Physicians' Academy for Cardiovascular Education

Novel antiarrhythmic drug safe but not clinically effective in patients with paroxysmal AF

A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation

Literature - Camm AJ, Dorian P, Hohnloser SH et al. - Eur Heart J - Cardiovasc Pharmacother 2018

Introduction and methods

Current antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with moderate efficacy and adverse effects. It is hypothesized that inhibition of I-kur (ultra-rapid activating delayed rectifier K+ current), a major repolarizing current present in the atria [1] but absent in the ventricles, results in antiarrhythmic effects by prolonging the atrial action potential, without cardiac adverse effects such as ventricular pro-arrhythmic effects [2].

S66913 (also known as XEN-D0103) is a selective and potent I-kur-inhibitor, developed for therapy in paroxysmal AF, which showed earlier promising antiarrhythmic activity in an experimental study using atrial tissue of patients with AF and sinus rhythm (SR). This makes I-kur-inhibitors attractive drugs for atrial-specific therapy in AF [3].

The randomized Double-blind, International study AssessinG efficacy of S66913 in paRoxysmal Atrial Fibrillation – I-kur-inhibitor (DIAGRAF – I-KUR) trial investigated the antiarrhythmic effects and safety of the I-kur-inhibitor S66913 versus placebo in patients with symptomatic paroxysmal AF, by using an insertable continuous monitoring (ICM). Adults (n=58) had an ICM implanted and only those with AF-burden of 1-70% and ≥3 AF-episodes in a 4-week baseline period, were randomized to either S66913 (5, 25 or 100 mg, n=16, 13 and 15, respectively)) or placebo (n=14) once daily for four weeks.

The primary outcome was the absolute change in AF-burden (percentage time spent in AF/atrial tachycardia (AT)), compared with baseline, measured by ICM.

Main results

Conclusion

The DIAGRAF-I-KUR was the first trial investigating the effect of AADs by using ICM-devices. The I-kur-inhibitor S66913 was safe, but not clinically meaningful in paroxysmal AF patients. However, more research is needed because of premature termination of the study and consequently insufficient power as a result of the limited sample size.

References

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Find this article online at Eur Heart J - Cardiovasc Pharmacother