A double-blind, randomised, placebo-controlled, cross-over study assessing the use of XEN-D0103 in patients with paroxysmal atrial fibrillation and implanted pacemakers allowing continuous beat-to-beat monitoring of drug efficacy.

Abstract

PURPOSE:

The ultrarapid delayed rectifier current (IKur) carried by Kv1.5 channels, which are solely expressed in the atrium, is a potential target for safer treatment of paroxysmal atrial fibrillation (PAF). XEN-D0103 is a nanomolar ion channel blocker that selectively inhibits potassium ion flux through the Kv1.5 ion channel. The efficacy of XEN-D0103 in reducing AF burden was assessed in patients with DDDRp permanent pacemakers (PPMs) and PAF.

METHODS:

A double-blind, placebo-controlled, cross-over study was performed in patients with PAF and DDDRp PPMs with advanced atrial and ventricular Holters allowing beat-to-beat arrhythmia follow-up. All anti-arrhythmic drugs were withdrawn before randomised treatment. After baseline assessment, patients were randomly assigned to two treatment periods of placebo then XEN-D0103 50 mg bd, or XEN-D0103 50 mg bd then placebo.

RESULTS:

Fifty-four patients were screened and 21 patients were eligible and included in the randomised trial. All 21 patients completed both treatment periods. The primary endpoint was change in AF burden assessed by PPM. There was no significant difference in AF burden on treatment with XEN-D0103 versus placebo. There was a reduction in the mean frequency of AF episodes (relative reduction 0.72, 95% CI 0.66 to 0.77; p < 0.0001). XEN-D0103 was safe and well tolerated, and there were no serious adverse events. XEN-D0103 did not have any apparent effect on heart rate compared to placebo.

CONCLUSIONS:

XEN-D0103 did not reduce AF burden in patients with PAF and dual chamber pacemakers providing beat-to-beat monitoring. XEN-D0103 was well tolerated and did not have any apparent effect on heart rate. Although single-ion channel blockade with XEN-D0103 did not affect AF in this study, there might be a potential for this agent to be used in combination with other atrially specific drugs in the treatment of AF.

EUDRACT TRIAL REGISTRATION NUMBER:

2013-004456-38.

• Authors: S R Shunmugam, Conn Sugihara, Nick Freemantle, Patrick Round, Steve Furniss, Neil Sulke
• Journal: Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing (J Interv Card Electrophysiol) Vol. 51 Issue 3 Pg. 191-197 (Apr 2018) ISSN: 1572-8595 [Electronic] Netherlands
• PMID: 29460236 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Anti-Arrhythmia Agents
• Delayed Rectifier Potassium Channels
• Potassium Channel Blockers

Topics

• Aged
• Anti-Arrhythmia Agents (administration & dosage, pharmacology)
• Atrial Fibrillation (diagnosis, drug therapy, therapy)
• Combined Modality Therapy
• Cross-Over Studies
• Delayed Rectifier Potassium Channels (antagonists & inhibitors)
• Double-Blind Method
• Electrocardiography (methods)
• Female
• Humans
• Male
• Middle Aged
• Monitoring, Physiologic (methods)
• Pacemaker, Artificial (statistics & numerical data)
• Patient Safety (statistics & numerical data)
• Patient Selection
• Potassium Channel Blockers (therapeutic use)
• Prognosis
• Prospective Studies
• Treatment Outcome