Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability.

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 increase 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 28 normal subjects had a mean baseline QTc=440 msec, yet 14 of the 28 normal subjects had at lease one of the 40 placebo ECGs with a QTc=440 msec. The 28 patients with cardiovascular disease had a mean QTc at baseline of 417 msec; yet 20 of 28 had at lease 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.

[1]  G. Kay,et al.  Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. , 1983, Journal of the American College of Cardiology.

[2]  H. Bazett,et al.  AN ANALYSIS OF THE TIME‐RELATIONS OF ELECTROCARDIOGRAMS. , 1997 .

[3]  D. Roden,et al.  Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. , 1986, American heart journal.

[4]  H. Kennedy,et al.  Torsades de pointes associated with drugs and toxins: recognition and management. , 1987, American heart journal.

[5]  E. Aliot,et al.  The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. , 1988, Progress in cardiovascular diseases.

[6]  S. Swiryn,et al.  Torsade de pointes due to quinidine: observations in 31 patients. , 1984, American heart journal.

[7]  M. Laks.  Long QT interval syndrome. A new look at an old electrocardiographic measurement--the power of the computer. , 1990, Circulation.

[8]  D. Mirvis,et al.  Spatial variation of QT intervals in normal persons and patients with acute myocardial infarction. , 1985, Journal of the American College of Cardiology.

[9]  R. Woosley,et al.  Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin , 1992, Clinical pharmacology and therapeutics.

[10]  B McNutt,et al.  Torsades de pointes occurring in association with terfenadine use. , 1991, JAMA.

[11]  C. L. Ferguson,et al.  Torsades de pointes occurring in association with terfenadine use. , 1990, JAMA.

[12]  C. Meinert.  Clinical Trials: Design, Conduct, and Analysis , 1986 .

[13]  B. Surawicz.  The QT interval and cardiac arrhythmias. , 1987, Annual review of medicine.

[14]  J. Morganroth,et al.  Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. , 1991, The American journal of cardiology.

[15]  D. Roden.  Role of the electrocardiogram in determining electrophysiologic end points of drug therapy. , 1988, The American journal of cardiology.

[16]  P. Lévy,et al.  Torsades de Pointes after treatment with terfenadine and ketoconazole. , 1992, European heart journal.

[17]  D. Wortham,et al.  Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. , 1993, JAMA.

[18]  C. Pratt,et al.  Risk of developing life-threatening ventricular arrhythmia associated with tefenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine. , 1994, The American journal of cardiology.

[19]  L. Horowitz,et al.  Torsades de Pointes: Electrophysiologic Studies in Patients Without Transient Pharmacologic or Metabolic Abnormalities , 1981, Circulation.

[20]  D L Kunze,et al.  Variability of the QTc interval: impact on defining drug effect and low-frequency cardiac event. , 1993, The American journal of cardiology.