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Ignacio Rodriguez, MD; Michael J. Kilborn, BMBCh,PhD; Xiao-Ke Liu, MD,PhD; John C. Pezzullo, PhD; Raymond L. Woosley, MD,PhD

JAMA. 2001;285:1322-1326.

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 during the menstrual cycle.

Objectives  To determine if the degree of QT prolongation in response to ibutilide 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 intervention conducted between November 1998 and November 2000 at a general clinical 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 for 10 minutes. Subjects were monitored for 120 minutes. Women received the intervention on 3 separate occasions to correspond with menstrual cycle phases, 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 variations in heart rate (QTc).

Results  Maximum (mean [SD]) millisecond increase in QTc after ibutilide infusion was greater for women during menses (63 [13]) and the ovulatory phase (59 [17]) compared with women during the luteal phase (53 [14]) and compared with men (46 [16]; P = .002 vs menses and P = .007 vs ovulation). Progesterone (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 ibutilide, with the greatest increase in QTc corresponding to the first half of the menstrual cycle.

Author Affiliations: Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Georgetown University Medical Center, Washington DC.

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