Effects of ethmozine® (moricizine HCl) on ventricular function using echocardiographic, hemodynamic and radionuclide assessments

Effectsof Ethmozine”(MoricizineHCI)on Ventricular FunctionUsingEchocardiographicY Hemodynamic and Radionuclide Assessments CRAIG M. PRATT, MD, PHILIP J. PODRID, MD, A. ALLEN SEALS, MD, JAMES B. YOUNG, MD, MICHAEL HESSION, MD, STEVEN LAMPERT, MD, MIGUEL QUIhONES, MD, and BERNARD LOWN, MD

arrhythmias who had a mean control LVEF of 40 f 19 % . No significant change during moricizine HCI therapy (38 f 19 % , p >0.05) was detected and exercise parameters were unchanged. Rest and exercise LV function was measured during rightsided heart catheterization in a placebo-controlled study of 20 patients with ventricular tachycardia. Moricizine HCI was well tolerated without hemodynamic deterioration in all but 3 patients, who could be identified by their inability to increase stroke volume index during exercise. Finally, the relation between initial LV function and resultant antiarrhythmic efficacy indicates that moricizine HCI controls arrhythmias best in patients with LVEF >30%. (Am J Cardiol 1987;60:73F-78F)

Ventricular arrhythmias combined with left ventricular (LV) dysfunction in patients portend a poor prognosis. Most antiarrhythmic agents have not been sufficiently investigated to adequately describe detrimental effects on LV function; we report the effects of moricizine HCI on ventricular function in 4 trials highlighting patients with LV dysfunction. Quantitative 2-dimensional echocardiography was used to evaluate 81 patients pre- and posttreatment. There was no change in mean global LV ejection fraction (EF) during placebo compared with moricizine HCI therapy (47 f 15% vs 48 f 14%, p >0.05). In a separate trial, radionuclide LVEF at rest and exercise tolerance testing were performed in 24 patients with life-threatening ventricular

M

easuring the effects of investigational antiarrhythmic drugs on ventricular function has clinical relevance. Multiple studies have established the interdependence of the frequency and complexity of ventricular arrhythmias with the status of left ventricular (LV) function.1-4 Data from the Seattle Heart Watch have emphasized that the majority of sudden cardiac deaths occur in patients with evidence of myocardial damage and underlying coronary heart disease.5 With the advent of ambulatory electrocardiographic monitoring, many investigators documented that patients with coronary artery disease and associated LV dysfunction are more likely to have complex and repetitive forms of ventricular arrhythmia than similar patients with From The Cardiac Arrhythmia Study Unit, Baylor College of Medicine, Houston, Texas, and Brigham and Women’s Hospital, Boston, Massachusetts. Address for reprints: Craig M. Pratt, MD, Section of Cardiology, The Methodist Hospital, Baylor College of Medicine, 6535 Fannin, MS F-1001, Houston, Texas 77030.

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preserved LV function .6-g In postinfarction patients, the combination of LV dysfunction with complex ventricular arrhythmia increases the risk of sudden cardiac deathY In a study of 1,739 men after myocardial infarction, Ruberman et al2 noted that, in a 5-year follow-up period, the group with the highest mortality initially had both complex ventricular arrhythmias and congestive heart failure. Previous small trials emphasized that sudden cardiac death after myocardial infarction occurred most often in patients whose LV ejection fraction (EF) was <40% .7An important study by Bigger et al evaluated the relation between ventricular arrhythmias and residual LV dysfunction and mortality in 766 patients post-myocardial infarction. Mortality risk was highest in those patients whose LVEF was <3O% who also had either runs of ventricular tachycardia [VT) and/or ventricular premature complexes (VPCs] (13 VPCs/hr).l Both ventricular arrhythmias and the status of LV function made additive, independent contributions to the risk of resultant mortality.

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TABLE I Two-Dimensional Echocardiographic Assessment Left Ventricular Ejection Fraction (LVEF): Comparison of Moricizine HCI Therapy and Placebo Placebo LVEF (%)

Moricizine

of

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TABLE II Radionuclide Assessment of Left and Right Ventricular Ejection Fraction During Moricirine HCI Therapy in Patients with Ventricular Tachycardia or Ventricular Fibrillation

HCI LVEF

Baseline LVEF

Study (n = LVEF (n = LVEF (n =

group 61) 245% 50) <45 % 31)

47f

15

46f

RVEF

14

57 f 6

57 f 6

31 f

31 f9

10

Moricizine

HCI

W)

Patients with complex ventricular arrhythmia are often treated with antiarrhythmic drugs. Although these agents may suppress arrhythmia, their negative inotropic activity may depress LV function. Little is known about the effect of the newer investigational agents on hemodynamic parameters. This article reviews current investigations of the effects of moricizine HCl on both left and right ventricular function. The investigations focus on the prognostically important group of patients who have complex ventricular arrhythmias and impaired LV function; assessment includes echocardiographic, radionuclide and hemodynamic evaluations,

Studyl-Effect of MoricizineHCIon Ventricular Function:Echocardiographic Assessment In our previously published studies of the antiarrhythmic efficacy of moricizine HCl,* we used &dimensional quantitative assessment of LV function at rest both with placebo and moricizine HCl therapy in a total of 81 patients .l”J1 This cumulative experience represents a population in which all patients had 140 VPCs/hr on a qualifying 24-hour ambulatory electrocardiographic recording (mean 472 f 101 VPCs/hr). This group included 55 men and 26 women whose mean age was 55 f 13 years. All 2-dimensional echocardiograms were performed on ATL@ Mark V Sector Scanners@ equipped with slow-motion, frame-byframe bidirectional playback video recorders. The LVEF was determined from the average of several diameters measured in multiple views by a method previously validated in our laboratory.12 All echocardiograms were interpreted by an echocardiographer blinded to the identity of the study medication. The mean daily moricizine HCl dosage was 10 mg/kg (range 6 to 14). The average daily dosage of moricizine HCl, 800 mg, was administered on a 3-times-daily schedule. The effects of moricizine HCl on %dimensional echocardiographic assessment of resting LV function are listed in Table I, There was no change in mean global LVEF during placebo and moricizine hC1 therapy (LVEF 47 f 15% vs 46 f 149'0,difference not significant, Table I). Patients with impaired LV function (LVEF <45%) were analyzed separately. This * Moricizine HCl is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozine@.

LVEF

RVEF

(%) Study group (n = 24)

40f

Patients with LVEF <45 % (n = 15)

27 f 9

l n=i4. LVEF = left ventricular fraction.

19

W) 51 f

18

38f

46 f

19”

25 f 8

ejection fraction;

19

48f

15

42 f

14”

RVEF = right ventricular

ejection

group had a mean LVEF of 31 f 10% with placebo, which was unchanged with moricizine HCl therapy. It is important to note that no individual patient had a decrease of 15% in LVEF during moricizine HCl compared with placebo therapy. Of the 31 patients treated with moricizine HCI whose initial LVEF was <45%, 2 patients developed severe congestive heart failure. One patient (initial LVEF 19%) developed pulmonary edema within 24 hours of moricizine HCl administration, and the drug was discontinued. The second patient (LVEF 267’01 developed pulmonary edema after 48 hours of moricizine HCl therapy, warranting drug discontinuation. In summary, moricizine HCl administration (mean daily dosage 10 mg/kg) resulted in no measurable change in either group or individual ventricular function as assessed by &dimensional echocardiography at rest, but there was clinical deterioration of LV function in 2 patients. The remaining 29 patients with LVEF <45% tolerated moricizine HCl well.

Study2-Effect of MoricizineHCIon Ventricular Function:Radionuclide Assessment Radionuclide assessment of both right and left ventricular function was performed by standard radionuelide ventriculography at a separate clinical center. This study included 24 patients who were at high risk for sudden cardiac death. These patients, whose mean age was 57 years [range 35 to 71) were referred for severe, life-threatening ventricular arrhythmias. Each patient was refractory to previous antiarrhythmic therapy involving an average of 3 drugs. Characterization of the presenting arrhythmias included ventricular fibrillation in 10 patients, sustained VT in 7 patients and symptomatic nonsustained VT in the remaining 7 patients. Coronary artery disease was documented in 15 patients, 14 of whom had had a myocardial infarction. Cardiac diagnosis in the remaining 9 patients included idiopathic cardiomyopathy (5 patients], valvular heart disease (2 patients), congenital heart disease (1 patient] and no demonstrable heart disease in the remaining patient. It is important to note that 15 of 24 of these patients had a history of symptomatic congestive heart

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failure. Moricizine HCl was administered to this population at an average dose of 908 mg daily (750 to 1,200 mg daily]. This resulted in an average blood level of 0.54 pg/ml (0.2 to 1.2 pg/ml). The initial mean LVEF was 39.5 f 19% (Table II). There was no change in global LV function during moricizine HCl therapy (LVEF 37.6 & 19%, difference not significant vs control). No patient had a significant change in LVEF during drug therapy. There was likewise no significant effect of moricizine HCl on global right ventricular function in the study group (Table II). The 15 patients with a history of symptomatic congestive heart failure and LVEF <45% were analyzed separately to detect any potential adverse effect of moricizine HCl on ventricular function. There was no significant deterioration in global ventricular function on moricizine HCl compared with the paired control measurements (25% vs 27%; difference not significant). In order to assessthe clinical significance of these radionuclide measurements relative to the patient’s functional status, standard exercise testing on a motorized treadmill using a Bruce protocol (a good index of functional heart failure status) was performed in all 24 patients during both control and moricizine HCl therapy phases. Exercise duration was unchanged during moricizine HCl therapy compared with control (6.3 f 2.6 minutes vs 6.2 f 2.3 minutes; difference not significant). Heart rate and blood pressure both at rest and during exercise were not affected. Likewise, exercise duration was unchanged during moricizine HCl therapy in the 15 patients whose initial LVEF was <45% (5.0 f 2.2 minutes during moricizine HCl vs 5.6 f 2.0 minutes at control, difference not significant]. Thus, assessment of both left and right ventricular function in this high-risk population failed to document any deterioration in ventricular function during moricizine HCl therapy. This was consistent with the observation of lack of any exercise impairment during moricizine HCI. There was a relation between initial LVEF and response to moricizine. Of 15 patients with an LVEF <45%, 5 of 15 (33%] responded to the drug while 6 of 9 patients (67%) with an initial LVEF of 245% responded.

tery disease diagnosed by coronary angiography was present in 12 patients, 5 of whom had had a previous myocardial infarction. The remlaining 8 patients had the following cardiac diagnoses: idliopathic cardiomyopathy (2 patients], hypertensive cardiomyopathy (2 patients], mitral valve prolapse (1 patient], valvular heart disease (1 patient) and no demonstrable organic heart disease in the other 2 patients. Of the 20 patients, 10 (50%) had a history of congestive heart failure treated with digitalis or diuretics. The mean placebo LVEF for the group was 36 f 10% as judged by quantitative Z-dimensional echocardiographic assessment, as previously described .I2 The baseline arrhythmia frequency for the study population was 904 f 206 VPCs/hr, 52 f 16 couplets/hr and 788 f 530 runs of VT (mean f standard error for each). Hemodynamic assessment was performed in the coronary care unit and initiated during placebo dosing. The patient was familiarized with supine bicycle exercise by performing a practice exercise session the day before right-sided heart catheterization. This established the maximum workload during all subsequent bicycle ergometry sessions, with all subsequent exercise sessions performed at identical peak workloads. Right?sided heart catheterization was performed using standard techniques. Right heart pressures were measured, and derived hemodynamic parameters were calculated using standard formulas.13 At the time of the repeat of rest and exercise hemodynamic measurements during moricizine HCl therapy (after 60 hours of administration], the mean peak moricizine HCl plasma concentration averaged 0.85 f 0.9 ,ug/ml with a corresponding trough level of 0.12 f 0.1 pg/ ml, respectively. Measured hemodynamic variables during rest and exercise are listed in Table III. There was no change in either rest or exercise heart rates or blood pressure during moricizine WC1therapy compared with respective placebo values (difference not significant for each). Evidence for the severity of the underlying heart disease in this study population was exemplified

Study3-Effect of MoricizineHCITherapyon VentricularFunction:Hemodynamic Assessment

Placebo

In order to assess subtle changes in LV function during moricizine HCl therapy, we performed a prospective, single-blind, placebo-controlled trial of 20 patients (17 men, 3 women) whose mean age was 59 f 11 years. These patients were at high risk for sudden cardiac death, having previous documentation of frequent nonsustained VT (210 runs of VT daily] on a screening 24-hour ambulatory electrocardiographic monitor. All of these patients had symptomatic palpitations, presyncope or both; additionally, 7 patients had documented sustained VT (defined as VT lasting 230 seconds with a rate of >120/min, requiring intervention) before enrollment in the study. Coronary ar-

TABLE Ill Hemodynamic Effects of Moricizine During Supine Bicycle Exercise

HR (beatslmin) Rest Exercise Mean BP (mm Hg) Rest Exercise Mean PAP (mm Hg) Rest Exercise Mean PCWP (mm Hg) Rest Exercise

HCI at Rest and

Moricizine

HCI

74f 14 108 f 13

76 f 12” 110 f 22”

98f IO 115 f 15

102 f 15” 119 f 15”

29 f 9 49f 14

33 * 15” 50 f 16”

19* 36f

24 f 11” 39 f 11’

7 15

* Difference not significant compared with identical parameters with placebo. BP = blood pressure; HR = heart rate: PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure.

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by the following finding: placebo resting mean pulmonary capillary wedge pressure average was 19 mm Hg [Table III]. Although resting mean pulmonary capillary wedge pressure increased to an average of 24 mm Hg during moricizine HCl therapy, this difference did not reach statistical significance (p = 0.25). There was also no statistically significant difference in peak exercise pulmonary capillary wedge pressure during moricizine HCl therapy compared with placebo measurements Despite the absence of any statistically significant group change in mean pulmonary capillary wedge pressure either at rest or during exercise with moricizine HCl, individual patients had clinically important increases in mean pulmonary capillary wedge pressure during moricizine HCl therapy. Three patients [initial LVEF of 26‘70, 32% and 489’0,respectively] had substantial (210 mm Hg) increases in both rest and exercise mean pulmonary capillary wedge pressure during moricizine HCl therapy compared with placebo values. All 3 patients developed signs of congestive heart failure. Two of these patients required only an increase in diuretic therapy. The third patient, whose initial mean LVEF was 269’0,deteriorated during moricizine HCl therapy and was discontinued from the trial after 2 days. Individual changes in mean pulmonary capillary wedge pressure during rest and exercise with both placebo and moricizine HCl are detailed in Figure 1. From the hemodynamic variables measured directly during this investigation, additional calculated hemodynamic indexes are listed in Table IV. There was no change in either rest or exercise mean cardiac index with moricizine HCl therapy compared with placebo. Although the group data suggest no adverse effects of moricizine HCl therapy, individual patients had a decrease of 20.5 liter/min/m2 in rest and exercise cardiac index during moricizine HCl therapy compared with placebo (Fig. 21. The 3 patients with documented deterioration in resting cardiac index with moricizine HCl therapy were the same patients

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who had substantial increases in mean pulmonary capillary wedge pressure, as noted previously. There was no change in stroke volume index, LV stroke work index or systemic vascular resistance in the groups during moricizine HCl therapy as compared with respective placebo values at either rest or exercise (Table IV]. Only 1 patient [the patient who developed pulmonary edema, LVEF 26%) had a deterioration in stroke volume index 210 ml/m2 with moricizine HCl therapy [Table IV]. It should be emphasized, however, that more patients increased their cardiac index with moricizine HCl during exercise compared with respective .exercise cardiac index measurements while taking placebo; this finding supports good tolerance of this drug in the majority of patients with LV dysfunction.

Study4-Relation of AntiarrhythmicOutcome to Initial left VentricularFunction A total of 50 patients entered a prospective, singleblind, placebo-controlled trial with the sole entrance criterion of 210 runs of nonsustained VT on a screening 24-hour ambulatory electrocardiographic recording.14 Twenty of these patients also were enrolled in the hemodynamic assessment previously described. Coronary artery disease was present in 31 patients, including 20 with previous myocardial infarction. The remaining 19 patients had clinical diagnoses, including idiopathic cardiomyopathy (4 patients], mitral valve prolapse (4 patients] and hypertensive heart disease (3 patients); the other 8 patients had no demonstrable organic heart disease. Two patients withdrew from study during the placebo phase. Of the remaining 48 patients taking moricizine HCl, the mean age was 57 f 10 years; there were 40 men and 8 women. A history of congestive heart failure was present in 60% of the patients. Patients failed an average of 2 conventional antiarrhythmic drugs before study enrollment. All patients had 2-dimensional echocardiographic quantification of LVEF.12 No patient had a change in LVEF of 24% during moricizine HCl therapy compared with

TABLE IV Hemodynamic Effects of Moricizine HCI at Rest and During Supine Bicycle Exercise: Calculated Variables

60

Placebo

or0

PL

PL

(60Mhr)

FIGURE 1. Individual changes lary wedge pressure (PCWP) HCI therapy. PL = placebo; notes mean PCWP for entire

(60Mhr)

in rest and exercise pulmonary capilon placebo compared with moricizine M = moricizine HCI. Darker bar congroup.

Cl (liters/min/ms) Rest Exercise SVI (ml/m*) Rest Exercise LVSWI (g-m/m*) Rest Exercise SVR (dynes-s-em-5) Rest Exercise

Moricizine

HCI

2.4 f 0.5 3.7 f 0.9

2.5 f 0.6” 4.1 f 1.7”

34f 11 35 f 9

34 f 9” 36 f 15’

38* 38f

37 f 16’ 43 f 22”

15 17

1,623 f 426 1,200 f 396

1,590 f 454’ 1,170 f 400’

* Difference not significant compared with identical parameters with placebo. Cl = cardiac index; LVSWI = left ventricular stroke work index: SVI = stroke volume index: SVR = systemic vascular resistance.

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respective measurements with placebo. The mean LVEF of the entire group was 36 f 16% (mean f standard error). In this population, characterized by VT and LV dysfunction, the initial LVEF was an important determinant of eventual outcome during moricizine HCI therapy. Throughout the trial, patients who withdrew due to lack of antiarrhythmic efficacy had a lower LVEF than moricizine HCI responders; response was defined as 175% VT suppression [Table V). The difference in LVEF between moricizine HCI responders compared with patient withdrawals was statistically significant at both the l- and 3-month intervals (p
Discussion Recognition that the risk for sudden cardiac death is primarily related to complex ventricular ectopy in association with LV dysfunction has increased the awareness of the need for detailed information regarding the potential adverse effects of investigational antiarrhythmic drugs on LV function. Studies limited to patients with normal LV function and benign ventricular arrhythmia provide little useful information with which to guide the clinician in the selection of investigational agents. Data from the Beta-Blocker Heart Attack TrialI highlight the importance of LV function, with the major benefit in reducing risk of sudden death noted in patients with LV dysfunction and prior myocardial infarction. In patients with congestive heart failure, the selection of antiarrhythmic agents with even a small adverse effect on LV dysfunction could have important clinical consequences. The investigations discussed herein include both noninvasive and invasive evaluation of LV function in patients presenting with ventricular arrhythmia characterized by LV dysfunction. More important, both the patients studied by radionuclide ventriculography and those studied during rest and exercise hemodynamic evaluation had potentially life-threatening ventricular arrhythmias. Results of these investigations are in contrast with the majority of published evaluations of the effects of investigational and clinically available antiarrhythmic drugs on LV function.16 Previous studies primarily reported findings on patients with preserved ventricular function, limiting any practical application to the group of patients likely to require antiarrhythmic drug therapy.17-21 A second important limitation of previous studies is that they usually evaluated only resting hemodynamits or only assessed resting ventricular function. In fact, published hemodynamic studies of clinically available or investigational antiarrhythmic drugs that include exercise as well as resting hemodynamic data are rare. One relevant study by Wisenberg et alz2 reported the effects of disopyramide, procainamide and quinidine during both rest and exercise on 17 patients, as assessed by radionuclide estimation of LVEF. Each patient had an identical workload test performed during a placebo-controlled phase. There was no differ-

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F P E 2 u

6-

-6

5-

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F g

3-

-3

2 0

2-

-2

l-

-1

4-

000

PL

PL

(60”hr)

(6oMhr)

FIGURE 2. Individual changes in rest and exercise cardiac index (Cl) on placebo compared with moricirine HCI therapy. PL = placebo; M = moricirine HCI. Darker bar connotes mean Cl for entire group.

of Antiarrhythmic Effectiveness TABLE V Interdependence Moricizine HCI on Initial LVEF in Patients with Ventricular Tachycardia

of

LVEF at Selected Trial Intervals 30 Days Efficacy Withdrawals

n 40 n 29

= f = f

30 16% 18 14% *

* p
90 Days n 42 n 32

= f = f

22 16% 26 16%t

with moricizine with moricizine

HCI. HCI.

ence in the rest or peak exercise LVEF during antiarrhythmic therapy with any of the 3 antiarrhythmic drugs compared with their respective placebos. Individual patients, however, had significant deterioration of LV function at rest and during exercise on these antiarrhythmic drugs. One patient had a 13% decrease in LVEF at rest and a 21% decrease in LVEF during exercise with disopyramide compared with respective placebo values. An additional patient had a 30% decrease in LVEF with procainamide and 25% decrease in LVEF with quinidine. Interestingly, there was a much smaller (6%) decrease in LVEF during disopyramide administration. The effect of 3 antiarrhythmic drugs on global LV function urges cautious use of these type I antiarrhythmics in patients with severely impaired LV function .22The inability of this study to document any deterioration in group mean rest or exercise LVEF with disopyramide might raise the question as to whether radionuclide assessment of global LVEF is sensitive enough to detect clinically important effects on LV function. In addition, only 4 of 17 patients had a rest placebo LVEF <45%-emphasizing the importance of selecting patient populations with impaired LV function in order to make clinically relevant observations.

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As with most antiarrhythmic agents, early published reports of disopyramide were limited mostly to patients with essentially normal LV function. These reports represent an excellent example of potentially misleading observations on the possible adverse effects of an antiarrhythmic drug on LV function. Once disopyramide was administered to patients with LV dysfunction, the substantial tendency to worsen congestive heart failure became aIlparent.23-25 It is clear from the data presented in these investigations that the majority of patients with LVEF <30% tolerated moricizine HCl well without measurable or clinically apparent deterioration in LV function. It is also apparent, however, that the use of resting LVEF as an index of ventricular function has practical limitations and may be insensitive. Whereas a number of patients with LVEF <30% tolerated moricizine HCl well, we observed 2 patients (LVEF of 19% and 26%, respectively] who had significant clinical deterioration of LV function. Clearly, assessment of resting LVEF alone cannot adequately characterize patients who will definitely deteriorate if given moricizine HCl. A total of 22 other patients with LVEF <30% have had no clinical deterioration of heart failure with moricizine HCl. Based on hemodynamic data presented in these investigations, we propose establishing a comprehensive profile to characterize patients who may have clinical deterioration of LV function during moricizine HCl therapy. In addition to global LVEF <30%, caution is advised in patients with (I] resting mean pulmonary capillary wedge pressure 220 mm Hg, (2) resting cardiac index <2.5 liters/min/mz, (3) inability to increase cardiac index during exercise by 11 liter/min/ mz and (4) inability to increase stroke volume index during exercise. Adequate characterization of other investigational antiarrhythmic drugs, similar to the data presented herein, could provide meaningful comparative data. Supine bicycle exercise, gated wall motion study with exercise and the simple but clinically relevant exercise test are useful procedures for obtaining data for a comprehensive hemodynamic investigation of a new antiarrhythmic drug. Acknowledgment: Gratitude is expressed to Paula Johnson for her patient secretarial assistance and to Sara Mahler, MD, for her expertise with study design.

References 1. Bigger IT, Fleiss JL, Kleiger R, Miller jP, Rolnitzky LM, and the MultiCenter Post-Infarction Research Group. The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the two years after myocardial infarction. Circulation 1984;69:250-258. 2. Ruberman W, Weinblatt E, Goldberg JD, Frank CW, Shapiro S. Ventricular

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premature beats and mortality after myacardial infarction. N Engl J Med 1977;297:750-757. 3. Bigger JT, Weld FM, Rolnitzky LM. Prevalence, characteristics and significance of ventricular tachycardia (23 complexes) detected with ambulatory electrocardiographic recording in the late hospital phase of acute myocardiol infarction. Am J Cardiol 1981;48:815-823. 4. Bigger JT. Definition of benign versus malignant ventricular arrhythmias; targets for treatment. Am J Cardiol1982;52:47C-54C. 5. Weaver WD, Larch GS, Alvarez HA, Cobb LA. Angiographic findings and prognostic indicators in patients resuscitated from sudden cardiac death. Circulation 1976;54:895-900. 6. Calvert A, Lown B, Gorlin R. Ventricular premature beats and anatomically defined coronary heart disease. Am J Cardiol1977;39:627-634. 7. Schulze R, Strauss H, Pitt B. Sudden death in the year following myocardial infarction. Relation to ventricular premature contractions in the late hospital phase and left ventricular ejection fraction. Am J Med 1977;62:192-199. 8. Winkle R, Derrington D, Schroeder J. Characteristics of ventricular tachycardia in ambulatory patients. Am J Cardiol1977:39:487-492. 9. Moss A, Davis H, DeCamilia J. Ventricular ectopic beats and their relation to sudden and nonsudden cardiac death after myocardial infarction. Circufation 1979;60:998-1003. 10. Pratt CM, Yepsen SC, Taylor AA, Mason DT, Miller RR, Quinones MA, Lewis RA. Ethmozine suppression of single and repetitive ventricular premature depolarizations during therapy: documentation of efficacy and long-term safety. Am Heart J 1983;106:85-91. 11. Pratt CM, Young JB, Francis MI, Taylor AA, Norton HI, English L, Mann DE, Kopelen H, Q&ones MA, Rdbe& R. Comparative kffeci of disopyramide and Ethmozine in suppressing complex ventricular arrhythmias by use of a double-blind, placebo-controlled, longitudinal crossover design. Circulation 1984;69:288-297. 12. Quinones MA, Waggoner AD, Reduto LA, Nelson JG, Young JB, Winters WL, Ribeiro LG, Miller RR. A new simplified and accurate method for determining ejection fraction by two-dimensional echocardiography. Circulation 1981;64:744-753. 13. Yang SS, Bentivoglio G, Maranhao V, Goldberg H. In: Yang SS, ed. From Cardiac Catheterization Data to Hemodvnamic Parameters. 2nd ed. Philadelphia: FA Davis, 1978:1-94. 14. Pratt CM, Wierman A, Seals AA, English L, Leon C, Young JB, Quinones MA, Roberts R. Efficacy and safety of moricizine in patients with ventricular tachycardia: results of a placebo-controlled, prospective, long-term clinical trial. Circulation 1986;73:718-726. 15. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. JAMA 1982;247: 1707-1714. 16. Pratt CM, Luck ]C, Mann DE, Wyndham CRC. Investigational antiarrhythmic drugs for the treatment of ventricular rhythm disturbances. Cardiol Clin 1984;2:35-46. 17. Hodges M, Salerno DM, Granrud G, and Flecainide Quinidine Research Group. Flecainide versus quinidine: results of a multi-center trial. Am J Cardiol1984;53:66B-71B. 18. Winkle R, Gradman A, Fitzgerald 1, Bell P. Antiarrhythmic drug effect assessedfrom ventricular arrhythmia reduction in ambulatory electrocardiogram and treadmill test: comparisons from procainamide and quinidine. Am J Cardiol1978;42:473-480. 19. Giardina EV, Fenster P, Bigger JT, Mayersohn M, Perrier D, Marcus F. Efficacy, plasma concentrations and adverse effects of a new sustained release procainamide preparation. Am J Cardiol1980;46:855-862. 20. Campbell NP, Zaidi SA, Adgey AA. Observations of hemodynamic effects of me&tine. Br Heart J 1979;41:182-186. 21. Vismara LA, Mason DT, Amsterdam EA. Disopyramide phosphate: clinical efficacy of a new oral antiarrhythmic drug. Clin Pharmacol Ther 1974;16:330-335. 22. Wisenberg G, Zawadowski G, Gebhardt VA, Prato FS, Goddard MD, Nichol PM, Rechnitzer PA, Gryfe-Becker B. Effects on ventricular function of disopyramide, procainamide and quinidine as determined by radionuclide angiography. Am J Cardiol 1984;53:1292-1297. 23. Podrid P, Schoenberger A, Lown B. Congestive heart failure caused by oral disopyramide. N Engl J Med 1980;302:614-616 24. Desai J, Scheinman M, Hirschfeld D, Gonzalez R, Peters R. Cardiovascular collapse associated with disopyramide therapy. Chest 1981;79:545-551. 25. Kowey P, Friedman P, Podrid P, Zielonka J, Lown B, Wynne J, Holman B. Use of radionuclide ventriculography for assessmentof changes in myocardial performance induced by disopyramide phosphate. Am Heart J 1982; 104:769-774.