Epiiepsy Research, 13 (1992) 141-145 0920-121 l/92/$05.00
0
141
1992 Elsevier Science Publishers B.V. All rights reserved
EPIRES 00514
Carbamazepine induced bradycardia - a problem in general or only in susceptible patients? A 24-h long-term electrocardiogram study
G. Kennebgck”, L. Bergfeldtb, T. Tomsonc, E. Spinad and 0. Edhag” Cardiac Division. Department of Medicine, Karolinska Institute at “Huddinge Hospiial and ‘Karolinska Hospital, “Department of Neurology, Karolinska Institute at South Hospital and dDepartment of Clinical Pharmacology, Karo~inska Institute at ~uddinge Hospital, ~tockha~m, Sweden
(Received 8 May 1992; accepted 28 June 1992) Key words: Carbamazepine; Cardiac function; Arrhythmia; Bradycardia; Electrocardiogram
Carbamazepine is a first line drug in the treatment of epilepsy and trigeminal neuralgia, but may exert negative chronotropic and dromotropic effects on the cardiac conduction system. Bradyarrhythmias of different types and severity have been described, especially in the elderly. but the prevalence of arrhythmias in a larger group of carbamazepine treated patients is unknown. Forty-eight patients, 40 years or older, on continuous carbamazepine treatment because of various neurologic disorders were investigated by interview, physical examination, 12-lead surface electrocardiogram, and 24-h long-term electrocardiogram recording. The prevalence of bradyarrhythmias was compared with that in an age-stratified reference group. There were no differences between the two groups, either in the number or the duration of pauses or in the type of pauses. In conclusion, carbamazepine does not increase the risk of bradyarrhythmias in the vast majority of patients.
Introduction Carbamazepine is a first line drug in the treatment of epilepsy and trigeminal neuralgia’. The indications for carbamazepine have been extended and it is now also used in the treatment of the alcohol withdrawal syndrome2, in affective and schizo-affective disorders3*4. A possible limitation of,the use of carbamazepine is its cardiac side effects that seem to be especially likely to occur in older people5. Previously published. reports, describing disturbances of all parts of the conducCorrespondence to: G(iran Kennebsck, M.D., Cardiac Division, Department of Medicine, Karolinska Institute at Huddinge Hospital, S-141 86 Huddinge, Sweden.
tion system, are summarized in Table I”15. Conduction system disturbances were more common in elderly patients and were completely reversible on withdrawal or at lower dose levels. Carbamazepine may also suppress the ventricular escape rhythm in patients with complete atrioventricular block16. Based on these case reports a cardiac evaluation has been recommended before initiation of carbamazepine therapy. A systematic study of the prevalence of cardiac conduction effects of carbamazepine in a defined population is, however, lacking. The aim of this study was to determine the prevalence of conduction system abnormalities in a neurologic out-patient population on carbamazepine treatment, in order to decide whether carba-
142
TABLE
I of 10 reports on cardiac conduction system disturbances at different sites induced at therapeutic levels of’ carbamazepine in
Summary
altogether I5 patients All but patients
8 and 9 were symptomatic.
Electrocardiogram
Patient&Ret)
None was treated
with other antiarrhythmi~
drugs.
Age/Sex
Carbamazepine
dose at symptom
85/f
800 +
1000
Yes, at 600 mg/day
1200
Yes, at withdrawal
diagnosis
(mg/day)
_I”*.
Sinus bradycardia
l/(7)
or sinus arrest
Reversible
.
disturbance
--
2/(8)
77/f
600 -+
310 1)
82/f
600
Wlf
86/f
400
Yes. at withdrawai
S/(14)
54/f
600
Yes, at withdrawal
6/(15)
76/f
600
Yes, at withdrawal”
Yes, at withdrawal
Junctional
2/W
77/f
600 -+
bradycardia
7/(9) 3/(1 I)
73/f
800
Yes, at 400 mg/day
82/f
600
Yes, at withdrawai
4/(lJ)
86/f
400 _~
1200
Yes, at withdrawal
Yes. at withdrawal
.._
-_...---
Dose
0
200
400
I
First degree
g/(12)
42/f
PR time
0.16
0.2
AV block
9/(12)
47/m
PR time
0.18
0.22 s
~0165)
66/f
800 +
i 200
Yes, at withdrawal’
77/f
600 -+
I200
Yes, at withdrawal
1Ii
80/f
600 +
800
12/(10)
78/m
800
Yes, at 400 mg/day Yes, at withdrawal
13/(11)
72/f
400
Yes, at withdrawal’
14/(13)
.55/f
800
Yes, at 400 mgjday
15/(13)
59/f
400 +
Second degree or complete
AV block
2/(8)
Unspecified
800
0.24 s
Yes, at withdrawal
bradycardia AV block, atrioventricular --t indicates
that symptoms
’ Tachycardia-bradycardia electrophysiologic of sinus arrests
testing. increased
block. occurred
when the carbamazepine
syndrome, During
sinus node
dose was increased.
dysfunction
electrocardiogram
monitoring
at baseline
and during
carbama~epine
no sinus arrest at baseline,
treatment
verified
but several on carbamazepine.
at invasive The number
dose dependently.
h Without
carbamazepine
constant
’ Without
carbamazepine
right bundle
2:l atrioventricular branch
block II without
symptom.
block and left anterolateral
mazepine induced bradyarrhythmias are a problem in general or only in some susceptible patients. Patients and methods
Forty-eight outpatients were included in the study. All met the following criteria: (a) maintenance therapy with carbamazepine, (b) no concomitant antiarrhythmic drug treatment, (c) age between .40 and 79 years, (d) compliant and willing to participate in the study. The indications for car-
fascicular
block.
bamazepine therapy were epilepsy (43 patients), trigeminal neuralgia (three patients) and clonic hemifacial spasm (one patient). The patients were recruited from two sources: 33 patients from a neurological outpatient clinic and 15 via the Department of Clinical Pha~acology at Huddinge Hospital. We identified all patients who had their carbamazepine concentration assessed during one year at the Department of Clinical Pharmacology. One hundred and six patients fulfilled the inclusion criteria and were further evaluated. Sixty-eight pa-
143
tients had to be excluded because of alcoholism, suspicion of poor compliance to treatment or inability to cooperate, and cerebral tumors. Fourteen patients did not want to participate, four patients had died. The death causes were generalized tonic-clonic seizures, Parkinson’s disease, acute myocardial infarction and cerebral hemorrhage. The cause of death was not related to a side effect of carbamazepine. Five patients did not respond. A detailed history was obtained from all patients, a physical examination was performed, and a 12lead standard electrocardiogram was recorded as screening for cardiac disease. Blood samples were drawn immediately before the morning dose of carbamazepine. The plasma concentrations of carbamazepine and its active metabolite, carbamazepine- 10,ll -epoxide, were determined using high performance liquid chromatography17. The following 24 h all patients carried a two-channel electrocardiogram cassette recorder (Medilog 2, Oxford Medical System). The recording quality was checked with regard to stability and ability to detect P-waves. The patients were asked to report all symptoms in a diary, and to use the event marker if symptoms occurred. The electrocardiogram recordings were analyzed both automatically and manually. The results of the 24-h electrocardiogram registration were compared with a healthy, age grouped reference population of 260 individuals’*, and the same electrocardiogram definitions for bradyarrhythmias were used. Thus a ‘pause’ was an interval between two QRS complexes >, 1500 ms, excluding compensatory pauses following premature QRS complexes and atrioventricular block; ‘post-acceleration pause’ was a pause preceded by a brief increase in heart rate and followed by a gradual return of the heart rate to the pre-pause level; ‘sinus arrest’ was a pause preceded by a regular sinus rhythm and followed by a gradual increase in heart rate to the pre-pause level; ‘blocked atria1 premature beat’ was a pause with a visible premature P-wave, preceded and followed by a regular sinus rhythm, excluding sinus bradycardia and sinoatrial block. Second and third degree atrioventricular blocks were also looked for. The chi-square test was used for statistical evaluation of comparisons between the study group
and the reference population. The study protocol was approved by the Medical Ethics Committee of the Karolinska Institute at Huddinge Hospital and the patients gave their consent. Re&t+S Plasma concentrations
The mean (range) plasma concentration of carbamazepine was 20.6 (6.2-42.0) pmol/l and for carbamazepine-lO,ll-epoxide 3.4 ((M.5) pmol/l. History and physical examination
The mean (SD, range) age was 59.9 (k9.7, 4279) years. One patient had had a myocardial infarction 14 years prior to this study, but had been asymptomatic since a coronary by-pass operation 9 years later. Two patients had mild hypertension (diastolic blood pressure > 100 mm Hg on two occasions), but had no antihypertensive treatment. Standard electrocardiogram
Two patients had left anterior fascicular block and one patient right bundle branch block. Two patients had signs of an old myocardial infarction. The remaining electrocardiograms were normal. Long-term electrocardiogram
recording
Pauses, in no case exceeding 2 s, were observed in 10 patients (21%). The median number of pauses in this group of 10 patients was 1.5. The duration and the type of pauses are given in Table II A, B. High degree atrioventricular block was observed in one patient, who had second degree atrioventricular block, Mobitz type 2 in combination with sinus arrests. No correlation was found between pauses and plasma concentrations of carbamazepine and carbamazepine- 10,ll -epoxide. All arrhythmias were asymptomatic. Treatment was interrupted in the patient with sinus arrests and second degree atrioventricular block. The number of pauses and episodes of second degree atrioventricular block was reduced by 80% from the first to the fifth day after withdrawal of carbamazepine. Tachyarrhythmias were not observed in any patient. We did not observe any significant effect of carbamazepine treatment on sinus node function in the study
144
TABLE
II
Pauses during 24-h electrocardiogram
recording
(A) The occurrence
to duration
Age group
of pauses
related
4049
in the carbamazepine
C
CBZ
None
8 (80)
62 (63)
> 1500 ms
2 (20)
36 (37)
> 1750ms
1 (10)
3 (3)
> 2000 ms
Post-acceleration
diagnosis
Sinus bradycardia
&79
All C
9 (82)
59 (69)
21 (78)
62 (82)
38 (79)
183 (70)
2 (18)
27 (31)
6 (22)
14 (18)
10 (21)
II (30)
1 (9)
4 (5)
1 (4)
5 (7)
3 (6)
12 (5)
1 (1)
2 (1)
of pauses
beat
CBZ (n= 10)
C (n = 77)
3 (30)
46 (60)
4 (40)
12 (16)
2 (20)
9 (12)
(2RR)
3 (4)
Miscellaneous Results are given as numbers
(C)l7
CBZ
pause