Contrasting time- and rate-based approaches for the assessment of drug-induced QT changes.
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.
Cardiology Department - Lariboisière University Hospital, 2 rue Ambroise Parè - 75010, Paris, France. Fabrice.extramiana@lrb.aphp.fr
Fabrice
F
Extramiana
Fabio
F
Badilini
Nenad
N
Sarapa
Antoine
A
Leenhardt
Pierre
P
Maison-Blanche
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects* / Q000494:pharmacology; D015716:Electrocardiography, Ambulatory / Q000379:methods*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis; D008297:Male; D008955:Models, Cardiovascular; D013015:Sotalol / Q000009:adverse effects* / Q000494:pharmacology; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D013015:Sotalol