Randomized, Double-Blind Comparison of Intravenous Amiodarone and Bretylium in the Treatment of Patients With Recurrent, Hemodynamically Destabilizing Ventricular Tachycardia or Fibrillation
Background After several days of loading, oral amiodarone, a class III antiarrhythmic, is highly effective in controlling ventricular tachyarrhythmias; however, the delay in onset of activity is not acceptable in patients with immediately life-threatening arrhythmias. Therefore, an intravenous form of therapy is advantageous. This study was designed to compare the safety and efficacy of a high and a low dose of intravenous amiodarone with bretylium, the only approved class III antiarrhythmic agent.
Methods and Results A total of 302 patients with refractory, hemodynamically destabilizing ventricular tachycardia or ventricular fibrillation were enrolled in this double-blind trial at 82 medical centers in the United States. They were randomly assigned to therapy with intravenous bretylium (4.7 g) or intravenous amiodarone administered in a high dose (1.8 g) or a low dose (0.2 g). The primary analysis, arrhythmia event rate during the first 48 hours of therapy, showed comparable efficacy between the bretylium group and the high-dose (1000 mg/24 h) amiodarone group that was greater than that of the low-dose (125 mg/24 h) amiodarone group. Similar results were obtained in the secondary analyses of time to first event and the proportion of patients requiring supplemental infusions. Overall mortality in the 48-hour double-blind period was 13.6% and was not significantly different among the three treatment groups. Significantly more patients treated with bretylium had hypotension compared with the two amiodarone groups. More patients remained on the 1000-mg amiodarone regimen than on the other regimens.
Conclusions Bretylium and amiodarone appear to have comparable efficacies for the treatment of highly malignant ventricular arrhythmias. Bretylium use, however, may be limited by a high incidence of hypotension.
Amiodarone has become a common therapy for patients with a variety of cardiac arrhythmias.1 2 The oral formulation has been marketed in the United States since 1986 and is indicated for the treatment of recurrent ventricular fibrillation (VF) and hemodynamically destabilizing ventricular tachycardia (VT) when other antiarrhythmic drugs are ineffective or cannot be tolerated.3 4 5 Intravenous amiodarone has been available for clinical use internationally and as an investigational drug in the United States for several years.6 7 8 9 Reports of its efficacy in patients with incessant and/or refractory ventricular arrhythmias have been widely published, with efficacy rates ranging from 50% to 75% in most series.10 11 12 13 14 15 Although several clinical studies showed it to be effective, most of these were uncontrolled, unblinded, and nonrandomized.
The present study is the third in a series of multicenter controlled trials that represent the first attempts to investigate the safety and efficacy of intravenous amiodarone (Cordarone Intravenous, Wyeth-Ayerst Laboratories) in a scientifically valid format. Because the intended study population was so ill, we designed a study in which all patients would receive active therapy with the study drug or an approved comparator. The comparator bretylium is the only intravenous class III antiarrhythmic agent currently approved in the United States for the treatment of life-threatening VT/VF.16 17 18
The study was a randomized, double-blind, parallel, positive-controlled, multicenter, inpatient design. Eighty-two centers participated; each enrolled between 1 and 27 patients. Patients were eligible for inclusion if they had incessant (recurring immediately after termination) VT, VF, or at least 2 (mean, 4.93) episodes of hemodynamically destabilizing VT or VF in the 24 hours before enrollment. Hemodynamic instability was defined as a loss of consciousness or a systolic blood pressure of <80 mm Hg with signs or symptoms of shock. All patients were refractory to or intolerant of lidocaine and procainamide in the 72 hours before enrollment. Patients were excluded if there was any evidence that their arrhythmias were drug induced or were secondary to cardiogenic shock. Other exclusions included use of bretylium or any investigational drug within 5 half-lives of study entry, concomitant use of other antiarrhythmic drugs, hypotension despite inotropic support, severe conduction disease (in the absence of a temporary or permanent pacemaker), a prolonged QT interval (>0.50 second), and clinically significant renal or hepatic dysfunction. β-Adrenergic blocking agents, calcium channel blockers, and digoxin could be used if they were not being used as antiarrhythmic drugs.
Each patient was to be treated with double-blind study drug for 48 hours. After 48 hours, the investigators had the option of starting antiarrhythmic therapy of their choice, including open-label intravenous amiodarone. The recruitment target was 100 patients for each of the three treatment groups. The dosage schedule for each treatment group is shown in Table 1⇓. The investigators were permitted to titrate downward for severe adverse effects such as hypotension or conduction disturbance. They were encouraged to continue blinded therapy for at least 6 hours if possible and to complete the loading infusion before proceeding to the next phase of therapy. After completion of the initial rapid infusion, supplemental double-blind doses of study drug (either 150 mg of amiodarone or 100 mg of bretylium, administered over 10 minutes) were permitted for control of hemodynamically destabilizing ventricular arrhythmia during the 48-hour double-blind period. If the episodes were not controllable with supplemental infusions, double-blind therapy could be discontinued and the patients could receive open-label antiarrhythmic therapy, including intravenous amiodarone or bretylium at a dose determined by the investigator.
The study was blinded to all except a designated third party who did not participate in the evaluation or care of the patient and had no contact with the case report form at any time. This person, usually a pharmacy representative, was responsible for drug preparation according to a blinded patient randomization schedule that was used to assign patients to the proper group. The blind was to be broken only in an emergency situation that required knowledge of the drug and dose assignment.
Patients were enrolled in the study after giving informed consent by signing a form approved by the Research Institutional Review Board of the respective institution. If the patient was unable to give consent, the form was signed by a spouse or legal guardian or an emergency exemption from informed consent was used. In addition to routine laboratory tests, as soon as feasible, patients were to have a measurement of left ventricular function by radionuclide ventriculogram, cardiac catheterization, or echocardiogram. All patients had continuous ECG telemetry monitoring while on blinded study drug or open-label intravenous amiodarone therapy.
Efficacy was defined as the ability of the study drug to prevent recurrent ventricular arrhythmias as assessed by clinical evaluation. The primary end point was the event rate (events per unit time for the double-blind study period). Secondary analyses included time to first event, proportion of patients in each group free of arrhythmias at specified time points, and number of supplemental infusions administered during the double-blind period. Additional planned data analyses included a mortality and proarrhythmia assessment, subset analysis according to primary cardiac or arrhythmic diagnosis or amount of left ventricular dysfunction, adverse effects, and a correlation of efficacy with study drug levels.
The data were analyzed according to the intent-to-treat principle. Once a patient had received study drug for at least 10 minutes, either under double-blind conditions or as a supplemental infusion, his or her data were included in the intent-to-treat analysis, as specified in the protocol. Two main definitions of treatment period were used for the statistical analysis. The first, the double-blind analysis, considered all hemodynamically destabilizing VT or VF event data reported from the end of the initial infusion (10 minutes) to the end of double-blind drug administration (up to 48 hours). The second, the 48-hour analysis, included all hemodynamically destabilizing VT or VF event data reported from the end of the initial infusion (10 minutes) to the end of the 48-hour period or the end of a patient’s participation in the study, regardless of whether the patient was maintained on double-blind therapy.
The sample sizes were selected on the basis of an estimate that 75 of the 100 patients in each treatment group would complete the study and be evaluable. On the basis of VT/VF event data from earlier controlled studies, this sample size should have provided ≈85% power for detecting a twofold difference in event rates between two treatment groups (two-sided level of α=.05). The event rates and the number of supplemental infusions were analyzed by the generalized Cochran-Mantel-Haenszel procedure, assigning rank scores to the response parameters. The time to first VT/VF event data and mortality data were characterized by a life-table approach. The Kaplan-Meier method, which takes censoring into account, was used. Comparisons among groups were based on the log-rank test. The proportion of patients without VT/VF recurrence was analyzed by a χ2 test, supplemented by a Fisher’s exact test for pairwise comparisons. No interim analyses of the data were performed.
Three hundred two patients were enrolled between September 31, 1990, and September 7, 1992, and were included in the analysis. Demographic information and concomitant medications are summarized for each treatment group in Tables 2 and 3, respectively. The three groups were comparable with respect to each of the variables reported in these tables. In addition, the median time intervals between the last episode of qualifying VT/VF and the start of blinded therapy were comparable among groups. A small number of patients in each group continued antiarrhythmic therapy during the study.
For the primary specified end point, hemodynamically destabilizing VT/VF events per hour during the double-blind period, we analyzed the data using rank scores and summarized the data using medians. The median is a better way of summarizing these data than the mean because the former is less influenced by patients who might have had a very large or small number of events at any given time point. As shown in Table 4⇓, there were no statistically significant differences in the overall event rate among the treatment groups (P=.237). However, there were significant differences among the groups at the 6-hour time point (P=.049), and the differences approached significance at the 12-hour time point (P=.091). An analysis of event rates during the initial hours of drug administration indicated that >80% of all events occurred in the first 12 hours (Fig 1⇓). In addition, >50% of the bretylium-treated patients discontinued blinded therapy before hour 16 and crossed over to open-label amiodarone.
The results of the time to first hemodynamically destabilizing VT/VF event analysis are shown (Fig 2⇓) as the cumulative percentage of patients who remained event-free at a given time. Most of the events in the study occurred in the first 12 hours, and there was a higher event rate for patients treated with the 125-mg/24-h dose of amiodarone. When this analysis was carried out for the first 12 hours, the log-rank test approached statistical significance (Fig 3⇓). By hour 48, the differences among the three treatment groups were indistinguishable because more patients had received supplemental infusions of study drug or had discontinued double-blind treatment and crossed over to open-label amiodarone therapy. In fact, the protocol-specified high-to-low amiodarone dose ratio of 8:1 was compressed to a dose ratio of only 1.8:1.
Although this study was not designed to determine the effects of these agents on the termination of arrhythmia, the incessant-VT population provided an opportunity to examine these effects. In this study, incessant VT was defined as recurrent VT despite attempted cardioversion. Because of the small number of patients enrolled while having incessant VT (ie, incessant VT at the time of initiation of double-blind therapy), there was insufficient power to detect statistically significant differences among treatment groups. A log-rank test revealed an overall among-group value of P=.62. However, numerical differences among groups were seen in the median time from initiation of therapy to termination of incessant VT, as follows: bretylium, 6.98 hours (n=9); low-dose amiodarone, 4.58 hours (n=13); and high-dose amiodarone, 4.23 hours (n=12).
Table 5⇓ illustrates the number of supplemental infusions administered to each group. The table summarizes the results by treatment group, the number of supplemental infusions administered during the double-blind phase of the study, and the number of supplemental infusions per hour during the double-blind phase. The number of supplemental infusions per hour was calculated to correct for the unequal length of time patients in each dose group remained in the study. This analysis counted only the first supplemental infusion (within 30 minutes) for each hemodynamically destabilizing VT/VF event. The difference in total number of supplemental infusions administered during the double-blind phase was dominated by the difference between the bretylium group and the 125-mg/24-h amiodarone dose group (P<.001), with some additional contribution from the 1000- versus 125-mg/24-h amiodarone dose comparison (P<.05). This difference, however, is negated in the analysis of supplemental infusions per hour. The loss of significance in the corrected analysis reflects the fact that bretylium recipients had a higher rate of withdrawal from double-blind therapy than patients in the amiodarone groups. Thus, since the bretylium-treated patients were in double-blind therapy for a shorter time, they had less time in which to receive blinded supplemental infusions.
Mortality was assessed by survival analysis methodology. Kaplan-Meier estimates of survival from the beginning of the initial infusion to 48 hours are shown in Fig 4⇓. Survival was comparable for all three treatment groups; 86% of the patients survived to 48 hours.
Several clinical variables were specified in the protocol as having the potential to influence the results of the primary efficacy analysis. These variables included arrhythmia at presentation, age, left ventricular function, and serum creatinine. Analyses adjusting for the first three variables are shown in Table 6⇓; the results are similar to those of the overall analysis, and thus, there was no bias effect. Only six patients had serum creatinine levels >3 mg/dL, too few to permit adequate analysis.
Blood levels were measured at the conclusion of the double-blind period. There was fairly wide variability, although the median amiodarone and desethylamiodarone concentrations were much higher in the 1000-mg/24-h amiodarone dose group (1.041 and 0.111 mg/L) compared with the 125-mg/24-h dose group (0.112 and 0.037 mg/L). Bretylium levels also had a wide range, with a median of 2.42 mg/L. There appeared to be no correlation between serum amiodarone, desethylamiodarone, or bretylium levels and efficacy.
A total of 259 patients (86%) had at least one adverse event. One hundred eighty-five patients (61%) had study events that were judged by the investigator to be drug related. The double-blind period was analyzed specifically because most patients were in the study for only 48 hours, and that was the only period during which patients actually received their assigned medication. During the double-blind period, more patients (P=.010) in the bretylium dose group (58%) had drug-related adverse effects compared with the 125-mg/24-h dose group (38%) or the 1000-mg/24-h dose group (42%). Drug-related adverse effects for the three treatment groups during the double-blind period are shown in Table 7⇓. Individual adverse effects for which a significant among-group difference was seen included hypotension, congestive heart failure, and diarrhea; all were significantly more frequent in the bretylium-treated patients than in amiodarone-treated patients. Both amiodarone and its excipient polysorbate 80 have vasodilatory and negative inotropic effects; this combination may have contributed to the acute hemodynamic effects seen in amiodarone-treated patients in this study. Hypotension caused by polysorbate 80, however, is usually transient.
Proarrhythmia was designated by the investigator and, by protocol definition, represented cases of torsade de pointes or new-onset VF in patients whose only predrug arrhythmia had been VT. Four proarrhythmic events occurred in the double-blind period, four in the open-label period, and two after study drug administration was discontinued; all were evenly distributed among the three treatment groups.
A total of 97 patients (32%) died during the 30-day study (Fig 5⇓). Most of the deaths were of cardiovascular origin; the most frequent cause was refractory arrhythmias (n=24, 26%). The leading causes of death during the first 48 hours were equally distributed among the treatment groups. A total of 83 patients died after discontinuing double-blind therapy (34 bretylium patients, 25 high-dose amiodarone patients, and 24 low-dose amiodarone patients). Twenty-five patients died while receiving open-label amiodarone (13 bretylium patients, 7 high-dose amiodarone patients, and 5 low-dose amiodarone patients). We also counted the number of deaths that occurred after discontinuation of study drug, either blinded or open-label. Fifty-eight patients died while not receiving any drug, including 21 randomly assigned to the bretylium group and 20 and 17 randomly assigned to the 1000- and 125-mg amiodarone dose groups, respectively. These 58 patients included 25 patients who died after being assigned “do not resuscitate” status at the request of their families.
Fig 6⇓ shows the cumulative number of patients in each treatment group who remained on double-blind therapy at each hour. This took into account treatment failures or adverse effects that might have prompted drug discontinuation. Overall, more patients withdrew from bretylium therapy than from amiodarone therapy (P=.070), with more bretylium patients discontinuing double-blind therapy in each category (treatment failures: bretylium, 22%; high-dose amiodarone, 19%; and low-dose amiodarone, 24%; adverse effects: bretylium, 10%; high-dose amiodarone, 6%; and low-dose amiodarone, <1%). During the first 6 and 12 hours, there were a significantly greater number of discontinuations from the bretylium dose group for both treatment failures and lack of efficacy than from the amiodarone dose groups (P=.004 and P=.036, respectively). For the remainder of the double-blind period, the curves paralleled each other, because the numbers of events in all groups were greatly reduced during the final 36 hours of the study.
The treatment of patients with life-threatening ventricular arrhythmias remains one of the most difficult challenges of contemporary medicine.19 20 Particularly difficult are cases in which the arrhythmias recur frequently and cause hemodynamic instability. The mortality of such patients, despite aggressive therapy, has been reported to be >80% to 90% in small uncontrolled series.21 22 Parenteral drugs currently available to treat such patients either are ineffective or cause potentially serious adverse effects, such as hypotension, heart block, torsade de pointes, cardiac arrest, and asystole, that contribute to hemodynamic deterioration.
Intravenous amiodarone is the newest agent to be used in this clinical situation. To date, the results of clinical trials have been quite encouraging, with reported response rates of 50% to 75% with a reasonable side-effect profile.10 11 12 13 14 15 Most of the studies have been limited by the lack of a control group or randomization, or they used retrospective analyses. We believed that the target population was too sick to be enrolled in a placebo-controlled study, even though such a study would have been ideal to gain approval from regulatory agencies.
To demonstrate the efficacy of intravenous amiodarone, three multicenter trials enrolled ≈1000 patients with life-threatening VT/VF. The first trial was a dose-ranging study.23 The second study, reported in this issue of Circulation (Scheinman et al), was also a dose-ranging study in which a broader dose range was examined. These studies were based on the principle that responses to different doses provide evidence of clinical effect. The second dose-ranging study demonstrated a difference in efficacy and tolerance among the three doses used. The study reported here was the third in the series. Two doses of intravenous amiodarone were compared with an approved drug, bretylium, recognized to be effective in patients with highly malignant arrhythmia. The high and low doses of amiodarone used in the second dose-ranging study were compared with the dose of bretylium recommended in its package insert. The patient population was quite ill, and thus, provisions were made for patients to receive only active therapy. Supplemental doses of study drug were permitted for breakthrough arrhythmias. In addition, investigators were permitted to switch to open-label intravenous amiodarone if supplemental doses of blinded study drug were not effective.
The demographic and clinical characteristics of the study population were typical of those with highly malignant arrhythmias. Most patients were men who had severe coronary artery disease, prior infarction, and poor left ventricular function. In addition, there appeared to be no significant differences among the treatment groups in any clinical characteristic that might have biased the results. The study was conducted fairly; the blind was rarely broken, and there were few protocol violations.
The study results suggest that the 1000-mg/d amiodarone regimen is at least as effective as bretylium in preventing recurrences of highly malignant ventricular arrhythmia. Due to the high bretylium dropout rate during the first 16 hours of the study, direct comparisons between bretylium and amiodarone over the 48-hour study period may not be meaningful. However, during hours 0 to 6, when the largest number of patients were on blinded therapy, high-dose amiodarone was more effective than bretylium in preventing arrhythmia recurrence (P=.087). The VT/VF event rates in the 1000- and 125-mg amiodarone dose groups were nearly identical to those seen in the second dose-ranging study in the series, reported in this issue.
Analyses of the primary and secondary end points seem to support the overall conclusions as well, although in these analyses, there was less discrimination between 1000- and 125-mg/24-h doses of amiodarone. Some of the difficulty in establishing an effective dose range was because of the latitude given to the investigators to deliver supplemental infusions of study drug and/or to cross patients over to open-label intravenous amiodarone therapy when blinded study drug was felt to be ineffective; as a result, patients in the 125-mg dose group may have received therapeutic levels of amiodarone. Additionally, by hour 15 of the study, more than 50% of the patients randomly assigned to bretylium had crossed over to open-label amiodarone. For these reasons, the most appropriate analyses would seem to be time to first VT/VF event on study drug and the analysis of events in the early phases of drug administration, since these were the parameters least contaminated by extra doses and crossovers. Finally, use of supplemental infusions led to a decrease in the dose ratio between the amiodarone groups, resulting in a diminution of the magnitude of the power to detect differences in the efficacy end points. We would expect that the end points affected most would be arrhythmic deaths and overall mortality, and these differences were the most difficult to describe.
Adverse effects were seen more frequently in bretylium-treated patients than in amiodarone-treated patients. Noncardiac toxic side effects were rare. This is an important observation, given amiodarone’s reputation for organ toxicity when used long-term, orally, and in high doses.1 More patients who received bretylium had hypotension than those who received amiodarone; in more of those cases, the study drug was discontinued when measures to support blood pressure failed. This is a clinically significant finding, because most of these patients were hemodynamically destabilized either because of their underlying heart disease or their incessant arrhythmia before study drug was started. Bretylium has long been known to produce hypotension in this clinical situation.24 25 Although amiodarone is also a systemic vasodilator as well as a negative inotrope when administered intravenously,26 its hemodynamic effects in this study were significantly less severe than those seen with bretylium. High-grade atrioventricular block was not seen frequently in this study, although it has been reported elsewhere as a side effect of amiodarone.27 We observed a low incidence of proarrhythmia for both drugs, although definitions of proarrhythmia are less clear in a group of patients having recurrent, refractory arrhythmia before therapy; this issue has never really been evaluated in such an ill population.
Our study has important limitations that need to be emphasized. There was no placebo arm. We believed that it would be unethical to implement a placebo-controlled study in such a population. Thus, although hard end points such as 48-hour and 40-day mortality appear fairly low compared with the expected mortality in such a sick population, the lack of a placebo control group limits definitive conclusions in this regard. Only one dose of bretylium was used because of the relatively small number of patients that were recruitable. The bretylium dose used was that recommended in the package insert. We have not proved or attempted to prove that intravenous amiodarone is superior to a comparably dosed oral amiodarone regimen.28 29 30 In fact, it is possible that intravenous amiodarone will have a different electrophysiological effect than the oral formulation.31 However, the use of an intravenous form was necessary in a significant proportion of our patients who could not take oral medication. Finally, patients were recruited from a very large number of centers. There did not appear to be any gross bias by center, but the numbers from some centers were too small to perform statistical analysis.
In summary, we have shown that 1000 mg/d of intravenous amiodarone suppresses highly malignant ventricular arrhythmias in patients with severe underlying heart disease. Further, this dose of amiodarone is at least as effective as bretylium, an established agent, and is better tolerated hemodynamically. Amiodarone appears to be more effective than bretylium during the first 12 hours of therapy.
List of Principal Investigators and Addresses (in Alphabetical Order)
Jeffrey L. Anderson, MD, LDS Hospital, 8th Ave and C St, Salt Lake City, UT 84143.
James N. Black, MD, Austin Cardiology Consultants, PA, 711 W 38th St, Medical Science Center No. C-5, Austin, TX 78708.
Kathleen Blake, MD, New Mexico Heart Clinic, 1001 Coal SE, Albuquerque, NM 87106.
William Brodine, MD, Research Medical Bldg, Tower T509, 6420 Prospect, Kansas City, MO 64132.
Kevin Browne, Jr, MD, Lakeland Regional Medical Center, 1324 Lakeland Hills Blvd, Lakeland, FL 33805.
Sheldon Brownstein, MD, St Vincent Medical Center, 2409 Cherry St, Suite 304, Toledo, OH 43608.
Thomas Buckingham, MD, Rush Presbyterian, St Luke’s Medical Center, 1653 W Congress Pkwy, Chicago, IL 60612.
Don Chilson, MD, Inland Cardiology Associates, 122 W 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.
Thomas F. Deering, MD, Georgia Baptist Medical Center, 285 Blvd NE, Suite 435, Atlanta, GA 30312.
Lorenzo DiCarlo, MD, Cardiology Associates of Ann Arbor PC, Reichert Health Center No. 3003, 5333 McAuley, Ypsilanti, MI 48197.
Kenneth Ellenbogen, MD, Medical College of Virginia, McGuire VA Medical Center, PO Box 980053, Richmond, VA 23298.
Kevin Ferrick, MD, Montefiore Hospital, 111 E 210th St, Bronx, NY 10467.
Ted Friehling, MD, 3020 Hamaker Ct, Suite 300, Fairfax, VA 22031.
Lawrence German, MD, St Thomas Medical Plaza, 4230 Harding Rd, Suite 900, Nashville, TN 37205.
Irvin Goldenberg, MD, Minneapolis Heart Institute, 920 E 28th St, Suite 160, Minneapolis, MN 55407.
Carolyn Goren, MD, Consultative Cardiology, 601 W Spruce St, Suite J, Missoula, MT 59802.
Mitchell Greenspan, MD, Life Mark Medical Center, 3 Life Mark Dr, Sellersville, PA 18960.
Arthur Hagan, MD, Tulsa Heart Center, 1435 S Utica, Tulsa, OK 74104.
Walter Hepp, MD, Heart Center of Sarasota, 1540 S Tamiani Trail, Sarasota, FL 34239.
John M. Herre, MD, Sentara Norfolk General Hospital, 600 Greshan Dr, Norfolk, VA 23507.
James R. Higgins, MD, Cardiology of Tulsa, Inc, 6585 S Yale, Suite 800, Tulsa, OK 74136.
James R. Hopson, MD, University of Iowa, Hospitals and Clinics, Iowa City, IA 52242.
S.K. Stephen Huang, MD, University of Massachusetts Medical Center, Division of Cardiovascular Medicine, 55 Lake Ave N, Worcester, MA 01655.
David Iansmith, MD, Cardiology Group of Memphis, 910 Madison Ave, Suite 609, Memphis, TN 38103.
James M. Irwin, MD, St Joseph’s Heart Institute, 3003 W Buffalo Ave, Tampa, FL 33607.
Denise Janosik, MD, St Louis University Medical Center, Cardiology Division, 3635 Vista Ave and Grand Blvd, St Louis, MO 63104.
Alan Kadish, MD, Northwestern Memorial Hospital, 250 E Superior St, Suite 524, Wesley Pavilion, Chicago, IL 60611.
Richard Kehoe, MD, Illinois Masonic Medical Center, 836 Wellington Ave, Chicago, IL 60657.
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.
James Kirchhoffer, MD, Baystate Medical Center, Department of Cardiology, Wright 4, 759 Chestnut St, Springfield, MA 01199.
Harry Kopelman, MD, Atlanta Cardiology Group, 5665 Peachtree-Dunwoody Rd, Atlanta, GA 30342.
Peter Kowey, MD, Cardiology Foundation of Lankenau, Lankenau Medical Office Building East, 100 Lancaster Ave West of City Line, Wynnewood, PA 19096-3425.
Mark Kremers, MD, Presbyterian Hospital, Belk Heart Center, 200 Hawthorne Ln, Charlotte, NC 28204.
Steven Kutalek, MD, Likoff Cardiovascular Institute, Hahnemann University, MS 470, Broad and Vine Streets, Philadelphia, PA 19102-1192.
Joseph Levine, MD, St Francis Hospital, 100 Fort Washington Blvd, Roslyn, NY 11576.
Bing Liem, DO, Cardiac Electrophysiology, Stanford University Medical Center, 300 Pasteur Dr, Room H 2146, Stanford, CA 94305.
Bruce Lindsay, MD, Barnes Hospital, Cardiology Division, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110.
Richard M. Luceri, MD, 6405 North Federal Hwy, Fort Lauderdale, FL 33308.
Paul Ludmer, MD, Cardiovascular Consultants, 365 Hawthorne Ave, Suite 201, Oakland, CA 94609.
Ali Massumi, MD, St Lukes Episcopal Hospital, 6720 Bertner St (MS1-191), Houston, TX 77030.
John McAnulty, MD, Division of Cardiology, L-462, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201.
Ron McCowan, MD, Charleston Cardiology Group, 3100 MacCorkle SE, Suite 709, Charleston, WV 25304.
Ronald Miller, MD, San Diego Cardiac Center, 8010 Frost St, Suite 200, San Diego, CA 92123.
Syed Mohiuddin, MD, Room 3519 Cardiac Research, Creighton Cardiac Center, 3006 Webster St, Omaha, NE 68131.
Douglas Morris, MD, Crawford Long Hospital of Emory, 550 Peachtree St NE, Atlanta, GA 30365-2225.
Allan Nichols, MD, Riverside Methodist Hospital, 3535 Olentangy Rd, Columbus, OH 43214.
Michael O’Toole, MD, Midwest Heart Research Foundation, 2340 Highland Ave, Suite 200, Lombard, IL 60148.
Antonio Pacifico, MD, 6560 Fannin, Suite 620, Houston, TX 77030.
David Pederson, MD, Wilford Hall USAF Medical Center, 2200 Bergquist Dr, Suite 1, Lackland AFB, San Antonio, TX 78236.
Edward V. Platia, MD, Washington Hospital Center, Department of Cardiology 291, 110 Irving St NW, Washington, DC 20010.
Vance Plumb, MD, University of Alabama Hospitals, 334 Zeigler Bldg, University Station, Birmingham, AL 35294.
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.
C. Pratap Reddy, MD, Cardiology Section, Louisiana State University Medical Center, 1501 Kingshighway, Shreveport, LA 71130.
Stephen Rothbart, MD, Newark Beth Israel Medical Center, 201 Lyons Ave, Newark, NJ 07112.
Melvin Scheinman, MD, Moffit Hospital M312, University of California Medical Center, 505 Parnassus Ave, San Francisco, CA 94143.
Kerry Schwartz, MD, Florida Heart Group, 615 E Princeton St, Suite 300, Orlando, FL 32803.
Igor Singer, MD, Humana University, 550 South Jackson St, Louisville, KY 40292.
Joel Sklar, MD, Marin General Hospital, 250 Bon Air Rd, Greenbrae, CA 94904.
Carmine Sorbera, MD, Westchester County Medical Center, Division of Cardiology, Valhalla, NY 10595.
Scott Spielman, MD, Albert Einstein Medical Center, Northern Division, York and Tabor Roads, Philadelphia, PA 19141.
Jonathan Steinberg, MD, St Lukes/Roosevelt Hospital Center, Division of Cardiology S&R 3, 114th St and Amsterdam Ave, New York, NY 10025.
Russell Steinman, MD, Harper Hospital, 3990 John Ave, Detroit, MI 48201.
Donald Switzer, MD, Buffalo Cardiology Associates, 5305 Main St, Williamsville, NY 14221.
Alan Thometz, MD, Billings Cardiology Associates PC, 1145 N 29th, Suite 304, Billings, MT 59101.
Jesus Val Mejias, MD, Wichita Institute for Clinical Research, 551 N Hillside, Suite 410, Wichita, KS 67214.
P.J. Varghese, MD, George Washington University Medical Center, 2150 Pennsylvania Ave NW, Washington, DC 20037.
Ferdinand Venditti, MD, Lahey Clinic Medical Center, 41 Mall Rd, Burlington, MA 01805.
Paul Walter, MD, Emory University Hospital, 4th Floor Cardiology, 1363 Clifton Rd NE, Atlanta, GA 30322.
Mark Weston, MD, 4 Columbia Dr, Suite 720, Tampa, FL 33606.
David Wilber, MD, Loyola University Medical Center, Cardiology Division, 2160 S First Ave, Maywood, IL 60153.
Daniel Wilkinson, MD, 1560 N 115 St, Suite 201, Seattle, WA 98133.
John Wilson, MD, Cardiology Associates, 2328 Auburn Ave, Cincinnati, OH 45219.
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.
Stephen Winters, MD, Morristown Memorial Hospital, 100 Madison Ave, Morristown, NJ 07962-1956.
Raymond Woosley, MD, PhD, Georgetown University, 403 E Medical Dental Bldg, 3900 Reservoir Rd NW, Washington, DC 20007.
Christopher Wyndham, MD, Presbyterian Hospital of Dallas, Section of Cardiology/Electrophysiology, 8230 Walnut Hill Ln, Suite 220, Dallas TX 75231.
Samuel Zimmern, MD, 1001 Blythe Blvd, Suite 300, Charlotte, NC 28203.
This study was supported by a grant from Wyeth-Ayerst Research. The authors wish to thank Rose Marie Wells for her help in preparing the manuscript and our referring physicians who graciously allowed their patients to be enrolled in this study.
↵1 See the appendix for a complete list of the investigators and their centers.
Dr Kowey 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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