Download Use of Metoprolol CR/XL to Maintain Sinus Rhythm After Conversion

Journal of the American College of Cardiology
© 2000 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 36, No. 1, 2000
ISSN 0735-1097/00/$20.00
PII S0735-1097(00)00693-8
Electrophysiology
Use of Metoprolol CR/XL to Maintain Sinus Rhythm
After Conversion from Persistent Atrial Fibrillation
A Randomized, Double-Blind, Placebo-Controlled Study
Volker Kühlkamp,* Alexander Schirdewan,† Karl Stangl,‡ Michael Homberg,§ Matthias Ploch,㛳
Otto A. Beck¶
Tübingen, Berlin, Mönchengladbach, and Peine, Germany
The primary objective of the present study was to assess the efficacy of metoprolol CR/XL to
reduce the risk of relapse after cardioversion of persistent atrial fibrillation to sinus rhythm.
BACKGROUND Indirect data from studies with d,l sotalol provide evidence that the beta-blocking effects of
the compound are important in maintaining sinus rhythm after cardioversion of atrial
fibrillation.
METHODS
After successful conversion to sinus rhythm, 394 patients with a history of persistent atrial
fibrillation were randomly assigned to treatment with metoprolol CR/XL or placebo. The two
treatment groups were similar with respect to all pretreatment characteristics. Patients were
seen on an outpatient basis for recording of resting electrocardiogram (ECG) after one week,
one, three and six months of follow-up or whenever they felt that they had a relapse into atrial
fibrillation or experienced an adverse event.
RESULTS
In the metoprolol CR/XL group, 96 patients (48.7%) had a relapse into atrial fibrillation
compared with 118 patients (59.9%) in the placebo group (p ⫽ 0.005). Heart rate in patients
after a relapse into atrial fibrillation was significantly lower in the metoprolol group (98 ⫾
23 beats/min) than in the placebo group (107 ⫾ 27 beats/min). The rate of adverse events
reported was similar in both groups when the difference in follow-up time was taken into
account.
CONCLUSIONS The results of this double-blind, placebo-controlled study in patients after cardioversion of
persistent atrial fibrillation showed that metoprolol CR/XL was effective in preventing relapse
into atrial fibrillation or flutter. (J Am Coll Cardiol 2000;36:139 – 46) © 2000 by the
American College of Cardiology
OBJECTIVES
Atrial fibrillation is the most common persistent arrhythmia
in the population, increasing in incidence with age (1,2). In
the Framingham study, cardiac disease and cardiovascular
risk factors were the predominant predisposing factors for
atrial fibrillation (3). Exercise capacity is significantly reduced with chronic atrial fibrillation when compared with
sinus rhythm (4). Hence, restoration and maintenance of
See page 147
sinus rhythm are important therapeutic goals. It has been
shown that drugs with class 1a, class 1c, and class 3
antiarrhythmic properties are suitable for maintaining sinus
rhythm (5–14). However, especially with class 1 antiarrhythmic drugs, there is concern that these drugs may
increase mortality (5,15–18). The risk of proarrhythmia is
not associated with beta-blocker treatment.
From *Eberhard-Karls-Universität, Tübingen; †Franz-Volhard-Klinik,
Humboldt-Universität, Berlin; ‡Charité, Humboldt-Universität, Berlin; §Krankenhaus Maria Hilf, Mönchengladbach; 㛳St. Antonius Hospital, Eschweiler, and
¶Kreiskrankenhaus, Peine, Germany. The study was supported by a grant from
AstraZeneca RD, Mölndal, Sweden, and BMBF Förderprojekt 01EC9405 (Volker
Kühlkamp).
Manuscript received April 27, 1999; revised manuscript received February 11,
2000, accepted March 6, 2000.
A nonselective beta-blocker with class 3 antiarrhythmic
activity, d,l sotalol, proved to be as effective as quinidine in
maintaining sinus rhythm after direct current cardioversion
(19); d-sotalol, the dextrorotatory optical isomer of the
racemate d,l sotalol, blocks the rapid component of the
delayed-rectifier current (IKr) and lacks clinically significant
beta-blocking properties (20). A study comparing d,l sotalol,
d-sotalol and placebo supported the finding that d,l sotalol
was effective in maintaining sinus rhythm. However, the
efficacy of d-sotalol was not significantly different from
placebo (21). Hence, there is indirect evidence that betablockade is important for maintaining sinus rhythm after
cardioversion. However, placebo-controlled data on the value
of beta-blockade after cardioversion of persistent atrial fibrillation or atrial flutter not associated with open heart surgery are
lacking. We therefore conducted a multicenter, placebocontrolled, randomized, double-blind trial to test the hypothesis that metoprolol CR/XL (controlled release), a selective
beta1 adrenoceptor blocking drug, is effective in preventing
relapse into atrial fibrillation following cardioversion.
METHODS
This was a prospective randomized, double-blind, parallel
group multicenter study comparing oral metoprolol CR/XL
140
Kühlkamp et al.
Metoprolol After Cardioversion of Atrial Fibrillation
Abbreviations and Acronyms
DC ⫽ direct current
ECG ⫽ electrocardiogram
with placebo after cardioversion of persistent atrial fibrillation. The study protocol was approved by the Institutional
Review Board at each of the 71 participating centers.
Informed written consent was obtained from each patient.
Patients were eligible if they had the persistent form of atrial
fibrillation that had lasted for a minimum of three days and
up to one year. The terminology used in the description of
atrial fibrillation in this report follows the recently suggested
recommendations (22). Patients had to be successfully
converted to sinus rhythm either by direct current (DC)
cardioversion or therapy with class 1 antiarrhythmic drugs.
Whether a patient underwent cardioversion or not, and
whether DC or a class 1 antiarrhythmic drug was used, was
left to the discretion of the physician at each site; however,
the use of DC cardioversion was recommended. A sufficient
anticoagulation before, and for at least one month after,
cardioversion was strongly recommended. The method of
anticoagulation (oral phenprocoumon or IV heparin) was
decided by the investigator at each site. After cardioversion
of atrial fibrillation, patients were randomized to either
metoprolol CR/XL (controlled release) or placebo. Patients
were allocated treatment according to a computer-generated
randomization list common to all centers.
The metoprolol CR/XL formulation is characterized by
its ability to produce an even plasma concentration over 24 h
(23). The metoprolol CR/XL tablets (50 mg and 100 mg)
and matching placebo were manufactured, packed, labeled
and distributed by the sponsor of the study (AstraZeneca
RD, Mölndal, Sweden). The placebo tablets were identical
in size, weight, color, and taste to the metoprolol CR/XL
tablets. Tablets were packed in bottles for each patient.
Compliance with the study medication was checked by pill
count at each visit.
The initial dose was 100 mg metoprolol CR/XL or
placebo given once daily. It was recommended to increase
the dose to 200 mg once daily. If the investigator felt it
necessary, however, the dose could be maintained at 100 mg
once daily or decreased to 50 mg once daily. Concomitant
drug therapy was not restricted. However, concomitant
therapy with any class 1 or class 3 antiarrhythmic drug,
beta-blockers or calcium channel blockers such as verapamil
or gallopamil, was considered as an exclusion criterion.
Patients were followed on an outpatient basis and were seen
at one week, one month, three months and six months
following inclusion or at the time of a relapse of atrial
fibrillation or in the case of adverse events. Patients were
encouraged to obtain an electrocardiogram (ECG) if they
had symptoms suggestive of a recurrence of atrial fibrillation. At each visit, a resting ECG was obtained. After study
closure, all ECGs were evaluated blindly at a central core
JACC Vol. 36, No. 1, 2000
July 2000:139–46
laboratory with respect to the prevailing rhythm and heart
rate at each visit. In the case of sinus rhythm, heart rate was
calculated as the mean of three consecutive beats, and in the
case of atrial fibrillation, as the mean of six consecutive
beats.
Major exclusion criteria were: contraindications to treatment with beta-adrenergic blocking agents (i.e., presence or
history of AV-block II/III, sick sinus syndrome, asthma),
chronic oral treatment with amiodarone within six months
prior to inclusion, concomitant treatment with any class 1 or
3 antiarrhythmic drug within five half-lives of that drug,
cardiac surgery in the previous two months, clinical need for
concomitant treatment with beta-blockers, and untreated
thyroid dysfunction. Excluded from the study were patients
with the paroxysmal form of atrial fibrillation or a history of
paroxysmal atrial fibrillation, defined as recurrent episodes
of atrial fibrillation alternating with sinus rhythm (22).
The primary end point of the study was to assess the
efficacy of metoprolol CR/XL, compared with placebo, with
respect to the cumulative number of patients relapsing into
atrial fibrillation or flutter during a period of six months
following cardioversion to sinus rhythm. Secondary objectives were to compare the effects of metoprolol CR/XL and
placebo on the ventricular rate in patients with relapse of
atrial fibrillation or flutter and to assess the tolerability of
metoprolol CR/XL.
At baseline, a two-dimensional echocardiogram was obtained in the left parasternal short axis and the left apical
four-chamber view. Left ventricular end-systolic and enddiastolic diameter, the thickness of the interventricular
septum and the posterior wall, fractional shortening, and
left atrial diameter were all determined.
Statistical analysis. The power calculation for the primary
end point, namely relapse of atrial fibrillation/flutter, indicated that 200 patients per group were needed. This power
calculation (80% power, ␣ ⫽ 0.05, two-sided) was made on
the assumption that 70% of patients in the placebo group
would have a relapse over the six-month follow-up period
and that metoprolol CR/XL would decrease this number to
55%.
For the primary end point, cumulative incidences were
compared using the log-rank test, with nominal two-tailed
p values. Patients were included in the statistical analysis
according to the intention-to-treat approach. Data on
patients with sinus rhythm were censored at the date of the
last follow-up visit. Data on heart rate were compared using
the t-test, and descriptive statistics were given for all other
variables.
RESULTS
Characteristics of the patients. Four hundred three
patients were enrolled into the trial. For the final evaluation,
nine patients (5 randomized to metoprolol CR/XL and 4
randomized to placebo) were withdrawn from analysis because
they had only a baseline ECG, without any follow-up infor-
JACC Vol. 36, No. 1, 2000
July 2000:139–46
Figure 1. Flow diagram of the study. AE: nonserious adverse event; SAE:
serious adverse event.
mation (Fig. 1). Hence, 394 patients were available for the
intention-to-treat analysis. One hundred and ninety-seven
patients were assigned to the metoprolol group and 197 to the
placebo group. The two treatment groups were similar with
respect to all pretreatment characteristics (Tables 1 and 2). In
particular, there was no difference in the duration of atrial
fibrillation prior to cardioversion and the proportion of patients
with prior antiarrhythmic or DC cardioversion. The majority
of patients were cardioverted by means of DC cardioversion
(n ⫽ 325, 82.5%). The subgroup cardioverted by class 1
antiarrhythmic drugs (n ⫽ 69, 17.5%) was not different in
baseline characteristics, compared with the patients cardioverted electrically. Most patients received 100 mg metoprolol
CR/XL (n ⫽ 122, 62%) or the corresponding dose of placebo
(n ⫽ 131, 67%) once daily. The dose of metoprolol was
reduced to 50 mg once daily in 36 patients (18.3%) from the
metoprolol CR/XL group and in 12 patients (6.1%) from the
Kühlkamp et al.
Metoprolol After Cardioversion of Atrial Fibrillation
placebo group. In 33 patients (16.8%), metoprolol was increased to 200 mg daily, whereas 50 patients (25.4%) in the
placebo group had a dose increase.
Primary end point. The intention-to-treat analysis showed
that 118 patients (59.9%) in the placebo group and 96
patients (48.7%) in the metoprolol CR/XL group relapsed
into atrial fibrillation or flutter (p ⫽ 0.005, Fig. 2). In the
group of patients in which electrical cardioversion was
performed, 106 of 163 patients (65.0%) in the placebo
group relapsed into atrial fibrillation, compared with 82 of
162 patients (50.6%) in the metoprolol group (p ⫽ 0.002,
Fig. 3). The median time to relapse of atrial fibrillation was
7.5 days in the placebo group and 13.0 days in the
metoprolol CR/XL group (p ⫽ 0.001). Mean follow-up in
the placebo group was 73 ⫾ 80 days, versus 93 ⫾ 81 days in
the metoprolol group.
The ability of metoprolol CR/XL to prevent a relapse to
atrial fibrillation was demonstrated in all subgroups analyzed. However, because the number of patients included in
our study was not sufficient to analyze subgroups, only
descriptive statistics for this comparison are given (Tables 3
and 4). The duration of atrial fibrillation prior to cardioversion and its impact on the efficacy of metoprolol CR/XL to
prevent a relapse to atrial fibrillation was analyzed only in
the subgroup with a documented duration of atrial fibrillation.
Secondary end point and effect on heart rate. Mean heart
rate of patients who relapsed into atrial fibrillation or flutter
in the placebo group was 107 ⫾ 27 beats/min, compared
with 98 ⫾ 23 beats/min in the metoprolol group (p ⫽
0.015). In patients remaining in sinus rhythm, mean heart
rate at study closure decreased from 74 ⫾ 14 beats/min to
64 ⫾ 11 beats/min in the metoprolol CR/XL group. The
corresponding figure in the placebo group was 70 ⫾
11 beats/min versus 72 ⫾ 13. The difference in heart rate
Table 1. Patient Baseline Characteristics I
Age (yrs)
Gender, n (%)
Patients with previous cardioversion, n (%)
Days in atrial fibrillation prior to cardioversion
(mean ⫾ SD)
Hypertension, n (%)
Coronary artery disease, n (%)
Heart failure, n (%)
Stroke/TIA, n (%)
Diabetes mellitus, n (%)
Concomitant cardiovascular medication at
baseline
Digoxin/digitoxin, n (%)
ACE inhibitor, n (%)
Diuretics, n (%)
Nitrates, n (%)
Calcium-channel blockers,* n (%)
141
Metoprolol (n ⴝ 197)
Placebo (n ⴝ 197)
61.0 ⫾ 11.7 (24.3–85.6)
乆 57 (28.9)
么 140 (71.1)
18 (9.1%)
85 ⫾ 117 (n ⫽ 82)
59.9 ⫾ 11.6 (25.3–79.9)
乆 60 (30.5)
么 137 (69.5)
22 (11.2%)
105 ⫾ 130 (n ⫽ 84)
96 (48.7)
52 (26.4)
51 (25.9)
15 (7.6)
23 (11.7)
91 (46.2)
48 (24.4)
49 (24.9)
12 (6.1)
17 (8.6)
94 (47.7)
65 (33.0)
33 (16.8)
35 (17.8)
16 (8.1)
92 (46.7)
56 (28.4)
32 (16.2)
32 (16.2)
9 (4.6)
ACE ⫽ angiotensin-converting enzyme; TIA ⫽ transient ischemic attack.
*Only calcium-channel blockers of the dihydropyridine type.
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Metoprolol After Cardioversion of Atrial Fibrillation
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Table 2. Patient Baseline Characteristics II
Weight (kg)
Height (cm)
NYHA I, n (%)
NYHA II, n (%)
NYHA III, n (%)
Systolic blood pressure (mm Hg, baseline)
Diastolic blood pressure (mm Hg, baseline)
Left atrial diameter (mm)
(n ⫽ 186/191)
Left ventricular end-diastolic
diameter (mm) (n ⫽ 181/184)
Left ventricular end-systolic
diameter (mm) (n ⫽ 169/158)
Fractional shortening (%)
(n ⫽ 169/158)
Interventricular septum (mm)
(n ⫽ 170/165)
Left ventricular posterior wall (mm)
(n ⫽ 161/159)
Metoprolol (n ⴝ 197)
Placebo (n ⴝ 197)
82.5 ⫾ 13.7 (54–124)
173.7 ⫾ 9.1 (145–200)
125 (63.5)
64 (32.5)
8 (4.1)
132 ⫾ 17 (100–190)
81 ⫾ 10 (60–110)
42.7 ⫾ 6.5
81.0 ⫾ 12.7 (50–124)
172.6 ⫾ 9.7 (150–196)
137 (69.5)
54 (27.4)
6 (3.1)
133 ⫾ 18 (90–175)
81 ⫾ 11 (58–110)
42.4 ⫾ 6.2
51.6 ⫾ 7.0
51.3 ⫾ 6.5
35.5 ⫾ 8.3
35.4 ⫾ 7.1
31.4 ⫾ 11.3
31.5 ⫾ 7.8
11.6 ⫾ 2.4
11.4 ⫾ 2.2
11.1 ⫾ 2.3
11.2 ⫾ 2.2
NYHA ⫽ New York Heart Association.
between the two study groups during follow-up was highly
significant (p ⫽ 0.0001).
Safety and tolerability of treatment. Serious adverse
events and adverse events causing withdrawal from the study
were seen in 20 patients in the metoprolol group and in 6
patients in the placebo group (Fig. 1 and Table 3). However, follow-up time was longer in the metoprolol group
than in the placebo group. The main reasons for premature
discontinuation of study medication in the metoprolol
CR/XL group were dizziness, AV-block II and exertional
dyspnea (Table 5). The number of patients included in the
safety analysis was not the same as that included in the
efficacy analysis. The safety population includes 399 patients
(199 placebo and 200 metoprolol CR/XL) and is defined as
all patients who received at least one dose of study drug, and
for whom post-dose data were available.
Three patients died, all in the metoprolol group. One of
the patients had dilated cardiomyopathy and experienced
Figure 2. Cumulative number of patients with relapse (atrial fibrillation/
atrial flutter), subdivided by treatment group. The log-rank test of equality
over treatment groups yielded a p value ⫽ 0.005; hence, the two treatment
groups differ significantly with regard to the rate of relapse. The p value
refers to the complete follow-up time (intention-to-treat approach).
sudden death. Another patient died from ischemic stroke,
and a third patient died from hemorrhagic stroke one week
after relapse of atrial fibrillation, while on oral anticoagulation with phenprocoumon.
Adverse events, not necessarily leading to discontinuation
of the study medication and observed in at least two
patients, are listed in Table 5. Dizziness, vertigo, nausea and
bradycardia were more commonly reported in the metoprolol CR/XL group than in the placebo group.
DISCUSSION
Our study shows that the proportion of patients relapsing
into atrial fibrillation during the study period of six months
was significantly lower on metoprolol CR/XL than on
placebo.
Figure 3. Cumulative number of patients who had DC cardioversion with
relapse (atrial fibrillation/atrial flutter), subdivided by treatment group. The
log-rank test of equality over treatment groups yielded a p value ⫽ 0.002;
hence, the two treatment groups differ significantly with regard to the rate
of relapse. The p value refers to the complete follow-up time (intentionto-treat approach).
Kühlkamp et al.
Metoprolol After Cardioversion of Atrial Fibrillation
JACC Vol. 36, No. 1, 2000
July 2000:139–46
Table 3. Reasons for Premature Discontinuation of Blind
Study Medication
Relapse of atrial fibrillation/flutter
Serious adverse event†‡
Nonserious adverse event‡
Other reasons
Metoprolol
CR/XL
(n ⴝ 197)*
Placebo
(n ⴝ 197)*
(n)
(%)
(n)
(%)
96
4
16
11
48.7
2.0
8.1
5.6
118
2
4
16
59.9
1.0
2.0
8.1
*Nine patients, five randomized to metoprolol CR/XL and four patients randomized
to placebo were not included in the intention-to-treat analysis as they only had a
baseline ECG without any follow-up information.
†In addition, six serious adverse events occurred in patients with relapse into atrial
fibrillation: three in the metoprolol CR/XL group and three in the placebo group.
‡Mean days in the study in the metoprolol CR/XL group, 93 days; in the placebo
group, 73 days.
Proarrhythmia: Comparison with class 1 and class 3
antiarrhythmic drugs. This study may have a potentially
important impact on drug treatment to maintain sinus
rhythm after cardioversion. As mentioned above, class 1
antiarrhythmic drugs bear the risk of proarrhythmia and
might increase mortality, at least in patients with organic
heart disease (5,15,17,18). Treatment with d,l sotalol is
effective in maintaining sinus rhythm after cardioversion,
although this treatment is associated with a significant risk
of proarrhythmia (19,24). Torsades de pointes has been
described with two new class 3 antiarrhythmic drugs.
However, this was not associated with an increased mortality (12,14). Similarly, amiodarone has not been shown to be
associated with an increased mortality (25–27). Severe
noncardiac side effects, however, require withdrawal of the
drug in a substantial proportion of patients (25–27). Hence,
although amiodarone seems to be very effective in maintaining sinus rhythm, it is not the drug of first choice in the
majority of patients with chronic atrial fibrillation (28 –31).
It has been shown, however, that beta-blocking drugs are
safe and improve the prognosis in patients with hyperten-
sion, after myocardial infarction and in patients with heart
failure (32–37). Thus, the use of beta-blocking agents does
not raise safety concerns. This study is the first to clearly
show that metoprolol CR/XL is effective in preventing a
relapse of atrial fibrillation after cardioversion to sinus
rhythm (Figs. 2 and 3).
Efficacy of treatment. Our findings are in accordance with
a recently published observational study reporting a marked
reduction of the risk for atrial fibrillation if patients were
treated with a beta-blocker (38). The effect of metoprolol
CR/XL cannot be attributed solely to a better control of the
underlying cardiac disease, because the ability of metoprolol
CR/XL to prevent a relapse to atrial fibrillation was of
similar magnitude in all subgroups analyzed (Table 4).
Although a direct comparison of different studies is difficult,
the efficacy of metoprolol CR/XL to prevent a relapse into
atrial fibrillation was found to be similar to that obtained in
studies with class 1 or class 3 antiarrhythmics (29).
Importance of the placebo group. One of the most
important points in our study design was the use of a
placebo group. Many studies published in recent years have
compared different active drug regimens for prevention of a
relapse to atrial fibrillation in patients with persistent atrial
fibrillation but have included no control group. Placebocontrolled studies in patients with atrial fibrillation have
been published only for quinidine in 1981 and 1984 (39,40).
About 50% of patients included in the controlled studies
using quinidine had atrial fibrillation associated with rheumatic heart disease (5). In our study, only 14 patients (3.6%)
had valvular heart disease. This is similar to some recent
studies and may reflect a temporal decline in rheumatic
heart disease and/or a change in the treatment of patients
with atrial fibrillation associated with rheumatic disease
(15,19,41). It is questionable whether data obtained in a
patient population with valvular heart disease as the main
cardiac diagnosis can be applied to a general patient popu-
Table 4. Number of Patients With a Relapse to Atrial Fibrillation in Subgroups
Placebo Group
Age ⱕ65 years
Age ⬎65 years
No heart failure
Heart failure
No organic heart disease*
Organic heart disease*
Heart rate at baseline ⱕ80 beats/min
Heart rate at baseline ⬎80 beats/min
Left atrial diameter ⱕ40 mm
Left atrial diameter ⬎40 mm
Atrial fibrillation ⬍30 days
Atrial fibrillation ⱖ30 days
Fractional shortening ⬎25%
Fractional shortening ⱕ25%
143
Metoprolol CR/XL Group
Total
Number of
Patients With
Relapse
Total
Number of
Patients
Number of
Patients With
Relapse
114
83
148
49
130
67
161
36
121
76
26
58
125
72
61 (53.5%)
57 (68.7%)
85 (57.4%)
33 (67.3%)
72 (55.4%)
46 (68.7%)
98 (60.9%)
20 (55.6%)
78 (64.5%)
40 (52.6%)
14 (53.8%)
33 (58.2%)
70 (56.0%)
48 (66.6%)
125
72
146
51
122
75
143
54
126
71
27
55
133
64
50 (40.0%)
37 (51.4%)
69 (47.3%)
27 (52.9%)
54 (44.3%)
42 (56.0%)
76 (53.1%)
20 (37.0%)
68 (54.0%)
28 (39.4%)
11 (40.7%)
27 (49.1%)
63 (47.4%)
33 (51.6%)
*Heart disease is either a history of cardiac failure, angina pectoris, history of myocardial infarction, or valvular heart disease.
144
Kühlkamp et al.
Metoprolol After Cardioversion of Atrial Fibrillation
Table 5. Number (%) of Patients by the Most Common
Adverse Events (Occurring for ⬎2 Patients)
Adverse Events
Dizziness/vertigo/
nausea
Headache
Bradycardia
Dyspnea
(aggravated)
Fatigue
Palpitation/tachycardia
(aggravated)
Infection of the
respiratory tract/
coughing
Hypertension
(aggravated)
Chest pain
Back pain
Hematuria
Vision abnormal
Agitation
Angina pectoris
(aggravated)
Cardiac failure
(aggravated)
Fracture
Hypotension
Viral infection
Physical fitness
decreased
Pruritus
Sexual dysfunction
Sleep disorder
Increased sweating
Metoprolol
Group
(n ⴝ 200)
Placebo
Group
(n ⴝ 199)
All
Patients
(n ⴝ 399)
20 (10.2)
6 (3.0)
26 (6.6)
7 (3.6)
14 (7.1)
9 (4.6)
10 (5.1)
0
4 (2.0)
17 (4.3)
14 (3.6)
13 (3.3)
9 (4.6)
8 (4.1)
4 (2.0)
4 (2.0)
13 (3.3)
12 (3.0)
5 (2.5)
6 (3.0)
11 (2.8)
5 (2.5)
5 (2.5)
10 (2.5)
4 (2.0)
3 (1.5)
1 (0.5)
4 (2.0)
0
1 (0.5)
4 (2.0)
2 (1.0)
3 (1.5)
0
3 (1.5)
2 (1.0)
8 (2.0)
5 (1.3)
4 (1.0)
4 (1.0)
3 (0.8)
3 (0.8)
3 (1.5)
0
3 (0.8)
2 (1.0)
2 (1.0)
2 (1.0)
6 (3.0)
1 (0.5)
1 (0.5)
1 (0.5)
0
3 (0.8)
3 (0.8)
3 (0.8)
6 (1.5)
2 (1.0)
3 (1.5)
2 (1.0)
2 (1.0)
1 (0.5)
0
1 (0.5)
1 (0.5)
3 (0.8)
3 (0.8)
3 (0.8)
3 (0.8)
The number of patients included in the safety analysis is not the same as that included
in the efficacy analysis. The safety population includes 399 patients (199 placebo and
200 metoprolol CR/XL) and is defined as all patients who received at least one dose
of study drug, and for whom post-dose data were available. Numbers in parentheses
refer to %.
lation with cardiac disease, where valvular heart disease is
present only in a minority of individuals.
Mechanism of action. The mechanism by which a plain
beta-blocker prevents relapse into atrial fibrillation remains
speculative. An increased sympathetic drive has been shown
to provoke atrial tachyarrhythmias (42). This accords with
our finding that the effect of metoprolol was more pronounced in patients with a sinus rate above 80/min, as
compared with the group with a sinus rate below 80/min
(Table 4). In addition, beta-adrenergic stimulation shortens
the action potential duration by increasing the magnitude of
IK (43). In pacing-induced atrial fibrillation, shortening of
the atrial refractoriness is thought to be an important
mechanism by which atrial fibrillation perpetuates itself
(44). Furthermore, it has been shown recently that the
ultrarapid delayed rectifier K⫹ current (IKUR) plays an
important role in human atrial repolarization (45). This
current is increased by isoproterenol and the effect of
JACC Vol. 36, No. 1, 2000
July 2000:139–46
isoproterenol is reversed by the addition of propranolol (46).
An increase of IKUR decreases action potential duration.
Hence, there is evidence from experimental observations
that stimulation of adrenoceptors might facilitate the induction and perpetuation of atrial fibrillation.
Study limitations. Some limitations of the present study
should be noted. It is known from patients with paroxysmal
atrial fibrillation that asymptomatic episodes are frequent
(47). In a recent study, atenolol was found to be equivalent
to d,l sotalol in reducing the number of episodes of symptomatic atrial fibrillation (48). Paroxysmal atrial fibrillation
or a history of it were exclusion criteria in our study. All
patients in our study required DC cardioversion or treatment with class 1 antiarrhythmic drugs to convert to sinus
rhythm. It seems unlikely, therefore, that we inadvertently
recruited a significant number of patients with paroxysmal
atrial fibrillation. Furthermore, recurrences of atrial fibrillation were homogeneously distributed over time, and they
were not more frequently observed at the visits during
long-term follow-up. Therefore, it seems unlikely that
metoprolol CR/XL treatment masked symptoms of relapse
into atrial fibrillation. Although it cannot be ruled out that
we might have missed asymptomatic episodes of atrial
fibrillation that terminated spontaneously, the main goal of
treatment in atrial fibrillation is the reduction of symptomatic episodes, as it has never been shown that atrial stabilization, for example, reduces the risk of stroke. Asymptomatic episodes might have been detected had we used
frequent transtelephonic monitoring, as suggested in two
published trials in patients with frequent paroxysmal atrial
fibrillation (10,11).
A further limitation of our study is that the results cannot
be applied to all patients with atrial fibrillation. The mean
age of the patients in this trial was about 60 years, whereas
in the general population the mean age of patients with
atrial fibrillation is about 75 years (19). However, this might
reflect the practice of avoiding cardioversion and prescribing
antiarrhythmic drugs to maintain sinus rhythm in the
elderly (15), at least in the setting of a clinical trial.
Finally, the 40% placebo efficacy at the six-month
follow-up is higher than previously reported; therefore, it
has not been proven that metoprolol CR/XL is as effective
in a group of patients with a high risk for a recurrence of
atrial fibrillation after cardioversion.
Conclusions. It is concluded that metoprolol CR/XL is
superior to placebo for prevention of relapse into atrial
fibrillation after cardioversion to sinus rhythm. Because
therapy with beta-adrenergic blocking drugs has been
shown to be safe, treatment with metoprolol CR/XL may
become the treatment of first choice in patients with atrial
fibrillation who require drug therapy to maintain sinus
rhythm.
Acknowledgments
We would like to thank all investigators and study nurses
who contributed to the successful completion of this study.
JACC Vol. 36, No. 1, 2000
July 2000:139–46
We thank Professor John Wikstrand, MD, PhD, the
Assistant Director of the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital,
Göteborg University, who is also Senior Medical Advisor at
AstraZeneca RD, Mölndal, Sweden, for his comments and
help during preparation of the manuscript.
ECG core laboratory. We also thank Eva-Lena Alenhag,
Anna Frödén, and Caroline Schmidt, laboratory technologists, Inger Wendelhag, PhD, and Nils Edvardsson, MD,
PhD, at the Wallenberg Laboratory for cardiovascular
research, Sahlgrenska University Hospital, Göteborg University, Sweden, for analysis of all ECGs in the study.
Study coordination. Thomas Lanz, PhD, Astra Germany,
Isabella Florén, and Margareta Thimell, AstraZeneca RD,
Mölndal, Sweden.
Statistical analysis. Jonas Carlsson AstraZeneca RD,
Mölndal Sweden.
Reprint requests and correspondence: Volker Kühlkamp,
Eberhard-Karls-Universität, Medizinische Klinik III, Otfried
Müller Strasse 10, 72076 Tübingen, Germany. E-mail:
[email protected].
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