Clinical assessment of drug-induced QT prolongation in association with heart rate changes.
BACKGROUND
The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes.


METHODS
A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis.


RESULTS
The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence.


CONCLUSIONS
The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.
Extramiana
Fabrice
F
Cardiology Department, Lariboisière Hospital, 2 rue Ambroise Paré, 75475 Paris Cedex 10. fabrice.extramiana@lrb.ap-hop-paris.fr
Maison-Blanche
Pierre
P
Cabanis
Marie-José
MJ
Ortemann-Renon
Catherine
C
Beaufils
Philippe
P
Leenhardt
Antoine
A
D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000328:Adult; D001372:Aza Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000379:methods; D015716:Electrocardiography, Ambulatory / Q000379:methods*; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011237:Predictive Value of Tests; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D016896:Treatment Outcome
D000317:Adrenergic alpha-Antagonists; D001372:Aza Compounds; D024841:Fluoroquinolones; D011799:Quinazolines; D011804:Quinolines; C047638:alfuzosin; D000077266:Moxifloxacin