Clin. Cardiol. 15, 53-57 (1992)

Encainide Dosing in Patients with Severe Renal Dysfunction: Report of a Case and Literature Review HENRYFRONC, M.D., R. STEPHEN PORTER, STEVEN P. KUTALEK,M.D.

PHARM.D., CHARLES

c . NYDEGGER, M.D., SCOTT E. HESSEN, M.D.,

Clinical Cardiac Electrophysiology Laboratory and the Section of Cardiovascular Pharmacology, Likoff Cardiovascular Institute, Hahnemann University Hospital, Philadelphia, Pennsylvania, USA

Summary: Dosage of encainide for patients with lethal ventricular arrhythmias is based on pharmacodynamic effects and efficacy of arrhythmia suppression, coupled with metabolizer phenotype and extent of renal and hepatic dysfunction. Decreased clearance in patients with renal dysfunction necessitates a reduction in dosage to avoid toxic and dose-related proarrhythmic effects. This case represents a patient with severe renal dysfunction and sustained ventricular tachycardia who achieved electrophysiologically guided suppression of induced ventricular tachycardia at a steady-state encainide dose of only 25 mg daily, significantly lower than package insert or compendial recommendations for initial dosage in patients with renal insufficiency. Documented “therapeutic” metabolite concentrations correlated to electrophysiologic response. Literature review illustrates the complexity of encainide dosage in such individuals and underscores the need for therapeutic drug monitoring to individualize dosage.

Key words: encainide, metabolites, antiarrhythmic drug dosage, renal dysfunction, ventricular tachycardia

Address for reprints: Steven P.Kutalek, M.D. Director, Clinical Cardiac Electrophysiology Likoff Cardiovascular Institute Hahnemann University Hospital Mail Stop 470 Broad and Vine Philadelphia, PA 19102-1192, USA Received: April 19, 1991 Accepted with revision: July 12, 1991

Introduction Encainide, a potent IC antiarrhythmic medication, markedly reduces the maximal rate of membrane depolarization, Vmaxof action potential phase 0, without affecting resting membrane potential. It has little effect on the duration of repolarization. As a sodium channel blocker, it also reduces action potential amplitude and decreases the duration of the action p~tential.I-~ Electropharmacology of at least two of the active metabolites suggests a pattern similar to type 1A or I11 antiarrhythmic agents.&1° Little information exists regarding the clinical utility of serial measurements of plasma concentrations of the parent drug (encainide) and its two major electrophannacologically active metabolites, 0-desmethyl encainide (ODE) and 3-methoxy 0-desmethyl encainide (MODE), as a guide to effective and safe encainide dosing in patients with severe renal dysfunction.” The goal of antiarrhythmic therapy in these patients remains the effective suppression of arrhythmias without accumulation of parent drug or metabolites to toxic plasma concentrations, as well as the avoidance of proarrhythmia. Although results of the Cardiac Arrhythmia Suppression Trial1*indicate a deleterious effect of encainide therapy in patients with nonsustained ventricular arrhythmia and ischemic cardiomyopathy, this agent still has utility for patients with sustained ventricular tachycardia who cannot be controlled medically with other antiarrhythmic drugs. In this report, we present a patient with severe renal dysfunction with electrophysiologically documented monomorphic sustained ventricular tachycardia (SUVT) suppressed by encainide. Therapeutic plasma concentrations of active metabolites as well as antiarrhythmic efficacy were achieved with chronic oral dosing at only 25 mg/day of the parent drug.

Case Report A 69-year-old white male, with a 10-year history of hypertension, congestive heart failure, and renal insuffi-

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Clin. Cardiol. Vol. 15, January 1992

ciency, was admitted to hospital after two witnessed syncopal episodes without seizure activity, incontinence, or head trauma. Eleven years previously he had suffered a left hemispheric cerebrovascular accident without residual effects; renal dysfunction (creatinine 4.0-4.5 mg/dl) was due to documented cholesterol emboli and hypertension. Premonitory phenomena prior to syncope included lightheadedness and diplopia but no palpitations or chest pain. He was transferred to Hahnemann University Hospital for cardiac electrophysiologic study (EP). Social history documented a 50 pack-year history of cigarette smoking and consumption of 2-3 beers per day. Physical examination and admission chest x-ray demonstrated pulmonary vascular congestion and emphysematous bulla formation. Electrocardiogram showed normal sinus rhythm, heart rate 80 beatdmin, left atrial conduction abnormality, borderline intraventricular conduction delay, high QRS voltage, and old inferior wall myocardial infarction. Telemetric monitoring revealed frequent ventricular premature complexes and nonsustained monomorphic ventricular tachycardia of 3 to 13 complexes in duration. Radionuclideleft ventricular ejection fraction was 25%. The left ventricle was markedly enlarged with severe hypokinesis and akinesis involving the distal two-thirds of the left ventricle, with apical dyskinesis. Basal motion was preserved. The right ventricle was normal in size and hyperdynamic. Admission SMA 12/60, complete blood count, and coagulation studies were all normal except for a hemoglobin of 11.4 g/dl, blood-urea nitrogen (BUN) 81 mg/dl, and creatinine 4.1 mg/dl. Calculated creatinine clearance by the Cockcroft and Gault f o r m ~ l a ,was ' ~ 14 d m i n . Medications at the time of EP included furosemide 80 mg p.0. daily, nifedipine 10 mg p.0. tid, dipyridamole 50 mg p.0. tid, allopurinol300 mg p.0. daily, and aspirin 325 mg p.0. daily. EP was performed using a standard protoc0114with ventricular extrastimuli introduced to refractoriness. Surface electrocardiographic intervals are described in Table I. Sinus nodal, atrial, atrioventricular (AV) nodal functions were normal. The HV interval was mildly prolonged at 59 ms. Double extrastimuli introduced at the right ventricular apex at a paced cycle length of 600 ms initiated monomorphic SUVT, cycle length 190 ms, with a right bundle-branch block superior axis morphology; this

TABLE I Surface electrocardiographicintervals (ms)

P PR QRS QT QTC

Baseline (initial EP)

On encainide 25 mg p.0. qd (12 days after defibrillator)

110 170 121 380 420

103 180

141 361 430

was accelerated by overdrive pacing to rapid polymorphic ventricular tachycardia accompanied by syncope requiring cardioversion.SUVT remained inducible after intravenous administration of 1000mg procainamide and on combination therapy with oral quinidine gluconate 324 mg p.0. q8h and tocainide 200 mg p.0 q12h. After quinidine gluconate and tocainide were discontinued, the patient continued to have up to 14 beat runs of monomorphic nonsustained VT (cycle length 280-320 ms). Encainide 25 mg p.0 q12h was initiated after 5 days off antiarrhythmic medications (serum creatinine 4.6 mg/dl). Spontaneous VT was eliminated within 24 hours. Cardiac catheterization revealed left ventricular thrombus, an occluded first marginal branch of the left circumflex coronary artery, and right coronary artery irregularities. No VT occurred for 6 days on encainide; the patient then developed repetitive episodes of nonsustained VT (cycle length 440 ms) of up to 6 complexes in duration. Refusing repeat EP on encainide, the patient elected implantation of a defibrillator since long-term suppression of SUVT on encainide could not be assured. At the time of defibrillator implantation, high defibrillation thresholds of 20-25 joules were noteI5 despite repeated reorientation of large anterior and posterior patches. Since the patient refused further assessment of the cycle length of VT on antimhythmic medication, a defibrillator with a relatively low fixed rate cutoff of 161 beatdmin was implanted. Postoperatively, encainide dosage was decreased to 25 mg p.0. daily. Ventricular premature complexes and ventricular couplets persisted, but there was no recurrence of VT. Several episodes of postoperative atrial flutter and atrial fibrillation with ventricular rates of up to 165 beatdmin resulted in defibrillator discharge. This required a short course of propranolol in addition to digoxin for ventricular rate control. Propranolol was subsequently discontinued. Postoperatively, the patient did consent to EP, which was performed on the twelfth postoperative day on encainide 25 mg p.0 daily. VT was not inducible at the right ventricular apex with single, double, or triple extrastimuli delivered to refractoriness at drive cycle lengths of 600 and 450 ms. Surface electrocardiographic intervals are recorded in Table I. Simultaneous encainide, ODE, and MODE levels were drawn at the beginning of the procedure, 2 hours after the last dose of encainide (Table II). Alternating current induced ventricular fibrillation which was appropriately sensed and terminated by the defibrillator. The patient was discharged on postoperative day 15 on encainide 25 mg daily, digoxin 0.125 mg daily (level 1.4 pg/ml), and diltiazem 30 mg every 6 hours.

Discussion While encainide itself has intrinsic antiarrhythmicactivits primary therapeutic benefit during chronic ity:, 5 , oral therapy is due to the activity of its two major metabolities 0-desmethyl encainide (ODE) and 3-methoxy-0-des-

H. Fronc et al. : Encainide in renal dysfunction

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TABLE I1 Plasma concentrations of encainide and its metabolites (levels in nglml)

Encainide ODE MODE

Patient presentedu

Recommended concentrationsh

80.7

265

335.5 360.3

30 100

“Plasma concentrations of the patient presented in this report on a dose of 25 mg p.0. daily 12 days after defibrillator implantation. “Minimal effective plasma concentrations recommended by Carey er al. I 6 and Barbey et aL5 for suppression of high frequency ventricular ectopic depolarizations when each agent is administered intravenously.

methyl encainide (MODE)?, On a molar basis, ODE and MODE are three to four times more potent as antiarrhythmic agents than the parent compound, and differ distinctly in terms of phannacokinetic and electrophysiologic properties. ODE is a stronger inhibitor of action potential maximal upstroke velocity6 than encainide, whereas MODE produces decidedly greater prolongation of action potential refractory period7, 23 in ventricular muscle than do either encainide or ODE?, I 6 The parent drug, encainide, differs markedly from its metabolities in clinical electrophysiologic effects. 2, 69* I 7 Sami et a1.* demonstrated, through assessment of electrophysiologic effects immediately after intravenous administration of the parent drug (i.e., before metabolite accumulation), that encainide prolongs His-Purkinje conduction time (HV interval) and intraventricular conduction time (QRS duration) with little effect upon repolarization (QTc interval) or other electrophysiologic parameters. ODE prolongs atrial and ventricular refractory periodsI0 as well as AH and HV intervals.8Its effect on the HV interval is more pronounced than that of either MODE or encainide.I6MODE, however, prolongs ventricular refractory periods more than encainide or ODE does.’ Both metabolities significantly prolong QRS duration, with ODE being far more potent in this regard, while only MODE prolongs repolarization. ODE, in fact, shortens myocardial repolarization time.5 These effects are rate dependent.24 Ninety-three percent of Caucasian patients metabolize encainide rapidly in the liver in a linear order to ODE and then MODE; these constitute the extensive metabolism phen~type.~ The subsequent disposition of ODE is also a function of metabolizer phenotype, whereas this is not the case with the terminal MODE.SIn extensive metabolizers (at “steady state”) during chronic oral therapy, serum concentrations of ODE and MODE are much higher than that of the parent drug, encainide. While there is great variability in the ratio of parent drug to metabolities in patients, a ratio of 1:5 at steady state during chronic oral therapy is considered to be representative of the extensive metabolizer phenotype.25 Early investigationsnoted little correlation between plasma concentrations of the parent drug encainide and pharmacodynamic effects, likely due in large part to extensive metabolism, resulting in variable parent drug to metabolite

ratios not reflected in the parent drug assay. this issue was further confounded by including study patients of both extensive and poor rnetabolizer phenotypes. Indeed, Carey and associatesI6documented a correlation between plasma encainide concentrations, ventricular arrhythmia suppression, and changes in surface electrocardiographic intervals only in poor metabolizers. In patients with normal renal function of the extensive metabolizer phenotype, plasma metabolite concentrations far exceed those of the parent drug, and elimination halflives of the metabolites are longer; i.e., encainide at 0.5-4 hours,”, 20, 26 ODE at 1.9-8.0 hours,5*25 and MODE >24 hours.27During drug withdrawal, Barbey et aL5 measured halflives of encainide at 3.1 f 1.4 hours, ODE 5.5f 1.6 hours, and MODE 17.1 f6.7 hours. The accumulation of high plasma concentrations of active metabolities relative to the parent drug concomitant with prolonged elimination times for metabolities raises the potential for toxic effects from ODE and MODE and stresses the need for a minimum of 3-5 days between dosage increments even in patients with normal renal fun~tion.~’, 28 The presence of significant renal or hepatic dysfunction in patients of the extensive rnetabolizer phenotype alters parent drug:metabolite ratios”, 29 by changing the electropharmacodynamic profile of the drug. The clearance of all three agents is reduced in patients with significant renal dysfunction, and since plasma levels of ODE and MODE become markedly higher than in patients with normal renal function, Woosley recommends that initial dosing of encainide in patients with abnormal renal function be decreased by approximately 50%.4 Bergstrand et al. l L compared the clearance and elimination of encainide and its metabolites in 7 patients with chronic renal failure and in 8 healthy controls, all of the extensive metabolizer phenotype. Clearance of the drug was significantly reduced in renal failure patients, both when dosed acutely and chronically. Systemic bioavailability appeared 70% greater in patients with renal function because of this reduction in clearance. Although encainide itself did not accumulate during chronic oral therapy, ODE and MODE levels in renal failure patients were 80 and 167% higher than in normal control subjects. Based on population kinetics, however, steady state was not achieved for the metabolities during this study.

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QRS prolongation and effective arrhythmia suppression appear to correlate best with ODE levels. The occurrence of proarrhythmia during encainide therapy may also cor30-32 Not relate with ODE at toxic plasma concentrations.28, only is there greater potential for rapid accumulation of ODE and MODE in renal failure patients, but washout of these metabolities after withdrawal from chronic oral therapy is prolonged, allowing for sustained antiarrhythmic and potentially arrhythmogenic effects. Animal studies suggest that high plasma ODE concentrations (300-600 ng/ml) correlate with decreased spontaneous ventricular fibrillation thresholds and increased energy requirements for defibrillation.This may render successful defibrillation less likely in the milieu of high plasma ODE concentrat i o n ~ . ' 33 ~ ,The relationship of ODE levels to increased mortality in the Cardiac Arrhythmia Suppression Trial is unknown.

Conclusion A patient of the extensive metabolizer phenotype of encainide with severe renal dysfunction is presented in whom electrophysiologically documented suppression of inducible SUVT occurred at low encainide:metabolite ratios. High therapeutic levels of ODE and MODE were achieved with chronic oral dosing of only 25 mg p.0. daily, one-third that generally recommended as an initial dose for patients with renal insufficiency. Contrary to early literature which noted little correlation between plasma encainide levels and the pharmacodynamic effects of the drug, this case illustrates the importance of monitoring plasma levels of both the parent compound, encainide, as well as its two major metabolities, ODE and MODE, and the need to tailor drug therapy with encainide individually in patients with renal dysfunction. We propose that encainide dosage of 25 mg p.0. daily may provide adequate suppression of lethal ventricular arrhythmias in patients of the rapid metabolizer phenotype with severe renal dysfunction. Clearly, the drug should not be used in patients with ischemic cardiomyopathy who manifest only nonsustained ventricular arrhythmias.12Combined monitoring of plasma drug concentrations and surface electrocardiographic criteria, together with serial cardiac electropharmacologictesting, can provide an optimal, individualized dosing regimen for patients with renal insufficiency who receive encainide.

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