European Review for Medical and Pharmacological Sciences
Carvedilol: something else than
a simple betablocker?
A. PALAZZUOLI, P. CALABRIA, M.S. VERZURI, A. AUTERI
Institute of Clinical and Experimental Medicine, University of Siena (Italy)
Abstract. – Carvedilol is a cardiovascular
drug of multifaceted therapeutic potential, with
beta-blocker and vasodilatative activity. These
actions confer to the above mentioned beta-
blocker some beneficial properties on several
processes involving cardiovascular system.
Carvedilol provides haemodynamic, antiis-
chemic, antiproliferative and antiarrhytmic bene-
fits, for its antioxidant neurohumoral and elec-
trophysiological effects. All these actions pro-
vide the basis for usefulness of the drug in the
treatment of hypertension, coronary heart dis-
ease, and congestive heart failure. In this review
we report the beneficial properties of Carvedilol
and we analyze the rational clinical use of this
betablocker taking special attention on recent
clinical trial in heart failure where it appears an
evidence supporting an important, favourable
effect of the drug.
Key Words:
Carvedilol, Hypertension, Coronary disease, Hearth
failure.
Introduction
In the last ten years there has been a grow-
ing interest on the use of beta-blockers in ma-
jor cardiovascular disease as coronary disease
and heart failure. Betablockade has demon-
strated an improving prognosis in several ran-
domized trials. However these studies are dif-
ferent for size, duration, objectives and sub-
ject recruitment; each beta-blocker has differ-
ent effects on the cardiovascular system and
the appropriate clinical use is not the same
for all these drugs.
Particular interest has been developed in
these drugs around the treatment of heart
failure: the failing heart is adrenergically acti-
vated and this phenomenon helps to maintain
2002; 6: 115-126
an adequate cardiac performance at short
term but it is damaged after an early period1.
This observation has encouraged several
Authors to study the effect of beta-blocker in
heart failure obtaining good results in mor-
bidity and mortality. Recent critical meta-
analysis showed different evidences on bene-
ficial effects and survival for various
betablocker employed2,3.
Carvedilol is one of the most analyzed
betablockers and the only one to have shown a
clear reduction in mortality; compared with
other drugs of the same class it has additional
advantageous properties and should be consid-
ered as part of the routine treatment of heart
failure. In this article we analyze molecular bi-
ological and potential activities of the drug.
Structure and Biological
Effects of Carvedilol
Beta-blockers are able to interfere in neu-
rohumoral modulation at various levels:
• block of the cathecolamines action and
inhibition of the sympathetic activation
through the block of b1 and b2 prejunc-
tional receptors of the heart and of the
surrenal marrow
• contrast receptorial alterations in heart
failure (down regulation of b 1 and up
regulation of b2 and b3 receptors) due to
high doses of norepinephrine which have
negative inotropic compound (NO medi-
ated) and a proarrhythmic effect
• restore the positive inotropic compound
cyclic-AMP dependent
• decrease plasmatic endothelin (which
are high in heart failure), powerful circu-
lating vessel constrictor
115
 A. Palazzuoli, P. Calabria, M.S. Verzuri, A. Auteri
• increase vagal activity (increasing R-R
variability and decreasing QTc disper-
sion, both related to arrhythmic risk)
B-receptors are divided in b 1-receptors
(mostly in heart muscle) and b2-receptors (in
bronchial and vascular muscle and in many
other districts such as liver, fat tissue, en-
docrine pancreas). No tissue contains just one
type of receptors but there is a prevalence of
one tie and so it’s difficult to have a complete
selective block of these receptors.
In recent years we have developed some
compounds with particular characteristics as
β1-selectivity and intrinsic simpathicomimetic
activity to obtain more effective drugs and
less side effects.
Carvedilol [1-[carbazolyl-(4)-oxy)-3-[(2-
methoxyphenoxyethyl1)amino]-2-propanol]
is a III generation b-blocker with a nonselec-
tive beta-adrenoreceptor blocking effect
combined with a vasodilating action based
primarily on a beta 1 -adrenoreceptor
blockade4. It doesn’t have sympathomimetic
activity, but it possesses some properties
called “ancillary”, such as antioxidant and an-
tiproliferative actions5.
Carvedilol is highly lipophilic and rapidly
and completely absorbed after oral admin-
istration4,6.
Oral Carvedilol undergoes extensive first-
pass metabolism in the liver with a bioavail-
ability of 20-25%. More than 95% of the drug
is bound to plasma proteins. Carvedilol is pri-
marily metabolised in the liver by cy-
tochrome P450 enzymes and several metabo-
lites are pharmacologically active.
The predominant way of excretion is
through biliary secretion7.
The pharmacokinetic profile is not altered
in the elderly or in patients whit renal disease8.
Thanks to the blockade of beta1, beta2 and
alfa1-adrenoreceptors Carvedilol is able to re-
duce blood pressure without associated reflex
tachycardia.
The vasodilatatory effect of Carvedilol
(with lowering of total peripheral vascular re-
sistances) is due to the blockade of alfa1-
adrenoreceptors.
This effect reduces afterload and offsets
the negative inotropic effect of beta-block in
cardiac muscle. Therefore, the stroke volume
and the cardiac output are maintained or
even increased6.
116
Carvedilol do not lower renal blood flow9.
The antioxidant effects of Carvedilol are
attributed to the presence of carbazole moi-
ety in the drug molecule. In myocardial cell
membrane Carvedilol inhibits lipid peroxida-
tion from oxygen species of chemical and cel-
lular origin10.
Carvedilol protects smooth muscle cells
(endothelial, neuronal and vascular cells)
from reactive oxygen species5.
Carvedilol inhibits superoxide anion (.O2–)
having an antioxidant activity approximately
10 times greater than vitamin E11.
A better answer to reactive oxygen species
damages permits a lower cardiovascular re-
modelling related to neutrophil activation in
the inflammation.
In fact Carvedilol inhibits the attachment
of the neutrophils to activated endothelial
cells and vascular smooth muscle cells
through a suppression of ICAM-1 gene tran-
scription which is necessary to neutrophils to
infiltrate an ischemic organ12.
Carvedilol has some effects on cardiac ac-
tion potential causing a moderate prolonga-
tion of action potential duration (APD) with-
out affecting other parameters. This APD
prolongation differs notably from that caused
by other class III antiarrhythmic drugs in
terms of frequency dependence: Carvedilol
has a minimal reverse frequency-dependence
and so incidences like torsades de pointes are
rarer13. A QT prolongation has not been ob-
served in patients treated with Carvedilol14.
Thanks to the alfa1-antagonism Carvedilol is
able to improve the peripheral muscle sensitiv-
ity to insulin in patients with hypertension15.
Carvedilol can also inhibit proliferation of
aortic vascular smooth cells induced by many
types of mitogens like angiotensin II, en-
dothelin, thrombin and growth factors, hav-
ing an antihypertrophic property too 16,17
(Table I).
Clinical Use of Carvedilol
Hypertension
The haemodynamic effects of beta and alfa
blockade of the drug are well recognize and
thanks to these cardiac and vascular effects
Carvedilol is now considered one of the most
important beta-blockers for the treatment of
hypertension18.
 Carvedilol: something else than a simple betablocker?
Table I. Potential effects of betablock on left ventricu-
lar remodelling.
• Reduction in heart rate
• Reduction in O2 consumption
• Modulation of β-receptors
• Protection from cathecolamine toxicity
• Reduction of renin-angiotensyn activity
• Antischemic and antiarrythmic effect
• Improvement in synthesis of miocardial proteins
• Peripheral vasodilation
• Decrease of heart work
• Antioxidant action
• Antiinflammatory action
In clinical trials, Carvedilol showed an effi-
cacy equivalent to other common beta
adrenoreceptor antagonists, dihydropyridine
Ca-antagonists, and ace-inibithors4,6,19,20.
Reduction of blood pressure level is ob-
tained without an impairment of systolic
function and change in heart rate: in fact the
beta-blocker effect is modulated to vasodi-
latative activity that reduces the above block-
ade with less slowing of cardiac frequency re-
spect to other drugs of the same type.
Respect to Metoprolol, Carvedilol demon-
strated to lower blood pressure and systemic
vascular resistance without reduction in car-
diac output20.
The mean dosage of Carvedilol in hyper-
tension is 25 or 50 mg alone or with other an-
tihypertensive drugs if blood pressure level is
not well controlled. The most common med-
ical associations are with angiotensin convert-
ing enzyme inhibitors, calcium antagonists
and diuretics5.
Coronary Disease
Carvedilol is useful in the treatment of sta-
ble, unstable angina and myocardial infarc-
tion. In stable angina it demonstrated to re-
duce ischemic attacks and to improve thresh-
old of chest pain; in a compared study with
verapamil, Carvedilol showed similar effect
on symptoms and ECG alterations21. Respect
to metoprolol it provides a major clinical
benefit in exercise tolerance with same antiis-
chemic and antianginal effects. This could be
due to the antioxidant and vasodilated prop-
erties that bring less adverse consequences in
comparison to traditional beta-blockers5,22.
In unstable angina Carvedilol added to
conventional therapy is able to reduce heart
rate, blood pressure, number and duration of
ischemic attacks23.
The beneficial effects of beta-blockers dur-
ing and after myocardial infarction are well
recognize although Carvedilol seems to have
additional benefits respect others beta-block-
ers: this is due to its ancillary, metabolic and
cardioprotective actions24,25. The most impor-
tant effect is the reduction of infarct size area
when administered during the first 24 hours
also at low dosage, this benefit is not joined
with a depression of ejection fraction or in-
dices of systolic function reduction. For its
properties in membrane stabilization,
Carvedilol is able to reduce dangerous ven-
tricular arrhythmias during early phases of is-
chemia14. Recently, a randomized trial pro-
vided a clinical evidence of its benefit in the
treatment of AMI at early and long term:
Carvedilol demonstrated to reduce cardiac
death, reinfarction, angina and heart failure.
Its use resulted in a significant reduction of
left ventricular remodeling together with in-
crease of systolic function. In addition, in pa-
tients with pump dysfunction it can be used
with good tolerability and efficacy starting
with low dosage and increasing after the first
week. The improvement of the contractility
allows a less parietal kinesis alteration and a
LV enlargement reduction26. These observa-
tions suggest that Carvedilol is one of the
most useful beta-blockers during myocardial
infarction in patients with or without systolic
dysfunction, it prevents other ischemic events
and adverses LV remodeling that lead to
heart failure27.
Hypertrophic Cardiomyopathy
Carvedilol seems to be able to reduce dias-
tolic performance linked to dysfunction of
myocardial releasing. This action could be
due to Ca-antagonist property. Beta-blocker
effect reduces oxygen myocardial consume
and vigorous contractile activity, leading to a
lowering in aorto-ventricular gradient 28
(Figure 1).
Carvedilol in Heart Failure
Congestive heart failure is the former
cause of death in the last past decade; more
than 40.000 subjects died annually for this
pathology and prognosis remains unaccept-
117
 A. Palazzuoli, P. Calabria, M.S. Verzuri, A. Auteri

Actions

Adrenoreceptor Glucose/lipid Neurohumoral Cardiac

Anti-oxidant
blockade metabolism factors electrophysiology

Haemodynamic benefits Cardiovascular protection

Reduction of cardiac work Anti-atherogenic action

Vasodilation Anti-hypertrophic action
Anti-ischemic action
Anti-arrhythmic action

Figure 1. Haemodynamic and biological properties of Carvedilol.

ably poor 29. Although introduction of an- diovascular indications. Improvement of

giotensin-converting enzyme has improved
mortality rate, this only therapy does not ap-
pear so effective if mortality after 5 years
from diagnosis is around 40%. The role of
beta-blocker in heart failure has been subject
of debate for many years but after recent
meta-analysis results confirming the benefi-
cial effects on mortality, morbidity and clini-
cal status, their use is entered in clinical prac-
tice30. Even if certain effects of beta-blockers
may be considered class effects, it is not yet
clear whether there are differences between
beta1-selective antagonists and non-selective
agents. Carvedilol appears to be more able
than others to reduce mortality (the mortality
is reduced from 7,8% to 3,2% whith a rate of
65%) with highly significant effect; this seems
a much larger average effect then that seen in
either CIBIS or MERIT-HF 2,31 . Actually
Carvedilol is the only beta-blocker approved
from Food and Drug Administration for the
treatment of heart failure while Bisoprolol
and Metoprolol are approved for other car-
symptoms and hospitalization reduction are
guaranteed, functional capacity to effort does
not change significantly because cardiac dou-
ble product remains the same. In fact cardiac
output increases but heart rate is reduced32.
Regarding morphological and functional as-
pects of left ventricle, Carvedilol reduces af-
ter a 6 months mean period LV volumes and
mass, increases LV ejection fraction and frac-
tional shortening reducing cardiac remodel-
ing. The treatment also decreases LV mass
LV sphericity causing a more elliptic mor-
phology33,34 (Figure 2). The starting dose is
low to prevent adverse and acute effects of
therapy, and must be increased during the
next weeks monitoring carefully blood pres-
sure heart rate and clinical conditions. The
optimized dosage is the best dose tolerated
ranging from 25 to 50 mg of the drugs. Once
heart failure subjects reach a maintenance
dose of beta-blocker treatment, this should
be maintained indefinitely because of the risk
of deterioration on withdrawal35.

118
 Carvedilol: something else than a simple betablocker?

Carvedilol Placebo

Carvedilol Placebo

Carvedilol Placebo

Time O 4 months 12 months

Figure 2. Reduction of LV volumes and improvement of EF during Carvedilol treatment.

The major actions of Carvedilol are the pre-
vention and antagonism of cardiac adrenergic
damage; heart rate lowering and reduction of
oxygen consumption are two other effects of an-
tagonism. In the failing heart strength-frequency
curve shows an inverse linear correlation, so an
increase of frequency is associated with a my-
ocardial contractility reduction. The chronic use
of beta-blocker is associated to an increase of
ejection fraction and lowering of oxygen re-
quest. This is due to the frequency reduction
and to the changes in cardiac metabolism from
fatty acid utilization towards aerobic glycolysis36.
Down regulation of beta-1 receptor is a typical
phenomenon of heart failure due to exposition
to elevated catecholamine levels: Carvedilol ex-
perimentally demonstrated to induce up-regula-
tion of these beta-1 receptors. Other potential
actions of Carvedilol are a recover in diastolic
function, reduction in renin-angiotensin activity,
increase in protein synthesis, antioxidant anti-
proliferative and anti-inflammatory effects. All
these actions contribute to ameliorate LV per-
formance and cardiac work capacity9.

119
 A. Palazzuoli, P. Calabria, M.S. Verzuri, A. Auteri

Although Carvedilol has multifaceted function, clinical status, morbidity and

properties, its use is standardized in mild to
moderate heart failure, but in advanced NY-
HA classes and in elderly patients remains
uncertain. The proportion of IV class is small
and the benefit is not clear: the beta-blocker
evaluation trial (BEST) failed to show a ben-
efit in sicker patients37. Recently two trials
(Copernicus and Cibis II) showed an im-
provement in rate mortality and re-hospital-
ization also in more compromised
patients38,39. These studies answered to an im-
portant question about the tolerance, the
beneficial and additional effect of beta-block-
er. Even in these patients, Carvedilol demon-
strated to reduce cardiac sudden death and
adverse cardiac remodelling with good toler-
ance.
However some questions remain to be ad-
dressed: does this benefit extend to patients
with ischemic and non-ischemic causes? Is
the benefit for all races the same? What is the
former mechanism that induces mortality re-
duction?
Clinical Trials Analysis of Carvedilol
The role of beta-blockers in heart failure
has been subject of debate for many years.
The results of recent prospective, placebo-
controlled studies of the addition of beta-
blockers to standard therapy in patients
with chronic heart failure have confirmed a
significant beneficial effect on ventricular
mortality.
MDC (Metoprolol in Dilated Cardiomio-
pathy) was the firs great randomized, multi-
centric, prospective and placebo controlled
trial on beta-blockers. The primary objec-
tive was to determine effects of metoprolol
on mortality in patients with MDC, EF <
40% in a follow up of 12-18 months. The
combined end point mortality-necessity of
heart transplantation was lowered of 34%.
There were also many clinical and instru-
mental significant improvements (NYHA
class, quality of life, haemodynamic profile,
EF, stress tolerance)40.
The most studied beta-blocker in heart
failure is Carvedilol (Table II).
The ANZ trial (Australian New Zeland
Heart Failure Research Collaborative
Group) studied patients with heart failure
secondary to ischemic heart disease in I-III
NYHA class with an EF < 45%. It has been
demonstrated that Carvedilol is able to in-
crease left ventricular ejection fraction, to de-
crease end-systolic and end-diastolic diame-
ters, so to improve significantly ventricular
function and to maintain the exercise capaci-
ty at a lower double product30,41.
The US Carvedilol programme trials (a cu-
mulative analysis of 4 sub-studies) has demon-
strated Carvedilol efficacy in lowering mortal-
ity, morbidity and hospitalizations in patients
with mild to moderate symptomatic heart fail-
ure of various ethiology. They enrolled pa-
tients in II-IV NYHA class of various ethiolo-

Table II. Major Carvedilol trials on heart failure.

Trials Cause of Nyha class Primary Odds ratio Risk

heart failure end point reduction

Metra IDC II-III Hemodynamics 1.00 –

Olsen IDC/CAD II-IV Hemodynamics 1.34 –
US Carvedilol IDC/CAD II-IV Hemodynamics – -65%
ANZ CAD I-III Exercise tolerance,
EF, morbidity+mortality 0.75 -26%
Krum IDC/CAD II-IV Hemodynamics 0.70 –
Bristow IDC/CAD II-IV Exercise tolerance 0.26 -73%
Packer IDC/CAD II-IV Exercise tolerance 0.39 -65%
Colucci IDC/CAD II-III Morbidity+mortality 0.22 –
Cohn IDC/CAD II-IV Quality of life – –
Copernicus IDC/CAD IV Morbidity+mortality – -35%
Capricorn CAD I-II Morbidity+mortality – -23%

IDC = idiopathic dilated cardiomyopathy; CAD = coronary artery disease.

120
 Carvedilol: something else than a simple betablocker?
gy (mostly dilatative cardiomiopathy) and
with EF < 35%. The end points of these stud-
ies were the control of the progression of
heart failure, the improvement in short-medi-
um time (follow-up period of 6 months) of LV
EF, the improvement in NYHA class and to
find the most adequate drug dosage.
The total number of patients studied in US
Carvedilol trial was lower than other trials
and the mean age of patients was only 58
years. Besides the mean follow up was short-
er than the other major beta-blocker trials, so
the results of risk reduction were too
favourable (in fact no patients were lost dur-
ing the study for death)42,43,44.
MacDonald et al.45 compared retrospectively
the outcome of Carvedilol treatment for 3-12
months in patients with NYHA class I-III and
IV. The results revealed that class IV patients
are more likely to develop adverse events dur-
ing initiation and dose titration compared with
less symptomatic patients, yet they are more
likely to show symptomatic improvements in
the long term. Carvedilol improved functional
classes in patients with severe heart failure who
were referred for transplantation. Taken togeth-
er Carvedilol may be a beneficial adjunctive
therapy, even with patients with serious left ven-
Probability of event-free survival
100 days
Figure 3. Difference in survival in non treated and treated patients.
tricular dysfunction and poor NYHA classifica-
tion. However, they require close observation
during initiation and titration of the drug.
Copernicus and Capricorn trials confirmed
these data:
The Copernicus Trial (Carvedilol Prospe-
ctive Randomized Cumulative Survival
Trial)39 extended the use of Carvedilol also in
more severe heart failure with beneficial ef-
fects on morbidity and mortality. In fact this
study enrolled NYHA IV class patients in a
phase of relative stability, with EF < 25% in a
10 months of follow-up period. The trial was
interrupted early on a Data and Safety
Monitoring Board order because the benefi-
cial effects were greater than those expected
in the end-points (Figure 3).
The Capricorn Trial (Carvedilol Post-
Infarct Survival Control in left ventricular dys-
function)46, a multicentric randomized trial,
was made to test the efficacy at long term of
Carvedilol therapy on morbidity and mortality
in patients with left ventricular dysfunction
secondary to IMA. These patients were at low
risk, few of them had heart failure. The prima-
ry end-point was to evaluate the mortality of
every cause. The follow up was of about 15
months. All the end-points showed a
Carvedilol
Placebo
200 days 300 days 400 days
Days of therapy
121
 A. Palazzuoli, P. Calabria, M.S. Verzuri, A. Auteri
favourable trend (total mortality, cardiovascu-
lar mortality, IMA, mortality due to heart fail-
ure o arrhythmias, ospedalizations).
Carvedilol has demonstrated a good effica-
cy also after thrombolysis for acute myocar-
dial infarction (AMI). This efficacy has been
tested in a trial from Basu et al.26, in which
Carvedilol was found to be safe and it signifi-
cantly reduced cardiac events in early phases
of AMI, also in patients with heart failure.
Such encouraging results gave the start to
numerous other randomized trials regarding
various problems of patients with heart fail-
ure. Among these the most important are:
SPIC, Christmas, Carmen and Comet.
SPIC (Italian Polycentric Study on
Cardiomiophaty) values the effects of
Carvedilol on quality of life, exercise toler-
ance, ventricular function and autonomic
tone in patients with idiopathic dilated car-
diomiophaty in II-IV NYHA class and with
EF < 35%.
Christmas Trial (Carvedilol Hibernation
Reversible Ischemic Trial; Marker of
Success) is studiyng how the answer to
Carvedilol in heart failure secondary to is-
chemic heart disease is conditioned by previ-
ous myocardial conditions47.
Carmen Trial (Carvedilol, ACE-inhibitor
remodelling mild heart failure evaluation),
a multicentric, randomized, double blind
trial, is trying to value the effects of
Carvedilol, of enalapril and of the associa-
tion of both the drugs on left ventricular
function and on ventricular remodelling in
heart failure48.
Comet Trial (Carvedilol or Metoprolol
European Trial) is controlling the efficacy on
morbidity and mortality of these two drugs in
patients with heart failure secondary to is-
chemic and non-ischemic causes49.
From various metanalyses of the trials, it
has been seen an important β-blocker addi-
tive and synergetic effect in patients previ-
ously in treatment with ACE-inhibitors also
on the duration or the quality of life.
Carvedilol has other synergetic effect:
• reduction of about 30% on global mor-
tality
• reduction of sudden death
• improvement in EF (of about 30%), and
in the NYHA class
• improvement in the exercise capacity
122
From all the examined data it is possible
to say that the beta-blockers can improve
haemodynamic parameters and these results
are most pronounced for Carvedilol therapy,
independently from the aetiology of heart
failure and probably even in advanced NY-
HA class and in more compromised
subjects3,50.
Therapeutic Contraindications
of Carvedilol
The main contraindications to β-blocker
therapy are peripheral vascular diseases, dia-
betes mellitus, chronic obstructive pulmonary
disease (COPD) and asthma. Most of these
side effects are due to the block of β2-recep-
tors, while the therapeutic effects are due to
the block of b1-receptors.
Some favourable reduction in side effects
has been obtained with further generation of
β-blockers like Carvedilol. Recent data seem
to show that these rules should not be applied
in a rigorous way. So the introduction of
Carvedilol and of the other new generation
drugs have been an important step to reduce
the side effects and to enlarge the therapeutic
possibilities but complete safety hasn’t been
reached yet.
Peripheral Vascular Disease
Beta-blockers should be avoided only in
those patients with vasospastic disorders,
rest pain with severe peripheral vascular dis-
ease or nonhealing lesions. In patients with
mild to moderate disease β-blockers can be
prescribed, remaining with careful surveil-
lance about an impairment of intermittent
claudicatio.
In 1991, Radak and Deck published a
metanalisys in patients with mild to moderate
peripheral vascular disease treated with β-
blockers. The β-blockers did not worsen the
peripheral disease51.
It is possible that compounds like
Carvedilol, thanks to vasodilated activity a1-
receptors-block related, could reduce this
kind of side effect.
Diabetes Mellitus
β-blockers can reduce the peripheral sen-
sibility to insulin and modificate in un-
favourable way the LDL-HDL equilibrium
 Carvedilol: something else than a simple betablocker?
in plasma 52-56 . However, clinical trials
showed that β-blocker therapy improvement
in mortality and morbidity exceeded the
negative influences on the glycemic and lipid
risk profile57.
In patients with heart failure, β-blockers
can induce hyperglycemia, but Carvedilol,
thanks to its vasodilatative activity, can im-
prove the peripheral sensitivity to insulin
for the better peripheral blood flow in the
muscles.
Another problem is that β-blockers can
mask the metabolic answer to hypoglycemia
blocking the autonomic symptoms of the neu-
rohumoral reaction to hypoglycemia.
Nevertheless, these symptoms are due to
many hormones not under the autonomic
control and one of the most important
(sweatness) seems to depend on the parasym-
pathetic stimulation. Therefore, β-blockers
must be used carefully in diabetic patients,
but not be avoided. In particular, the use of
Carvedilol is contraindicated only in decom-
pensated type II diabetes.
Chronic Obstructive Polmunary Disease
and Asthma
β-blockers in patients with COPD and
asthma must be used carefully. In asthmatic
patients β-blockers-induced bronchoconstric-
tion is conditioned by many and often impre-
dictable variables58,59. So it’s very difficult to
identify high risk patients.
Bronchial hyperactivity and reversibility of
bronchoconstriction are very important ele-
ments to calculate the risk of β-blockers ther-
apy. Particularly, non selective β-blockers are
absolutely contraindicated when certain diag-
nosis of asthma is present, when COPD is
moderate to severe (and not in mild cases), in
patients on chronic bronchodilator treatment,
in chronic airflow limitation with reversibility
in obstruction in response to inhaled salbuta-
mol. β-blockers can be used when FEV1 is >
50% of the predicted value, controlling the
stability of ventilatory conditions.
Bradycardia
The use of β-blockers is contraindicated
when heart rate is < 50-55 bpm. Often pa-
tients are already in treatment with drugs de-
termining heart rate reduction (digitalis,
amiodarone). Often it’s difficoult to choose
between these two types of treatment, how-
ever digitalis and amiodarone had not
showed effects on mortality and survival. For
this reason it seems well founded to intro-
duce β-blockers (favouring Carvedilol) re-
ducing or suspending other drugs determin-
ing heart rate reduction if they are not toler-
ated all togheter60.
Hypotension
We must be careful when hypotension is
symptomatic or when systolic pressure is <
80-90 mmHg. Before contraindicating the
use of β-blockers it’s necessary to increase
the pressure by modifying the associated
therapy61.
Atrial Sinus Knot Diseases
β-blockers are able to neutralise electro-
physiological effects of β-adrenergic stimula-
tion improving the slope of the 4th phase of
action potential and increasing junctional
conduction61. So β-blockers are contraindicat-
ed in Sick Sinus Syndrome and in II and III
degree atrial sinus block because they are
able to inhibit the atrial sinus automatism.
Atrio-Ventricular Block
β-blockers have a remarkable effect on
junction conduction in proportion to the
power of the used β-blocker and to the sin-
gle dose administered. In particular, β-block-
ers are contraindicated in II and III degree
A-V block (in bi- and tri-fascicular blocks,
also if bi-fascicular blocks are not an ab-
solute contraindication) because the exten-
sion of the A-V conduction time could be
dangerous for the capacity to induce a
marked bradiarrhythmia. Thus, patients
with A-V conduction diseases and intraven-
tricular delay must be monitored to avoid a
further QRS time extension or an increase
of A-V conduction time62,63.
Alteration of Liver Function
Carvedilol is highly lipophilic and it is
metabolised in the liver and several metabo-
lites are pharmacologically active. Its use is
contraindicated when liver alterations are
clinically evident64.
Kidney Diseases
β-blockers must be administrated carefully
in renal insufficiency secondary to angiosclero-
sis and tubulopathy. In reno-vascular diseases
123
 A. Palazzuoli, P. Calabria, M.S. Verzuri, A. Auteri
β-blockers are contraindicated for their vaso-
constrictive effects on the afferent arteria.
However, Carvedilol has a demonstrated effi-
cacy in patients with renal insufficiency and
hypertension submitted to haemodialysis62,63.
Cardiogenic Shock
β-blockers effects on pressure, automatism
and on the adrenergic answer make the use
of this drug contraindicated in this condition.
In conclusion, we can say that traditional
contraindications to β-blockers can be rivalu-
tated because the introduction of the new
generation of this drugs (like Carvedilol) and
the new knowledges permit a larger use and
and a better prevedibility of the side effects61.
Infact, clinical trials have demonstrated the
importance of Carvedilol in the improvement
of morbidity and mortality also in patients
who were excluded in the past from this ther-
apy because the benefits exceed eventual bad
influences on risk profile.
Conclusions
β-blockers cannot be considered as drugs
with negative inotropic effects, their employ-
ment is effective in the treatment of heart
failure and the chronic use has favorable ac-
tions on the LV remodeling and myocardial
contractility. These actions are clear after a
few months of therapy but they remain for
long time. In particular, Carvedilol showed a
good tolerance also in more compromised pa-
tients thanks to its vasodilator properties
which allow to less bradycardia and less acute
haemodynamic impairment43. Carvedilol also
demonstrated minor adverse effects than oth-
er beta-blockers and it can be administered in
elderly, in diabetes, in mild peripheral disease
with good safety, monitoring during drugs
titration clinical and laboratory conditions65.
Carvedilol provides cardiovascular protec-
tion through its antiatherogenic antiischemic
and antihypertrophic actions for all ancillary
molecular properties its use should increase
in cardiac disease leading to a clinical benefit
and antagonizing adverse patophysiologic
processes. The combination of all these bene-
fits encourages its use in the treatment of hy-
pertension, coronary heart disease and car-
diac failure.
124
References
1) PACKER M. The neurohormonal hypothesis: a theo-
ry to explain the mechanism of disease progres-
sion in heart failure. J Am Coll Cardiol 1992; 20:
248-254.
2) H EIDENREICH PA, L EE TT, M ASSIE BM. Effect of
betablockade on mortality in patients with heart
failure: a meta-analysis of randomized clinical tri-
als. J Am Coll Cardiol 1997; 30: 27-34.
3) MCMURRAY JV. Major betablocker mortality trials in
chronic heart failure: a critical review. Heart 1999;
82 (Suppl IV): 14-22.
4) M C T AVISH D, C AMPOLI -R ICHARDS D, S ORKIN EM.
Carvedilol: a review of its pharmacodynamic and
pharma-cokinetic properties and therapeutic effi-
cacy. Drugs 1993; 45: 232-258.
5) R UFFOLO RR, F EUERSTEIN GZ. Pharmacology of
carvedilol: Rationale for use in hypertension,
coronary heart disease, and congestive heart fail-
ure. Cardiovasc Drugs Ther 1997; 11: 247-256.
6) DUNN CJ, LEA AP, WAGSTAFF AJ. Carvedilol. A reap-
praisal of its pharmacological properties and ther-
apeutic use in cardiovascular disorders. Drugs
1997: 54: 161-185.
7) MORGAN T. Clinical pharmacokinetics and pharma-
codynamics of carvedilol. Clin Pharmacokinet
1994; 26: 335-346.
8) GEHR TWB, TENERO DM, BOYLE DA, QIAN Y, SICA DA,
S H U S T E R M A N NH. The pharmacokinetics of
carvedilol and its metabolites after single and
multiple dose oral administration in patients with
hypertension and renal insufficiency. Eur J Clin
Pharmacol 1999; 55: 269-277.
9) CHENG J KAMIYA K, KODAMA I. Carvedilol: Molecular
and cellular basis for its multifaceted therapeutic
potential. Cardiovasc Drug Rev; 19: 152-171.
10) YUE T-L, MCKENNA J, GU JL, CHENG HY, RUFFOLO RR,
FEUERSTEIN GZ. Carvedilol, a new vasodilating be-
ta-adrenoceptor blocker antihypertensive drug,
protects endothelial cells from damage initiated
by xanthine--xanthine oxidase and neutrophils.
Cardiovasc Res 1994; 28: 400-406.
11) FEUERSTEIN G, YUE TL, MA X, RUFFOLO RR. Novel
mechanisms in the treatment of heart failure:
Inhibition of oxygen radicals and apoptosis by
carvedilol. Prog Cardiovasc Dis 1998: 41 (Suppl
1): 17-24.
12) YUE TL, WANG X, GUE JL, RUFFOLO RR JR., FEUERSTEIN
GZ. Carvedilol, a new vasodilating beta-adrenore-
ceptor blocker, inhibits oxidation of low density
lipoproteins by vascular smooth muscle cells and
prevents leukocyte adhesion to smooth muscle
cells. J Pharmacol Exp Ther 1995; 273: 1442-
1449.
13) HONDEGHEM LM, SNYDERS DJ. Class III antiarrythmic
agents have a lot of potential but a long way to
go. Reduced effectiveness and dangers of re-
verse use dependence. Circulation 1990: 81:
686-690.
 Carvedilol: something else than a simple betablocker?
14) SENIOR R, MULLER-BECKMANN B, DASGUPTA P, VAN DER
DOES R, LAHIRI A. Effects of carvedilol on ventricu-
lar arrhythmias. J Cardiovasc Pharmacol 1992;
19: S117-S121.
15) JACOB S, RETT K, HENRIKSEN EJ. Antihypertensive
therapy and insulin sensitivity: Do we have to re-
define the role of beta-blocking agents? Am J
Hypertens 1998: 11: 1258-1265.
16) SUNG C-P, ARLETH AL, OHLSTEIN EH. Carvedilol in-
hibits vascular smooth muscle cell prolifera-
tion. J Cardio-vasc Pharmacol 1993; 21: 221-
227.
17) OHLSTEIN EH, VICKERY L, ARLETH A, et al. Carvedilol,
a novel cardiovascular agent, inhibits develop-
ment of vascular and ventricular hypertrophy in
spontaneously hypertensive rats. Clin Exp
Hypertens 1994; 16: 163-177.
18) MOSER M, FRISHMAN WH. Results of therapy with
carvedilol a betablocker vasodilator with antioxi-
dant propierties in hypertensive patients. Am J
Hypertens 1998; 11: 15S-22S.
19) OSTERGREN J, STORSTEIN L, KARLBERG BE. Quality of
life in hypertensive patients treated with either
carvedilol or enalapril. Bood Press 1996; 5: 41-
49.
20) WEBER K, BOHMEKE T, VAN DER DOES R, TAYLOR SH.
Hemodynamic differences between metoprolol
and carvedilol in hypertensive patients. Am J
Hypertens 1998; 11: 614-617.
21) HAUF-ZACHARIOU U, BLACKWOOD RA, GUNAWARDENA
KA, O’DONNEL JG, GARNHAM S, PFARR E. Carvedilol
versus verapamil in chronic stable angina: a mul-
ticentre trial. Eur J Clin Pharmacol. 1997; 52: 95-
100.
22) V AN D ER D OES R, H AUF -Z ACHARIOU U, P FARR E.
Comparison of safety and efficacy of carvedilol
and metoprolol in stable angina pectoris. Am J
Cardiol 1999; 83: 643-649.
23) B RUNNER M, FABER TS, G REVE B. Usefunless of
carvedilol in unstable angina pectoris. Am J
Cardiol 2000; 85: 1173-1178.
24) N ICHOLS AJ, S ULPIZIO AC, A SHTON DJ, H IEBLE JP,
RUFFOLO RR. In vitro pharmacologic profile of the
novel beta-adrenoreceptor antagonist and va-
sodilator, carvedilol. Pharmacology 1989; 39:
327-336.
25) K H A N D O U D I N, P E R C E VA U LT-A L B A D I N A J, B R I L A.
Comparative effect of carvedilol and metoprolol
on cardiac ischemia-reperfusion injury. J
Cardiovasc Pharmacol 1998; 32: 443-451.
26) B ASU S, S ENIOR R, R AVAL U, V AN D ER D OES R,
BRUCKNER T, LAHIRI A. Benefical effects of intra-
venous and oral carvedilol treatment in acute my-
ocardial infarction. A placebo controlled random-
ized trial. Circulation 1997; 96: 183-191.
27) SENIOR R, BASU S, KINSEY C, SCHAEFFER S, LAHIRI A.
Carvedilol prevents remodeling in patients with
left ventricular dysfunction after acute myocardial
infarction. Am Heart J 1999; 137: 646-652.
28) OCHIAI N, FURUKAWA K, EBIZAWA T, et al. Is myocar-
dial impairment in idiopathic dilated hypertrophic
cardiomyopathy reversible by carvedilol? J
Cardiol 2000; 36: 183-189.
29) CLEELAND JG, GEMMELL I, KHAND A, BODDY A. Is the
prognosis of heart failure improving? Eur J Heart
Fail 1999; 3: 229-241.
30) MACMAHON S, AUSTRALIA/NEW ZELAND HEART FAILURE
COLLABORATIVE GROUP. Randomized, placebo con-
trolled trial of carvedilol in patients with conges-
tive heart failure due to ischaemic heart disease.
Lancet 1997; 349: 374-380.
31) CIBIS INVESTIGATORS AND COMMITTEES. A randomized
trial of beta-blockade in heart failure: the Cardiac
Insufficiency Bisoprolol Study (CIBIS). Circulation
1994; 90:1 765-773.
32) BRISTOW MR. Beta adrenergic receptor blockade in
chronic heart failure. Circulation 2000; 101: 558-
569.
33) SHARPE N, DOUGHTY RN. Left ventricular remodel-
ling and improved long term outcomes in chronic
heart failure. Eur Heart J 1998; 19B: B36-B39.
34) LOWES BD, GILL EA, ABRAHAM WT, et al. Effects of
carvedilol on left ventricular mass chamber
geometry and mitral regurgitation in chronic heart
failure. Am J Cardiol 1999; 83: 1201-1205.
35)) SWEDBERG K, HJALMARSON A, WAAGSTEIN F, WALLENTIN
I. Adverse effect of betablockade withdrawal in
patients with congestive cardiomyopathy Br Heart
J 1980; 44: 134-142.
36) FEUERSTEIN GZ, BRIL A, RUFFOLO RR. Protective ef-
fects of carvedilol in the myocardium. Am J
Cardiol 1997; 80 (11A): 41L-45L.
37) ANDERSON JL, GREENBERG B, BODEN W, et al. Design
of the betablocker evaluation survival trial BEST.
Am J Cardiol 1995; 75: 1220-1223.
38) THE CARDIAC INSUFFICIENCY BISOPROLOL STUDY II A RAN-
DOMIZED TRIAL INVESTIGATION AND COMMITTEES. Lancet
1999; 353: 9-13.
39) PACKER M, COATS AJS, FOWLER MB, et al. Effect of
carvedilol on survival in severe chronic heart fail-
ure. N Engl J Med 2001; 344: 1651-1658.
40) W AAGSTEIN F, B RISTOW MR, S WEDBERG K, et al.
Metoprolol in Dilated Cardiomyopathy (MDC)
Trial Study Group. Beneficial effects of metoprolol
in idiopathic dilated cardiomyopathy. Lancet
1993; 342: 1441-1446.
41) A USTRALIAN N EW Z EALAND H EART FAILURE R ESEARCH
COLLABORATIVE GROUP. Effects of carvedilol, a va-
sodilator-beta-blocher in patients with congestive
heart failure due to ischemic heart disease.
Circulation 1995; 92: 212-218.
42) Bristow MR, Gilbert EM, Abraham WT, et al.
Multicenter oral Cavedilol heart failure assess-
ment (MOCHA): a six months dose-response
evaluation in class II-IV patients. Circulation
1995; 92-8 (Suppl I): I-142.
125
 A. Palazzuoli, P. Calabria, M.S. Verzuri, A. Auteri
43) C O L U C C I WS, P A C K E R M, B R I S T O W MR, et al.
Carvedilol inhibits disease progression in patients
with mild heart failure. Circulation 1995; 92-8
(Suppl I): I-395.
44) PACKER M, COLUCCI WS, SACKNER-BERNSTEIN J, et al.
Prospective randomized evaluation of carvedilol
in patients with moderate to severe heart failure.
The PRECISE trial. Prospective randomized eval-
uation of Carvedilol on symptoms and exercise.
Circulation 1996; 94: 2793-2799.
45) MACDONALD PS, KEOGH AM, ABOYOUN CL, LUND M,
AMOR R, MCCRAFFEY DJ. Tolerability and efficacy of
carvedilol in patients with New York Heart
Association Class IV heart failure. J Am Coll
Cardiol 1999; 33: 924-931.
46) THE CAPRICORN INVESTIGATORS. Effect of carvedilol on
outcome after myocardial infarction in patients
with left-ventricular dysfunction: the CAPRICORN
randomised trial. Lancet 2001; 357: 1385-1390.
47) CLELAND JG, PENNEL D, RAY S, et al. The carvedilol
hibernation reversible ischaemia trial; marker of
success (CHRISTMAS). The CHRISTMAS Study
Steering Committee and Investigators. Eur J
Heart Fail 1999; 1: 191-196.
48) THE CARVEDILOL AND ACE-INHIBITOR REMODELLING MILD
HEART FAILURE EVALUATION TRIAL (CARMEN)-RATIONALE
AND DESIGN. Cardiovasc Drugs Ther 2001; 15: 69-
77.
49) POOLE-WILSON PA, CLELAND JG, DI LEARDA A, et al.
Rationale and design of the carvedilol or meto-
prolol European trial in patients with chronic heart
failure: COMET. Eur J Heart Fail 2002; 4: 321-
329.
50) LECHAT P, PACKER M, CHALON S, CUCHERAT M, ARAB T,
BOISSEL JP. Clinical effect of beta-adrenergic block-
ade in chronic heart failure: a meta-analysis of
double blind placebo controlled randomised trial.
Circulation 1998; 98: 1184-1191.
51) RADAK K, DECK C. Beta-adrenergic blocker therapy
does not worsen intermittent claudication in sub-
jects with peripheral arterial disease. Arch Intern
Med 1991; 151: 1769-1776.
52) GOLDSTEIN S. Beta-blockers in hypertensive and
coronary heart disease. Arch Intern Med 1996;
156: 1267-1276.
126
53) F R A G A S S O G, C AT TA N E O N, L O C AT E L L I M, et al.
Differential ef-fects of selective beta-adrenergic
blockade on insulin sensi-tivity and release in
control subjects and in patients with angina and
normal coronary arteries (syndrome X). G Ital
Cardiol 1998; 28: 623-629.
54) TSE WY, KENDALL M. Is there a role for beta-block-
ers in hy-pertensive diabetic patients. Diabet Med
1994; 11: 137-144.
55) JACOB S. RETT K, HENRIKSEN EJ. Antihypertensive
therapy and insulin sensitivity: do we have to re-
define the role of beta-blocking agents? Am J
Hypertens 1998; 11: 12581265.
56.) HAENNI A, LITHELL H. Treatment with a beta-blocker
with be-ta-agonism improves glucose and lipid
metabolism in es-sential hypertension.
Metabolism 1994; 43: 455-461.
57) KJEKSHUS J, GILPIN E, CALI G, BLACKEY AR, HENNING H,
ROSS J. Diabetic patients and beta-blockers after
acute myocar-dial infarction. Eur Heart J 1990;
11: 43-50.
58) LIGGETT SB. Polymorphisms of the beta-adrenergic
receptor and asthma. Am J Respir Crit Care Med
1997; 156 (Part 2): S156-S162.
59) IM-ILOF IV. Beta-blockers and bronchial asthma.
Schweiz Rundsch Med Prax 1995; 84: 319-320.
60) WEISSWANGE A. Is bradycardia a contraindication?
Cardiology 1978; 63 (Suppl 1): 58-61.
61) LAMA PJ. Systemic adverse effects of beta-adren-
ergic blockers: an evidence based assessment.
Am J Opthalmol 2002; 134: 749-760.
62) J OYE F. Beta-blocker intoxication. Presse Med
2000; 29:1027-1033.
63) HANTSON P, LAMBERMONT JY, SIMOENS G, MAHIEU P.
Carvedilol overdose. Acta Cardiol 1997; 52: 369-
371.
64) HAGMEYER KO, STEIN J. Hepatotoxicity associated
with carvedilol. Ann Pharmacother 2001; 35:
1364-1366.
65) C L E E L A N JG, S W E D B E R G K, P O O L E -W I L S O N P.
Successes and failures of current treatment of
heart failure. Lancet 1998; (Suppl) 352: 19-28.