Drug-induced QT prolongation in women during the menstrual cycle

Context Women have a higher incidence of torsades de pointes than men, but it is not known if the risk of drug-induced torsades de pointes varies duri ng the menstrual cycle, Objectives To determine if the degree of QT prolongation in response to ibu tilide varies with the menstrual cycle phase and to compare QT prolongation between women and men. Design and Setting Cohort study of men and women who received the same inte rvention conducted between November 1998 and November 2000 at a general cli nical research center of a university hospital. Participants A volunteer sample of 58 healthy adults (38 men and 20 women) aged 21 to 40 years. Intervention A low dose of ibutilide (0.003 mg/kg), infused intravenously f or 10 minutes. Subjects were monitored for 120 minutes. Women received the intervention on 3 separate occasions to correspond with menstrual cycle pha ses, which were verified by using hormonal assays. Main Outcome Measure QT interval, recorded from electrocardiogram at timed intervals during and after ibutilide infusion and standardized for variatio ns in heart rate (QTc), Results Maximum (mean [SD]) millisecond increase in QTc after ibutilide inf usion was greater for women during menses (63 [13]) and the ovulatory phase (59 [17]) compared with women during the luteal phase (53 [14]) and compar ed with men (46 [16]; P = .002 vs menses and P = .007 vs ovulation), Proges terone (r = -0.40) and progesterone-to-estradiol ratio (r = -0.41), but not estradiol (r = 0.14) or testosterone (r = 0.09), were inversely correlated with ibutilide-induced QT prolongation. Conclusions Menstrual cycle and sex differences exist in QTc responses to i butilide, with the greatest increase in QTc corresponding to the first half of the menstrual cycle.