Long-term mexiletine for ventricular arrhythmia

Long-term

mexiletine

for ventricular

arrhythmia

Use of mexiletine was evaluated in 313 patients with ventricular tachyarrhythmias refractory to conventional antiarrhythmic drugs. Therapy with mexiletine was continued long term in 107 patients who responded to the drug and were free of side effects during a short-term evaluation in hospital. During an average follow-up of 22.8 months (0.1 to 70 months), 19 patients died (17.8%). Eleven patients had sudden death (3.8% per year), while six patients died of progressive congestive heart failure and two of noncardiac causes. Nonfatal ventricular arrhythmia recurred in 14 patients (4.9% per year). Overall, 25 patients had recurrent arrhythmia (incidence of 5.5% per year). Side effects occurred in 13 patients after an average of 5.1 months and were primarily gastrointestinal and neurologic. Sixty-one patients (57%) have continued on mexiletine therapy for an average of 32.2 months (1 to 70 months). Outcome during long-term therapy was not related to drug dose, blood level, or presenting arrhythmia. We conclude that if therapy with mexiletine is carefully evaluated and individualized, the drug is effective and well tolerated during long-term use. (AM HEART J 107:1Ogl, 1984.)

Joseph Stein, M.D., Philip J. Podrid, M.D., Steven Lampert, M.D., Geoffrey Hirsowitz, M.D., and Bernard Lawn, M.D. Boston, Muss.

In the past decade clinical attention has been focused increasingly on the treatment of ventricular arrhythmias. This stems in large measure from contemporary appreciation that certain types of ventricular ectopic beats constitute a risk factor for sudden cardiac death among patients with ischemic heart disease.1-4 An additional factor stimulating interest in ventricular arrhythmias is the evergrowing number of patients resuscitated from cardiac arrest who are threatened with recurrence unless they are treated. 5,6Furthermore, the widespread use of ambulatory ECG monitoring and exercise stress testing has exposed potentially serious ventricular arrhythmias in many patients who suffer from significant myocardial dysfunction and are therefore at risk for sudden death. Identification of those at risk immediately confronts the physician with the problem of initiating an adequate antiarrhythmic drug prograra6 However, conventional agents such as quinidine, procainamide, and disopyramide are frequently either ineffective or toxic. The dire need to

From the Cardiovascular School of Public Health, Medicine, Brigham and

Laboratories, Department and the Cardiovascular Women’s Hospital.

of Nutrition, Harvard Division, Department of

Supported in part from funds of the Rappaport International Cardiology and by Grant No. HL-07776 from the National and Blood Institute, National Institutes of Health, U.S. Service, Bethesda, Maryland. Reprint Harvard 02115.

requests: School

Philip of Public

J. Podrid, Health,

Program of Heart, Lung Public Health

M.D., Department of Nutrition, 665 Huntington Ave., Boston, MA

expand the antiarrhythmic armamentarium has stimulated development of newer drugs. One such agent is mexiletine. Mexiletine is an oral lidocaine congener.7 Shortterm trials show that it is an effective antiarrhyth-

mic drug.8,g To date, data about its efficacy during extended use remain limited.‘O We used mexiletine to treat 313 patients referred for management of refractory ventricular arrhythmia. From among these, 107 patients who responded continued on

long-term mexiletine basis for this report.

therapy

and constitute

the

METHODS

Selection of patients for long-term therapy with mexiletine was based on drug testing with adherence to a protocol that consisted of four phases.6~g~11 Protocol

O-Control. Upon admissionof patients to the hospital, all antiarrhythmic drugs were discontinued with the exception of digoxin when administered for congestive heart failure and P-blocking drugs when prescribed for control of angina pectoris. After 24 to 36 hours off antiarrhythmic agents, each patient underwent 48 hours of ambulatory monitoring’* and a symptom-limited exercise test on a motorized treadmill with adherence to a Bruce protocol. 13, I4 Routine chemistries,antinuclear antibody (ANA), and complete blood count were obtained. Ventricular ectopic activity was categorized by the Lawn grading system6*? grade O-no ventricular premature beats (VPBs); grade IA-fewer than 30 VPBs per hour Phase

and less than one per minute; grade ML-fewer VPBs per hour and occasionally more than

than 30 one per 1091

1092

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et al.

American

2 18

PATIENT8

~““‘“‘^““‘~N’^“‘?

0

176 NO

LON

TERM

XILETINE’

v 208

‘s.moxllotlnr b..tdO c.othw

Inoffootlvo affOCt

drug

weterred

Fig. 1. Flowchart of entire population of 313 patients. Noninvasive techniques were used for drug evaluation in 267 patients while 46 had invasive electrophysiologic studies.From these two groups 107patients continued on long-term mexiletine therapy and 206 patients did not becauseof drug ineffectiveness,side effects, or preference for another agent.

minute; grade 2-more than 30 VPBs per hour; grade 3-multiform VPBs; grade 4A-repetitive VPBs/couplets; grade 4B-repetitive VPBs, ventricular tachycardia (more than three successivecycles); and grade 5-earlycycle VPBs (R on T). Data acquired during the control phasepermitted selection of the therapeutic strategy, namely, whether to proceed with targeting VPBs in order to assessdrug efficacy or whether to employ invasive electrophysiologic testing. A noninvasive approach was used when a highdensity or reproducible ventricular arrhythmia was present on either monitoring or exercise testing. Antiarrhythmic drug action wasthen evaluated by these means. Patients with a low-density or nonreproducible arrhythmia required invasive electrophysiologic testing for evaluation of drug efticacy. The protocol for electrophysiologic testing has been previously reported.16A hexapolar electrode catheter was inserted under fluoroscopic guidance into the left subclavian vein and positioned at the right ventricular apex. Programmed premature stimulation was performed during both sinus rhythm and ventricular pacing at a cycle length of 500msecwith the useof up to three extra stimuli (S,, S?, S,) with energies of twice and three times the middiastolic threshold. The endpoint for the study was the reproducible induction of nonsustained ventricular tachycardia defined asthree or more repetitive ventricular responsesoccurring after the last stimulated premature beat.

may, 1984 Heart Journal

Phase l-Acute drug testing. At the conclusion of the control period (phase 0) patients underwent acute drug testing93 I7 with mexiletine. A single dose of 400 mg of mexiletine was administered after a 30-minute baseline period of continuous recording by trendscription,‘s including exercise on a bicycle ergometer. Trendscription was continued for 3 hours with bicycle ergometry repeated each hour. Vital signswere measuredand an ECG strip at 50 mm/set was recorded hourly for P-R, QRS, and Q-T intervals. When evaluation was by means of invasive testing, electrophysiologic study was repeated 2 hours after the dose of mexiletine. Phase a-short-term maintenance. Phase 2 of the protocol permitted evaluation of both the effectivenessof mexiletine and patient tolerance during a short period of maintenance therapy. Three doses of mexiletine were administered daily with food to minimize gastrointestinal side effects, for a total of 900mg daily. If after 36 hours of therapy no side effects were encountered but arrhythmia persisted,asevaluated by telemetric monitoring, the daily dosecould be increasedto 1200mg. If sideeffects emerged during initial dosing, mexiletine dosewas reduced to 600 mg daily. Drug action wasevaluated after 36 hours on the maximally tolerated doseby repeat ambulatory monitoring and exercise testing or by electrophysiologic study. Blood samples for determinations of mexiletine level, complete blood count, routine chemistries,and ANA titer were obtained immediately after the exercise test or the electrophysiologic study. Phase 3-Long-term therapy, If mexiletine was the most effective and best tolerated of several antiarrhythmic drugs evaluated, it wascontinued long term. A second effective antiarrhythmic wasadministered in patients who had experienced ventricular fibrillation.” The adjunctive drug consistedof either digoxin, a B-blocker, or a second membrane-active agent. Noninvasive or invasive test procedureswere repeated when another antiarrhythmic drug was added to the program. Patients were followed every 3 to 6 months at the Cardiovascular Laboratories of the Harvard School of Public Health. Routine laboratory tests, an ECG, exercise testing, and ambulatory monitoring were performed at these visits. Long-term follow-up outcomeswere categorized as follows: A. Alive-free of arrhythmia B. Alive-recurrent arrhythmia 1. Symptomatic-with or without ECG documentation 2. Asymptomatic-with recurrent ventricular tachycardia during monitoring or exercisetesting C. Drug discontinued becauseof side effects D. Dead 1. Noncardiac 2. Cardiac a. Sudden death b. Nonsudden death Criteria for drug efficacy. The criteria for drug efficacy during phases 1 to 3 were as follows: noninuasiue approach (monitoring and exercise testing)-( 1) total

Volume Number

Table

107 5, Part 2

I. Patient

Long-term

profile Total p0pdatiCVZ

(%)

No. of patients Males Females Average age (yr) Cardiac diagnosis Coronary heart disease Cardiomyopathy Valvular heart disease No structural heart disease Presenting arrhythmia Ventricular fibrillation Ventricular tachycardia Sustained Nonsustained Congestive heart failure

313 238 (79) 75 (21) 55

Lang-term patients (%)

71 (67) 12 (11)

78 (25) 235 (75)

28 (26) 79 (74) 51 (48) 28 (26) 49 (46)

101 (32) 134 (43) 134 (43)

Table II. Daily dosage and blood level during mexiletine therapy in 107 patients Average follow-up Range Daily dose 600 mg 900 mg 1200 mg Average dose (mg) Average blood level*

107 80(75) 27 (25) 56

207 (66) 38 (12) 34 (11) 34 (11)

mexiletine

*Among

1093

long-term

22.8 mo 0.1-70 mo 48 52 7 800 (k221)

1.51 * 0.9 pg/ml

78 patients.

14 (13) 10 (9)

elimination of salvos of ventricular tachycardia, (2) 2 90% decrease in the frequency of couplets, and (3) > 50 % reduction in the number of VPBs per 24 hours and during exercise testing; and invasive approach (electrophysiologic study)-inability to provoke three or more ventricular responses during both sinus rhythm and ventricular pacing when up to three extrastimuli were added at twice and three times middiastolic threshold. Mexiletine blood assay. The method for determining mexiletine blood levels has been previously reported.lg One milliliter of plasma was mixed with 1.0 ml of O.lM sodium carbonate, to which 3 ml of diethyl ether was added. After centrifugation, the ethyl ether layer was separated and allowed to evaporate in a water bath. The residue was reconstituted with isopropyl alcohol and analyzed by high-pressure liquid chromatography. Statistical analysis. Categorical data were analyzed by the chi-square test. Analysis of variance was performed for multigroup comparisons. The criterion of significance was a p value of less than 0.05. Results are expressed as mean + SD. Probability of survival based on al1 cardiac death and sudden cardiac death and the analysis for recurrence of arrhythmia was calculated by means of life-table methods of Kaplan and Meier.20 RESULTS

Of the 313 patients who underwent phase 1 and phase 2 testing with mexiletine, 107 were selected for long-term therapy with this drug (Fig. 1). Mexiletine was chosen by virtue of efficacy and it proved to be the best tolerated of the antiarrhythmic agents tested. There were no differences in the presence and type of underlying heart disease, presenting arrhythmia, and percentage of patients with congestive heart failure among those receiving long-term mexiletine, compared with the 313 patients who had been tested with this drug (Table I). The daily dose of mexiletine and average blood

level for the 107 patients are presented in Table II. Mexiletine was the only cardioactive drug administered in 40 patients (37.4%), while 41 (36.3 % ) were also receiving a P-blocking agent and 54 (50.5%) were receiving digoxin. Mexiletine was used in combination with another antiarrhythmic drug in 26 patients (24.3%), including quinidine in 12 patients, phenytoin in three, amiodarone in five, aprindine in two, and disopyramide, propafenone, ethmozine, and procainamide in one patient each. The average follow-up for the 107 patients was 22.8 months (0.1 to 70 months) (Fig. 2). During the follow-up there were 19 deaths (17.8%), while 14 patients (13.1% ) had a nonfatal recurrence of arrhythmia and were subsequently treated with another ant&rhythmic agent. Mexiletine was discontinued in 13 patients (12.1%) because of side effects. The remaining 61 patients (57 % ) have continued on mexiletine for an average of 32.2 months (1 to 70 months). No adverse toxic reactions have been reported during the follow-up. Seventeen patients have developed positive ANA titers, but in all cases these have been stable and not associated with symptoms. Drug interactions with digoxin, b-blocking agents, or other membrane-stabilizing drugs were not observed. Mortality during mexiletine therapy. Nineteen patients died during mexiletine therapy. The average survival in this group was 11.4 months (range 0.1 to 54 months) (Table III). The annual mortality from all causes was 4.2%. Sudden cardiac death occurred in 11 of the 19 patients, or 3.6% per year (Fig. 3). In six cases the patient was found dead or was observed to collapse and was not resuscitated. Four patients who collapsed received bystanderinitiated cardiopulmonary resuscitation. Three were successfully resuscitated, but for this analysis are considered as having sustained sudden death. One patient died of unknown causes and is considered to have had sudden death. Of the 11 sudden cardiac deaths, six occurred within 2 months of initiating mexiletine therapy. Of

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III. Mortality patients Table

ALIVE

OFA& I 19(18%

wezxq

FOLLOWUP

22.8

Average follow-up Range Annual mortality Cause of death Noncardiac Cardiac Congestive heart Sudden death Annual sudden death

term mexiletine. Nineteen patients died during the followup period. Eight-eight patients are alive, but mexiletine therapy has been continued in only 61 patients (57%). The drug wasdiscontinued in the other 27 becauseof side effects or nonfatal recurrence of arrhythmia.

SlJDDENDEATHONMEXlLETlNE

.6250 .5000 3750 .2500

0.000

L

I 3.50

0.00

7.00

I 10.5

I 14.0

during mexiletine therapy in 19 11.4 mo 0.1-54 mo 4.2',,

failure mortality

2 17 6 11 3.6:;s

MONTHS

Fig. 2. Follow-up of the 107patients who received long-

CUMULATIVE PROPORTION SURVIVING

May, 1984 Heart Journal

I 17.5

I 21.0

I 24.5

I

I 31.5

26.0

I 35.0

I 38.5

I 42.0

I( 45.5 49.0

FOLLOW-UP (mos)

Fig. 3. Incidence of suddencardiac death amongthe 107

patients receiving long-term mexiletine therapy. Sudden death occurred in 11 patients, or 3.6% per year.

the remaining eight patients who died,

six succumbed to progressive congestive heart failure after an average of 14 months. In each case congestive failure was present before initiation of mexiletine therapy and the drug was not considered responsible for progression of cardiac decompensation. Two patients died of noncardiac causes.

Nonfatal recurrence of arrhythmia during mexiletlne therapy. Nonfatal ventricular arrhythmia recurred in

14 patients, or 4.9% per year (Fig. 4). Five patients had a recurrence of a sustained symptomatic ventricular arrhythmia that required an intervention for termination. In three patients mexiletine was discontinued when asymptomatic nonsustained salvos of ventricular tachycardia were observed during

routine follow-up monitoring or exercise testing. Three patients experienced symptoms suggestive of ventricular arrhythmia without electrocardiographic documentation. These patients were considered to have had a nonfatal recurrence. In two patients arrhythmia emerged in the setting of an acute myocardial infarction, while in one patient ventricular arrhythmia redeveloped during a transient period of hypokalemia (K+ = 2.6 mEq/L). Of the 14 patients with recurrent ventricular arrhythmia, eight (2.8 % per year) had well-documented arrhythmia and no evident acute precipitating factors. Overall 25 patients had a fatal or nonfatal recurrence of arrhythmia while receiving long-term mexiletine therapy (annual recurrence = 5.5%) (Fig. 5). The groups with and without arrhythmia recurrence were not distinguishable on the basis of the average daily dose and the average blood mexiletine level (Table IV). Incidence of recurrence was analyzed on the basis of the presenting arrhythmias, i.e., ventricular fibrillation, ventricular tachycardia with syncope, sustained ventricular tachycardia without syncope, or nonsustained ventricular tachycardia (Table V). When fatal and nonfatal recurrences are combined, the annual recurrence rates were similar among patients with the four types of presenting arrhythmia-3.4%, 7.1%, 4.9%, and 8.2%, respectively. The incidence of sudden cardiac death was also similar among these groups. In contrast, there were differences in recurrence based on underlying heart disease (Table VI). Annual arrhythmia recurrence in patients with a cardiomyopathy was 21.2% compared with 6.6%) 1.6%) and 2.3% in coronary, valvular, and normal heart groups, respectively (p < 0.05). Side effects. Intolerable side effects occurred in 13 patients, who discontinued taking mexiletine after an average of 5.1 months (Table VII). Gastrointestinal complaints, primarily nausea, occurred in eight patients despite scheduling doses with food. Three

Volume Number

107 5, Part 2

Long-term

‘OOo \-.8750 -

\ --L

-----\-

\-,

LB---

'C-w

.7500 -

CUMULATIVE PROPORTION FREE OF RECURRENCE

CUMULATl\iE PROPORTION FREEOF RECURRENT ARRHYTHMIAS

.6250 .5000 .3750 -

NON-FATALRECURRENCE ON MEXILETENE

---

.2500 -

.3750 t

t

,,-SCOANONON-FATAL RECURRENCEONMEXILETINE

0.00

0.000

Irttlltlttlll 10.5 7.00

17.5 14.0

\---\ "L--,,

.1250

3.50

1095

.6250

.2500

.1250

0.000 I-

mexiletine

24.5 21.0

31.5 28.0

38.5 35.0

45.5 42.0

3.50 49.0

0.00

FOLLOW-UP(mos)

10.5 7.00

17.5 14.0

245 21.0

31.5 28.0

38.5 35.0

45.5 42.0

49.0

FOLLOW-UP(mos)

Fig.

4. Nonfatal recurrence among the 107 patients receiving mexiletine on a long-term basis. Fourteen patients had a nonfatal recurrence of arrhythmia during the follow-up. This included both sustainedand nonsustained ventricular tachycardia.

Fig. 5. Incidence of all recurrent arrhythmias, including those who died suddenly (SCD) aswell asthose who had a nonfatal recurrence of arrhythmia. Arrhythmia recurred in 25 of the 107patients during the follow-up period. The annual recurrence rate was 5.5%.

patients had neurologic

Table

problems, including severe headaches, acute psychosis, and a profound change in personality, each occurring in one patient. One patient developed congestive heart failure that resolved upon discontinuance of mexiletine, and one patient had a skin rash. DISCUSSION

Antiarrhythmic drugs are in widespread and increasing use for suppression of ventricular arrhythmia. The goal of long-term therapy is the prevention of sustained ventricular arrhythmia or sudden cardiac death. However, data are scarce on the long-range effectiveness of specific drugs in patients known to be at risk. One group with enhanced predisposition for sudden death consists of patients who have recovered from acute myocardial infarction. A number of randomized trials have assessed efficacy of antiarrhythmic drugs in preventing sudden death in such patients.21-23 Results have been uniformly disappointing, but this may be due to statistical and methodologic problems with these trials. The limited numbers of patients enrolled and the short duration of follow-up may have precluded a statistically significant result. Patients were randomized to drug or placebo groups without regard to the type or frequency of arrhythmia present during the predrug period. Thus patients at low risk for sudden death were treated, thereby lowering the incidence of death in placebo-treated groups. Patients received uniform doses of ant&rhythmic drugs and no attempts were made to titrate dose to effect on arrhythmia or occurrence of side effects. Methods for defining arrhythmia either were not reported or

IV. Outcome as related to dose and blood level among 107 patients

Alive Sudden death Nonfatal recurrence Side effects The p value is not significant

Daily dose (4

Blood level (dml)

753 857 847 750

1.64 1.32 1.29 1.31

for all groups.

were inadequate. Finally, there was no certainty that the drug studied effectively suppressed arrhythmia, especially since the endpoint of the trials was death. This is especially important since each antiarrhythmic has the potential for aggravating ventricular arrhythmia and may precipitate sudden cardiac death.24 Although antiarrhythmic drugs have hitherto not been shown to protect post-myocardial infarction patients, encouraging reports have appeared dealing with other patient groups, especially those who have survived an episode of out-of-hospital sudden cardiac death. Graboys et al.‘j examined the outcome of 123 patients who had a documented history of malignant ventricular arrhythmia, namely, ventricular fibrillation or ventricular tachycardia with hemodynamic compromise. Therapy in these patients was guided by the suppression of advanced grades of VPBs. The protocol followed for drug selection was the same as outlined in the present study. These authors reported that when repetitive forms, primarily salvos of ventricular tachycardia, were suppressed by a drug, the incidence of sudden cardiac death was reduced.

May, 1984

1096

Table

Stein et al.

American

VF

VT (sync)

Sust VT

28 5

42

NSVT

0

8

5

12

28 2 4 6

(sync) = sustained ventricular tachycardia; SCD = sudden

tacbycardia with cardiac death.

4

Abbreviations: VF = ventricular fibrillation: VT without syncope; NSVT = nonsustained ventricular

Total

9 0 2 2 syncope;

Sust

VT = sustained

P

107

NS

11

NS

14 25

NS NS

ventricular

tachycardia

VI. Long-term follow-up and underlying heart disease

No. of patients SCD Nonfatal recurrence Total recurrence Abbreviations: cardiac death.

CAD

= coronary

artery

CAD

CMP

Valve

NHD

Total

71

12

14

10

107

3

1

0

11

12 19

1

0

1

14

NS NS

4

1

1

25

<0.05

disease;

CMP

= cardiomyopathy;

Valve

VII. Patients developing side effects during longterm mexiletine therapy No.

Side effect Gastrointestinal Neurologic Congestive failure Rash follow-up

P

7

Table

Average

Journal

V. Long-term follow-up and presenting arrhythmia

No. of patients SCD Nonfatal recurrence Total recurrence

Table

Heart

of

patients 8 3 1 1

= 5.1 months

Ruskin et a1.25studied a similar group of patients, although drug selection was based on invasive electrophysiologic studies. When an effective drug was identified, there were no instances of sudden death during a E-month follow-up. Although different methods were used to evaluate drug efficacy, the important conclusion is that if a drug suppresses either spontaneously occurring or provoked arrhythmia, recurrence is largely prevented. In this report mexiletine was selected for longterm therapy on the basis of its efficacy during short-term in-hospital evaluation. The frequency of sudden death and nonfatal recurrent arrhythmia was low. The lack of a carefully matched control population limits interpretation of our findings. However, the gravity of the presenting rhythm disorder precluded a randomized trial. Treatment was compelled by the threat of potentially lethal recurrence. One can reach tentative conclusions by comparing the results of this study with data already available.

= valvular

heart

disease;

NHD

= no structural

heart

disease:

SCD

= sudden

Since outcome may relate to the nature of the presenting rhythm disorder, we subgrouped our patients into those who presented with ventricular fibrillation, ventricular tachycardia with syncope, ventricular tachycardia without syncope, and nonsustained ventricular tachycardia. Studies from the Seattle Heart Watch program5 and from Goldstein et a1.26have reported that among patients surviving an episode of out-of-hospital cardiac arrest, the recurrence rate is 28% to 30% per year when empiric therapy is used. Seventy patients in our group had out-of-hospital sudden death resulting from either ventricular fibrillation (n = 28) or ventricular tachycardia with syncope (n = 42). These previous reports indicate that 21 patients would be expected to die suddenly during the first year. However, sudden death occurred in only nine patients during the 2-year follow-up. A second subgroup includes patients presenting with sustained ventricular tachycardia without syncope. The incidence of recurrent ventricular tachycardia in untreated patients is unknown. Therefore the only available comparison group includes those patients in whom arrhythmia remains inducible during electrophysiologic study despite antiarrhythmic drugs. In a report involving 239 patients with ventricular tachycardia who underwent electrophysiologic testing, Swerdlow et al.27 reported that when arrhythmia was still inducible despite administration of drugs, the first year mortality was 31%. Therefore eight of 28 patients with sustained ventricular tachycardia would be expected to have died

Volume Number

107

Long-term

5, Part 2

in the first year, but sudden death occurred in only two and nonfatal recurrence in four during the a-year follow-up. The occurrence of salvos of nonsustained ventricular tachycardia in patients with coronary artery disease and a recent myocardial infarction enhances the risk of sudden death. Bigger et al.4 have reported that in such patients the yearly sudden death rate was 30%. In the present study, there were no deaths in the subset of patients who presented with nonsustained ventricular tachycardia, although two of the nine patients had a nonfatal recurrence. The present data suggest that mexiletine therapy substantially improved survival among patients when compared with historic controls, although a definitive conclusion is precluded by the absence of a suitable control study group. Unlike the various randomized trials of antiarrhythmic drugs, we used a rigorously disciplined and systematic approach to drug selection and assessment of efficacy and safety. Mexiletine was chosen for long-term therapy if it suppressed repetitive ventricular arrhythmia, thereby defining an effective program for the individual patient. Similar results were obtained by DiMarco et al.28 They evaluated the response to mexiletine therapy with an electrophysiologic study protocol and continued the drug only in those patients who responded. Maintenance drug therapy requires not only that standards of efficacy be met but also that side effects be minimal. In previous studies, up to 60% of patients developed untoward effects that necessitated discontinuation of mexiletine.7*8 In contrast with these studies, only 12% of our patients developed side effects requiring withdrawal of the drug. We believe this low incidence of untoward reactions is due to the phases of drug evaluation and observation before long-term therapy was initiated. Mexiletine was chosen only if it was well tolerated during phase 1 and phase 2 studies. Merely gastrointestinal and neurologic side effects were encountered in the follow-up period extending for 200 patient-years. Positive ANA titers developed in 17 patients but a lupus-like syndrome did not occur, as it has in patients on procainamide therapy.2g Although 46% of patients had a history of congestive heart failure, only one patient developed cardiac decompensation during long-term therapy. This result is in marked contrast to our experience with disopyramide, during which 55% of patients with left ventricular dysfunction developed cardiac decompensation during long-term use of drug.30 We conclude that mexiletine therapy, if carefully

mexiletine

1097

individualized to the patient, is effective and well tolerated. When evaluated by a systemic protocol such as the one outlined here, long-term therapeutic success is to be expected. Side effects and recurrent ventricular arrhythmia occur infrequently. Mexiletine promises to be a useful addition to the armamentarium of antiarrhythmics. REFERENCES

1. Hinkle LE, Carver ST, Stevens M: The frequency of asymptomatic disturbances of cardiac rhythm and conduction in middle aged men. Am J Cardiol 24629, 1969. 2. The Coronary Drug Project Research Group: Prognostic importance of premature beats following myocardial infarction. Experience in the Coronary Drug Project. JAMA 223:1116, 1973. 3. Ruberman W, Weinblatt E, Goldberg JD, Frank LW, Chaudhary BS, Shapiro S: Ventricular premature complexes and sudden death after myocardial infarction. Circulation 64:297, 1981. 4. Bigger JT, Weld FM, Rolnitzky LM: Prevalence, characteristics and significance of ventricular tachycardia (three or more complexes) detected with ambulatory electrocardiographic recording in the late hospital phase of acute myocardial infarction. Am J Cardiol 46:815, 1981. 5 Shaffer WA, Cobb LA: Recurrent ventricular fibrillation and modes of death in survivors of out of hospital ventricular fibrillation. N Engl J Med 293:259, 1975. 6. Graboys TB, Lown B, Podrid PJ, DeSilva R: Long-term survival of patients with malignant ventricular arrhythmias treated with antiarrhythmic drugs. Am J Cardiol 50:437, 1982. 7. Campbell NPS, Kelly JG, Shanks RG, Chaturvedi NC, Strong JE, Pantridge JF: Mexiletine in the management of ventricular dysrhythmias. Lancet 2:404, 1973. 8. Campbell NPS, Pantridge JF, Adgey AAJ: Mexiletine in the management of ventricular arrhythmias. Eur J Cardiol6:245, 1977. 9. Podrid PJ, Lown B: Mexiletine for ventricular arrhythmias. Am J Cardiol 47:895, 1981. 10. Talbot RG, Julian DG, Prescott LF: Long-term treatment of ventricular arrhythmias with oral mexiletine. Am Heart J 91:58, 1976. 11. Lown B, Podrid PJ, DeSilva RA, Graboys TB: Sudden cardiac death. Management of the patient at risk. Curr Probl Cardiol4:1, 1980. 12. Lown B, Calvert AF, Armington R, Ryan M: Monitoring for serious arrhythmias and high risk of sudden death. Circulation Sl(suppl 1):189, 1975. 13. Jelinek MV, Lown B: Exercise stress testing for exposure of cardiac arrhythmia. Prog Cardiovasc Dis l&467, 1974. 14. Doan AE. Peterson DR. Blackman JR. Bruce RA: Mvocardial ischemia ‘after maximal exercise in healthy men. A method of detecting potential coronary heart disease. AM HEART J 69:11,

1965.

Lown B, Wolf M: Approaches to sudden death from coronary heart disease. Circulation 44:130, 1971. 16. Podrid PJ, Schoeneberger A, Lown B, Lampert S, Matos J, Porterfield J, Raeder E, Corrigan E: Use of nonsustained ventricular tachycardia as a guide to antiarrhythmic drug therapy in patients with malignant ventricular arrhythmia. 15.

AM HEART J 105:181.

1988.

Gaughan CE, Lown B, Lanigan J, Voukydis P, Besser W: Acute oral testing for determining antiarrhvthmic drue efficacy. I. Quinidine. Am J Cardiol 36:677, 1976. 18. Lown B, Matta RJ, Besser HW: Programmed trendscription. A new approach to electrocardiographic monitoring. JAMA 232:39, 1975. 17.

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19. Ridgefield CT: Company procedure for analysis of plasma. 1977, Boehringer Ingelheim. 20. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 58:457, 1958. 21. Collaborative Group: Phenytoin after recovery from myocardial infarction. Controlled trial in 568 patients. Lancet 2:1055, 1971. 22. Jones DT, Kostuk WJ, Gunton RW: Prophylactic quinidine for the prevention of arrhythmia after acute myocardial infarction. Am J Cardiol 33:655, 1974. 23. Ryden L, Arnman K, Conradson TB, Hofuendahl S, Mortensen 0, Sonedgard P: Prophylaxis of ventricular tachyarrhythmias with intravenous and oral tocainide in patients with and recovering from acute myocardial infarction. AM HEART J 100:1006, 1980. 24. Ruskin JN, McGovern B, Garan H, DiMarco J, Kelly E: Antiarrhythmic drugs-A possible cause of sudden death. N Engl J Med 309:1302, 1983.

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May, 1984 Heart Journal

25. Ruskin JN, DiMarco J, Garan H: Out-of-hospital cardiac arrest. Electrophysiologic observations and selection of longterm antiarrhythmic therapy. N Engl J Med 303:607, 1986. 26. Goldstein S. Landis dR. Leiahton R: Characteristics of the resuscitated out-of-hospital cardiac arrest victim with coronary heart disease. Circulation 64:977, 1981. 27. Swerdlow CD, Winkle RA, Mason JW: Determinants of survival in patients with ventricular tachyarrhythmias. N Engl J Med 308:1436, 1983. 28. DiMarco JP, Garan H, Ruskin JN: Mexiletine for refractory arrhythmias. Results using serial electrophysiologic testing. Am J Cardiol 47:131, 1981. 29. Kosowsky BD, Taylor J, Lown B, Ritchie RJ: Long-term use of procainamide following acute myocardial infarction. Circulation 47:1204, 1973. 30. Podrid PJ, Schoeneberger A, Lown B: Precipitation of congestive heart failure by oral disopyramide. N Engl J Med 320:614, 1980.