Kentaro Suzuki1, Yuji Matsumaru2, Masataka Takeuchi3, Masafumi Morimoto4, Ryuzaburo Kanazawa5, Yohei Takayama6, Yuki Kamiya7, Keigo Shigeta8, Seiji Okubo9, Mikito Hayakawa2, Norihiro Ishii10, Yorio Koguchi11, Tomoji Takigawa12, Masato Inoue13, Hiromichi Naito14, Takahiro Ota15, Teruyuki Hirano16, Noriyuki Kato17, Toshihiro Ueda18, Yasuyuki Iguchi19, Kazunori Akaji20, Wataro Tsuruta21, Kazunori Miki22, Shigeru Fujimoto23, Tetsuhiro Higashida5, Mitsuhiro Iwasaki4, Junya Aoki1, Yasuhiro Nishiyama1, Toshiaki Otsuka24, Kazumi Kimura1. 1. Department of Neurology, Nippon Medical School, Tokyo, Japan. 2. Division of Stroke Prevention and Treatment, Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan. 3. Department of Neurosurgery, Seisho Hospital, Kanagawa, Japan. 4. Department of Neurosurgery, Yokohama Shintoshi Neurosurgery Hospital, Kanagawa, Japan. 5. Department of Neurosurgery, Nagareyama Central Hospital, Chiba, Japan. 6. Department of Neurology, Akiyama Neurosurgical Hospital, Kanagawa, Japan. 7. Department of Neurology, Showa University Koto Toyosu Hospital, Tokyo, Japan. 8. Department of Neurosurgery, National Hospital Organization Disaster Medical Center, Tokyo, Japan. 9. Department of Cerebrovascular Medicine, NTT Medical Center Tokyo, Tokyo, Japan. 10. Department of Neurosurgery, New Tokyo Hospital, Chiba, Japan. 11. Department of Neurology and Neurosurgery, Chiba Emergency Medical Center, Chiba, Japan. 12. Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Saitama, Japan. 13. Department of Neurosurgery, National Center for Global Health and Medicine, Tokyo, Japan. 14. Department of Neurosurgery, Funabashi Municipal Medical Center, Chiba, Japan. 15. Department of Neurosurgery, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan. 16. Department of Stroke and Cerebrovascular Medicine, Kyorin University, Tokyo, Japan. 17. Department of Neurosurgery, Mito Medical Center, Ibaraki, Japan. 18. Department of Strokology, Stroke Center, St Marianna University Toyoko Hospital, Kanagawa, Japan. 19. Department of Neurology, the Jikei University School of Medicine, Tokyo, Japan. 20. Department of Neurosurgery, Mihara Memorial Hospital, Gunma, Japan. 21. Department of Endovascular Neurosurgery, Toranomon Hospital, Tokyo, Japan. 22. Department of Endovascular Surgery, Tokyo Medical and Dental University, Tokyo, Japan. 23. Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan. 24. Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan.
Abstract
IMPORTANCE: Whether intravenous thrombolysis is needed in combination with mechanical thrombectomy in patients with acute large vessel occlusion stroke is unclear. OBJECTIVE: To examine whether mechanical thrombectomy alone is noninferior to combined intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome. DESIGN, SETTING, AND PARTICIPANTS: Investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in Japan from January 1, 2017, to July 31, 2019, with final follow-up on October 31, 2019. INTERVENTIONS: Patients were randomly assigned to mechanical thrombectomy alone (n = 101) or combined intravenous thrombolysis (alteplase at a 0.6-mg/kg dose) plus mechanical thrombectomy (n = 103). MAIN OUTCOMES AND MEASURES: The primary efficacy end point was a favorable outcome defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 2 at 90 days, with a noninferiority margin odds ratio of 0.74, assessed using a 1-sided significance threshold of .025 (97.5% CI). There were 7 prespecified secondary efficacy end points, including mortality by day 90. There were 4 prespecified safety end points, including any intracerebral hemorrhage and symptomatic intracerebral hemorrhage within 36 hours. RESULTS: Among 204 patients (median age, 74 years; 62.7% men; median National Institutes of Health Stroke Scale score, 18), all patients completed the trial. Favorable outcome occurred in 60 patients (59.4%) in the mechanical thrombectomy alone group and 59 patients (57.3%) in the combined intravenous thrombolysis plus mechanical thrombectomy group, with no significant between-group difference (difference, 2.1% [1-sided 97.5% CI, -11.4% to ∞]; odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ∞]; P = .18 for noninferiority). Among the 7 secondary efficacy end points and 4 safety end points, 10 were not significantly different, including mortality at 90 days (8 [7.9%] vs 9 [8.7%]; difference, -0.8% [95% CI, -9.5% to 7.8%]; odds ratio, 0.90 [95% CI, 0.33 to 2.43]; P > .99). Any intracerebral hemorrhage was observed less frequently in the mechanical thrombectomy alone group than in the combined group (34 [33.7%] vs 52 [50.5%]; difference, -16.8% [95% CI, -32.1% to -1.6%]; odds ratio, 0.50 [95% CI, 0.28 to 0.88]; P = .02). Symptomatic intracerebral hemorrhage was not significantly different between groups (6 [5.9%] vs 8 [7.7%]; difference, -1.8% [95% CI, -9.7% to 6.1%]; odds ratio, 0.75 [95% CI, 0.25 to 2.24]; P = .78). CONCLUSIONS AND RELEVANCE: Among patients with acute large vessel occlusion stroke, mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, failed to demonstrate noninferiority regarding favorable functional outcome. However, the wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000021488.
IMPORTANCE: Whether intravenous thrombolysis is needed in combination with mechanical thrombectomy in patients with acute large vessel occlusion stroke is unclear. OBJECTIVE: To examine whether mechanical thrombectomy alone is noninferior to combined intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome. DESIGN, SETTING, AND PARTICIPANTS: Investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in Japan from January 1, 2017, to July 31, 2019, with final follow-up on October 31, 2019. INTERVENTIONS: Patients were randomly assigned to mechanical thrombectomy alone (n = 101) or combined intravenous thrombolysis (alteplase at a 0.6-mg/kg dose) plus mechanical thrombectomy (n = 103). MAIN OUTCOMES AND MEASURES: The primary efficacy end point was a favorable outcome defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 2 at 90 days, with a noninferiority margin odds ratio of 0.74, assessed using a 1-sided significance threshold of .025 (97.5% CI). There were 7 prespecified secondary efficacy end points, including mortality by day 90. There were 4 prespecified safety end points, including any intracerebral hemorrhage and symptomatic intracerebral hemorrhage within 36 hours. RESULTS: Among 204 patients (median age, 74 years; 62.7% men; median National Institutes of Health Stroke Scale score, 18), all patients completed the trial. Favorable outcome occurred in 60 patients (59.4%) in the mechanical thrombectomy alone group and 59 patients (57.3%) in the combined intravenous thrombolysis plus mechanical thrombectomy group, with no significant between-group difference (difference, 2.1% [1-sided 97.5% CI, -11.4% to ∞]; odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ∞]; P = .18 for noninferiority). Among the 7 secondary efficacy end points and 4 safety end points, 10 were not significantly different, including mortality at 90 days (8 [7.9%] vs 9 [8.7%]; difference, -0.8% [95% CI, -9.5% to 7.8%]; odds ratio, 0.90 [95% CI, 0.33 to 2.43]; P > .99). Any intracerebral hemorrhage was observed less frequently in the mechanical thrombectomy alone group than in the combined group (34 [33.7%] vs 52 [50.5%]; difference, -16.8% [95% CI, -32.1% to -1.6%]; odds ratio, 0.50 [95% CI, 0.28 to 0.88]; P = .02). Symptomatic intracerebral hemorrhage was not significantly different between groups (6 [5.9%] vs 8 [7.7%]; difference, -1.8% [95% CI, -9.7% to 6.1%]; odds ratio, 0.75 [95% CI, 0.25 to 2.24]; P = .78). CONCLUSIONS AND RELEVANCE: Among patients with acute large vessel occlusion stroke, mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, failed to demonstrate noninferiority regarding favorable functional outcome. However, the wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000021488.
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