Arturo Renú1,2, Mónica Millán3, Luis San Román4, Jordi Blasco4, Joan Martí-Fàbregas5, Mikel Terceño6, Sergio Amaro1,2,7, Joaquín Serena8, Xabier Urra1,2,7, Carlos Laredo1,2, Roger Barranco9, Pol Camps-Renom5, Federico Zarco4, Laura Oleaga4, Pere Cardona10, Carlos Castaño11, Juan Macho4, Elisa Cuadrado-Godía12, Elio Vivas13, Antonio López-Rueda4, Leopoldo Guimaraens13, Anna Ramos-Pachón3, Jaume Roquer12, Marian Muchada14, Alejandro Tomasello15, Antonio Dávalos3,5, Ferran Torres16,17, Ángel Chamorro1,2,7. 1. Department of Neuroscience, Comprehensive Stroke Center, Hospital Clinic of Barcelona, Barcelona, Spain. 2. Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Barcelona, Spain. 3. Stroke Unit, Department of Neuroscience, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 4. Neuroradiology Service, Hospital Clinic of Barcelona, Barcelona, Spain. 5. Department of Neurology, Stroke Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 6. Neuroradiology Service, Hospital Universitari de Girona Doctor Josep Trueta, Girona, Spain. 7. School of Medicine, University of Barcelona, Barcelona, Spain. 8. Neurology Service, Stroke Unit, Institut d'Investigació Biomèdica de Girona (IDIBGI), Hospital Universitari de Girona Doctor Josep Trueta, Girona, Spain. 9. Department of Interventional Neuroradiology, Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, Spain. 10. Department of Neurology, Bellvitge University Hospital, Barcelona, Spain. 11. Interventional Neuroradiology Unit, Department of Neuroscience, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 12. Department of Neurology, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autònoma de Barcelona, Barcelona, Spain. 13. Department of Neuroradiology, Hospital del Mar, Barcelona, Spain. 14. Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain. 15. Department of Neuroradiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. 16. Medical Statistics Core Facility, Clinical Pharmacology Service, IDIBAPS, Hospital Clínic Barcelona, Barcelona, Spain. 17. Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
Abstract
Importance: 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. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, Setting, and Participants: 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. Interventions: 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). Main Outcomes and Measures: 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. Results: 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%; P = .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%). Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.
Importance: 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. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, Setting, and Participants: 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. Interventions: 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). Main Outcomes and Measures: 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. Results: 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%; P = .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%). Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.