Oral Contraceptives, Sans Beta Blockade, Can Raise Risk for Sudden Death in LQTS

August 02, 2021

Contemporary oral contraceptives (OC) in general don't seem to worsen the risk for sudden cardiac death (SCD) in women with congenital long-QT syndrome (LQTS), but that potential risk varies by type of OC, which contain different hormones at a variety of dosages. Also not well understood: whether the beta blockers taken by many women with LQTS can lessen any such risk.

A new registry analysis offers possible answers to those questions. Women with congenital LQTS who had been on progestin-only OC without beta blockers on board had almost triple the risk for cardiac events (CE), such as syncope, cardiac arrest, and SCD, compared with those not on OC.

Those on progestin-only OC along with beta blockers showed no such elevated risk. Nor was the risk increased among LQTS women on other OC formulations, such as combined estrogen and progestin, regardless of beta blocker therapy.

The findings suggest that all women with congenital LQTS on progestin-only OC should also be taking beta blockers and — Ilan Goldenberg, MD, told theheart.org | Medscape Cardiology — they shouldn't be on that kind of OC at all if they can't tolerate beta blockers at maximal dosages.

Also, the effect of progestin-only OC on risk in the entire LQTS cohort was magnified further, several times, among the one-fourth identified with the LQT2 genotype.

"In LQT2 women, we should be very cautious in administering any type of oral contraceptives, especially if women will not be able to tolerate maximal dosages of beta blockers," said Goldenberg, from the University of Rochester Medical Center, New York, who presented the study July 20 at the Heart Rhythm Society 2021 Scientific Sessions, held virtually and live in Boston. He is also lead author on its same-day publication in Heart Rhythm.

"Your study clearly showed that progestin increases the risk of these cardiac events, and that the risk really was nicely mitigated by beta blocker therapy," Kimberly A. Selzman, MD, MPH, said to Goldenberg as an invited discussant after the study's formal HRS presentation.

But she cautioned that there were only 80 patients on progestin-only OC in the registry, which included more than 1600 LQTS women. Only about 22% were on any kind of OC.

Because this isn't a randomized study, perhaps few LQTS women were on progestin-only OC because they were perceived to be at higher risk to begin with, possibly creating bias, proposed Selzman, University of Utah, Salt Lake City.

"I was a little surprised about the low beta blocker use in the patients, especially in those not on oral contraceptives," which is a hint that the OC group might have been sicker, added Mark Link, MD, University of Texas Southwestern, Dallas, another invited discussant. In the study presentation, only 49% of the overall cohort was on beta blockers, including 79% and 40% of those taking and not taking OC, respectively (P < .001).

His take-away from the study, Link said, is that "progesterone alone is a problem and should probably not be used in these patients, that long-QT-2 is a problem and has to be of special concern, and that nonuse of beta blockers is a real problem."

And it points to the importance of maximally tolerated beta blockers in all adult women with LQTS, Link added. "I will never again see a woman with long-QT over 18 and not recommended a beta blocker."

When his patients with LQTS perform exercise tests, sometimes "you see much uglier QTs than you do at rest," suggesting that risk stratification based on a single resting ECG can be misleading, said Andrew Krahn, MD, University of British Columbia, Vancouver, Canada, who moderated the session. That, he added, argues for beta blocker therapy in such patients "whose resting QTs aren't terribly long."

The registry population consisted of 1659 LQTS women who completed annual questionnaires, providing information such as OC use and menarche, pregnancy, and menopause, Goldenberg reported. Their age at LQTS diagnosis averaged about 19 years, and their subsequent follow-up averaged almost 22 years. Arrhythmic cardiac events were tracked from menarche to age 40.

About 35% of the participants on OC and 15% of those not on OC had had implantable defibrillators (ICDs).

Of those on OC, 57% were taking progestin–estrogen combinations, 22% were taking progestin-only, and 21% were taking preparations with estrogen as the only hormone.

There were 2027 instances of CE — the primary outcome, which included syncope, aborted cardiac arrest, LQTS-related SCD, or appropriate ICD shocks — over a cumulative follow-up of 35,797 years.

In multivariate analysis, progestin-only OC was associated with about 2.5 times the risk for a first CE, compared with no OC (P = .03), and beta blocker therapy was followed by a 34% drop in such risk (P = .002)

Among the LQTS women on progestin-only OC, the CE hazard ratio (HR) for those not on beta blockers, compared with those not on OC, was 2.86 (95% CI, 1.26 - 6.54; P = .01), and for those on beta blockers, it was 0.54 (95% CI, 0.49 - 1.14; P = 0.19). The interaction with beta blocker therapy was significant (P = .006).

Beta blockers did not show such a protective effect among women on estrogen-only OC, compared with no OC, and there was a protective effect of only marginal significance among women on combined estrogen-progestin OC (interaction P = .048).

The HR for CE among the 23% of women genotyped with LQT2, compared with the 26% of those identified with LQT1, was 1.71 (95% CI, 1.38 - 2.15; P < .001).

Hazard Ratio (HR) for Arrhythmic CE Among LQT2 Women Not on Beta Blocker, Type of OC vs No OC
Type of OC HR (95% CI) P Value Interaction P*
Progestin-only 8.03 (4.22–15.29) <.001 .002
Combined estrogen–progestin 1.51 (0.78–2.93) .23 .037
Estrogen-only 10.05 (2.60–38.89) .001 .008
*Beta blockers vs no beta blockers

The findings could potentially apply well beyond the study's narrow female congenital-LQTS population, Goldenberg proposed. They have implications for people with LQTS induced by commonly prescribed QT-prolonging medications, which include some antibiotics, antidepressants, and antiarrhythmics.

Drug-induced LQTS shares with LQT2 some of the same underlying potassium-channel mechanisms, so his group is studying whether different OC formulations similarly influence CE risk in people with LQTS associated with such agents.

Goldenberg, Selzman, Link, and Krahn report nothing relevant to disclose.

Heart Rhythm. July 30, 2021. Full Text

Heart Rhythm Society 2021 Scientific Sessions: Late Breaking Clinical Trial Updates. Presented July 30, 2021.

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