Effects of ziprasidone on the QTC interval: A pooled data analysis

Abstract

Background: Second generation antipsychotics have been associated with QTc interval prolongation [1]. Previously clinical studies for ziprasidone have reported a dose-dependent modest increase in the mean QTc interval over the range of 40-320 mg/day [2]. All Pfizer-sponsored, controlled randomized trials for schizophrenia or bipolar disorder have evaluated the effects of ziprasidone on the QTc interval [3]. We present pooled analyses of these trials. Methods: Studies were pooled into group 1: placebo and active-comparator controlled oral adult trials, group 2: active-comparator controlled intramuscular (IM) adult trials, and group 3: placebo-controlled pediatric trials. We report the change from baseline to last available QTc measurement (mean, SD and range), categorical QTc prolongation (increase of(greater-than or equal to) 30, 60, and 75 ms), and highest measured QTc (threshold of (greater-than or equal to)450, 480, and 500 ms). All reported QTc interval data used the Fridericia correction formula. Serious adverse events (AEs) and discontinuations related to QTc prolongation are also outcomes of interest. Results: In total, 3787 adult subjects received oral ziprasidone in the group 1 studies. Amongst these subjects there were no reports of QTc (greater-than or equal to) 480 ms; 20 subjects (0.5%) had a QTc (greater-than or equal to) 450 ms. QTc prolongation (greater-than or equal to)30 ms was observed in 337 subjects (8.9%); 22 (0.6%) had QTc prolongation (greater-than or equal to)60 ms; and 5 (0.1%) had QTc prolongation (greater-than or equal to)75 ms. Mean change from baseline to endpoint in QTc was 3.1 msec (20.31 ms) from a baseline mean of 387.0 ms (21.90 ms). Comparable mean (SD) QTc change values (in ms) in the pooled placebo (N = 829), haloperidol (N= 865), olanzapine (N = 387), and risperidone (N= 341) subjects were -0.6 (20.45), -1.5 (20.77), -1.8 (19.86), and -0.8 (23.09), respectively. Data from group 2 and 3 demonstrate similar QTc changes as seen in group 1. Conclusion: The present analyses of Pfizer clinical trial data show that ziprasidone causes a small mean increase in QTc interval. However, the incidence of subjects reaching a clinically significant threshold for increase from baseline in QTc interval of (greater-than or equal to)60 ms is rare, with infrequent reports of QTc interval (greater-than or equal to)480 ms