Ziprasidone and the Corrected QT Interval: A Comprehensive Summary of Clinical Data

CNS Drugs, 03/30/2012

The analyses provide the first comprehensive summary of QT interval (QTc) changes associated with ziprasidone based on Pfizer–sponsored phase II–IV randomized controlled trials (RCTs), safety reports and post–marketing surveillance. The results of the analyses of pooled data from phase II–IV RCTs in adults demonstrate a modest mean increase in QTc, infrequent QTc prolongation ≥60 ms and rare observation of QTc ≥480 ms. These data are consistent with results from ziprasidone clinical pharmacology studies, safety reports and post–marketing surveillance. Taken together, they provide the most comprehensive evidence published to date that ziprasidone appears to be safe when used as indicated in patients with schizophrenia or bipolar disorder.

Methods

  • The following analyses of data were conducted to obtain a comprehensive summary of QTc data on ziprasidone:
    • Post hoc analyses (using primarily descriptive statistics) of pooled QTc data (Fridericia correction) from more than 40 phase II-IV adult ziprasidone RCTs organized according to the following subgroups: all monotherapy studies in schizophrenia and bipolar disorder, all intramuscular (IM) studies, adjunctive studies in bipolar disorder and fixed-dose oral studies
    • Post hoc analyses from 36 phase II-IV adult ziprasidone RCTs exploring the relationship between QTc change from baseline and baseline QTc in adults
    • Post hoc analyses from phase II-IV adult ziprasidone RCTs modelling QTc change as a function of ziprasidone concentration in both adult (17 studies) and paediatric (5 studies) subjects
    • Cardiac adverse event (AE) reports from all phase II-IV adult ziprasidone RCTs in schizophrenia
    • A large simple trial entitled Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) in 18,154 subjects with schizophrenia (the only previously reported results included here); and
    • Cardiac-related AEs presented in a ziprasidone post-marketing surveillance report created in 2007.

Results

  • A total of 4306 adults received ziprasidone in placebo- and active-comparator phase II–IV RCTs and had evaluable QTc data.
  • One subject reached a QTc ≥480 ms; 33 (0.8%) had a QTc ≥450 ms.
  • QTc prolongation ≥30 ms was observed in 389 subjects (9.0%); ≥60 ms in 30 (0.7%); and ≥75 ms in 12 (0.3%).
  • In the placebo-controlled studies, mean change in QTc from baseline to end of study was 3.6 (± 20.8) ms in the ziprasidone group; the corresponding QTc change in the pooled placebo group was -0.3 (± 20.6) ms.
  • Data from IM studies, and bipolar studies in which ziprasidone was used adjunctively with lithium, valproate or lamotrigine, demonstrated similar QTc effects.
  • A scatter-plot of QTc prolongation against baseline QTc showed QTc prolongation ≥60 ms exclusively in adult subjects with a baseline QTc ≤400 ms.
  • The final concentration-response analysis model, comprising 2966 data points from 1040 subjects, estimates an increase in QTc of 6 ms for each 100 ng/mL increase in ziprasidone concentration.
  • The large simple trial (ZODIAC) failed to show that ziprasidone is associated with an elevated risk of non-suicidal mortality relative to olanzapine in real-world use.
  • Post-marketing data over a 5-year period did not show a signal of increased cardiac AEs.

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