QTc prolongation and risk of ventricular arrhythmia during amiodarone treatment: a nationwide Danish cohort study

Background Amiodarone is associated with QTc prolongation and ventricular arrhythmias including ventricular tachycardia (VT) and ventricular fibrillation (VF). However, it is not known when QTc prolongation and risk of arrythmia is likely to occur during treatment with amiodarone. Furthermore, sex-specific differences has not been carefully investigated. Purpose To investigate the temporal QTc development and the associated risk of VT/VF among patients treated with amiodarone in a nationwide cohort. Methods Using Danish nationwide health registers and the Nationwide electrocardiogram (ECG) Cohort between 2009–2022, we identified all individuals who redeemed an amiodarone prescriptions and had at least one ECG. Patients were followed from amiodarone initiation until event (VT/VF), death, censoring (end of treatment or emigration) or end-of-study. VT/VF were identified by hospital admissions. End-of-treatment was defined as a gap of over 30 days between prescriptions. QTc was calculated using Fridericia’s formula. Time-updated Cox proportional hazards models with interval-based follow-up were used to predict the association between QTc and incident VT/VF. Models were stratified by sex and adjusted for age and heart rate. 1-year risks of VT/VF from time of first amiodaron prescription redemption were estimated from model-based baseline hazards. In QTc interval according to amiodarone duration analysis, we stratified by sex and amiodarone dose. Results We included a total of 437,438 patients (156,852 men and 280,586 women). 55,457 received 100 mg of amiodarone vs 381,981 for 200 mg. At time of amiodarone initiation, the median age of women was 69.8 years and 75.0 years for men. Overall patients receiving 100 mg were older than those with 200 mg (77 vs 72 years). Both men and women demonstrated an initial decline in QTc following amiodarone initiation (Median QTc for women using 200 mg at baseline vs at 180 days: 467 ms vs 459 ms; for men 460 ms vs 453 ms). However, after approximately 4.5 years (1644 days) of follow-up, women exhibited a gradual increase in QTc, whereas QTc remained relatively stable among men (Figure 1). During follow-up, 455 VT/VF events occurred. Higher QTc was independently associated with increased VT/VF risk. Each 10 ms increase in QTc was associated with a 12.6% higher risk of VT/VF (HR 1.13; 95% CI 1.11–1.14). Women consistently demonstrated higher absolute risk across QTc values (Figure 2). At QTc 450 ms, the observed 1-year VT/VF risk was 1.43% in men and 3.82% in women. At QTc 500 ms, men had a risk of 2.59% while women had a risk of 6.90% (Figure 2). Conclusion Among amiodarone-treated patients, women demonstrated higher QTc intervals during long amiodarone usage, while men had a more stable QTc interval. Women had also consistently higher risks of VT/VF compared to men across QTc ranges. These findings support that sex-specific amiodarone outpatient visit intervals may be warranted.