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Comparative Study of Encainide and Quinidine in the Treatment of Ventricular Arrhythmias

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Comparative Study of Encainide and Quinidine in the Treatment of Ventricular Arrhythmias JACC Vol 7, No I 9 January 19869-16 Comparative Study of Encainide and Quinidine in the Treatment of Ventricular Arrhythmias JOEL MORGANROTH, MD, FACC, JOHN C. SOMBERG, MD, FACC, PETER E. POOL, MD, FACC, PING-HWA HSU, PHD, IAN K. LEE, MD, CHB, JOHN DURKEE, RPH, for the ENCAINIDE• QUINIDINE RESEARCH GROUP* Philadelphia, Pennsylvania The antiarrhythmic efficacy and safety of oral encainide ment resulting in advancement to the next study period hydrochloride and quinidine sulfate were compared in occurred in 12 patients taking encainide and 38 patients a nine center double-blind crossover study in 187 out• taking quinidine (p < 0.05). PR and QRS intervals in• patients with benign or potentially lethal ventricular ar• creased significantly during encainide treatment, as did rhythmias. Patients with at least 30 premature ventric• QTc and JT intervals during quinidine treatment. No ular complexes/Ii were randomized to receive either adverse reactions resulted from these electrocardio• encainide, 25 mg four times/day, or quinidine, 200 mg graphic changes. four times/day, for :z weeks. These doses were continued Adverse reactions were more ~ommon with quinidine for another 2 weeks if a, 75% or greater reduction in than with encainide. A proarrhythmic effect was noted premature ventricular compiexes was observed. If this in eight patients taking encainide (five had an increase reduction was not seen, encainide was increased to 50 in premature ventricular complex frequency and three mg four times/day or quinidine to 400 mg four times/day an increase in the duration of asymptomatic ventricular for an additional 2 weeks. tachycardia) and in four patients taking quinidine (one Both drugs produced a statistically significant reduc• had an increase in premature ventricular complex fre• tion in premature ventriCUlar complex frequency com• quency and two an increase in the duration of asymp• pare(l with baseline values. Encainide produced a sta• tomatic ventricular tachycardia; and syncope developed . tistically significant greater mean reduction in total in one) (p = NS). Thus, encainide appears to be more premature ventricular complexes than did quinidine effective and has fewer sidE! effects than quinidine and during the initial dose phase and after dose adjustment. may be a reasonable alternative to quinidine therapy for More patients required dose iitcreases of quinidine (60%) ventricular arrhythmias. than of encainide (51 %). Early discontinuation of treat- (J Am Coli CardioI1986;7:9-16) Evidence is mounting that sudden cardiac death is due to prescribed antiarrhythmic agent in the United States (5) and ventricular tachyarrhythmias iri most patients (1) and that studies (2,5-7) have established its effectiveness and safety the patient at high risk for such an event can be identified in approximately 60 to 80% of patients with benign and by the presence of premature ventricular complexes and left potentially lethal ventricular arrhythmias. ventricular dysfunction (2,3). A search for more effective Encaihide is a potent new class Ie antiarrhythmic agent and better tolerated antiarrhythmic agents has been under• (2). It lengthens intraatrial, atrioventricular (A V) node, His• way for use in studies designed to test whether sudden Purkinje and intraventricular conduction (8). It has no sig• cardiac death can be prevented by elimination of such ar• nificant negative inotropic effect (9) and thus may be val• rhythmias (2,4), Quinidine is the oldest and the most widely uable in patients with severe left ventricular dysfunction who benefit most from control of ventricular arrhythmias. *See Appendix for the list of the Encainide-Quimdine Research Group. Placebo-controlled studies using appropriate standards (10) From the National Cardiovascular Research Center, Haddonfield, New have demonstrated that encainide is effective in 70 to 80% Jersey and the Likoff Cardiovascular Institute of Hahnemann University, Philadelphia, Pennsylvania. of patients with ventricular arrhythmias. The effective dose Manuscript received May 21, 1985; revised manuscript received July appears to be between 25 and 50 mg three to four times/day 9, 1985, accepted August 16, 1985. (11-13). Aggravation of arrhythmias (proarrhythmia) from Address for reprints: Joel Morganroth, MD. Llkoff Cardiovascular Institute, Hahnemann University Hospital, Broad and Vine Street, Phila• encainide has been previously reported in approximately delphia, Pennsylvania 19102-1192. 10% of patients with benign and potentially lethal ventric- © 1986 by the American College of Cardiology 0735-1097/86/$3 50 10 MORGANROTH ET AL. JACC Vol. 7, No.1 ENCAINIDE VERSUS QUINIDINE FOR ARRHYTHMIAS January 1986:9-16 ular arrhythmias (11-13). Patients with more lethal arrhyth• cainide or quinidine. Patients were also excluded if they mias and more severe degrees of left ventricular dysfunction had evidence of sick sinus syndrome, required the presence have a higher incidence of proarrhythmic events (14,15). of a pacemaker, had a baseline QRS duration of more than Our study was designed to compare the safety and efficacy 0.14 second, a PR interval of more than 0.24 second or a of encainide and quinidine with emphasis on the safety of QTc interval of more than 0.50 second. Uncontrolled hy• initiating each agent in outpatients with benign or potentially pertension, congestive heart failure, angina pectoris, seizure lethal ventricular arrythmias. disorders, abuse of alcohol or significant renal or hepatic failure were other criteria for exclusion from the study. Patients with evidence of acute myocardial infarction or use Methods of amiodarone within 90 days before enrollment were also Patient selection. Nine clinical centers enrolled patients excluded. 18 years or older who demonstrated at least 30 premature Protocol (Table 1). This was a multicenter, 14 week, ventricular complexes/h on a 24 hour Holter monitor re• double-blind, randomized, crossover comparative study of cording taken near the end of 1 week of placebo therapy encainide versus quinidine in outpatients. It included six (baseline). The initial placebo period was preceded by a 1 consecutive periods: 1) washout; 2) initial placebo; 3) first week washout period in which all prior antiarrhythmic ther• active drug; 4) second placebo; 5) second active drug; and apy was discontinued and a qualifying Holter monitor re• 6) final placebo. After the initial 7 day washout period, cording was obtained to determine eligibility. Patients were patients qualifying (those with premature ventricular com• included in the study only if their ventricular arrhythmias plexes averaging 2:30/h) on the first 24 hour Holter monitor required therapy in the judgment of the investigator. Patients recording received placebo for 1 week and underwent a were excluded if they had hemodynamically significant, second Holter recording. Eligible patients were then entered severe, life-threatening ventricular arrhythmias (4) or a his• into the first active drug period to receive either encainide tory of severe intolerance or allergic reaction to either en- or quinidine for 4 weeks. At the end of 2 weeks, the dose Table 1. Procedures and Observations in the Encainide-Quinidine Comparison Study Period (weeks) First Active Second Active Final Procedures and Washout Placebo Drug* Placebo Drug* Placebo Observations (I) (I) (3 to 6) (7 to 8) (9 to 12) (13 to 14) 24 hour Holter tnonitor X X X X(X)t X X Plasma for assay (2 h X X X X X postdose) Concomitant X X X X X X medications Medical history X Physical examination X X and vital signs Laboratory tests X X 12 lead ECG (2 h X X X X X X postdose) CheSt X-ray film X (unless done within 6 months) Capsule count X X X X X Interim assessment X X X X (induding vital signs) On-therapy condition X X X X X reports Final assessment X Blood samples for X X X serum digoxin assay (21 pts.) *Procedures and observations were perfonned twice (near the end of the second and fourth week) in each active drug period. tlf a patient's premature ventricular complex rate did not return to at least 50% of baseline level (first placebo), a repeat 24 hour Holter recording was perfonned to detennine whether the patient was eligible for participation in the second active drug period. ECG = electrocardiogram; pts. = patients. JACC Vol 7. No 1 MORGAN ROTH ET AL 11 January 19869 16 ENCAINlDE VERSUS QUINIDINE FOR ARRHYTHMIAS of active medication could be increased if a 75o/c reduction Holter tapes randomly inserted into the system. In addition, in premature ventricular complex frequency compared with to ensure reproducibility, the same tapes were repeatedly the initial placebo period had not been obtained. A two analyzed at different times. Precise quantitation of the fre• week second placebo period followed the first active drug quency of premature ventricular complexes, couplets and period. During this second placebo penod a reappearance beats of ventricular tachycardia were performed. Validation of at least 50% of the baseline premature ventricular com~ of this method has been reported previously (6). To reduce plex frequency was required for continuatIOn In the study the right skewness of their distribution, the hourly rates of Patients eligible to contmue received the alternate medi• total premature ventricular complexes, couplets and beats cation in the second active period in a manner identical to of ventricular tachycardia were transformed by adding one that of the first active drug period. The study ended with a and taking the natural logarithm before computing the change 2 week final placebo penod in which a 24 hour Holter from the appropriate placebo baseline study. recording was obtained. Statistics. A linear model of analysis of variance was All placebo and active drug formulatIOns were identical used on data from patients who completed both active drug in appearance and were prepackaged, labeled and provided periods to determine whether data from all study centers in individual dose packets. The quinidine capsules used in could be pooled for analysis of efficacy and to compare the the study were bioequivalent to commercially available efficacy of the two agents.
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