- Email: [email protected]
Treatment of ventricular arrhythmias with oral tocainide
Treatmerit of ventricular oral tocainide
arrhythmias
with
Michael D. Young, M.D., Ph.D., Zarch Hadidian, Ph.D., Howard R. Horn, M.D., Jeanne L. Johnson, A.B., and Helen G. Vassallo, Ph.D. Framingham, Mass. This
is a report
with other
a high therapy.
oral
of a multicenter bioavailability, The majority
open
study
in the of patients
of the
use
of tocainide,
a new
lidocaine-like
treatment of life-threatening ventricular have received 1,200 to 2,400 mg daily
antiarrhythmic
arrhythmias in divided
refractory doses and
to have
been treated for over 6 months and some for longer than 3 years. Overall, 61% of the patients responded successfully to tocainide therapy. In the 262 patients with documented, severe, symptomatic arrhythmias, 71% responded, and the majority (87%) showed a total abolition of symptomatic events. Gastrointestinal and I 1% had to discontinue
central
nervous system therapy: however,
events were the remaining
the most common adverse 89% tolerated kocainide
Lidocaine is the antiarrhythmic agent of choice for the acute intravenous treatment of ventricular arrhythmias,‘-” especially those occurring early after acute infarction. However, lidocaine is extensively metabolized by the liver in a first-pass effect and therefore cannot be given orally. Consequently, it has been necessary to use other antiarrhythmics for continuous oral therapy. Recent efforts directed toward the development of an oral antiarrhythmic of the same type as lidocaine resulted in the synthesis of tocainide, a new lidocaine analogue that has a high bioavailability when given orally and has an excellent spectrum of antiarrhythmic activity. In this study we report on the use of tocainide for the chronic treatment of ventricular arrhythmias in a multicenter study involving many investigators. The arrhythmias were refractory to other therapy, and all patients had either failed to respond to or were unable to tolerate other antiarrhylthmic agents, including quinidine, procainamide, disopyramide, and propranolol. Material
and
methods
A total of 819 patients with severe refractory arrhythmias received the drug,, of whom 628 had From
Astra
Pharmaceutical
Reprint requests: Michael ucts, Inc., P.O. Box 1089,
0002-8703/80/131041
Products,
Inc.,
Framingham,
Mass.
Young, M.D., Astra Pharmaceutical Framingham, MA 01701.
+ 05$00.50/00
1980
The
Prod-
C. V. Mosby
Co.
experiences, satisfactorily.
and
an adequate trial of treatment and were documented sufficiently to allow an evaluation of the efficacy of tocainide therapy. Males outnumbered females by more than 2:l, and their agesranged from 9 to 86 years, with the majority of patients being between 40 and 70 years old (Table I). The most common etiology of the patients’ cardiac diseasewas atherosclerotic heart disease; however, a significant number of patients had cardiomyopathies or valvular heart disease (Table H). The patients had either ventricular tachycardia or frequent and/or complex ventricular ectopic beats. The severity of their cardiac status was evaluated and 63% of them were categorized as New York Heart Association Class III or IV prior to tocainide therapy, (Table III). A further indication of the severity of the patients’ disease was the fact that 54% of them were receiving digitalis glycosides and 42% required treatment with diuretics at some time during the study. Tocainide therapy was initiated on a 1,200 mg daily dose either as 400 mg t.i.d. or 600 mg b.i.d., which was then adjusted according to the patient’s response. The majority of patients received 1,200 to 2,400 mg daily in divided doses, as shown in Table IV, which shows the final regimen the patient received regardless of whethAmerican
Heart
Journal
1041
Q-39 40-63 70-89 Unknown
83 438 96 11
Total
Be II.
-G-
tiology
47 76 72 45
53 24 28 55
-E
-IiF
of patients’
1,200 1,200 1,600 1,800 2,400 2,4CO
400 600 400 600 600 800
q8h
109
17
qlL2h q6h q8h q6b q8h
30 37 147 30 73
5 6 23 5 12
arrhythmias
Etiology Atherosclerotic heart disease Post AM1 Other Cardiomyopathy Mitral valve prolapse Rheumatic heart disease
Unknown AMI
= acuk
myocardial
infarction.
ie BBP. New York Heart Association functional classification of cardiac status prior to treatment Class Ii II III IV Unknown
53 139 209 122 105
er a lower dose had been adequate for some time previously. The treatment is still ongoing. At the time of this review of the program, the majority of the patients had been treated for over 6 months and some for more than 3 years (Table V).
E%cacy was assessed by the inciividual physician responsible for the patient. The parameters used were clinical response and laboratory testing, incEuding Wolter monitoring, telemetry, rhythm strips, exercise testmg, controEled weaning after successful therapy, and in a few cases, ed electrical stimulation studies. Pwz ion, we have arbitrarily decided that no In patients woulid be considered to have been successfully treated if therapy was not given continuously for at least 1 month. Therefore, this is an
evaluation of the efficacy of chronic oral therapy with toeainide. Overall, 61% of the patients responded successfully to tocainide (Table VI). Of the 628 patients, 252 (40%) had documented severe symptomatic arrhythmias anti their symptomatic response to treatment was dramatic. A total of 178 patients (71%) with symptomatic ventricular arrhythmias responded to tocainide, and the majority of such responders (87%) showed total abolition of symptomatic arrhythmic events, as shown in Table VII. MSO, a d&&d evaluation of the symptoiiatic patients showed there was a greater than 90% reduction in emergency hospital admissions, DC cardioversions, syncope, or presyneope during treatment with tocainia”e (Table VIII). Tocainide had no clinically significant negative inotropic effect and was not noted to prolong Q-T is chronic therapy s anterva1s during study. We obtained ECG ta from pat,Q,tS on chronic therapy an excess 0 months (Table JX). The ‘“early during treatment” vajlues were obtained from the first tracing taken after a steady-state level of tocainide had been reached, and the “‘Pate during treatment” values were obtained from the last tracing available for each patient, but in no case were these values obtained less than 6 months mto therapy. The statistically significant reduction in Q-T Interval was not considered to be clinically significant. side effects were generally either gastrointestinal or neurologic, and of the 628 patients, only 71 (11.3%) ha~I to discontinue therapy because of an adverse experience, as shown an Table X.
Qver a period of almost two decades, lidocaine has become established as the most effective agent for the suppression of ventricular arrhyt
Treatment’
Table
V. Duration Duration
of treatment with tocainide
of treatment
No.
Greater than 3 yr From 2 to 3 yr From 1 to 2 yr 6 mo to 1 yr From 1 to 6 mo Less than 1 mo
( 3%) ( 7%) (14%) (18%) (25%) (34%)
mias.‘e6Unfortunately, lidocaine cannot be used effectively by oral administration Tocainide is a lidocaine-like agent that is active orally. It has been reported to be effective in the treatment of ventricular arrhythmias in patients with coronary, valvular, and myopathic disease.‘.g This study evaluated the responsesto tocainide therapy of patients with severe, refractory ventricular arrhythmias, and the program was initiated as a humanitarian effort to treat these particularly difficult cases. The severity of the patients’ condition was documented by the fact that 63% were New York Heart Association Class III or IV when tocainide therapy commenced and also by the fact that all the patients had failed to respond adequately to, or could not take, full dosages of other oral antiarrhythmic agents, including quinidine, procainamide, propranolol, and, when available, disopyramide. In fact, many patients could-not be controlled adequately even on combinations of these agents, The etiologies of the patients cardiovascular diseasesare shown in Table II and clearly indicate that although .the majority of patients had atherosclerotic heart disease, a considerable number had valvular and myopathic disease. Much has been written about the difficulty inherent in evatluating the response to antiarrhythmic therapy because of the variability in the frequency of ventricular ectopic beats in longterm ECG monitoring.‘O-‘” Despite this, long-term ECG monitoring is the basic parameter used to monitor the response to an antiarrhythmic agent. Over 570 physicians were involved in this multicenter study of 628 patients, and they evaluated the response to tocainide therapy by means of telemetry, ECG rhythm strips, 24-hour Holter recordings, exercise testing, and in a few cases programmed electrical stimulation; also noted was the presence or absence of symptoms of ventricular arrhythmias. In addition, since these patients required maintenance therapy for con-
American
Heart
Jouma
I
with oral tocainide
VI. Response to treatment
Table
of patients
16 46 88 110 156 212
of uentrica2cx.r arrhythmias
Therapeutic
response
with tocainide of patients
No.
Success Failure
383 (61%) 245 (39%)
VII. Degree of response of severe symptomatic arrhythmias to tocainide therapy Table
Duration treatment
of
Over 3 yr 2 to 3 yr 1 to 2 yr 6 mo to 1 yr 1 to 6 mo Less than 1 mo Total
I
Total abolition 12 22 23 36 61 154 (61%)
Substantial I reduction 3 10 6 5 24 (10%)
No response
2 18 54 74 (29%)
siderable periods, this study evaluated treatment in excess of 1 month’s duration. That is to say, although patients might be judged to have failed to respond to tocainide after an initial trial of as little as 3 days, no patients were evaluated as showing a successful response to tocainide unless they had had at least 1 month’s therapy. In fact, the majority of patients had been treated for over 6 months with tocainide. Overall, 61% of the patients responded successfully to tocainide (Table VI) despite the refractory nature of the arrhythmias being treated, and the most usual dosage was 600 mg t.i.d. Of the 628 patients it was particularly interesting to consider the symptomatic response to treatment of the 252 who had documented severely symptomatic arrhythmias. Severe symptoms were defined as repeated occurrence of hospitalization, ventricular tachycardia-ventricular fibrillation, DC cardioversion, syncope, or multiple presyncopal episodes. A total of 178 patients (71%) with these severe symptomatic ventricular arrhythmias responded to tocainide, and of them the majority (87%) showed a total abolition of all symptomatic arrhythmic events (Table VII). Also, a detailed evaluation of the symptomatic patients showed there was a greater than 90% reduction in emergency hospital admissions, DC cardioversions, syncope, or presyncope during treatment with tocainide (Table VIII). This represents a considerable improvement in
1043
Emergency admission for VTNF DC cardioversion for VT/VF Episodes of syncope Episodes of presyncope
IKE
Pretreatment Eariy awing treatment Late during treatment
intervals
0.173
i
8.021
0.0171
+- 0.021
0.175
I 0.025
129 11‘2 104 57
before and during
0.093 i
0.030
364 512 403 756
long-
0.450
k 0.044
0.093 -+ 0.038
O.4348
I 0.046
0.095 _t 0.029
0.436*
* 0.055
Adverse experiences resulting in uation of tocainide in 628 patients were valid for evaluation of e
who
4.9 2.4 1.6 2.1 0.3
2. 3. 4.
11.3 Abbreviations: CMS = central nervous CMF = congestive heart failure.
system, Cl = gastrointestinal,
the morbidity rate for these severely symptomatic patients. Tocainide had no clinically significant negative instropic effect in hemodynamic studies’ and ‘was not noted to prolong RS intervals in electrophysioiogic studies.” During this chronic therapy study, we obtained ECG data from patients on therapy in excess of 6 months. The “early during treatment” values (Table IX) were obtained from the first tracing taken after a steady-state level of tocainide had been reached, and the ‘“late during treatment” values were obtained from the last tracing available for each patient, but in no case was the value obtained less
93 97 97 99
than 6 months into therapy. There was no significant prolongation of either Q-T or QRS intervals. A statistically significant reduction in Q-T interval was seen; however, this was not considered to be clinically significant. The side effects to tocainide are generally those to be expected far a hdocaine analogue and have been discussed in detail elsewhere.‘” In this study only 11% of the 628 patients treated with tocainide had to discontinue therapy because of side effects and the remaining 89% tolerated the tocainide therapy satisfactorily. We conclude that tocainide is an effective and safe agent for the management of refractory ventricular arrhythmias.
1. CNS GI CWS/GI Rash Increased CHF
26 17 11 6
5.
6.
7.
8.
9.
10.
Model! W: Drugs of choice 1980-1981. St. Louis, 1980, The CV Mosby Company, pp 398-399. American Medical Association drug evaluations, ed. 4. New York, 1980, John Wiley & Sons, Inc, p 515. The Medical Letter Series, vol. 20. New York, 1978, The Medicai Letter, Inc., pp 116-117. IIarrison DC, Sprouse JR, Morrow AC: hntiarrhythmic properties of lidocaine and procainamide: Clinical and pbysioiogic studies of their cardiovascular effects in man. Circulation 23:486-91, 1963. Gianelly R, Van der Groeben JO, Spivack AP, Harrison DC: Effect of Iidocaine on ventricular arrhythmias in patients with coronary heart disease. N Engl J Med 277:1215-21, 1967. Lown B, Kosowsky BD, Klein MD: Bathogenesis, prevention and treatment of arrhythmias in myocardial infarction Circulation 40:261-65, 1968. Coltart IX, Rerridt TB, Harrison DC: Antiarrhythmic and circulatory effects of Astra W36095: A new lidocainelike agent. Am J Cardiol 34:35-41, 1974. Moore EN, Spear JF, Horrowitz LN, Feldman HS, MoIIar RA: Eiectrophysiologic properties of the new antiarrhythmic drug, tocainide. Am J Cardiol 47 :7O3-9, 1978. Woosley RL, McDevitt DC, Nies AS, Smith RF, Williamson AR, Oates JR: Suppression of ventricular ectopic depolarizations by tocainide. Circulation 56:980-4, 1977. Winkle RA, MeAn PJ, Fitzgerald JW, Rarrison DC: Clinical efficacy and pharmacokinetics of a new orally effective antiarrhythmic, tocainide. Circuiation 54:884-9, 1971.
Treatment
11.
12.
arrhythmias
with oral tocainide
Morganroth ME, Pearlman tine long-term ventricular 1978. Winkle RA, ide therapy
J, Michelson EL, Horrowitz LN, Josephson AS, Dunkman WB: Limitations of rouelectrocardiographic monitoring to assess ecta’pic frequency. Circulation 58:408-14, Meffin PJ, Harrison DC: Long-term tocainfor ventricular arrhythmias. Circulation
Kraemer HC: Principles and problems of controlled study design. Proceedings of Symposium on Cardiac Arrhythmias: A Decade of Progress-1980. Boston, G K Hall & Co (In press.) Horn HR, Hadidian Z, Johnson JL, Vassallo HG, Williams JH, Young MD: Safety evaluation of tocainide in the American Emergency Use Program. AM HEART J
57:1008-16,
1978.
100:1037-40,
American
Heart
13.
of ventricular
14.
Journal
1980.
1045
arrhythmias
with
Michael D. Young, M.D., Ph.D., Zarch Hadidian, Ph.D., Howard R. Horn, M.D., Jeanne L. Johnson, A.B., and Helen G. Vassallo, Ph.D. Framingham, Mass. This
is a report
with other
a high therapy.
oral
of a multicenter bioavailability, The majority
open
study
in the of patients
of the
use
of tocainide,
a new
lidocaine-like
treatment of life-threatening ventricular have received 1,200 to 2,400 mg daily
antiarrhythmic
arrhythmias in divided
refractory doses and
to have
been treated for over 6 months and some for longer than 3 years. Overall, 61% of the patients responded successfully to tocainide therapy. In the 262 patients with documented, severe, symptomatic arrhythmias, 71% responded, and the majority (87%) showed a total abolition of symptomatic events. Gastrointestinal and I 1% had to discontinue
central
nervous system therapy: however,
events were the remaining
the most common adverse 89% tolerated kocainide
Lidocaine is the antiarrhythmic agent of choice for the acute intravenous treatment of ventricular arrhythmias,‘-” especially those occurring early after acute infarction. However, lidocaine is extensively metabolized by the liver in a first-pass effect and therefore cannot be given orally. Consequently, it has been necessary to use other antiarrhythmics for continuous oral therapy. Recent efforts directed toward the development of an oral antiarrhythmic of the same type as lidocaine resulted in the synthesis of tocainide, a new lidocaine analogue that has a high bioavailability when given orally and has an excellent spectrum of antiarrhythmic activity. In this study we report on the use of tocainide for the chronic treatment of ventricular arrhythmias in a multicenter study involving many investigators. The arrhythmias were refractory to other therapy, and all patients had either failed to respond to or were unable to tolerate other antiarrhylthmic agents, including quinidine, procainamide, disopyramide, and propranolol. Material
and
methods
A total of 819 patients with severe refractory arrhythmias received the drug,, of whom 628 had From
Astra
Pharmaceutical
Reprint requests: Michael ucts, Inc., P.O. Box 1089,
0002-8703/80/131041
Products,
Inc.,
Framingham,
Mass.
Young, M.D., Astra Pharmaceutical Framingham, MA 01701.
+ 05$00.50/00
1980
The
Prod-
C. V. Mosby
Co.
experiences, satisfactorily.
and
an adequate trial of treatment and were documented sufficiently to allow an evaluation of the efficacy of tocainide therapy. Males outnumbered females by more than 2:l, and their agesranged from 9 to 86 years, with the majority of patients being between 40 and 70 years old (Table I). The most common etiology of the patients’ cardiac diseasewas atherosclerotic heart disease; however, a significant number of patients had cardiomyopathies or valvular heart disease (Table H). The patients had either ventricular tachycardia or frequent and/or complex ventricular ectopic beats. The severity of their cardiac status was evaluated and 63% of them were categorized as New York Heart Association Class III or IV prior to tocainide therapy, (Table III). A further indication of the severity of the patients’ disease was the fact that 54% of them were receiving digitalis glycosides and 42% required treatment with diuretics at some time during the study. Tocainide therapy was initiated on a 1,200 mg daily dose either as 400 mg t.i.d. or 600 mg b.i.d., which was then adjusted according to the patient’s response. The majority of patients received 1,200 to 2,400 mg daily in divided doses, as shown in Table IV, which shows the final regimen the patient received regardless of whethAmerican
Heart
Journal
1041
Q-39 40-63 70-89 Unknown
83 438 96 11
Total
Be II.
-G-
tiology
47 76 72 45
53 24 28 55
-E
-IiF
of patients’
1,200 1,200 1,600 1,800 2,400 2,4CO
400 600 400 600 600 800
q8h
109
17
qlL2h q6h q8h q6b q8h
30 37 147 30 73
5 6 23 5 12
arrhythmias
Etiology Atherosclerotic heart disease Post AM1 Other Cardiomyopathy Mitral valve prolapse Rheumatic heart disease
Unknown AMI
= acuk
myocardial
infarction.
ie BBP. New York Heart Association functional classification of cardiac status prior to treatment Class Ii II III IV Unknown
53 139 209 122 105
er a lower dose had been adequate for some time previously. The treatment is still ongoing. At the time of this review of the program, the majority of the patients had been treated for over 6 months and some for more than 3 years (Table V).
E%cacy was assessed by the inciividual physician responsible for the patient. The parameters used were clinical response and laboratory testing, incEuding Wolter monitoring, telemetry, rhythm strips, exercise testmg, controEled weaning after successful therapy, and in a few cases, ed electrical stimulation studies. Pwz ion, we have arbitrarily decided that no In patients woulid be considered to have been successfully treated if therapy was not given continuously for at least 1 month. Therefore, this is an
evaluation of the efficacy of chronic oral therapy with toeainide. Overall, 61% of the patients responded successfully to tocainide (Table VI). Of the 628 patients, 252 (40%) had documented severe symptomatic arrhythmias anti their symptomatic response to treatment was dramatic. A total of 178 patients (71%) with symptomatic ventricular arrhythmias responded to tocainide, and the majority of such responders (87%) showed total abolition of symptomatic arrhythmic events, as shown in Table VII. MSO, a d&&d evaluation of the symptoiiatic patients showed there was a greater than 90% reduction in emergency hospital admissions, DC cardioversions, syncope, or presyneope during treatment with tocainia”e (Table VIII). Tocainide had no clinically significant negative inotropic effect and was not noted to prolong Q-T is chronic therapy s anterva1s during study. We obtained ECG ta from pat,Q,tS on chronic therapy an excess 0 months (Table JX). The ‘“early during treatment” vajlues were obtained from the first tracing taken after a steady-state level of tocainide had been reached, and the “‘Pate during treatment” values were obtained from the last tracing available for each patient, but in no case were these values obtained less than 6 months mto therapy. The statistically significant reduction in Q-T Interval was not considered to be clinically significant. side effects were generally either gastrointestinal or neurologic, and of the 628 patients, only 71 (11.3%) ha~I to discontinue therapy because of an adverse experience, as shown an Table X.
Qver a period of almost two decades, lidocaine has become established as the most effective agent for the suppression of ventricular arrhyt
Treatment’
Table
V. Duration Duration
of treatment with tocainide
of treatment
No.
Greater than 3 yr From 2 to 3 yr From 1 to 2 yr 6 mo to 1 yr From 1 to 6 mo Less than 1 mo
( 3%) ( 7%) (14%) (18%) (25%) (34%)
mias.‘e6Unfortunately, lidocaine cannot be used effectively by oral administration Tocainide is a lidocaine-like agent that is active orally. It has been reported to be effective in the treatment of ventricular arrhythmias in patients with coronary, valvular, and myopathic disease.‘.g This study evaluated the responsesto tocainide therapy of patients with severe, refractory ventricular arrhythmias, and the program was initiated as a humanitarian effort to treat these particularly difficult cases. The severity of the patients’ condition was documented by the fact that 63% were New York Heart Association Class III or IV when tocainide therapy commenced and also by the fact that all the patients had failed to respond adequately to, or could not take, full dosages of other oral antiarrhythmic agents, including quinidine, procainamide, propranolol, and, when available, disopyramide. In fact, many patients could-not be controlled adequately even on combinations of these agents, The etiologies of the patients cardiovascular diseasesare shown in Table II and clearly indicate that although .the majority of patients had atherosclerotic heart disease, a considerable number had valvular and myopathic disease. Much has been written about the difficulty inherent in evatluating the response to antiarrhythmic therapy because of the variability in the frequency of ventricular ectopic beats in longterm ECG monitoring.‘O-‘” Despite this, long-term ECG monitoring is the basic parameter used to monitor the response to an antiarrhythmic agent. Over 570 physicians were involved in this multicenter study of 628 patients, and they evaluated the response to tocainide therapy by means of telemetry, ECG rhythm strips, 24-hour Holter recordings, exercise testing, and in a few cases programmed electrical stimulation; also noted was the presence or absence of symptoms of ventricular arrhythmias. In addition, since these patients required maintenance therapy for con-
American
Heart
Jouma
I
with oral tocainide
VI. Response to treatment
Table
of patients
16 46 88 110 156 212
of uentrica2cx.r arrhythmias
Therapeutic
response
with tocainide of patients
No.
Success Failure
383 (61%) 245 (39%)
VII. Degree of response of severe symptomatic arrhythmias to tocainide therapy Table
Duration treatment
of
Over 3 yr 2 to 3 yr 1 to 2 yr 6 mo to 1 yr 1 to 6 mo Less than 1 mo Total
I
Total abolition 12 22 23 36 61 154 (61%)
Substantial I reduction 3 10 6 5 24 (10%)
No response
2 18 54 74 (29%)
siderable periods, this study evaluated treatment in excess of 1 month’s duration. That is to say, although patients might be judged to have failed to respond to tocainide after an initial trial of as little as 3 days, no patients were evaluated as showing a successful response to tocainide unless they had had at least 1 month’s therapy. In fact, the majority of patients had been treated for over 6 months with tocainide. Overall, 61% of the patients responded successfully to tocainide (Table VI) despite the refractory nature of the arrhythmias being treated, and the most usual dosage was 600 mg t.i.d. Of the 628 patients it was particularly interesting to consider the symptomatic response to treatment of the 252 who had documented severely symptomatic arrhythmias. Severe symptoms were defined as repeated occurrence of hospitalization, ventricular tachycardia-ventricular fibrillation, DC cardioversion, syncope, or multiple presyncopal episodes. A total of 178 patients (71%) with these severe symptomatic ventricular arrhythmias responded to tocainide, and of them the majority (87%) showed a total abolition of all symptomatic arrhythmic events (Table VII). Also, a detailed evaluation of the symptomatic patients showed there was a greater than 90% reduction in emergency hospital admissions, DC cardioversions, syncope, or presyncope during treatment with tocainide (Table VIII). This represents a considerable improvement in
1043
Emergency admission for VTNF DC cardioversion for VT/VF Episodes of syncope Episodes of presyncope
IKE
Pretreatment Eariy awing treatment Late during treatment
intervals
0.173
i
8.021
0.0171
+- 0.021
0.175
I 0.025
129 11‘2 104 57
before and during
0.093 i
0.030
364 512 403 756
long-
0.450
k 0.044
0.093 -+ 0.038
O.4348
I 0.046
0.095 _t 0.029
0.436*
* 0.055
Adverse experiences resulting in uation of tocainide in 628 patients were valid for evaluation of e
who
4.9 2.4 1.6 2.1 0.3
2. 3. 4.
11.3 Abbreviations: CMS = central nervous CMF = congestive heart failure.
system, Cl = gastrointestinal,
the morbidity rate for these severely symptomatic patients. Tocainide had no clinically significant negative instropic effect in hemodynamic studies’ and ‘was not noted to prolong RS intervals in electrophysioiogic studies.” During this chronic therapy study, we obtained ECG data from patients on therapy in excess of 6 months. The “early during treatment” values (Table IX) were obtained from the first tracing taken after a steady-state level of tocainide had been reached, and the ‘“late during treatment” values were obtained from the last tracing available for each patient, but in no case was the value obtained less
93 97 97 99
than 6 months into therapy. There was no significant prolongation of either Q-T or QRS intervals. A statistically significant reduction in Q-T interval was seen; however, this was not considered to be clinically significant. The side effects to tocainide are generally those to be expected far a hdocaine analogue and have been discussed in detail elsewhere.‘” In this study only 11% of the 628 patients treated with tocainide had to discontinue therapy because of side effects and the remaining 89% tolerated the tocainide therapy satisfactorily. We conclude that tocainide is an effective and safe agent for the management of refractory ventricular arrhythmias.
1. CNS GI CWS/GI Rash Increased CHF
26 17 11 6
5.
6.
7.
8.
9.
10.
Model! W: Drugs of choice 1980-1981. St. Louis, 1980, The CV Mosby Company, pp 398-399. American Medical Association drug evaluations, ed. 4. New York, 1980, John Wiley & Sons, Inc, p 515. The Medical Letter Series, vol. 20. New York, 1978, The Medicai Letter, Inc., pp 116-117. IIarrison DC, Sprouse JR, Morrow AC: hntiarrhythmic properties of lidocaine and procainamide: Clinical and pbysioiogic studies of their cardiovascular effects in man. Circulation 23:486-91, 1963. Gianelly R, Van der Groeben JO, Spivack AP, Harrison DC: Effect of Iidocaine on ventricular arrhythmias in patients with coronary heart disease. N Engl J Med 277:1215-21, 1967. Lown B, Kosowsky BD, Klein MD: Bathogenesis, prevention and treatment of arrhythmias in myocardial infarction Circulation 40:261-65, 1968. Coltart IX, Rerridt TB, Harrison DC: Antiarrhythmic and circulatory effects of Astra W36095: A new lidocainelike agent. Am J Cardiol 34:35-41, 1974. Moore EN, Spear JF, Horrowitz LN, Feldman HS, MoIIar RA: Eiectrophysiologic properties of the new antiarrhythmic drug, tocainide. Am J Cardiol 47 :7O3-9, 1978. Woosley RL, McDevitt DC, Nies AS, Smith RF, Williamson AR, Oates JR: Suppression of ventricular ectopic depolarizations by tocainide. Circulation 56:980-4, 1977. Winkle RA, MeAn PJ, Fitzgerald JW, Rarrison DC: Clinical efficacy and pharmacokinetics of a new orally effective antiarrhythmic, tocainide. Circuiation 54:884-9, 1971.
Treatment
11.
12.
arrhythmias
with oral tocainide
Morganroth ME, Pearlman tine long-term ventricular 1978. Winkle RA, ide therapy
J, Michelson EL, Horrowitz LN, Josephson AS, Dunkman WB: Limitations of rouelectrocardiographic monitoring to assess ecta’pic frequency. Circulation 58:408-14, Meffin PJ, Harrison DC: Long-term tocainfor ventricular arrhythmias. Circulation
Kraemer HC: Principles and problems of controlled study design. Proceedings of Symposium on Cardiac Arrhythmias: A Decade of Progress-1980. Boston, G K Hall & Co (In press.) Horn HR, Hadidian Z, Johnson JL, Vassallo HG, Williams JH, Young MD: Safety evaluation of tocainide in the American Emergency Use Program. AM HEART J
57:1008-16,
1978.
100:1037-40,
American
Heart
13.
of ventricular
14.
Journal
1980.
1045