¹Department of Neurology, Nippon Medical School, Tokyo, Japan
²Division of Stroke Prevention and Treatment, Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
³Department of Neurosurgery, Seisho Hospital, Kanagawa, Japan
⁴Department of Neurosurgery, Yokohama Shintoshi Neurosurgery Hospital, Kanagawa, Japan
⁵Department of Neurosurgery, Nagareyama Central Hospital, Chiba, Japan
⁶Department of Neurology, Akiyama Neurosurgical Hospital, Kanagawa, Japan
⁷Department of Neurology, Showa University Koto Toyosu Hospital, Tokyo, Japan
⁸Department of Neurosurgery, National Hospital Organization Disaster Medical Center, Tokyo, Japan
⁹Department of Cerebrovascular Medicine, NTT Medical Center Tokyo, Tokyo, Japan
¹⁰Department of Neurosurgery, New Tokyo Hospital, Chiba, Japan
¹¹Department of Neurology and Neurosurgery, Chiba Emergency Medical Center, Chiba, Japan
¹²Department of Neurosurgery, Dokkyo Medical University Saitama Medical Center, Saitama, Japan
¹³Department of Neurosurgery, National Center for Global Health and Medicine, Tokyo, Japan
¹⁴Department of Neurosurgery, Funabashi Municipal Medical Center, Chiba, Japan
¹⁵Department of Neurosurgery, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan
¹⁶Department of Stroke and Cerebrovascular Medicine, Kyorin University, Tokyo, Japan
¹⁷Department of Neurosurgery, Mito Medical Center, Ibaraki, Japan
¹⁸Department of Strokology, Stroke Center, St Marianna University Toyoko Hospital, Kanagawa, Japan
¹⁹Department of Neurology, the Jikei University School of Medicine, Tokyo, Japan
²⁰Department of Neurosurgery, Mihara Memorial Hospital, Gunma, Japan
²¹Department of Endovascular Neurosurgery, Toranomon Hospital, Tokyo, Japan
²²Department of Endovascular Surgery, Tokyo Medical and Dental University, Tokyo, Japan
²³Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan
²⁴Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan

SKIP Study Investigatorsfor the

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Original Investigation

Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Ischemic Stroke

Bruce C. V. Campbell, PhD; Peter J. Mitchell, MMed; Leonid Churilov, PhD; Nawaf Yassi, PhD; Timothy J. Kleinig, PhD; Richard J. Dowling, MBBS; Bernard Yan, DMedSci; Steven J. Bush, MBBS; Vincent Thijs, PhD; Rebecca Scroop, MBBS; Marion Simpson, MBBS; Mark Brooks, MBBS; Hamed Asadi, MBBS; Teddy Y. Wu, PhD; Darshan G. Shah, MBBS; Tissa Wijeratne, MD; Henry Zhao, MBBS; Fana Alemseged, MD; Felix Ng, MBBS; Peter Bailey, MD; Henry Rice, MBBS; Laetitia de Villiers, MBBS; Helen M. Dewey, PhD; Philip M. C. Choi, MBChB; Helen Brown, MB BCh BAO; Kendal Redmond, MBBS; David Leggett, MBBS; John N. Fink, MBChB; Wayne Collecutt, MBBS; Thomas Kraemer, MD; Martin Krause, MD; Dennis Cordato, PhD; Deborah Field, MBBS; Henry Ma, PhD; Bill O’Brien, MBBS; Benjamin Clissold, MBBS; Ferdinand Miteff, MBBS; Anna Clissold, MBBS; Geoffrey C. Cloud, MBBS; Leslie E. Bolitho, MBBS; Luke Bonavia, MBBS; Arup Bhattacharya, MBBS; Alistair Wright, MBBS; Abul Mamun, MBBS; Fintan O’Rourke, MBBS; John Worthington, MBBS; Andrew A. Wong, PhD; Christopher R. Levi, MBBS; Christopher F. Bladin, MD; Gagan Sharma, MCA; Patricia M. Desmond, MD; Mark W. Parsons, PhD; Geoffrey A. Donnan, MD; Stephen M. Davis, MD; EXTEND-IA TNK Part 2 investigators; James Taylor; Craig Kurunawai; Edmund Cheong; Anna Balabanski; Michael J Waters; Jackson Harvey; Lavenia Cagi; Nicholas Chia; Anthony Khoo; Roy Drew; Jennifer Cranefield; Thomas J Oxley; Cameron Williams; Edrich Rodrigues; Patrick Salvaris; Angela Dos Santos; Jo-Lyn Ng; Skye Coote; Carolyn Beltrame; Elizabeth Mackey; Kanaga Lagma; Amy McDonald; David Jackson; Jessica Tsoleridis; Lauren Pesavento; Ashu Jhamb; Amy Brodtmann; Alexandra Warwick; Bronwyn Coulton; Dennis Young; Justin Whitley; Carol Bendall; Hans TH Tu; Sherisse Celestino; Essie Low; Arman Sabet; Sachin Mishra; Berzenn Urbi; Tanya Frost; Jessie Chen; Siew Kar Chen; Melissa Y Tang; Kara Nowak; Rodrigo Martins; Channa Senanayake; Charmaine H Yam; Daniel Barber; Francesca M Bridge; Joseph ZW Wong; Grace Thomas; Jennifer Liu; Naila Pachani; Rose Lee; Ramesh Sahathevan; Casey Hair; Timothy J Harrington; Brendan Steinfort; Kenneth Faulder; Susan Day; Allan J McDougall; Cecilia Cappelen-Smith; Jason Wenderoth; Andrew Cheung; Nathan Manning; Andrew Moey; Vanessa Maxwell; Thanh Phan; Shaloo Singhal; John Ly; Winston Chong; Ronil V Chandra; Lee-Anne Slater; James Evans; Deborah Alchin; Paul Talman; Cameron Shaw; Abhishek Malhotra; Rohitha Makonahalli; Neil Spratt; Carlos Garcia-Esperon; Lara Kaauwai; Patrick Groot; Anoop Madan; Carlos Chung; Andrea Moore; Robert Krones; Nancy Bilkhu; Helen Haines; Franz Eversheim; Erin Ray; Tessa Coupland; Timothy Ang; Stephen Winters; David Brunacci; Geoffrey Parker; Kylie Tastula; Claire Muller; Alan Coulthard; John Clouston; Ken Mitchell; Kate Mahady; Yvonne Liu; Ye Min Kuang; Aileen Wu; Karen Smith; Michael Stephenson; Emily Andrew; Matthew Ligtermoet; Matthew Lee-Archer; John N Fink; James Beharry; Andrew Laing; Martin Krauss; Jane Eagle; Gerhard Uys; Lauren Arthurson; Krishna Mandaleson; Anne Van Berkel; Rohan Grimley; Wayne Skoien; Neil Mahant; P. Alan Barber; Ben McGuinness; Ayton Hope; Stefan Brew; Maurice Moriarty; Lily Zhao; Michele Sallaberger; Barry Snow; John Kolbe; Richard Stark; John King; Richard Macdonnell; John Attia; Cate D'Este
Original Investigation

Effect of Endovascular Treatment With vs Without IV Alteplase on Functional Independence After Acute Ischemic Stroke

Wenjie Zi, MD; Zhongming Qiu, MD; Fengli Li, MD; Hongfei Sang, MD; Deping Wu, MD; Weidong Luo, MD; Shuai Liu, MD; Junjie Yuan, MD; Jiaxing Song, MD; Zhonghua Shi, MD; Wenguo Huang, MD; Min Zhang, MS; Wenhua Liu, MD; Zhangbao Guo, MS; Tao Qiu, MD; Qiang Shi, MS; Peiyang Zhou, MD; Li Wang, MD; Xinmin Fu, MD; Shudong Liu, MD; Shiquan Yang, MD; Shuai Zhang, MD; Zhiming Zhou, MD; Xianjun Huang, MD; Yan Wang, MD; Jun Luo, MS; Yongjie Bai, MD; Min Zhang, MS; Youlin Wu, MS; Guoyong Zeng, MD; Yue Wan, MD; Changming Wen, MD; Hongbin Wen, MD; Wentong Ling, MS; Zhuo Chen, MS; Miao Peng, MS; Zhibing Ai, MD; Fuqiang Guo, MD; Huagang Li, MD; Jing Guo, MS; Haitao Guan, MD; Zhiyi Wang, MS; Yong Liu, MS; Jie Pu, MD; Zhen Wang, MD; Hansheng Liu, MD; Luming Chen, MD; Jiacheng Huang, MD; Guoqiang Yang, MD; Zili Gong, MD; Jie Shuai, MD; Raul G. Nogueira, MD; Qingwu Yang, MD, PhD; DEVT Trial Investigators
Correction

Incorrect P Value and Figure Label Error
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Functional Outcomes Among Patients With Acute Ischemic Stroke After Mechanical Thrombectomy With or Without Intravenous Thrombolysis—Reply

Kazumi Kimura, MD, PhD; Toshiaki Otsuka, MD, PhD; Kentaro Suzuki, MD, PhD
Comment & Response

Functional Outcomes Among Patients With Acute Ischemic Stroke After Mechanical Thrombectomy With or Without Intravenous Thrombolysis

Hui Mai, MD, PhD; Tao Chen, PhD; Bin Zhao, MD
Original Investigation

Thrombolysis and Thrombectomy vs Thrombectomy Alone for Ischemic Stroke

Jonathan M. Coutinho, MD; David S. Liebeskind, MD; Lee-Anne Slater, MD; Raul G. Nogueira, MD; Wayne Clark, MD; Antoni Dávalos, MD; Alain Bonafé, MD; Reza Jahan, MD; Urs Fischer, MD; Jan Gralla, MD; Jeffrey L. Saver, MD; Vitor M. Pereira, MD

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Key Points

Question In patients with acute large vessel occlusion stroke, is mechanical thrombectomy alone noninferior to combined intravenous thrombolysis using 0.6-mg/kg alteplase plus mechanical thrombectomy regarding functional outcomes?

Findings In this randomized clinical trial of 204 patients, a favorable functional outcome occurred in 59.4% of those randomized to mechanical thrombectomy alone and in 57.3% of those randomized to combined intravenous thrombolysis plus mechanical thrombectomy (odds ratio, 1.09 [95% confidence limit below the noninferiority margin of 0.74]).

Meaning The findings failed to demonstrate noninferiority of mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, for favorable functional outcome following acute large vessel occlusive ischemic stroke, although the wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority.

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

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Article Information

Corresponding Author: Kazumi Kimura, MD, PhD, Department of Neurology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan (k-kimura@nms.ac.jp).

Accepted for Publication: November 18, 2020.

Correction: This article was corrected on May 4, 2021, to fix a P value reported in the Results section and Table 2, as well as labels in Figure 3.

Author Contributions: Drs Kimura and Suzuki had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The first and subsequent drafts of the manuscript were written by Drs Suzuki and Kimura, incorporating input from all authors.

Concept and design: Suzuki, Matsumaru, Fujimoto, Higashida, Kimura.

Acquisition, analysis, or interpretation of data: Suzuki, Takeuchi, Morimoto, Kanazawa, Takayama, Kamiya, Shigeta, Okubo, Hayakawa, Ishii, Koguchi, Takigawa, Inoue, Naito, Ota, Hirano, Kato, Ueda, Iguchi, Akaji, Tsuruta, Miki, Fujimoto, Higashida, Iwasaki, Aoki, Nishiyama, Otsuka, Kimura.

Drafting of the manuscript: Suzuki, Higashida, Kimura.

Critical revision of the manuscript for important intellectual content: Suzuki, Matsumaru, Takeuchi, Morimoto, Kanazawa, Takayama, Kamiya, Shigeta, Okubo, Hayakawa, Ishii, Koguchi, Takigawa, Inoue, Naito, Ota, Hirano, Kato, Ueda, Iguchi, Akaji, Tsuruta, Miki, Fujimoto, Iwasaki, Aoki, Nishiyama, Otsuka, Kimura.

Statistical analysis: Suzuki, Higashida, Otsuka.

Obtained funding: Suzuki, Kimura.

Administrative, technical, or material support: Suzuki, Takeuchi, Morimoto, Kanazawa, Takayama, Kamiya, Shigeta, Okubo, Ishii, Koguchi, Inoue, Naito, Ota, Hirano, Kato, Ueda, Iguchi, Akaji, Tsuruta, Miki, Higashida, Iwasaki, Aoki, Nishiyama, Kimura.

Supervision: Matsumaru, Fujimoto, Otsuka, Kimura.

Conflict of Interest Disclosures: Dr Suzuki reported receiving grants from the Japanese Society for Neuroendovascular Therapy during the conduct of the study and a scholarship to study abroad from the Uehara Memorial Foundation. Dr Matsumaru reported receiving personal fees from Medtronic Co Ltd, Stryker Co Ltd, Sanofi Co Ltd, Daiichi Sankyo Co Ltd, Otsuka Pharmaceutical Co Ltd, and Biomedical Solutions outside the submitted work. Dr Takeuchi reported receiving lecture fees from Stryker Co Ltd outside the submitted work. Dr Kamiya reported receiving personal fees from Daiichi Sankyo Co Ltd and grants from Bristol-Myers Squibb Co Ltd outside the submitted work. Dr Hirano reported receiving personal fees from Bayer Healthcare Co Ltd, Daiichi Sankyo Co Ltd, Nippon Boehringer Ingelheim Co Ltd, Bristol-Myers Squibb Co Ltd, Medtronic Co Ltd, Sanofi Co Ltd, Otsuka Pharmaceutical Co Ltd, Mitsubishi Tanabe Pharma Co, CSL Behring KK, Astellas Pharma Inc, and Pfizer Japan Inc outside the submitted work. Dr Iguchi reported receiving grants and personal fees from Sanofi SA, Daiichi-Sankyo Co Ltd, and Boehringer Ingelheim GmbH, Bayer AG; personal fees from Pfizer Inc and Bristol-Myers Squibb; and lecture fees from Bayer Healthcare Co Ltd, Pfizer Japan Inc, Nippon Boehringer Ingelheim Co Ltd, Takeda Pharmaceutical Co Ltd, Otsuka Pharmaceutical Co Ltd, and Daiichi Sankyo Co Ltd outside the submitted work. Dr Fujimoto reported receiving personal fees from Daiichi Sankyo Co Ltd, Bayer Yakuhin Ltd, Nippon Boehringer Ingelheim Co Ltd, Bristol-Myers Squibb Co, Pfizer Japan Inc, Takeda Pharmaceutical Co Ltd, Otsuka Pharmaceutical Co Ltd, Sanofi KK, MSD KK, and Dai-Nippon Sumitomo Pharma Co Ltd outside the submitted work. Dr Nishiyama reported receiving personal fees from Daiichi Sankyo Co Ltd outside the submitted work. Dr Kimura reported receiving grants from 38th Mihara Cerebrovascular Disorder Research Promotion Fund Ltd during the conduct of the study and grants from Teijin Pharma Ltd, Medtronic Co Ltd, Pfizer Japan Inc, Daiichi Sankyo Co, and Nippon Boehringer Ingelheim Co Ltd, personal fees from Daiichi Sankyo Co, personal fees from Bayer Healthcare Co Ltd and personal fees from Nippon Boehringer Ingelheim Co Ltd and Bristol-Myers Squibb Co Ltd outside the submitted work. No other disclosures were reported.

Funding/Support: Funding was provided by the Japanese Society for Neuroendovascular Therapy.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The SKIP Study Investigators are listed in Supplement 3.

Additional Contributions: We thank Akio Morita, MD, PhD (Department of Neurosurgery, Nippon Medical School Hospital, Tokyo, Japan), as the independent data monitoring committee without compensation and Hiroyuki Yokota, MD, PhD (Department of Emergency and Critical Care Medicine, Nippon Medical School Hospital, Tokyo, Japan), as the event evaluation committee without compensation.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic StrokeThe SKIP Randomized Clinical Trial

Thrombolysis and Thrombectomy vs Thrombectomy Alone for Ischemic Stroke

Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Ischemic Stroke

Intravenous Thrombolysis Before Endovascular Thrombectomy for Acute Ischemic Stroke

Effect of Endovascular Treatment With vs Without IV Alteplase on Functional Independence After Acute Ischemic Stroke

Incorrect P Value and Figure Label Error

Functional Outcomes Among Patients With Acute Ischemic Stroke After Mechanical Thrombectomy With or Without Intravenous Thrombolysis—Reply

Functional Outcomes Among Patients With Acute Ischemic Stroke After Mechanical Thrombectomy With or Without Intravenous Thrombolysis

See More

Thrombolysis Before Thrombectomy for Stroke

Thrombolysis Before Thrombectomy for Stroke

AMA CME Accreditation Information

Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic StrokeThe SKIP Randomized Clinical Trial

Thrombolysis and Thrombectomy vs Thrombectomy Alone for Ischemic Stroke

Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Ischemic Stroke

Intravenous Thrombolysis Before Endovascular Thrombectomy for Acute Ischemic Stroke

Effect of Endovascular Treatment With vs Without IV Alteplase on Functional Independence After Acute Ischemic Stroke

Incorrect P Value and Figure Label Error

Functional Outcomes Among Patients With Acute Ischemic Stroke After Mechanical Thrombectomy With or Without Intravenous Thrombolysis—Reply

Functional Outcomes Among Patients With Acute Ischemic Stroke After Mechanical Thrombectomy With or Without Intravenous Thrombolysis

See More

Thrombolysis Before Thrombectomy for Stroke

Thrombolysis Before Thrombectomy for Stroke

See More About

AMA CME Accreditation Information

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