Dose-Ranging Study of Intravenous Amiodarone in Patients With Life-Threatening Ventricular Tachyarrhythmias
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.
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.
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.
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 β-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.
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.
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.
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.
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).
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).
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.
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.
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.
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, γ-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.
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.
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.
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.
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.
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.
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.
This study was supported, in part, by a grant from Wyeth-Ayerst Research.
↵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.
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
- Received February 6, 1995.
- Revision received June 15, 1995.
- Accepted August 8, 1995.
- Copyright © 1995 by American Heart Association
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