Circulation. 1999;100:2025-2034
(Circulation. 1999;100:2025-2034.)
© 1999 American Heart Association, Inc.
Evidence-Based Analysis of Amiodarone Efficacy and Safety
Stuart J. Connolly, MD
From McMaster University, Faculty of Health Sciences, Hamilton, Ontario,
Canada.
Key Words: Cardiovascular Drugs amiodarone ventricular tachycardia atrial fibrillation
 |
Introduction
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Amiodarone was initially developed 3 decades ago for
angina.
On the basis of the number of prescriptions filled in retail
pharmacies,
amiodarone was the most-often-prescribed
antiarrhythmic agent,
accounting for 24.1% of the total antiarrhythmic
prescriptions
in 1998. Amiodarone accounted for 34.5% of
prescriptions in
Europe, 32.8% in North America, 73.8% in Latin
America, and
0.3% in Japan and the Philippines. Amiodarone use
has increased
globally in 1998 at a rate greater than that of the whole
antiarrhythmic
market, with striking growth in North America, a 20.0%
increase
from 1997 to 1998 (according to International Medical
Statistics,
Medical Data Index, and Scott Levin drug and diagnosis
audit,
obtained with the assistance of J. Jones, Sanofi Pharma Inc,
Paris,
France). Amiodarone is used to manage virtually all
forms of
supraventricular and ventricular
tachycardia. This review focuses
on the arrhythmias
most commonly requiring antiarrhythmic therapysustained
ventricular
tachycardia (VT),
ventricular fibrillation (VF), and atrial
fibrillation
(AF)because they are the most clinically
significant and have been
the focus of most studies published.
This review will analyze
the evidence that amiodarone is a safe
and effective
antiarrhythmic drug.
 |
Pharmacokinetics
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To exploit the antiarrhythmic properties of amiodarone
fully,
the clinician needs to be familiar with its pharmacokinetics,
because
they differ markedly from those of other cardiac drugs.
Amiodarone
is markedly lipophilic, which may account for some
of its unusual
pharmacokinetic features.
1 It is
incompletely absorbed (35%
to 65%) after oral
administration.
2 3 4 It is taken up very
extensively by
tissue, with marked interindividual variation.
5 Estimates
of the elimination half-life of amiodarone vary,
depending on
how it has been measured. The relatively short
half-life for
disappearance of amiodarone from plasma after
intravenous
administration is likely a measure of drug
redistribution from
vascular space into tissue and not true body
elimination.
6 After long-term oral therapy,
amiodarone has a true elimination
half-life of up to 60
days.
7 8 9 Slow distribution to tissue
results in a
requirement of very long loading periods, up to
several months, before
reaching steady-state tissue concentrations.
Large loading doses of
oral therapy, typically 800 to 1600 mg/d
in 3 to 4 divided doses, can
accelerate the onset of activity.
However, even with loading,
arrhythmia recurrence during the
first months of
therapy does not necessarily predict long-term
inefficacy.
Amiodarone plasma concentration measurements are
of marginal
clinical utility for several reasons.
6 Amiodarone
is
deethylated to an active metabolite desethyl-amiodarone,
concentrations
of which exceed those of the parent compound during
long-term
therapy. There is also marked intersubject variability
in plasma
concentrations of amiodarone and
desethyl-amiodarone concentrations
associated with arrhythmic
suppression.
10 Plasma concentrations
>2.5 mg/L have been
associated with increased risk of toxicity.
11 12 The
optimal dose of amiodarone has not been systematically
studied.
Generally doses of 200 to 400 mg/d have been used during
long-term
therapy of supraventricular and ventricular
arrhythmia,
but doses as low as 100 mg/d have been shown to be
effective
in some patients.
11
 |
Electrophysiology
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The electrophysiological actions of
amiodarone are complex and
incompletely understood.
Amiodarone has generally been classified
as a Vaughan-Williams
class III agent, prolonging repolarization
by inhibition of outward
potassium channels.
12 It also has
been shown to have
use-dependent class I activity, inhibition
of the inward sodium
currents,
13 14 and class II activity.
The
antiadrenergic effect of amiodarone,
however, is different
from that of ß-blocker drugs because it
is noncompetitive
and additive to the effect of
ß-blockers.
15
Amiodarone depresses automaticity of the sinoatrial node,
resulting in slowing of the heart rate in sinus rhythm. It both slows
conduction and increases refractoriness of the AV
node,16 17 18 properties useful in the management of
supraventricular arrhythmia. Its class III activity
results in increases in atrial and ventricular
refractoriness and in prolongation of the QTc interval.
Amiodarone prolongs VT cycle length by 20% to 25% during
long-term therapy.18 19 20 The effects of oral
amiodarone on sinoatrial and AV nodal function are maximal
within 2 weeks, whereas the effects on VT and ventricular
refractoriness tend to emerge more gradually during oral therapy,
becoming maximal at
10 weeks.18
 |
Ventricular Tachyarrhythmias
|
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Amiodarone has been widely used to control
symptomatic ventricular
arrhythmias,
primarily to prevent recurrence of VT and VF. Although
amiodarone
is accepted as effective against VT and VF, there is
little
supportive evidence from placebo-controlled studies.
Nonetheless,
amiodarone is approved for use against VT and VF
by most regulatory
agencies worldwide and has a high profile as a
useful drug.
21 Its high rate of use against VT or
VF is based largely on
considerable clinical experience and concern
about the safety
of other drugs.
21
Amiodarone suppresses ventricular premature
depolarizations (VPDs) and episodes of nonsustained
VT.10 11 18 This is clearly demonstrated in several of the
primary prevention trials of amiodarone in postmyocardial
infarction and congestive heart failure (CHF) patients in whom baseline
and follow-up 24-hour ambulatory ECGs were performed. In the Canadian
Amiodarone Myocardial Infarction Arrhythmia Trial
(CAMIAT) pilot study,22 which enrolled patients with
frequent or repetitive asymptomatic VPDs, 86% of
amiodarone patients were observed to have almost complete
suppression of VPDs and nonsustained VT compared with 50% of placebo
patients. In the Veterans Affairs Congestive Heart Failure
Amiodarone Study,23 after 2 weeks of therapy, 33%
of patients on amiodarone had VT events on Holter ECGs compared
with 76% of placebo patients (P=0.001).
There have not been any placebo-controlled trials of amiodarone
against sustained VT and VF. Virtually all available publications
merely report the outcomes of patients with resuscitated cardiac arrest
or recurrent VT treated with amiodarone.25 26 27 28 29 30 31 32 33 34 35
Most reports conclude that amiodarone is an effective
agent,8 25 26 27 28 29 although some suggest that
amiodarone is not as effective as claimed by early enthusiastic
reports.34 It is not possible to draw any firm conclusions
about the efficacy of amiodarone from these uncontrolled
reports. Nonetheless, they formed the basis for regulatory
approval.24
In one of the earliest papers, Rosenbaum et al25 reported
"excellent" results in 119 of 145 patients (82%) with
symptomatic VT or VF. There was total suppression of
arrhythmia in 34 of 44 patients (72%) who had incessant or
frequently recurrent VT (mean of 22 episodes in the prior month). The
largest follow-up report of amiodarone treatment included 589
patients with supraventricular arrhythmia, 83% of
whom had VT or VF (17% nonsustained VT).36 The 5-year
cumulative risk of sudden death was 22%; of total death, 46%. The
cumulative risk of drug failure, defined as sudden death,
ventricular arrhythmia recurrence, or drug
discontinuation at 5 years, was 50%. Amiodarone has been
compared in 2 nonrandomized retrospective trials to other
antiarrhythmic therapy for the management of VT.29 34 Both
reported an advantage with amiodarone.
The Cardiac Arrest in Seattle: Conventional Versus Amiodarone
Drug Evaluation (CASCADE) study is the only randomized trial of
amiodarone against other antiarrhythmic drugs for treatment of
VF.37 High-risk survivors of out-of-hospital VF were
randomized to receive either amiodarone (n=113) or
"conventional" antiarrhythmic therapy (n=115). The conventional
therapy consisted primarily of Vaughan-Williams class I antiarrhythmic
drug therapy, guided by serial ambulatory ECG monitoring or
electrophysiological testing. Approximately
halfway through the study, all patients received an implantable
cardioverter-defibrillator (ICD) in addition to randomized therapy. The
risk of the primary outcome, which was a composite of cardiac death,
sustained VT/VF, or syncopal ICD shock, was significantly reduced by
amiodarone. At 4 years of follow-up, event-free survival was
52% for amiodarone and 36% for conventional care, a 44%
increase. Cardiac death and all-cause mortality rates were also lower
on amiodarone. Although small, this study provides considerable
support for a benefit of amiodarone over class I drugs. There
is evidence from other sources, however, that class I drugs are
proarrhythmic and may increase all-cause mortality.21 38
Accordingly, the observed difference in outcomes in the CASCADE study
may have been due to harmful effect of conventional therapy, a
beneficial effect of amiodarone, or most likely, their
combination. In summary, the direct evidence that amiodarone
prevents recurrent VT and VF is based mostly on clinical experience and
not on randomized trials.
The general view that amiodarone is the most useful drug for VT
and VF, notwithstanding the rather modest evidence from randomized
trials, led to its being adopted as the standard medical therapy in
several recent randomized secondary prevention trials evaluating the
ICD. In the Canadian Implantable Defibrillator Study (CIDS) and
Antiarrhythmics Versus Implantable Defibrillators (AVID) study,
patients with either VF or sustained VT were randomized to receive an
ICD or medical therapy.39 40 41 42 In CIDS, medical therapy was
amiodarone; in AVID, it was amiodarone or sotalol. (In
practice, however, virtually all AVID study patients received
amiodarone, mostly because of physician preference.)
Amiodarone was 1 of 3 drugs that were randomly compared with
the ICD in the Cardiac Arrest Study, Hamburg (CASH), which enrolled
only cardiac arrest survivors.43 All 3 studies observed
improved survival with the ICD compared with amiodarone, with
relative risk reductions ranging from 20% to 40%. In the AVID
study,41 all-cause mortality was statistically
significantly reduced by ICD therapy, whereas in both CASH and CIDS,
ICD therapy was associated with nonsignificant reductions in all-cause
death. A recently reported meta-analysis of the 3 trials has
shown that they are consistent and that there is a
statistically significant mortality reduction of 27% with the ICD
compared with amiodarone.
 |
Prophylaxis Against Sudden Death
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Over the decade from 1985 to 1995, many trials were done to
assess
the effect of amiodarone in the prevention of death in
patients
who had never had a sustained ventricular
arrhythmia
but were nonetheless at high risk of death from
arrhythmia.
22 23 44 45 46 47 48 49 50 51 52 53 54 Several randomized trials,
varying
in size from 34 to 1486 patients, were performed. Eight studies
enrolled
patients with recent myocardial infarction, and 5 enrolled
patients
with CHF. Most of the trials screened potentially eligible
patients
by means of left ventricular ejection fraction
assessment, Holter
ECG, or both to identify a particularly high-risk
group. Only
3 of the trials reported a statistically significant
reduction
of all-cause mortality with amiodarone. Several
others observed
statistically significant reductions in arrhythmic
death but
without a significant (or in some cases any) reduction in
all-cause
mortality. A meta-analysis of these trials based on
individual
patient data yielded a relative risk reduction in all-cause
mortality
of 13% to 15%, which was of borderline statistical
significance
(
P=0.03 or 0.06, depending on analytical method
used).
55 The
reduction in all-cause death was due to
a relative 29% decrease
in arrhythmic deaths (
P=0.003),
which accounted for somewhat
less than half of all deaths. There was no
effect of amiodarone
on nonarrhythmic deaths. The Figure

shows
the individual trial
results and overall treatment effect for the
outcomes of all-cause
mortality and arrhythmic/sudden death. The 13%
relative risk
reduction in all-cause mortality is entirely
consistent with
a 29% reduction in arrhythmic deaths and with
no effect on the
nonarrhythmic deaths. The treatment benefit was
uniform across
the CHF and postmyocardial infarction trial patients
and
was independent of major prognostic variables, such as left
ventricular
function.

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Figure 1. Overview of 13 amiodarone trials. Each trial is
represented by square and line. Squares show trial estimate
of OR, and size of square is proportional to number of events
contributed by study to overall OR. Lines represent 95% CI of
OR estimate. Test of association indicates whether overall OR is
different from unity, and test of heterogeneity
measures inherent similarity of individual study results. Overall OR
was calculated with assumption of a fixed effect. Adapted with
permission from Reference 55.
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Because there is good evidence that ß-blocking drugs reduce sudden
death after myocardial infarction,56 it is tempting to
attribute the prophylactic benefit of amiodarone
against sudden death to its antiadrenergic effect.
However, the available data indicate that this is unlikely because
amiodarone interacts positively with ß-blocker therapy in
postmyocardial infarction patients. In both the European Myocardial
Infarction Amiodarone Trial (EMIAT)45 and Canadian
Amiodarone Myocardial Infarction Arrhythmia Trial
(CAMIAT),44 2 of the large randomized trials of
amiodarone after myocardial infarction, patients receiving
ß-blockers at baseline had a statistically significantly better
effect from amiodarone than those not receiving a ß-blocker.
This significant interaction remains even after adjustment for
differences in baseline prognostic variables.57 This
finding suggests that the amiodarone effect in reducing
arrhythmic death is separate from and complementary to the effect of
ß-blockers in these patients.
Widespread clinical experience indicates that amiodarone is
useful against VT and VF; thus, it was used in 3 major multicenter
trials as best medical therapy for these lethal conditions. Yet hard
evidence that amiodarone is effective against VT and VF is
scant. The initial acceptance of amiodarone was based
almost entirely on uncontrolled clinical experience. Subsequently,
several randomized trials were performed, but in these,
amiodarone was compared with other questionable drug treatments
or evaluated as primary prophylaxis against arrhythmic death.
Nonetheless, 3 decades of clinical experience worldwide and a clear-cut
reduction in arrhythmic death in the randomized placebo-controlled
prophylactic trials provide somewhat indirect but
convincing evidence that amiodarone is effective against VT/VF
recurrence, although the degree of benefit remains imprecise.
On the other hand, it is now clear from randomization trials that
amiodarone is not as effective as the ICD for prevention of
lethal arrhythmia. What is the proper role of
amiodarone in the prevention of recurrent VT and VF?
Amiodarone will surely continue to be useful for control of
VT/VF both as an adjunct to ICD therapy and as primary therapy when
there are economic constraints on ICD use. The potential benefits of
amiodarone in ICD patients require more careful evaluation in
randomized studies. Amiodarone has not lived up to the
expectation that it would be a highly effective
prophylactic agent in postmyocardial infarction or heart
failure patients. The primary prevention trials have shown quite
clearly that amiodarone reduced arrhythmic death, but the
beneficial effect on all-cause mortality is too small to justify
routine prophylactic use.
 |
Short-Term Control of VT/VF
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Intravenous amiodarone is available for rapid
control of recurrent
VT or VF, and its effectiveness has recently been
evaluated
in 3 randomized controlled trials.
58 59 60 The
target patient
populations of these trials were identical: patients
with recurrent
in-hospital, hemodynamically unstable VT
or VF with

2 episodes
within the past 24 hours. Additionally,
patients were required
to have failed to respond to or be intolerant of
lidocaine,
procainamide, and (in 2 of the trials) bretylium.
Study patients
were severely ill; about a quarter were on a mechanical
ventilator
or intra-aortic balloon pump before enrollment, and 10%
were
undergoing cardiopulmonary resuscitation at the time of
enrollment.
One study compared 3 doses of intravenous
amiodarone: 525, 1050, and 2100 mg/d, a 4-fold difference
between high and low doses.58 Because of the use of
investigator-initiated, intermittent, open-label amiodarone
boluses for recurrent VT, the actual mean amiodarone doses
received by the 3 groups were 742, 1175, and 1921 mg/d. There was no
statistically significant difference in the number of patients without
VT/VF recurrence during the 1-day study period: 32 of 86
(41%), 36 of 92 (45%), and 42 of 92 (53%) for the low-, medium-, and
high-dose groups, respectively. The number of supplemental
amiodarone 150-mg bolus infusions given by blinded
investigators was statistically significantly less in those randomized
to higher dose of amiodarone (P=0.0043).
A wider range of amiodarone doses (125, 500, and 1000 mg/d) was
evaluated by Sheinman et al,59 including a low dose that
was expected to be subtherapeutic. This stronger study design, however,
was also confounded by open-label bolus amiodarone injections
given by study investigators. There was, however, a trend toward a
relationship between intended amiodarone dose and VT/VF
recurrence rate (P=0.067). After adjustment for
baseline imbalances, the median 24-hour recurrence rates of
VT/VF, from lowest to highest doses, were 1.68, 0.96, and 0.48 events
per 24 hours (P=0.043).
The third study compared 2 amiodarone doses (125 and 1000 mg/d)
to bretylium (2500 mg/d).60 Once again, the target
amiodarone dose ratio of 8 to 1 was compressed to 1.8 to 1 as a
result of open-label boluses. There was no significant difference in
the primary outcome, which was median VT/VF recurrence rate
over 24 hours. For low-dose amiodarone, high-dose
amiodarone, and bretylium, these rates were 1.68, 0.48, and
0.96 events per 24 hours, respectively (P=0.237). There was
no difference between high-dose amiodarone and bretylium;
however, >50% of patients had crossed over from bretylium to
amiodarone by 16 hours.
The failure of these studies to provide clear evidence of
amiodarone efficacy may be related to the "active-control"
study design used, a lack of adequate statistical power, high rates of
supplemental amiodarone boluses, and high crossover rates.
Nonetheless, these studies provide some evidence that IV
amiodarone (1 g/d) is moderately effective during a 24-hour
period against VT and VF.
Recently, the Amiodarone in the Out-of-Hospital Resuscitation
of Refractory Sustained Ventricular Tachycardia
(ARREST) study was presented.61 In patients
with out-of-hospital cardiac arrest still in VT or VF after 3
direct-current shocks, amiodarone was evaluated in a
randomized, placebo-controlled trial of 504 patients. With
amiodarone added to the advanced cardiac life support protocol,
the number of patients admitted to hospital alive increased from 35%
to 44% (P<0.03). Other planned or ongoing trials,
including a randomized comparison against lidocaine, are evaluating
intravenous amiodarone in the management of acute
VF.
Although amiodarone appears useful in short-term management of
VT and VF, its role vis-à-vis other antiarrhythmic drugs is
unclear. On the basis of a meta-analysis of class I and III
drugs,55 56 the proarrhythmic potential of
amiodarone probably is lower than that of lidocaine or
procainamide; however, its use as a primary agent probably
should wait until the results of direct comparative trials become
available. Amiodarone is a reasonable alternative to
bretylium.
 |
Amiodarone for AF
|
|---|
Although amiodarone is widely used to control AF, it is
not
approved in North America for any supraventricular
arrhythmia.
Pharmacological control of AF is a useful clinical
goal and
a reasonable clinical trial outcome. Management of AF entails
a
variety of approaches in different patients and at different
times.
These include maintenance of sinus rhythm, conversion
of
AF to sinus rhythm, control of ventricular rate, and
primary
prevention of AF. Amiodarone has been evaluated with
randomized
trials in all of these settings (see the
Table

).
All randomized trials of amiodarone for long-term
maintenance of sinus rhythm in patients with recurrent AF have
used active-control groups. Three studies compared amiodarone
with quinidine.62 63 64 One brief report indicated improved
maintenance of sinus rhythm at 1 month after cardioversion in a
randomized comparison of amiodarone 200 mg/d with quinidine
(32.5% versus 13.3%, P=0.042).62 Vitolo
et al63 found amiodarone to be superior to
quinidine in a study of 54 patients randomly allocated to either
therapy after cardioversion. After 6 months, the percentage of patients
in sinus rhythm was 79% for amiodarone and 46% for quinidine
(P=0.014). However, Zehender et al,64 in a
randomized trial of amiodarone against the
quinidine/verapamil combination in 40 patients, found no
difference in either the conversion rate of AF to sinus rhythm or in
long-term maintenance of sinus rhythm during up to 2 years of
follow-up. Kochiadakis et al65 recently reported the
results of a small study comparing amiodarone with sotalol for
maintenance of sinus rhythm in paroxysmal AF. During follow-up
of slightly <1 year, amiodarone outperformed sotalol, with 10
of 35 amiodarone patients developing AF compared with 21 of 35
sotalol patients (P=0.008). It is therefore likely that
amiodarone is effective for maintenance of sinus rhythm
in the patient with recurrent AF, and there is modest evidence of
superiority over other agents.
Several studies evaluated intravenous amiodarone
for conversion of acute AF to sinus rhythm. There are 6 trials with
nonactive control groups: 2 that formally compared
intravenous amiodarone to
digoxin,66 67 3 that were placebo controlled with digoxin
use in all patients,68 69 70 and 1 that compared
amiodarone with intravenous
verapamil.71 Digoxin and verapamil
have little efficacy for conversion of AF. Three of these trials
observed a significantly higher rate of acute conversion to sinus
rhythm with amiodarone: 67% versus 90%,
P=0.02966 ; 71% versus 92%
P= 0.004865 ; and 77% versus 0%
P<0.001.71 The other 3 showed
nonsignificant trends to better conversion with amiodarone:
56% versus 59%, P=NS68 ; 60% versus
68%, P=0.53265 ; and 75% versus
83%, P=NS.64 Control of
ventricular rate in AF was evaluated in 2
placebo-controlled studies, both of which reported significantly lower
ventricular rates with
amiodarone.69 70 Thus, amiodarone is
effective for acute conversion of AF and has a beneficial effect on
heart rate in AF.
Several active-control short-term conversion studies have been
reported. Two of these compared intravenous
amiodarone with oral quinidine for management of acute AF. In
an 80-patient study of postoperative AF, the 8-hour conversion rate was
superior with quinidine (64%) compared with amiodarone (41%),
P=0.04.72 In another 75-patient study of
conversion of acute AF, amiodarone and quinidine were both
highly effective, with conversion rates of 92% and 100% for
intravenous amiodarone and oral quinidine,
respectively.73 Conversion of chronic AF (lasting >3
weeks) was evaluated in a 32-patient randomized study.74
There was no significant difference between intravenous
amiodarone and oral quinidine in 24-hour conversion rates or
control of ventricular response.
Amiodarone has been compared with class 1C drugs for acute AF
conversion. In 1 of these studies, amiodarone and flecainide
had similar rates of conversion.70 Two studies of
intravenous amiodarone and propafenone in
postoperative AF of 40 and 84 patients, respectively, observed little
difference between drugs, although there was a small trend in each
study in favor of amiodarone at 24 hours with conversion rates
of 67% versus 77% (P=NS)75 and 68%
versus 83% (P=NS).76 Interestingly,
in both studies, early (1 hour) conversion rates were significantly
better with propafenone, suggesting a more delayed onset of action with
amiodarone. Other small, randomized studies of acute AF
conversion have found intravenous amiodarone to be
similar to intravenous procainamide,77
and in 1 trial, significantly less effective than magnesium
sulfate.78
Primary prevention of AF is a worthwhile goal that has been studied in
1 heart failure trial and extensively in patients recovering from
open-heart surgery, in whom AF occurs in about 30% of patients. Four
placebo-controlled trials of amiodarone have been published.
Redle et al79 reported a nonsignificant, modest reduction
in postoperative AF in a study of 127 patients after CABG surgery
receiving oral amiodarone beginning 1 to 3 days before surgery.
In a study of 120 patients, Butler et al80 reported a
significant reduction in postoperative AF with amiodarone.
Hohnloser et al81 observed a significant reduction in
postoperative AF (from 21% to 5%, P<0.05) with
intravenous amiodarone started postoperatively.
Another study of 124 patients using oral amiodarone at least 7
days preoperatively reported a reduction in postoperative AF from 53%
to 25% (P=0.003).82 Finally, in a
subanalysis of Congestive Heart FailureSurvival Trial of
Antiarrhythmic Therapy (CHF-STAT), a mortality trial of
prophylactic amiodarone in heart failure, patients
on amiodarone were significantly less likely to develop AF than
those on placebo, and patients with AF at baseline were also more
likely to convert to sinus rhythm if they received
amiodarone.83
In summary, there is reasonable evidence from many rather small,
randomized controlled trials that amiodarone is effective for
conversion of AF and maintenance of sinus rhythm. However, the
available active-control studies provide little evidence that it is
superior to other effective drugs. It should be noted that
active-control studies inherently pose a greater challenge to the
demonstration of efficacy than do placebo-controlled trials, because
the differences one can expect to observe in comparison with other
effective agents are usually small. Thus, active-control studies need
to be more rigorously designed and include larger numbers of patients.
The Canadian Trial of Atrial Fibrillation (reported in March 1999), a
trial of 400 patients with AF, reported a significant reduction in AF
recurrence with amiodarone compared with either sotalol
or propafenone (personal communication, D. Roy, Institute of
Cardiology, Montreal, Canada). In addition, a large
substudy of the AFFIRM trial (Atrial Fibrillation Follow-up
Investigation of Rhythm Management) is comparing amiodarone to
other drugs for control of AF.
 |
Cardiac Safety of Amiodarone
|
|---|
There is good evidence that amiodarone is effective
against
a variety of arrhythmias and that it possibly is
superior to
other drugs in some settings. These benefits do not explain
why
amiodarone has become the most used antiarrhythmic drug.
Clinical
decision making balances assessment of effectiveness against
risk
of adverse outcomes, and amiodarone has been shown to be a
relatively
safe drug, especially in patients with serious heart
disease.
Amiodarone can result in severe toxicity of lung,
liver, thyroid,
nerves, and skin. However, early concern about its
noncardiac
side effects
24 29 30 31 has been replaced by
appreciation of
its low cardiovascular
toxicity.
36 55 To help understand the
evidence that
amiodarone is relatively safe, one should understand
the safety
concerns regarding other antiarrhythmic drugs. On
the basis of the
results of several clinical trials and subsequent
meta-analysis,
considerable evidence accumulated in the early
1990s that many
antiarrhythmic drugs increase the risk of death in the
very
patients who could benefit most from effective arrhythmia
prevention,
those with serious underlying myocardial and
coronary artery
disease.
22 38 56 84 Although the
mechanism of this adverse
effect is unclear, proarrhythmic and adverse
hemodynamic actions
are the most likely culprits.
The cardiovascular safety of amiodarone can be
assessed from various case series and from randomized trials.
Assessment of the risk of proarrhythmic effects of drugs can be
difficult because few features distinguish a proarrhythmic effect from
breakthrough of the underlying arrhythmia. The 1 finding that
is virtually diagnostic of drug-induced arrhythmia
is torsade de pointes, polymorphic VT in the presence of marked QT
interval prolongation. Even so, QT prolongation occurs in virtually all
amiodarone-treated patients, and polymorphic VT can occur
spontaneously; thus, there is some lack of reliability even from case
studies and follow-up studies reporting torsade de pointes. Ultimately,
the most reliable safety data come from randomized, controlled
trials.
There have been many case reports of amiodarone-induced torsade
de pointes.85 86 87 88 In most, the typical arrhythmia
occurred in the presence of marked QT prolongation, with resolution in
many cases after drug discontinuation and/or heart rate
acceleration.86 88 The incidence of this complication
appears to be low (<0.5%). Many large follow-up studies have reported
no cases,8 29 31 including the 2 largest (with 462 and 589
patients, respectively).35 36
Use of programmed electrical stimulation can define a different type of
potential proarrhythmic effect of antiarrhythmic drugs. Whereas
amiodarone usually slows the rate of VT, faster VT has been
reported after amiodarone in some cases.89 90 91
Other studies have shown conversion of nonsustained to sustained VT or
induction of VT with fewer extrastimuli with amiodarone and
other drugs.19 91 92 No study has used a
placebo-controlled approach to evaluate this risk. Furthermore, the
results of programmed electrical stimulation and the spontaneous
occurrence of VT can vary over time, making clinical interpretation of
these data problematic.
The results of randomized, controlled studies in high-risk patients are
a more reliable way to assess the potential of amiodarone to
worsen outcomes. In several of these trials of amiodarone,
there was a reduction in arrhythmic death,44 45 and in the
meta-analysis55 summarizing all these trials, the
risk of arrhythmic death was significantly reduced by 29%. Thus, while
it is possible that in individual patients amiodarone might
cause death by proarrhythmia or bradycardia, the net effect in
groups of patients is beneficial. Therefore, the clinician should be
watchful because the individual patient receiving amiodarone
may have an adverse arrhythmic event. He or she can be confident that
these are rare and that the overall risk of death from
arrhythmia or any cause with amiodarone is likely
reduced.
Amiodarone is generally well tolerated in patients with CHF,
although 1 intravenous study demonstrated depression of
contractility in patients with compromised left
ventricular function.93 Several randomized
trials of amiodarone in patients with severe left
ventricular dysfunction have reported that it is well
tolerated. Doval et al51 reported that amiodarone
significantly reduced admission to hospital for CHF and improved
functional class in a trial of 516 heart failure patients randomized to
amiodarone or usual care. In CHF-STAT,23 a
randomized placebo-controlled trial of amiodarone in 674
patients with heart failure, there was significant improvement in left
ventricular ejection fraction with amiodarone
compared with placebo. In 2 small, randomized trials of
amiodarone in heart failure, there was either no significant
effect on left ventricular ejection fraction94
or significant improvement compared with placebo.54
Amiodarone may induce severe bradycardia requiring a permanent
pacemaker, but reports of severe complications caused by bradycardia
induced by amiodarone are not common.35 36 The
1-year risk of bradycardia requiring medication discontinuation in the
meta-analysis of double-blind, placebo-controlled, primary
prevention trials was 2.4% on amiodarone and 0.8% on
placebo.55
Some case series have reported an increased risk of marked bradycardia
and hypotension immediately after cardiac surgery in patients already
on amiodarone at the time of surgery.95 96 Other
case-control studies, however, have not reproduced this
finding.97 98 None of the placebo-controlled trials of
prophylactic amiodarone for
perioperative AF prevention found any adverse
cardiovascular effects of the drug.81 82 83 84
Thus, it is relatively unlikely that amiodarone poses a serious
cardiovascular risk to the postoperative patient. Case
reports and case series of postoperative acute pulmonary
toxicity are similarly lacking in the rigor of randomized controlled
methodology.95 96 97 98 99
Several animal and human studies have reported the effects of long-term
oral amiodarone on the energy required for cardiac
defibrillation. Animal studies have been somewhat contradictory, with
some studies reporting an increase in defibrillation
threshold100 101 and others not.102 103 Human
studies104 105 106 have mostly indicated an increase in
defibrillation threshold in patients receiving long-term oral
amiodarone, although 1 study found no change.107
These studies are methodologically weak, because amiodarone
therapy was not allocated randomly. It is possible that the same
factors resulting in amiodarone use also increase
defibrillation threshold. This area requires further study.
In summary, there is considerable evidence that amiodarone has
less cardiovascular toxicity than other antiarrhythmic
drugs. This is based largely on an analysis of the results of
several placebo-controlled trials of both amiodarone and other
drugs and on meta-analysis of these trials. These trials
indicate increased cardiovascular mortality from
several class I drugs38 56 and with 1 class III
drug.84 With amiodarone, there is neutral or
slightly improved mortality.55 Large follow-up studies of
amiodarone confirm this view.35 36
 |
Noncardiac Toxicity
|
|---|
Amiodarone may result in serious noncardiac toxicity,
particularly
pulmonary infiltrates, hepatic dysfunction,
thyroid dysfunction,
and peripheral neuropathy.
Pulmonary toxicity can be severe
and occasionally
fatal.
97 The diagnosis is most often made
by observing
patchy interstitial infiltrates on chest x-ray,
usually
associated with a subacute presentation of dyspnea.
Typically,
once the differential diagnosis of pulmonary edema
has been
excluded, amiodarone discontinuation is indicated.
Estimates
of the risk of pulmonary toxicity during long-term
oral therapy
vary and may be dose related. The most reliable estimate
of
the 1-year risk of this complication comes from double-blind,
placebo-controlled,
randomized trials, because there is a tendency to
overdiagnose
the condition in patients receiving open-label
amiodarone. Meta-analysis
of the double-blind trials
indicates an absolute 1% net risk
(amiodarone rate less
placebo rate) of this complication during
1 year, with some fatal cases
reported.
55
The same meta-analysis also reported that the 1-year net risk
of events (severe enough to cause study drug discontinuation) was 0.6%
for hepatic toxicity, 0.3% for peripheral
neuropathy, and 0.9% for hyperthyroidism. Hypothyroidism
was quite common, occurring in 6% during the first year of treatment,
but usually it is easily managed by thyroid hormone replacement
concurrent with continuation or discontinuation of amiodarone.
During long-term management of patients on amiodarone, routine
toxicity screening is required. This includes periodic (usually every 6
months) measurement of thyroid (sensitive serum T4), hepatic (AST), and
pulmonary function (chest x-ray), as well as clinical
evaluation.
 |
Conclusions
|
|---|
Amiodarone is currently the leading antiarrhythmic drug
because
of proven efficacy and safety. There is reasonable evidence
of
effectiveness against several clinical important arrhythmias.
However,
good randomized trials evaluating the efficacy of
amiodarone
are still needed, especially comparative studies
against other
drugs for control of AF and a placebo-controlled trial
against
VT. Amiodarone is particularly useful because its
safety has
been clearly demonstrated by a large body of evidence,
including
several randomized trials. Compared with many other
antiarrhythmic
drugs, amiodarone causes few
cardiovascular adverse effects;
however, its overall
tolerance is limited by considerable noncardiac
toxicity.
Although amiodarone will continue to give way to the ICD as
primary therapy for many patients presenting with sustained VT or
VF, it is likely that amiodarone use will continue in ICD
patients to prevent ICD discharges. Evaluation of combined use of
amiodarone and the ICD may provide the first opportunity to do
a placebo-controlled trial of amiodarone efficacy against VT
recurrence. Pharmacological therapy remains the major approach
to management of AF, and use of amiodarone is likely to
increase in future years.
 |
Acknowledgments
|
|---|
Thanks are due to Dr John A. Cairns, University of British
Columbia,
and Professor Michael Gent, McMaster University, for their
helpful
criticism of the manuscript. Dr Connolly has received
research
grants from Sanofi Pharma Inc and has been a speaker for
Wyeth-Ayerst
Pharmaceuticals.
 |
Footnotes
|
|---|
Reprint requests to Stuart J. Connolly, MD, Hamilton Health
Sciences Corporation, Hamilton General Site, 237 Barton St E,
Hamilton, ON L8L 2X2, Canada.
 |
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