Survival With Oral d&otalol in Patients With Left Ventricular Dysfunction After Myocardial Infarction: Rationale, Design, and Methods (the SWORD Trial) Albert L. Waldo, MD, A. John Camm, MD, H. deRuyter, MD, Peter L. Friedman, MD, PhD, Daniel J. MacNeil, MD, Bertram Pitt, MD, Craig M. Pratt, MD, Bruce E. Rodda, PhD, and Peter J. Schwartz, MD, for the SWORD Investigators* Impaired left ventricular function after acute myocar- dial infarction (AMI) is associated with an increased risk of death. Despite recent advances in the management of these patients, sudden death accounts for up to 50% of this mortality, and effective treatment strategies have et to be identified. Preliminary trials with amiodarone Kave offered promise that drugs that prolong action potential duration by blocking the potassium channel ma be useful in reducing this mortality. The Survival Wi K 0~11 d-Sotalol (SWORD) trial is a multicenter, mul- tinational study which tests the hypothesis that the class Ill agent d-sotalol will reduce all-cause mortality in high- risk survivors of AMI. The trial will enroll 6,400 patients with left ventricular dysfunction (ejection fraction do%) and a recent (6 to 42 days) or a remote (~42 days) AMI with overt heart failure (New York Heart Association class II or Ill). In approximately 500 centers through- out the world, men and women aged 218 years will be enrolled and randomized to placebo or d-sotalol (200 mg/day). The minimal follow-up will be 18 months. The trial has a 90% power to detect a 20% reduction in all- cause mortali . The rationale, design, and trial meth- “6 ods are descri ed. (Am J Cardiol 1995;75: 1023-l 027) d -Sotalol is the dextrorotatory isomer of the racemate d,l-sotalol. Like the racemate, it is a class III antia.r- rhythmic drug that prolongs the action potential dura- tion and refractoriness of cardiac tissue by blocking the delayed rectifier current of the potassium channel.’ It is antifibrillatory in some ischemic models,2 but not in models that are associated with sympathetic hyperactiv- ity.3 Unlike d,l-sotalol, it has only minimal P-blocking activity in animals,4and this activity is not clinically sig- nificant in humans.5 After oral administration, it is near- ly 100%absorbed,and is excreted unmetabolized by the kidneys (data on file, Bristol-Myers Squibb, Princeton, New Jersey). In clinical trials, d-sotalol has been well tolerated,with a low incidence of reportedadverse events. Torsades de pointes has occurred in approximately 1.2% of those exposedto the drug (data on file, Bristol-Myers Squibb, Princeton, New Jersey). This report describes the protocol of a study that com- paresd-sotalol with placebo in the treatmentof high-risk survivors of acute myocardial infarction (AMI). The expectedtreatment differencesrequire a large study pop- ulation that necessitates a multicenter, multinational design. The trial provides the fist opportunity to inves- tigate the benefit of an antiarrhythmic drug that selec- tively prolongs action potential duration by blockade of the delayed rectifier current of the potassium channel. From the Division of Cardiology, University Hospitals of Cleveland, Cleveland, Ohio. This study was supported by a grant from Bristol- Myers Squibb, Princeton, New Jersey. Manuscript received July 22, 1994; revised manuscript received and accepted March 2, 1995. Address for reprints: Albert L. Waldo, MD, Division of CardioC ogy, Universiv Hospitals of Cl eveland, 1 1 100 Euclid Avenue, Cleve land, Ohio 44106. *See appendix for participating centers. The results of Survival With Oral d-Sotalol (SWORD) will define the role of d-sotalol as a classIII agent in this high-risk population and contribute to a more rational management of these patients. METHODS Obiectives: The primary objective of SWORD is to determine whether d-sotalol will reduce all-cause mor- tality compared with placebo in patients with left ven- tricular dysfunction and coronary artery diseasemani- fested by a prior AMI. It also will compare the safety and tolerance of d-sotalol and placebo when adminis- tered long-term to these patients. Design: SWORD is a multinational, multicenter, ran- domized,double-blind, placebo-controlled trial in approx- imately 500 centers worldwide. The study will enroll 6,400 men and women, aged218 years, who have a left ventricular ejection fraction of 540% determined by either radionuclide or contrast angiography or echocar- diography performed within 6 months of randomization. In addition, these patients must have evidence of a pri- or AMI. Two such groups will be identiiied. Group 1 (acute group) will consist of patients with an AM1 6 to 42 daysbefore randomization with or without overt heart failure. Group 2 (remote group) will consist of patients with an AM1 occurring ~42 days before randomization who also have a history of overt heart failure (New York Heart Association functional class II or III). Criteria for an AM1 arethe presence of 22 of the following: (1) char- acteristic myocardial ischemic pain in the precordium or associated referral areaslasting 220 minutes; (2) eleva- tion of creatine kinase to twice the upper limit of nor- mal for the given hospital in the absence of other expla- nation, or the presenceof creatine kinase-MB >6% of total; (3) development of new (>30 ms) Q waves in 22 ARRHYTHMIAS AND CONDUCTION DISTURBANCES/o-SOTALOL IN PATIENTS WITH iV DYSFUNCTION 1023