Wikstrand Et Al-2014-Journal of Internal Medicine

Original Article
doi: 10.1111/joim.12141
The large-scale placebo-controlled beta-blocker studies in

systolic heart failure revisited: results from CIBIS-II,
COPERNICUS and SENIORS-SHF compared with stratified
subsets from MERIT-HF
J. Wikstrand1, H. Wedel2, D. Castagno3 & J. J. V. McMurray4
From the 1Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University; 2Nordic School of Public
Health, Gothenburg, Sweden; 3Division of Cardiology, Department of Medical Sciences, University of Turin, Turin, Italy; and 4BHF Glasgow
Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
Abstract. Wikstrand J, Wedel H, Castagno D,

McMurray JJV (Gothenburg University; Nordic
School of Public Health, Gothenburg, Sweden;
University of Turin, Turin, Italy; University of
Glasgow, Glasgow, UK). The large-scale placebocontrolled beta-blocker studies in systolic heart
failure revisited: results from CIBIS-II, COPERNICUS
and SENIORS-SHF compared with stratified subsets
from MERIT-HF. J Intern Med 2014; 275: 134143.
Aims. The four pivotal beta-blocker trials in heart
failure (HF) had different inclusion criteria, making
comparison difficult without patient stratifying. The
aim of this study was to compare, in similar patients,
the effects of bisoprolol, metoprolol controlled
release/extended release (CR/XL), carvedilol and
nebivolol on (i) total mortality, (ii) all-cause mortality
or hospitalization due to cardiovascular causes (time
to first event), (iii) all-cause mortality or hospitalization because of HF and (iv) tolerability, defined as
discontinuation of randomized treatment.
Methods. We compared stratified (s) subsets in
MERIT-HF with patients in CIBIS-II [New York
Heart Association (NYHA) class III/IV and ejection
fraction (EF) 35%] and COPERNICUS (NYHA III/
IV and EF <25%) and in patients with systolic HF in
SENIORS-SHF (age 70 years and EF 35%).
Introduction
Beta-blockers have, without doubt, been one of the
pivotal therapeutic advances in the management of
patients with heart failure. In landmark clinical
trials, the four agents bisoprolol, metoprolol succinate controlled release/extended release (CR/XL),
carvedilol and nebivolol demonstrated improvement
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2013 The Association for the Publication of the Journal of Internal Medicine
Results. The annual mortality rates in the placebo and

beta-blocker arms were: (i) CIBIS-II (n = 2647),
13.2% vs. 8.8% (relative risk reduction 34%, 95%
CI: 1946, P < 0.0001) and MERIT-HFs (n = 2002),
14.8% vs. 8.6% (relative risk reduction 42%, 95% CI:
2456, P < 0.0001); (ii) COPERNICUS (n = 2289),
19.7% vs. 12.8% (relative risk reduction 35%, 95%
CI: 1948, P = 0.0014) and MERIT-HFs (n = 795),
19.1% vs. 11.7% (relative risk reduction 39%; 95%
CI: 1158, P = 0.0086); (iii) SENIORS-SHF (n =
1359), 11.3% vs. 9.7% (relative risk reduction
16%, NS) and MERIT-HFs (n = 985), 14.8% vs.
10.1% (relative risk reduction 32%, 95% CI: 253,
P = 0.038). The effects on the other outcomes
assessed were similar. Analyses indicated fewer
discontinuations from randomized treatment on
beta-blockers compared with placebo in COPERNICUS and the MERIT-HFs subsets.
Conclusion. The efficacy and tolerability of bisoprolol,
carvedilol and metoprolol CR/XL are similar in
patients with systolic HF, irrespective of NYHA
class or ejection fraction. Nebivolol is less effective
and not better tolerated.
Keywords: beta-blockers, clinical trials, heart failure.
in outcome and were subsequently approved and

marketed for the treatment of heart failure. The key
trials were the second Cardiac Insufficiency Bisoprolol Study (CIBIS-II, n = 2647) [1], the Metoprolol
CR/XL Randomized Intervention Trial in Congestive
Heart Failure (MERIT-HF, n = 3991) [2, 3], the
Carvedilol Prospective Randomized Cumulative
Survival Trial (COPERNICUS, n = 2289) [4, 5] and
J. Wikstrand et al.
the Study of the Effects of nebivolol Intervention on

Outcomes and Rehospitalization in Seniors with
Heart Failure Trial (SENIORS, n = 2128) [6, 7]. The
characteristics of patients included, however, differed in each of these trials (i.e. due to differing
inclusion and exclusion criteria), particularly with
respect to age, symptom severity, as assessed by
New York Heart Association (NYHA) class, and left
ventricular ejection fraction. Notably, whereas three
of the four trials enrolled only patients with systolic
heart failure [15], SENIORS also included patients
with preserved ejection fraction [6, 7]. SENIORS also
had a different primary end-point [a composite of allcause mortality or hospitalization due to cardiovascular causes (time to first event)] compared with the
other trials (which had all-cause mortality as the
primary outcome), and secondary outcomes also
varied amongst these trials. Consequently, assessment of the relative efficacy and tolerability of these
evidence-based beta-blockers is difficult as likewith-like comparison is not possible from the published data. Therefore, we have used original data
from the largest of the trials, MERIT-HF, to create
stratified subsets of patients of sufficient size to
enable such comparisons to be made; outcomes
were compared between CIBIS-II-like and COPERNICUS-like patients in MERIT-HF and patients in
the CIBIS-II and COPERNICUS trials, respectively.
Similarly, original data from both MERIT-HF and
SENIORS [7] were used to create a common subset of
older patients with systolic heart failure for comparison. We focused on all-cause mortality (the
primary end-point in CIBIS-II, COPERNICUS and
MERIT-HF), the composite of all-cause mortality or
hospitalization due to cardiovascular causes, analysed as time to first event (the primary end-point in
SENIORS), all-cause death or hospitalization
because of heart failure (a commonly used disease-specific end-point in heart failure trials) and
discontinuation of study drug (to assess tolerability), using original data from each trial to create this
common set of outcomes for all comparisons.
Methods
Study patients and randomized treatment
Metoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure (n = 3991)
Important inclusion criteria. The important inclusion criteria in the MERIT-HF study were age
4080 years, NYHA class IIIV for 3 months before
randomization despite optimal standard therapy
Beta-blockers in systolic HF revisited
[defined as any combination of diuretics and an

angiotensin-converting enzyme (ACE) inhibitor or
an angiotensin receptor blocker (ARB)] and ejection fraction 0.40 [2, 3]. To achieve a large
proportion of randomly assigned patients at high
risk, the protocol stated that the investigators
should aim to include less than 40% of patients
in NYHA class II (i.e. more than 60% in NYHA III or
IV). Patients with ejection fractions between 0.36
and 0.40 were included only if their maximum
walking distance was 450 m (500 yards) during a
6-min walk test.
Important exclusion criteria. The exclusion criteria
in this study were acute myocardial infarction or
unstable angina within 28 days before randomization, indication or contraindication for treatment
with beta1-blockade, heart failure secondary to
systemic disease or alcohol abuse, unstable
decompensated heart failure (pulmonary oedema
or hypoperfusion), supine systolic blood pressure
<100 mmHg, heart rate <68 beats per min (bpm) at
enrolment and other serious disorders that might
complicate management during follow-up. There
were no exclusion criteria related to the level of
serum creatinine at baseline [8].
Randomized treatment. After a single-blind placebo run-in phase of 2 weeks, patients were randomly assigned to metoprolol CR/XL [9] or placebo
with starting doses of 12.5 or 25 mg once daily.
The lower starting dose was recommended for
patients in NYHA class III/IV. The study protocol
stated that the dose should be doubled every
second week to a target of 200 mg once daily, or
the highest tolerated dose. The titration schedule
could be modified according to written guidelines,
and at the discretion of the investigator.
Cardiac Insufficiency Bisoprolol Study-II (n = 2647)
Important inclusion criteria. The important inclusion criteria in the CIBIS-II study were age 18
80 years, NYHA class IIIIV for at least 3 months
before enrolment, ejection fraction 0.35 and
optimal standard therapy, defined as any combination of diuretics and an ACE inhibitor (or ARB)
[1].
in this study were similar to those applied in
MERIT-HF. In addition, according to the protocol,
Journal of Internal Medicine, 2014, 275; 134143
135
J. Wikstrand et al.
heart rate <60 bpm as well as renal failure (serum

creatinine >300 lmol L 1) were exclusion criteria.
Randomized treatment. Patients were started on
bisoprolol 1.25 mg or placebo once daily, and the dose
of bisoprolol was increased successively to 2.5, 3.75,
5, 7.5 and 10 mg according to tolerance. Patients
received the first three concentrations for 1 week
each, and the higher concentrations for 4 weeks.
Carvedilol Prospective Randomized Cumulative Survival Trial (n = 2289)
Important inclusion criteria. The important inclusion criteria in the COPERNICUS study were symptoms of severe heart failure (equated in this analysis
to NYHA class III or IV), ejection fraction <0.25 and
optimal standard therapy, defined as any combination of diuretics and an ACE inhibitor (or ARB) [4, 5].
in this study were similar to those applied in MERITHF. However, contraindication to beta-blockade
referred to nonselective beta-blockade and systolic
blood pressure to <85 mmHg. In addition, severe
pulmonary, renal (serum creatinine >247 lmol L 1)
or hepatic disease were exclusion criteria.
3.125 mg carvedilol or matching placebo twice
daily for 2 weeks, and the carvedilol dose was then
increased at 2-week intervals (if tolerated), first to
6.25 mg, then to 12.5 mg and finally to a target
dose of 25 mg twice daily.
SENIORS subgroup with impaired left ventricular
function (n = 1359 with systolic heart failure,
referred to as SENIORS-SHF)
Important inclusion criteria. The important inclusion criteria in the SENIORS-SHF study were age
70 years, ejection fraction 0.35 within the last
6 months and optimal standard therapy, defined
as any combination of diuretics and an ACE
inhibitor (or ARB) [6, 7].
in this study were similar to those applied in CIBISII, but systolic blood pressure <90 mmHg and renal
failure denoted by serum creatinine 250 lmol L 1.
In addition, significant hepatic dysfunction was an
exclusion criterion in SENIORS-SHF.
1.25 mg nebivolol or matching placebo once daily
136
and, if tolerated, the nebivolol dose was increased

to 2.5 and 5 mg, every 12 weeks, reaching a
target of 10 mg once daily over a maximum of
16 weeks.
Statistical analyses
For CIBIS-II, COPERNICUS and SENIORS-SHF,
P-values, point estimates and 95% confidence
interval (CI) values for the prespecified end-points
were taken from the published reports [1, 4, 5, 7].
For the stratified subsets in MERIT-HF, the logrank test was used for the comparison of the two
randomized groups, and a Cox proportional hazards model was used to calculate relative risk with
95% CI. The number of patients needed to treat for
1 year to avoid one event included in a prespecified
end-point was estimated using the following formula: 1/(yearly event rate in placebo group yearly
event rate in the beta-blocker group). Yearly event
rate (expressed in percentage) was defined as
events multiplied by 100 divided by the total
number of patient-years of follow-up for the event
in question. Patient-years of follow-up were not
available for combined end-points in SENIORSSHF so these were estimated from reported data [6,
7]. Data indicated that the placebo mortality rate
(risk) was unexpectedly low in SENIORS-SHF
compared with the stratified MERIT-HF subset
(Fig. 1). To determine whether this could be
explained by a lower baseline risk as estimated
from baseline risk factors, a prognostic index was
compared between SENIORS-SHF and the stratified MERIT-HF subset. The index was based on
data from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) study,
which used baseline risk factors to predict mortality [10]. All analyses were by intention to treat.
Results
Comparison of stratified MERIT-HF subgroup and CIBIS-II
Table 1 shows that 2002 of the 3991 patients
randomly assigned to treatment in MERIT-HF fulfilled the CIBIS-II inclusion criteria (NYHA III or IV
and ejection fraction 0.35). Mean age was slightly
lower in CIBIS-II, compared with the MERIT-HF
CIBIS-II-like subset (61.0 and 64.2 years, respectively). Ejection fraction was 0.28 and 0.25, and
19% and 24% of patients were female, respectively.
Mean beta-blocker dose at last visit was 6.2 mg
bisoprolol once daily in CIBIS-II and 149 mg
metoprolol CR/XL once daily in the MERIT-HF
CIBIS-II-like subset.
J. Wikstrand et al.
Total Mortality
All Patients in NYHA III or IV with EF < 0.35
CIBIS II
Placebo vs. Bisoprolol
MERIT-HF
Placebo vs. Meto CR/XL
No./pat. yrs (%)
20.0
15.0
14.8
13.2
8.8
8.6
34%
P < 0.0001
42%
P < 0.0001
10.0
5.0
0.0
No of
Events:
228
156
142
87
Total Mortality
COPERNICUS
Placebo vs. Carvedilol
No./pat. yrs (%)
20.0
MERIT-HF
19.7
15.0
19.1
12.8
11.7
10.0
5.0
0.0
No of
Events:
35%
P = 0.0014
190
39%
P = 0.0086
130
72
45
Total Mortality
All Patients > 70 years with EF < 0.35
SENIORS
Placebo vs. Nebivolol
MERIT-HF
No./pat. yrs (%)
20.0
15.0
14.8
11.3
10.0
10.1
9.7
5.0
0.0
No of
Events:
16%
ns
135
115
32%
P = 0.038
68
49
Fig. 1 Bar charts illustrating yearly risk and risk reduction for all-cause mortality in CIBIS-II (upper panel),
COPERNICUS (middle panel) and SENIORS-SHF (lower
panel) compared in each panel with the respective stratified subsets from MERIT-HF.
In CIBIS-II, the placebo-corrected reduction in

heart rate with bisoprolol at 2 months was
9.6 bpm; the corresponding reduction with metoprolol CR/XL in the stratified MERIT-HF subgroup
at 2 months was 11.4 bpm.
In CIBIS-II, 228 patients died in the placebo
group and 156 in the bisoprolol group corresponding to a yearly mortality rate of 13.2% and
8.8%, respectively (relative risk reduction 34%,
95% CI: 1946, P < 0.0001; Fig. 1). Corresponding data for the stratified MERIT-HF subgroup
were 142 vs. 87 deaths and a yearly mortality rate
of 14.8% vs. 8.6% (42% risk reduction, 95%
CI: 2456, P < 0.0001). The number to treat for
1 year to save one life was 23 patients in CIBIS-II
and 16 patients in the stratified MERIT-HF subgroup.
In CIBIS-II, 510 patients died or were hospitalized
due to cardiovascular causes in the placebo group
and 408 in the bisoprolol group, corresponding to
a yearly event rate of 36.4% and 27.1%, respectively (risk reduction 25%, 95% CI: 1434,
P < 0.0001; Fig. 2). Corresponding data for the
stratified MERIT-HF subgroup were 365 and 285
events and a yearly event rate of 45.3% and
33.1%, respectively (27% risk reduction, 95% CI:
1437, P < 0.0001). The number to treat for 1 year
to avoid one event included in this combined endpoint was 11 patients in CIBIS-II and eight
patients in the stratified MERIT-HF subgroup.
In CIBIS-II, 383 patients died or were hospitalized
because of worsening heart failure in the placebo
group and 264 in the bisoprolol group corresponding to a yearly event rate of 28.6% vs. 18.2% (risk
reduction 36%, 95% CI: 2545, P < 0.0001; Fig. 3).
Corresponding data for the stratified MERIT-HF
subgroup were 285 and 202 events, with a yearly
event rate of 33.2% and 21.8%, respectively (34%
risk reduction, 95% CI: 2145, P < 0.0001). The
number to treat for 1 year to avoid one event
included in this combined end-point was 11
patients in CIBIS-II and nine patients in the
MERIT-HF CIBIS-II-like group.
In CIBIS-II, a similar number of patients discontinued randomized treatment in the bisoprolol
group compared with the placebo group (Table 2).
In the stratified MERIT-HF subgroup, 12% fewer
patients discontinued metoprolol CR/XL compared
with placebo (NS) (Table 2).
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J. Wikstrand et al.
Table 1 Baseline characteristics and drug treatment in the three different study groups reviewed. Inclusion criteria are:
CIBIS-II, NYHA class III or IV and ejection fraction 0.35 at randomization; COPERNICUS, NYHA class III or IV and ejection
fraction <0.25; and SENIORS subgroup with impaired left ventricular function (SENIORS-SHF), age 70 years and ejection
fraction 0.35. The MERIT-HF stratified subsets (MERIT-HFs) have been stratified for each of the other studies to accord with
these different criteria, respectively
CIBIS-II criteria
Characteristics
COPERNICUS criteria
SENIORS-SHF criteria
CIBIS-II
MERIT-HFs
COPERN
MERIT-HFs
SEN-SHF
MERIT-HFs
n = 2647
n = 2002
n = 2289
n = 795
n = 1359
n = 985
Mean age (SD) years
61.0 (11)
64.2 (9.7)
63.3 (11)
64.6 (9.7)
76.0 (4.7)
74.4 (2.8)
Female%
19
24
21
23
30
27
II
53
34
III
83
94
NA
91
42
61
IV
17
NA
5
25 (6)
NYHA class%
Ejection fraction%
28 (6)
25 (6)
20 (4)
19 (4)
29 (5)
SBP mmHg
130 (19)
128 (17)
123 (19)
124 (17)
136 (20)
132 (19)
DBP mmHg
80 (11)
78 (9)
76 (11)
77 (9)
79 (11)
76 (9)
81 (15)
84 (11)
83 (12)
85 (11)
79 (14)
81 (10)
25.7 (3.9)
Heart rate bpm

2
26.8 (4.1)
27.2 (4.8)
NA
26.5 (4.9)
26.7 (4.0)
104 (29)
109 (34)
134 (37)
112 (35)
106 (34)
117 (38)
Previous myocardial infarction%
55
50
NA
48
49
56
History of hypertension%
43
43
NA
41
53
44
History diabetes mellitus%
12
28
NA
25
27
24
Diuretics%
99
86
99
96
93
93
Digitalis%
52
69
66
70
43
62
ACE inhibitor%
96
88
NA
86
81
86
ARB%
NA
NA
10
10
Body mass index kg m
Serum creatinine lmol L
ACE inhibitor or ARB%
NA
96
97
95
NA
94
ASA%
41
45
NA
43
NA
49
Statin%
NA
22
NA
21
26
20
COPERN, COPERNICUS; SEN, SENIORS; NYHA, New York Heart Association; SBP, systolic blood pressure; DBP, diastolic
blood pressure; bpm, beats per min; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ASA, acetyl
salicylic acid (aspirin).
Comparison of stratified MERIT-HF subgroup and COPERNICUS

Table 1 shows that 795 of the 3991 patients randomly assigned to treatment in MERIT-HF fulfilled
the COPERNICUS inclusion criteria (NYHA III or IV
and ejection fraction <0.25). Mean age was similar in
COPERNICUS and MERIT-HF: 63.3 years and
64.6 years, respectively; ejection fraction was 0.20
and 0.19, and 21% and 23% of patients were female,
respectively (Table 1). Reported concomitant treatments at baseline were also similar. Mean betablocker dose at last visit was 18.75 mg carvedilol
138
twice daily and 148 mg metoprolol CR/XL once

daily, respectively.
Reduction in heart rate with carvedilol was not
reported in COPERNICUS; the reduction with
metoprolol CR/XL in the stratified MERIT-HF subgroup was 11.3 bpm at 2 months, 12.2 bpm at
3 months and 13.3 bpm at 6 months.
In COPERNICUS, 190 patients died in the placebo
group and 130 in the carvedilol group, corresponding to a yearly mortality rate of 19.7% and 12.8%,
J. Wikstrand et al.
Total Mortality/CV hospitalization
Total Mortality/CHF hospitalization
CIBIS II
MERIT-HF
CIBIS II
50.0
45.3
50.0
36.4
33.1
27.1
30.0
20.0
10.0
0.0
No of
Events:
No./pat. yrs (%)
No./pat. yrs (%)
60.0
40.0
40.0
30.0
510
408
27%
P < 0.0001
365
285
No of
Events:
COPERNICUS
30.2
35.7
20.0
10.0
0.0
No of
Events:
50.0
41.6
30.0
40.0
395
314
39%
P < 0.0001
175
118
No of
Events:
357
271
SENIORS
MERIT-HF
44.0
34.1
24.1
20.0
21.4
10.0
No./pat. yrs (%)
No./pat. yrs (%)
31%
P < 0.0001
44%
P < 0.0001
144
88
40.0
No of
Events:
24.9
MERIT-HF
50.0
50.0
0.0
25.5
60.0
30.0
MERIT-HF
10.0
SENIORS
202
20.0

285
44.6
37.9
30.0
0.0
27%
P < 0.0001
264
COPERNICUS
MERIT-HF
No./pat. yrs (%)
No./pat. yrs (%)
40.0
383
34%
P < 0.0001
58.1
60.0
36%
P < 0.0001

21.8
18.2
10.0
0.0
25%
P < 0.0001
33.2
28.6
20.0
50.0
MERIT-HF
40.0
31.4
30.0
20.0
16.5
10.0
0.0
14%
ns
247
218
22%
P = 0.026
173
143
Fig. 2 Bar charts illustrating yearly risk and risk reduction

for the combined end-point of all-cause mortality and
hospitalization due to cardiovascular causes (time to first
event) in CIBIS-II (upper panel), COPERNICUS (middle
panel) and SENIORS-SHF (lower panel) compared in each
panel with the respective stratified subsets from MERIT-HF.
22.4
15.6
No of
Events:
6%
ns
181
170
28%
P = 0.012
132
101
Fig. 3 Bar charts illustrating yearly risk and risk reduction for the combined end-point of all-cause mortality and
hospitalization because of worsening of congestive heart
failure (CHF; time to first event) in CIBIS-II (upper panel),
COPERNICUS (middle panel) and SENIORS-SHF (lower
panel) compared in each panel with the respective stratified subsets from MERIT-HF.
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J. Wikstrand et al.
Table 2 Number of patients who discontinued study drug during follow-up in CIBIS-II (bisoprolol), COPERNICUS (carvedilol),
SENIORS-SHF (nebivolol) and in the stratified (strat) subsets from MERIT-HF (metoprolol CR/XL)
End-point
Placebo, n
Beta-blocker, n
CIBIS-II
192
194
1.00 (0.821.22)
Relative risk (95% CI)
P-value
NS
MERIT-HF strat for CIBIS-II
174
159
0.88 (0.711.09)
NS
COPERNICUS
295
231
0.77 (0.620.96)
0.02
MERIT-HF strat for COPERNICUS
86
62
0.69 (0.500.96)
0.027
SENIORS-SHF
170
170
NA
NS
MERIT-HF strat for SENIORS-SHF
91
89
0.95 (0.711.27)
NS
respectively (risk reduction 35%, 95% CI: 1948,

P = 0.0014; Fig. 1). Corresponding data for the
stratified MERIT-HF COPERNICUS-like patients
were 72 and 45 deaths and a yearly mortality rate
of 19.1% and 11.7% (39% risk reduction, 95% CI:
1158, P = 0.0086). The number needed to treat for
1 year to save one life was 14 patients in both
studies.
In COPERNICUS, 395 patients died or were hospitalized due to cardiovascular causes in the placebo
group and 314 in the carvedilol group corresponding to a yearly event rate of 41.6% and 30.2%,
respectively (risk reduction 27%, 95% CI: 1637,
P < 0.0001; Fig. 2). Corresponding data for the
stratified MERIT-HF subset were 175 and 118
events, and a yearly event rate of 58.1% and
35.7%, respectively (39% risk reduction, 95% CI:
2251, P < 0.0001). The number to treat for 1 year
to avoid one event included in this combined endpoint was nine patients in COPERNICUS and five
patients in the stratified MERIT-HF subgroup.
In COPERNICUS, 357 patients died or were hospitalized because of worsening heart failure in the
placebo group and 271 in the carvedilol group
corresponding to a yearly event rate of 37.9% and
25.5%, respectively (risk reduction 31%, 95% CI:
1941, P < 0.0001; Fig. 3). Corresponding data for
the stratified MERIT-HF COPERNICUS-like
patients were 144 and 88 events, and a yearly
risk reduction, 95% CI: 2757%, P < 0.0001). The
included in this combined end-point was eight
patients in COPERNICUS and five patients in the
MERIT-HF COPERNICUS-like subgroup.
In COPERNICUS, 23% fewer patients discontinued
randomized treatment in the carvedilol group
compared with the placebo group (P = 0.02,
140
Table 2). Corresponding data for the matched

MERIT-HF subgroup showed that 31% fewer
patients discontinued metoprolol CR/XL compared
with placebo (P = 0.027, Table 2).
Comparison of stratified MERIT-HF subgroup and SENIORS-SHF
Table 1 shows that 985 of the 3991 patients
randomly allocated to treatment in MERIT-HF
fulfilled the SENIORS-SHF inclusion criteria (age
70 years and ejection fraction 0.35). Mean age in
SENIORS-SHF and MERIT-HF was 76.0 and
74.4 years, respectively; ejection fraction was
0.29 and 0.25, and 30% and 27% of patients were
female, respectively. Reported concomitant treatments at baseline were similar. Mean beta-blocker
dose at last visit was 7.4 mg nebivolol and 141 mg
metoprolol CR/XL once daily, respectively.
In SENIORS-SHF, the placebo-corrected reduction
in heart rate with nebivolol at 4 months was
8.8 bpm; the corresponding reduction with metoprolol CR/XL in the stratified MERIT-HF subgroup
at 3 months was 12.5 bpm and at 6 months was
12.8 bpm (heart rate was not recorded at 4 months
in MERIT-HF).
In SENIORS-SHF, 135 patients died in the placebo
group and 115 in the nebivolol group corresponding to a yearly mortality rate of 11.3% and 9.7%,
respectively (risk reduction 16%, NS; Fig. 1). Corresponding data for the stratified MERIT-HF subgroup were 68 and 49 deaths, and a yearly
mortality rate of 14.8% and 10.1%, respectively
(32% risk reduction, 95% CI: 253, P = 0.038). The
number to treat for 1 year to save one life was 63
patients in SENIORS-SHF (NS) and 21 patients in
the stratified MERIT-HF subgroup.
In SENIORS-SHF, 247 patients died or were hospitalized due to cardiovascular causes in the
J. Wikstrand et al.
MERIT-HF subset, 5% fewer patients discontinued

metoprolol CR/XL compared with placebo (NS,
Table 2).
placebo group and 218 in the nebivolol group

21.4%, respectively (risk reduction 14%, NS;
Fig. 2). Corresponding data for the matched
MERIT-HF subgroup were 173 and 143 events,
and a yearly event rate of 44.0% and 34.1%,
respectively (22% risk reduction, 95% CI: 338,
P = 0.026). The number to treat for 1 year to avoid
one event included in this combined end-point was
37 patients in SENIORS-SHF (NS) and 10 patients
in the stratified MERIT-HF subgroup.
Comparison of baseline risk in SENIORS-SHF and

the stratified MERIT-HF subgroup
The observed yearly total mortality rate in the
placebo arm was 11.3% in SENIORS-SHF and
14.8% in the stratified MERIT-HF subset; that is,
a 24% lower rate in SENIORS-SHF compared with
the MERIT-HF subset. A number of analyses were
performed to determine whether differences in
baseline risk factors (Table 1) could explain this
difference in yearly mortality rate observed during
follow-up (Table 3). The results showed that the
analysed baseline risk factors indicated an
expected 28% lower mortality rate in the placebo
group during follow-up in SENIORS-SHF compared with the stratified MERIT-HF placebo
subset.
In SENIORS-SHF, 181 patients died or were hospitalized because of worsening heart failure in the
placebo group and 170 in the nebivolol group
15.6%, respectively (risk reduction 6%, NS; Fig. 3).
Corresponding data for the matched MERIT-HF
subgroup were 132 and 101 events, and a yearly
risk reduction, 95% CI: 745, P = 0.012). The
included in this combined end-point was 111
patients in SENIORS-SHF (NS) and 11 patients in
the stratified MERIT-HF subgroup.
Discussion
Our attempt to stratify patients from MERIT-HF
with those in the other pivotal beta-blocker trials
resulted in subsets of patients with good correspondence with respect to baseline characteristics
and background treatment in CIBIS-II and COPERNICUS. However, the baseline characteristics of
patients in SENIORS-SHF indicated that they were
In SENIORS-SHF, similar number of patients discontinued randomized treatment in the nebivolol

group compared with the placebo group (170
patients in each group, Table 2). In the stratified
Table 3 Estimation of relative follow-up risk of total mortality in placebo group comparing SENIORS-SHF with MERIT-HF
subgroup stratified for SENIORS-SHF inclusion criteria (age 70 years and ejection fraction 0.35). Follow-up risk has been
defined from several predefined baseline risk factors (see Methods)
Variables
SEN-SHF
MERIT-HF
n = 1 359
n = 985
Delta-value
b-coeffa
Productb
Age/10 years
7.6
7.44
0.16
0.258
0.0413
Female sex
0.30
0.27
0.03
0.166
0.00497
0.66
0.22
0.286
0.0629
4.00
0.0321
0.128
NYHA class III/IV
0.44
Ejection fraction
29
25
Systolic blood pressure/10 mmHg
13.6
13.2
0.40
0.00455
0.0182
7.9
8.1
0.20
0.117
0.0235
26.7
25.7
1.00
0.0554
0.0554
10.6
11.7
1.10
0.0782
0.0860
0.030
0.309
Heart rate/10 bpm

BMI kg m
Serum creatinine/10 lmol L

Diabetes mellitus
0.27
0.24
0.00927
Global sum
0.329
Hazard ratio
0.72
SEN, SENIORS; coeff, coefficient; NYHA, New York Heart Association; bpm, beats per min; BMI, body mass index.
a
From the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) study, which used baseline risk factors
to predict mortality (10).
b
Delta-value multiplied by b-coefficient.
141
J. Wikstrand et al.
at lower risk of death compared with the stratified

MERIT-HF subgroup (see below). The MERIT-HF
subsets were sufficiently large to provide robust
estimates of event rates and treatment effects. We
found important similarities and differences in
both the clinical outcomes examined and in the
effects of the different beta-blockers tested.
First with regard to clinical outcomes, the most
objective end-point (and the one least influenced by
local practice), all-cause mortality, normalized for
duration of follow-up, was remarkably similar in the
subsets of stratified patients in MERIT-HF compared
with CIBIS-II and COPERNICUS. However, mortality
rate in the placebo group was lower in SENIORS-SHF
(11.3%) than in the stratified MERIT-HF subset
(14.8%). One explanation for this discrepancy is very
likely to be differences in baseline risk factors
(Tables 1 and 3). Our analyses using predefined
important baseline risk factors for mortality indicated a 28% lower baseline risk in SENIORS-SHF
patients (see Table 3), which is consistent with the
24% lower mortality rate in the placebo arm compared with the stratified MERIT-HF subset observed
during follow-up (Fig. 1, lower panel).
There was less agreement between event rates in
the matched CIBIS-II-like and COPERNICUS-like
cohorts within MERIT-HF and the patients in
CIBIS-II and COPERNICUS, respectively, for the
composite of all-cause death or hospitalization due
to cardiovascular causes, possibly because of
varying definitions of what was meant by cardiovascular in each trial and different practices in the
participating countries. There was much more
consistency for the composite of all-cause mortality
or hospitalization because of heart failure amongst
these three trials, reflecting the more homogenous
definition of hospitalization for heart failure. However, once again SENIORS-SHF had much lower
event rates in the placebo arm than the stratified
MERIT-HF placebo subset (e.g. the rate in the
placebo arm of the composite of death or hospitalization because of heart failure, time to first event,
was 47% lower than in the stratified MERIT-HF
subset, 16.5% vs. 31.4%, Fig. 3, lower panel). The
close correlation between the event rates in
matched patients in MERIT-HF, CIBIS-2 and
COPERNICUS suggests that SENIORS-SHF is the
outlier, for reasons that are commented upon
above (lower baseline risk).
The same general pattern was apparent with
respect to the beneficial effects of treatment. The
142
large reductions in all-cause mortality with metoprolol CR/XL in CIBIS-II-like and COPERNICUSlike patients in MERIT-HF were similar to those of
bisoprolol and carvedilol in CIBIS-II and COPERNICUS, respectively. This finding was consistent
for the other efficacy outcomes examined, with
particularly large relative and absolute risk reductions in COPERNICUS-like patients.
However, these findings contrasted strikingly with
those for the comparison between SENIORSSHF-like patients in MERIT-HF and patients in
SENIORS-SHF. Whereas treatment with metoprolol CR/XL reduced each of the efficacy outcomes significantly, no outcome was significantly
improved with nebivolol. This difference could not
be explained on the basis of inadequate statistical
power as the number of patients experiencing each
outcome was considerably larger in the subset from
the SENIORS-SHF; there were 250 deaths amongst
patients in SENIORS-SHF compared with 117 in
the stratified subgroup of patients from MERIT-HF.
One potentially relevant difference, however, was
in the reduction in heart rate obtained with nebivolol (placebo-corrected decrease of 8.8 bpm at
4 months in SENIORS) compared with metoprolol
CR/XL (decrease in 12.5 bpm at 3 months and
12.8 bpm at 6 months in SENIORS-like patients in
MERIT-HF) as the degree of reduction in heart rate
seems to be associated with the magnitude of
clinical benefit of beta-blockers [11].
Study-drug tolerability differed between trials but
less so amongst the patient cohorts; for example,
discontinuations from randomized treatment in the
placebo group in the COPERNICUS-like, CIBISII-like and SENIORS-SHF-like subsets from
MERIT-HF were very similar. Remarkably, the
discontinuation rates for bisoprolol in CIBIS-II,
carvedilol in COPERNICUS and metoprolol CR/XL
in the corresponding stratified patient cohorts were
lower than in the corresponding placebo groups. Of
note, discontinuation of active therapy was significantly less than that of placebo in those with the
most advanced heart failure (i.e. COPERNICUSlike patients). However, again, nebivolol proved to
be the exception, with a similar discontinuation
rate in the active therapy and placebo groups in
SENIORS-SHF.
Our study has a number of limitations. First, direct
comparisons are preferable to indirect comparisons; realistically, however, a trial of comparison to
evidence-based beta-blockers is unlikely to be
J. Wikstrand et al.
conducted. Secondly, stratification of patients in

MERIT-HF to those in the other trials was based
only on two variables (NYHA class and ejection
fraction in CIBIS-II and COPERNICUS; age and
ejection fraction in SENIORS-SHF), although the
patients in the resultant MERIT-HF cohorts were in
fact quite similar to those in CIBIS-II and COPERNICUS and, for three of these trials, the mortality
rates were also similar. Finally, we were only able
to compare patients in MERIT-HF with the subgroup of SENIORS patients with systolic heart
failure. Arguably, this could have resulted in
reduced power to observe an effect of nebivolol
but the number of events in SENIORS-SHF was
still larger than in the corresponding subset of
patients from MERIT-HF in which a clear benefit of
metoprolol CR/XL was demonstrated.
In conclusion, the efficacy and tolerability of bisoprolol, carvedilol and metoprolol CR/XL are similar
in patients with systolic heart failure, irrespective
of NYHA class or ejection fraction. Nebivolol is less
effective and is not better tolerated.
Conflict of interest statement

JW was formerly a scientific advisor on cardiovascular research to AstraZeneca, M
olndal, Sweden.
JJVMcM was involved in other trials sponsored by
AstraZeneca (CHARM and CORONA) for which his
employer, Glasgow University, was paid for his time
spent as an Executive Committee member. HW was
a member of the Executive Committees of MERITHF and CORONA for which he received consulting
fees. DC has no conflicts of interest to declare.
References
1 CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS II). Lancet 1999; 353: 913.
2 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: 20017.
3 Hjalmarson
A, Goldstein S, Fagerberg Bet al. for the MERIT-HF study Group. Effects of controlled-release metoprolol
10
11
on total mortality, hospitalizations, and well-being in patients

with heart failure. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA
2000; 283: 1295302.
Packer M, Coats AJS, Fowler MB et al. for the Carvedilol
Prospective Randomized Cumulative Survival Study Group.
Effect of carvedilol on survival in severe chronic heart failure.
N Engl J Med 2001; 344: 16518.
Packer M, Fowler MB, Roecker EB et al. for Carvedilol
Prospective Randomized Cumulative Survival (COPERNICUS)
Study Group. Effect of carvedilol on the morbitity of patients
with severe chronic heart failure. Circulation 2002; 106:
21949.
Flather MD, Shibata MC, Coats JS et al. for the SENIORS
Investigators. Randomized trial to determine the effect of
nebivolol on mortality and cardiovascular hospital admission
in elderly patients with heart failure (SENIORS). Eur Heart J
2005; 26: 21525.
Veldhuisen DJ, Cohen-Solal A, B
ohm M et al. on behalf of the
SENIORS investigators. Beta-blockade with nebivolol in
elderly heart failure patients with impaired and preserved
left ventricular ejection fraction. J Am Coll Cardiol 2009; 53:
21508.
Ghali JK, Wikstrand J, Veldhuisen DJ et al. for the MERIT-HF study group. The influence of renal function on clinical
outcome and response to beta-blockade in systolic heart
failure. J Cardiac Fail 2009; 15: 3108.
Wikstrand J, Andersson B, Kendall MJ, Stanbrook H, Klibaner M. Pharmacokinetic considerations of formulation:
extended-release metoprolol succinate in the treatment of
heart failure. J Cardiovasc Pharmacol 2003; 41: 1517.
Wedel H, McMurray JJV, Lindberg M et al. for the CORONA
Study Group. Predictors of fatal and nonfatal outcomes in the
Controlled Rosuvastatin Multinational trial in heart failure
(CORONA): incremental value of apolipoprotein A-1,
high-sensitivity C-reactive peptide and N-terminal pro B-type
natriuretic peptide. Eur J of Heart Fail 2009; 11: 28191.
Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of
randomized controlled trials on the effect of magnitude of
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Cardiol 2008; 101: 8659.
Correspondence: Dr John Wikstrand, Wallenberg Laboratory

for Cardiovascular Research, Sahlgrenska University Hospital,
SE-413 45 Gothenburg, Sweden.
(e-mail: john.wikstrand@wlab.gu.se).
and
Professor John McMurray, BHF Cardiovascular Research Centre,
126 University Place, Glasgow, G12 8TA, UK.
(e-mail: john.mcmurray@glasgow.ac.uk)
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Wikstrand Et Al-2014-Journal of Internal Medicine

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Original Article

The large-scale placebo-controlled beta-blocker studies in

Abstract. Wikstrand J, Wedel H, Castagno D,

Results. The annual mortality rates in the placebo and

in outcome and were subsequently approved and

the Study of the Effects of nebivolol Intervention on

Beta-blockers in systolic HF revisited

[defined as any combination of diuretics and an

heart rate <60 bpm as well as renal failure (serum

Beta-blockers in systolic HF revisited

and, if tolerated, the nebivolol dose was increased

Beta-blockers in systolic HF revisited

Placebo vs. Bisoprolol

Placebo vs. Meto CR/XL

No./pat. yrs (%)

Placebo vs. Carvedilol

No./pat. yrs (%)

Placebo vs. Meto CR/XL

Placebo vs. Nebivolol

Placebo vs. Meto CR/XL

No./pat. yrs (%)

In CIBIS-II, the placebo-corrected reduction in

Beta-blockers in systolic HF revisited

Mean age (SD) years

Heart rate bpm

Previous myocardial infarction%

History diabetes mellitus%

Body mass index kg m

Serum creatinine lmol L

ACE inhibitor or ARB%

Comparison of stratified MERIT-HF subgroup and COPERNICUS

twice daily and 148 mg metoprolol CR/XL once

Beta-blockers in systolic HF revisited

Total Mortality/CV hospitalization

Total Mortality/CHF hospitalization

All Patients in NYHA III or IV with EF < 0.35

All Patients in NYHA III or IV with EF < 0.35

Placebo vs. Bisoprolol

Placebo vs. Meto CR/XL

Placebo vs. Bisoprolol

No./pat. yrs (%)

No./pat. yrs (%)

Placebo vs. Carvedilol

Placebo vs. Nebivolol

No./pat. yrs (%)

No./pat. yrs (%)

All Patients > 70 years with EF < 0.35

Placebo vs. Meto CR/XL

Placebo vs. Meto CR/XL

Total Mortality/CHF hospitalization

Placebo vs. Meto CR/XL

All Patients > 70 years with EF < 0.35

Total Mortality/CV hospitalization

Placebo vs. Meto CR/XL

No./pat. yrs (%)

No./pat. yrs (%)

Total Mortality/CHF hospitalization

All Patients in NYHA III or IV with EF < 0.25

All Patients in NYHA III or IV with EF < 0.25

Total Mortality/CV hospitalization

Placebo vs. Meto CR/XL

Fig. 2 Bar charts illustrating yearly risk and risk reduction

Beta-blockers in systolic HF revisited

Relative risk (95% CI)