Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke
Authors: Arturo Renú, Mónica Millán, Luis San Román, Jordi Blasco, Joan Martí-Fàbregas, Mikel Terceño, Sergio Amaro, Joaquín Serena, Xabier Urra, Carlos Laredo, Roger Barranco, Pol Camps-Renom, Federico Zarco, Laura Oleaga, Pere Cardona, Carlos Castaño, Juan Macho, Elisa Cuadrado-Godía, Elio Vivas, Antonio López-Rueda, Leopoldo Guimaraens, Anna Ramos-Pachón, Jaume Roquer, Marian Muchada, Alejandro Tomasello, Antonio Dávalos, Ferran Torres, Ángel Chamorro, Laura Llull, Martha Vargas, Victor Obach, Salvatore Rudilosso, Alejandro Rodríguez-Vázquez, Daniel Santana, Napoleón Macías, Elena Serrano, Javier Moreno, Natalia Pérez de la Ossa, Laura Dorado, Maria Hernández-Pérez, Meritxell Gomis, Lucia Muñoz, P. Rodríguez-Molinos, Martí Boix, Ernest Palomeras, F. Núñez, Sebastián Remollo, Mariano Werner, Victor Vera, Laura Paul, Laura Pardo, Montserrat Reina, Saima Bashir, Ursula Bojaryn, Yolanda Silva, Marina Guasch, Alan Murillo, Juan Rodríguez Álvarez-Cienfuegos, M. Comas, B. Martínez, E. Nogué, Oscar Chirife, Helena Quesada, Blanca Lara, Andres Paipa, Lucia Aja, Paloma Mora, Maria Angel de Miquel, Sónia Aixut, Anna Maria Ferrer, R. Marín, Luis Prats-Sánchez, Raquel Delgado-Mederos, A Martínez-Domeño, Joan Branera, R. Guerrero, J, Villalba, A, Rodríguez, N. Berga, Elena Jiménez-Xarrié, G. Romeral, Ángel Ois, Jordi Jiménez, C. Avellaneda, N, Cayuela, Ana Rodríguez, Eva Giralt, M Espona, J. Saldaña, David Hernández, Marc Ribó, Carlos Piñana, Noelia Rodríguez, Sandra Boned, Carlos Molina, Marta Rubiera, Jesús Juega, David Rodríguez-Luna, Juan Pagola, Alvaro Garcia-Tonel, Matias Deck, V Sala, Estela Sanjuan, K. Santana, C. Losada, P. Suñe, Tudor G. Jovin, Enrique Leira, José Rios
Journal: JAMA (2022)

<h3>Importance</h3> It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits. <h3>Objective</h3> To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. <h3>Design, Setting, and Participants</h3> Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3. <h3>Interventions</h3> Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52). <h3>Main Outcomes and Measures</h3> The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death. <h3>Results</h3> The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%;<i>P</i> = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, −3.8%; 95% CI, −13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, −7.2%; 95% CI, −19.2% to 4.8%). <h3>Conclusions and Relevance</h3> Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03876119; EudraCT Number:2018-002195-40