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Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression after Myocardial Infarction
List of authors.Abstract
The occurrence of ventricular premature depolarizations in survivors of myocardial infarction is a risk factor for subsequent sudden death, but whether antiarrhythmic therapy reduces the risk is not known. The Cardiac Arrhythmia Suppression Trial (CAST) is evaluating the effect of antiarrhythmic therapy (encainide, flecainide, or moricizine) in patients with asymptomatic or mildly symptomatic ventricular arrhythmia (six or more ventricular premature beats per hour) after myocardial infarction.
As of March 30, 1989, 2309 patients had been recruited for the initial drug-titration phase of the study: 1727 (75 percent) had initial suppression of their arrhythmia (as assessed by Holter recording) through the use of one of the three study drugs and had been randomly assigned to receive active drug or placebo. During an average of 10 months of follow-up, the patients treated with active drug had a higher rate of death from arrhythmia than the patients assigned to placebo. Encainide and flecainide accounted for the excess of deaths from arrhythmia and nonfatal cardiac arrests (33 of 730 patients taking encainide or flecainide [4.5 percent]; 9 of 725 taking placebo [1.2 percent]; relative risk, 3.6; 95 percent confidence interval, 1.7 to 8.5). They also accounted for the higher total mortality (56 of 730 [7.7 percent] and 22 of 725 [3.0 percent], respectively; relative risk, 2.5; 95 percent confidence interval, 1.6 to 4.5). Because of these results, the part of the trial involving encainide and flecainide has been discontinued.
We conclude that neither encainide nor flecainide should be used in the treatment of patients with asymptomatic or minimally symptomatic ventricular arrhythmia after myocardial infarction, even though these drugs may be effective initially in suppressing ventricular arrhythmia. Whether these results apply to other patients who might be candidates for antiarrhythmic therapy is unknown.
Appendix
Participants in CAST are as follows: University of Alabama at Birmingham, Birmingham, Ala.: William J. Rogers, M.D. (principal investigator), Andrew E. Epstein, M.D., Joaquin G. Arciniegas, M.D., Sharon M. Dailey, M.D., G. Neal Kay, M.D., Randall E. Little, M.D., William A.H. MacLean, M.D., Silvio E. Papapietro, M.D., Vance J. Plumb, M.D., Sigmund Silber, M.D., Andrea R. Baker, R.N., Melanie Cox, Carolynn Thomas, R.N., Donna Von Hagel, R.N., and Annie E. Walton, R.N.; Baylor College of Medicine, Houston: Craig M. Pratt, M.D. (principal investigator), John Mahmarian, M.D., Terry Eaton, R.N., and Gail Morris, R.N.; Beth Israel Medical Center, New York: Thomas Killip, M.D. (principal investigator), Andrew Van Tosh, M.D. (principal investigator), Susan R. Hecht, M.D., George A. Gabor, M.D., Warren A. Kossowsky, M.D., Martin Dolgin, M.D., John E. Madias, M.D, Orest B. Bartoszyk, M.D., Ann Grayeski, R.N., B.S.N., Melissa Flon, R.N., B.S., Ann M. Kelly, R.N., B.S.N., Mary Louise Conte, R.N., B.S.N.; Brown University Affiliated Hospitals Center, Providence: Robert J. Capone, M.D. (principal investigator), Lawrence Gorkin, Ph.D., Abdul Hakim Khan, M.D., Kenneth Korr, M.D., Andrew Ross, M.D., Kathy Alberti, R.N., B.S., Emily Connolly, R.N., Pat Rubbert, R.N., B.S., and Tina Cameron, R.N.; University of Calgary and Cooperating Hospitals, Calgary, Alb.: D. George Wyse, M.D., Ph.D. (principal investigator), Henry J. Duff, M.D., L. Brent Mitchell, M.D., Anne M. Gillis, M.D., J. Wayne Warnica, M.D., Robert S. Sheldon, M.D., Ph.D., N. Robert Lesoway, M.D., Joyce Kellen, R.N., B.N., Charlotte Hale, R.N., and Karen Hillier, R.N.; Case Western Reserve University, Cleveland: Albert L. Waldo, M.D. (principal investigator), Richard W. Henthorn, M.D., Mark D. Carlson, M.D., Joel B. Holland, M.D., Dale Adler, M.D., Robert C. Bahler, M.D., Frank X. Pamelia, M.D., Carol Buchter, M.D., Pamela Redmon, R.N., B.S., Melinda A. Vargas, R.N., B.S.N., and Christopher E. Kobus, R.N., B.S.N.; Columbia University Affiliated Hospitals, New York: J. Thomas Bigger, Jr., M.D. (principal investigator), Jonathan S. Steinberg, M.D., Judith S. Hochman, M.D., Robert Case, M.D., Henry M. Greenberg, M.D., Edward M. Dwyer, Jr., M.D., John J. Gregory, M.D., Stephen T. Rothbart, M.D., Annmarie Squatrito, R.N., Madeline Kelly, R.N., Jeanne M. Campion, R.N., Deborah Tormey, R.N., Robin Anthony, R.N., Elizabeth Callaghan, R.N., Maureen Chapnick, R.N., Barbara Ripley, R.N., and Cheryl Fontana, R.N.; Emory University School of Medicine, Atlanta: Robert C. Schlant, M.D. (principal investigator), Daniel Arensberg, M.D., John D. Cantwell, M.D., J. Arturo Corso, M.D., John W. Hurst, Jr., M.D., Lawrence M. Lesser, M.D., Douglas C. Morris, M.D., Corinne F. Quinn, M.D., Stanley W. Sherman, M.D., Barry D. Silverman, M.D., Mark E. Silverman, M.D., Shirley K. Ballou, M.S., Velma D. Jeffries, R.N., Joy Lee Crowe, R.N., and Janice M. Parrott, R.N.; George Washington University Medical Center, Washington, D.C.: Richard J. Katz, M.D. (principal investigator), George A. Besch, M.D., David Brill, M.D., Robert DiBianco, M.D., Dennis Donohue, M.D., Gregory Fisher, M.D., Cleveland Francis, M.D., Dennis Friedman, M.D., Daniel Goldberg, M.D., Samuel Goldberg, M.D., Gregorio Koss, M.D., Louis Larca, M.D., Roger Leonard, M.D., Keith Lindgren, M.D., James Ronan, M.D., Arnold Rosenblatt, M.D., Douglas Rosing, M.D., Allan Ross, M.D., Alberto Rotsztain, M.D., Harry Schwartz, M.D., Fayez Shawl, M.D., Thomas Sinderson, M.D., Roger Stevenson, M.D., Bruce Tinker, M.D., Jacob Varghese, M.D., Mark Weinstein, M.D., John Yackee, M.D., Kay Cross, R.N., Joan Daly, R.N., and Mary Beth Swisher, R.N.; Göteborg University, Göteborg, Sweden: Lars Wilhelmsen, M.D. (principal investigator), Robert Bergstrand, M.D. (principal investigator), Bengt-Olof Fredlund, M.D., Christer Gottfridsson, M.D., Axel Sigurdsson, M.D., Sverker Jern, M.D., Ramon Sivertsson, M.D., Karl Swedberg, M.D., Gunnel Schlyter, R.N., Svisse Haegelind, R.N., Gunnel Hedelin, R.N., and Margareta Leijon, R.N.; Hahnemann University, Philadelphia: Joel Morganroth, M.D. (principal investigator), Joseph Carver, M.D., Leonard Horowitz, M.D., Steven Kutalek, M.D., Louis Papa, D.O., James Sandberg, M.D., Mark Victor, M.D., Sharon Cesare, R.N., Brenda Krein, R.N., Chris Vrabel, R.N., Donna Trigone, R.N., Karen Talarico, R.N., Karen Nuschke, R.N., Susan Luhmann, R.N., and Donna Palazzo; Henry Ford Hospital, Detroit: Sidney Goldstein, M.D. (principal investigator), A. David Goldberg, M.D., Howard Frumin, M.D., Douglas Westveer, M.D., Michael DeButlier, M.D., John Schairer, D.O., Robert Stomel, D.O., Diane M. Frank, R.N., B.S.N., Regina Jarandilla, R.N., B.S.N., Debbie Davey, R.N., Karen Stemmer, R.N., B.S.N., Chris Thorn, R.N., and Elaine Martin, R.N.; University of Kentucky, Lexington, Ky.: Anthony N. DeMaria, M.D. (principal investigator), Chien-Suu Kuo, M.D., James M. Kammerling, M.D., Chris Dunn, R.N., Debra M. Powers, R.N., and Jody Corum, R.N.; University of Maryland, Baltimore: Robert Peters, M.D. (principal investigator), Frederick Sutton, M.D., Stephen Gottlieb, M.D., Lisa Martin, M.D., Laurie Todd, R.N., B.S.N., and Cynthia Cusack, R.N., B.S.N.; University of Massachusetts Medical School, Worcester, Mass.: Joseph S. Alpert, M.D. (principal investigator), Joel M. Gore, M.D. (principal investigator), S.K. Steven Huang, M.D., Mary Ryan, R.N., and Carol Shustak, R.N.; University of Minnesota, Minneapolis: M. Hodges, M.D. (principal investigator), D.M. Salerno, M.D., Ph.D., B. Anderson, M.D., W. Hession, M.D., M. Manoles, M.D., J.M. Haugland, M.D., C. Gornick, M.D., M. Tolins, M.D., D. Berman, M.D., G. Granrud, M.D., J. McBride, M.D., D. Dunbar, M.D., D. Benditt, M.D., S. Riendl, M.D., A. Ettinger, R.N., S. Tait Peterson, R.N., R. Piper, R.N., and R. Slivken, R.N.; Montreal Heart Institute, Montreal: Denis Roy, M.D. (principal investigator), Pierre Theroux, M.D., Robert Lemery, M.D., Doris Morissette, R.N., Louise Girard, and Suzanne Ranger; Oregon Health Sciences University, Portland, Oreg.: John H. McAnulty, M.D. (principal investigator), Steven E. Reinhart, M.D., Gordon Maurice, M.D., Edward S. Murphy, M.D., Joel E. Cutler, M.D., Jack Kron, M.D., Christy Marchant, R.N., Janie Boxer, R.N., Laurie Princehouse, and the cardiologists at Southwest Washington Hospitals, Tuality Hospital, Good Samaritan Hospital, Portland Veteran's Administration Hospital, and Providence Medical Center; University of Ottawa Heart Institute, Ottawa: Donald Beanlands, M.D. (principal investigator), Richard Davies, M.D., Martin Green, M.D., William Williams, M.D., Michael J. Baird, M.D., Linda Warriner, R.N., B.Sc.N., Janet Borthwick, R.N., Liliane Marois, R.N., and Kirsten Woodend, R.N., B.Sc.N.; University of Rochester, Rochester, N.Y.: Toshio Akiyama, M.D. (principal investigator), William B. Hood, M.D., Paul N. Yu, M.D., S. Serge Barold, M.D., Robert Easley, Jr., M.D., Richard Kunis, M.D., Gerald Ryan, M.D., John Gillespie, M.D., Laura L. Butler, B.S., Phyllis A. Gehring, R.N., B.S.N., Marcia L. Keller, R.N., B.S.N., Michael Roache, P.A., and Polly Stanley; Rush–Presbyterian–St. Luke's Medical Center, Chicago: Pablo Denes, M.D. (principal investigator, 1986 to 1988), James A. Schoenberger, M.D. (principal investigator, 1989 to present), Philip R. Liebson, M.D., Philip E. Hill, M.D., A. Tom Petropoulos, M.D., Joanne Kocourek, R.N., and Cathleen Daly, R.N.; Salt Lake Clinic Research Foundation, Salt Lake City: Allan H. Barker, M.D. (principal investigator), Jeffrey L. Anderson, M.D., Robert E. Fowles, M.D., Thomas B. Keith, M.D., C. Basil Williams, M.D., Fidela Moreno, M.D., Ellen N. Doran, Barbara Fowler, Kaye Summers, R.N., and Carla White, L.P.N.; St. Louis University Medical Center, St. Louis: Jerome D. Cohen, M.D. (principal investigator), Harold L. Kennedy, M.D., M.P.H., William P. Hamilton, M.D., Thomas A. Buckingham, M.D., Sondra M. Seiler, E.A., and Sally S. Anderson, R.N. B.S.N.; State University of New York Health Science Center at Brooklyn, Brooklyn, N.Y.: Nabil ElSherif, M.D. (principal investigator), Shantha N. Ursell, M.D., Soad Bekheit-Saad, M.D., Arnold M. Einhorn, M.D., Mary Lynn Brezsnyak, R.N., Ann V. Porter, R.N. and Patricia M. Rosa, R.N.; Vanderbilt University, Nashville: Raymond L. Woosley, M.D., Ph.D. (principal investigator, 1986 to 1988), Dan M. Roden, M.D. (principal investigator, 1988 to present), W. Barton Campbell, M.D., Debra S. Echt, M.D., John T. Lee, M.D., Judi Diekhoff Spell, R.N., M.S.N., Susan T. Bonhotal, R.N., M.S.N., Leslie L. Jared, R.N., M.S.N., and Tina Ingle Thomas, R.N.; Medical College of Virginia, Virginia Commonwealth University, Richmond: David W. Richardson, M.D. (principal investigator), Donald W. Romhilt, M.D., Kenneth A. Ellenbogen, M.D., Robert A. Bauernfeind, M.D., Barbara B. Bane, Jeanne K. Sanders, R.N., M.S.N., and Sherry F. Shrader, R.N., B.S.N.; Washington Hospital Center, Washington, D.C.: Edward V. Platia, M.D. (principal investigator), Susan O'Donoghue, M.D., Cynthia M. Tracy, M.D., Nayab Ali, M.D., Patrick Bowen, M.D., Andrew I. Cohen, M.D., Kenneth M. Brooks, M.D., Andrew J. Keller, M.D., William Oetgen, M.D., Lawrence T. Weston, M.D., Sue Barrett, R.N., Maria R. Johnson, R.N., Diane E. Law, R.N., and Dulce Obias-Manno, R.N.; Drug Distribution Center, VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, N.M.: Clair M. Haakenson, R.Ph., M.S., Mike R. Sather, R.Ph., M.S., and Loretta A. Malone; Coordinating Center, University of Washington, Seattle: Alfred P. Hallstrom, Ph.D. (principal investigator), Mary Jo Gillespie, M.S., H. Leon Greene, M.D., Yudianto Pawitan, Ph.D., Ruth McBride, Robert Ledingham, M.S., Salvador Munoz, Robin Reynolds-Haertle, M.S., Melissa Huther, Margit Scholz, Linda Stefan, and Surena Khatir; Program Office, Clinical Trials Branch, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md.: Lawrence M. Friedman, M.D., Eleanor Schron, R.N., M.S., Joel Verter, Ph.D., and Cheryl Jennings; and Data and Safety Monitoring Board: J. David Bristow, M.D. (chairman), David L. DeMets, Ph.D., Charles Fisch, M.D., Alan S. Nies, M.D., Jeremy Ruskin, M.D., Harold Strauss, M.D., and Leroy Walters, Ph.D.
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