The Pill Can Spell Trouble for Long QTc

Some oral contraceptives were associated with greater cardiovascular risk among women with inherited long QT syndrome (LQTS), a registry study showed.

Progestin-only oral contraceptive users had a 2.54-fold higher risk (95% CI 1.09-1.51) of a cardiac event compared with LQTS women not on oral contraceptives in multivariate analysis.

Beta-blocker use appeared to mitigate that risk, with the cardiac event rate falling 78%, from 14 to three events per 100 patient-years, Ilan Goldenberg, MD, of the University of Rochester Medical Center in New York, and colleagues found in a study appearing in Heart Rhythm.

“We believe that after the onset of adolescence, LQTS women, especially LQT2 and those with potassium-channel abnormality, should get beta-blockers,” Goldenberg argued at the hybrid Heart Rhythm Society (HRS) meeting, held online and in Boston, where the findings were simultaneously reported.

“It really has practical implications,” agreed Mark Link, MD, of UT Southwestern Medical Center in Dallas and a session study discussant. “I will never again see a woman with long QT over [age] 18 and not recommend a beta-blocker.”

“Regardless of QTc, I agree,” responded Goldenberg.

Corrected QT (QTc) measurements at rest can be misleadingly reassuring, noted session moderator Andrew Krahn, MD, of the University of British Columbia in Vancouver, and president-elect of the HRS.

For women who cannot tolerate maximal beta-blockers, progestin-only oral contraceptive should be avoided, Goldenberg recommended. “Careful consideration should be exercised when prescribing any oral contraceptive to LQT2 women.”

The study included the 1,656 women in the LQTS Registry based out of Goldenberg’s center who completed an annual questionnaire on menstruation, oral contraceptive use, pregnancy, and menopause and had a genotype positive for LQTS or a QTc interval ≥450 ms and were identified clinically as having LQTS.

Syncope, aborted cardiac arrest, LQTS-related sudden cardiac death, or appropriate shocks from an implanted cardioverter-defibrillator most commonly recurred among progestin contraceptive users as well, with a rate of 1.6 events per woman over 25 years of follow-up.

Risk of recurrence was even more pronounced for those women using progestin-only oral contraceptives without beta-blocker therapy (HR 2.86, 95% CI 1.26-6.54), especially when they had the LQT2 genotype (HR 8.03, 95% CI 4.22-15.29).

Without a beta-blocker, women with the LQT2 genotype also showed higher risk with estrogen-only oral contraceptives (HR 10.05, 95% CI 2.60-38.89).

“Actually, based on our prior data, we were expecting estrogen to be the culprit,” Goldenberg said at the late-breaking trial session. The reason combined progestin and estrogen oral contraceptives showed no elevated risk might have been because anti-androgenic components are included in such formulations to reduce side effects, he speculated.

Progestin-only contraceptives may exert an influence on events through antiandrogenic effect, he noted.

The findings likely would generalize to non-oral routes of hormone-based contraceptives, such as intrauterine devices and subcutaneous formulations, Goldenberg added, noting that the few such cases in the registry showed the same trends.

And in fact, he said at an HRS press conference, there may be wider implications for drug-induced long QTc that can be seen from anxiety medications, antibiotics, and antipsychotic medications. His group is now studying the impact of oral contraceptives on acquired LQTS.