Literature review and pilot studies of the effect of QT correction formulas on reported beta2-agonist-induced QTc prolongation.

BACKGROUND: Drugs that stimulate the beta2-adrenergic receptor have been reported to prolong the QT interval corrected for heart rate (QTc interval), a potential mechanism for cardiac toxicity.
OBJECTIVE: This study evaluated whether beta2-adrenergic agonist drugs prolong the QTc interval when different correction formulas for the effect of heart rate are used.
METHODS: Healthy subjects of both sexes aged 19 to 33 years were recruited with advertisements. In pilot studies, subjects took a preparation containing the beta2-agonist ephedrine, or they participated in a postural study of the effect of endogenous beta-agonists. The study-drug group took 3 pills of the ephedra preparation per day for 2 days and then 6 pills per day for the next 2 days. Electrocardiograms (ECGs) were recorded before and at 1, 3, and 82 hours after the first study-drug dose and both before and after standing in the standing-up group. QT intervals obtained by automatic measurement were corrected for heart rate with 3 formulas: Bazett (QTc[B]), Framingham (QTc[F]), and Fridericia (QTc[Fr]). For the literature review, PubMed was searched using the search terms beta2-agonist drugs, QT, QTc, EKG, ECG, or electrocardiogram for studies that reported prolongation of the QTc by beta2-agonist drugs. We analyzed the method by which 11 different studies corrected QT interval for heart rate after the use of formoterol, salmeterol, terbutaline, salbutamol, and fenoterol.
RESULTS: The ephedra study included 20 healthy subjects (35% men; mean [SD] age, 25 [4] years). Two hours after the last dose, QTc[B] had increased significantly from baseline by 19 ms (P=0.02). QTc[F] and QTc[Fr] did not change significantly. In the postural study, 19 healthy subjects (68% men; mean [SD] age, 32 [8] years) stood up and QTc[B] increased by a mean (SD) of 8 (15) ms (P=0.03). In these subjects, the QTc[B]/RR regression slope was significantly different from 0 (r=0.60, P=0.002), and the Bazett formula did not eliminate the dependence of QTc on heart rate. However, QTc[F] and QTc[Fr] did not change significantly, meaning that these formulas eliminated the dependence of QTc on heart rate. Eleven publications reported prolongation of QTc[B] by 5 beta2-adrenergic agonists for asthma. The change in QTc[B] interval from these publications was still dependent on the change in heart rate (r=0.63, P=0.004), but this dependence was eliminated after using QTc[F] and QTc[Fr]. The increase in QTc[B] would have been up to 30 ms less if QTc[F] or QTc[Fr] had been reported instead.
CONCLUSIONS: The Bazett correction is the one typically reported by computerized ECG machines and the medical literature. This review suggests that QTc[B] may overestimate QTc when heart rate increases. Because the beta2-adrenergic agonist drugs increase heart rate, a systematic bias may have implicated these drugs in prolongation of cardiac repolarization. Prospective, large studies with a placebo and active control group are needed to evaluate the effect of beta2 agonists on QTc using formulas other than Bazett.