Heart Vessels

DOI 10.1007/s00380-013-0340-3

ORIGINAL ARTICLE

Efficacy and safety of bisoprolol fumarate compared

with carvedilol in Japanese patients with chronic heart failure:
results of the randomized, controlled, double-blind, Multistep
Administration of bisoprolol IN Chronic Heart Failure II
(MAIN-CHF II) study
Masatsugu Hori • Ryozo Nagai • Tohru Izumi •

Masunori Matsuzaki
Received: 10 October 2012 / Accepted: 8 March 2013
Ó Springer Japan 2013

Abstract Bisoprolol fumarate (bisoprolol) is a b-blocker
widely used to treat chronic heart failure (CHF). However,
few studies have compared its efficacy and safety with
those of the widely used b-blocker carvedilol in Japanese
patients with CHF. We designed a confirmatory trial of
bisoprolol using carvedilol as a control drug; however, the
trial was discontinued after an off-label use of bisoprolol
was approved during the study. Bisoprolol and carvedilol
were administered for 32 weeks in 31 and 28 patients,
respectively. The mean maintenance doses of bisoprolol
and carvedilol were 3.3 and 13.6 mg/day, respectively, and
the mean durations of treatment were 188.2 and 172.9 days,
respectively. Heart-rate changes were similar in both
groups. The mean changes from baseline to Week 32 in left
ventricular (LV) ejection fraction (EF) (bisoprolol vs car-
vedilol groups; 11.7 % ± 8.6 % vs 10.1 % ± 10.5 %), LV
end-diastolic volume (-37.5 ± 48.7 vs -24.7 ± 29.4 ml),
and LV end-systolic volume (-41.9 ± 43.0 vs -29.3 ±
25.9 ml) revealed a decrease in LV volume and an increase
in LVEF in both groups. The cumulative event-free rate for
a composite of cardiovascular death or admissions to
hospital for worsening of CHF was 92.4 % and 94.7 % in
the bisoprolol and carvedilol groups, respectively. Overall,
90.3 % and 85.7 % of patients were titrated up to the
maintenance doses of bisoprolol and carvedilol, respec-
tively. Bisoprolol, at half the dose used in other countries,
is well tolerated and is as effective as carvedilol for treating
Japanese patients with mild to moderate CHF.
Keywords Bisoprolol
Carvedilol
Chronic heart
failure
Japan
Left ventricular function

Randomized controlled trial
Introduction

M. Hori (&)
Osaka Medical Center for Cancer and Cardiovascular Diseases,
1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan
e-mail: hori-ma@mc.pref.osaka.jp
R. Nagai
Department of Cardiovascular Medicine, Graduate
School of Medicine, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
T. Izumi
Department of Cardio-Angiology, Kitasato University
School of Medicine, 1-15-1 Kitasato, Minami-ku,
Sagamihara, Kanagawa 252-0374, Japan
M. Matsuzaki
Department of Medicine and Clinical Science,
Division of Cardiology, Yamaguchi University Graduate
School of Medicine, 1-1-1 Minamikogushi, Ube,
Yamaguchi 755-8505, Japan
b-Blockers are well established for reducing the mortality
of patients with chronic heart failure (CHF) [1–5]. Biso-
prolol fumarate (bisoprolol; a b1 adrenergic receptor
blocker), carvedilol (a nonselective b1/b2/a1 adrenoceptor
blocker), and metoprolol succinate (a b1 receptor blocker)
are the most widely used drugs in this setting. Based on the
clinical evidence accumulated to date, these drugs are
recommended for the treatment of CHF in Japanese, United
States, and European clinical guidelines [6–8]. However, at
the time of planning the study, only carvedilol had been
approved for the treatment of CHF in Japan.
Of note, the appropriate dose of bisoprolol for Japanese
patients with CHF has not been determined. Therefore, we
conducted a double-blind, noninferiority study of bisopro-
lol with carvedilol as a comparator in Japanese patients
with CHF to obtain approval of bisoprolol for the treatment

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of CHF from the Pharmaceuticals and Medical Devices
Agency. However, the study was discontinued during the
study period because an additional indication for off-label
use of bisoprolol (Maintate tablets) for the treatment of
CHF was approved based on publicly available data.
Accordingly, the objectives of the study were revised to
compare the efficacy and safety profiles of bisoprolol with
those of carvedilol in Japanese patients with CHF, and
exploratory analyses were conducted.
Patients and methods
Study population
Patients fulfilling the following criteria were eligible for this
study: age 20 to\80 years; stable CHF caused by ischemic
heart disease or dilated cardiomyopathy, including dilated-
phase hypertrophic cardiomyopathy; New York Heart
Association (NYHA) class IIM or III; left ventricular ejec-
tion fraction (LVEF) B40 %; and current treatment with an
angiotensin-converting enzyme (ACE) inhibitor or angio-
tensin receptor blocker (ARB) and a diuretic. Patients with
any of the following criteria were excluded: systolic blood
pressure (SBP) \100 mmHg; bradycardia (\60 beats/min);
hypertrophic obstructive cardiomyopathy; advanced car-
diomyopathy; cardiogenic shock; serious arrhythmia or
atrioventricular block of grade II or III; severe valvular
regurgitation; valvular stenosis; history of unstable angina
pectoris, coronary spastic angina, angina at rest, or myo-
cardial infarction within 3 months before the study; history
of stroke or serious cerebrovascular accident within 1 year
before the study; prior heart transplantation (including an
artificial heart). Patients were also excluded if they had one
of the following conditions: presence of diseases/conditions
listed in the Contraindications or Precautions for Admin-
istration sections of the package insert for bisoprolol;
presence of malignant tumors or other clinically significant
diseases, except those underlying heart failure (HF); preg-
nancy; and participation in other clinical studies. Patients
requiring treatment with b-blockers, ab-blockers, cardio-
tonic agents (excluding digitalis), human atrial natriuretic
peptide, surgery, or assisted circulation were also excluded.
Written informed consent was obtained from all patients
before enrollment in the study.
Study design
This study was conducted at 59 study sites in Japan from
2010 to 2011. The study was approved by institutional
review boards at each study site, and was conducted in
accordance with the ethical principles of the Helsinki
Declaration, the Pharmaceutical Affairs Law, Good
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Heart Vessels
Clinical Practice, and the approved protocol. The trial was
registered with the Japan Pharmaceutical Information
Center (registration number JapicCTI-101045).
This was a prospective, randomized, double-blind,
active (carvedilol)-controlled, multicenter, parallel-group
study. Patients were equally randomized to receive either
bisoprolol or carvedilol using a dynamic allocation proce-
dure where etiology, LVEF at randomization, and study
site were used as stratification factors.
Bisoprolol was started at a dose of 0.625 mg/day (Step
1); this was then increased stepwise to 1.25 mg/day (Step
2), 2.5 mg/day (Step 3), 3.75 mg/day (Step 4), and 5 mg/day
(Step 5) until Week 16, providing the preceding dose
was tolerated. Treatment with carvedilol was started at
2.5 mg/day (Step 1); this was then increased to 5 mg/day
(Step 2), 10 mg/day (Step 3), and 20 mg/day (Steps 4 and 5).
Thereafter, patients were maintained at the highest dose
level achieved. The interval of dose increases was more
than 2 weeks. Upward titration was stopped if the patient
showed worsening of HF, fluid retention, bradycardia, and
hypotension as well as other b-blocker-related adverse
symptoms. Bisoprolol and carvedilol were orally admin-
istered twice daily for a total of 32 weeks.
Data collection
The patients visited the study site at weeks 0, 4, 8, 12,
16, 20, 24, 28, and 32 of the study, and whenever
additional visits were required. At each visit, the
patients underwent clinical examinations. Efficacy end
points included cardiac function tests (LVEF, left ven-
tricular end-diastolic volume (LVEDV), and left ven-
tricular end-systolic volume (LVESV)), NYHA class (I,
IIS, II M , III, and IV), medical evangelism training and
strategies (METS) [9], and Short Form (SF)-36. Safety
end points included cardiovascular (CV) events, treat-
ment withdrawal for CV causes, adverse events, plasma
brain natriuretic peptide (BNP) concentrations, SBP,
diastolic blood pressure (DBP), and heart rate (HR). LV
function was assessed, using two-dimensional echo-
cardiographic views (apical four-chamber and two-
chamber views) [10, 11].
Statistical analysis
The full analysis set (FAS) was defined as randomized
subjects excluding the patients who did not receive the
study drug, had no assessment data, and did not meet the
major inclusion criteria. The per-protocol set (PPS) was
defined as all patients in the FAS, excluding those without
primary end-point assessment data and patients with any
serious protocol deviation. The safety analysis set was
defined as all patients administered the study drug,
Heart Vessels
excluding those in whom no safety data were recorded.
Analyses of adverse events, BP, and HR were performed in
the safety analysis set. All other analyses were performed
in the FAS. Since the sample size was small, no analyses
were performed using the PPS. LVEDV, LVESV, and
LVEF were assessed three times at each visit. The mean
LVEDV, LVESV, and LVEF at each assessment were
calculated and analyzed.
Summary statistics were obtained for LVEF, LVEDV,
and LVESV at each measurement time, and their changes
from baseline were also obtained. Changes in both groups
were compared using repeated-measures analysis of
covariance, with treatment group, measurement time,
etiology, and an interaction effect between treatment
group and measurement time as factors, and values at
randomization (baseline) as a covariate. Least-squares
(LS) means and standard error are shown for each treat-
ment group. The point estimate for the between-group
difference was determined as the LS mean for bisoprolol
minus the LS mean for the carvedilol group, with 95 %
confidence intervals (CI) and P values. Summary statistics
(mean ± standard deviation (SD); n (%)) at each visit and
changes from baseline were calculated for METS, SF-36,
physical and mental component scores (PCS and MCS),
BNP concentrations (including log-transformed values),
BP, and HR. The cumulative event-free rate estimated by
the Kaplan–Meier method, incidence of CV events, and
Fig. 1 Patient disposition. *The reason for these patients’ withdrawal from the study was that health insurance became applicable to treatments
for patients with CHF with publicly available data
rate of treatment withdrawal for CV causes were also
assessed.
Results
Patient disposition
The target number of patients was 300 (150 patients per
group) for randomization. However, the study was
discontinued during the study period because an addi-
tional indication for off-label use of bisoprolol for
treatment of CHF was approved based on publicly
available data. At the time of discontinuation, 59
patients of 103 who had given informed consent had
been randomized, including 31 to the bisoprolol group
and 28 to the carvedilol group (Fig. 1). All of these
patients were included in the FAS and the safety anal-
ysis set. Two patients allocated to carvedilol were
excluded from the PPS for violation of the eligibility
criteria in one patient and concomitant use of prohibited
medications in one patient.
Dosing and exposure
Overall, 90.3 % and 85.7 % of patients in the bisoprolol
and carvedilol groups, respectively, reached the
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 Heart Vessels

maintenance dose. The highest doses (Step 5) of bisoprolol Table 1 Patient characteristics at baseline
(5 mg/day) and carvedilol (20 mg/day) were reached in Bisoprolol Carvedilol P value
35.7 % and 25.0 % of patients, respectively. The majority of
patients in both groups (78.6 % in the bisoprolol group and N 31 28
83.3 % in the carvedilol group) reached Step 3 (2.5 mg/day Sex, n (%) 0.027*
bisoprolol and 10 mg/day carvedilol). The mean mainte- Males 23 (74.2) 27 (96.4)
nance dose of bisoprolol and carvedilol was 3.3 and 13.6 Females 8 (25.8) 1 (3.6)
mg/day, respectively, and the mean duration of treatment Age (years) 62.9 ± 11.4 63.8 ± 9.9 0.772 
was 188.2 and 172.9 days, respectively. Body weight (kg) 64.9 ± 15.3 67.5 ± 12.3 0.467 
Height (cm) 162.3 ± 10.0 165.4 ± 6.8 0.178 
Patient characteristics Duration of HF, median 0.83 (0.1–16.6) 0.96 (0.1–18.0) 0.849à
(minimum–maximum)
(years)
The baseline characteristics of patients were compara-
Etiology, n (%) 0.591*
ble between in both groups (Table 1). However, there were
Ischemic heart disease 11 (35.5) 8 (28.6)
slight imbalances between the two groups in terms of sex
and NYHA class (Fisher’s exact test; both, P \ 0.15). Dilated cardiomyopathy§ 20 (64.5) 20 (71.4)
Prior MI, yes, n (%) 9 (29.0) 8 (28.6) 1.000*
Vital signs Patient status, n (%) 1.000*
Inpatient 2 (6.5) 1 (3.6)
Changes in HR were similar in both groups. In the bisoprolol Outpatient 29 (93.5) 27 (96.4)
group, HR had decreased by 10.5 ± 12.7 beats/min at 12 Presence of complications, 30 (96.8) 28 (100.0) 1.000*
yes, n (%)
weeks after starting treatment (Fig. 2a). The changes in SBP
Diabetes mellitus 12 (38.7) 7 (25.0)
from baseline to Week 32 were 3.6 ± 17.7 and -3.3 ± 17.0
Hyperlipidemia 14 (45.2) 15 (53.6)
mmHg in the bisoprolol and carvedilol groups, respectively
(Fig. 2b). The respective changes in DBP were -0.9 ± 13.1 Atrial fibrillation 10 (32.3) 6 (21.4)

and -3.7 ± 12.6 mmHg (Fig. 2c). Other 29 (93.5) 26 (92.9)

NYHA functional 0.114*
LVEF and BNP classification
IIM 27 (87.1) 28 (100.0)
Mean LVEF increased from baseline in both groups. The III 4 (12.9) 0
changes in LVEF from baseline to Week 32 were 11.7 % ± 8.6 SBP (mmHg) 117.6 ± 13.3 122.8 ± 18.5 0.219 
% and 10.1 % ± 10.5 % in the bisoprolol and carvedilol groups, DBP (mmHg) 71.8 ± 10.5 71.8 ± 11.0 0.997 
respectively (Fig. 3). The estimated difference between biso- HR (beats/min) 77.9 ± 11.2 75.1 ± 11.0 0.333 
prolol and carvedilol was 1.49 % (95 % CI -1.63 to 4.61, BNP concentration, median 145.4 74.3 0.208à
P = 0.342), with no significant difference between the two (min–max) (5.9–1510.9) (4.0–868.5)

groups. LVEF (%) 30.7 ± 5.7 31.0 ± 5.0 0.830 

BNP concentrations showed a small, transient increase LVEDV (ml) 152.8 ± 69.6 162.9 ± 65.9 0.573 
in both groups during the dose-adjustment period, but LVESV (ml) 108.2 ± 57.6 114.4 ± 52.5 0.673 
decreased thereafter and were below baseline levels at METS, median 6.0 (1.0–8.0) 6.5 (2.5–7.5) 0.236à
(minimum–maximum)
Week 32 in both groups (Fig. 4).
SF-36
LVEDV and LVESV PCS 40.5 ± 14.3 39.6 ± 14.0 0.828 
MCS 52.9 ± 9.6 52.9 ± 11.0 0.988 
Mean LVEDV and LVESV decreased from baseline in Values are mean ± SD, unless otherwise specified
both groups. The mean changes in LVEDV and LVESV at HF heart failure, MI myocardial infarction, NYHA New York Heart
Week 32 were -37.5 ± 48.7 and -41.9 ± 43.0 ml, Association, SBP systolic blood pressure, DBP diastolic blood pressure,
respectively, in the bisoprolol group, and -24.7 ± 29.4 and HR heart rate, BNP brain natriuretic peptide, LVEF left ventricular ejec-
tion fraction, LVEDV left ventricular end-diastolic volume, LVESV left
-29.3 ± 25.9 ml, respectively, in the carvedilol group
ventricular end-systolic volume, METS medical evangelism training and
(Fig. 5). The mean decreases in LVEDV and LVESV in the strategies, SF Short-Form, PCS physical component summary score, MCS
bisoprolol group were larger than those in the carvedilol mental component summary score
group, although they were not statistically significant * Fisher’s exact test;   t test; à Wilcoxon rank sum test; §
includes
(P = 0.132 for LVEDV and P = 0.098 for LVESV). hypertrophic cardiomyopathy in the dilated phase

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Heart Vessels

Fig. 2 Changes over time in

a heart rate (HR), b systolic
blood pressure (SBP), and
c diastolic blood pressure
(DBP). Values are mean ± SD

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 Heart Vessels

Fig. 3 Changes over time in

left ventricular ejection fraction
(LVEF). Values are mean ± SD

Fig. 4 Changes over time in

brain natriuretic peptide (BNP)
concentrations. Values are mean ±
SD. BNP concentrations are shown
as log-transformed values

NYHA functional classification, METS, and SF-36
NYHA functional classification improved in both groups at
Week 32 (I, IIS, and IIM in 42.9 % (9/21), 23.8 % (5/21),
and 33.3 % (7/21) of patients in the bisoprolol group, and
21.4 % (3/14), 50.0 % (7/14), and 28.6 % (4/14) of patients
in the carvedilol group). The median changes in METS
from baseline to Week 32 were 0.3 and 0.8 in the biso-
prolol and carvedilol groups, respectively. SF-36 PCS
scores increased by 1.2 ± 12.3 and 5.1 ± 12.7, and MCS
increased by 1.2 ± 5.9 and 2.6 ± 9.5 in the bisoprolol and
carvedilol groups, respectively.
CV events and treatment withdrawals for CV causes
Three patients treated with bisoprolol and two patients
treated with carvedilol experienced CV events or withdrew
from the treatment because of CV events (Tables 2, 3). The

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Heart Vessels

Fig. 5 Changes over time in

a left ventricular end diastolic
volume (LVEDV) and b left
ventricular end systolic volume
(LVESV). Values are mean ±
SD

Table 2 CV events and permanent treatment withdrawals for CV causes

Treatment Type of CV event or reason CV death or admission All- CV CV Admissions to Permanent
of treatment withdrawal for to hospital for cause deaths hospital hospital for treatment
CV causes worsening of HF deaths admissions worsening of HF withdrawal for CV
causes

Bisoprolol Stroke x x
Bisoprolol Sudden death x x x x
Bisoprolol Worsening of HF x x x x
Carvedilol Sudden death x x x x
Carvedilol Worsening of HF x
CV cardiovascular, HF heart failure

cumulative event-free rate on Day 210 for a composite of Adverse events

CV deaths or admissions to hospital for worsening HF was
92.4 % in the bisoprolol group and 94.7 % in the carvedilol The incidences of adverse events in the bisoprolol and
group. carvedilol groups were 80.6 % (25 of 31 patients) and

123

Table 3 Incidence of CV events or permanent treatment withdrawals
for CV causes
Bisoprolol Carvedilol
(n = 31) (n = 28)
CV deaths or admissions to hospital for 2 (6.5) 1 (3.6)
worsening of HF
All-cause deaths 1 (3.2) 1 (3.6)
CV deaths 1 (3.2) 1 (3.6)
CV hospital admissions 2 (6.5) 0 6.9 % for carvedilol [18]. Thus, administration of bisoprolol at
Admissions to hospital for worsening of HF 1 (3.2) 0
Permanent treatment withdrawal for CV 3 (9.7) 2 (7.1)
causes
Values are n (% of patients)
CV cardiovascular, HF heart failure
82.1 % (23 of 28 patients), respectively. The incidences of
adverse drug reactions were 25.8 % (8 of 31 patients) and
35.7 % (10 of 28 patients), respectively. The incidence of
serious adverse events was 12.9 % (4 of 31 patients) in the
bisoprolol group and 10.7 % (3 of 28 patients) in the car-
vedilol group. In terms of serious non-CV events (for CV
events, see Table 2), ischemic colitis and hemorrhagic
gastric ulcer occurred in one patient each (both 3.2 %) in
the bisoprolol group, while diabetes mellitus and gastro-
intestinal bleeding also occurred in one patient each (both
3.6 %) in the carvedilol group.
Discussion
HR reduction is one of the most important therapeutic
effects of b-blockers on mortality risk in patients with
CHF. Indeed, a meta-analysis of b-blocker therapy reported
that every reduction of 5 beats/min in HR reduced the
mortality rate by 18 % [12]. In the present study, bisoprolol
decreased HR by 10.2 beats/min at Week 32, which is a
similar HR reduction to that reported in the meta-analysis
(median reduction, 12 beats/min) [12]. Interestingly, the
dose of bisoprolol in the present study (up to 5 mg/day)
was only half that used in other countries (up to 10 mg/day).
The reduction in HR observed in the present study was
similar in the bisoprolol and carvedilol groups (Fig. 2).
The proportions of patients reaching the maximum dose
allowed in our study were comparable with those reported
as reaching the maximum dose in the CIBIS-ELD trial [13]
(24 % in the bisoprolol group and 25 % in the carvedilol
group). In our study, the majority of patients (78.6 % in the
bisoprolol group and 83.3 % in the carvedilol group)
received the study drug at greater than half the target dose,
at which it was well tolerated.
In this study, a substantial reduction in HR was
obtained. However, no reductions in mean SBP and DBP
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Heart Vessels
were obtained, consistent with the findings of previous
trials of b-blockers in patients with HF [14, 15].
The increases in LVEF (11.7 % for bisoprolol and 10.1 %
for carvedilol) in both groups were similar to those reported in
other previous studies in Japan; 9.96 % for bisoprolol in the
MAIN-CHF study [16] and 13.2 % for carvedilol in the
MUCHA study [17]. The increases in LVEF were also similar
to those reported in other countries: 12.0 % for bisoprolol and
half the dose used in other countries decreased HR and
increased LVEF as much as did the larger dose of b-blockers
used in other countries.
BNP concentrations are a widely recognized biomarker
for the severity of CHF [19–21]. However, to our
knowledge no blinded study has measured changes in
BNP concentrations over time in relation to b-blocker
treatment in patients with CHF. In this study, BNP con-
centrations increased transiently in both groups during the
dose-adjustment period, but decreased below baseline
levels thereafter. These changes may be attributed to a
transient increase in the cardiac mechanical load during
the period of upward titration and subsequent improve-
ments in cardiac function owing to sustained b-blocker
treatment.
Ventricular remodeling accompanied by enlargement of
the ventricular chamber is regarded as a predictor of
mortality risk in patients with CHF [22–24]. In this study,
LVEDV and LVESV tended to decrease, especially in the
bisoprolol group (Fig. 5), although the decreases were not
statistically significant in either group. The changes were
similar to those reported for bisoprolol (LVEDV, -52.5 ml;
LVESV, -63.0 ml) and carvedilol (LVEDV, -26.7 ml;
LVESV, -33.9 ml) in an earlier meta-analysis [18], which
examined the correlation between ventricular remodeling
and mortality. In this small study we were unable to assess
the effect of b-blocker treatment on mortality, although
decreases in HR and LV volume comparable to those
reported in earlier studies may suggest comparable improve-
ments in prognosis.
Of note, no worsening was detected in NYHA cardiac
function classification, SF-36, or METS, which show the
effects on cardiac status and quality of life, in either group,
and there were no between-group differences. Interestingly,
although the CIBIS-ELD trial [13] showed differences in
tolerability between the bisoprolol and carvedilol groups,
with bradycardia occurring more often in the bisoprolol
group and pulmonary adverse events occurring more often
in the carvedilol group, no such differences were found in
the present study. Thus, although the authors of the study
recommended differential use of the two b-blockers
between patients with a low resting HR and those with
pulmonary disease, we found no such evidence supporting
the differential use of these drugs.
Heart Vessels
The incidence of the composite of CV death or admis-
sions to hospital for worsening of HF in this study was
lower in both groups than was reported in other countries,
and was also lower than the predicted value (7 % per study
period) taken from the MAIN-CHF and MUCHA studies.
In the MAIN-CHF study, 9 of 100 patients treated with
bisoprolol were admitted to hospital for worsening of HF
during the dose-adjustment period [16]. In the present
study, to prevent HF deterioration during the dose-adjust-
ment period we slowly titrated the dose of bisoprolol
upward from 2.5 to 5 mg/day. We also scheduled more
frequent visits to the study site after dose adjustment for
careful follow-up. By implementing these approaches, no
patients were admitted to hospital for worsening of HF
during the dose-adjustment period in this study, and the
incidence of events was comparable to that in the carve-
dilol group. Thus, the results of the present study show that
our protocol for dose adjustment of bisoprolol may be
acceptable for further clinical application. There may also
be some potential to increase the bisoprolol dose to 10 mg/day,
as used in other countries. However, clinical studies would
need to verify the clinical relevance of this higher dose in
Japanese patients in terms of improvements in LV function
and adverse event profile.
In conclusion, the present study demonstrated that
bisoprolol up to 5 mg/day shows effects on clinical
symptoms, hemodynamics, and LV remodeling compara-
ble with those of carvedilol up to 20 mg/day in patients
with CHF. Tolerability of bisoprolol and carvedilol was
also comparable; thus, these results suggest that bisoprolol
at 5 mg/day is a useful and effective treatment option for
Japanese patients with CHF.
Study limitations
This study was discontinued because an application for
using bisoprolol to treat CHF was approved based on
publicly available data. At the time of study discontinua-
tion, 59 patients had been enrolled, with 31 and 28 patients
randomized to the bisoprolol and carvedilol groups,
respectively. Thus there was insufficient statistical power
to test the noninferiority of bisoprolol versus carvedilol in
terms of efficacy and safety. Nevertheless, to our knowl-
edge this is the only randomized, double-blind study to
compare the efficacy and safety of bisoprolol and carve-
dilol for treating CHF in Japan; therefore, the results pro-
vide a valuable head-to-head comparison of bisoprolol and
carvedilol for the treatment of CHF.
Acknowledgments We wish to thank the members of the event
evaluation committee and the cardiac function evaluation committee:
Dr Hiroyuki Tsutsui, Dr Shin-ichi Momomura, Dr Issei Komuro, Dr
Yoshihiko Saito, and Dr Tohru Masuyama. We also thank the staff at
each study site for helping with patient enrollment and data
collection. We thank Daiichi Sankyo Co., Ltd for providing carvedilol
and Mitsubishi Tanabe Pharma Corporation for sponsoring this clin-
ical trial. The trial sites were: Kihara Cardiovascular Clinic; Sapporo
Kosei General Hospital; Hitachi General Hospital; Gunma Prefectural
Cardiovascular Center; Kan-etsu Chuo Hospital; Cardiovascular
Hospital of Central Japan; National Hospital Organization Saitama
National Hospital; Shuwa General Hospital; Dokkyo Medical Uni-
versity Koshigaya Hospital; Saitama Medical Center Jichi Medical
University; Saitama Medical University International Medical Center;
The Jikei University Kashiwa Hospital; Toho University Omori
Medical Center; Tokyo Medical University Hospital; Kanto Central
Hospital of the Mutual Aid Association of Public School Teachers;
Sempo Tokyo Takanawa Hospital; National Hospital Organization
Tokyo Medical Center; National Hospital Organization Tokyo Hos-
pital; Nihon University Nerima Hikarigaoka Hospital; Fussa Hospital;
Kanagawa Cardiovascular and Respiratory Center; Kitasato Univer-
sity Hospital; Fukui General Clinic; NHO Matsumoto Medical Center
Matsumoto Hospital; Ogaki Municipal Hospital; Japanese Red Cross
Takayama Hospital; Nagoya Daini Red Cross Hospital; Nagoya City
University Hospital; Social Insurance Chukyo Hospital; Fujita Health
University Hospital; National Hospital Organization Toyohashi
Medical Center; Mie University Hospital; Kusatsu General Hospital;
Social Insurance Kyoto Hospital; Mitsubishi Kyoto Hospital; Kitano
Hospital, The Tazuke Kofukai Medical Research Institute; Osaka
General Medical Center; Osaka Police Hospital; Osaka Red Cross
Hospital; Osaka Medical Center for Cancer and Cardiovascular Dis-
eases; Osaka Rosai Hospital; Hokusetsu General Hospital; Takatsuki
General Hospital; National Hospital Organization Osaka National
Hospital; National Hospital Organization Kobe Medical Center; Hy-
ogo College Of Medicine; Nara Medical University Hospital; Tenri
Hospital; Japanese Red Cross Okayama Hospital; KKR Takamatsu
Hospital; Kagawa Prefectural Central Hospital; Fukuokaken Saiseikai
Futsukaichi Hospital; Fukuoka Red Cross Hospital; Medical Corpo-
ration Chiyukai Fukuoka Wajiro Hospital; Shinkoga Hospital;
National Hospital Organization Ureshino Medical Center; Oita Oka
Hospital; Seijinkai Ikeda Hospital; and Tenyoukai Chuo Clinic.
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