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

2023; Elsevier BV; Volume: 402; Issue: 10396 Linguagem: Inglês

10.1016/s0140-6736(23)00776-6

1474-547X

Bruce S. Stambler, A. John Camm, Marco Alings, Paul Dorian, Hein Heidbüchel, Jaco H. Houtgraaf, Peter R. Kowey, José Luís Merino, Blandine Mondésert, Jonathan P. Piccini, Sean D. Pokorney, Philip T. Sager, Atul Verma, J. Marcus Wharton, David B. Bharucha, Francis Plat, Silvia Shardonofsky, Michael Chen, James E. Ip, James E. Ip, Alonzo Jones, Bruce S. Stambler, David E. Schleinkofer, Stephen L. Winters, Wilson Lam, Robert E. Goldstein, Isaac Dor, Sandeep Talwar, Padraig Gearoid O’Neill, Michael Koren, Sean C. Beinart, Srivani R. Ambati, Sean Mazer, Robert M. Kinn, Karine Roy, Ramin Manshadi, Richard S. Kuk, Aditya Verma, Timothy Phelan, Alexandru A Stoian, Kenneth A. Ellenbogen, J. Vijay Jayachandran, T. P. Connelly, Marcos Daccarett, Gaurang Gandhi, Suneet Mittal, Amir Abdel-Wahab, Ralph Augostini, James E. Ip, Denise M. Sorrentino, Jean-François Roux, Ramandeep Brar, Clarence Khoo, Matthew T. Bennett, Eric Lo, Benoit Coutu, Laurence D. Sterns, G. Stephen Greer, Pradeep Gujja, Robert A Gianfagna, Vijendra Swarup, Felix Sogade, Stephen B. Wilton, Christopher P. Ruisi, Saverio J. Barbera, Javier E. Banchs, Victoria Korley, Christopher Schulze, Roger S. Damle, Jeff S. Healey, A. Shekhar Pandey, Jeffrey L. Anderson, K Venkatachalam, Peter A. Noseworthy, Blandine Mondésert, Atul Verma, Douglas G Friars, Thomas R. Kambur, Evan Lockwood, Glenn R. Meininger, Greg Olsovsky, Alonzo Jones, G. Stephen Greer, Rohit Mehta, Saleem Akbar, Malik Salman, Bhola Rama, Ramesh Arora, Dhirenkumar Shah, Rakesh Shah, Michael Cammarata, Andrew P. Owens, Katherine J. Ludington, Marcus Wharton, Michael Bagheri, Mohammed Khan, Kenneth Warren Carr, Sultan M. Siddique, Sunthosh V. Parvathaneni, Subodh Devabhaktuni, Assad Mouhaffel, George E. Mark, Luigi Di Biase, Sunil Rangappa, Jared Morton, Hirad Yarmohammadi, Amin Karim, A. Fleites, Thomas Nero, Qaiser Shafiq, Benoit Coutu, Shekhar Pandey, Yaariv Khaykin, Jacqueline Joza, Gilbert Gosselin, Allen Skanes, John Vyselaar, Daniel Savard, Hein Heidbüchel, Olivier Xhaët, Emmanuel Catez, Johan Vijgen, Pascal Godart, Rubén Casado-Arroyo, Georges H. Mairesse, Tom Rossenbacker, Peter Haemers, E Hoffer, Pierre Hausman, András Vértes, Gabor Z. Duray, Erzsebet Szolnoki, Zoltán Csanádi, Ferenc Lakatos, Marco Alings, Reinhart Dorman, Ype S. Tuininga, W Jansen, Sebastiaan Velthuis, Barbara Van Bemmel, Gerhard Jan Willem Bech, Ron Pisters, Suzanne D.A. Valk, Tjeerd J. Römer, Justin Luermans, Driek Beelen, M. van Eck, Jaco H. Houtgraaf, Thijs M. W. J. Vet, Dirk Shellings, Thomas Oosterhof, Paweł Miękus, Waldemar Bebenek, Agata Bielecka‐Dąbrowa, Jacek Gniot, Witold Żmuda, Michał Kasprzak, Wojciech Balak, Paweł Ptaszyński, Jacek Nowak, Janusz Prokopczuk, Andrzej Przybylski, I. Wozniak‐Skowerska, Paweł Derejko, Danuta Czarnecka, Adam Janas, José Luís Merino, Luís Tercedor, Andrés Íñiguez, R. Ruiz Granell, José Ramón González–Juanatey, Domingo A. Pascual‐Figal, Manuel Martínez‐Sellés, Ignacio Anguera Camos, Alicia Ibáñez-Críado, Javier Basterra, Álvaro Izquierdo, Nuria Rivas‐Gándara, J. Colomé, Diego Pérez Díez, Miguel Hervás, Maria Medina, José María Segura Saint‐Gerons, Alonso Pedrote Leal, Ignacio Fernández Lozano, Aurelio Quesada, María José Guerra Palmero, Axel Sarrias, Javier Ramos Maqueda, Jacques Mansourati, Pascal Defaye, Laurence Guédon-Moreau, Antoine Milhem, Maxime De Guillebon, Philippe Chevalier, Marc Badoz, Charalampos Kriatselis, Gregor Simonis, Thorsten Lewalter, Markus Zarse, Andreas Wilke, Fabian Kraemer, Ayham Al-Zoebi,

Cardiovascular Syncope and Autonomic Disorders

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. 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. 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. 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. Milestone Pharmaceuticals.