Mexiletine in drug-refractory ventricular arrhythmias: real-world effectiveness and tolerability

Background Drug-refractory ventricular arrhythmias (VAs) remain a major therapeutic challenge despite optimized ICD programming, catheter ablation, and guideline-recommended medical therapy. Mexiletine is increasingly used off-label as an adjunctive class Ib antiarrhythmic, yet real-world data on its effectiveness and safety in this setting remain limited. Purpose To evaluate the effectiveness and safety of mexiletine in patients with structural heart disease and an ICD experiencing recurrent ventricular arrhythmias despite optimized medical therapy and catheter ablation where indicated. Methods We performed a retrospective cohort study of consecutive adults with structural heart disease and an ICD who received mexiletine between January 2020 and January 2024 for recurrent sustained VT/VF or frequent appropriate ICD therapies despite optimized medical therapy and catheter ablation where indicated. VA burden and ICD therapies were assessed for 6 months before and up to 36 months after mexiletine initiation. The primary endpoint was the change in VA burden, defined as the total number of sustained VT/VF episodes and appropriate ICD therapies. Results A total of 23 patients were included (median age 68 years, 91% male); 78% had ischaemic cardiomyopathy, median LVEF was 36%, and 30% had undergone prior VT ablation. During the 6 months preceding mexiletine initiation, the median overall VA burden was 1.04 (IQR 0.54–2.10) events per month. Following mexiletine initiation, with a median follow-up of 23 months, the overall VA burden decreased to 0.30 (IQR 0.08–0.75) events per month (p<0.01). Overall, 65% of patients achieved a ≥50% reduction in VA event rate. Mexiletine was discontinued in 5 patients (26%), primarily due to hypotension (n=3) and neurological adverse effects (n=2). During follow-up, four patients died, all due to cardiovascular causes, and two underwent heart transplantation. Conclusion In patients with structural heart disease and recurrent ventricular arrhythmias despite optimized therapy, mexiletine was associated with a significant reduction in arrhythmia burden. Adverse effects were frequent, and overall mortality remained high, reflecting advanced underlying disease. Prospective studies are warranted to clarify its role in this setting.