Heart Failure Reviews, 9, 131137, 2004

C 2005 Springer Science + Business Media, Inc.

Pharmacokinetics and Pharmacodynamics of Beta Blockers

in Heart Failure
Robert L. Talbert, Pharm D, FCCP, BCPS
Professor, Division of Pharmacotherapy, College of Pharmacy,
The University of Texas at Austin and Professor, Departments of
Medicine and Pharmacology, University of Texas Health Science
Center at San Antonio, TX 78229-3900, USA

Abstract. Although beta-blockers have been used for nearly

three decades in the management of heart failure, only recent randomized clinical trials have demonstrated substantial benefit in reducing morbidity and mortality. Carvedilol,
metoprolol succinate and bisprolol have evidence supporting their use in heart failure while other beta blockers either
lack evidence supporting their use or have not been shown
to be useful in heart failure. The only currently approved
beta-blockers in the U.S. for heart failure are metoprolol
succinate and carvedilol.
Beta-blockers differ in their pharmacokinetic and pharmacodynamic properties. It should not be assumed that
potential benefit in heart failure is a class effect since
differences in the half-life, volume of distribution, protein
binding, and route of elimination may give rise to differences in duration of beta blockade and potential drug interactions. Furthermore, pharmacodynamic differences exist because of selectivity for 1 , 2 or 1 adrenoreceptor
blockade among the beta-blockers. Receptor kinetics also
differ among the beta-blockers and this may influence the
extent and duration of beta and alpha blockade across the
category.
Carvedilol is an inherently long-acting beta-blocker
while the duration of beta blockade for metoprolol is dependent on the salt and formulation, which is used. Metoprolol
tartrate is a short-acting form of metoprolol while metoprolol succinate is a longer acting salt and the commercially
available product is designed as a once daily formulation. A
recently published trial, the Carvedilol or Metoprolol European Trial (COMET) tested carvedilol given twice daily versus metoprolol tartrate given twice daily in patients with
chronic heart failure. Although carvedilol reduced all cause
mortality when compared with metoprolol tartrate, extrapolation to similar findings with metoprolol succinate are not
possible since the pharmacokinetic and pharmacodynamic
effects of these two formulations are different. Furthermore, the dosing of metoprolol tartrate in COMET may have
been inadequate based on prior studies. Additional studies
are needed to compare carvedilol directly to metoprolol succinate before concluding inequivalency exists for these two
beta-blockers in heart failure.
Key Words. beta blockers, pharmacokinetics,
pharmacodynamics, metabolism

Introduction
The concept of heart failure as a disease of progressive left ventricular (LV) dysfunction and car-

diac pump failure is still an essential model upon

which therapies have been developed to relieve
symptoms and improve outcomes. However, the
importance of neurohormonal blockade, particularly the renin-angiotension system (RAS) and the
sympathetic nervous system (SNS) in improving
survival as well as symptomatic improvement has
become apparent with publication of recent experimental and clinical research [1,2]. Integration of
the hemodynamic model with the neurohormonal
model of heart failure has led to the recommendation of agents to suppress the RAS and SNS, specifically angiotension-converting enzyme inhibitors
(ACEI), and/or angiotension receptor blockade and
-blockers, respectively for the routine treatment
of heart failure, along with therapies targeting
symptom relief but not affecting mortality, diuretics and digoxin [35].
The current integral role of -blockers, which
inhibit the SNS at the -adrenergic receptor level,
in heart failure management represents a striking change in practice from the past, when these
agents were considered contraindicated in heart
failure because of their negative inotropic actions [6]. Recent large-scale trials have demonstrated that the -blockers bisoprolol, carvedilol,
and extended-release (ER) metoprolol succinate
each significantly reduce all-cause mortality in patients with heart failure by 34 to 35%, sudden
death by >40%, and hospitalizations for heart failure by >30%, compared with standard therapy
without -blockade [711]. Similar clinical benefits were seen in patients with severe as well as
mild-to-moderate heart failure with carvedilol and
ER metoprolol succinate [9,12].
Randomized clinical trial results clearly support the routine use of -blockers in heart failure
for all classes of heart failure due to systolic dysfunction, unfortunately these data have not been

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
131

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Talbert

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.

Design of the COMET Trial

COMET was a multicenter, double-blind, parallelgroup study designed to compare the effects of
carvedilol, which provides nonselective blockade
of the 1 /2 /1 -adrenergic receptors, with those
of IR metoprolol tartrate, which provides selective
1 -blockade, in 3029 patients with chronic heart
failure [25]. Patients were enrolled with New York
Heart Association Class IIIV heart failure (96%
were Class II or III) and a LVEF <35%, who were
optimally treated with diuretics (99%) and ACEI
(9192%). About 60% were receiving digitalis and
only 11% were receiving aldosterone antagonists.
The co-primary endpoints were all-cause mortality and the composite of all-cause mortality or
all-cause hospital admission. Subjects were randomized to carvedilol 3.125 mg twice daily (N =
1511) or IR metoprolol tartrate 5 mg twice daily
(N = 1518). Each drug was to be up-titrated every 2 weeks to achieve target doses of 25 mg twice
daily and 50 mg twice daily for carvedilol and IR
metoprolol tartrate, respectively, as tolerated. The
mean daily dose at the beginning of the trials
maintenance phase was 42 mg in the carvedilol
group and 85 mg in the IR metoprolol tartrate
group. After a mean follow-up of 58 months, allcause mortality was 34% (annual rate 8.3%) in
the carvedilol group and 40% (annual rate 10.0%)
among those treated with IR metoprolol tartrate,
representing a relative risk reduction of 17% with
carvedilol (P = .0017). There were no significant
differences between the treatment groups in the
composite primary endpoint of all-cause mortality
or all-cause hospital admission, or in the number
of hospitalizations. Study drug was permanently
discontinued by 32% of the subjects in both treatment groups, and the incidence of adverse effects
was similar in both groups.
Despite an identical mean baseline heart rate
in both treatment groups (81 beats per minute),
carvedilol reduced heart rate by 13.3 beats per

Pharmacokinetics and Pharmacodynamics of Beta Blockers in Heart Failure

Fig. 1. Resting heart rate reductions (beats per minute) with

carvedilol and immediate release metoprolol tartrate in the
COMET (reference 26) study over five years. Error bars are 1
standard error. p = 0.0022; p = 0.0034; p = 0.004.

minute (bpm) at 4 months, compared with an

11.7 bpm reduction with IR metoprolol tartrate
(Fig. 1). Significant differences in heart rate
reduction continued between the two groups
through the first 16 months of follow-up. Of note,
heart rate was determined randomly so that
neither peak or trough effect of -blockade on
heart rate was assessed systematically. Similarly, although baseline blood pressure (BP) was
identical in both groups, a significantly greater
reduction in systolic BP (SBP) was observed at 4
months in the carvedilol group compared with the
IR metoprolol tartrate group (3.8 vs. 2.0 mmHg,
respectively). Significant differences in both SBP
and diastolic BP (DBP) between the two groups
were observed throughout the trial [26]. These
findings, less heart reduction and higher blood
pressures, are indicative of unequal -blockade
between the two treatment groups. However,
concerns have been raised regarding the choice
of IR metoprolol tartrate as the appropriate comparator agent in COMET, as well as regarding the
dosing of IR metoprolol tartrate used in the trial
[26]. In any trial directly comparing two different
drugs sharing a common mechanism of action,
the administered dose and dosage regimen of
each agent may be as important as the selection
of agents in determining the results [27].

Dosing of -Blockers in COMET

Reduction in heart rate is considered to the
clinically relevant parameter to assess the extent
of -blockade [28]. To address the issue of 1
alone versus 1 , 2 , 1 blockade, an equivalent
reduction in exercise heart must be achieved. If
equivalent reduction in exercise heart rate is not

133

achieved, then equipotent -blocking doses are

not being used between two agents. This point
is acknowledged by the COMET investigators in
the primary outcomes paper [25]. Since resting
heart rate was determined randomly in COMET,
it is possible that heart rate differences between
carvedilol and IR metoprolol tartrate could be
even larger since metoprolol tartrate has a
shorter pharmacologic half-life than carvedilol. If
heart rate was assessed at a trough interval after
dosing of metoprolol tartrate, differences in heart
rate between carvedilol and metoprolol tartrate
would have been underestimated.
Systolic and diastolic blood pressures were
identical for patients randomized to carvedilol and
metoprolol tartrate (126/77 mmHg). The significant differences in BP reduction further support
the argument that the trial failed to achieve equal
degrees of 1 -blockade. Indeed, the differences in
BP alone (e.g., 3.8 mm Hg with carvedilol versus 2.0 mm Hg with IR metoprolol tartrate at
4 months) may have accounted for part of the difference in overall mortality observed between the
two groups.
The target doses of carvedilol and metoprolol tartrate in COMET were 25 mg twice daily
and 50 mg twice daily, respectively. The IR metoprolol tartrate target dose was determined [25]
based on the Metoprolol in Dilated Cardiomyopathy (MDC) trial, in which the target dose of metoprolol was 100 to 150 mg daily (given 23 times
daily). However, 72% of the patients were able
to achieve a dose of 50 mg 3 times daily, with
a mean achieved daily dose of 108 mg [29]. The
mean daily dose of IR metoprolol tartrate achieved
in COMET (85 mg) was therefore well below that
achieved in the MDC trial, in which no mortality
benefit was observed, even at the higher dose. The
target dose of carvedilol (25 mg twice daily) was
based on the dose-ranging US Carvedilol Heart
Failure Program [30]. Further, the mean daily
dose of carvedilol achieved in COMET (42 mg)
was greater than that achieved in the Carvedilol
Prospective Randomized Cumulative Survival
(COPERNICUS) study (37 mg), a successful morbidity and mortality trial [8,9], suggesting the introduction of design bias, given the doses used of
the two study drugs in COMET. The COPERNICUS trial was conducted in patients with more
severe heart failure and this may account, in part,
for the lower on-treatment achieved dose.
Is the reduction in heart rate dose-related and
does the extent of heart reduction matter in heart
failure patients? The answer to both of these
questions appears to be yes based on the Multicenter Oral Carvedilol Heart Failure Assessment
(MOCHA) study, studies done in patients with
angina, and in observational analyses done in
large databases [3133].

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Talbert

Metoprolol Tartrate Versus

Metoprolol Succinate
Metoprolol is a racemic mixture (the S-enantiomer
is about 30 times more potent as a -antagonist as
its antipode) and is moderately lipid soluble (lipid
solubility log Kp 2.15 vs. 0.23 for atenolol, very
water soluble), with a half-life of 3 to 7 hours. Significant pharmacokinetic and pharmacodynamic
differences exist between IR metoprolol tartrate
and ER metoprolol succinate. While IR metoprolol tartrate has a 6- to 12-hour duration of action
and is generally dosed 2- to 3-times daily, ER metoprolol succinate is a once-daily medication, with a
full 24-hour duration of action.
The ER formulation was designed to extend absorption time within the gastrointestinal tract,
thereby prolonging the duration of therapeutic
action and decreasing the frequency of administration. This is accomplished in the case of ER
metoprolol succinate by the use of a multiple-unit
system, in which each tablet contains approximately 16001800 controlled-release pellets. After ingestion, the ER metoprolol succinate tablet
disintegrates and rapidly disperses microcapsules
into the gastrointestinal tract [3436]. Each microcapsule acts as a diffusion cell, delivering metoprolol at a nearly constant rate over 20 hours,
independent of food intake, pH, and other physiologic factors such as peristalsis; the 3- to 7hour half-life of metoprolol provides coverage
for the remaining 4 hours of the dosing interval. In contrast, IR metoprolol tartrate demonstrated rapid absorption in vivo, ranging from 1
to 2 hours. Because of a slower absorption rate
than IR metoprolol tartrate, ER metoprolol succinate displays a greater first-pass effect, and
a relative bioavailability to IR metoprolol tartrate between 68 and 102% [39]. Despite this
lower bioavailability, ER metoprolol succinate provides a smoother degree of 1 -blockade than does
IR metoprolol tartrate throughout the 24-hour
period [37].
Maximal -blockade is seen with metoprolol
plasma concentrations in the range of 300400
nmol/L. Peaks above this range result in no
greater therapeutic -blockade and loss of 1 selectivity leading to more adverse effects. Troughs
at the end of the dosing interval with IR metoprolol tartrate if the drug is dosed at 12 hour intervals, leads to loss of b-blockade and may result in
loss of blood pressure control, increase in anginal
episodes or silent ischemia or heart rates that are
too high for heart failure patients.
Metoprolol is metabolized by CYP2D6, which
is inhibited by many drugs (e.g., fluoxetine,
celecoxib, quinidine, amiodarone, and diphenhydramine) [3840]. Therefore, in patients
who are CYP2D6 extensive metabolizers, co-

administration with another agent inhibiting this

isoenzyme may cause the plasma concentration of
metoprolol to increase several-fold. This increase
leads to the high plasma concentration peaks
characteristic of IR metoprolol tartrate and
potentially cause excessive 1 -blockade, loss of
selectivity, and unwanted effects [41].
The pharmacokinetic and pharmacodynamic
properties of ER metoprolol succinate and IR
metoprolol tartrate were compared in 12 healthy
men [35]. In this single-blind crossover study,
all subjects received each of three treatment
regimensER metoprolol succinate 100 mg once
daily, IR metoprolol tartrate 50 mg twice daily,
or IR metoprolol tartrate 100 mg once dailyfor
5 consecutive days, in randomized order, with at
least 5 drug-free days between each treatment period. Extended-release metoprolol succinate was
associated with a considerably lower peak plasma
concentration of metoprolol compared with both
dosing regimens of IR metoprolol tartrate, and
with a significantly higher plasma concentration
at 24 hours compared with IR metoprolol tartrate
100 mg once daily (Fig. 2). Importantly, the fluctuation in the steady-state plasma concentration
of metoprolol was significantly less with ER metoprolol succinate compared with IR metoprolol tartrate (P < .001 vs. 100 mg once daily; P < .05 vs.
50 mg twice daily) (Fig. 2). Extended-release metoprolol succinate 100 mg provided approximately
55 to 75% of the maximum 1 -blockade over the
entire dosing interval. Corresponding changes in
exercise heart rate were noted with IR metoprolol tartrate inducing greater reductions coinciding with peak plasma concentrations and loss of

Fig. 2. Comparison of immediate release metoprolol tartrate

50 mg twice daily, immediate release metoprolol tartrate
100 mg once daily, and extended release metoprolol 100 mg
once daily on suppression of exercise heart rate (beats per
minute) and plasma concentrations (nmol/L) at
corresponding testing periods (reference 35).

Pharmacokinetics and Pharmacodynamics of Beta Blockers in Heart Failure

heart rate suppression at the end of the dosing

interval with trough concentrations following IR
metoprolol tartrate 100 mg once daily or 50 mg
twice daily. The implication of this finding is that
IR metoprolol tartrate dosed twice daily even at
100 mg will not provide the same consistent heart
rate reduction as ER metoprolol succinate. Other
studies with ER metoprolol succinate show doseindependence over a dosing range of 100 to 400 mg
per day [42].
In heart failure patients, similar differences
in pharmacokinetics and pharmacodynamics have
been demonstrated by Andersson et al. [43]. In this
comparison of IR metoprolol tartrate 50 mg three
times per day versus ER metoprolol succinate in
15 patients with heart failure, ER metoprolol succinate provided consistent plasma concentrations
over time while IR metoprolol tartrate produced
high peak concentrations two hours after dosing
with low trough levels six to eight hours (Fig. 3).
Plasma concentrations with ER metoprolol succinate 200 mg per day were consistently around 200
nmol/L through much of the dosing interval. There
was a more consistent exercise heart rate reduction with 200 mg per day compared with that seen
with three times per day dosing at the 24 hour
trough interval (Fig. 4).
Carvedilol has a half life of 610 hours and
heart failure patients, carvedilol area under the
curve (AUC) is increased in more advanced stages
of heart failure (Table 1) [44,45]. Metabolites of
carvedilol may contribute to its long -blocking activity (but not its -blocking activity). Carvedilol
also has different kinetics for the -receptor: it appears to very slowly dissociate from it, whereas
metoprolol possesses more rapid offset kinet-

135

Fig. 4. Reduction in exercise heart with immediate release

metoprolol tartrate 50 mg three times daily and extended
release metoprolol 100 mg and 200 mg once daily 24 hours
after dosing (reference 43).

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

Fig. 3. Comparison of plasma concentrations with immediate

release metoprolol tartrate 50 mg three times daily and
extended release metoprolol 100 mg and 200 mg once daily in
heart failure patients (reference 43).

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.

136

Talbert

However, the clinical significance of this possibility remains unclear.

Metoprolol, in contrast, does not possess blocking activity and is nearly exclusively metabolized by CYP2D6 [49]. While the absence of 1
blockade with metoprolol has been cited as a possible advantage for carvedilol, the clinical relevance
of this effect and the persistence over time has
been questioned [22]. Plasma concentrations of
the S-isomer of metoprolol are 35% higher in poor
metabolizers compared with extensive metabolizers of debrisoquine, a marker drug for CYP2D6
metabolism [49]. Total peak concentrations of IR
metoprolol tartrate are about 3 times greater in
CYP2D6 poor metabolizers than in extensive metabolizers. One study found that after one dose of
IR metoprolol tartrate 200 mg, the mean metoprolol area under the curve was 6 times higher in poor
metabolizers compared with extensive metabolizers of debrisoquine [50]. Evidence of -blockade
(exercise heart rate) was present 24 hours after an
oral dose of IR metoprolol tartrate in poor metabolizers (but not in extensive metabolizers) [49,50].

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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