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0091270007302953v1
47/9/1129    most recent
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CLINICAL STUDIES

Contrasting Time- and Rate-Based Approaches for the Assessment of Drug-Induced QT Changes

Fabrice Extramiana, MD, PhD, Fabio Badilini, PhD, Nenad Sarapa, MD, Antoine Leenhardt, MD and Pierre Maison-Blanche, MD

From Lariboisière University Hospital—APHP—Paris 7 University, France (Dr Extramiana, Dr Leenhardt, Dr Maison-Blanche); AMPS LLC, New York (Dr Badilini); and Daiichi Sankyo Pharma Development, Edison, New Jersey (Dr Sarapa).

The authors aim to highlight the pitfalls of different validated methods used for the assessment of drugs' effect on QT duration. Digital 12-lead Holter electrocardiograms were recorded at baseline and after a single dose of sotalol in 39 healthy subjects (age = 27.4 ± 8.0 years). Using both time- and rate-based approaches, the authors obtained averaged QRS-T complexes every minute ("time bins") and at different RR intervals ("rate bins"). Time bins were corrected for heart rate using a subject-specific approach. The individual {alpha} coefficients increased from placebo (0.309 ± 0.052) to sotalol (0.454 ± 0.136), P < .0001. When the placebo individual {alpha} coefficients were applied to correct the QT interval on sotalol, the changes were >5 ms smaller than those obtained using the ON drug {alpha} coefficients. The "rate"-averaging process leads to a complete loss of the time course of drug effect. In conclusion, the individual correction formula calculated from the placebo condition cannot always be used for QT correction on the drug.

Key Words: QT interval • sotalol • Holter ECG

Address for correspondence: Fabrice Extramiana, MD, PhD, Cardiology Department—Lariboisière University Hospital, 2 rue Ambroise Parè—75010, Paris, France; e-mail: Fabrice.extramiana{at}lrb.aphp.fr.


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