title: Use of ECG restitution (beat-to-beat QT-TQ interval analysis) to assess arrhythmogenic risk of QTc prolongation with guanfacine.
abstract: BACKGROUND
  Guanfacine (Intuniv) is a centrally active alpha-2A adrenergic agonist for the new indication of attention-deficit/hyperactivity disorder. QTc (QTcF and QTcNi) was prolonged at both therapeutic (4 mg) and supratherapeutic (8 mg) doses of a thorough QT study even though guanfacine has had a safe clinical history of over 3 million prescriptions for the treatment of hypertension. In an attempt to understand this disparity, retrospective evaluation of the continuous ECG data utilized dynamic beat-to-beat and ECG restitution analyses was performed.
  
  
  METHODS
  Sixty healthy subjects using 24-hour Holters were examined in a 3-arm, placebo- and positive-controlled, double-blind crossover study for effects on beat-to-beat QT, TQ, and RR intervals.
  
  
  RESULTS
  ECG restitution analyses indicated that, at all time points, a disproportionate effect to increase the TQ interval (rest) occurred more in relationship to each QT interval lengthening resulting in a placebo-adjusted reduced QT/TQ ratio of 21% after 4 mg and 31% after 8 mg (both antiarrhythmic responses). Additionally, the percentage of time and magnitude of stress on the heart, as measured by the upper limits of the QT/TQ ratio, were reduced with guanfacine by 22% to 24%. In contrast to guanfacine, moxifloxacin did not show a significant improvement in any restitution parameters but reflected a trend toward proarrhythmia with an increase in the QT/TQ ratio of up to 11%.
  
  
  CONCLUSIONS
  These results indicate that guanfacine causes a stabilizing effect on cardiac restitution that helps reconcile the clinical evidence for a lack of arrhythmia liability despite apparent increases in typical QT/QTc prolongation measures.
authors.affiliation: iCardiac Technologies, Rochester, NY.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Fossa
authors.forename: Meijian
authors.initials: M
authors.lastname: Zhou
authors.forename: Antoine
authors.initials: A
authors.lastname: Robinson
authors.forename: Jaideep
authors.initials: J
authors.lastname: Purkayastha
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015716:Electrocardiography, Ambulatory / Q000187:drug effects* / Q000379:methods*; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage; D016316:Guanfacine / Q000494:pharmacology*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D000077266:Moxifloxacin; D012016:Reference Values; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D024841:Fluoroquinolones; D016316:Guanfacine; D000077266:Moxifloxacin
keywords: QTc/QT prolongation; arrhythmia; beat-to-beat; guanfacine; restitution; risk assessment