Intranasal ‘spray-in-the-pocket’ treatment for conversion of supraventricular tachycardia: safe, effective but not definite

Comment on ‘Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): a multicentre, randomised trial’ published in The Lancet 2023; 402:118–28. doi.org/10.1016/S0140-6736(23)00776-6. In this industry-funded, multicentre, randomized, double-blind, placebo-controlled trial, the authors compared the efficacy and safety of etripamil, a fast-acting intranasally administered L-type calcium-channel blocker, with placebo in patients with symptomatic episodes of sustained atrio-ventricular-nodal-re-entrant paroxysmal supraventricular tachycardia (AVRNT).1 The trial was conducted at 160 sites in North America and Europe. Before randomization, two doses of open-label intranasal etripamil (2 × 70-mg, 10 min apart) were administered while subjects were in sinus rhythm (SR). 184 subjects (mean age 54 years, 71% female) who tolerated the test doses were randomly assigned in a 1:1 ratio to receive etripamil or placebo, using an interactive response technology (IRT). In the case of an at-home AVRNT episode, patients applied an electrocardiogram (ECG) monitor and performed a previously taught vagal manoeuvre. If this was unsuccessful, a patient would then self-administer the randomized treatment. If symptoms persisted 10 min later, a repeat dose of the same treatment was administered. The ECG monitor recording was continued for 5 h regardless of resolution of symptoms and a medical coach was available for phone questions. Adjudicated conversion of confirmed AVRNT to SR for at least 30 s within 30 min of drug administration served as the primary efficacy outcome. Secondary efficacy endpoints were time to conversion, percentage of patients requiring additional antiarrhythmic therapy, and rating on three satisfaction scales. Adjudicated clinical adverse events (such as nose bleed, syncope, and presyncope), arrhythmias, and conduction disorders detected by 12-lead ECG within 24 h of drug administration served as the principal safety outcome. The primary efficacy outcome occurred in 63 (64%) of 99 patients in the etripamil group compared with 26 (31%) of 85 patients in the placebo group [HR at 30 min: 2.62; 95% confidence interval (CI), 1.66–4.15; P < .0001]. The median time to conversion was 17 min with etripamil compared with 53 min with placebo. A repeat dose was used by 66% of patients in etripamil group and 79% in the placebo group. Most adverse events were reported as mild or moderate without significant differences between the two groups. Recurrence of AVRNT after conversion to SR occurred in 3% of the etripamil group and 4% of the placebo group. No serious adverse events occurred within 24 h after etripamil administration. Atrio-ventricular nodal re-entrant paroxysmal supraventricular tachycardia (AVNRT), the most commonly encountered supraventricular tachycardia (SVT), is a re-entrant tachycardia with well-described heterogeneity of both fast and slow conduction patterns.1 Thus, specific electrophysiological manoeuvres may be required for differential diagnosis of typical and, especially, atypical AVNRT from focal atrial tachycardia or from atrio-ventricular re-entrant tachycardia due to a concealed septal pathway. As indicated by ESC 2019 Guidelines, catheter ablation (CA) of AVRNT is the current treatment of choice for symptomatic patients because it substantially improves the quality of life, reduces costs and radiation exposure.2,3 This approach offers a success rate of 97%, with a low recurrence rate, and has been associated with a risk of AV block <1%.2 Moreover, a randomized clinical trial that compared CA as first-line treatment with antiarrhythmic drugs demonstrated significant benefits of CA in arrhythmia-related hospitalizations.4 However, from 2008 to 2016 in the USA, only 15% of patients with a diagnosis of SVT underwent CA.5 In patients awaiting CA and with minimal symptoms and infrequent episodes of AVRNT, chronic antiarrhythmic drug therapy (with beta-blockers or calcium-channel blockers) is used for the rapid conversion to SR, with success rates ranging from 13% to 82%.2 In this clinical setting, etripamil, similarly to non-dihydropyridine calcium-channel blockers, appears to slow atrio-ventricular node conduction and increase its refractory period.6 It has been evaluated as a potential patient-administered treatment for rapid termination of symptomatic episodes of AVRNT, with a peak plasma concentration at 8 min following an intranasal dose of 70 mg.6,7 Importantly, unlike prior studies of etripamil in SVT, the RAPID trial allowed patients to administer a second 70-mg dose if symptoms persisted beyond 10 min.7 Safety and tolerability findings were consistent with those seen in the phase-3, multicentre, double-blind, and placebo-controlled NODE-301 study.8 These results are hypothesis-generating regarding the potential of etripamil to decrease the number of patients seeking medical intervention for their SVT and consequently the annual number of emergency department visits. The implementation of etripamil in the clinical setting might have some limitations. In the real-world, the safety of etripamil is likely to depend on applying the strict inclusion criteria of the RAPID trial. Indeed, patients with perceived SVT not confirmed as atrio-ventricular dependent, e.g. patients with latent ventricular pre-excitation and anterograde accessory pathway conduction, do not have the appropriate profile for etripamil treatment.9 This represents the main limitation of the RAPID trial. The confirmation of AVRNT, limited by single channel ECG recordings, was obtained by an adjudication committee of expert electrophysiologists; in addition, the trial offered to all patients a phone medical coach available for medical questions during the 5 h ECG recording, with management of possible side effects. In the real-world, the self-administered modality without a confirmed diagnosis of AVRNT by ECG would not allow adequate control of the repeat dose of etripamil. In addition to the treatment heterogeneity due to self-administered single or double etripamil dose, the RAPID trial enrolled 184 patients in 160 centres in North America and Europe, with a potential heterogeneity in the recruitment procedure. In conclusion, larger data are needed to understand the applicability of etripamil in the real-world setting. In particular, in patients not eligible for CA, an intranasal ‘spray-in-the-pocket’ strategy should be compared with chronic pharmacological therapy in terms of efficacy and safety. M.L.N. received an educational grant from Biotronik, Boston Scientific, and a grant from Impulse Dynamics, and grant support from the Italian Minister of Health (PNRR), outside the submitted work.