Use of oral contraceptives without β-blockers may up cardiac risk in women with long QT syndrome

Women with congenital long QT syndrome (LQTS) taking progestin-only oral contraceptives (OC) without concomitant β-blocker therapy were almost thrice as likely to develop cardiac events than those on β-blockers in a new registry analysis, prompting researchers to urge caution. 

“This suggests that progestin-only OC should not be administered to these women without a beta-blocker onboard,” said lead author Dr Ilan Goldenberg from the University of Rochester Medical Center, New York, US, during his presentation at HRS 2021.“In women with LQT2 genotype, we should be extra cautious in administering any type of OC, especially if those women cannot tolerate β-blockers at optimal dosages.”

Goldenberg and colleagues followed over 1,650 women with LQTS from September 2010 to March 2021. Of these women,  370 were taking an OC. There were 2,027 cardiac events, including syncope, cardiac arrest, and sudden cardiac death, or appropriate ICD shocks over a cumulative follow-up of 35,797 years. [Heart Rhythm 2021;doi.org/10.1016/j.hrthm.2021.07.058]

Progestin-only OC was associated with a 2.86-fold increased risk of cardiac events (p=0.01) in women who did not receive β-blocker therapy whereas β-blockers were highly protective when used with progestin-only OC treatment (hazard ratio [HR], 0.22; p=0.001). The interaction with β-blocker treatment was significant (p=0.006).

The elevated risk was not observed in those taking oestrogen-only or oestrogen plus progestin OC, regardless of β-blocker therapy. As for women with the LQT2 genotype, the risk for cardiac events was elevated (hazard ratio [HR] 1.71; p<0.001) with the use of any OC.

LQT2 results from mutations in the KCNH2 gene on chromosome 7. [J Korean Med Sci 2013;28:1388–1393] Auditory stimuli, for example, a ringing telephone or an alarm clock may provoke LQT2 onset.

Risk attenuated by β-blockers

“Your study clearly showed that progestin increases the risk of cardiac events and that the risk was nicely mitigated by β-blockers,” commented Dr Kimberly Selzman, invited discussant for the study. However, she noted that there were only 80 patients taking progestin-only OC in the registry, which included more than 1,600 women with LQTS, and only about 22 percent were taking any type of OC.

Co-discussant, Dr Mark Link from the University of Texas Southwestern, Dallas, US, said  he was surprised that “the use of beta-blockers was low in these patients.” Only 49 percent of the full cohort was on β-blockers, 79 percent in those taking OC, and 40 percent in those not taking OC (p<0.001).

“This is a hint that the OC group might have been sicker,” he added. “It looks like progesterone alone is a problem and probably should not be used in these patients. The long QT2 is a problem and has to be of special concern, but non-use of β-blockers is a real problem.”

Link said the data emphasize the importance of using maximally tolerated β-blockers in women with LQTS.

Session moderator Dr Andrew Krahn from the University of British Columbia, Vancouver, Canada said patients with LQTS sometimes had uglier QTs when they perform exercise tests than when at rest. “Therefore, risk stratification based on a single resting ECG can be misleading,” he explained. That argues for β-blocker therapy in such patients “whose resting QTs aren’t terribly long.”

The study also supports genotyping of women with LQTS for risk stratification and appropriate management.