Antiarrhythmic and arrhythmic effects of an Ikr-blocking class III agent. A clinical and electrocardiographic study of almokalant

Abstract: The interest in class III drugs has increased over the last decades as being potent antiarrhythmic agents in their mode of action by prolongation of repolarization and with no effect on conduction. Class I antiarrhythmic agents have proven effective in conversion of atrial fibrillation (AF), but may cause serious proarrhythmia. Older class III drugs, i.e. amiodarone and sotalol, are also afflicted with adverse effects, which limit their use. However, the pure class III antiarrhythmic drugs, potassium channel blockers, may also induce proarrhythmia, i.e. torsades de pointes (TdP).Almokalant is a selective potassium - Ikr- channel blocker. The aims of the present thesis were to assess the antiarrhythmic and proarrhythmic effects of a 6-hour infusion of almokalant when given to 100 patients with chronic AF or flutter (AFL) aiming at conversion to sinus rhythm (SR), and to find predictors of conversion, and development of TdP in case it should occur. On the following day an identical infusion was given for 90 minutes during SR to 61 of the patients.Paper I evaluated the efficacy of almokalant in conversion of AF or AFL to SR. A second aim was to find predictors of conversion to SR. The electrophysiological effects of almokalant were assessed by surface 12-lead electrocardiogram (ECG) and transesophageal atrial electrograms (TAE). Thirty-two patients converted to SR. The ECG changes observed were consistent with a class III effect. The QT, corrected QT, QTtop intervals and QT dispersion increased, the T wave amplitude and atrial rate decreased, with no differences between patients converting to SR and those who did not. A decrease in T wave amplitude early during infusion was a predictor of conversion to SR.Paper II assessed the proarrhythmic effect of almokalant and ECG variables associated with TdP. Six patients developed TdP, five of these after conversion to SR. Patients who developed TdP were characterized by an abnormal ventricular repolarization when exposed to the drug and, soon after the start of infusion, developed a pronounced QT prolongation, a larger QT dispersion, and marked morphological T wave changes. These ECG changes were observed during AF, as well as after conversion to SR, before the proarrhythmic event. Predictors of TdP were at baseline: female gender, PVCs, diuretics and, after 30 minutes of infusion, the development of sequential bilateral bundle branch aberrancy, PVCs in bigeminy, and a biphasic T wave.Paper III assessed QT dispersion, as a measure of the inhomogeneity of ventricular repolarization, during AF and SR in sixty-one patients, who received almokalant infusion on both study days. QT dispersion did not differ during AF and SR at normal ventricular repolarization. At prolonged repolarization, QT dispersion was larger during SR than during AF. QT dispersion was not related to the QT or RR interval or almokalant plasma concentration. Increased QT dispersion may contribute to the increased risk of TdP shortly after conversion to SR.Paper IV evaluated the occurrence of aberrant conduction during AF at rest and during exercise prior to and during almokalant infusion in 92 of the patients. Almokalant caused a marked, and dose-related, increase in the number of patients with intermittent aberration during rest, which was further increased during exercise. Predictors of the development of aberrant conduction on almokalant were decreased left ventricular ejection fraction, female gender, longer arrhythmia duration, while the use of calcium antagonists decreased the risk. Aberration is an expression of the class III effect and seems to be more common in patients with more advanced myocardial disease