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Efficacy and tolerance of ethmozine® (moricizine HCl) in placebo-controlled trials
EfficacyandToleranceof Ethmozine” (MoricizineHCI) in Placebo-Controlled Trials MARC
JOEL MORGANROTH, MD, CRAIG M. PRATT, MD, HAROLD L. KENNEDY, MD, MPH, STEVEN N. SINGH, MD, L. PLATT, MD, BONNIE J. BAKER, MD, and DEAN T. MASON,
To investigate the tolerance and efficacy of moricizine HCI, single-blind placebo-controlled trials were conducted. The early protocols involved patients hospitalized for 14 days, and daily Holter monitoring was used to document efficacy and the degree of spontaneous variability of ventricular premature complexes (VPCs). Moricizine HCI was given orally from 2.9 to 15.3 mg/kg 3 times daily. Patients with lethal ventricular arrhythmias were excluded. Additional outpatient trials were conducted to define long-term efficacy and safety. A doseresponse relation between moricizine HCI and the percentage of reduction in frequency of benign or potentially lethal ventricular arrhythmias was
MD
documented. Eighty-five percent of patients achieved a reduction in VPCs >75% with daily dosages ranging from 10.1 to 15 mg/kg. This corresponded to a 95% decrease in mean frequency of VPCs. Long-term studies demonstrated no evidence of compromise in left ventricular function, and the proarrhythmic rate was only 2 % . Symptomatic side effects were mild and usually well tolerated. Nausea, the most common, occurred in 11% of patients and dizziness in 9 % . These results indicate that moricizine HCI is an effective and well-tolerated antiarrhythmic agent. (Am J Cardiol 1987;80:48F-51F)
F
inding well-tolerated and effective antiarrhythmic agents has been the goal of much clinical investigation in the last few years. The available drugs have efficacy rates ranging from only 40% to about 7O%, with side effect rates of 20% to 40% .l The controversy over the use of these agents in the treatment of ventricular premature complexes (VPCs) became better defined when such arrhythmias were classified into benign, potentially lethal or lethal types1 Lethal ventricular arrhythmias require treatment because they produce hemodynamic symptoms. Benign ventricular arrhythmias usually need no antiarrhythmic treatment, because there is little risk of sudden death in these patients, who have no structural or functional cardiac abnormality. The vast majority of ventricular arrhythmias occur in the setting of structural or functional cardiac disease, and even though the arrhythmia itself is not hemodynamically comproFrom the Likoff Cardiovascular Institute, Hahnemann University, Philadelphia, Pennsylvania. Address for reprints: Joel Morganroth, MD, Likoff Cardiovascular Institute, Hahnemann University Hospital, 230 North Broad Street, Philadelphia, Pennsylvania 19102.
mising, its presence identifies a patient at high risk of sudden cardiac death. Unfortunately, no data unequivocally prove whether suppression of potentially lethal ventricular arrhythmias will prevent sudden cardiac death. The availability of new, well-tolerated and effective antiarrhythmic agents makes it more rational to treat these arrhythmias before this question is answered and may allow for a proper clinical trial to be conducted without high withdrawal rates because of side effects. Moricizine HCl (Ethmozine@]* has been shown to be well tolerated and effective.2-6 This article reviews dose titration of moricizine HCl in placebo-controlled trials in the US.
Methodsand Patients Table I lists a protocol for single-blind placebocontrolled trials of moricizine HCl in patients hospitalized for 14 days in US clinical research units. Daily 24hour ambulatory electrocardiographic (Holter] monitoring was used throughout the 2 weeks to document * Moricizine HCl is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozine”.
48F
October 16. 1987
TABLE I Standard Protocol for Initial, Single-Blind, Controlled Moricizine HCI Trials Drug Study Day Holter ECG Lab tests
Screen
X X
Placebo 1 2 3
4
5
Moricizine 6 7
xxxxxxxxxxx X X
HCI 8 9
IO
x
X
Volume 60
Patients with Efficacy*
49F
Patients:
Moricizine Daily Dose (mgM)
PtS.
(n)
n
%
Mean Decrease in Frequency of VPCS (%)
1.6-5.0 5.1-10.0 10.1-15.0 Overall
9 49 27 85
3 36 23 62
33 73 85 73
-58 -85 -95 -88
X
Thirteen day protocol shows precisely when 24-hour Holter monitoring, 12lead electrocardiogram (ECG) at rest and routine blood and urine laboratory tests were conducted.
* 275%
TABLE II
OF CARDIOLOGY
Placebo 12 13 x
X X
JOURNAL
TABLE Ill Moricizine HCI Dose Titration in Hospitalized Efficacy for Ventricular Premature Complexes (VPCs)
Placebo-
11
THE AMERICAN
reduction
in VPCs/hr
Clinical Diagnoses of Study Patients
Hypertension Coronary artery disease Idiopathic cardiomyopathy Prior myocardial infarction Congestive heart failure Valvular heart disease
Inpatients (%) (n = 83)
Outpatients (%) (n = 88)
41 30 39 21 18 11
57 53 17 34 25 1
the spontaneous variability of ventricular arrhythmias and to define the effective dose range for moricizine HCl. Electrocardiographic and laboratory tests were performed frequently as safety measures. Oral moricizine HCI therapy was begun in a range of 2.9 to 15.3 mg/kg daily. This allowed for dose titration from 50 to 300 mg 3 times daily. Patients were enrolled in these trials if they had benign or potentially lethal ventricular arrhythmias defined as at least 30 VPCs/hr or at least 30 atria1 premature complexes/hr on baseline Holter monitoring. Patients with lethal ventricular arrhythmias (defined as a sustained ventricular tachyarrhythmia) were excluded. In addition, patients who had had myocardial infarction or cardiac surgery within 3 months or who had severe renal, hepatic, hematologic or metabolic abnormalities were excluded. Unstable chronic illnesses, use of monoamine oxidase inhibitors or previous intolerance to phenothiazines also formed a basis for exclusion. Patients with sick sinus syndrome or second- or third-degree atrioventricular nodal block were not eligible for the study. A similar trial was conducted by Hodges (Minneapolis, Minnesota) and Singh [Washington, DC] using a single-blind placebo-controlled protocol with an oral dose of moricizine HCI from 900 to 1,650 mg 3 times daily. These hospitalized patients received placebo for 2 to 3 days followed by moricizine HCl for 10 days and a placebo washout for 3 days. Twenty-four hour Holter monitoring was obtained on each day of placebo to serve as the baseline and was repeated on days 1,2,5,6 and 10 of moricizine HCI therapy. Additional outpatient trials with similar enrollment criteria have been conducted using a single-blind placebo-controlled design. Placebo was administered for up to 7 days, and 4 sequential 24-hour Holter recordings were obtained to serve as baseline. Moricizine HCl was administered for 1 month, starting at 10 mg/
kg on days 1 through 7. If the frequency of VPCs decreased by Xi%, the patient continued this dosage for the full 28 days. If this decrease did not occur, moricizine HCl was increased to 12 mg/kg daily from days 8 through 14. If no effect was noted from days 15 through 28,15 mg/kg daily was used. Patients in these trials were allowed to enter the long-term study of moricizine HCI, in which Holter monitoring was performed during months 2, 3, 4, 5, 6 and 9 and then every 3 months. At these visits, 12-lead electrocardiograms, complete urine and blood laboratory determinations, plasma levels and vital signs were obtained.
Results The dose titration in-hospital protocols involved 85 patients who ranged in age between 22 and 72 years [mean 55 f 11.9j. Sixty-nine were men and 21 were women. Sixty-two percent of patients had been treated with antiarrhythmic drugs, ranging from 1 to 4 agents per patient. Therefore, this group was relatively resistant to antiarrhythmic therapy. Twenty-four percent of these patients were receiving digitalis and 42% were receiving diuretics. Table II lists the diagnostic categories represented. Table III shows the reduction in VPCs achieved by moricizine HCl. These data detail the percentage of patients whose total reduction in VPCs was 175% and the mean percentage of decrease in total VPCs. The data demonstrate a clear dose-response relation in which 85% of patients are expected to achieve a 75% reduction in frequency of VPCs at a dose of 10.1 to 15 mg/kg, corresponding to a 95% mean reduction in frequency of ventricular ectopic activity. Only 14 patients had atria1 premature complexes in which efficacy could be determined. Twelve of the 14 patients (86%) had a 75% reduction in frequency of atria1 premature complexes, which corresponded to a mean decrease of 92%. No dose-response relation was noted; however, there were too few patients at various dose levels to be certain of this finding. No statistically significant differences in adverse reactions were observed between patients given placebo and those given moricizine HCl. Thirty-one patients (33%) receiving placebo had symptoms compared with 30 patients (32%) receiving moricizine HCl. The number of days in which adverse reactions occurred was also not different between the 2 groups:
50F
A SYMPOSIUM:
ETHMOZINF?
(MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
73 days with placebo (13%) and 62 days with moricizine HCl (9%). Light-headedness or dizziness occurred in 13% of patients, headache in 770, weakness or tiredness in 5% and paresthesias and nervousness in 4%. Less than 3% of the study population complained of nausea, abdominal discomfort, diarrhea, palpitations or dry mouth. In these studies no evidence of proarrhythmia or left ventricular dysfunction was identified. The high dose in-hospital study by Hodges and Singh involved 17 patients, 12 of whom (71%) had a >80% reduction in frequency of VPCs. The mean number of VPCs/hr with placebo was 308. On day 1, a mean of 250 VPCs was noted, which decreased to 90 on day 2,13 on day 5,17 on day 6,26 on day 9 and 35 on day 10. During the last 3 days when placebo was again administered, the mean frequency of VPCs/hr increased from 88 to 245 to 362, respectively. The use of moricizine HCl for longer periods of therapy was studied in 5 separate trials involving 88 outpatients. The 80 men and 8 women ranged in age from 28 to 79 years (mean 57.9 f 10.3). Seventy-eight TABLE IV Moricizine HCI Dose Titration in Outpatients: LongTerm Efficacy for Ventricular Premature Complexes (VPCs) Moricizine
HCI Dose (mglkg daily)
Pk.
(n)
‘(IO
54
28 (53%)
10.1-12.0
12.1-16.0
Efficacy*
* Patients with 270%
TABLE V
Tolerance
13 (59%)
30 (63%)
reduction in frequency
to Moricizine
Adverse Reactions
TABLE VI
Tolerance
of Moricizine
Studies
% 11 9 4 4 3 3 2 2 2 2 51
Nausea Dizziness Abdominal discomfort Weakness Headache Palpitations Constipation Nervousness Dry mouth Blurred vision Others
HCI in Long-Term Studies
Adverse Reactions Leading to Patient Discontinuation
pt. (n)
%
Ventricular tachycardia, arrest Hemiblock, right bundle branch block Proarrhythmia Anxiety, depression Dizziness, syncope Abnormal liver function
3” 3 2 2 2 I+
2.5 2.5 1.7 1.7 1.7
* All 3 were considered by the investigator disease and not drug related. t Not drug related, per investigator.
percent of patients had used antiarrhythmic drugs, from 1 to 7 agents per patient. Twenty-three percent of patients were receiving digitalis and 55% diuretics. Moricizine HCl was administered in doses from 6.6 to 16.0 mg/kg, with a mean of 11.3 f 2.0 mg/kg. Table IV illustrates the reduction of VPCs corresponding to dose. In this study approximately 60% of patients responded with a 170% reduction in frequency of VPCs. As shown in Table V, the most common adverse reaction reported with moricizine was nausea (11% of patients) followed by dizziness (9”/0]. In most patients nausea could be eliminated if the drug was taken with meals, although in some patients this symptom persisted. Very few patients experienced any other debilitating side effects that could not be easily dealt with by changing the way the medication was taken. To date, 118 patients in 4 centers have participated in the long-term studies of moricizine. The daily dosage has ranged from 5.5 to 12.9 mg/kg (mean 10 f 1.3). The average patient received the drug for 272 days (range 1 to 946). Fifty-eight percent of patients reported sustained efficacy, a figure that corresponds to a mean reduction in VPCs from 86% to 98%. Long-term adverse reactions leading to patient discontinuation are shown in Table VI. A proarrhythmic effect occurred in approximately 2% of patients. Three patients had ventricular tachycardia or cardiac arrest, believed by the investigators to be due to inherent cardiac disease rather than to a proarrhythmic drug effect because of the duration of therapy and lack of any evidence of worsening arrhythmia before the event.
Discussion
of VPCs.
HCI in Outpatient
AGENT
to be due to inherent cardiac
To evaluate ventricular arrhythmias, studies must carefully characterize the nature of the patient’s cardiac disease and hemodynamic status. In this way, 3 separate groups of patients with ventricular arrhythmias in whom antiarrhythmic therapy should be considered can be defined. It is quite ‘common to study patients with benign ventricular .arrhythmias who do not require treatment, to determine dose and tolerance. In controlled clinical trials patients with potentially lethal ventricular arrhythmias can be safely used for outpatient study when comparing new antiarrhythmic drugs with placebo or standard agents. Patients with lethal ventricular arrhythmias should be studied only after baseline electrophysiologic, hemodynamic and dose-efficacy parameters are defined. This article summarizes the early dose-response studies that were single-blind and placebo-controlled. They predominantly involved patients with benign and potentially lethal ventricular arrhythmias. In addition, outpatient and long-term placebo-controlled trial data are provided. The data in Table III demonstrate the clear doseresponse relation identified for moricizine HCl in the hospitalized patients studied in the early trials. Although low doses produced virtually no side effects, only one-third to one-half of patients responded with a 75% reduction in VPC frequency. An 85% response rate was observed in patients who received 10.1 to 15 mg/kg of moricizine HCl daily, which compares favor-
October 16, 1987
ably with the more potent antiarrhythmic agents. In outpatient trials performed under less contrblled conditions, approximately 60% of patients responded at doses of 10 to 15 mg/kg daily. Moricizine HCl, in contrast to other antiarrhythmic agents, appears to be extremely well tolerated with only minimal symptoms, even when higher doses are administered. In long-term trials approximately 10% of patients had nausea or dizziness, which were often eliminated by ingesting the drug with meals. The lack of important changes on the electrocardiogram, the low potential for proarrhythmia (only 2% of patients in long-term trials had this adverse reaction) and the scant evidence of negative inotropy suggest that moricizine is a promising antiarrhythmic agent. Because it is particularly well tolerated and has good efficacy rates, moricizine HCI would be appropriate for use in a properly conducted large trial to deterniine whether the treatment of potentially lethal ventricular arrhythmias will prevent sudden cardiac death.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 60
51F
Acknowledgment: We acknowledge the data contributed by Frank I. Marcus, MD, to the patient data base.
References 1. Morganroth J. Premature ventricular complexes. Diagnosis and indications for therapy. [AMA 1984;252:673-676. 2. Morganroth ], Pearlman AS, Dunkman WB, Horowitz LN, Josephson ME, Michelson E. Ethmozin: a new antiarrhythmic agent developed in the USSR. Efficacy and tolerance. Am Heart f 1979;98:621-628. 3. Kennedy HL, Pescarmona JE, Joyner V, Caralis D,Poblete P. The efficacy and tolerance of ethmozin for chronic ventricular ectopy [abstr]. Circulation 1978;57:suppJII1177. 4. Podrid PJ. Lown B. Ethmozin therapy for malignant ventricular arrhythmia (abstr]. Am 1 CardioI1982;49:1015. 5. Singh SN, DiBianco R, Gottdiener IS, Ginsberg R, Fletcher R. Effect of mori&ine hydrochloride in reducing chronic high-frequency ventricular arrhvthmia: results of a orosnective. controlled trial. Am I Cardiol 1984; 53:745-750. 6. Pratt CM, Young JB, Francis MJ. Comparative effect of dysopyramide and Ethmozine in suppressing complex ventricular arrhythmias by use of a double-blind, placebo-controlled, longitudinal crossover design. Circulation 1984;69:288-297. ,
1
JOEL MORGANROTH, MD, CRAIG M. PRATT, MD, HAROLD L. KENNEDY, MD, MPH, STEVEN N. SINGH, MD, L. PLATT, MD, BONNIE J. BAKER, MD, and DEAN T. MASON,
To investigate the tolerance and efficacy of moricizine HCI, single-blind placebo-controlled trials were conducted. The early protocols involved patients hospitalized for 14 days, and daily Holter monitoring was used to document efficacy and the degree of spontaneous variability of ventricular premature complexes (VPCs). Moricizine HCI was given orally from 2.9 to 15.3 mg/kg 3 times daily. Patients with lethal ventricular arrhythmias were excluded. Additional outpatient trials were conducted to define long-term efficacy and safety. A doseresponse relation between moricizine HCI and the percentage of reduction in frequency of benign or potentially lethal ventricular arrhythmias was
MD
documented. Eighty-five percent of patients achieved a reduction in VPCs >75% with daily dosages ranging from 10.1 to 15 mg/kg. This corresponded to a 95% decrease in mean frequency of VPCs. Long-term studies demonstrated no evidence of compromise in left ventricular function, and the proarrhythmic rate was only 2 % . Symptomatic side effects were mild and usually well tolerated. Nausea, the most common, occurred in 11% of patients and dizziness in 9 % . These results indicate that moricizine HCI is an effective and well-tolerated antiarrhythmic agent. (Am J Cardiol 1987;80:48F-51F)
F
inding well-tolerated and effective antiarrhythmic agents has been the goal of much clinical investigation in the last few years. The available drugs have efficacy rates ranging from only 40% to about 7O%, with side effect rates of 20% to 40% .l The controversy over the use of these agents in the treatment of ventricular premature complexes (VPCs) became better defined when such arrhythmias were classified into benign, potentially lethal or lethal types1 Lethal ventricular arrhythmias require treatment because they produce hemodynamic symptoms. Benign ventricular arrhythmias usually need no antiarrhythmic treatment, because there is little risk of sudden death in these patients, who have no structural or functional cardiac abnormality. The vast majority of ventricular arrhythmias occur in the setting of structural or functional cardiac disease, and even though the arrhythmia itself is not hemodynamically comproFrom the Likoff Cardiovascular Institute, Hahnemann University, Philadelphia, Pennsylvania. Address for reprints: Joel Morganroth, MD, Likoff Cardiovascular Institute, Hahnemann University Hospital, 230 North Broad Street, Philadelphia, Pennsylvania 19102.
mising, its presence identifies a patient at high risk of sudden cardiac death. Unfortunately, no data unequivocally prove whether suppression of potentially lethal ventricular arrhythmias will prevent sudden cardiac death. The availability of new, well-tolerated and effective antiarrhythmic agents makes it more rational to treat these arrhythmias before this question is answered and may allow for a proper clinical trial to be conducted without high withdrawal rates because of side effects. Moricizine HCl (Ethmozine@]* has been shown to be well tolerated and effective.2-6 This article reviews dose titration of moricizine HCl in placebo-controlled trials in the US.
Methodsand Patients Table I lists a protocol for single-blind placebocontrolled trials of moricizine HCl in patients hospitalized for 14 days in US clinical research units. Daily 24hour ambulatory electrocardiographic (Holter] monitoring was used throughout the 2 weeks to document * Moricizine HCl is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozine”.
48F
October 16. 1987
TABLE I Standard Protocol for Initial, Single-Blind, Controlled Moricizine HCI Trials Drug Study Day Holter ECG Lab tests
Screen
X X
Placebo 1 2 3
4
5
Moricizine 6 7
xxxxxxxxxxx X X
HCI 8 9
IO
x
X
Volume 60
Patients with Efficacy*
49F
Patients:
Moricizine Daily Dose (mgM)
PtS.
(n)
n
%
Mean Decrease in Frequency of VPCS (%)
1.6-5.0 5.1-10.0 10.1-15.0 Overall
9 49 27 85
3 36 23 62
33 73 85 73
-58 -85 -95 -88
X
Thirteen day protocol shows precisely when 24-hour Holter monitoring, 12lead electrocardiogram (ECG) at rest and routine blood and urine laboratory tests were conducted.
* 275%
TABLE II
OF CARDIOLOGY
Placebo 12 13 x
X X
JOURNAL
TABLE Ill Moricizine HCI Dose Titration in Hospitalized Efficacy for Ventricular Premature Complexes (VPCs)
Placebo-
11
THE AMERICAN
reduction
in VPCs/hr
Clinical Diagnoses of Study Patients
Hypertension Coronary artery disease Idiopathic cardiomyopathy Prior myocardial infarction Congestive heart failure Valvular heart disease
Inpatients (%) (n = 83)
Outpatients (%) (n = 88)
41 30 39 21 18 11
57 53 17 34 25 1
the spontaneous variability of ventricular arrhythmias and to define the effective dose range for moricizine HCl. Electrocardiographic and laboratory tests were performed frequently as safety measures. Oral moricizine HCI therapy was begun in a range of 2.9 to 15.3 mg/kg daily. This allowed for dose titration from 50 to 300 mg 3 times daily. Patients were enrolled in these trials if they had benign or potentially lethal ventricular arrhythmias defined as at least 30 VPCs/hr or at least 30 atria1 premature complexes/hr on baseline Holter monitoring. Patients with lethal ventricular arrhythmias (defined as a sustained ventricular tachyarrhythmia) were excluded. In addition, patients who had had myocardial infarction or cardiac surgery within 3 months or who had severe renal, hepatic, hematologic or metabolic abnormalities were excluded. Unstable chronic illnesses, use of monoamine oxidase inhibitors or previous intolerance to phenothiazines also formed a basis for exclusion. Patients with sick sinus syndrome or second- or third-degree atrioventricular nodal block were not eligible for the study. A similar trial was conducted by Hodges (Minneapolis, Minnesota) and Singh [Washington, DC] using a single-blind placebo-controlled protocol with an oral dose of moricizine HCI from 900 to 1,650 mg 3 times daily. These hospitalized patients received placebo for 2 to 3 days followed by moricizine HCl for 10 days and a placebo washout for 3 days. Twenty-four hour Holter monitoring was obtained on each day of placebo to serve as the baseline and was repeated on days 1,2,5,6 and 10 of moricizine HCI therapy. Additional outpatient trials with similar enrollment criteria have been conducted using a single-blind placebo-controlled design. Placebo was administered for up to 7 days, and 4 sequential 24-hour Holter recordings were obtained to serve as baseline. Moricizine HCl was administered for 1 month, starting at 10 mg/
kg on days 1 through 7. If the frequency of VPCs decreased by Xi%, the patient continued this dosage for the full 28 days. If this decrease did not occur, moricizine HCl was increased to 12 mg/kg daily from days 8 through 14. If no effect was noted from days 15 through 28,15 mg/kg daily was used. Patients in these trials were allowed to enter the long-term study of moricizine HCI, in which Holter monitoring was performed during months 2, 3, 4, 5, 6 and 9 and then every 3 months. At these visits, 12-lead electrocardiograms, complete urine and blood laboratory determinations, plasma levels and vital signs were obtained.
Results The dose titration in-hospital protocols involved 85 patients who ranged in age between 22 and 72 years [mean 55 f 11.9j. Sixty-nine were men and 21 were women. Sixty-two percent of patients had been treated with antiarrhythmic drugs, ranging from 1 to 4 agents per patient. Therefore, this group was relatively resistant to antiarrhythmic therapy. Twenty-four percent of these patients were receiving digitalis and 42% were receiving diuretics. Table II lists the diagnostic categories represented. Table III shows the reduction in VPCs achieved by moricizine HCl. These data detail the percentage of patients whose total reduction in VPCs was 175% and the mean percentage of decrease in total VPCs. The data demonstrate a clear dose-response relation in which 85% of patients are expected to achieve a 75% reduction in frequency of VPCs at a dose of 10.1 to 15 mg/kg, corresponding to a 95% mean reduction in frequency of ventricular ectopic activity. Only 14 patients had atria1 premature complexes in which efficacy could be determined. Twelve of the 14 patients (86%) had a 75% reduction in frequency of atria1 premature complexes, which corresponded to a mean decrease of 92%. No dose-response relation was noted; however, there were too few patients at various dose levels to be certain of this finding. No statistically significant differences in adverse reactions were observed between patients given placebo and those given moricizine HCl. Thirty-one patients (33%) receiving placebo had symptoms compared with 30 patients (32%) receiving moricizine HCl. The number of days in which adverse reactions occurred was also not different between the 2 groups:
50F
A SYMPOSIUM:
ETHMOZINF?
(MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
73 days with placebo (13%) and 62 days with moricizine HCl (9%). Light-headedness or dizziness occurred in 13% of patients, headache in 770, weakness or tiredness in 5% and paresthesias and nervousness in 4%. Less than 3% of the study population complained of nausea, abdominal discomfort, diarrhea, palpitations or dry mouth. In these studies no evidence of proarrhythmia or left ventricular dysfunction was identified. The high dose in-hospital study by Hodges and Singh involved 17 patients, 12 of whom (71%) had a >80% reduction in frequency of VPCs. The mean number of VPCs/hr with placebo was 308. On day 1, a mean of 250 VPCs was noted, which decreased to 90 on day 2,13 on day 5,17 on day 6,26 on day 9 and 35 on day 10. During the last 3 days when placebo was again administered, the mean frequency of VPCs/hr increased from 88 to 245 to 362, respectively. The use of moricizine HCl for longer periods of therapy was studied in 5 separate trials involving 88 outpatients. The 80 men and 8 women ranged in age from 28 to 79 years (mean 57.9 f 10.3). Seventy-eight TABLE IV Moricizine HCI Dose Titration in Outpatients: LongTerm Efficacy for Ventricular Premature Complexes (VPCs) Moricizine
HCI Dose (mglkg daily)
Pk.
(n)
‘(IO
54
28 (53%)
10.1-12.0
12.1-16.0
Efficacy*
* Patients with 270%
TABLE V
Tolerance
13 (59%)
30 (63%)
reduction in frequency
to Moricizine
Adverse Reactions
TABLE VI
Tolerance
of Moricizine
Studies
% 11 9 4 4 3 3 2 2 2 2 51
Nausea Dizziness Abdominal discomfort Weakness Headache Palpitations Constipation Nervousness Dry mouth Blurred vision Others
HCI in Long-Term Studies
Adverse Reactions Leading to Patient Discontinuation
pt. (n)
%
Ventricular tachycardia, arrest Hemiblock, right bundle branch block Proarrhythmia Anxiety, depression Dizziness, syncope Abnormal liver function
3” 3 2 2 2 I+
2.5 2.5 1.7 1.7 1.7
* All 3 were considered by the investigator disease and not drug related. t Not drug related, per investigator.
percent of patients had used antiarrhythmic drugs, from 1 to 7 agents per patient. Twenty-three percent of patients were receiving digitalis and 55% diuretics. Moricizine HCl was administered in doses from 6.6 to 16.0 mg/kg, with a mean of 11.3 f 2.0 mg/kg. Table IV illustrates the reduction of VPCs corresponding to dose. In this study approximately 60% of patients responded with a 170% reduction in frequency of VPCs. As shown in Table V, the most common adverse reaction reported with moricizine was nausea (11% of patients) followed by dizziness (9”/0]. In most patients nausea could be eliminated if the drug was taken with meals, although in some patients this symptom persisted. Very few patients experienced any other debilitating side effects that could not be easily dealt with by changing the way the medication was taken. To date, 118 patients in 4 centers have participated in the long-term studies of moricizine. The daily dosage has ranged from 5.5 to 12.9 mg/kg (mean 10 f 1.3). The average patient received the drug for 272 days (range 1 to 946). Fifty-eight percent of patients reported sustained efficacy, a figure that corresponds to a mean reduction in VPCs from 86% to 98%. Long-term adverse reactions leading to patient discontinuation are shown in Table VI. A proarrhythmic effect occurred in approximately 2% of patients. Three patients had ventricular tachycardia or cardiac arrest, believed by the investigators to be due to inherent cardiac disease rather than to a proarrhythmic drug effect because of the duration of therapy and lack of any evidence of worsening arrhythmia before the event.
Discussion
of VPCs.
HCI in Outpatient
AGENT
to be due to inherent cardiac
To evaluate ventricular arrhythmias, studies must carefully characterize the nature of the patient’s cardiac disease and hemodynamic status. In this way, 3 separate groups of patients with ventricular arrhythmias in whom antiarrhythmic therapy should be considered can be defined. It is quite ‘common to study patients with benign ventricular .arrhythmias who do not require treatment, to determine dose and tolerance. In controlled clinical trials patients with potentially lethal ventricular arrhythmias can be safely used for outpatient study when comparing new antiarrhythmic drugs with placebo or standard agents. Patients with lethal ventricular arrhythmias should be studied only after baseline electrophysiologic, hemodynamic and dose-efficacy parameters are defined. This article summarizes the early dose-response studies that were single-blind and placebo-controlled. They predominantly involved patients with benign and potentially lethal ventricular arrhythmias. In addition, outpatient and long-term placebo-controlled trial data are provided. The data in Table III demonstrate the clear doseresponse relation identified for moricizine HCl in the hospitalized patients studied in the early trials. Although low doses produced virtually no side effects, only one-third to one-half of patients responded with a 75% reduction in VPC frequency. An 85% response rate was observed in patients who received 10.1 to 15 mg/kg of moricizine HCl daily, which compares favor-
October 16, 1987
ably with the more potent antiarrhythmic agents. In outpatient trials performed under less contrblled conditions, approximately 60% of patients responded at doses of 10 to 15 mg/kg daily. Moricizine HCl, in contrast to other antiarrhythmic agents, appears to be extremely well tolerated with only minimal symptoms, even when higher doses are administered. In long-term trials approximately 10% of patients had nausea or dizziness, which were often eliminated by ingesting the drug with meals. The lack of important changes on the electrocardiogram, the low potential for proarrhythmia (only 2% of patients in long-term trials had this adverse reaction) and the scant evidence of negative inotropy suggest that moricizine is a promising antiarrhythmic agent. Because it is particularly well tolerated and has good efficacy rates, moricizine HCI would be appropriate for use in a properly conducted large trial to deterniine whether the treatment of potentially lethal ventricular arrhythmias will prevent sudden cardiac death.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 60
51F
Acknowledgment: We acknowledge the data contributed by Frank I. Marcus, MD, to the patient data base.
References 1. Morganroth J. Premature ventricular complexes. Diagnosis and indications for therapy. [AMA 1984;252:673-676. 2. Morganroth ], Pearlman AS, Dunkman WB, Horowitz LN, Josephson ME, Michelson E. Ethmozin: a new antiarrhythmic agent developed in the USSR. Efficacy and tolerance. Am Heart f 1979;98:621-628. 3. Kennedy HL, Pescarmona JE, Joyner V, Caralis D,Poblete P. The efficacy and tolerance of ethmozin for chronic ventricular ectopy [abstr]. Circulation 1978;57:suppJII1177. 4. Podrid PJ. Lown B. Ethmozin therapy for malignant ventricular arrhythmia (abstr]. Am 1 CardioI1982;49:1015. 5. Singh SN, DiBianco R, Gottdiener IS, Ginsberg R, Fletcher R. Effect of mori&ine hydrochloride in reducing chronic high-frequency ventricular arrhvthmia: results of a orosnective. controlled trial. Am I Cardiol 1984; 53:745-750. 6. Pratt CM, Young JB, Francis MJ. Comparative effect of dysopyramide and Ethmozine in suppressing complex ventricular arrhythmias by use of a double-blind, placebo-controlled, longitudinal crossover design. Circulation 1984;69:288-297. ,
1