Oral Progesterone May Effectively Reduce Risk of Drug-Induced QT_c Interval Prolongation

Oral progesterone may be effective at reducing risk of drug-induced QT_c interval (Bazett’s-corrected QT interval) prolongation, according to an initial proof-of-concept study published in JACC: Clinical Electrophysiology.

Torsades de pointes (TdP)—a polymorphic ventricular tachycardia associated with QT interval prolongation—can be induced by more than 100 medications available in the United States. The authors explained that TdP risk increases as the QT_c interval increases and therefore, QTc interval prolongation is used as a risk marker for TdP.

In addition, previous research has demonstrated that female sex can be an independent risk factor for TdP in patients with acquired or congenital long-QT syndrome. Sex hormones have thought to be responsible for the difference in QT_c intervals, given that women have longer intervals than men.

Researchers tested the hypothesis that higher serum progesterone concentrations could be protective against drug-induced QT interval lengthening.

They enrolled 15 healthy and premenopausal women between the ages of 21 and 40 years in this prospective, randomized, double-blind, placebo-controlled, crossover study at the Indiana Clinical Research Center. Patients either received progesterone 400 mg/d for 7 days or matching placebo.

On the seventh day, patients were given ibutilide 0.003 mg/kg via infusion over the course of 10 minutes, after which QT intervals were recorded and blood samples collected.

Outcomes included  pre-ibutilide QT_cI (individualized heart rate-corrected QT interval) and QT_F (Fridericia-corrected QT interval) intervals, maximum QT_cI and QT_F intervals after ibutilide administration, maximum ibutilide-induced percent change in QT_cI and QT_F intervals, and area under the QT_cI and QT_F interval-time curves within the first hour following ibutilide therapy.

The study consisted of a pre-randomization phase to determine each participant’s QT interval heart rate-correction, and the randomized, and double-blind progesterone and placebo phases. Patients were also screened for serum potassium, magnesium, creatinine, transaminases, hemoglobin, and hematocrit, and tested for pregnancy.

Researchers noted that each phase “was conducted during the menses phase of the menstrual cycle (defined as 24-60 hours after menses onset), when serum estradiol and progesterone concentrations are at their lowest, to minimize effects of endogenous sex hormones.”

Maximum serum ibutilide concentrations were similar between progesterone and placebo phases (1247 ± 770 vs 1172 ± 709 pg/mL; P=.43). However, serum progesterone concentrations were higher during the progesterone phase (16.2 ± 11.0 vs 1.2 ± 1.0 ng/mL; P<.0001), but serum estradiol concentrations were similar in both phases (89.3 ± 62.8 vs 71.8 ± 31.7 pg/mL; P=.36).

During the progesterone phase, pre-ibutilide lead II QT_cI was significantly lower (412 ± 15 vs 419 ± 14 ms; P=.04). In addition, maximum ibutilide-associated QT_cI, maximum percent increase in QT_cI from pretreatment, and area under the effect (QT_cI) curve during the first hour after ibutilide were all lower during the progesterone phase.

Fatigue/malaise and vertigo were among the adverse affects associated with progesterone, but were usually mild.

“These findings suggest that oral progesterone could be effective for reducing the risk of drug-induced QT_c interval prolongation in patients requiring therapy with QT_c interval-prolonging drugs,” researchers wrote.

Researchers encouraged future studies to be conducted in such targeted patient populations to determine the effects of oral progesterone on QT_c interval-prolonging therapy.

Reference

Tisdale JE, Jaynes, Overholser BR, Sowinski KM, Flockhart DA, Kovacs RJ. Influence of oral progesterone administration on drug-induced QT interval lengthening: a randomized, double-blind, placebo-controlled crossover study. JACC Clin Electrophysiol. 2016. doi:10.1016/j.jacep.2016.02.015.