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Antiarrhythmic significance of dosing intervals in beta receptor blocking therapy of hypertension with acebutolol
REPORTS ON THERAPY
Antiarrhythmic Significance of Dosing Intervals in Beta Receptor Blocking Therapy of Hypertension With Acebutolol
M. HEIKKI FRICK, RISTO KALA, MD
MD,
FACC
Helsinki, Finland
From the Cardiovascular Laboratory, First De&rtment of Medicine, University Central Hospital, Helsinki, Finland. Manuscript received February 18, 1981; revised manuscript received May 27, 1981, accepted June 1, 1981. Address for reprints: M. Heikki Frick, MD, First Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki 29, Finland.
Six hypertensive patients with daily ventricular arihythmias underwent a double-blind crossover study to examine whether a once daily regimen of beta receptor blockade was equipotent in antihypertensive and antiarrhythmic activity to a twice daily regimen. Acebutolol, a relatively cardioselective beta blocking compound with intrinsic sympathomimetic properties, was given in two regimens: 200 mg twice daily or 400 mg once daily. Ventricular ectopic beats were analyzed both during physical exercise and with multiple 24 hour ambulatory electrocardiographic (Halter) recordings. Serum concentrations of acebutolol and its acetyl metabolite were determined using high pressure liquid chromatography. The two regimens of acebutolol were equally potent in reducing the blood pressure and heart rate at rest and during physical exertion. The hourly heart rates during 24 hours were reduced to the same extent by both regimens. The single daily 400 mg dose did not significantly reduce the incidence of arrhythmias, whereas 2dO mg twice daily evoked a significant reduction during 24 hours. Serum concentrations of acebutolol were twice as great with the twice daily regimen as with the single dose. Both treatments significantly shortened the O-T, interval. The data suggest that, despite apparent beta receptor blockade and good blood pressure control, beta blooking agents with a relatively short plasma half-life lose their antiarrhythmic potency when administered on a once daily basis. This property seems to be more closely related to the plasma concentration of the compound than to the degree of clinically assessed beta receptor blockade.
Unsatisfactory patient compliance is one of the recognized problems in the treatment of hypertension. Iv2Among the various reasons for this problem are poor motivation to continue therapy in mostly asymptomatic patients and the frequent dosage required for some antihypertensive agents. Several studies 34 have shown that, despite pharmacokinetic differences, most beta receptor blocking agents can be successfully administered once daily in the treatment of hypertension, and this presumably results in better patient compliance. Some studies798 have suggested that the cardiovascular prognosis of hypertension can be improved with beta receptor blocking agents in contrast to treatment not including such agents.gJO Because the antihypertensive potency of beta blocking agents is not superior to that of.several alternative treatments, the ancillary properties of these agents, hotably their antiarrhythmic action, may play a part. We set out to examine whether beta blocking agents have similar antihypertensive and antiarrhythmic actions in hypertensive patients when they are administered one and two times daily. Some preliminary data have been rep0rted.l’ Methods Study patients: During a 20 month period of screening a large number of hypertensive patients, six patients were found with a reliable history of frequent
November 1991
The American Journal of CARDIOLOGY
Volume 49
911
BETA
BLOCKING
AGENTS,
ARRHYTHMIA
AND
HYPERTENSION-FRICK
AND
daily ectopic activity verified by prolonged 24 hour ambulatory (Holter) electrocardiographic monitoring. Patients with valvular heart disease, cardiomyopathy or manifest coronary heart disease were excluded. The study group consisted of three men and three women aged 31 to 57 years (mean 44). The duration of hypertension ranged from 2 to 15 years (mean 7). Four patients were in World Health Organization (WHO) class I and two in class II (left ventricular hypertrophy by electrocardiographic criteria). All patients were undergoing treatment with various beta adrenergic blocking agents; two were receiving additional antiarrhythmic therapy. Study design: The antihypertensive and antiarrhythmic therapy was stopped and the study was started with a 2 week placebo period at the end of which two consecutive 24 hour Holter recordings and two submaximal exercise tests were performed (Fig. 1). Thereafter the patients were randomly allocated to a double-blind crossover phase consisting of two 3 week periods of treatment with acebutolol, either 400 mg once daily or 200 mg twice daily. During these treatment periods, as well as during the 2 week placebo period between them, exercise tests and 24 hour Holter recordings were performed (Fig. 1). Throughout the trial the patients were fully ambulatory and performed their usual daily activities.
of
ectopic beats and at a paper speed of 50 mm/s for short periods to record the Q-T interval. The blood pressure was recorded during the final 30 seconds of each work load. Holter monitoring: Bipolar chest electrodes were attached after exercise. The 24 hour recording was performed with a two channel electrocardiographic recorder (model 445, Avionics) and the tapes were analyzed with a model 660 A Avionics Electrocardioscanner. The automatic counter of the scanner was adjusted separately for each tape with a proper combination of three criteria to detect ventricular ectopic beats (prematurity, width and amplitude of the QRS complex) in order to count the hourly ectopic beats. The speed used in the scanning was 60 times normal, and continuous visual assessment was applied to assess true arrhythmia. The number of heartbeats per hour was automatically counted by the scanner. Acebutolol serum assays: The morning dose of acebutolol was taken after the tests in the laboratory. Thus the data collected represent 24 hours after the last dose with the regimen of 400 mg once daily and 12 hours after the last dose with the regimen of 200 mg twice daily. The serum of the blood samples was stored at -20°C until assayed. Assays were performed at the Department of Clinical Chemistry, Beckomberga Hospital, Stockholm, Sweden, without knowledge of the treatment sequence. Acebutolol and its acetyl metabolite were selectively extracted into ethylacetate, separated by high pressure liquid chromatography fitted with an ultraviolet detector. Internal standards of both acebutolol and the metabolite were prepared in order to calibrate a suitable concentration range. The lowest detectable serum concentration with this method is 0.02 pmol/liter and the measuring accuracy for both acebutolol and the metabolite is 3 percent (Carlberger G, personal communication). Statistical analysis: The coefficient of variation of the number of ectopic beats during the placebo periods was calculated as standard deviation (SD) X loo/mean. The Q-T interval was rate-corrected as follows: Q-T, = Q-T measured/R-R in seconds. Paired and unpaired t tests were used to test the significance of the differences.
Laboratory Procedures
The patients entered the laboratory in the morning and were made to rest for 15 minutes in a supine position during which the electrodes were attached for electrocardiography and a venous blood sample was taken for the determination of acebutolol concentration. The blood pressure was measured with the cuff method and the pressure reading on the disappearance of Korotkoff sounds was taken as the diastolic pressure. The heart rate was determined from the electrocardiogram. Exercise testing: Blood pressure and heart rate measurements were repeated with the patients seated on a bicycle ergometer (Elema-Schonander, Sweden). Two exercise periods of 4 minutes each without an intervening pause were used. The work loads were 200 and 400 kilopond-meters (kpm)/min for women and 300 and 600 kpm/min for men, representing light and moderate exercise, respectively. During exercise the electrocardiogram was continuously recorded with six chest-head electrodes at a paper speed of 10 mm/s for the detection
ACEBUTOLOL 2 x 200 MG
KALA
ACEBUTOLOL1 x WI
Pu\CEBO
MG 4
EX
k---
EX
3 WEEKS +
ACEBlJTO.LOL 1 x .400 EX
EX
,
EX EX I2
912
November
1981
The American
Journal
EX 2 iit
z
2
MG
EX
EX EX
EX EX no no
WEEKS
3
.t
PLACEBO
.
WEEKS
-+
ACEBIJTOLOL2 x, 200 m
EX EX no
EX
EX
w
Ha
of CARDIOLOGY
EX EX II0
Volume 48
FIGURE 1. Study design. EX = exercise test; HO = 24 hour Holter monitoring.
BETA BLOCKING AGENTS, ARRHYTHMIA AND HYPERTENSION-FRICK
AND KALA
TABLE I Blood Pressure (BP, mm Hg) and Heart Rate (HR, beatslmin) of the mean) Supine
Light Exercise
Sitting
BP
Intervention
During Different Testing Procedures (mean f standard error
HR
BP
HR
Moderate Exercise
BP
HR
BP
HR
105 f 2.2
184 f 5.1 102 f 1.3
126 f 3.1
Placebo
154 f 4.5 101 f 2.5
79 f
1.8
144 f 4.0 102 f 2.6
91 f 2.4
162 f 3.9 100 f 2.4
Acebutolol (2 X 200 mg)
139 f 2.9% 93 f 2.1‘
66 f
1.85
130 f 3.3’ 95 f 2.1’
73 f 2.09
149 f 3.9’ 92 f 2.2’
86 f 2.35
162 f 4.7t 94 f 1.0t
103 f 3.09
Acebutolol (1 X 400 mg)
142 f 4.7+ 94 f 2.5’
66 f
1.49
136 f 5.6 93 f 2.3+
73 f
148 f 4.2’ 91 f 2.3+
85 f
167 f 4.4+ 96 f 1.9+
105 f
l
p <0.05.
+ p <0.02.
f p
*
1.95
1.89
1.95
p
The difference in the number of ectopic beat8 was analyzed after logarithmic transformation (log n+l). Results Blood pressure and heart rate: Acebutolol, 200 mg administered twice daily, significantly reduced the blood pressure and heart rate both at rest and during exercise (Table I). A commensurate reduction occurred when 400 mg was administered once daily, except in the blood pressure in the sitting position. There were no statistically significant differences between the responses to the two regimens. Analysis of the 24 hour heart rate (Fig. 2) revealed that both treatments greatly reduced the heart rate during the early morning hours. During the night the reduction was only moderate. Ventricular ectopic beats: No ventricular tachycardia was noted. The ventricular ectopic beats were usually coupled beats with mostly fixed coupling intervals; in some instances multiform beats were observed. Acebutolol, 200 mg administered twice daily, reduced the ectopic beats recorded during exercise by
35 percent (Table II); in the single 400 mg daily dose, it did not change the number of ectopic beats during exercise. The coefficient of variation of the number of ectopic beats during the four 24 hour recordings in the placebo period averaged 41 percent. The 24 hour monitoring periods were divided into two 12 hour periods for the analysis (morning-evening and evening-morning). Table III shows the results of the two treatments. Acebutolol, 200 mg twice daily, evoked a consistent reduction of 50 percent throughout the 24 hours; in the single 400 mg daily dose, it reduced the number of ectopic beats during the first 12 hours by 23 percent, but the 24 hour reduction was only 7 percent. The reduction in the number of ectopic beats with the two times daily regimen was considerable in some patients (73 percent in five patients) whereas no clear pattern emerged when 400 mg was given once daily (Fig. 3). There were two men with left ventricular hypertrophy as assessed from electrocardiographic criteria. In these patients the ectopic beats averaged 298lhour
FIGURE 2. Effect of acebutolol in different dosages on 24 hour heart rate (mean f standard deviation). 0.D. = twice daily: O.D. = once daily.
November 1991
The American Journal of CARDIOLOGY
Volume 48
913
BETA BLOCKING AGENTS, ARRHYTHMIA AND HYPERTENSION-FRICK
TABLE
AND KALA
II
TABLE
Effect of Acebutolol on Ventricular Ectopic Beats During Exercise (mean f standard error of the mean)
Ventricular Monitoring
Ventricular Ectopic Beats?
Intervention Placebo’ Acebutolol’ 2 X 200 mg
Ectopic Periods
Intervention
37f 10 24 f 6
Placebo Acebutolol 2 X 200 mg
0.05 < 0.10 35 f a
A:ebutolol‘ 1 X 400 mg P
Ill
A?zebutolol 1 X 400 mg P
0.80 < 0.90
Mean of four exercise tests. t Number of ectopic beats during the entire test. p = probability values for acebutolol versus placebo.
Beats During Different
First 12 Hours
Following 12 Hours
24 Hours
163 f 46 97 f 45
214 f 56 116 f 52
<0.02 205 f 87
0.05 < 0.10 196 f 66
<0.05 201 f 74
0.20 < 0.30
0.10 < 0.20
0.80 < 0 90
266f69’ 136 f 60
l
Beats/hour, mean f standard error of the mean. p = probability. l
and it does not increase heart size,16 in contrast to propranolol and metoprolol, l7 which are devoid of intrinsic agonist activity. Oral acebutolol has a verified antihypertensive action,ls and it has been found to possess a distinct antiarrhythmic effect both experimentallylg and clinically.20-24 The plasma half-life of acebutolol is about 2.5 hours; its acetyl metabolite has a slower decay. 23 The precise actions of this metabolite in man are not known although animal data suggest that it differs from the parent compound in its antiarrhythmic effects and cardioselectivity.24 Antiarrhythmic versus antihypertensive effects of acebutolol: The antihypertensive effect of acebutolol was amply confirmed in this study. Both dosage regimens decreased the blood pressure at rest and during physical exertion, a finding not previously made. However, a sustained antiarrhythmic effect was observed only when the drug was given twice daily. All previous studies on the antiarrhythmic action of oral acebutolol have applied multiple daily dosing.20-22 One inherent difficulty in assessing the antiarrhythmic effect of any compound is the spontaneous variability of ventricular arrhythmias, and several 24 hour recordings are usually required to obtain a reliable baseline and drug response.25 In our study four 24 hour recordings were performed for placebo and two 24 hour recordings for each dosage regimen. The careful selection of appropriate patients for the study was also advantageous and resulted in a reasonable average coefficient of
during the four placebo periods. This was considerably greater than the corresponding mean of 172 beats/hour in the four patients without left ventricular hypertrophy. In the patients with left ventricular hypertrophy, acebutolol, 400 mg administered once daily, evoked a 57 percent reduction and 200 mg given twice daily a 77 percent reduction in the number of ectopic beats. In the four patients without left ventricular hypertrophy the corresponding values were +38 and -19 percent, respectively. Because of the limited sample size these data were not subjected to statistical treatment. Serum concentration of acebutolol (Table IV): None of the blood samples taken during the placebo periods contained any acebutolol or its acetyl metabolite. The serum concentration of acebutolol on the regimen of 200 mg twice daily was twice as great as that on the regimen of 400 mg once daily, and the concentration of the metabolite was 34 percent greater with the twice daily than with the once daily regimen. The Q-T, interval (Table V): Both regimens shortened the Q-T, interval at rest and during exercise; there were no significant differences between the responses. Discussion Acebutolol is a relatively cardioselective beta receptor blocking compound with membrane-stabilizing and intrinsic sympathomimetic properties.12J3 It has been found useful in the management of angina pectoris14J5
“T
“T
/
./
j!/:-l:~“/;“* (
0
2
4
6
a
0
2
4
6
a
PLACEBO
PUCEDO
VENTRICULAR ECTOPIC BEATS.LOGN + 1
914
November 1991
The American Journal of CARDIOLOGY
Volume 48
FIGURE 3. Effect of two different acebutolol dosages (200 mg twice daily, left, and 400 mg once daily, right) on ventricular ectopic beats/hour during 24 hour Holter monitoring. All six patients had two 24 hour recordings on both regimens. These 12 readings are plotted against respective placebo data. The data show a reduction in ectopic beats with the twice daily regimen and no change with the once daily regimen.
BETA BLOCKING AGENTS, ARRHYTHMIA
TABLE
IV
TABLE
Serum Concentrations (mean f standard error of the mean) of Acebutolol and Its Main Metabollte During Different Dosing Schedules
AND HYPERTENSION-FRICK
AND KALA
V
Effect of Acebutolol standard deviation)
on Q-T,
Interval
(mean
f
Q-T, 6) Plasma Concentration (~mol/liter) Acebutolol Dosing
Acebutolol
Acetyl Metabolite
Total
2 X 200 mg 1 X 400 mg P
0.30 f 0.02 0.15 f 0.04
0.79 f 0.05 0.59 f 0.10 co.02
1.10 f 0.08 0.73 f 0.09
Intervention
At Rest
Light Exercise
Moderate Exercise
Placebo Acebutolol 2 X 200 mg
0.52 f 0.04 0.46 f 0.02
0.59 f 0.03 0.54 f 0.05
0.65 f 0.03 0.58 f 0.04
<0.05 0.47 f 0.04
<0.05 0.53 f 0.03
0.10 < 0.20
<0.02
<0.02
AFebutolol 1 X 400 mo w P
p = probability values for acebutolol versus placebo.
p = probability (comparison of 2 times and 1 times daily dosing).
variation in the number of ectopic beats during the placebo periods. With the regimen of 200 mg administered twice daily, the reduction in the number of ectopic beats averaged 73 percent in five patients; in one patient the reduction was negligible. Patients with left ventricular hypertrophy had more episodes of arrhythmia than patients without left ventricular hypertrophy and the response to acebutolol was also more pronounced in patients with cardiac involvement. Role of slowing of heart rate, Q-T, interval and serum concentration in antiarrhythmic effect: Both regimens produced a commensurate degree of beta receptor blockade as judged from the heart rate data at rest and during bicycle exercise (Table I) and from the reduction in hourly heart rates during 24 hours (Fig. 2). The antiarrhythmic effect of the 200 mg twice daily regimen cannot therefore be easily attributed to beta blockade alone. The antiarrhythmic implications of the shortening of the Q-T, interval are difficult to judge. In this respect acebutolol resembles propranolol, which also shortens the Q-T, interval when given intravenously.26T27 Prolongation of the action potential is considered advantageous and represents a class 3 antiarrhythmic effect. 28 However, sotalol, which is a beta blocking compound with a class 3 effect, has been shown to produce Q-T, prolongation and dangerous ventricular arrhythmias in excessive dosages.29 In any event, the shortening of the Q-T, interval observed in our study was similar with both treatments and hence cannot explain the difference in antiarrhythmic potency. One clear difference between the two dosing schemes was a significantly higher serum concentration of acebutolol with the 200 mg twice daily regimen (Table
IV), and it seems plausible to conclude that the antiarrhythmic effect of acebutolol is more closely related to its plasma concentration than to the degree of clinically assessed beta blockade. Multiple plasma samples during the 24 hour monitoring periods would have strengthened this thesis but we were unable to obtain these in the fully ambulatory patients. However, our reasoning on the importance of the drug plasma levels is supported by the exercise data recorded immediately after the blood samples were obtained in the morning. During exercise, the 200 mg twice daily regimen of acebutolol evoked a reduction in the number of ectopic beats in contrast to the 400 mg once daily regimen (Table II) despite the similarity of heart rate and blood pressure responses in the two regimens (Table I). Therapeutic implications: For the sake of patient compliance it is probably advantageous to administer any beta receptor blocking agent once daily in the treatment of hypertension. However, the present data suggest that acebutolol and presumably other beta blocking agents with similar pharmacokinetic properties should be given at least twice daily if the desired cardioprotective effect is to be sustained for 24 hours. This line of reasoning might especially apply to patients with left ventricular hypertrophy who are at increased risk for sudden death.30 Acknowledgment We express our grateful thanks to Roeinton B. Khambatta, MD, May & Baker Ltd, England, who provided the acebutolol capsules used in the study, and to Gunnar Carlberger, MD, and Lars-G&an Allgen, MD, of the Beckomberga and St. Erik Hospitals, Sweden, who performed the assays of acebutolol serum concentration.
References 1. Francis V, Korsch BM, Morris MJ. Gaps in doctor-patient communication: patients’ response to medical advice. N Engl J Med 1969;280:535-40. 2. Caldwell JR, Cobb S, Dowllng MD, De Jongh D. The dropout problem in antihypertensive treatment. A pilot study of social and emotional factors influencing a patient’s ability to follow antihypertensive treatment. J Chron Dis 1970;22:579-92. 3. Wilson M, Morgan G, Morgan 1. The effect on blood pressure of
beta-adrenoceptor blocking drugs administered once daily and their duration of action when therapy is ceased. Br J Clin Pharmacol 1976;3:857-61. 4. Douglas-Jones AP, Crulckshank JM. Oncedaily dosing with atenolol in patients with mild or moderate hypertension. Br Med J 1976:1:990-l. 5. Wilcox RG. Randomized study of six beta-blockers and a thiazide diuretic in essential hypertension. Br Med J 1978;2:383-5.
November 1981
The American Journal of CARDIOLOGY
Volume 48
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BETA BLOCKING AGENTS, ARRHYTHMIA
AND HYPERTENSION-FRICK
6. Reybrouck T, Amery A, Fagard R, Jousten P, Lijnen P, Meulepas E. Beta-blockers: once or three times a day? Br Med J 1978;l: 1386-8. 7. Stewart M&G. Compared incidence of first myocardial infarction in hypertensive patients under treatment containing propranolol or excluding beta-receptor blockade. Clin Sci Mot Med 1976;51: 509-16. 8. Berglund G, Wilhelmsen L, Sannerstedt R, et al. Coronary heart-disease after treatment of hypertension. Lancet 1978;l: l-5. 9. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. I. Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967;202:1028-34. 10. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effect of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970;213:1143-52. 11. Frick MH, Kala II. Once daily versus twice daily beta-blockers: effects on arrhythmias and hypertension [letter]. Lancet 1980; 2:588. 12. Cuthbert MF, Owusu-Ankomah K. Effect of M 8 B 17803A, a new P-adrenoceptor blocking agent, on the cardiovascular responses to tilting and to isoprenaline in man. Br J Pharmacol 1971;43: 639-48. 13. Basil B, Jordan R, Loveless AH, Maxwell DR. &adrenoceptor blocking properties and cardioselectivity of M 8. B 17,803A. Br J Pharmacol 1973;48:198-211. 14. Lewis BS, Bakst A, Kitchiner DJ, Gotsman MS. Sectral in the management of angina pectoris. S Afr Med J 1973;47: 1455-9. 15. Khambatta RB. Comparison of a new beta-receptor blocking agent acebutolol (Sectral) and propranolol. Clin Trials J 1974;11:5967. 16. Frick MH, Valle M, Korhola 0, Hekall P, Riihlmaki E. Response of left ventricular myocardial perfusion and cavity size to betablockade by acebutolol. Ann Clin Res 1978; 10:66-70. 17. Frick MH, Luurlla 0. Double-blind titrated-dose comparison of metoprolol and propranolol in the treatment of angina pectoris. Ann Clin Res 1976;8:385-92. 18. Menard J, Bertagna X, N’Guyen PT, Dagoulet P, Corvol P. Rapid identification of patients with essential hypertension sensitive to
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The American Journal of CARDIOLOGY
AND KALA
19.
20. 21.
22.
23.
24. 25.
26.
27.
28.
29.
30.
acebutolol (a new cardioselective beta-blocker). Am J Med 1976;60:886-90. Basil B, Jordan R, Loveless AH, Maxwell DR. A comparison of the experimental anti-arrhythmic properties of acebutolol (M 8 B 17,803). propranolol and practolol. Br J Pharmacol 1974;50: 323-33. Lewis BS, Mitha AS, Gotsman MS. Acebutolol in cardiac arrhythmias. S Afr Med J 1974;48:821-4. Gradman AH, Winkle RA, Fitzgerald JW, et al. Suppression of premature ventricular contractions by acebutolol. Circulation 1977;55:785-91. De Soyza N, Kane JJ, Murphy ML, Laddu AR, Doherty JE, Blsaat JK. The long-term suppression of ventricular arrhythmias by oral acebutolol in patients with coronary artery disease. Am Heart J 1980;100:631-8. Winkle RA, Meffin PJ, Ricks WB, Harrison DC. Acebutolol metabolite plasma concentration during chronic oral therapy. Br J Clin Pharmacol 1977;4:519-22. Collins RF. Pharmacocinetique de I’acebutolol. Nouv Presse Med 1975;4:3223-8. Morganroth J, Michelson EL, Horowitz LN, Josephson ME, Pearlman AS, Dunkman WB. Limitations of routine long-term ambulatory electrocardiographic monitoring to assess ventricular ectopic frequency. Circulation 1978;58:408-14. Stern S, Eisenberg S. The effect of propranolol (Inderal) on the electrocardiogram of normal subjects. Am Heart J 1969;77: 192-5. Seides SF, Josephson ME, Bataford WP, Weiafegel GM, Lau SH, Damato AN. The electrophysiology of propranolol in man. Am Heart J 1974;88:733-41. Vaughan Williams EM. Classification of antiarrhythmic drugs. In: Sandee E, Flensted-Jensen E. Olesen KH, eds. Cardiac Arrhythmias. Sodertalje, Sweden: Astra Ltd, 1970:449-69. Elonen E, Neuvonen PJ, Taraaanen L, Kala R. Sotalol intoxication with prolonged Q-T interval and severe tachyarrhythmias [letter]. Br Med J 1979;1:1184. Kannel WB, Gordon T, Castelli WP, Margolis JR. Electrocardiographic left ventricular hypertrophy and risk of coronary heart disease. The Framingham Study. Ann Intern Med 1970;72:81322.
Volume 48
Antiarrhythmic Significance of Dosing Intervals in Beta Receptor Blocking Therapy of Hypertension With Acebutolol
M. HEIKKI FRICK, RISTO KALA, MD
MD,
FACC
Helsinki, Finland
From the Cardiovascular Laboratory, First De&rtment of Medicine, University Central Hospital, Helsinki, Finland. Manuscript received February 18, 1981; revised manuscript received May 27, 1981, accepted June 1, 1981. Address for reprints: M. Heikki Frick, MD, First Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki 29, Finland.
Six hypertensive patients with daily ventricular arihythmias underwent a double-blind crossover study to examine whether a once daily regimen of beta receptor blockade was equipotent in antihypertensive and antiarrhythmic activity to a twice daily regimen. Acebutolol, a relatively cardioselective beta blocking compound with intrinsic sympathomimetic properties, was given in two regimens: 200 mg twice daily or 400 mg once daily. Ventricular ectopic beats were analyzed both during physical exercise and with multiple 24 hour ambulatory electrocardiographic (Halter) recordings. Serum concentrations of acebutolol and its acetyl metabolite were determined using high pressure liquid chromatography. The two regimens of acebutolol were equally potent in reducing the blood pressure and heart rate at rest and during physical exertion. The hourly heart rates during 24 hours were reduced to the same extent by both regimens. The single daily 400 mg dose did not significantly reduce the incidence of arrhythmias, whereas 2dO mg twice daily evoked a significant reduction during 24 hours. Serum concentrations of acebutolol were twice as great with the twice daily regimen as with the single dose. Both treatments significantly shortened the O-T, interval. The data suggest that, despite apparent beta receptor blockade and good blood pressure control, beta blooking agents with a relatively short plasma half-life lose their antiarrhythmic potency when administered on a once daily basis. This property seems to be more closely related to the plasma concentration of the compound than to the degree of clinically assessed beta receptor blockade.
Unsatisfactory patient compliance is one of the recognized problems in the treatment of hypertension. Iv2Among the various reasons for this problem are poor motivation to continue therapy in mostly asymptomatic patients and the frequent dosage required for some antihypertensive agents. Several studies 34 have shown that, despite pharmacokinetic differences, most beta receptor blocking agents can be successfully administered once daily in the treatment of hypertension, and this presumably results in better patient compliance. Some studies798 have suggested that the cardiovascular prognosis of hypertension can be improved with beta receptor blocking agents in contrast to treatment not including such agents.gJO Because the antihypertensive potency of beta blocking agents is not superior to that of.several alternative treatments, the ancillary properties of these agents, hotably their antiarrhythmic action, may play a part. We set out to examine whether beta blocking agents have similar antihypertensive and antiarrhythmic actions in hypertensive patients when they are administered one and two times daily. Some preliminary data have been rep0rted.l’ Methods Study patients: During a 20 month period of screening a large number of hypertensive patients, six patients were found with a reliable history of frequent
November 1991
The American Journal of CARDIOLOGY
Volume 49
911
BETA
BLOCKING
AGENTS,
ARRHYTHMIA
AND
HYPERTENSION-FRICK
AND
daily ectopic activity verified by prolonged 24 hour ambulatory (Holter) electrocardiographic monitoring. Patients with valvular heart disease, cardiomyopathy or manifest coronary heart disease were excluded. The study group consisted of three men and three women aged 31 to 57 years (mean 44). The duration of hypertension ranged from 2 to 15 years (mean 7). Four patients were in World Health Organization (WHO) class I and two in class II (left ventricular hypertrophy by electrocardiographic criteria). All patients were undergoing treatment with various beta adrenergic blocking agents; two were receiving additional antiarrhythmic therapy. Study design: The antihypertensive and antiarrhythmic therapy was stopped and the study was started with a 2 week placebo period at the end of which two consecutive 24 hour Holter recordings and two submaximal exercise tests were performed (Fig. 1). Thereafter the patients were randomly allocated to a double-blind crossover phase consisting of two 3 week periods of treatment with acebutolol, either 400 mg once daily or 200 mg twice daily. During these treatment periods, as well as during the 2 week placebo period between them, exercise tests and 24 hour Holter recordings were performed (Fig. 1). Throughout the trial the patients were fully ambulatory and performed their usual daily activities.
of
ectopic beats and at a paper speed of 50 mm/s for short periods to record the Q-T interval. The blood pressure was recorded during the final 30 seconds of each work load. Holter monitoring: Bipolar chest electrodes were attached after exercise. The 24 hour recording was performed with a two channel electrocardiographic recorder (model 445, Avionics) and the tapes were analyzed with a model 660 A Avionics Electrocardioscanner. The automatic counter of the scanner was adjusted separately for each tape with a proper combination of three criteria to detect ventricular ectopic beats (prematurity, width and amplitude of the QRS complex) in order to count the hourly ectopic beats. The speed used in the scanning was 60 times normal, and continuous visual assessment was applied to assess true arrhythmia. The number of heartbeats per hour was automatically counted by the scanner. Acebutolol serum assays: The morning dose of acebutolol was taken after the tests in the laboratory. Thus the data collected represent 24 hours after the last dose with the regimen of 400 mg once daily and 12 hours after the last dose with the regimen of 200 mg twice daily. The serum of the blood samples was stored at -20°C until assayed. Assays were performed at the Department of Clinical Chemistry, Beckomberga Hospital, Stockholm, Sweden, without knowledge of the treatment sequence. Acebutolol and its acetyl metabolite were selectively extracted into ethylacetate, separated by high pressure liquid chromatography fitted with an ultraviolet detector. Internal standards of both acebutolol and the metabolite were prepared in order to calibrate a suitable concentration range. The lowest detectable serum concentration with this method is 0.02 pmol/liter and the measuring accuracy for both acebutolol and the metabolite is 3 percent (Carlberger G, personal communication). Statistical analysis: The coefficient of variation of the number of ectopic beats during the placebo periods was calculated as standard deviation (SD) X loo/mean. The Q-T interval was rate-corrected as follows: Q-T, = Q-T measured/R-R in seconds. Paired and unpaired t tests were used to test the significance of the differences.
Laboratory Procedures
The patients entered the laboratory in the morning and were made to rest for 15 minutes in a supine position during which the electrodes were attached for electrocardiography and a venous blood sample was taken for the determination of acebutolol concentration. The blood pressure was measured with the cuff method and the pressure reading on the disappearance of Korotkoff sounds was taken as the diastolic pressure. The heart rate was determined from the electrocardiogram. Exercise testing: Blood pressure and heart rate measurements were repeated with the patients seated on a bicycle ergometer (Elema-Schonander, Sweden). Two exercise periods of 4 minutes each without an intervening pause were used. The work loads were 200 and 400 kilopond-meters (kpm)/min for women and 300 and 600 kpm/min for men, representing light and moderate exercise, respectively. During exercise the electrocardiogram was continuously recorded with six chest-head electrodes at a paper speed of 10 mm/s for the detection
ACEBUTOLOL 2 x 200 MG
KALA
ACEBUTOLOL1 x WI
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MG 4
EX
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3 WEEKS +
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EX
,
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November
1981
The American
Journal
EX 2 iit
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2
MG
EX
EX EX
EX EX no no
WEEKS
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ACEBIJTOLOL2 x, 200 m
EX EX no
EX
EX
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of CARDIOLOGY
EX EX II0
Volume 48
FIGURE 1. Study design. EX = exercise test; HO = 24 hour Holter monitoring.
BETA BLOCKING AGENTS, ARRHYTHMIA AND HYPERTENSION-FRICK
AND KALA
TABLE I Blood Pressure (BP, mm Hg) and Heart Rate (HR, beatslmin) of the mean) Supine
Light Exercise
Sitting
BP
Intervention
During Different Testing Procedures (mean f standard error
HR
BP
HR
Moderate Exercise
BP
HR
BP
HR
105 f 2.2
184 f 5.1 102 f 1.3
126 f 3.1
Placebo
154 f 4.5 101 f 2.5
79 f
1.8
144 f 4.0 102 f 2.6
91 f 2.4
162 f 3.9 100 f 2.4
Acebutolol (2 X 200 mg)
139 f 2.9% 93 f 2.1‘
66 f
1.85
130 f 3.3’ 95 f 2.1’
73 f 2.09
149 f 3.9’ 92 f 2.2’
86 f 2.35
162 f 4.7t 94 f 1.0t
103 f 3.09
Acebutolol (1 X 400 mg)
142 f 4.7+ 94 f 2.5’
66 f
1.49
136 f 5.6 93 f 2.3+
73 f
148 f 4.2’ 91 f 2.3+
85 f
167 f 4.4+ 96 f 1.9+
105 f
l
p <0.05.
+ p <0.02.
f p
*
1.95
1.89
1.95
p
The difference in the number of ectopic beat8 was analyzed after logarithmic transformation (log n+l). Results Blood pressure and heart rate: Acebutolol, 200 mg administered twice daily, significantly reduced the blood pressure and heart rate both at rest and during exercise (Table I). A commensurate reduction occurred when 400 mg was administered once daily, except in the blood pressure in the sitting position. There were no statistically significant differences between the responses to the two regimens. Analysis of the 24 hour heart rate (Fig. 2) revealed that both treatments greatly reduced the heart rate during the early morning hours. During the night the reduction was only moderate. Ventricular ectopic beats: No ventricular tachycardia was noted. The ventricular ectopic beats were usually coupled beats with mostly fixed coupling intervals; in some instances multiform beats were observed. Acebutolol, 200 mg administered twice daily, reduced the ectopic beats recorded during exercise by
35 percent (Table II); in the single 400 mg daily dose, it did not change the number of ectopic beats during exercise. The coefficient of variation of the number of ectopic beats during the four 24 hour recordings in the placebo period averaged 41 percent. The 24 hour monitoring periods were divided into two 12 hour periods for the analysis (morning-evening and evening-morning). Table III shows the results of the two treatments. Acebutolol, 200 mg twice daily, evoked a consistent reduction of 50 percent throughout the 24 hours; in the single 400 mg daily dose, it reduced the number of ectopic beats during the first 12 hours by 23 percent, but the 24 hour reduction was only 7 percent. The reduction in the number of ectopic beats with the two times daily regimen was considerable in some patients (73 percent in five patients) whereas no clear pattern emerged when 400 mg was given once daily (Fig. 3). There were two men with left ventricular hypertrophy as assessed from electrocardiographic criteria. In these patients the ectopic beats averaged 298lhour
FIGURE 2. Effect of acebutolol in different dosages on 24 hour heart rate (mean f standard deviation). 0.D. = twice daily: O.D. = once daily.
November 1991
The American Journal of CARDIOLOGY
Volume 48
913
BETA BLOCKING AGENTS, ARRHYTHMIA AND HYPERTENSION-FRICK
TABLE
AND KALA
II
TABLE
Effect of Acebutolol on Ventricular Ectopic Beats During Exercise (mean f standard error of the mean)
Ventricular Monitoring
Ventricular Ectopic Beats?
Intervention Placebo’ Acebutolol’ 2 X 200 mg
Ectopic Periods
Intervention
37f 10 24 f 6
Placebo Acebutolol 2 X 200 mg
0.05 < 0.10 35 f a
A:ebutolol‘ 1 X 400 mg P
Ill
A?zebutolol 1 X 400 mg P
0.80 < 0.90
Mean of four exercise tests. t Number of ectopic beats during the entire test. p = probability values for acebutolol versus placebo.
Beats During Different
First 12 Hours
Following 12 Hours
24 Hours
163 f 46 97 f 45
214 f 56 116 f 52
<0.02 205 f 87
0.05 < 0.10 196 f 66
<0.05 201 f 74
0.20 < 0.30
0.10 < 0.20
0.80 < 0 90
266f69’ 136 f 60
l
Beats/hour, mean f standard error of the mean. p = probability. l
and it does not increase heart size,16 in contrast to propranolol and metoprolol, l7 which are devoid of intrinsic agonist activity. Oral acebutolol has a verified antihypertensive action,ls and it has been found to possess a distinct antiarrhythmic effect both experimentallylg and clinically.20-24 The plasma half-life of acebutolol is about 2.5 hours; its acetyl metabolite has a slower decay. 23 The precise actions of this metabolite in man are not known although animal data suggest that it differs from the parent compound in its antiarrhythmic effects and cardioselectivity.24 Antiarrhythmic versus antihypertensive effects of acebutolol: The antihypertensive effect of acebutolol was amply confirmed in this study. Both dosage regimens decreased the blood pressure at rest and during physical exertion, a finding not previously made. However, a sustained antiarrhythmic effect was observed only when the drug was given twice daily. All previous studies on the antiarrhythmic action of oral acebutolol have applied multiple daily dosing.20-22 One inherent difficulty in assessing the antiarrhythmic effect of any compound is the spontaneous variability of ventricular arrhythmias, and several 24 hour recordings are usually required to obtain a reliable baseline and drug response.25 In our study four 24 hour recordings were performed for placebo and two 24 hour recordings for each dosage regimen. The careful selection of appropriate patients for the study was also advantageous and resulted in a reasonable average coefficient of
during the four placebo periods. This was considerably greater than the corresponding mean of 172 beats/hour in the four patients without left ventricular hypertrophy. In the patients with left ventricular hypertrophy, acebutolol, 400 mg administered once daily, evoked a 57 percent reduction and 200 mg given twice daily a 77 percent reduction in the number of ectopic beats. In the four patients without left ventricular hypertrophy the corresponding values were +38 and -19 percent, respectively. Because of the limited sample size these data were not subjected to statistical treatment. Serum concentration of acebutolol (Table IV): None of the blood samples taken during the placebo periods contained any acebutolol or its acetyl metabolite. The serum concentration of acebutolol on the regimen of 200 mg twice daily was twice as great as that on the regimen of 400 mg once daily, and the concentration of the metabolite was 34 percent greater with the twice daily than with the once daily regimen. The Q-T, interval (Table V): Both regimens shortened the Q-T, interval at rest and during exercise; there were no significant differences between the responses. Discussion Acebutolol is a relatively cardioselective beta receptor blocking compound with membrane-stabilizing and intrinsic sympathomimetic properties.12J3 It has been found useful in the management of angina pectoris14J5
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VENTRICULAR ECTOPIC BEATS.LOGN + 1
914
November 1991
The American Journal of CARDIOLOGY
Volume 48
FIGURE 3. Effect of two different acebutolol dosages (200 mg twice daily, left, and 400 mg once daily, right) on ventricular ectopic beats/hour during 24 hour Holter monitoring. All six patients had two 24 hour recordings on both regimens. These 12 readings are plotted against respective placebo data. The data show a reduction in ectopic beats with the twice daily regimen and no change with the once daily regimen.
BETA BLOCKING AGENTS, ARRHYTHMIA
TABLE
IV
TABLE
Serum Concentrations (mean f standard error of the mean) of Acebutolol and Its Main Metabollte During Different Dosing Schedules
AND HYPERTENSION-FRICK
AND KALA
V
Effect of Acebutolol standard deviation)
on Q-T,
Interval
(mean
f
Q-T, 6) Plasma Concentration (~mol/liter) Acebutolol Dosing
Acebutolol
Acetyl Metabolite
Total
2 X 200 mg 1 X 400 mg P
0.30 f 0.02 0.15 f 0.04
0.79 f 0.05 0.59 f 0.10 co.02
1.10 f 0.08 0.73 f 0.09
Intervention
At Rest
Light Exercise
Moderate Exercise
Placebo Acebutolol 2 X 200 mg
0.52 f 0.04 0.46 f 0.02
0.59 f 0.03 0.54 f 0.05
0.65 f 0.03 0.58 f 0.04
<0.05 0.47 f 0.04
<0.05 0.53 f 0.03
0.10 < 0.20
<0.02
<0.02
AFebutolol 1 X 400 mo w P
p = probability values for acebutolol versus placebo.
p = probability (comparison of 2 times and 1 times daily dosing).
variation in the number of ectopic beats during the placebo periods. With the regimen of 200 mg administered twice daily, the reduction in the number of ectopic beats averaged 73 percent in five patients; in one patient the reduction was negligible. Patients with left ventricular hypertrophy had more episodes of arrhythmia than patients without left ventricular hypertrophy and the response to acebutolol was also more pronounced in patients with cardiac involvement. Role of slowing of heart rate, Q-T, interval and serum concentration in antiarrhythmic effect: Both regimens produced a commensurate degree of beta receptor blockade as judged from the heart rate data at rest and during bicycle exercise (Table I) and from the reduction in hourly heart rates during 24 hours (Fig. 2). The antiarrhythmic effect of the 200 mg twice daily regimen cannot therefore be easily attributed to beta blockade alone. The antiarrhythmic implications of the shortening of the Q-T, interval are difficult to judge. In this respect acebutolol resembles propranolol, which also shortens the Q-T, interval when given intravenously.26T27 Prolongation of the action potential is considered advantageous and represents a class 3 antiarrhythmic effect. 28 However, sotalol, which is a beta blocking compound with a class 3 effect, has been shown to produce Q-T, prolongation and dangerous ventricular arrhythmias in excessive dosages.29 In any event, the shortening of the Q-T, interval observed in our study was similar with both treatments and hence cannot explain the difference in antiarrhythmic potency. One clear difference between the two dosing schemes was a significantly higher serum concentration of acebutolol with the 200 mg twice daily regimen (Table
IV), and it seems plausible to conclude that the antiarrhythmic effect of acebutolol is more closely related to its plasma concentration than to the degree of clinically assessed beta blockade. Multiple plasma samples during the 24 hour monitoring periods would have strengthened this thesis but we were unable to obtain these in the fully ambulatory patients. However, our reasoning on the importance of the drug plasma levels is supported by the exercise data recorded immediately after the blood samples were obtained in the morning. During exercise, the 200 mg twice daily regimen of acebutolol evoked a reduction in the number of ectopic beats in contrast to the 400 mg once daily regimen (Table II) despite the similarity of heart rate and blood pressure responses in the two regimens (Table I). Therapeutic implications: For the sake of patient compliance it is probably advantageous to administer any beta receptor blocking agent once daily in the treatment of hypertension. However, the present data suggest that acebutolol and presumably other beta blocking agents with similar pharmacokinetic properties should be given at least twice daily if the desired cardioprotective effect is to be sustained for 24 hours. This line of reasoning might especially apply to patients with left ventricular hypertrophy who are at increased risk for sudden death.30 Acknowledgment We express our grateful thanks to Roeinton B. Khambatta, MD, May & Baker Ltd, England, who provided the acebutolol capsules used in the study, and to Gunnar Carlberger, MD, and Lars-G&an Allgen, MD, of the Beckomberga and St. Erik Hospitals, Sweden, who performed the assays of acebutolol serum concentration.
References 1. Francis V, Korsch BM, Morris MJ. Gaps in doctor-patient communication: patients’ response to medical advice. N Engl J Med 1969;280:535-40. 2. Caldwell JR, Cobb S, Dowllng MD, De Jongh D. The dropout problem in antihypertensive treatment. A pilot study of social and emotional factors influencing a patient’s ability to follow antihypertensive treatment. J Chron Dis 1970;22:579-92. 3. Wilson M, Morgan G, Morgan 1. The effect on blood pressure of
beta-adrenoceptor blocking drugs administered once daily and their duration of action when therapy is ceased. Br J Clin Pharmacol 1976;3:857-61. 4. Douglas-Jones AP, Crulckshank JM. Oncedaily dosing with atenolol in patients with mild or moderate hypertension. Br Med J 1976:1:990-l. 5. Wilcox RG. Randomized study of six beta-blockers and a thiazide diuretic in essential hypertension. Br Med J 1978;2:383-5.
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BETA BLOCKING AGENTS, ARRHYTHMIA
AND HYPERTENSION-FRICK
6. Reybrouck T, Amery A, Fagard R, Jousten P, Lijnen P, Meulepas E. Beta-blockers: once or three times a day? Br Med J 1978;l: 1386-8. 7. Stewart M&G. Compared incidence of first myocardial infarction in hypertensive patients under treatment containing propranolol or excluding beta-receptor blockade. Clin Sci Mot Med 1976;51: 509-16. 8. Berglund G, Wilhelmsen L, Sannerstedt R, et al. Coronary heart-disease after treatment of hypertension. Lancet 1978;l: l-5. 9. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. I. Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967;202:1028-34. 10. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effect of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970;213:1143-52. 11. Frick MH, Kala II. Once daily versus twice daily beta-blockers: effects on arrhythmias and hypertension [letter]. Lancet 1980; 2:588. 12. Cuthbert MF, Owusu-Ankomah K. Effect of M 8 B 17803A, a new P-adrenoceptor blocking agent, on the cardiovascular responses to tilting and to isoprenaline in man. Br J Pharmacol 1971;43: 639-48. 13. Basil B, Jordan R, Loveless AH, Maxwell DR. &adrenoceptor blocking properties and cardioselectivity of M 8. B 17,803A. Br J Pharmacol 1973;48:198-211. 14. Lewis BS, Bakst A, Kitchiner DJ, Gotsman MS. Sectral in the management of angina pectoris. S Afr Med J 1973;47: 1455-9. 15. Khambatta RB. Comparison of a new beta-receptor blocking agent acebutolol (Sectral) and propranolol. Clin Trials J 1974;11:5967. 16. Frick MH, Valle M, Korhola 0, Hekall P, Riihlmaki E. Response of left ventricular myocardial perfusion and cavity size to betablockade by acebutolol. Ann Clin Res 1978; 10:66-70. 17. Frick MH, Luurlla 0. Double-blind titrated-dose comparison of metoprolol and propranolol in the treatment of angina pectoris. Ann Clin Res 1976;8:385-92. 18. Menard J, Bertagna X, N’Guyen PT, Dagoulet P, Corvol P. Rapid identification of patients with essential hypertension sensitive to
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AND KALA
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acebutolol (a new cardioselective beta-blocker). Am J Med 1976;60:886-90. Basil B, Jordan R, Loveless AH, Maxwell DR. A comparison of the experimental anti-arrhythmic properties of acebutolol (M 8 B 17,803). propranolol and practolol. Br J Pharmacol 1974;50: 323-33. Lewis BS, Mitha AS, Gotsman MS. Acebutolol in cardiac arrhythmias. S Afr Med J 1974;48:821-4. Gradman AH, Winkle RA, Fitzgerald JW, et al. Suppression of premature ventricular contractions by acebutolol. Circulation 1977;55:785-91. De Soyza N, Kane JJ, Murphy ML, Laddu AR, Doherty JE, Blsaat JK. The long-term suppression of ventricular arrhythmias by oral acebutolol in patients with coronary artery disease. Am Heart J 1980;100:631-8. Winkle RA, Meffin PJ, Ricks WB, Harrison DC. Acebutolol metabolite plasma concentration during chronic oral therapy. Br J Clin Pharmacol 1977;4:519-22. Collins RF. Pharmacocinetique de I’acebutolol. Nouv Presse Med 1975;4:3223-8. Morganroth J, Michelson EL, Horowitz LN, Josephson ME, Pearlman AS, Dunkman WB. Limitations of routine long-term ambulatory electrocardiographic monitoring to assess ventricular ectopic frequency. Circulation 1978;58:408-14. Stern S, Eisenberg S. The effect of propranolol (Inderal) on the electrocardiogram of normal subjects. Am Heart J 1969;77: 192-5. Seides SF, Josephson ME, Bataford WP, Weiafegel GM, Lau SH, Damato AN. The electrophysiology of propranolol in man. Am Heart J 1974;88:733-41. Vaughan Williams EM. Classification of antiarrhythmic drugs. In: Sandee E, Flensted-Jensen E. Olesen KH, eds. Cardiac Arrhythmias. Sodertalje, Sweden: Astra Ltd, 1970:449-69. Elonen E, Neuvonen PJ, Taraaanen L, Kala R. Sotalol intoxication with prolonged Q-T interval and severe tachyarrhythmias [letter]. Br Med J 1979;1:1184. Kannel WB, Gordon T, Castelli WP, Margolis JR. Electrocardiographic left ventricular hypertrophy and risk of coronary heart disease. The Framingham Study. Ann Intern Med 1970;72:81322.
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