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Antiarrhythmic Efficacy of Azimilide in Patients With Atrial
Fibrillation. Maintenance of Sinus Rhythm After Conversion to Sinus
Rhythm
Edward L.C. Pritchett; Peter
Kowey, MD; Stuart Connolly, MD; Richard L. Page, MD; Charles Kerr, MD;
William E. Wilkinson, PhD
Am Heart J. 2006;151(2):1043-1049. ?2006 Mosby,
Inc.
Posted 05/18/2006
Abstract and IntroductionAbstractBackground: Azimilide dihydrochloride (azimilide)
is an investigational antiarrhythmic drug that has been tested in
patients with a variety of arrhythmias. In patients with atrial
fibrillation, it has shown excellent efficacy in some previous trials
and minimal efficacy in others. IntroductionAzimilide dihydrochloride (azimilide) is an investigational antiarrhythmic drug that has been tested in patients with a variety of arrhythmias, including atrial fibrillation, paroxysmal supraventricular tachycardia, ventricular tachycardia with implanted defibrillators, and recent myocardial infarction.[1-4] In previous studies of atrial fibrillation, azimilide was given to patients with a history of this arrhythmia who were in sinus rhythm, and efficacy was measured as time to recurrence of a symptomatic arrhythmia.[2] These studies yielded mixed results.[5] In the current study, azimilide was given to patients who were in atrial fibrillation to explore the value of azimilide in maintaining sinus rhythm after it was restored. MethodsThis multicenter randomized clinical trial was conducted at sites in Canada and the United States. It was called the Azimilide?CardiOversion MaintenancE Trial?I and is known by the acronym A-COMET-I. Entry CriteriaMen and women who were ≥18 years were eligible for enrollment if they had a history of symptomatic atrial fibrillation documented by 12-lead electrocardiogram that had been present for >48 hours and <6 months. Cardiovascular exclusion criteria were systolic blood pressure of >180 mm Hg or diastolic blood pressure of >100 mm Hg; ventricular rate of <70 beat/min; corrected QT interval of >440; atrial fibrillation due to electrolyte imbalance, hyperthyroidism, pericarditis, or other reversible illness; unstable angina; class IV heart failure; Wolff-Parkinson-White syndrome unless treated with successful ablation; moderate or severe hypertrophic, restrictive, or infiltrative heart disease; severe valvular heart disease; single-chamber or DVI pacemaker; implanted defibrillator; a history of syncope or angina precipitated by an arrhythmia; a history of torsades de pointes, any polymorphic ventricular tachycardia, sustained monomorphic ventricular tachycardia, or cardiac arrest; a history of failed electric cardioversion; a history of second- or third-degree atrioventricular block unless a pacemaker had since been implanted; a history of myocardial infarction, cardiac surgery, thoracic surgery, stroke, or reversible ischemic neurologic deficit within the preceding 1 month; a history of treatment with ticlopidine or clopidogrel within the preceding 1 month; a history of prolonged QT syndrome; and family history of prolonged QT syndrome. Patients were also excluded if they had failed efficacy of any class III antiarrhythmic drug. Previous class I or III antiarrhythmic drugs had to be discontinued for >5 half-lives before beginning randomized treatment; amiodarone had to be discontinued for 1 month. Patients were required to have anticoagulation therapy according to standard practice before electric cardioversion. Randomization and Follow-upAzimilide 125 mg and placebo were prepared in identical cellulose film?coated tablets and randomly assigned to patients in a double-blind fashion in a 1:1 ratio. Investigational treatment was given twice daily for days 1 to 3 of the study, during which time patients were hospitalized and monitored. Patients then received the blinded study medication once daily for up to 6 months if sinus rhythm was restored and maintained. If patients were in sinus rhythm on day 4, 5, or 6, they were considered to have "spontaneously cardioverted." Patients who were not in sinus rhythm by this time underwent electric cardioversion. Patients were withdrawn from the study if they did not have sinus rhythm restored by either spontaneous or electric cardioversion. Patients who had sinus rhythm restored entered the "efficacy period" and had scheduled return visits at weeks 2, 4, 6, 8, 10, 12, and 26. They also were asked to return to the study site if they had symptoms of recurrent atrial fibrillation. Patients with a recurrent arrhythmia could remain in the study if they had successful restoration of sinus rhythm after their first recurrence and could continue to be followed for up to 26 weeks. Informed consent for this study complied with US CFR (title 21, Code of Federal Regulations [CFR] 50.25 and 50.27), the International Conference on Harmonization (ICH) Harmonized Tripartite Guideline for Good Clinical Practice, and the Declaration of Helsinki. Informed consent also was approved by review boards for each study site. Electrocardiograms were reviewed and deaths were classified by an event committee whose members were blinded to treatment. Statistical AnalysisThe protocol defined the "intent-to-treat population" as all randomized patients who ingested at least 1 dose of study medication. The primary efficacy analysis was performed on the subgroup of the intent-to-treat population that had structural heart disease. Structural heart disease was defined as any of the following: ischemic heart disease (with or without history of myocardial infarction), congestive heart failure, valvular heart disease, cardiomyopathy, hypertension with left ventricular hypertrophy, hypertension with left ventricular dysfunction, left atrial enlargement, or conduction system disease. The classification of structural heart disease was made before the database was locked and before the study was unblinded and was based on information contained in the case report forms. The diagnosis of an "arrhythmic event" required (1) an electrocardiogram that was interpreted by the event committee as consistent with atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia and (2) duration of ≥24 hours or that required electric cardioversion or hospitalization. The "primary efficacy event" was a compound variable defined as any of the following: (1) symptomatic arrhythmic event on day 4 or later in a patient who had sinus rhythm restored spontaneously or by electric cardioversion; (2) asymptomatic arrhythmic event on day 4 or later in a patient who had sinus rhythm restored spontaneously or by electric cardioversion; (3) symptomatic arrhythmic event that required hospitalization or electric cardioversion; (4) asymptomatic arrhythmia event that required hospitalization or electric cardioversion; (5) failure to be in sinus rhythm either spontaneously or by electric cardioversion on day 4, 5, or 6; and (6) withdrawal before day 4. The primary efficacy analysis compared the survival function between the azimilide and placebo group for the occurrence of a primary efficacy event in the intent-to-treat population with structural heart disease using the log-rank test, 2-sided.[6] The relative risk for recurrence (placebo:azimilide) with 95% CIs was calculated using Cox regression analysis. Using the primary efficacy event, analyses were done in 2 other populations. The first was the intent-to-treat population, and the second was limited to patients in the intent-to-treat population who had structural heart disease and had sinus rhythm on day 4. Power calculations assumed that 75% of patients in the placebo group would have outcome events during the study. With 157 patients per treatment group in the primary efficacy analysis, the study had 80% power to detect a (placebo:azimilide) hazard ratio of 1.50. All patients in the intent-to-treat population were included in the safety analysis. Deaths were classified by the event committee using a variant of the Hinkle system; serious adverse events were defined by current industry guidelines.[7,8] Study ChronologyThe first patient was randomized on September 26, 2000, and the last patient observation was on October 20, 2004. The statistical analysis plan, an amendment to the protocol, was submitted to the Food and Drug Administration before the database was locked and unblinded. ResultsStudy PopulationAmong 446 patients in the intent-to-treat population, 219 were randomly assigned to placebo and 227 were assigned to azimilide. Within this population, 155 placebo patients and 159 azimilide patients had structural heart disease ( Table I ) and were included in the primary efficacy analysis. Primary Efficacy AnalysisSix patients in each treatment group were withdrawn before the start of the efficacy period, and 25 patients in each group failed electric cardioversion ( Table II ). The remaining 124 patients in the placebo group and 128 patients in the azimilide group entered the efficacy period. There was no significant difference between the placebo group and the azimilide group in time to a primary efficacy event (P = .4596, n = 314). The median time to recurrence in both groups was 13 days (Figure 1), and the relative risk for recurrence (placebo:azimilide) was 1.104 (95% CI 0.849-1.436). 
Figure 1. Additional Efficacy AnalysesIn the intent-to-treat population, there was no significant difference between time to a primary efficacy event (P = .4282, n = 446); the hazard ratio (placebo:azimilide) was 1.092 (95% CI 0.878-1.360). In the population of patients who had structural heart disease and were in sinus rhythm on day 4, there was also no significant difference between treatment groups (P = .4293, n = 256, hazard ratio = 1.133, 95% CI 0.832-1.543). SafetyWithin the intent-to-treat population, 1 placebo patient and 3 azimilide patients died during the study. The event committee classified the cause of death in the placebo patient as noncardiovascular, and it classified the cause of all 3 in the azimilide group as cardiac arrhythmic. A total of 153 (69.9%) placebo patients reported 502 adverse events, and 179 (78.9%) azimilide patients reported 609. Sixteen (7.3%) placebo patients reported 27 serious adverse events, and 37 (16.3%) azimilide patients reported 46. Thirteen (5.9%) placebo patients reported 17 serious cardiovascular adverse events, and 26 (11.5%) azimilide patients reported 32. Serious cardiovascular adverse events with frequency in the azimilide group that exceeded the incidence in the placebo group by ≥1% were prolonged QT interval (3.5% vs 0.5%), torsades des pointes (1.8% vs 0.0%), and syncope (1.3% vs 0.0%). Two other azimilide patients had torsades des pointes that was not reported as a serious adverse event, so the total number of azimilide patients with torsades des pointes was 6 (2.6%); 3 (1.3%) occurred during the loading period. One patient with torsades de pointes during the initial hospitalization recovered from this arrhythmia, had study medication discontinued, and then died after hospital discharge. DiscussionThe main finding in this study was the lack of an important benefit of azimilide on reducing the risk for arrhythmia recurrence in the population of patients with structural heart disease who were in atrial fibrillation at the time study treatment began (the primary efficacy analysis). This finding was consistent in the larger intent-to-treat population and in the smaller subpopulation of patients who were in sinus rhythm on day 4; this latter population excluded patients who withdrew during the loading period or failed to achieve sinus rhythm spontaneously or by electric cardioversion. Previous studies of azimilide (using the same 125 mg dose used in this trial) in patients with atrial fibrillation have yielded mixed results.[2,5] A study known as SVA3 tested the 125 mg dose in patients with a history of atrial fibrillation who were in sinus rhythm at the time treatment began.[2] The hazard ratio was highly favorable (1.83, 95% CI 1.24-2.70), but another study (known as SVA4) failed to replicate a treatment effect of this magnitude despite using the same dose. The hazard ratio in this latter study was 1.14 (95% CI 0.89-1.47). A subgroup analysis of the previous azimilide studies, however, suggested that the best efficacy was observed in subgroup of patients defined by structural heart disease or by the occurrence of either ischemic heart disease or congestive heart failure.[5] The primary efficacy analysis in the current study was, therefore, done in patients with structural heart disease; but the current hazard ratio was 1.104, more like the weaker result observed in SVA4 than SVA3. Another new feature in the current protocol compared with previous azimilide protocols was to extend the study population to patients who were in atrial fibrillation at the time that treatment began and who required sinus rhythm to be restored before entering follow-up in the efficacy period. Dofetilide was studied successfully in this population.[9] The current protocol provided an opportunity to test the impression that antiarrhythmic drugs work best in the population of patients who require electric or pharmacologic cardioversion, but azimilide in this population was not more effective than was observed in previous studies that used other populations. The median time to recurrence in this study was 13 days. In 2 other studies using a population of patients who required cardioversion, the median was 5.3 days in a study of dronedarone and 27 days in a study of dofetilide.[9,10] In studies of azimilide in patients who were in sinus rhythm when treatment began, the median was 17 days in SVA3 and 27 days in SVA4.[5] The current protocol also provided an opportunity to collect safety observations with azimilide. There were 3 deaths in the azimilide group compared with 1 in the placebo group. These numbers are very small, and this imbalance may have been due to chance. A large randomized clinical trial of azimilide assessed mortality in postinfarction patients and found that azimilide had neither a positive nor a negative effect.[3] There were 6 (2.6%) occurrences of torsades de pointes in the current protocol, which is a higher rate than reported previously and may reflect a higher incidence of serious forms of heart disease in the population of patients studied in this protocol. The best estimate of the rate of torsades de pointes in patients taking azimilide will come from combining data from all clinical studies. ConclusionThe current study extended experience with azimilide to the population of patients who were in atrial fibrillation at the time treatment began, and it did not demonstrate important efficacy. There may be a modest benefit of azimilide in patients with atrial fibrillation, somewhere between the strong efficacy estimate found in SVA3 and the weaker estimates found in SVA4 and in this current study. .gif){kind=spacer} Table I. Baseline Observations (intent-to-treat population)
Table II. Primary Efficacy Analysis (distribution of event types)
References
Appendix: Study Sites and CommitteesStudy sites (investigator, institution, city, state or province, study coordinators): Richard Abben, MD, Cardiovascular Institute of the South, Houma, LA, Nadine Scott, Jolie Bell; Brian Abbott, MD, Veteran's Administration Connecticut Health Care System, West Haven, CT, Luisa Sheehan; Peter Abel, MD, Cardiovascular Institute of the South, Morgan City, LA, Tammy Albritton; Pierre Abi-Mansour, MD, Advocate Christ Medical Center, Oak Lawn, IL, Diane Braun; Stuart Adler II, MD, St Paul Heart Clinic, St Paul, MN, Jane Rameth, Joy Gilliam; Abdel Ahmed, MD, Altru Health System Research Center, Grand Forks, ND, Dianne Vold; Tristram Bahnson, MD, Duke University Medical Center, Durham, NC, Melissa Holbrook; Anil Bhandari, MD, Los Angeles Cardiology Associates, Los Angeles, CA, Stephanie Mullin; Kevin Browne, MD, Watson Clinic, Lakeland, FL, Barbara Donley; Gregory Buser, MD, Heart and Vascular Institute of Texas, San Antonio, TX, Steve Farris, Renee Zunker; Sam Butman, MD, University of Arizona Sarver Heart Center, Tucson, AZ, Elyse Hannah; Anthony Caruso, MD, Cardiovascular Associates of Virginia, Richmond, VA, Janet Barrett; Yellapragada Chandrashekhar, MD, Veteran's Administration Medical Center, Minneapolis, MN, Barbara Lervik; Mahesh Changlani, MD, Cardiovascular Institute of the South, New Iberia, LA, Amy Chauvin, Joy Bonin; Chiayu Chen, MD, Inland Clinical Research, Riverside, CA, Tina Mercado; Stuart Connolly, MD, Hamilton Health Sciences Center, Hamilton, Ontario, Victoria Malcolm; Benoit Coutou, MD, Recherche Cardiologie, Montreal, Quebec, Melanie Depatie, Barbara Desbiens; Jay Curwin, MD, Morristown Memorial Hospital, Morristown, NJ, Roberta Orzepowski, Arlene Regan; Joel Cutler, MD, Maine Medical Center, Portland, ME, Claire Berg, Jennifer Powers; Bart Denys, MD, Cardiovascular Institute of the South, Thibodaux, LA, Denitra Peltier, Jill Trosclair; Paul Dorian, MD, St Michael's Hospital, Toronto, Ontario, Marnie Kowalewski; Samuel Dudley, Jr, MD, Veteran's Administration Medical Center, Decatur, GA, Alberta Lane; Victor Echenqiue, MD, Medical Research Institute, Slidell, LA, Debbie Carter; Leo Egbujiobi, MD, Beloit Clinic, Beloit, WI, Diane Betz; Uri Elkayam, MD, Los Angeles County University of Southern California Medical Center, Los Angeles, CA, Salman Khan; Louis Essandoh, MD, Cardiac Consultants, Annapolis, MD, Kim Marie Walker; Raed Fahmy, MD, FHS Research Center, Tacoma, WA, Chris Biljan, Julie Sullivan; Mark Geller, MD, Cardiovascular and Critical Care Associates, Pittsburgh, PA, Lisa Swackhammer; Bartolomeo Giannattsio, MD, University Hospitals of Cleveland, Cleveland, OH, Jill Kandrac, Lisa King; Richard Gilmore, MD, Lake Charles, LA, Myra Thomas, Cindi Reed; Steven Goldman, MD, Southern Arizona Veteran's Administration Health Care System, Tucson, AZ, Beth Gregario; Daniel Gottlieb, MD, Seattle, WA, Rachel Ono; Martin Green, MD, University of Ottawa Heart Institute, Ottawa, Ontario, Marilynn Luce; Bruce Greenspahn, MD, Center for Advanced Cardiology, Park Ridge, IL, Paulette Feiereisel, Suzie McGann; William Grossman, MD, Charleston Cardiology, Charleston, SC, Leila Forney; David Henderson, MD, Cardiology Research Associates, Ormond Beach, FL, Diane Martin; David Hill, MD, San Diego Cardiovascular Research Associates, Encinatas, CA, Diane Solic; Michael Imburgia, MD, Louisville Cardiology Medical Group, Louisville, KY, Paula Tucker, Teri Stickler, Renee Boehnlein; Karen Hulsmeyer; John Ip, MD, Thoracic & Cardiovascular Healthcare Foundation, Lansing, MI, Anne Crockett, Denise Grimes; Bruce Jackson, MD, ARI Clinical Trials, Redondo Beach, CA, Josef Edelstein, Donna Wolf; Craig January, MD, University of Wisconsin at Madison, Madison, WI, Cassondra VanderArk; Dean Kereiakes, MD, Lindner Clinical Trial Center, Cincinnati, OH, Ersela McGary; Charles Kerr, MD, St Paul's Hospital, Vancouver, British Columbia, Mary Jo Race; Gregory Kidwell, Akron General Medical Center, Akron, OH, Debra K. Hudock, Jane Waterman; Kim Klanke, MD, Cardiology Consultants, Daytona Beach, FL, Marcia Bayer, Robin Thygesen; Jeffrey Kluger, MD, Hartford Hospital, Hartford, CT, Arben Ademi; Michael Koren, MD, Jacksonville Center for Clinical Research, Jacksonville, FL, Kishia Harris, Robert Allee; Peter Kowey, MD, Mainline Heart Center, Wynnewood, PA, Susan Heaney, Jill Schein; Jack Kron, MD, Oregon Health Sciences University, Portland, OR, Dave Calhoun, Christy Marchant; Teresa Kus, MD, Hospital Sacre?Coeur de Montreal, Montreal, Quebec, Ann Langlois; Sung Lee, MD, George Washington University, Washington, DC, Ann Marie Cangialosi; Patrick Ma, MD, Heart Health Institute, Calgary, Alberta, Nicki Desaulniers, Candace Swanson; Norman Marcus, MD, Heart Care Group, Allentown, PA, Sandy Stufflet; Scott Mattson, MD, Heart Center Medical Group, Ft Wayne, IN, Julie Diehl; Frank McGrew, MD, Stern Cardiovascular Center, Memphis, TN, Barbara Hamilton, Sherron Koerber; James McKinnie, MD, Tulane University, New Orleans, LA, Kirt Ross; Shahid Mecci, MD, Neureka Research Corporation, Sudbury, Ontario, Rupinder Dhaliwal; Allan Murphy, MD, Riverside Regional Medical Center, Newport News, VA, Sheila Gessner, Carol Tate, Cheryl White; Mani Nallasivan, MD, Merced Heart Associates, Merced, CA, Robin Arguelles; Imran Niazi, MD, Wisconsin Center for Clinical Research, Milwaukee, WI, JoAnn Kiemen; Asim Nisar, MD, Elgin Cardiology Associates, Elgin, IL, Benita Lasky; J Michael O'Dowd, MD, The Heart Group, Mobile, AL, Susan Bryan, Mary Ann Smith; Gilles O'Hara, MD, Quebec Heart Institute, Sainte Foy, Quebec, Lyne Charbonneau; William Olney, MD, Rochester, NH, Tracy deGanbody; P Gearoid O'Neill, MD, Regional Cardiology Associates, Sacramento, CA, Shelley Allen, Anne Skadsen, Ellie Vierra; Daniel Peterson, MD, Dean Foundation Medical Research, Madison, WI, Elisha Terre, Korrine Winkler; Scott Pollack, MD, Florida Cardiology, Orlando, FL, Jennifer Yocca; Craig Pratt, MD, Methodist Hospital, Houston, TX, Candace Jordan; Steve Promisloff, MD, Hillsboro Cardiology, Hillsboro, OR, Kimberly Harrison; Eric Prystowsky, MD, The Care Group, Indianapolis, IN, Regina Margiotti; Joseph Puma, MD, Advanced Health Institute, Mount Airy, NC, Hilda Stone; James Reiffel, MD, New York Presbyterian Hospital at Columbia University, New York, NY, Kathleen Hickey; Felix Rogers, MD, Down River Cardiology, Trenton, MI, Lori Bondy; Laurence Rosenthal, MD, University of Massachusetts, Worcester, MA, Karen Rofino; Denis Roy, MD, Montreal Heart Institute, Montreal, Quebec, Suzanne Cormier; John Rozanski, MD, The Heart Center, Ft Lauderdale, FL, Amy Siebert; Andrea Russo, MD, Presbyterian Medical Center, Philadelphia, PA, Deborah Shellenberger; Alan Schwartz, MD, Cardiovascular Associates of the Peninsula, Burlingame, CA, Kyoko Hattori; Robert Sheldon, MD, University of Calgary, Calgary, Alberta, Debbie Ritchie, Patricia Larose; Igor Singer, MD, University of Louisville, Louisville, KY, Lisa Hatter; Bramah Singh, MD, West Los Angeles Veteran's Administration Medical Center, Los Angeles, CA, Nitin Wadhani; Steven Singh, MD, Veteran's Administration Medical Center, Washington, DC, Jamie Sinks; William Slemenda, MD, Tri-State Medical Group, Beaver, PA, Gretchen Callamack, Carla Pallante; Steven Smart, MD, Gunderson Lutheran Medical Center, La Crosse, WI, Lynette Storlie; Leland Sprinkle, MD, La Mesa Cardiac Center, La Mesa, CA, Mary Barrett; Charles Tsai, MD, Sutter Gould Medical Foundation, Modesto, CA, Loretta Serpa; Humberto Vidaillet, MD, Marshfield Clinic Research Foundation, Marshfield, WI, Karen Maassen; Nampali Vijay, MD, Western Cardiology Associates, Denver, CO, Melinda Washam; Lynne Wagoner, MD, University Hospital, Cincinnati, OH, Liz Huntz, Ginger Conway; Robert Weiss, MD, Androscoggin Cardiology Associates, Auburn, ME, Rachel Barry; John Werthheimer, MD, Albert Einstein Medical Center, Philadelphia, PA, Doranne Swan, Amy Meyers; Michael Wilson, MD, Madigan Army Medical Center, Tacoma, WA, Sheila Graham; Deborah Wolbrette, MD, Milton S Hershey Medical Center, Hershey, PA, Karen Dwyer, Paula Ulsh, Eileen Westley-Hetrick; Kevin Wolfe, MD, Health Sciences Centre, Winnipeg, Manitoba, Cindy Kozman; Raymond Yee, MD, Cardiac Investigation Unit, London, Ontario, Bonnie Spindler; Laurence Yellen, MD, Cardiology Associates, San Diego, CA, Nancy Hunter. Committee members: Event committee: Mark D. Carlson, MD, University Hospitals of Cleveland, Cleveland, OH; Stuart Cobbe, MD, Glasgow Royal Infirmary, Glasgow, UK; Anne Curtis, MD, University of Florida Medical Center, Gainesville, FL; Mark Hamer, MD, Rochester Cardiopulmonary Group, Rochester, NY; Federico Lombardi, MD, University of Milan, Milan, Italy; Katherine T. Murray, MD, Vanderbilt University School of Medicine, Nashville, TN; Richard L. Page, MD (committee chair), University of Washington School of Medicine, Seattle, WA; Elizabeth A. McCarthy, RN, MSN (nonvoting), Duke University Medical Center, Durham, NC. Data and Safety Monitoring Committee: D George Wyse, MD, PhD (committee chair), University of Calgary, Calgary, Alberta; Sam Kaddoura, MD, Chelsea and Westminster Hospital, London, England, UK; Eugene Passamani, MD, Suburban Hospital, Bethesda, MD; William Stevenson, MD, Brigham and Women's Hospital, Boston, MA; Juan Tamargo, MD, Faacultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain; Nanette Wenger, MD, Emory University School of Medicine, Atlanta, GA; Janet Wittes, PhD, Statistics Collaborative, Inc, Washington, DC; William Wilkinson, PhD (nonvoting), Duke University Medical Center, Durham, NC. Scientific Advisory Committee: Stuart J. Connolly, MD (coprincipal investigator), Hamilton Health Sciences Corporation, Hamilton, Ontario; Preston Dunnmon, MD, PhD, Procter and Gamble Pharmaceuticals, Mason, OH. Charles R. Kerr, MD, St Paul's Hospital, Vancouver, British Columbia. Peter R. Kowey, MD (coprincipal investigator), Mainline Heart Center, Wynnewood, PA. Richard L. Page, MD, University of Washington School of Medicine, Seattle, WA. Martin Phillips, MD, Procter and Gamble Pharmaceuticals, Mason, OH. Edward L.C. Pritchett, MD (committee chair), Duke University Medical Center, Durham, NC. Mikhail Ruda, MD, Myasnikov Institute of Cardiology, Moscow, Russia. Witold Ruzyllo, MD, Klinika Kardiologii Ogolnej, Warszawa, Poland. Chyon-Hwa Yeh, PhD, Procter and Gamble Pharmaceuticals, Mason, OH. James B. Young, MD, The Cleveland Clinic Foundation, Cleveland, OH. Michael K. Sheehan (nonvoting), Procter and Gamble Pharmaceuticals, Mason, OH. William E. Wilkinson, PhD (nonvoting), Duke University Medical Center, Durham, NC. Elizabeth A. McCarthy, RN, MSN (nonvoting), Duke University Medical Center, Durham, NC. Maria J. Spyt, MD, (nonvoting), Procter and Gamble Pharmaceuticals, Staines, Middlessex, UK. Funding Information
This study was sponsored by Procter & Gamble Pharmaceuticals, Mason, OH. At the time it was conducted, all authors were members of the scientific advisory committee for it and were either consultants or investigators for Procter & Gamble Pharmaceuticals. Reprint
Address
Edward L.C. Pritchett, MD, PMB 301, 1821 Hillandale Rd, Suite 1B, Durham, NC 27705. Email: ed.pritchett@edwardpritchett.com Edward L.C. Pritchett,a
Peter Kowey, MD,b Stuart
Connolly, MD,c
Richard L. Page, MD,d Charles
Kerr, MD,e William E. Wilkinson,
PhD,a aDuke University Medical Center, Durham, NC; bMainline Heart Center, Wynnewood, PA; cHamilton Health Sciences Center, Hamilton, Ontario, Canada; dUniversity of Washington, Seattle, WA; eSt Paul's Hospital Vancouver, British Columbia, Canada Disclosure: At the time the
manuscript was written, Dr Pritchett, Dr Kowey, and Dr Wilkinson were
consultants for Procter & Gamble Pharmaceuticals, and Dr Page received
grant support from Procter & Gamble Pharmaceuticals through the
University of Washington. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
