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Long-term efficacy of mexiletine alone and in combination with class la antiarrhythmic drugs for refractory ventricular arrhythmias
Long-term efficacy of mexiletine alone and in combination with class la antiarrhythmic drugs for refractory ventricular arrhythmias The efficacy of mexiletine used alone, and in combination with a class la antiarrhythmic drug, was assessed in 159 previously drug-refractory patients with ventricular tachycardia (VT) during serial electrophysiologic studies and during long-term (S-year) clinical follow-up. Electrically-inducible ventricular tachycardia was suppressed by mexiletine alone in 23% of patients tested, and a combined antiarrhythmic drug regimen was effective in 29% of the trials performed. Mexiletine was much more likely to be effective in patients presenting with nonsustained VT or ventricular fibrillation than in patients with sustained VT (p < 0.005). After 1 and 4 years of treatment, 18% and 42% of the patients treated with mexiletine alone had died suddenly or suffered recurrent symptomatic VT, compared to 11% and 25% of patients treated with the combined antiarrhythmic drug regimens (p = NS). Mexiletine therapy was associated with frequent, though readily reversible, adverse reactions. However, mexiletine treatment had to be discontinued permanently in 8 of 92 patients (9%) because of intolerable side effects. We conclude that the added efficacy and possible improved arrhythmia-free survival associated with combining mexiletine with a class la agent should be further investigated. (AM HEART J 1988;115:360.)
Eric G. Whitford, M.B., F.R.A.C.P., Brian McGovern, M.D., Mark H. Schoenfeld, M.D., Hasan Garan, M.D., John B. Newell, B.A., Mary McElroy, and Jeremy N. Ruskin, M.D. Boston, Muss.
Mexiletine is a local anesthetic, ant&rhythmic drug that is structurally similar to both lidocaine and tocainide. It has high oral bioavailabi1ity.l Initially developed as an anorectic agent, it was subsequently investigated for its anticonvulsant properties before its potential utility as an antiarrhythmic drug was recognized.2 It has been available for clinical use in some countries since 1971 and has recently been approved for treating ventricular arrhythmias in the United States. The reported efficacy of mexiletine in controlling ventricular arrhythmias that have not been satisfactorily controlled by conventional class Ia antiarrhythmic drugs has been variable, regardless of whether therapy was guided by noninvasive or inva-
From
the Cardiac
Arrhythmia
Service,
Massachusetts
General
Hospital.
Supported by Grant ROl HL25992-OlAl from the National Institutes of Health, Bethesda, Md. Dr. Garan is the recipient of an American Heart Association, Established Investigatorship (84-209), American Heart Association, Inc., Dallas, Texas. Dr. Ruskin is the recipient of an American Heart Association Established Investigatorship (81.177), American Heart Association, Dallas, Texas. Received Reprint General
360
for publication requests: Hospital,
Brian Boston,
Jan.
22, 1987;
McGovern, MA 02114.
accepted M.D.,
Cardiac
Sept.
8, 1987. Unit,
Massachusetts
sive means.3-17 We have previously reportedls the efficacy of mexiletine in suppressing ventricular tachycardia provoked by programmed cardiac stimulation. In addition, our group and others1g-21 have observed that combining mexiletine with a class Ia antiarrhythmic drug may suppress ventricular tachycardia when mexiletine alone is ineffective. In this study, we examine the efficacy of oral mexiletine used alone or in combination with class Ia antiarrhythmic drugs in suppressing ventricular tachycardia induced at electrophysiology study in 159 patients with drug-refractory ventricular arrhythmias. In addition, the clinical efficacy of mexiletine in preventing recurrent arrhythmia and sudden death is analyzed over 6 years of follow-up surveillance. METHODS Between 1978 and December, 1984, 159 patients referred to the cardiac arrhythmia service of the Massachusetts General Hospital for evaluation of ventricular arrhythmias were included in this study. To be eligible for. inclusion, all patients had ventricular tachycardia induced by programmed cardiac stimulation while off all antiarrhythmic drugs and had a subsequent electrophysiologic study performed after at least 48 hours of loading with
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Mexiletine
CONTROL
EPS
ON MEXILETINE (n=128)
ELECTROPHYSIOLOGIC (n=159)
STUDY
and class Ia drugs for VT
(EPS)
ALONE
EPS ON MEXILETINE CLASS IA DRUG (t-.=111)
DISCHARGED MEXILETINE
361
ON ALONE
(n=28)
DISCHARGED MEXILETINE CLASS IA
+
ON + DRUG
(n=64)
Fig.
1. Electrophysiologic studies in 159 patients.
either oral mexiletine alone or oral mexiletine in combination with other antiarrhythmic therapy. To be considered for treatment with mexiletine, all patients had either electrically inducible or spontaneous symptomatic ventricular tachycardia while on therapy with conventional antiarrhythmic drugs, or had been unable to tolerate these drugs. If a patient wastaking digoxin or beta blockers and it wasfelt these should not be stopped, they were continued throughout the period of electrophysiologic assessment. If mexiletine alone was ineffective, a class Ia antiarrhythmic drug was then added to mexiletine. The specific classIa antiarrhythmic agent chosen was determined by previous tolerance or by physician preference. The study protocol was prospectively designed. All patients evaluated with this protocol are presented in this study. Other patients presenting with ventricular tachycardia or fibrillation were managedby nonpharmacologic modalities if this was considered preferable by their physicians. Similarly, the decision to dischargea patient on mexiletine alone or in combination with a classIa drug wasmadeby the responsibleclinician, basedon the results of the electrophysiologic studies, on the availability of alternate therapies, and on patient preference. Patient population. In the population studied, there were 131 men and 28 women. The mean age was 58 + 11 years and the mean resting left ventricular ejection fraction was 32 t- 15%. The cardiac diagnosiswas coronary artery diseasein 137.patients (86%). Thirteen patients had dilated cardiomyopathy, four had mitral valve prolapse, three had other valvular heart disease,and one patient had hypertensive heart disease.In one patient there was no evidence of structural heart disease.Sixtyeight patients had documented sustained ventricular tachycardia (VT), 42 patients had been resuscitated from
cardiac arrest, 25 patients had documented nonsustained VT, 24 patients had syncope or near-syncope and documented high-grade ventricular ectopy. Following a control electrophysiologic study (EPS) on no antiarrhythmic drugs, 128 of the 159 patients (80%) were studied after oral loading with mexiletine alone. The remaining 31 patients were not tested on mexiletine alone but were tested on mexiletine in combination with a class Ia antiarrhythmic drug. Seventy-four of the 128 patients initially tested on mexiletine alone were subsequently tested on mexiletine in combination with a class Ia ant&rhythmic drug. Thesesubgroupsare outlined in Fig. 1. All patients who were discharged on mexiletine were reviewed on an outpatient basis3 months after discharge, and subsequently every 6 months. At each outpatient visit, the patient was asked about symptoms, had a physical examination, a If-lead ECG, and underwent routine biochemical and hematologic screening. Electrophysiologic studies. The catheterization procedure and cardiac stimulation protocol have beendescribed in detail elsewhere.18 Ventricular pacing wasperformed at the right ventricular apex with the use of a rectangular pulse of 2 msecduration applied at 2 to 5 times diastolic threshold. The ventricular stimulation protocol included: (1) Premature ventricular stimulation wasperformed with single and double extrastimuli during sinus rhythm and subsequently during fixed rate ventricular pacing at three basic drive cycle lengths (600, 500, and 400 msec). (2) If sustainedventricular tachycardia was not induced by the programmed electrical stimulation outlined above, then three- to five-beat bursts of rapid ventricular pacing were delivered asynchronously to the right ventricular apex at progressively shorter cycle lengths until 1:l capture could no longer be achieved, VT was induced, or a paced rate of
362
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et al.
300 bpm was reached. From 1982 on, three synchronized premature ventricular depolarizations during sinus rhythm were used instead of rapid ventricular pacing. Seventy of the 159 patients (44 % ) were studied after 1982. (3) Programmed premature ventricular stimulation with triple extrastimuli during fixed-rate pacing was only used when steps 1 and 2 above failed to induce VT in patients with documented sustained VT or with prior cardiac arrest. The ventricular stimulation protocol used during serial drug testing was identical to that used in the control study in each patient. The results in patients treated before and after the 1982 protocol change were similar. Definitions. VT was considered nonsustained if 5 or more but fewer than 100beats were reproducibly induced by programmed electrical stimulation. The mean cycle length of the tachycardia was calculated over three consecutive beats at least three beats after the onset of the tachycardia. Sustained VT was defined as tachycardia that lasted at least 100 beats or that was associatedwith hemodynamic collapseand required pacing or cardioversion for termination. VT was consideredsuppressedduring antiarrhythmic drug testing if the stimulation protocol was completed without the initiation of five or more nonstimulated ventricular responses. Ejection fraction was determined either from right anterior oblique left ventricular angiogramsor from gated nuclear cardiac blood pool scans. Sudden death was defined as witnesseddeath occurring unexpectedly in the presence or absence of acute symptoms of less than 6 hours’ duration, or any unwitnessed unexpected death where no noncardiac cause of death was identified. The time of follow-up was measuredto either the time of the most recent outpatient visit, to the date of stopping of the drug, to recurrence of symptomatic VT, or to death. Statistical analysis. Values are expressed as mean i standard deviation. Clinical, hemodynamic, and electrophysiologic variables were examined by stepwise logistic regressionanalysis, with the BMDP statistical software package (University of California, Los Angeles, Calif.)T2 Life-table analysiswas performed by meansof the generalized Wilcoxon (Mantel-Cox) statistic to test the equality of the survival curves. The Cox proportional hazards model was used to define the relationship of prognostic factors.23One-way and two-way analysis of variance, as appropriate, were usedto comparegroups for demographic differences. RESULTS
Therapy with mexiletine alone or mexiletine in combination with other antiarrhythmic therapy resulted in complete suppression of EPS-inducible VT in 62 of 159 (39%) patients. The presenting clinical arrhythmia was a potent predictor of suppression of electrically-induced VT. Patients with nonsustained VT or ventricular
fibrillation
as the
presenting arrhythmia were more likely to have suppression of VT by mexiletine. Electrically inducible VT was suppressed in 23 of 42 patients (55%)
who presented in ventricular fibrillation, and in 22 of 49 patients (45%) who presented with nonsustained VT or high-grade ventricular ectopic activity. In contrast, VT was suppressed in only 17 of 68 patients (25%) whose clinical arrhythmia was sustained VT (p < 0.005). Similarly, the nature of the provoked ventricular arrhythmia during control electrophysiologic study was predictive of the suppression of ventricular arrhythmias by mexiletine, as assessed by repeat electrophysiologic testing. When sustained VT was induced at the control electrophysiologic study, the efficacy of mexiletine, alone or in combination with other antiarrhythmic drugs, in suppressing sustained VT was 34% (35 of 104), while the efficacy in suppressing nonsustained VT was 43% (20 of 46), and in suppressing ventricular fibrihation it was 56% (five of nine) (p < 0.05). Clinical and patients tested
electrophysiologic observations in on mexiletine alone. One hundred
twenty-eight patients previously unresponsive to or intolerant of conventional antiarrhythmic drugs underwent electrophysiologic study on mexiletine alone (Fig. 1). At the control study (on no antiarrhythmic drugs), 75 of 128 patients (59% ) developed sustained VT, 46 of 128 (36%) developed nonsustained VT, and 7 of 128 (5 % ) developed ventricular fibrillation. When these 128 patients were subsequently studied after at least 48 hours of oral loading with mexiletine at a mean dose of 871 & 221 mg/day, sustained VT could still be induced in 62 of 128 (48 % ) and nonsustained VT could be induced in 36 of 128 (28%). Complete suppression of EPSinduced VT was observed in 29 of 128 (23%). Programmed electrical stimulation did not induce ventricular fibrillation in any of the patients. The effect of mexiletine alone on the arrhythmias induced at the control electrophysiologic study was variable. Of the 75 patients with sustained VT induced at the control study, 50 of 75 (67%) had persistent sustained VT on mexiletine, 11 of 75 (15%) developed nonsustained VT, and 14 of 75 (19%) had no inducible arrhythmias. Of the 46 patients with nonsustained VT, VT was no longer inducible on mexiletine alone in 14 (31%), nonsustained VT was inducible in 22 (49%), while sustained VT was provoked in nine patients (20%). Of the seven patients with ventricular fibrillation, nonsustained VT was induced in three on therapy with mexiletine and sustained VT was induced in a further three patients. VT was not inducible on mexiletine in one patient. The mean cycle length of the VT induced at control study in the patients suppressed on mexile-
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l
and class Ia drugs for VT
363
.**-. Mexiletine Mexiletine + Class 1A Drug
0
12
24
36
48
60
72
MONTHS Fig. 2. Sudden death arkarrhythmic drug.
in natients *
treated
with
mexiletine
tine alone was 261 + 66 mssec. In the patients who had VT induced on mexiletine, the mean VT cycle length overall increased to 301 -I- 76 msec compared with 267 +- 64 at control (p < O.Ol), but the effect of mexiletine on the cycle length of the tachycardia during EPS in individual cases was variable. The tachycardia cycle length on mexiletine was at least 50 msec longer in 28% of the patients, at least 50 msec shorter in 9% of the patients, and no more than 50 msec different in 38% of the patients. The mean ejection fraction of the patients in whom VT was suppressed on mexiletine alone was 30 rt_ 12 % . This was not significantly different from the mean ejection fraction of those not suppressed on mexiletine alone, 33 * 15%. Clinical and electrophysiologic observations in patients tested on mexiletine in combination with class la antiarrhythmic drugs. Of the patients who had EPS
on mexiletine alone and who still had VT induced, there were 80 patients who had a subsequent EPS on mexiletine in combination with a class Ia antiarrhythmic drug. The mean dose of mexiletine was 876 + 217 mg/day. The class Ia drug used was quinidine in 58 patients, procainamide in 46, and disopyramide in seven patients. VT could not be provoked in 24 of these 80 patients (30 % ) while they were taking mexiletine combined with a class Ia antiarrhythmic drug. Nonsustained VT was induced in a further 15 of 80 (19%) of patients. Sustained VT remained inducible in 41 of 80 (51% ) patients. A further 31 patients were not tested on mexiletine alone but did have a control EPS on no antiarrhythmic drugs and a follow-up EPS on mexiletine in
alone
and in combination
with
a class Ia
combination with a class Ia antiarrhythmic drug. On this combination antiarrhythmic therapy, VT was suppressed in 24 patients (30%). Sustained VT was induced in 18 of 31 (58%) patients, while nonsustained VT was provoked in a further 5 of 31 (16%) of these patients. There was no difference in the rates of suppression of VT between the different class Ia drugs used. Observations in patients discharged on mexiletine. A total of 92 patients were discharged on mexiletine. Thirty-eight of the patients were discharged on mexiletine alone and the other 62 were discharged on mexiletine in combination with a class Ia antiarrhythmic drug. The patient follow-up ranged from 1 week to 76 months, with a mean of 17 + 10 months. At 12 months follow-up the cumulative percentage of patients who had died from all causes was 14% and at 4 years it was 59 % . The cumulative percentage of patients who had either sustained an episode of symptomatic recurrent VT or who had died suddenly was 18% at 1 year and 38% at 4 years. The mean dose of mexiletine in the 30 patients discharged on mexiletine alone was 848 + 166 mg/ day. Follow-up ranged from 1 week to 60 months (mean 12 rt 9 months) in this subgroup. Six patients died suddenly and four patients had symptomatic recurrent VT (Figs. 2 and 3). In 7 of these 10 patients, EPS on mexiletine had shown that inducible VT had been suppressed. At 12 months followup the cumulative percentage of patients who had died from all causes was 21% and the cumulative percentage of patients who had an episode of symptomatic recurrent VT or who had died suddenly was
February
364
Whitford
et al.
American
Heart
1988 Journal
too $ i
75 . . . . . . . * . . . . . . a. . . . . :. :. . . . . . . . . ..
P
I$ B 8
50
’ b
25
kl
E8
,o
; ” . ... . .. . .
...**v. Mexiletine Mexiletine + Class VA Drug
12
24
p = 0.26
36 MoNTiYS
46
60
h.s.1
72
3. Sudden death and recurrent symptomatic ventricular tachycardia in patients treated with mexiletine alone and in combination with a classIa antiarrhythmic drug.
Fig.
I. Adverse reactions in 42 of 92 patients discharged Table
Nausea Anorexia Dizziness Tremor Ataxia Fatigue, lethargy Insomnia Abdominal pain Seizures Anxiety Impotence Psychosis Headaches
13 patients 11 patients 10 patients I patients 4 patients 3 patients 3 patients 2 patients 2 patients 2 patients 1 patient 1 patient 1 patient
18 % . At 4 years follow-up, 42 % had died suddenly or had suffered recurrent VT. The mean dose of mexiletine in the 62 patients discharged on mexiletine in combination with a class Ia antiarrhythmic drug was 866 + 228 mg/day. Follow-up ranged from 1 week to 76 months. The mean was 19 ~fr 11 months. Seven patients (9%) died suddenly and five patients (7 % ) had symptomatic recurrent VT (see Figs. 2 and 3). At 12 months the cumulative percentage of patients who had died from all causes was 10% and the cumulative percentage of patients who had died suddenly or had symptomatic recurrent VT was 11%. After 4 years’ follow-up surveillance, 25 % had either died suddenly or had suffered recurrent VT. Side effects. Side effects thought to be related to mexiletine therapy occurred in 42 patients (Table I).
In 8 (9%) of the 92 patients discharged on mexiletine, the drug had to be discontinued because of intolerable side effects. In a further 18 patients (20%), the dose of mexiletine had to be reduced. There were three episodes of recurrent VT but no episodes of sudden death in the patients in whom the dosage of mexiletine was reduced because of adverse effects. The most common side effects were either of the neurologic or gastrointestinal systems. Adverse side effects were often minimized by taking the medication with food. Seizures occurred after bolus injections of lidocaine in two patients taking mexiletine. Possible proarrhythmic responses were noted in 37 patients (23%) during serial electrophysiologic studies, but no clinical evidence of exacerbation of ventricular arrhythmias was noted in these patients. Precipitation or worsening of cardiac failure by mexiletine was not observed. DISCUSSION
The efficacy of mexiletine in suppressing premature ventricular beats has been demonstrated.“s4 Mexiletine was as effective as conventional class Ia drugs when these agents were compared.5-7 In addition, several recent studies*-lo suggest that mexiletine may suppress ventricular arrhythmias in some patients in whom conventional antiarrhythmic drugs have been ineffective. The number of patients studied has been small, however, and the results of at least one study are contradictory. Duff et a1.l’ found that the efficacy of mexiletine was enhanced by combining mexiletine and quinidine in patients with ventricular arrhythmias not suppressed by
Volume
115
Number
2
either drug alone. In addition, because lower doses of both drugs were used in the combined antiarrhythmic drug regimen, there was a lower incidence of adverse reactions. The efficacy of mexiletine for ventricular tachyarrhythmias as evaluated by programmed cardiac stimulation is variable. Four groups have reported’3. 17.20923 suppression of induced VT by mexiletine in about one third of their patients, while three groups reported minimal efficacy. The different reported effects of mexiletine may be related to lack of homogeneity of the patient populations studied, to differences in the stimulation protocols, or in the criteria for suppression of VT. In this study, VT Iprovoked by programmed cardiac stimulation was suppressed by mexiletine as a single antiarrhythmic agent in 23% of patients in whom convention,al antiarrhythmic drugs had been ineffective. Suppression of the induced arrhythmia was more likely in patients presenting with nonsustained VT or witb ventricular fibrillation than in patients presenting with sustained VT (p < 0.005). Long-term survival of patients with ventricular tachyarrhybhmias treated with mexiletine has been reported. Stein et al. l4 followed 107 patients discharged on treatment with mexiletine alone or in combination with other antiarrhythmic drugs. The discharge drug regimen was chosen on the basis of antiarrhytbmic efficacy demonstrated by serial cardiac monitoring or by EPS. Nineteen (17.8%) of the 107 patients died during an average follow-up period of 23 months. Eleven of these 19 patients died suddenly. The authors did not distinguish recurrent arrhythmia in patients treated with mexiletine as a sole antiarrhythmic agent from recurrent arrhythmia in patilents treated with combined antiarrhythmic drug regimens. Recently, Poole et a1.17reported survival in 32 patients treated with mexiletine and followed over an average period of 17 months of outpatient treatment. Thirteen (41%) of these patients died during follow-up; six (19%) died suddenly. The:re appeared to be no difference in outcome between patients treated with mexiletine alone, or with mexiletine combined with a class Ia antiarrhythlmic drug. However, there was evidence of antiarrhythmic efficacy in only 14 of these patients during serial EPS prior to hospital discharge. Of these 14 patients, 5 had recurrent arrhythmia, but none died suddenly. Mexiletine had to be discontinued in about 25% of patients during the outpatient follow-up phase because of intolerable side elects. In our study, the overall survival was 86% at 1 year and 61% at 4 years. Sudden deaths occurred in 13 patients, all in the first 2 years
Mexiletine
and class Ia drugs for VT
365
after discharge. Although there was a strong trend toward more sudden deaths and recurrent VT in patients treated with mexiletine alone in comparison to patients treated with mexiletine in combination with a class Ia drug, these trends did not reach statistical significance at the time of this analysis (Fig. 2). Comparison of clinical, angiographic, and electrophysiologic variables showed no significant differences between patients treated with mexiletine alone and those treated with the combined regimens. Caution in interpreting these observations is warranted, as the groups compared may have had differences in unmeasured variables that influence recurrent arrhythmia and sudden death. Nevertheless, the possibility that mexiletine in combination with other antiarrhythmic drugs is more effective than mexiletine alone in preventing sudden death should be considered and further investigated. Adverse reactions during chronic treatment with mexiletine were common, and necessitated dose reduction in 20% of patients and drug discontinuation in 9% despite initial tolerance to mexiletine while in the hospital. However, although adverse reactions are relatively common, they are generally predictable and rapidly reversible. We found24,25 a lower incidence of life-threatening side effects than when flecainide or amiodarone were used in similar populations. We conclude from this study that in patients with symptomatic ventricular arrhythmias in whom class Ia antiarrhythmic, agents have been ineffective and in whom VT is inducible at EPS, mexiletine alone or in combination with a class Ia antiarrhythmic drug will suppress inducible VT in about one third of the patients. VT is more likely to be suppressed in patients who present with nonsustained VT or ventricular fibrillation. The incidence of sudden death and recurrent VT was higher in patients treated with mexiletine alone than in patients treated with the combined antiarrhythmic drug regimens, although the difference was not statistically significant. The use of mexiletine was limited by the occurrence of side effects, necessitating dose reduction or drug withdrawal in 28% of the patients after discharge from the hospital. The additive efficacy of combining a class Ia agent to mexiletine as well as the improved arrhythmia-free survival noted warrant further investigation. REFERENCES
1. Woosley RL, Wang T, Stone W, et al. Pharmacology physiology, and pharmacokinetics of mexiletine. 1984;107:1058.
electro-
AM HEART J
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et al.
2. Middleton D. Baseline pharmacology, electrophysiology and pharmacokinetics of mexiletine. Acta Cardiol 1980; 25(Suppl):45. 3. Talbot RG, Clark RA, Nimmo J, Neilson JMM, Julian DG, Prescott LF. Treatment of ventricular arrhythmias with mexiletine (Ko 1173). Lancet 1973;2:399. 4. Campbell NPS, Chaturvedi NK, Kelly JE, Strong JE, Shanks RG, Pantridge JF. Mexiletine in the management of ventricular dysrhythmias. Lancet 1973;2:404. 0. Campbell RWF, Talbot RG, Dolder MA, Murray A, Prescott LF, Julien DG. Comparison of procainamide and mexiletine in the prevention of arrhythmias after acute myocardial infarction. Lancet 19?5;1:1257. 6. Campbell NPS, Pantridge JF, Adgey AAJ. Long-term antiarrhythmic therapy with mexiletine. Br Heart J 19?8;40:?96. 7. Cady WJ, Wilson CS, Chambers WA, Miles RR, Holcslaw TL, Forder AD. Mexiletine in the treatment of refractory ventricular arrhythmias: a report of five cases. AM HEART J 1980;99:58. 8. Mehta J, Conti CR. Mexiletine, a new antiarrhythmic agent for treatment of premature ventricular complexes. Am J Cardiol 1982;49:455. 9. Abinader EG, Cooper M. Mexiletine: use in control of drug-resistant ventricular arrhythmia. JAMA 19?9;242:33?. 10. Podrid PJ. Lown B. Mexiletine for ventricular arrhvthmias. Am J Car&o1 1981;4?:895. 11. Heger JJ, Nattel S, Rinkenberger RL, Zipes DP. Mexiletine therapy in 15 patients with drug-resistant ventricular tachycardia. Am J Cardiol 1980:45:62?. 12. Duff HJ, Roden D, Primm RK, Oates JA, Woosley RL. Mexiletine in the treatment of resistant ventricular arrhythl mias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine. Circulation 1983;6?:1124. 13. 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;51:11?5. 14. Stein J, Podrid PJ, Lampert S, Hirsowitz G, Lown B. Long-term mexiletine for ventricular arrhythmia. AM HEART J 1984;107:1091.
15. 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;50:10?5. 16. Kim SG, Seiden SW, Matos JA, Waspe LE, Fisher JD. Discordance between ambulatory monitoring and pro: grammed stimulation in assessing efficacy of mexiletine in patients with ventricular tachycardia. AM HEART J 1986; 11214. 17. Poole JE, Werner JA, Bardy GH, Graham EL, Pulaski WP, Fahrenbruch CE, Greene HL. Intolerance and ineffectiveness of mexiletine in patients with serious ventricular arrhythmias. AM HEART J 1986;112:322. 18. DiMarco JP, Garan H, Ruskin JN. Mexiletine for refractory ventricular arrhythmias: results using serial electrophysioiogic testing. Am J Cardiol 1981;4?:131. 19. McGovern B, Garan H, Stavens CS, Schoenfeld MH, Estes NAM, Fallon MP, Ruskin JN. Treatment of refractory ventricular tachyarrhythmias with a combination of mexiletine and a class Ia antiarrhythmic drug. J Am Co11 Cardiol 1984;3:55?. 20. Schoenfeld MH, Whitford E, McGovern B, Garan H, Ruskin JN. Oral mexiletine in the treatment of refractory ventricular arrhythmias: the role of electrophysiologic technique. AM HEART J 1984;107:1071. 21. Greenspan AM, Spielman SR, Webb CR, Sokoloff NM, Rae AP, Horowitz LN. Efficacy of combination therapy with mexiletine and a type Ia agent for inducible ventricular tachyarrhythmias secondary to coronary artery disease. Am J Cardiol 1985;56:2??. 22. Dixon WJ, Brown MB, Engelman L, et al. BMDP statistical software. Los Angeles: University of California Press, 1981. 23. Cox DR. Regression models and life tables. J R Stat Sot (B) 19?2;34:198.24. McGovern B, Garan H, Kelly E, Ruskin JN. Adverse reactions during treatment with amiodarone hydrochloride. Br Med J 1983;287:1?5. 25. Platia EV, Estes NAM, Heine DL, et al. Flecainide: electrophysiologic and antiarrhythmic properties in refractory ventricular tachycardia. Am J Cardiol 1985;55:956.
Eric G. Whitford, M.B., F.R.A.C.P., Brian McGovern, M.D., Mark H. Schoenfeld, M.D., Hasan Garan, M.D., John B. Newell, B.A., Mary McElroy, and Jeremy N. Ruskin, M.D. Boston, Muss.
Mexiletine is a local anesthetic, ant&rhythmic drug that is structurally similar to both lidocaine and tocainide. It has high oral bioavailabi1ity.l Initially developed as an anorectic agent, it was subsequently investigated for its anticonvulsant properties before its potential utility as an antiarrhythmic drug was recognized.2 It has been available for clinical use in some countries since 1971 and has recently been approved for treating ventricular arrhythmias in the United States. The reported efficacy of mexiletine in controlling ventricular arrhythmias that have not been satisfactorily controlled by conventional class Ia antiarrhythmic drugs has been variable, regardless of whether therapy was guided by noninvasive or inva-
From
the Cardiac
Arrhythmia
Service,
Massachusetts
General
Hospital.
Supported by Grant ROl HL25992-OlAl from the National Institutes of Health, Bethesda, Md. Dr. Garan is the recipient of an American Heart Association, Established Investigatorship (84-209), American Heart Association, Inc., Dallas, Texas. Dr. Ruskin is the recipient of an American Heart Association Established Investigatorship (81.177), American Heart Association, Dallas, Texas. Received Reprint General
360
for publication requests: Hospital,
Brian Boston,
Jan.
22, 1987;
McGovern, MA 02114.
accepted M.D.,
Cardiac
Sept.
8, 1987. Unit,
Massachusetts
sive means.3-17 We have previously reportedls the efficacy of mexiletine in suppressing ventricular tachycardia provoked by programmed cardiac stimulation. In addition, our group and others1g-21 have observed that combining mexiletine with a class Ia antiarrhythmic drug may suppress ventricular tachycardia when mexiletine alone is ineffective. In this study, we examine the efficacy of oral mexiletine used alone or in combination with class Ia antiarrhythmic drugs in suppressing ventricular tachycardia induced at electrophysiology study in 159 patients with drug-refractory ventricular arrhythmias. In addition, the clinical efficacy of mexiletine in preventing recurrent arrhythmia and sudden death is analyzed over 6 years of follow-up surveillance. METHODS Between 1978 and December, 1984, 159 patients referred to the cardiac arrhythmia service of the Massachusetts General Hospital for evaluation of ventricular arrhythmias were included in this study. To be eligible for. inclusion, all patients had ventricular tachycardia induced by programmed cardiac stimulation while off all antiarrhythmic drugs and had a subsequent electrophysiologic study performed after at least 48 hours of loading with
Volume Number
115 2
Mexiletine
CONTROL
EPS
ON MEXILETINE (n=128)
ELECTROPHYSIOLOGIC (n=159)
STUDY
and class Ia drugs for VT
(EPS)
ALONE
EPS ON MEXILETINE CLASS IA DRUG (t-.=111)
DISCHARGED MEXILETINE
361
ON ALONE
(n=28)
DISCHARGED MEXILETINE CLASS IA
+
ON + DRUG
(n=64)
Fig.
1. Electrophysiologic studies in 159 patients.
either oral mexiletine alone or oral mexiletine in combination with other antiarrhythmic therapy. To be considered for treatment with mexiletine, all patients had either electrically inducible or spontaneous symptomatic ventricular tachycardia while on therapy with conventional antiarrhythmic drugs, or had been unable to tolerate these drugs. If a patient wastaking digoxin or beta blockers and it wasfelt these should not be stopped, they were continued throughout the period of electrophysiologic assessment. If mexiletine alone was ineffective, a class Ia antiarrhythmic drug was then added to mexiletine. The specific classIa antiarrhythmic agent chosen was determined by previous tolerance or by physician preference. The study protocol was prospectively designed. All patients evaluated with this protocol are presented in this study. Other patients presenting with ventricular tachycardia or fibrillation were managedby nonpharmacologic modalities if this was considered preferable by their physicians. Similarly, the decision to dischargea patient on mexiletine alone or in combination with a classIa drug wasmadeby the responsibleclinician, basedon the results of the electrophysiologic studies, on the availability of alternate therapies, and on patient preference. Patient population. In the population studied, there were 131 men and 28 women. The mean age was 58 + 11 years and the mean resting left ventricular ejection fraction was 32 t- 15%. The cardiac diagnosiswas coronary artery diseasein 137.patients (86%). Thirteen patients had dilated cardiomyopathy, four had mitral valve prolapse, three had other valvular heart disease,and one patient had hypertensive heart disease.In one patient there was no evidence of structural heart disease.Sixtyeight patients had documented sustained ventricular tachycardia (VT), 42 patients had been resuscitated from
cardiac arrest, 25 patients had documented nonsustained VT, 24 patients had syncope or near-syncope and documented high-grade ventricular ectopy. Following a control electrophysiologic study (EPS) on no antiarrhythmic drugs, 128 of the 159 patients (80%) were studied after oral loading with mexiletine alone. The remaining 31 patients were not tested on mexiletine alone but were tested on mexiletine in combination with a class Ia antiarrhythmic drug. Seventy-four of the 128 patients initially tested on mexiletine alone were subsequently tested on mexiletine in combination with a class Ia ant&rhythmic drug. Thesesubgroupsare outlined in Fig. 1. All patients who were discharged on mexiletine were reviewed on an outpatient basis3 months after discharge, and subsequently every 6 months. At each outpatient visit, the patient was asked about symptoms, had a physical examination, a If-lead ECG, and underwent routine biochemical and hematologic screening. Electrophysiologic studies. The catheterization procedure and cardiac stimulation protocol have beendescribed in detail elsewhere.18 Ventricular pacing wasperformed at the right ventricular apex with the use of a rectangular pulse of 2 msecduration applied at 2 to 5 times diastolic threshold. The ventricular stimulation protocol included: (1) Premature ventricular stimulation wasperformed with single and double extrastimuli during sinus rhythm and subsequently during fixed rate ventricular pacing at three basic drive cycle lengths (600, 500, and 400 msec). (2) If sustainedventricular tachycardia was not induced by the programmed electrical stimulation outlined above, then three- to five-beat bursts of rapid ventricular pacing were delivered asynchronously to the right ventricular apex at progressively shorter cycle lengths until 1:l capture could no longer be achieved, VT was induced, or a paced rate of
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300 bpm was reached. From 1982 on, three synchronized premature ventricular depolarizations during sinus rhythm were used instead of rapid ventricular pacing. Seventy of the 159 patients (44 % ) were studied after 1982. (3) Programmed premature ventricular stimulation with triple extrastimuli during fixed-rate pacing was only used when steps 1 and 2 above failed to induce VT in patients with documented sustained VT or with prior cardiac arrest. The ventricular stimulation protocol used during serial drug testing was identical to that used in the control study in each patient. The results in patients treated before and after the 1982 protocol change were similar. Definitions. VT was considered nonsustained if 5 or more but fewer than 100beats were reproducibly induced by programmed electrical stimulation. The mean cycle length of the tachycardia was calculated over three consecutive beats at least three beats after the onset of the tachycardia. Sustained VT was defined as tachycardia that lasted at least 100 beats or that was associatedwith hemodynamic collapseand required pacing or cardioversion for termination. VT was consideredsuppressedduring antiarrhythmic drug testing if the stimulation protocol was completed without the initiation of five or more nonstimulated ventricular responses. Ejection fraction was determined either from right anterior oblique left ventricular angiogramsor from gated nuclear cardiac blood pool scans. Sudden death was defined as witnesseddeath occurring unexpectedly in the presence or absence of acute symptoms of less than 6 hours’ duration, or any unwitnessed unexpected death where no noncardiac cause of death was identified. The time of follow-up was measuredto either the time of the most recent outpatient visit, to the date of stopping of the drug, to recurrence of symptomatic VT, or to death. Statistical analysis. Values are expressed as mean i standard deviation. Clinical, hemodynamic, and electrophysiologic variables were examined by stepwise logistic regressionanalysis, with the BMDP statistical software package (University of California, Los Angeles, Calif.)T2 Life-table analysiswas performed by meansof the generalized Wilcoxon (Mantel-Cox) statistic to test the equality of the survival curves. The Cox proportional hazards model was used to define the relationship of prognostic factors.23One-way and two-way analysis of variance, as appropriate, were usedto comparegroups for demographic differences. RESULTS
Therapy with mexiletine alone or mexiletine in combination with other antiarrhythmic therapy resulted in complete suppression of EPS-inducible VT in 62 of 159 (39%) patients. The presenting clinical arrhythmia was a potent predictor of suppression of electrically-induced VT. Patients with nonsustained VT or ventricular
fibrillation
as the
presenting arrhythmia were more likely to have suppression of VT by mexiletine. Electrically inducible VT was suppressed in 23 of 42 patients (55%)
who presented in ventricular fibrillation, and in 22 of 49 patients (45%) who presented with nonsustained VT or high-grade ventricular ectopic activity. In contrast, VT was suppressed in only 17 of 68 patients (25%) whose clinical arrhythmia was sustained VT (p < 0.005). Similarly, the nature of the provoked ventricular arrhythmia during control electrophysiologic study was predictive of the suppression of ventricular arrhythmias by mexiletine, as assessed by repeat electrophysiologic testing. When sustained VT was induced at the control electrophysiologic study, the efficacy of mexiletine, alone or in combination with other antiarrhythmic drugs, in suppressing sustained VT was 34% (35 of 104), while the efficacy in suppressing nonsustained VT was 43% (20 of 46), and in suppressing ventricular fibrihation it was 56% (five of nine) (p < 0.05). Clinical and patients tested
electrophysiologic observations in on mexiletine alone. One hundred
twenty-eight patients previously unresponsive to or intolerant of conventional antiarrhythmic drugs underwent electrophysiologic study on mexiletine alone (Fig. 1). At the control study (on no antiarrhythmic drugs), 75 of 128 patients (59% ) developed sustained VT, 46 of 128 (36%) developed nonsustained VT, and 7 of 128 (5 % ) developed ventricular fibrillation. When these 128 patients were subsequently studied after at least 48 hours of oral loading with mexiletine at a mean dose of 871 & 221 mg/day, sustained VT could still be induced in 62 of 128 (48 % ) and nonsustained VT could be induced in 36 of 128 (28%). Complete suppression of EPSinduced VT was observed in 29 of 128 (23%). Programmed electrical stimulation did not induce ventricular fibrillation in any of the patients. The effect of mexiletine alone on the arrhythmias induced at the control electrophysiologic study was variable. Of the 75 patients with sustained VT induced at the control study, 50 of 75 (67%) had persistent sustained VT on mexiletine, 11 of 75 (15%) developed nonsustained VT, and 14 of 75 (19%) had no inducible arrhythmias. Of the 46 patients with nonsustained VT, VT was no longer inducible on mexiletine alone in 14 (31%), nonsustained VT was inducible in 22 (49%), while sustained VT was provoked in nine patients (20%). Of the seven patients with ventricular fibrillation, nonsustained VT was induced in three on therapy with mexiletine and sustained VT was induced in a further three patients. VT was not inducible on mexiletine in one patient. The mean cycle length of the VT induced at control study in the patients suppressed on mexile-
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.**-. Mexiletine Mexiletine + Class 1A Drug
0
12
24
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48
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treated
with
mexiletine
tine alone was 261 + 66 mssec. In the patients who had VT induced on mexiletine, the mean VT cycle length overall increased to 301 -I- 76 msec compared with 267 +- 64 at control (p < O.Ol), but the effect of mexiletine on the cycle length of the tachycardia during EPS in individual cases was variable. The tachycardia cycle length on mexiletine was at least 50 msec longer in 28% of the patients, at least 50 msec shorter in 9% of the patients, and no more than 50 msec different in 38% of the patients. The mean ejection fraction of the patients in whom VT was suppressed on mexiletine alone was 30 rt_ 12 % . This was not significantly different from the mean ejection fraction of those not suppressed on mexiletine alone, 33 * 15%. Clinical and electrophysiologic observations in patients tested on mexiletine in combination with class la antiarrhythmic drugs. Of the patients who had EPS
on mexiletine alone and who still had VT induced, there were 80 patients who had a subsequent EPS on mexiletine in combination with a class Ia antiarrhythmic drug. The mean dose of mexiletine was 876 + 217 mg/day. The class Ia drug used was quinidine in 58 patients, procainamide in 46, and disopyramide in seven patients. VT could not be provoked in 24 of these 80 patients (30 % ) while they were taking mexiletine combined with a class Ia antiarrhythmic drug. Nonsustained VT was induced in a further 15 of 80 (19%) of patients. Sustained VT remained inducible in 41 of 80 (51% ) patients. A further 31 patients were not tested on mexiletine alone but did have a control EPS on no antiarrhythmic drugs and a follow-up EPS on mexiletine in
alone
and in combination
with
a class Ia
combination with a class Ia antiarrhythmic drug. On this combination antiarrhythmic therapy, VT was suppressed in 24 patients (30%). Sustained VT was induced in 18 of 31 (58%) patients, while nonsustained VT was provoked in a further 5 of 31 (16%) of these patients. There was no difference in the rates of suppression of VT between the different class Ia drugs used. Observations in patients discharged on mexiletine. A total of 92 patients were discharged on mexiletine. Thirty-eight of the patients were discharged on mexiletine alone and the other 62 were discharged on mexiletine in combination with a class Ia antiarrhythmic drug. The patient follow-up ranged from 1 week to 76 months, with a mean of 17 + 10 months. At 12 months follow-up the cumulative percentage of patients who had died from all causes was 14% and at 4 years it was 59 % . The cumulative percentage of patients who had either sustained an episode of symptomatic recurrent VT or who had died suddenly was 18% at 1 year and 38% at 4 years. The mean dose of mexiletine in the 30 patients discharged on mexiletine alone was 848 + 166 mg/ day. Follow-up ranged from 1 week to 60 months (mean 12 rt 9 months) in this subgroup. Six patients died suddenly and four patients had symptomatic recurrent VT (Figs. 2 and 3). In 7 of these 10 patients, EPS on mexiletine had shown that inducible VT had been suppressed. At 12 months followup the cumulative percentage of patients who had died from all causes was 21% and the cumulative percentage of patients who had an episode of symptomatic recurrent VT or who had died suddenly was
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364
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3. Sudden death and recurrent symptomatic ventricular tachycardia in patients treated with mexiletine alone and in combination with a classIa antiarrhythmic drug.
Fig.
I. Adverse reactions in 42 of 92 patients discharged Table
Nausea Anorexia Dizziness Tremor Ataxia Fatigue, lethargy Insomnia Abdominal pain Seizures Anxiety Impotence Psychosis Headaches
13 patients 11 patients 10 patients I patients 4 patients 3 patients 3 patients 2 patients 2 patients 2 patients 1 patient 1 patient 1 patient
18 % . At 4 years follow-up, 42 % had died suddenly or had suffered recurrent VT. The mean dose of mexiletine in the 62 patients discharged on mexiletine in combination with a class Ia antiarrhythmic drug was 866 + 228 mg/day. Follow-up ranged from 1 week to 76 months. The mean was 19 ~fr 11 months. Seven patients (9%) died suddenly and five patients (7 % ) had symptomatic recurrent VT (see Figs. 2 and 3). At 12 months the cumulative percentage of patients who had died from all causes was 10% and the cumulative percentage of patients who had died suddenly or had symptomatic recurrent VT was 11%. After 4 years’ follow-up surveillance, 25 % had either died suddenly or had suffered recurrent VT. Side effects. Side effects thought to be related to mexiletine therapy occurred in 42 patients (Table I).
In 8 (9%) of the 92 patients discharged on mexiletine, the drug had to be discontinued because of intolerable side effects. In a further 18 patients (20%), the dose of mexiletine had to be reduced. There were three episodes of recurrent VT but no episodes of sudden death in the patients in whom the dosage of mexiletine was reduced because of adverse effects. The most common side effects were either of the neurologic or gastrointestinal systems. Adverse side effects were often minimized by taking the medication with food. Seizures occurred after bolus injections of lidocaine in two patients taking mexiletine. Possible proarrhythmic responses were noted in 37 patients (23%) during serial electrophysiologic studies, but no clinical evidence of exacerbation of ventricular arrhythmias was noted in these patients. Precipitation or worsening of cardiac failure by mexiletine was not observed. DISCUSSION
The efficacy of mexiletine in suppressing premature ventricular beats has been demonstrated.“s4 Mexiletine was as effective as conventional class Ia drugs when these agents were compared.5-7 In addition, several recent studies*-lo suggest that mexiletine may suppress ventricular arrhythmias in some patients in whom conventional antiarrhythmic drugs have been ineffective. The number of patients studied has been small, however, and the results of at least one study are contradictory. Duff et a1.l’ found that the efficacy of mexiletine was enhanced by combining mexiletine and quinidine in patients with ventricular arrhythmias not suppressed by
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either drug alone. In addition, because lower doses of both drugs were used in the combined antiarrhythmic drug regimen, there was a lower incidence of adverse reactions. The efficacy of mexiletine for ventricular tachyarrhythmias as evaluated by programmed cardiac stimulation is variable. Four groups have reported’3. 17.20923 suppression of induced VT by mexiletine in about one third of their patients, while three groups reported minimal efficacy. The different reported effects of mexiletine may be related to lack of homogeneity of the patient populations studied, to differences in the stimulation protocols, or in the criteria for suppression of VT. In this study, VT Iprovoked by programmed cardiac stimulation was suppressed by mexiletine as a single antiarrhythmic agent in 23% of patients in whom convention,al antiarrhythmic drugs had been ineffective. Suppression of the induced arrhythmia was more likely in patients presenting with nonsustained VT or witb ventricular fibrillation than in patients presenting with sustained VT (p < 0.005). Long-term survival of patients with ventricular tachyarrhybhmias treated with mexiletine has been reported. Stein et al. l4 followed 107 patients discharged on treatment with mexiletine alone or in combination with other antiarrhythmic drugs. The discharge drug regimen was chosen on the basis of antiarrhytbmic efficacy demonstrated by serial cardiac monitoring or by EPS. Nineteen (17.8%) of the 107 patients died during an average follow-up period of 23 months. Eleven of these 19 patients died suddenly. The authors did not distinguish recurrent arrhythmia in patients treated with mexiletine as a sole antiarrhythmic agent from recurrent arrhythmia in patilents treated with combined antiarrhythmic drug regimens. Recently, Poole et a1.17reported survival in 32 patients treated with mexiletine and followed over an average period of 17 months of outpatient treatment. Thirteen (41%) of these patients died during follow-up; six (19%) died suddenly. The:re appeared to be no difference in outcome between patients treated with mexiletine alone, or with mexiletine combined with a class Ia antiarrhythlmic drug. However, there was evidence of antiarrhythmic efficacy in only 14 of these patients during serial EPS prior to hospital discharge. Of these 14 patients, 5 had recurrent arrhythmia, but none died suddenly. Mexiletine had to be discontinued in about 25% of patients during the outpatient follow-up phase because of intolerable side elects. In our study, the overall survival was 86% at 1 year and 61% at 4 years. Sudden deaths occurred in 13 patients, all in the first 2 years
Mexiletine
and class Ia drugs for VT
365
after discharge. Although there was a strong trend toward more sudden deaths and recurrent VT in patients treated with mexiletine alone in comparison to patients treated with mexiletine in combination with a class Ia drug, these trends did not reach statistical significance at the time of this analysis (Fig. 2). Comparison of clinical, angiographic, and electrophysiologic variables showed no significant differences between patients treated with mexiletine alone and those treated with the combined regimens. Caution in interpreting these observations is warranted, as the groups compared may have had differences in unmeasured variables that influence recurrent arrhythmia and sudden death. Nevertheless, the possibility that mexiletine in combination with other antiarrhythmic drugs is more effective than mexiletine alone in preventing sudden death should be considered and further investigated. Adverse reactions during chronic treatment with mexiletine were common, and necessitated dose reduction in 20% of patients and drug discontinuation in 9% despite initial tolerance to mexiletine while in the hospital. However, although adverse reactions are relatively common, they are generally predictable and rapidly reversible. We found24,25 a lower incidence of life-threatening side effects than when flecainide or amiodarone were used in similar populations. We conclude from this study that in patients with symptomatic ventricular arrhythmias in whom class Ia antiarrhythmic, agents have been ineffective and in whom VT is inducible at EPS, mexiletine alone or in combination with a class Ia antiarrhythmic drug will suppress inducible VT in about one third of the patients. VT is more likely to be suppressed in patients who present with nonsustained VT or ventricular fibrillation. The incidence of sudden death and recurrent VT was higher in patients treated with mexiletine alone than in patients treated with the combined antiarrhythmic drug regimens, although the difference was not statistically significant. The use of mexiletine was limited by the occurrence of side effects, necessitating dose reduction or drug withdrawal in 28% of the patients after discharge from the hospital. The additive efficacy of combining a class Ia agent to mexiletine as well as the improved arrhythmia-free survival noted warrant further investigation. REFERENCES
1. Woosley RL, Wang T, Stone W, et al. Pharmacology physiology, and pharmacokinetics of mexiletine. 1984;107:1058.
electro-
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2. Middleton D. Baseline pharmacology, electrophysiology and pharmacokinetics of mexiletine. Acta Cardiol 1980; 25(Suppl):45. 3. Talbot RG, Clark RA, Nimmo J, Neilson JMM, Julian DG, Prescott LF. Treatment of ventricular arrhythmias with mexiletine (Ko 1173). Lancet 1973;2:399. 4. Campbell NPS, Chaturvedi NK, Kelly JE, Strong JE, Shanks RG, Pantridge JF. Mexiletine in the management of ventricular dysrhythmias. Lancet 1973;2:404. 0. Campbell RWF, Talbot RG, Dolder MA, Murray A, Prescott LF, Julien DG. Comparison of procainamide and mexiletine in the prevention of arrhythmias after acute myocardial infarction. Lancet 19?5;1:1257. 6. Campbell NPS, Pantridge JF, Adgey AAJ. Long-term antiarrhythmic therapy with mexiletine. Br Heart J 19?8;40:?96. 7. Cady WJ, Wilson CS, Chambers WA, Miles RR, Holcslaw TL, Forder AD. Mexiletine in the treatment of refractory ventricular arrhythmias: a report of five cases. AM HEART J 1980;99:58. 8. Mehta J, Conti CR. Mexiletine, a new antiarrhythmic agent for treatment of premature ventricular complexes. Am J Cardiol 1982;49:455. 9. Abinader EG, Cooper M. Mexiletine: use in control of drug-resistant ventricular arrhythmia. JAMA 19?9;242:33?. 10. Podrid PJ. Lown B. Mexiletine for ventricular arrhvthmias. Am J Car&o1 1981;4?:895. 11. Heger JJ, Nattel S, Rinkenberger RL, Zipes DP. Mexiletine therapy in 15 patients with drug-resistant ventricular tachycardia. Am J Cardiol 1980:45:62?. 12. Duff HJ, Roden D, Primm RK, Oates JA, Woosley RL. Mexiletine in the treatment of resistant ventricular arrhythl mias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine. Circulation 1983;6?:1124. 13. 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;51:11?5. 14. Stein J, Podrid PJ, Lampert S, Hirsowitz G, Lown B. Long-term mexiletine for ventricular arrhythmia. AM HEART J 1984;107:1091.
15. 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;50:10?5. 16. Kim SG, Seiden SW, Matos JA, Waspe LE, Fisher JD. Discordance between ambulatory monitoring and pro: grammed stimulation in assessing efficacy of mexiletine in patients with ventricular tachycardia. AM HEART J 1986; 11214. 17. Poole JE, Werner JA, Bardy GH, Graham EL, Pulaski WP, Fahrenbruch CE, Greene HL. Intolerance and ineffectiveness of mexiletine in patients with serious ventricular arrhythmias. AM HEART J 1986;112:322. 18. DiMarco JP, Garan H, Ruskin JN. Mexiletine for refractory ventricular arrhythmias: results using serial electrophysioiogic testing. Am J Cardiol 1981;4?:131. 19. McGovern B, Garan H, Stavens CS, Schoenfeld MH, Estes NAM, Fallon MP, Ruskin JN. Treatment of refractory ventricular tachyarrhythmias with a combination of mexiletine and a class Ia antiarrhythmic drug. J Am Co11 Cardiol 1984;3:55?. 20. Schoenfeld MH, Whitford E, McGovern B, Garan H, Ruskin JN. Oral mexiletine in the treatment of refractory ventricular arrhythmias: the role of electrophysiologic technique. AM HEART J 1984;107:1071. 21. Greenspan AM, Spielman SR, Webb CR, Sokoloff NM, Rae AP, Horowitz LN. Efficacy of combination therapy with mexiletine and a type Ia agent for inducible ventricular tachyarrhythmias secondary to coronary artery disease. Am J Cardiol 1985;56:2??. 22. Dixon WJ, Brown MB, Engelman L, et al. BMDP statistical software. Los Angeles: University of California Press, 1981. 23. Cox DR. Regression models and life tables. J R Stat Sot (B) 19?2;34:198.24. McGovern B, Garan H, Kelly E, Ruskin JN. Adverse reactions during treatment with amiodarone hydrochloride. Br Med J 1983;287:1?5. 25. Platia EV, Estes NAM, Heine DL, et al. Flecainide: electrophysiologic and antiarrhythmic properties in refractory ventricular tachycardia. Am J Cardiol 1985;55:956.