Progestin OCs Triple CV Events in Women With Congenital Long QT

Women with congenital long QT syndrome (LQTS) need to be cautious when taking an oral contraceptive (OC), observational data suggest—those on progestin-only pills are nearly three times more likely to experience recurrent cardiac events than if they hadn’t been on birth control. The same risks aren’t seen with estrogen-only or combination pills.

Yet the potential harm posed by a progestin-based OC can be sharply reduced by beta-blockers in female patients with LQTS, Ilan Goldenberg, MD (University of Rochester Medical Center, NY), reported today at the Heart Rhythm Society (HRS) 2021 Scientific Sessions. The results were simultaneously published in the journal Heart Rhythm.

LQTS on its own “is commonly associated with cardiac events such as syncope, cardiac arrest, and sudden cardiac death,” Goldenberg and colleagues point out in their paper. Women with the disorder are known to be at increased risk of such events after the onset of adolescence, after pregnancy, and during perimenopause, especially if they have the LQT2 genotype. Men with LQTS, however, see their risk attenuate after they reach adolescence.

“Those opposing trends may possibly be due to the effects of sex hormones on the potassium channels that are associated with this inherited arrhythmic disorder,” Goldenberg said in a press conference. Oral contraceptives, which contain various combinations of sex hormones, thus merit attention in the LQTS setting, he explained.

Goldenberg told TCTMD this study is the first to draw a connection between cardiac events and OC use among women with LQTS. “Before there was very little awareness of the fact that oral contraceptives may be harmful,” he said. “This also has implications for the wider population, because . . . there are many patients [with] drug-induced long QT syndrome: simple antibiotics, antianxiety medications, antipsychotic medications.” If those medications are affecting QTc, they may interact with sex hormones and perhaps OCs, as well, Goldenberg noted. They are now looking into this possibility in an American Heart Association-funded study.

The takeaway for now, he stressed in his presentation, is that “progestin oral contraceptives should not be administered in congenital LQTS women without concomitant beta-blocker treatment. We also believe that careful consideration should be exercised before prescribing any oral contraceptive to women with the LQT2 genotype, especially those who cannot tolerate maximal dosages of beta-blockers.”

Long QT Syndrome Registry

Using data from the Rochester, NY-based Long QT Syndrome Registry, the researchers identified 1,659 women with LQTS who completed yearly questionnaires about menstruation, OC use, pregnancy, and menopause. The information was collected from September 2010 through March 2021. To account for changes in OC type over the years, use was modeled as a time-dependent variable.

Around one-quarter of women (22%) took OCs at some point in the study; among them 57% were on combined formulations, while 21% were on estrogen-only OC and 22% on progestin-only OC. Those not taking an OC also did not use other forms of hormone-based contraception.

Age of menarche was similar with versus without OC use (mean 12.3 years), as were the proportion of women who became pregnant (72% overall) and the distribution of genotype (26% LQT1, 23% LQT2, and 7% LQT3). Those on OC had an average QTc duration that was slightly shorter (491 ms vs 495 ms). They also were more likely to receive beta-blockers (79% vs 40%) and to have an implantable cardioverter-defibrillator (35% vs 15%). That said, beta-blocker use did not vary among the different OC types (79%, 80%, and 77%, respectively, for combined, estrogen, and progestin)

Forty-one percent of the women with LQTS had a first cardiac event after their periods began; slightly more than half of the events were syncope, 19% aborted cardiac arrest, 11% LQTS-related death. Calculated over a cumulative follow-up of 35,797 years, there were 2,027 first and recurrent cardiac events after menarche.

Adjusted for genotype, QTc duration, and time-dependent beta-blocker use, progestin-only OCs were linked to an almost tripled risk of recurrent cardiac events compared with no OC use. Adding a beta-blocker on top of a progestin-only OC was associated with a 78% lower risk (HR 0.22; 95% CI 0.07-0.74) compared with an OC alone. Neither estrogen-only nor combined OC types were associated with cardiac events, though in the latter group there was a “marginally statistically significant risk” difference by beta-blocker use, the researchers note, suggesting that here, too, the drug class might be protective.

Risk of Recurrent Cardiac Events With vs Without OC

For women with the LQT2 genotype, a progestin-only OC without beta-blockers was particularly risky, carrying an eightfold increase in risk of recurrent cardiac events in comparison to no OC (HR 8.03; 95% CI 4.22-15.29). Estrogen-only OCs also were linked to harm in this subgroup, carrying a tenfold higher risk (HR 10.05; 95% CI 2.60-38.89), while combination pills were not.

Mark S. Link (UT Southwestern, Dallas, TX), discussing the findings, said they have “incredible practical applications.”

“What I took away from this [is that] progestin alone is a problem and should probably not be used in these patients, that long QT, too, is a problem and has to be of special concern, and that nonuse of beta-blockers is a real problem,” said Link. In his own practice, he now believes all women with LQTS “should be on beta-blockers to the maximally tolerated dose.”

The session’s other discussant, Kimberly A. Selzman, MD (George E. Wahlen VA Medical Center, Salt Lake City, UT), agreed the study addresses a “practical and clinically relevant question.”

While the patterns it found are clear, she said it’s worth remembering a few caveats. Only 81 patients within the entire data set were on progestin, for instance. Selzman also questioned whether there may be confounders, such as ICD use and baseline QT interval, influencing risk and asked for more details on the timing of events. “I just want to stress that those are fully adjusted models” that account for those characteristics, as well as time, Goldenberg replied.

Moderator Andrew D. Krahn, MD (University of British Columbia, Vancouver, Canada), forwarded a question from the audience: if progestin is responsible, why didn’t the combo pill also augment risk and fall along a “dose-response curve,” with estrogen at the low end?

Goldenberg said that, in fact, based on basic research and the clinical course of women with LQTS over their lifetimes, the researchers had expected estrogen to be the culprit—their data on progestin-based drugs came as a surprise. It may be that progestin itself isn’t the issue. Rather, it may be that newer-generation progestin OCs, in order to reduce side effects, contain antiandrogenic components; these, he proposed, may be the true root of the risk. “This may be the reason the combined medication [which lack these elements] did not increase the risk. It’s more balanced. This is the hypothesis.”