title: Literature review and pilot studies of the effect of QT correction formulas on reported beta2-agonist-induced QTc prolongation.
abstract: 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.
authors.affiliation: Department of Medicine, University of California, San Diego 92103-8341, USA.
authors.forename: Milos
authors.initials: M
authors.lastname: Milic
authors.forename: Xuping
authors.initials: X
authors.lastname: Bao
authors.forename: Demetri
authors.initials: D
authors.lastname: Rizos
authors.forename: Fujun
authors.initials: F
authors.lastname: Liu
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ziegler
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000009:adverse effects*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000009:adverse effects*; D004562:Electrocardiography / Q000187:drug effects*; D029789:Ephedra / Q000009:adverse effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D010865:Pilot Projects
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents