Intravenous dantrolene for class iii antiarrhythmic drug resistant refractory ventricular arrhythmias in patients with heart failure: final results of a phase ii study

Background

Lethal ventricular arrhythmias remain a major complication in patients with heart failure. In failing hearts, destabilization of the ryanodine receptor (RyR2) tetramer induces diastolic calcium leak, leading to triggered activity and ventricular arrhythmias. We have previously demonstrated that dantrolene stabilizes the tetrameric structure of RyR2, thereby normalizing intracellular calcium handling and suppressing ventricular arrhythmias in both experimental and clinical settings. This study is the final report of a phase II clinical trial evaluating intravenous dantrolene therapy for class III antiarrhythmic drug–resistant refractory ventricular arrhythmias in patients with heart failure.

Purpose

To assess the efficacy and safety of intravenous dantrolene in patients with heart failure who developed guideline-directed medical therapy–resistant lethal ventricular arrhythmias, including ventricular tachycardia (VT) storm or sustained VT.

Methods

This was a single-center, open-label, prospective, non-controlled interventional study. Patients with heart failure who developed VT storm or sustained VT refractory to class III antiarrhythmic drugs and β-blockers were enrolled. Intravenous dantrolene was initiated at 20 mg, followed by up-titration from 1 mg/kg up to a maximum of 7 mg/kg until VT termination was achieved. Maintenance dosing of 0.5–1.0 mg/kg was subsequently administered every 4–8 hours. The primary endpoints were VT termination, prevention of VT recurrence within 48 hours, and safety.

Results

Seventeen consecutive patients with heart failure and VT storm or sustained VT were enrolled; four patients (23.5%) were female. The median age was 70 years, ischemic heart disease was present in 24%, and the median left ventricular ejection fraction was 29%. VT termination was achieved in 16 patients (94%; Figure 1). Excluding one patient who died from progression of the underlying disease within 48 hours, prevention of VT recurrence within 48 hours was achieved in 14 of the remaining 16 patients (88%).

The number of ventricular tachyarrhythmia events significantly decreased after dantrolene administration (median difference, 17.5 events; 95% confidence interval, 1.0–185.0; Wilcoxon signed-rank test; Figure 2). The median rapid intravenous dose was 3 mg/kg. The median maintenance dose was 0.48 mg/kg, with a median dosing interval of 8 hours. Within one month after dantrolene administration, two patients died from VT and one from heart failure; all deaths were attributed to the underlying disease, with no apparent causal relationship to dantrolene.

Conclusion

Intravenous dantrolene was effective for both termination and short-term prevention of refractory lethal ventricular arrhythmias in patients with heart failure, without drug-related serious adverse events.Figure 1For image description, please refer to the figure legend and surrounding text.Figure 2For image description, please refer to the figure legend and surrounding text.