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Electrophysiology of ethmozine® (moricizine HCl) for ventricular tachycardia
Electrophysiology of Ethmozine”(MoricizineHCI) for VentricularTachycardia CHRISTOPHER R. C. WYNDHAM, MD, CRAIG M. PRATT, MD, DAVID E. MANN, MD, ROGER A. WINKLE, MD, JOHN SOMBERG, MD, ANTHONY N. DE MARIA, MD, and MARK E. JOSEPHSON, MD
moricizine HCI therapy, sustained VT was induced in 31 patients and nonsustained VT in 7 patients. In individual patients, suppression of VT induction was obtained in 18 % of patients with sustained VT and in 27% of patients with nonsustained VT. Cycle length of induced VT was significantly prolonged by moricizine HCI therapy. During prospective follow-up of 37 patients, electrophysiologic study predicted recurrence or nonrecurrence of VT wtth a sensitivity value of 82% and specificity of 65 % . (Am J Cardiol 1987;60:67F-72F)
Moricizine HCI, an antiarrhythmic phenothiazine drug, was investigated for its efficacy against ventricular tachycardia (VT) in a group of 60 patients from 8 institutions using electrophysiologic testing before and after oral administration. Moricizine HCI significantly prolonged PR, QRS, AH and HV intervals and cycle length for atrioventricular nodal block, but had minimal or no effect on repolarization or cardiac refractory periods. Induction of sustained VT (in 33 patients) and nonsustained VT (in 14 patients j occurred at baseline. During
M
more than 5 half-lives, and repeat electrophysiologic study after at least 3 days of oral moricizine HCl administration were also required. Patients were excluded if they had myocardial infarction within the preceding month, unstable angina, serious systemic disorders, previous therapy with amiodarone or incomplete drug washout. Sixty adult patients fulfilled these criteria. These 60 patients were taken from a total of 83 American patients in whom electrophysiologic studies were performed during oral moricizine HCl administration from 1981 to 1985. Five patients were excluded due to absence of a baseline electrophysiologic study; 3 patients due to absence of a follow-up study; 10 patients because follow-up study was performed after <3 days of oral moricizine HCl therapy and 5 patients because of the possible confounding effects of other antiarrhythmic drugs. The 60 patients were treated by the 8 institutions listed in Table I. They were 51 men and 9 women, ranging in age from 27 to 78 years (mean 55). Cardiac diagnoses are listed in Table II. For purposes of this study, sustained VT was defined as VT lasting at least 30 seconds and requiring cardioversion or other intervention because of serious hemodynamic compromise. Nonsustained VT was defined as lasting >5 but <30 seconds. These criteria were used both for
oricizine HCl* is an effective agent in the management of ventricular premature beats and nonsustained ventricular tachycardia (VT)?3 Its efficacy against sustained VT has not been established.4-6 This study was undertaken to define the cardiac electrophysiologic effects of moricizine HCI on the human conduction system and the drug’s effects on the induction of VT in the cardiac electrophysiology laboratory, and to correlate these effects with outcome in patients treated with an oral moricizine HCl regimen. Criteria for selection of patients included recurrent, symptomatic VT, ventricular fibrillation or cardiac arrest and resistance of these arrhythmias to treatment with multiple antiarrhythmic drugs. Electrophysiologic study in the control state after drug withdrawal for From the Department of Medicine, Baylor College of Medicine, Houston, Texas. This study was supported by Biomedical Research Support Grant P16, General Clinical Research Center, National Institutes of Health, Bethesda, Maryland, and by a research grant from the E. I. Du Pont de Nemours Pharmaceutical Division, Wilmington, Delaware. Computational assistance was provided by the CLINFO project, grant RR-00350, Division of Research Resources, National Institutes of Health, Bethesda, Maryland. Address for reprints: Christopher R. C. Wyndham, MD, Section of Cardiology/FlOOl, The Methodist Hospital, 6535 Fannin, Houston, Texas 77030.
* Moricizine HCl is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozine@‘. 67F
68F
A SYMPOSIUM:
TABLE I
Contributing
ETHMOZINE@ (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
TABLE II
Institutions
AGENT
Cardiac Diagnoses Pts. (n)
Pts. (n) 34 6 6 2 6 4 1 1 60*
Baylor College of Medicine Albert Einstein College of Medicine Stanford University Western Pennsylvania Hospital University of Pennsylvania University of Kentucky Hahnemann Medical Center University of Arizona Total * Includes 60/63 patients with complete during moricizine HCI therapy.
electrophysiologic
data before and
the classification of spontaneous arrhythmia and of arrhythmia induced in the cardiac electrophysiologic laboratory. In the 60 patients, the spontaneous arrhythmia was ventricular fibrillation or sustained VT in 38 patients, and nonsustained VT in 22 patients. These 60 patients were studied under a variety of investigational protocols under the auspices of E. I. DuPont de Nemours & Co. Thirty-four patients were studied in 2 prospective trials at Baylor College of Medicine, using ambulatory electrocardiographic monitoring as the principal method of definition of efficacy. Slightly different dosing regimens were used in these 2 trials. Eighteen patients were studied with prospective trials using electrophysiologic studies as the principal estimate of endpoint of therapy, and 8 patients were studied during an early emergency use protocol. Oral administration of moricizine HCl was as follows. On day 1, a loading dose of 500 mg was given. This was followed 8 hours later by the first dose of a 3times-daily schedule. Total daily dosage was titrated within the range of 10 to 15 mg/kg daily to achieve the maximum tolerated dose. After baseline electrophysiologic study, electrophysiologic testing was repeated, after at least 3 days of drug therapy. In all patients, mean oral dosage was 900 f 210 (X!Z standard deviation) mg daily. Table III lists the electrophysiologic protocol. After discontinuation of other antiarrhythmic drugs, patients were studied in the nonsedated, postabsorptive state. Two to 3 multipolar electrode catheters were advanced percutaneously from the femoral, subclavian or antecubital veins. Cardiac conduction intervals and refractory periods were measured and programmed stimulation was performed at the right ventricular apex. This consisted of the delivery of single premature beats, or S2, during sinus rhythm and at cycle lengths of 600,500 or 400 ms. If VT was not induced, a second extrastimulus, or S3, was delivered after fixing the timing of S2 just outside ventricular refractoriness. This was conducted at cycle lengths of 600, 500 or 400 ms. If VT was still not induced, a third extrastimulus, or 54, was delivered in a similar manner. Burst ventricular stimulation was then performed at decreasing cycle lengths down to the cycle length at which loss of 1:l ventricular capture occurred. In some institutions a
lschemic heart disease Cardiomyopathy Valvular heart disease No heart disease Tumor Congenital heart disease Total
38 12 5 3 1 r 60
second right ventricular site was examined and a fourth extrastimulus, or S5, was delivered. The electrophysiologic effects of moricizine HCl are shown in Figures 1 through 4. Figure 1 shows the effects of moricizine HCl on sinus node function. Sinus cycle length significantly shortened from 792 to 735 ms after administration. There was no significant effect on maximum sinus node recovery time, which was 1,098 ms before and 1,060 ms after moricizine HCl administration. There was also no significant effect on corrected sinus recovery time, 291 ms before and 319 ms after administration, nor on calculated sinoatrial conduction time, 102 ms before and after moricizine HCl administration. Figure 2 shows the effects of moricizine HCl on cardiac conduction intervals. It significantly lengthened all of these intervals: PR interval, from 173 to 211 ms; QRS duration, from 110 to 130 ms; AH interval, from 86 to 103 ms; HV interval, from 56 to 71 ms. Figure 3 shows the effects on repolarization. No significant effect occurred in the QT interval, which measured 380 ms before and 389 ms after moricizine HCl administration. Slight but statistically significant lengthening occurred, however, in the QT interval, corrected according to the Bazett formula, from 427 to 452 ms. This increase reflected both the increase in heart rate and in QRS duration, as shown by an analysis of the corrected JT interval (JT,), i.e., the interval from the end of the QRS complex to the end of the T wave, corrected for heart rate. JT, interval showed no significant change: it was 301 ms before and 291 ms after moricizine HCl administration. Figure 4 shows the effects on cardiac refractory periods. The effective refractory period of the atrium did not change significantly (from 252 to 241 ms) after moricizine HCl administration. The cycle lengths at which atrioventricular nodal Wenckebach periods occurred as a measure of atrioventricular nodal refractoriness measured 394 ms before and 386 ms after administration (difference not significant). There was a slight but significant increase in effective refractory period of the right ventricular apex, from 241 to 253 ms, after moricizine HCl administration. To summarize the electrophysiologic effects: moricizine HCl, as has been shown by others, delays impulse conduction velocity in the atrioventricular node, His-Purkinje system and ventricular myocardium. It has little effect on cardiac refractoriness, with only a slight prolongation of right ventricular refractory peri-
October
16, 1987
od. In these respects it somewhat resembles many other agents in class IC.5 The results of programmed stimulation of the right ventricle before and after moricizine HCl therapy in this population with symptomatic VT or ventricular fibrillation are shown in Figure 5. In 38 patients with sustained VT and/or ventricular fibrillation and in 22 patients with nonsustained VT, programmed stimulation in the control state yielded sustained VT in 33 patients. Thirteen patients had nonsustained VT induced and 14 patients had no VT induced by programmed stimulation. Twenty-nine of the patients with induced, sustained VT came from the group of patients with spontaneous sustained VT and 4 from the group with nonsustained VT. Among the 13 patients with nonsustained VT induced in the laboratory, 8 had spontaneous sustained tachycardia and 5 had spontaneous nonsustained VT. The 14 patients in whom VT was noninducible included 13 from the group with spontaneous nonsustained VT and 1 with spontaneous sustained VT. Programmed stimulation using identical protocols after at least 3 days of oral moricizine HCl therapy showed that 31 patients had sustained VT induced. Seven patients had nonsustained VT induced, and in 22 patients tachycardia was noninducible. Of 31 patients with sustained VT during moricizine HCl therapy, 25 had sustained VT induced in the control state, 5 had nonsustained VT in the control state and 1 had no inducible tachycardia in the control state. Of 7 patients with nonsustained VT induced during moricizine HCl
TIIE AMERICAN
,IOLIRNAL
OF
CARDIOLOGY
Volume 60
64F
therapy, 2 had sustained VT induced previously, 3 had nonsustained VT induced previously and 2 had no tachycardia induced in the control state. Of 22 patients in whom VT was not induced during moricizine HCl therapy, 11 were from the group in which tachycardia
p
0
CONTROL
q
MORICIZINE
HC
200
E
p
150
100
50
u
0 I AH
HV
FIGURE 2. Effect of moricizine HCI on cardiac conduction intervals. All values in milliseconds (mean f standard deviation). PR = PR interval; QRS = QRS duration; AH = AH interval; HV = HV interval.
500
p=O.lOi n=56
p=o.o01 n=44
T
0
CONTROL
q
MORICIZINE
HCI
p=o.555 n=44
400
E
TABLE Ill
Electrophysiologic
Protocol
200
Discontinuation of antiarrhythmic drugs Conduction intervals, refractory periods RV Apex programmed stimulation S2 in sinus rhythm, CL 600, 500,400 ms S3 at CL 600,500,400 ms 54 at CL 600,500,400 ms Burst stimulation to loss of capture
100
s
QT
JTc
600
p=O.215 n=38
T1
QTC
FIGURE 3. Effect of moricirine HCI on repolarization. All values in milliseconds (mean f standard deviation). QT = QT interval; QTc = corrected QT interval (QT/dm); JT, = corrected JT interval.
CL = cycle length; RV = right ventricular.
1200
3000 i
p=O.756 n=39
500
q
MORICIZINE
T
HCI 400
T
0
CONTROL
q
MORICIZINE
HCI
E
p=o.191 n=40
200
100 : SINUS
CL
SRT,,X
CSRT
SACT
FIGURE 1. Effect of moricizine HCI on sinus node function. All values in milliseconds (mean f standard deviation). CL = cycle length; SRT,,. = maximum sinus recovery time; CSRT = corrected - sinus CL); SACT = calculated sinus recovery time (SRT,,, unidirectional sinoatrial conduction time.
3000 i ERP-ATRIUM
AVN-WENCK
ERP-RV
FIGURE 4. Effect of moricizine HCI on cardiac refractory periods. All values in milliseconds (mean f standard deviation). ERP = effective refractory period; AVN-WENCK = cycle length at which atrial pacing induced atrioventricular nodal Wenckebach periods; RV = right ventricular apex.
7OF
A SYMPOSIUM:
ETHMOZINP
STUDY POPULATION
(MORICIZINE
HCI)-A
VT INDUCED CONTROL
NEW ANTIARRHYTHMIC
VT INDUCED MORICIZINE HCI
FIGURE 5. Effect of moricizine HCI on induction of ventricular tachycardia by programmed stimulation in the electrophysiologic laboratory. Numbers refer to patients. VT = ventricular tachycardia; SUS = sustained; NS = nonsustained; NI = noninducible.
0 CONTROL
MORICIZINE
HCI
FIGURE 6. Effect of moricirine HCI on cycle length of induced ventricular tachycardia in 30 patients with inducible ventricular tachycardia before and after moricizine HCI therapy. Values in milliseconds (mean f standard deviation).
had not been induced in the control state, 5 from the group with nonsustained VT in the control state, and 6 from the group with inducible sustained VT. The efficacy of moricizine HCl in the management of induced VT is summarized as follows. Of 38 patients with sustained spontaneous tachycardia, 7 (18.5%) were classified as being better during oral moricizine HCl therapy because of the change from induced sustained to induced nonsustained tachycardia, or by abolition of induced tachycardia during moricizine HCl. All but 1 of these patients had a change from sustained inducible tachycardia to no inducible tachycardia. Four patients (10.5%) were classified as being worse after moricizine HCl therapy, either by having induction of tachycardia with moricizine HCl when no induction had been seen in the control state or by having a change from nonsustained to sustained tachycardia while taking moricizine HCl. In 27 patients (71%], no change in type or duration of tachycardia occurred as a result of moricizine HCl therapy. In the 22 patients with spontaneous nonsustained tachycardia, 6 (27.3%) were classified as better by the same criteria, 4 (18.2%) were deemed worse and 12 (54.5%) were considered to have had no change in inducible tachycardia after moricizine HCl therapy.
AGENT
Of the total group of 60 patients, 13 (22%) were considered better, 8 (13%) were considered worse and the condition of 39 (65%) was judged unchanged. In 30 patients, VT was induced both in the control state and during moricizine HCl therapy, and cycle lengths of VT were compared, as shown in Figure 6. There was a significant slowing of rate of VT, as reflected by an increase in cycle length from 265 ms in the control state to 308 ms during moricizine HCl therapy. Even when no change in inducibility of tachycardia occurs, it may be deduced that some benefit may accrue to patients from the slowing of rate during VT. Follow-up data from patients who received continuous oral moricizine HCl therapy are shown in Figures 7 and 8. Of the original group of 83 patients, 37 patients (including 34 with complete electrophysiologic data) studied at the Baylor College of Medicine had complete follow-up data. In this portion of the study, patients were given continuous moricizine HCI therapy regardless of the results of electrophysiologic testing during drug therapy. Data from an original group of 10 patients studied prospectively as previously reported6 are shown in Figure 7. Four patients were entered in the study due to sustained VT and 6 due to nonsustained VT. All 10 patients were restudied after oral moricizine HCl therapy. One patient refused further therapy with moricizine HCl after having experienced induction of sustained VT in the electrophysiologic laboratory. The other 9 patients received therapy for at least 4 days. Of these, 1 from the sustained tachycardia group experienced a recurrence of sustained VT on day 5, leaving a total of 8 patients who received moricizine HCl for more than 7 days. The 2 patients with sustained VT both experienced a recurrence during follow-up. One died suddenly and 1 had sustained VT. Of 6 patients with nonsustained VT treated for more than 7 days, 1 died suddenly (sudden cardiac death], 1 had recurrence of nonsustained VT and 4 elected to have the drug discontinued for subsequent protocol evaluations. During a total follow-up of 126 f 201 days, 4 patients from the nonsustained VT group remained free of VT until death or last follow-up. Similar follow-up data from the other 27 patients studied on prospective protocols at the Baylor College of Medicine are shown in Figure 8. Nine of the 27 patients had sustained VT and 18 had nonsustained tachycardia. Eight of the 9 (sustained VT] and 14 of the 18 (nonsustained VT] were restudied in the electrophysiologic laboratory after moricizine HCl therapy. Of the 9 patients with sustained VT, 3 experienced a recurrence before the end of 7 days of therapy, and drug therapy was withdrawn. Of the 18 patients with nonsustained VT, 1 died of an acute myocardial infarction on day 5,3 experienced a recurrence of nonsustained VT during the first week and 1 refused to continue therapy. The remaining 6 patients with sustained VT and 12 with nonsustained VT were treated for more than 7 days with oral moricizine HCl. Of the 6 patients with sustained VT, 1 died suddenly (sudden cardiac death) on day 26 and 1 had recurrence of sustained VT on day 90. Of the 12 patients with nonsustained tachycardia treated for more than 7 days, 1
October 16, 1987
succumbed to sudden cardiac death on day 305; 2 died of pulmonary embolism and congestive heart failure on days 26 and 351, respectively; 1 had recurrence of nonsustained VT on day 93; 5 elected to discontinue drug therapy, and 1 patient was noncompliant. Thus, during a follow-up of 276 f 298 days, 6 patients continued with moricizine HCI therapy with control of VT and 19 patients remained free of VT until death or last follow-up. Survival was related to left ventricular function. The 21 survivors had a mean left ventricular ejection
FIGURE 7. Follow-up of 10 patients treated with moricirine HCI on an earlier prospective protocol. SUS VT = sustained ventricular tachycardia; NONSUS VT = nonsustained ventricular tachycardia; SCD = sudden cardiac death; DC = discontinuation.
THE AMERICAN
JOURNAL
OF CARIIIOLOGY
TABLE IV Prediction of Outcome During Therapy Based on Results of Electrophysiologic Testing with Moricizine HCI Recurrence
VT inducible with moricizine
HCI
of VT/SCD Yes
No
9 2
7 13
Yes No
N=31. x* = 4.5; p <0.02. SCD = sudden cardiac death; VT = ventricular
tachycardia.
1 REFUSED
ORAL 1 SUS VT
MORICIZINE
1 SCD
HCI
/
*MORICIZINE
OVER 7 DAYS MORICIZINE HC
HCI
/
1 SUS VT
SCD I
VT FREE UNTIL DEATH OR LAST FOLLOW-UP
I
NON SUS VT 4 ELECTIVE
CURRENT MORICIZINE
HCI
CURRENT MORICIZINE
HCI
\
:: g 1:: El RE&%lED
14 ta! RESTUDIED
4!%, ORAL MORICIZINE
DC
NONSUS VT
SUS VT
FIGURE 8. Follow-up of 27 patients treated with moricizine HCI on later prospective protocols. NC = noncompliance; NSD = non-sudden death; other abbreviations as in Figure 7.
71F
Volume 60
1 NSD
KEEN> HCI
CURRENT I MORICIZINE HCI &
NSD NON SUS VT NC
I CURRENT &M~RICIG.IE HCI
VT FREE UNTIL DEATH OR LAST FOLLOW-UP
SCD NSD NON SUS VT ELECTIVE DC NC
72F
A SYMPOSIUM:
ETHMOZINE@ (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
fraction (LVEF] of 36% compared with an LVEF of 23% in those who died. This difference was statistically significant. The mean LVEF for the group as a whole was 33 f 1670, which underscores the degree of left ventricular dysfunction in this study population. Finally, an attempt was made to determine whether recurrence of arrhythmia was predictable from the results of electrophysiologic testing. Thirty-one of 37 patients are analyzed in Table IV. These 31 patients had electrophysiologic studies before and after moricizine HCl administration and were followed for the purpose of evaluation of continuous drug therapy. Of 11 patients with recurrence of VT or sudden cardiac death, 9 had VT inducible in the electrophysiologic laboratory during moricizine HCl therapy. On the other hand, of 20 patients with no recurrence of VT during continuous moricizine HCl therapy, 13 had no tachycardia inducible in the electrophysiologic laboratory during moricizine HCl therapy. This result is statistically significant. Thus, it is concluded that electrophysiologic study may be used to predict responsiveness of seriously ill patients to continuous moricizine HCl therapy, with a sensitivity value of 8270, and a specificity of 65%. In summary, electrophysiologic testing during moricizine HCl therapy demonstrates an approximate 20% decrease in inducibility of VT in patients with sustained VT or ventricular fibrillation, and an approximate 30% improvement in patients with nonsustained VT. Long-term follow-up of these patients has shown a close correlation between inducibility of VT in the electrophysiologic laboratory during moricizine HCl therapy and subsequent recurrence of tachycar-
AGENT
dia during follow-up. Overall efficacy of moricizine HCl in the management of patients with life-threatening tachycardia appears to be similar to the efficacy of other class I antiarrhythmic drugs, as predicted by electrophysiologic testing. Acknowledgment: The authors acknowledge the substantial contributions of Frank I. Marcus, MD, Sharon A. Magro, PA, Joel Morganroth, MD, and of investigators at the collaborating institutions [Table I]; the careful collation of data by Dr. Michael Borland of DuPont; the artwork by Joseph Martinez; and the manuscript preparation by Kalene Farley. The data in this study were previously reported in the American Heart Journal 1986;112:237.
References 1. Podrid PH, Lyakishev A, Lown B, Mazur N. Ethmozine, a new antiarrhythmic drug for suppressing ventricular premature complexes. Circulation 1980;61:450-457. 2. Pratt CM, Yepsen SC, Taylor AA, Mason DT, Miller RR, Quinones MA, Lewis RA. Ethmozine suppression of single and repetitive ventricular premature depolarizations during therapy: documentation of efficacy and long-term safety. Am Heart J 1983:106:85-91. 3. Pratt CM, Young JB, Francis MJ, Taylor AA, Norton J, English LL, Mann D, Koeplen H, Quinones MA, Roberts R. Comparative effect of disopyramide and ethmozine in suppressing complex ventricular arrhythmias by use of a double-blind, placebo-controlled, longitudinal crossover design. Circulation 1984;69:288-297. 4. Podrid PJ, Lown B. Ethmozine therapy for malignant ventricular arrhythmia (abstr). Am J CardioIl982;49:1015. 5. Kelliher GJ, Kowey P, Engel T, Wetstein L. Clinical pharmacology of antiarrhythmic agents. In: Dreifus LS, ed. Cardiac Arrhythmias: Electrophysiologic Techniques and Management. Philadelphia: F.A. Davis Co., 1985:287-305. 6. Mann DE, Luck JC, Herre JM, Magro SA, Yepsen SC, Griffin JC, Pratt CM, Wyndham CRC. Electrophysiologic effects of ethmozine in patients with ventricular tachycardia. Am Heart J 1984;107:674-679.
moricizine HCI therapy, sustained VT was induced in 31 patients and nonsustained VT in 7 patients. In individual patients, suppression of VT induction was obtained in 18 % of patients with sustained VT and in 27% of patients with nonsustained VT. Cycle length of induced VT was significantly prolonged by moricizine HCI therapy. During prospective follow-up of 37 patients, electrophysiologic study predicted recurrence or nonrecurrence of VT wtth a sensitivity value of 82% and specificity of 65 % . (Am J Cardiol 1987;60:67F-72F)
Moricizine HCI, an antiarrhythmic phenothiazine drug, was investigated for its efficacy against ventricular tachycardia (VT) in a group of 60 patients from 8 institutions using electrophysiologic testing before and after oral administration. Moricizine HCI significantly prolonged PR, QRS, AH and HV intervals and cycle length for atrioventricular nodal block, but had minimal or no effect on repolarization or cardiac refractory periods. Induction of sustained VT (in 33 patients) and nonsustained VT (in 14 patients j occurred at baseline. During
M
more than 5 half-lives, and repeat electrophysiologic study after at least 3 days of oral moricizine HCl administration were also required. Patients were excluded if they had myocardial infarction within the preceding month, unstable angina, serious systemic disorders, previous therapy with amiodarone or incomplete drug washout. Sixty adult patients fulfilled these criteria. These 60 patients were taken from a total of 83 American patients in whom electrophysiologic studies were performed during oral moricizine HCl administration from 1981 to 1985. Five patients were excluded due to absence of a baseline electrophysiologic study; 3 patients due to absence of a follow-up study; 10 patients because follow-up study was performed after <3 days of oral moricizine HCl therapy and 5 patients because of the possible confounding effects of other antiarrhythmic drugs. The 60 patients were treated by the 8 institutions listed in Table I. They were 51 men and 9 women, ranging in age from 27 to 78 years (mean 55). Cardiac diagnoses are listed in Table II. For purposes of this study, sustained VT was defined as VT lasting at least 30 seconds and requiring cardioversion or other intervention because of serious hemodynamic compromise. Nonsustained VT was defined as lasting >5 but <30 seconds. These criteria were used both for
oricizine HCl* is an effective agent in the management of ventricular premature beats and nonsustained ventricular tachycardia (VT)?3 Its efficacy against sustained VT has not been established.4-6 This study was undertaken to define the cardiac electrophysiologic effects of moricizine HCI on the human conduction system and the drug’s effects on the induction of VT in the cardiac electrophysiology laboratory, and to correlate these effects with outcome in patients treated with an oral moricizine HCl regimen. Criteria for selection of patients included recurrent, symptomatic VT, ventricular fibrillation or cardiac arrest and resistance of these arrhythmias to treatment with multiple antiarrhythmic drugs. Electrophysiologic study in the control state after drug withdrawal for From the Department of Medicine, Baylor College of Medicine, Houston, Texas. This study was supported by Biomedical Research Support Grant P16, General Clinical Research Center, National Institutes of Health, Bethesda, Maryland, and by a research grant from the E. I. Du Pont de Nemours Pharmaceutical Division, Wilmington, Delaware. Computational assistance was provided by the CLINFO project, grant RR-00350, Division of Research Resources, National Institutes of Health, Bethesda, Maryland. Address for reprints: Christopher R. C. Wyndham, MD, Section of Cardiology/FlOOl, The Methodist Hospital, 6535 Fannin, Houston, Texas 77030.
* Moricizine HCl is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozine@‘. 67F
68F
A SYMPOSIUM:
TABLE I
Contributing
ETHMOZINE@ (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
TABLE II
Institutions
AGENT
Cardiac Diagnoses Pts. (n)
Pts. (n) 34 6 6 2 6 4 1 1 60*
Baylor College of Medicine Albert Einstein College of Medicine Stanford University Western Pennsylvania Hospital University of Pennsylvania University of Kentucky Hahnemann Medical Center University of Arizona Total * Includes 60/63 patients with complete during moricizine HCI therapy.
electrophysiologic
data before and
the classification of spontaneous arrhythmia and of arrhythmia induced in the cardiac electrophysiologic laboratory. In the 60 patients, the spontaneous arrhythmia was ventricular fibrillation or sustained VT in 38 patients, and nonsustained VT in 22 patients. These 60 patients were studied under a variety of investigational protocols under the auspices of E. I. DuPont de Nemours & Co. Thirty-four patients were studied in 2 prospective trials at Baylor College of Medicine, using ambulatory electrocardiographic monitoring as the principal method of definition of efficacy. Slightly different dosing regimens were used in these 2 trials. Eighteen patients were studied with prospective trials using electrophysiologic studies as the principal estimate of endpoint of therapy, and 8 patients were studied during an early emergency use protocol. Oral administration of moricizine HCl was as follows. On day 1, a loading dose of 500 mg was given. This was followed 8 hours later by the first dose of a 3times-daily schedule. Total daily dosage was titrated within the range of 10 to 15 mg/kg daily to achieve the maximum tolerated dose. After baseline electrophysiologic study, electrophysiologic testing was repeated, after at least 3 days of drug therapy. In all patients, mean oral dosage was 900 f 210 (X!Z standard deviation) mg daily. Table III lists the electrophysiologic protocol. After discontinuation of other antiarrhythmic drugs, patients were studied in the nonsedated, postabsorptive state. Two to 3 multipolar electrode catheters were advanced percutaneously from the femoral, subclavian or antecubital veins. Cardiac conduction intervals and refractory periods were measured and programmed stimulation was performed at the right ventricular apex. This consisted of the delivery of single premature beats, or S2, during sinus rhythm and at cycle lengths of 600,500 or 400 ms. If VT was not induced, a second extrastimulus, or S3, was delivered after fixing the timing of S2 just outside ventricular refractoriness. This was conducted at cycle lengths of 600, 500 or 400 ms. If VT was still not induced, a third extrastimulus, or 54, was delivered in a similar manner. Burst ventricular stimulation was then performed at decreasing cycle lengths down to the cycle length at which loss of 1:l ventricular capture occurred. In some institutions a
lschemic heart disease Cardiomyopathy Valvular heart disease No heart disease Tumor Congenital heart disease Total
38 12 5 3 1 r 60
second right ventricular site was examined and a fourth extrastimulus, or S5, was delivered. The electrophysiologic effects of moricizine HCl are shown in Figures 1 through 4. Figure 1 shows the effects of moricizine HCl on sinus node function. Sinus cycle length significantly shortened from 792 to 735 ms after administration. There was no significant effect on maximum sinus node recovery time, which was 1,098 ms before and 1,060 ms after moricizine HCl administration. There was also no significant effect on corrected sinus recovery time, 291 ms before and 319 ms after administration, nor on calculated sinoatrial conduction time, 102 ms before and after moricizine HCl administration. Figure 2 shows the effects of moricizine HCl on cardiac conduction intervals. It significantly lengthened all of these intervals: PR interval, from 173 to 211 ms; QRS duration, from 110 to 130 ms; AH interval, from 86 to 103 ms; HV interval, from 56 to 71 ms. Figure 3 shows the effects on repolarization. No significant effect occurred in the QT interval, which measured 380 ms before and 389 ms after moricizine HCl administration. Slight but statistically significant lengthening occurred, however, in the QT interval, corrected according to the Bazett formula, from 427 to 452 ms. This increase reflected both the increase in heart rate and in QRS duration, as shown by an analysis of the corrected JT interval (JT,), i.e., the interval from the end of the QRS complex to the end of the T wave, corrected for heart rate. JT, interval showed no significant change: it was 301 ms before and 291 ms after moricizine HCl administration. Figure 4 shows the effects on cardiac refractory periods. The effective refractory period of the atrium did not change significantly (from 252 to 241 ms) after moricizine HCl administration. The cycle lengths at which atrioventricular nodal Wenckebach periods occurred as a measure of atrioventricular nodal refractoriness measured 394 ms before and 386 ms after administration (difference not significant). There was a slight but significant increase in effective refractory period of the right ventricular apex, from 241 to 253 ms, after moricizine HCl administration. To summarize the electrophysiologic effects: moricizine HCl, as has been shown by others, delays impulse conduction velocity in the atrioventricular node, His-Purkinje system and ventricular myocardium. It has little effect on cardiac refractoriness, with only a slight prolongation of right ventricular refractory peri-
October
16, 1987
od. In these respects it somewhat resembles many other agents in class IC.5 The results of programmed stimulation of the right ventricle before and after moricizine HCl therapy in this population with symptomatic VT or ventricular fibrillation are shown in Figure 5. In 38 patients with sustained VT and/or ventricular fibrillation and in 22 patients with nonsustained VT, programmed stimulation in the control state yielded sustained VT in 33 patients. Thirteen patients had nonsustained VT induced and 14 patients had no VT induced by programmed stimulation. Twenty-nine of the patients with induced, sustained VT came from the group of patients with spontaneous sustained VT and 4 from the group with nonsustained VT. Among the 13 patients with nonsustained VT induced in the laboratory, 8 had spontaneous sustained tachycardia and 5 had spontaneous nonsustained VT. The 14 patients in whom VT was noninducible included 13 from the group with spontaneous nonsustained VT and 1 with spontaneous sustained VT. Programmed stimulation using identical protocols after at least 3 days of oral moricizine HCl therapy showed that 31 patients had sustained VT induced. Seven patients had nonsustained VT induced, and in 22 patients tachycardia was noninducible. Of 31 patients with sustained VT during moricizine HCl therapy, 25 had sustained VT induced in the control state, 5 had nonsustained VT in the control state and 1 had no inducible tachycardia in the control state. Of 7 patients with nonsustained VT induced during moricizine HCl
TIIE AMERICAN
,IOLIRNAL
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CARDIOLOGY
Volume 60
64F
therapy, 2 had sustained VT induced previously, 3 had nonsustained VT induced previously and 2 had no tachycardia induced in the control state. Of 22 patients in whom VT was not induced during moricizine HCl therapy, 11 were from the group in which tachycardia
p
0
CONTROL
q
MORICIZINE
HC
200
E
p
150
100
50
u
0 I AH
HV
FIGURE 2. Effect of moricizine HCI on cardiac conduction intervals. All values in milliseconds (mean f standard deviation). PR = PR interval; QRS = QRS duration; AH = AH interval; HV = HV interval.
500
p=O.lOi n=56
p=o.o01 n=44
T
0
CONTROL
q
MORICIZINE
HCI
p=o.555 n=44
400
E
TABLE Ill
Electrophysiologic
Protocol
200
Discontinuation of antiarrhythmic drugs Conduction intervals, refractory periods RV Apex programmed stimulation S2 in sinus rhythm, CL 600, 500,400 ms S3 at CL 600,500,400 ms 54 at CL 600,500,400 ms Burst stimulation to loss of capture
100
s
QT
JTc
600
p=O.215 n=38
T1
QTC
FIGURE 3. Effect of moricirine HCI on repolarization. All values in milliseconds (mean f standard deviation). QT = QT interval; QTc = corrected QT interval (QT/dm); JT, = corrected JT interval.
CL = cycle length; RV = right ventricular.
1200
3000 i
p=O.756 n=39
500
q
MORICIZINE
T
HCI 400
T
0
CONTROL
q
MORICIZINE
HCI
E
p=o.191 n=40
200
100 : SINUS
CL
SRT,,X
CSRT
SACT
FIGURE 1. Effect of moricizine HCI on sinus node function. All values in milliseconds (mean f standard deviation). CL = cycle length; SRT,,. = maximum sinus recovery time; CSRT = corrected - sinus CL); SACT = calculated sinus recovery time (SRT,,, unidirectional sinoatrial conduction time.
3000 i ERP-ATRIUM
AVN-WENCK
ERP-RV
FIGURE 4. Effect of moricizine HCI on cardiac refractory periods. All values in milliseconds (mean f standard deviation). ERP = effective refractory period; AVN-WENCK = cycle length at which atrial pacing induced atrioventricular nodal Wenckebach periods; RV = right ventricular apex.
7OF
A SYMPOSIUM:
ETHMOZINP
STUDY POPULATION
(MORICIZINE
HCI)-A
VT INDUCED CONTROL
NEW ANTIARRHYTHMIC
VT INDUCED MORICIZINE HCI
FIGURE 5. Effect of moricizine HCI on induction of ventricular tachycardia by programmed stimulation in the electrophysiologic laboratory. Numbers refer to patients. VT = ventricular tachycardia; SUS = sustained; NS = nonsustained; NI = noninducible.
0 CONTROL
MORICIZINE
HCI
FIGURE 6. Effect of moricirine HCI on cycle length of induced ventricular tachycardia in 30 patients with inducible ventricular tachycardia before and after moricizine HCI therapy. Values in milliseconds (mean f standard deviation).
had not been induced in the control state, 5 from the group with nonsustained VT in the control state, and 6 from the group with inducible sustained VT. The efficacy of moricizine HCl in the management of induced VT is summarized as follows. Of 38 patients with sustained spontaneous tachycardia, 7 (18.5%) were classified as being better during oral moricizine HCl therapy because of the change from induced sustained to induced nonsustained tachycardia, or by abolition of induced tachycardia during moricizine HCl. All but 1 of these patients had a change from sustained inducible tachycardia to no inducible tachycardia. Four patients (10.5%) were classified as being worse after moricizine HCl therapy, either by having induction of tachycardia with moricizine HCl when no induction had been seen in the control state or by having a change from nonsustained to sustained tachycardia while taking moricizine HCl. In 27 patients (71%], no change in type or duration of tachycardia occurred as a result of moricizine HCl therapy. In the 22 patients with spontaneous nonsustained tachycardia, 6 (27.3%) were classified as better by the same criteria, 4 (18.2%) were deemed worse and 12 (54.5%) were considered to have had no change in inducible tachycardia after moricizine HCl therapy.
AGENT
Of the total group of 60 patients, 13 (22%) were considered better, 8 (13%) were considered worse and the condition of 39 (65%) was judged unchanged. In 30 patients, VT was induced both in the control state and during moricizine HCl therapy, and cycle lengths of VT were compared, as shown in Figure 6. There was a significant slowing of rate of VT, as reflected by an increase in cycle length from 265 ms in the control state to 308 ms during moricizine HCl therapy. Even when no change in inducibility of tachycardia occurs, it may be deduced that some benefit may accrue to patients from the slowing of rate during VT. Follow-up data from patients who received continuous oral moricizine HCl therapy are shown in Figures 7 and 8. Of the original group of 83 patients, 37 patients (including 34 with complete electrophysiologic data) studied at the Baylor College of Medicine had complete follow-up data. In this portion of the study, patients were given continuous moricizine HCI therapy regardless of the results of electrophysiologic testing during drug therapy. Data from an original group of 10 patients studied prospectively as previously reported6 are shown in Figure 7. Four patients were entered in the study due to sustained VT and 6 due to nonsustained VT. All 10 patients were restudied after oral moricizine HCl therapy. One patient refused further therapy with moricizine HCl after having experienced induction of sustained VT in the electrophysiologic laboratory. The other 9 patients received therapy for at least 4 days. Of these, 1 from the sustained tachycardia group experienced a recurrence of sustained VT on day 5, leaving a total of 8 patients who received moricizine HCl for more than 7 days. The 2 patients with sustained VT both experienced a recurrence during follow-up. One died suddenly and 1 had sustained VT. Of 6 patients with nonsustained VT treated for more than 7 days, 1 died suddenly (sudden cardiac death], 1 had recurrence of nonsustained VT and 4 elected to have the drug discontinued for subsequent protocol evaluations. During a total follow-up of 126 f 201 days, 4 patients from the nonsustained VT group remained free of VT until death or last follow-up. Similar follow-up data from the other 27 patients studied on prospective protocols at the Baylor College of Medicine are shown in Figure 8. Nine of the 27 patients had sustained VT and 18 had nonsustained tachycardia. Eight of the 9 (sustained VT] and 14 of the 18 (nonsustained VT] were restudied in the electrophysiologic laboratory after moricizine HCl therapy. Of the 9 patients with sustained VT, 3 experienced a recurrence before the end of 7 days of therapy, and drug therapy was withdrawn. Of the 18 patients with nonsustained VT, 1 died of an acute myocardial infarction on day 5,3 experienced a recurrence of nonsustained VT during the first week and 1 refused to continue therapy. The remaining 6 patients with sustained VT and 12 with nonsustained VT were treated for more than 7 days with oral moricizine HCl. Of the 6 patients with sustained VT, 1 died suddenly (sudden cardiac death) on day 26 and 1 had recurrence of sustained VT on day 90. Of the 12 patients with nonsustained tachycardia treated for more than 7 days, 1
October 16, 1987
succumbed to sudden cardiac death on day 305; 2 died of pulmonary embolism and congestive heart failure on days 26 and 351, respectively; 1 had recurrence of nonsustained VT on day 93; 5 elected to discontinue drug therapy, and 1 patient was noncompliant. Thus, during a follow-up of 276 f 298 days, 6 patients continued with moricizine HCI therapy with control of VT and 19 patients remained free of VT until death or last follow-up. Survival was related to left ventricular function. The 21 survivors had a mean left ventricular ejection
FIGURE 7. Follow-up of 10 patients treated with moricirine HCI on an earlier prospective protocol. SUS VT = sustained ventricular tachycardia; NONSUS VT = nonsustained ventricular tachycardia; SCD = sudden cardiac death; DC = discontinuation.
THE AMERICAN
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TABLE IV Prediction of Outcome During Therapy Based on Results of Electrophysiologic Testing with Moricizine HCI Recurrence
VT inducible with moricizine
HCI
of VT/SCD Yes
No
9 2
7 13
Yes No
N=31. x* = 4.5; p <0.02. SCD = sudden cardiac death; VT = ventricular
tachycardia.
1 REFUSED
ORAL 1 SUS VT
MORICIZINE
1 SCD
HCI
/
*MORICIZINE
OVER 7 DAYS MORICIZINE HC
HCI
/
1 SUS VT
SCD I
VT FREE UNTIL DEATH OR LAST FOLLOW-UP
I
NON SUS VT 4 ELECTIVE
CURRENT MORICIZINE
HCI
CURRENT MORICIZINE
HCI
\
:: g 1:: El RE&%lED
14 ta! RESTUDIED
4!%, ORAL MORICIZINE
DC
NONSUS VT
SUS VT
FIGURE 8. Follow-up of 27 patients treated with moricizine HCI on later prospective protocols. NC = noncompliance; NSD = non-sudden death; other abbreviations as in Figure 7.
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Volume 60
1 NSD
KEEN> HCI
CURRENT I MORICIZINE HCI &
NSD NON SUS VT NC
I CURRENT &M~RICIG.IE HCI
VT FREE UNTIL DEATH OR LAST FOLLOW-UP
SCD NSD NON SUS VT ELECTIVE DC NC
72F
A SYMPOSIUM:
ETHMOZINE@ (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
fraction (LVEF] of 36% compared with an LVEF of 23% in those who died. This difference was statistically significant. The mean LVEF for the group as a whole was 33 f 1670, which underscores the degree of left ventricular dysfunction in this study population. Finally, an attempt was made to determine whether recurrence of arrhythmia was predictable from the results of electrophysiologic testing. Thirty-one of 37 patients are analyzed in Table IV. These 31 patients had electrophysiologic studies before and after moricizine HCl administration and were followed for the purpose of evaluation of continuous drug therapy. Of 11 patients with recurrence of VT or sudden cardiac death, 9 had VT inducible in the electrophysiologic laboratory during moricizine HCl therapy. On the other hand, of 20 patients with no recurrence of VT during continuous moricizine HCl therapy, 13 had no tachycardia inducible in the electrophysiologic laboratory during moricizine HCl therapy. This result is statistically significant. Thus, it is concluded that electrophysiologic study may be used to predict responsiveness of seriously ill patients to continuous moricizine HCl therapy, with a sensitivity value of 8270, and a specificity of 65%. In summary, electrophysiologic testing during moricizine HCl therapy demonstrates an approximate 20% decrease in inducibility of VT in patients with sustained VT or ventricular fibrillation, and an approximate 30% improvement in patients with nonsustained VT. Long-term follow-up of these patients has shown a close correlation between inducibility of VT in the electrophysiologic laboratory during moricizine HCl therapy and subsequent recurrence of tachycar-
AGENT
dia during follow-up. Overall efficacy of moricizine HCl in the management of patients with life-threatening tachycardia appears to be similar to the efficacy of other class I antiarrhythmic drugs, as predicted by electrophysiologic testing. Acknowledgment: The authors acknowledge the substantial contributions of Frank I. Marcus, MD, Sharon A. Magro, PA, Joel Morganroth, MD, and of investigators at the collaborating institutions [Table I]; the careful collation of data by Dr. Michael Borland of DuPont; the artwork by Joseph Martinez; and the manuscript preparation by Kalene Farley. The data in this study were previously reported in the American Heart Journal 1986;112:237.
References 1. Podrid PH, Lyakishev A, Lown B, Mazur N. Ethmozine, a new antiarrhythmic drug for suppressing ventricular premature complexes. Circulation 1980;61:450-457. 2. Pratt CM, Yepsen SC, Taylor AA, Mason DT, Miller RR, Quinones MA, Lewis RA. Ethmozine suppression of single and repetitive ventricular premature depolarizations during therapy: documentation of efficacy and long-term safety. Am Heart J 1983:106:85-91. 3. Pratt CM, Young JB, Francis MJ, Taylor AA, Norton J, English LL, Mann D, Koeplen H, Quinones MA, Roberts R. Comparative effect of disopyramide and ethmozine in suppressing complex ventricular arrhythmias by use of a double-blind, placebo-controlled, longitudinal crossover design. Circulation 1984;69:288-297. 4. Podrid PJ, Lown B. Ethmozine therapy for malignant ventricular arrhythmia (abstr). Am J CardioIl982;49:1015. 5. Kelliher GJ, Kowey P, Engel T, Wetstein L. Clinical pharmacology of antiarrhythmic agents. In: Dreifus LS, ed. Cardiac Arrhythmias: Electrophysiologic Techniques and Management. Philadelphia: F.A. Davis Co., 1985:287-305. 6. Mann DE, Luck JC, Herre JM, Magro SA, Yepsen SC, Griffin JC, Pratt CM, Wyndham CRC. Electrophysiologic effects of ethmozine in patients with ventricular tachycardia. Am Heart J 1984;107:674-679.