This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pritchett, E. L. C. Search for Related Content PubMed PubMed Citation Articles by Pritchett, E. L. C.

CLINICAL STUDY

Antiarrhythmic effects of azimilide in atrial fibrillation: efficacy and dose-response

Edward L. C. Pritchett, MD^a, Richard L. Page, MD, FACC^*, Stuart J. Connolly, MD, FACC, Stephen R. Marcello, MD, FACC, Daniel J. Schnell, PhD, William E. Wilkinson, PhD the Azimilide Supraventricular Arrhythmia Program 3 (SVA-3) Investigators

^a Department of Medicine, Divisions of Cardiology and Clinical Pharmacology, Duke University Medical Center, Durham, North Carolina, USA
^* Department of Medicine, Cardiovascular Division, University of Texas Southwestern Medical Center, Parkland Memorial Hospital, Dallas, Texas, USA
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Procter and Gamble Pharmaceuticals, Cincinnati, Ohio, USA
Department of Community and Family Medicine, Division of Biometry, Duke University Medical Center, Durham, North Carolina, USA

Manuscript received July 2, 1999; revised manuscript received March 1, 2000, accepted April 13, 2000.

Reprint requests and correspondence: Dr. Edward L.C. Pritchett, Room 04280, Duke South Hospital, DUMC-3477, Durham, North Carolina 27710
ed.pritchett{at}duke.edu

	Abstract

Top Abstract Methods Results Discussion Appendix References

 
OBJECTIVES

The purpose of this study was to assess the effectiveness of azimilide, a class III antiarrhythmic drug, in reducing the frequency of symptomatic arrhythmia recurrences in patients with atrial fibrillation, atrial flutter or both.

BACKGROUND

Atrial fibrillation is an increasingly common disorder of the heart rhythm, and most patients with this problem are identified because they have symptoms associated with their arrhythmia. New antiarrhythmic therapies are needed to treat patients with this problem.

METHODS

A total of 384 patients with a history of atrial fibrillation, atrial flutter or both were randomly assigned to receive once daily doses of placebo or azimilide; recurrent symptomatic arrhythmias were documented using transtelephonic electrocardiogram (ECG) recording. Azimilide 50 mg, 100 mg or 125 mg was tested; the primary efficacy analysis compared the time to first symptomatic recurrence in the combined azimilide 100 mg and 125 mg dose groups with that in the placebo group using the log-rank test.

RESULTS

In the primary efficacy analysis, the time to first symptomatic arrhythmia recurrence was significantly prolonged in the combined azimilide 100 mg and 125 mg daily dose group compared with the placebo group (chi-square 7.96, p = 0.005); the hazard ratio (placebo:azimilide) for this comparison was 1.58 (95% confidence interval [CI] = 1.15, 2.16). In comparisons between individual doses and placebo, the hazard ratio for the 50 mg daily dose was 1.17 (95% CI = 0.83, 1.66; p = 0.37); for the 100 mg group, dose was 1.38 (95% CI = 0.96, 1.98; p = 0.08), and for the 125 mg group, dose was 1.83 (95% CI = 1.24, 2.70; p = 0.002).

CONCLUSIONS

Azimilide significantly lengthened the symptomatic arrhythmia-free interval in patients with a history of atrial fibrillation, atrial flutter or both.

Abbreviations and Acronyms   AF = atrial fibrillation   BID = twice daily   CI = confidence interval   ECG = electrocardiogram   QD = daily

	Methods

Top Abstract Methods Results Discussion Appendix References

 
Entry criteria.   To be eligible, male or female patients with age 18 years were required to have a history of symptomatic AF, atrial flutter or both and to be candidates for antiarrhythmic therapy based on the judgment of the investigator enrolling them. Investigators were required to provide an electrocardiogram (ECG) showing AF or atrial flutter that had been recorded within 24 months of the date of randomization, and patients were required to be in sinus rhythm at the time of randomization. Important cardiovascular exclusions were angina at rest; symptoms of heart failure at rest; thoracic surgery, cardiac surgery or myocardial infarction within two months; a history of torsade de pointes or any other polymorphic ventricular tachycardia; resting heart rate <50 beats/min or QTc on an ECG recording in sinus rhythm >440. Other exclusion criteria were blood urea nitrogen >50 mg/dl or serum creatinine >2.0 mg/dl.

Randomization and follow-up.   A permuted block randomization scheme was used to assign equal numbers of patients to four treatment groups: placebo or azimilide 50 mg, 100 mg or 125 mg. The assigned treatment was given twice a day (BID) for three days (the loading period) and then the frequency was reduced to QD during the efficacy period for up to 180 days. If a patient had a symptomatic arrhythmia recurrence during the loading period and the arrhythmia was present at midnight of day 3, then the efficacy period was adjusted to begin at the first time the patient had documented resumption of sinus rhythm. If sinus rhythm was not restored (spontaneously or by pharmacologic or direct current cardioversion) by day 10, the patient was withdrawn from the trial.

When initiating randomized therapy, no titration was used and no dose adjustments were made for weight, gender, serum creatinine, associated diseases or concomitant medications. Treatment was initiated in both inpatients and outpatients. Symptomatic arrhythmia recurrence was documented using transtelephonic ECG monitoring. Electrocardiograms recorded during hospital stays or emergency department visits also were obtained; all ECGs from symptomatic arrhythmia recurrences were reviewed by an event committee that was blinded to the patient’s treatment assignment and arrhythmia history. Transtelephonic ECG monitoring also was used every two weeks during follow-up to record an ECG when patients were asymptomatic. Patients completed follow-up by having a symptomatic recurrence of their arrhythmia documented by ECG or by finishing 180 days with no arrhythmia recurrence.

Data analysis.   The protocol explicitly specified primary, secondary and additional efficacy analyses. Statistical analyses were done using SAS/STAT (SAS Institute Inc., Cary, North Carolina). The primary outcome variable was the time to first symptomatic arrhythmia recurrence documented by an ECG consistent with AF, atrial flutter or paroxysmal supraventricular tachycardia (completion events). The Kaplan-Meier life-table method was used to display the outcome data and to estimate the median recurrence time for each group (3). Differences between groups were compared with the log-rank test. The Cox proportional hazards model was used to calculate a hazard ratio (placebo:azimilide) for each comparison (3).

The protocol-specified primary efficacy analysis compared the placebo group with the combined 100 mg QD and 125 mg QD doses during the efficacy period (excluding the three-day loading period); this analysis used a two-sided log-rank test and alpha = 0.05. Combining the 100 mg and 125 mg dose groups increased the statistical power of the primary data analysis compared with doing multiple analyses of individual doses. Additional protocol-specified efficacy analyses compared individual doses with placebo.

Because the primary efficacy analysis excluded symptomatic arrhythmia events that occurred during the loading period, all efficacy analyses were repeated using data from the loading period as well as the efficacy period (called day 1 analyses). These latter analyses, which were specified in the protocol, were planned to assess whether including the loading period, when blood azimilide concentrations should have been lower compared with the efficacy period, decreased the magnitude of the treatment effect.

A log-rank trend test was done across all doses to test for a dose response. A secondary efficacy analysis specified in the protocol compared heart rate during arrhythmia recurrences. Finally, asymptomatic arrhythmia occurrences were tabulated in the four treatment groups in an exploratory analysis.

Adverse events were counted for all randomized patients from day 1 and, therefore, included both the loading period and the efficacy period. Patients were required to withdraw for QTc >525. Adverse events were included in the safety analysis if they occurred within 30 days of patient withdrawal for any reason. Safety variables reported here are deaths, torsades de pointes, withdrawal for 12-lead ECG with QTc 525 and withdrawals for any other adverse event. The QTc was measured on day 4 from a 12-lead ECG and compared with the QTc measured on a baseline (pretreatment) ECG.

Study chronology.   The first patient was enrolled on September 4, 1996, and the last patient finished follow-up on October 6, 1997. The protocol was approved by an institutional review board for clinical investigations at each study site. One protocol amendment was filed to change the statistical analysis plan; this amendment was filed before the study data base was locked or unblinded.

	Results

Top Abstract Methods Results Discussion Appendix References

 
Study population.   A total of 384 patients were recruited at 97 sites and randomized among the four treatments: 93 patients to placebo, 101 patients to azimilide 50 mg QD, 97 to 100 mg QD and 93 to 125 mg QD. Twenty-eight patients (5.3%) were in the hospital at the time they received their first dose of blinded therapy. Demographic and baseline cardiovascular characteristics were well balanced among the treatment groups (Table 1) as was the use of common concomitant medications (Table 2). Overall 76.8% of patients had some form of structural heart disease, which was defined as a diagnosis of coronary artery disease (with or without myocardial infarction), congestive heart failure, valvular heart disease, hypertension with cardiomyopathy, hypertension with left ventricular hypertrophy, left atrial enlargement by echocardiogram or conduction system disease. Thirty-four percent had a history of treatment with direct current cardioversion before randomization.

Primary efficacy analysis.   Among the 384 randomized patients, 367 entered the efficacy period in sinus rhythm after the end of the loading period. The primary efficacy analysis compared placebo patients (n = 87) who entered the efficacy period with a combined group of patients who received azimilide 100 mg QD and patients who received azimilide 125 mg QD (n = 181). The log-rank test p value for this comparison was 0.005 (chi-square 7.96), and the hazard ratio was 1.58 (95% confidence interval [CI] = 1.15, 2.16). The median time to completion event in the placebo group was 17 days compared with 60 days in the combined azimilide group (Fig. 1). The result of the primary efficacy analysis was consistent across subgroups (Fig. 2); that is, efficacy in none of the subgroups was significantly different from efficacy in the overall primary analysis.

View larger version (17K): [in this window] [in a new window]   Figure 1 Primary efficacy analysis. Time to symptomatic arrhythmia recurrence was significantly longer in the combined azimilide 100 mg QD and 125 mg QD dose group compared with the placebo group (chi-square 7.96, p = 0.005). QD = daily.

View larger version (16K): [in this window] [in a new window]   Figure 2 Efficacy in subgroups. None of the subgroups demonstrated efficacy that was significantly different from the overall primary efficacy analysis. CHF = congestive heart failure; HD = heart disease; SHD = structural heart disease.

Individual dose efficacy.   Higher doses of azimilide were associated with better efficacy (Fig. 3) in the comparison of individual dose groups with the placebo group measured during the efficacy period. A log-rank trend test across all doses was significant (chi-square = 9.8, p = 0.002); that is, as dose increased from placebo to 125 mg QD, efficacy improved. The hazard ratios uniformly improved across doses: 50 mg 1.17 (95% CI = 0.83, 1.66; p = 0.37), 100 mg 1.38 (95% CI = 0.96, 1.98; p = 0.08) and 125 mg 1.83 (95% CI = 1.24, 2.70; p = 0.002). Also, the median time to first symptomatic arrhythmia recurrence was 17 days in the placebo group compared to 22 days in the azimilide 50 mg QD group, 41 days in the 100 mg group and 130 days in the 125 mg group.

View larger version (23K): [in this window] [in a new window]   Figure 3 Efficacy in individual doses compared with placebo. Time to first symptomatic arrhythmia recurrence increased across doses as the dose changed from placebo to 50 mg QD, 100 mg QD and 125 mg QD. CHF = congestive heart failure; QD = daily.

The mean heart rates shown on the ECGs recorded at the time of completion events were 123.1 beats per min in the placebo group compared with 113.1 beats per min in the azimilide 50 mg QD group (p = 0.04), 112.9 in the 100 mg QD group (p = 0.06) and 113.6 in the 125 mg QD group (p = 0.08). For the comparison of groups used in the primary efficacy analysis (combined azimilide 100 mg and 125 mg dose group with placebo, as specified in the protocol), the heart rate on azimilide was significantly slower (123.1 beats/min vs. 113.2 beats/min, p = 0.04).

Asymptomatic atrial fibrillation and atrial flutter were occasionally recorded by transtelephonic ECG monitoring at the time of the biweekly routine contacts. These asymptomatic rhythms were recorded from 9.2% of patients in the placebo group compared with 8.1% of the azimilide 50 mg QD group, 4.3% of the 100 mg dose group and 4.4% of the 125 mg dose group (p > 0.20 for all comparisons vs. placebo).

Safety.   The variables analyzed to assess safety in all randomized patients included deaths, episodes of torsade de pointes and withdrawals due to adverse events. There were no deaths in the placebo group or the azimilide 100 mg dose group; there were two deaths in the azimilide 50 mg dose group and one in the 125 mg group. One of the deaths in patients receiving azimilide 50 mg QD was a 71-year-old woman who died of a stroke 29 days after beginning randomized therapy and 21 days after discontinuing randomized therapy. The other death in a patient receiving azimilide 50 mg QD was unobserved, presumed sudden death 35 days after randomization. This patient was a 61-year-old man with diabetes and a history of myocardial infarction and exercise-induced angina. The death in a patient receiving azimilide 125 mg QD was a 70-year-old man with a history of coronary artery disease, bypass grafting, heart failure, stroke, transient ischemic attacks and carotid endarterectomy two weeks before randomization. This patient had unwitnessed and presumed sudden death eight days after randomization.

One patient in the 100 mg dose group, an 86-year-old woman, had torsade de pointes on day 4 of blinded therapy while she was in atrial flutter with 2.72 s pauses. She recovered and discontinued protocol therapy.

The QTc measured on day 4 was compared with the baseline QTc and showed a mean (± standard deviation) change of +1.0% (±6.6%), +5.3% (±8.2%), +6.2% (±8.3%), +8.5% (±9.1%) in the placebo, 50 mg, 100 mg and 125 mg azimilide groups, respectively. Seven patients were required to withdraw for QTc >525 on ECGs recorded 4 to 187 days after randomization. One of these patients was receiving azimilide 50 mg QD, three were receiving 100 mg QD, and three were receiving 125 mg QD. In addition, withdrawal from the study due to an adverse event occurred in 0, 4, 2 and 2 patients in the placebo, 50 mg, 100 mg and 125 mg dose groups, respectively. The four patients who withdrew from the azimilide 50 mg group had (one each) a skin rash, abnormal liver function tests, diarrhea and a flu-like illness with weakness, dizziness and paresthesias. Two patients withdrew from the 100 mg dose group for (one each) dizziness and syncope. The latter patient was also taking the antiarrhythmic drug disopyramide, a protocol violation; an explanation for the syncope was not found. The two patients who withdrew from the 125 mg dose group had nonsustained ventricular tachycardia during hypokalemia (one patient) and premature ventricular beats (one patient).

	Discussion

Top Abstract Methods Results Discussion Appendix References

 
Efficacy of azimilide.   This randomized clinical trial demonstrated that azimilide is an effective antiarrhythmic drug to reduce the frequency of symptomatic arrhythmia recurrences in patients with AF, atrial flutter or both, and it demonstrated the effective dose range for azimilide. In the primary efficacy analysis, the combined azimilide 100 mg and 125 mg dose group was significantly better than placebo (p = 0.005). The hazard ratio for this comparison was 1.58 (95% CI = 1.15, 2.16), and the median time to first symptomatic arrhythmia recurrence was lengthened from 17 days in the placebo group to 60 days in the combined azimilide group. The analysis of individual doses defined the effective dose range for azimilide. The 50 mg QD dose showed no relevant treatment effect while the 100 mg and 125 mg QD doses both showed clinically important effects.

An event committee reviewed all ECGs from symptomatic events and classified completion events as most consistent with either AF, atrial flutter or paroxysmal supraventricular tachycardia, and AF was the rhythm recorded during completion events in the vast majority of patients in all treatment groups. Importantly, higher doses of azimilide did not appear to increase the occurrence of atrial flutter compared with AF as has been reported with some other antiarrhythmic drugs (4). There was a modest decrease in heart rate during completion events when the combined azimilide 100 mg and 125 mg group was compared with the placebo group. This decrease in heart rate, however, was not accompanied by evidence of an increase in the occurrence of asymptomatic arrhythmias detected by routine biweekly monitoring (5). In fact, asymptomatic arrhythmias appeared to decrease slightly or higher doses of azimilide although the decrease was not statistically significant. It is not known, of course, whether asymptomatic AF is associated with any important adverse patient outcome, nor is it known whether treating asymptomatic AF with an antiarrhythmic drug is associated with beneficial effects. The effect of antiarrhythmic therapy on asymptomatic arrhythmias, however, warrants further study.

Safety.   More than 90% of patients began randomized therapy with azimilide as an outpatient, and azimilide was well tolerated. Torsade de pointes occurred in only one patient in this study. Three deaths occurred during the study. All occurred in patients with coronary artery disease, and all were thought to have a cardiovascular cause. Two of the deaths were in patients receiving azimilide 50 mg QD, the lowest dose tested and a dose not associated with clinical efficacy. An efficacy study of this size with only three deaths among 384 randomized patients is insufficient to establish the presence or absence of an effect of azimilide on mortality.

Patient withdrawals due to adverse events occurred infrequently and did not appear to increase with the higher doses tested. A precise estimate, however, of the rate at which these events occur in patients taking azimilide will require studying more patients.

Trial design.   This randomized trial included some novel features. Simple inclusion and exclusion criteria were designed to enroll a study population that was representative of many patients with AF and atrial flutter who are prescribed antiarrhythmic drug therapy; patients with all types of AF were included rather than limiting the trial to a single classification such as "paroxysmal" or "chronic" as has been done in many previous trials (6–10). The patients’ arrhythmia histories demonstrated the frequent prior occurrence of multiple arrhythmias in these patients. Azimilide predominantly was begun in an outpatient setting, and no dose titration was used for patients receiving higher doses. Transtelephonic ECG monitoring provided objective documentation of the rhythm at the time of symptoms, and event committee review of all symptomatic ECGs assured a uniform standard for interpretation of these ECGs.

Conclusions.   Azimilide may be a promising new antiarrhythmic drug, but additional data on both efficacy and safety are required to establish its role in clinical practice. In this randomized clinical trial, azimilide was initiated in an outpatient setting, was administered once daily, did not require dose titration, showed promising efficacy and was well tolerated.(Appendix)

	Appendix

Top Abstract Methods Results Discussion Appendix References

 
Investigators, Subinvestigators, Study Coordinators, Institution Name, Number of Patients Enrolled, City: Steven Turner, MD, Cynthia M. Turner, RN, BSN, Heart Clinic of the Ozarks, Inc. (24), Springfield, Missouri; Jay L. Dinerman, MD, Jacksonville Heart Center (20), Jacksonville Beach, Florida; Steven Promisloff, MD, Michael Toren, MD, Danielle Jones, Rebecca Baird, Hillsboro Cardiology (13), Hillsboro, Oregon; Laurence Yellen, MD, Thomas J. Karras, MD, Olga B. Anspe, CCRC, Nancy Junker, CCRC, Cardiology Association Medical Group of East San Diego, Inc. (13), San Diego, California; Daniel Gottlieb, MD, Barbara Westcott, MFA, South Seattle Consulting Physicians (11), Seattle, Washington; Imran K. Niazi, MD, Raed Sweidan, MD, Charles Lanzarotti, MD, Joann Kiemen, RN, Concetta Wagner, RN, Wisconsin Center for Clinical Research (11), Milwaukee, Wisconsin; Richard Wolf, MD, FACC, Abdel Ahmed, MD, Noah Chelliah, MD, Emad Dodin, MD, Dianne Vold, LPN, Kelly Hagen, RN, Denise Carter, RN, United Hospital (11), Grand Forks, North Dakota; David P. Margolis, MD, Oklahoma Heart (10), Tulsa, Oklahoma; C. Andrew DeAbate, MD (9), New Orleans, Louisiana; Rokay Kamyar, MD, Jack S. Madowitz, MD, David Jinich, MD, George P. Reynolds, RCPT, Institute of HealthCare Assessment, Inc. (9), San Diego, California; Nampalli Vijay, MD, Western Cardiology Associates (9), Denver, Colorado; C. Basil Williams, MD, G. Thomas Blanch, MD, Barbara Fowler, Ogden Research Foundation (9), Odgen, Utah; Bart G. Denys, MD, Sandeed A. Patel, MD, Kenneth E. Wong, MD, Stacy M. Henry, CCRC, Cardiovascular Institute of the South Thibodaux (8), Thibodaux, Louisiana; Jose J. Fernandez, MD, Donald Gleason, MD, Robert Hirsch, MD, Jerome Rothbaum, MD, Leonard Joffe, MD, Cynthia Cengic, RN, BSN, Cathy Revere Darby, Advanced Clinical Theapeutics, an affiliate of Affiliated Research Center (8), Tucson, Arizona; Thomas Parker, MD, San Gabriel Clinic (8), Georgetown, Texas; Leland Sprinkle, FACC, MD, M. Joseph McGreevy, MD, FACC, Ronald K. Goldberg, MD, FACC, Sylvia Gerry, BS, C-CVT, Mary Barrett, Cardiology Medical Group of San Diego (8), La Mesa, California; Stuart J. Connolly, MD, Cathrine LeFeuvre, Lorraine Morrison, RN, Hamilton General Hospital (7), Hamilton, Ontario, Canada; Michael Famularo, FACC, MD, Michael Wichman, MD, FACC, Spencer Kulick, MD, FACC, Robert Doria, MD, FACC, Steven Pontius, MD, FACC, Mark Sada, MD, Lawrence VonDollen, MD, FACC, Elizabeth Peck, RN, Coastal Cardiology (7), San Luis Obispo, California; Bruce Goldreyer, MD, Robert Grossman, MD, Norman Zinner, MD, Christina Dyer, Laura Blaszkiewicz, RN, Mandy Sauzzi-Carnes, RN, Western Clinical Research (7), Torrance, California; Michael Imburgia, MD, Teri Stickler, RN, BSN, Louisville Cardiology (7), Louisville, Kentucky; Ronald P. Karlsberg, MD, Joshua Penn, MD, Eli Gang, MD, Tracey S. Gerez, BS, MA, Susan E. Jackman, RN, MS, Cardiovascular Research Institute of Southern California (7), Beverly Hills, California; Steven West, MD, Southwest Florida Heart Group (7), Fort Myers, Florida; Steven Borzak, MD, Charles R. Webb, MD, Stephen Smith, MD, James Tisdale, MD, Theresa Cruz, RN, Henry Ford Hospital (6), Detroit, Michigan; Ira Mitchell Dauber, MD, J. Kern Buckner, MD, Steve Glow, FNP, Terry Wilcox, ANP, Christie Brown, FNP, Shari Bowden, RN, South Denver Cardiology Associates (6), Denver, Colorado; Jacques H.F. Lenis, MD, Peter Carmichael, RN, Nathalie Pilon, RN, INVASCOR Clinical Research (6), Longueuil, Quebec, Canada; Alan Mobley, MD, Bonnie Stevens (6), Conroe, Texas; Melvin Tonkon, FACC, FACP, MD, Cathy Fox, BS, Anaheim Heart and Research Institute (6), Anaheim, California; Jerome Blumenthal, MD, Jean Warren, RCVT, Cardiology & Internal Medicine Associates (5), Marietta, Georgia; Wynne Crawford, MD, C. McGavock Porter, MD, John L. Finklea, MD, H. Forrest Flemming, MD, David Jenkins, MD, David N. Goerge, MD, Paul B. Moore, MD, Laura Thompson, PA, R. Eric Crum, MD, Michael Salvia, MD, Robert Robichaux, MD, W. Ross Davis, MD, Eliyya G. Abbud, MD, Theresa Garrett, RN, R. Rena Grines, RN, Ernest Parker, RN, Mark Platt, RN, Montgomery Cardiovascular Associates, P.C. (5), Montgomery, Alabama; Harold Fleming, MD; Ronald Littlefield, MD; Deborah Weathers, RN; Susan Brown, CCRC; MedQuest, Inc. (5), Greer, South Carolina; Martin Frey, MD, Walter Hepp, MD, Mary Healy, ARNP, Kori Thomas, CNMT, EMT, Heart Center (5), Sarasota, Florida; William Grossman, MD, Charleston Cardiology (5), Charleston, South Carolina; David Kraus, FACC, MD, Massimo F. Giusti, MD, Lisa Burch, RN, Cindy Lee, RN, Cardiology Associates of Memphis (5), Memphis, Tennessee; Robin A. Kuritzky, MD, Royal Columbia Hospital (5), New Westminster, British Columbia, Canada; G. Calvin MacCallum, MD, Sheila Griffiths-Beresford, RN, Health Care Corporation of St. John’s General Hospital Site (5), St. John’s, Newfoundland, Canada; P.F. Adrian Magee, MD, Vasilies Papademetriou, MD, Puneet Narayan, MD, Mrinal Sharma, MD, Erica Marino, CRC, Mary Ellen Royalty, RN, Clinical Research Institute of Northern Virginia (5), Springfield, Virginia; Dennis Ruff, MD, Emanuel P. DeNoia, MD, Donna Griffin, LVN, Healthcare Discoveries (5), San Antonio, Texas; James W. Smith, MD, Karl P. Undesser, PhD, MD, Molly B. Kennedy, RT, MS, Boise Heart Clinic (5), Boise, Idaho; Stephen Winters, MD, Jay H. Curwin, MD, John S. Banes, Jr., MD, Jennifer Heric, RN, MSN, Morristown Memorial Hospital (5), Morristown, New Jersey; Robert Benson, FACC, MD, Candy Ledbetter, RN, BSN, Jacksonville Center for Clinical Research (4), Jacksonville, Florida; John Boulet, MD, ACRC/Arizona Clinical Research Center (4), Tucson, Arizona; Luis Campos, MD, Salah El Hafi, MD, Rick Keister, LVN, CRC, Med-Tech, Inc. (4), Houston, Texas; Harry Colfer, MD, Peter Levamovich, MD, Denise Antonishen, RN, Colleen Shaw, RN, Burns Clinic (4), Petoskey, Missouri; Stuart Damore, MD, Karen Ratner, LVN, Center for Clinical Research (4), Austin, Texas; Robert Davidson, MD, Tower Cardiology Research (4), Los Angeles, California; Mark Geller, MD, Anita R. Betschart, RN, BS (4), Pittsburgh, Pennsylvania; Richard Henthorn, MD, The Christ Hospital (4), Cincinnati, Ohio; William K. K. Hui, MBBS, FRCP (Edin), FRCP (C), FACC, MD, Neil Brass, BSc, MD, FRCP (C), Randall G. Williams, MD, FRCP (C), FACC, Kenneth O’Reilly, BSc, MD, FRCP, Linda Kvill, RN, BSC, N, Royal Alexandra Hospital (4), Edmonton, Alberta, Canada; John King, MD (4), Laguna Hills, California; Wai Hung Lee, MD, Joseph Covello, MD, Daniel Kreichbaum, PharmD, Helen Orvis, CCRC, Health Advance Institute (4), South Bend, Indiana; Louis Rosenfield, MD, Paul K. Albert, ARNP, MSN, Paul Eubanks, CMA, BSN, Cardiology Associates (4), Port Charlotte, Florida; Manfred Sandler, MD, E. Edward Proctor, MD, Searls Videlfsky, MD, Corrine F. Quinn, MD, James E. Barnhill, III, MD, Larisa Brust, RN, BSN, PrevisionMed, Inc. (4), Duluth, Georgia; Frederick Zugibe, MD; Anna R. Zugibe; Newark Cardiovascular Clinic (4), Newark, New York; Arthur Green, DO, James Roberts, MD, Benigno Bobon, MD, Carolyn Goddard, RN, The Crucible Group (3), Tucker, Georgia; Steven Kutalek, MD; Christine Saari, MSN, CCRN, CCRC; Hahnemann University Hospital (3), Philadelphia, Pennsylvania; Donald Meacham, MD, Cardiology Consultants, P.A. (3), Little Rock, Arkansas; Robert Mittleman, MD, University of Massachusetts (3), Worcester, Massachusetts; Douglas Rothrock, MD, Scott B. Baron, MD, Daniel C. Fisher, MD, Teri Seim, RN, Pacific Coast Clinical Coordinators (3), Carmichael, California; U.R. Shettigar, MD, George H. Barbier, MD, M. Siddique, MD, M. Schmiedt, MD, M. Bialow, MD, Doreen Appunn, BSN, Rebecca Diemer, RN, VA Medical Center, Clinical Research (3), Bay Pines, Florida; Eric Spivack, MD, Clinical Cardiology Associates (3), Aventura, Florida; Jeffrey L. Anderson, MD, Sanjeev Trehan, MD, Joseph B. Muhlestein, MD, Kirti Salunkhe, MD, LDS Hospital (2), Salt Lake City, Utah; David Benditt, MD, University of Minnesota Medical School (2), Minneapolis, Minnesota; Jorge Bonet, MD, Kathryn G. Ilott, ARCT, Apex Clinical Research Ltd. (2), Victoria, British Columbia, Canada; Frank Cardello, MD, James V. Felicetta, MD, Nicolette Estrada, RN, MSFNP-C, Sharon Pebbus, RN, BSN, CCRC, Carl T. Hayden, VAMC (2), Phoenix, Arizona; Andrew Cohen, MD, Aurora Denver Cardiology Associates (2), Aurora, Colorado; Luis Constantin, MD, Steven Zelenkofske, DO, Mary Ann Gergits, RN, Heart Care Group (2), Allentown, Pennsylvania; Paul Dorian, MD, D. Newman, MS, Jan Mitchell, RN, St. Michael’s Hospital (2), Toronto, Ontario, Canada; Boris Kerzner, MD (2), Baltimore, Maryland; George Klein, MD, University Hospital (2), London, Ontario, Canada; Claude Nadeau, MD, Deborah G. O’Connor, LPN, Lewis-Gale Clinic, Inc. (2), Salem, Virginia; Kevin Rapeport, MD, George P. Reynolds, RCPT, Harold J. Guy, MD, Institute of HealthCare Assessment, Inc. (2), San Diego, California; Anita Robinson, MD, Future Scripts (2), Spokane, Washington; David Sackin, MD, Ira Klimberg, MD, J. Robert Mcghee, MD, Chan Das, MD, Sid Clevinger, MD, Cary Harbater, CCRC, Urology Center of Florida (2), Ocala, Florida; Joel Sklar, MD, Cardiology Associates of Marin & San Francisco Medical Group, Inc. (2), Larkspur, California; Karen Beckman, MD, Mario Gonzalez, MD, Tammy Denton, RN, University of Oklahoma (1), Oklahoma City, Oklahoma; Anil Bhandari, MD, Beverly Firth, RN, MN, Good Samaritan Hospital (1), Los Angeles, California; R.K. Bhargava, FRCPC, MD, Optimum Clinical Research (1), Oshawa, Ontario, Canada; Paul Colavita, MD, John Fedor, MD, Robert Svenson, MD, John Gallagher, MD, Samuel Zimmon, MD, Connie Dellinger, RN, BSN, Gale Schwarz, RN, The Sanger Clinic, P.A./Carolinas Medical Center (1), Charlotte, North Carolina; George Dennish, MD, Damluji-Bari Clinic (1), San Diego, California; David Fitzgerald, MD, Bowman Gray School of Medicine (1), Winston-Salem, North Carolina; James J. Heger, MD, Lisa Knepper, RN, BSN, Stucky Research Center (1), Fort Wayne, Indiana; Charles W. Karpen, MD, Yi W. Karpen, MS, Decatur Memorial Hospital (1), Decatur, Illinois; Shane Kimber, MD, University of Alberta (1), Edmonton, Alberta, Canada; Greg Koshkarian, FACC, FCCP, MD, Erica C. Forsyth, RN, Desert Cardiology of Tucson (1), Tucson, Arizona; Neal Lerner, MD, Janice Samimi, RN, Manitoba Clinic (1), Winnipeg, Manitoba, Canada; A. R. Zaki Masud, MD, Buffalo Heart Group (1), Buffalo, New York; David M. Mokotoff, MD, David W. Kohl, MD, John G. Finn, MD, Barry S. Weinstock; MD, Solomon Fishman, MD, Bruce Rice, PA-C, Christine Conner, RN, Bay Area Heart Center (1), St. Petersburg, Florida; Richard L. Page, MD, Jose A. Joglar, Patrick J. Welch, Lauren Nelson, BSN, RN, University of Texas Southwestern Medical Center (1), Dallas, Texas; Michael Ptasnik, MD, J.T. Okin, MD, R.K. Law, MD, J.T. Ferrell, MD, J.D. Rubinstein, MD, D.C. Thompson, MD, R.D. Spangler, MD, J.T. Svinarich, MD, F.G. Thurman, MD, C.K. Benedict, MD, Barbara J. McKinster, Cardiovascular Associates, PC (1), Denver, Colorado; Antone F. Salel, MD, A Medical Corporation (1), Encinitas, California; Robert Schnitzler, MD (1), San Antonio, Texas; Matthew Schwinger, MD, Eugene Dula, MD, Teri Matta, CCRC, Cardiovascular Consultants Medical Group (1), Van Nuys, California; Yoseph Shalev, MD, Terry Hornik, RN, Milwaukee Heart Institute (1), Milwaukee, Wisconsin; Sudeep Singh, MD, SARC Research Center (1), Fresno, California; J. Thomas Suh, MD, Kathy Vittum, RN, Regions Hospital (1), St. Paul, Minnesota; John Walker, MD, James E. Carley, MD, David L. Williams, MD, Dianne Tracy, RN, Cardiology Research Associates (1), Ormond Beach, Florida; John Wilson, MD, Cardiology Associates of Cincinnati, Inc. (1), Cincinnati, Ohio; Scientific Advisory Committee: Edward L.C. Pritchett, MD (Chairman), Duke University Medical Center, Durham, North Carolina; Stuart J. Connolly, MD, McMaster University, Hamilton, Ontario, Canada; Stephen R. Marcello, MD, Procter and Gamble Pharmaceuticals, Cincinnati, Ohio; Richard L. Page, MD, University of Texas Southwestern Medical Center, Dallas, Texas; Daniel Schnell, PhD, Procter and Gamble Pharmaceuticals, Cincinnati, Ohio; Elizabeth A. McCarthy, RN (nonvoting), Duke University Medical Center, Durham, North Carolina; Martin D. Phillips, MD (nonvoting), Procter and Gamble Pharmaceuticals, Cincinnati, Ohio; William E. Wilkinson, PhD (nonvoting), Duke University Medical Center, Durham, North Carolina. Data and Safety Monitoring Board: D. George Wyse, MD, PhD (Chairman), University of Calgary, Calgary, Alberta, Canada; Eugene Passamani, MD, Suburban Hospital, Bethesda, MD; William G. Stevenson, MD, Brigham and Women’s Hospital, Boston, Massachusetts; Nanette K. Wenger, MD, Emory University School of Medicine, Atlanta, Georgia; Janet T. Wittes, PhD, Statistics Collaborative, Inc., Washington, DC; William E. Wilkinson, PhD (nonvoting), Duke University Medical Center, Durham, North Carolina; Event Committee: Richard L. Page, MD (Chairman), University of Texas Southwestern Medical Center, Dallas, Texas; Mark D. Carlson, MD, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio; Anne B. Curtis, MD, University of Florida, Gainesville, Florida; Mark E. Hamer, MD, Evanston Hospital, Northwestern University Medical School, Evanston, Illinois; Katherine T. Murray, MD, Vanderbilt University School of Medicine, Nashville, Tennessee; Elizabeth A. McCarthy, RN (nonvoting), Duke University Medical Center, Durham, North Carolina; Lesley R. Hudson, BS, MT, Quintiles Laboratory Limited, Smyrna, Georgia; Linda Brokaw, BS, Kathleen Walsh, BA, Karen Ferretti, Premier Research Worldwide, Philadelphia, Pennsylvania; Maureen Pieper, MSN, Mary Baugh, RPh, Peter E. Djuric, PharmD, Kendle International, Cincinnati, Ohio.

	Footnotes

 
This study was supported by grants from Procter and Gamble Pharmaceuticals, Cincinnati, Ohio.

	References

Top Abstract Methods Results Discussion Appendix References

 
1. Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation. 1997;96:2455–2461[Abstract/Free Full Text]

2. Salata JJ, Brooks RR. Pharmacology of azimilide dihydrochloride (NE-10064), a class III antiarrhythmic agent. Cardiovasc Drug Rev. 1997;15:137–156[CrossRef]

3. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York: John Wiley; 1980.

4. Crijns HJGM, van Gelder IC, Lie KI. Supraventricular tachycardia mimicking ventricular tachycardia during flecainide treatment. Am J Cardiol. 1988;62:1303–1306[CrossRef][Medline]

5. Page RL, Wilkinson WE, Clair WK, McCarthy EA, Pritchett ELC. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. Circulation. 1994;89:224–227[Abstract/Free Full Text]

6. Anderson JL, Gilbert EM, Alpert BL, et al. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Circulation. 1989;80:1557–1570[Abstract/Free Full Text]

7. Boissel JP, Wolf E, Gillet J, et al. Controlled trial of a long-acting quinidine for maintenance of sinus rhythm after conversion of sustained atrial fibrillation. Eur Heart J. 1981;2:49–55[Abstract/Free Full Text]

8. Juul-Moller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation. 1990;82:1932–1939[Abstract/Free Full Text]

9. Gallagher MM, Camm AJ. Classification of atrial fibrillation. PACE. 1997;20:1603–1605

10. Levy S, Novella P, Richard P, Paganelli F. Paroxysmal atrial fibrillation: a need for classification. J Cardiovasc Electrophysiol. 1995;6:67–74

This article has been cited by other articles:

				A. Arya, J. Silberbauer, S. L. Teichman, P. Milner, N. Sulke, and A. J. Camm A preliminary assessment of the effects of ATI-2042 in subjects with paroxysmal atrial fibrillation using implanted pacemaker methodology Europace, April 1, 2009; 11(4): 458 - 464. [Abstract] [Full Text] [PDF]

				I. Savelieva and J. Camm Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches Europace, June 1, 2008; 10(6): 647 - 665. [Abstract] [Full Text] [PDF]

				B. N. Singh and E. Aliot Newer antiarrhythmic agents for maintaining sinus rhythm in atrial fibrillation: simplicity or complexity? Eur. Heart J. Suppl., September 1, 2007; 9(suppl_G): G17 - G25. [Abstract] [Full Text] [PDF]

				K. M Dale and C M. White Dronedarone: An Amiodarone Analog for the Treatment of Atrial Fibrillation and Atrial Flutter Ann. Pharmacother., April 1, 2007; 41(4): 599 - 605. [Abstract] [Full Text] [PDF]

				F. Lombardi, M. Borggrefe, W. Ruzyllo, B. Luderitz, and for the A-COMET-II Investigators Azimilide vs. placebo and sotalol for persistent atrial fibrillation: the A-COMET-II (Azimilide-CardiOversion MaintEnance Trial-II) trial Eur. Heart J., September 2, 2006; 27(18): 2224 - 2231. [Abstract] [Full Text] [PDF]

				Writing Committee Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 651 - 745. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]

				C. M. Pratt, S. N. Singh, H. R. Al-Khalidi, J. M. Brum, M. J. Holroyde, S. R. Marcello, P. J. Schwartz, A. J. Camm, and ALIVE Investigators The efficacy of azimilide in the treatment of atrial fibrillation in the presence of left ventricular systolic dysfunction: Results from the Azimilide Postinfarct Survival Evaluation (ALIVE) trial J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1211 - 1216. [Abstract] [Full Text] [PDF]

				I. Singer, H. Al-Khalidi, I. Niazi, P. Tchou, T. Simmons, R. Henthorn, M. Holroyde, and J. Brum Azimilide decreases recurrent ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators J. Am. Coll. Cardiol., January 7, 2004; 43(1): 39 - 43. [Abstract] [Full Text] [PDF]

				R. L. McNamara, L. J. Tamariz, J. B. Segal, and E. B. Bass Management of Atrial Fibrillation: Review of the Evidence for the Role of Pharmacologic Therapy, Electrical Cardioversion, and Echocardiography Ann Intern Med, December 16, 2003; 139(12): 1018 - 1033. [Abstract] [Full Text] [PDF]

				A. Capucci and D. Aschieri Antiarrhythmic drug therapy: what is certain and what is to come Eur. Heart J. Suppl., September 1, 2003; 5(suppl_H): H8 - H18. [Abstract] [PDF]

				P. Touboul, J. Brugada, A. Capucci, H. J.G.M. Crijns, N. Edvardsson, and S. H. Hohnloser Dronedarone for prevention of atrial fibrillation: A dose-ranging study Eur. Heart J., August 2, 2003; 24(16): 1481 - 1487. [Abstract] [Full Text] [PDF]

				R. L. Page, T. W. Tilsch, S. J. Connolly, D. J. Schnell, S. R. Marcello, W. E. Wilkinson, E. L.C. Pritchett, and for the Azimilide Supraventricular Arrhythmia Prog Asymptomatic or "Silent" Atrial Fibrillation: Frequency in Untreated Patients and Patients Receiving Azimilide Circulation, March 4, 2003; 107(8): 1141 - 1145. [Abstract] [Full Text] [PDF]

				P. Khairy and S. Nattel New insights into the mechanisms and management of atrial fibrillation Can. Med. Assoc. J., October 29, 2002; 167(9): 1012 - 1020. [Abstract] [Full Text] [PDF]

				M. R. Rosen Blunderbuss to Mickey Mouse: The Evolution of Antiarrhythmic Targets Circulation, September 3, 2002; 106(10): 1180 - 1182. [Full Text] [PDF]

				W. S. Aronow Management of the Older Person With Atrial Fibrillation J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2002; 57(6): M352 - 363. [Abstract] [Full Text]

				J. A. Reiffel Is it Rational, Reasonable or Excessive, and Consistently Applied? One View of the Increasing FDA Emphasis on Safety First for the Release and Use of Antiarrhythmic Drugs for Supraventricular Arrhythmias Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2001; 6(4): 333 - 339. [PDF]

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pritchett, E. L. C. Search for Related Content PubMed PubMed Citation Articles by Pritchett, E. L. C.