Reduction of ventricular ectopic beats with oral acebutolol: A double-blind, randomized crossover study

Reduction of ventricular ectopic beats with oral acebutolol: A double-blind, randomized crossover study The antiarrhythmic efficacy of oral acebutolol, a new cardioselective B-blocking agent, was assessed in a randomized double-blind, placebo-controlled study. Twenty-five pattents with 230 ventricular ectopic beats (VEB) per hour on three control ambulatory monitoring8 were studied. Mean VEB reduction from the control period was 35% with placebo and 45% and 50% with the use of acebutolol 200 mg and 400 mg, respectively. Eleven patients had 270% reduction in VEB with acebutolol and nine of them had 190 VEB reduction. Among these 11 patients, the mean VEB suppression was 51% after placebo but significantly higher following the two doses of acebutolol at 71% (p < 0.05) and 86% (p < 0.01). The mean reduction of paired VEB compared to placebo was 71% (p < 0.05) and 75% (p < 0.01) following 200 mg and 400 mg of acebutolol and only 49% after placebo. Complete suppression of paroxysmal ventricular tachycardia was also noted in five patients. Mean PR interval only increased slightly when patlents took 400 mg of acebutolol, but there was no significant change in either the QRS or QTc intervals. A significant decrease in heart rate from that during control periods was noted after acebutolol. No significant adverse reactions were noted durlng the study. Acebutolol appears to be an effective and well-tolerated antiarrhythmic agent in the treatment of VEB and higher grades of ventricular ectopy. (AM HEART J 105722, 1983.)

Lee, M.D., Raja Dhurandhar, M.D., Elizabeth J. Hungate, B.S., Atul Laddu, M.D., Peter Dietrich, B.S., and Dean T. Mason, M.D. Davis and Sacramento, C&if. Henry

K. Lui,

M.D.,

Garrett

Since there is a strong association between the presence of ventricular ectopic beats and sudden death1,2 there is a continual need for clinically effective antiarrhythmic drugs. Acebutolol, a new P-adrenergic-blocking agent,3 is currently under clinical trial for the treatment of cardiac arrhythmias as well as angina and hypertension. Preliminary data suggest that acebutolol is as effective as propranolol in obliterating experimentally induced ventricular arrhythmias.4 In one study, among 90% of patients with ventricular arrhythmias, acebutolol achieved >75% suppression of ventricular arrhythmias.5 In another report, acebutolol reduced early ventricular arrhythmias in patients with acute myocardial infarction without deleterious cardiac or hemodynamic effects6 The major antiarrhythmic action of acebutolol is to reduce cardiac sympathetic activity, prolong AV nodal conduction, and decrease ventricular automaticity and re-entry.7 In addition,

From Davis Received Reprint Center,

722

the Division of Cardiovascular Medicine, School of Medicine, and the University for publication requests: 1295 N.W.

Feb.

15, 1982;

accepted

Garrett Lee, M.D., Cardiac 14th St., Cedars South-Suite

University of California Medical Center. March

22, 1982.

Center, Cedars Medical K, Miami, FL 33125.

at

it has membrane-stabilizing effects which may also play a minor role in the prevention of ventricular arrhythmias. 3+7 Unlike propranolol, acebutolol is cardioselective and has less tendency to produce bronchospasm. This study was undertaken to investigate the effects of oral acebutolol on the frequency of ventricular ectopic beats by means of a placebocontrolled, double-blind, randomized crossover method. METHODS Patient population. Twenty-five patients, 13 men and 12 women, mean age 49.8 (range 23 to 69 years), participated in and completed this study after consenting to the human research protocol. Among 13 patients who had evidence of coronary artery disease, seven had a previous myocardial infarction, seven had angina pectoris, and three had undergone coronary artery bypass graft surgery at least 6 months prior to entering this study. Further, three had mitral valve prolapse, two had hypertension, and one had Prinzmetal’s angina with normal coronary arteries. Six patients had no known cardiac disease but had symptoms from their ventricular ectopic beats. Protocol design. Al antiarrhythmic drugs were discontinued at least 5 days before patients were entered into the study. A baseline 12-lead ECG, chest x-ray, and blood tests evaluating hematologic, hepatic, and renal function

Volume Number

105 5

Acebutolol

I. Study designfor double-blind crossoveradministration of acebutolol or placebo

VEB reduction:

Randomized

crossover study

723

Table

Duration Md 2* 1

2* 1

2* 1 2* 1

Group I

Group II

1 Placebo 1 1 Wean 1 Acebutolol 200 mg tid 1 Wean 1 Placebo 2 1 Wean 1 Acebutolol 400 mg tid 1 Wean

1 Acebutolol 200 mg tid 1 Wean 1 Placebo 1 1 Wean 1 Acebutolol400 mg tid 1 Wean 1 Placebo 2 1 Wean

*Twenty-four-hour Holter monitors, done at the end of each period.

ECG, and physical examination

60 I--

were

were obtained. None of the patients had significant renal disease,hepatic disease,diabetes mellitus, hyperthyroidism, asthma, chronic obstructive pulmonary disease,permanent pacemaker, or uncompensated congestive heart failure. All patients started the study by taking placebo three times a day for 2 weeks.During the 2-week control period, three 24-hour ambulatory ECG recordings were performed with the use of a simultaneoustwo-channel (modified precordial leads V, and V,) Avionics 445 recorder. Those patients who were selected for the study had an averageof more than 30 ventricular ectopic beatsper hour in each of the three 24-hour ambulatory monitorings during the 2-week control period. Following the control period, these patients were randomized into one of two groups, starting with acebutolol or placebo and later crossingover to the other medication; one-weekweaning periods followed each placebo and acebutolol period according to the schedulein Table I. A physical examination, la-lead ECG, and 24-hour ambulatory ECG monitoring were performed after each period of acebutolol or placebo. Patients were instructed to report immediately any adverse effects. At the conclusion of the study, a repeat 12-lead ECG, chest x-ray, blood tests, and a physical examination were performed. Data analysis. Twenty-four-hour ambulatory ECG monitoring tapeswere analyzed by meansof an operatorinteractive computer system on the Avionics 660-680 scanner. The number of ventricular ectopic beats and paired ventricular beats, averaged for the three 24-hour periods during the placebo control periods, as compared with the total number of ventricular e&epic beats for each acebutolol and placebo period, and percentage of suppressionwas calculated for each patient. Paroxysmal ventricular tachycardia (three or more beats in a row) was assessed as being present or not on the monitoring

Placebo

200 mg

400mg

Acebutolol Fig. 1. Mean percentage of reduction of ventricular ectopic beats from the control period while patients were administered placebo or acebutolol, 200 mg or 400 mg (n = 25). VEB = ventricular ectopic beats.

tapes. The PR, QRS, and QT intervals were measured from the ECGs performed during each period. The QT interval was corrected (QTc) according to the formula: QTc = ~-~~~rr~

. The mean- values in

each placebo and acebutolol group were analyzed by means of Student’s paired t ratio for nonindependent means.A p value of lessthan 0.05 was consideredto be statistically significant. RESULTS Effects on resting heart rate. Both acebutolol doses produced a significant decrease in heart rate (p < 0.01). There was a further minor attenuation of heart rate when the 400 mg dose (64.5/min f 1.9) was used as compared to the 200 mg dose (65.6/ min + 2.21, but it was not statistically significant. Reduction of ventricular arrhythmias. The average number of ventricular ectopic beats during the three 24-hour ambulatory ECG monitors in the control periods was used to compare with the number of ventricular ectopic beats recorded in the acebutolol and placebo periods. Mean ventricular ectopic beat reduction from the control period was 34.9 % during the two placebo periods (Fig. 1). The two individual placebo periods were not significantly different from one another. FolIowing acebutolol, mean ectopic beat suppression was greater although not statistically significant when compared to placebo at 44.9% and 49.5% using 200 mg and 400 mg, respectively (Fig. 1). However, among the 11 patients who

724

Lui et al.

American

may, 1983 Hear1 Journal

r

30

Placebo

200 mg

400mg

Placebo

1

I

P<.OI

I

I

p<.05

200mq 400mq fcebutolql -

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Fig. 2. Comparison during the control period of the responseof acebutolol, 200mg and 400mg, versusplacebo amongthose patients with ~70% ventricular ectopic beat reduction while on acebutolol (n = 11). VEB = ventricular ectopic beats.

Fig. 3. Comparison during the control period of the

achieved at least 70% ventricular ectopic beat reduction from the control period, the mean ectopic beat reduction compared to placebo was significant-

teen of 25 patients showed episodes of paired ventricular ectopic beats (couplets) on control ambula-

was significantly higher than placebo at 70.5% @ < 0.05) and 74.5% (p < 0.01) with the use of acebutolol 200 mg and 400 mg, respectively, compared to 48.8% during the placebo periods (Fig. 3). Nine of these 19 patients had no further couplets on 400 mg of acebutolol. Fifteen patients (79%) also had >70% ventricular ectopic beat suppression on acebutolol. Again, the two individual placebo periods were not significantly different from each other. Reduction of ventricular tachycardia. Paroxysmal ventricular tachycardia was noted in 13 patients during the control period. Five patients who had ventricular tachycardia during both control and placebo periods had complete suppression of this dangerous arrhythmia during the acebutolol period. All except one of the five patients had >70% ventricular ectopic beat reduction on acebutolol. On the other hand, four patients who had paroxysmal ventricular tachycardia during both acebutolol and placebo periods did not achieve at least 70% sup-

tory monitoring. The mean reduction of paired beats

pression of ventricular

ly higher at 71.3% (p < 0.05) and 66.4% (p < 0.01) following 200 mg and 400 mg acebutolol treatment, respectively (Fig. 2). These same patients had only 51% suppression during their placebo periods (Fig. 2). Although there was a tendency for more ectopy suppression when the higher beta-blocking dose was used, it was not statistically significant. Fourteen of 25 patients (56% ) had greater than 60% reduction in ventricular ectopic beats with either the 200 mg or 400 mg acebutolol dose (p < 0.01). Further, 11 of 25 (44%) had 70% reduction in ventricular ectopic beats with either dose (p < 0.01). Strikingly, seven of the patients had greater than 90% ventricular ectopic beat suppression with 400 mg of acebutolol @ < 0.01). Reduction

of paired

ventricular

ectopic

beats.

Nine-

responseof acebutolol, 200mg and 400 mg, versusplacebo among those patients with paired ventricular ectopic beats on control ambulatory monitor (n = 19). VEB = ventricular ectopic beats.

ectopy

during acebutolol

Volume

105

Number

5

Acebutolol

treatment. Further, four patients who had ventricular tachycardia detected during control monitoring had no further subsequent episodes during both drug and placebo periods even though ventricular tachycardia was found during control monitoring. Electrophysioiogic effects. The mean QRS and QTc intervals revealed no significant difference as compared to the control period. The mean PR interval increased slightly from 0.15 to 0.16 second @ < 0.01) following acebutolol 400 mg when compared to the placebo control period (Table II). Although the mean QTc interval on 200 mg of acebutolol decreased to 0.39 as compared to the control period, it was not statistically significant. Adverse effects. There were no significant adverse effects related to acebutolol administration. Patients did not develop any bronchospasm, significant bradycardia, heart block, congestive heart failure, or any central nervous system adverse effect. It is noteworthy that none of the seven angina patients mentioned had increased episodes of chest pain. DISCUSSION

Beta-blocking agents have been shown to be effective in the management of angina,hg hypertenarrhythmias.11~‘2 Fursion,‘O and supraventricular thermore, recent studies indicate that these drugs are efficacious in reducing the mortality rate following myocardial infarction.13 The latter may be due, in part, to the beta-blocking drugs’ ability to decrease myocardial oxygen demands but also to the ability to suppress ventricular arrhythmias. Propranolol, for example, had been demonstrated by 24-hour ambulatory ECG to effectively control ventricular ectopy.” Present

randomized

antiarrhythmic

efficacy

study.

The present investigation represents the first report of a controlled, double-blind crossover study using the new cardioselective beta-blocking drug, acebuto101, or placebo in patients with documented ventricular ectopy. The data revealed that acebutolol is effective as an oral antiarrhythmic agent in the treatment of VEB and higher grades of ventricular ectopy. Approximately half of the patients had >70% and one third had >90% suppression of ventricular ectopic beats. Among the patients who responded with >70% attenuation of ventricular ectopic beats, acebutolol200 mg and 400 mg demonstrated significantly greater suppression than placebo (Fig. 2). Although a placebo effect was evident, the two placebo periods were similar in relation to the quantity of ventricular ectopic beat suppression. In agreement with our findings are other oral acebuto101 studies involving single-blind protocol.15-17

Table

VEB reduction:

Randomized

crossover

study

725

II. Mean PR, QRS, QT, intervals, and heart rate Heart rate Dose

Control Acebutolol 200 mg Acebutolol 400 mg Placebo (combined)

(bpm)

70.9 65.6 64.5 73.4

+ zi t f

2.4 2.2 0.9 2.5

PR

QRS

QTc

(see)

(set)

(see)

0.15 0.15 0.16 0.15

0.06 0.06 0.06 0.06

0.40 0.39 0.40 0.40

Suppression of paired VEB. Noteworthy was the of ventricular couplets acebutolol suppression (mean 72.5 % ) among those patients who had paired ventricular ectopic beats on control monitor (Fig. 3). The majority of the treated patients also had 70% or greater reduction in single ectopic beats. Again there was significant difference between placebo periods even though a placebo effect was noted. Patients who developed paroxysmal ventricular tachycardia during their control and placebo periods and had complete suppression following acebutolol also had >70% reduction in ventricular ectopy. Thus there may be a greater likelihood for control of ventricular couplets and ventricular tachycardia when ~70% ventricular ectopy reduction was achieved. Furthermore, there was a trend for greater suppression of ventricular arrhythmias with the use of the higher 400 mg dose of acebutolol. Antiarrhythmic mechanism. Since sympathetic stimulation increases automaticity by increasing phase 4 depolarization in automatic fibers, the antiarrhythmic properties of beta-blocking drugs are considered to be principally the result of inhibition of adrenergic stimulation of the heart.6*7y l2 Resting heart rate was lowered following beta blockade. While beta blockers can increase the functional refractory period of the AV node,7 only the larger dose of acebutolol in this study produced a slight prolongation of the PR interval without any major changes in the QRS or QTc intervals. Other investigators have reported similar findings?, 7,~7l7 Conclusions. In summary, acebutolol is well tolerated and is effective in reducing the number of single ectopic beats as well as, and more important, in suppressing higher grades of ventricular arrhythmias associated with sudden death (including paired ectopic beats and ventricular tachyarrhythmias). REFERENCES

1. Kolter M N, Tabatznik B, Mower M M, Tominaga S: Prognostic significance of ventricular ectopic beats with respect to sudden death in the late post-intraction period. Circulation 47:959, 1973. 2. The Coronary Drug Project Research Group: Prognostic significance of premature beats following myocardial infarction. JAMA 223:1116, 1973.

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hi et al.

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hydrochlorothiazide in essential hypertension. Clin Pharmaco1 Ther 28:296, 1980. Williams D 0, Tatelbaum R, Most A S: Effective treatment 01 supraventricular arrhythmias with acebutolol. Am J Cardiol 44:521, 1979. Lewis B S, Mitha A S, Gotsman M S: Acebutolol in cardiac arrhythmias. S Afr Med J 48:821, 1974. Norwegian Muiticenter Study Group: Timol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 304:801, 1981. Rigo P, Johnson A, Detwiler J, Crawford M, Ross J Jr, O’Rourke R: Comparative effectiveness of quinidine and propranolol for treating ventricular arrhythmias in patients myocardial infarction (abstrl. Circulation with prior 52(suppl IIi:230, 1975. Burckhardt D, Raeder E .4: The effect of acebutolol on cardiac arrhythmias in patients with coronary artery disease. AM HEAKT J 99:443, 1960. deSoyxa N, Kane J J, Murphy M L, Laddu A R, Doherty J E, Bissett J K: The long-term suppression of ventricular arrhythmia by oral acebutolol in patients with coronary artery disease. AM HEART J 100:631, 1980. Gradman A H, Winkle R A, Fitzgerald J W, Mefhn I’ J, Stoner J, Bell I’ A, Harrison D C: Suppression of premature ventricular contractions by acebutolol. Circulation 55:785, 1977.