title: The combined use of ibutilide as an active control with intensive electrocardiographic sampling and signal averaging as a sensitive method to assess the effects of tadalafil on the human QT interval.
abstract: OBJECTIVE
  This study was designed to evaluate effects of tadalafil, a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction (ED), on the QT interval.
  
  
  BACKGROUND
  Cardiovascular disease is common in men with ED. Men with cardiovascular disease and ED may have decreased cardiac repolarization reserve.
  
  
  METHODS
  Effects of tadalafil (100 mg by mouth), ibutilide (0.002 mg/kg intravenously), and placebo on the QT interval in healthy men were compared (placebo and tadalafil [n = 90], with a subset [n = 61] receiving all treatments; mean age 30 years, range 18 to 53 years). Electrocardiographic sampling was done for two days before treatment and on treatment days. The QT was corrected for RR interval with five correction methods, including an individual correction (QTcI). Plasma concentrations of tadalafil were measured to evaluate concentration-QT effect relationships.
  
  
  RESULTS
  At the time corresponding to maximum plasma concentration of tadalafil, the mean difference in the change in QTcI between tadalafil and placebo was 2.8 ms; tadalafil was equivalent to placebo (a priori, upper limit of 90% confidence interval < 10 ms [actual = 4.4 ms]; post hoc, upper limit of 95% confidence interval < 5 ms [actual = 4.8]). The active control, ibutilide, significantly increased QTcI by 6.9 and 8.9 ms compared with tadalafil and placebo, respectively. Similar statistical results were obtained with four additional QT correction methods. No subject had a QTcI > or = 450 ms or an increase in QTcI > or = 30 ms with any treatment.
  
  
  CONCLUSIONS
  Based on the a priori statistical test of equivalence, placebo and high-dose tadalafil produced equivalent effects on the QT interval. This study reliably discerned 5- to 10-ms changes in corrected QT in the ibutilide active control group.
authors.affiliation: Lilly Research Laboratories, Indianapolis, Indiana 46285, USA. cmbeasleyj@lilly.com
authors.forename: Charles M
authors.initials: CM
authors.lastname: Beasley
authors.forename: Malcolm I
authors.initials: MI
authors.lastname: Mitchell
authors.forename: Alex A
authors.initials: AA
authors.lastname: Dmitrienko
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Emmick
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Costigan
authors.forename: Alun W
authors.initials: AW
authors.lastname: Bedding
authors.forename: Michael A
authors.initials: MA
authors.lastname: Turik
authors.forename: Arash
authors.initials: A
authors.lastname: Bakhtyari
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Warner
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Ruskin
authors.forename: Louis R
authors.initials: LR
authors.lastname: Cantilena
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kloner
mesh_terms: D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002243:Carbolines / Q000009:adverse effects* / Q000494:pharmacology; D016022:Case-Control Studies; D004562:Electrocardiography; D004594:Electrophysiology; D007172:Erectile Dysfunction / Q000188:drug therapy; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D010919:Placebos; D013449:Sulfonamides / Q000494:pharmacology*; D000068581:Tadalafil; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D002243:Carbolines; D010726:Phosphodiesterase Inhibitors; D010919:Placebos; D013449:Sulfonamides; C067192:ibutilide; D000068581:Tadalafil