Old concerns about the safety of rhythm control drugs for atrial fibrillation (Afib or AF) resurfaced in a contemporary large Korean population-based study.

Afib patients prescribed antiarrhythmic drugs (AADs) had several-fold higher risks of cardiac events believed to be related to a decline in heart rate. Compared with other Afib patients, these AAD users showed more frequent:

• Pacemaker implantation or syncope: 16.3 vs 4.8 events per 1,000 person-years (adjusted HR 3.50, 95% CI 3.29-3.71)
• Syncope: 5.5 vs 2.6 events per 1,000 person-years (adjusted HR 2.14, 95% CI 1.95-2.35)
• Pacemaker implantation: 11.3 vs 2.2 events per 1,000 person-years (adjusted HR 5.26, 95% CI 4.86-5.70)

The association between AADs and risk of pacemaker implantation or syncope was consistent across various subgroups. In fact, older people and women appeared to be disproportionately susceptible to these events after starting AAD therapy, reported Jong-Il Choi, MD, PhD, MHS, MSc, of Korea University College of Medicine and Korea University Anam Hospital in Seoul, and colleagues in the Journal of the American College of Cardiology.

“Although rhythm control is an established treatment strategy for patients with new-onset AF, the potential for bradycardia-related adverse effects of AADs, including pill-in-the-pocket strategy, should be considered,” the authors urged.

“The progressive nature of sick sinus syndrome and atrioventricular node block is another concern for patients with AF taking prolonged AAD treatment,” they added.

The AADs analyzed in this study were flecainide, propafenone, pilsicainide, amiodarone, dronedarone, and sotalol.

As a treatment for new-onset Afib, early rhythm control therapy with AADs had been controversial since the old AFFIRM trial showed no clear benefit of rhythm control over rate-controlling drugs, with a numerical excess in all-cause deaths to boot. Cardiac arrest due to pulseless electrical activity or bradycardia was significantly more common in the rhythm control group in AFFIRM, Choi’s group noted.

Fast forward nearly two decades later, however, and EAST-AFNET 4 showed that rhythm control, when initiated early in the contemporary era with newer therapies, significantly reduced the risk of the composite endpoint of cardiovascular death, stroke, or hospitalization for worsening heart failure or acute coronary syndrome — the downside being a nonsignificant trend for more bradycardia or syncope.

The EAST-AFNET 4 trial nevertheless made AADs a mainstream treatment strategy for new-onset Afib in recent years.

The present Korean study is a reminder of the bradycardia risk being “an important and heretofore relatively ignored aspect of AAD use,” commented a trio led by Sanjay Dixit, MD, of the Hospital of the University of Pennsylvania in Philadelphia.

“It is worth noting that although the HR of the primary endpoint was highest in the initial 6 months after starting AADs, this risk persisted for more than 2 years. This is an important observation, and it raises the question of whether AF patients on long-term AADs who are at a higher risk for developing bradyarrhythmias may benefit from extended monitoring by insertable cardiac monitors?” they posed in an accompanying editorial.

“It is, however, encouraging to note that the overall occurrence of syncope and [permanent pacemaker] implantations in this large database was quite low. Nevertheless, these observations should certainly make us more cautious when using AADs, especially in older patients and women,” according to the editorialists.

They noted that catheter ablation, used as endorsed by the guidelines, could be considered an alternative to achieve rhythm control.

“Whether catheter ablation is superior to AADs for reducing adverse clinical events is unclear; however, it can be a good alternative for patients contraindicated or intolerant to AADs,” Choi and colleagues agreed.

Their study was based on prescription history and billing claims from the Korean National Health Insurance Service system.

Study authors identified 770,977 new-onset Afib diagnoses from 2013-2019 and identified 142,141 patients who had been prescribed AADs within 1 year of Afib diagnosis. People with a history of syncope or permanent pacemaker implantation were excluded.

Around 60% of the included patients were age 65 or older. The AAD user subgroup had a significantly greater proportion of men (59.2% vs 51.5%) and fewer people with a prior stroke (6.7% vs 10.4%) compared with controls.

Propensity score-matched analysis supported the main result of the study, namely a significant association between AAD use and the risk of pacemaker implantation or syncope.

The observational, retrospective study left room for selection bias with regard to prescribers choosing AADs for healthier Afib patients.

“Physicians probably use AADs in patients without history of bradycardia, dizziness, and syncope. Use of AADs in this study showed more than a 3-fold increased risk of syncope or pacemaker implantation despite such potential selection bias,” Choi and colleagues maintained.

Other study limitations include its limited generalizability due to the enrollment of only East Asian individuals, and an incomplete prescription and medical history for each person.

Dixit’s group highlighted the lack of information on the dose of prescribed AADs and patient compliance, concurrent use of atrioventricular nodal blockers, and baseline sinus node dysfunction and conduction system disease.

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