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.

Adverse Events in Healthy Individuals and MDR-TB Contacts Treated with Anti-Tuberculosis Drugs Potentially Effective for Preventing Development of MDR-TB: A Systematic Review

“…In the other two studies however, no such effect was found [39],[40]. In these two studies the percentage adverse events was higher compared to the first study [37].…”

“…In one of the three placebo-controlled studies the data suggest that mild gastrointestinal adverse events occur twice as often after use of moxifloxacin compared to placebo (RR 2.03, 95% CI 1.13–3.64) [37]. In the other two studies however, no such effect was found [39],[40].…”

“…Six studies on levofloxacin were included [32]–[36], [47] (eight study arms; three RCTs were placebo controlled [33]–[35]), five RCTs studied moxifloxacin [36]–[40] (five study arms; three placebo controlled [37],[39],[40] though the first of these three was blinded for the drug of primary interest, aliskiren, but not for moxifloxacin [37]), four reports were on ofloxacin [41]–[43], [46] (six study arms; two placebo controlled [41],[43]), two RCTs studied rifabutin [44],[45] (three study arms; none placebo controlled).…”

“…All but one study had small sample sizes, ranging between 10 and 41 participants. One RCT randomized 298 persons, of which 76 received moxifloxacin [37]. In 15 of 22 study arms (68%) the volunteers were treated for seven days [32]–[38],[41],[42],[46],[47] and in seven (32%) for 8 to 13 days [33],[39],[40],[44],[45].…”

“…Six trials were at high risk of bias because of lack of blinding of study staff and/or participants [32],[36],[37],[42],[44],[45]. These were all actively controlled trials.…”