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Effects of Aliskiren, a Direct Renin Inhibitor, on Cardiac Repolarization and Conduction in Healthy Subjects

From Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Ayalasomayajula, Dr Yeh, Dr Vaidyanathan, Mr Flannery, Dr Howard, Dr Bedigian); Novartis Pharma AG, Basel, Switzerland (Dr Dieterich); and Novartis Institutes for Biomedical Research Inc, Cambridge, Massachusetts (Dr Dole).

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 (1%) were similar or lower than placebo (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.

Key Words: Aliskiren • moxifloxacin • QT interval • cardiac repolarization

Address for reprints: William P. Dole, MD, Novartis Institutes for Biomedical Research Inc, 400 Technology Square, Building 605-820, Cambridge, MA 02139.

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