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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, Results. The annual mortality rates in the placebo and
McMurray JJV (Gothenburg University; Nordic beta-blocker arms were: (i) CIBIS-II (n = 2647),
School of Public Health, Gothenburg, Sweden; 13.2% vs. 8.8% (relative risk reduction 34%, 95%
University of Turin, Turin, Italy; University of CI: 1946, P < 0.0001) and MERIT-HFs (n = 2002),
Glasgow, Glasgow, UK). The large-scale placebo- 14.8% vs. 8.6% (relative risk reduction 42%, 95% CI:
controlled beta-blocker studies in systolic heart 2456, P < 0.0001); (ii) COPERNICUS (n = 2289),
failure revisited: results from CIBIS-II, COPERNICUS 19.7% vs. 12.8% (relative risk reduction 35%, 95%
and SENIORS-SHF compared with stratified subsets CI: 1948, P = 0.0014) and MERIT-HFs (n = 795),
from MERIT-HF. J Intern Med 2014; 275: 134143. 19.1% vs. 11.7% (relative risk reduction 39%; 95%
CI: 1158, P = 0.0086); (iii) SENIORS-SHF (n =
Aims. The four pivotal beta-blocker trials in heart 1359), 11.3% vs. 9.7% (relative risk reduction
failure (HF) had different inclusion criteria, making 16%, NS) and MERIT-HFs (n = 985), 14.8% vs.
comparison difficult without patient stratifying. The 10.1% (relative risk reduction 32%, 95% CI: 253,
aim of this study was to compare, in similar patients, P = 0.038). The effects on the other outcomes
the effects of bisoprolol, metoprolol controlled assessed were similar. Analyses indicated fewer
release/extended release (CR/XL), carvedilol and discontinuations from randomized treatment on
nebivolol on (i) total mortality, (ii) all-cause mortality beta-blockers compared with placebo in COPERNI-
or hospitalization due to cardiovascular causes (time CUS and the MERIT-HFs subsets.
to first event), (iii) all-cause mortality or hospitaliza-
tion because of HF and (iv) tolerability, defined as Conclusion. The efficacy and tolerability of bisoprolol,
discontinuation of randomized treatment. carvedilol and metoprolol CR/XL are similar in
patients with systolic HF, irrespective of NYHA
Methods. We compared stratified (s) subsets in class or ejection fraction. Nebivolol is less effective
MERIT-HF with patients in CIBIS-II [New York and not better tolerated.
Heart Association (NYHA) class III/IV and ejection
fraction (EF) 35%] and COPERNICUS (NYHA III/ Keywords: beta-blockers, clinical trials, heart failure.
IV and EF <25%) and in patients with systolic HF in
SENIORS-SHF (age 70 years and EF 35%).

in outcome and were subsequently approved and


Introduction
marketed for the treatment of heart failure. The key
Beta-blockers have, without doubt, been one of the trials were the second Cardiac Insufficiency Biso-
pivotal therapeutic advances in the management of prolol Study (CIBIS-II, n = 2647) [1], the Metoprolol
patients with heart failure. In landmark clinical CR/XL Randomized Intervention Trial in Congestive
trials, the four agents bisoprolol, metoprolol succi- Heart Failure (MERIT-HF, n = 3991) [2, 3], the
nate controlled release/extended release (CR/XL), Carvedilol Prospective Randomized Cumulative
carvedilol and nebivolol demonstrated improvement Survival Trial (COPERNICUS, n = 2289) [4, 5] and

134 2013 The Association for the Publication of the Journal of Internal Medicine
J. Wikstrand et al. Beta-blockers in systolic HF revisited

the Study of the Effects of nebivolol Intervention on [defined as any combination of diuretics and an
Outcomes and Rehospitalization in Seniors with angiotensin-converting enzyme (ACE) inhibitor or
Heart Failure Trial (SENIORS, n = 2128) [6, 7]. The an angiotensin receptor blocker (ARB)] and ejec-
characteristics of patients included, however, dif- tion fraction 0.40 [2, 3]. To achieve a large
fered in each of these trials (i.e. due to differing proportion of randomly assigned patients at high
inclusion and exclusion criteria), particularly with risk, the protocol stated that the investigators
respect to age, symptom severity, as assessed by should aim to include less than 40% of patients
New York Heart Association (NYHA) class, and left in NYHA class II (i.e. more than 60% in NYHA III or
ventricular ejection fraction. Notably, whereas three IV). Patients with ejection fractions between 0.36
of the four trials enrolled only patients with systolic and 0.40 were included only if their maximum
heart failure [15], SENIORS also included patients walking distance was 450 m (500 yards) during a
with preserved ejection fraction [6, 7]. SENIORS also 6-min walk test.
had a different primary end-point [a composite of all-
cause mortality or hospitalization due to cardiovas- Important exclusion criteria. The exclusion criteria
cular causes (time to first event)] compared with the in this study were acute myocardial infarction or
other trials (which had all-cause mortality as the unstable angina within 28 days before randomiza-
primary outcome), and secondary outcomes also tion, indication or contraindication for treatment
varied amongst these trials. Consequently, assess- with beta1-blockade, heart failure secondary to
ment of the relative efficacy and tolerability of these systemic disease or alcohol abuse, unstable
evidence-based beta-blockers is difficult as like- decompensated heart failure (pulmonary oedema
with-like comparison is not possible from the pub- or hypoperfusion), supine systolic blood pressure
lished data. Therefore, we have used original data <100 mmHg, heart rate <68 beats per min (bpm) at
from the largest of the trials, MERIT-HF, to create enrolment and other serious disorders that might
stratified subsets of patients of sufficient size to complicate management during follow-up. There
enable such comparisons to be made; outcomes were no exclusion criteria related to the level of
were compared between CIBIS-II-like and COPER- serum creatinine at baseline [8].
NICUS-like patients in MERIT-HF and patients in
the CIBIS-II and COPERNICUS trials, respectively. Randomized treatment. After a single-blind pla-
Similarly, original data from both MERIT-HF and cebo run-in phase of 2 weeks, patients were ran-
SENIORS [7] were used to create a common subset of domly assigned to metoprolol CR/XL [9] or placebo
older patients with systolic heart failure for com- with starting doses of 12.5 or 25 mg once daily.
parison. We focused on all-cause mortality (the The lower starting dose was recommended for
primary end-point in CIBIS-II, COPERNICUS and patients in NYHA class III/IV. The study protocol
MERIT-HF), the composite of all-cause mortality or stated that the dose should be doubled every
hospitalization due to cardiovascular causes, anal- second week to a target of 200 mg once daily, or
ysed as time to first event (the primary end-point in the highest tolerated dose. The titration schedule
SENIORS), all-cause death or hospitalization could be modified according to written guidelines,
because of heart failure (a commonly used dis- and at the discretion of the investigator.
ease-specific end-point in heart failure trials) and
discontinuation of study drug (to assess tolerabil-
Cardiac Insufficiency Bisoprolol Study-II (n = 2647)
ity), using original data from each trial to create this
common set of outcomes for all comparisons. Important inclusion criteria. The important inclu-
sion 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
Methods
optimal standard therapy, defined as any combi-
Study patients and randomized treatment nation of diuretics and an ACE inhibitor (or ARB)
[1].
Metoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure (n = 3991)
Important exclusion criteria. The exclusion criteria
Important inclusion criteria. The important inclu- in this study were similar to those applied in
sion criteria in the MERIT-HF study were age MERIT-HF. In addition, according to the protocol,
4080 years, NYHA class IIIV for 3 months before
randomization despite optimal standard therapy

2013 The Association for the Publication of the Journal of Internal Medicine 135
Journal of Internal Medicine, 2014, 275; 134143
J. Wikstrand et al. Beta-blockers in systolic HF revisited

heart rate <60 bpm as well as renal failure (serum and, if tolerated, the nebivolol dose was increased
creatinine >300 lmol L 1) were exclusion criteria. to 2.5 and 5 mg, every 12 weeks, reaching a
target of 10 mg once daily over a maximum of
Randomized treatment. Patients were started on 16 weeks.
bisoprolol 1.25 mg or placebo once daily, and the dose
of bisoprolol was increased successively to 2.5, 3.75,
Statistical analyses
5, 7.5 and 10 mg according to tolerance. Patients
received the first three concentrations for 1 week For CIBIS-II, COPERNICUS and SENIORS-SHF,
each, and the higher concentrations for 4 weeks. P-values, point estimates and 95% confidence
interval (CI) values for the prespecified end-points
Carvedilol Prospective Randomized Cumulative Sur- were taken from the published reports [1, 4, 5, 7].
vival Trial (n = 2289) For the stratified subsets in MERIT-HF, the log-
rank test was used for the comparison of the two
Important inclusion criteria. The important inclu-
randomized groups, and a Cox proportional haz-
sion criteria in the COPERNICUS study were symp-
ards model was used to calculate relative risk with
toms of severe heart failure (equated in this analysis
95% CI. The number of patients needed to treat for
to NYHA class III or IV), ejection fraction <0.25 and
1 year to avoid one event included in a prespecified
optimal standard therapy, defined as any combina-
end-point was estimated using the following for-
tion of diuretics and an ACE inhibitor (or ARB) [4, 5].
mula: 1/(yearly event rate in placebo group yearly
event rate in the beta-blocker group). Yearly event
Important exclusion criteria. The exclusion criteria
rate (expressed in percentage) was defined as
in this study were similar to those applied in MERIT-
events multiplied by 100 divided by the total
HF. However, contraindication to beta-blockade
number of patient-years of follow-up for the event
referred to nonselective beta-blockade and systolic
in question. Patient-years of follow-up were not
blood pressure to <85 mmHg. In addition, severe
available for combined end-points in SENIORS-
pulmonary, renal (serum creatinine >247 lmol L 1)
SHF so these were estimated from reported data [6,
or hepatic disease were exclusion criteria.
7]. Data indicated that the placebo mortality rate
(risk) was unexpectedly low in SENIORS-SHF
Randomized treatment. Patients were started on
compared with the stratified MERIT-HF subset
3.125 mg carvedilol or matching placebo twice
(Fig. 1). To determine whether this could be
daily for 2 weeks, and the carvedilol dose was then
explained by a lower baseline risk as estimated
increased at 2-week intervals (if tolerated), first to
from baseline risk factors, a prognostic index was
6.25 mg, then to 12.5 mg and finally to a target
compared between SENIORS-SHF and the strati-
dose of 25 mg twice daily.
fied MERIT-HF subset. The index was based on
data from the Controlled Rosuvastatin Multina-
SENIORS subgroup with impaired left ventricular
tional Trial in Heart Failure (CORONA) study,
function (n = 1359 with systolic heart failure,
which used baseline risk factors to predict mortal-
referred to as SENIORS-SHF)
ity [10]. All analyses were by intention to treat.
Important inclusion criteria. The important inclu-
sion criteria in the SENIORS-SHF study were age Results
70 years, ejection fraction 0.35 within the last
Comparison of stratified MERIT-HF subgroup and CIBIS-II
6 months and optimal standard therapy, defined
as any combination of diuretics and an ACE Table 1 shows that 2002 of the 3991 patients
inhibitor (or ARB) [6, 7]. randomly assigned to treatment in MERIT-HF ful-
filled the CIBIS-II inclusion criteria (NYHA III or IV
Important exclusion criteria. The exclusion criteria and ejection fraction 0.35). Mean age was slightly
in this study were similar to those applied in CIBIS- lower in CIBIS-II, compared with the MERIT-HF
II, but systolic blood pressure <90 mmHg and renal CIBIS-II-like subset (61.0 and 64.2 years, respec-
failure denoted by serum creatinine 250 lmol L 1. tively). Ejection fraction was 0.28 and 0.25, and
In addition, significant hepatic dysfunction was an 19% and 24% of patients were female, respectively.
exclusion criterion in SENIORS-SHF. Mean beta-blocker dose at last visit was 6.2 mg
bisoprolol once daily in CIBIS-II and 149 mg
Randomized treatment. Patients were started on metoprolol CR/XL once daily in the MERIT-HF
1.25 mg nebivolol or matching placebo once daily CIBIS-II-like subset.

136 2013 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 275; 134143
J. Wikstrand et al. Beta-blockers in systolic HF revisited

Total Mortality In CIBIS-II, the placebo-corrected reduction in


All Patients in NYHA III or IV with EF < 0.35 heart rate with bisoprolol at 2 months was
CIBIS II MERIT-HF 9.6 bpm; the corresponding reduction with meto-
Placebo vs. Bisoprolol Placebo vs. Meto CR/XL prolol CR/XL in the stratified MERIT-HF subgroup
at 2 months was 11.4 bpm.
20.0
14.8
No./pat. yrs (%)

15.0 13.2 In CIBIS-II, 228 patients died in the placebo


group and 156 in the bisoprolol group corre-
10.0 8.8 8.6 sponding to a yearly mortality rate of 13.2% and
8.8%, respectively (relative risk reduction 34%,
5.0 95% CI: 1946, P < 0.0001; Fig. 1). Correspond-
ing data for the stratified MERIT-HF subgroup
0.0
34% 42% were 142 vs. 87 deaths and a yearly mortality rate
No of P < 0.0001 P < 0.0001 of 14.8% vs. 8.6% (42% risk reduction, 95%
Events: 228 156 142 87 CI: 2456, P < 0.0001). The number to treat for
1 year to save one life was 23 patients in CIBIS-II
Total Mortality and 16 patients in the stratified MERIT-HF sub-
All Patients in NYHA III or IV with EF < 0.25 group.
COPERNICUS MERIT-HF
Placebo vs. Carvedilol Placebo vs. Meto CR/XL In CIBIS-II, 510 patients died or were hospitalized
19.7
due to cardiovascular causes in the placebo group
20.0 19.1
and 408 in the bisoprolol group, corresponding to
No./pat. yrs (%)

15.0
a yearly event rate of 36.4% and 27.1%, respec-
12.8
11.7 tively (risk reduction 25%, 95% CI: 1434,
10.0 P < 0.0001; Fig. 2). Corresponding data for the
stratified MERIT-HF subgroup were 365 and 285
5.0 events and a yearly event rate of 45.3% and
33.1%, respectively (27% risk reduction, 95% CI:
0.0
35% 39% 1437, P < 0.0001). The number to treat for 1 year
No of P = 0.0014 P = 0.0086 to avoid one event included in this combined end-
Events: 190 130 72 45 point was 11 patients in CIBIS-II and eight
patients in the stratified MERIT-HF subgroup.
Total Mortality
All Patients > 70 years with EF < 0.35 In CIBIS-II, 383 patients died or were hospitalized
because of worsening heart failure in the placebo
SENIORS MERIT-HF
Placebo vs. Nebivolol Placebo vs. Meto CR/XL group and 264 in the bisoprolol group correspond-
ing to a yearly event rate of 28.6% vs. 18.2% (risk
20.0 reduction 36%, 95% CI: 2545, P < 0.0001; Fig. 3).
14.8 Corresponding data for the stratified MERIT-HF
No./pat. yrs (%)

15.0
11.3 subgroup were 285 and 202 events, with a yearly
9.7 10.1
10.0 event rate of 33.2% and 21.8%, respectively (34%
risk reduction, 95% CI: 2145, P < 0.0001). The
5.0 number to treat for 1 year to avoid one event
included in this combined end-point was 11
0.0
16% 32% patients in CIBIS-II and nine patients in the
ns P = 0.038 MERIT-HF CIBIS-II-like group.
No of
Events: 135 115 68 49
In CIBIS-II, a similar number of patients discon-
tinued randomized treatment in the bisoprolol
Fig. 1 Bar charts illustrating yearly risk and risk reduc-
group compared with the placebo group (Table 2).
tion for all-cause mortality in CIBIS-II (upper panel),
COPERNICUS (middle panel) and SENIORS-SHF (lower In the stratified MERIT-HF subgroup, 12% fewer
panel) compared in each panel with the respective strat- patients discontinued metoprolol CR/XL compared
ified subsets from MERIT-HF. with placebo (NS) (Table 2).

2013 The Association for the Publication of the Journal of Internal Medicine 137
Journal of Internal Medicine, 2014, 275; 134143
J. Wikstrand et al. Beta-blockers in systolic HF revisited

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 COPERNICUS criteria SENIORS-SHF criteria


CIBIS-II MERIT-HFs COPERN MERIT-HFs SEN-SHF MERIT-HFs
Characteristics 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
NYHA class%
I 0 0 0 0 3 0
II 0 0 0 0 53 34
III 83 94 NA 91 42 61
IV 17 6 NA 9 2 5
Ejection fraction% 28 (6) 25 (6) 20 (4) 19 (4) 29 (5) 25 (6)
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)
Heart rate bpm 81 (15) 84 (11) 83 (12) 85 (11) 79 (14) 81 (10)
2
Body mass index kg m 26.8 (4.1) 27.2 (4.8) NA 26.5 (4.9) 26.7 (4.0) 25.7 (3.9)
Serum creatinine lmol L 1
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 8 NA 10 10 8
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).

twice daily and 148 mg metoprolol CR/XL once


Comparison of stratified MERIT-HF subgroup and COPERNICUS
daily, respectively.
Table 1 shows that 795 of the 3991 patients ran-
domly assigned to treatment in MERIT-HF fulfilled Reduction in heart rate with carvedilol was not
the COPERNICUS inclusion criteria (NYHA III or IV reported in COPERNICUS; the reduction with
and ejection fraction <0.25). Mean age was similar in metoprolol CR/XL in the stratified MERIT-HF sub-
COPERNICUS and MERIT-HF: 63.3 years and group was 11.3 bpm at 2 months, 12.2 bpm at
64.6 years, respectively; ejection fraction was 0.20 3 months and 13.3 bpm at 6 months.
and 0.19, and 21% and 23% of patients were female,
respectively (Table 1). Reported concomitant treat- In COPERNICUS, 190 patients died in the placebo
ments at baseline were also similar. Mean beta- group and 130 in the carvedilol group, correspond-
blocker dose at last visit was 18.75 mg carvedilol ing to a yearly mortality rate of 19.7% and 12.8%,

138 2013 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 275; 134143
J. Wikstrand et al. 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
CIBIS II MERIT-HF CIBIS II MERIT-HF
Placebo vs. Bisoprolol Placebo vs. Meto CR/XL Placebo vs. Bisoprolol Placebo vs. Meto CR/XL

60.0 50.0
50.0 45.3 40.0

No./pat. yrs (%)


No./pat. yrs (%)

33.2
40.0 36.4 33.1 28.6
30.0
30.0 27.1 21.8
20.0 18.2
20.0
10.0
10.0
0.0
0.0 36% 34%
25% 27%
No of P < 0.0001 P < 0.0001
No of P < 0.0001 P < 0.0001
Events: 383 264 285 202
Events: 510 408 365 285

Total Mortality/CV hospitalization 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

COPERNICUS MERIT-HF COPERNICUS MERIT-HF


Placebo vs. Carvedilol Placebo vs. Meto CR/XL Placebo vs. Carvedilol Placebo vs. Meto CR/XL

60.0 58.1 50.0 44.6


50.0 40.0 37.9
No./pat. yrs (%)
No./pat. yrs (%)

41.6
40.0 30.0 25.5 24.9
30.2 35.7
30.0 20.0
20.0
10.0
10.0
0.0
0.0 31% 44%
27% 39%
No of P < 0.0001 P < 0.0001
No of P < 0.0001 P < 0.0001
Events: 357 271 144 88
Events: 395 314 175 118
Total Mortality/CHF hospitalization
Total Mortality/CV hospitalization
All Patients > 70 years with EF < 0.35 All Patients > 70 years with EF < 0.35

SENIORS MERIT-HF SENIORS MERIT-HF


Placebo vs. Nebivolol Placebo vs. Meto CR/XL
Placebo vs. Nebivolol Placebo vs. Meto CR/XL
50.0
60.0
40.0
No./pat. yrs (%)

50.0 44.0
No./pat. yrs (%)

31.4
40.0 34.1 30.0
22.4
30.0 24.1 20.0 16.5 15.6
21.4
20.0 10.0
10.0
0.0
0.0 6% 28%
14% 22% ns P = 0.012
No of
No of ns P = 0.026
Events: 181 170 132 101
Events: 247 218 173 143
Fig. 3 Bar charts illustrating yearly risk and risk reduc-
Fig. 2 Bar charts illustrating yearly risk and risk reduction tion for the combined end-point of all-cause mortality and
for the combined end-point of all-cause mortality and hospitalization because of worsening of congestive heart
hospitalization due to cardiovascular causes (time to first failure (CHF; time to first event) in CIBIS-II (upper panel),
event) in CIBIS-II (upper panel), COPERNICUS (middle COPERNICUS (middle panel) and SENIORS-SHF (lower
panel) and SENIORS-SHF (lower panel) compared in each panel) compared in each panel with the respective strat-
panel with the respective stratified subsets from MERIT-HF. ified subsets from MERIT-HF.

2013 The Association for the Publication of the Journal of Internal Medicine 139
Journal of Internal Medicine, 2014, 275; 134143
J. Wikstrand et al. Beta-blockers in systolic HF revisited

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 Relative risk (95% CI) P-value


CIBIS-II 192 194 1.00 (0.821.22) 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, Table 2). Corresponding data for the matched
P = 0.0014; Fig. 1). Corresponding data for the MERIT-HF subgroup showed that 31% fewer
stratified MERIT-HF COPERNICUS-like patients patients discontinued metoprolol CR/XL compared
were 72 and 45 deaths and a yearly mortality rate with placebo (P = 0.027, Table 2).
of 19.1% and 11.7% (39% risk reduction, 95% CI:
1158, P = 0.0086). The number needed to treat for
Comparison of stratified MERIT-HF subgroup and SENIORS-SHF
1 year to save one life was 14 patients in both
studies. Table 1 shows that 985 of the 3991 patients
randomly allocated to treatment in MERIT-HF
In COPERNICUS, 395 patients died or were hospi- fulfilled the SENIORS-SHF inclusion criteria (age
talized due to cardiovascular causes in the placebo 70 years and ejection fraction 0.35). Mean age in
group and 314 in the carvedilol group correspond- SENIORS-SHF and MERIT-HF was 76.0 and
ing to a yearly event rate of 41.6% and 30.2%, 74.4 years, respectively; ejection fraction was
respectively (risk reduction 27%, 95% CI: 1637, 0.29 and 0.25, and 30% and 27% of patients were
P < 0.0001; Fig. 2). Corresponding data for the female, respectively. Reported concomitant treat-
stratified MERIT-HF subset were 175 and 118 ments at baseline were similar. Mean beta-blocker
events, and a yearly event rate of 58.1% and dose at last visit was 7.4 mg nebivolol and 141 mg
35.7%, respectively (39% risk reduction, 95% CI: metoprolol CR/XL once daily, respectively.
2251, P < 0.0001). The number to treat for 1 year
to avoid one event included in this combined end- In SENIORS-SHF, the placebo-corrected reduction
point was nine patients in COPERNICUS and five in heart rate with nebivolol at 4 months was
patients in the stratified MERIT-HF subgroup. 8.8 bpm; the corresponding reduction with meto-
prolol CR/XL in the stratified MERIT-HF subgroup
In COPERNICUS, 357 patients died or were hospi- at 3 months was 12.5 bpm and at 6 months was
talized because of worsening heart failure in the 12.8 bpm (heart rate was not recorded at 4 months
placebo group and 271 in the carvedilol group in MERIT-HF).
corresponding to a yearly event rate of 37.9% and
25.5%, respectively (risk reduction 31%, 95% CI: In SENIORS-SHF, 135 patients died in the placebo
1941, P < 0.0001; Fig. 3). Corresponding data for group and 115 in the nebivolol group correspond-
the stratified MERIT-HF COPERNICUS-like ing to a yearly mortality rate of 11.3% and 9.7%,
patients were 144 and 88 events, and a yearly respectively (risk reduction 16%, NS; Fig. 1). Cor-
event rate of 44.6% and 24.9%, respectively (44% responding data for the stratified MERIT-HF sub-
risk reduction, 95% CI: 2757%, P < 0.0001). The group were 68 and 49 deaths, and a yearly
number to treat for 1 year to avoid one event mortality rate of 14.8% and 10.1%, respectively
included in this combined end-point was eight (32% risk reduction, 95% CI: 253, P = 0.038). The
patients in COPERNICUS and five patients in the number to treat for 1 year to save one life was 63
MERIT-HF COPERNICUS-like subgroup. patients in SENIORS-SHF (NS) and 21 patients in
the stratified MERIT-HF subgroup.
In COPERNICUS, 23% fewer patients discontinued
randomized treatment in the carvedilol group In SENIORS-SHF, 247 patients died or were hos-
compared with the placebo group (P = 0.02, pitalized due to cardiovascular causes in the

140 2013 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 275; 134143
J. Wikstrand et al. Beta-blockers in systolic HF revisited

placebo group and 218 in the nebivolol group MERIT-HF subset, 5% fewer patients discontinued
corresponding to a yearly event rate of 24.1% and metoprolol CR/XL compared with placebo (NS,
21.4%, respectively (risk reduction 14%, NS; Table 2).
Fig. 2). Corresponding data for the matched
MERIT-HF subgroup were 173 and 143 events, Comparison of baseline risk in SENIORS-SHF and
and a yearly event rate of 44.0% and 34.1%, the stratified MERIT-HF subgroup
respectively (22% risk reduction, 95% CI: 338, The observed yearly total mortality rate in the
P = 0.026). The number to treat for 1 year to avoid placebo arm was 11.3% in SENIORS-SHF and
one event included in this combined end-point was 14.8% in the stratified MERIT-HF subset; that is,
37 patients in SENIORS-SHF (NS) and 10 patients a 24% lower rate in SENIORS-SHF compared with
in the stratified MERIT-HF subgroup. the MERIT-HF subset. A number of analyses were
performed to determine whether differences in
In SENIORS-SHF, 181 patients died or were hos- baseline risk factors (Table 1) could explain this
pitalized because of worsening heart failure in the difference in yearly mortality rate observed during
placebo group and 170 in the nebivolol group follow-up (Table 3). The results showed that the
corresponding to a yearly event rate of 16.5% and analysed baseline risk factors indicated an
15.6%, respectively (risk reduction 6%, NS; Fig. 3). expected 28% lower mortality rate in the placebo
Corresponding data for the matched MERIT-HF group during follow-up in SENIORS-SHF com-
subgroup were 132 and 101 events, and a yearly pared with the stratified MERIT-HF placebo
event rate of 31.4% and 22.4%, respectively (28% subset.
risk reduction, 95% CI: 745, P = 0.012). The
number to treat for 1 year to avoid one event
Discussion
included in this combined end-point was 111
patients in SENIORS-SHF (NS) and 11 patients in Our attempt to stratify patients from MERIT-HF
the stratified MERIT-HF subgroup. with those in the other pivotal beta-blocker trials
resulted in subsets of patients with good corre-
In SENIORS-SHF, similar number of patients dis- spondence with respect to baseline characteristics
continued randomized treatment in the nebivolol and background treatment in CIBIS-II and COPER-
group compared with the placebo group (170 NICUS. However, the baseline characteristics of
patients in each group, Table 2). In the stratified patients in SENIORS-SHF indicated that they were

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)

SEN-SHF MERIT-HF
Variables 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
NYHA class III/IV 0.44 0.66 0.22 0.286 0.0629
Ejection fraction 29 25 4.00 0.0321 0.128
Systolic blood pressure/10 mmHg 13.6 13.2 0.40 0.00455 0.0182
Heart rate/10 bpm 7.9 8.1 0.20 0.117 0.0235
2
BMI kg m 26.7 25.7 1.00 0.0554 0.0554
Serum creatinine/10 lmol L 1
10.6 11.7 1.10 0.0782 0.0860
Diabetes mellitus 0.27 0.24 0.030 0.309 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.

2013 The Association for the Publication of the Journal of Internal Medicine 141
Journal of Internal Medicine, 2014, 275; 134143
J. Wikstrand et al. Beta-blockers in systolic HF revisited

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

142 2013 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 275; 134143
J. Wikstrand et al. Beta-blockers in systolic HF revisited

conducted. Secondly, stratification of patients in on total mortality, hospitalizations, and well-being in patients
MERIT-HF to those in the other trials was based with heart failure. The Metoprolol CR/XL Randomized Inter-
vention Trial in Congestive Heart Failure (MERIT-HF). JAMA
only on two variables (NYHA class and ejection
2000; 283: 1295302.
fraction in CIBIS-II and COPERNICUS; age and 4 Packer M, Coats AJS, Fowler MB et al. for the Carvedilol
ejection fraction in SENIORS-SHF), although the Prospective Randomized Cumulative Survival Study Group.
patients in the resultant MERIT-HF cohorts were in Effect of carvedilol on survival in severe chronic heart failure.
fact quite similar to those in CIBIS-II and COPER- N Engl J Med 2001; 344: 16518.
NICUS and, for three of these trials, the mortality 5 Packer M, Fowler MB, Roecker EB et al. for Carvedilol
Prospective Randomized Cumulative Survival (COPERNICUS)
rates were also similar. Finally, we were only able
Study Group. Effect of carvedilol on the morbitity of patients
to compare patients in MERIT-HF with the sub- with severe chronic heart failure. Circulation 2002; 106:
group of SENIORS patients with systolic heart 21949.
failure. Arguably, this could have resulted in 6 Flather MD, Shibata MC, Coats JS et al. for the SENIORS
reduced power to observe an effect of nebivolol Investigators. Randomized trial to determine the effect of
but the number of events in SENIORS-SHF was nebivolol on mortality and cardiovascular hospital admission
still larger than in the corresponding subset of in elderly patients with heart failure (SENIORS). Eur Heart J
2005; 26: 21525.
patients from MERIT-HF in which a clear benefit of
7 Veldhuisen DJ, Cohen-Solal A, B ohm M et al. on behalf of the
metoprolol CR/XL was demonstrated. SENIORS investigators. Beta-blockade with nebivolol in
elderly heart failure patients with impaired and preserved
In conclusion, the efficacy and tolerability of biso- left ventricular ejection fraction. J Am Coll Cardiol 2009; 53:
prolol, carvedilol and metoprolol CR/XL are similar 21508.
in patients with systolic heart failure, irrespective 8 Ghali JK, Wikstrand J, Veldhuisen DJ et al. for the MER-
IT-HF study group. The influence of renal function on clinical
of NYHA class or ejection fraction. Nebivolol is less
outcome and response to beta-blockade in systolic heart
effective and is not better tolerated. failure. J Cardiac Fail 2009; 15: 3108.
9 Wikstrand J, Andersson B, Kendall MJ, Stanbrook H, Kliba-
ner M. Pharmacokinetic considerations of formulation:
Conflict of interest statement
extended-release metoprolol succinate in the treatment of
JW was formerly a scientific advisor on cardiovas- heart failure. J Cardiovasc Pharmacol 2003; 41: 1517.
10 Wedel H, McMurray JJV, Lindberg M et al. for the CORONA
cular research to AstraZeneca, M olndal, Sweden.
Study Group. Predictors of fatal and nonfatal outcomes in the
JJVMcM was involved in other trials sponsored by Controlled Rosuvastatin Multinational trial in heart failure
AstraZeneca (CHARM and CORONA) for which his (CORONA): incremental value of apolipoprotein A-1,
employer, Glasgow University, was paid for his time high-sensitivity C-reactive peptide and N-terminal pro B-type
spent as an Executive Committee member. HW was natriuretic peptide. Eur J of Heart Fail 2009; 11: 28191.
a member of the Executive Committees of MERIT- 11 Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of
HF and CORONA for which he received consulting randomized controlled trials on the effect of magnitude of
heart rate reduction on clinical outcomes in patients with
fees. DC has no conflicts of interest to declare.
systolic chronic heart failure receiving beta-blockers. Am J
Cardiol 2008; 101: 8659.

Correspondence: Dr John Wikstrand, Wallenberg Laboratory


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2013 The Association for the Publication of the Journal of Internal Medicine 143
Journal of Internal Medicine, 2014, 275; 134143

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