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Introduction
The concept of heart failure as a disease of progressive left ventricular (LV) dysfunction and car-
Address for correspondence: Robert L. Talbert, Clinical Pharmacy Program, University of Texas Health Science Center at
San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 782293900, USA. Tel.: 210-567-8318; E-mail: talbert@uthscsa.edu
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translated into routine clinical practice [13]. Surveys indicate that the utilization of -blockers in
patients with heart failure is suboptimal in terms
of a low utilization of -blockers in appropriate
patients, a failure to up-titrate to -blocker doses
proven to be effective in large-scale clinical trials, and selection of -blockers not formally studied in patients with heart failure [14]. One of the
potential reasons for lack of adoption of routine
-blocker therapy in heart failure is ill-conceived
concern over adverse effects. Although -blockers
are associated with increased risk of hypotension,
dizziness and bradycardia, the benefits gained in
reduced all-cause mortality, heart failure hospitalizations and worsening heart failure far outweigh
these potential adverse effects [15]. The proper
use of -blockers has thus emerged as a major issue in the management of chronic heart failure
[14].
A controversial question is whether there are
significant and clinically meaningful differences
in effectiveness among the various -blockers
that should influence the appropriate choice
of agent [16]. Although bisoprolol, carvedilol,
and ER metoprolol succinate demonstrated similar clinical benefits in patients with chronic
heart failure, pharmacodynamic differences exist
among the -blockers, particularly with regard to
adrenergic receptor selectivity. Whereas metoprolol and bisoprolol selectively block 1 -receptors,
carvedilol provides nonselective adrenergic blockade, inhibiting the 1 -, 2 -, and 1 -receptors [16].
Carvedilol also possesses antioxidant property
which may play a role in limiting cytokine induced autoimmune myocarditis [17]. In addition,
carvedilol binds tightly to and dissociates slowly
from the -receptor providing inherently longer
duration of -blockade, in contrast to metoprolol
which has fast offset kinetics [18].
Nonselective versus selective beta-adrenergic
receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by pre-junctional beta2 -adrenergic
receptors. Several small studies have shown differences between carvedilol and metoprolol altering cardiac norepinephrine spillover and improvement in ejection fraction, however, these studies
often used short-acting metoprolol tartrate dosed
twice daily and at less than full -blocking doses
based on studies done using exercise heart rate
limitation as the major method of assessing the extent of -blockade in humans [19,20]. In contrast,
other studies have failed to show any differences in
LV function, neurohormonal activation, exercise
capacity, symptoms and quality of life in patients
with heart failure or cardiomyopathy between
carvedilol and metoprolol [2124]. None of the
studies examining the effects of carvedilol or metoprolol on surrogate end points are large enough to
detect clinically meaning changes in cardiovascular mortality or morbidity and only the Carvedilol
or Metoprolol European Trial (COMET) has been
sufficiently powered to assess these end points
[25]. The COMET trial demonstrated a significant risk reduction for all-cause mortality in heart
failure patients treated with carvedilol compared
with immediate release (IR) metoprolol tartrate,
although no differences for hospitalizations were
observed. Because the COMET results could have
substantial impact on the choice of -blocker in
the management of heart failure, they deserve
further analysis. This review will closely examine
the design of COMET, with a focus on important
pharmacologic issues, in order to provide a careful
scientific interpretation of the results.
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135
ics [18]. The extended T1/2 and long terminalelimination phase, the slow dissociation kinetics from the -receptor, plus the persistent contribution of possibly active metabolite(s), make
carvedilol a longer-acting -blocker than metoprolol, irrespective of formulation.
Both carvedilol and metoprolol undergo stereoselective metabolism by CYP2D6, but with differing pharmacodynamic results [16,46,47]. Like
metoprolol, carvedilol is commercially available as
a racemic mixture: the S-enantiomer is a much
more potent -blocker than the R-enantiomer
and the R-enantiomer may blunt the effect of
the S-enantiomer [48]. There are also differences in metabolism: S-carvedilol is more reliant
upon CYP2D6 (though not exclusively so) for
catalysis, whereas R-carvedilol is a substrate for
CYP2C9. Therefore, patients who are phenotypically CYP2D6 poor metabolizers (5 to 10% of Caucasians) may have higher serum concentrations of
the 1 -blocker R-isomer, leading to a higher degree of hypotension in this group of patients [47].
Table 1. Comparison of pharmacokinetics between carvedilol
and immediate release metoprolol tartrate
IR Metoprolol
tartrate
F (%)
Protein binding (%)
Vdss
Half-life
CYP450 substrate
40
10
4 L/kg
37 hours
CYP2D6
Active metabolites
No
Carvedilol
25
95
1.5 L/kg
610 hours
CYP2D6 (R>S)
CYP2C9 (S>R)
Yes
F, fraction absorbed with oral dosing; IR, immediate release; Vdss , volume of distribution as steady state; CYP, Cytochrome; R, R-enantiomer;
S, S-enantiomer.
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5.
6.
7.
8.
9.
10.
11.
Summary
Immediate-release metoprolol tartrate is shorter
acting that carvedilol, based upon its pharmacokinetics (elimination rate and T1/2 ) and its pharmacodynamics (-receptor kinetics) metoprolol does
not provide consistent plasma levels nor attenuation of exercise heart rate in normals or patients
with heart failure unless it is dosed three times per
day. ER metoprolol succinate provides sustained
plasma concentrations over a 24 hour period and
a more consistent effect on exercise heart rate.
Metoprolol tartrate and metoprolol succinate are
not interchangeable and only metoprolol succinate
has been approved in the U.S. for the treatment of
heart failure.
12.
13.
14.
15.
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