Electrophysiologic and antiarrhythmic actions of bepridil

Electrophysiologic

and Antiarrhythmic

Actions of Bepridil

Comparison with Verapamil and Ajmaline for Atrioventricular Reentrant Tachycardia EDWARD ROWLAND, MB, WILLIAM J. McKENNA,

MD, and DENNIS M. KRIKLER, MD

Bepridil (2 mg/kg intravenously) was given to 20 patients with atrioventricular (AV) reentrant tachycardia and its effects were compared with those of verapamil (0.15 mg/kg intravenously) in 8 patients and ajmaline (0.75 mg/kg intravenously) in 12. After baseline electrophysiologic measurements, the drugs were given during sustained AV reentrant tachycardia (8 patients had dual AV nodal pathways and 12 had an accessory AV pathway). Verapamil terminated AV reentrant tachycardia in 7 patients and bepridil terminated it in 8. In 8 of the patients who received ajmaline, AV reentrant tachycardia was terminated and in 8 of this group beprldil did so. Bepridil was more successful in terminating AV reentrant tachycardia in those with dual AV nodal pathways than in those with an accessory AV pathway. Bepridil slowed sinus rate by 10% (p
tively) and increased the Wenckebach cycle length of the AV node (24% and 25 %, respectively) to a significant degree (p <0.05). Bepridil also lengthened atrial and ventricular effective refractory periods (p
Bepridil is a novel calcium entry blocker that is an effective antianginal agent1-3 and has additional experimental and clinical electrophysiologic properties. It appears to act by producing selective blockade of slow channels in both myocardial cells4 and coronary vessels,5 thereby decreasing coronary vascular resistance and increasing coronary blood flo~.~*~ In specialized conducting tissue bepridil impairs atrioventricular (AV) conduction and slows sinus rate.7-s However, bepridil has additional electrophysiologic actions on myocardial tissue. The amplitude and upstroke velocity of the atrial action potential are decreasedlo and the atria1 effective refractory period is prolonged.7 Higher concentrations are required to demonstrate similar actions on the action potential of ventricular muscle.4J1 Studies of the electrophysiologic effects of bepridil in humans showed

that in addition to the impairment of AV nodal function, myocardial refractoriness was indeed prolonged.12-l4 If these actions of both fast and slow channel inhibition are of clinical use, bepridil could have important ant&rhythmic activity, possibly with a wider spectrum of activity than other calcium antagonists. In this study we investigated the electrophysiologic profile of bepridil, which was given intravenously and then orally in patients with reentrant AV tachycardia. The acute effects were contrasted with those of verapamil or ajmaline, administered to the same patients in similar fashion. The antiarrhythmic efficacy of the drugs was assessed by administering them during sustained reentrant AV tachycardia and observing their ability to terminate the arrhythmia. Further data on the electrophysiologic and antiarrhythmic actions of bepridil were obtained by restudying the patients after 3 to 5 days of oral therapy.

From the Cardiovascular Unit, Hammersmith Hospital, London, England. This study was supported in part by a grant from Organon Laboratories, Oss, The Netherlands. Manuscript received October 24, 1984; revised manuscript received February 14, 1985, accepted February 18, 1985. Dr. Rowland’s current address and address for reprints: National Heart Hospital, Westmoreland Street, London W 1, England.

Methods Twenty patients who were undergoing investigation for paroxysmal supraventricular tachycardia were admitted to the study. All previous ant&rhythmic agents had been dis1513

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continued for at least 5 elimination half-lives for the respective substances. No patient had received amiodarone. Electrophysiologic investigation was undertaken according to our usual techniqueis; premeditation with diazepam was given when necessary.Under local anesthesia 3 electrode wires were introduced percutaneously and positioned at the high right atrium, adjacent to the His bundle, at the apex of the right ventricle and in the coronary sinus. The signals were displayed on a multichannel ink-jet recorder and also stored on magnetic tape. The use of a programmable stimulator allowed 1 or 2 premature stimuli, at twice diastolic threshold and with a pulse duration of 2 ms, to be delivered during sinus and paced (cycle lengths 600,500 and 430 ms) rhythms up to myocardial refractoriness. Local atrial endocardial mapping during induced tachycardia and the response to critically timed premature stimulation defined the pathways involved in the reentrant circuit. During a period of control evaluation the following electrophysiologic variables were measured in the following order: (1) Sinus cycle length. (2) Intracardiac conduction intervals (PA, AH, HV and QRS) during sinus rhythm as well as QT interval, QTc was calculated using the Bazett formula. The AH interval was also measured while pacing the right atrium at a constant cycle length of 500 ms. (3) Atrial and ventricular myocardial effective refractory periods, measured at atrial and ventricular paced cycle lengths of 500 ms, respectively. (4) Effective refractory period of the AV node at a right atrial paced cycle length of 500 ms. Continuous incremental right atrial pacing was performed until type 1 second-degree (Wenckebach) AV nodal block occurred in those without anterograde conduction through an accessory AV pathway. (5) During reentrant AV tachycardia the cycle length and component regional intracardiac conduction intervals were measured once the arrhythmia had stabilized. Tachycardia was induced by programmed premature atrial or ventricular stimulation. In each patient drugs were administered during sustained reentry tachycardia. In 8 patients verapamil, 0.15 mg/kg, was given as a rapid intravenous (i.v.) bolus; ajmaline, 0.75 mg/kg, was given in a similar fashion to the other 12 patients. In patients in whom termination was not achieved within 5 minutes, sinus rhythm was reestablished by pacing-induced termination of the arrhythmia. After the

VERAPAMIL

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Sinus

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return to sinus rhythm, electrophysiologic variables were reevaluated within 5 to 15 minutes of drug administration. Measurements made after this time were not included in the results. An intend of at least 90 minutes was allowed after verapamil or ajmaline adminstration before bepridil were given: during this period further electrophysiologic measurements were performed. Bepridil was given only after these measurements had returned to control levels.In 4 patients residual drug ,effects were believed to be present at 90 minutes and these patients were returned to an observation ward for 3 to 16 hours. Only at this stage was the second part of the study undertaken. Bepridil, 2.0 mg/kg, was administered intravenously under the same circumstances as the other drugs except that it was given over 5 minutes. Again, programmed stimulation was used to regain sinus rhythm in the absence of drug-induced termination 5 minutes from the completion of the infusion. Electrophysiologic variables were assessed5 to 15 minutes after the end of drug administration; measurements made later were not included. The blood pressure was monitored by sphygmomanometer cuff measurement in the first 7 patients studied; monitoring in the remainder was only undertaken if symptoms suggested hypotension. At the completion of the study a subclavian electrode wire, positioned with its tip in the right atrium, was left in situ Oral bepridil was started in a dose of 300 mg every 8 hours for 24 hours, followed by a maintenance dose of 100 mg every 8 hours. A limited electrophysiologic study was undertaken between the third and fifth day in 19 patients and the atrial effective refractory period was measured. In patients with a normal pattern of anterograde AV conduction, continuous incremental right atria1 pacing was performed until seconddegree (Wenckebach) AV block occurred. Right atrial programmed stimulation was performed in an attempt to induce reentrant tachycardia; if this was unsuccessful the electrode wire was advanced to the coronary sinus and subsequently the right ventricular apex. The full stimulation protocol was used until tachycardia was initiated or the protocol was completed. Statistical analysis was performed using the t test for paired data.

time

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FIGURE 1. Sinus cycle length and atrioventricular (AV) nodal conduction time (AH interval) at an atrial paced cycle lenglh (CL) of 500 rns before and after verapamil and bepridil administration. NS = not significant.

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FIGURE 3. Atrial (PA) and His-Purkinje (HV) conduction intervals before and after ajmaline and bepridil administration. Open circles represent patients with overt preexcttation. No significant change (NS) in HV interval in those wlth normal conduction was found after administration of either drug.

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length at which type 1 second-degree AV nodal block occurred (Fig. 2); data could be obtained in only 6 of the 8 patients who received both drugs. Atria1 conduction time, His-Purkinje conduction time, QRS duration, QTc interval and atria1 and ventricular effective refractory period were unaltered by verapamil treatment. Ajmaline: In the 12 patients who received ajmaline (all but 1 had an accessory AV pathway) tachycardia terminated in 8, the arrhythmia persisting, albeit at a slower rate, in the remainder. In each case the mode of termination was by retrograde block. During sinus rhythm after ajmaline administration, the PA interval was prolonged and in 2 patients preexcitation was abolished (Fig. 3). In those with normal AV conduction no significant change in the HV interval was seen. Ajmaline produced a significant prolongation in atria1

AV reentrant tachycardia was initiated in all 20 patients; it was associated with an accessory AV pathway in 12 (9 left-sided, 3 right-sided) and dual AV nodal pathways in the remainder. Six patients had overt preexcitation during sinus rhythm. Verapamil: Verapamil was administered to 8 patients during reeentrant tachycardia (7 with dual AV nodal pathways and 1 with an accessory AV pathway), resulting in termination of tachycardia in all but 1 patient, who had dual AV nodal pathways. After drug administration AV nodal conduction time at an atria1 pacing cycle length of 500 ms was significantly lengthened from a control value of 94 f 26 ms to 135 f 42 ms (Fig. 1). Similarly, there was prolongation in both the AV nodal effective refractory period and the cycle

FffiURE 2. Atrioventricular (AV) nodal effective refractory period (ERP) and cycle length of type 1 seconddegree AV nodal block (Wenckebach cycle length [WCL]) before and after verapamil and bepridil administration.

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effective refractory period, but the ventricular effective refractory period did not change (Fig. 4). Bepridik There were no significant differences in the cycle length of tachycardia, regional intracardiac conduction intervals during tachycardia or other electrophysiologic variables at the time of bepridil administration compared with the point at which the other drugs were given. Bepridil terminated tachycardia in 6 of the 8 patients who received verapamil and 6 of the 12 who received ajmaline. In 10 patients tachycardia terminated with anterograde block in the AV node; in the other 2, both of whom had dual AV nodal pathways, there was block in the retrograde direction. Ten minutes after bepridil administration there was significant prolongation of both sinus cycle length (688 f 137 to 757 f 142 ms) and AH interval (75 f 6 to 87 f 25 ms) (Fig. 5). PA and HV intervals were unchanged; the latter was unchanged both in those with preexcita-

HP

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tion and those with normal conduction. When the effects of bepridil were contrasted with those of verapamil in the same patients (Fig. l), the 2 drugs had opposing actions on sinus cycle length, while both drugs prolonged AH interval (measured at a cycle length of 500 ms) to a similar degree (verapamil from 94 f 24 to 131 f 37 ms; bepridil, from 94 f 26 to 135 f 42 ms). More detailed analysis of the changes imposed on AV nodal function by the 2 drugs (Fig. 2) showed that bepridil prolonged AV nodal effective refractory period (from 269 f 22 to 315 f 54 ms) and Wenckebach cycle length (from 306 f 39 to 381 f 63 ms) to an extent that was statistically similar to the effects of verapamil administration (effective refractory period from 268 f 22 to 316 f 40 ms; Wenckebach cycle length from 300 f 50 to 372 f 48 ms). Data from the whole group indicated that bepridil prolonged both atrial and ventricular effective refrac-

ms

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I p
FIGURE 4. Atrial fective refractory and after ajmaline &ration. NS = not

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FIGURE 5. Sinus cycle length and atrloventrlcular (AV) conduction before and after intravenous bepridil administration. NS = not significant.

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tory period (Fig. 6), although both changes were relatively small: there was a 7% increase in atria1 effective refractory period (from 217 f 24 to 233 f 22 ms) and a 9% prolongation in ventricular effective refractory period (220 f 10 to 239 f 15 ms). In concert with changes in myocardial refractoriness the QT interval was also significantly prolonged from (from 349 f 37 to 383 f 41 ms) (Fig. 7). This alteration in repolarization was not dependent on the slowing of heart rate, because the QTc interval also lengthened significantly (from 423.8 f 29.2 to 443 f 38.9 ms; p
THE

FIGURE 7. Sinus cycle standard travenous

length and QT interval (mean deviation) for the 19 Patients who received and oral bepridil.

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casions that it was initiated, and always with anterograde block. Two patients became nauseated (one requiring discontinuation of the medication and the other associated with vomiting) during the high doses taken during the first 24 hours. One patient noted flushing and tremor and in 4 patients phlebothrombosis developed at the site of the intravenous bepridil injection. Discussion Calcium channel blockers such as verapanS and diltiazemls have proved effective both for the termiQT interval

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nation of sustained supraventricular arrhythmias and for prophylaxis against them.19 Bepridil has slow channel antagonistic properties similar to those of verapamL4 However, not only are there possible differences in the manner in which verapamil and bepridil affect the slow inward current,9 but it appears that bepridil may also influence fast channel-dependent components of the action potential Both fast and slow channel inhibition of the action potential in frog atria has been shown,2O as has reduction in upstroke velocity at high concentration in guinea-pig ventricle.4 The upstroke velocity in both Purkinje and ventricular muscle fibers of the sheep was reduced, but whereas action potential duration was shortened in the former it was prolonged in the latter.ll Although reduction in upstroke velocity and lengthening of action potential has been shown in cat atria,lc prolongation of atrial effective refractory period without change in monophasic action potential was found in anesthetized dogs.2i In this latter study no change in ventricular refractoriness was found. Despite some discrepancies in the experimental effects of bepridil on ventricular refractoriness, clinical studies have uniformly shown that it is prolonged. To characterize these additional electrophysiologic actions we also compared the actions of bepridil with those of ajmaline, a short-acting, quinidine-like drug. Clinical electrophysiologic effects: As in previous studies, bepridil slowed the sinus rate when given intravenously. This contrasted with the tendency for the heart rate to increase after verapamil. Both drugs share common direct effects on sinus pacemaker cells in the rabbits; bepridil, however, produces bradycardia irrespective of cardiac innervation,6 whereas the direct slowing action of verapamil is antagonized by a reflex increase in sympathetic tone.22 Heart rate decreased further when the patients received oral bepridil. Bradycardia with oral bepridil has not always been found in previous studies,2v3 but may be related to the dose used and the plasma levels achieved.23 AV Wenckebach CL

Atrial ERP ms

ms

Intravenous bepridil prolonged conduction through the AV node without altering atrial, His-Purkinje or ventricular conduction intervals. In absolute terms the change in AV nodal conduction was less with bepridil than with verapamil; however, the sinus bradycardia induced by bepridil tends to oppose the slowing of AV nodal conduction. When we compared the effects of bepridil and verapamil at the same heart rate, the changes imposed on AV nodal conduction were more similar. Bepridil also prolonged the AV nodal effective refractory period and reduced the AV nodal Wenckebath cycle length. Comparison of the changes imposed by the 2 drugs on these variables, which are not influenced by dissimilar actions on sinus rhythm, showed that the effects were again similar. At the restudy we did not record the His bundle electrogram and thus measured the AV, rather than specifically the AV nodal, Wenckebach cycle length. As we neither saw bundle branch block during incremental atrial pacing nor had intra- or infra-Hisian block been present at the control study, we do not feel we are being uncritical in comparing these values. The AV Wenckebach cycle length had returned towards the control value for AV nodal Wenckebach and suggests that a less powerful AV nodal action was present at the restudy. Clearly the electrophysiologic actions of bepridil are not restricted to its AV nodal blocking activity: both atrial and ventricular effective refractory periods were prolonged but myocardial conduction was unchanged. The patients who received both ajmaline and bepridil had atypical responses in that ventricular refractoriness did not change with either drug. In contrast to bepridil, ajmaline prolonged atria1 conduction time. Further evidence of the myocardial influence of bepridil was seen in the prolongation of QT interval, which appeared after i.v. administration but became more striking after oral treatment. Although the ventricular refractory period was not determined at the repeat study, the atrial effective refractory period, like the QT interval, was lengthened further. Bepridil reduces ventricular ar-

n = 13

n =15 500

300

250 FIGURE 8. Atrial effective refractory period (ERP) and cycle length (CL) of type 1 seamMegeeatrioventrkular (AV) block (Wenckebach CL) after intravenous and oral bepridii.

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150 p
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rhythm& associated with experimental ischemia,ll but extensive clinical experience in treating ventricular arrhythmias is awaited. However, the potential for provoking ventricular arrhythmias in association with QT prolongation, also seen with class I drugs as well as other calcium blockers such as prenylamine,24 must be recognized. Such complications have already been described with bepridil.25 In none of our patients in whom ventricular stimulation was undertaken in order to initiate AV reentrant tachycardia were ventricular arrhythmias induced. Clinical antiarrhythmic effects: Bepridil proved an effective drug for the termination of reentrant AV tachycardia, more so when there were dual AV nodal pathways than in those with an accessory AV pathway. The method of drug administration, as an infusion over 5 minutes (chosen because of initial concern over possible negative inotropic action), may, in this context, militate against optimal antiarrhythmic efficacy. Both verapamil and ajmaline are well established drugs for the conversion of these arrhythmias and both can be given safely as a rapid bolus. Both drugs were better than bepridil, but it is possible that bepridil could achieve similar rates of success if given in similar fashion. We observed no case of profound hypotension following i.v. administration in our patients. The efficacy of bepridil in preventing initiation of sustained tachycardia at the time of restudy was conspicuous. The limited nature of the electrophysiologic restudy did not allow us to obtain detailed information on the mechanism of antiarrhythmic action. However, in those in whom 1 or more complexes of tachycardia could be initiated, termination of the arrhythmia was by anterograde block, presumably in the AV node. It was not the purpose of this repeat study to examine the effect of bepridil on retrograde conduction; therefore, we do not know whether there were actions on both anterograde and retrograde components of the reentry circuit. Alteration in the level of autonomic tone between the main study and the repeat study could have influenced the inducibility of tachycardia, increased sympathetic tone at the initial study making the arrhythmia more likely to become sustained. However, all patients presented with a history of sustained symptomatic tachycardia that was confirmed at the initial study; 6 of 10 patients had inducible tachycardia at the repeat study, but it was slower than at control and was not sustained. Pharmacokinetic data have shown that bepridil has a long elimination half-life, 30 to 50 hours, and although a number of possible metabolites have been identified, there is no evidence that any have important electrophysiologic properties.26 The prolonged duration of action of bepridil necessitated the administration of either verapamil or ajmaline, both of which have relatively short durations of action, before bepridil. Although the presence of a small residual effect of verapamil or ajmaline cannot be excluded at the time of bepridil administration in some of the patients, in all cases we allowed sufficient time between giving the drugs for measurements at rest to return to control. Clinical implications: Bepridil has electrophysiologic properties that suggest a useful role in the treat-

1, 1985

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ment of supraventricular arrhythmias, most particularly as an oral agent. As with other drugs that impair AV nodal function, control of the ventricular response may be achieved in arrhythmias such as atrial fibrillation. However the additional ability of prolonging myocardial refractoriness may act to prevent the onset of atrial arrhythmias or prevent atrial extrasystoles that trigger AV reentrant tachycardia. The role of bepridil in the treatment of ventricular arrhythmias remains to be clarified, as does the dose-response relation, in order to avoid problems related to QT prolongation. References 1. Canicave

JC, Dsu J, Jacq J, Paiiiet R. Un nouvei antiangoreux,

ie bepridii. par i’epreuve d’effort au tours d’un essai Therapie 1980;35:607-612. 2. Narshara KA, Shaplro W, Weiiky I, Park J. Evaluation of beprtdii, a new antkrginai agent: clinical and hemodynamic alterations during the treatment of stable angina pectoris. Am J Cardioi 1984;53:29-34. Appreciation de son efficacite a double insu contre placebo.

3. Dibianco it, Aiperl J, Katz RJ, Spann J, Chester E, Ferri DP, Larca W, Costello RB, Gore JM. Bepridii for chronic stable angina pectoris: results of a pmspecttve multicenter. placebo-controlled, patients. Am J Cardioi 1984;53:35-41.

4. V

I S, Crrsrtpton

R, Spsmiakis

dose-ranging

study in 77

N. Biockada

of myocardtai slow channels byTl pridil (CERM-1978). J Pharmacoi Exp Ther 1979210:378-385. 5. Harder DR, Sperelakis N. Bepridii blOCkage of Ca2.Cdependent action potentials in vascular smooth muscle of do9 coronary artery. J Cardbvasc Pharmacol 1981;3:906-914.

6. Cosnier

D, Duchene-Maruilaz

vascular pharmacoiogy Arch int Pharmacodyn

P, Rispat

0, Streichenberger

of bepridii, a new potential Ther 1977;225:133-151.

7. Chalssaing

0. Cardlo-

anttanginai

compound.

C, Moins N, Lavarenne J, Duchenna-Maruiiaz P. Effets compares du b&prMil, de la perhexiiene, de i’amiodarone et de la quinidine sur ies pbiodes refractaires auricuioventricuiaires du chien narcose. J Pharmacoi 1977;8:503-514. augharvi M, Duchema-Marella P. Comparative 8. YichsiinMT,Chawk-Ba effects of amiodarone. beprkfii and oerhexiiene on coronarv venous flow and several cardiovascukr parameters. Arch int Pharmkdyn 1980; 245~238-248. 9. Beatghard Y, Ferrier ;o,he

bradycardia

10. Wfnblow

E.‘Kane

ological effects 1981:3:655-667.

antianginal

12. Va&e

JC. Leboeul

J, Piris P. Studies

Br J Pharmacol

1982;75:293-

KA. Suoraventricuiar

E. Antttsrhylhmic and eiectrophysioiogicai agent, bepridii. J Cardiovasc Pharmacoi

PE Beiin A Chentir

&ectroohv~oboiau& 1982;3i:i09-4id.

13. Ponsomallie

C, Lamar

by beprtdii.

antidvsrhvthmic and electroohvsiof bepridii; a new anttanginai a&k J Cardiovasc Pi-r&n&

11. Kana KA, Mow ;oyw

M, Lakid induced

T Lehner

du beortdi .

JP Tricot

R Or&rot

Cl. Effets Ann Cardioi Anoeloi

sur ie coeu; humain.

J, Chron B, Threii F, Heiilgenslein

&ctrophystologiquas 1982;75:1415-1423.

effects of 1980;2:193-

D, Gras H. Etuds des effets

du beprtdil utilis9 par voie veinuese.

Arch Mai Coeur

14. Flammang

D, Waynber9er M, Jansen FH, Paiiiet R, Coutnel P. Electroprofile of beprktii, a new antianginai bug with calcium blocking Eur Heart J 1983:4:647-654. 15. Roinrland E, Krikier DM. Intracardiac eiectrography and the investigation of cardiac arrhythmias. in: Sleight P, Vann Jones J eds. Scientific Foundations of Cardiology. London: William Heinemann, 1983:350-360. 16. Desoutter P, Haiat R. Modifications eiectrocardiographiques induites par le Wpridil. Un nouvel lnhibiteur caicique. Arch Mai Coeur 1980;73: 1237-1238. 17. Krikter DM, Spurreit RAJ. Verapamii in the treatment of paroxysmal ;y3ntrant supraventrrcuiar tachycardia. POStgrad bled J 1974;50:447physbto9iml properties.

19. Rowiand

E, McKenna WJ, Gtiiker H, Krikier DM. Tha comparative effects of dittiazem and verapamil on atrioventricuiar conduction and atriicuiar reentry tachycardia. Circ Res 1983;52:183-168.

19. Rillkell Zipas BP. T ttt;

r RL, Prystowsky

EN, Heger JJ, Troup

PJ, Jackman

WM,

ffects of intravenous and oral verapamii administration in pawith supraventncuiar tachyarrthymias. Ctrcuiabon 1980;62:996-

membrane interactions wttti bepridil, EXD Ther 1979:211:546-554.

21. &sins

a new antttnginal

agent. J Pharmacol

A, Masse

C, FaJurl A, Hirsch JL, Labrid C, Puech P. Electroeffects of bepndil in the anesthetized do9 studied by endocardtac Am .I Cardiol 1984:53:1707-1711. 22. Breithardt 0, Selpei L, Weibrl haus E, &&I F. Effects of verapamil on sinus node function in man. ? ur J Cardioi 1978;8:379-394. 23. Kanteilp JP, Duchinne-Maruilaz P, Troiese JF, Po9nat JF. Influence du beprtdii SW ia frequence cardtaque du sujet sain. Correlation avec ies taux plasmatiques. Arch f&l Coeur 1983;76:221-228. physioiogtic electrodes.

24. Bans JL, Duboisset

M, Guiret JC, Lesbre

torsades de pointes induites Coeur 1973;66:1427-1430.

25. Leclerq

ou favorls9es

JP, Bernaeconl

JF, Kurai S, Valere PE. Bepridii et torsades

1983:76:341-348. New Drug Brochure Laboratories, 1982.

P. Synccpes

par la prenylamine.

Arch

de pointes.

par Mal

Arch Mai

Coeur

26. InvestigatIonal

on Bepridil

HCI. Cranbury.

NJ: Wallace