
80±14
124±16
77±19
80/20
27 (12%)
39 (17%)
61±10
81/19
100%
27±4
28±6
81±16
131±22
80±11
82/18
37 (13%)
54 (19%)
61±11
80/20
99%
27±6
27±4
81±16
132±19
81±11
84/16
91 (11%)
171 (21%)
0.27
0.92
0.51
0.002
0.38
0.94
0.0001
0.0001
0.39
0.66
0.24
0.55
118
32
84
13
74
83
21
116
28
126
43
223
99
232
145
146
32
100
9
71
64
18
178
30
134
48
265
119
274
186
390
93
325
23
217
204
42
482
61
410
115
786
340
804
431
a
Low=1.25, 2.50 or 3.75 mg/day.
Moderate=5.0 or 7.50 mg/day.
c
High=10 mg/day.
b
(57%)
(12%)
(31%)
(4%)
(33%)
(30%)
(7%)
(56%)
(12%)
(50%)
(18%)
(95%)
(42%)
(98%)
(66%)
(50%)
(14%)
(36%)
(6%)
(32%)
(36%)
(9%)
(50%)
(12%)
(54%)
(18%)
(95%)
(42%)
(99%)
(62%)
(46%)
(12%)
(42%)
(3%)
(21%)
(22%)
(5%)
(80%)
(7%)
(50%)
(14%)
(98%)
(40%)
(99%)
(57%)
(53%)
(11%)
(36%)
(3%)
(26%)
(23%)
(7%)
(64%)
(11%)
(48%)
(17%)
(95%)
(43%)
(99%)
(67%)
(47%)
(12%)
(41%)
(1%)
(19%)
(22%)
(4%)
(57%)
(6%)
(56%)
(10%)
(96%)
(39%)
(98%)
(53%)
(48%)
(12%)
(40%)
(3%)
(27%)
(25%)
(5%)
(60%)
(8%)
(51%)
(14%)
(97%)
(42%)
(100%)
(53%)
0.013
0.001
0.006
0.07
0.23
0.001
0.07
0.001
0.18
0.67
0.19
0.001
0.13
0.26
0.002
0.10
0.003
0.052
0.45
0.21
0.17
0.98
0.29
0.001
556
Table 2
Simon et al.
Risks of outcome events in bisoprolol dose groups
Event
Low dose
(1.25, 2.50 or 3.75 mg/day)
Moderate dose
(5.0 or 7.50 mg/day)
High dose
(10.0 mg/day)
All-cause mortality
All CV causes of death
Pump failure death
Sudden death
Other CV causes of death
All-cause hospitalizations
All CV cause hospitalizations
1
1
1
1
1
1
1
0.49
0.44
0.20
0.74
0.28
0.62
0.63
0.30
0.26
0.16
0.45
0.17
0.38
0.33
mortality risk in patients with PTW was 1.79 (95%
CI=1.14–2.82, p⫽0.01), 1.95 (95% CI=0.74–5.16,
p⫽0.18) and 10.17 (95% CI=3.85–26.86, p<0.0001)
in LD, MD and HD bisoprolol groups, respectively.
Mortality and morbidity outcomes
Death occurred in 384 patients, 156 patients in the
bisoprolol and 228 in the placebo groups. After
adjustment for baseline differences and PTW during follow-up, the probability of all-cause mortality
in bisoprolol group was significantly reduced in high
dose (RH=0.30, 95% CI=0.19–0.46, p⫽0.0001), and
moderate dose groups (RH=0.49, 95% CI=0.32–0.75,
p⫽0.001) compared to low dose group (Table 2).
The risk of cardiovascular deaths, all-cause hospitalizations and cardiovascular hospitalizations
were lower in the high and moderate doses of
bisoprolol compared to low dose (Table 2).
Mortality was also reduced with increasing doses
of placebo compared to low dose (RH=0.28, 95%
CI=0.20–0.40 and RH=0.76, 95% CI=0.54–1.09 for
high dose and moderate dose groups, respectively).
However, compared to placebo, bisoprolol was
associated with a significant reduction of all-cause
mortality regardless of the dose level considered
(Fig. 1). Compared to placebo, the reduction of
mortality with bisoprolol treatment was 34% with
low doses (RH=0.66, 95% CI=0.48–0.92), 67% with
moderate doses (RH=0.33, 95% CI=0.21–0.51) and
41% with high doses (RH=0.59, 95% CI=0.40–0.89).
Bisoprolol also reduced significantly cardiovascular
deaths, all-cause and cardiovascular hospitalizations regardless of the tolerated dose as compared
to placebo (Table 3).
Discussion
The titration of the beta-blockers in the randomized trials has been performed with a gradual
increase in the dosage guided by tolerance until the
target dose was achieved. Whether all patients
need to reach this target dose in order to obtain a
(0.32–0.75)
(0.27–0.71)
(0.07–0.59)
(0.35–1.55)
(0.09–0.84)
(0.48–0.79)
(0.48–0.84)
(0.19–0.46)
(0.16–0.43)
(0.06–0.43)
(0.21–0.95)
(0.06–0.50)
(0.30–0.48)
(0.25–0.44)
relevant benefit in terms of survival remains uncertain. The major findings of the present additional
analysis of CIBIS II data are the reduction of mortality with all tolerated doses of bisoprolol compared to placebo and the confirmation of the deleterious impact of bisoprolol withdrawal13 on the
risk of mortality. Therefore for a given patient,
bisoprolol should be up-titrated guided by the
tolerance. If necessary, physicians should maintain
low doses rather than interrupting the beta-blocker
treatment.
Baseline clinical characteristics and
tolerated dose
Clearly the tolerated dose in CIBIS II was dependent
on the severity of the chronic heart failure in both
placebo and bisoprolol groups and was independent
of the randomized treatment. In both groups,
patients tolerating only low doses were significantly older with more severe NYHA functional
class and higher frequency of co-morbidities.
Whereas a similar proportion of patients interrupted placebo or bisoprolol during follow-up, the
treatment withdrawal was more frequent and
occurred earlier in those receiving low doses. At the
time CIBIS II trial was performed, the results of the
other large-scale trials were unknown. Since the
two treatment regimens were given in a doubleblinded fashion, it is possible that physicians have
been fearful and increased doses more cautiously
or interrupted treatments (bisoprolol and placebo)
more easily in the patients with more severe forms
of heart failure. Therefore the tolerated dose in
CIBIS II patients may have been influenced in some
extent to the physician's tolerability.
Permanent treatment withdrawal and risk
of death
The discontinuation of bisoprolol was significantly associated with an increase risk of mortality.
Interestingly, the deleterious impact of bisoprolol
Bisoprolol dose–response relationship
557
Fig. 1 Kaplan–Meier survival curves in patients receiving placebo and bisoprolol at LD, MD and HD. p is given by the multivariate Cox
analysis adjusted to baseline differences and PTW.
558
Table 3
Simon et al.
Risks of the outcome events with bisoprolol compared to placebo
Events
Low dose
Moderate dose
High dose
All-cause mortality
All CV-cause of death
All-cause hospitalizations
All CV cause hospitalizations
0.66
0.69
0.72
0.68
0.33
0.34
0.55
0.56
0.59
0.64
0.70
0.70
(0.48–0.92)
(0.48–1.00)
(0.57–0.89)
(0.53–0.86)
(0.21–0.51)
(0.21–0.57)
(0.42–0.71)
(0.41–0.74)
(0.40–0.89)
(0.40–1.02)
(0.56–0.87)
(0.54–0.91)
RHs were estimated by cox multivariate analysis stratified on PTW.
withdrawal on survival was related to the dose,
uppermost in the high dose group. This may be due
to an increased unopposed upregulation of adrenoreceptors at withdrawal. However, because
this finding is based on a limited number of deaths
(n⫽6), it should be taken with great caution and
needs to be confirmed by further trials.
The increased risk of events is consistent with
previous findings of the risk of deterioration after
beta-blocker withdrawal.12,13 Patients who interrupted bisoprolol were not sicker than those who
stopped placebo. Interestingly, the main cause of
PTWs was due to the investigator's or patient's
personal decision and not due to medical reasons.
Moreover, time from withdrawal to death and
the causes of death were similar in patients who
interrupted treatment, regardless of the dose.
The beneficial effects of bisoprolol on mortality
and other outcome events remained significant
after adjustment for PTWs and baseline characteristics of patients.
Tolerated doses and risk of death
As shown in Table 2, a significant reduction of
all-cause mortality within the bisoprolol group was
observed with the high and moderate tolerated
doses of bisoprolol compared to low dose. A doserelated reduction of mortality has been previously
observed in the MOCHA trial, a 6-month, dose–
response evaluation of carvedilol (6.25, 12.5 and
25 mg bid vs. placebo) in 345 patients with mild to
moderate stable CHF.6 The study found no beneficial effect from carvedilol on submaximal exercise,
the main objective of the trial, but a dose-related
reduction in mortality was observed among the 25
patients who died of whom 13 were treated by
placebo. Because of the low number of deaths, the
likelihood of chance finding is not negligible. However, surprisingly we also observed a similar pattern of reduced mortality with patients tolerating
increasing doses of placebo, reinforcing the finding
that regardless of the randomized treatment,
patients in low doses were more severe than those
receiving higher doses.
Interestingly compared to placebo a significant
reduction of death and all other outcome events
was found with bisoprolol regardless of the tolerated dose (Table 3). The proportion of general
patients with CHF in whom the target dose can be
reached is lower than those in clinical trials since
the patients are older with higher frequency of
comorbidities. Compared to placebo, even low
doses of bisoprolol conferred benefit in our study.
Therefore the therapy should be continued if low
doses of bisoprolol are the only doses tolerated.
This finding is consistent with the recent analysis
of MERIT data.15 Although placebo mortality
rate was also higher in the low dose group, a
significant reduction of mortality was observed
with metoprolol in both low (<100 mg daily) and
high dose groups (<100 mg daily) compared to
placebo.15
Previous studies have shown the link between
heart rate reduction and survival in CHF.16,17 In
CIBIS II, heart rate reduction was not the single
mechanism responsible for bisoprolol-induced
benefit in CHF.17 The heart rate reduction with
bisoprolol (baseline to 2 months) was similar
regardless of the tolerated dose: −9±13, −10±15 and
−11±15 bpm with LD, MD and HD of bisoprolol,
respectively, (p⫽0.15).
To what extent is it beneficial to reduce the
effects of sympathetic stimulation by beta-blockers
remains questionable. In the present analysis, a
significant 34, 67 and 41% relative risk reduction of
mortality was found with low, moderate and high
dose of bisoprolol, respectively, compared to
placebo. Similarly the relative risk reduction for all
other outcomes was also more pronounced with the
moderate dose level (Table 3). However, within the
bisoprolol group, the highest reduction of mortality
was observed in the high dose group (Table 2).
Since the present study was not a dose-ranging
trial, it is not possible to prove that a particular
dose is optimal or that all doses are equivalent. The
treating physician should try to take the patient to
the high dose group, since a priori there is no way
to determine other than with forced up-titration to
the highest tolerated dose.
Bisoprolol dose–response relationship
The present study is limited by the post hoc
nature of its analyses. Patients were not randomized to receive different doses of bisoprolol.
Up-titration of bisoprolol and placebo were clearly
influenced by the patient's status and physician's
decision.
Conclusions
Bisoprolol reduced significantly the risk of mortality in CHF patients for all tolerated dose levels.
The withdrawal of bisoprolol increased significantly
the risk of mortality. All efforts should be made to
maintain bisoprolol therapy based on the individual patient's tolerability and decrease the dose
if necessary in case of intolerance. Further randomized dose-ranging studies are needed to
establish the benefit/risk ratio at each dose level.
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