Reducing the Risk of Drug-Induced QT Interval Lengthening in Women

Project: Research

Investigators

  • James E Tisdale (PI)

Description

Torsades de pointes (TdP) is a catastrophic arrhythmia associated with corrected QT (QTc) interval prolongation, which can be induced by > 150 commonly prescribed drugs. TdP risk is higher in women, and is modulated by the ratio of serum progesterone and estradiol; the higher the serum progesterone and progesterone:estradiol ratio, the lower the risk, and vice-versa. Some data suggest that protective QTc interval effects of progesterone may be lessened by estradiol, which lengthens QTc interval, and may be diminished during phases of the menstrual cycle when estradiol concentrations are highest. TdP risk also increases with age, likely due to declining postmenopausal progesterone concentrations. Methods to reduce TdP risk in younger and postmenopausal women requiring therapy with QTc interval-prolonging drugs have not been developed. We have previously shown that oral progesterone attenuates QTc interval lengthening in young women during the menses phase when serum estradiol concentrations are low. However, the efficacy of oral progesterone for attenuating drug-induced QTc interval lengthening in premenopausal women with higher serum estradiol concentrations or in postmenopausal women is unknown. Specific Aims: to determine the efficacy of oral progesterone as a preventive method to diminish drug-induced QTc interval lengthening in: Aim 1: Premenopausal women during the ovulation phase of the menstrual cycle when serum estradiol concentrations are high, and Aim 2: Postmenopausal women. Two prospective, randomized, double-blind, placebo-controlled two-way crossover studies will be conducted in 1) Premenopausal women 21-40 years of age (n=16) studied during the ovulation phase when serum estradiol concentrations are high, and 2) Postmenopausal women > 55 years of age (n=16). QTc interval response to low-dose ibutilide will be assessed. Primary outcome measures: 1) Baseline (pre-ibutilide) Fridericia (QTFrid) and Framingham (QTFram)-corrected QT intervals and 2) Maximum QTFrid and QTFram intervals following ibutilide. Secondary outcome measures: 1) Maximum % change in QTFrid and QTFram intervals following ibutilide, 2) Area under the QTFrid and QTFram interval-time curves, 3) Incidence of progesterone and ibutilide adverse effects. These studies will establish oral progesterone as a safe and effective method of attenuating drug-induced QTc interval lengthening in women at increased risk of drug-induced QTc interval prolongation and TdP.
Award amount$300,000.00
Award date07/01/2018
Program typeTransformational Project Award
Award ID18TPA34170523
Effective start/end date07/01/201806/30/2021
StatusActive