title: Effects of aliskiren, a direct Renin inhibitor, on cardiac repolarization and conduction in healthy subjects.
abstract: This multicenter, double-blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo-adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time-matched analysis) and for values averaged across the dosing period (baseline-averaged analysis). In time-matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <10 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline-averaged analysis was consistent with time-matched analysis. Instances of QTcF interval >450 milliseconds or a >30-millisecond increase from baseline with aliskiren (< or = 1%) were similar or lower than placebo (< or = 4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4-fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Surya
authors.initials: S
authors.lastname: Ayalasomayajula
authors.forename: Ching-Ming
authors.initials: CM
authors.lastname: Yeh
authors.forename: Sujata
authors.initials: S
authors.lastname: Vaidyanathan
authors.forename: Brian
authors.initials: B
authors.lastname: Flannery
authors.forename: Hans Armin
authors.initials: HA
authors.lastname: Dieterich
authors.forename: Dan
authors.initials: D
authors.lastname: Howard
authors.forename: Martin P
authors.initials: MP
authors.lastname: Bedigian
authors.forename: William P
authors.initials: WP
authors.lastname: Dole
mesh_terms: D000328:Adult; D000577:Amides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D005650:Fumarates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000494:pharmacology; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D005650:Fumarates; D000077266:Moxifloxacin; D011804:Quinolines; D000092502:Renin Inhibitors; C446481:aliskiren