Open AccessEffect of anagrelide on cardiac repolarization in healthy volunteers: a randomized, double‐blind, placebo‐ and positive‐controlled, thorough QT study
Author(s) -
Troy Steven,
Parks Virginia,
Purkayastha Jaideep,
Gossart Sophie,
Goodman Daniel B.,
Achenbach Heinrich,
Armstrong Martin,
Martin Patrick T.
Publication year - 2014
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.80
Subject(s) - qt interval , medicine , placebo , anagrelide , crossover study , randomized controlled trial , confidence interval , cardiology , heart rate , long qt syndrome , anesthesia , blood pressure , alternative medicine , pathology , essential thrombocythemia , polycythemia vera
The aim of this study was to assess the effect of low and high therapeutic doses of anagrelide (0.5 and 2.5 mg) on cardiac repolarization, measured by the QT cNi (individual correction) and QT cF (Fridericia's correction), compared with placebo and moxifloxacin 400 mg (positive control) in healthy subjects. In this randomized, double‐blind, crossover trial, 60 healthy volunteers were enrolled and randomized. Anagrelide 0.5 and 2.5 mg rapidly increased mean heart rate ( HR ) by 7.8 and 29.1 bpm respectively. For anagrelide 2.5 mg, the maximum time‐matched change (one‐sided 95% upper confidence bound) in mean QT cNi and QT cF was 13.0 msec (15.7 msec) and 10.0 msec (12.7 msec), respectively, at 1 h post dose. However, time‐matched changes in QT cNi and QT cF quickly decreased to <6 msec by 2 h post dose, despite high stable HR and high plasma concentrations of anagrelide and its active metabolite at these times. For anagrelide 0.5 mg, the maximum time‐matched change in mean QT cNi and QT cF was 7.0 msec (9.8 msec) and 5.0 msec (8.0 msec) respectively. No new safety concerns were reported. The increase in QT c interval met the definition for a positive thorough QT / QT c study only when HR was increasing rapidly, suggesting that the increased QT c may be related to the rapidly increasing HR rather than a direct effect of anagrelide plasma concentrations. However, the direct causal relationship of anagrelide on cardiac repolarization cannot be completely excluded, and caution is advised when treating patients with known risk factors for QT interval prolongation.