1. health and fitness
2. disease

European Heart Journal Supplements (2006) 8 (Supplement C), C43–C50
doi:10.1093/eurheartj/sul013
How to begin treatment in chronic heart failure?
Results of CIBIS III
Ronnie Willenheimer*
KEYWORDS
Congestive heart failure;
Therapy;
Beta-blocker;
Angiotensin-converting
enzyme inhibitor;
Sequence of drug initiation
Aims To compare the effect of initial monotherapy with either bisoprolol or enalapril,
followed by their combination, on mortality and hospitalization in patients with
mild-to-moderate CHF.
Methods and results One thousand and ten patients with mild-to-moderate CHF and
left ventricular ejection fraction 35%, without ACE-inhibitor, beta-blocker, or
angiotensin-receptor-blocker therapy were randomized to open-label monotherapy
with either bisoprolol (target dose 10 mg od, n ¼ 505) or enalapril (target dose 10 mg
bid, n ¼ 505) for 6 months, followed by their combination for 6–24 months. The combined primary endpoint was all-cause mortality or hospitalization; bisoprolol-first was
considered non-inferior to enalapril-first if the upper limit of the 95% CI for the absolute
between-group difference was below þ5%, corresponding to HR 1.17. In the
intention-to-treat population, the primary endpoint occurred in 178 patients allocated
bisoprolol-first vs. 186 allocated enalapril-first: absolute difference, 21.6%; 95% CI,
27.6 to þ4.4%; HR, 0.94; 95% CI, 0.77–1.16. Thus, non-inferiority was demonstrated
in the intention-to-treat population. In the per-protocol population, the primary endpoint occurred in 163 patients in the bisoprolol-first group vs. 165 in the enalapril-first
group: absolute difference, 20.7%; 95% CI, 26.6 to þ5.1%; HR, 0.97; 95% CI,
0.78–1.21. With bisoprolol-first, 65 patients died vs. 73 with enalapril-first (HR, 0.88;
95% CI, 0.63–1.22; between-group difference P ¼ 0.44), and 151 vs. 157 patients
were hospitalized (HR, 0.95; 95% CI, 0.76–1.19; between-group difference P ¼ 0.66).
Post hoc analysis of data from the first year indicated that a bisoprolol-first strategy
reduced mortality by 31%, compared with an enalapril-first strategy (HR, 0.69; 95%
CI, 0.46–1.02; between-group difference P ¼ 0.065).
Conclusion Initiating treatment with bisoprolol is as effective and well-tolerated as
initiating treatment with enalapril. Post hoc analysis suggests that starting treatment
with bisoprolol may reduce the risk of death, especially in the first year of treatment.
Introduction
Current guidelines recommend initiating treatment for CHF
with an ACE-inhibitor and then adding a beta-blocker,1,2
but this sequence is not evidence-based. Until, now,
there has been no answer to the important clinical question
of which agent to use first: ACE-inhibitor or beta-blocker?
The Cardiac Insufficiency Bisoprolol Study-III (CIBIS-III)
* Corresponding author. Tel: þ46 40 33 10 00; fax: þ46 40 33 62 09.
E-mail address: [email protected]
addressed this issue by comparing starting treatment
with the beta1-selective beta-blocker bisoprolol or
the ACE-inhibitor enalapril, followed by addition of the
other agent (i.e. it compared bisoprolol-first with
enalapril-first).
The rationale, aims and design of CIBIS-III have been
published previously in the European Journal of Heart
Failure 3 and are reviewed by Ponikowski in this
Proceedings. The results of CIBIS-III were published in
September 2005,4 and are reviewed here with the kind
permission of the Editor of Circulation.
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected]
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¨, Sweden
Department of Cardiology, Lund University, University Hospital, S-205 02 Malmo
C44
R. Willenheimer
Results and interpretation
antiplatelet agents in 67%, and about 15% were receiving
hypoglycaemic treatment.
Baseline data
Table 1 Baseline data in the CIBIS III trial
Bisoprolol-first Enalapril-first
(n ¼ 505)
(n ¼ 505)
Mean age (years)
Males (%)
NYHA class II (%)
NYHA class III (%)
Median duration of CHF
(months)
Mean LVEF (%)
Mean serum creatinine
(mmol/L)
Mean heart rate (bpm)
Mean systolic BP (mm Hg)
Aetiologya
Coronary artery disease (%)
Hypertension (%)
Valvular heart disease (%)
Primary cardiomyopathy (%)
Other (%)
Baseline diuretic
treatment (%)
Thiazide diuretics (%)
Loop diuretics (%)
Potassium sparing
diuretics (%)
Aldosterone-receptor
blockers (%)
Baseline antiplatelet
medication (%)
Baseline cardiac glycoside
treatment (%)
Baseline hypoglycaemic
medication (%)
72.4
65.9
48.5
51.5
20
72.5
70.5
49.5
50.5
18
28.8
99.6
28.8
101.9
78.8
134.5
79.5
133.7
61.2
39.0
2.2
9.7
13.5
63.6
34.1
3.0
10.1
9.9
85.1
83.4
19.2
71.5
10.3
22.8
66.9
10.5
14.3
12.3
68.3
66.1
32.9
30.7
14.3
17.0
The bisoprolol-first and enalapril-first groups were well-matched at
baseline.4
a
More than one aetiology may be given for each patient.
Statistical analysis
The primary endpoint was analysed by the log-rank test.
Differences in time to event (in days from randomization)
of mortality, the combined endpoint of mortality and hospital admission, and of relevant serious adverse events
not covered by the primary endpoint were assessed by
the log-rank test. Survival curves were calculated using
Kaplan–Meier estimates. The proportion of patients
with events was analysed by Fisher’s exact test.
The intention-to-treat-population included all 1010
patients randomized at baseline. The per-protocolpopulation excluded nine patients entirely from the
analysis: four who never took the study medication
(one randomized to bisoprolol-first and three to
enalapril-first), one with unstable CHF, three with inadmissible prior therapy, and one who did not meet the
inclusion criteria. A further 152 had some data excluded
from the per-protocol analysis at time points subsequent
to other protocol violations (11 never started the second
drug, five showed inadequate compliance, 54 had medically illegitimate introduction of the second drug, and
96 had medically illegitimate permanent treatment
cessation).
A P-value , 0.025 (unilateral test) denotes statistical
significance for non-inferiority. For all other comparisons,
P , 0.05 denotes statistical significance.
Achievement of target treatment regimen
During monotherapy, in the bisoprolol-first group, 65% of
patients were uptitrated to the target dose (10 mg od)
and 82% to at least 5 mg od. In the enalapril-first group,
84% were uptitrated to the target dose (10 mg bid) and
94% to at least 5 mg bid. There was no significant difference between the groups in the percentage started on
the additional treatment at the beginning of the combined therapy phase: 89% of patients allocated to
bisoprolol-first were started on additional enalapril, and
85% of enalapril-first patients were started on additional
bisoprolol (P ¼ 0.13).
However, in both study groups, the first-initiated
therapy was significantly more likely to be given at
higher doses (i.e. at 50% of the target dose) during
the combined-therapy phase (Table 2). This observation
underscores the findings of prior surveys that the
first-initiated therapy stands a better chance of being
uptitrated to the target dose.5–7
Primary endpoint (death or hospitalization
due to any cause)
Overall, the bisoprolol-first and enalapril-first groups
were clinically comparable with regard to the primary
endpoint (death or hospitalization owing to any cause).
The Kaplan–Meier plots for the intention-to-treat and
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CIBIS-III enrolled 1010 patients at 128 centres in 18
countries in Europe, and in Tunisia and Australia, who
were followed up for a mean of 1.22 + 0.42 years
(maximum 2.10 years). The two groups had similar clinical and demographic baseline characteristics (Table 1).
The mean age was 72.4 years and 68.2% were male.
The most common aetiology of CHF was ischaemic
heart disease (62.4%); in 36.5% it was considered to be
hypertension. Mean left ventricular ejection fraction
(LVEF) was 28.8%, and patients were evenly distributed
between NYHA classes II and III. About 50% of the patients
had a history of acute myocardial infarction, 10% had a
history of peripheral vascular disease, 10% a history of
cerebrovascular disease, and 20% diabetes. Baseline cardiovascular medication was similar in the two groups,
with 84.3% of the patients receiving diuretics (mostly
loop diuretics). Fewer than 15% were receiving aldosterone antagonists. A cardiac glycoside was used in 31%,
Results of CIBIS III
C45
Table 2 Achievement of 50% of the target dose at the end of the CIBIS-III study
End-of-study doses
Bisoprolol-first (%)
Enalapril-first (%)
P-value
Bisoprolol given at 50% of target
Enalapril given at 50% of target
86
82
72
90
,0.001
,0.001
In both study groups, the first-initiated therapy was more likely to be last prescribed at 50% of the target dose during the
combined-therapy phase.
Figure 1 Kaplan–Meier plots of the combined primary endpoint (death or
hospitalization) in the intention-to-treat protocol (A) and per-protocol
(B) populations in CIBIS-III. Reproduced with permission from Willenheimer
et al. Effect on survival and hospitalization of initiating treatment for
chronic heart failure with bisoprolol followed by enalapril, as compared
with the opposite sequence. Results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 2005;112:2426–2435.
Secondary endpoints and post hoc analyses
All analyses of secondary endpoints were performed on
the intention-to-treat population only. Overall, no significant differences were found between groups with regard
to secondary endpoints at the end of the study period
(e.g. total and cardiovascular mortality, hospitalizations,
worsening of CHF requiring hospitalization or while in
hospital). However, post hoc analysis of mortality
revealed a trend towards fewer deaths in the bisoprolol
group, especially during the early study phase (see
below).
Death or hospitalization due to any cause
There was no significant difference between the groups in
the secondary endpoint of death or hospitalization due
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per-protocol populations were virtually superimposable
(Figure 1).
In the intention-to-treat population, the primary
endpoint occurred in 178 patients (35.2%) allocated
bisoprolol-first vs. 186 (36.8%) allocated enalapril-first:
absolute difference, 21.6%; 95% CI 27.6 to þ4.4%; HR,
0.94; 95% CI, 0.77–1.16; non-inferiority for bisoprolol-first
vs. enalapril-first, P ¼ 0.019. Thus, the intention-to-treat
analysis met the pre-specified non-inferiority limits for the
upper confidence interval of þ5% for absolute difference
(¼relative risk of 1.125) and 1.17 for HR.
In the per-protocol population (Figure 1), there were
163 events (32.4%) in the bisoprolol-first group vs. 165
(33.1%) in the enalapril-first group. However, despite
the near-identical result compared with the intentionto-treat analysis, because of the smaller size of the perprotocol population, the non-inferiority analysis did not
quite reach statistical significance. The absolute difference for the primary endpoint was 20.7%; 95% CI; 26.6
to þ5.1%; HR, 0.97; 95% CI, 0.78–1.21; non-inferiority
P ¼ 0.046. Thus, the pre-specified non-inferiority criterion (upper limit of 95% CI for the absolute difference
of less than þ5%, corresponding to a HR of 1.17) was
not met. However, the upper limit of þ5.1% for the 95%
CI of the absolute difference was very close to the
target of less than þ5%.
The field of non-inferiority in clinical trials has been
constantly evolving during recent years. The per-protocol
analysis is traditionally the preferred and most conservative approach with regard to non-inferiority, but was originally developed for use in short-term trials comparing the
pharmacological effects of drugs (e.g. proprietary vs.
generic formulations). However, the appropriate population for non-inferiority testing in mortality and morbidity trials is more controversial. In trials with relatively
long follow-up periods, such as CIBIS-III, the per-protocol
sample becomes difficult to define (despite a blinded
definition of the per-protocol sample by the endpoint
committee in CIBIS-III). Some experts believe that the
intention-to-treat analysis may be considered equally relevant in terms of non-inferiority in long-term mortality
and morbidity trials. As the number of patients in the perprotocol sample rapidly diminished with time in CIBIS-III
(as in other long-term intervention trials) as a result of
protocol violations and withdrawals, this analysis provided less statistical power than the intention-to-treat
analysis. This lack of power is considered to be the
cause for the lack of statistical significance for noninferiority in the per-protocol sample. Most importantly,
the result in the per-protocol analysis was quite consistent
with that of the intention-to-treat analysis.
C46
R. Willenheimer
to any cause at the end of the monotherapy phase
(6 months), which occurred in 109 patients in the
bisoprolol-first group vs. 108 in the enalapril-first group
(HR, 1.02; 95% CI, 0.78–1.33; between-group difference
P ¼ 0.90). In a post hoc analysis of the first year, the
longest time period during which all patients were
followed-up, 155 patients with bisoprolol-first vs. 165
with enalapril-first experienced death or hospitalization due to any cause (HR, 0.94; 95% CI, 0.76–1.17;
between-group difference P ¼ 0.59).
All-cause mortality
Figure 2 Intention-to-treat analysis of all-cause mortality throughout
the study (A) and up to 1 year (B). There was a trend towards reduced
1-year mortality in the bisoprolol-first group, which approached statistical significance. (A) Reproduced with permission from Willenheimer
et al. Effect on survival and hospitalization of initiating treatment for
chronic heart failure with bisoprolol followed by enalapril, as compared
with the opposite sequence. Results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 2005;112:2426–2435.
All-cause hospitalization
Over the entire study period, the number of patients hospitalized was similar in the two groups: 151 with
bisoprolol-first vs. 157 with enalapril-first: HR, 0.95;
95% CI, 0.76–1.19; between-group difference P ¼ 0.66
(Figure 3). The total number of hospitalizations was
also similar: 242 with bisoprolol-first vs. 249 with
enalapril-first (between-group difference P ¼ 0.73).
With regard to the secondary endpoint of hospitalizations
at the end of the monotherapy phase (6 months), 99
bisoprolol-first vs. 92 enalapril-first patients had a hospitalization (HR, 1.08; 95% CI, 0.81–1.43; between-group
difference P ¼ 0.59). This non-significant imbalance in
favour of the enalapril group may be related to a slightly
higher frequency in the bisoprolol-first group of worsening of CHF requiring hospitalization or occurring in
hospital (see below).
Cardiovascular mortality
There was no significant difference in the number of
patients dying of cardiovascular causes in the two
groups: 55 with bisoprolol-first vs. 56 with enalapril-first:
HR, 0.97; 95% CI, 0.67–1.40 (between-group difference
P ¼ 0.86).
Worsening of CHF requiring hospitalization or
occurring in hospital
Although there was no significant between-group difference with regard to the secondary endpoint of worsening
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Over the whole study period, 65 patients died in the
bisoprolol-first group vs. 73 in the enalapril-first group:
HR, 0.88; 95% CI, 0.63–1.22; between-group difference
P ¼ 0.44. The overall number of deaths in the two
groups was not statistically different; nor was the difference in the number of patients dying of cardiovascular
causes in the two groups: 55 with bisoprolol-first vs. 56
with enalapril-first.
However, there was a trend towards fewer deaths in
the bisoprolol group, especially early in treatment. At
the end of the monotherapy phase, 23 patients had
died in the bisoprolol-first group vs. 32 in the enalaprilfirst group (HR, 0.72; 95% CI, 0.42–1.24; between-group
difference P ¼ 0.24) representing a 28% mortality
reduction. Furthermore, post hoc analysis (Figure 2)
showed that at the end of the first year, 42 patients
had died in the bisoprolol-first group vs. 60 in the
enalapril-first group (HR, 0.69; 95% CI, 0.46–1.02;
between-group difference P ¼ 0.065). This amounts to a
31% reduction in mortality, which narrowly misses statistical significance.
The trend towards reduced early mortality in the
bisoprolol-first group might be explained by a reduction
in sudden cardiac death, and these data will be analysed
and published in due course. Sudden death is the commonest mode of death in early and mildly symptomatic
CHF.8–10 Beta-blockers have a marked effect on sudden
death in CHF,8,11,12 whereas ACE-inhibitors have not
been convincingly shown to reduce sudden death.13,14
In newly diagnosed CHF, patients may have to remain
on the first-initiated neurohormonal inhibitor therapy
for several weeks, or even months, while the dose is
slowly uptitrated and their condition stabilized. During
this period, before the initiation of combination
therapy, beta-blockade might be particularly valuable
in improving survival through its action on the sympathetic nervous system. More patients might then survive
to go on to combination treatment.
Results of CIBIS III
report heart failure worsening while in hospital as an
endpoint. Importantly, as more patients survived the
early phase of the study, more patients were at risk of
worsening of CHF. This circumstance alone might
explain the difference between the two study groups in
the worsening of CHF events.
A trend towards temporary worsening of heart failure
leading to hospitalization might be partly due to physicians’ limited experience of uptitrating a beta-blocker
in patients not on an ACE-inhibitor. With more experience, worsening of CHF during initial uptitration of the
beta-blocker might be avoided.
Other secondary endpoints
There was no significant difference between groups in the
need for early introduction of the second drug, or with
regard to treatment discontinuation during the study
overall or during the monotherapy phase (Table 3).
Pre-specified subgroup analyses
Figure 3 Intention-to-treat analysis of all-cause hospitalization throughout the study. There was no significant difference in hospitalizations
between the two groups.
In the pre-specified subgroup analyses, with regard to
LVEF, there was a significant interaction regarding the
primary endpoint (P ¼ 0.001) (Figure 5). Among patients
with LVEF ,28%, those receiving bisoprolol-first were significantly less likely to die or be hospitalized than those
receiving enalapril-first (HR, 0.61; 95% CI, 0.44–0.85;
P ¼ 0.003), whereas there was an opposite trend among
those with LVEF 28% (HR, 1.23; 95% CI, 0.94–1.61;
P ¼ 0.13). The same pattern was seen if the median LVEF
value of 30% was used as cut-off (interaction P ¼ 0.036).
However, these findings may be explained by an imbalance
between the groups in non-cardiovascular hospitalizations
during the monotherapy phase, and are probably not of
any clinical significance. Other pre-specified subgroup
analyses showed no significant differences in the effect
of treatment on different subgroups (in relation to sex,
age, NYHA class, digitalis use, or heart rate, blood
pressure, or serum creatinine at baseline).
Table 3 Other secondary endpoints in the CIBIS-III study
Early introduction of
second drug (%)
Permanent treatment
cessation
Monotherapy phase (%)
Combination phase
Bisoprolol (%)
Enalapril (%)
Figure 4 Intention-to-treat analysis of worsening heart failure requiring
hospitalization or occurring in hospital. There was a non-significant trend
in favour of enalapril. Reproduced with permission from Willenheimer
et al. Effect on survival and hospitalization of initiating treatment for
chronic heart failure with bisoprolol followed by enalapril, as compared
with the opposite sequence. Results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 2005;112:2426–2435.
Total (%)
Bisoprolol-first
Enalapril-first
39 (7.7%)
37 (7.3%)
35 (6.9%)
47(9.7%)
19 (3.8%)
47 (9.3%)
24 (4.7%)
16 (3.2%)
101 (20.0%)
89 (17.6%)
There was no significant difference between groups in the need for
early introduction of the second drug because of poor control of CHF,
or with regard to treatment discontinuation during the study overall
or during the monotherapy phase.
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of CHF requiring hospitalization or occurring in hospital,
there was a non-significant trend in favour of enalaprilfirst (Figure 4). Heart failure worsening occurred in 63
patients in the bisoprolol-first group vs. 51 in the enalaprilfirst group: HR, 1.25; 95% CI, 0.87–1.81; between-group
difference P ¼ 0.23. The total number of worsening
events was 84 in the bisoprolol-first group vs. 66 in the
enalapril-first (between-group difference P ¼ 0.27).
In the long-term, beta-blockers decrease hospitalization in CHF.8,11,12 However, it is well-known that
initiation and uptitration of a beta-blocker may cause
minor and temporary worsening of heart failure symptoms (followed by improvement).1,2 It is conceivable
that bisoprolol was uptitrated too aggressively for the
predominantly elderly population included in CIBIS-III.
However, this explanation is considered unlikely, as the
uptitration schedule was slower than that used in
CIBIS-II.11 It is possible that the early negative inotropic
effect of beta-blockade might appear differently in
patients not receiving background ACE-inhibition.
Temporary worsening of symptoms is usually handled by
an increase in the dose of diuretic, and this alone
might have been enough reason for some physicians to
C47
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R. Willenheimer
Safety
The two strategies were comparable in terms of serious
and total adverse events (Table 4). During the entire
trial, 119 patients were formally withdrawn from the
Table 4 Serious adverse events and adverse events in the
safety population in CIBIS-III (all patients who received at
least one dose of randomised treatment)4
Number of patients (%)
Monotherapy
Serious adverse events
Adverse events
Entire study
Serious adverse events
Adverse events
Bisoprolol-first
(n ¼ 504)
Enalapril-first
(n ¼ 502)
113 (22.4)
316 (62.7)
111 (22.1)
319 (63.5)
184 (36.5)
396 (78.6)
187 (37.3)
395 (78.7)
study, 60 from the bisoprolol-first group and 59 from
the enalapril-first group. Discontinuations due to
adverse events were similar in the two groups: 48 in
the bisoprolol-first group vs. 51 in the enalapril-first
group.
Both regimens had similar effects on blood pressure,
during both the monotherapy and combined therapy
phases. Mean systolic blood pressure in the bisoprololfirst group was 134.5 mmHg at baseline and
124.8 mmHg at 1 year, compared with 133.7 mmHg at
baseline and 124.8 mmHg at 1 year in the enalapril-first
group. Mean diastolic blood pressure in the bisoprololfirst group was 80.4 mmHg at baseline and 74.5 mmHg
at 1 year, compared with 80.7 mmHg at baseline and
75.0 mmHg at 1 year in the enalapril-first group. There
was a more pronounced heart-rate-lowering effect
during the monotherapy phase in the bisoprolol-first
group, from a mean of 78.8–67.9 bpm, compared with
79.5–78.6 in the enalapril-first group. After 1 year (i.e.
after half a year in the combined phase), heart rate
was similar in both groups: 66.7 bpm in the bisoprololfirst group vs. 67.5 bpm in the enalapril-first group.
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Figure 5 Pre-specified subgroup analyses with regard to the primary endpoint in the intention-to-treat population. Reproduced with permission from
Willenheimer et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence. Results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 2005;112:2426–2435.
Results of CIBIS III
Conclusions
There was an intriguing trend towards improved survival with bisoprolol-first, especially during the first year of
treatment. With bisoprolol-first, fewer patients died and
the deaths occurred later in the study. In the first year,
bisoprolol-first reduced mortality by 31%, compared
with enalapril-first (P ¼ 0.065). It may be speculated
that this difference is related to the known protective
effect of beta-blockade against sudden death, which is
particularly common in early and mildly symptomatic
CHF.8–10 As illustrated in Figure 6, the priority at this
critical time is to inhibit the sympathetic system, which
is achievable with beta-blockers, but not ACE-inhibitors.
A beta-blocker-first strategy may therefore be particularly relevant in early CHF.
Patients had to be at least 65 years of age to be included
in the CIBIS-III study, and the mean age of the included
patients was around 74 years at the end of the study,
which is close to the mean age of around 75 years in the
general population of CHF patients in clinical practice.5,16
In addition, many of the patients in CIBIS-III had
co-morbidities such as hypertension and diabetes, again
reflecting the real-life situation. Physicians can therefore
be confident that a slow uptitration to the maximum tolerated dose within the target levels recommended by
current guidelines is safe and well tolerated even in
elderly patients and those with co-morbidities.1,2
The findings of CIBIS-III challenge the current recommendation that treatment of CHF should begin with
an ACE-inhibitor followed by a beta-blocker, and imply
that physicians should be free to initiate CHF treatment
with either class of drug, according to their clinical judgement in individual patients.19,20 The daily practice of
some physicians will probably change as a result of
CIBIS-III. Although, European and US guidelines have
only recently been revised, and are not due to be
updated for some time, the evidence from CIBIS-III will
probably be incorporated into national guidelines in the
near future, contributing in a practical way to the
rational and effective management of CHF.
Conflict of interest: R.W. has served in the Steering Committee
of CIBIS-III and has received lecture fees from Merck KGaA,
Darmstadt, Germany.
References
Figure 6 Goals of treatment in CHF in relation to disease progression
in CHF: the need for prevention of sudden cardiac death in the early
stages of the disease. Reproduced with permission from Willenheimer
and Silke. Possible clinical implications of the Cardiac Insufficiency
Bisoprolol (CIBIS) III trial. Br J Cardiol 2005;12:448–454.
1. Swedberg K, Cleland J, Dargie H et al. Guidelines for the diagnosis
and treatment of chronic heart failure: executive summary (update
2005): The Task Force for the Diagnosis and Treatment of Chronic
Heart Failure of the European Society of Cardiology. Eur Heart J
2005;26:1115–1140.
2. Hunt SA, Abraham WT, Chin MH et al. ACC/AHA 2005 Guideline
Update for the Diagnosis and Management of Chronic Heart Failure
in the Adult–Summary Article: A Report of the American College of
Cardiology/American Heart Association Task Force on Practice
Guidelines (Writing Committee to Update the 2001 Guidelines for
the Evaluation and Management of Heart Failure). Circulation
2005;112:1825–1852.
3. Willenheimer R, Erdmann E, Follath F et al. Comparison of treatment
initiation with bisoprolol vs. enalapril in chronic heart failure patients:
rationale and design of CIBIS-III. Eur J Heart Fail 2004;6:493–500.
4. Willenheimer R, van Veldhuisen DJ, Silke B et al. Effect on survival
and hospitalization of initiating treatment for chronic heart failure
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ACE-inhibitors and beta-blockers are standard treatments for CHF, as recommended by international guidelines.1,2 CIBIS-III3,4 is the first large randomized
controlled trial to examine whether the order of
initiation of these two important treatments makes any
difference to morbidity and mortality. This is important,
as although combination treatment is highly desirable,
many CHF patients do not receive this combination.
Some patients may receive inadequate doses, or remain
on the first-initiated drug for extended periods.5,15,16
CIBIS-III, therefore, provides a clear answer to a clinically
relevant question. The bisoprolol-first and enalapril-first
groups in CIBIS-III were clinically comparable with regard
to the primary endpoint (all-cause mortality and hospitalization) and all secondary endpoints. Bisoprolol-first was
demonstrated to be non-inferior to enalapril-first in the
intention-to-treat analysis of the primary endpoint. Both
strategies were equally safe and well tolerated.
It is important to note that in CIBIS-III, the doses of both
drugs were titrated up to maximum tolerated levels
depending on the individual response to treatment.
Uptitration was mandatory unless intolerance occurred,
but could be carried out more slowly than planned if this
was helpful in any individual patient. Individual dose
adaptations of beta-blockers based on maximum tolerability do not seem to lead to an inferior effect on survival
and morbidity.17,18 However, there is limited experience
of uptitration of beta-blockers in the absence of
ACE-inhibitors, and this may be relevant to the observed
non-significant increase in the worsening of CHF requiring
hospitalization or occurring in hospital. The bisoprololfirst strategy could be further improved with greater
experience of uptitration of the beta-blocker-first,
leading to less worsening of CHF. In this regard, it is
important to consider the fact that more patients survived
the early phase of the study in the bisoprolol-first group.
Consequently, more patients were at risk of worsening
of CHF in the bispoprolol-first group.
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C50
5.
6.
7.
8.
9.
10.
12.
with bisoprolol followed by enalapril, as compared with the opposite
sequence. Results of the Randomized Cardiac Insufficiency Bisoprolol
Study (CIBIS) III. Circulation 2005;112:2426–2435.
Cleland JG, Cohen-Solal A, Aguilar JC et al. Management of
heart failure in primary care (the IMPROVEMENT of Heart
Failure Programme): an international survey. Lancet 2002;360:
1631–1639.
Davies M, Hobbs F, Davis R et al. Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of
England Screening study: a population based study. Lancet 2001;
358:439–444.
Komajda M, Lapuerta P, Hermans N et al. Adherence to guidelines is a
predictor of outcome in chronic heart failure: the MAHLER survey. Eur
Heart J 2005;26:1653–1659.
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart
failure: METOPROLOL CR/XL Randomized Intervention Trial in
Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–2009.
Uretsky BF, Sheahan RG. Primary prevention of sudden cardiac death
in heart failure: will the solution be shocking? J Am Coll Cardiol
1997;30:1589–1597.
Aliot E, de Chillou C, Sadoul N. Ventricular instability and sudden
death in patients with heart failure: lessons from clinical trials. Eur
Heart J 2002;4(Suppl. D):D31–D42.
CIBIS II Investigators and Committees. The Cardiac Insufficiency
Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;
353:9–13.
Packer M, Coats AJ, Fowler MB et al. Effect of carvedilol on survival in
severe chronic heart failure. N Engl J Med 2001;344:1651–1658.
13. Cleland JG, Massie BM, Packer M. Sudden death in heart failure:
vascular or electrical? Eur J Heart Fail 1999;1:41–45.
14. Garg R, Yusuf S. Overview of randomized trials of angiotensinconverting enzyme inhibitors on mortality and morbidity in patients
with heart failure. Collaborative Group on ACE Inhibitor Trials.
JAMA 1995;273:1450–1456.
15. Komajda M, Lapuerta P, Hermans N et al. Adherence to guidelines is a
predictor of outcome in chronic heart failure: the MAHLER survey.
Eur Heart J 2005;26:1653–1659.
16. Komajda M, Follath F, Swedberg K et al. The EuroHeart Failure Survey
programme—a survey on the quality of care among patients with
heart failure in Europe. Part 2: treatment. Eur Heart J 2003;
24:464–474.
17. Wikstrand J, Hjalmarson A, Waagstein F et al. Dose of metoprolol
CR/XL and clinical outcomes in patients with heart failure: analysis
of the experience in metoprolol CR/XL randomized intervention
trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol
2002;40:491–498.
18. Simon T, Mary-Krause M, Funck-Brentano C, Lechat P, Jaillon P.
Bisoprolol dose-response relationship in patients with congestive
heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS II). Eur Heart J 2003;24:552–559.
19. Willenheimer R, Silke B. Possible clinical implications of the Cardiac
Insufficiency Bisoprolol (CIBIS) III trial. Br J Cardiol 2005;12:448–454.
20. Willenheimer R. Implications of CIBIS III: a commentary. JRAAS
2005;6:115–120.
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11.
R. Willenheimer