Comparison of twice daily with thrice daily administered encainide for ...

Comparison of dministered En Lethal Vent

ice Daily Potentially ythmias

Stefan H. Hohnloser, MD, Markus Zabel, MD, Manfred Zehender, MD, Thomas Meinertz, MD, and Hanjarg Just, MD

The antiarrhythmic efficacy of encainide administered 2 (group A) or 3 times daily (group B) was evaluated in a randomized, placebo-controlled trial involving 101 patients with benign or potentially malignant ventricular arrhythmias. In group A, encainide was titrated at dosages of 35,50 and 75 mg twice daily and in group B at dosages of iS, 35 and 50 mg 3 times daily. Drug efficacy, as judged by repeated ambulatory monitoring, was defined as >75% reduction in ventricular premature complexes combined with a >90% abolition of pairs and runs of nonsustained ventricular tachycardia. In group A, 27 of 52 patients (52%) had their arrhythmia suppressed by the drug compared with 34 of 49 (69%) in group B (difference not significant). There was a trend toward better arrhythmia control in group B if a total daily dose of >lOO mg was necessary for arrhythmia suppression. Side effects were frequent in both groups (24 vs 28%, difference not significant). Thus, encainide administered twice daily effectively suppresses ventricular arrhythmias in this patient population. (Am d Cardioi 1969;

-From the Department of Cardiology, Freiburg University Hospital, Freiburg, Federal Republic of Germany. Manuscript received July 19, 1988; revised manuscript received and accepted August 12, 1988. Address for reprints: Stcfan H. Hohnloser, MD, Department of Cardiology, University Hospital, Hugstetterstrasse 55, 7800 Freiburg, West Germany.

is a new class IC antiarrhythmic drug ccessfully for arrhythmia suppression in with benign arrhythmia,’ in postinfarcand in sudden death survivors.3,4 The elimination half-life of encainide averages 2.3 f 0.3 hours in approximately 90% of patients, in whom the drug is rapidly biotransformed to 0-desmethyl encainide (ODE) and 3-methoxy-0-desmethyl encainide (3MODE).5 These metabolites persist in the plasma hours after encainide itself is no longer detectable. Because ODE and 3-MODE appear to be responsible for at least part of the antiarrhythmic efficacy of the drug,5 it has been postulated that the time course of pharmacologic effect will be considerably longer than the short half-life originally described for encainide.6 In most published studies, encainide has been administered every 6 to 8 hours.r-4,7,8 Thus, the present investigation was performed to compare the efficacy and safety of encainide administered twice or thrice daily to patients with frequent and symptomatic ventricular ectopic activity. METHODS Patients:

The study population consisted of 118 patients, 62 men and 56 women, with an average age of 61 years (range 23 to 89). Underlying cardiac disease included coronary artery disease in 50 patients (42%) (prior myocardial infarction in 25), dilated cardiomyopathy in 19 (16%), hypertensive heart disease in 9 (8%) and valvular heart disease in 5 (4%). No structural heart disease could be documented in 35 patients (30%). To qualify for the study, each patient had to exhibit >30 ventricular premature complexes/hour in two 24” hour Molter monitorings during the control and the placebo periods, respectively. The following exclusion criteria were used: history of life-threatening ventricular tachyarrhythmia or syncope, conduction defects (BQ >240 ms, QRS >140 ms), recent myocardial infarction (4 mg/dl) and led electrolyte disorders. un pr~t~co~~ The study was performed as a multicenter outpatient trial and its protocol is shown in Figure 1. All patients had a first Bolter monitoring after washout of previous antiarrhythmic drugs for at least 5 half-lives. No patient had been receiving amiodarone. Patients qualifying for the trial were randomized to receive placebo twice (group A) or 3 times daily (group THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 1. 1989

TWICE VS THRICE

)I

TABLE

ADMINISTERED

I Baseline Arrhythmia

BID TID BID Resp TID Resp BID Nonr TID Nonr

52

49 27 34 25

201 193

177 206 229

ENCAINIDE

>30 to 50% of baselinevalue or aggravationof arrhythmia were encountered. Statistical analysis: Student t test and Fisher exact test were used. To correct for skewed distribution and unequal variances, arrhythmia frequencieswere transformed to their natural logarithm [ln (1 + frequency)]. The level of significance was a p value of 75% reduction in and in 6 from group B. ventricular premature beats accompanied by a >90% Drug efficacy: In group A, 27 of 52 patients (52%) abolition of repetitive forms (pairs, runs of nonsustained had their arrhythmia suppressedby encainidecompared ventricular tachycardia) on the highest dose tolerated. with 34 patients (69%) in group B. As listed in Figure 2, Drug administration was stopped when serious side ef- there was a trend toward better arrhythmia suppression fects such as PQ prolongation above 280 ms, second-or in group B at the highest doselevel. However, this difthird-degree atrioventricular block, QRS widening of ference did not reach statistical significance (p = 0.10, Fisher exact test). In order to evaluate possiblecauses for this trend, arrhythmia suppressiontoward the end of Study Prbtocol the dosing intervals in group A was examined in detail to exclude arrhythmia breakthrough during these time 15

Nonr = nonresponders;

101

Ambulatory

164

Resp = responders;

VPC = ventricular

premature

complex-

Patients I

Monitoring

BID Placebo

TID Placebo Ambulatory

Monitoring

35 mg BID Ambulatory

25 mg TID Monitoring


Monitoring


Monitoring

patients

-All

Monitoring

FIGURE 74

A=BlD B=TID

LowDose

MiddleDose

HIghDose

I

FIGURE 2. Response rate during twice (A) or thrice (B) encainide therapy.

1. Study protocol.

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periods. There was, however, no significant difference in the frequency of ventricular extrasystoles between 6 and 10 A.M. and 5 and 10 P.M. in both treatment groups. The average daily encainide dose amounted to 92 mg for group A responders and 98 mg for those in group B (difference not significant). In group A, 16 patients had their arrhythmia suppressed with the low encainide dose, 6 with the middle and 5 with the high doses. These numbers compared with 20, 6 and 8 for group B, respectively (differences not significant). Figures 3 and 4 show the reduction in ventricular extrasystoles/hour and pairs/24 hours on the 3 dose levels for all patients. A 215% increase in the PQ interval occurred in 60% of group A and in 55% of group B patients (difference not significant), a 115% widening in QRS complex in 4.2% of patients in group A as well as in those from group B (difference not significant). Plasma concentration of ODE averaged 111 f 107 rig/ml in the 8 group A patients and 93 f 131 rig/ml in the 8 group B patients (difference not significant). The values for 3-MQDE were 119 f 62 and 129 f 94 rig/ml, respectively (difference not significant). Side effects: Fourteen patients (24%) in group A experienced adverse reactions during encainide therapy compared with 16 (28%) in group B (difference not significant). The most frequently noted untoward reactions were cardiovascular and central nervous system side effects. Worsening of congestive heart failure occurred in 1 patient in each group and proarrhythmic effects (new onset of sustained ventricular tachycardia or fibrillation) were observed in 1 group A and in 2 group B patients. IMSCOSSION The main objective of the present study was to evaluate whether encainide administered twice daily is as effective in arrhythmia suppression as a thrice daily regimen using the same total daily dosages in patients with benign or potentially lethal arrhythmia.‘O A 275% reduction in VPBs together with a >90% abolition in repetitive forms was achieved in about 60% of patients.

This overall drug efficacy is comparable to the results of several other trials examining the effects of encainide on In group A, the efficacy ventricular arrhythmia. 1,2~1r,12 rate was 52% compared with 69% in group B. Although this difference did not reach statistical significance, a trend toward better arrhythmia suppression in the thrice-daily group became evident at the highest dose (Figure 2). This was not due to an arrhythmia breakthrough in group A patients at the end of the dosing intervals and therefore, one has to conclude that encainide can be given twice daily up to a total daily dose of 100 mg. When higher dosages are needed for effective arrhythmia control, the drug should be given every 8 hours. The reason for sustained arrhythmia suppression with encainide administration every 8 to 12 hours results from the pharmacokinetic and pharmacodynamic profile of the substance. In >90% of patients encainide is rapidly biotransformed in the liver to its major metabolites ODE and 3-MODE.5 These metabolites persist in the plasma hours after the parent compound itself is no longer detectabie.5 Carey et al6 have shown that arrhythmia suppression did not correlate with encainide plasma concentration but with that of ODE and, to a lesser extent, to 3-MODE.6 These investigators concluded that encainide effects during oral therapy are mediated in most patients by metabolites of the parent compound. This point of view is further strengthened by experimental studies. 13,14The results of our study were obtained in patients with benign or potentially lethal arrhythmias. lo Caution is therefore warranted in extrapolating the data to other patient cohorts. Tordjman et alI5 have shown in a group of patients with lethal ventricular tachyarrhythmias that encainide administered 4 times daily was effective in 48% of patients tested noninvasively and in only 30% of those evaluated by electrophysiologic testing. Furthermore, they demonstrated


JANUARY 1,1989

TWICE VS THRICE

ADMINISTERED

ENCAINIDE

higher drug effectiveness in patients with a left ventricular ejection fraction >35%, as it has been shown for several other antiarrhythmic agentsI The incidence of side effects was substantial in both groups. As shown in earlier studies, encainide has only very limited negative inotropic effects,” but has the potential for aggravation of arrhythmia.‘” This serious side effect was observed in 3 patients, an incidence in agreement with the findings of Horowitz and Morganroth.18 These investigators noted encainide-induced aggravation in approximately 1% of patients with benign or potentially lethal arrhythmias compared with 10% in patients with lethal arrhythmias. In conclusion, encainide therapy can be initiated successfully with a dose of 35 mg administered twice daily in patients with benign or potentially lethal arrhythmias. When repeated Holter monitoring shows insufficient arrhythmia control at a daily dose of 100 mg, encainide administration every 8 hours might be more effective in suppressing the arrhythmia in some patients. Acknowledgment: The following investigators participated in this study: G. Baitsch, MD, U. Brocks, MD, G. Fobbe, MD, G. Gebhard, MD, W. Guckqnbiehl, MD, B. Hochbruck, MD, K. Koch, MD, .I. Kijlsch, MD, W. Kutulla, MD, T. Lingenscheidt, MD, E. Liomin, MD, M. Meeske, MD, W. Reisen, MD, B. Schmaltz, MD, G. Schwarz, MD, A. Szanto, MD, and W. Tekook, MD.

REFERENCES 1. Morganrorh J. Pwl P. Miller R, I Isu P-11. I cc I. Clark Dbl. Dose-response range ofcncainide for benign and potentinlly lethal wntricular arrhythmias. AN .I C'crrdiol 1986;.57:769 774. 2. The Cardiac \rrhyrhmia Pilot Study (CAPS) Invc~tigatora. Effccrs 01 encai-

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nide, llecainidc. imipraminc and moricizine on vcn(ricuIu arrhythmias during the year afrer acuw mywardial infarction the CAPS. .IIII J (irrdiol lYSX.61 501 50'). 3. C‘hcsnic 13. Podrid P, Lawn 13. Racdcr I(. I:nc:linide for rcfr;wory vcntriular tachyarrhyrhmia. Inr J C'ardiol /YX3:52:4Y.( 500. 4. llorowit~ LN. Izncainidc in lethal ventricular arrhythmia:, c\;duatcd bg eleclrophqsiologic lesring and dccrcasc in ~.w~proms. Am J C ardiol /986:SN:Y3('-

Y6C'. 5. K&II DM. Word /\JJ. Wilkinson GR. WoosIcy RI.. Dispaiiion kinetics of encainide and merabolihx AIH J C'nrdiol lY86;.%:4C YC. 6. Care) IX, Duff 11.1. Rodcn DM. Primm RK. Wilkinton GR, Wang T. 0~1~s .JA. Woo+ RL. lincainide and it> mctsboli~c~. C‘ompnrative effects in man on vcnrricular arrhythmia\ and clectnr;~rdiographic in~crvals. J (‘/VI lnwcl 1984:

73.539 547. 7. DiBianco K.

Flacher RD.Cohcn Al.Gortdiener JS.Smgh Sh. Kau RJ. Raw t IR.Sauerbrunn I3 Tre:~lmcmof frequent ventricular arrhythmu \\ilh encainide: ;wcssmcm sing serial arnhula~ory clectrtrnrdiogramb: intracardiac elcctrophy& ologic studies, treadmill cxercisz tws. and radionuclidc cineangiogrnphic arudxs. ~‘in~lrlolio,r /‘)X2:65:1 134 I/47. 8. Duff HJ. Roden DM. Carey El.. Wang 1’. Primm K, H’oasle~ KL. Spcctrum of antiarrh)rhmic response 10 encaimde. Am .I Curdio/ /985,56:KN7 RYI. 9. V&bit V. I’odrid I’. I.o%n 1~. Cohen Htl. Grabqr TB. A-ggrawtion and prowation of ventricular arrhythmia, by antiarrhghmic drugs.