TY - JOUR
T1 - Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram
T2 - Distinguishing a drug effect from spontaneous variability
AU - Pratt, Craig M.
AU - Ruberg, Stephen
AU - Morganroth, Joel
AU - McNutt, Bruce
AU - Woodward, James
AU - Harris, Stuart
AU - Ruskin, Jeremy
AU - Moyé, Lemuel
N1 - Funding Information:
From the aSection of Cardiology, Department of Internal Medicine, Baylor College of Medicine; bMarion Merrell Dow; cPhiladelphia Heart Institute and the University of Pennsylvania; dSouth Florida Bioavailability Clinic; eMassachusetts General Hospital; and fUniversity of Texas Health Science Center, School of Public Health. Supported by a grant from Marion Merrell Dow. Received for publication June 22, 1995; accepted Aug. 2, 1995. Reprint requests: Craig M. Pratt, MD, Baylor College of Medicine, 6535 Fannin MS F1001, Houston, TX 77030. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 411/69480
PY - 1996
Y1 - 1996
N2 - The primary goal of this investigation was to describe the effect of terfenadine on the QT interval corrected for heart rate (QTc) of the scalar electrocardiogram (ECG). The design was double-blind, four-period crossover, dose escalation, which involved 28 normal healthy volunteers and 28 patients with stable cardiovascular disease. At baseline, the normal subjects had a mean QTc interval of 407 msec, whereas the patients with cardiovascular disease had a mean QTc interval of 417 msec (p < 0.01). The largest increase in mean QTc on terfenadine was 24 msec in a normal subject and 28 msec in a patient with cardiovascular disease. The longest average QTc observed was 449 msec and 501 msec in any normal subject and patient with cardiovascular disease, respectively. Compared to baseline, terfenadine 60 mg twice daily is associated with a QTc increase of 6 msec in normal subjects and a 12 msec increase in patients with cardiovascular disease (p < 0.01 vs baseline; p > 0.05 when the two populations were compared). Although the QTc increases from baseline are statistically significant, the magnitude of the spontaneous variability in QTc in the same patients is much greater. Because 40 ECGs were obtained while taking placebo in each participant, the spontaneous variability in QTc interval with placebo was also described. Only one of the 20 normal subjects had a mean baseline QTc ≥440 msec, yet 14 of the 28 normal subjects had at least one of the 40 placebo ECGs with a QTc ≥440 msec. The 20 patients with cardiovascular disease had a mean QTc at baseline of 417 msec; yet 20 of 28 had at least one ECG on placebo with a QTc interval ≥440 msec. On the average, the QTc fluctuated 56 msec in each patient during placebo administration. From the observed placebo variability, we calculated that an increase in QTc of ≥35 msec while receiving drug therapy is likely to represent a drug effect at the 95% confidence interval.
AB - The primary goal of this investigation was to describe the effect of terfenadine on the QT interval corrected for heart rate (QTc) of the scalar electrocardiogram (ECG). The design was double-blind, four-period crossover, dose escalation, which involved 28 normal healthy volunteers and 28 patients with stable cardiovascular disease. At baseline, the normal subjects had a mean QTc interval of 407 msec, whereas the patients with cardiovascular disease had a mean QTc interval of 417 msec (p < 0.01). The largest increase in mean QTc on terfenadine was 24 msec in a normal subject and 28 msec in a patient with cardiovascular disease. The longest average QTc observed was 449 msec and 501 msec in any normal subject and patient with cardiovascular disease, respectively. Compared to baseline, terfenadine 60 mg twice daily is associated with a QTc increase of 6 msec in normal subjects and a 12 msec increase in patients with cardiovascular disease (p < 0.01 vs baseline; p > 0.05 when the two populations were compared). Although the QTc increases from baseline are statistically significant, the magnitude of the spontaneous variability in QTc in the same patients is much greater. Because 40 ECGs were obtained while taking placebo in each participant, the spontaneous variability in QTc interval with placebo was also described. Only one of the 20 normal subjects had a mean baseline QTc ≥440 msec, yet 14 of the 28 normal subjects had at least one of the 40 placebo ECGs with a QTc ≥440 msec. The 20 patients with cardiovascular disease had a mean QTc at baseline of 417 msec; yet 20 of 28 had at least one ECG on placebo with a QTc interval ≥440 msec. On the average, the QTc fluctuated 56 msec in each patient during placebo administration. From the observed placebo variability, we calculated that an increase in QTc of ≥35 msec while receiving drug therapy is likely to represent a drug effect at the 95% confidence interval.
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U2 - 10.1016/S0002-8703(96)90525-6
DO - 10.1016/S0002-8703(96)90525-6
M3 - Article
C2 - 8604626
AN - SCOPUS:0029883856
SN - 0002-8703
VL - 131
SP - 472
EP - 480
JO - American Heart Journal
JF - American Heart Journal
IS - 3
ER -