Electrophysiologic effects and clinical efficacy of mexiletine used alone or in combination with class IA agents for refractory recurrent ventricular tachycardias or ventricular fibrillation

ElectrophysiologicEffectsand ClinicalEfficacy of MexiletineUsedAloneor in Combinationwith ClassIA Agentsfor RefractoryRecurrent VentricularTachycardiasor VentricularFibrillation SO0 G. KIM, MD, SAMUEL D. FELDER, MD, LAWRENCE E. WASPE, MD, and JOHN D. FISHER, MD

The electrophysiologic effects and clinical efficacy of mexjletine used alone or in combination with class IA agents were studied in 35 patients with recurrent sustained ventrfcular tachycardia (VT) or ventricular fibrillation refractory to nonexpertmental antiarrhythmic agents. At basellne before therapy, all patients had inducible VT by programmed stimulation (1 to 3 extrastimuli) and frequent (at least 30/hour) ventricular premature complexes (VPCs) during Holter monitoring. Mexiletine therapy was effective by programmed stimulation (VT no leer inducible or 15 or less beats) in 8 and ineffective in 27 patients. Twehty patients were discharged with mexiletine (14 of whom took an additional class IA agent). The discharge regimen was effective by programmed stimulation in 8 of these 20 patients. In 14 patients the discharge regimen was Ineffective by programmed stimulation, but all patients had a marked reduction of ventricular ectopic activity (at least 83% reduction of VPCs and abolitlon of non

sustained VT). During the follow-up period of 18 f 13 months (mean f standard deviation), 4 patients had recurrences (3 with an ineffective regimen by programmed stimulation and 1 with an effective regimen by programmed stimulation). Arrhythmiafree survival rates at 12 and 24 months were 86% and 77 % , as determined by the Kaplan-Meier method, in patients with an ineffective regimen by programmed stimulation, and 80 % and 80 % in patients with an effective regimen by programmed stimulation (p = 0.979 by log rank test). This nonrandomized study suggests that in selected patients with inducible VT and frequent VPCs at baseline, persistent induction of VT by programmed stimulation during mexiletine therapy (alone or in combination with class IA agents) may not preclude good clinical outcome when it is accompanied by a marked reduction of spontaneous ventricular ectopic activity. (Am J Cardiol 1986;58:485-490)

M

exiletine, an investigational type IB antiarrhythmic agent, has been undergoing clinical trials for many years.l-g Many investigators have used programmed stimulation and report that suppression of induction of ventricular tachycardia (VT) by programmed stimulation predicts the long-term clinical efficacy of mexileFrom the Department of Medicine, Division of Cardiology, Arrhythmia Service, Montefiore Medical Center-Montefiore Hospital/Moses Division and the Albert Einstein College of Medicine, Bronx, New York. Manuscript received February 20,1986; revised manuscript received April 10, 1986, accepted April 14, 1986. Address for reprints: Soo G. Kim, MD, Division of Cardiology, Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467. 485

tine.6-g Other investigators5 report that suppression of ventricular premature complexes (VPCs) during Holter monitoring in patients taking mexiletine predicts good clinical outcome. Because both programmed stimulatiorFg and Holter monitoring5 are reported to be predictive in assessing the efficacy of mexiletine, efficacy assessment by the 2 methods should probably be concordant. However, programmed stimulation and Holter monitoring are frequently discordant in assessing the efficacy of mexiletine.lo In addition, many patients with persistent induction of VT by programmed stimulation during mexiletine therapy have a marked reduction of VPCs.lOSince suppression of VPCs during mexiletine therapy reportedly predicts good clinical outcome,5 some of these patients may have a good clinical out-

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come despite persistent induction of VT by programmed stimulation during mexiletine therapy. In addition, Wellens et all1 recently questioned the value of programmed stimulation in predicting inefficacy of antiarrhythmic agents. Others12-14have also raised questions regarding the value of programmed stimulation in assessing efficacy of antiarrhythmic agents. We determined the outcome of these patients with a persistent induction of VT and a marked reduction of spontaneous ventricular ectopic activity during therapy with mexiletine, alone or in combination with a class IA agent.

Methods Patients: We studied 35 patients (30 men, 5 women, mean age 60 f 9 years) with recurrent sustained VT with hemodynamic compromise (33 patients) or ventricular fibrillation (2 patients) refractory to conventional antiarrhythmic agents. Fourteen patients had coronary artery disease and a remote myocardial in; farction, 11 had coronary artery disease and a remote myocardial infarction with left ventricular aneurysm and 10 had dilated cardiomyopathy. No arrhythmias were associated with an acute myocardial infarction or remediable causes (such as hypokalemia, digitalis toxicity or drug-induced arrhythmia]. Criteria for admission to the study also included frequent (at least 3O/ hour] VPCs during Holter monitoring15J6 and inducible sustained VT by programmed stimulation requiring intervention for termination during a baseline study in the absence of antiarrhythmic agents. Patients with arrhythmias refractory to conventional nonexperimental drugs or with intolerable side effects from conventional drugs were entered into this study. Programmed stimulation: The programmed stimulation protocol used in this study has been reportedal One, 2 and 3 extrastimuli were given during sinus rhythm initially and then during ventricular pacing at cycle lengths of 600 to 400 ms. The treatment was considered effective by programmed stimulation when VT previously induced was no longer inducible or was nonsustained (no more than 15 beats).1a-23 Ambulatory monitoring: A continuous 24-hour ambulatory electrocardiogram was recorded on an Avionics@ 445 &channel recorder. The tape was analyzed on a computerized Cardio Data System@scanner. Total numbers of VPCs, couplets and nonsustained VT (3 or more VPCs at a rate higher than 100 beats/min) were generated by the scanner. Accuracy of the system has been previously validated.24 Results were verified by 1 of the investigators. Mean VPCs and couplets per hour were calculated by dividing the total number of VPCs and couplets by the number of hours recorded. A marked reduction of ventricular ectopy on Holter monitoring was defined as 83% or more reduction of VPCs and abolition of nonsustained VT on Holter.25-28 Study design: All patients gave informed consent before the study for serial drug testing by programmed stimulation and ambulatory monitoring. All patients underwent baseline 24-hour ambulatory electrocardi-

ography and programmed stimulation study at least 5 half-lives after discontinuation of all antiarrhythmic medications. If needed for other reasons, digoxin and propranolol were continued throughout the study. Mexiletine was given orally every 6 hours. The dose of mexiletine was adjusted to the maximum tolerated by the patient. Programmed stimulation and 24-hour ambulatory monitoring were repeated after the patient had received mexiletine at a constant dose for at least 5 doses to achieve steady-state blood levels. A type IA antiarrhythmic agent (quinidine, procainamide or disopyramide) was added to mexiletine therapy in some patients. The decision to add a class IA agent was made arbitrarily based on the results of programmed stimulation and Holter monitoring during therapy with mexiletine alone. When mexiletine was effective by programmed stimulation criteria, the patient was discharged from the hospital regardless of results of Holter monitoring. When mexiletine was ineffective by programmed stimulation criteria but a marked reduction of ventricular ectopy was noted on Holter monitoring, the patient was also discharged with mexiletine. Four patients with a marked reductipn of ventricular ectopic activity and persistent induction of tachycardia received other therapies. When mexiletine was ineffective as shown by both Holter and programmed stimulation criteria, the patient received other treatments. The endpoint of follow-up was recurrence of sustained VT or sudden death, death from other causes, discontinuation of the discharge regimen because of adverse effects or arrhythmia-free survival as of November 30, 1985. Statistical analysis: The Kaplan-Me& method was used to generate actuarial survival rates of each group. Differences between, groups were tested by the log rank test for statistical significance. Unpaired or paired t test or Fisher’s exact test were used to compare appropriate variables between groups. A &tailed p value <0.05 was considered significant. The mean Z!Z standard deviation was used as the index of dispersion of observed values.

Results Mexiletine therapy: The mean dose of mexiletine was 718 f 213 mg/day (range 400 to 1,200). Sixteen of 35 patients were receiving an additional type IA antiarrhythmic agent. Efficacy of mexiletine by acute drug testing: At baseline before therapy, all 35 patients had inducible sustained monomorphic VT by programmed stimulation at the right ventricular apex requiring,intervention for termination. Mexiletine therapy (alone or in combination with a class IA agent) was effective by programmed stimulation criteria in 8 of 35 patients (23%] and ineffective in 27 patients. The mean cycle lengths of induced VTs were 291 f 65 ms before and 347 f 80 ms after therapy (p
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TABLE I

Results of Long-Term

Clinical

Follow-Up

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Pt

D

VTlVF

1 2 3 4 5 6 7 a 9 IO 11 12 13 14 15 16 17 18 19 20

73M 68M 64M 63M 62M 62M 61M 53M 52M 49M 64M 55M 49M 45M 71M 71M 60M 65M 54M 41F

CAD CAD CAD CAD CAD CAD CAD CAD CAD CAD DC DC DC DC CAD CAD CAD DC DC DC

VT VT VT VT VT VT VT VT VT VT VT VT VT VT VT VT VT VF VF VT

Type IA Agent

Q Q D D D Q Q D .

Q D Q Q Q D

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Study VT Induction

Age (~0 & Sex

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Pre-Rx v+2 s+3 v+3 v+3 s+3 v+2 v+3 v+2 v+2 s+3 s+3 v+1 s+3 vt2 s+3 v+1 vt3 v+3 vt3 vt3

Follow-Up

Post-Rx Holter Monitor

Post-Rx

VPCS

v+2 s+3 s+3 v+i s/3 v+2 v+1 Vfl v+2 s+3 s+3 s+3 v+3 v+2 No VT No VT No VT No VT No VT No VT

0 11% 0.5% 0.15% 0.34% 0.11% 0.1% 1.2% 0.03% 0.26% 0.25% 0 13.5% 0.2% 7% 9.4% 0.35% 0.66% 0.03% 0.

Couplets

VT

Duration (mo)

0

0 0 0 0 0 0 0 0 0 * 0 0 0 0 0 0 * 23% 0 0

2 25 13 6 26 20 16 17 37 29 44 36 5 6 8 29 3 5 21 12

8.5% 0 0 0 0.1% 0 0 0 0 0 0 2.4% 0 0 0.4% 11.1% 0.25% 0 0

Recurrence + 0 + 0 0 0 0 0 0 0 0 0 t 0 0 0 0 t 0 0

* These patients had no nonsustained ventricular tachycardia on baseline Holter recordings. CAD = coronary artery disease; D = disopyramide: DC = dilated cardiomyopathy: D = diagnosis; Q = quinidine; Rx = therapy: S -I- 1,2 or 3 = sinus rhythm + 1, 2 or 3 extrastimull; V t I., 2 or 3 = ventricular pacing •I 1, 2 or 3 extrastimuli; VF = ventricular fibrillation; VPCs = ventricular premature complexes; VT = nonsustained ventricular tachycardia; % = % of baseline VPCs, couplets or VT in each patient.

12.5 f 20.2 and 59.6 f 142.6 before and 62 &,129,1.5 f 4.5 and 1.8 f 5.9 after therapy, respectively (p
Programmed stimulation: Results of programmed stimulation in these 20 patients with follow-up data are shown in Tables I and II. In.14 patients with persistent induction of VT, the configuration of VT induced during therapy was similar to that of VT at baseline judged by leads I, II, aVF and V1. Cycle length of VT in 14 patients with persistent induction of VT was significantly longer after therapy (p <0.05]. Mexiletine was effective by programmed stimulation criteria in 6 patients with no inducible VT or VT of no more than 6 beats in duration. The changes in the mode of induction of VT during therapy were analyzed in 14 patients (group 1) with a persistent induction of VT. Compared with baseline, induction of VT was easier (requiring fewer extrastimuli) in 5 patients, unchanged (requiring same number of extrastimuli) in 8 and harder in 1. (One patient (no. 12) who had VT induced by 1 extrastimulus during ventricular pacing but not by 3 extrastimuli during sinus rhythm at baseline, had VT induced by 3 extrastimuli during sinus rhythm while taking mexiletine. This patient was considered. to have easier induction.) Holter monitoring: Results of Holter monitoring in 20 patients with follow-up data are summarized in Tables I and III. Compared with baseline, frequencies of VPCs and couplets per hour were reduced to 8.5 f 16.0% and 2.4 f 6.2%, respectively (p
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TABLE II Results of Programmed Siimulatlon

No. of pts with VT by SR + 1 PES SR + 2 PES SR + 3 PES VP t 1 PES VP + 2 PES VP+3PES No. of pts noninducible/inducible VT cycle length (ms) PES = programmed extrastimuli; pacing; VT = ventricular tachycardia.

SR f

TABLE III Results of Halter Monitoring

Before Rx

After Rx

0 0 6 2 5 7 0120 293 f 77

0 1 6 2 4 1 6114 364 6 64

sinus rhythm;

VPCslhour Couplets/hour VT events/24 hour No. of pts with a marked reduction of ventricular ectopy

Before Rx

After Rx

284 f 279 11.3 f 19.6 61 f 167 0

35 zk 103 (6.5 f 16.0%) 3.80 f 0.85 (2.4 f 6.2%) 1.6 f 6.9 (1.3 f 5.4%) 190f 20

VPCs = ventricular premature complexes: VT = ventricular tyachycardia; % = % of baseline value before therapy in each patient. See text for the definition of a marked reduction of ventricular ectopy.

VP = ventricular

tion in identifying an effective regimen in patients with VT.?8-22However, the rate of efficacy in the overall population with VT remains low (25%) even after extensive multiple drug testing.ll This fact has raised questions regarding the value of programmed stimulation in predicting ineffective drug regimens, because not every patient with an ineffective regimen by programmed stimulation, (75% of all patients) is likely to have an arrhythmia recurrence in the near future.ll Our study suggeststhat programmed stimulation may have a poor predictive value in identifying an ineffective regimen in patients taking mexiletine alone or in combination with class IA agents, with a marked suppression of ventricular ectopy during Holter monitoring. A poor predictive value of VT induced by Discussion programmed stimulation in patients taking amiodaThis study suggests that whereas negative pro- rone2g:30or propafenone 31has been reported. Howgrammed stimulation (suppression of inducible VT] in ever, there have been no reports by other investigators patients taking mexiletine has a good predictive value suggesting a poor predictive value of VT induced by as reported previously, positive programmed stimula- programmed stimulation in patients taking mexiletine tion (persistent induction of VT] has a poor predictive (alone or in combination with class IA agents).In fact, value in patients taking mexiletine if accompanied by no studies have been done to determine the value of a marked suppression of spontaneous ventricular ec- programmed stimulation in predicting inefficacy of topic activity. No other investigators have studied the mexiletine in patients with persistent induction of outcomes of patients with a persistent induction of VT tachycardia and marked suppression of ectopies. The specificity of induction of VT by a protocol that and a marked reduction of ventricular ectopic activity is “too aggressive” has been questioned.11~32 Although during mexiletine therapy. Patient selection and efficacy criteria: To assess 7 patients in our study required 3 extrastimuli on their the predictive value of persistent induction of VT in discharge regimen, all except 1 patient (no. 12) repatients with a marked suppression of spontaneous quired 3 extrastimuli for induction of VT at baseline ventricular ectopic activity, only patients with fre- before therapy. Therefore, good outcome in our paquent (at least 3O/hour) VPCs at baseline were includ- tients .with persistent induction of VT cannot be ased.15J6J5 Patients with infrequent (fewer than 3O/hour) cribed to our stimulation protocol using 3 extrastimuli. VPCs are not candidates for Holter assessment.15,16J5 Most of our patients required 3 extrastimuli for inPatients with persistent induction of VT without a sig- duction of VT at baseline; this may have been because nificant reduction of spontaneous ventricular ectopic our stimulation protocol calls for 3 extrastimuli during activity during mexiletine therapy were not dis- sinus rhythm before 1 and 2 extrastimuli during vencharged with mexiletine because the purpose of this tricular pacing. One should not attempt to estimate the predictive study was to determine the outcome of patients with persistent induction of ventricular arrhythmia with a value of efficacy by Halter monitoring criteria in patients taking mexiletine based on this study. Twelve marked reduction of ventricular ectopic activity. The efficacy criteria by programmed stimulation of 20 patients had, 98% ,or more reduction of VPCs used in this study are similar to those used by other during mexiletine therapy. We do not know if patients with a less dramatic reduction of ventricular ectopinvestigators.1s-23 Predictive values of programmed stimulation and ic activity and persistent induction of VT by proHolter monitoring: Many investigators have reported grammed stimulation will have similarly favorable an excellent predictive value of programmed stimula- prognoses.

Iinefficacy by programmed stimulation] and i2.7 f lo.3 months in group 2 (efficacy by programmed stimulation) (difference not significant). Four patients had recurrences (3 in group 1, at 2,5 and 13 months, and 1 in group 2 at 5 months). Excluding patients with recurrences and 2 patients with a follow-up period of 6 months, all patients in group 1 had follow-up periods of at least 16 months (range 16 to 44). Arrhythmia-free survival rates by the Kaplan-Meier method at 6,12, i8 and 24 months were 86%,86%, 77% and 77% in group 1 and 80%, 80%,80% and fjO% in group 2, respectively. The differences were not significant (p = 0.993by log rank test).

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Several investigators have recently questioned the value of programmed stimulation in assessing efficacy of antiarrhythmic agent+l4 and suggested tiontrolled studies. This study, although addressing the question raised by others,11:14was not designed to determine sensitivity, specificity, negative predictive value, positive predictive value and predictive accuracy of programmed stimulation or Holter monitoring. Randomized “parallel study” as suggested by Wellens et all1 or studies suggested by Friedman et all4 could only answer the question. Our study, however, has demonstrated that predictive value of programmed stimulation may be poor in 1 subgroup of patients with persistent induction of VT and a marked redutition of ventricular ectopy during Holter monitoring. ,It has been reported that at least 50% of patients with persistent induction of VT during a therapy have a marked reduction of ventricular ectopy by Holter monitoring during the same therapy. l”+17This subgroup, therefore, is a major subgroup and a significant proportion of patients with recurrent VT belongs to this group. Comfiarison of this study and other studies: The efficacy rates of mexiletine in this study are somewhat higher than those of other reports.5-g These. high rates may be due to the fact that many of our patients were taking an additional type IA agent. The combination of mexiletine and type IA agents is more effective than mexiletine alone as judged by Holter monitoring33 or programmed stimulation.34 Limitations of this study: Our study was nonrandomized. Some patients with an inducible VT and a marked suppression of spontaneous ventricular ectopic activity who could tolerate mexiletine therapy were not discharged with mexiletine. Had they been discharged with the regimen, the follow-up results of group 1 may have been different. Some patients were taking an additional type IA antiarrhythmic agent. The results may have been different if we had studied patients taking mexiletine alone or class IA agents alone. The decision to add a class IA agent was made based on the results obtained during a therapy with mexiletine alone. This may have influenced the results of this study. The size of our study group is another limitation However, the small number of patients in group 2 (efficacy by programmed stimulation) is probably not critical because there is little controversy regarding the clinical outcome of such patients. Swerdlow and Peterson35reported that about 30% of patients with sustained VT are not suitable for management by serial Holter monitoring. Our study group was highly selected with frequent VPCs at baseline and recurrent VT refractory to conventional medications. Most of our patients had coronary artery disease. Our results may not be applicable to other patient populations. Randomized long-term follow-up studies in a larger population should be done to validate the results of this study and to further evaluate positive and negative predictive values of programmed stimulation during mexiletine therapy.

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Acknowledgment: We express our appreciation to Virginia Wengerter and Lori Fields for secretarial assistance in the preparation of this manuscript.

References 1. Talbot RG, Julian DG, Prescott LF. Long-term treatment of ventricular arrhythmias with oral mexiletine. Am Heart J 1976;93:58-65. 2. Campbell NPS, Pantridge JF, Adgey AAJ. Long-term oral antiarrhythmic therapy with mexiletine. Br Heart J 1978;40:796-801. 3. Abinader EG. Cooper M. Mexiletine: use in control of chronic drug-resistant ventricular arrhythmias. JAMA 1979;242:337-339. 4. Cady WJ, Wilson CS, Chambers WS, Miles RR, Holcslaw TL, Forker AD. Mexiletine in the treatment of refractory ventricular arrhythmias: a report of five cases. Am Heart [ 1980;99:181-184. 5. Podrid PJ, Lown B. Mexiletine for ventricular arrhythmia. Am J Cardiol 1961;47:895-902. 6. Waspe LE, Waxman HL, Buxton AE, Josephson ME. Mexiletine for control of drug-resistant ventricular tachycardia: clinical and electrophysiologic results in 44 patients. Am J Cardiol 1983;51:1175-1181. 7. Palileo EV, Welch W. Hoff J, Strasberg B, Bauernfeind RA, Swiryn S, Coelho A, Rosen KM. Lack of effectiveness of oral mexiletine in patients with drug-refractory paroxysmal sustained ventricular tachycardia, a study utilizing programmed stimulation. Am J Cardiol 1982;50:1075-2081. 8. DiMarco JP, Garan H, Ruskin JN. Mexiletine for refractory ventricular arrhythmias: results using serial electrophysiologic testing. Am J Cardiol 1981;47:131-138. 9. Flaker GC, Madigan NP, Alpert MA, Moser SA. Mexiletine for recurring ventricular arrhythmias: assessment by long-term electrocardiographic recordings and sequential eiectrophysiologic studies. Am Heart J 1984;108:490495. 10. Kim SG, Seiden SW, Matos JA, Waspe LE. Fisher JD. Discordance between Halter monitoring and programmed stimulation in assessingefficacy of mexiletine in patients with ventricular tachycardia. Am Heart J. in press. 11. Wellens HJJ, Brugada P, Stevenson WG. Programmed electrical stimulation of the heart in patients with life-threatening ventricular arrhythmias. What is the significance of induced arrhythmias and what is the correct stimulation protocol? Circulation 1985;72:1-7. 12. Woosley RL. The role of programmed electrical stimulation in the evaluation of investigational antiarrhythmic drugs. Overview of the workshop. Circulation 1986;73:suppIII:If-112-H-113. 13. Brugada P, Wellens HJJ. Programmed electrical stimulation of the heart in ventricular arrhythmias. Am J Cardiof 1985;56:187-190. 14. Friedman L, Yusuf S. Does therapy directed by programmed electrical stimuhrtion provide a satisfactory clinical response? Circulation 1986; 73:supp1 II:II-59-11-66.

15. Lown B. Management of patients at high risk of sudden death. Am Heart J 1982;103:689-697. 16. Podrid PJ. Schoeneberger A, Lawn B, Lampert S, Mates J, Porterfield J, Raeder E, Corrigan E. Use of nonsustained ventricular tachycardia as a guide to antiarrhythmic therapy in patients with malignant ventricular arrhythmia, Am Heart J 1983;105:181-188. 17. Kim SG. Seiden SW. Matos IA. Wasoe LE. Fisher ID. Discordance between ambulatory monitoring and progra*mmed stimulaiion in assessingefficacy of class fA agents in patients with ventricular tachycardia. TACC 1985;6:539-544.

18. Fisher JD, Cohen HL, Mehra R, Furman S. Cardiac pacing and pacemakers II. Serial electrophysiologic-pharmacologic testing for control of recurrent tachyarrhythmias, Am Heart J 1977;93:658-668. 19. Mason JW, Winkle RA. Electrode-catheter arrhythmia induction in the selection and assessmentof antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circulation 1978;58:971-985, 20. Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM. Recurrent sustained ventricular tachycardia 3. Role of electrophysiologic study in selection of antiarrhythmic regimens. Circulation 1978;58:986-997. 21. Mason JW, Winkle RA. Accuracy of the ventricular tachycardia induction study for predicting long-term efficacy and inefficacy of antiarrhythmic drugs. N Engl [ Med 1980;303:1073-1077. 22. Josephson ME, Horowitz LN. Electrophysiologic approach to therapy of recurrent sustained ventricular tachycardia. Am J Cardiol1979;43:631-641. 23. Swerdlow CD, Winkle RA. Mason JW. Prognostic significance of the number of induced ventricular complexes during assessment of therapy for ventricular tachyarrhythmias. Circulation X983:68:400-405. 24. Kim SG, Seiden SW, Matos JA, Waspe LE, Fisher JD. Combination of procoinamide and quinidine for better tolerance and additive effects for ventricular arrhythmias. Am J Cardiol 1985:56:84-88. 25. Morganroth J, Michelson EL, Horowitz LN, Josephson ME, Pearlman AS, Dunkman WB. Limitations of routine long-term electrocardiographic monitoring to assessventricular ectopic frequency. Circulation 1978;58:408-414. 26. Vlay SC, Kallman CH, Reid PR. Prognostic assessment of survivors of ventricular tachycardia and ventricular fibrillation with ambulatory monitor-

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ing. Am J Cardiof 1984:54x37-90. 27. Marchlinski FE, Buxton AE, Flores BT, Doherty JU, Wsxmsn HL, Josephson ME. Value of Hoher monitorine in identifvine risk for sustained ventricufar arrhythmia recurrence on am~odarone.‘~m”J Cardiol 1985;55:709-712. 28. Hoffmann A, Schiitz E, White R, Follath F, Burckhardt D. Suppression of high-grade ventricular ectopic activity by antiarrhythmic drug treatment as a marker for survival in patients with chronic coronary artery disease. Am Heart 1 1984:107:1108-Ii08 29. Heger JJ, Prystowsky EN, Jackman WM. Naccarelli GV, Warfel KA, Ringkenberger RL, Zipes DP. Amiodarone: clinical efficacv and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-544. 30. Nademanee K, Hendrickson J, Kammar R, Singh BN. Antiarrhythmic efficacy and electrophysiologic actions of amiodarone in patients with life threatening arrhythmias: potent suppression of spontaneous occurring tachyarrhythmia versus inconsistent abolition of induced ventricular tachycardia. Am Heart J 1982;103:950-958. 31. Chilson DA, Heger JJ,Zipes DP, Browne KF. Prystowsky EN. Electrophys-

31. Chilson DA, Heger JJ,Zipes DP, Browne KF, Prystowsky EN. Electrophysiologic effects and clinical efficacy of oral propafenone therapy in patients with ventricular tachycardia. JACC 1985;5:1407-1413. 32. Swerdlow CD, Blum J, Winkle RA, Griffin JC, Ross DL, Mason JW. Decreased incidence of antiarrhythmic drug efficacy at electrophysiologic study associated with the use of a third extrastimulus. Am Heart J 1982; 104:1004-1011. 33. Duff HJ, Roden D, Primm RK, Oates JA, Woosley RL. Mexiletine in the treatment of resistant ventricular arrhythmias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine. Circulation 1983;67:1124-1128. 34. Greenspan AM, Spielman SK, Webb CR, Sokoloff NM, Rae AP, Horowitz LN. Efficacy of combination therapy with mexiletine and type IA agent for inducible ventricular tachyarrhythmias secondary to coronary artery disease. Am T Cardiol 1985;56:277-284. 35. Swerdlow CD, Peterson J. Prospective comparison of Holter monitoring and electrophysiologic study in patients with coronary artery disease and sustained ventricular tachyarrhythmia. Am J Cardiol 1985;56:577-580.