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Sotalol vs metoprolol for ventricular rate control in patients with chronic atrial fibrillation who have undergone digitalization: a single-blinded crossover study
Europace (2001) 3, 73–79
doi:10.1053/eupc.2000.0140, available online at http://www.idealibrary.com on
Sotalol vs metoprolol for ventricular rate control in patients with chronic atrial fibrillation who have undergone digitalization: a single-blinded crossover study G. E. Kochiadakis, E. M. Kanoupakis, M. D. Kalebubas, N. E. Igoumenidis, K. E. Vardakis, H. E. Mavrakis and P. E. Vardas Cardiology Department, University Hospital of Heraklion, Crete, GreeceAims To compare the effects of sotalol and metoprolol on
(116 9 bpm for sotalol vs 125 11 bpm for metoprolol,
heart rate, during isotonic (ITE) and isometric (IME)
P<0·001). During isometric exercise, sotalol produced a
exercise and daily activities, in digitalized patients with
lower maximum heart rate than did metoprolol (113 22 vs
129 18 bpm, respectively). Both agents produced a lowermean heart rate than placebo over 24 h (P<0·001 for all),
Methods and Results The study had a randomized,
while sotalol produced a lower mean heart rate than
single-blinded, crossover design. Twenty-three patients
metoprolol during the daytime (P<0·01).
with chronic atrial fibrillation received placebo for 4weeks, followed by a 4-week period of treatment with
Conclusion Sotalol is a safe and effective agent for control
sotalol and metoprolol in random order. At the end of
of heart rate in digitalized patients with atrial fibrillation.
each period, the patients were assessed with 24-h ECG
Sotalol is superior to metoprolol at submaximal exercise,
monitoring, a cardiopulmonary exercise test and a handgrip
resulting in better rate control during daily activities. (Europace 2001; 3: 73–79)
Both agents produced a lower heart rate than placebo at
2001 The European Society of Cardiology
rest and at all levels of isotonic exercise (P<0·001) withoutaffecting oxygen uptake. Sotalol produced a lower heart
Key Words: Chronic atrial fibrillation, sotalol, metoprolol,
rate than metoprolol only at submaximal exercise
Introduction
limited by a range of adverse reactions, of which the
most serious is their negative inotropic action.
Beta-blockers have been shown to be effective for the
Sotalol is a non-selective beta-blocker that also has a
control of heart rate at rest and during exercise in
class III action (prolongation of action potentials).
patients with chronic atrial fibrillation[. Indeed, a
This property could contribute to sotalol’s ability to
recent study assumes that the combination of beta-
prolong AV node refractoriness and thus to control the
blocker and digoxin is the most effective regimen, re- ventricular response in chronic atrial fibrillation more
flecting a synergistic effect on the atrioventricular (AV) effectively than a conventional beta-blocker. Further-
node of the vagomimetic actions of the cardiac glycoside
more, sotalol is considered to have a less negative
and the prolongation of AV node refractoriness by
inotropic action than conventional beta-blockers, and
beta-blockers. However, the use of beta-blockers is
this could be an additional reason for its administration.
However, in spite of its theoretical advantages, the
superiority of sotalol over conventional beta-blockers in
Manuscript submitted 21 June 2000, revised 11 October 2000, and
controlling heart rate in patients with chronic atrial
fibrillation has not been proven to date. The aim of this
Correspondence: Prof. P. E. Vardas, MD, PhD (London), FESC,
study was to assess the effects of sotalol at rest and
FACC, Cardiology Department, Heraklion University Hospital,
during programmed exercise and daily activities in a
P.O. Box 1352, Stavrakia Heraklion, Crete, Greece. E-mail:
group of patients with chronic atrial fibrillation who had
2001 The European Society of Cardiology
undergone digitalization, and to compare the results
metoprolol for each patient enrolled, as determined by a
with those of a conventional beta-blocker, metoprolol.
decrease in resting heart rate to c70 bpm.
Sotalol was initiated at a dose of 40 mg twice daily.
The dose was titrated up in 40–80 mg increments every
48–72 h until the target reduction in heart rate was
achieved. The final maintenance dose of sotalol was
adjusted downwards if adverse effects were noted by the
patients, or if the rate-corrected QT interval exceeded
Twenty-three patients (13 men, 10 women, mean age
63 8 years) with atrial fibrillation for >1 month (de-
Metoprolol therapy was initiated at a dose of 25 mg
fined in this study as chronic atrial fibrillation) made up
twice daily. The dose was titrated up in 25–50 mg
the study group. These patients were selected from a
increments every 48–72 h with the same aim. Treatment
total population of 146 inpatients with chronic atrial
with any antiarrhythmic agent except digoxin was
fibrillation who were examined in the authors’ depart-
stopped for at least five half-lives before the study
ment in a 2-year period. Fifteen of them had a history of
unsuccessful electrical attempts to restore sinus rhythm,
and eight patients relapsed after electrical cardioversion,
Before the start of the study, all patients underwent a
even though they received propafenone to prevent atrial
trial cardiopulmonary exercise test in order to familiar-
fibrillation recurrence. All patients were carefully evalu-
ize themselves with the equipment and the procedure.
ated by history, physical examination, ECG, chest X-ray
Patients exercised on a calibrated, motor-driven tread-
and echocardiography, and satisfied the following selec-
mill (Max-1, Marquette, Milwaukee, USA) with an
tion criteria: no history or signs of heart failure; absence
incremental exercise workload using a modified Naugh-
of severe valvular heart disease; no evidence of ischaemic
ton protocol. A rhythm strip lasting 6 s was recorded at
heart disease; no evidence of renal, hepatic, endocrine,
rest (after standing for 2 min) and at the end of each
pulmonary or neurological disease; no history of un-
minute during exercise and until the fourth minute of
toward reaction to any of the medications used in the
recovery, in order to evaluate the heart rate, with a
present study; and the ability to undergo a treadmill
paper speed of 25 mm . s 1. A six-lead ECG was also
recorded at a paper speed of 50 mm . s 1 at rest, at
All patients were treated with digoxin and were given
submaximal and at maximal exercise. The longest QT
anticoagulation therapy with acenocoumarol (INR 2·5–
interval in any of the six leads was recorded and
3·5). While receiving digoxin therapy, these patients
averaged from the measurement of six consecutive
were required to have a resting heart rate >90 bpm.
QRS-T complexes. The QT interval was corrected (QTc)
All patients gave their consent to the protocol, which
for rate using Bazett’s formula, as follows: QTc=
was approved by the local Ethics Committee for Human
QT/√RR, where RR is the preceding RR interval.
Blood pressure was measured with a cuff sphyg-
momanometer at rest and at 2-min intervals during the
Gas exchange analysis and determination of anaerobic
The study had a randomized, single-blinded, crossover
design. It consisted of an initial 4-week placebo treat-
During testing, the patients breathed atmospheric air
ment period (2 tablets twice daily), followed by random-
through a low-resistance mask. The partial pressures of
ization to either metoprolol or sotalol treatment for a
respiratory O2 and CO2 were measured using a special
4-week period, and then (after a placebo washout for
gas analyser (Oxycon A, Mijnhard). The signals were
1 week) the alternative medication for the same length
processed through analogue-to-digital conversion for
breath-by-breath gas exchange analysis. The gas analy-
The digoxin treatment was maintained throughout the
ser was recalibrated before each test. Gas exchange
study. The dosage was adjusted until the serum concen-
variables were measured continuously and averaged at
tration came within the range 0·8–2·0 ng . ml 1 before
30-s intervals during the 2-min rest period and through-
out the test. The variables measured included oxygen
At the end of each treatment period, patients were
uptake (VO2, ml . kg 1 min 1), respiratory exchange
assessed with 24-h ECG monitoring, a maximal,
ratio (RER, VCO2/VO2) and oxygen pulse (oxygen
symptom-limited cardiopulmonary exercise test, an iso-
uptake/heart rate). These parameters were determined at
metric exercise test with a handgrip dynamometer, and
submaximal exercise (speed 3 mph, 0% grade), at the
evaluation of subjective wellbeing and adverse events.
anaerobic threshold and at peak exercise. The gas ex-
change anaerobic threshold, determined as outlined by
Beaver et al., was taken as the mean of estimations
Before the study, an open-label titration phase estab-
performed by two independent observers who were
lished the optimal therapeutic dose of sotalol or
unaware of the patient’s treatment or other data. Ventricular rate control in chronic AF patients 75
To evaluate the ventricular response to isometric exer-
cise, a sustained handgrip test was performed. First, the
subjects tested their maximal voluntary contraction,
then, after a break of at least 2 min, the patients were
asked to maintain their contraction at 30% of maximum
for 150 s under continuous ECG monitoring. Heart rate
was determined at rest and every 30 s on 6 s rhythm
Continuous data are summarized as mean standard
deviation. The effect of the three different treatment Figure 1 Time course of heart rate during isotonic
schemes on heart rate changes over time was assessed
exercise in patients with chronic atrial fibrillation receiv-
with repeated measures analysis of variance with two
ing sotalol (), metoprolol () and placebo (). The
factors: one for temporal effect (at 24 levels for the changes during the first 8 min were chosen because all the
circadian variation, nine levels for the isotonic exercise
exercise tests contained complete data for this duration. During the early stages of exercise (until the fourth
test and six levels for the isometric) and one for treat-
minute), the difference between sotalol and metoprolol is
ment effect (three levels). The isotonic exercise test apparent.
had nine levels (one resting and eight consecutive
minutes’ heart rate recording) because all patients
completed at least 8 min of exercise. For the isometric
test, the six levels corresponded to one at rest and five at
with mean values significantly lower than those of
30-s intervals during the test. In case of significant
metoprolol during the first 4 min of exercise. By the fifth
findings, post hoc tests were also performed. Separate
minute, the heart rate on sotalol had almost reached the
subanalyses were also performed to examine the day
(7:00–23:00) and night (23:01–6:59) effect. A P value
The mean exercise parameters and gas exchange vari-
<5% was the criterion for significance in all statistical
ables at different exercise levels are shown in
The mean exercise duration was similar in all treatment
groups. Both sotalol and metoprolol produced a lower
mean heart rate than placebo at all exercise levels
(P<0·001 for all). Sotalol gave a lower mean heart rate
than metoprolol at submaximal exercise (P<0·01),
All patients completed the study uneventfully. No
whereas at other levels, there was no difference.
patient converted to sinus rhythm, but all maintained a
There were no significant differences in blood pressure
resting heart rate c70 bpm. Thirteen of them had no between the three treatment groups at all exercise levels.
evidence of underlying heart disease, eight had hyperten-
VO2 was similar in all three groups, at all exercise
sive cardiovascular disease (signs of left ventricular
hypertrophy on the echocardiogram or ECG), and two
patients had surgically corrected mitral stenosis. All
patients were in NYHA class I or II, and their mean
Ventricular rate changes during isometric
The mean drug dosages were 206 37 mg . day 1 for
sotalol and 182 44 mg. day 1 for metoprolol.
Repeated measures ANOVA showed that there were
also significant time, group and interaction effects
(P<0·001 for all) on changes in heart rate during iso-
Ventricular rate changes during isotonic
For all three treatments, heart rate followed an in-
creasing course during the first 90 s and then remained
According to ANOVA with repeated measures, there
at a plateau for the following 60 s. Heart rate was much
were time, group and interaction effects (P<0.001) on higher under placebo than under the other two treat-
heart rate changes during exercise. For placebo, the
ments throughout the period of observation (quadratic
exercise curves showed a curvilinear course, with an
trend), with a steeper rise during the first 30 s. Sotalol
initial sharp rise followed by a gradual increase. Meto-
and metoprolol had a similar pattern of changes, more
prolol gave a similar pattern, but the values were lower
or less linear. However, although heart rate started out
throughout the period of observation. For sotalol, the
at the same level, it quickly diverged, increasing at a
exercise curve showed a smoother, more linear path,
slower rate under sotalol. The maximum heart rate
Table 1 Exercise parameters and gas exchange variables at rest, submaximal exercise, anaerobic threshold and maximal exercise in patients with chronic atrial fibrillation under treatment with placebo, metoprolol and sotalol
*P<0·001 QT duration at exercise vs resting.
†P<0·01 sotalol vs metoprolol.
‡P<0·001 sotalol or metoprolol vs placebo.
BP, blood pressure; bpm, beats per minute; HR, heart rate; RER, respiratory exchange ratio;
Ventricular rate control over 24 h
Regardless of treatment, heart rate showed a significant
circadian pattern, with higher values during the day than
at night (time effect P<0·001 for all). However, the
particular course of heart rate changes over the 24-h
period was strongly treatment dependent (treatment and
ffect P<0·001 for all). Under placebo, mean
heart rate was higher throughout than in the other two
groups, with a steeper rise in the morning until 13:00,
then a steeper fall from the early afternoon until 23:00.
Sotalol and metoprolol had similar effects on mean HR,
except during the early afternoon (13·00–16·00) when
heart rate was higher in the metoprolol group
Figure 2 Time course of heart rate during isometric exercise in patients with chronic atrial fibrillation receiv- ing sotalol (), metoprolol () and placebo (). There are clear differences between the three treatments, in terms of both the patterns of change and the values of heart rate.
During the open-label phase, no patient suffered side-
effects that would necessitate exclusion from the study.
Nor was it necessary to withdraw medication from any
under placebo was 155 20 bpm, significantly higher
patient during the study because of side-effects. There
than that for metoprolol (129 18) bpm, P<0·001) and
was no evidence of sotalol-associated torsade de pointes
sotalol (113 22 bpm, P<0·001). The difference between or proarrhythmia during either the study or the open-
metoprolol and sotalol was also significant (P<0·01). Ventricular rate control in chronic AF patients 77
maintains a lower heart rate than does metoprolol. It is
important to note that this lower heart rate under sotalol
was accompanied by slightly higher levels of O2 con-
sumption. A possible explanation of this is the different
effects of the two agents on myocardial function, given
that previous investigators have reported that sotalol
has a lesser negative inotropic action than conventional
beta-blockers, or even a positive inotropic effect on the
myocardium. As a result, the more negative chrono-
tropic effect of sotalol at that stage may be counter-
balanced by a better use of the stroke volume reserve
compared with metoprolol. The fact that oxygen pulse
was significantly higher on sotalol than on metoprolol
during only the initial stages of exercise, first of all
Figure 3 Mean hourly ventricular rate over 24 h under the three treatments. The circadian pattern is maintained
To the authors’ knowledge, there is only one study in
in all three cases and the difference between the medi- which it was observed that the heart rate in patients with cations is clear. , sotalol; , metoprolol; , placebo.
chronic atrial fibrillation increased at the start of an
isometric exercise test and remained high throughout the
The QT interval on sotalol was longer than on the
test. This pattern corresponds to that reported from
other two treatments at rest (P<0·001 for both). It
previous observations in normal subjects, suggesting
shortened significantly as the exercise level increased in
that it is due to an initial vagal withdrawal and to the
all three treatment groups, until at maximal levels there
increased sympathetic tone which exists during isometric
were no differences between the groups. At submaximal exercise.
exercise, however, the QT interval on sotalol was longer
The present study showed that the increase in heart
than on the other two treatments (P<0·001 for both,
rate during isometric exercise in patients with chronic
No significant changes were observed in the
atrial fibrillation is large and digoxin is insufficient for
corrected QT interval during exercise and there were no
rate control. In contrast, agents with antiadrenergic
differences between the groups either at rest or during properties seem to be able to control the heart rate
response during isometric exercise in these patients.In
this case, sotalol appears to be superior to conventional
beta-blockers, causing a greater decrease in heart rate.
The most likely explanation for this is that the cardiac
Discussion
stimulation during isometric exercise does not reach
sufficient levels for the class III action of sotalol to
Ventricular rate control at rest and during
This study first of all confirms the findings of previous
Ventricular rate control during daily
studies, that sotalol, combined with digoxin, is a safe
and very effective means of controlling heart rate, both
at rest and during exercise, in patients with chronic atrial
fibrillation. According to the present results during
This study used 24-h Holter recordings to investigate the
exercise, this therapeutic combination reduces heart rate
effectiveness of the studied medications on ventricular
at all levels, achieving a linear increase in heart rate and
rate control during patients’ daily activities. The results
eliminating the abrupt increase which is seen in atrial
showed that during the day, when sympathetic tone is
fibrillation during the early stages of exercise.It should
increased, digoxin is insufficient for rate control in
also be noted that, despite the significant reduction in
patients with chronic atrial fibrillation. Sotalol, how-
heart rate that sotalol causes, exercise performance was
ever, was shown to be effective in achieving this aim, and
not significantly affected. As oxygen pulse, which reflects was superior to a conventional beta-blocker, especially
stroke volume, increases under sotalol, this suggests that
during the daytime. The most likely explanation of this
the study population were able to use their stroke
is that during daily activities the patients do not reach
volume reserve to compensate for the negative chrono-
maximum exercise levels and so sotalol retains its class
tropic effects of sotalol. The study’s major finding, III action.
however, was that the effects of sotalol on exercise show
certain differences from those of conventional beta-
blockers, such as metoprolol, that are targeted at low
levels of exercise. Specifically, while the two agents have
the same effect on exercise capacity and heart rate at Both drugs were administered after the patients had
maximal levels, in the early stages of exercise, sotalol
been digitalized. Digoxin has traditionally been used for
control of heart rate in these patients, but its relative
The present study suggests that this position could be
importance has declined because, as the present findings
filled by sotalol, a non-selective beta-blocker that also
show, although it reduces the resting heart rate, it fails to
has a class III effect. According to the results of this
control exercise-induced tachycardia. How-
study, this agent, combined with digoxin, is safe and is
ever, the administration of digoxin in combination with
more effective in controlling heart rate than conven-
other medications has been proved to produce a greater
tional beta-blockers in patients with chronic atrial fibril-
decrease in heart rate than either digoxin or the
lation during daily activities, when the patient does not
additional agent alone. Furthermore, it allows for the
reach maximal levels of exercise. Further studies are
use of smaller dosages of the drugs and thus fewer
needed to compare the effectiveness of sotalol in control-
ing ventricular rate in patients with chronic atrial fibril-
lation, with that of other treatments, such as calcium
The present study showed that both sotalol and meto-
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Wurzeln, Wind und bunte Blätter Aus den Träumen des Frühlings wird im Herbst Marmelade gemacht. Die Wiesen und Wegränder werden allmählich farblos und kahl, die Gartenpflanzen sehen immer müder aus, verlieren ihre Blüten und Blätter, die Wälder dagegen verwandeln sich in ein buntes Farbspektakel - der Herbst ist da! Der astronomische Herbstanfang findet mit dem Herbst-Equinox oder