Electrophysiologic Effects and Long-Term Efficacy of Bepridil for Recurrent Supraventricular Tachycardias

DENIS ROY, MD, MARTINE MONTIGNY, MD, GEORGE J. KLEIN, MD, ARJUN D. SHARMA, MD, and DENNIS CASSIDY, MD

Thirteen patients underwent electrophysiologic eval- uation for recurrent supraventricular tachycardia (SVT). The effects of intravenous bepridil (4 mg/ kg) were evaluated during the initial study in 5 pa- tients, and 12 patients underwent repeat study 7 to 10 days later taking oral bepridil, 300 to 400 mg/ day. Intravenous bepridil increased the pacing cycle length inducing atrioventricular (AV) (276 4- 43 vs 334 4- 31 ms, p <0.01) and ventriculoatrial (VA) block (268 -I- 34 vs 310 4- 35 ms, p <0.001) , the retrograde refractory period of the accessory path- way (251 4- 17 vs 295 4- 25 ms, p <0.05) and the ventricular refractory period (216 4- 17 vs 226 4- 11 ms, p <0.05) , and prevented induction of sustained SVT in 3 patients. Oral bepridil increased the sinus cycle length (723 -I- 64 vs 800 4- 118 ms, p <0.05), corrected (;IT (403 4- 14 vs 431 4- 21 ms, p <0.05) and the pacing cycle inducing AV

(288 4- 63 vs 353 4- 78 ms, p <0.01) and VA block (271 -F 31 vs 408 4- 124 ms, p <0.01) . It prolonged the refractory period of the atrium (195 -I- 29 vs 233 -I- 36 ms, p <0.05), AV node (264 -I- 35 vs 303 4- 22 ms, p <0.05), ventricle (221 4- 16 vs 245 -I- 21 ms, p <0.01) , accessory pathway in the AV (290 -I- 47 vs 329 -I- 54 ms, p <0.05) and VA (244 -t- 17 vs 342 4- 60 ms, p <0.01) di- rection and prevented induction of sv'r in 6 patients. During a mean follow-up of 5.5 4- 2.5 months, 7 patients (64%) who continued to receive bepridil reported symptomatic improvement. Only 1 of the 6 patients without and all 5 patients with inducible SVT at repeat testing had recurrent sv'r during fol- low-up (p <0.05). In conclusion, intravenous or oral bepridil may provide an attractive alternative to con- ventional therapy of paroxysmal SVT.

(Am J Cardiol 1987;59:89-92)

B epridil is a new long-acting calcium antagonist that appears to have a wide spectrum of electrophysiologic effects. 1-6 Its suppression of ventricular arrhythmias has been reported 7-9 and Rowland et al 1° suggested that bepridil may be useful in the treatment of supra- ventricular arrhythmias.

The present study was undertaken in patients with recurrent supraventricular tachycardia (SVT) to deter- mine (1) the electrophysiologic effects of intravenous and oral bepridil; {2} the value of oral bepridil in the long-term control of SVT; and (3} if the results of elec-

From the Montreal Heart Institute, University of Montreal, Montreal, Quebec, and the University Hospital, University of Western Ontario, London, Ontario, Canada. This study was sup- ported in part by the Montreal Heart Institute Research Fund and the Heart and Stroke Foundation, Toronto. Manuscript re- ceived April 11, 1986; revised manuscript received July 24, 1986, accepted July 25, 1986.

Address for reprints: Denis Roy, MD, Montreal Heart Insti- tute, 5000 East Belanger Street, Montreal, Quebec HIT 1C8, Canada.

trophysiologic testing predict the response to long- term oral treatment.

Methods Patients {Table I}: Thirteen patients (7 men, 6 wom-

en) were studied. Mean age was 41 years (range 22 to 62). One patient had coronary artery disease, 1 had mild systemic hypertension and 11 patients had no identifiable cardiovascular disease. Seven patients had electrocardiographic evidence of preexcitation in sinus rhythm. All patients had recurrent episodes (mean 3 per month) of SVT and 12 had been unsuc- cessfully treated with I to 3 antiarrhythmic drugs. Each patient gave informed consent before the study.

Y.lectrophysiologic studies: Antiarrhythmic drug therapy was discontinued at least 72 hours before the initial study. Two patients had received amiodarone therapy, which was discontinued 2 and 9 months be- fore they entered the trial. Right-sided cardiac cathe- terization was performed with patients in the non- sedated, postabsorptive state. Quadripolar catheters were introduced percutaneously and positioned in the

89

90 BEPRIDIL FOR SUPRAVENTRICULAR TACHYCARDIA

TABLE I Patient Characteristics

Frequency Previous Case Age (yr) & Sex of SVT Therapy Diagnosis

1 28M 1/month B WPW 2 37F 2/month D CBT 3 38M 4/year CBT 4 42M 4/month B,V AVN-Mahaim 5 43F 1/month V WPW 6 36M 2/month D,Q,V WPW 7 59M 20/month Q,B CBT 8 26M 1/month D WPW 9 39F 2/month A,P AVN

10 48F 1/month A,Q WPW 11 22M 1/month B,Q,V WPW 12 62F 1/month B AVN 13 54F 2/month B,D,Q WPW

A = amiodarone; AVN = atrioventricular nodal; B = /3-blocking drugs; CBT = concealed bypass tract; D = disopyramide; P = procainamide; Q = quinidine; SVT = supraventricular tachycardia; V = verapamil; WPW = Wolf f-Parkinson-White syndrome.

right atrium, coronary sinus, right ventricular apex and across the tricuspid valve to record the His bundle. Intracardiac electrograms were filtered at 30 to 500 Hz and simultaneously displayed with 3 electrocardio- graphic leads (1, aVF, V1) on a multichannel oscillo- scope and were recorded with an ink-jet recorder a t paper speeds of 100 to 250 mm/s. After recording base- line intracardiac conduction intervals, cardiac stimu- lation was initiated with a programmable stimulator that delivered rectangular pulses 1.5 ms in duration. The stimulation protocol consisted of: (1) rapid atrial pacing until 1:1 atrioventricular (AV) conduction was no longer maintained; (2) atrial and ventricular extra- stimulus testing during 2 paced cycle lengths (600 and 400 ms) to determine refractory periods and to induce SVT; (3) incremental ventricular pacing to the paced cycle length that induced ventriculoatrial (VA) block; and (4) delivery of atrial and ventricular extrastimuli during SVT. The criteria used to define concealed ac- cessory pathways were: (1) ability to preexcite the atri- um with a ventricular extrastimulus during SVT; (2) smooth AV nodal refractory curve; and (3) atrial and ventricle required to initiate and sustain SVT.

Intravenous bepridil administration: Intravenous bepridil hydrochloride was administered in 5 patients (cases 1 through 5) during the initial study after per- forming control measurements and determining the characteristics of the SVT. The drug was given by con- tinuous infusion pump over 35 minutes, 3 mg/kg in- fused over 5 minutes, and then a 1 mg/kg infusion over 30 minutes. Programmed stimulation was repeated in the final 20 minutes of the infusion using the previous- ly described protocol.

Oral treatment and follow-up: After the initial electrophysiologic study was completed patients be- gan oral bepridil therapy with 200 mg twice daily for the first 3 days and 300 to 400 mg/day in a single dose for the following days. Twelve of the 13 patients un- derwent a second electrophysiologic study after at least 7 days (range 7 to 10) of oral bepridil therapy. All 12 patients were then enrolled in a long-term oral

TABLE II Electrophysiologic Effects of Intravenous Bepridil

Control Bepridil Measure n (ms) (ms) p Value

SCL 5 710 4- 55 665 -I- 89 NS CSRT 5 328 4- 115 214 4- 32 NS AH 5 57 -4- 7 61 4- 13 NS HV 3 55 4- 5 55 4- 13 NS AERP 5 192 4- 38 200 4- 44 NS AVNERP 3 293 -I- 23 295 4- 28 NS AVBTERP 2 288 4- 18 315 4- 57 NS CLVAB 5 276 4- 43 334 4- 31 <0.01 CLVAB 5 268 4- 34 310 -I- 35 <0.001 VABTERP 4 251 4- 17 295 4- 25 <0.05 RVERP 5 216 4- 17 226 -I- 11 <0.05 SVT CL 5 335 4- 53 395 4- 38 NS SVT AH 4 151 4- 44 178 4- 31 NS SVT HV 4 53 4- 10 54 4- 8 NS SVT VA 5 129 4- 36 167 -I- 36 NS

AERP = atrial effective refractory period; AH = AH interval; AVBTERP = anterograde bypass tract effective refractory period; AVNERP = atrioven- tricular (AV) nodal effective refractory period; CLAVB -- longest paced atrial cycle length inducing 2 ° AV block; CLVAB = longest paced ventricular cy- cle length inducing 2 ° VA block; CSRT --- corrected sinus node recovery time; HV = HV interval; NS = not significant; RVERP -- right ventricular ef- fective refractory period; SCL --- sinus cycle length; SVT = supraventricular tachycardia; VABTERP -- retrograde bypass tract effective refractory period.

treatment phase and were seen at the outpatient clinic I week later and every month thereafter. Dosage mod- ifications were made as necessary to limit drug-related side effects and maintain effective control of the SVT. No other antiarrhythmic agents were allowed during the trial. A clinical history, physical examination and 12-lead electrocardiogram were done during each vis- it. Patients were observed with telemetric monitoring during the in-hospital phase of the study and 24-hour ambulatory Holter recordings were performed before entry into the study and at 4 and 12 weeks of long-term treatment. A laboratory profile, including a complete blood count, platelet count, urinalysis, blood sugar, blood urea nitrogen, creatinine, bilirubin, liver en- zymes, serum electrolytes, creatine kinase, magne- sium, and inorganic phosphorus was obtained before entry into the study, after 12 weeks of drug therapy and at the end of the study.

Statistical methods: Values are mean 4- standard deviation and were analyzed with the paired Student t test or the chi-square test as appropriate.

Results Sustained SVT was initiated during the control

study in all 13 patients. The mechanism of the SVT was AV nodal reentry in 3 patients and AV accessory path- way (concealed in 3) in 10 patients. One patient with AV nodal reentry exhibited bystander activation of a nodofascicular Mahaim fiber (Table I).

Electrophysiologic effects of intravenous bepridil (Table II): The longest atrial paced cycle length induc- ing AV block increased from 276 4- 43 to 334 4- 31 ms (p <0.01) and the ventricular paced cycle length inducing VA block increased from 268 4. 34 to 310 4- 35 ms after bepridil (p <0.001). The ventricular effective refracto- ry period increased from 216 4. 17 ms before to 226 4-

January 1, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 91

11 ms after bepridil (p <0.05). The retrograde effective refractory period of the accessory pathway (cases 1, 2, 3 and 5) increased from 251 4. 17 to 295 4. 25 ms after bepridil {p <0.05). After intravenous bepridil the SVT could still be induced in all 5 patients, but became nonsustained (less than 10 beats) in 3 by spontaneous block in the AV node (cases 2 and 4) and by either VA block in the accessory pathway or AV block below the bundle (case 5). Bepridil produced a nonsignificant lengthening of the SVT cycle length (from 335 4- 53 to 395 4- 38 ms} with AH (from 151 ± 44 ms to 178 4- 31 ms, difference not significant INS]} and VA conduction delay (from 129 4- 36 to 167 4. 36 ms, NS). Atrial fibrilla- tion was initiated in the control state and after bepridil in 4 patients (cases 1, 2, 3 and 5}. It caused a nonsignifi- cant lengthening of mean RR (from 415 4. 64 to 470 4- 91 ms, NS) and an increase in the shortest RR between preexcited (cases i and 5) beats (268 4. 25 to 330 4- 49 ms, NS) during atrial fibrillation.

Electrophysiologic effects of oral bepridil (Table III}: Oral bepridil produced a lengthening of the sinus cycle length (723 4- 64 vs 800 4.118 ms, p <0,05) but did not significantly modify the corrected sinus node re- covery time {309 4. 80 vs 304 4. 100 ms), AH {77 4- 20 vs 74 4- 22 ms) or HV intervals {47 4- 10 vs 49 4. 6 ms). The corrected QT interval was compared in the 6 patients without preexcitation and increased from 403 4. 14 ms before to 431 4- 21 ms after bepridil {p <0.05}. Oral bepridil caused an increase in atrial {from 195 4. 20 to 233 4- 36 ms, p <0.05} and ventricular effective refrac- tory periods (from 221 4. 16 to 245 4- 21 ms, p <0.01). The AV nodal effective refractory period was com- pared in 6 patients (cases 2, 3, 5, 6, 7 and 12} and increased from 264 4- 35 ms before to 303 4- 22 ms after bepridil (p <0.05). The anterograde effective refracto- ry period of the accessory pathway could be compared in 4 patients (cases 4, 5, 6 and 8) and increased from 290 4- 47 ms before to 329 4- 54 ms after bepridil (p <0.05). The retrograde effective refractory period (cases 2, 3, 5, 7, 8, 10 and 13) of the accessory pathway was also prolonged by bepridil (from 244 4- 17 to 342 4- 60 ms, p <0.01). The longest atrial paced cycle length inducing AV block increased from 288 4- 63 ms to 353 4. 78 ms (p <0.01} and the longest paced ventricular cycle length inducing VA block increased from 271 4. 31 to 408 4. 124 ms (p <0.01} after bepridil. After oral bepridil, sustained SVT could be reinitiated in 6 patients (cases 6, 8, 9, 10, 11 and 13), nonsustained SVT occurred in 4 (cases 2 to 5} and no SVT was induced in 2 {cases 7 and 12). Nonsustained SVT terminated spontaneously af- ter 5 to 10 beats by anterograde block in the AV node {case 2}, retrograde block in the AV node {case 4), retro- grade block in the accessory pathway {case 5) and by block in either the AV node or accessory pathway {case 3}. Bepridil produced a lengthening of the SVT cycle length (from 320 4- 26 to 391 4- 54 ms, p <0.001}, which was associated with AH {from 135 4- 27 to 189 4. 55 ms, p <0.01} and VA conduction delay {from 136 4. 29 to 168 4- 18 ms, NS}.

Follow-up: The 13 patients initially received oral bepridil, 300 mg (8 patients} or 400 mg (5 patients} in a single daily dose. The drug was discontinued before

TABLE III Electrophysiologic Effects of Oral Bepridil

Control Bepridil Measure n (ms) (ms) p Values

SCL 12 723 4- 64 800 4- 118 <0.05 CSRT 12 309 4- 80 304 4- 100 NS AH 12 77 4- 20 74 4- 22 NS HV 6 47 4- 10 49 4- 6 NS QTc 6 403 4- 14 431 4- 21 <0105 AERP 11 195 4- 29 233 4- 36 <0.05 AVNERP 6 264 4- 35 303 4- 22 <0.05 AVBTERP 4 290 4- 47 329 4- 54 <0.05 CLAVB 12 288 4- 63 353 4- 78 <0.01 CLVAB 9 271 4- 31 408 4- 124 <0.01 VABTERP 7 244 4- 17 342 4- 60 <0.01 RVERP 11 221 4- 16 245 4- 21 <0.01 SVT CL 10 320 4- 26 391 4- 54 <0.001 SVT AH 9 135 4- 27 189 4- 55 <0.01 SVT HV 9 48 4- 7 45 =E 8 NS SVT VA 8 136 4- 29 168 4- 18 NS

AERP = atrial effective refractory period; AH = AH interval; AVBTERP = anterograde bypass tract effective refractory period; AVNERP = AV nodal effective refractory period; CLAVB = longest paced atrial cycle length in- ducing second-degree AV block; CLVAB = longest paced ventricular cycle length inducing second-degree VA block; CSRT = corrected sinus node re- covery time; HV = HV interval; NS = not significant; OTc = corrected QT interval; RVERP = right ventricular effective refractory period; SCL = sinus cycle length; SVT = supraventricular tachycardia; VABTERP = retrograde bypass tract effective refractory period.

the repeat electrophysiologic study in 1 patient be- cause of an allergic skin rash and in a second patient 1 week later because of diarrhea and abdominal pain. The other 11 patients were followed for a mean of 5.5 4- 2.5 months (range 1.5 to 10). Five of these patients were protected from SVT and 6 had recurrences, but the episodes were less frequent in 2. Only 1 of the 6 patients without inducible sustained SVT at the repeat study during oral bepridil therapy and all 5 patients with inducible SVT had recurrences during follow-up (p <0.05). Although the medication was successful in preventing recurrences it had to be discontinued in another patient at 3 month follow-up because of poor memory and nervousness. The dosage was decreased to 200 mg/day in 3 other patients because of dizziness. No patient had significant ventricular arrhythmias during bepridil treatment.

Discussion Electrophysiologic effects: Intravenous bepridil

significantly prolonged the cycle length producing AV and VA block, the retrograde refractory period of the accessory pathway and the ventricular refractory peri- od, and prevented induction of SVT in 3 of 5 patients. Although the difference was not significant, the drug lengthened the anterograde refractory period of the accessory pathway and slowed the ventricular re- sponse in atrial fibrillation. Oral bepridil had more marked electrophysiologic effects. It significantly in- creased the sinus cycle length, the corrected QT and the pacing cycle length producing AV and VA block. No change in corrected sinus node recovery time was observed in this group of patients without sinus node dysfunction. It prolonged the refractory period of the atrium, AV node, ventricle and accessory pathway.

92 BEPRIDIL FOR SUPRAVENTRICULAR TACHYCARDIA

Further, oral bepridil prevented the induction of sus- tained SVT in half of the patients. The weak link of the tachycardia occurred in either the anterograde or ret- rograde direction. Bepridil did not modify the AH or HV in sinus rhythm but significantly increased the AH during SVT, suggesting a frequency-dependent effect of the drug on the AV node. These results suggest that both intravenous and oral bepridil have salutary ef- fects on SVT. The electrophysiologic data are in agree- ment with those of Singh et al 5 and Rowland et al 1° and suggest that bepridil affects slow-channel-dependent nodal tissues, as do verapamil and diltiazem. 11-14 However, unlike other calcium antagonists, bepridil also has quinidine-like properties. Fast channel and slow channel inhibition of the action potential by bepridil has been shown in frog atria 15 Our findings on the atrium, ventricle and accessory pathway refrac- toriness are in accord with the in vitro effects of the drug.

Long-term therapy: Of the 11 patients who contin- ued to receive bepridil therapy, 7 (64%) were either free of recurrent SVT or reported symptomatic im- provement. The results indicate that oral bepridil in single doses of 200 to 400 ms/day is effective for long- term control of SVT. Further, electrophysio]ogic test- ing may be used to predict subsequent clinical out- come. Although 3 of the 13 patients (23%) had adverse effects that required discontinuation of therapy, none of these reactions were life-threatening.

Limitations: Since we did not analyze plasma drug concentration, the observed differences between the intravenous and oral drug and the reason for the lack of effect in some patients remains speculative. Larger doses or faster infusion rates of the drug may well produce more marked electrophysiologic effects. Be- cause of the small number of patients and the differ- ences in type of SVT in this study group, no definite conclusions can be drawn concerning the comparative effects of bepridil on AV nodal vs AV bypass tract SVT.

Clinical implications: Intravenous and oral bepri- dil has beneficial electrophysiologic effects on either AV nodal or orthodromic SVT. In contrast to what has been reported with intravenous verapamil, 16 our data suggest that intravenous bepridil, because of its quint- dine-like effects on the accessory pathway, is unlikely to accelerate the ventricular response and may be use- ful in atrial fibrillation complicating Wolff-Parkinson- White syndrome. The effectiveness of oral verapamil in preventing recurrent episodes of SVT is controver- sial. 17-19 Our results indicate that oral bepridil has a

wide range of electrophysiologic effects and is an at- tractive alternative to conventional antiarrhythmic therapy of recurrent SVT. An advantage of oral bepri- dil over previous calcium antagonists is its long elimi- nation half-life, 42 4- 12 hours, 2° which allows for a once-a-day dose regimen.

References 1. Kane KA. Winslow E. Antidysrhythmic and electrophysiological effects of a new antianginal agent, bepridil. [ Cardiovasc Pharmacal 1980:2:193-203. g. Valere PE. Belin A. Chentir T. Lehner ]P, Gu6rot CK Tricot R. Effets 6lectrophysiologiques du bepridil sur le coeur humain. Ann Cardiol Ang~iol 1982:31:409-415. 3. Ponsonnaile ], Citron B. Threil F, Heiligenstein D, Gras H. Etude des effets ~lectrophysiologiques du bepridil utilis~ par voie veineuse. Arch Mal Coeur 1982:75:1415-1423. 4. Flammang D, Waynberger M, Jansen FH. Paillet R Coumel P. Electrophys- iological profile of bepridil a new anti-anginal drug with calcium blocking properties. Eur Heart [ 1983:4:647-654 5. Singh BN, Nademanee K. Feld G. Pionte KM, Schwab M. Comparative electrophysiologic profiles of calcium antagonists with particular reference to bepridil. Am [ Cardial 1985:55:14C-19C. 6. Prystowsky EN. Electrophysiologic and antiarrhythmic properties of bepridil. Am ] Cardio] 1985:55:59C-62C, 7. Rio A. Chauvin M. Brechenmacher C. The effect of bepridil on ventricular extrasystoles in patients with stable coronary insufficiency. Rev Med 1983:24/ 28:1333-1335. 8. Davy 1M, Lathe ]F, Sebag C, Matte G, Bepridil. a new calcium antagonist for the treetment of ventricular tachycardia (abstr). Circulation 1983:68:suppl I11:111-310. 9. Levy S, Melge M, Cointe R. Faugere G, Valeix B, Gerard R. Treatment of recurrent ventricular tachycardias with bepridil, a slow and fast channel blocking agent [abstr). Circulation 1983;68:suppl 11I:Ili-272. 10. Rowland E, McKenna W[, Krikler DM, Electrophysiologic and antler- rhythmic actions of bepridil. Comparison with verapamil and ajmaline for atrioventricular reentrant tuchycardia. Am ] Cardiol 1985;55:1513-1519. 11. Singh BN. Hecht HS, Nademanee K, Chew CYC. Electrophysiologic and hemodynamic effects of slow-channel blocking drugs. Prog Cardiovasc Dis 1982:25:108-132. 12. Kawai C. Koniahi T, Matsuyama E, Okazaki H. Comparative effects of three calcium antagonists: diltiazem, verapamil and nifedipine, on the sino- atrial and atriaventricular nodes. Experimental and clinicaJ studies. Circula- tion 1981:63:1035-1042. 13. Rozanski J]. Zaman L, Castellanos A. Electrophysiologic effects of diltia- zem hydrochloride on supraventricular tachyeordia. Am J Cardiol 1982:49: 621-628. 14. Roy D. Marchand E. Chabot M, Gagn6 P. Waters DD. Bourassa MG. Electrophysiologic effects of intravenous diltiazem in patients with recurrent supraventricular tachycardias. Can I Cardio] 1985;1:302-305. 15. Labrid C. Grosset A. Dureng G, Mironneau [, Duchenne-Marullaz P. Some membrane interactions with bepridil, a new antionginal agent. [ Phar- maeol Exp Ther 1979:211:546-554. 16. Gulamhusein S. Ko P, Carruthers SG. Klein G]. Acceleration of the ven- tricular response during atrial fibrillation in the Wolff-Parkinson-White syn- drome after verapamil. Circulation 1982:65:348-354. 17. Rinkenberger RL, Prystowsky EN. Heger ]], Troup P], ]ackman WM. Zipes DP. Effects of intravenous and chronic oral verapamil administration in patients with supraventricular tachyarrhythmias. Circulation 1980:62:996- 1010, 18. Tonkin AM. Aylward PE, Joel SE. Heddle WF. Verapamil in prophylaxis of paroxysmal atrioventricular nodal reentrant tachycardia. [ Cardiovasc Pharm 1980;2:473-486. 19. Mauritson DR, Winniford MD, Walker WS, Rude RE, Cary JR, Hillis D. Oral verapamil for paroxysmal supraventrieular tachycardia: a long-term, double-blind randomized trial. Ann Intern Med 1982;96:409-412. 20. Benet LZ. Pharmacokinetics and metabolism of'bepridil. Am [ Cardiol 1985;55:8C-13G.