VARIABILITY OF THE QT(C) INTERVAL - IMPACT ON DEFINING DRUG EFFECT AND LOW-FREQUENCY CARDIAC EVENT

Prolongation of the QT interval corrected for heart rate (QT(c)) can l ead to the development of torsades de pointes, a life-threatening form of polymorphic ventricular tachycardia. However, the QT(c) interval d uration exhibits a high degree of spontaneous variability and is not n ecessarily a direct predictor of the risk of torsades. This observatio n holds implications for the assessment of the potential prooarrhythmi c effects of noncardiac pharmacologic agents. To date, the antihistami ne terfenadine is the only noncardiac drug than has undergone a compre hensive and systematic evaluation related to the consequences of its c ausing QT(c) prolongation. The results suggest that QT(c) prolongation resulting solely from terfenadine at clinical doses does not have an important impact on clinically relevant endpoints. The risk of serious ventricular arrhythmias with terfenadine using epidemiologic data is the same or less than that associated with traditional first-generatio n antihistamines. The risk of a clinical cardiac event (QT(c)) prolong ation, ventricular arrgythmias, syncope, or sudden death) with terfena dine is similar to that of other antihistamines. Factors associated wi th increased risk in patients taking terfenadine include significant l iver disease, hypokalemia, overdose, and concomitant administration of ketoconazole-like agents or erythromycin; use of terfenadine is relat ively contrainidicated in these settings. No increased risk of serious arrhythmias has been confirmed in conjunction with the use of terfena dine in patients with cardiac disease.