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Beta-Blockers
and Heart Failure
Beta-blockers, which used to be contraindicated in heart failure, now form
part of the standard therapeutic armamentarium and even represent the
best approach in terms of absolute value.
By Michel Samson, MD
Dr. Samson is staff cardiologist,
Centre Hospitalier Universitaire de
Québec (CHUQ) Pavilion, CHUL,
Laval, Quebec. His areas of
medical interest include acute
coronary syndrome, congestive
heart failure and atrial fibrillation.
H
eart failure has become one of the main
causes of hospitalization for elderly
patients, and carries a higher risk of mortality
than many cancers. The total five-year mortality
rate is nearly 50%. For functional class II or III
patients, the annual mortality rate is nearly
15%.1 In the past few years, randomized studies
have clarified the place of various individual
therapeutic approaches. For instance, studies
The Canadian Journal of CME / July 2001 63
Beta-Blockers
+ Inotropic
b1
Heart rate
a1
Peripheral vasodilation
b2
Peripheral coronary
vasoconstriction
(Bronchodilation)
— Inotropic
b3
(Lipolysis in fat cells)
Figure 1. Differing properties of b and a receptors.
have shown the following: improved survival
with angiotensin-converting enzyme (ACE)
inhibitors and aldactone; digitalis had little
effect either way; and mortality increased with
positively inotropic agents.
Although the negative inotropic effect of
beta-blockers resulted in their contraindication
in left ventricular dysfunction until very recently, there is now evidence that, not only are they
tolerated, but they greatly improve prognosis.
This article, therefore, deals with the pathophysiologic basis for their use. Details of relevant
randomized studies during which beta-blockers
have been administered will follow, together
with differences between the beta-blockers studied. Lastly, their use will be discussed.
Pathophysiology
Left ventricular dysfunction results in neurohormonal activation (renin-angiotensin-aldosterone system, sympathetic system, cytokine
release), which, although beneficial in acute
cases, is responsible for a gradual deterioration
in myocardial function. For instance, in response
to a decrease in cardiac output, an increase in
circulating norepinephrine (NE) can be seen,
which acts on the sympathetic myocardial receptors—particularly beta-1—thus increasing
myocardial contractility. In addition, by stimulating peripheral alpha receptors, NE induces
peripheral vasoconstriction, which helps maintain blood pressure (Figure 1). This effect is
counterbalanced by peripheral beta-2 stimulaThe Canadian Journal of CME / July 2001 65
Beta-Blockers
tion, and consequent vasodilation. Prolonged
exposure of the heart to alpha- and beta-receptor
stimulation unfortunately promotes left ventricular modeling, cell death due to necrosis or
apoptosis, and water/salt retention.2
The roles played by beta-1 and beta-2 myocardial receptors in cardiovascular homeostasis differ
in normal and heart failure patients. In normal
cases, there is little expression of beta-2 receptors
at the myocardium, but they retain their full
importance peripherally where they mediate
vasodilation. In heart failure, however, beta-2
receptors can represent up to 40% of total adrenergic receptors, because of the greatly diminished
density of beta-1 receptors (down-regulation).3
There have been recent reports of the presence of
beta-3 receptors, responsible for a negatively
inotropic effect, and their density would appear to
increase in heart failure.4 Currently, no specific
treatment involving these receptors is available.
Finally, an inter-relationship also exists
between the sympathetic and renin-angiotensinaldosterone systems. Activation of the sympathetic system stimulates the release of renin, and
thus angiotensin 2. This accentuates left ventricular remodeling and peripheral vasodilation, aggravating the heart failure.
Studies
Initial trials conducted in the late 1980s were small,
and not designed to study total mortality. For example, the Metoprolol in Dilated Cardiomyopathy
(MDC) study covered 383 patients,5 and the
Cardiac Insufficiency Bisoprolol Study I (CIBIS I)
had 681 patients.6 Both studies showed an improvement in ventricular function and morbidity, but
results were not significant with respect to mortality. More recently, four large-scale multicenter randomized studies (Table 1) convincingly demonstrated the efficacy of beta-blockers in improving
the survival of functional class II, III and IV
heart failure patients.7-10 The drugs used in these
studies were metoprolol, bisoprolol and
carvedilol.
A significant decrease ranging from 34% to
65% in the relative risk of mortality was documented. The hospitalization rate for heart failure
also was significantly reduced. Results were,
however, equivocal with respect to bucindolol
(not available in Canada).11 The majority of
patients in these four studies were class II or III.
Prolonged exposure of the heart to
alpha- and beta-receptor stimulation
promotes left ventricular modeling, cell
death due to necrosis or apoptosis, and
water/salt retention.
The only study to include class IV patients
exclusively was the Carvedilol Prospective
Randomized Cumulative Survival (COPERNICUS) trial.10 The trial showed a 35% reduction
in the relative risk of mortality in 2,200 patients.
More recently, the Carvedilol Post-Infarct
Survival Control in Left Ventricular Dysfunction
(CAPRICORN) study examined carvedilol in a
group of symptomatic and non-symptomatic
post-infarction patients with a lowered ejection
fraction.12 Once again, beneficial effects were
confirmed, extending expected benefits to cover
class I patients.
It is remarkable to think that these results
occurred when more than 90% of patients were
already receiving ACE inhibitors. It should be
remembered that ACE inhibitors reduce total
mortality by some 20% to 25%, meaning that
approximately 75 patients had to be treated
The Canadian Journal of CME / July 2001 67
Beta-Blockers
Table 1
Largest Randomized Studies
Study
N
NYHA
Class
Avg. Avg.
EF (%) dose (mg)
Mortality Mortality
RR (%)
placebo active
(%)
treatment (%)
NNT
U.S. Carvedilol 1,094
(Carvedilol)
2,3,4
22
45
7.8
3.2
P < 0.001
65
21
CIBIS-II
(Bisoprolol)
2,647
3,4
27
40% = 10
11% = 7.5
13% = 5
17.3
11.8
34
P < 0.0001
18
MERIT-HF
(Metoprolol)
CR/XL)
3,991
2,3,4
28
159
11
7.2
P = 0.00009
38
26
BEST
(Bucindolol)
2,695
3,4
23
—
33
30.2
P = NS
5.7
4
< 25
74%
= 25 (bid)
18.5
11.4
35
P = 0.00014
COPERNICUS 2,200
(Carvedilol)
—
14
N = Number of patients; NYHA = New York Heart Association; EF = Ejection fraction; RR = Reduction in risk; NNT = Number of
patients needed to treat; CIBIS-II = The Cardiac Insufficiency Bisoprolol Study II; MERIT-HF = Metoprolol CR/XL Randomized
Intervention Trial in Congestive Heart Failure; BEST = Beta-blockers Evaluation Survival Trial; COPERNICUS = Carvedilol
Prospective Randomized Cumulative Survival Trial
annually for every life saved. This is compared
with an average decrease in total mortality of
30% to 35% with beta-blockers (or the equivalent of 20 patients treated annually for every life
saved).13
Different Types of Beta
Blockers Studied
Not all beta-blockers available are appropriate
for the treatment of cardiac insufficiency. For
example, d-sotalol (additional anti-arrhythmia
activity) increased mortality rates in the Survival
with Oral d-sotalol (SWORD) study,14 possibly
through pro-arrhythmia. Xamoterol (additional
intrinsic sympathomimetic activity) also had a
negative effect as far as the mortality rates of
70 The Canadian Journal of CME / July 2001
heart failure patients were concerned.15 This
raised the possibility that the properties of the
individual beta-blockers give different clinical
results (Table 2).
One of the beta-blockers that improved survival rates in cardiac insufficiency, carvedilol,
has no selective beta-1 properties, but it,
nonetheless, presents an affinity for this receptor,
which is 12 times greater than that of metoprolol.
Carvedilol also blocks beta-2 and alpha-1 receptors, and has a potent antioxidant effect.16
Theoretically, therefore, it could block the
remodeling and cytotoxic/hemodynamic effects
induced by NE more fully.
The literature, however, shows the greater part
of the negative effect of sympathetic activation is
Beta-Blockers
Table 2
Properties of Beta-blockers Used In Cardiac Insufficiency
Agents
B 1/B 2
selectivity
a1 blocker
Vasodilation
Other properties Dosage
Propranolol
No
—
—
—
Contraindicated
Metoprolol
+
—
—
—
12.5-100 bid
Bisoprolol
++
—
—
—
12.5-10 qid
Bucindolol
No
—
+
—
3-100 bid
Not indicated
Carvedilol
No
Yes
+ (via a1)
Antioxidant
3.125-25 bid
mediated by activation of the beta-1 receptor.16
The positive results of the CIBIS-II 17 and
Metoprolol CR/XL Randomized Intervention
Trial in Congestive Heart Failure (MERIT-HF)8
studies appear to confirm this. Unlike carvedilol,
bisoprolol and metoprolol also have the effect of
re-establishing the activity of beta-1 receptors
(up-regulation), resulting in greater cardiac sensitivity to NE.2 This could help re-establish
myocardial contractility, but may equally aggravate NE toxicity. It is still not clear, therefore,
whether the difference in carvedilol properties
on the one hand, and those of metoprolol and
bisoprolol on the other, are significant in a practice setting.
Recently, a randomized study compared
metoprolol and carvedilol in congestive heart
failure patients to quantify the differential
effects of these drugs.18 The study documented a
greater improvement in maximum exercise
capacity with metoprolol, which could possibly
be explained by a less depressed heart rate upon
exertion. Carvedilol caused a greater improvement in left ventricular function, possibly
because of more complete blockage of sympathetic receptors. On the other hand, patients’
symptoms, perception of quality of life, and tolerance of submaximal effort were identical in
both groups.
While awaiting a direct comparison of mortality from the Carvedilol or Metoprolol
European Trial (COMET) study, we must concluded that all three agents have proved useful in
class II and III heart failure patients, but only
carvedilol is appropriate in class IV patients.
Use in Practice
Current recommendations are to consider the
addition of a beta-blocker in the case of patients
presenting with functional class II or III congestive heart failure if caused by systolic dysfunction.19 This does not apply when classic betablocker contraindications are present (i.e., asthma, atrioventricular block, symptomatic bradycardia, diabetes with frequent hypoglycemia).
This does not apply either in patients hospitalized for acute decompensation who require
intravenous diuretics or intravenous inotropic
support. Usually, diuretics and ACE inhibitors
are started during hospitalization for decompensation, and beta-blockers are started later. In
The Canadian Journal of CME / July 2001 71
Beta-Blockers
Patients starting treatment must always
be advised that all beta-blockers can
cause a temporary deterioration in cardiac insufficiency for a week or two, as
well as dizziness and hypotension.
highly fragile patients, treatment should begin
ideally in a heart failure clinic, but, in most
cases, patients can be safely treated in an outpatient environment, providing certain rules are
respected.
First of all, treatment should be started at
extremely low doses: carvedilol, 3.125 mg twice
daily (bid); bisoprolol, 1.25 mg daily (od); or
metoprolol 12.5 mg bid. This dosage should be
maintained for at least two to four weeks, and is
doubled only if the patient has tolerated it well,
aiming for the maximum dosage studied (Table
72 The Canadian Journal of CME / July 2001
1). If the patient does not tolerate the increased
dosage, the medication should not be considered
a failure and treatment should be maintained at
the tolerated dose. Significant benefits are
already felt at the low dose, as shown in the
Multicenter Oral Carvedilol Heart Failure
Assessment (MOCHA) study,20 and with a number of beta-blockers in an Ontario-based observation study.21 Patients starting treatment must
always be advised that all beta-blockers can
cause a temporary deterioration in symptoms for
a week or two, as well as dizziness and hypotension (particularly with carvedilol, because of its
more complete sympathetic blockade). The
patient’s diuretic dosage must be properly
adjusted, up or down as required, without hesitation. The physician should confirm the disappearance of any side effects before considering
an increase in the patient’s dosage.
If the above steps are taken, most patients will
be able to tolerate high doses of beta-blockers.
In practice, patients often see a subjective
improvement in their condition, but there will
also be benefits in terms of reduced hospitalization and mortality, even if there is no subjective
improvement.
Many patients will obviously have to be
rehospitalized at some point for clinical decompensation. Depending on the individual case, the
beta-blockers can be continued by simply
increasing diuretic dosage, or be decreased temporarily. In rare cases, they will have to be
stopped completely. In such cases, every effort
should be made to try to reintroduce them gradually.
Class IV patients form a specific group for
whom carvedilol is now appropriate, based on
the COPERNICUS study. Treatment should not
be instituted, however, in the acute phase and,
given the fragility of these patients, introduction
of the treatment should be left to specialists.
Beta-Blockers
Finally, while still awaiting the results of
direct comparative studies, the choice of a specific beta-blocker will depend on the attending
physician’s preference and the patient’s specific
profile, except in the case of class IV patients.
Conclusion
Beta-blockers, which used to be contraindicated in
heart failure, now form part of the standard therapeutic armamentarium and even represent the best
approach in terms of absolute value. This new
indication for one of the oldest classes of cardiovascular drugs represents a major change in our
understanding and treatment of the cardiac insufficiency syndrome. CME
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