Background Atrial fibrillation and paroxysmal supraventricular tachycardia are common disorders of the heart rhythm for which antiarrhythmic drug therapy is commonly prescribed. The Atrial Fibrillation Investigation with Bidisomide (AFIB) study was a randomized, placebo-controlled clinical trial designed to accomplish three goals in a single protocol: (1) to determine the efficacy of the antiarrhythmic drug bidisomide in the treatment of these two arrhythmias; (2) to establish the appropriate dose range for bidisomide; and (3) to detect an adverse mortality effect of bidisomide if one were present in patients with atrial fibrillation.
Methods and Results In this clinical trial, 1227 patients with atrial fibrillation and 187 with paroxysmal supraventricular tachycardia were randomly assigned to bidisomide (200, 400, or 600 mg BID) or placebo; patient groups with each arrhythmia were analyzed separately. Symptomatic recurrences of atrial fibrillation and paroxysmal supraventricular tachycardia were documented with the use of transtelephonic ECG monitoring. The time to the first symptomatic arrhythmia recurrence was measured in each patient and compared among treatment groups. Among the atrial fibrillation patients, there was no significant difference in the time to first symptomatic recurrence between the placebo group and any of the three bidisomide treatment groups; the hazard ratios (placebo:treatment) were 1.19, 1.03, and 1.14 for bidisomide 200, 400, and 600 mg BID, respectively. Among paroxysmal supraventricular tachycardia patients, there was a similar lack of a significant treatment effect; the hazard ratios were 1.30, 1.93, and 1.59 for bidisomide 200, 400, and 600 mg BID, respectively. In the primary safety analysis of mortality, 3 of 493 patients taking placebo died, compared with 9 of 488 patients taking one of the two higher doses of bidisomide (P>.10).
Conclusions Bidisomide in the doses tested did not have a clinically important antiarrhythmic effect. The AFIB study provided a novel clinical trial design to test antiarrhythmic drugs for both safety and efficacy.
In patients who have atrial fibrillation or paroxysmal supraventricular tachycardia, normal sinus rhythm is punctuated by episodes of symptomatic arrhythmia. Current antiarrhythmic drug therapy for these conditions is imperfect, and there is a continuing need to develop new compounds for these common clinical problems, which appear to account for ≈40% of hospitalizations in the United States for arrhythmias.1 Bidisomide is a class I antiarrhythmic drug that had shown promising pharmacological effects in a variety of human and basic science studies.2 3 4 5 6 The purpose of the Atrial Fibrillation Investigation with Bidisomide (AFIB) trial, therefore, was to conduct a randomized, double-blind, placebo-controlled clinical trial to establish the clinically effective dose range for bidisomide, to evaluate the efficacy of bidisomide at these doses, and to establish the safety of bidisomide in patients with atrial fibrillation or paroxysmal supraventricular tachycardia.
Patients were required to (1) have ECG documentation of a qualifying arrhythmia within 2 years before enrollment (atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia, which were referred to as “index” arrhythmias), (2) be in sinus rhythm at the time the first dose of study medication was administered, (3) have reached the legal age of majority in the state or province where enrolled, and (4) give written, informed consent.
The principal cardiac exclusion criteria were the following: (1) qualifying arrhythmia documented only by continuous ambulatory Holter monitoring or only within the first 2 months after an acute myocardial infarction, a cardiac or thoracic surgical procedure, or acute pericarditis; (2) presence of an implantable cardioverter defibrillator; (3) acute myocardial infarction, cardiac surgical procedure, or reversible ischemic neurological deficit within 3 months before enrollment; (4) second- or third-degree AV block that was not treated with a pacemaker; (5) resting sinus rate <40 bpm; (6) history of ventricular tachycardia that lasted >30 seconds or caused presyncope or syncope; (7) prolonged QT interval or history of torsade de pointes; (8) class IV congestive heart failure or angina; and (9) transient ischemic attacks, congestive heart failure, or angina precipitated by arrhythmia recurrence.
Initiating Randomized Therapy
Patients were randomly assigned to bidisomide (200, 400, or 600 mg BID) or placebo BID. Medications were packaged identically, and patients took three capsules twice daily, regardless of regimen. Patients with atrial fibrillation and atrial flutter were grouped as a single index arrhythmia for randomization as the atrial fibrillation group; the paroxysmal supraventricular tachycardia group was randomized as a separate index arrhythmia. A permuted block randomization scheme was used in which 40% of patients with each index arrhythmia received placebo and each of the three doses of bidisomide was given to 20% of the patients.
Treatment was initiated in both inpatients and outpatients; the protocol recommended that patients with class III heart failure have therapy initiated as inpatients. The first 3 days of study treatment were considered the study-drug–loading period. Patients were assumed to have reached steady-state plasma bidisomide concentrations at midnight of the third treatment day. At this time, the follow-up period began, unless the patient had one of the qualifying arrhythmias documented during the study-drug–loading period. In this case, the start of the follow-up period was postponed until the patient was known to be back in sinus rhythm. If these patients had no sinus rhythm recorded during the first 7 days of the follow-up period, they were withdrawn from the study.
At the time the AFIB trial began, patients were to continue taking study medication for 52 weeks. Throughout the study, routine ECGs were recorded every 2 weeks, as well as during symptoms of arrhythmia recurrence, by transtelephonic ECG monitoring provided by a central service that was under contract for the study (Premier Research Worldwide, Philadelphia, Pa). All ECGs recorded during symptoms were reviewed by a committee of investigators that assigned the diagnosis used for the efficacy analysis. This same committee assigned a cause to all deaths during the study, and another committee reviewed strokes and potential embolic events to apply uniform diagnostic criteria. Records of hospitalizations and emergency department visits during the study were reviewed to determine if an arrhythmia was recorded that was not captured by the transtelephonic ECG monitoring system.
Data Analysis and Sample-Size Calculations
The primary outcome variable for the efficacy analysis was the tachycardia-free period, measured in each patient from the beginning of the follow-up period to the first symptomatic recurrence of a qualifying arrhythmia.7 For each index arrhythmia and each treatment, the proportion of patients remaining free of arrhythmia at each day of follow-up was calculated by use of the Kaplan-Meier product-limit method.8 The median recurrence time was estimated by use of the Kaplan-Meier method, and we estimated the mean recurrence time by assuming that the distribution of recurrence times was exponential. For each index arrhythmia, the efficacy of each dose of bidisomide was compared with placebo by use of the Cox proportional hazards model with an indicator variable for each of the three bidisomide doses.8 The primary safety analysis compared the total mortality observed in the atrial fibrillation patients assigned to placebo with that of the combined group of patients assigned to the 400 and 600 mg BID bidisomide doses; patients in these treatment arms were “at risk” as long as they continued taking study medication and for 30 days after withdrawal for any reason.
Because it was anticipated that the 200 mg BID dose of bidisomide would have no effect or be a minimally effective dose, this treatment arm was excluded from the power calculations for both efficacy and safety; only atrial fibrillation patients were considered in the power calculations.9 For the efficacy analysis, the time to first symptomatic arrhythmia recurrence in the placebo group was conservatively estimated to be as long as 720 days. The sample-size criterion for the efficacy analyses required 90% power in a two-sided test at the 2.5% significance level to detect a halving of the arrhythmia recurrence rate with either of the two higher bidisomide doses compared with placebo; thus, overall type I error for the two primary efficacy analyses was controlled at 5%. For the safety analysis, the placebo total mortality rate was estimated to be 4% per year on the basis of mortality reported for various subgroups in the Stroke Prevention in Atrial Fibrillation (SPAF) study.10 The sample-size criterion for the safety analysis required 80% power in a one-sided test at the 5% significance level to detect a doubling of the placebo mortality rate in the combined group of patients assigned to the two higher bidisomide doses. At the time the AFIB trial began, projected enrollment was 1165 atrial fibrillation patients and 255 paroxysmal supraventricular tachycardia patients.
The first patient was enrolled in AFIB on August 30, 1993. On August 25, 1994, the protocol was amended to extend enrollment to March 31, 1995, and to set the completion date for all patients at June 30, 1995; the purpose of this amendment was to maintain the desired power for the mortality analysis, which was being eroded by a higher than expected withdrawal rate after the first symptomatic recurrence of one of the qualifying arrhythmias but before the completion of 52 weeks of study medication. This change would have resulted in a projected enrollment of 1900 atrial fibrillation patients. However, in a meeting on January 25, 1995, the Data and Safety Monitoring Committee (DSMC), concerned about an unfavorable albeit statistically insignificant mortality trend, decided that this safety concern should be balanced by substantial evidence of efficacy, to which the DSMC had heretofore remained blinded. These data demonstrated a clear lack of efficacy, particularly in the atrial fibrillation stratum. On January 31, 1995, the study was terminated by the executive committee.
Enrollment and Demographic Data
When the AFIB trial was terminated, 130 sites had enrolled 1227 patients with atrial fibrillation and 187 patients with paroxysmal supraventricular tachycardia. Atrial fibrillation patients were older, included a smaller proportion of women, and had more associated heart diseases than paroxysmal supraventricular tachycardia patients (Table⇓). Among atrial fibrillation patients, 33.4% were not known to have any form of heart disease or hypertension; 17.3% were younger than 60 years of age and were not known to have any form of heart disease or hypertension. Among the atrial fibrillation patients, 372 (30.3%) had been cardioverted at least once at some time before they enrolled in the present study. Among the most recent cardioversions, 184 took place on the day the patient began randomized treatment or the day before; the remainder took place at widely distributed intervals that were as much as 24 years before therapy was initiated in the present study. Among atrial fibrillation patients, 366 (29.8%) received their first dose of study medication as a hospital inpatient; among paroxysmal supraventricular tachycardia patients, 33 (17.6%) began treatment as inpatients.
In both the atrial fibrillation group and the paroxysmal supraventricular tachycardia group, the distribution of baseline demographic variables and use of cardiovascular medications were balanced among treatment groups.
Among the 1227 patients in the atrial fibrillation group, 246 were assigned to bidisomide 200 mg BID, 244 to bidisomide 400 mg BID, 244 to bidisomide 600 mg BID, and 493 to placebo; 1189 of these 1227 patients were included in the primary efficacy analysis. Thirty-eight randomized atrial fibrillation patients were excluded from the primary efficacy analysis because they were enrolled <4 days before the study was terminated (n=1), they withdrew from the study during the study-drug–loading period (n=25), or they were in atrial fibrillation at the end of the loading period and did not return to sinus rhythm within the first 7 days of the follow-up period (n=12).
Two hundred fifty-nine of the atrial fibrillation patients assigned to placebo had a symptomatic arrhythmia recurrence during the follow-up period; the median time to first recurrence was 86 days (95% CI: 42, 118), and the mean recurrence time was estimated to be 124 days. There was no significant difference in the time to first symptomatic recurrence between the placebo group and any of the three bidisomide treatment groups (Fig 1⇓); the hazard ratios (placebo:treatment) were 1.19 (95% CI: 0.96, 1.48), 1.03 (95% CI: 0.83, 1.27), and 1.14 (95% CI: 0.91, 1.41) for bidisomide 200, 400, and 600 mg BID, respectively.
Among 187 patients in the paroxysmal supraventricular tachycardia group, 37 were assigned to bidisomide 200 mg BID, 39 to bidisomide 400 mg BID, 40 to bidisomide 600 mg BID, and 71 to placebo; 184 were included in the primary efficacy analysis. Three paroxysmal supraventricular tachycardia patients were excluded from the primary efficacy analysis because they withdrew from the study during the study-drug–loading period.
Among the paroxysmal supraventricular tachycardia patients randomly assigned to placebo, 39 had a symptomatic arrhythmia recurrence during the follow-up period. The median time to first symptomatic arrhythmia recurrence was 60 days (95% CI: 32, 200). There was no significant difference in the time to first symptomatic recurrence between the placebo group and any of the three bidisomide treatment groups (Fig 2⇓). The hazard ratios were 1.30, 1.93, and 1.59 for bidisomide 200, 400, and 600 mg BID, respectively. There appeared to be a small favorable therapeutic effect demonstrated in the 400 mg BID treatment group, but this marginal effect was not clinically important and did not meet the criterion for significance specified by the protocol.
There were 3 deaths in the placebo group, and 0, 2, and 7 deaths in the groups receiving bidisomide 200, 400, and 600 mg BID, respectively. The protocol specified that the primary safety analysis would compare mortality in the placebo group with that in the combined groups treated with the two higher doses of bidisomide. There were 3 deaths among the 493 patients taking placebo and 9 deaths among the 488 patients taking one of the two higher bidisomide doses (Fig 3⇓; P>.10 by log-rank test). The hazard ratio (bidisomide:placebo) for the primary mortality analysis was 2.82 (95% CI: 0.76, 10.45). The 1-year mortality rate in the placebo arm was 0.8% (95% CI: 0.2%, 2.4%).
The AFIB study demonstrated conclusively that bidisomide in doses of 200, 400, or 600 mg BID was not an effective antiarrhythmic drug in patients with either atrial fibrillation or paroxysmal supraventricular tachycardia. Beyond this obvious and disappointing conclusion, however, the study had substantial scientific merit because the 1414 patients randomized made it the largest placebo-controlled trial ever conducted to test the efficacy of an antiarrhythmic drug to reduce the frequency of symptomatic arrhythmia recurrences in patients with atrial fibrillation or paroxysmal supraventricular tachycardia. In addition to the large scale of the study, unusually high scientific standards were imposed by committees of investigators who reviewed and classified every symptomatic ECG, death, and neurological event that occurred.
The characteristics of the patients recruited into this study were interesting.
With identical entry criteria for patients with the two index arrhythmias, atrial fibrillation patients outnumbered paroxysmal supraventricular tachycardia patients almost 7 to 1. As might have been expected, patients with atrial fibrillation were older, had more associated heart diseases, and were taking more concomitant cardiovascular drugs (except verapamil) than patients with paroxysmal supraventricular tachycardia. Among atrial fibrillation patients, 81.1% were taking some additional drug that tended to slow AV nodal conduction. Atrial fibrillation patients also were more likely to be hospitalized at the time of their first dose of randomized therapy than patients with paroxysmal supraventricular tachycardia. Lone atrial fibrillation was present in 33.4% of patients as defined by Brand et al11 in the Framingham Heart Study and in 17.3% using the more conservative definition proposed by Kopecky et al12 at the Mayo Clinic. The latter definition excludes patients aged >60 years, as well as patients with heart disease and hypertension. Interestingly, among the atrial fibrillation patients, only 30.3% had ever been treated with DC cardioversion to restore sinus rhythm, and only 15.0% had their most recent cardioversion immediately before enrolling in the study.
The estimated mean time to first recurrence of a symptomatic arrhythmia was 124 days in the placebo-treated patients with atrial fibrillation. Thus, if atrial fibrillation is considered to be a recurring process in these patients, then the “typical” patient with atrial fibrillation would be expected to have about three symptomatic arrhythmia events yearly.7 The range of expected event rates would be very broad in atrial fibrillation patients, with some having daily events and others having none in a year. The median recurrence time of 86 days was much longer than the 7-day median recurrence time reported for 33 atrial fibrillation patients by Clair et al,13 the 3 days reported by Anderson et al14 in multicenter trials of flecainide, or the 5 days reported in multicenter trials of propafenone.15 Similarly, the median recurrence time for paroxysmal supraventricular tachycardia patients was 60 days, compared with estimates of 28 days from Clair et al,13 15 days from Henthorn et al,16 and 17 days from the clinical trials of propafenone.15 The median time to recurrence in the AFIB study is probably a better estimate of the population median because this study involved more centers and more patients and because the entry criteria were much broader. For example, in the multicenter trials of flecainide, patients were screened for high frequency of symptomatic arrhythmia recurrence before being randomized. For future studies of antiarrhythmic drug efficacy using these methods, a median recurrence time in the placebo group of ≈90 days for atrial fibrillation patients and 60 days for paroxysmal supraventricular tachycardia would be most appropriate for planning purposes.
The 1-year mortality rate among the placebo-treated patients with atrial fibrillation was surprisingly low at 0.8%, compared, for example, with the annual mortality rate reported in the SPAF study, which was 5.3% in the aspirin-treated group and 6.5% in the placebo-treated group (from the aspirin versus placebo comparison). The mean age in SPAF patients was 67 years compared with 63 years in AFIB patients, and this difference may account for some of the lower mortality. Also, most patients in the SPAF study were permanently in atrial fibrillation, whereas in the present study, all patients were required to be in sinus rhythm at the time randomized therapy began; the pathology in the heart may be less severe in the latter patients. Like the primary efficacy analysis, the primary safety analysis did not demonstrate a significant difference between the treatment groups (placebo group versus the two higher doses of bidisomide combined); however, the hazard ratio of 2.82 suggests an adverse trend similar in magnitude to the effect size seen in the Cardiac Arrhythmia Suppression Trial17 and in a meta-analysis of clinical trials of quinidine in patients with atrial fibrillation.18 Future development programs for antiarrhythmic drugs should continue to include strategies to evaluate safety as well as efficacy.
In conclusion, this trial failed to demonstrate a useful therapeutic effect of an antiarrhythmic drug that had shown substantial promise in preclinical testing, confirming the difficulties of using basic pharmacological effects to predict important clinical outcomes in antiarrhythmic drugs. The study also established new standards of scale and scientific rigor for clinical trials of antiarrhythmic drug therapy of patients with atrial fibrillation. The long time to first recurrence of symptomatic arrhythmia and the low annual mortality rate in the hundreds of patients assigned to placebo provide important insights into the behavior of untreated patients with these disorders.
AFIB Investigators, Subinvestigators, and Study Coordinators
Note: The number of patients enrolled for each site is given in parentheses.
Michael J. Koren, MD, FACC; Cynthia Buda, RN, BSN; Jacksonville (Fla) Cardiovascular Clinic (34).
William Henry, MD; W. Travis Ellison, MD; John M. Milas, MD; Marlene Morgan, LPN; Upstate Clinical Research, Inc (31), Greer, SC.
Leland Sprinkle, MD, FACC; M.J. McGreevy, MD, FACC; Ronald K. Goldberg, MD, FACC; Sylvia Gerry, BS, C-CVT; Mary Barrett, LVN; Cardiology Medical Group of San Diego (30), La Mesa, Calif.
Stuart Connolly, MD; Loree Morrison, RN; McMaster University (30), Hamilton, Ontario, Canada.
David C. Abrahamson, MD; Chris Somogyi; Orange County Heart Institute (28), Orange, Calif.
Robert J. Weiss, MD; David N. Abisalih, MD; Carol Ridley, RN; Androscoggin Cardiology Associates (28), Auburn, Me.
Kevin F. Browne, Jr, MD; Noreen McGowan, BSN; Watson Clinic (27), Lakeland, Fla;
Robert J. Hariman, MD; Marianne Tully, RN; Hines (Ill) VA Hospital (25).
Joseph Bissett, MD; Rose May, RN; University of Arkansas for Medical Sciences (24), Little Rock.
J. Thomas Heywood, MD; Sharon Fabbri, RNP, BSN; Jerry Pettis Memorial Veterans Hospital (24), Loma Linda, Calif.
Wynne Crawford, MD; Mark Platt, RN; Montgomery Cardiovascular Associates, PA (22), Montgomery, Ala.
Dean Bramlet, MD; Cheryl Morgan, RN; Cardiology Consultants Research (21), St. Petersburg, Fla.
Michael C. Dillon, MD; Steven Roark, MD; Burton Silverstein, MD; Nancy Marquis, CVT; Cardiology Associates of Gainesville (21), Fla.
Richard L. Page, MD; Robert C. Canby, MD; Rodney P. Horton, MD; Gigi Ash, RN; University of Texas Southwestern Medical Center (21), Dallas.
U.R. Shettigar, MD; George Barbier, MD; Doreen Appunn, RN; VA Medical Center (21), Bay Pines, Fla.
Fabio Leonelli, MD; Tonya McFarland, RN; Kathleen Rajkovich, RN; University of Kentucky Medical Center (20), Lexington.
Edward L.C. Pritchett, MD; Mary Ann Tormey, RN; Duke University Medical Center (20), Durham, NC.
John L. Walker, MD; James E. Carley, MD; Dianne M. Tracy, RN; Ormond Beach, Fla (20).
Jeffrey L. Anderson, MD; Labros A. Karagounis, MD; Kaye Summers, RN, BSN; University of Utah, Latter Day Saints Hospital (19), Salt Lake City.
Allan H. Barker, MD; Robert E. Fowles, MD; Michael J. Preece, MD; Ellen N. Doran; Salt Lake Clinic Research Foundation (19), Salt Lake City, Utah.
Denis Roy, MD; Mario Talajic; Marc Dubuc; Danielle Beaudoin, RN; Montreal Heart Institute (19), Quebec, Canada.
Osamu Fujimura, MD; Doris Aceron, RN; UCSD Medical Center (18), San Diego, Calif.
John Onufer, MD; Rebecca Barciano, RN; Cardiovascular Associates Ltd (18), Norfolk, Va.
Douglas Cameron, MD; Barbara Weller; Toronto Hospital (17), Ontario, Canada.
Margaret Drehobl, MD; Jerome Brodkin, MD; Bill Joswig, MD; Michael Barker, MD; Donna Schu, RN, CCRC; Center for Health Care (17), San Diego, Calif.
Mark S. Kremers, MD; Diane Whisnant, RN; Presbyterian Hospital Belk Heart Center (17), Charlotte, NC.
Mark Lurie, MD; Annelie Brinkley, LVN; Torrance,Calif (17).
Scott J. Pollak, MD; Shelly Nicholls; Central Florida Cardiology Group, PA (17), Orlando.
Dennis Bloomfield, MD; Maria DeStefano, RN; Nancy King, RN; Billy Geris, MD; St. Vincent’s Medical Center of Richmond (16), Staten Island, NY.
Martin Green, MD; Anthony S. L. Tang, MD; Marilynn Luce; Ottawa Civic Hospital (16), Ontario, Canada.
M. El Shahawy, MD; Mary Wagner, RN; Jacqueline Rudge, LPN; Sarasota, Fla (16).
Jonathan S. Steinberg, MD; Edith Tan, RN, MSN; St. Luke’s–Roosevelt Hospital Center (16), New York, NY.
Raymond Yee, MD; George J. Klein, MD; Marilyn Braney, RN; University Hospital (16), London, Ontario, Canada.
Richard Backes, MD; Kathy Miller; North Central Heart Institute (15), Sioux Falls, SD.
Marcelo Branco, MD; Denise Myers, RN, MSN; Tammy Suggs; West Florida Medical Center Clinic, PA (15), Pensacola.
Arvindkumar Shah, MD, FACC, FRCPE, MRCP (LON); Beth Heus, RN, BSN; Cindy Trizzino, RN; St. Alexis Medical Arts Building (15), Cleveland, Ohio.
William J. Grossman, MD; Kathleen Fletcher, RN; Charleston (SC) Cardiology (15).
Irving K. Loh, MD; Chris Smith; Kay DeGennaro; Ventura Heart Institute, HCA Los Robles Medical Center (15), Thousand Oaks, Calif.
Igor Singer, MBBS, FRACP, FACP, FACC, FACA; Aida Cicic, MD; University of Louisville (14), Ky.
M. Noelle Langan, MD; J. Anthony Gomes, MD; Davendra Mehta, MD, PhD; Elena Pe, RN, MA; The Mount Sinai Medical Center (14), New York, NY.
Philip T. Sager, MD; David Ploss, MD; Mina Attin, MSN; Mark Lueken, MSN; West Los Angeles (Calif) VA Medical Center (14).
Richard J. Gray, MD; Noah N. Chelliah, MD; Kelly Hagen, RN; Denise Carter, RN, BSN; Carolyn Gray, RN, BSN; University of North Dakota, United Hospital (14), Grand Forks.
Anne B. Curtis, MD; Jamie B. Conti, MD; Laura Salvetti, RN; University of Florida (13), Gainesville.
Robert Sheldon, MD, PhD; Debbie Ritchie, MN; Calgary General Hospital (13), Alberta, Canada.
Kenneth Ellenbogen, MD; Mark A. Wood, MD; Nancy Michaels, RN; Medical College of Virginia (13), Richmond.
Jack H. Hall, MD; Dottie Fausset, RN, MBA; Pam Linden, RN; Medical Research Consortium (13), Indianapolis, Ind.
Charles Schulman, MD; Kenneth Gershengorn, MD; Stephen Saltz, MD; Ellen Kinsman; Cardiology Associates of Greater Boston (13), Brookline, Mass.
Kirk Jacobson, MD; Frank Littell, MD; Jane Mossberg, MD; Kim Dauw, RN; Oregon Research Group (12), Eugene.
Ronald P. Karlsberg, MD; Tracey Gerez, MA; Cardiovascular Research Institution of Southern California (12), Beverly Hills.
Fredric M. Tobis, MD; Erin Rasmussen, RN, BSN; Summit Cardiology (12), Bellevue, Wash.
Mark Carlson, MD; Bridget Walker; University of Cleveland (Ohio) Hospitals (11), Case Western Reserve University.
Barry Silverman, MD; Susan Banasik, RN; Northside Hospital (11), Atlanta, Ga.
Michael Rubin, MD, FACC; Janet Busch, RN, BSN, CCRC; Lee Coast Research Center, Inc (10), Ft. Myers, Fla.
Terrence C. Hack, MD, FACC; Maureen Criasia; Ayer, Mass (10).
Robert Florek, MD; Mary Hamlin, RN; Good Samaritan Hospital and Medical Center (10), Portland, Ore.
Jon Friedman, MD; Aya Dinning, RN, BS; Yelena Misaljevic, MD; Healthcare Partners (10), Los Angeles, Calif.
Mark Keller, MD; Nelson Trajillo, MD (echo substudy); Devora Anderson, RN, MS; Veterans Administration Medical Center (10), Denver, Colo.
Alan Wagshal, MD; Karen Rofino; University of Massachusetts Medical Center (10), Worcester.
Mario Motta, MD, FACC; Lawrence S. Block, MD, FACC; Daniel C. Wistran, MD, FACC; Maureen Criasia, RN, BSN; Cardiology Physicians, Inc (9), Salem, Mass.
E. Wayne Grogan, MD; Beth Sommerfeldt; Jackson Foundation for Medical Research (9), Madison, Wis.
Douglas Rothrock, MD; Scott Baron, MD; Susan Stedfield, RN, BSN; Carmichael, Calif (9).
Lyle Swenson, MD; Barb Gilbert, RN; St. Paul–Ramsey Medical Center (9), St. Paul, Minn.
Victoria Bernstein, MD; Charles Kerr, MD; Karen MacDonald, RN; Susan Mooney, RN; University Hospital UBC site (8), Vancouver, British Columbia, Canada.
Martin S. Bilsker, MD; Max Kamerman; University of Miami (8), Fla.
James Bradley, MD; Terri Peacock, RN; Doctors Clinic (8), Vero Beach, Fla.
Peng-Sheng Chen, MD; Jeffrey S. Goodman, MD; C. Thomas Peter, MD; Mary Schoenbaum, RN; Stanley Conte, RN; Cedars-Sinai Medical Center and UCLA School of Medicine (8), Los Angeles, Calif.
Paul Curlee, MD; Ray Booker; St. Mary’s Hospital (8), Grand Junction, Colo.
Lorenzo A. DiCarlo, MD; James H. Kappler, MD; Stuart A. Winston, DO; Mary Adolphson, RN; Michigan Heart and Vascular Institute (8), Ypsilanti.
Richard Henthorn, MD; Judy Lipps, RN; Karen Ibanez, RN; The Christ Hospital Cardiovascular Research Center (8), Cincinnati, Ohio.
W. Ben Johnson, MD; Mark Polich; Iowa Heart Center (8), Des Moines.
David T. Martin, MD; Gail Woodhead; Lahey Clinic (8), Burlington, Mass.
Stephen L. Moore, DO; Sandy Mishak, LPN; Sandy Manholt, LPN, CRC; North Ohio Heart Center (8), Elyria.
H. Elizabeth Noll, MD; Judy G. Kelley, CCRC; Sharp Rees–Stealy Medical Center (8), San Diego, Calif.
Richard Perlman, MD; Jessica Guido, RN; Partners in Medical Research (8), Baltimore, Md.
Bruce Stambler, MD; Donna Sargent, RN; McGuire VA Medical Center (8), Richmond, Va.
Joseph Stein, MD; Richard Willis; Mercy Hospital and Medical Center (8), San Diego, Calif.
W.W. Stoever, DO; Phyllis Cotham; Kevin Mason; Jeanne Gaber; Healthcare Research Consultants (8), Tulsa, Okla.
Stephen L. Winters, MD; Jay H. Curwin, MD; John S. Banas, Jr, MD; Linda J. Enright, MS, RPh; Morristown (NJ) Memorial Hospital (8).
Michael Brodsky, MD; Susan Chaim, PharmD; University of California Irvine Medical Center (7), Orange, Calif.
Harold Carlson, MD; Elaine Furka, RN, CCRC; Atlanta, Ga (7).
James Daubert, MD; Toshio Akiyama, MD; Dennis Flynn, RN; Celeste Ocampo, RN; University of Rochester (NY) Medical Center (7).
Robert A. Erdin, Jr, MD; Tracy A. Heiges, RRT, CRC; High Point, NC (7).
Keith Kadel, MD; Eric D. Stucky, MD; Mona Rittenhouse, CMA; Northside Cardiology (7), Spokane, Wash.
John McAnulty, MD; Julie Timberg; Oregon Health Sciences University (7), Portland.
J. Frederick McNeer, MD; Brenda Smith, RN; Tulsa, Okla (7).
Katherine T. Murray, MD; Kristy Norris; Vanderbilt University Medical Center (7), Nashville, Tenn.
Marc Platt, MD; Carol Edgett, RN; Torrance, Calif (7).
John L. Sorensen, MD; Barbara Adelman, RN; Southwest Medical Group (7), Las Vegas, Nev.
Donald Stoner, MD; Howard Offenberg, MD; Linda Arnow; Halifax Clinical Research Center (7), Daytona, Fla.
Gurdarshan Thind, MD; Cathy Faughn, CMA; University of Louisville (Ky), Health Sciences Center (7).
David Williams, MD; Elizabeth Hendricks; Atlantic Institute of Clinical Research (7), Daytona Beach, Fla.
Brian Friedman, MD; Willy Payne, RN; VA Medical Center (6), Medical Research Services, Kansas City, Mo.
Charlie E. Fuenzalida, MD; Melinda Washam, RN; Western Heart Specialists, PC (6), Denver, Colo.
James Heinsimer, MD; Mary G. Lentini, BSN; St. Joseph Mercy Hospital–Oakland (6), Pontiac, Mich.
David M. Weinberg, MD; Cathy Fox; Cardiology Associates Medical Group (6), Anaheim, Calif.
Ronald McCowan, MD; Faith S. Cook, RN; Charleston (WV) Cardiology Group (6).
Susan O’Donoghue, MD; Jean Fenton, RN, MSN; Washington Hospital Center (6), Washington, DC.
Mina Chung, MD; Gregory A. Kidwell, MD; Fred J. Jaeger, DO; Donald R. Holmes, MSN, RN; Victor A. Morant, MD; Richard G. Trohman, MD; Bruce L. Wilkoff, MD; Sergio L. Pinski, MD; Patrick J. Tchou, MD; Don Holmes, MSN, RN; Cleveland (Ohio) Clinic Foundation (5).
Nicholas Z. Kerin, MD; Kathy Faitel, RN, BSN; Sinai Hospital (5), Detroit, Mich.
Nicholas J. Stamato, MD; Debra Whiting, RN; Binghamton, NY (5).
Raj K. Bhalla, MD; Terri Hicks; Nassau Bay, Tex (4).
Patrick Bianchi, MD; Wanda Hamilton; Tallassee, Ala (4).
Don Chilson, MD; Joni Baxter, RN, BSN; Inland Cardiology Associates, PS (4), Spokane, Wash.
Daniel S. Contrafatto, MD; Darla Afshari, RN; St. Francis Medical Centre (4), Pittsburgh, Pa.
Thomas Guarnieri, MD; Karen Bolderman; MidAtlantic Cardiovascular Consultants, PA (4), Baltimore, Md.
P. David Margolis, MD; Jolene Durham; Oklahoma Heart, Inc (4), Tulsa.
Hugh M. Martin, MD; Cathy E. Wayand, RN; Tampa (Fla) Medical Research Associates, Inc (4).
Frank McGrew, MD; Betti Wilson, RN; The Cardiology Group of Memphis, PA (4), Memphis, Tenn.
Koonlawee Nademanee, MD; Sheila Smith; Denver (Colo) General Hospital (4).
Arjun Sharma, MD; Gearoid O’Neill, MD; Anne Skadsen, RN; Sacramento, Calif (4).
David Ware, MD; Gaylene Malmberg, RN, BSN; University of Texas Medical Branch at Galveston (4).
Michael Wilson, MD; Edward Bednarczyk, PharmD; Mary Bateson, RN; Millard Fillmore Hospital (4), Buffalo, NY.
Phillip D. Zinn, MD; Elizabeth Robles, CCRC; Diane Cullors, RN; Cardiology Clinic of San Antonio, PA (4), San Antonio, Tex.
George Crossley, MD; Kathleen Davis-O’Brien, RN; Bowman Gray School of Medicine (3), Winston-Salem, NC.
William H. Frishman, MD; Lee Root, MD; Betty Blanco, BS; Suzanne Furia, RN; Hospital of the Albert Einstein College of Medicine (3), Bronx, NY.
Lloyd Goodman, MD; Sarah Jones-Lanier, CCRC; Memorial Medical Center, Inc (3), Savannah, Ga.
Abraham Kocheril, MD; Allison Winecoff, PharmD; Medical College of Georgia (3), Augusta.
Douglas Packer, MD; Kay Cosberg; Mayo Foundation (3), Rochester, Minn.
Jean T. Barbey, MD; Jan Hewett-Meulman; Georgetown University (2), Washington, DC.
John Wertheimer, MD; Jeffrey Fierstein, MD; Cathy Benene, RN; Albert Einstein Medical Center (2), Philadelphia, Pa.
Jodie Hurwitz, MD; Lori Alexander, PhD; Brenda Wimberly, RN; Presbyterian Heart Institute (2), Dallas, Tex.
Norbert Overweg, MD; Vilma Mejia; Eastside Comprehensive Medical Services (2), New York, NY.
Antonio Pacifico, MD; Monica Farrell; Texas Arrhythmia Institute (2), Houston.
Russell Steinman, MD; St. John Hospital (2), Detroit, Mich.
Jesus ValMejias, MD; Pat Patterson, RN, BSN, MHS; Galichia Medical Center (2), Wichita, KS.
John Wilson, MD; Linda Enright; Good Samaritan Hospital (2), Cincinnati, Ohio.
Ed Dyckman, MD; Susan Banasik, RN; Southeast Clinical Resources (1), Atlanta, Ga.
Bill Harris, MD; Pam Raines; Cardiology Associates of Lexington (1), Lexington, Ky.
Thomas Paul, MD; Tina Blackman, RN; Future HealthCare (1), Birmingham, Ala.
James G. Porterfield, MD; Linda M. Porterfield, PhD; Arrhythmia Consultants (1), Memphis, Tenn.
James Roth, MD; Jean Vagnoni; Medical College of Wisconsin (1), Milwaukee.
Edward L.C. Pritchett, MD (Chairman), Duke University Medical Center, Durham, NC; Jeffrey L. Anderson, MD, University of Utah, Latter Day Saints Hospital, Salt Lake City; Stuart J. Connolly, MD, McMaster University, Hamilton, Ontario, Canada; G. Steven Geis, PhD, MD, GD Searle and Co, Skokie, Ill; Richard L. Page, MD, University of Texas Southwestern Medical Center, Dallas; David G. Sherman, MD, University of Texas Health Science Center at San Antonio; J. Gerald Toole, MD, GD Searle and Co, Skokie, Ill; Candace K. Bryan, PharmD (nonvoting), Kendle, Cincinnati, Ohio; Lorri J. Erhardt, BS, MT (nonvoting), GD Searle and Co, Skokie, Ill; Elizabeth A. McCarthy, RN (nonvoting), Duke University Medical Center, Durham, NC; and William E. Wilkinson, PhD (nonvoting), Duke University Medical Center, Durham, NC.
Arrhythmia and Mortality Event Committee
Richard L. Page, MD (Chairman), University of Texas Southwestern Medical Center, Dallas; Mark D. Carlson, MD, University Hospitals of Cleveland (Ohio), Case Western Reserve University; Peng-Sheng Chen, MD, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif; Katherine T. Murray, MD, Vanderbilt University School of Medicine, Nashville, Tenn; Douglas L. Packer, MD, Mayo Foundation, Rochester, Minn; and Elizabeth A. McCarthy, RN (nonvoting), Duke University Medical Center, Durham, NC.
Stroke Event Committee
David G. Sherman, MD (Chairman), University of Texas Health Science Center at San Antonio; Robert G. Hart, MD, University of Texas Health Science Center at San Antonio; John F. Rothrock, MD, University of South Alabama Medical Center, Mobile; and Elizabeth A. McCarthy, RN (nonvoting), Duke University Medical Center, Durham, NC.
Data and Safety Monitoring Committee
J. David Bristow, MD (Chairman), Oregon Health Sciences University, Portland; Elliott M. Antman, MD, Brigham and Women’s Hospital, Boston, Mass; Kanu Chatterjee, MD, University of California–San Francisco; David L. DeMets, PhD, University of Wisconsin Medical School, Madison; Nanette Kass Wenger, MD, Emory University School of Medicine, Atlanta, Ga; D. George Wyse, MD, PhD, The University of Calgary, Alberta, Canada; and William E. Wilkinson, PhD (nonvoting), Duke University Medical Center, Durham, NC.
Searle (Skokie, Ill)
G. Steven Geis, PhD, MD; J. Gerald Toole, MD; Lorri J. Erhardt, BS, MT; Shawn J. McDonald, MS; Susan Marie Garthwaite, PhD; W.A.T. Archambault, Jr, PhD; Edward Lakatos, PhD; Vicki R. Santos, MA, MS; Marge Schrempf; and Tammy Sulaiman, BA.
Kendle (Cincinnati, Ohio)
Peter E. Djuric, PharmD; Ann Hagen, MD; and Brenda Hoeper, MS.
Premier Research Worldwide (Philadelphia, Pa)
Linda M. Brokaw, BS, and Michael G. Muro, BS.
Corning SciCor Laboratories (Indianapolis, Ind)
Marietta M. Henry, MD, and Gordon F. Kapke, PhD.
Writing Committee for this manuscript (in alphabetical order)
Jeffrey L. Anderson, MD; Stuart J. Connolly, MD; G. Steven Geis, PhD, MD; Richard L. Page, MD; Edward L. C. Pritchett, MD; David G. Sherman, MD; J. Gerald Toole, MD; William E. Wilkinson, PhD.
This study was supported by contracts from Searle, Skokie, Ill.
↵1 A complete listing of investigators is included in the “Appendix.”
- Received January 28, 1997.
- Revision received May 6, 1997.
- Accepted May 28, 1997.
- Copyright © 1997 by American Heart Association
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