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Aprindine for treatment of supraventricular tachycardias
Aprindine for Treatment of Supraventricular Tachycardias With Particular Application to Wolff-Parkinson-White Syndrome
DOUGLAS WINSTON PETER R. KENNETH
DELON WU, MD FERNANDO AMAT-Y-LEON, R. JOE
Ten patients with recurrent or continuous supraventricular tachycardia difficult to control with conventional antiarrhythmic agents were treated with aprindine, a new antiarrhythmic drug. Nine patients had Wolff-Parkinson-white syndrome. An electrophysiologic study was performed before and during oral administration of aprindine. At the time of the first study, circus movement supraventricular tachycardia was initiated in Patients 1 to 8. During administration of aprindine, circus movement supraventricular tachycardia could no longer be initiated in Patients 1 to 4 but was initiated with difficulty in Patients 5 and 8 and with greater ease in Patients 7 and 8. In Patient 9, aprindine therapy slowed the ventricular response during atrial flutter from 1:l conduction over the accessory pathway to 2:l conduction over the normal pathway; in Patient 10, it slowed the ventricular rate during atrial fibrillation from 140-180 to 8’0-100 beats/min. Patients 1 to 8, 9 and 10 had an excellent clinical response, but treatment with aprindine was discontinued in Patients 7 and 8. Electrophysiologic evaluation revealed that aprindine produced complete block or increased refractoriness of the accessory pathway in an antegrade direction in all patients and in a retrograde direction in all but two (Patients 7 and 8) tested. Aprindine also slowed conduction in the accessory pathway and, when supraventricular tachycardia could still be initiated, it occurred at a slower rate. Neurologic side effects occurred primarily during the initial administration and dose adjustment of aprindine.
P. ZIPES, MD, FACC E. GAUM, MD, FACC FOSTER, MD M. ROSEN, MD, FACC
NOBLE,
MD,
MD
FACC
Indianapolis, Indiana Chicago, Illinois
From the Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, and the Veterans Administration Hospital, Indianapolis, Indiana; and The Abraham Lincoln School of Medicine, University of Illinois, Chicago, Illinois. This study was supported in part by the Herman C. Krannert Fund, Indianapolis, Indiana; Grants HL-06308, HL-05363, HL-07182 and HL-18795 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; American Heart Association, Indiana Affiliate, Inc. Indianapolis, Indiana; and Eli Lilly and Company, Indianapolis, Indiana. Manuscript received February 28, 1977, accepted April 27, 1977. Address for reprints: Douglas P. Zipes, MD, Indiana University School of Medicine, 1100 West Michigan Street, Indianapolis, Indiana 46202.
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1977
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Aprindine, a new antiarrhythmic agent with local anesthetic properties, has been used in man to suppress both atria1 and ventricular arrhythmias.l-g Initial animallo and clinical studies2,3,7,8 have suggested that aprindine might also be effective in treating patients with supraventricular tachycardias, particularly those whose arrhythmia is associated with the Wolff-Parkinson-White syndrome. In this report, we present the results obtained when aprindine was administered to nine patients who had hard-to-control supraventricular tachycardias associated with the Wolff-Parkinson-White syndrome and to one patient who had a drug-resistant supraventricular tachycardia unrelated to the WolffParkinson-White syndrome. Methods Patient Selection Patients were referred for treatment with aprindine because of supraventricular tachycardia that was difficult to control with conventional drugs given singly or in combinations. The arrhythmia was present continuously in some patients but in others occurred at intervals ranging from several days to 1 month. All patients had had symptoms related to the tachycardia for at least 4 months. One patient (Table I) had had the tachycardia intermittently for 25 years. Eight patients (Cases 1 to 7 and 9) were studied and treated at the Indiana University School of Medicine and two (Cases 8 and 10) at the Abraham Lincoln School of Medicine.
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All patients were aware that aprindine was approved for experimental use only and gave their written informed consent to a trial of therapy with aprindine and for invasive electrophysiologic investigations performed both before and during drug administration.
Both electrophysiologic studies were completed in all but Patients 8 and 10. Patient 8 underwent only one study because aprindine, given intravenously at the time of the study, facilitated induction of supraventricular tachycardia and was
I
TABLE Patient
“0.
ET AL.
therefore discontinued. Patient 10 did not have an invasive electrophysiologic study because of the presence of chronic atria1 fibrillation. Type A Wolff-Parkinson-White syndrome in this patient was established with scalar tracings recorded during normal sinus rhythm and during atria1 fibrillation. Procedure: At the time of the electrophysiologic study, three or four tripolar or quadripolar electrode catheters were used. Generally, two catheters were introduced into each femoral vein; occasionally, a single catheter was inserted into the left antecubital &in. Electrodes were separated by 10 mm. The catheters were positioned in the high right atrium, in the
Electrophysiologic StuUy
Case
TACHYCARDIA-ZIPES
Profile
Age (Yr) 82 Sex
Heart Disease
Type of WPW
Type of SVT
Frequency of SVT
Signs or Symptoms Related to SVT
1
46F
None
None
A-V nodal reentry
Weekly 4 vr
2
33M
None
A
Ante NP, retro AP
Continuous for 2 yr
Mild shortness of breath, fatigue cardiomegaly, mitral insufficiencv
3
58M
None
A’
Ante NP, retro AP
Twice weekly over past 6mo
Shortness of breath, fatigue
4
28M
None
A
2 types: (1) Ante NP, retro AP; (2) atrial fibrillation
Weekly for 6 mo
Shortness of breath, fatigue
for
Shortness of breath, fatigue
Presyncope
5
47M
None
A”
Ante NP, retro AP
Almost continuous for 6mo
Shortness of breath, dizzv
6
40M
None
8
2 types: (I) Ante NP, retro AP; (2) atrial fibrillation Ante NP, retro AP
Weekly for 25 yr
None
7
40M
None
A
8
50M
CAD
A
Ante NP, retro AP
Every 2-3 wk for 4 vr Monthly for past 1 yr
9
59M
Cardiomyopathy
A
Atrial flutter, 1: 1 conduction over AP
Every 2-3 days for 1 vr
10
38M
Cardiomyopathy
A
Atrial fibrillation
Continuous for 4 mo despite repeated cardioversions
Shortness of breath, presyncope Shortness of breath, fatigue Angina
Syncope, shortness of breath, fatigue, seizure; cardiomegalv Shortness of breath, fatigue, edema, cardiomegaly
Unsuccessful
Drug Trials
Digoxin, 0.25 mg daily; quinidine, 200 mg every 6 hours; procainamide. 500 mg every 4 hours; propranolol, 80 mg every 6 hours; diphenylhydantoin, 100 mg every 6 hours Digoxin, 0.25 mg daily; quinidine, 400 mg every 6 hours; procainamide, 500 mg every 6 hours; propranolol, 50 mg every 6 hours; disopyramide, 150 mg every 4 hours Digitoxin, 0.1 mg daily. quinidine, 300 mg every 8 hours; propranolol, 40 mg every 6 hours Digoxin, 0.25 mg every 12 hours; quinidine, 200 mg every 6 hours; procainamide, 500 mg every 6 hours; propranolol, 40 mg every 6 hours Digoxin, 0.25 mg daily; quinidine, 400 mg every 6 hours; propranolol. 40 mg every 6 hours Digoxin, 0.25 mg daily; quinidine, 300 mg every 8 hours
Digoxin, 0.25 mg daily; quinidine, 200 mg every 6 hours Digoxin, 0.25 mg daily; quinidine, 200 mg every 6 hours Ouabain, 0.7 mg; procainamide, 350 mg in 20 min; propranolol, 7 mg; disopyramide, 280 mg in 1 hour* Digoxin, 0.25 mg daily: quinrdine, 200 mg every 6 hours; propranolol, 40 mg every 6 hours Digoxin, 0.125 mg daily; quinidine, 300 mg every 4 hours; procainamide, 1 g every 4 hours; propranolol, 20 mg every 6 hours
*Retrograde conduction only. t Drugs given intravenously on sequential days; paroxysmal supraventricular tachycardia initiated on each day. Ante = antegrade direction; AP = accessory pathway; A-V = atrioventricular; CAD = coronary artery disease; NP = normal pathway; retrograde direction; SVT = supraventricular tachycardia; WPW = Wolff-Parkinson-White conduction.
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Retro =
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APRINDINE FOR SUPRAVENTRICULAR TACHYCARDIA-ZIPES
TABLE
ET AL.
II
Electrophysiologic
Variables
Before
and During
Aprindine
Therapy Effective
RA Case no.
LA
RV
(values in msec)
Refractory
Period
Accessory
Pathway
Ante
Normal
Retro
C
Apr
C
Apr
C
Apr
:
500 600
200 180
260 270
200 <220
220 250
240 *
260 270
None 220
None 81
None <400
None 540
3
700
*
370
300
260
250
BI
81
4
600
200
240
190
250
200
230
290
BI
>300, <400 <240
5
500
190
260
200
260
230
250
BI
BI
250
290
6
600
230
330
230
370
250
260
320
BI
<260
7
450
230
240
200
210
200
230
350
<260
8 9 10
600 700 . .
260 250
2;io
: ::
<200 170
.
190
.
290 <320 <240§
Apr
BI BI 55500
C
(A-V
Ante
BCL
C
Pathway
Node) Retro
C
Apr
220 <220
<290 <330
<250
81
300
<390
t
81
BI
210
<320
t
520
<220
<300
<250
3290
<320
<365
t
t
<230
<250
t
t
<270
*
t
t
t
<300
Apr
<305 240
C
l
Aor BI >540
1::
*Could not obtain because of recurrent supraventricular tachycardia. t Could not obtain because of conduction over accessory pathway. $ Varied. 8 Estimated from A-R cycle length during atrial fibrillation.
coronary sinus or in the left atrium through a patent foramen ovale, in the right ventricle and across the septal leaflet of the tricuspid valve to record His bundle activation. No patient was receiving any cardiac medication other than aprindine at the time of study. One patient (Case 3) had been taking propranolol just before the first study. Tracings were stored on a frequency modulation tape recorder (Hewlett-Packard) and were also recorded on a multichannel oscilloscopic recorder (Electronics for Medicine DR 8) at a paper speed of 100 mm/set, using filter settings of 40 and 500 hertz for the intracardiac electrograms and of 0.1 to 20 hertz for the surface electrocardiograms. Time lines of 1 second were used. The right atrium, the apex of the right ventricle and the left atrium directly or through the coronary sinus were each stimulated using a programmable stimulator (Medtronic 5325, Bloom Associates or WP Instruments, Inc.), with rectangular stimuli of 1 to 2 msec duration at an intensity equal to twice the diastolic excitability threshold. The stimulator could be programmed to deliver one or more premature stimuli after pacing or sensing a driven or spontaneous basic train of complexes. Stimuli and the local electrogmm recorded at the site of stimulation (using the Medtronic 5235) were displayed on a separate channel. Initiation of tachycardia: Refractory periods were determined during one or more pacing cycles using the single extrastimulus techniques,li which was generally sufficient to initiate supraventricular tachycardia.12 For simplicity, only data derived at one cycle length are presented (Table II). Multiple premature stimuli and rapid pacing at different cycle lengths were used in an attempt to initiate supraventricular tachycardia when single stimuli failed to do so. In addition, maximal 1:1 conduction was established when possible while stimulating the atrium and ventricle at progressively shorter cycle lengths. The mode of initiating the supraventricular
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tachycardia and the duration of echo zones were carefully documented. Echo zones were defined as the zone of Ai-Az, Al-As-As or Vi-V2 intervals that initiated supraventricular tachycardia (Table II). In attempting to initiate supraventricular tachycardia during administration of aprindine, premature stimuli were also applied outside those echo zones and at different cycle lengths. Rapid atria1 pacing was used to induce atria1 fibrillation in Patients 4 and 6 and atria1 flutter in Patient 9 because these arrhythmias also occurred spontaneously in these patients. Aprindine Administration Aprindine was administered orally in capsule form, sometimes after a loading dose given intravenously, to all except Patient 8, who received only the intravenous loading dose. The oral dose of aprindine was 200 mg initially, followed by 100 mg 1 hour later and an additional 100 mg 6 hours later. The next day, the patient received 150 mg every 12 hours and on the 3rd day, 100 mg every 12 hours. Thereafter, the dose was individualized according to each patient’s response.*
Since completion of this study, the dosing schedule for oral and intravenously administered aprindine has been changed although the total amount given remains the same. At present, the oral schedule is 100 mg every 6 hours on the 1st day, 75 mg every 6 hours on the 2nd day and 50 mg every 6 hours on the 3rd day. Intravenously, 200 mg of aprindine is administered at a constant infusion rate of 2 mg/min. Thirty minutes after the first 200 mg is given, 100 mg is administered at a rate of 2 mg/min. Six hours after the first injection of aprindine is begun, the final 100 mg is infused at a rate of 2 mg/min. l
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TABLE II (Cont’d)
Minimal
I:1 CL
Ante
C
Retro
250 (NP) <275 (AP) <380
(NP)
220 (NP), 330 (AP) 250 (NP) <330 (AP), <340 (NP) 230 (NP), <230 (AP) 300 (API <240 (AP) <240 (AP) 5
Ante length; Retro mature
C
Apr
Mode of SVT C
Apr
<500 <275
(NP) CAP)
610 (NP) <700 (API Complete
400
(NP)
<380
(AP)
330
(NP)
<255
(AP)
550
300 (NP)
<270
(AP)
360-510
retro bl
(NP) (AP)s
RA S, 320-400. S, 230-270 Spontaneous PACs, PJCs, LA S,: 220 RA or LA S,: 330-500
None None
1.3 1.54
None
2.4
RA S, 240-290, LA S, 220-280 RA or LA S,: 220-260
None
0.88
(NP)
<340
CAP)
<390
(AP)
RA S, 330-400,
250 330 300 >270 550
(NP), (AP) (NP) (NP) (NP) 3
<360
(AP)
<440
(AP)
LA S, 200; RA S, 250-300, S, 250-260; RV S, 200 RA S, 270-290 Rapid RA pacing
285 (API
..
Aw
-
<390
270 (API
S, 300-340
LA S,: 270-280, RV pacing, <500 Rapid RA pacing
Definitions The following definitions are used in this study: Effective refractory period of the atrium: the longest S1-Ss in-
terval, delivered to the right or left atrium, at which Ss failed to elicit an atria1 depolarization.
Effective
refractory
1.60 msec 1.63
RA S, 240-300, RV S, 250 RA S,*-370 Rapid RA pacing
= antegrade direction; AP = accessory pathway; Apr = aprindine; BCL = basic cycle length; BI = complete LA = left atrium; NP = normal pathway; PACs = premature atrial complexes; PJCs = premature junctional = retrograde; RV = right ventricle; S, = a sing!e premature stimulus induced paroxysmal supraventricular stimuli needed to induce paroxysmal supraventricular tachycardia.
The loading dose given intravenously was 200 mg of aprindine administered in 25 mg aliquots at intervals of 2 to 5 minutes. Additional doses of 100 mg were given in the same fashion, 1 and 6 hours later. The following day, the patient received orally administered aprindine according to the schedule described previously. Patients underwent a repeat electrophysiologic study after 3 to 20 days of oral administration of aprindine. Venous blood samples for assay of aprindine concentration were drawn immediately before the electrophysiologic study. We chose to study the effects of orally administered aprindine because previous canine studies bad shown that the myocardium rapidly binds the drug after intravenous administration, initially producing very high myocardial concentrations and prominent electrophysiologic changes. During the 1st hour after completion of intravenous administration, the myocardial concentration greatly decreases and the prominent electrophysiologic changes diminish. These changes prevent creation of a steady state immediately after intravenous administration of aprindine.ls Follow-up: All but Patients 7 and 8 have been taking orally administered aprindine for 3 to 12 months. Patients have been seen by a physician weekly for the 1st month and then at monthly intervals; any recurrence of supraventricular tachycardia has been detected by noting the patient’s symptoms and obtaining a 12 lead electrocardiogram and 24 hour Holter recording at each visit.
Apr Serum Level At Time of StudY (fig/ml)
Initiation
0.48
6.84
block; C = control; CL = cycle complexes; RA = right atrium; tachycardia; S,, S; = two pre-
period of the ventricle:
Sl-Ss interval, delivered to the right ventricle, failed to elicit a ventricular depolarization.
the longest at which Ss
Antegrade effective refractory period of the accessory pathway: the longest Al-As interval, determined on the same
side as the accessory pathway, at which As failed to conduct to the ventricle over the accessory pathway. Retrograde effective refractory period of the accessory pathway: the longest VI-Vs interval, determined from the
right ventricle, at which Vs failed to conduct to the atrium over the accessory pathway. Antegrade effective refractory period of the atrioventricular (A-V) node: the longest Al-As interval, measured in the
His bundle electrogram, at which As failed to conduct through the A-V node to the bundle of His. Retrograde effective refractory period of the A-V node: the longest VI-H2 interval, determined from the right ventricle, at which Hs failed to conduct to the atrium through the A-V node.
All but one patient (Case 1) had the Wolff-Parkinson-white syndrome. Six patients had a left-sided accessory pathway (type A) that conducted in both directions,14 two had a left-sided accessory pathway that conducted only in a retrograde direction15 and one patient had a right-sided accessory pathway (type B) that conducted in both directions.12 Two patients had a cardiomyopathy associated with excessive ingestion of alcohol and one patient had coronary artery disease; the remaining seven-patients had no clinically detectable heart disease.
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TACHYCARDIA-ZIPES
Aprlndlne 200
ET AL
tient 6, the atria1 echo zone for premature stimulation was eliminated, and rapid atria1 pacing was required to initiate paroxysmal supraventricular tachycardia. In both patients, brief periods of competitive atria1 or ventricular pacing promptly terminated the paroxysmal supraventricular tachycardia. The echo zone widened in Patients 7 and 8 during treatment with aprindine, thus facilitating induction of paroxysmal supraventricular tachycardia. In addition, paroxysmal supraventricular tachycardia was more difficult to terminate, requiring long periods of rapid competitive atria1 or ventricular pacing to restore sinus rhythm. In the four patients in whom paroxysmal supraventricular tachycardia could be initiated during treatment with aprindine (Patients 5 to 8), the cycle length of the tachycardia was longer than before treatment.
mg/d
“I
Response of Atrial Flutter and Atrial Fibrillation to Aprindine Clinically, Patient 9 had recurrent atria1 flutter with 1:l conduction to the ventricle over the accessory pathway, and Patient 10 had chronic atria1 fibrillation with ventricular rates of 140 to 180/min while receiving maximal doses of quinidine (300 mg every 4 hours; peak serum concentration 10.4 mg/liter) and procainamide (1 g every 4 hours; peak serum concentration 13.0 mg/liter). Patients 4 and 6 experienced, in addition to paroxysmal supraventricular tachycardia, atria1 fibrillation with very rapid ventricular rates due to conduction primarily over the accessory pathway. Administration of aprindine resulted in a marked decrease in the ventricular rate during atria1 fibrillation (Fig. 1) in Patients 6 and 10 and in 2:l conduction to the ventricle over the normal pathway in Patient 9, who had atria1 flutter. In addition, the cycle length of the atria1 flutter increased from 240 to 270 msec in this patient. Atria1 fibrillation could no longer be induced in Patient 4.
“6
FIGURE 1. Patient 10. Electrocardiograms before and during treatment with aprindine in a patient with type A Wolff-Parkinson-White syndrome. Left, control recording before administration of aprindine, revealing atrial fibrillation, rapid ventricular response at a rate of approximately 200 beats/min and type A preexcitation. Right, recording obtained while the patient was receiving aprindine, 200 mg/day orally. The ventricular rate is approximately 80 beatslmin and conduction occurs almost exclusively by way of the normal pathway.
Response of Paroxysmal Supraventricular Tachycardia to Aprindine
Clinical Response to Aprindine
Before administration of aprindine, paroxysmal supraventricular tachycardia was initiated in Patients 1 to 8 and echo zones were established (Table II). During treatment with aprindine, paroxysmal supraventricular tachycardia could no longer be initiated in Patients 1 to 4 by one or more premature atria1 or ventricular stimuli delivered during stimulation at multiple basic cycle lengths or during rapid atria1 or ventricular pacing. In Patients 5 to 8, paroxysmal supraventricular tachycardia could still be started in spite of administration of aprindine. However, the atria1 echo zone was narrowed in Patient 5 and paroxysmal supraventricular tachycardia could be initiated from the atrium only during premature left atria1 stimulation. Right ventricular pacing at cycle lengths of less than 500 msec also initiated paroxysmal supraventricular tachycardia in this patient after administration of aprindine. In Pa-
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Aprindine increased the incidence of paroxysmal supraventricular tachycardia in Patients 7 and 8 and was discontinued in these two patients. Patient 7, treated with digitoxin (0.1 mg daily), propranolol (40 mg every 6 hours) and quinidine (200 mg every 6 hours), continued to have self-terminating episodes of paroxysmal supraventricular tachycardia in the 8 month follow-up period. Patient 8 had partial interruption of the accessory pathway at operation and had only one recurrence of tachycardia in the 5 months since then. Correlation with electrophysiologic responses: The remaining eight patients had a beneficial clinical response to aprindine therapy over a follow-up period of 3 to 12 months (mean 5.9 months). Six patients still have episodes of supraventricular tachycardia but far less often than when they received conventional agents. In general, a beneficial clinical response correlated with the results obtained during the second electrophysiologic study. However, there was not complete correla-
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tion, after administration of aprindine, between the ability to induce supraventricular tachycardia with pacing and the spontaneous recurrence of supraventricular tachycardia. Paroxysmal supraventricular tachycardia could not be initiated in Patients 1 to 4 at the time of the second electrophysiologic study when the patients were receiving aprindine, yet each patient had one or two recurrences of paroxysmal supraventricular tachycardia, terminating spontaneously (Cases 2 and 4), with pharmacologic therapy (Case 3) or with direct current cardioversion (Case 1). Patient 2 had both recurrences during upper respiratory infections, and Patients 1 and 3 had recurrences at a time when their serum concentrations of aprindine were low because of reductions in oral dosage. When therapeutic concentrations of aprindine were restored in these two patients, they had no further recurrences of paroxysmal supraventricular tachycardia. Paroxysmal supraventricular tachycardia could be initiated in Patients 5 and 6 at the time of the second electrophysiologic study during administration of aprindine. Patient 6 had a 12 second episode of paroxysmal supraventricular tachycardia during a Holter recording, but spontaneous recurrence of paroxysmal supraventricular tachycardia in Patient 5 was not observed. In some patients the episodes of paroxysmal supraventricular tachycardia may be more frequent than is recognized either by the patient or by the examiners during monthly examinations and 24 hour Holter recordings; this possibility is likely because the ventricular rate during paroxysmal supraventricular tachycardia is much slower when the patient is receiving aprindine. Six patients are receiving (in two or three divided doses) 150 mg of aprindine daily, one patient 120 mg daily and one patient 200 mg daily. The mean serum aprindine concentration for Patients 1 to 6,9 and 10, based on the most recent sample, is 1.7 f 0.8 pg/ml (mean f standard error). Clinical features of the recurrent tachycardias modified by aprindine: Several clinical points should be emphasized to highlight the symptomatic nature of the supraventricular tachycardia and the response to aprindine therapy (Table I). Patient 1 required more than 90 electrical cardioversions to terminate paroxysmal supraventricular tachycardia in the several years before aprindine therapy and has had only one recurrence of paroxysmal supraventricular tachycardia in 10 months since the start of this therapy. Patient 2 had experienced continuous paroxysmal supraventricular tachycardia, at a rate of 200 to 220lmin for 2 years, in spite of receiving procainamide, quinidine, digitalis and propranolol simultaneously. He presented with cardiomegaly and a murmur of mitral insufficiency. Several hours after his first oral doses (300 mg) of aprindine, the tachycardia terminated and has recurred only transiently on two occasions in 12 months. His heart size has returned to normal and the murmur of mitral insufficiency has disappeared. Patient 9 had recurrent syncope with seizure activity during atria1 flutter with 1:l conduction to the ventricles. At the time of the second electrophysiologic study,
TACHYCARDIA-ZIPES
ET AL,
atria1 flutter was initiated and allowed to persist for 10 days. During that entire 10 day interval, the patient was ambulatory and experienced only 2:l conduction over the normal pathway, except for a 15 minute period on the day after the electrophysiologic study when, possibly owing to a low serum concentration of aprindine, 1:l conduction transiently occurred over the accessory pathway. On the 10th day, direct current cardioversion was used to terminate the atria1 flutter, and the arrhythmia has not recurred since the start of aprindine therapy. Patient 10 had experienced refractory congestive heart failure due to uncontrolled ventricular rates during atria1 fibrillation. After he was treated with aprindine, the ventricular response during atria1 fibrillation slowed to rates of less than 100 beats/min and the patient then lost more than 13.5 kg of edema fluid in 2 weeks and had a striking decrease in heart size. After 2 months of aprindine therapy, long-standing atria1 fibrillation spontaneously reverted to normal sinus rhythm, which has remained. Finally, two patients (Cases 4 and 6) had recurrent paroxysmal supraventricular tachycardia that produced symptoms but, for unknown reasons, these patients had recently experienced atria1 fibrillation. The latter, because of the rapid ventricular rate, exacerbated their symptoms, produced presyncope and led to their referral. While receiving aprindine, Patient 4 had a transient recurrence of supraventricuiar tachycardia that was easily tolerated; Patient 6 has experienced no recurrence. Side Effects
During the initial 1 to 2 weeks of administration of aprindine, several patients had experienced transient side effects, including fine tremor of the hands (Cases 2 and 6), ataxia (Cases 9 and 10) and nausea (Case 5). Neither the patients nor the physicians considered these side effects sufficiently severe to warrant discontinuation of therapy, and they disappeared with a reduction in dosage. The most severe problem occurred in Patient 4. He had received 400 mg of aprindine on the 1st day of therapy, 300 mg on the 2nd day, 200 mg on the 3rd day and 225 mg on each of the next 4 days (75 mg every 8 hours). This dose was not reduced because he appeared to tolerate the drug well and had no neurologic side effects or electrocardiographic signs of toxicity. At the precise moment of catheter withdrawal upon completion of the second electrophysiologic study, he had a grand ma1 seizure from which he recovered uneventfully. Subsequent neurologic evaluation, electroencephalogram and brain scan were normal. Although the serum concentration of aprindine was within a therapeutic range (0.88 ctgiml) and higher concentrations (such as 1.26 pg/ml) produced no problems in this patient, aprindine cannot be excluded as the cause of the seizure. With a reduced dose of aprindine (50 mg every 8 hours), he has no further side effects, except for a transient elevation of hepatic enzymes in the serum. All patients except Patient 3 have no side effects at their present daily dosage of aprindine. Patient 3 has a slight fine tremor. Because reduction of this patients
October 1977
The American Journal of CARDIOLOGY
Volume 40
591
APRINDINE
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TACHYCARDIA-ZIPES
ET AL.
FIGURE 2. Patient 4. Control recording before treatment with aprindine. Determination of the antegrade effective refractory period of the accessory pathway and initiation of paroxysmal supraventricular tachycardia in a patient with type A Wolff-Parkinson-White syndrome. After the last driven impulse of the basic train, premature stimulation of the right atrium at a coupling interval of 300 msec resulted in antegrade conduction over the accessory pathway (left). Activation of the bundle of His occurred after the onset of the QRS complex. Premature right atrial stimulation at a coupling interval of 290 msec blocked in antegrade fashion in the accessory pathway, conducted to the ventricle with a right bundle branch block and initiated paroxysmal supraventricular tachycardia, during which activation of the left atrium preceded activation of the low and high right atrial sites (right). These findings are consistent with the presence of a left-sided bypass tract. From top to bottom: right atrial electrogram (RA); His bundle electrogram (HBE); left atrial electrogram (LA); scalar leads I, II, Ill and VI; and stimulus channel (St.). Paper speed is 100 mm/set; numbers indicate msec. A = atrial potential; e = electrogram recorded at the site of stimulation; H = His bundle potential; V = ventricular potential. Of the paced beats, only the last in the basic train and the premature stimulus are displayed
CONTROL
FIGURE 3. Patient 4. Complete antegrade and retrograde block in the accessory pathway during administration of aprindine. The top panels display the last driven beat of the basic train and the premature right atrial stimulus, delivered at coupling intervals of 500, 400 and 250 msec, respectively. Both the basic and premature beats are conducted to the ventricles over the normal pathway, with a right bundle branch block similar to the contour of the QRS complex initiated during supraventricular tachycardia seen in Figure 2. His bundle activation was slurred and delayed after premature stimulation at intervals of 500 and 400 msec; after premature stimulation at 250 msec, a clear His bundle spike could not be recorded. Supraventricular tachycardia could not be initiated at any coupling interval. The bottom panel shows the right ventricle being stimulated at a constant cycle length of 560 msec. Note that low right atrial activation preceded high right atrial activation, and that the latter preceded left atrial activation. This sequence of retrograde atrial activation is entirely different from the corresponding sequence that occurred during supraventricular tachycardia seen in Figure 2. Complete retrograde block in the accessory pathway is present. Note also that a retrograde Wenckebach block occurred in the normal pathway; the V-A interval progressively lengthened, culminating in V-A block after the third QRS complex. The third P wave is probably a sinusinitiated P wave. Conventions as in Figure 2.
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1977
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APRINDINE
Journal of CARDIOLOGY
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APRINDINE FOR SUPRAVENTRICULAR
FIGURE 4. Patient 3. Control recording before treatment with aprindine. Initiation of paroxysmal supraventricular tachycardia in a patient with a “concealed” leftsided accessory pathway. Premature right atrial stimulation at an interval of 330 msec initiated supraventricular tachycardia (top). Note that during retrograde atrial activation, left atrial activation preceded high and low right atrial discharge. Atrial activation recorded in the distal coronary sinus (CSJ preceded that recorded in the proximal coronary sinus (CS,) (inset, top right). No evidence of antegrade conduction over an accessory pathway occurred at any cycle length during pacing of the right or the left atrium. Right ventricular pacing at a constant cycle length of 700 msec (bottom) initiated the same sequence of retrograde atrial activation as seen during the supraventricular tachycardia, thus confirming the presence of retrograde atrial activation over a “concealed” left lateral accessory pathway. Conventions as in Figure 2.
TACHYCARDIA-ZIPES
ET AL.
CONTROL
APRINDINE
dosage to less than 150 mglday resulted in two episodes of paroxysmal supraventricular tachycardia, he has continued to take 150 mglday, preferring the fine tremor to a recurrence of paroxysmal supraventricular tachycardia. No patient has had jaundice or hematologic abnormalities. Electrophysiologic Effects of Aprindine The ability of aprindine to totally prevent, hinder or facilitate induction of supraventricular tachycardia and the effect of the drug on the ventricular response during atria1 flutter and atria1 fibrillation may be explained by its electrophysiologic effects on refractoriness and conduction (Table II). Effective refractory period of atria and ventricles (Table II): Aprindine increased the effective refractory period of the atria (mean f standard error) from 211.4 f 25.4 to 265.7 f 30.5 msec (P
st-L,ii-
‘L
FIGURE 5. Patient 3. Complete retrograde block in both the normal and accessory pathways during treatment with aprindine (continuous recording). Right ventricular (RV) pacing at a cycle length of 700 msec revealed the presence of complete V-A retrograde block. The atria are under sinus control and are totally dissociated from ventricular activity. Although a high right atrial recording is not present, it is apparent that low right atrial activation preceded atrial activation recorded in the coronary sinus (CS). The atrial cycle length was relatively constant and, intermittently, the atria captured the ventricles to produce a normal QRS complex. Conventions as in Figure 2.
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ET AL.
APRINDINE
FIGURE 6. Patient 8. Before treatment with aprindine (lop), the first premature right atrial stimulus delivered at a coupling interval of 250 msec is conducted over the accessory pathway. The second premature right atrial stimulus, also delivered at a coupling interval of 250 msec, blocked in antegrade fashion in the accessory pathway and initiated supraventricular tachycardia, which occurred with a left bundle branch block contour. During the tachycardia, left atrial activation preceded low right atrial activation, which occurred slightly in advance of high right atrial depolarization. With aprindine therapy (bottom), a single premature right atrial stimulus at a coupling interval of 250 msec initiated supraventricular tachycardia. Conventions as in Figure 2.
6. In Patients 7 and 8, whose retrograde effective refractory period did not lengthen, administration of aprindine facilitated induction of paroxysmal supraventricular tachycardia (Fig. 6). Minimal 1:l cycle length (Table II): The shortest cycle length at which the atria1 impulse conducted to the ventricles over the accessory pathway lengthened after administration of aprindine in all seven patients (Cases 2,4 and 6 to 10) who had exhibited antegrade conduction over an accessory pathway before drug administration. The shortest cycle length at which the ventricular impulse conducted to the atrium over the accessory pathway could be accurately assessed in four patients (Cases 3 to 5 and 8) and lengthened in each instance with administration of aprindine. In Patient 5, the ability for retrograde conduction over the accessory pathway varied during aprindine therapy. When conduction in the accessory pathway was relatively intact (the shortest ventricular cycle length conducting to the atrium over the accessory pathway was 360 msec), paroxysmal supraventricular tachycardia could be initiated. When the ability for conduction in the accessory pathway was diminished (the shortest. ventricular cycle length conducting to the atrium over the accessory pathway was 510 msec), paroxysmal supraventricular tachycardia could not be initiated. The shortest cycle length at, which the atria1 impulse conducted to the ventricles over the normal pathway could be accurately determined in five patients (Cases 1,3 to 5 and 7) and was lengthened in each instance by treatment with aprindine. These changes in refractoriness and conduction are consistent with the decreased ventricular response noted during atria1 flutter and atria1 fibrillation during administration of aprindine.
Conduction times before and after administration of aprindine: At the time of the second study, the the shortest R-R interval for Wolff-Parkinson-White syndrome beats, prolongation of the antegrade effective refractory period in the patient with atria1 fibrillation (Case 10). Among the patients whose retrograde effective refractory period of the accessory pathway could be determined before and during aprindine therapy, Patient 4 (Fig. 2 and 3) and Patient 3 (Fig. 4 and 5) had complete retrograde block in the accessory pathway, and Patients 2 and 5 had an increase in retrograde effective refractory period. Ventricular refractoriness limited determination of retrograde effective refractory period in three patients, but based on the shortest VI-V2 response, the retrograde effective refractory period probably did not change in two (Cases 7 and 8) and increased in one patient (Case 6). Thus, aprindine produced complete antegrade block or lengthened the antegrade effective refractory period of the accessory pathway in all patients and produced complete retrograde block or lengthened the retrograde effective refractory period of the accessory pathway in four of seven patients tested. The retrograde effective refractory period probably also lengthened in Patient
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The American Journal of CARDIOLOGY
following variables lengthened (determined at the same cycle length and during normal atrioventricular conduction for both studies): A-H interval (mean f standard error) from 63.3 f 9.3 to 89.2 f 16.3 msec (P
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APRINDINE FOR SUPRAVENTRICULARTACHYCARDIA--ZtPES ET AL.
(P
accessory pathway. If aprindine delays antegrade conduction over the normal pathway and does not prolong, or prolongs minimally, retrograde refractoriness in the accessory pathway, it may widen the echo zone during which paroxysmal supraventricular tachycardia can be initiated and make it more difficult to terminate the tachycardia. This response occurred in Patients 7 and 8 and forced us to discontinue aprindine therapy in these two patients. A similar observation was made in patients treated with amiodarone.20 Our remaining patients with paroxysmal supraventricular tachycardia (Case 1 to 6) had a very beneficial response. Aprindine also suppresses premature atria1 and ventricular extrasystolesl-s and may prevent initiation of supraventricular tachycardia in this fashion (Patient 2). Significantly, some patients with Wolff-ParkinsonWhite syndrome intermittently may have atria1 fibrillation as well as paroxysmal supraventricular tachycardia. Although digitalis may be quite beneficial for treating paroxysmal supraventricular tachycardia, during which one of the pathways includes the normal A-V node, it may result in more rapid ventricular rates during atria1 fibrillation. 24 Indeed, one should question whether digitalis alone is ever warranted to treat paroxysmal supraventricular tachycardia in these patients because of the possibility that atria1 fibrillation may develop at some time. A drug like aprindine, which lengthens the refractory period and conduction time in the accessory pathway as well as in the A-V node, should be ideal to treat patients with Wolff-Parkinson-White syndrome who experience atria1 fibrillation or atria1 flutter. Side effects: These occurred during the period of initial administration and dose adjustment, except in Patient 3, who has a fine tremor of the hands. In previous studies with aprindine, neurologic side effects have been most prominent and were dose-related.g Recently, cholestatic jaundice and agranulocytosis were reported to occur in association with the use of aprindine.25 Jaundice and agranulocytosis did not occur in our group of patients. Because the therapeutic-toxic levels appear fairly close, further studies are necessary to establish the benefit-to-risk ratio of aprindine. Acknowledgment We express our appreciation to Paul Troup, MD, Mark Lambert, MD, Steven M. Peskoe, MD and Samuel L. Wann, MD for help during the electrophysiologic studies and to Rachael Glasser, MS and Ann deB Nicoll, RN for research assistance.
References 1. Kesteloot H, van Mieghem W, De Geest H: Aprindine (AC 1802) a new antiarrhythmic drug. Acta Cardiol 28:145-165, 1973 2. Kesteloot H: General aspects of antiarrhythmic treatment with aprindine. Acta Cardiol (Brux) Suppl 18:303-317. 1974 3. Fasola AF, Carmichael R: The pharmacology and clinical evaluation of aprindine, a new antiarrhythmic agent. Acta Cardiol (Brux) Suppl 18:317-335, 1974
4. van Durme JP, Rousseau M, Mbuyamba P: Treatment of chronic ventricular dysrhythmias with a new drug: aprindine (AC 1802). Acta Cardiol (Brux) Suppl 18:335-341, 1974 5. Breithardt G, Gleichmann U, Seipel L, et al: Long-term oral antiarrhythmic therapy with aprindine. Acta Cardiol (Brux) Suppl 18:341-353, 1974 6. Bollen G, Enderle J: Preliminary experience in the treatment of
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APRINDINE FOR SUPRAVENTRICULAR TACHYCARDIA-ZIPES
7.
8.
9.
10. 11.
12.
13.
14.
15. 16.
596
ET AL.
cardiac arrhythmias with aprindine. Acta Cardiol (Brux) Suppl 18:355-361, 1974 Palma-Gamiz JL, Boedo C, Lopez-Pujol FJ, et al: Etude clinique d’un nouvel anti-arythmique: aprindine. Acta Cardiol (Brux) Suppl 18:361-368, 1974 Neuss H, Schlepper M: Influence of various antiarrhythmic drugs (aprindine, ajmaline, verapamil, oxyprenolol, orciprenaline) on functional properties of accessory A-V pathways. Acta Cardiol (Brux) Suppl 18:279-288, 1974 Fasola AF, Noble RJ, Zipes DP: Treatment of recurrent ventricular tachycardia and fibrillation with aprindine. Am J Cardiol 39: 903-909, 1977 Elharrar V, Foster PR, Zipes DP: Effects of aprindine HCI on cardiac tissues. J Pharmacol Exp Ther 195201-205, 1975 Krayer 0, Mandoki JJ, Mendez C: Studies on veratrum alkaloids. XVI. The action of epinephrine and of veratramine on the functional refractory period of the auriculoventricular transmission in the heart-lung preparation of the dog. J Pharmacol Exp Ther 103: 412-419,195l Durrer D, Schoo L, Schuilenburg RM, et al: The role of premature beats in the initiation and the termination of supraventricular tachycardia in the Wolff-Parkinson-White syndrome. Circulation 36:644-662, 1967 Zipes DP, Noble RJ, Carmichael RH, et al: Relations between aprindine concentration, heart rate and ventricular fibrillation in dogs (abstr). Am J Cardiol 35: 179, 1975 Wellens HJJ, Schuilenburg RM, Durrer D: Electrical stimulation of the heart in patients with the Wolff-Parkinson-White syndrome, type A. Circulation 43:99-l 14, 1971 Zipes DP, DeJoseph RL, Rothbaum DA: Unusual properties of accessory pathways. Circulation 44: 1200-l 2 11, 1974 Flensted-Jensen E: Natural history of the Wolff-Parkinson-White
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17.
18.
19.
20.
21.
22.
23.
24.
25.
syndrome. In, Symposium on Cardiac Arrhythmias (Sandoe E, Flensted-Jensen E, Olsen KH, ed.) Sodertalje, Sweden, Astra AB, 1972, p 351-365 Gallagher JJ, Gilbert M, Svenson RH, et al: Wolff-Parkinson-White syndrome. The problem, evaluation and surgical correction. Circulation 51:767-785, 1975 Gallagher JJ, Sealy WC, Kasell J, et al: Multiple accessory pathways in patients with the pm-excitation syndrome. Circulation 54571-591, 1976 Rosenbaum MB, Chiale PA, Ryba D, et al: Control of tachyarrhythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 34:215-223, 1974 Wellens HJJ, Lie KI, Bar FW, et al: Effect of amiodarone in the Wolff-Parkinson-White syndrome. Am J Cardiol 38:189-194, 1976 Disertori M, Molinis G, Vergara 6, et al: Effetti del’ amiodarone sulla conduzione atrio-ventricolare e ventricolo-atriale nella sindrome di Wolff-Parkinson-White. G ltal Cardiol 6:792-802, 1976 Rosenbaum MB, Chiale PA, Halpern MS, et al: Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 38: 934-944, 1976 Wellens HJJ, Durrer D: Effect of procaicamide, quinidine and ajmaline in the Wolff-Parkinson-White syndrome. Circulation 50:114-120, 1974 Wellens HJJ, Durrer D: Effect of digitalis on atrioventricular conduction and circus movement tachycardias in patients with Wolff-Parkinson-White syndrome. Circulation 47:1229-1233, 1973 van Leeuwen R, Meyboom RHB: Agranulocytosis and aprindine
(abstr). Lancet 2:1137, 1976
Volume 40
DOUGLAS WINSTON PETER R. KENNETH
DELON WU, MD FERNANDO AMAT-Y-LEON, R. JOE
Ten patients with recurrent or continuous supraventricular tachycardia difficult to control with conventional antiarrhythmic agents were treated with aprindine, a new antiarrhythmic drug. Nine patients had Wolff-Parkinson-white syndrome. An electrophysiologic study was performed before and during oral administration of aprindine. At the time of the first study, circus movement supraventricular tachycardia was initiated in Patients 1 to 8. During administration of aprindine, circus movement supraventricular tachycardia could no longer be initiated in Patients 1 to 4 but was initiated with difficulty in Patients 5 and 8 and with greater ease in Patients 7 and 8. In Patient 9, aprindine therapy slowed the ventricular response during atrial flutter from 1:l conduction over the accessory pathway to 2:l conduction over the normal pathway; in Patient 10, it slowed the ventricular rate during atrial fibrillation from 140-180 to 8’0-100 beats/min. Patients 1 to 8, 9 and 10 had an excellent clinical response, but treatment with aprindine was discontinued in Patients 7 and 8. Electrophysiologic evaluation revealed that aprindine produced complete block or increased refractoriness of the accessory pathway in an antegrade direction in all patients and in a retrograde direction in all but two (Patients 7 and 8) tested. Aprindine also slowed conduction in the accessory pathway and, when supraventricular tachycardia could still be initiated, it occurred at a slower rate. Neurologic side effects occurred primarily during the initial administration and dose adjustment of aprindine.
P. ZIPES, MD, FACC E. GAUM, MD, FACC FOSTER, MD M. ROSEN, MD, FACC
NOBLE,
MD,
MD
FACC
Indianapolis, Indiana Chicago, Illinois
From the Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, and the Veterans Administration Hospital, Indianapolis, Indiana; and The Abraham Lincoln School of Medicine, University of Illinois, Chicago, Illinois. This study was supported in part by the Herman C. Krannert Fund, Indianapolis, Indiana; Grants HL-06308, HL-05363, HL-07182 and HL-18795 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; American Heart Association, Indiana Affiliate, Inc. Indianapolis, Indiana; and Eli Lilly and Company, Indianapolis, Indiana. Manuscript received February 28, 1977, accepted April 27, 1977. Address for reprints: Douglas P. Zipes, MD, Indiana University School of Medicine, 1100 West Michigan Street, Indianapolis, Indiana 46202.
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1977
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Journal
Aprindine, a new antiarrhythmic agent with local anesthetic properties, has been used in man to suppress both atria1 and ventricular arrhythmias.l-g Initial animallo and clinical studies2,3,7,8 have suggested that aprindine might also be effective in treating patients with supraventricular tachycardias, particularly those whose arrhythmia is associated with the Wolff-Parkinson-White syndrome. In this report, we present the results obtained when aprindine was administered to nine patients who had hard-to-control supraventricular tachycardias associated with the Wolff-Parkinson-White syndrome and to one patient who had a drug-resistant supraventricular tachycardia unrelated to the WolffParkinson-White syndrome. Methods Patient Selection Patients were referred for treatment with aprindine because of supraventricular tachycardia that was difficult to control with conventional drugs given singly or in combinations. The arrhythmia was present continuously in some patients but in others occurred at intervals ranging from several days to 1 month. All patients had had symptoms related to the tachycardia for at least 4 months. One patient (Table I) had had the tachycardia intermittently for 25 years. Eight patients (Cases 1 to 7 and 9) were studied and treated at the Indiana University School of Medicine and two (Cases 8 and 10) at the Abraham Lincoln School of Medicine.
of CARDIOLOGY
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40
APRINDINE FOR SUPRAVENTRICULAR
All patients were aware that aprindine was approved for experimental use only and gave their written informed consent to a trial of therapy with aprindine and for invasive electrophysiologic investigations performed both before and during drug administration.
Both electrophysiologic studies were completed in all but Patients 8 and 10. Patient 8 underwent only one study because aprindine, given intravenously at the time of the study, facilitated induction of supraventricular tachycardia and was
I
TABLE Patient
“0.
ET AL.
therefore discontinued. Patient 10 did not have an invasive electrophysiologic study because of the presence of chronic atria1 fibrillation. Type A Wolff-Parkinson-White syndrome in this patient was established with scalar tracings recorded during normal sinus rhythm and during atria1 fibrillation. Procedure: At the time of the electrophysiologic study, three or four tripolar or quadripolar electrode catheters were used. Generally, two catheters were introduced into each femoral vein; occasionally, a single catheter was inserted into the left antecubital &in. Electrodes were separated by 10 mm. The catheters were positioned in the high right atrium, in the
Electrophysiologic StuUy
Case
TACHYCARDIA-ZIPES
Profile
Age (Yr) 82 Sex
Heart Disease
Type of WPW
Type of SVT
Frequency of SVT
Signs or Symptoms Related to SVT
1
46F
None
None
A-V nodal reentry
Weekly 4 vr
2
33M
None
A
Ante NP, retro AP
Continuous for 2 yr
Mild shortness of breath, fatigue cardiomegaly, mitral insufficiencv
3
58M
None
A’
Ante NP, retro AP
Twice weekly over past 6mo
Shortness of breath, fatigue
4
28M
None
A
2 types: (1) Ante NP, retro AP; (2) atrial fibrillation
Weekly for 6 mo
Shortness of breath, fatigue
for
Shortness of breath, fatigue
Presyncope
5
47M
None
A”
Ante NP, retro AP
Almost continuous for 6mo
Shortness of breath, dizzv
6
40M
None
8
2 types: (I) Ante NP, retro AP; (2) atrial fibrillation Ante NP, retro AP
Weekly for 25 yr
None
7
40M
None
A
8
50M
CAD
A
Ante NP, retro AP
Every 2-3 wk for 4 vr Monthly for past 1 yr
9
59M
Cardiomyopathy
A
Atrial flutter, 1: 1 conduction over AP
Every 2-3 days for 1 vr
10
38M
Cardiomyopathy
A
Atrial fibrillation
Continuous for 4 mo despite repeated cardioversions
Shortness of breath, presyncope Shortness of breath, fatigue Angina
Syncope, shortness of breath, fatigue, seizure; cardiomegalv Shortness of breath, fatigue, edema, cardiomegaly
Unsuccessful
Drug Trials
Digoxin, 0.25 mg daily; quinidine, 200 mg every 6 hours; procainamide. 500 mg every 4 hours; propranolol, 80 mg every 6 hours; diphenylhydantoin, 100 mg every 6 hours Digoxin, 0.25 mg daily; quinidine, 400 mg every 6 hours; procainamide, 500 mg every 6 hours; propranolol, 50 mg every 6 hours; disopyramide, 150 mg every 4 hours Digitoxin, 0.1 mg daily. quinidine, 300 mg every 8 hours; propranolol, 40 mg every 6 hours Digoxin, 0.25 mg every 12 hours; quinidine, 200 mg every 6 hours; procainamide, 500 mg every 6 hours; propranolol, 40 mg every 6 hours Digoxin, 0.25 mg daily; quinidine, 400 mg every 6 hours; propranolol. 40 mg every 6 hours Digoxin, 0.25 mg daily; quinidine, 300 mg every 8 hours
Digoxin, 0.25 mg daily; quinidine, 200 mg every 6 hours Digoxin, 0.25 mg daily; quinidine, 200 mg every 6 hours Ouabain, 0.7 mg; procainamide, 350 mg in 20 min; propranolol, 7 mg; disopyramide, 280 mg in 1 hour* Digoxin, 0.25 mg daily: quinrdine, 200 mg every 6 hours; propranolol, 40 mg every 6 hours Digoxin, 0.125 mg daily; quinidine, 300 mg every 4 hours; procainamide, 1 g every 4 hours; propranolol, 20 mg every 6 hours
*Retrograde conduction only. t Drugs given intravenously on sequential days; paroxysmal supraventricular tachycardia initiated on each day. Ante = antegrade direction; AP = accessory pathway; A-V = atrioventricular; CAD = coronary artery disease; NP = normal pathway; retrograde direction; SVT = supraventricular tachycardia; WPW = Wolff-Parkinson-White conduction.
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Volume 40
Retro =
587
APRINDINE FOR SUPRAVENTRICULAR TACHYCARDIA-ZIPES
TABLE
ET AL.
II
Electrophysiologic
Variables
Before
and During
Aprindine
Therapy Effective
RA Case no.
LA
RV
(values in msec)
Refractory
Period
Accessory
Pathway
Ante
Normal
Retro
C
Apr
C
Apr
C
Apr
:
500 600
200 180
260 270
200 <220
220 250
240 *
260 270
None 220
None 81
None <400
None 540
3
700
*
370
300
260
250
BI
81
4
600
200
240
190
250
200
230
290
BI
>300, <400 <240
5
500
190
260
200
260
230
250
BI
BI
250
290
6
600
230
330
230
370
250
260
320
BI
<260
7
450
230
240
200
210
200
230
350
<260
8 9 10
600 700 . .
260 250
2;io
: ::
<200 170
.
190
.
290 <320 <240§
Apr
BI BI 55500
C
(A-V
Ante
BCL
C
Pathway
Node) Retro
C
Apr
220 <220
<290 <330
<250
81
300
<390
t
81
BI
210
<320
t
520
<220
<300
<250
3290
<320
<365
t
t
<230
<250
t
t
<270
*
t
t
t
<300
Apr
<305 240
C
l
Aor BI >540
1::
*Could not obtain because of recurrent supraventricular tachycardia. t Could not obtain because of conduction over accessory pathway. $ Varied. 8 Estimated from A-R cycle length during atrial fibrillation.
coronary sinus or in the left atrium through a patent foramen ovale, in the right ventricle and across the septal leaflet of the tricuspid valve to record His bundle activation. No patient was receiving any cardiac medication other than aprindine at the time of study. One patient (Case 3) had been taking propranolol just before the first study. Tracings were stored on a frequency modulation tape recorder (Hewlett-Packard) and were also recorded on a multichannel oscilloscopic recorder (Electronics for Medicine DR 8) at a paper speed of 100 mm/set, using filter settings of 40 and 500 hertz for the intracardiac electrograms and of 0.1 to 20 hertz for the surface electrocardiograms. Time lines of 1 second were used. The right atrium, the apex of the right ventricle and the left atrium directly or through the coronary sinus were each stimulated using a programmable stimulator (Medtronic 5325, Bloom Associates or WP Instruments, Inc.), with rectangular stimuli of 1 to 2 msec duration at an intensity equal to twice the diastolic excitability threshold. The stimulator could be programmed to deliver one or more premature stimuli after pacing or sensing a driven or spontaneous basic train of complexes. Stimuli and the local electrogmm recorded at the site of stimulation (using the Medtronic 5235) were displayed on a separate channel. Initiation of tachycardia: Refractory periods were determined during one or more pacing cycles using the single extrastimulus techniques,li which was generally sufficient to initiate supraventricular tachycardia.12 For simplicity, only data derived at one cycle length are presented (Table II). Multiple premature stimuli and rapid pacing at different cycle lengths were used in an attempt to initiate supraventricular tachycardia when single stimuli failed to do so. In addition, maximal 1:1 conduction was established when possible while stimulating the atrium and ventricle at progressively shorter cycle lengths. The mode of initiating the supraventricular
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The American Journal of CARDIOLOGY
tachycardia and the duration of echo zones were carefully documented. Echo zones were defined as the zone of Ai-Az, Al-As-As or Vi-V2 intervals that initiated supraventricular tachycardia (Table II). In attempting to initiate supraventricular tachycardia during administration of aprindine, premature stimuli were also applied outside those echo zones and at different cycle lengths. Rapid atria1 pacing was used to induce atria1 fibrillation in Patients 4 and 6 and atria1 flutter in Patient 9 because these arrhythmias also occurred spontaneously in these patients. Aprindine Administration Aprindine was administered orally in capsule form, sometimes after a loading dose given intravenously, to all except Patient 8, who received only the intravenous loading dose. The oral dose of aprindine was 200 mg initially, followed by 100 mg 1 hour later and an additional 100 mg 6 hours later. The next day, the patient received 150 mg every 12 hours and on the 3rd day, 100 mg every 12 hours. Thereafter, the dose was individualized according to each patient’s response.*
Since completion of this study, the dosing schedule for oral and intravenously administered aprindine has been changed although the total amount given remains the same. At present, the oral schedule is 100 mg every 6 hours on the 1st day, 75 mg every 6 hours on the 2nd day and 50 mg every 6 hours on the 3rd day. Intravenously, 200 mg of aprindine is administered at a constant infusion rate of 2 mg/min. Thirty minutes after the first 200 mg is given, 100 mg is administered at a rate of 2 mg/min. Six hours after the first injection of aprindine is begun, the final 100 mg is infused at a rate of 2 mg/min. l
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TACHYCARDIA-ZIPES
ET AL.
TABLE II (Cont’d)
Minimal
I:1 CL
Ante
C
Retro
250 (NP) <275 (AP) <380
(NP)
220 (NP), 330 (AP) 250 (NP) <330 (AP), <340 (NP) 230 (NP), <230 (AP) 300 (API <240 (AP) <240 (AP) 5
Ante length; Retro mature
C
Apr
Mode of SVT C
Apr
<500 <275
(NP) CAP)
610 (NP) <700 (API Complete
400
(NP)
<380
(AP)
330
(NP)
<255
(AP)
550
300 (NP)
<270
(AP)
360-510
retro bl
(NP) (AP)s
RA S, 320-400. S, 230-270 Spontaneous PACs, PJCs, LA S,: 220 RA or LA S,: 330-500
None None
1.3 1.54
None
2.4
RA S, 240-290, LA S, 220-280 RA or LA S,: 220-260
None
0.88
(NP)
<340
CAP)
<390
(AP)
RA S, 330-400,
250 330 300 >270 550
(NP), (AP) (NP) (NP) (NP) 3
<360
(AP)
<440
(AP)
LA S, 200; RA S, 250-300, S, 250-260; RV S, 200 RA S, 270-290 Rapid RA pacing
285 (API
..
Aw
-
<390
270 (API
S, 300-340
LA S,: 270-280, RV pacing, <500 Rapid RA pacing
Definitions The following definitions are used in this study: Effective refractory period of the atrium: the longest S1-Ss in-
terval, delivered to the right or left atrium, at which Ss failed to elicit an atria1 depolarization.
Effective
refractory
1.60 msec 1.63
RA S, 240-300, RV S, 250 RA S,*-370 Rapid RA pacing
= antegrade direction; AP = accessory pathway; Apr = aprindine; BCL = basic cycle length; BI = complete LA = left atrium; NP = normal pathway; PACs = premature atrial complexes; PJCs = premature junctional = retrograde; RV = right ventricle; S, = a sing!e premature stimulus induced paroxysmal supraventricular stimuli needed to induce paroxysmal supraventricular tachycardia.
The loading dose given intravenously was 200 mg of aprindine administered in 25 mg aliquots at intervals of 2 to 5 minutes. Additional doses of 100 mg were given in the same fashion, 1 and 6 hours later. The following day, the patient received orally administered aprindine according to the schedule described previously. Patients underwent a repeat electrophysiologic study after 3 to 20 days of oral administration of aprindine. Venous blood samples for assay of aprindine concentration were drawn immediately before the electrophysiologic study. We chose to study the effects of orally administered aprindine because previous canine studies bad shown that the myocardium rapidly binds the drug after intravenous administration, initially producing very high myocardial concentrations and prominent electrophysiologic changes. During the 1st hour after completion of intravenous administration, the myocardial concentration greatly decreases and the prominent electrophysiologic changes diminish. These changes prevent creation of a steady state immediately after intravenous administration of aprindine.ls Follow-up: All but Patients 7 and 8 have been taking orally administered aprindine for 3 to 12 months. Patients have been seen by a physician weekly for the 1st month and then at monthly intervals; any recurrence of supraventricular tachycardia has been detected by noting the patient’s symptoms and obtaining a 12 lead electrocardiogram and 24 hour Holter recording at each visit.
Apr Serum Level At Time of StudY (fig/ml)
Initiation
0.48
6.84
block; C = control; CL = cycle complexes; RA = right atrium; tachycardia; S,, S; = two pre-
period of the ventricle:
Sl-Ss interval, delivered to the right ventricle, failed to elicit a ventricular depolarization.
the longest at which Ss
Antegrade effective refractory period of the accessory pathway: the longest Al-As interval, determined on the same
side as the accessory pathway, at which As failed to conduct to the ventricle over the accessory pathway. Retrograde effective refractory period of the accessory pathway: the longest VI-Vs interval, determined from the
right ventricle, at which Vs failed to conduct to the atrium over the accessory pathway. Antegrade effective refractory period of the atrioventricular (A-V) node: the longest Al-As interval, measured in the
His bundle electrogram, at which As failed to conduct through the A-V node to the bundle of His. Retrograde effective refractory period of the A-V node: the longest VI-H2 interval, determined from the right ventricle, at which Hs failed to conduct to the atrium through the A-V node.
All but one patient (Case 1) had the Wolff-Parkinson-white syndrome. Six patients had a left-sided accessory pathway (type A) that conducted in both directions,14 two had a left-sided accessory pathway that conducted only in a retrograde direction15 and one patient had a right-sided accessory pathway (type B) that conducted in both directions.12 Two patients had a cardiomyopathy associated with excessive ingestion of alcohol and one patient had coronary artery disease; the remaining seven-patients had no clinically detectable heart disease.
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tient 6, the atria1 echo zone for premature stimulation was eliminated, and rapid atria1 pacing was required to initiate paroxysmal supraventricular tachycardia. In both patients, brief periods of competitive atria1 or ventricular pacing promptly terminated the paroxysmal supraventricular tachycardia. The echo zone widened in Patients 7 and 8 during treatment with aprindine, thus facilitating induction of paroxysmal supraventricular tachycardia. In addition, paroxysmal supraventricular tachycardia was more difficult to terminate, requiring long periods of rapid competitive atria1 or ventricular pacing to restore sinus rhythm. In the four patients in whom paroxysmal supraventricular tachycardia could be initiated during treatment with aprindine (Patients 5 to 8), the cycle length of the tachycardia was longer than before treatment.
mg/d
“I
Response of Atrial Flutter and Atrial Fibrillation to Aprindine Clinically, Patient 9 had recurrent atria1 flutter with 1:l conduction to the ventricle over the accessory pathway, and Patient 10 had chronic atria1 fibrillation with ventricular rates of 140 to 180/min while receiving maximal doses of quinidine (300 mg every 4 hours; peak serum concentration 10.4 mg/liter) and procainamide (1 g every 4 hours; peak serum concentration 13.0 mg/liter). Patients 4 and 6 experienced, in addition to paroxysmal supraventricular tachycardia, atria1 fibrillation with very rapid ventricular rates due to conduction primarily over the accessory pathway. Administration of aprindine resulted in a marked decrease in the ventricular rate during atria1 fibrillation (Fig. 1) in Patients 6 and 10 and in 2:l conduction to the ventricle over the normal pathway in Patient 9, who had atria1 flutter. In addition, the cycle length of the atria1 flutter increased from 240 to 270 msec in this patient. Atria1 fibrillation could no longer be induced in Patient 4.
“6
FIGURE 1. Patient 10. Electrocardiograms before and during treatment with aprindine in a patient with type A Wolff-Parkinson-White syndrome. Left, control recording before administration of aprindine, revealing atrial fibrillation, rapid ventricular response at a rate of approximately 200 beats/min and type A preexcitation. Right, recording obtained while the patient was receiving aprindine, 200 mg/day orally. The ventricular rate is approximately 80 beatslmin and conduction occurs almost exclusively by way of the normal pathway.
Response of Paroxysmal Supraventricular Tachycardia to Aprindine
Clinical Response to Aprindine
Before administration of aprindine, paroxysmal supraventricular tachycardia was initiated in Patients 1 to 8 and echo zones were established (Table II). During treatment with aprindine, paroxysmal supraventricular tachycardia could no longer be initiated in Patients 1 to 4 by one or more premature atria1 or ventricular stimuli delivered during stimulation at multiple basic cycle lengths or during rapid atria1 or ventricular pacing. In Patients 5 to 8, paroxysmal supraventricular tachycardia could still be started in spite of administration of aprindine. However, the atria1 echo zone was narrowed in Patient 5 and paroxysmal supraventricular tachycardia could be initiated from the atrium only during premature left atria1 stimulation. Right ventricular pacing at cycle lengths of less than 500 msec also initiated paroxysmal supraventricular tachycardia in this patient after administration of aprindine. In Pa-
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Aprindine increased the incidence of paroxysmal supraventricular tachycardia in Patients 7 and 8 and was discontinued in these two patients. Patient 7, treated with digitoxin (0.1 mg daily), propranolol (40 mg every 6 hours) and quinidine (200 mg every 6 hours), continued to have self-terminating episodes of paroxysmal supraventricular tachycardia in the 8 month follow-up period. Patient 8 had partial interruption of the accessory pathway at operation and had only one recurrence of tachycardia in the 5 months since then. Correlation with electrophysiologic responses: The remaining eight patients had a beneficial clinical response to aprindine therapy over a follow-up period of 3 to 12 months (mean 5.9 months). Six patients still have episodes of supraventricular tachycardia but far less often than when they received conventional agents. In general, a beneficial clinical response correlated with the results obtained during the second electrophysiologic study. However, there was not complete correla-
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tion, after administration of aprindine, between the ability to induce supraventricular tachycardia with pacing and the spontaneous recurrence of supraventricular tachycardia. Paroxysmal supraventricular tachycardia could not be initiated in Patients 1 to 4 at the time of the second electrophysiologic study when the patients were receiving aprindine, yet each patient had one or two recurrences of paroxysmal supraventricular tachycardia, terminating spontaneously (Cases 2 and 4), with pharmacologic therapy (Case 3) or with direct current cardioversion (Case 1). Patient 2 had both recurrences during upper respiratory infections, and Patients 1 and 3 had recurrences at a time when their serum concentrations of aprindine were low because of reductions in oral dosage. When therapeutic concentrations of aprindine were restored in these two patients, they had no further recurrences of paroxysmal supraventricular tachycardia. Paroxysmal supraventricular tachycardia could be initiated in Patients 5 and 6 at the time of the second electrophysiologic study during administration of aprindine. Patient 6 had a 12 second episode of paroxysmal supraventricular tachycardia during a Holter recording, but spontaneous recurrence of paroxysmal supraventricular tachycardia in Patient 5 was not observed. In some patients the episodes of paroxysmal supraventricular tachycardia may be more frequent than is recognized either by the patient or by the examiners during monthly examinations and 24 hour Holter recordings; this possibility is likely because the ventricular rate during paroxysmal supraventricular tachycardia is much slower when the patient is receiving aprindine. Six patients are receiving (in two or three divided doses) 150 mg of aprindine daily, one patient 120 mg daily and one patient 200 mg daily. The mean serum aprindine concentration for Patients 1 to 6,9 and 10, based on the most recent sample, is 1.7 f 0.8 pg/ml (mean f standard error). Clinical features of the recurrent tachycardias modified by aprindine: Several clinical points should be emphasized to highlight the symptomatic nature of the supraventricular tachycardia and the response to aprindine therapy (Table I). Patient 1 required more than 90 electrical cardioversions to terminate paroxysmal supraventricular tachycardia in the several years before aprindine therapy and has had only one recurrence of paroxysmal supraventricular tachycardia in 10 months since the start of this therapy. Patient 2 had experienced continuous paroxysmal supraventricular tachycardia, at a rate of 200 to 220lmin for 2 years, in spite of receiving procainamide, quinidine, digitalis and propranolol simultaneously. He presented with cardiomegaly and a murmur of mitral insufficiency. Several hours after his first oral doses (300 mg) of aprindine, the tachycardia terminated and has recurred only transiently on two occasions in 12 months. His heart size has returned to normal and the murmur of mitral insufficiency has disappeared. Patient 9 had recurrent syncope with seizure activity during atria1 flutter with 1:l conduction to the ventricles. At the time of the second electrophysiologic study,
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atria1 flutter was initiated and allowed to persist for 10 days. During that entire 10 day interval, the patient was ambulatory and experienced only 2:l conduction over the normal pathway, except for a 15 minute period on the day after the electrophysiologic study when, possibly owing to a low serum concentration of aprindine, 1:l conduction transiently occurred over the accessory pathway. On the 10th day, direct current cardioversion was used to terminate the atria1 flutter, and the arrhythmia has not recurred since the start of aprindine therapy. Patient 10 had experienced refractory congestive heart failure due to uncontrolled ventricular rates during atria1 fibrillation. After he was treated with aprindine, the ventricular response during atria1 fibrillation slowed to rates of less than 100 beats/min and the patient then lost more than 13.5 kg of edema fluid in 2 weeks and had a striking decrease in heart size. After 2 months of aprindine therapy, long-standing atria1 fibrillation spontaneously reverted to normal sinus rhythm, which has remained. Finally, two patients (Cases 4 and 6) had recurrent paroxysmal supraventricular tachycardia that produced symptoms but, for unknown reasons, these patients had recently experienced atria1 fibrillation. The latter, because of the rapid ventricular rate, exacerbated their symptoms, produced presyncope and led to their referral. While receiving aprindine, Patient 4 had a transient recurrence of supraventricuiar tachycardia that was easily tolerated; Patient 6 has experienced no recurrence. Side Effects
During the initial 1 to 2 weeks of administration of aprindine, several patients had experienced transient side effects, including fine tremor of the hands (Cases 2 and 6), ataxia (Cases 9 and 10) and nausea (Case 5). Neither the patients nor the physicians considered these side effects sufficiently severe to warrant discontinuation of therapy, and they disappeared with a reduction in dosage. The most severe problem occurred in Patient 4. He had received 400 mg of aprindine on the 1st day of therapy, 300 mg on the 2nd day, 200 mg on the 3rd day and 225 mg on each of the next 4 days (75 mg every 8 hours). This dose was not reduced because he appeared to tolerate the drug well and had no neurologic side effects or electrocardiographic signs of toxicity. At the precise moment of catheter withdrawal upon completion of the second electrophysiologic study, he had a grand ma1 seizure from which he recovered uneventfully. Subsequent neurologic evaluation, electroencephalogram and brain scan were normal. Although the serum concentration of aprindine was within a therapeutic range (0.88 ctgiml) and higher concentrations (such as 1.26 pg/ml) produced no problems in this patient, aprindine cannot be excluded as the cause of the seizure. With a reduced dose of aprindine (50 mg every 8 hours), he has no further side effects, except for a transient elevation of hepatic enzymes in the serum. All patients except Patient 3 have no side effects at their present daily dosage of aprindine. Patient 3 has a slight fine tremor. Because reduction of this patients
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FIGURE 2. Patient 4. Control recording before treatment with aprindine. Determination of the antegrade effective refractory period of the accessory pathway and initiation of paroxysmal supraventricular tachycardia in a patient with type A Wolff-Parkinson-White syndrome. After the last driven impulse of the basic train, premature stimulation of the right atrium at a coupling interval of 300 msec resulted in antegrade conduction over the accessory pathway (left). Activation of the bundle of His occurred after the onset of the QRS complex. Premature right atrial stimulation at a coupling interval of 290 msec blocked in antegrade fashion in the accessory pathway, conducted to the ventricle with a right bundle branch block and initiated paroxysmal supraventricular tachycardia, during which activation of the left atrium preceded activation of the low and high right atrial sites (right). These findings are consistent with the presence of a left-sided bypass tract. From top to bottom: right atrial electrogram (RA); His bundle electrogram (HBE); left atrial electrogram (LA); scalar leads I, II, Ill and VI; and stimulus channel (St.). Paper speed is 100 mm/set; numbers indicate msec. A = atrial potential; e = electrogram recorded at the site of stimulation; H = His bundle potential; V = ventricular potential. Of the paced beats, only the last in the basic train and the premature stimulus are displayed
CONTROL
FIGURE 3. Patient 4. Complete antegrade and retrograde block in the accessory pathway during administration of aprindine. The top panels display the last driven beat of the basic train and the premature right atrial stimulus, delivered at coupling intervals of 500, 400 and 250 msec, respectively. Both the basic and premature beats are conducted to the ventricles over the normal pathway, with a right bundle branch block similar to the contour of the QRS complex initiated during supraventricular tachycardia seen in Figure 2. His bundle activation was slurred and delayed after premature stimulation at intervals of 500 and 400 msec; after premature stimulation at 250 msec, a clear His bundle spike could not be recorded. Supraventricular tachycardia could not be initiated at any coupling interval. The bottom panel shows the right ventricle being stimulated at a constant cycle length of 560 msec. Note that low right atrial activation preceded high right atrial activation, and that the latter preceded left atrial activation. This sequence of retrograde atrial activation is entirely different from the corresponding sequence that occurred during supraventricular tachycardia seen in Figure 2. Complete retrograde block in the accessory pathway is present. Note also that a retrograde Wenckebach block occurred in the normal pathway; the V-A interval progressively lengthened, culminating in V-A block after the third QRS complex. The third P wave is probably a sinusinitiated P wave. Conventions as in Figure 2.
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FIGURE 4. Patient 3. Control recording before treatment with aprindine. Initiation of paroxysmal supraventricular tachycardia in a patient with a “concealed” leftsided accessory pathway. Premature right atrial stimulation at an interval of 330 msec initiated supraventricular tachycardia (top). Note that during retrograde atrial activation, left atrial activation preceded high and low right atrial discharge. Atrial activation recorded in the distal coronary sinus (CSJ preceded that recorded in the proximal coronary sinus (CS,) (inset, top right). No evidence of antegrade conduction over an accessory pathway occurred at any cycle length during pacing of the right or the left atrium. Right ventricular pacing at a constant cycle length of 700 msec (bottom) initiated the same sequence of retrograde atrial activation as seen during the supraventricular tachycardia, thus confirming the presence of retrograde atrial activation over a “concealed” left lateral accessory pathway. Conventions as in Figure 2.
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dosage to less than 150 mglday resulted in two episodes of paroxysmal supraventricular tachycardia, he has continued to take 150 mglday, preferring the fine tremor to a recurrence of paroxysmal supraventricular tachycardia. No patient has had jaundice or hematologic abnormalities. Electrophysiologic Effects of Aprindine The ability of aprindine to totally prevent, hinder or facilitate induction of supraventricular tachycardia and the effect of the drug on the ventricular response during atria1 flutter and atria1 fibrillation may be explained by its electrophysiologic effects on refractoriness and conduction (Table II). Effective refractory period of atria and ventricles (Table II): Aprindine increased the effective refractory period of the atria (mean f standard error) from 211.4 f 25.4 to 265.7 f 30.5 msec (P
st-L,ii-
‘L
FIGURE 5. Patient 3. Complete retrograde block in both the normal and accessory pathways during treatment with aprindine (continuous recording). Right ventricular (RV) pacing at a cycle length of 700 msec revealed the presence of complete V-A retrograde block. The atria are under sinus control and are totally dissociated from ventricular activity. Although a high right atrial recording is not present, it is apparent that low right atrial activation preceded atrial activation recorded in the coronary sinus (CS). The atrial cycle length was relatively constant and, intermittently, the atria captured the ventricles to produce a normal QRS complex. Conventions as in Figure 2.
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FIGURE 6. Patient 8. Before treatment with aprindine (lop), the first premature right atrial stimulus delivered at a coupling interval of 250 msec is conducted over the accessory pathway. The second premature right atrial stimulus, also delivered at a coupling interval of 250 msec, blocked in antegrade fashion in the accessory pathway and initiated supraventricular tachycardia, which occurred with a left bundle branch block contour. During the tachycardia, left atrial activation preceded low right atrial activation, which occurred slightly in advance of high right atrial depolarization. With aprindine therapy (bottom), a single premature right atrial stimulus at a coupling interval of 250 msec initiated supraventricular tachycardia. Conventions as in Figure 2.
6. In Patients 7 and 8, whose retrograde effective refractory period did not lengthen, administration of aprindine facilitated induction of paroxysmal supraventricular tachycardia (Fig. 6). Minimal 1:l cycle length (Table II): The shortest cycle length at which the atria1 impulse conducted to the ventricles over the accessory pathway lengthened after administration of aprindine in all seven patients (Cases 2,4 and 6 to 10) who had exhibited antegrade conduction over an accessory pathway before drug administration. The shortest cycle length at which the ventricular impulse conducted to the atrium over the accessory pathway could be accurately assessed in four patients (Cases 3 to 5 and 8) and lengthened in each instance with administration of aprindine. In Patient 5, the ability for retrograde conduction over the accessory pathway varied during aprindine therapy. When conduction in the accessory pathway was relatively intact (the shortest ventricular cycle length conducting to the atrium over the accessory pathway was 360 msec), paroxysmal supraventricular tachycardia could be initiated. When the ability for conduction in the accessory pathway was diminished (the shortest. ventricular cycle length conducting to the atrium over the accessory pathway was 510 msec), paroxysmal supraventricular tachycardia could not be initiated. The shortest cycle length at, which the atria1 impulse conducted to the ventricles over the normal pathway could be accurately determined in five patients (Cases 1,3 to 5 and 7) and was lengthened in each instance by treatment with aprindine. These changes in refractoriness and conduction are consistent with the decreased ventricular response noted during atria1 flutter and atria1 fibrillation during administration of aprindine.
Conduction times before and after administration of aprindine: At the time of the second study, the the shortest R-R interval for Wolff-Parkinson-White syndrome beats, prolongation of the antegrade effective refractory period in the patient with atria1 fibrillation (Case 10). Among the patients whose retrograde effective refractory period of the accessory pathway could be determined before and during aprindine therapy, Patient 4 (Fig. 2 and 3) and Patient 3 (Fig. 4 and 5) had complete retrograde block in the accessory pathway, and Patients 2 and 5 had an increase in retrograde effective refractory period. Ventricular refractoriness limited determination of retrograde effective refractory period in three patients, but based on the shortest VI-V2 response, the retrograde effective refractory period probably did not change in two (Cases 7 and 8) and increased in one patient (Case 6). Thus, aprindine produced complete antegrade block or lengthened the antegrade effective refractory period of the accessory pathway in all patients and produced complete retrograde block or lengthened the retrograde effective refractory period of the accessory pathway in four of seven patients tested. The retrograde effective refractory period probably also lengthened in Patient
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following variables lengthened (determined at the same cycle length and during normal atrioventricular conduction for both studies): A-H interval (mean f standard error) from 63.3 f 9.3 to 89.2 f 16.3 msec (P
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accessory pathway. If aprindine delays antegrade conduction over the normal pathway and does not prolong, or prolongs minimally, retrograde refractoriness in the accessory pathway, it may widen the echo zone during which paroxysmal supraventricular tachycardia can be initiated and make it more difficult to terminate the tachycardia. This response occurred in Patients 7 and 8 and forced us to discontinue aprindine therapy in these two patients. A similar observation was made in patients treated with amiodarone.20 Our remaining patients with paroxysmal supraventricular tachycardia (Case 1 to 6) had a very beneficial response. Aprindine also suppresses premature atria1 and ventricular extrasystolesl-s and may prevent initiation of supraventricular tachycardia in this fashion (Patient 2). Significantly, some patients with Wolff-ParkinsonWhite syndrome intermittently may have atria1 fibrillation as well as paroxysmal supraventricular tachycardia. Although digitalis may be quite beneficial for treating paroxysmal supraventricular tachycardia, during which one of the pathways includes the normal A-V node, it may result in more rapid ventricular rates during atria1 fibrillation. 24 Indeed, one should question whether digitalis alone is ever warranted to treat paroxysmal supraventricular tachycardia in these patients because of the possibility that atria1 fibrillation may develop at some time. A drug like aprindine, which lengthens the refractory period and conduction time in the accessory pathway as well as in the A-V node, should be ideal to treat patients with Wolff-Parkinson-White syndrome who experience atria1 fibrillation or atria1 flutter. Side effects: These occurred during the period of initial administration and dose adjustment, except in Patient 3, who has a fine tremor of the hands. In previous studies with aprindine, neurologic side effects have been most prominent and were dose-related.g Recently, cholestatic jaundice and agranulocytosis were reported to occur in association with the use of aprindine.25 Jaundice and agranulocytosis did not occur in our group of patients. Because the therapeutic-toxic levels appear fairly close, further studies are necessary to establish the benefit-to-risk ratio of aprindine. Acknowledgment We express our appreciation to Paul Troup, MD, Mark Lambert, MD, Steven M. Peskoe, MD and Samuel L. Wann, MD for help during the electrophysiologic studies and to Rachael Glasser, MS and Ann deB Nicoll, RN for research assistance.
References 1. Kesteloot H, van Mieghem W, De Geest H: Aprindine (AC 1802) a new antiarrhythmic drug. Acta Cardiol 28:145-165, 1973 2. Kesteloot H: General aspects of antiarrhythmic treatment with aprindine. Acta Cardiol (Brux) Suppl 18:303-317. 1974 3. Fasola AF, Carmichael R: The pharmacology and clinical evaluation of aprindine, a new antiarrhythmic agent. Acta Cardiol (Brux) Suppl 18:317-335, 1974
4. van Durme JP, Rousseau M, Mbuyamba P: Treatment of chronic ventricular dysrhythmias with a new drug: aprindine (AC 1802). Acta Cardiol (Brux) Suppl 18:335-341, 1974 5. Breithardt G, Gleichmann U, Seipel L, et al: Long-term oral antiarrhythmic therapy with aprindine. Acta Cardiol (Brux) Suppl 18:341-353, 1974 6. Bollen G, Enderle J: Preliminary experience in the treatment of
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7.
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cardiac arrhythmias with aprindine. Acta Cardiol (Brux) Suppl 18:355-361, 1974 Palma-Gamiz JL, Boedo C, Lopez-Pujol FJ, et al: Etude clinique d’un nouvel anti-arythmique: aprindine. Acta Cardiol (Brux) Suppl 18:361-368, 1974 Neuss H, Schlepper M: Influence of various antiarrhythmic drugs (aprindine, ajmaline, verapamil, oxyprenolol, orciprenaline) on functional properties of accessory A-V pathways. Acta Cardiol (Brux) Suppl 18:279-288, 1974 Fasola AF, Noble RJ, Zipes DP: Treatment of recurrent ventricular tachycardia and fibrillation with aprindine. Am J Cardiol 39: 903-909, 1977 Elharrar V, Foster PR, Zipes DP: Effects of aprindine HCI on cardiac tissues. J Pharmacol Exp Ther 195201-205, 1975 Krayer 0, Mandoki JJ, Mendez C: Studies on veratrum alkaloids. XVI. The action of epinephrine and of veratramine on the functional refractory period of the auriculoventricular transmission in the heart-lung preparation of the dog. J Pharmacol Exp Ther 103: 412-419,195l Durrer D, Schoo L, Schuilenburg RM, et al: The role of premature beats in the initiation and the termination of supraventricular tachycardia in the Wolff-Parkinson-White syndrome. Circulation 36:644-662, 1967 Zipes DP, Noble RJ, Carmichael RH, et al: Relations between aprindine concentration, heart rate and ventricular fibrillation in dogs (abstr). Am J Cardiol 35: 179, 1975 Wellens HJJ, Schuilenburg RM, Durrer D: Electrical stimulation of the heart in patients with the Wolff-Parkinson-White syndrome, type A. Circulation 43:99-l 14, 1971 Zipes DP, DeJoseph RL, Rothbaum DA: Unusual properties of accessory pathways. Circulation 44: 1200-l 2 11, 1974 Flensted-Jensen E: Natural history of the Wolff-Parkinson-White
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17.
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syndrome. In, Symposium on Cardiac Arrhythmias (Sandoe E, Flensted-Jensen E, Olsen KH, ed.) Sodertalje, Sweden, Astra AB, 1972, p 351-365 Gallagher JJ, Gilbert M, Svenson RH, et al: Wolff-Parkinson-White syndrome. The problem, evaluation and surgical correction. Circulation 51:767-785, 1975 Gallagher JJ, Sealy WC, Kasell J, et al: Multiple accessory pathways in patients with the pm-excitation syndrome. Circulation 54571-591, 1976 Rosenbaum MB, Chiale PA, Ryba D, et al: Control of tachyarrhythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 34:215-223, 1974 Wellens HJJ, Lie KI, Bar FW, et al: Effect of amiodarone in the Wolff-Parkinson-White syndrome. Am J Cardiol 38:189-194, 1976 Disertori M, Molinis G, Vergara 6, et al: Effetti del’ amiodarone sulla conduzione atrio-ventricolare e ventricolo-atriale nella sindrome di Wolff-Parkinson-White. G ltal Cardiol 6:792-802, 1976 Rosenbaum MB, Chiale PA, Halpern MS, et al: Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 38: 934-944, 1976 Wellens HJJ, Durrer D: Effect of procaicamide, quinidine and ajmaline in the Wolff-Parkinson-White syndrome. Circulation 50:114-120, 1974 Wellens HJJ, Durrer D: Effect of digitalis on atrioventricular conduction and circus movement tachycardias in patients with Wolff-Parkinson-White syndrome. Circulation 47:1229-1233, 1973 van Leeuwen R, Meyboom RHB: Agranulocytosis and aprindine
(abstr). Lancet 2:1137, 1976
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