For personal use only. Not to be reproduced without permission of The Lancet. ARTICLES 2052 THE LANCET • Vol 356 • December 16, 2000 Summary Background Arrhythmias cause much morbidity and mortality after myocardial infarction, but in previous trials, antiarrhythmic drug therapy has not been convincingly eﬀective. Dofetilide, a new class III agent, was investigated for eﬀects on all-cause mortalityand morbidityin patients with left-ventricular dysfunction after myocardial infarction. Methods In 37 Danish coronary-care units, 1510 patients with severe left-ventricular dysfunction (wall motion index ⭐1·2, corresponding to ejection fraction ⭐0·35) were enrolled in a randomised, double-blind study comparing dofetilide (n=749) with placebo (n=761). The primary endpoint was all-cause mortality. Secondary endpoints included cardiac and arrhythmic mortality and total arrhythmic deaths. Analyses were by intention to treat. Findings No signiﬁcant diﬀerences were found between the dofetilide and placebo groups in all-cause mortality (230 [31%] vs 243 [32%]), cardiac mortality (191 [26%] vs 212 [28%]), or total arrhythmic deaths (129 [17%] vs 140 [18%]). Atrial ﬁbrillation or ﬂutter was present in 8% of the patients at study entry. In these patients, dofetilide was signiﬁcantly better than placebo at restoring sinus rhythm (25 of 59 vs seven of 56; p=0·002). There were seven cases of torsade de pointes ventricular tachycardia, all in the dofetilide group. Interpretation In patients with severe left-ventricular dysfunction and recent myocardial infarction, treatment with dofetilide did not aﬀect all-cause mortality, cardiac mortality, or total arrhythmic deaths. Dofetilide was eﬀective in treating atrial ﬁbrillation or ﬂutter in this population. Lancet 2000; 356: 2052–58 Introduction Survivors of acute myocardial infarction have high rates of subsequent morbidity and mortality, 1 especially when left- ventricular dysfunction is present. 2–7 Long-term treatment with angiotensin-converting-enzyme (ACE) inhibitors has improved survival after myocardial infarction by reducing the number of deathsattributed to progressive heart failure. 8 Atrial ﬁbrillation is one important factor increasing morbidity and mortality; in one study, survivors of myocardial infarction with atrial ﬁbrillation were more likely to die from presumed arrhythmias than of heart failure. 9 ACE inhibitors may help to prevent the development of atrial ﬁbrillation, but they have little or no eﬀect on the risk of sudden, unexplained, and presumably arrhythmic death. 8,10–13 With the exception of ⭐-blockers, prophylactic antiarrhythmic therapy has not been successfulin lowering all-cause mortality after myocardial infarction. 10 In the Cardiac Arrhythmia Suppression Trial (CAST), mortality increased in patients given prophylactic therapy with encainide and ﬂecainide, and the results with moricizine were inconclusive. 14–17 To date, amiodarone is the only extensively studied agent used for its antiarrhythmic properties that is not associated with increased mortality in survivors of myocardial infarction. In the Basel Antiarrhythmic Study of Infarct Survival, prophylactic use of amiodarone decreased the risk of death in patients who had had a myocardial infarction. 18 This ﬁnding has not been conﬁrmed in larger double- blind, placebo-controlled trials. 19,20 In both the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) and the European Myocardial Infarct Amiodarone Trial (EMIAT), amiodarone was associated with lower numbers of arrhythmic deaths but it had no eﬀect on all-cause mortality. 19,20 Although amiodarone does not adversely aﬀect left-ventricular performance, 21,22 its use is limited by signiﬁcant adverse eﬀects. 23,24 Especially in patients with left-ventricular dysfunction, antiarrhythmic treatment can increase the risk of death, and at present there is no safe treatment available for atrial ﬁbrillation. Dofetilide, a new class III antiarrhythmic agent, selectively inhibits the rapid component of the delayed rectiﬁer potassium current, which prolongs the eﬀective refractory period. 25,26 It does not aﬀect cardiac conduction or sinus-node function. 27,28 It is eﬀective in the treatment of supraventricular arrhythmias, 29–32 and decreased the frequency of hospital admission in patients with severe congestive heart failure without aﬀecting mortality. 33 Dofetilide is haemodynamically neutral, 27 and it has no signiﬁcant extracardiactoxic eﬀects. Clearance of dofetilide is about 50% renal and 50% hepatic, and plasma concentration strongly depends on renal function. The Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND)-MI study was designed to ﬁnd out whether long-termtreatment with dofetilide aﬀects mortality and morbidity in survivors of myocardial infarction with left-ventricular dysfunction. Eﬀect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial Lars Køber, Poul Erik Bloch Thomsen, Mogens Møller, Christian Torp-Pedersen, Jan Carlsen, Erik Sandøe, Kenneth Egstrup, Erik Agner, Jørgen Videbæk, Bradley Marchant, A John Camm, on behalf of the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) Study Group Departments of Cardiology, Gentofte University Hospital (L Køber MD , P E Bloch Thomsen MD , C Torp-Pedersen MD ) and Odense University Hospital, Denmark (M Møller MD ); Medicon contract research organisation, Birkerød (J Carlsen MD ); Departments of Cardiology, Rigshospitalet, Copenhagen (E Sandøe MD ), Haderslev Hospital (K Egstrup MD ), Elsinore Hospital (E Agner MD ), and Bispebjerg Hospital (J Videbæk MD ), Denmark; Pﬁzer Limited, Sandwich, Kent, UK (B Marchant MD ); and Department of Cardiology, St George’s Hospital, London, UK (Prof A J Camm MD ) Correspondence to: Dr Lars Køber, Department of Cardiology, Gentofte University Hospital, DK 2900 Hellerup, Denmark (e-mail: lk@heart.dk)