Document 6579160

European Heart Journal (1996) 17, 1629-1639
Evidence-based Cardiology
Beta-blocking agents in heart failure
Should they be used and how?
J. G. F. Cleland*, M. R. Bristowf, E. Erdmannf, W. J. Remme§, K. Swedberg||
and F. WaagsteinU
* Clinical Research Initiative in Heart Failure, University of Glasgow, Glasgow, U.K.; ^Division of Cardiology,
University Hospital, University of Colorado Health Sciences Center, Denver, Colorado, U.S.A.; %Klinik fur Innere
Medizin, Universitat zu Koln, Koln, Germany; §Sticares Cardiovascular Research Foundation, Rotterdam,
The Netherlands; ^Department of Medicine, Ostra Hospital, Goteborg, Sweden; ^Wallenberg Laboratory,
Sahlgrenska University Hospital, Goteborg, Sweden
Mechanisms of the effect of y9-blockers
Although early reports1'1 suggested that propranolol
could cause worsening of chronic heart failure, this was
not a consistent feature of/S-adrenoceptor blockade. In
recent decades, the view has emerged that sympathetic
activation in chronic heart failure, although initially
serving to maintain cardiac output, is deleterious to
cardiac function and survival in the long term. This has
led clinicians to attempt to reduce sympathetic activity
or its consequences.
In 1974 Waagstein el al. reported that the /?,selective blocker practolol was well tolerated in patients
with acute myocardial infarction despite signs of heart
failure121. Relief of ischaemia rather than a beneficial
effect on the failing circulation could have been responsible for any benefit observed. In an attempt to exclude
improvement in ischaemia as the cause of benefit, further studies were conducted, and showed improvement
in dilated cardiomyopathy131, suggesting that relief of
ischaemia may not be the only mechanism of benefit.
Subsequently, observational reports, small controlled trials and withdrawal studies showed benefits of
/?-blockers on symptoms, exercise capacity, ventricular
function, neurohormonal activity and mortality in
chronic heart failure13""6'. Recently, several large placebocontrolled, randomized trials have reinforced the evidence for the clinical benefits of /?-blockade in chronic
heart failure and suggested that they may also reduce
mortality. This article reviews these results and discusses
whether yS-blocking agents should be used in chronic
heart failure and if so, how.
/?-blockers could improve the prognosis of chronic heart
failure by preserving or improving cardiac function
through several mechanisms.
In-vitro studies show that propranolol protects
cardiac myocytes from the cardiotoxic effects of catecholamines17'81. /?,-adrenoceptors are downregulated in
chronic heart failure, /?2-adrenoceptors are uncoupled
from adenylyl cyclase19""1, Gi proteins are upregulated1'2"151 and /?-adrenoceptor phosphorylation is
increased1'''.
Selective1'6' and non-selective /J-blockers1'7'
reduce renin secretion. This may mimic some of the
actions of angiotensin-converting enzyme (ACE) inhibitors or prevent 'escape' of angiotensin II suppression
from long-term ACE inhibition1'8', providing a theoretical rationale for believing that ACE inhibitors and
/?-blockers may act in synergy in chronic heart failure.
The effect of yS-blockers on plasma noradrenaline is
inconsistent1'7'19"221 and may depend on the baseline
level of neurohormonal activation1231. The lack of increase in plasma noradrenaline is of interest as blockade
of receptor systems commonly leads to an increase of the
relevant agonist. Myocardial dysfunction and necrosis in
chronic heart failure may be related to the concentration
of catecholamines in the myocardial interstitium rather
than the plasma concentration. In this respect, it is
interesting that carvedilol, but not metoprolol, may
selectively reduce cardiac adrenergic drive124'. Enhanced
baroreflex function may improve ventriculo-arterial
coupling, reducing aortic impedance and improving
circulatory efficiency.
Key Words: Chronic heart failure, mortality, ^-blockade, clinical
trials.
Correspondence: Dr John G. F. Cleland, British Heart Foundation
Senior Fellow, Medical Research Council Clinical Research
Initiative in Heart Failure, West Medical Building, University of
Glasgow, Glasgow G12 8QQ, Scotland, U.K.
y?-blockers may improve cardiac function by reducing heart rate, resulting in lower myocardial energy
expenditure125', prolonged diastolic filling122' and increased effective myocardial blood flow due to the
prolonged coronary vascular diastolic perfusion time126'.
0195-668X/96/111629+11 $25.00/0
1996 The European Society of Cardiology
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Introduction
PI
3
<
o
Studies (n ;> 40) of the effects of $-blockers on symptoms, exercise capacity and ventricular function in patients with heart failure
First author, year
Drug
Duration [Ref no]
n
Mean
age (years)
Aetiology
NYHA
LVEF
ber 1996
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Z
o<
Table I
Initial, Max +
(Average dose)
Symptoms and
morbidity
Exercise capacity
Ventricular function
Selective ^-blocking agents
MDC trial, 1992
n = 383
Metoprolol
49
12-18 months1"1
DCM 100%
11/111
22%
5 mg day ~ '-50 mg t.d.s.
(108 mg. day" 1 )
QoL />=001
NYHA />=0-01
Bicycle max.
Better P<005
LVEF+6% P<0-00l
PCWP reduced,
CO increased,
SVR no change
Fisher, 1994
Metoprolol
6 months15"1
n = 50
63
IHD 100%
Il/lll
23%
6-25 mg b.d.-50 mg b.d.
(87mg.day"')
NYHA />=002
Bicycle max
Better /><0-01
LVEF + 4% /><005
CIBIS, 1994
Bisoprolol
23 months""1
n = 64l
60
DCM 36%, IHD 55%
hypertension 6%, valve 4%
III
25%
1 -25 mg . day " '-5 mg . day ~ ' NYHA P<0Oi
(3-8 mg day" 1 )
Not done
Not done
12-5 mg b.d. 100 mg b.d.
(85 mg b.d.)
Treadmill max1 ns
LVEF+4% (rest and ex.)
/><0-05
PCWP reduced
Non-selective vasodilating ^-blocking agents
Woodley, 1991
n = 50
DCM 56%, IHD 44%
Bucindolol
52
Il/lll
3 months1"1
23%
QoL ns
NYHA ns
Fall in VO,
P=005
12 5, 50 or 200 mg day" 1
QoL ns
NYHA ns
Treadmill max:
Worse /><004
Walk ns
LVEF + 5-0%
/>=0-02
LVEDD reduced
Vasodilating /(-blocking agents with a i adrenoceptor blocking activity
Krum, 1995
n = 56
IHD 27%, DCM 63%, valve 10%
Carvedilol
58
Il/III/IV
17 1
3-5 months "
16%
3-125 mg b.d-25mg b.d.
NYHA P=0O08
Symptoms P<00OI
6-min walk:
Better P<001
No increase in VO2 max
LVEF+7 0%
/>=0005
PAP reduced
P<000\
Metra, 1994
Carvedilol
6 months1"1
6-25 mg b.d.-25 mg b.d.
(40mg.day"')
QoL P<000l
NYHA P<000l
Bicycle max.
No change
Subma.x:
Better / ) <0001
LVEF+11%
/><000l
PCWP and SVR reduced,
CO increased
Bristow, 1994
Bucindolol
3 months1"1
n=14l
55
n = 40
51
DCM 71%, IHD 29%
11/111
25%
DC 100%
III
20%
Table 1 Continued
First author, year
Drug
Duration [Ref no]
n
Mean
age (years)
Aetiology
NYHA
LVEF
Exercise capacity
Ventricular function
Vasodilating /(-blocking agents with a, adrenoceptor blocking activity
Olsen, 1995
n = 60
DCM 72%, IHD 28%
3-125 m g b d . - 5 0 m g b d .
52
Carvedilol
I I/Ill
(80mg.day~')
4 months'681
20%
QoL P<0-05
NYHA ns
Bicycle max and submax:
No effect
LVEF+ 10% (rest and ex.)
P<0-0001
PCWP reduced
MOCHA 1995
Carvedilol
6 months'731*
n = 345
59
DCM 60%, IHD 40%
I I/I 11
£35%
Dose-ranging study
6-25, 12 5 and 25 mg b.d.
NYHA not reported
Fewer pts required
hospitalizations (P<0-005)
6 and 9-min walk:
No effect
Up to +9% at 25 mg b.d.
All P<0-005 vs P.
PRECISE 1995
Carvedilol
6 months'691*
n = 276
59
DCM 60%, IHD 40%
Il/HI
£35%
6 25 mg b.d.-50 mg b.d.
QoL P<005
NYHA P=0 01
Pt ass P=0001
Physician ass. P<0-001
6-min walk:
Better P=007
9-min walk:
No effect
LVEF+5%
P=0-0001
Colucci 1995
Carvedilol
12 months'741*
n = 264
59
DCM 60%, IHD 40%
11/111
£35%
6-25 mg b.d.-50 mg b.d.
Reduction of progression
P=0011
Not reported
LVEF + 9-2%
P=00001
Cohn 1995
Carvedilol
6 months1761*
n=IOO
59
DCM 60%, IHD 40%
I1I/IV
£35%
6-25 mg b.d -50 mg b.d
QoL ns
NYHA: ns
Pt ass. P=0-032
Physician ass. P=0-023
6 min walk:
No change
LVEF+9%
P=0-004
ANZ 1995
Carvedilol
18 months'7'-72'1
n=415
67
IHD 100%
Mostly II
29%
3-125 mg b.d.-25 mg b.d.
Trend to worse symptoms
at 6 months
See Table 2
Treadmill max and
Walk TestNo change
LVEF+5%
P<00001
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Symptoms and
morbidity
Initial, Max +
(Average dose)
3
LVEF=change in absolute %. CO=cardiac output, PCWP=pulmonary capillary wedge pressure; SVR = systemic vascular resistance; QoL = quality of life score; NYHA = New York Heart
Association Class. Under exercise capacity: Max = maximal; Submax = submaximal; VO2=peak oxygen consumption. DCM=dilated cardiomyopathy; IHD = ischaemic heart disease;
PAP = pulmonary artery pressure; Pt ass=patient global assessment; Physician ass=physician assessment; ns = not significant; 'abstract.
I
1632 J. G. F. Cleland et al.
Eur Heart J. Vol. 17, November 1996
muscle cell proliferation could retard the progression of
coronary atheroma and alter the vascular remodelling
that occurs in chronic heart failure. A beneficial effect of
other /?-blockers on the atherosclerotic process has been
reported, although this effect remains controversial'53'.
Carvedilol has also been reported to downregulate
cellular adhesion molecules, thereby inhibiting inflammatory infiltration and reducing tissue damage in
response to infarction'54'.
Objectives of treatment of heart failure
The objectives of treatment of chronic heart failure can
be defined as to prolong and improve active life. Treatment should aim to improve or maintain the quality of
life, to prevent major morbid events such as hospitalization or recurrent myocardial infarction, and to delay
death. Preventing progression of cardiac dysfunction is
an integral part of achieving these aims. Measuring
quality of life is difficult and must not be solely equated
with improving symptoms. Treatment could improve the
symptoms of the disease but be associated with severe
side-effects thereby reducing overall quality of life.
Do /7-blockers improve quality of life in
heart failure?
The principal placebo-controlled, double-blind, randomized studies of /?-blockers reported in chronic heart
failure are summarized in Table 1. Trials of less than
3 months' duration or on fewer than 40 patients
are excluded. Studies that enrolled over 200 patients are
further described in Table 2.
A patient's quality of life can be assessed in terms
of NYHA class, symptom scores or global assessment by
the physician or patient. Most studies with /?,-selective
agents have shown an improvement in symptoms.
Larger studies with metoprolol'55'56', as well as
some'31-57-58' but not all'16'221 smaller studies, have shown
an improvement in NYHA class and this has also been
reported with bisoprolol'59'. A trial of acebutolol'60', a
^-blocker with high intrinsic sympathomimetic activity,
suggested that patients deteriorated on active therapy,
but the adverse outcome in this study may have been
related to the absence of a dose-titration phase. Xamoterol could also be considered a /?-blocker with high
intrinsic sympathomimetic activity and it increased mortality in patients with advanced chronic heart failure161'.
However, this study also omitted a dose-titration phase.
The adverse outcome in trials of ^-blockers with intrinsic
sympathomimetic activity may have been related to the
smaller reduction in heart rate compared with drugs
without intrinsic sympathomimetic activity, or to the
absence of a titration phase in these studies. In contrast,
the outcome of studies with non-selective ^-blockers has
not been consistent. Bucindolol and nebivolol have
generally not improved quality of life121'62"65'.
f
]
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Improvements in myocardial force-frequency relationships have also been reported'27"29'. At heart rates in the
physiological range, the normal myocardium increases
its force of contraction as heart rate increases, whereas
the force of contraction of the failing myocardium may
decline. The failing heart may be most efficient at a
reduced heart rate. Global subendocardial ischaemia
may contribute to ventricular dysfunction in patients
with chronic heart failure even when epicardial coronary
artery disease is absent' 3031 '. A reduction in recurrent
infarction, as demonstrated in the post-myocardial infarction studies'32331, could also contribute to the benefits of /^-blockade on ventricular dysfunction and
prognosis.
It is important to note that, at least with nonvasodilating /?-blockers, there may be an acute fall in
ejection fraction and that even after 1 month of
treatment no improvement may be observed'34'. Improvements in ejection fraction and reduction in cardiac
volumes are apparent by 3 months and further improvement may be expected up to 18 months after
initiation'34'.
The immediate effect of /? adrenoceptor blockade
in chronic heart failure is a rise in systemic vascular
resistance. This increase is reversed with longer term
therapy'35', possibly a response to improving cardiac
function'36' or reduced sympathetic drive1371. After acute
administration to patients with chronic heart failure,
carvedilol appears to reduce systemic vascular resistance, whereas propranolol increases it and metoprolol
has a variable effect'35-38'39'. The vasodilating activity of
carvedilol, and possibly other vasodilating /?-blockers,
may prevent the acute rise in systemic vascular
resistance.
/?-blockers could reduce the progression of, and
mortality in, chronic heart failure by reducing the frequency of supraventricular and ventricular arrhythmias.
In addition to the direct electrophysiological effects of
/^-blockade, reductions in sympathetic drive, heart rate
and myocardial ischaemia, improved baroreflex function
and the prevention of episodic hypokalaemia resulting
from surges in sympathetic activity with stress or
exercise'40"43' could all contribute to the anti-arrhythmic
effects of /(-blockers. Improved cardiac function could
also reduce the propensity to arrhythmias.
Several /?-blockers have vasodilating activity,
mediated by a,-adrenoceptor antagonism in the case of
carvedilol'44' and labetalol'451 but independent of adrenoceptor blockade with bucindolol'46-471 and nebivolol'48'.
Vasodilating activity could bring benefits in patients
with chronic heart failure by reducing pre- and afterload (though hypotension may be more likely after
acute administration). Blockade of /?,- and /?2- and
a,-adrenoceptors may protect the myocardium from
elevated catecholamines to a greater extent than
/?! -blockade alone.
Carvedilol has antioxidant properties invitro' 4950 ' and inhibits vascular smooth muscle cell proliferation'51'52'. These actions seem to be independent
of /7-receptor blockade. Inhibition of vascular smooth
Evidence-based Cardiology
The one published trial on labetalol, on only 12
patients, reported an improvement in NYHA class'661.
More recently, carvedilol, which is also an a,- and a
non-selective /?-blocker, has also been shown to improve quality of life167-691, NYHA class'67'69-701 or
patient and physician global assessment'69'70'. As these
trials cumulatively included over 1000 patients, this is
powerful evidence of symptomatic benefit. In contrast,
the Australia-New Zealand (ANZ) trial reported a
trend towards worse symptoms and worsening NYHA
class at 6 months17'1, although by 18 months such
differences had disappeared'721. The lack of symptomatic benefit in this population may reflect the fact
that they had mild chronic heart failure (30% NYHA
class I, 60% class II).
The positive effects described above were obtained in studies of longer than 3 months. In interpreting
) these observations, it is important to consider the dur•* ation of treatment as well as the properties of the drug.
Do /7-blockers retard the progression of
heart failure?
at 18 months, there was a reduction in the combined
end-point of total hospitalization or death1721.
The increase in left ventricular ejection fraction
with /?-blockers could partly be the result of a reduction
in heart rate. However, if a reduction in heart rate was
the sole cause of the increase in left ventricular ejection
fraction, an increase in cardiac volumes might have been
expected. Studies of ^-blockers in chronic heart failure
have shown either no change in cardiac volume121>621 or a
decrease1761. Early evidence suggests that ^-blockers can
also, long-term, prevent progressive left ventricular
hypertrophy in chronic heart failure1341, similar to the
effect observed with ACE inhibitors'771.
Effects of y9-blockers on exercise
performance
Most studies with metoprolol, a /?,-selective blocker,
show an improvement in exercise capacity in the long
term'55-581. The effects of bisoprolol on exercise performance have not been reported. A short-term study
of acebutolol suggested an adverse effect'601. In contrast, studies with non-selective /?-blockers including
bucindolol'21'62-641 and nebivolol'651 and most of the
studies on carvedilol have shown no improvement in
maximal or submaximal exercise capacity169-731. Some
of the small studies with carvedilol'67™1 and labetalol'661 have suggested that /?-blockers with a,-blocking
activity improve exercise capacity but improvement in
exercise capacity has not been a consistent feature
in the larger trials of carvedilol. No comparative trial
of exercise performance between /?-blockers has been
carried out.
The relevance of exercise testing to the quality of
daily life is complex; exercise capacity may not be a
useful measurement of the efficacy of /?-blockers'781.
Reduction of the increase in heart rate during exercise
may limit increases in cardiac output that could, in
turn, prevent improvements in ventricular function
being translated into improved exercise performance.
Metoprolol appears to induce upregulation of /?,adrenoceptors, in contrast to carvedilol and, to some
extent, bucindolol'79-801. /?2-receptors contribute to the
increase in heart rate during exercise. /?,-receptor upregulation and lack of /?2-receptor inhibition with metoprolol may allow improvement in exercise capacity not
observed consistently with other /f-blockers. Inhibition
of /?2-adrenoceptor-mediated peripheral vasodilatation
during exercise may also be important in limiting the
effects of non-selective drugs.
Caution in interpreting the results of exercise
tests on carvedilol is required. If an agent reduces
mortality then more patients with severe chronic heart
failure will be eliminated in the placebo arm leading to
an apparent improvement in performance on placebo.
A lack of difference in exercise performance between
placebo and carvedilol could conceal a true benefit with
the ^-blocker.
Eur Heart J, Vol. 17, November 1996
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During long-term therapy, /?-blockers increase the left
ventricular ejection fraction by about 5-9% compared
with placebo121'315660^63-67-741. In contrast, ACE inhibitors increase left ventricular ejection fraction by
only 2%'75].
In the Metoprolol in Dilated Cardiomyopathy
(MDC) trial, patients receiving metoprolol experienced
reduction in hospitalization, a reduced need for cardiac
transplantation and a trend towards a reduction in a
combined endpoint of death and the need for cardiac
transplantation'551. The Cardiac Insufficiency Bisoprolol
Study (CIBIS) trial, in patients with dilated cardiomyopathy or ischaemic heart disease, reported a significant reduction in hospitalization for worsening chronic
heart failure1591. No striking difference in other cardiovascular events (myocardial infarction, stroke or heart
transplantation) was seen between the placebo and
bisoprolol groups.
The U.S. trial programme on carvedilol enrolled
patients into one of four protocols according to their
degree of functional impairment (mild, moderate or
severe impairment, and a dose-ranging study in patients
with moderate impairment). A reduction in a combined
endpoint of chronic heart failure progression was noted
in patients with mild functional impairment'741. A reduction in cardiovascular hospitalization was noted in
patients with moderate functional impairment1691 and
hospitalization for all causes was reduced in the doseranging protocol'731. In the ANZ trial'7'1, all the patients
had chronic heart failure due to ischaemic heart disease.
Despite improvements in left ventricular ejection fraction, patients receiving carvedilol did not show a reduction in worsening chronic heart failure, though
the combined end-point of myocardial infarction, unstable angina or need for revascularization fell and,
1633
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c
Ci
o
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1
2 Studies (n ;> 200,) o/ fhe effects offy-blockerson morbidity in heart failure
Study
(Ref no)
Drug
Doses:
Initial
Maximum
Mean
n
Mean
age (years)
Aetiology
NYHA
LVEF
M DC Trial I993 1 " 1
Metoprolol (M)
n = 383
49
DCM
100%
11/111
22%
5 mg . day ~ '
50 mg t.d.s.
108 mg. d a y " '
CIBIS 19941591
Bisoprolol (B)
n = 641
60
DCM 36%;
IHD 55%;
HBP 6%;
Valve 4%
III
25%
ANZ Trial, I995 17 "
Carvedilol (C)
n=415
67
IHD 100%
U S trials I9961811
Carvedilol (C)
n=IO94
59
DCM 53;
IHD 47%
Worsening
HF
n
ft"
a
ft.
Hospitalization
Myocardial infarction
Other endpoints
Not stated
51 readmissions
on M, 83 on P
(/><0-05)
Not stated (patients
with IHD excluded)
Death or need for transplantation:
reduced from 20 1% to 12 9%
(/>=0-058)
Transplantation: reduced from
10-1% to 1%(/>=00001)
1-25 mg . d a y " '
5 mg . d a y " '
3-8 mg . d a y " '
Reduced from
48% to 33%
(/><0-001)
For HF:
reduced 280% to 19%
(P<001)
Only 5 Mis reported
(3 on B, 2 on P)
Not done
Mostly II
29%
3-125 mgb.d.;
25 mg b.d.
ns
All cause:
reduced by 33%
(P=0-052)
Trend to reduction in Ml,
unstable angina or need
for revascularization
Death or hospitalization for all
causes reduced by 41% on C
(P=002)
II-IV
23%
6-25 mg b.d.,
50 mg b.d.
Reduced by C
Cardiovascular:
reduced from
19-6% to 141%
(/•=0-036)
Reduced from 2% to < 1 %
(/>=0-06)
89% completed C versus
83% completing P (P=0-002)
Risk of death or hospitalization
reduced from 24-6% to 15 8%
(/><0001)
MI = myocardial infarction; HF = heart failure; DCM = dilated cardiomyopathy; IHD = ischaemic heart disease; ns = not significant; P=placebo.
Evidence-based Cardiology
Table 3
Effects of ^-blockade on mortality in the large placebo-controlled trials
Number of patients Number of deaths (mortality)
Re.ative^hange
follow-up
Tnal
Placebo ^-blockade
MDC
CIBIS
ANZ
U.S. trials
Totals
1635
189
321
208
398
193
320
207
696
1116
1416
Placebo
19
67
26
31
(101%)
(20-9%)
(12-5%)
(7-8%)
143 (12-8%)
Lives saved per Lives saved per 1000
treated/year#
1000 treated
^-blockade
23
53
20
22
(11-9%)
(16-6%)
(9-7%)
(3-2%)
118 (8-3%)
+ 19% (ns)
- 20% (ns)
- 23% (ns)
- 65%
(/>=00001)
- 35%
(/>=0001)
15
21
18
6-5
months
months
months
months
13-3 months
(approx)
18 excess deaths
43 saved
28 saved
46 saved
14 excess deaths
25 saved
19 saved
85 saved
45 saved'
41 saved
#This is a crude adjustment to compensate for different trial durations and assumes constant benefit with time.
*For comparison about 35 lives would have been saved in the SOLVD treatment study comparing enalapril and placebo over the same
duration.
Do /J-blockers reduce mortality in heart
failure?
As almost all patients in these trials were receiving ACE inhibitors, the effects of /^-blockade on mortality were in addition to those resulting from ACE
inhibition. There is very little experience of the effects of
^-blockade on patients with chronic heart failure who
are not receiving ACE inhibitors.
Altogether, the MDC trial, the CIBIS, the U.S.
carvedilol trial programme and the ANZ trial enrolled
over 2500 patients with chronic heart failure of varying
degrees of severity and of ischaemic and non-ischaemic
Which patients should (and should
not) be treated?
Decompensated patients and those dependent on intravenous inotropic agents should not be given a /?-blocker
until they have reverted to a compensated state on oral
therapy. Patients with bronchial asthma should not receive a /?-blocker, while great caution should be exercised
before using them in chronic obstructive airways disease.
It is difficult to extrapolate from the /?-blocker
.trial populations to the wider community with chronic
heart failure. In the mortality studies of ^-blockade, the
mean age of patients has ranged from 49 years to 67
years, whereas the mean age of chronic heart failure
patients in the community is 74 years'831. Dilated cardiomyopathy constituted 100% of patients in the MDC
trial, about 55% in the U.S. trials and about 35% in the
CIBIS. The results of these trials, supported by smaller
studies, indicate that patients with proven symptomatic
dilated cardiomyopathy should be treated with a
Eur Heart J, Vol. 17, November 1996
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The MDC trial reported a reduction in the combined
endpoint of death and the need for heart transplantation, but a non-significant 19% relative excess of
deaths was seen in the metoprolol group1551. In CIBIS,
the effect on overall mortality (relative risk reduction
20%) was not significant, though mortality was significantly reduced in patients without a history of myocardial infarction (relative risk reduction 47%) and those
with dilated cardiomyopathy (relative risk reduction
52%)'59'. Two of the individual protocols in the U.S. trial
programme showed a significant reduction in mortality'73'74'. The combined analysis of the entire programme indicated a 65% relative reduction in mortality
with carvedilol (/ ) =0001), which was similar in patients
with mild or more severe chronic heart failure, and with
ischaemic or non-ischaemic aetiology1811. Sudden deaths
and deaths from pump failure were reduced to a similar
extent by carvedilol. The ANZ trial, conducted exclusively in patients with mild chronic heart failure, showed
a non-significant (23%) reduction in mortality with
carvedilol at 18 months'72', the result possibly reflecting
the fairly good overall prognosis in this population. It is
not clear if the greater effect of carvedilol on mortality in
the U.S. trials reflects differences between yS-blockers,
different study populations or just the greater size of the
U.S. trial. The clinical significance of the pharmacological differences between /?-blockers can be elucidated only
by controlled comparative trials.
origin (Table 3). The mortality on placebo was 12-8%
falling to 8-3% on a yS-blocker (F<0001) over a
follow-up of about 13 months, a relative risk reduction
of about 37% and an absolute benefit of 45 lives saved
per 1000 treated. The absolute benefit is similar to that
of ACE inhibition in the SOLVD treatment trial'82', in
which about 35 lives had been saved per 1000 treated
with enalapril at 15 months.
In the SOLVD treatment trial, 1-year mortality
was 16% in the placebo group; this fell to 12% with
enalapril'82'. In the U.S. carvedilol trials, mortality at a
median follow-up of 6-5 months in the placebo group
was 7-8%. By extrapolation, the mortality of this population, almost all of whom were receiving ACE inhibitors, was similar to that observed in the active treatment
group of the SOLVD treatment trial. Thus, despite
differences in the study populations, mainly a higher
proportion of dilated cardiomyopathy in the carvedilol
trials, their prognosis was very similar.
1636 J. G. F. Cleland et al.
/?-blocker, in addition to diuretics, digoxin and ACE
inhibitors. Dilated cardiomyopathy, however, accounts
for only a minority of patients with chronic heart failure,
whereas ischaemic heart disease is responsible for most
cases'841. The evidence that patients with ischaemic heart
disease should routinely receive yS-blockers in addition to
standard treatment is less clear. However, the U.S.
carvedilol trials suggest that the mortality benefits of
carvedilol are similar in patients with or without ischaemic heart disease18'1 while/?-blockers have been shown to
have important prognostic benefits in patients exhibiting
chronic heart failure after myocardial infarction. Benefits were similar in patients with differing degrees of
functional impairment and in patients above and below
the median age in the U.S. carvedilol trial. The ANZ
study comes closest to representing mild chronic heart
failure in the community, as all patients had ischaemic
heart disease and their mean age was 67 years. Although
this population did not derive a symptomatic benefit
from carvedilol the reduction in the combined end-point
of hospitalization and death again supports benefit.
What are the optimal doses of
/?-blockers?
Starting dose
In patients with chronic heart failure, yS-blockers should,
as a rule, be started at a low dose and titrated up slowly.
It is advisable to introduce /^-blockade at the starting
doses used in the large clinical trials: carvedilol, 3-125—
6-25 mg b.d.[69'7'-741, metoprolol, 5 mg b.d.[55] or 6-25 mg
b.d.'3'1 and bisoprolol, 1-25 mg/day1591. The dose should
be doubled at weekly or 2-weekly intervals, according
to clinical response, towards the target dose. Sicker
patients should generally be titrated more slowly than
patients with less severe disease. The benefits of
/?-blockers on the clinical progression of chronic heart
failure suggest that they might be most effective if
introduced early in the course of the condition. Patients
with less severe chronic heart failure might have less
hypotension and early worsening of chronic heart failure
during introduction of ^-blocker therapy than patients
with advanced chronic heart failure, adding to the safety
of treatment. However, /J-blockade will probably be less
well tolerated in a less carefully selected population in
whom the inclusion and exclusion criteria of a clinical
trial are not imposed1871, or if dose titration is not
employed.
Eur Heart J, Vol. 17, November 1996
Dose-response studies of carvedilol and bucindolol have
suggested that higher doses are associated with greater
increases in left ventricular ejection fraction. The doseranging study of carvedilol also suggested a greater
reduction in mortality with higher doses'731. Further
studies are required to determine the optimum dose of
each /?-blocker. Until then, it is appropriate to use the
target doses in the clinical trials (carvedilol 25-50 mg
b.d., metoprolol 50 mg b.d.-t.d.s, or bisoprolol 5 mg/
day. The results of clinical trials suggest that up to 3
months' treatment may be required before symptoms
improve.
When should /?-blockers be stopped?
Clinical trials indicate that /?-blockers are much safer to
use than has been previously suggested, provided careful
dose titration is employed. However, about 5% of
patients who, on the basis of criteria used for clinical
trials, are thought to be suitable for ^-blockade will not
tolerate its introduction because they develop hypotension or worsening chronic heart failure; this percentage
is higher in severe chronic heart failure. In patients who
experience worsening symptoms of chronic heart failure,
the doses of ACE inhibitor or diuretic, or both, should
be increased, whereas the doses of these agents should
be reduced in the event of symptomatic hypotension.
Patients who require an increase in diuretic therapy to
control worsening chronic heart failure during the
introduction of carvedilol nonetheless appear to benefit
from long-term ^-blockade18*1. If adjustment of other
medications does not relieve side-effects, reduction or
withdrawal of ^-blockade should be considered.
Another scenario is the patient who has tolerated
the introduction of a /?-blocker and shows clear signs of
benefit, but who later deteriorates. Should /?-blockers be
withdrawn if such patients fail to respond to other
simple measures? We do not know.
Summary
Experience accumulated from several large trials
strongly suggests that /?-blockers should be used for the
management of chronic heart failure1871. It is appropriate
to add ^-blockade to conventional therapy such as
diuretics, ACE inhibitors and digoxin, as this was the
approach used in the major trials. It is appropriate to
treat patients with mild, moderate and, when stable,
severe chronic heart failure. The benefits obtained include improvements in left ventricular function, reductions in symptoms and morbidity, improvement of
quality of life, and delay of clinical progression, reflected
in a reduced need for cardiac transplantation and,
probably, a reduction in mortality. /?-blockers are much
better tolerated, when used appropriately in selected
patients, than was previously supposed.
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The post-myocardial infarction studies of propranolol, metoprolol and timolol also support a benefit
of /^-blockade on morbidity and mortality in patients
with chronic heart failure in the acute phase and with
large infarcts, respectively'41 >85>861. Interestingly, longterm studies of non-selective ^-blockers without intrinsic
sympathomimetic activity generally showed larger reductions in mortality than did studies with selective
y3-blockers'411.
Target dose
Evidence-based Cardiology 1637
To confirm the improvement in survival recently
reported with carvedilol, further prospective trials using
different /?-blockers are warranted. No major comparative trials have been carried out between /?-blockers in
chronic heart failure, therefore it is not known whether
the differences between them are clinically significant.
The optimal dose of /?-blocker and the effect in patient
groups excluded from or poorly represented in the
clinical trials (e.g. elderly patients) have yet to be determined. Placebo-controlled mortality trials with bucindolol (BEST) and bisoprolol (CIBIS-II) are under
way189'901. A large study of carvedilol versus metoprolol
(COMET), added to conventional treatment, is planned.
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