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

• Published in: Journal of clinical pharmacology 2007-09, Vol.47 (9), p.1129-1137
• Main Authors: Extramiana, Fabrice, Badilini, Fabio, Sarapa, Nenad, Leenhardt, Antoine, Maison-Blanche, Pierre
• Format: Article
• Language: English
• Subjects: Adult; Anti-Arrhythmia Agents - adverse effects; Anti-Arrhythmia Agents - pharmacology; Arrhythmia; Dosage and administration; Drug therapy; Electrocardiography, Ambulatory - methods; Female; Heart beat; Heart Rate - drug effects; Holter ECG; Humans; Long QT Syndrome - chemically induced; Long QT Syndrome - diagnosis; Male; Models, Cardiovascular; Physiological aspects; Properties; QT interval; Sotalol; Sotalol - adverse effects; Sotalol - pharmacology; Time Factors
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270007302953

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 α coefficients increased from placebo (0.309 ± 0.052) to sotalol (0.454 ± 0.136), P < .0001. When the placebo individual α coefficients were applied to correct the QT interval on sotalol, the changes were >5 ms smaller than those obtained using the ON drug α 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.