— Healthy woman on drospirenone saw longest drug-induced QTc prolongation Healthy women on oral contraceptives may have a higher risk for drug-induced alterations of ventricular repolarization, according to a study from France. In a group of nearly 500 non-menopausal women who received 80 mg of oral sotalol (Betapace), certain oral contraceptives were associated with sotalol-induced corrected QT (QTc) prolongation, reported Joe-Elie Salem, MD, PhD, of Hôpital Pitié-Salpêtrière in Paris, and colleagues. Specifically, QTc prolongation was higher 3 hours after exposure to sotalol in those taking drospirenone compared with women who were not on any oral contraceptives (mean increase 31.2 milliseconds from baseline versus 24.6 milliseconds, P=0.005). QTc prolongation was also greater among those on drospirenone versus women on levonorgestrel (31.2 milliseconds versus 24.2 milliseconds, P=0.005), the group wrote in a brief report in JAMA Cardiology. These changes in QTc duration were associated with plasma levels of sotalol within the 3 hours after exposure (r=0.44, P<0.001), and were also linked to kalemia (r=0.01, P=0.05). However, these QTc changes weren't tied to age or baseline QTc duration. Furthermore, women who experienced a QTc prolongation of 50 milliseconds or longer were more likely to be on drospirenone (8.1%) or gestodene (5.9%) compared with those on desogestrel (0%), levonorgestrel (4.4%), or those not on any oral contraception (1.4%, P=0.003). With observation of T-wave notches 3 hours after sotalol dosing, more women on drospirenone and gestodene experienced sotalol-included T-wave alteration compared with women on other types of oral contraception (P=0.01 across all): Drospirenone: 21% experienced alteration Gestodene: 19.6% Levonorgestrel: 14.6% Desogestrel: 7.3% No oral contraceptives: 11.6% The appearance of these notches was also associated with plasma sotalol 4 hours after exposure (r=0.2, P<0.001), although wasn't tied to kalemia or age of the woman. The findings were supported by a disproportionality analysis between drospirenone and levonorgestrel -- also known as a case/non-case analysis -- conducted using the European pharmacovigilance database, according to the authors. They found a higher rate of oral contraceptive-induced prolonged QT (reporting odds ratio 6.2, 95% CI 1.3-30.8, P=0.01) among women on drospirenone compared with those on levonorgestrel. These women also experienced a higher rate of ventricular arrhythmias (ROR 3.3, 95% CI 1.7-6.3, P<0.001) and cardiac arrest (ROR 8.0, 95% CI 5.6-11.4, P<0.001). "These results generate the hypothesis that drospirenone may be a risk factor for drug-induced TdP [torsade de pointes] and sudden death in women receiving this oral contraceptive," the authors wrote, adding that the finding was supported by the disproportionality analysis, which found the higher rate of oral contraceptive-inducted ventricular arrhythmias and cardiac death for women on drospirenone. "More data are required on whether anti-androgenic oral contraceptive use will lead to clinically significant adverse events in patients taking QTc-prolonging drugs, such as class III antiarrhythmic medications," they stated. The findings can be helpful in "shared decision making" among women and their healthcare providers, particularly those with pre-existing risk factors for drug-induced TdP, the authors noted. All study participants were non-menopausal, healthy women enrolled in the Genome Wide Analysis of Sotalol-Induced IKr Inhibitor During Ventricular Repolarization (GENEREPOL) study. Over 200 women received no oral contraceptives after the single dose of oral sotalol. Most women on oral contraception received levonorgestrel (Mirena, Skyla, etc.), followed by 62 on drospirenone (Angeliq, Yasmin, etc.), 51 on gestodene (Femodene, Minulet, etc.), and 41 on desogestrel (Cerazette, Mircette, etc.) All of the oral contraceptives have different types of progestin with various levels of androgenic potency. Specifically, drospirenone has anti-androgenic properties, levonorgestrel has high androgenic potency, while desogestrel and gestodene both have intermediate androgenic potency. Most women on some form of oral contraception also received ethinyl-estradiol. ECG duration and morphology was evaluated both at baseline and 3 hours after dosing of sotalol. At baseline, QTc duration was similar between all groups. The authors said they did not assay plasma endogenous or synthetic progestin levels, which was a study limitation. They also did not have data on associated drugs and concomitant predisposing conditions. The study was supported by the Institut National de la Santé et de la Recherche Médicale/Direction de l'Hospitalisation et de l'Organisation des Soins and the French Ministry of Health. Salem and some co-authors disclosed holding a patent related to the use of some progestin to prevent and treat torsade de pointes, a patent related to QTc technology, and support from the Institut National de la Santé et de la Recherche Médicale/Direction de l'Hospitalisation et de l'Organisation des Soins and the French Ministry of Health. Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner —— LAST UPDATED 08.01.2018