Background: Pharmacologic termination of paroxysmal supraventricular tachycardia (PSVT) often requires medically supervised intervention. Intranasal etripamil, is an investigational fast-acting, nondihydropyridine, L-type calcium channel blocker, designed for unsupervised self-administration to terminate atrioventricular nodal–dependent PSVT. Phase 2 results showed potential safety and efficacy of etripamil in 104 patients with PSVT. Methods: NODE-301, a phase 3, multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of etripamil nasal spray administered, unsupervised in patients with symptomatic sustained PSVT. After a medically supervised etripamil test dose while in sinus rhythm, patients were randomized 2:1 to receive etripamil 70 mg or placebo. When PSVT symptoms developed, patients applied a cardiac monitor and attempted a vagal maneuver; if symptoms persisted, they self-administered blinded treatment. An independent Adjudication Committee reviewed continuous electrocardiogram recordings. The primary efficacy endpoint was termination of adjudicated PSVT within 5 hours after study drug administration. Results: NODE-301 accrued 156 positively adjudicated PSVT events treated with etripamil (n=107) or placebo (n=49). The hazard ratio for the primary endpoint, time-to-conversion to sinus rhythm during the 5-hour observation period, was 1.086 (95% CI, 0.726–1.623; P =0.12). In predefined sensitivity analyses, etripamil effects (compared with placebo) occurred at 3, 5, 10, 20, and 30 minutes ( P <0.05). For example, at 30 minutes, there was a 53.7% of SVT conversion in the treatment arm compared to 34.7% in the placebo arm (hazard ratio, 1.87 [95% CI, 1.09–3.22]; P =0.02). Etripamil was well tolerated; adverse events were mainly related to transient nasal discomfort and congestion (19.6% and 8.0%, respectively, of randomized treatment-emergent adverse events. Conclusions: Although the primary 5-hour efficacy endpoint was not met, analyses at earlier time points indicated an etripamil treatment effect in terminating PSVT. Etripamil self-administration during PSVT was safe and well tolerated. These results support continued clinical development of etripamil nasal spray for self-administration during PSVT in a medically unsupervised setting. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03464019.

The human voltage‐gated sodium channel Na_v1.5 (hNa_v1.5/SCN5A) plays a critical role in the initiation and propagation of action potentials in cardiac myocytes, and its modulation by various drugs has significant implications for cardiac safety. Drug‐dependent block of Na_v1.5 current (I_Na) can lead to significant alterations in cardiac electrophysiology, potentially resulting in conduction slowing and an increased risk of proarrhythmic events. This review aims to provide a comprehensive overview of the mechanisms by which various pharmacological agents interact with Na_v1.5, focusing on the molecular determinants of drug binding and the resultant electrophysiological effects. We discuss the structural features of Na_v1.5 that influence drug affinity and specificity. Special attention is given to the concept of state‐dependent block, where drug binding is influenced by the conformational state of the channel, and its relevance to therapeutic efficacy and safety. The review also examines the clinical implications of I_Na block, highlighting case studies of drugs that have been associated with adverse cardiac events, and how the Vaughan‐Williams Classification system has been employed to qualify “unsafe” sodium channel block. Furthermore, we explore the methodologies currently used to assess I_Na block in nonclinical and clinical settings, with the hope of providing a weight of evidence approach including in silico modeling, in vitro electrophysiological assays and in vivo cardiac safety studies for mitigating proarrhythmic risk early in drug discovery. This review underscores the importance of understanding Na_v1.5 pharmacology in the context of drug development and cardiac risk assessment.

Background: Self‐administration of investigational intranasal L‐type calcium channel blocker etripamil during paroxysmal supraventricular tachycardia (PSVT) appeared safe and well‐tolerated in the phase 3 NODE‐301 (Multi‐Centre, Randomized, Double‐Blind, Placebo‐Controlled, Efficacy, and Safety Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia) trial of adults with sustained atrioventricular nodal‐dependent PSVT. The NODE‐302 open‐label extension further characterized etripamil safety and efficacy. Methods and Results: Eligible patients were monitored via self‐applied cardiac monitoring system for 5 hours after etripamil self‐administration. The primary end point was time‐to‐conversion of positively adjudicated PSVT to sinus rhythm after etripamil treatment. Probability of conversion to sinus rhythm was reported via Kaplan‐Meier plot. Adverse events were based on self‐reported symptoms and clinical evaluations. Among 169 patients enrolled, 105 self‐administered etripamil ≥1 time for perceived PSVT (median [range], 232 [8–584] days' follow‐up). Probability of conversion within 30 minutes of etripamil was 60.2% (median time to conversion, 15.5 minutes) among 188 PSVT episodes (92 patients) positively adjudicated as atrioventricular nodal dependent by independent ECG analysis. Among 40 patients who self‐treated 2 episodes, 75% had a significantly consistent response by 30 minutes; 9 did not convert on either episode, and 21 converted on both episodes (χ ² =8.09; P =0.0045). Forty‐five of 105 patients (42.9%) had ≥1 treatment‐emergent adverse event, generally transient and mild‐to‐moderate, including nasal congestion (14.3%), nasal discomfort (14.3%), or rhinorrhea (12.4%). No serious cardiac safety events were observed within 24 hours of etripamil. Conclusions: In this extension study, investigational etripamil nasal spray was well tolerated for self‐treating recurrent episodes of PSVT without medical supervision. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03635996.