A prospective comparison of class IA, B, and C antiarrhythmic agents in combination

with amiodarone in patients with inducible, sustained ventricular tachycardia.

L Toivonen, A Kadish and F Morady
Circulation. 1991;84:101-108
doi: 10.1161/01.CIR.84.1.101
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 1991 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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101

A Prospective Comparison of Class IA, B,

and C Antiarrhythmic Agents in Combination
With Amiodarone in Patients With Inducible,
Sustained Ventricular Tachycardia
Lauri Toivonen, MD; Alan Kadish, MD; and Fred Morady, MD

Background. Clinical experience suggests that combinations of antiarrhythmic agents

provide more effective control of ventricular tachyarrhythmias than does therapy with single
agents.
Methods and Results. Antiarrhythmic and electrophysiological effects of three class I
antiarrhythmic agents, one from each subclass A, B, and C, were assessed in single use and
in combination with amiodarone in patients with inducible, sustained ventricular tachycardia that was not suppressed by monotherapy with these agents. Thirty-one patients
underwent an electrophysiology test on four occasions: at baseline; after 2-4 days of
treatment with quinidine, mexiletine, or encainide; after 2 weeks of treatment with 1,200
mg/day amiodarone; and last, after 2-4 days of treatment with both amiodarone and the
previously tested class I agent. The combination of a class I agent and amiodarone prevented
the induction of sustained ventricular tachycardia in only one of 31 (3%) patients.
Ventricular tachycardia became hemodynamically stable in 11 of 31 (34%) patients because
of a marked prolongation in the tachycardia cycle length. It increased from 323+39 to
423+84 msec (n = 11, p<0.01) by adding encainide to amiodarone therapy, and it showed a
tendency to lengthen when quinidine was added to amiodarone (from 373 77 to 42558
msec; n=10, NS). Each class I agent increased amiodarone-induced depression in myocardial conduction, but the extent of the additional depression seemed to differ among the three
subclasses. Ventricular refractoriness was increased by all class I agents when used in
combination with amiodarone, although not by mexiletine or encainide when used alone.
Conclusions. Class I antiarrhythmic agents slow ventricular conduction and increase
ventricular refractoriness when used in combination with amiodarone. When amiodarone
and class I drugs by themselves do not suppress the induction of ventricular tachycardia, the
combination of amiodarone and a class I agent seldom results in noninducibility; however,
it often lengthens the ventricular tachycardia cycle length and may render the ventricular
tachycardia hemodynamically stable. (Circulation 1991;84:101-108)
linical experience suggests that combinations
of antiarrhythmic agents provide more effective control of ventricular tachyarrhythmias
than does therapy with single agents.1-3 For example, the combination of a class I agent with amiodarone has been shown to suppress the induction of
sustained ventricular tachycardia when amiodarone
alone is ineffective.4 The addition of a class I agent
to amiodarone therapy has also been demonstrated
C

From the Division of Cardiology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Address for correspondence: Lauri Toivonen, MD, Helsinki
University Central Hospital, First Department of Medicine,
Haartmaninkatu 4, SF-00290 Helsinki, Finland.
Received August 2, 1990; revision accepted February 26, 1991.

to result in slowing of the rate of induced ventricular tachycardia.5-7 However, no prior studies have

compared the electrophysiological effects of the

various types of class I agents in combination with
amiodarone.
The aim of this prospective study was to compare
See p 429
the effects of class I agents in combination with
amiodarone to determine the regimen most likely to
improve the therapeutic response when amiodarone
by itself is ineffective. One agent from each subclass8,9 was used: quinidine from subclass A, mexiletine from subclass B, and encainide from subclass C.
Their effects were assessed individually and in com-

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102

Circulation Vol 84, No 1 July 1991

bination with amiodarone in patients with inducible,

sustained ventricular tachycardia.
Methods
Characteristics of Subjects
The subjects of this study were selected from a
pool of 72 consecutive patients who were referred for
the evaluation and treatment of ventricular arrhythmias and who had inducible, sustained monomorphic
ventricular tachycardia during a clinically indicated
electrophysiology test. A class I agent was administered in all patients, and electrophysiological testing
was performed in 67. Sustained ventricular tachycardia was not inducible in 12 patients. Among the
remaining patients, 48 were then treated with amiodarone, and 46 of these underwent electrophysiological testing. Eleven patients had a favorable response,
and a combination regimen was started in the remaining 35 patients. An electrophysiology test was
then performed in 31 patients, and these patients
make up the population of the present study.
There were 30 men and one woman, and their
mean (+SD) age was 629 years. All patients had
coronary artery disease and a history of remote
myocardial infarction. The mean left ventricular ejection fraction, determined by contrast or radionuclide
ventriculography, was 0.29+0.09 (range, 0.15-0.40).
The presenting arrhythmia was sustained, monomorphic ventricular tachycardia in 14 patients; cardiac
arrest with documented ventricular fibrillation in
three patients; symptomatic, nonsustained monomorphic ventricular tachycardia in 10 patients; and unexplained syncope in four patients.

Electropharmacological Testing Protocol

After sustained, monomorphic ventricular tachycardia was induced during a baseline electrophysiology test, oral therapy was started with quinidine,
mexiletine, or encainide. The choice of the antiarrhythmic agent was random, except that agents that
had caused adverse effects or that had failed on a
clinical basis to control the patient's arrhythmia were
not used. If sustained ventricular tachycardia was
inducible despite treatment with the class I agent,
therapy with amiodarone was initiated. If sustained
and hemodynamically unstable ventricular tachycardia was still inducible, the previously used class I
antiarrhythmic agent was used in combination with
amiodarone.
In assessing the therapeutic response to an antiarrhythmic regimen, the noninducibility of ventricular
tachycardia and the induction of nonsustained or
hemodynamically stable sustained ventricular tachycardia were considered to be adequate therapeutic
end points. Ventricular tachycardia with a cycle
length of more than 400 msec and a mean arterial
pressure of 80 mm Hg or more was considered hemodynamically stable.
The daily dosages of quinidine, mexiletine, and
encainide were 1,460-1,940 mg (quinidine glu-

conate), 600-750 mg, and 105-150 mg, respectively,

and were given orally in three divided daily doses at
8-hour intervals. The daily dosage of amiodarone was
1,200 mg during the loading period. The electrophysiology study was performed after at least 2 days of
therapy with quinidine and mexiletine and after 4
days of treatment with encainide, either when used
alone or in combination with amiodarone, and after
14 days of treatment with amiodarone. Electrophysiological testing was performed during the last hour
of the dosing interval, and the blood samples for
determination of the plasma drug concentrations
were drawn at the end of the test.
Programmed Electrical Stimulation
The study protocol was approved by the Human
Research Committee at the University of Michigan.
Electrophysiology tests were performed in the fasting, unsedated state after informed consent was
obtained. The baseline studies were performed at
least five half-lives after discontinuation of treatment
with all antiarrhythmic medications.
Two quadripolar electrode catheters were positioned in the right atrium and across the tricuspid
valve to record the atrioventricular conduction intervals during sinus rhythm and atrial pacing, then were
advanced to the right ventricle. A short SF cannula
that was inserted into a femoral artery was used to
continuously record the arterial pressure. Leads I,
III, and V1 and the intracardiac electrograms were
recorded on a Mingograf 7 recorder (SiemensElema, Solna, Sweden) at a paper speed of 100-200
mm/sec. Stimulation was performed with a programmable stimulator (Bloom Associates, Reading, Pa.)
with an impulse duration of 2 msec and a current
intensity of twice the late diastolic threshold, which
was always 1 mA or less.
The AH, HV, and QT intervals were measured
during sinus rhythm and atrial pacing at a cycle
length of 600 msec. The QT interval was corrected
for heart rate with Bazett's method. The ventricular
effective refractory period was determined with an
eight-beat basic drive train at cycle lengths of 600 and
400 msec and with 5-msec decrements in the extrastimulus coupling interval. The duration of the QRS
complex during ventricular pacing was determined
after 15 cycles of pacing from the right ventricular
apex at cycle lengths of 600 and 350 msec.
Programmed stimulation to induce ventricular tachycardia was performed at the right ventricular apex and
outflow tract with drive cycle lengths of 600 and 400
msec. One and two extrastimuli were delivered at
both ventricular sites and drive cycle lengths, after
which three extrastimuli were delivered. The coupling intervals of the extrastimuli were shortened in
steps of 10 msec. Ventricular tachycardia lasting at
least 30 seconds or requiring prompt termination was
considered sustained.

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Toivonen et al Amiodarone Combined With Class I Drugs

103

TABLE 1. Patients With Combined Antiarrhythmic Treatment and Responses in the Electrophysiology Studies
Antiarrhythmic
Electrophysiology
test result
combination
Noninducible
Sustained VT
Started
Tested*
Sustained VT
(n)
stablet (n)
(n)
(n)
(n)
Patients receiving class I agents
0
6
10
10
10
Quinidine
1
1
13
10
9
Mexiletine
0
4
12
11
11
Encainide
31
30
1
11
All patients
35
VT, ventricular tachycardia.
*Not tested in four patients because of side effects: central nervous system side effects in three patients receiving
mexiletine and worsening of heart failure in one patient receiving encainide.
tSustained ventricular tachycardia with a cycle length of more than 400 msec and mean blood pressure 80 mm Hg
or more.

Statistical Analysis
A two-way analysis of variance with repeated measures was used to compare differences in continuous
variables during various treatment phases. A Wilcoxon's signed-rank test was used to analyze changes in
the number of extrastimuli required to induce ventricular tachycardia. Linear regression analysis was
used to examine correlations between electrophysiological variables and ventricular tachycardia cycle
length. Continuous variables are expressed as
mean+ SD. Ap value less than 0.05 was considered to
be statistically significant.
Results

Effects on Ventricular Tachycardia

Noninducibility of sustained ventricular tachycardia
was achieved in one of 31 patients with a combination
of a class I agent (mexiletine) and amiodarone. Ventricular tachycardia became hemodynamically stable
in 11 patients during combination therapy (Table 1).
The number of extrastimuli required to induce
sustained ventricular tachycardia decreased during
combination therapy compared with treatment with a
TABLE 2. Cycle Length of Induced Ventricular Tachycardia

Treatment group (n)

Quinidine Mexiletine Encainide All groups

(10)

(9)

(11)

(30)

Control phase 26427

26339

28163

27045

Test phase

agent

310)48

+ 17%t
+12%
30451
30859

Amiodarone

37377

32451

+18%*

Class

+29%t

32339

34060

+36%*
+13%
+6%
42384
36281
Combination 425+58
The ventricular tachycardia cycle length (mean+SD) is given in
msec. Changes from the control phase and from the amiodarone
phase are indicated in percentages.
Comparison is performed between the baseline and the class I
agent phase and between the amiodarone and the combination
phases in the three parallel treatment groups. In addition, the
amiodarone phase is compared with the baseline in the whole
group.

*p<0.01, tp<0.05, tp<0.001.

class I agent only, from an average of 2.4 to 1.9

(p<0.O5).

Quinidine and mexiletine increased the tachycardia

cycle length, whereas no significant change occurred
with encainide (Table 2). The greatest increase occurred with amiodarone. Encainide increased the
tachycardia cycle length when combined with amiodarone. Overall, quinidine and mexiletine had no
significant additive effect on the tachycardia cycle
length in combination with amiodarone. However,
individual responses varied within treatment groups.
In 12 of 30 patients, the morphology of the induced
ventricular tachycardia was identical in all four study
phases (in 3, 4, and 5 patients in the quinidine,
mexiletine, and encainide groups, respectively). In 18
patients, it was different during at least one of the
phases. The cycle length of the induced ventricular
tachycardia increased in patients with an identical
tachycardia morphology from 270+44 at baseline to
31047, 337+60 and 423+88 msec during treatment
with a class I agent, amiodarone, and a combination,
respectively. The cycle lengths increased from
268+48 to 306+52, 343+63, and 39472 msec in the
respective phases in patients with nonidentical tachycardia morphologies. The cycle lengths did not differ
significantly between these two subgroups.
Effects on Ventricular Conduction and Refractoriness
The duration of the paced QRS complex was
prolonged by each class I agent and amiodarone
(Table 3). The degree of prolongation was similar,
except with mexiletine, which had the least effect.
The increase in the duration of the paced QRS
complex during treatment with the class I agents was
not rate dependent. In contrast, amiodarone had a
greater effect at a cycle length of 350 than at 600
msec (p<0.001). When used with amiodarone, all
class I agents increased further the duration of the
paced QRS complex. The increase was greater with
encainide than with quinidine and mexiletine. The
additive effects of the class I agents on the QRS
duration during combination therapy were not dependent on rate (Table 3).

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104

Circulation Vol 84, No 1 July 1991

TABLE 3. Duration of the Paced QRS Complex

Quinidine
Test phase
Pacing cycle length, 600 msec
Control phase

Class I agent
Amiodarone

Combination
Pacing cycle length, 350 msec
Control phase
Class I agent

(10)

Treatment groups (n)

Mexiletine
Encainide

(10)

(11)

+23%*
20520

16816
+5%t
17720

16831
+22%
202+27

21229
+7%t
22630

19622
+6%*
20824

19532
+16%t
22536

16816
+28%*
21419

16719
+7%t
17923

17032
+23%X
20635

16822

All groups

(31)
16823

+20%*
20128

16823

+30%*
21835
21530
20538
23534
+ 19%*
+7%
+8%t
24848
24931
22936
Combination
Duration of the QRS complex (mean+SD) is given in msec. Changes from the control phase and from the
amiodarone phase are indicated in percentages.
Comparison is performed between the baseline and the class I agent phase and between the amiodarone and the
combination phases in the three parallel treatment groups. In addition, the amiodarone phase is compared with the
baseline in the whole group.

Amiodarone

*p<0.001, tp<0.05, tp<0.01.

The ventricular effective refractory period was

prolonged by quinidine and amiodarone (Table 4).
The changes were similar with the 600- and 400 -msec
drive cycle lengths. Mexiletine and encainide by
themselves did not increase refractoriness. In combination, encainide increased the amiodarone-induced
prolongation in the ventricular effective refractory
period determined at both drive cycle lengths. At the
400-msec drive cycle length, quinidine and mexiletine in combination with amiodarone also prolonged
ventricular refractoriness (Table 4). Therefore, each
of the class I agents increased the ventricular effective refractory period when used in combination with
amiodarone and each tended to do so more at a drive
cycle length of 400 than at 600 msec.
The cycle length of induced ventricular tachycardia
correlated with the ventricular effective refractory
period (basic drive cycle length, 400 msec) during
treatment with amiodarone (r=0.51, n =31, p <0.001)
but not with the class I agents. The duration of the
paced QRS complex did not correlate with the
tachycardia cycle length during any treatment regimen, even when the analysis was restricted to identical tachycardia morphologies.
Inclusion only of patients who had an ineffective
response in the next study phase may have biased the
assessment of the electrophysiological variables if the
efficacy was related to the extent of the electrophysiological changes. In this respect, nine patients who
responded to quinidine were compared with 15 nonresponders, and 11 patients who responded to amiodarone were compared with 35 nonresponders. The

success rate with mexiletine and encainide was not

sufficient for a similar analysis. There were no statistically significant differences between the responders and nonresponders in the duration of the paced
QRS complex, ventricular effective refractory period, and the QT interval.

Electrocardiographic Variables, Atrioventricular

Conduction, Blood Pressure, and Adverse Reactions
The sinus cycle length was increased by amiodarone from 780+40 to 880+170 msec (n=31,
p<0.001). The class I agents had no significant influence on the sinus cycle length when used alone or in
combination with amiodarone. The AH interval was
not affected by the class I agents during monotherapy. It was increased by amiodarone from 108 39 to
192+72 msec (n=21, p<0.001) during atrial pacing.
In combination, only encainide increased the AH
interval, from 195+79 msec with amiodarone alone
to 222+ 94 msec in combination (n=9, p<0.05). The
HV interval was increased by encainide from 55 + 13
to 67+22 msec (n=9, p<0.05) and by amiodarone
from 53+11 to 64+15 msec (n-21,p<0.001) during
atrial pacing. During combination of encainide and
amiodarone the HV interval was further increased,
to 74+20 msec (n=9,p<0.05). No significant changes
occurred in the HV interval during quinidine or
mexiletine.
The QT interval during sinus rhythm was prolonged from 388+30 to 44239 msec by quinidine
(n=10,p<0.001) and to 47140 msec by amiodarone
(p<0.001), but their combination did not result in a

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Toivonen et al Amiodarone Combined With Class I Drugs

105

TABLE 4. Ventricular Effective Refractory Period

Test phase
Drive cycle length, 600 msec
Control phase
Class I agent

Amiodarone
Combination

Quinidine
(8)

Treatment groups (n)

Encainide
Mexiletine
(9)
(9)

25120
+9%*
27621

25823
-0%
25718

26119
+2%
26525

29423
+6%
30732

28013
+3%*
28834

28915
+6%*
30821

All groups
(26)
25521

+12%t
28519

Treatment groups (n)

Test phase
Drive cycle length, 400 msec
Control phase

Quinidine
(8)
23417

+9%:t
25517

Class I agent

Mexiletine
(10)

Encainide
(9)

All groups
(27)

24119
-1%
23713

23715
+6%
24925

23717

258+16

268+14
+7%*

26417

+12%t
Amiodarone

27023
+ 10%t
29430

+4%*

Combination
27120
28921
Ventricular effective refractory period (meanSD) is given in msec. Changes from the control phase and from the
amiodarone phase are indicated in percentages.
Comparison is performed between the baseline and the class I agent phase and between the amiodarone and the
combination phases in the three parallel treatment groups. In addition, the amiodarone phase is compared with the
baseline in the whole group.

*p<0.01, tp<O.001, tp<0.05.

further increase (477+t60 msec, NS). Neither mexiletine nor encainide prolonged the QT interval when
added to amiodarone therapy. The findings were
basically similar with the corrected QT interval.
The class I antiarrhythmic agents had no significant effect individually or in combination with amiodarone on the mean arterial pressure during sinus
rhythm. The mean arterial pressure increased during
amiodarone therapy from 90+ 13 to 95+ 14 mm Hg
(p<0.001). No proarrhythmic events occurred during
combination therapy.
Plasma Drug Concentrations
The mean plasma amiodarone concentration was
1.7+0.5 mg/l after 14 days of therapy and was
1.7+0.6 mg/l during combination therapy. The respective plasma desethylamiodarone concentrations
were 0.9+0.3 and 1.0+0.2 mg/i. The mean plasma
quinidine concentration was 2.3+0.7 mg/l during
monotherapy and was 2.7+0.7 mg/i during combination therapy. The mean plasma mexiletine concentration was 0.7+0.2 mg/l during monotherapy and
was 0.70.3 mg/l during combination therapy. The
mean plasma encainide concentration was 3020
ng/l during monotherapy and 4020 ng/l during
combination therapy. The respective concentrations
during monotherapy and combination therapy were

13060 and 14060 ng/l for O-desmethyl encainide

and 13070 and 13070 ng/l for 3-methoxy-Odesmethyl encainide. Only the plasma quinidine concentration differed significantly (p<0.05) between
monotherapy and combination therapy.
Discussion
Main Findings
In this prospective study, the electrophysiological
and antiarrhythmic effects of quinidine, mexiletine,
and encainide were assessed in combination with
amiodarone in patients who had inducible, sustained
ventricular tachycardia. The design of the study allowed a comparison of the individual effects of class
IA, B, and C antiarrhythmic agents with their effects
in combination with amiodarone in the same patients.
Amiodarone-induced slowing of myocardial conduction was accentuated by agents from all subclasses but most prominently by the class IC agent,
encainide. This indicates that, when used in combination, the class I agents and amiodarone both
contribute to depression of myocardial conduction,
consistent with blockade of sodium channels.10
Agents from all subclasses also had an additive effect
on ventricular refractoriness when combined with
amiodarone. Both mexiletine and encainide potenti-

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Circulation Vol 84, No 1 July 1991

ated the effect of amiodarone on the ventricular

effective refractory period; however, neither agent
had an effect on refractoriness when used alone.
The combination of a class I agent with amiodarone
rarely resulted in the noninducibility of ventricular
tachycardia when the individual agents were ineffective
in suppression of induction of ventricular tachycardia.
However, quinidine and encainide in combination with
amiodarone markedly decreased the rate of ventricular
tachycardia and often resulted in unstable ventricular
tachycardia becoming hemodynamically stable. This
may be a clinically significant effect because prior
studies demonstrated that hemodynamically stable ventricular tachycardia is an adequate therapeutic end
point in patients treated with amiodarone."11,2

Effects on Conduction
Quinidine and encainide slowed myocardial conduction (as reflected in the paced QRS duration)
more than mexiletine did. The depression in conduction was similar at slow and fast rates, although
quinidine tended to have a greater effect during the
faster rate. Class I agents should demonstrate usedependent slowing of myocardial conduction during
ventricular pacing,10'13 but the methods used in the
present study may not have been accurate enough to
detect small changes with statistical significance.
Amiodarone prolonged the paced QRS complex to a
greater extent at the faster rate, indicating a rate
dependency that is consistent with the known usedependent properties of amiodarone.14,15
The additional depression of myocardial conduction produced by combining mexiletine and encainide to amiodarone was equal to the individual effect
of these drugs. In contrast, the slowing of conduction
produced by combining quinidine to amiodarone was
less than quinidine's individual effect.
Antiarrhythmic subclasses IA, B, and C differ in
respect to their time constants of sodium channel
blockade.8-10'16-18 The subclass B has the fastest,
subclass A has an intermediate, and subclass C has
the slowest kinetics. Amiodarone inhibits the sodium
channel by binding to the receptors in the inactivated
state, has rapid recovery kinetics, and also prolongs
the duration of the action potential.'4"15 It has been
hypothesized that antiarrhythmic agents that have
rapid recovery constants competitively inhibit the
sodium channel blockade exerted by agents with
slower kinetics.7'19-21 Amiodarone may, therefore,
inhibit the depression of myocardial conduction by
quinidine and encainide. This can explain why the
slowing of conduction in the ventricular muscle during the combination of quinidine and amiodarone
was less than the sum of their individual effects.
However, similar attenuation of the combined effect
was not seen with encainide, which also has slow
kinetics.9"16'22-24 This difference may be caused by the
state of the sodium channel on which the drugs exert
their influence. Encainide affects sodium channels
when they remain inactivated during the plateau of
the action potential,9,2223 whereas quinidine affects

open channels.1718 Therefore, amiodarone-induced

prolongation in the duration of the action potential
may enhance the effect of encainide. Amiodarone
should not markedly change the effect of mexiletine
because both have rapid kinetics.14'52526 Accordingly, their combined effect on conduction was equal
to the sum of their individual effects.

Effects on Refractoriness and Repolarization

Ventricular refractoriness was prolonged by agents
from all three subclasses in combination with amiodarone. Of note is that encainide and mexiletine,
when used by themselves, did not lengthen the
ventricular effective refractory period either in the
present or in previous studies.22,25,27 Therefore, the
effects on ventricular refractoriness may represent
complex pharmacodynamic interactions that are not
equivalent to the sum of the effects of the individual
drugs.
Combining quinidine with amiodarone did not
further prolong the QT interval and did not result in
proarrhythmia. Therefore, the combination of antiarrhythmic agents from classes IA and III may not
markedly accentuate the risk of provoking ventricular
arrhythmias associated with a long QT interval.28'29
In addition, neither of the other combinations resulted in adverse electrophysiological effects, although the HV conduction time was further prolonged by encainide.

Role of Drug Metabolites

The pharmacological influence of oral administration of encainide is exerted mainly by its metabolites
O-desmethyl encainide and 3 -methoxy-O-desmethyl
encainide, which are electrophysiologically similar to
encainide.23'24 The metabolites accumulate to produce steady plasma concentrations within 4 days. The
main metabolite of amiodarone, desethylamiodarone, has electropharmacological properties similar to amiodarone, except it depresses the sodium
channel to a greater extent.30,3' A stable ratio of this
metabolite and the parent compound is achieved
within 2 weeks.32
The metabolism of the class I agents can be
influenced by amiodarone33 which may distort the
comparison of their individual and combined pharmacological effects. However, in the present study,
only the quinidine plasma concentration was higher
during combination therapy than during monotherapy and only by a mean of 0.4 mg/l.
Antiarrhythmic Efficacy
Suppression of the induction of sustained ventricular tachycardia during electropharmacological testing is predictive of long-term antiarrhythmic drug
efficacy.1"34 A marked reduction in the tachycardia
rate resulting in hemodynamic stability of the ventricular tachycardia suggests protection from arrhythmia-related mortality, although not necessarily from
arrhythmia recurrence.11,12

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Toivonen et al Amiodarone Combined With Class I Drugs

Although only 3% of patients became noninducible, 34% of patients achieved hemodynamic stability
of ventricular tachycardia during combination therapy. The results of this study indicate that the
potential to slow the tachycardia rate may be greater
with quinidine and encainide than with mexiletine.
Limitations of the Study
Evaluation of the effects of combination therapy
may have been influenced by 2-4 additional days of
therapy with amiodarone. However, given the known
time course of the onset of the electropharmacological effects of amiodarone,3235'36 the observed
changes in cardiac effects between the amiodarone
and the combination phases cannot be attributed to
2-4 days of additional therapy with amiodarone. The
antiarrhythmic effect of amiodarone requires several
weeks to reach its maximum32,34,35
The efficacy of combination therapy may have
been underestimated because only agents that failed
in monotherapy were evaluated in combination. Nevertheless, the present findings are relevant to clinical
practice because antiarrhythmic combinations are
generally used only when therapy with single agents
is ineffective.
A limitation of this study is that the outcome of
long-term combination therapy was not examined. A
later deterioration in cardiac function by the negative
inotropic effect of the drugs and a possible late
incidence of proarrhythmia37 may counteract the
initial beneficial effects of combination therapy.
Therefore, the long-term outcome of the combination therapy needs further study.

Clinical Implications
This study demonstrates that the combination of
class I antiarrhythmic agents with amiodarone can be
helpful in the management of patients with inducible,
sustained ventricular tachycardia. Noninducibility is
rarely achieved, but the rate of the tachycardia often
becomes markedly slower. An improvement in hemodynamic stability during ventricular tachycardia may
be likely, especially when agents from subclasses IA
and IC are added to amiodarone. The relatively small
population size in this study does not exclude the
possibility of adverse electropharmacological and
proarrhythmic effects with combination therapy.

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17.
18.

References
1. Duff HJ, Mitchell LB, Manyari D, Wyse GD: Mexiletinequinidine combination: Electrophysiologic correlates of a
favorable antiarrhythmic interaction in humans. J Am Coll
Cardiol 1987;10:1149-1156
2. Levy S: Combination therapy for cardiac arrhythmias. Am J
Cardiol 1988;61:95A-1O1A
3. Whitford EG, McGovern B, Shoenfeld MH, Garan H, Newell
JB, McElroy M, Ruskin JN: Long-term efficacy of mexiletine
alone and in combination with class Ia antiarrhythmic drugs
for refractory ventricular arrhythmias. Am Heart J 1988;115:
360-366
4. Bellocci F, Santarelli P, Montenero A, Giasiolla F, Nobile A:
Value of electrophysiologic testing of amiodarone alone or in

19.

20.

21.

107

combination with class I antiarrhythmic drugs for ventricular

tachycardia (abstract). Circulation 1985;72(suppl II):II-274
Marchlinski FE, Buxton AE, Josephson ME, Schmitt C:
Predicting ventricular tachycardia cycle length after procainamide by assessing cycle length-dependent changes in paced
QRS duration. Circulation 1989;79:39-46
Marchlinski FE, Buxton AE, Kindwall KE, Miller JM,
Rosenthal ME, Gottlieb CD, Bloom RB, Josephson ME:
Comparison of individual and combined effects of procainamide and amiodarone in patients with sustained ventricular
tachyarrhythmias. Circulation 1988;78:583-591
Waxman HL, Groh WC, Marchlinski FE, Buxton AE, Sadowski LM, Josephson ME, Kastor JA: Amiodarone for
control of sustained ventricular tachycardia. Am J Cardiol
1982;50:1066-1070
Vaughan Williams EM: A classification of antiarrhythmic
actions reassessed after a decade of new drugs. J Clin Pharmacol 1984;24:129-147
Campbell TJ: Kinetics of onset of rate-dependent effects of
class I antiarrhythmic drugs are important in determining their
effects on refractoriness in guinea-pig ventricle, and provide a
theoretical basis for their subclassification. Cardiovasc Res
1983;17:344-352
Buchanan JW, Saito T, Gettes LS: The effects of antiarrhythmic drugs, stimulation frequency, and potassium-induced resting membrane potential changes on conduction velocity and
dV/dt(max) in guinea-pig myocardium. Circ Res 1985;56:
696-703
Waller TJ, Kay HR, Spielman SR, Kutalek SP, Greenspan
AM, Horowitz LN: Reduction in sudden death and total
mortality by antiarrhythmic therapy evaluated by electrophysiologic drug testing: Criteria of efficacy in patients with
sustained ventricular tachyarrhythmia. JAm Coll Cardiol 1987;
10:83-89
Kadish AH, Buxton AE, Waxman HL, Flores B, Josephson
ME, Marchlinski FE: Usefulness of electrophysiologic study to
determine the clinical tolerance of arrhythmia recurrences
during amiodarone therapy. JAm Coll Cardiol 1987;10:90-96
Morady F, DiCarlo LA, Baerman JM, Krol RB: Ratedependent effects of intravenous lidocaine, procainamide and
amiodarone on intraventricular conduction. JAm Coll Cardiol
1985;6:179-185
Mason JW, Hondeghem LM, Katzung BG: Block of inactivated sodium channels and of depolarization-induced automaticity in guinea-pig papillary muscle by amiodarone. Circ Res
1984;55:277-285
Anderson KP, Walker R, Dustman T, Lux RL, Ershler PR,
Kates RE, Urie PM: Rate-related electrophysiologic effects of
long-term administration of amiodarone on canine ventricular
myocardium in vivo. Circulation 1989;79:948-958
Campbell TJ: Resting and rate-dependent depression of depolarization (Vm,,.) in guinea pig ventricular action potentials by
mexiletine, disopyramide, and encainide. J Cardiovasc Pharmacol 1983;5:291-296
Courtney KR: Review: Quantitative structure/activity relations based on use-dependent block and repriming kinetics in
myocardium. J Mol Cell Cardiol 1987;19:319-330
Packer DL, Grant AO, Strauss HC, Starmer CF: Characterization of concentration- and use-dependent effects of quinidine from conduction delay and declining conduction velocity
in canine Purkinje fibers. J Clin Invest 1989;83:2109-2119
Clarkson CW, Hondeghem LM: Evidence for a specific receptor site for lidocaine, quinidine, and bupivacaine associated
with cardiac sodium channels in guinea pig ventricular myocardium. Circ Res 1985;56:496-506
Sheldon RS, Hill RJ, Duff HJ: Antiarrhythmic drugs and the
cardiac sodium channel: Current models. Clin Chem 1989;35:
748-754
Clarkson CW, Hondeghem LM: Electrophysiologic evidence
that local anesthetics and antiarrhythmic drugs bind to a
specific receptor site in cardiac sodium channels: Displacement of bupivacaine by lidocaine. Proc West Pharmacol Soc
1984;27:23-25

Downloaded from http://circ.ahajournals.org/ by guest on November 21, 2014

108

Circulation Vol 84, No 1 July 1991

22. Carey EL, Duff HJ, Roden DM, Primm RK, Wilkinson GR,
Wang T, Oates JA, Wooseley RL: Encainide and its metabolites: Comparative effects in man on ventricular arrhythmia
and electrocardiographic intervals. J Clin Invest 1984;73:
539-544
23. Barbey JT, Thompson KA, Echt DS, Woosley RL, Roden
DM: Antiarrhythmic activity, electrocardiographic effects and
pharmacokinetics of the encainide metabolites O-desmethyl
encainide and 3-methoxy-O-desmethyl encainide in man. Cir-

culation 1988;77:380-391
24. Roden DM, Lee JT, Woosley RL, Echt DS: Antiarrhythmic
efficacy, clinical electrophysiology, and pharmacokinetics of
3-methoxy-O-desmethyl encainide (MODE) in patients with
inducible ventricular tachycardia or fibrillation. Circulation
1989;80:1247-1258
25. Hohnloser SJ, Weirich J, Antoni H: Effects of mexiletine on
steady-state characteristics and recovery kinetics of V(max)
and conduction velocity in guinea pig myocardium. J Cardiovasc Pharmacol 1982;4:232-239
26. Valenzuela C, Sanchez-Chapula J: Electrophysiologic interactions between mexiletine-quinidine and mexiletine-ropitoin in
guinea pig papillary muscle. J Cardiovasc Phannacol 1989;14:
783-789
27. Campbell RWF: Mexiletine. N Engl J Med 1987;316:29-34
28. Bauman JL, Bauernfeind RA, Hoff JV, Strasberg B, Swiryn S,
Rosen KM: Torsade de pointes due to quinidine: Observations
in 31 patients. Am Heart J 1984;107:425-430
29. Sclarowsky S, Lewin RF, Kracoff 0: Amiodarone-induced
polymorphous ventricular tachycardia. Am Heart J 1983;105:
6-12
30. Yabek SM, Kato R, Singh BN: Effects of amiodarone and its
metabolite, desethylamiodarone, on the electrophysiologic

properties of isolated cardiac muscle. J Cardiovasc Pharmacol

1986;8:197-207
31. Talajic M, DeRoode MR, Nattel S: Comparative electrophysiologic effects of intravenous amiodarone and desethylamiodarone in dogs: Evidence for clinically relevant activity of the
metabolite. Circulation 1987;75:265-271
32. Mitchell LB, Wyse DG, Gillis AM, Duff HJ: Electropharmacology of amiodarone therapy initiation: Time courses of onset
of electrophysiologic and antiarrhythmic effects. Circulation
1989;80:34-42
33. Saal AK, Werner JA, Greene HL, Sears GK, Graham EL:
Effect of amiodarone on serum quinidine and procainamide
levels. Am J Cardiol 1984;53:1264-1267
34. Wilber DJ, Garan H, Finkelstein D, Kelly E, Newell J,
McGovern B, Ruskin JN: Out-of-hospital cardiac arrest: Use
of electrophysiologic testing in the prediction of long-term
outcome. N Engl J Med 1988;318:19-24
35. Krafchek J, Lin H-T, Beckman KJ, Nielsen AP, Magro SA,
Hargis J, Wyndham CRC: Cumulative effects of amiodarone
on inducibility of ventricular tachycardia: Implications for
electrophysiological testing. PACE 1988;11:434-444
36. Greenspon AJ, Volosin KJ, Greenberg RM, Jefferies L,
Rotmensch HH: Amiodarone therapy: Role of early and late
electrophysiologic studies. JAm Coll Cardiol 1988;11:17-123
37. The Cardiac Arrhythmia Suppression Trial Investigators: Preliminary report: Effect of encainide and flecainide on mortality
in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406-410

KEY WORDS * amiodarone * quinidine * mexiletine

encainide * ventricular tachycardia

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