JACC Vol. 9. NO.2
February 1987:459-63
459
EDITORIAL REVIEWS
Second Generation Antiarrhythmic Agents: Have We Reached
Antiarrhythmic Nirvana?
LEONARD N. HOROWITZ, MD, FACC, JOEL MORGANROTH, MD, FACC
Philadelphia, Pennsylvania
During the first half of the 20th century, antiarrhythmic
therapy was principally directed toward supraventricular arrhythmia; only relatively recently has therapy of ventricular
arrhythmias been emphasized. In fact, significant pharmacologic treatment of ventricular arrhythmias was minimal
until routine use of quinidine and procainamide began in
the 1950s (1,2). The first generation oral antiarrhythmic
drugs, quinidine, procainamide and disopyramide, previously constituted the principal antiarrhythmic agents for longterm treatment of ventricular arrhythmias in the United States.
Compared with modem regulatory standards, the data on
which the use of these drugs was based were modest at best
and rudimentary at worst. However, because good clinical
judgment compensates for a multitude of deficiencies, we
have been able to provide effective antiarrhythmic therapy
to many patients with this rather limited pharmacopoeia.
Two beta-adrenergic blocking agents, propranolol and
acebutolol, have been approved for the treatment of ventricular arrhythmias by the Food and Drug Administration.
Unlike the first generation of antiarrhythmic drugs and the
recently released agents which effect their antiarrhythmic
action by direct alteration of electrophysiologic properties,
the beta-blockers presumably act indirectly by blunting sympathetic tone. Although they are effective, either alone or
as an adjunct to classic antiarrhythmic therapy, they will
not be considered in this discussion of membrane-active
antiarrhythmic agents.
In slightly more than 12 months, four new antiarrhythmic
drugs, tocainide, mexiletine, ftecainide and amiodarone,
have been released for the treatment of ventricular arrhythmias. A fifth drug, encainide, is likely to be released within
a year. These drugs are "second generation," not only
because their electrophysiologic properties are new and in
* Editorials published in Journal ofthe American College ofCardiology
reflect the views of the authors and do not necessarily represent the views
of JACC or the American College of Cardiology.
From the Division of Clinical Cardiac Electrophysiology and Sudden
Death Prevention Program of the Likoff Cardiovascular Institute, Hahnemann University and Hospital, Philadelphia, Pennsylvania.
Manuscript received March 4, 1986; revised manuscript received July
1,1986, accepted July 21,1986.
Address for reprints: Leonard N. Horowitz, MD. Philadelphia Heart
Institute, Presbyterian-University of Pennsylvania Medical Center, 39th
and Market Streets, Philadelphia, Pennsylvania 19104.
© 1987 by tbe American College of Cardiology
some cases novel, but because their preapproval evaluations
followed a more rigorous and circumspect path. More information is available to us so we can decide when and how
these agents should be employed.
Like all antiarrhythmic drugs of the first generation, the
new agents have the potential to provoke or worsen ventricular arrhythmias. These proarrhythmic effects vary in
incidence and may present a major problem in certain patient
groups such as those with sustained ventricular tachyarrhythrnias, reduced left ventricular function and conduction
disturbances. In common with other antiarrhythmic drugs,
the second generation drugs have not been shown to prevent
sudden death in patients with ventricular ectopic activity.
These factors, along with efficacy and potential toxicity,
must be considered in selecting antiarrhythmic regimens for
an individual patient.
Tocainide
Efficacy. Tocainide hydrochloride, a class IB agent, has
electrophysiologic and antiarrhythmic characteristics similar
to those of lidocaine, of which it is a congener; however,
it can be prescribed for oral administration. Tocainide is
indicated for the "suppression of symptomatic ventricular
arrhythmias, including frequent premature ventricular contractions, unifocal or multifocal , couplets and ventricular
tachycardia" (3). It has been reported to significantly reduce
(decrease by at least 70% in frequency) ventricular premature complexes in 20 to 50% of patients (4). When compared with quinidine or procainamide, tocainide has been
less effective in suppressing ventricular premature complexes (5). In patients with malignant ventricular arrhythmias (ventricular tachycardia with hemodynamic compromise or ventricular fibrillation) tocainide has been shown to
be effective in 10 to 15% of patients; however, notable
exceptions with higher efficacy rates have been reported (6).
These and other data provide support for the indications for
tocainide.
Adverse effects. Tocainide commonly produces minor,
transient, gastrointestinal and neurologic adverse effects.
These side effects have been reported in 30 to 40% of
patients. Intolerable adverse reactions may require discontinuation of tocainide therapy in 10 to 20% of patients. The
0735-1097/87/$3.50
460
HOROWITZ AND MORGANROTH
EDITORIAL REVIEW
manufacturer has warned that blood dyscrasias, which are
possibly drug related, have been reported in patients receiving tocainide, and frequent monitoring of hematologic
variables is recommended. Pulmonary fibrosis has also been
reported. Tocainide has produced minimal negative inotropic effects and most patients, even those with evidence
of significant left ventricular dysfunction, can tolerate tocain ide without worsening of congestive heart failure. Moreover, tocainide can be administered with other cardioactive
medications without significant interactions.
Mexiletine
Efficacy. Mexiletine hydrochloride, a class IB agent, is
structurally similar to lidocaine and tocainide and has similar
antiarrhythmic potency. Mexiletine is indicated for
"suppression of symptomatic ventricular arrhythmias including premature ventricular contractions, unifocal or multifocal, couplets and ventricular tachycardia" (7). Mexiletine has been effective in reducing the frequency of ventricular
premature complexes in 30 to 50% of patients (6-8). Comparisons with procainamide, quinidine and disopyramide
have shown no significant difference in efficacy. In patients
with more serious ventricular arrhythmias evaluated by noninvasive methods, the efficacy of mexiletine has been reported to be good (8). However, in patients with sustained
ventricular tachycardia evaluated by electrophysiologic testing, mexiletine when used alone has generally been reported
to have minimal efficacy (9). In this group of patients,
however, the combination of mexiletine with procainamide
or quinidine has been shown to be very effective (10).
Adverse effects. Mexiletine commonly produces gastrointestinal and neurologic adverse reactions. Upper gastrointestinal distress has been reported in more than 40% of
patients and light-headedness, tremor and coordination difficulties have been reported in 10 to 20% of patients (7).
The manufacturer has noted that liver injury and elevation
of certain hepatic enzymes have been noted in a small number of patients treated with mexiletine and may be related
to it. Appropriate clinical follow-up is indicated.
lACC Vol. 9. No.2
February 1987:459-63
cardia, or both, during flecainide therapy, and the median
reduction in ventricular premature complexes for all patients
approximates 95% (12). F1ecainide has been shown to be
more effective than quinidine in suppressing ventricular premature complexes (12). In patients with refractory lifethreatening ventricular arrhythmias, it has been effective in
25% of patients evaluated by noninvasive or invasive techniques, or both (13,14). Although flecainide has not been
directly compared with first generation antiarrhythmic drugs
in this latter group of patients, in most of the patients treated
with flecainide previous therapy with first generation agents
had been unsuccessful.
Adverse effects. The most common adverse effects noted
with patients treated with flecainide have been central nervous system disturbances. These occur in 10 to 20% of
patients. Discontinuation of treatment because of these effects has been reported in 5 to 10% of patients (11,15).
The manufacturer has warned that flecainide can cause
new or worsened arrhythmias. This proarrhythmic effect
has been reported in 7O/c of the patients treated with flecainide and its frequency appears to be related to the dose,
the method of dose titration and the underlying cardiac disease. The incidence of proarrhythrnic effect is highest among
patients who have sustained ventricular tachycardia or whose
dose is rapidly titrated upward, or both. When high initial
doses and rapid upward titration were used in early studies
of patients with sustained ventricular tachycardia, a proarrhythmic event occurred in 26% of patients, and in 10% of
the patients treated, a proarrhythmic event resulted in death.
With the current dosing recommendations, however, the
incidence of proarrhythmic events resulting in death has
decreased to 0.5%. Thus, it is extremely important to follow
the recommended dosing schedule.
In addition. flecainide has a negative inotropic effect and
can cause or worsen congestive heart failure. This effect
is particularly noted in patients with cardiomyopathy or
preexisting severe heart failure. Because flecainide has potent depressant effects on cardiac conduction, patients with
sinoatrial node and atrioventricular (AV) conduction disturbances must be carefully observed for the development
of worsening of these abnormalities.
Flecainide
F1ecainide acetate, a class IC agent, markedly depresses
the sodium channel and is the first released agent of a group
of agents with potent negative dromotropic effects which
have been classified as IC agents.
Efficacy. Flecainide is indicated for the "treatment of
documented life-threatening ventricular arrhythmias, such
as sustained ventricular tachycardia" and "symptomatic
nonsustained ventricular tachycardia and frequent premature
ventricular complexes" (11). More than 80% of patients
will achieve greater than 75% suppression of ventricular
premature complexes, or elimination of ventricular tachy-
Encainide
Encainide hydrochloride also markedly slows intracardiac conduction and is classified as a class IC antiarrhythmic
agent. Its antiarrhythmic effects are similar to those of flecainide. Encainide was recommended for approval by the
Cardio-renal Advisory Committee in July 1985 and is in the
latter stages of the Food and Drug Administration's review
process. It will probably be released within a year.
Efficacy. Encainide will be indicated for the treatment
of ventricular arrhythmias similar to those for which flecainide is indicated. The efficacy of encainide in suppressing
JACC Vol. 9. NO.2
February 1987:459-63
HOROWITZ AND MORGANROTH
EDITORIAL REVIEW
both ventricular premature complexes and malignant ventricular arrhythmias is similar to that of flecainide. It produces
adequate suppression of ventricular premature complexes in
approximately 80% of patients and complete abolition in 30
to 40% of patients (16,17). Encainide is more effective than
quinidine in suppressing ventricular premature complexes
(18). When evaluated by electrophysiologic techniques. it
has been reported to be effective in approximately 25% of
patients with malignant ventricular arrhythmias (19).
Adverse effects. The adverse effects produced by encainide during long-term oral use are predominantly neurologic. Blurred vision, dizziness and ataxia are reported in
10 to 20% of patients.
Encainide will probably carry a proarrhythmia warning
similar to that in the flecainide package insert. A proarrhythmic effect has been reported in 5 to 10% of patients
receiving encainide, most commonly in patients with left
ventricular dysfunction and malignant ventricular arrhythmia (20,21). This proarrhythmic effect may also be dose
related (22). Like flecainide, encainide may depress sinus
node function and AV conduction particularly in patients
with preexisting disturbances. It is not expected that encainide will carry a warning relative to heart failure because
minimal hemodynamic effects have been reported and heart
failure uncommonly complicates the use of encainide even
in patients with preexisting heart failure (23).
Amiodarone
Amiodarone, a benzofuran derivative, was initially introduced as a coronary vasodilator for treatment of angina
pectoris but was found to have antiarrhythmic properties.
Amiodarone increases the action potential duration and prolongs repolarization. In addition, it is a noncompetitive adrenergic antagonist.
Efficacy. Because of its potentially life-threatening side
effects and the substantial management difficulties associated with its use, amiodarone is indicated for the treatment
of "documented, life-threatening recurrent ventricular arrhythmias [recurrent ventricular fibrillation and recurrent
hemodynamically unstable ventricular tachycardia]. when
these have not responded to documented adequate doses of
other adequate available antiarrhythmics or when alternative
agents could not be tolerated" (24). Because of its substantial toxicity, amiodarone should not be used for the
treatment of ventricular premature complexes, even when
these occur in repetitive forms. The efficacy of amiodarone
in the treatment of sustained life-threatening ventricular arrhythmias ishighly variable, ranging from 30t080%(25-28).
Controversy continues regarding the utility of electrophysiologic testing in evaluating amiodarone. Considerable recent evidence suggests that it may be useful in identifying
patients who will not have recurrent arrhythmia and those
461
patients who will have nonlife-threatening recurrent arrhythmia (27,28).
Toxicity and adverse effects. Because its use is accompanied by substantial toxicity, amiodarone is indicated only
for use in patients with life-threatening ventricular arrhythmias. Amiodarone has several potentially lethal toxicities,
the most notable of which is pulmonary toxicity. Although
the incidence of this adverse effect is debated, rates between
5 and 15% have been routinely reported and death may
occur from this complication in as many as 10% of those
with the adverse effect. It may cause a worsening of congestive heart failure and arrhythmias. Moreover, amiodarone
poses major management problems because of its unusual
pharmacokinetics and other less severe adverse effects.
Amiodarone has been reported to cause hepatic injury, corneal microdeposits and uncommonly, impairment of vision,
cutaneous photosensitivity, thyroid abnormalities and a
number of drug interactions. It has significant interactions
with other antiarrhythmic drugs. digitalis and warfarin anticoagulants.
Antiarrhythmic Therapy in 1986
Clinical approach to antiarrhythmic therapy. Have
we, therefore, entered antiarrhythmic nirvana? Can we and
should we abandon the use of first generation antiarrhythmic
agents because newer drugs are now available? What is the
role of these new agents and where do they fit in the therapeutic algorithm for patients with ventricular arrhythmia?
Clearly we have not attained perfection in antiarrhythmic
therapy. All of the second generation agents have limitations
and thus. none is the perfect antiarrhythmic agent. Such an
"ideal" antiarrhythmic agent would have minimal adverse
effects and be effective in the majority of patients, particularly those with malignant ventricular arrhythmias. Its metabolism and pharmacokinetics would be simple and unvarying in different patient populations. It would be nice if
it were effective in treating supraventricular arrhythmias as
well! We do not have and probably are not likely to have
such an agent. The advantage of having twice as many
agents available is that there is a greater variety from which
to match an individual patient with a specific regimen and
there are more choices from which to select an effective
regimen that is well tolerated by the patient. It has recently
been emphasized (29) that the selection of an antiarrhythmic
regimen is more commonly based on consideration of toxicity profiles rather than on the relative efficacies of the
various agents. It is now encumbent on us to develop rational
and clinically useful approaches to the use of this larger
number of antiarrhythmic agents (Table I).
The use of first generation antiarrhythmic drugs should
not be abandoned. Quinidine and procainarnide, in particular, are useful in the treatment of supraventricular arrhythmias. and all of these agents are useful in the treatment of
HOROWITZ AND MORGANROTH
EDITORIAL REVIEW
462
lACC Vol. 9. No.2
February 1987:459-63
Table 1. Characteristics of Current Antiarrhythmic Agents*
Efficacy
Drug
VPCs
MVA
Quinidine
Procainamide
Disopyramide
Tocainide
Mexiletine
Flecainide
Encainide
Amiodarone
+++
+++
++
++
++
++++
++++
++
++
++
+
+
++
++
+++
NA
Effect on
LV Function
0
t
t t t
0
0
t t
0
t
Incidence of
Proarrhythmia (%)t
VPCs
MVA
3
3
3
2
2
<I
<I
NA
7
7
7
3
3
Incidence of Significant
Noncardiac Side Effects (%)
25
25
35
10
10
40
40
10
10
5
75
*This is a highly subjective summary of pertinent features of our current antiarrhythmic armamentarium. In the absence of controlled comparative
trials. such estimates are based on personal experience and a review of available data. Efficacy and left ventricular function scales are 0 to 4. t lncludes
an estimate of serious and potentially life-threatening proarrhythmic effects. LV = left ventricular; MVA = malignant ventricular arrhythmia; NA =
not applicable; VPC = ventricular premature complexes.
ventricular arrhythmias, both ventricular premature complexes and malignant or life-threatening ventricular arrhythmias. The addition of the new agents allows better tailoring
of antiarrhythmic regimens for individual patients.
Patients with benign ventricular premature complexes or potentially lethal ventricular arrhythmias (30).
In these patients antiarrhythmic regimens should be selected
after consideration of the goals of antiarrhythmic therapy,
efficacy and toxicity of specific agents in this patient group
and the individual patient's previous drug history and clinical status. In patients with few complicating factors, flecainide or encainide would be appropriate as a first choice
because of their higher efficacy and lower incidence of toxicity. In patients with conduction disturbances, quinidine or
procainamide might be better initial choices. In patients with
severely depressed left ventricular function or severe
congestive heart failure, the choice of an agent that has
minimal or only modest negative inotropic potential, such
as encainide, tocainide, mexiletine or quinidine, would be
appropriate. Subsequent choices should be based on the
patient's response, particularly side effects, to previously
evaluated drugs. Thus, for patients with ventricular premature complexes, therapy should be guided by a consideration of the adverse effects of the available agents and the
appropriate selection of initial therapy can be made by a
knowledge of the patient's clinical status and the effects of
the antiarrhythmic drugs.
Patients with life-threatening or malignant ventricular arrhythmias. In these patients the complicating cardiovascular factors are usually many. Most of these patients
have left ventricular dysfunction and conduction disturbances and the use of concomitant medications is common.
Because of the severity of the arrhythmia, no argument
exists regarding whether these patients should be treated.
Whether they are evaluated by noninvasive or invasive techniques, it is critical that the antiarrhythmic regimens in such
patients be quantitatively evaluated and the patients be followed closely.
In this group of patients, the reported efficacy of class
IA (quinidine-like) agents and class IC (flecainide-like) agents
is similar; however, class IB agents (mexiletine or tocainide)
are less often effective alone. The selection of which agent
is the first choice for treatment requires weighing the risk
and benefit of a specific regimen in an individual patient.
The key is individualization of therapy. Quinidine or procainamide is effective in approximately 25% of these patients but each has frequent noncardiac toxic effects that
may cause discontinuation of treatment in as many as onethird of patients. Flecainide and encainide, similarly, are
effective in 25% of patients in this group but have a greater
proarrhythmic potential, and flecainide can worsen left ventricular function. In patients with left ventricular dysfunction
and congestive heart failure or severe conduction disturbance, quinidine and procainamide should be evaluated initially. Adjunctive use of mexiletine or tocainide augments
efficacy with these agents and should also be considered.
Even in patients with malignant ventricular arrhythmias
without complicating heart failure or conduction abnormalities, ftecainide and encainide should not be considered
initially because of their probably higher proarrhythmic potential. Particularly in patients with severe heart failure,
encainide should be used before ftecainide. Clinical judgment is required in making the initial choice in therapy for
these highest risk patients, and one must weigh the clinical
toxicity of the quinidine-like and lidocaine-like drugs against
the probably higher potential of proarrhythmia of encainide
and ftecainide and heart failure of ftecainide. The approach
in using this larger array of drugs should not be hierarchical.
The choice of ftecainide for initial therapy does not mean
that a first generation agent will not be effective if ftecainide
proves unsuitable and vice versa.
Before initiating amiodarone therapy in patients with ma-
HOROWITZ ANDMORGANROTH
EDITORIAL REVIEW
lACC Vol. 9, No.2
February
1987:459~63
lignant ventricular arrhythmias, other less commonly used
drugs or beta-adrenergic blockers can be tried. Treatment
with amiodarone, alone or in combination with first generation or any of the newer agents, should always follow
thorough evaluation of all other appropriate pharmacologic
alternatives. It is also important to remember that in many
patients alternative therapy with electrical devices or surgery
is available and rational in patients in whom pharmacologic
therapy is ineffective or not well tolerated.
Although we have not reached a state of perfection in
the treatment of ventricular arrhythmias, the advent of second generation antiarrhythmic drugs provides a significant
advance in our ability to treat these disorders. Although
much more remains to be learned about the mechanisms
and treatment of ventricular arrhythmias, a significant advance in our ability to treat them has been made.
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