Plain language summary of the safety and effectiveness of etripamil for atrioventricular-nodal-dependent supraventricular tachycardia: the RAPID study.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a clinical research study called RAPID. The study looked at the potential for how safe and effective etripamil was at stopping an episode of rapid heartbeats in people with atrioventricularnodal-dependent supraventricular tachycardia (AV-node-dependent SVT). An episode is used to describe the period of time when a person experiences an abnormally very fast heartbeat. This was done by comparing an investigational drug called etripamil with a placebo, each administered via a rapidly acting nasal spray. AV-node-dependent SVT affects the rhythm of the heart, causing it to suddenly beat rapidly. The condition often requires medical treatment to help return the heart to its normal, healthy heartbeat pattern and speed, called 'sinus rhythm'. Researchers are looking at ways of improving the management of supraventricular tachycardias (SVT) by reducing the need for patients to attend an urgent care clinic, emergency ward or hospital for treatment. In the RAPID study, participants used a nasal spray containing either 70 mg etripamil or a placebo solution when they experienced an episode of SVT. The researchers wanted to know how long it took for each participant's rapid heartbeat to return to sinus rhythm after administering the etripamil or placebo nasal spray. Participants in the study were considered successfully treated if their heartbeats returned to sinus rhythm for at least 30 seconds within 30 minutes of using the nasal spray. Although 30 seconds may seem brief, it's medically important because it shows that a person's heartbeat has been temporarily stabilized and returned to normal functioning. WHAT WERE THE RESULTS?: Out of 99 people who used etripamil during an SVT episode, 63 participants (64%) experienced a return to sinus rhythm for at least 30 seconds within 30 minutes after using the nasal spray. In contrast, 26 out of 85 participants (31%) who used the placebo nasal spray experienced a return to sinus rhythm for at least 30 seconds within 30 minutes after use. Furthermore, the average time taken for the return to sinus rhythm was 17 minutes for the etripamil group which was 3-times faster than the placebo group at 53 minutes. Also, in the study no serious side effects occurred that were related to etripamil. WHAT DO THE RESULTS OF THE STUDY MEAN?: The RAPID study supports the potential that etripamil may be safe and well tolerated by participants as a treatment for episodes of rapid heartbeat in people with AV-node-dependent SVT. The results also showed a significant improvement in symptoms following treatment with etripamil.

Pharmacokinetics and Pharmacodynamics of Etripamil, an Intranasally Administered, Fast-Acting, Nondihydropyridine Calcium Channel Blocker.

Etripamil, a fast-acting nondihydropyridine L-type calcium channel blocker, is under investigation for potential self-administration for the acute treatment of supraventricular tachyarrhythmias in a medically unsupervised setting. We report detailed pharmacokinetics and pharmacodynamics of intranasally administered etripamil in healthy adults from 2 Phase 1, randomized, double-blind studies: Study MSP-2017-1096 (sequential dose-escalation, crossover study design, n = 64) and NODE-102 (single dose, 4-way crossover study, n = 24). Validated bioanalytical assays determined plasma concentrations of etripamil and its inactive metabolite. Noncompartmental pharmacokinetic parameters were calculated. Pharmacodynamic parameters were determined for PR interval, blood pressure, and heart rate. Etripamil was rapidly absorbed intranasally, with time to maximal plasma concentration of 5-8.5 minutes, corresponding to a rapid greater than 10% increase in mean maximum PR interval from baseline within 4-7 minutes of doses of 60 mg or greater. Following peak plasma concentrations, systemic etripamil levels declined rapidly within the first 15 minutes following dosing and decreased more gradually thereafter. PR interval prolongation greater than 10% from baseline was generally sustained for about 45 minutes at doses of 60 mg or greater. The mean terminal half-life ranged from about 1.5 hours with 60 mg to about 2.5-3 hours for the 70- and 105-mg doses. Etripamil was generally well tolerated without symptomatic hypotension. Adverse events were primarily mild to moderate and related to the administration site; no serious adverse events or episodes of atrioventricular block occurred. Intranasal etripamil administration, at doses of 60 mg or greater, produced rapidly occurring slowing of atrioventricular nodal conduction with a limited duration of effect without hemodynamic or electrocardiographic safety signals in healthy volunteers.

Multicenter, Phase 2, Randomized Controlled Study of the Efficacy and Safety of Etripamil Nasal Spray for the Acute Reduction of Rapid Ventricular Rate in Patients With Symptomatic Atrial Fibrillation (ReVeRA-201).

BACKGROUND: Despite chronic therapies, atrial fibrillation (AF) leads to rapid ventricular rates (RVR) often requiring intravenous treatments. Etripamil is a fast-acting, calcium-channel blocker administered intranasally affecting the atrioventricular node within minutes. METHODS: Reduction of Ventricular Rate in Patients with Atrial Fibrillation evaluated the efficacy and safety of etripamil for the reduction of ventricular rate (VR) in patients presenting urgently with AF-RVR (VR ≥110 beats per minute [bpm]), was randomized, double-blind, placebo-controlled, and conducted in Canada and the Netherlands. Patients presenting urgently with AF-RVR were randomized (1:1, etripamil nasal spray 70 mg: placebo nasal spray). The primary objective was to demonstrate the effectiveness of etripamil in reducing VR in AF-RVR within 60 minutes of treatment. Secondary objectives assessed achievement of VR <100 bpm, reduction by ≥10% and ≥20%, relief of symptoms and treatment effectiveness; adverse events; and additional measures to 360 minutes. RESULTS: Sixty-nine patients were randomized, 56 dosed with etripamil (n=27) or placebo (n=29). The median age was 65 years; 39% were female patients; proportions of AF types were similar between groups. The difference of mean maximum reductions in VR over 60 minutes, etripamil versus placebo, adjusting for baseline VR, was -29.91 bpm (95% CI, -40.31 to -19.52; P<0.0001). VR reductions persisted up to 150 minutes. Significantly greater proportions of patients receiving etripamil achieved VR reductions <100 bpm (with longer median duration <100 bpm), or VR reduction by ≥10% or ≥20%, versus placebo. VR reduction ≥20% occurred in 66.7% of patients in the etripamil arm and no patients in placebo. Using the Treatment Satisfaction Questionnaire for Medication-9, there was significant improvement in satisfaction on symptom relief and treatment effectiveness with etripamil versus placebo. Serious adverse events were rare; 1 patient in the etripamil arm experienced transient severe bradycardia and syncope, assessed as due to hypervagotonia. CONCLUSIONS: Intranasal etripamil 70 mg reduced VR and improved symptom relief and treatment satisfaction. These data support further development of self-administered etripamil for the treatment of AF-RVR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04467905.

Podcast on Self-administered Intranasal Etripamil for Symptomatic Paroxysmal Supraventricular Tachycardia: The RAPID Trial.

Paroxysmal supraventricular tachycardia (PSVT) is commonly seen in clinical practice and represents a significant burden to the healthcare system and to patients. First-line treatments include calcium channel blockers (CCB), although they are intravenous and require medical supervision. Etripamil is an investigational self-administered intranasal L-type CCB for unsupervised treatment of PSVT. In this podcast, we discuss the RAPID trial (NCT03464019), which was a phase 3 study that evaluated the safety and efficacy of etripamil in terminating PSVT episodes using a repeat-dosing regimen. RAPID was a multicenter, randomized trial that enrolled adults with electrocardiograph (ECG)-documented PSVT episodes lasting ≥ 20 min. Patients who tolerated test doses of etripamil were randomized 1:1 to receive either etripamil or placebo. Upon perceiving PSVT symptoms, patients began ECG monitoring and performed a vagal maneuver. If arrhythmia termination was unsuccessful, they self-administered 70 mg of etripamil or placebo, followed by an optional second dose after 10 min. The primary endpoint was time to conversion of PSVT to sinus rhythm within 30 min of the initial dose and sustained for ≥ 30 s. The safety group included all patients who self-administered the study treatment. Of 692 enrollees, 184 self-administered the study drug (99 etripamil, 85 placebo) for ECG-confirmed PSVT. Conversion of PSVT to sinus rhythm within 30 min was achieved in 64.3% of etripamil-treated subjects versus 31.2% of placebo-treated subjects. A significant threefold reduction in the median time to conversion of 17.2 min was observed in the etripamil group versus 53.5 min in the placebo group. Treatment-emergent adverse events were mild or moderate and primarily included transient nasal discomfort, nasal congestion, and rhinorrhea. If etripamil is approved by the US FDA, it can potentially address a significant unmet need for PSVT treatment outside a clinical setting, reducing the need for intravenous treatments that require medical supervision.Podcast available for this article.

Etripamil Nasal Spray for Conversion of Repeated Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia During Long-Term Follow-Up: Results From the NODE-302 Study.

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 (χ2=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.

Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): a multicentre, randomised trial.

BACKGROUND: Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min. METHODS: RAPID was a multicentre, randomised, placebo-controlled, event-driven trial, conducted at 160 sites in North America and Europe as part 2 of the NODE-301 study. Eligible patients were aged at least 18 years and had a history of paroxysmal supraventricular tachycardia with sustained, symptomatic episodes (≥20 min) as documented by electrocardiogram. Patients were administered two test doses of intranasal etripamil (each 70 mg, 10 min apart) during sinus rhythm; those who tolerated the test doses were randomly assigned (1:1) using an interactive response technology system to receive either etripamil or placebo. Prompted by symptoms of paroxysmal supraventricular tachycardia, patients self-administered a first dose of intranasal 70 mg etripamil or placebo and, if symptoms persisted beyond 10 min, a repeat dose. Continuously recorded electrocardiographic data were adjudicated, by individuals masked to patient assignment, for the primary endpoint of time to conversion of paroxysmal supraventricular tachycardia to sinus rhythm for at least 30 s within 30 min after the first dose, which was measured in all patients who administered blinded study drug for a confirmed atrioventricular-nodal-dependent event. Safety outcomes were assessed in all patients who self-administered blinded study drug for an episode of perceived paroxysmal supraventricular tachycardia. This trial is registered at ClinicalTrials.gov, NCT03464019, and is complete. FINDINGS: Between Oct 13, 2020, and July 20, 2022, among 692 patients randomly assigned, 184 (99 from the etripamil group and 85 from the placebo group) self-administered study drug for atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia, with diagnosis and timing confirmed. Kaplan-Meier estimates of conversion rates by 30 min were 64% (63/99) with etripamil and 31% (26/85) with placebo (hazard ratio 2·62; 95% CI 1·66-4·15; p<0·0001). Median time to conversion was 17·2 min (95% CI 13·4-26·5) with the etripamil regimen versus 53·5 min (38·7-87·3) with placebo. Prespecified sensitivity analyses of the primary assessment were conducted to test robustness, yielding supporting results. Treatment-emergent adverse events occurred in 68 (50%) of 99 patients treated with etripamil and 12 (11%) of 85 patients in the placebo group, most of which were located at the administration site and were mild or moderate, and all of which were transient and resolved without intervention. Adverse events occurring in at least 5% of patients treated with etripamil were nasal discomfort (23%), nasal congestion (13%), and rhinorrhea (9%). No serious etripamil-related adverse events or deaths were reported. INTERPRETATION: Using a symptom-prompted, self-administered, initial and optional-repeat-dosing regimen, intranasal etripamil was well tolerated, safe, and superior to placebo for the rapid conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm. This approach could empower patients to treat paroxysmal supraventricular tachycardia themselves outside of a health-care setting, and has the potential to reduce the need for additional medical interventions, such as intravenous medications given in an acute-care setting. FUNDING: Milestone Pharmaceuticals.

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.

Rationale for and design of a multicenter, placebo-controlled, phase 3 study to assess efficacy and safety of intranasal etripamil for the conversion of paroxysmal supraventricular tachycardia.

Presently, acute pharmacological termination of paroxysmal supraventricular tachycardia (PSVT) unresponsive to patient-initiated vagal maneuvers requires in-hospital intervention. Etripamil, a fast-acting, nondihydropyridine, L-type calcium channel blocker, is formulated as an intranasal spray to rapidly terminate atrioventricular (AV) nodal-dependent PSVT in a medically unsupervised setting. The NODE-301 study did not meet its prespecified primary end point of PSVT conversion over 5 hours following a single dose of etripamil 70 mg. However, analysis at earlier time points demonstrated etripamil treatment effect during the first 30 minutes, consistent with its expected rapid onset and short duration of action. This led to the design of the RAPID study, which includes a new dosing regimen (up to 2 etripamil 70 mg doses separated by 10 minutes) to increase the exposure and pharmacodynamic effect of etripamil. The primary objective of RAPID (NCT03464019) is to determine if etripamil self-administered by patients is superior to placebo in terminating PSVT in an at-home setting. The secondary objective is to evaluate the safety of etripamil when self-administered by patients without medical supervision. Additional efficacy end points include the proportion of patients requiring additional medical intervention in an emergency department to terminate PSVT and patient-reported outcomes. After successfully completing a test dose to assess the safety of 2 70 mg doses of etripamil during sinus rhythm, approximately 500 patients will be randomized 1:1 to etripamil or placebo to accrue 180 positively adjudicated AV nodal-dependent PSVT events for treatment with the study drug. Etripamil may offer a new alternative to the current in-hospital treatment modality, providing for safe and effective at-home termination of PSVT.

2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders.

This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by the Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs.

Subcutaneous implantable cardioverter-defibrillator electrode fracture: Follow-up, troubleshooting, and evaluation.

The subcutaneous-implantable cardioverter-defibrillator (S-ICD) and its electrode were developed to avoid long-term complications of transvenous leads in the vasculature. We report a case of unexpected, inappropriate S-ICD shocks due to oversensing of high-amplitude, nonphysiologic, electrical noise artifacts that were not preceded by high-impedance alerts or sensing electrogram noise detections. Following explant, high-magnification X-ray imaging of the S-ICD electrode demonstrated partial fracture of the distal sensing conductor located near a short radius bend in the electrode at the electrode-header interface. Clinicians should be aware of a potential for fatigue failure fracture of the S-ICD electrode. Recommendations for systematic S-ICD follow-up and troubleshooting are discussed.

Atrial natriuretic peptide accelerates onset and dynamics of ventricular fibrillation during hypokalemia in isolated rabbit hearts.

BACKGROUND: Atrial natriuretic peptide (ANP), which is released by the heart in response to acute cardiac stretch, possesses cardiac electrophysiological properties that include modulation of ion channel function and repolarization. However, data regarding whether ANP can directly modulate electrical instability or arrhythmias are largely lacking. OBJECTIVE: This study sought to determine whether ANP modifies onset or electrophysiological characteristics of ventricular fibrillation (VF) induced by severe hypokalemia in an isolated heart model. METHODS: Langendorff-perfused rabbit hearts in the absence and presence of 10 nM ANP (n = 9 in each group) were subjected to a low potassium (K+) perfusate (1.2 mM K+). Left ventricular (LV) epicardial monophasic action potential (MAP) and pressure were monitored continuously. Incidence and time to onset of VF and dominant frequency during VF determined by spectral analysis were evaluated. RESULTS: ANP did not alter ventricular repolarization (MAP duration) or LV pressure during perfusion with physiologic, K+-containing solution. Within the first 30 s after low K+ perfusion, ANP accelerated the onset of beat-to-beat repolarization alternans (100% vs. 33% in ANP-treated vs. non-treated hearts, p < 0.01). During low K+ perfusion, the incidence of VF did not differ between ANP-treated and non-treated hearts (8 of 9 [89%] in each group). However, VF occurred sooner (3.75 ± 0.33 vs. 5.78 ± 0.70 min, P < 0.05) and immediately after VF onset, peak dominant frequency was higher (24.1 ± 7.3 vs. 14.2 ± 2.3 Hz, P = 0.01) in ANP-treated than in non-treated hearts. CONCLUSIONS: ANP accelerates initiation of VF and increases maximum dominant frequency during VF in isolated hearts subjected to severe hypokalemia.

LV only pacing-mediated electrical storm with cardiac resynchronization therapy managed by simultaneous biventricular pacing.

Ventricular arrhythmia (VA) is a rare complication of cardiac resynchronization therapy (CRT). Little is known about ventricular proarrhythmia related to the pacing vector of CRT. This case report describes the elimination of ventricular arrythmia using biventricular pacing in a patient with VT-storm related to LV only pacing as part of the AdaptivCRT algorithm (Medtronic Inc). Simultaneous biventricular pacing was effective in eliminating polymorphic ventricular tachycardia. Changing the pacing vector is a noninvasive treatment strategy that should be considered to manage VA due to CRT.

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).