Antiarrhythmic efficacy of ethmozine® (moricizine HCl) compared with disopyramide and propranolol

Antiarrhythmic Efficacyof Ethmozine” (MoricizineHCI) Compared with Disopyramide andPropranolol CRAIG M. PRATT, MD, SAMUEL M. BUTMAN, MD, JAMES B. YOUNG, MD, MARGARET KNOLL, RDMS, and La DEAN ENGLISH, LVN

In the investigation of new antiarrhythmic drugs, comparative trials with clinically available antiarrhythmic agents provide a perspective from which to judge the new investigational agent. Two clinical investigations of moricizine HCI, each using a placebo-controlled, double-blind, crossover design, are summarized. In the first study, 18 patients with > 30 ventricular premature complexes (VPCs) per hour (mean 389 f 95) were given propranolol (120 mg daily) compared with moricizine HCI (818 f 103 mg daily). Propranolol suppressed 38% of VPCs in the study group, moricizine HCI, 81% of VPCs, and the combination of both drugs, 87%. Moricizine HCI was more effective than propranolol in suppressing VPCs at all individual levels >70% (p <0.05, McNemar’s test). The combination of moricizine HCI and propranolol was well tolerated. The second investigation used a placebo-controlled,

double-blind, crossover design to compare the efficacy of disopyramide (600 mg daily) and moricizine HCI (800 mg daily) in 27 patients. Patients had 240 VPCs/hr on a 24-hour ambulatory electrocardiogram. During moricizine HCI administration, the mean VPC frequency decreased from 524 to 151 VPCs/hr (71.2% reduction). In contrast, disopyramide reduced VPC frequency from 535 to 253 VPCs/hr (52.8% reduction) and demonstrated significantly greater side effects (p <0.05). Moricizine HCI was more effective than disopyramide in suppressing VPCs at all individual percent reduction levels >70% (p <0.05, McNemar’s test). Moricizine HCI was more effective in suppressing VPCs than either disopyramide or propranolol, with significantly fewer side effects. (Am J Cardiol 1987;60:52F-58F)

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pyramide) antiarrhythmic drugs, none has been shown to reduce risk for sudden death after myocardial infarction.8 In addition, the currently available antiarrhythmic drugs have multiple shortcomings. Type I antiarrhythmic drugs have limited efficacy in suppressing ventricular premature complexes (VPCs).g These agents, moreover, cause frequent side effects, have potentially serious toxicity and may significantly depress left ventricular function.lOJ1 A number of clinically available (aswell as investigational] antiarrhythmic drugs have also been documented to “aggravate” ventricular arrhythmia, even causing torsades de pointes ventricular tachycardia (VT).12J3 In previous studies by our group and others, Ethmozinc@* (moricizine HCl] has demonstrated a number of desirable characteristics, warranting further investigation as a promising antiarrhythmic drug. Moricizine HCl has been shown to suppress VPCs effectively with few and minor side effects. In preliminary studies

mbulatory electrocardiographic recordings have become the standard for identifying and quantifying ventricular arrhythmias. 1-ZThe presence of frequent and complex ventricular arrhythmias in certain patient populations increases the risk for sudden cardiac death.3-5 Although p blockers reduce risk for sudden death after myocardial infarction, ,their usefulness is limited in some patients because of undesirable side effects and in other patients because of severely depressed ventricular function.6,7 Despite the widespread use of type I (quinidine, procainamide, diso-

From the Baylor College of Medicine, Houston, Texas, and Long Branch Veterans Administration Medical Center, University of California, Irvine, California. This study was supported in part by research grants from Du Pont Pharmaceuticals. Computational assistance provided by the CLINFO project, funded by grant RR-00350, Division of Research Resources, National Institutes of Health, Bethesda, Maryland. Address for reprints: Craig M. Pratt, MD, Section of Cardiology, The Methodist Hospital, 6535 Fannin, MS F-1001, Houston, Texas 77030.

*Moricizine HCl is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozinea. 52F

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involving patients with benign ventricular arrhythymias, it had minimal effect on the QT interval of the scalar electrocardiogram and a low reported incidence of “arrhythmia aggravation.“l4Js The 2 studies described in this article were doubleblind and crossover, which allowed for appropriate assessment of the relative efficacy of moricizine HCl, as well as comparison of side-effect profiles of moricizine HCl with both propranolol and disopyramide. Preliminary results of a trial examining the comparative and additive effects of moricizine HCl and propranolol are presented first. This trial is unique in that it reports the potential additive antiarrhythmic efficacy and tolerance of the 2 antiarrhythmic drugs used in combination. This has relevance for postinfarction patients. The second clinical trial compares moricizine HCl to the type I antiarrhythmic drug disopyramide. Both studies allow a direct comparison of the sideeffect profile of the 2 clinically available drugs with the new investigational agent. Because of the trial design (crossover to placebo], these investigations are limited to patients with non-life-threatening arrhythmia. Extrapolation of these results to patients with lifethreatening arrhythmias is not valid.

StudyI-Comparative andAdditiveEffects of MoricizineHCIand Propranololin Treatment of FrequentVentricularPrematureComplexes Methods: Patient population and design: This study was a placebo-controlled, double-blind, 3-way crossover design. Of the 21 patients who entered the trial, 18 completed the protocol and are the basis of this analysis. The single inclusion criterion for this trial was a 24hour ambulatory electrocardiogram, demonstrating the presence of 130 VPCs/hr. The 18 patients, whose mean age was 60 f 6 years (range 50 to 721,were all men. Cardiac diagnosis included coronary artery disease in 78% of the patients; 39% had a previous myocardial infarction. Clinically available antiarrhythmic drugs had been administered to 56% of the patients. At time of entry into the trial, 28% were receiving digitalis and 17% diuretics. Patients were excluded from consideration in this trial if they had cardiac surgery or myocardial infarction within the previous 3 months. Electrocardiographic exclusions included second- or third-degree heart block, significant sinus node dysfunction, PR prolon-

TABLE I

Double-Blind, Placebo (week 1)

Holter aECG Lab tests Echo Blood* *

xx X X X X

Three-Way Drug* (week 2) xx X X X X

Crossover Placebo (week 3) xx X X X X

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gation X.26 seconds or QRS duration >0.12 second. Patients were also excluded if they had decompensated congestive heart failure, significant hypotension or other severe medical illness. Table I lists details of the study design. Ambulatory electrocardiographic recordings (Holter recordings] were performed for 48 hours at the end of each week of the protocol. Moricizine HCl was administered on a 3-timesdaily basis. Total mean daily dosage was 816 f 103 mg or lo.4 f 0.9 mg/kg. Propranolol was administered orally at a fixed daily dosage of 120 mg (40 mg, 3 times daily). This resulted in a range of doses from 1.1 to 2.1 mg/kg/day. Appropriate placebo was likewise administered on a ×-daily schedule. Results: All patients entering the trial had a %-hour screening ambulatory electrocardiographic recording documenting the presence of 130 VPCs/hr. The initial mean placebo arrhythmia data were: 369 f 95 VPCs/ hr, 9.1 f 4.6 couplets/hr and 1.1 f 0.9 runs of VT/hr. Figure 1 summarizes the relative and combined efficacy of propranolol and moricizine HCl compared with their placebo periods, which took place immediately before study periods. Propranolol was effective in suppressing 38% of mean VPCs for the entire group. In contrast, moricizine HCI suppressed 819'0 of VPCs compared with each patient individually immediately before placebo period. As seen in Figure 2, the combination of propranolol and moricizine HCl resulted in a

q q

PROP

(38%)

MORIC (81%)

PLACEBO ACTIVE DRUG

PROP + MOW

POST

(87%)

FIGURE 1. Efficacy of propranolol (Prop), moricizine HCI (Moric) and propranolol plus moricizine HCI for ventricular premature complexes (VPCs)/hr, and logarithm of VPCs/hr. Pre = preceding placebo administration; Post = post-placebo administration.

Study Design Drug* (week 4) xx X X X X

Placebo (week 5) xx X X X X

aECG = ambulatory electrocardiogram; Echo = echocardiogram. * moricizine HCI and propranolol randomly assigned (weeks 2, 4); combined testing.

Drug” (week 6) xx X X X X

Placebo (week 7) xx X X X X

(week 6). ** routine laboratory

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further suppression of VPCs (87%) compared with the’ placebo period of each patient. The 81% of VPC suppression with moricizine HCI and 87% VPC suppression with the combination of propranolol and moricizine HCI were significantly different from placebo (p
PROPRANOLOL

MORICIZINE (n=18)

PROPRANOLOL i MORICIZINE

FIGURE 2. Individual and combined efficacy of both propranolol and moricizine HCI for each patient. Pre = preceding placebo administration; Post = post-placebo administration; VPCs = ventricular premature complexes.

TABLE II Comparative and Additive Efficacy of Moricizine HCI (M) and Propranolol (P) in Suppressing Ventricular Premature Complexes (VPCs) Suppression of VPCs Compared with Placebo W)

100 299 290 180 175 170

260 250

P

M

M+P

0118 0118 0118 2118 2118 2/18 7118 7118

2118 3118 6/18” 9118” 11118” 11/18* III18 ii/18

ill8 6118’ 8118' 10118’ 11118” 12118" 12118 12118

* p <0.05 for moricizine HCI versus propranolol (McNemar’s test).

TABLE Ill

propranolol

Protocol Design for Moricirine

or moricizine

HCI Compared

HCI +

24-hr aECG Echo 2D Bruce ETT 12-lead ECG Serum levels (peak and trough) Routine lab Vital signs Symptom diary aECG = ambulatory

electrocardiogram;

1-4

5 x

X

ETT = exercise

X X

statistical significance. More important, suppression of VPCs by moricizine HCl alone or the combination of moricizjne HCl plus propranolol was more effective in suppressing VPCs than propranolol alone (p <0.05, Fig. 1). The individual and combined antiarrhythmic effectiveness of both moricizine HCl and propranolol for each patient is listed in Table II. For any given level of arrhythmia suppression, moricizine HCl suppressed VPCs in a larger number of patients than did propranolol. This reached statistical significance over the range of VPC suppression from 70% to 90% (p <0.05, McNemar’s test). Compared with moricizine HCl alone, the combination of moricizine HCI and propranolol was significantly more effective in suppressing VPCs at the 99% level (p
StudyII-ComparativeEfficacyof Disopyramide and MoricizineHCIin the Treatmentof Frequent VentricularPrematureComplexes Methods: Patient population and design: We previously reported a randomized, placebo-controlled, double-blind, crossover trial of 33 patients, with the presence of 140 VPCs/hr on at least 2 consecutive ambuIatory eIectrocardiographic recordings as the sole entrance criterion.16 Of 33 patients randomized to receive treatment, 27 completed the trial and form the basis of this report. All previous investigational or clinically available antiarrhythmic drugs were discontinued for 7 days before the study. The 27 patients analyzed were 18 men and 9 women whose mean age was 56 years [range 36 to 721.Cardiac diagnosis included coronary artery disease in 13, 10 of whom had documented myocardial infarction. Of the remaining 14 patients, 3 had hypertensive heart disease, 5 had mitral valve prolapse and 1 had idiopathic cardiomyopathy;

with Disopyramide

Placebo 1 Days

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6 x X X X x xxx x testing.

7 x

8-14

15

16

17

x

x X X X x

x

x X x

xxx x

Drug B

Placebo 2

Drug A 18-24

26

27

x

x X X X x

x

x X x

x

25

x

xxx x

28-34

36

37

x

x X X X x

x

x X x

x

35

x

xxx x

x

x X x

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and the other 5 patients had no demonstrable organic heart disease, based on clinical and echocardiographic assessment. Table III lists the protocol design. Important aspects of the study design included obtaining 3 continuous days of ambulatory electrocardiographic recordings at the end of each treatment phase. Plasma levels of both disopyramide and moricizine HCl were obtained on the final 2 days of drug administration, with both trough and peak values obtained. The specific hours that plasma samples were obtained were correlated with hourly VPC reductions during both peak and trough plasma sampling. Also, &dimensional echocardiographic assessment of left ventricular function was performed by a method previously established and reported from our laboratory.14 Disopyramide was given orally in a dosage of 600 mg daily (150 mg, 4 times daily]. Moricizine HCl was given in a total daily dosage of 10 mg/kg, averaging 800 mg daily (3 times daily]. During moricizine HCl and disopyramide administration, additional placebo tablets were provided so that timing of dosing sequences was identical with all study drugs. Results: Fourteen patients were randomized to sequence A, in which moricizine HCl was the first active antiarrhythmic drug. The other 13 patients were randomized to sequence B, in which disopyramide was the first active antiarrhythmic drug. The 14 patients in sequence A had an initial mean placebo VPC frequency of 465 f 289 VPCs/hr and 19 f 30 couplets/hr. Further, 7 of these 14 patients also had nonsustained VT, averaging 422 f 722 runs of VT daily. The comparable placebo baseline arrhythmia frequencies of the 13 patients in sequence B were 570 f 518 VPCs/hour and 25 f 39 couulets/hr; 12 patients also had nonsustained VT (mean frequency 57 f 95 runs of VT daily). There were no significant differences in baseline comparability of the placebo VPC frequencies or VPC variability in the 2 treatment sequences. Group responses to moricizine HCl and disopyramide: During moricizine I-ICI administration, the mean frequency of VPCs decreased from 524 to 151 VPCs/hr (71.2% reduction), significant at the p
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TABLE IV Comparative Efficacy of Mortcizine HCI (M) and Disopyramide (R) in Suppressing Ventricullar Premature Complexes EVPCs) Suppression of VPCs Compared with Placebo (%)

M

0

100 199 290 180 175 270 260 250

5127' 8127" 12127' 15127' 16127' 17127 22127 22127

0127 O/27 4127 6127 %I27 11127 12127 15127

* p <0.05 for each, moricizine

HCI versus disopyramide

TABLE V Comparative Efficacy Disopyramide (D) in Suppressing Tachycardia (VT) Suppression of VT Compared with Placebo (%) 100 299 190 280 175 270 260 250

TABLE VI Ventricular

(McNemar’s

test).

of Moricizine HCI (M) and Nonsustained Ventricular

No. of Patients with VT Runs M

0

11116 II/16 12116 12116 12116 12116 14116 14116

12i18 13f18 1311% 16118 16118 16118 17118 1ai1a

Plasma Levels of Moricizine HCI: Relation to Premature Complex (VPC) Frequency Moricizine Peak Level

(&ml) Range Mean (% standard deviation) VPCslhr

0.12-3.5 0.66 f 0.8 160 f 283

HCI Trough Level

b.WW 0.01-0.31 0.1 f 0.08’ 132f205

* p
reduction in any of the 27 patients-a difference significant at p <0.05 (McNemar’s test). Although moricizine HCl was more effective than disopyramide in suppressing VPCs, both drugs effectively eliminated runs of nonsustained VT in the majority of patients (Table V), with no difference in efficacy between the 2 drugs. Relation of plasma moricizine HCl and disopyramide levels to antiarrhythmic efficacy: Plasma samples of the 2 antiarrhythmic drugs were obtained both at peak (1 hour after administration) and trough (1 hour before) periods. The correlation of peak and trough plasma moricizine HCl concentrations to arrhythmia frequency is listed in Table VI. The difference in peak and trough plasma moricizine HCl concentrations for

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TABLE VII Plasma Levels of Disopyramide: Relation to Ventricular Premature Complex (VPC) Frequency

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TABLE VIII Side-Effect Profile for the Moricirine with Disopyramide Study

Disopyramide

Range Mean (& standard deviation) VPCslhr

Peak Level (Mml)

Trough Level (t&W

0.96-4.1 2.6 f 0.9 300 f 390

0.83-4.2 2.2 f 0.9 389 f 52

the group (0.66 f 0.8 pg/ml vs 0.1 f 0.08 pg/ml] was significantly different (p
Discussion Selected aspects of study design: Both these trials had a double-blind, longitudinal, crossover design, which has specific advantages when comparing 2 antiarrhythmic drugs. This study design allows for the relative comparison of efficacy and safety of 2 antiarrhythmic drugs in the same patient; i.e., the patient is his own control. The 7- to lo-day placebo washout interval between active antiarrhythmic administration intervals is far in excess of the drug half-lives of propranolol, disopyramide and moricizine HCl. In the moricizine HCl-disopyramide trial, we demonstrated that “physiologic washout” of each antiarrhythmic drug had occurred by documenting the return to baseline of VPC frequency during the intervening placebo intervals. Based on our analysis, a successful random-

HCI Compared

Symptom

Placebo (no. of pts.)

Moricizine HCI (no. of pts.)

Disopyramide (no. of pts.)

Headache Weakness Bowel changes Dry mouth Nausea Palpitations Urinary complaints Lightheadedness

a/27 ai27 5127 2127 5127 5127 2127 4127

5127 6127 O/27 2127 II27 6127 l/27 6127

8127 6l27 8127 10/27* 6127 6127 7127’ 6127

l

Both p <0.05 versus placebo or moricizine.

ization as well as an adequate drug washout were demonstrated in the 2 dosing sequences, A and B.16 Longitudinal crossover design trials such as the 2 presented here have an additional advantage. The observational placebo intervals are of similar length to the administration interval of the investigational drug. This allows for accurate comparison of each antiarrhythmic drug for both side effects and possible toxicity. The placebo intervals also provide important information about placebo side effects. Frequently, trials of antiarrhythmic drugs compare short intervals of placebo administration with long antiarrhythmic drug administration intervals, an aspect of study design that may overestimate the frequency of drug side effects.17 A final aspect of study design relates to the frequency of obtaining ambulatory electrocardiographic recordings. Based on the spontaneous variability of VPCs, a 66% VPC reduction is required to establish “drug effect” in an individual patient at the 95% confidence level if 2 days of placebo and treatment recordings are used.18 These estimates are obtained from a pooled analysis of variance. In the moricizine HCl-proprano101trial, a definite individual drug effect was noted in 69% of patients given moricizine HCl, 28% of patients given propranolol and 75% of patients given moricizine HCl and propranolol. In the moricizine HCldisopyramide trial, 3 days of ambulatory electrocardiographic recordings were used in each treatment phase. Thus, a 58% VPC reduction was required to establish individual “drug effect.” It was achieved in 44% of patients during disopyramide and 80% during moricizine HCl regimens. Comparison of the antiarrhythmic efficacy of moricizine HCl and propranolol: In the doses administered in this trial, moricizine HCl was superior to propranolol in the suppression of VPCs (81% vs 38% VPC suppression, p <0.05). In analyzing individual patient response to the 2 drugs, data supporting the superiority of moricizine HCl in reducing VPCs are even more striking. Whereas half of the patients given moricizine HCl had a 180% VPC reduction, only 11% of the patients had a similar VPC reduction while receiving propranolol. Although these differences are striking and statistically significant, any conclusions should be tempered by the relatively low dose of propranolol administered in this trial: compared with the

dose of moricizine HCl, which was given in doses comparable to those reported in other trials, the dose of propranolol was less than that required for demonstration of p blockade in most patients.lg In a study of patients with mitral prolapse and frequent VPCs, Winkle et alzOdemonstrated a 275% VPC suppression in 5 of 9 patients, using a propranolol dosage regimen of 160 mg daily. Woosley et a12*demonstrated an incremental increase in the effectiveness of propranolol in suppressing VPCs, with increasing doses administered. In patients who received 160 mg of propranolol daily, only one-third demonstrated a 170% suppression. An additional 4@% of patients responded to propranolol in dosages of 200 mg to 640 mg daily.21 Thus, the propranolol doses reported in other trials were greater than those in the present trial. Although this preliminary trial has limitations in optimal comparison of relative antiarrhythmic efficacy, the study design resulted in important information about the efficacy and safety of combining propranolol and moricizine HCl. During the last 20 years, several clinical trials have examined the effect of @blockers on risk for sudden death after acute myocardial infarction.2z The combined evidence of long-term randomized clinical trials of /3 blockers, based on more than 8,000 patients, yields consistent and statistically significant reductions in risk for sudden death after myocardial infarction. Propranolol, metoprolol and timolol have been successfully used in clinical trials, unequivocally resulting in a reduction in rate of sudden cardiac death. Although administration of ,f3blockers has resulted in a decrease of sudden death of up to 50% in the first year after myocardial infarction, there is always the possibility of adding another antiarrhythmic drug, possibly to decrease risk for sudden death further. Such a trial is currently being conducted (Cardiac Arrhythmia Suppression Trial/CAST] by the National Heart, Lung, and Blood Institute (RFP-NHLBI-85-20) Therefore, information on the interaction, additive efficacy and side-effect profile of new investigational agents added to fl blockers is of clinical importance. This trial established that moricizine HCI can be used safely and effectively with propranolol at the doses selected. The small additive antiarrhythmic effect did not reach statistical significance. Comparative efficacy of moricizine HCl and disopyramide: Both disopyramide and moricizine HCl effectively suppressed VPCs compared with respective placebo values; however, moricizine HCl was superior to disopyramide in suppressing VPCs. For the study population, moricizine HCl reduced VPCs 71.2%, as contrasted to 52.8% with disopyramide therapy. In comparing individual patient responses, the superiority of moricizine HCl was clearly shown. Total or neartotal abolition of VPCs was seen in 30% of patients during moricizine HCl therapy but in none of the patients during disopyramide administration. These differences in individual patient antiarrhythmic responsiveness were statistically significant (p <0.05, McNemar’s test). Side effects and toxicity: Comparison of moricizine HCI, propranolol and disopyramide: The prelim-

inary trial comparing moricizine HCl and propranolol revealed that moricizine HCI was well tolerated in all 18 patients. Surprisingly, :3 of ‘16 patients given propranolol developed lethargy and depression, requiiring early discontinuation of therapy despite the low daily dosage. Importantly, the combination of moricizine HCl and propranolol was well tolerated by all patients. In the comparative trial of moricizine HCl and disopyramide, there was no symptom noted more frequently during moricizine HCI therapy than the placebo effect. In contrast, disopyramide frequently caused troubling side effects-including dry mouth and urinary symptoms-of a sufficient magnitude that patients, when asked, replied that they would not have considered continuing the medication on a long-term basis. Peak serum levels of disopyramide in patients who experienced significant side effects were not different from those levels in patients without complaints. These observations on moricizine HCl are consistent with published data from our group and others: moricizine HCl has a low incidence of minor side effects and lacks serious toxicity.

Conclusions Compared with placebo control, moricizine HCl was more effective in suppressing VPCs than either disopyramide or propranolol. A limitation of the propranolol trial was the relatively low dose of proprano101administered (120 mg daily). This was not the case in the disopyramide trial, in which adequate doses of disopyramide were administered (600 mg daily), resulting in a 30% incidence of intolerable side effects. Whereas disopyramide had been given to tolerance in most patients, doses of moricizine HCI could have been increased. These data support the potential clinical utility of moricizine HC1 as an effective antiarrhythmic agent in the suppression of VPCs with a favorable side-effect profile. Acknowledgment: Gratitude is expressed to Paula Johnson for her patient secretarial assistance and to Sara Mahler, MD, for her expertise with study design.

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16. Pratt CM, Young JB, Francis MJ, Taylor AA, Norton HJ, English L, Mann DE, Kopelen H, Quinones MA, Roberts R. Comparative effect of disopyramide and Ethmozine in suppressing complex ventricular arrhythmias by use of a double-blind. placebo-controlled, longitudinal crossover design. Circufation 1984;69:288-297. 17. Pratt CM, Luck JC, Mann DE, Wvndham C. Investigational antiarrhvthmic drugs for the treatment of ventricular rhythm disturbances. Cardiol Ciin 1984;2:35-46. 16. Pratt CM, Slymen DJ, Wierman AM, Young JB, Francis MJ, Seals AA, Quinones MA, Roberts R. Analysis of the spontaneous variability of ventricular arrhythmias: consecutive ambulatory electrocardiographic recordings of ventricular tachycardia. Ani J Cardiol 1985;56:67-72. 19. Coltart DJ, Shand DG. Plasma propranolol levels in the quantitative assessmentof beta-adrenergic blockade in man. Br Med J 1978;8:781-784. 20. Winkle R, Lopes M, Goodman D, Fitzgerald J, Schroeder J, Harrison D. Arrhythmias in patients with mitral valve prolapse. Circulation 1375;52:7381. 21. Woosley RL, Kornhauser D, Smith R, Reele S, Higgins SB, Nies AS, Shand DG, Oates JA. Suppression of chronic ventricular arrhythmias with propranoJof. Circulation 1979;60:819-827. 22. Pratt CM, Roberts R. Chronic beta-blockade therapy in patients after myocardial infarction. Am 1 Cardiof 1983;52:661-664.