(Circulation. 1995;92:3264-3272.)
© 1995 American Heart Association, Inc.
Articles |
Dose-Ranging Study of Intravenous Amiodarone in Patients With Life-Threatening Ventricular Tachyarrhythmias
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
Correspondence to Melvin Scheinman, MD, MU East Tower, 4th Floor South, Box 1354, University of California, San Francisco, CA 94143-1354.
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Abstract |
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Background Oral amiodarone effectively suppresses ventricular arrhythmias; however, full activity may take days or weeks. In patients with frequent, life-threatening ventricular arrhythmias, this delay is not acceptable. Thus, in these patients, the speed and dosing accuracy of an intravenous formulation would be beneficial. The goal of this study was to demonstrate the efficacy of intravenous amiodarone in patients with refractory, recurrent hemodynamically destabilizing ventricular tachycardia or ventricular fibrillation by determining a dose response among three regimens.
Methods and Results A total of 342 patients were enrolled at 46 medical centers in the United States. Patients received one of three randomized, double-blind dose regimens delivering 125, 500, or 1000 mg during the first 24 hours. Supplemental infusions (150 mg) of intravenous amiodarone could be given to treat breakthrough ventricular arrhythmias. The key efficacy end points were the arrhythmia event rate, time to first arrhythmic event, and number of supplemental infusions administered. The event rate decreased with increasing doses: median values were 0.07, 0.04, and 0.02 events per hour for the 125-, 500-, and 1000-mg dose groups, respectively, representing a significant decrease from baseline event rates (P=.043), and approached significance in the overall test for trend (P=.067). There was a significant dose-related increase in the time to first event (trend test P=.025) and a significant dose-related decrease in the number of supplemental boluses per hour (trend test P=.043). Hypotension was the most common (26%) treatment-emergent adverse event during intravenous amiodarone therapy; there was no dose-response relationship. Seventy-eight percent of the patients survived to at least 48 hours.
Conclusions Intravenous amiodarone is effective for the treatment of recurrent, life-threatening ventricular tachyarrhythmias.
Key Words: amiodarone • fibrillation • tachycardia
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Oral amiodarone is approved in the United States for the treatment of ventricular tachycardia (VT) and ventricular fibrillation (VF) that is resistant to other therapy. Although oral amiodarone is effective in controlling ventricular tachyarrhythmias, expression of full antiarrhythmic activity may take days or weeks.1 2 3 This delay in achieving maximal efficacy is not practical in patients with very frequent, rapid VT or VF. In addition, many acutely ill patients may be unable to take oral medication. To address these situations, the present study was designed to evaluate the efficacy and safety of the intravenous (IV) formulation of amiodarone (Cordarone Intravenous, Wyeth-Ayerst Laboratories) for patients with hemodynamically destabilizing VT or VF.
Results from uncontrolled studies suggested that IV amiodarone was highly effective in suppressing ventricular tachyarrhythmias with rapid onset of action4 5 6 7 8 9 ; however, there are no controlled clinical trials with the IV formulation. Therefore, a series of controlled, multicenter trials was developed to evaluate the efficacy and safety of IV amiodarone. The objective of this study was to demonstrate a dose-response relationship among three dosage regimens of IV amiodarone in the treatment of patients with hemodynamically destabilizing VT or VF refractory to conventional antiarrhythmic therapy.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Protocol
Patients were eligible for the study if they had incessant (recurrent, despite attempted cardioversion), hemodynamically destabilizing VT or at least two episodes of hemodynamically destabilizing VT or VF within the 24 hours before enrollment. Hemodynamically destabilizing was defined as a fall in systolic blood pressure to <80 mm Hg and/or clinical signs and symptoms of shock requiring immediate nonpharmacological intervention. They were also required to be refractory to or intolerant of standard doses of lidocaine, procainamide, and bretylium within the 72 hours before enrollment. Patients refractory to clinically adequate doses of mexiletine or tocainide in the 72 hours before enrollment did not require a lidocaine challenge.
Patients were excluded from the study if
they had drug- and/or
electrolyte-induced arrhythmias. Additional exclusions
included acute pulmonary edema, cardiogenic shock not related
to the ventricular arrhythmia, systolic
blood pressure <90 mm Hg during sinus rhythm, treatment with
amiodarone within 6 months of entry into the study, or a QT
interval 
0.55 second. Patients with symptomatic
bradycardia (heart rate <50 beats per minute) or
atrioventricular block (second degree or higher) were
also excluded unless a functioning pacemaker was in place.
Institutional review board approval was obtained. When possible, written informed consent was obtained from either the patients or their immediate families before enrollment in the study; otherwise, emergency exception from informed consent was obtained. The study was blinded to all study participants except a designated third party who did not participate in the evaluation or care of the patient and did not have any contact with the case report forms. The unblinded third party in most cases was a pharmacy representative who prepared the study drug according to a randomized schedule used to assign patients to their proper treatment group.
Patients received IV
amiodarone during the 48-hour study period
according to one of three dosage regimens as outlined in Table
1
. After the initial rapid infusion, open-label
supplemental infusions of IV amiodarone (150 mg over 10
minutes) could be administered to treat episodes of breakthrough
hemodynamically destabilizing VT or VF; this allowance
was made to prevent patients from being withdrawn from the study
prematurely. If the hemodynamically destabilizing VT or
VF events persisted despite these supplemental doses, the investigators
could terminate the double-blind phase of the study. Additionally,
blinded therapy could be slowed or stopped temporarily if severe
hypotension, congestive heart failure, or other severe adverse study
events occurred. If blinded therapy was discontinued because of either
refractory arrhythmias or adverse events, patients could be
treated with open-label IV amiodarone therapy and/or other
therapy of the investigator's choice.
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All medications being administered for the treatment of ventricular arrhythmias were required to be discontinued before the start of double-blind IV amiodarone treatment. Other necessary therapies, such as ß-adrenergic antagonists, calcium channel blocking agents, IV inotropic medications, and digoxin, could be continued as long as they were not being used to treat ventricular arrhythmias. No other investigational drugs or devices were permitted during IV amiodarone therapy. Temporary ventricular antitachycardia pacing was allowed.
A medical history was obtained during the baseline evaluation. Patients underwent a complete physical examination, a 12-lead ECG recording, vital signs measurement, a complete laboratory evaluation, and a left ventricular ejection fraction evaluation (if feasible). The laboratory evaluation included routine hematology, electrolytes, blood chemistry, hepatic and renal profiles, thyroid function tests, and urinalysis. Serial blood samples were obtained during the 48-hour observation period for determination of serum amiodarone and desethylamiodarone levels.
All patients were monitored in an intensive care unit, and a 48-hour ECG was recorded. Arrhythmia event recurrence was defined as an occurrence of hemodynamically destabilizing VT or VF. Because of the inherent difficulty of identifying proarrhythmia in this patient population, proarrhythmia was prospectively defined as torsade de pointes or new-onset VF. One month after discontinuation of IV amiodarone therapy, patients underwent a follow-up examination including a complete physical examination, laboratory evaluation, serum drug level determination, and 12-lead ECG recording.
Efficacy Assessments
The primary efficacy end point was the
VT/VF event rate. This
was defined as the number of hemodynamically
destabilizing VT or VF events per hour during the double-blind
observation period. The event rate was to provide a quantitative
measure of the effectiveness of amiodarone over time. However,
the provision in the protocol permitting the administration of
supplemental infusions for breakthrough hemodynamically
destabilizing VT or VF episodes made event rate analysis less
accurate, since it served to narrow the separation between assigned
dose regimens. For example, although the planned ratio between the
highest and lowest doses of amiodarone was 8:1, the actual
ratio was reduced to only 2.6:1.
A second efficacy end point used was the time to the first hemodynamically destabilizing VT or VF event. This end point was thought to be the clearest way to characterize the effects of the various doses of IV amiodarone on ventricular arrhythmias. In contrast to the event rate, time to first event was unaffected by the addition of supplemental infusions because supplemental infusions were administered only after a hemodynamically destabilizing VT or VF event occurred. The 48-hour intent-to-treat group was used for the time to first event analysis to ensure that the analysis included patients who had their first hemodynamically destabilizing VT or VF event soon after double-blind therapy was discontinued. These patients would be censored in the double-blind analysis but not in the 48-hour analysis.
Another end point, time to failure, was defined as the time to first hemodynamically destabilizing VT or VF event, death, or withdrawal from therapy because of adverse effects, whichever occurred first. This worst-case analysis expanded the time to first event analysis by counting deaths and withdrawals from therapy as drug-related events. This analysis was done to determine whether deaths and withdrawals affected the time to first event data.
Additional secondary efficacy end points, including the number of supplemental infusions required for each group, the proportion of patients requiring supplemental infusions, and 48-hour and 30-day survival, were also analyzed.
Statistical Methods
Two intent-to-treat patient populations
were defined for
analysis. The first was the double-blind population, which
included all patients for the extent of time they received
double-blind therapy. The second, the 48-hour population, included
all patients for the full 48-hour observation period regardless of the
therapy being administered.
Nonparametric statistical methods were used to analyze both the efficacy and survival data. Initially, an overall trend test was performed on each parameter to determine whether there was a dose-response relationship. The overall trend test was followed by paired comparisons when statistical significance (P<.048) or strong statistical tendencies (P<.100) existed. All probability values reported are two-sided.
The event rates and supplemental infusions were analyzed by the generalized Cochran-Mantel-Haenszel procedure, assigning rank scores to both the treatment groups and response parameters.
Two statistical approaches were used for the analyses of time to first event, time to failure, and survival. The first method was a test of the homogeneity of the survival curves among the dose groups (ie, differences among dose groups), unadjusted for any prognostic variables. The second method was a trend test of the association between survival time and dose groups (ie, a log-rank test), adjusted for whether cardiopulmonary resuscitation was being used at study entry. This second test was the primary survival analysis specified in the protocol.
Hourly summaries of the product-limit (Kaplan-Meier) estimates were used to graphically represent the time to first event data. In graphs depicting product-limit estimates, the time (t) after the dose is plotted on the x axis, and the cumulative percentage of patients who remained event-free as of time t is plotted on the y axis. The log-rank test and product-limit survival estimates take into account patients who were withdrawn before hour 48 or who completed 48 hours without an event (ie, censored data).
The key end points were also analyzed for the influence of prognostic variables, including arrhythmia type, age, left ventricular ejection fraction, and serum creatinine levels. None of these variables affected the results of the analyses.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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A total of 342 patients were enrolled in the study between February 19, 1990, and September 14, 1991. There were no significant differences in baseline demographics (Table 2
) among the
three treatment groups, including age, sex, presence of
coronary artery disease, acute myocardial infarction, incidence
of VT versus VF, or ejection fraction. In addition, the median time
intervals between the last episode of qualifying VT/VF and the onset of
amiodarone therapy were comparable among the dose groups. The
number of patients randomized to each group and the numbers completing
each phase of the study are given in Table 3. The most
common reasons for patient dropouts were arrhythmia
recurrence and/or death.
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VT/VF Event Rate
As specified by the protocol, arrhythmias
occurring after
the initial infusion (minute 10 to hour 48) were analyzed in
patients receiving double-blind study drug at the time of the event
(double-blind analysis). The median (rather than the mean)
event rates were used for data analysis because the means were
skewed by the effects of outliers.
The median event rates were 1.68,
0.96, and 0.48 events per 24 hours
for the 125-, 500-, and 1000-mg dose groups, respectively (Fig
1). This trend approached statistical significance
(P=.067). With adjustment for the baseline event frequency
(Fig 2) by comparison of the median number of events
during the 24-hour period before initiation of therapy with the first
24 hours on therapy, there was an 88% reduction from baseline for the
1000-mg dose group compared with a 44% decrease from baseline for the
125-mg dose group (P=.043).
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Time to First VT/VF Event
There was a statistically
significant dose-related increase
(P=.025) in the time to first event (Fig 3).
There was a significant difference between the 125- and 1000-mg dose
groups (P<.030) but not between the 125- and 500-mg
(P=.100) or 500- and 1000-mg dose groups
(P=.500). The results of the time to failure
analysis (Fig 4) were almost identical to those
of the time to first event analysis (trend test
P=.031).
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Termination of Incessant VT
Although this study was not
designed to assess arrhythmia
termination, evaluation of the subset of patients entering the study in
incessant VT may provide a partial indicator of the capability of
amiodarone to terminate arrhythmias. Because of the
small number of patients enrolled with incessant VT, there was
insufficient power to detect statistically significant differences
among treatment groups; a log-rank test revealed an overall
among-group value of P=.26. However, numerical
differences among groups were seen in the median time to termination of
incessant VT as follows: low dose, 0.94 hours (n=8); moderate dose,
1.92 hours (n=14); and high dose, 0.85 hours (n=15). When data
from
this clinical trial and the bretylium comparison trial reported in this
issue of Circulation (Kowey et al) were combined, the median
time to termination of incessant VT for the low-dose group was 3.11
hours (n=21), and the median for the high-dose group was 1.42 hours
(n=27) (P=.15).
Supplemental Infusion Analyses
The total number of amiodarone
supplemental doses
administered during the 48-hour study period was counted. Since this
was a double-blind study, investigators did not know the dose group
to which patients were assigned. The mean number of supplemental
infusions used decreased significantly with increasing blinded
amiodarone dose (125-mg dose group, 2.44±3.1; 500-mg dose
group, 2.49±4.0; and 1000-mg dose group, 1.75±2.6;
P=.038). Patients in the 1000-mg dose group received
significantly fewer supplemental infusions than patients in the 125-mg
dose group (P=.032). Finally, the proportion of patients in
each dose group requiring supplemental infusions was analyzed
(Table 4). There was a significant inverse
dose-response relationship because more patients in the 125-mg dose
group required supplemental infusions to control breakthrough
hemodynamically destabilizing VT or VF events than
patients in either the 500- or 1000-mg dose groups (P=.036).
This suggests that the 125-mg dose was less effective than the higher
doses in controlling hemodynamically destabilizing VT
or VF events.
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Amiodarone Concentrations
Serum amiodarone levels were
measured at the end of the
48-hour double-blind period. The median amiodarone levels were
much higher in the 1000-mg dose group (1.17 mg/L) than in the 125-mg
dose group (0.31 mg/L). In each group, patients who were therapy
failures tended to have higher amiodarone concentrations. This
was not unexpected, because those patients who continued to have
breakthrough hemodynamically destabilizing VT or VF
received additional supplemental infusions of study drug.
Adverse Effects
The incidence of the most common treatment
emergent adverse events
is summarized in Table 5. The most common nonarrhythmic
complication was hypotension, which occurred in 26% of the patients.
There was no significant difference in the incidence of hypotension
among the three dose groups. Similarly, there was no significant
difference among dose groups in the incidence of bradycardia, asystole,
or electromechanical dissociation. There were no significant changes in
the PR, QRS, or QT intervals during double-blind IV
amiodarone therapy. We found a trend toward increased QT
intervals with increased dose, but this was not statistically
significant. Increases in the QTc interval of 15%, 20%,
and 25% occurred in 62 (18%), 38 (11%), and 24 (7%) of patients,
respectively. There was no dose-response relationship in the
increase of the QTc interval among the groups.
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Proarrhythmia was infrequent in this trial. Only three reports were received; all were torsades de pointes. These were reported for 1 patient in the 1000-mg dose group (QTc=0.42 ms) and in 2 patients in the 500-mg dose group (QTc=0.58 and 0.50 ms, respectively).
The most frequent noncardiovascular adverse
events
were abnormal liver function tests, fever, and nausea, as shown in
Table 5
. The typical adverse events common to chronic oral
amiodarone therapy, such as pulmonary toxicity, thyroid
dysfunction, central nervous system problems, or skin discoloration,
were not observed in this trial. This may be due in part to the
relatively short observation period (30 days) as well as the short IV
dose administration period. Some hepatic toxicity was seen
(<5%). However, there were no dose-proportional increases in
alanine aminotransferase, 
-glutamyl transferase, or bilirubin
(which are more specific measures of hepatic dysfunction). Most
reported pulmonary effects were nonspecific, such as rales,
wheezes, pulmonary congestion or edema, pleural effusion, or
pneumonia. Adult respiratory distress syndrome was seen in 2% of the
patients. Overall, IV amiodarone was well tolerated by these
critically ill patients; dropouts due to adverse effects occurred in
fewer than 5% of patients. Most adverse events were successfully
managed by either reduction of the infusion rate or discontination of
therapy.
Survival
Kaplan-Meier estimates of survival time are plotted
in Fig 5. There were no significant dose-related trends in
mortality for the 48-hour period. Approximately 80% of patients
survived the 48-hour study period. The causes of death during the
48-hour observation period are listed in Table 6. The
most common causes of death during the entire 30-day follow-up
period were similar to those seen during the first 48 hours: refractory
ventricular arrhythmias, cardiogenic shock, and
asystole, with 
60% of patients surviving to the 30-day
follow-up visit.
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Discussion |
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There is a large body of published data that reflect global experience and describe the efficacy of IV amiodarone in populations comparable to that in this study. These reports indicate that IV amiodarone is effective in controlling refractory life-threatening VT/VF.5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 These studies evaluated the effects of IV amiodarone in patients with VT or VF that was refractory to standard therapy. Results were reported for 355 patients. All studies followed a similar dosage regimen: Initial rapid infusions of 5.0 to 7.5 mg/kg over 15 to 30 minutes were followed by sustaining infusions of 0.9 to 2.0 g/24 h. Most investigators used doses of
1
g/24 h for the sustaining infusion. Infusions were continued for 72
hours in most trials; some continued longer if patients were unable to
take oral medication. The acute response rate, representing
eradication of the ventricular arrhythmias during
the first 24 to 72 hours of infusion, ranged from 50% to 100%, with a
mean of 71%. The reasons for this wide range in response are not
entirely clear but probably relate to variations in dosage regimens,
clinical setting, concomitant medications, timing and criteria for
efficacy, and small or heterogeneous patient
populations. Our study is one in a series of randomized, double-blind, dose-ranging studies designed to assess the efficacy and safety of IV amiodarone. Since placebo control subjects were not feasible, efficacy was to be established by demonstrating a dose-response relationship for arrhythmia control.
Analysis of the primary efficacy end point, the overall VT/VF event rate, was confounded by the use of supplemental infusions of amiodarone to treat breakthrough VT episodes. Although the planned dose ratio between the high- and low-dose groups was 8:1, due to the use of supplemental infusions, the actual dose ratio was reduced to only 2.6:1. This reduced the power to detect differences among dose groups. Even so, a positive dose-related trend still was seen in the event rate (P=.067). Adjusting for arrhythmia frequency during the 24-hour baseline resulted in a significant dose-response relation among dose groups (P=.043).
The time to first event analysis was not confounded by supplemental drug administration. The trend analysis demonstrated a significant dose-related increase (P=.025) in time to arrhythmia recurrence. This was mainly due to differences between the 1000- and 125-mg dose groups, while patients in the 1000- and 500-mg dose groups tended to respond similarly. One possible flaw in the analysis of time to first event was that a patient who died or dropped out before having a hemodynamically destabilizing VT or VF event would be censored. Therefore, a modified parameter, time to failure, was also analyzed. In this analysis, patients who died or dropped out were considered to have had their first event at that time. As with time to first event, the time to failure increased significantly (P=.031) with increasing doses. This confirms that the time to first event data were not affected by omission of deaths or dropouts before the first recurrence of a hemodynamically destabilizing VT or VF event.
The product-limit (Kaplan-Meier) plots of the time to first
event data for the 125- and 1000-mg dose groups (Fig 2)
separated early
and continued to diverge throughout the first 27 hours. From hours 27
to 48, there was a consistent 14% to 16% separation between
the 125- and 1000-mg dose groups. These findings suggest that the drug
exerted a beneficial effect throughout the study.
If a dose-response relationship existed, the number of supplemental infusions required to achieve arrhythmia control should have been greater for patients in the 125-mg dose group than for those in the 500- and 1000-mg dose groups. In fact, there was a significant decrease in the total number of supplemental infusions as well as the number of supplemental infusions per hour for those receiving higher doses (P=.038). These differences were due largely to the differences between the 1000- and 125-mg dose groups.
Clinical Benefit
The patients studied in this trial are
representative of some of the most difficult cases
treated in cardiac care units. This was an elderly population (27% of
patients >70 years old; mean, 63 years) with severe cardiac disease
(mean ejection fraction, 31%). Eighty percent of the patients had at
least one prior myocardial infarction, and 13% had an acute infarction
at study entry. All patients were refractory to conventional
antiarrhythmic therapy, including lidocaine, procainamide, and
bretylium. All patients had at least two episodes of
destabilizing arrhythmia within the prior 24 hours (mean, 5.37
episodes). Thirty percent of the patients were in incessant VT at the
start of blinded therapy, and 10% were actively receiving
cardiopulmonary resuscitation. In this setting, clinical
benefit is measured in minutes and hours of arrhythmia
suppression. Stabilization of rhythm affords time both for natural
healing and, when appropriate, for other interventions such as surgery
or devices to be used.
The clinical goal of IV amiodarone therapy, as
with any
antiarrhythmic therapy, is to terminate arrhythmias and to
prevent further recurrences of the arrhythmia. If
arrhythmia recurrences cannot be eliminated, then the
objective is to delay the onset of recurrent VT or VF events and to
minimize the frequency of the recurrences. It should be noted
that this study was not designed or powered to evaluate termination of
ongoing arrhythmias but rather to evaluate the
recurrence rate and the time to recurrence of
arrhythmias. After 48 hours, 26% of the patients in the
1000-mg dose group remained arrhythmia free, compared with 16%
of patients in the 125-mg dose group—a 63% decrease between the
1000- and the 125-mg doses. In patients who did have recurrence
of arrhythmia, the median time to recurrence in the
1000- and 500-mg dose groups was increased by 40% and 67%,
respectively, compared with patients in the 125-mg dose group. This
increase represented an 4- to 6.5-hour delay in the
period without an episode of life-threatening
ventricular arrhythmia. Additionally, the rate of
recurrence of patients in the 1000-mg dose group (median, 0.48
events per day) was less than one third that of the 125-mg dose group
(median, 1.68 events per day) and represented an 88%
reduction in hemodynamically destabilizing VT or VF
event frequency from baseline versus a 44% reduction from baseline for
the 125-mg group.
The faster onset of action for the IV formulation compared with the oral formulation may be a result of faster delivery, increased blood levels, and increased bioavailability, resulting in the exposure of cardiac tissues to higher amiodarone concentrations. It has been hypothesized that tissue saturation is necessary for full expression of antiarrhythmic activity. The high blood levels of amiodarone attained during IV administration may permit sufficient amounts of the drug to penetrate tissues and cause an antiarrhythmic effect. Therefore, although oral amiodarone must be given in high doses for days or weeks to adequately accumulate in peripheral compartments, the rapid onset of action of IV amiodarone may permit immediately effective treatment of patients with life-threatening ventricular arrhythmias. The mechanism of action of IV amiodarone appears to differ from that of chronic oral therapy. The available data suggest that acute IV amiodarone does not prolong the action potential duration or exert use-dependent sodium channel blockade. IV amiodarone does, however, block calcium current and has potent antisympathetic activity.
Adverse Effects
The overall safety data are similar to those
reported in
uncontrolled trials of IV
amiodarone.6 7 8 19 23 24 25
Hypotension was common (26%) and usually occurred early in the study
during the highest rate of drug delivery. There was no significant
dose-related increase in hypotension during this study. In many
patients, hypotension resolved with continued dose administration
either with or without a dose adjustment. Hypotension may have been
due, in part, to polysorbate 80, an excipient with vasodilator
properties. As with hypotension, there was no dose-related increase
in bradycardia.
Three cases of proarrhythmia were reported; all were considered by the investigator to be torsades de pointes. Unfortunately, rhythm strips were not available for independent review, since all of the events occurred during the open-label period after removal of the 48-hour double-blind Holter monitors. The protocol, however, prospectively defined torsade de pointes as polymorphic VT with a QTc interval >0.44 second. Two of the patients had electrolyte abnormalities with low K+ and Mg2+ levels; one of these patients also had a prior history of torsade de pointes, and the other had an acute MI complicated by multiple organ failure at the time of the event. The third patient had received three boluses (150 mg) of amiodarone within 30 minutes and was also receiving concomitant lidocaine at 2 mg/min to treat recurrent VT. In all three cases, the investigators spontaneously reported concurrent conditions that were considered potentially arrhythmogenic. Hence, the relationship of IV amiodarone to these potentially serious arrhythmias is unclear.
Elevated liver enzymes have been reported in patients treated with oral and IV amiodarone. In the current trial, 51% of patients had at least one hepatic abnormality in aspartate aminotransferase and lactate dehydrogenase at baseline. Patients with preexisting elevated liver abnormalities did not have a greater incidence of on-therapy abnormalities in aminotransferases, and many individuals with abnormal baseline values actually had improvement during amiodarone treatment. Furthermore, no cases of frank hepatitis were reported as study events, and no deaths were attributed solely to hepatic injury in this study. In the literature, however, two cases of fatal hepatic necrosis after IV amiodarone treatment have been reported.30 Both patients received a loading dose of 1500 mg over 6 hours, which was a much faster rate than those used in this trial.
Pulmonary fibrosis seen with chronic oral amiodarone treatment was not reported during IV amiodarone treatment. It was not possible to determine whether the adult respiratory distress syndrome seen in some patients was drug related or a consequence of heart failure, shock, sepsis, or other underlying disorder.
Limitations of the Study
The ideal scientific studies would
have included a placebo group
to serve as the control for efficacy assessment. However, since
life-threatening hemodynamically destabilizing VT
or VF requires immediate treatment, the use of placebo in these gravely
ill patients was deemed unethical by the investigators. In the absence
of a placebo control group, a dose-comparison study design was used
to demonstrate efficacy.
Because the protocols prohibited the use of concomitant antiarrhythmic medications for the treatment of the hemodynamically destabilizing VT or VF and because some patients were to be randomized to a potentially subtherapeutic dose regimen, supplemental 150-mg infusions of IV amiodarone were permitted for the control of recurrent ventricular tachyarrhythmias. This was allowed so that investigators would not prematurely terminate patients from double-blind therapy. However, the administration of additional study drug created the potential for the separation among dose groups to become obscured, thus confounding interpretation of event rate dose-response relationships. In addition to the supplemental infusions, 72% of the patients were switched from double-blind to open-label IV amiodarone during the 48-hour observation period, which also affected subsequent event rate analyses.
Summary
We established the presence of a beneficial
dose-response
relationship using IV amiodarone for patients with
life-threatening cardiac arrhythmias. Patients treated with
500- to 1000-mg/d doses of IV amiodarone showed significantly
lower event rates and longer times to arrhythmia
recurrence than patients in the 125-mg/d dose group. In
addition, there was less need for supplemental infusions compared with
the 125-mg dose group. Adverse effects observed were predominantly
cardiovascular events, mainly extensions of the
pharmacological action of amiodarone, and were not dose
related. These events were usually well tolerated and easily
controlled. In these patients with severe underlying cardiac disease,
withdrawals from the study due to adverse drug effects were rare
(5%). These data suggest that IV amiodarone at an initial dose
of 1000 mg in the first 24 hours of therapy is a safe and effective
treatment for VF and hemodynamically destabilizing
VT.
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Acknowledgments |
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This study was supported, in part, by a grant from Wyeth-Ayerst Research.
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Footnotes |
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1 See the appendix for the complete list of the investigators and their centers.
Dr Scheinman was an investigator for three amiodarone protocols funded by Wyeth-Ayerst Research. The grant to his institution did not provide salary support.
List of Principal Investigators and Addresses (in Alphabetical
Order)
Elliot Antman, MD, Brigham and Women's Hospital, 75
Francis St,
Boston, MA 02115.
Karen Beckman, MD, VAMC, 921 NE 13th St, Oklahoma City, OK 73104.
William Brodine, MD, Research Medical Bldg, Tower T509, 6420 Prospect, Kansas City, MO 64132.
David S. Cannom, MD, Good Samaritan Medical Center, Los Angeles, CA 90016.
Don Chilson, MD, Inland Cardiology Associates, W 122 7th Ave, Suite 450, Spokane, WA 99204.
Barry Crevey, MD, Methodist Hospital of Indiana, 1701 N Senate, Indianapolis, IN 46202.
Karl Crossen, MD, Jewish Hospital, 216 S Kingshighway, St Louis, MO 63110.
Kevin Ferrick, MD, Montefiore Hospital, 111 E 210th St, Bronx, NY 10467.
Ted Friehling, MD, 3020 Hamaker Ct, Suite 300, Fairfax, VA 22031.
Frank Gold, MD, Proctor Hospital, Peoria, IL 61614.
J. Anthony Gomes, MD, The Mount Sinai Medical Center, New York, NY 10029.
Mitchell Greenspan, MD, Life Mark Medical Center, 3 Life Mark Dr, Sellersville, PA 18960.
Lawrence Griffith, MD, The Johns Hopkins Hospital, Baltimore, MD 21205.
Arthur Hagan, MD, Tulsa Heart Center, 1435 S Utica, Tulsa, OK 74104.
Leonard Horowitz, MD, Presbyterian Medical Center, Philadelphia, PA 19104.
Dean Kereiakes, MD, The Christ Hospital, Cardiovascular Research Center, 2123 Auburn Ave, Suite 139, Cincinnati, OH 45219.
Nicholas Kerin, MD, Sinai Hospital of Detroit, 6767 W Outer Dr, Detroit, MI 48235.
Harry Kopelman, MD, Atlanta Cardiology Group, 5665 Peachtree-Dunwoody Rd, Atlanta, GA 30342.
Peter Kowey, MD, Cardiology Foundation of Lankenau, Lankenau Medical Office Bldg East, 100 Lancaster Ave West of City Line, Wynnewood, PA 19096-3425.
Michael E. Lehmann, MD, Haraper Hospital, 14800 W McNichols, Detroit, MI 48235.
Joseph Levine, MD, St Francis Hospital, 100 Fort Washington Blvd, Roslyn, NY 11576.
Bruce Lindsay, MD, Barnes Hospital, Cardiology Division, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110.
Ali Massumi, MD, St Lukes Episcopal Hospital, 6720 Bertner St (MS1-191), Houston, TX 77030.
Syed Mohiuddin, MD, Room 3519 Cardiac Research, Creighton Cardiac Center, 3006 Webster St, Omaha, NE 68131.
Joel Morganroth, MD, Graduate Hospital, Philadelphia, PA 19146.
Nelson Mostow, MD, MetroHealth Medical Center, Cleveland, OH 44109.
Gerald Naccarelli, MD, University of Texas Medical School, Houston, TX 77225.
David Navratil, MD, Wilford Hall, USAF Medical Center, Lackland AFB, San Antonio, TX 78236.
Antonio Pacifico, MD, 6560 Fannin, Suite 620, Houston, TX 77030.
Edward V. Platia, MD, Washington Hospital Center, Department of Cardiology 291, 110 Irving St NW, Washington, DC 20010.
Scott Pollak, MD, Central Florida Cardiology, 500 E Colonial Dr, Orlando, FL 32803.
Eric Prystowsky, MD, Northside Cardiology PC, St Vincent Professional Bldg, 8402 Harcourt Rd, Suite 230, Indianapolis, IN 46260.
Melvin Scheinman, MD, MU East Tower, 4th Floor South, Box 1354, University of California, San Francisco, CA 94143-1354.
Kerry Schwartz, MD, Florida Heart Group, 615 E Princeton St, Suite 300, Orlando, FL 32803.
Nicholas Stamato, MD, Wilson Memorial Regional Medical Center, 30 Harrison St, Johnson City, NY 13790.
Chris Stavens, MD, Cardiovascular Consultants of Louisville, 250 E Liberty St, Louisville, KY 40202.
Jonathan Steinberg, MD, St Lukes/Roosevelt Hospital Center, Division of Cardiology S&R 3, 114th St and Amsterdam Ave, New York, NY 10025.
Jesus Val Mejias, MD, Wichita Institute for Clinical Research, 551 N Hillside, Suite 410, Wichita, KS 67214.
P.J. Varghese, MD, The George Washington University Medical Center, 2150 Pennsylvania Ave NW, Washington, DC 20037.
David Wilber, MD, Loyola University Medical Center, Cardiology Division, 2160 S First Ave, Maywood, IL 60153.
John Windle, MD, University of Nebraska Medical Center, 600 S 42nd St, Omaha, NE 68198-2265.
Roger Winkle, MD, 770 Welch Rd, Suite 100, Palo Alto, CA 94304.
Alan Woelfel, MD, University of North Carolina, Chapel Hill, NC 27599.
Raymond Woosley, MD, PhD, Georgetown University, 403 E Medical Dental Bldg, 3900 Reservoir Rd, NW, Washington, DC 20007.
Received February 6, 1995; revision received June 15, 1995; accepted August 8, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
|---|
-
Podrid PH, Lown B. Amiodarone
therapy in symptomatic, sustained refractory atrial and
ventricular tachyarrhythmias.
Am Heart J. 1981;101:374-379. [Medline]
[Order article via Infotrieve]
-
Rakita L, Sobol SM. Amiodarone in the
treatment of refractory ventricular
arrhythmias. JAMA. 1983;250:1293-1295. [Abstract]
-
Rosenbaum MB, Chiale PA, Halpern MS, Nau GJ,
Przybylski J, Levi RJ, Lazzari JO, Elizari MV. Clinical efficacy
of amiodarone as an antiarrhythmic agent. Am J
Cardiol. 1976;38:934-944. [Medline]
[Order article via Infotrieve]
-
Chapman JR, Boyd MJ. Intravenous
amiodarone in ventricular fibrillation.
Br Med J. 1981;282:951-952.
-
Leak D. Intravenous
amiodarone in the treatment of refractory life-threatening
cardiac arrhythmias in the critically ill patient.
Am Heart J. 1986;111:456-462. [Medline]
[Order article via Infotrieve]
-
Helmy I, Herre JM, Gee G, Sharkey H, Malone P, Sauve
MJ, Griffin JC, Scheinman MM. Use of intravenous
amiodarone for emergency treatment of life-threatening
ventricular arrhythmias. J
Am Coll Cardiol. 1988;12:1015-1022. [Abstract]
-
Schmidt A, Konig W, Binner L, Mayer U, Stauch
M. Efficacy and safety of intravenous
amiodarone in acute refractory arrhythmias.
Clin Cardiol. 1988;11:481-485. [Medline]
[Order article via Infotrieve]
-
Klein RC, Machell C, Rushforth N, Standefur J.
Efficacy of intravenous amiodarone as
short-term treatment for refractory ventricular
tachycardia. Am Heart J. 1988;115:96-101. [Medline]
[Order article via Infotrieve]
-
Nalos PC, Ismail Y, Pappas JM, Nyitray W, DonMichael
TA. Intravenous amiodarone for
short-term treatment of ventricular
tachycardia or fibrillation. Am Heart J. 1991;122:1629-1632. [Medline]
[Order article via Infotrieve]
-
Somberg JC, Tepper D, Keefe DL. Incessant VT
treated with i.v. amiodarone: rapid onset of action with a long
half-life agent. J Clin Pharmacol. 1986;26:541-560. [Medline]
[Order article via Infotrieve]
-
Horowitz LN, Mattleman SJ, Spielman SR, Frye SJ,
Greenspan AM, Swanson BN, Vlasses PH, Rotmensch HH.
Intravenous amiodarone loading for
ventricular tachycardia.
Circulation. 1982;66(suppl II):II-222. Abstract.
-
Mostow ND, Rakita L, Vrobel TR, Noon D, Blumer
J. Amiodarone: intravenous loading for rapid
suppression of complex ventricular
arrhythmias. J Am Coll Cardiol. 1984;4:97-104. [Abstract]
-
Armstrong PW, Brien JF, Brennan FJ.
Intravenous amiodarone in malignant
ventricular arrhythmias.
Circulation. 1984;70(suppl II):II-438. Abstract.
-
Kerin NZ, Blevins RD, Frumin H, Faitel K, Rubenfire
M. Intravenous and oral loading versus oral loading
alone with amiodarone for chronic refractory
ventricular arrhythmias. Am J
Cardiol. 1985;55:89-91. [Medline]
[Order article via Infotrieve]
-
Kutalek SP, Horowitz LN, Spielman SR, Greenspan
AM. Emergent use of intravenous amiodarone
for refractory ventricular
tachyarrhythmia.
Circulation. 1985;72(suppl III):III-274. Abstract.
-
Estes NAM, Uricchio F, Cameron J. Combined
intravenous and oral amiodarone loading for
refractory ventricular tachycardia: acute
safety and efficacy. Clin Res. 1985;33:183A.
Abstract.
-
Hoogenhuyze D, Burg P, de Wilde A, Remme WJ, Krauss
XH. Acute effects of intravenous amiodarone
in patients with complex ventricular dysrhythmias.
Am J Cardiol. 1982;49:1001. Abstract.
-
Palakurthy PR, Weiss M, Leight L, Sohi G.
Intravenous amiodarone for patients with drug
refractory ventricular tachycardia and
fibrillation: long term outcome. Clin Res. 1986;34:334. Abstract.
-
Morady F, Scheinman MM, Shen E, Shapiro W, Sung RJ,
DiCarlo L. Intravenous amiodarone in the
acute treatment of recurrent symptomatic
ventricular tachycardia. Am J
Cardiol. 1983;51:156-162. [Medline]
[Order article via Infotrieve]
-
Alves LE, Rose EP, Cahill TB.
Intravenous amiodarone in the treatment of
refractory arrhythmias. Crit Care Med. 1985;13:750-758. [Medline]
[Order article via Infotrieve]
-
Drexler H, Meinertz T, Zeiher A, Kapser H, Just
H. Effectiveness of amiodarone i.v. in the acute therapy
of lidocaine: refractory ventricular
tachycardia. Intensivmedizin. 1986;23:179-182.
-
Marcus FI, Carlson KC. Safety and efficacy of
amiodarone in patients with acute myocardial infarction and
recurrent ventricular tachycardia.
Clin Res. 1983;31:13A. Abstract.
-
Mooss AN, Mohiuddin SM, Hee TT, Esterbrooks DJ,
Hilleman DE, Rovang KS, Sketch MH. Efficacy and tolerance of
high-dose intravenous amiodarone for recurrent,
refractory ventricular tachycardia.
Am J Cardiol. 1990;65:609-614. [Medline]
[Order article via Infotrieve]
-
Ochi RP, Goldenberg IF, Almquist A, Pritzker M,
Milstein S, Pedersen W, Gobel FL, Benditt DG.
Intravenous amiodarone for the rapid treatment of
life-threatening ventricular arrhythmias in
critically ill patients with coronary artery disease.
Am J Cardiol. 1989;64:599-603. [Medline]
[Order article via Infotrieve]
-
Schutzenberger W, Leisch F, Kerschner K, Harringer W,
Herbinger W. Clinical efficacy of intravenous
amiodarone in the short term treatment of recurrent sustained
ventricular tachycardia and
ventricular fibrillation. Br Heart J. 1989;62:367-371.
[Abstract/Free Full Text]
-
Saksena S, Rothbart ST, Shah Y, Capello G.
Clinical efficacy and electropharmacology of continuous
intravenous amiodarone infusion and chronic oral
amiodarone in refractory ventricular
tachycardia. Am J Cardiol. 1984;54:347-352. [Medline]
[Order article via Infotrieve]
-
Kentsch M, Berkel H, Bleifeld W.
Intravenous amiodarone application for refractory
ventricular fibrillation.
Intensivmedizin. 1988;25:70-74.
-
Wolfe CL, Nibley C, Bhandari A, Chatterjee K, Scheinman
M. Polymorphous ventricular
tachycardia associated with acute myocardial
infarction. Circulation. 1991;84:1543-1551.
[Abstract/Free Full Text]
-
Williams ML, Woelfel A, Cascio WE, Simpson RJ, Gettes
LS, Foster JR. Intravenous amiodarone during
prolonged resuscitation from cardiac arrest. Ann Intern
Med. 1989;110:839-842.
-
Kalantzis N, Gabriel P, Mouzas P, Tiniakos D, Tsigas G,
Tiniakos G. Acute amiodarone-induced
hepatitis. Hepatogastroenterology. 1991;38:71-74.[Medline]
[Order article via Infotrieve]
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