title: First clinical trial of specific IKACh blocker shows no reduction in atrial fibrillation burden in patients with paroxysmal atrial fibrillation: pacemaker assessment of BMS 914392 in patients with paroxysmal atrial fibrillation.
abstract: OBJECTIVE
  To assess the efficacy of BMS 914392 on atrial fibrillation (AF) burden reduction in 20 patients with pacemakers and paroxysmal atrial fibrillation (PAF). BMS 914392 is a potent, selective, oral inhibitor of the IKACh current and has been shown to suppress AF, whilst having no effect on the ventricular refractory period. This is the first efficacy study of BMS 914392 in patients with PAF.
  
  
  RESULTS
  The study was a four-way, crossover, double-blind design. A total of 20 patients with PAF and dual-chamber pacemakers were recruited. The pacemakers allowed beat-to-beat monitoring. Anti-arrhythmic drugs were withdrawn. Patients received low-dose (10 mg OD), medium-dose (10 mg TDS), and high-dose (20 mg TDS) BMS 914392 or placebo for 3 weeks before being crossed to the next phase. Patients underwent a washout period, four treatment phases and a final washout phase. Atrial fibrillation burden was downloaded from their pacemakers at the end of each study phase. BMS 914392 did not reduce AF burden when compared with placebo (10 mg OD P = 0.56, 10 mg TDS P = 0.22, 20 mg TDS P = 0.23). Heart rate and corrected QT (QTc) were not affected by BMS 914392. Adverse event (AE) rates did not differ from placebo in any of the treatment groups, with no serious AEs recorded.
  
  
  CONCLUSIONS
  BMS 914932 has not been shown to reduce AF burden in patients with PAF and pacemakers using beat-to-beat pacemaker monitoring throughout the study. BMS 914392 was well tolerated and did not affect QTc or reduce heart rate.
  
  
  BACKGROUND
  Clinicaltrials.gov: NCT01356914.
authors.affiliation: Cardiology Research Department, East Sussex Healthcare NHS Trust, Eastbourne District General Hospital, Kings Drive, Eastbourne, East Sussex BN21 2UD, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Podd
authors.affiliation: Department of Primary Care and Population Health, PRIMENT Clinical Trials Unit, UCL Medical School, London, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Freemantle
authors.affiliation: Cardiology Research Department, East Sussex Healthcare NHS Trust, Eastbourne District General Hospital, Kings Drive, Eastbourne, East Sussex BN21 2UD, UK.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Furniss
authors.affiliation: Cardiology Research Department, East Sussex Healthcare NHS Trust, Eastbourne District General Hospital, Kings Drive, Eastbourne, East Sussex BN21 2UD, UK neil.sulke@esht.nhs.uk.
authors.forename: Neil
authors.initials: N
authors.lastname: Sulke
mesh_terms: D000200:Action Potentials; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D058406:Cardiac Resynchronization Therapy; D058409:Cardiac Resynchronization Therapy Devices; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography; D004739:England; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D011714:Pyrans / Q000009:adverse effects / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000889:Anti-Arrhythmia Agents; C000613081:BMS 914392; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D026902:Potassium Channel Blockers; D011714:Pyrans; D011804:Quinolines
keywords: AF burden; Anti-arrhythmic drugs; Atrial-specific antiarrhythmic drugs; IKACh current; Pacemaker monitoring; Paroxysmal atrial fibrillation