First Randomized, Multicenter, Placebo-Controlled Study of Self-Administered Intranasal Etripamil for Acute Conversion of Spontaneous Paroxysmal Supraventricular Tachycardia (NODE-301).

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.

Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm.

BACKGROUND: There is no nonparenteral medication for the rapid termination of paroxysmal supraventricular tachycardia. OBJECTIVES: The purpose of this study was to assess the efficacy and safety of etripamil nasal spray, a short-acting calcium-channel blocker, for the rapid termination of paroxysmal supraventricular tachycardia (SVT). METHODS: This phase 2 study was performed during electrophysiological testing in patients with previously documented SVT who were induced into SVT prior to undergoing a catheter ablation. Patients in sustained SVT for 5 min received either placebo or 1 of 4 doses of active compound. The primary endpoint was the SVT conversion rate within 15 min of study drug administration. Secondary endpoints included time to conversion and adverse events. RESULTS: One hundred four patients were dosed. Conversion rates from SVT to sinus rhythm were between 65% and 95% in the etripamil nasal spray groups and 35% in the placebo group; the differences were statistically significant (Pearson chi-square test) in the 3 highest active compound dose groups versus placebo. In patients who converted, the median time to conversion with etripamil was <3 min. Adverse events were mostly related to the intranasal route of administration or local irritation. Reductions in blood pressure occurred predominantly in the highest etripamil dose. CONCLUSIONS: Etripamil nasal spray rapidly terminated induced SVT with a high conversion rate. The safety and efficacy results of this study provide guidance for etripamil dose selection for future studies involving self-administration of this new intranasal calcium-channel blocker in a real-world setting for the termination of SVT. (Efficacy and Safety of Intranasal MSP-2017 [Etripamil] for the Conversion of PSVT to Sinus Rhythm [NODE-1]; NCT02296190).

Shock on T versus direct current voltage for induction of ventricular fibrillation: a randomized prospective comparison.

VF is induced during ICD implantation to determine efficacy of therapy. Establishing the best clinical method of induction of VF would potentially be beneficial in reducing the number of induction attempts and reducing the frequency of inadvertent induction of VT. Commonly used methods to induce VF include shock in the T wave vulnerable period (T shock) and high frequency stimulation. This study compared the efficacy of T shock with a new induction method using a 9-V DC pulse. The study was a randomized, prospective, case crossover trial in patients receiving ICDs. VF was induced by T shock and DC in a randomized sequence during an ICD implant. VF was induced at least four times in each patient (two T shocks and two DC inductions) and with each induction; attempts were continued with modifications until successful. A paired evaluation between the T shock/DC induction was performed in 37 patients (28 men, age 64 +/- 12 years) with a left ventricular ejection fraction of 0.40 +/- 0.20. Arrhythmia indications were VT (n = 23), VF (n = 10), and VT/VF (n = 4). Drug therapy included amiodarone (n = 10), metoprolol (n = 6), digoxin (n = 1), and lidocaine (n = 1). The average T shock voltage was 207.0 +/- 16.1 V. The S1 cycle drive length was consistently 400 ms, and the mean S2 coupling interval was 317.8 +/- 19.6 ms. The length of time DC applied averaged 3.8 +/- 1.4 seconds. A total of 148 episodes of VF were included in the analysis. T shock induced VF with a cycle length of 213.5 +/- 35.1 ms, and DC induced VF with a cycle length of 214.6 +/- 34.5 ms (P = 0.86). Although VF was eventually induced for each randomization, the number of attempts required were dependent on the method of induction. The successful DC first attempt VF induction rate was 96%, with three patients requiring two attempts during one of the DC inductions. T shock had a 68% first attempt success rate with 21 patients requiring multiple T shocks to induce VF. All nine female patients had at least one unsuccessful first attempt T shock, which contributed to an overall unsuccessful first attempt induction rate significantly higher in women then men (36.1% vs 12.5%, P = 0.001). A constant DC voltage induction of VF may be more effective than T shock for induction of VF in a clinical setting because it reduces the number of attempts required to induce VF. By either method, VF appears to be more difficult to induce in women. DC induction has the advantage of simple programming of only duration of stimulation. These findings have implications particularly for ICD implantation with conscious sedation.