Flecainide: Steady state electrophysiologic effects in patients with remote myocardial infarction and inducible sustained ventricular arrhythmia

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Flecainide: Steady State Electrophysiologic Effects in Patients With Remote Myocardial Infarction and Inducible Sustained Ventricular Arrhythmia CHARLES R. WEBB, MD, FACC, JOEL MORGANROTH, MD, FACC, SHEILA SENIOR, RN, SCOTT R. SPIELMAN, MD, FACC, ALLAN M. GREENSPAN, MD, FACC, LEONARD N. HOROWITZ, MD, FAce Philadelphia, Pennsylvania

The effect of f1ecainide in 24 patients with inducible sustained ventricular arrhythmia and a history of remote myocardial infarction was determined. Flecainide was administered in oral doses individually adjusted to suppress all spontaneous ventricular tachycardia and 80% of ventricular premature complexes on 24 hour ambulatory (Holter) electrocardiography. Antiarrhythmic therapy, as assessed by Holter monitoring, was adequate in 20 (83%) of the study patients at a mean dose of 144 ± 28 mg every 12 hours; the mean plasma f1ecainide level was 583 ± 329 ng/ml, In 18 patients, the mean sinus cycle length, sinus node recovery time and atrial, atrioventricular nodal and ventricular refractory periods were unchanged. The AH interval increased by 15 ± 15%, the HV interval by 35 ± 32% and the QRS duration by 24 ± 21 %. Toxicity or failure to suppress ventricular premature complexes and ventricular tachycardia by Holter monitoring precluded electrophysiologic study with f1ecainide in four patients; two patients refused electrophysiologic study with f1ecainide for nonmedical reasons. Ventricular tachycardia was not

Sudden cardiac death due to arrhythmia is a major health problem in the United States (I), particularly in survivors of remote myocardial infarction (2-4). F1ecainide effectively suppresses ventricular premature depolarizations in stable patients (5-9), and has been shown to be useful in patients with nonsustained ventricular tachycardia (10, I I). However, the experience in patients with a history of rnyoFrom the Clinical Cardiac Electroph ysiology Laboratory . Likoff Cardiovascular Institute . Hahncmann University. Philadelphia. Pennsylvania . This study was presented in part at the 34lh Annual Scientific Session of the American College of Cardiology. Anaheim . California . March 1985. Manuscript received August 20, 1985; revised manuscript received February 10, 1986, accepted February 20 , 1986. Address for reprints: Charles R. Webb, MD, Cardiac Electrophysiology. WC-56? Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202. © 1986 by the American College of Cardiology

inducible in 4 (22%) of 18 patients receiving f1ecainide. Sustained arrhythmia remained inducible in 14 patients (78%) despite evidence of antiarrhythmic efficacy on Holter monitoring, but the rate of the induced ventricular tachycardia was slower and symptoms were alleviated during ventricular tachycardia in 10 (56%) of 18 patients. The 4 patients who had no inducible ventricular tachycardia with f1ecainide, and the 10 patients who had inducible ventricular tachycardia with a longer cyclelength and alleviation oftheir symptoms, have been followed up as outpatients for 16 ± 7 months. No death or spontaneous arrhythmic event has occurred among the four patients with no inducible arrhythmia. Ventricular tachycardia has occurred in 4 of to and sudden cardiac death in I of 10 patients whose tachycardia remained inducible with f1ecainide. Thus, even after optimal f1ecainide dosing by Holter monitoringcriteria, electrophysiologic assessmentof drug efficacy provides for additional risk stratification. (J Am Coil Cardiol 1986;8:214-20)

cardial infarction and inducible sustained ventricular tachycardia is limited (12,13). The purpose of this study was to I) determine the safety of ftecainide administration and electrophysiologic evaluation in this patient population, and 2) determine the effect of ftecainide at doses optimized by ambulatory electrocardiographic monitoring on reproducibly inducible sustained ventricular tachycardia.

Methods Study patients. The study sample consisted of 24 patients with a history of remote (8 ± 7 years, mean ± SD) myocardial infarction and reproducibly inducible sustained ventricular tachyarrhythmia by the ventricular extrastimulus technique. The clinical indications for electrophysiologic 0735- 1097/86/$3.50

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study were sudden cardiac death events in nine patients, sustained ventricular tachycardia in seven, nonsustained ventricular tachycardia in three and syncope of unknown origin in five. Sustained ventricular arrhythmia during programmed electrical stimulation was defined as a rapid heart rhythm (rate> 100 beats/min) of ventricular origin for 30 seconds or more, or resulting in hemodynamic compromise or symptoms requiring termination in less than 30 seconds. Ventricular fibrillation was said to be the induced arrhythmia if within 3 seconds after the initiation of a sustained arrhythmia, fibrillation was apparent on any surface electrocardiographic lead. There were 21 men and 3 women whose age ranged from 38 to 75 years (mean 65 ± 8). According to the New York Heart Association functional classification, 14 were in class II, 8 in class III and I each in classes I and IV. The mean radionuclear left ventricular ejection fraction was 34 ± 16%. Each patient had previously undergone a mean of 1.7 ± 1.6 clinical and 1.3 ± 1.1 electrophysiologic trials with standard or investigational antiarrhythmic agents that were unsuccessful because of drug inefficacy (95 .8%) or intolerance (34.3%), or both. Study design. Each patient was hospitalized on continuous telemetric monitoring. After written informed consent was obtained (protocol approved by the Hahnemann Institutional Review Board on January 2, 1983) , flecainide acetate , 100 mg, was administered orally every 12 hours for 3 days to achieve steady state levels. The patient was examined and his or her medical record was reviewed daily by the research nurse (S.S .) and a physician investigator to assure adherence to the protocol and to determine any symptomatic or objective effects. On the fourth day, if no ventricular tachycardia was present on telemetric monitoring, a 24 hour Holter electrocardiographic recording was made. If complete ventricular tachycardia and 80% ventricular premature complex suppression were achieved, electrophysiologic testing was performed. However, if either of these variables was not achieved and the plasma flecainide level was less than 1,000 ng/ml, the dose was increased to 150 mg orally every 12 hours and the arrhythmia was reevaluated on the fourth day of this higher dosage regimen to determine efficacy or the need for a further dosage increase to 200 mg every 12 hours for 3 days . If suppression of ventricular premature complexes by Holter monitoring was not demonstrated on 200 mg every 12 hours, the drug was considered inefficacious, electrophysiologic testing was not performed, flecainide was discontinued and other antiarrhythmic therapy was offered to the patient. Once a plasma level of 1,000 ng/ml was achieved, the dose was not further increased because previous data (14) had demonstrated a higher incidence of toxicity at this level. Noninvasive evaluation of antiarrhythmic efficacy. Twenty-four hour Holter monitor recordings were made on

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a reel to reel tape recorder (model445B Electrocardiocorder; DelMar Avionics) and a computer analysis of the taped recordings was performed (Cardio-Data Systems of United Medical Corporation) . The accuracy and quality control of this method have been published previously (15). Proarrhythmic effect was assessed by the criteria of Morganroth and Horowitz (14). Predrug electrophysiologic evaluation. All antiarrhythmic drugs were discontinued at least five drug halflives before the predrug study. Digoxin, beta-adrenergic blocking agents and nifedipine were continued at their longterm dosage schedule throughout the investigational period. All patients were studied in the postabsorptive state under mild diazepam sedation. Three intracardiac electrode catheters were inserted through the femoral veins by the Seldinger technique with 10 to 15 ml of bupivacaine, 0.25% weight/volume in saline solution, infiltrated for local anesthesia. A 6F quadripolar electrode catheter was positioned in a stable position in the high right atrium and another at the right ventricular apex with fluoroscopic monitoring . A 7F tripolar electrode catheter was positioned at the atrioventricular (AV) junction in a position to optimally record a proximal His bundle potential. Surface leads I, aVF and V" the three intracardiac electrograms and 10 ms time lines were displayed simultaneously on a multichannel oscilloscope (Electronics for Medicine VR-16) and recorded on magnetic tape (Honeywell model 5600c). For determination of cycle lengths, morphology and duration of ventricular tachycardia, hard copy recordings were made with an eight channel ink-jet recorder (Siemens-Elema Mingograph) at a paper speed of 100 mm/s . Intraatrial conduction, AH and HV intervals were determined at a paper speed of 250 mm/s. Programmed intracardiac electrical stimulation was performed with a constant current DTU 101 programmable stimulator (Bloom Associates, Ltd.). Stimulation was performed at twice late diastolic threshold with a rectangular waveform 1.0 ms in duration and a stimulus amplitude of less than 2.0 rnA. Standard techniques were used for the determination of sinus node recovery times after multiple atrial pacing cycle lengths, the atrial refractory period, atrioventricular (AV) nodal effective and functional refractory periods and the maximal pacing cycle length resulting in AV nodal block. The ventricular stimulation protocol consisted of scanning electrical diastole with single ventricular extrastimuli during sinus rhythm and ventricular pacing at 600 ms and then at 450 seconds. Next, double ventricular extrastimuli were given during sinus rhythm and the two pacing cycle lengths, and finally triple ventricular extrastimuli were delivered. If no sustained arrhythmia was induced by stimulation at the right ventricular apex , the catheter was repositioned at the right ventricular outflow tract and the protocol was repeated. The end point of ventricular stimulation was

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induction of sustained ventricular arrhythmia or completion of the entire protocol if sustained arrhythmia was not induced. Each patient in this study group had sustained ventricular tachyarrhythmia induced from the right ventricular apex during the predrug study. If the patient's symptoms and hemodynamic status during induced tachycardia permitted, arrhythmia termination was attempted by a hierarchical approach: first single ventricular extrastimuli, then double ventricular extrastimuli, overdrive pacing, overdrive and extrastimuli and finally cardioversion. In two patients who remained alert during sustained monomorphic ventricular tachycardia, ventricular pacing methods failed to terminate the tachycardia and lidocaine, 50 mg, was administered intravenously. Electrophysiologic drug evaluation. After steady state drug levels were achieved and noninvasive evidence of arrhythmia suppression was documented, the electrophysiologic protocol was repeated. The ventricular stimulation protocol was followed until a sustained ventricular arrhythmia was induced, or the entire protocol was completed at two right ventricular sites. A patient was said to have no inducible ventricular arrhythmia if no more than 15 consecutive repetitive ventricular responses were induced. The most severe symptom experienced during the induced arrhythmia before and with flecainide therapy was scored by an arbitrary ordered ranking system for nonparametric statistical analysis (Table 1) (16). Determination of serum f1ecainide levels. The concentrations of flecainide in plasma were determined by gasliquid chromatography with electron capture detection (Riker Laboratories) (17). Outpatient follow-up. Patients who had no inducible arrhythmia were maintained with flecainide as outpatients. Patients with inducible arrhythmia with flecainide also had long-term follow-up with oral flecainide if the induced ventricular tachycardia cycle length was increased by 100 ms or more, symptoms were alleviated and cardioversion was not required for termination of the tachycardia. Each patient who continued receiving oral flecainide was examined in the outpatient clinic after 6 weeks and then every 3 months. No patient received concurrent antiarrhythmic therapy or underwent cardiac surgery during the study period. Statistical methods. Data are expressed as the arithmetic mean ± SO. Drug effects on electrophysiologic measurements were compared by the paired t test. Correlations were Table 1. Scoring System for Severity of Symptoms I 2 3 4 5 6

=

No arrhythmia

= Asymptomatic during arrhythmia = Palpitation = Angina pectoris =

Near syncope

= Loss of consciousness

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evaluated by linear regression analysis to determine Pearson's r value. Nonquantitative symptoms and laboratory data were compared by the Wilcoxon test statistic (16).

Results Predrug electrophysiologic study. Predrug evaluation of 24 patients revealed inducible sustained ventricular arrhythmia in each patient. Ventricular tachycardia was induced by a single ventricular extrastimulus in 3 patients, double extrastimuli in 12 and triple extrastimuli in 6. Ventricular fibrillation was induced in three patients (in two by double extrastimuli and in one by triple extrastimuli). The cycle lengths of the predrug ventricular tachycardias ranged from 160 to 410 ms (mean 262 ± 59). Loss of consciousness or near-syncope occurred during the induced tachyarrhythmia in 20 patients, angina pectoris in 2 and palpitation in 2. Termination of the tachycardia required cardioversion in 13, pacing in 9, acute intravenous drug (lidocaine) administration in I and both lidocaine and pacing in 1 patient. Noninvasive results (Holter monitoring). Predrug 24 hour Holter monitoring revealed a mean of 199 ± 460 ventricular premature complexes/h, 406 ± 1,260 ventricular premature complex pairs/day, 19 ± 59 nonsustained ventricular tachycardia episodes/day and 66 ± 195 ventricular tachycardia complexes/day. Suppression of all spontaneous ventricular tachycardia and more than 80% of ventricular premature complexes on 24 hour Holter monitoring was achieved with flecainide in 20 (83%) of the 24 patients. Noninvasive monitoring data during flecainide therapy resulted in elimination of four patients from the study before electrophysiologic study because of inadequate suppression of ventricular premature complexes or ventricular tachycardia in two patients and the occurrence of second degree heart block in two patients. No study patient had evidence of a proarrhythmic effect from flecainide. The mean ftecainide dose was 144 ± 28 mg every 12 hours and the mean plasma flecainide level was 583 ± 329 ng/ml in patients in whom arrhythmia suppression was achieved. The mean dosage and plasma flecainide level for patients demonstrating inefficacy by Holter monitoring were 150 ± 50 mg twice a day and 694 ± 144 ng/ml, respectively. The mean dosage and level for those developing heart block were 125 ± 25 mg twice a day and 845 ng/ml, respectively. Steady state electrophysiologic data. Although asymptomatic, two patients refused eiectrophysiologic evaluation with flecainide. Therefore, electrophysiologic data are available for 18 patients both in the predrug state with no antiarrhythmic agents and with a noninvasively titrated flecainide dose. The mean QRS, AH and HV intervals increased significantly, but there was considerable interpatient variation. The JT intervals were unchanged (Table 2).

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Table 2. Electrophysiologic Effects of Flecainide (in milliseconds) Before Drug Administration Sinus cycle length Sinus node recovery time Corrected sinus recovery time Atrial refractory period AV nodal effective refractory period AV nodal functional refractory period AH interval HV interval QRS interval JT interval Right ventricular effective refractory period

850 ± 1,242 ± 344 ± 268 ± 405 ± 487 ± 109 ± 54 ± 117 ± 266 ± 260 ±

146 217 98 32 110 102 21 7 18 47 14

With F1ecainide 838 1,330 477 282 398 498 124 76 144 262 276

± 147 ± 567 ± 152 ± 53 ± 86 ± 99 ± 23 ± 17 ± 25 ± 57 ± 33

p Value NS NS NS NS NS NS 0.04 <0.001 <0.01

NS NS

AV = atrioventricular.

The sinus cycle length, the uncorrected and corrected sinus node recovery time, atrial refractory period and AV nodal effective and functional refractory periods were normal for each patient at the predrug study and were uncnanged with therapeutic doses of flecainide (Table 2), except in one case where the uncorrected and corrected sinus node recovery times increased from normal to 3.27 and 2.54 seconds, respectively, without sequelae, despite continuation of flecainide. There was no change in the mean right ventricular effective refractory periods. Although there was an increase in six patients, neither the effective refractory period nor the increment in refractory period correlated with the cycle length of the induced ventricular tachycardia or the number of extrastimuli required for induction. Flecainide prevented induction of sustained ventricular tachycardia in 4 (22%) of 18 patients (Table 3). The cycle length of the induced tachycardia was increased in each of the remaining patients, except one who had ventricular fibrillation before drug administration and while receiving ftecainide. Among the patients with inducible sustained ventricular tachycardia with flecainide, the cycle length of the induced tachycardia correlated with the plasma flecainide level (r = 0.65, P = 0.01). Ten patients had tachycardia with a cycle length at least lOOms longer than that of the predrug tachycardia and did not require cardioversion for termination of the arrhythmia (Fig. 1). The symptoms and characteristics of the sustained ventricular arrhythmias induced while patients received flecainide were compared with the predrug data in 14 patients. Although II (79%) of 14 lost consciousness during ventricular tachycardia before administration, only 4 (29%) of 14 lost consciousness during ventricular tachycardia while receiving flecainide. Nonparametric comparison revealed an overall decrease in symptoms (p = 0.01). There was no significant change, however, in the modes of induction. Outpatient follow-up. The four patients who had no inducible ventricular tachycardia with flecainide have had no ventricular tachycardia or sudden cardiac death during

20 ± 3 months of outpatient follow-up. Among the 10 patients with inducible ventricular tachycardia, 4 have had a nonfatal clinical occurrence of ventricular tachycardia and I died suddenly during 14 ± 7 months of follow-up.

Discussion F1ecainide is a potent suppressor of premature ventricular complexes in humans (5-9). Doses that suppress these complexes and nonsustained ventricular tachycardia slow conduction in all cardiac tissues, as indicated by increased AH, HV and QRS intervals. However, doses that suppress arrhythmias on Holter monitoring do not necessarily prevent induction of ventricular tachycardia at electrophysiologic

Table 3. Arrhythmias Induced and Symptoms Before Drug Administration

With Flecainide

Patient

ARR

Symp

ARR

Symp

I 2

S-VT S-VT S-VT S-VT S-VT S-VT VF S-VT S-VT S-VT S-VT S-VT S-VT S-VT S-VT S-VT S-VT S-VT

6 4 5 5 5 6 6 6 4 6 3 6 5 6 6 6 6

S-VT S-VT None S-VT S-VT None VF S-VT S-VT S-VT S-VT None None S-VT S-VT S-VT S-VT S-VT

3 3

3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18

5

I

3 2 I

6 6 4 5 2 2 2 2 4 2 2 6

ARR = arrhythmia induced; S-VT = sustained ventricular tachycardia; Symp = symptoms during the laboratory-induced arrhythmia, coded as described in Table I; VF = ventricular fibrillation.

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600

x

500

x=423msec

u... .§4oo s:

g.... ...

-l

~

U

~

300 X=268 msec

200 N:12

p
Pre Drug

Figure 1. Steady state effect of oral f1ecainide therapy on the cycle length of inducible sustained ventricular tachycardia (VT). All patients with sustained ventricular tachycardia induced with fiecainide had an increase in the ventricular tachycardia cycle length . Solid lines represent patients who had an increase in the tachycardia cycle length of 100 ms or more and did not require cardioversion for termination of the tachycardia and were discharged from the hospital receiving flecainide therapy. The dotted lines represent patients who had an increase in' the tachycardia cycle length of less than 100 ms; flecainide administration was stopped in these patients and other antiarrhythmic therapy was prescribed.

study. The latter, however, may serve to further substratify patients into levels of risk of arrhythmia during therapy. Noninvasive data. The Flecainide-Quinidine Research Group (q) found elimination of all spontaneous ventricular tachycardia, all couplets and at least 80% of premature ventricularcomplexeson a 24 hour Holter monitorrecording in 68% of patients who were selected because of frequent (2: 30th) premature ventricular complexes. In our study group, 20 (83%) of 24 patients with a remote myocardial infarction and inducible sustained ventricular tachycardia met these criteria while receiving flecainide. Thus, flecainide is also a potent suppressor of arrhythmia as evaluated by Holter monitoring criteria in patients with electrophysiologically inducible arrhythmias and a history of myocardial infarction. Electrophysiologic measurements. Increasing QRS, AH and HV intervals suggest a generalized slowing of myo-

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cardial conduction. The variable prolongation of the HV interval, occasionally from a normal predrug mean value of 54 ± 7 to 76 ± 17 ms, suggests that cautious evaluation of patients with underlying His-Purkinje disease, perhaps by electrophysiologic study during and after flecainide loading, may be prudent. In contrast to previous clinical reports (12,18,19), we found no significant mean increase in the right atrial or ventricular effective refractory periods. Although an increase of greater than lOOms did occur in three patients, this did not correlate with the magnitude of the increase of the cycle length of the induced ventricular tachycardia. Therefore, the increase in the ventricular tachycardia cycle length in the absence of a change in the ventriculareffective refractory period suggests a profound slowing of intramyocardial conduction as the mechanism of slowing of the ventricular tachycardia rates. Comparison with previous electrophysiologic studies with ftecainide. The success rate for prevention of induction of ventricular tachycardia by flecainide in our study compares favorably with experience with other antiarrhythmic agents (20), particularly when one considers that our study group had failed a mean of 3.0 trials with other agents. Nonetheless, the success rate in our study is lower than previously reported for flecainide . This may be explained by more stringent inclusion criteria. All of our patientshad a remotemyocardial infarction. Furthermore, only patients with inducible sustained ventricular arrhythmias at the predrug study were included because the clinical implications of serial drug testing for nonsustained ventricular tachycardia are currently unclear. Anderson et al. (12) studied five patients with inducible sustained ventricular tachycardia and found that in two (40%) the tachycardia was noninducible with flecainide; neither of these patients had evidence of organic heart disease. However, among patients with only nonsustained ventricular tachycardia inducible at the predrug study, flecainide prevented tachycardia induction in 7 (70%) of 10 patients. Similarly, Flowers et al. (18) reported noninducibility in 65% of patients, but only half (21 of 40) had sustained ventriculartachycardia at the predrug study, 8 did not have organic heart disease and the mean left ventricular ejection fraction was 45%. Both studies included many patients with only nonsustained ventriculartachycardia inducible. Higher drug success rates for nonsustained ventricular tachycardia than for sustainedventriculartachycardiahave beenreported previously for other antiarrhythmic drugs and drug combinations (20). Apparently this concept also applies to the evaluation of flecainide . In our study sample of patients with remote myocardial infarction and reproducibly inducible sustained ventricular tachycardia. 22% of those studied by the ventricular extrastimulus technique with triple ventricular extrastimuli at three different drive cycle lengths at two right ventricular

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sites had no inducible ventricular tachycardia with flecainide. Proarrhythmic effect. Proarrhythmic events were reported in 7% of patients receiving flecainide in a multicenter study (14). Platia et al. (19) reported a 29% incidence of worsening of arrhythmia at electrophysiologic study as compared with the baseline arrhythmia induced . Despite previous reports of serious proarrhythmic events, particularly in patients with coronary artery disease , compromised ejection fraction and lethal arrhythmias, we observed no proarrhythmic effect in this group of patients. The absence of a proarrhythmic effect might be explained by avoidance of concomitant use of other antiarrhythmic agents, careful upward dose titration with increases no earlier than every fourth day and avoidance of plasma levels greater than 1,000 ng/ml in our study, as opposed to the downward dose titration (starting at 200 mg twice a day in all patients) and higher plasma levels used in the study of Platia et al. (19). Comparison of Holter monitoring and electrophysiologic therapeutic end points. Suppression of all spontaneou s ventricular tachycardia , 90% of paired ventricular premature complexes and 80% of all ventricular premature complexes was achieved in 83% of patients receiving titrated flecainide doses . However, ventricular tachycardia remained inducible by the ventricular extrastimulus technique in 79% of these patients . Similarly, a multicenter trial (19) of patients with coronary artery disease , with unspecified diagnostic criteria, found the tachycardia to be noninducible in only 12% of patients despite suppression of arrhythmia on Holter monitoring. Discrepancies between Holter monitor result s and electrophysiologic induction of arrhythmia may occur with amiodarone (21-24) and other antiarrhythmic agents (25). Duff et al. (26) found discrepancies in a group of patients receiving another type IC agent, encainide; Herling et al. (27) reported discrepancies after surgical management of ventricular arrhythmias.

unnecessarily increased to assure noninducibility. Other investigators (12,13,18 ,19 ) have also observed an increa sed cycle length of the induced ventri cular tachycardia with flecainide , but have not described the resultant alleviation of symptoms. Patients with no arrhythmia inducible with flecainide have a better clinical prognosis than do those who continue to have inducible arrhythmia . However, as observed with other antiarrhythmic agents (28), careful observation of the cycle length and symptoms during laboratory-induced arrhythmias with drug therapy may allow selection of patients who will have an intermediate clinical response . Although such patients are more likely to have a recurrence, electrophysiologic assessment distinguishes individuals for whom any recurrence is likely to be compatible with survival from those likely to have fatal recurrence. Thus , in the four patients with no inducible arrhythmia , there was no sudden death or recurrence of ventricular tachycardia. Among the 10 patients with ventricular tachycardia induc ible during flecainide therapy at a significantly increased ventricular cycle length and with symptomatic improvement,5 had a clinical recurrence but only one of these resulted in sudden death. Conclusions. Flecainide may be safely administered to patient s with a history of remote myocardial infarction and inducible sustained ventricular tachycardia after a precise protocol for dose titration . Holter monitoring and electrophysiologic data appear to provide complementary information regarding long-term efficacy.

Although noninducibility is an ideal electrophysiologic end point for antiarrhythmic therapy . partial responses to

2. Kannel WB, Sorlie P. McNamara PM. Prognosis after myocardial infarction. Am J Cardiol 1979;44:53-9.

certain antiarrhythmic agents may pred ict a long-term beneficial effect (28). Therefore , 10 patients with lengthening of the ventricular tachycardia cycle length and alleviation of symptoms who did not require cardioversion with flecainide were followed up as outpatients. Because all recurrences were within this group , with no recurrences among patients with no inducible arrhythmia, the ventricular extrastimulus technique may be more sensitive than Holter monitoring alone as a predictor of the tendency for recurrent ventricular tachycardia. Clinical implications. Perhaps the simplistic electrophysiologic criterion of inducibility versus noninducibility is too severe and must be refined to allow for intermediate responses that might also predict a safe therapeutic regimen and avoid the increased risk of toxicity if drug doses are

3. Helmers C, Lundman T , Maasing R. Mortality pattern among initial survivors of acute myocardia l infarction using a life-table technique. Acta Med Scand 1976;200:469-73.

We gratefully acknowledge the secretarial assistance of Judy Heggemeyer.

References I. Kuller L. Sudden death in arteriosclerotic disease. The case for preventive medicine. Am J Cardiol 1969;24:617-28 .

4. Rubennan W. Weinblall E, Goldberg JD . Ventricular premature beats and mortality after myocardial infarction. N Engl J Med 1977;297:750-7 . 5. Anderson J, Stewart J, Perry B, et al. Oral ftecainide acetate for the treatment of ventricular arrhythmias. N Engl J Med 1981;305:473-7 . 6. Conard G, Cronheim G, Klempt H. Relationship between plasma concentration s and suppression of ventricular extrasystoles by flecainide acetate (R-8 18). a new antiarrhythm ic, in patients . Drug Res 1982;32:2, 155-9. 7. Hodges M, Haugland M. Granrud G. et al. Suppression of ventricular ectopic depolarization s by ftecainide acetate, a new antiarrhythmic agent. Circulation 1982;65:879-85 . 8. Abitbol H. Califano J. Abate C. Beili s P. Castellano s H. Use of flecainide acetate in the treatment of premature ventricular contractions. Am Heart J 1983;105:227-30. 9. Flecainide-Quinidine Research Group. Flecainide versus quinidine for

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treatment of chronic ventricular arrhythmias: a multicenter clinical trial. Circulation 1983;67: 1117-23. 10. Duff H, Roden D, Maffucci R, et al. Suppression of resistant ventricular arrhythmias by twice daily dosing with f1ecainide. Am J Cardiol 1981;48: 1133-40. I I. Duran D, Platia E, Griffith L, Adhar G, Reid P. Suppression of complex ventricular arrhythmias by oral f1ecainide. Clin Pharmacol Ther 1982;32:554-61. 12. Anderson JL, Lutz JR, Allison S8. Electrophysiologic and antiarrhythmic effects of oral f1ecainide in patients with inducible ventricular tachycardia. J Am Coli Cardiol 1983;2:105-14. 13. Lal R, Chapman P, Naccarrelli G, et al. Short- and long-term experience with f1ecainide acetate in the management of refractory lifethreatening ventricular arrhythmias. J Am Coli Cardiol 1985;6:772-9. 14. Morganrotb J, Horowitz LN. Flecainide: its proarrhythmic effect and expected changes on the surface electrocardiogram. Am J Cardiol I984;53:89B-948 . 15. Klein MD, Baker S, Feldman CL, Hubelbank M, Lane B. A validation technique for computerized Holter tape processing systems used in drug efficacy testing. In: Proceedings of the Computers in Cardiology Conference (IEEE 77 ChI 254-2C), Rotterdam, Netherlands. New York: Institute of Electrical and Electronics Engineers, 1977:199-20 I. 16. Moses LE, Emerson JD, Hosseini H. Analyzing data from ordered categories. N Engl J Med 1984;7:442-8. 17. Johnson JD, Carlson GL, Fox JM, Miller AM, Chang SF, Conrad GJ. Quantitation of f1ecainide acetate (R-818), a new antiarrhythmic, in biologic fluids by gas-liquid chromatography with electron capture detection. J Pharm Sci 1984;73:1469-71. 18. Flowers D, O'Gallagher D, Torres V, Miura D, Somberg ic. Flecainide: long-term treatment using a reduced dosing schedule. Am J Cardiol 1985;55:79-83. 19. Platia EV, Estes NAM, Heine DL, et al. Flecainide: electrophysiologic and antiarrhythmic properties in refractory ventricular tachycardia. Am J Cardiol 1985;55:956-62.

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20. Rae AP, Greenspan AM, Spielman SR, et al. Antiarrhythmic drug efficacy for ventricular arrhythmias associated with coronary artery disease as assessed by electrophysiologic studies. Am J Cardiol 1985;55:1494-9. 21. Hamer AW, Finerman WB Jr, PeterT, Mandel WJ. Disparity between the clinical and electrophysiologic effects of amiodarone in the treatment of recurrent ventricular arrhythmias. Am Heart J 1981; 102:922-1000. 22. Heger 11, Prystowski EN, Jackman WM, et al. Arniodarone: clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-45. 23. Waxman HL, Groh WC, Marchlinski FE, et al. Amiodarone for control of sustained ventricular tachyarrhythmia: clinical and electrophysiologic effects in 51 patients. Am J Cardiol 1982;50:1066-74. 24. Kennedy EE, Batsford WP, Rosenfeld LE, Borstelmann NA, Gradman AH. Predicting therapeutic efficacy with amiodarone: a combined Holter/electrophysiologic approach (abstr). J Am Coli Cardiol 1984;3:605. 25. Kim SG, Seiden SW, Matos JA, Waspe LE, Fisher 10. Discordance between ambulatory monitoring and programmed stimulation in assessing efficacy of class IA antiarrhythmic agents in patients with ventricular tachycardia. J Am Coli Cardiol 1985;6:539-44. 26. Duff JH, Roden DM, Rawson AK, Oates JA, Smith RF, Woosly RK. Comparison of the effects of placebo and encainide on programmed electrical stimulation and arrhythmia frequency. Am J Cardiol 1982;50:305-12. 27. Herling EM, Horowitz LN, Josephson ME. Ventricular ectopic activity after medical and surgical treatment for recurrent sustained ventricular tachycardia. Am J Cardiol 1980;45:633-9. 28. Horowitz LN, Greenspan AM, Spielman SR, et al. Usefulness of electrophysiologic testing in evaluation of amiodarone therapy for sustained ventricular arrhythmias associated with coronary heart disease. Am J Cardiol 1985;55:367-71.