Effect of Almokalant, a Selective Potassium Channel Blocker, on the Termination and Inducibility of Paroxysmal Supraventricular Tachycardias

Almokalant is a newly developed selective blocker of the delayed outward K+ current and exhibits the electrophysiological properties of a class III antiarrhythmic agent. In a Scandinavian multicenter, placebocontrolled trial, the antiarrhythmic efficacy of almokalant was investigated in patients with paroxysmal supraventricular tachycardia: 87 patients with mean age of 50 ± 14 years (range 21–71 years), with reciprocating tachycardia due to either Wolff-Parkinson-White (WPW) syndrome (n = 58) or atrioventricular nodal reentry tachycardia (AVNRT) (n = 29) were studied with transesophageal atrial stimulation. After a baseline procedure, during which sustained tachycardia was induced and overdrive terminated, tachycardia was reinduced and an intravenous (i.v.) infusion of either placebo or almokalant (aiming at a pseudoequilibrium plasma level of 20, 50, 100, or 150 nM) (Cpl 20-Cpl 150), was administered. Each patient was studied at two Cpl. Thirty-nine patients were randomly assigned in a double-blind fashion to either placebo + almokalant at Cpl 20 or Cpl 20 + Cpl 50; 26 patients were studied openly at Cpl 50 + Cpl 100, and 22 were studied openly at Cpl 100 + Cpl 150 almokalant. The antiarrhythmic efficacy was assessed as the ability to terminate induced tachycardia and to suppress inducibility: The proportion of patients in which the tachycardia was terminated was placebo 3 of 20 (15%); Cpl 20, 7 of 36 (19%): Cpl 50, 10 of 36 (28%); Cpl 100, 14 of 35 (40%); and Cpl 150, 5 of 9 (56%). The proportion of patients in which the tachycardia became noninducible was placebo 0 of 20 (0%); Cpl 20, 10 of 36 (28%); Cpl 50, 12 of 36 (33%); Cpl 100, 17 of 39 (44%); and Cpl 150, 12 of 18 (67%). As compared with placebo, there was a significant increase in the ability to suppress induction of tachycardia at ≥Cpl 20 nM and a significant increase in the ability to terminate induced tachycardia at Cpl ≥100 nM. There was a significant trend (Cochran-Armitage trend test) toward increasing antiarrhythmic efficacy with increasing doses. One patient, who was studied at the highest dose level, developed markedly prolonged QT intervals and a torsade de pointes tachycardia that required direct current (DC) conversion. Almokalant exhibited a significant dose-dependent antiarrhythmic effect with regard to tachycardia termination and suppressed inducibility in patients with supraventricular reciprocating tachycardias. One patient developed torsade de pointes, underscoring the need for a better understanding of the prerequisites of this proarrhythmic response with almokalant.