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Original Investigation
January 19, 2021

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

Author Affiliations
  • 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
JAMA. 2021;325(3):244-253. doi:10.1001/jama.2020.23522
Visual Abstract. Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis in Acute Ischemic Stroke
Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis in Acute Ischemic Stroke
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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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