Intravenous 3-Methoxy-O-Desmethyl-Encainide in Reentrant Supraventricular Tachycardia: A Randomized Double-Blind Placebo-Controlled Trial in Patients Undergoing EP Study DAVID L. WARE, JOHN T. LEE, KATHERINE T. MURRAY, JAMES J. HANYOK,* DAN M. RODEN, and DEBRA S. ECHT From the departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, and *Bristol Myers Pharmaceutical Division, Wallingford, Connecticut

WARE, D.L., ET AL.: Intravenous 3-Methoxy-O-Desmethyl-Encainide in Reentrant Supraventricular Tachycardia: A Randomized Double-Blind Placebo-Controlled Trial in Patients Undergoing EP Study. Encainide is an agent effective in atrioventricular and atrioventricular nodal reentrant tachycardia. The metabolites O-desmethyJ encainide and 3-methoxy-O-desmethyl encainide {MODE} are responsible for the cJinicaJ effects of encainide in most patients. In this study, intravenous MODE was evaluated in eight patients with reentrant supraventricuJar tachycardia undergoing eJectrophysioJogicaJ testing. After tachycardia was induced at least twice to ensure reproducibility, MODE (30 |xg/kg/min x 15 min, then 7.5 jjLg/kg/minJ or placebo was administered in a douibJe-bJind fashion. If tachycardia remained inducible, the infusion was unbJinded; in nonresponding subjects who received placebo, MODE was then administered. Placebo was ineffective in 3/3 patients. MODE prevented tachycardia induction in 5/8 patients and increased the tachycardia cycle length from 302 ± 38 to 413 ± 67 msec in the other three. At a mean concentration of 774 ± 229 ng/ml, MODE prolonged PR, AH, HV, QRS, and QT intervals, right ventricular and accessory pathway effective refractory periods, and slowed or blocked antegrade accessory pathway conduction. Changes in intracardiac conduction were rate independent between cycle lengths 400 to 600 msec, while changes in ventricular effective refractory periods were most pronounced at rapid pacing rates. No adverse effects, hemodynamic changes, or conduction disturbances occurred. Thus, MODE can modify or suppress induction of reentrant atrioventricular or atrioventricular nodal tachycardia. The study design used here is well suited for the evaluation of newer antiarrhythmic agents by electrophysiological testing. [PACE, Vol. 14, September 1991] supraventricular tachycardia, encainide, 3-methoxy-O-desmethyl encainide, study design, electrophysiology

Introduction The encainide metabolites 3-methoxy-O-desmethyl encainide (MODE) and 0-desmethyl encainide (ODE] are active and mediate drug effects

Supported in part by grants from the U.S. Public Health Service (GM31304, HL36274) and from Bristol Myers Pharmaceutical Division, Wallingford, Connecticut. Address for reprints: Debra S. Echt, M.D., Division of Cardiology, CC-2218 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232-2170. Fax; (615) 343-3460. Received March 4,1991; revision May 21,1991; accepted June 11, 1991.

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in most patients receiving chronic oral encainide therapy.^"^ MODE elimination half-life is longer and less variable than that of ODE,"* and MODE, unlike ODE and encainide, prolongs ventricular refractoriness in dogs* and QT intervals in man,^-^° and does not raise energy requirements for defibrillation." MODE has been shown to suppress spontaneous new ectopic activity and to prevent or slow induced ventricular tachycardia in man.^'^° We report here an assessment of its antiarrhythmic efficacy in patients with reproducibly inducible reentrant supraventricular tachycardia.

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Few prior studies have used a double-blind, placebo controlled design to assess the effects of intravenous drug therapy during electrophysiological testing of patients with supraventricular tachycardia.^^~^^ In this study, a randomized, double-blind placebo controlled design was used to evaluate the electrophysiological effects of intravenous MODE and its ability to suppress supraventricular tachycardia (SVT] induction in patients undergoing electrophysiological testing. In addition, crossover of placebo patients to active drug was incorporated into the design, and pharmacokinetic techniques were used to ensure stable, predetermined (target] plasma drug concentrations during the phase of active drug testing.

Methods Overview Patients ages 18-75 years who were cared for by the Vanderbilt University Arrhythmia Service and who had documented or suspected sustained reentrant atrioventricular (AV] nodal or AV tachycardia were eligible to participate. Pregnant patients and patients with heart failure, unstable angina, a myocardial infarction within the preceding 3 months, uncontrolled hypertension, and renal, hepatic, or hemotologic diseases were excluded. Electrocardiographic criteria for exclusion were a QRS > 140 msec, PR > 240 msec, QT > 500 msec in the drug-free, nonpreexcited state, or evidence of sinus node dysfunction. All cardioactive medication was discontinued for at least five elimination half-lives. Patients were then taken to the Electrophysiology Laboratory in the fasting, unsedated state. Following acquisition of all baseline data as described below, each patient in whom tachycardia was reproducibly inducible was randomly assigned to either intravenous MODE or placebo in a double-blind fashion (Fig. 1]. All electrophysiological measurements and programmed stimulation were repeated. In those patients in whom arrhythmias remained inducible, the identity of the infusion was unblinded by a third party; patients with persistently inducible arrhythmias who had received placebo then received an infusion with active drug, and electrophysiological measurements and programmed stimulation were repeated. The protocol was approved by the Vanderbilt Committee

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BASELINE MEASUREMENTS AND EPS HANDOMIZED, BLINDED ADMINISTRATION OF MODE OR PLACEBO

REPEAT MEASUREMENTS AND EPS

NONINDUCIBLE PLACEBO NO FURTHER TESTING OPEN LABEL MODE NO FURTHER TESTING REPEAT MEASUREMENTS AND EPS

Figure 1. Scheme of study design. Patients with reproducibJy inducible supraventricular tachycardia were randomly administered intravenous MODE or piacebo in a doubJe-blind fashion. In patients with persistently inducibie arrhythmias after repeat programmed stimuiation, the identity of the infusion was unbiinded; inducibie patients who had received placebo then received active drug and electrophysioiogicaJ (EP] testing was repeated.

for the Protection of Human Subjects, and informed consent was obtained from each patient prior to entry to the Electrophysiology Laboratory. MODE (during either the blinded or unblinded phase] was administered as a 30 (xg/kg/ min loading infusion for 15 minutes followed by a maintenance infusion of 7.5 (xg/kg/min for the duration of the electrophysiological study. This dosage regimen was predicted to achieve and maintain plasma MODE concentrations of 828 to 847 ng/mL (for a 70 kg subject] in the maintenance study period.^^ Acquisition of repeat electrophysiological data was begun 15 minutes after the start of the maintenance infusion. Blood samples for determination of plasma MODE were collected in all patients during the double-blind infusion and in the patients receiving open-label drug. Samples were obtained immediately before drug administration and every 15 minutes following the start of the maintenance infusion. Plasma MODE was measured using a modified high pressure liquid chromatography method.^'' Electrophysiological Measurements Intracardiac electrograms filtered between 30 and 250 Hz were obtained from four 6 French

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quadripolar catheters placed under fluoroscopic guidance in the right atrium, coronary sinus, His bundle region, and right ventricular apex. Surface ECG leads I, II, III, aVL, Vi, and femoral artery pressure (obtained via an indwelling 5 French femoral artery catheter) were continuously monitored on an oscilloscope and recorded on tape and hard copy. One percent carbocaine was used for local anesthesia; intravenous midazolam (1-5 mg] was used for sedation. Baseline intervals (RR, PR, QRS, QT, AH, and HV) were obtained during sinus rhythm and during high right atrial pacing at a cycle length of 500 msec. Sinus node recovery times and corrected sinus node recovery times were determined by pacing the right atrium for 30 seconds at cycle lengths of 600, 500, 430, and 400 msec. The intervals between the last paced beat and first spontaneous electrogram in the right atrium were measured, and the longest of these intervals was designated the sinus node recovery time. The corrected sinus node recovery time was calculated by subtracting the baseline cycle length from the sinus node recovery time. Decremental atrial pacing starting at 400 msec and decreasing the cycle length by 10 msec every 5 seconds was performed to determine the AV nodal Wenckebach cycle length. Atrial and AV nodal refractoriness were assessed by inserting atrial extrastimuli 10 to 20 msec decrements after every eight to ten beats during sinus rhythm and following eight atrially paced drive beats at a cycle length of 500 msec; 2-second intertrain pauses were used. The atrial effective refractory period was defined as the longest sinus-A2 or A1-A2 interval, which failed to produce a propagated A2 depolarization. The AV nodal effective refractory period was defined as the longest sinus-A2 or A1-A2 interval failing to produce AV nodal transmission. Dual AV node pathways were identified by an increment of > 50 msec in H1-H2 with a 10-msec decrement in AjA2. Single ventricular extrastimuli were delivered from the right ventricular apex following eight ventricular drive beats at cycle lengths 600, 500, 430, and 400 msec for determination of right ventricular effective refractory period. In patients with accessory AV connections, the following measurements were performed in addition to those described above. Decremental

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atrial pacing was performed to determine the cycle length at which 1:1 AV transmission across the bypass tract failed. The antegrade refractory period of the accessory pathway was assessed with atrial premature stimuli during sinus rhythm and atrial pacing at a cycle length of 500 msec, and the retrograde refractory period of the accessory pathway was assessed using ventricular prematures following eight ventricular paced beats at a cycle length of 500 msec. If the above maneuvers had not already induced reciprocating tachycardia, two and/or three right atrial or coronary sinus extrastimuli were used. Standard criteria were used to define the mechanism of the tachycardia as AV nodal or AV reentry.^^ Only those patients in whom reproducible sustained (defined as > 15 seconds) reciprocating tachycardia was induced at baseline proceeded with the study. Statistics Electrophysiological measurements obtained during administration of placebo and MODE were compared to baseline measurements using the Student's paired t-test and Bonferroni's correction for multiple pairwise comparisons,^'^ with a corrected significance level of P ^ 0.05. All values are expressed as mean ± 1 SD.

Results Patient Characteristics Nine patients entered the study. All patients bad presented with recurrent episodes of palpitations and had documentation of SVT and/or ventricular preexcitation. One patient was excluded from drug infusion and analysis because of failure to demonstrate reproducibly inducible reentrant tachycardia during baseline electrophysiological testing. The clinical characteristics of the remaining eight patients are presented in Table I. The tachycardia mechanism was AV nodal reentrant tachycardia in one patient; the remainder had orthodromic AV reentry mediated via an accessory pathway (one nodoventricular and six AV]. Coexisting structural heart disease was present in only one patient with Ebstein's anomaly and an atrial septal defect.

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Table 1. Patient Characteristics

Patient #

Age

Gender

1 2 3 4 5 6 7 8

61 18 23

F M M M F IVI M M

19

52 34 26 35

Mechanism of Reentrant SVT AV Nodal Conceaied AP WPW Nodoventricular Concealed AP WPW* WPW WPW

* Patient had coexisting Ebstein's anomaly and atrial septal defect. AP = accessory pathway; AV = atrioventricular; WPW = Wolff-Parkinson-White syndrome; SVT = supraventricular tachycardia.

Programmed Electrical Stimulation Three patients received placebo, and repeated testing again resulted in reinduction of reentrant tachycardia and did not result in any change in the SVT cycle length or other electrophysiological parameters (Table II]. MODE administration prevented reentrant tachycardia induction in five of eight patients (62.5%). Of the five patients in whom tachycardia was noninducible during MODE, two were tested blindly and three were tested following open-label administration of MODE. The tachycardia cycle length increased in each of the three patients in whom tachycardia remained inducible despite (blinded) MODE administration (302 ± 38 to 413 ± 67 msec). No abnormality of sinus node function occurred following infusion of MODE. Table II details the changes in other electrophysiological parameters that occurred with infusion of MODE, and compares them to baseline. Statistical analysis of the changes in PR, ORS, QT, and HV intervals that occurred with MODE was performed only in those patients without ventricular preexcitation (n = 4). During sinus rhythm PR and QRS intervals increased significantly, and significant increases in AH, HV, and QT intervals were seen during atrial pacing. A trend towards increasing atrial and AV nodal effective refractory periods, and AV nodal Wenckebach cycle length occurred

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with MODE but not placebo. MODE significantly increased the QRS duration during ventricular pacing at cycle lengths 600, 500, and 400 msec; the percentage increase was independent of paced cycle length. Right ventricular effective refractory periods determined using the same ventricular pacing cycle lengths increased following MODE; a statistically significant increase compared to baseline was achieved at a cycle length of 400 msec. Changes in the electrophysiological characteristics of accessory pathways in six patients that could be evaluated before and after the infusion of MODE are summarized in Table III. With MODE, 1:1 antegrade and retrograde accessory pathway conduction blocked at longer paced cycle lengths, and antegrade and retrograde accessory pathway effective refractory periods were increased. Total block in formerly intact antegrade accessory pathway conduction (with loss of delta wave] occurred in one patient, and block of retrograde accessory pathway conduction occurred in two patients. Reentrant tachycardia remained inducible following MODE administration in three of the seven patients with accessory pathways. Ventriculoatrial (VA] conduction intervals measured from coronary sinus electrograms during tachycardia increased 35-105 msec with MODE administration, and the mean cycle lengths of these tachycardias increased 30-177 msec. In two of the patients still inducible with MODE, the tachycardia terminated in the accessory pathway, in one patient spontaneously and in the other patient with ventricular extrastimuli. In the third patient, the tachycardia terminated in the AV node following ventricular extrastimuli. In the single patient with AV nodal reentrant tachycardia, retrograde AV nodal conduction that had been present at baseline was abolished and tachycardia was not inducible following MODE administration. The shortest atrial pacing cycle length at which 1:1 AV nodal conduction could be maintained increased only slightly following MODE administration (350 to 370 msec], as did the AV nodal effective refractory periods of the fast and slow pathways (350 to 370 msec, 260 to 320 msec, respectively]. During the testing period, which followed the first MODE plasma concentration determination

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Tabie 11. Electrophysiological Changes Baseline versus MODE

Baseline versus Placebo

RR PR QRS QT QTc AH HV PR 500 QRS 500 QT500 AH 500 HV500 AERP AERP 500 AVNERP AVNERP 500 AVN WCL SVTCL RVERP RVERP 600 RVERP 500 RVERP 400 QRS 600 QRS 500 QRS 400

n

Baseline

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

794 120 100 403 448 67 45 123 107 343 113 27 235 255 320 317 310 353 262 237 220 217 133 127 132

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

67 26 17 33 38 6 5 46 46 42 17 36 35 5 16 31 36 50 8 21 10 21 23 21 16

Placebo 753 128 103 385 447 70 40 130 95 347 98 36 240 223 277 293 287 353 248 230 222 213 145 137 128

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

57 38 23 33 42 10 10 52 30 21 20 15 20 1 51 58 50 60 14 26 13 23 13 15 10

n

Baseline

8 4 4 4 4 7 4 4 4 4 6 4 6 7 7 8 4 3 7 4 6 7 6 7 6

734 140 89 375 424 73 45 150 81 318 111 46 239 235 306 283 298 302 260 235 218 210 140 140 138

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

90 8 3 33 33 14 4 0 6 15 11 5 25 21 25 34 39 28 31 17 8 16 17 18 14

MODE 718 ± 71 180 ± 8t 99 ± 6* 383 ± 40 461 ± 53 86 ± 8 58 ± 9 188 ± 22 93 ± 10 355 ± 25* 127 ± 13t 65 ± 6t 268 ± 50 257 ± 31 334 ± 46 320 ± 36 365 ± 53 413 ± 67 276 ± 27 253 ± 25 240 ± 25 237 ± 20* 169 ± 20t 171 ± 18t 166 ± 21t

*P < 0.05, t P < 0.01. All values are in msec (mean ± 1 SD). AERP = atrial effective refractory periocJ; AVNERP = AV nocJal effective refractory period; AVNWCL = AV nodal Wenckebach cycle length; QTc = corrected QT interval; RVERP = right ventricular effective refractory period; SVT CL = cycle length of supraventricular tachycardia; SVT = supraventricular tachycardia. Values for PR, QRS, QT, and HV intervals are for patients with pre-excitation at baseline only. The numbers 600, 500, 400 indicate the cycle lengths of constant rate pacing during the time of data collection. Table III. Effects of MQDE on Accessory Pathway Conduction

Patient 2 3 5 6 7 8

Antegrade APERP, CL 500 BL PL M Concealed 310 280 Concealed 280 — 270 — 290 —

370 330 320 B

Retrograde APERP, CL 500 BL PL M 260 310 320 CNM 280 CNM

260 CNM — — — —

380 B B CNM 320 CNM

1:1 Antegrade BL PL M Concealed 280 240 Concealed CNM — < 240 — 280 —

520 CNM 350 B

1; 1 Retrograde BL PL M CNM 320 370 CNM < 240 250

260 290 — — — —

330 B B CNM 320 > 370

All values in msec APERP, CL 500 = accessory pathway effective refractory period, following a paced drive train at 500 msec. B = block in accessory pathway, BL = baseline, CNM = could not measure, M = MQDE, PL = placebo. Patients 2 and 5 had no antegrade accessory pathway conduction at baseline (no delta wave). Patient 4 could not be evaluated for these parameters.

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• Obs«r«ad plasma MODE (±SD) '-- Pradicted plasma MODE

1500 •

Previous Studies

Plasma 1000 MODE (ng/ml) 500 0 30 MODE infusion 15 (fjg/kg/min)

0

15

30

45

60

75

90

105

Time (mini Figure 2. Observed MODE mean piasma concentrations ± standard deviation (SD) before and during the course of electrophysiological (EP) testing. Predicted plasma MODE concentrations'^ for these patients (mean weight 77 kg) are shown in the dashed line.

at 15 minutes, MODE levels remained stable throughout the course of the infusion (Fig. 2). The overall mean MODE plasma concentration was 774 ± 229 ng/mL and varied from 420 ± 12 to 961 ± 112 ng/mL in individual patients. No patient experienced adverse symptoms, hemodynamic changes, or conduction disturbances while receiving MODE. Discussion The protocol used in this study comprehensively evaluated the effects of intravenous MODE on the inducibility of SVT by (1] repeating the entire electrophysiological testing protocol in every patient following the first (double-blind) infusion of either placebo or active drug; (2) maintaining a predetermined pseudosteady-state plasma MODE level throughout the course of repeat electrophysiological testing on active drug; and (3) comparing all findings during placebo and active drug administration to those obtained at baseline. Administration of placebo resulted in no significant changes in electrocardiographic or electrophysiological intervals, tachycardia inducibility, or tachycardia cycle length. All patients were eventually retested on active MODE, which prevented the reinduction of tachycardia in five

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of eight patients, and slowed the cycle lengths of those tachycardias, which remained inducible.

Prior clinical trials in patients with reentrant SVT""^"* have used variations of a double-blind, placebo-controlled, randomized study design primarily to evaluate the effects of acute drug and/or placebo administration during ongoing tachycardia. The electrophysiological effects of MODE found in patients in this study during testing in sinus rhythm were similar to those we previously described in patients with ventricular arrhythmias.^•^° Potential Mechanisms The changes in electrocardiographic and electrophysiological parameters suggest that the conduction slowing and prolongation of refractoriness produced by MODE prevent the induction of supraventricular tachycardia. AV nodal, intraventricular, and retrograde and antegrade accessory pathway conduction was slowed or blocked. MODE had little effect on antegrade AV nodal conduction, but blocked the retrograde (fast] limb of the reentrant circuit in the patient with AV nodal reentrant tachycardia in a manner consistent with previous evidence that this limb is the more sensitive to sodium channel blocking agents.^^'^° Frequency-dependent increases in QRS duration during ventricular pacing were not present over a range of 400 to 600 msec, compatible with a long time constant for recovery from sodiuin channel block similar to encainide^^ or flecainide,^^ and to that observed in our prior study with MODE.^° Prolongation of refractoriness and action potential duration by MODE may suppress SVT induction, although in this study increases in QT intervals and right ventricular effective refractory periods occurred in patients in whom SV was suppressed and remained inducible. A frequency-dependent increase in refractoriness consistent with one prior study of MODE^° was suggested in this study by an increase in right ventricular effective refractory period which was significant only at the shortest cycle length tested (400 msec). Clinical Implications Oral encainide is effective in the treatment of patients with AV nodal""^"^ and AV reentrant

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ODE and MODE are two active metabolites largely responsible for encainide's antiarrhythmic effect.**'^"'^^-^^ Unlike encainide and ODE, however, MODE'S disposition kinetics are more uniform and predictable, because its metabolism is not dependent on the presence of a specific hepatic cytochrome P-450, virhich is functionally absent in 7% of patients.^'^° MODE'S electrophysiological properties also differ somewhat from encainide and ODE. It is less potent a sodium channel blocker, and has more pronounced effects on repolarization and refractoriness than either encainide or ODE.''"^" Canine studies^^ have indicated that agents that primarily block sodium channels increase, whereas agents that primarily prolong action potential duration decrease defibrillation energy requirements. The relative sodium channel blocking and action potential prolonging activities of these agents may explain their variable effects on defibrillation energy requirements: encainide and ODE increase the energy required for successful defibrillation, while MODE does not." Because MODE affects repolarization, a potential disadvantage might be torsade de pointes arrhythmia secondary to QT prolongation. However, extreme QT prolongation presumably caused by MODE has been reported in only one patient taking encainide in whom the QTU interval was 600 msec and associated with a MODE plasma concentration of only 237.4 ng/ mL.^^ No arrhythmia occurred, and the ECG returned to normal with discontinuation of encainide. Potential Limitations This study is limited primarily by the small numbers of patients entered, vi^hich has reduced the statistical power and the statistical significance of the changes observed during MODE administration. It was also not possible to obtain complete data (e.g., accessory pathway effective refractory periods) for every patient entered. Conclusions MODE was effective in suppressing the reinduction of SVT during electrophysiological testing. Changes in electrophysiological parameters following MODE administration indicate that its conduction slowing and/or action potential pro-

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longing activities were responsible for its antiarrhythmic effect. The effects of MODE on reentrant circuits (either AV or AV nodal] are similar to those of oral encainide; however, MODE has more predictable pharmacokinetics. Thus MODE shows promise as an agent for the treatment of reentrant SVT. The design of this study is well suited for the evaluation by electrophysiological testing of newer antiarrhythmic agents.

Acknowiedgments: The expert nursing assistance of Diane Crawford, Karen Horrell, and Patty Hofstetter, and the secretarial support of Julie Macpherson and Linda Hawkins are greatly appreciated.

References 1, Carey EL, Duff H], Roden DM, et al Encainide and its metabolites: Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals. J Clin Invest 1984; 73:539-547. 2, Elharrar V, Zipes DP, Effects of encainide and metabolites (MJ 14030 and MJ 9444) on canine cardiac Purkinje and ventricular fibers, J Pharmacol Exp Ther 1982; 220:440-447, 3, Dresel PE, Effect of encainide and its two major metabolites on cardiac conduction, J Pharmacol Exp Ther 1984; 228:180-186, 4, Davy ]M, Dorian P, Kantelip JP, et al. Qualitative and quantitative comparison of the cardiac effects of encainide and its three major metabolites in the dog, J Pharmacol Exp Ther 1986; 237:907-911, 5, Duff HJ, Dawson AK, Roden DM, et al. Electrophysiologic actions of 0-demethyl encainide: An active metabolite. Circulation 1983; 68:385-391, 6, Winkle RA, Peters F, Kates RE, et al. Possible contribution of encainide metabolites to the long term antiarrhythmic efficacy of encainide. Am) Cardioi 1983; 51:1182-1188, 7, Kerr MJ, Allen JD, Harron DWC, et al. The effects of encainide and its major metabolites, 0-demethyl encainide and 3-methoxy-O-demethyl encainide, on experimental cardiac arrhythmias in dogs, J Cardiovasc Pharmacol 1985; 7:449-457, 8, Comoll AW, Byrne JE, Mayol RF, Comparative antiarrhythmic actions of encainide and its major metabolites. Arch Int Pharmacodyn Ther 1986; 281:277-297, 9, Barbey JT, Thompson KA, Echt DS, et al, Antiarrhythmic activity, electrocardiographic effects and pharmacokinetics of the encainide metabolites Odesmethyl encainide and 3-methoxy-O-desmethyl encainide in man. Circulation 1988; 77:380-391, 10, Roden DM, Lee JT, Woosley RL, et al, Antiarrhythmic efficacy, clinical electrophysiology and pharmacokinetics of 3-methoxy-O-desmethyl encainide (MODE) in patients with inducible ven-

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11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22. 23.

1350

tricular tachycardia or fibrillation. Circulation 1989; 80:1247-1258. Fain ES, Dorian P, Davy JM, et al. Effects of encainide and its metabolites on energy requirements for defibrillation. Circulation 1986; 73:1334-1341. Hammill SC, McLaran CJ, Wood DL, et al. Doubleblind study of intravenous propafenone for paroxysmal supraventricular reentrant tachycardia. J Am Coll Cardiol 1987; 9:1364-68. Shen EN, Keung E, Huycke E, et al. Intravenous propafenone for termination of reentrant supraventricular tachycardia. Ann Int Med 1986; 105:655-661. Huycke EC, Sung RJ, Dias VC, et al. Intravenous diltiazem for termination of reentrant supraventricular tachycardia: A placebo controlled, randomized, double blind, multicenter study. J Am Coll Cardiol 1989; 13:538-544. Wang T, Siddoway LA, Thompson KA, et al. The development and testing of intravenous dosing regimens: Application to flecainide for the suppression of ventricular arrhythmias. Clin Pharmacol Ther 1988; 43:499-508. Mayol RF, Gammans RE, Labudde JA. Analysis of encainide and its metabolites in using a new high pressure liquid chromatographic method, (abstract) Clin Pharmacol Ther 1981; 29:265-266. Josephson ME, Seides SF. Supraventricular tachycardias. In ME Josephson, SF Seides (eds.): Clinical Cardiac Electrophysiology, Techniques and Interpretations. Philadelphia, PA, Lea and Febiger, 1979, pp. 147-190. Godfrey K. Comparing the means of several groups. In JC Bailer, F Mosteller, (eds): Medical Uses of Statistics. Waltham, MA, New England Journal of Medicine Books, 1986, pp. 218-222. Bauernfeind RA, Wyndham CR, Dhingra RC, et al. Serial electrophysiologic testing of multiple drugs in patients with atrioventricular nodal reentrant paroxysmal tachycardia. Circulation 1980; 62:1341-1349. Miles WM, Zipes DP, Rinkenberger RL, et al. Encainide for treatment of atrioventricular reciprocating tachycardia in the Wolff-Parkinson-White syndrome. Am J Cardiol 1988; 62:20L-25L. Campbell TJ. Resting and rate-dependent depression of maximum rate of depolarization (Vmax) in guinea pig ventricular action potentials i)y mexiletine, disopyramide, and encainide. J Cardiovasc Pharmacol 1983; 5:291-296. Page RL, Frame LH, Hoffman BF. Flecainide: Unusual use-dependent kinetics. J Am Coll Cardiol 1984; 3:616. Miles WM, Chang MS, Heger JJ, et al. Electrophy-

24.

25.

26.

27.

28.

29.

30.

31.

32. 33. 34. 35.

36.

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siologic and antiarrhythmic effects of oral encainide in patients with atrioventricular nodal reentry or nodoventricular reentry. Am Heart J 1987; 114:26-33. Naccarelli GV, Jackman WM, Akhtar M, et al. Efficacy and electrophysiologic effects of encainide for atrioventricular nodal reentrant tachycardia. Am J Cardiol 1988; 62:31L-36L. Chimienti M, Li BM, Moizi M, et al. Electrophysiologic and clinical effects of oral encainide in paroxysmal atrioventricular node reentrant tachycardia. J Am Coll Cardiol 1989; 14:992-998. Niazi I, Naccarelli G, Dougherty A, et al. Treatment of atrioventricular node reentrant tachycardia with encainide: Reversal of drug effect with isoproterenol. J Am Coll Cardiol 1989; 13:904-910. Chimienti M, Moizi M, Salerno JA, et al. Electrophysiologic and clinical effects of intravenous and oral encainide in patients with Wolff-ParkinsonWhite syndrome and paroxysmal atrial fibrillation. Eur Heart J 1987; 8:282-290. Abdollah H, Brugada P, Green M, et al. Clinical efficacy and electrophysiologic effects of intravenous and oral encainide in patients with accessory atrioventricular pathways and supraventricular arrhythmias. Am J Cardiol 1984; 54:544-549. Kunze KP, Kuck KH, Schluter M, et al. Electrophysiology and clinical effects of intravenous and oral encainide in accessory atrioventricular pathways. Am J Cardiol 1984; 54:323-329. Prystowsky EN, Klein GJ, Rinkenberger RL, et al. Clinical efficacy and electrophysiologic effects of encainide in patients with Wolff-Parkinson-White syndrome. Circulation 1984; 69:278-287. Markel ML, Prystowsky EN, Heger JJ, et al. Encainide for treatment of supraventricular tachycardias associated with the Wolff-ParkinsonWhite syndrome. Am J Cardiol 1986; 58:4lC-48C. Roden DM, Reele SB, Higgins SB, et al. Total suppression of ventricular arrhythmias by encainide. New Engl J Med 1980; 302:877-882. Kates RE, Harrison DC, Winkle RA. Metabolite cumulation during long term encainide administration. Clin Pharmacol Ther 1982; 31:427-432. Roden DM, Wood AJJ, Wilkinson GR, et al. Disposition kinetics of encainide and metabolites. Am J Cardiol 1986; 58:4C-9C. Echt DS, Black JN, Barbey JT, et al. Evaluation of antiarrhythmic drugs on defibrillation energy requirements in dogs, sodium channel block and active potential prolongation. Circulation 1989; 79:1106-1117. Davies W, Jazayeri M, Tchou P. Marked QT prolongation due to encainide therapy. Cardiovasc Drugs Ther 1988; 2:283-286.

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