Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic Stroke: The SKIP Randomized Clinical Trial | Cerebrovascular Disease | JAMA | JAMA Network
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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
Figure 1.  Flowchart of Enrollment, Randomization, and Treatment of the SKIP Randomized Clinical Trial
Flowchart of Enrollment, Randomization, and Treatment of the SKIP Randomized Clinical Trial

Patients were randomly assigned in a 1:1 ratio to the mechanical thrombectomy alone group or the intravenous thrombolysis plus mechanical thrombectomy group using a permuted block design stratified by site. Each site was not required to provide screening logs during the recruitment phase. Thus, the number of patients assessed for eligibility is not available. ASPECTS indicates Alberta Stroke Program Early CT Score; mRS, modified Rankin Scale.

aASPECTS too low indicates ASPECTS less than 5 on initial diffusion-weighted imaging or less than 6 on initial computed tomography.

Figure 2.  Functional Outcomes at 90 Days From Onset According to the Modified Rankin Scale Score
Functional Outcomes at 90 Days From Onset According to the Modified Rankin Scale Score

Scores on the modified Rankin Scale range from 0 to 6, with 0 indicating no symptoms; 1, symptoms without clinical disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death.

Figure 3.  Subgroup Plot Showing the Adjusted Treatment Effect for Favorable Outcome, With P Values for Heterogeneity Across Subgroups
Subgroup Plot Showing the Adjusted Treatment Effect for Favorable Outcome, With P Values for Heterogeneity Across Subgroups

ASPECTS indicates Alberta Stroke Program Early CT Score; M1, middle cerebral artery M1 segment; and NIHSS, National Institutes of Health Stroke Scale. To convert glucose to mmol/L, multiply by 0.0555.

Table 1.  Characteristics of the Patients at Baseline
Characteristics of the Patients at Baseline
Table 2.  Primary and Secondary Efficacy End Points and Adverse Eventsa
Primary and Secondary Efficacy End Points and Adverse Eventsa
Conversations with Dr Bauchner (21:48)

Intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) both improve outcomes for patients with acute ischemic stroke. Jeffrey L. Saver, MD, director of UCLA’s Comprehensive Stroke and Vascular Neurology Program and a JAMA Associate Editor, discusses 2 randomized trials comparing outcomes for stroke patients treated with IVT prior to EVT vs EVT alone.

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Goyal  M, Fargen  KM, Turk  AS,  et al.  2C or not 2C: defining an improved revascularization grading scale and the need for standardization of angiography outcomes in stroke trials.   J Neurointerv Surg. 2014;6(2):83-86. doi:10.1136/neurintsurg-2013-010665PubMedGoogle ScholarCrossref
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Mori  E, Minematsu  K, Nakagawara  J, Yamaguchi  T, Sasaki  M, Hirano  T; Japan Alteplase Clinical Trial II Group.  Effects of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral artery occlusion: Japan Alteplase Clinical Trial II (J-ACT II).   Stroke. 2010;41(3):461-465. doi:10.1161/STROKEAHA.109.573477PubMedGoogle ScholarCrossref
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Adams  HP  Jr, Bendixen  BH, Kappelle  LJ,  et al.  Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial: TOAST, Trial of Org 10172 in Acute Stroke Treatment.   Stroke. 1993;24(1):35-41. doi:10.1161/01.STR.24.1.35PubMedGoogle ScholarCrossref
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Leker  RR, Pikis  S, Gomori  JM, Cohen  JE.  Is bridging necessary? a pilot study of bridging versus primary stentriever-based endovascular reperfusion in large anterior circulation strokes.   J Stroke Cerebrovasc Dis. 2015;24(6):1163-1167. doi:10.1016/j.jstrokecerebrovasdis.2015.01.008PubMedGoogle ScholarCrossref
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Rai  AT, Boo  S, Buseman  C,  et al.  Intravenous thrombolysis before endovascular therapy for large vessel strokes can lead to significantly higher hospital costs without improving outcomes.   J Neurointerv Surg. 2018;10(1):17-21. doi:10.1136/neurintsurg-2016-012830PubMedGoogle ScholarCrossref
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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
Conversations with Dr Bauchner (21:48)
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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

Introduction

Randomized trials have consistently shown that mechanical thrombectomy with or without intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) can improve the outcome in patients with acute stroke due to large vessel occlusion.1-7 Intravenous thrombolysis (with dosage of 0.9-mg/kg alteplase) prior to mechanical thrombectomy is recommended by national guidelines for patients with large vessel occlusion, within 4.5 hours of symptom onset.8-10

A meta-analysis of 5 randomized clinical trials reported that outcomes following mechanical thrombectomy did not differ significantly between patients receiving and not receiving intravenous thrombolysis.11 However, this concerned an observational comparison because intravenous thrombolysis was withheld only in the presence of contraindications for rt-PA. A retrospective study also showed that the outcomes between mechanical thrombectomy alone and combined intravenous thrombolysis plus mechanical thrombectomy were not significantly different.12 However, a meta-analysis showed the combined intravenous thrombolysis plus mechanical thrombectomy was associated with favorable outcome compared with mechanical thrombectomy alone.13

Quiz Ref IDIntravenous thrombolysis performed in addition to mechanical thrombectomy in patients with large vessel occlusion has some potential benefits, such as earlier therapy initiation and increased chance of reperfusion. However, intravenous thrombolysis in addition to mechanical thrombectomy may increase the risk of intracerebral hemorrhage and other bleeding complications.14 Noninferiority of mechanical thrombectomy alone, compared with combined therapy, would have potential clinical consequences because the extra cost and stroke team labor associated with intravenous thrombolysis could be avoided if outcomes of mechanical thrombectomy alone were not worse than outcomes of combined therapy.

The Direct Mechanical Thrombectomy in Acute LVO Stroke (SKIP) study was designed to evaluate whether the outcomes with mechanical thrombectomy alone were noninferior than the outcomes with combined thrombolysis and mechanical thrombectomy.

Methods
Trial Design and Oversight

This trial was approved by the institutional review board (IRB) of each hospital. Enrolled patients or their relatives provided written informed consent. This trial was an investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial. Detailed aspects of the study design are provided in the final trial protocol with summary of all changes (Supplement 1), the final statistical analysis plan with summary of all changes (Supplement 2), and a prior trial design publication.15 The study was to test whether mechanical thrombectomy alone was noninferior to combined intravenous thrombolysis plus mechanical thrombectomy with regard to functional outcome in intravenous thrombolysis–eligible patients. All patients were required to have large vessel occlusion without large ischemic core lesions.

Patients and Participating Centers

Quiz Ref IDThis study was performed at 23 stroke centers capable of endovascular therapy in Japan. Patients were allowed to be evaluated in another hospital and transferred to one of the study centers. Eligible patients were 18 to 85 years old, had acute stroke with internal carotid artery (ICA) or M1 occlusion evaluated by magnetic resonance angiography (MRA) or computed tomographic angiography (CTA), had a baseline Alberta Stroke Program Early CT Score (ASPECTS) (range, 0 to 10, with higher scores indicating fewer early ischemic changes) of 6 to 10 or Diffusion-Weighted Imaging (DWI)–ASPECTS (range, 0 to 10, with higher scores indicating fewer early ischemic changes) of 5 to 10, initial National Institutes of Health Stroke Scale (NIHSS) score (range, 0 [no symptoms] to 42 [most severe neurologic deficits]) equal to 6 or greater, were functionally independent prior to stroke, with modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) of 0 to 2 , and met the criteria of the Japanese guidelines for treatment with the lower dose of 0.6 mg/kg of alteplase as intravenous thrombolysis within 4.5 hours from onset.16 The NIHSS score was assessed at baseline. The mRS score was assessed at 90 days after onset. For detailed inclusion and exclusion criteria, see eBox 1 in Supplement 3.

Randomization and Interventions

Patients were randomly assigned in a 1:1 ratio to 1 of 2 treatment groups using a web-based data management system: the mechanical thrombectomy alone group or the combined group. Using a stratified permuted block method (a block size of 4), we balanced the number of patients into the 2 treatment groups of each hospital. Alteplase was used at the only dosage (0.6 mg/kg) approved by the Japanese government. Mechanical thrombectomy was performed with any device approved by the Ministry of Health, Labour, and Welfare of Japan. Balloon guide catheter was selected as the guiding catheter on mechanical thrombectomy. Concomitant stenting and angioplasty of cervical and intracranial ICA occlusive lesions were permitted without device restrictions. All stroke centers were required to start mechanical thrombectomy within 30 minutes from randomization. rt-PA infusion was continued during mechanical thrombectomy for those in the combined intravenous thrombolysis plus mechanical thrombectomy group.

Radiologic Assessment

At admission, the baseline clinical characteristics were assessed by research physicians at each hospital, including the NIHSS score, occluded artery site17 at admission and start of mechanical thrombectomy, ASPECTS on MRI or CT, and expanded Thrombolysis in Cerebral Infarction (eTICI) scale score (range, 0-3, higher scores indicate better reperfusion) on digital subtraction angiography. After enrolling all patients, a core imaging assessment committee (2 expert neurologists, S.F. and T. Hirano), who were blinded to the intervention, independently reassessed the occlusion site, ASPECTS, and presence of intracerebral hemorrhage as prespecified adverse events. Quiz Ref IDClot migration was defined as change of occlusion site on findings between initial MRA/CTA and initial digital subtraction angiography.

Outcome Measures

The mRS score was assessed by physical examination or telephone interview at 90 days after onset by site personnel who were blinded to treatment group assignment. The primary outcome measure was favorable outcome defined as an mRS score of 0 to 2 at 90 days. In a sensitivity analysis, primary outcome results were analyzed using per-protocol analysis.

The prespecified secondary outcome measures were shift analysis of disability levels on the mRS; mRS score of 5 to 6; mRS score of 0 to 1; mRS score of 0 to 3; mortality at 90 days; successful reperfusion defined as an eTICI scale18 score of 2b to 3 on end-of-procedure catheter angiography; recanalization, defined as modified Mori scale19 score of 2 to 3 (scale ranges from 0 [no recanalization] to 3 [nearly complete recanalization]) on 48-hour CTA/MRA.

The prespecified adverse events were any intracerebral hemorrhage at 36 hours from onset; symptomatic intracerebral hemorrhage defined by the National Institute of Neurological Disorders and Stroke (NINDS) criteria20; symptomatic intracerebral hemorrhage defined by Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS-MOST) criteria21; and other major bleeding events (eBox 2 in Supplement 3).

In the initial protocol, the investigators requested that the IRB allow use of mRS scores of 0 to 2 for noninferiority in the primary analysis. However, the IRB suggested to the investigators to change from an mRS score of 0 to 2 for noninferiority to an mRS score of 5 to 6 for superiority in the primary analysis prior to study start because there were no confirmed data to support the mRS score of 0 to 2 approach compared with the mRS score of 5 to 6 approach. After 103 patients had been enrolled in this trial, Weber et al22 reported an observational study that provided more data regarding the end point of an mRS score of 0 to 2. Consequently, the IRB accepted the use of an mRS score of 0 to 2 for noninferiority in the primary analysis. Therefore, on August 1, 2018, the primary outcome was changed from superiority for poor outcome to noninferiority for favorable outcome. Study investigators had not reviewed any patient data before the primary outcome change. The study investigators included stroke neurologists, neurosurgeons, and statisticians. This trial was monitored by an independent data monitoring committee and event evaluation committee.

Noninferiority Margin and Sample Size Calculations

In a retrospective analysis of patients eligible for intravenous thrombolysis, Weber et al22 reported favorable functional outcome (mRS score 0-2) in 48.6% of patients (n = 70) who had received mechanical thrombectomy alone and 35.2% of those (n = 105) who received intravenous thrombolysis plus mechanical thrombectomy. As described in detail in the published study protocol for this study,15 the noninferiority margin was set as the odds ratio of 0.74 using the fixed-margin approach, which was derived from a previous meta-analysis of combined intravenous thrombolysis plus mechanical thrombectomy compared with the best medical treatment.11 Based on those results, it was estimated that 178 patients (89 patients in each group) were needed to statistically show the noninferiority of the odds ratio for the primary outcome in the mechanical thrombectomy alone group compared with the intravenous thrombolysis plus mechanical thrombectomy group, based on comparison of the 2 proportions with a 1-sided α level of .025 and a power of 0.80. Therefore, the target enrollment was set at 200 patients because of considering possible treatment failures, protocol violations, and dropouts. Detailed information on the calculation of sample size is described in the statistical analysis plan in Supplement 2.

Statistical Analysis

All analyses were performed using the primary analysis set, which was defined as all patients enrolled to the trial.

In the primary analysis, patients were analyzed according to the group to which they were randomized. The primary analysis involved testing for noninferiority of the rate of a favorable outcome at 90 days of mechanical thrombectomy alone compared with combined intravenous thrombolysis plus mechanical thrombectomy. Unadjusted logistic regression analysis was used to test noninferiority. As described in detail in the protocol,15 we set an odds ratio of 0.74 as the noninferiority margin, using the fixed-margin approach, which was derived from a previous meta-analysis of combined intravenous thrombolysis plus mechanical thrombectomy compared with the best medical treatment.11 As sensitivity analysis of the primary outcome, noninferiority analyses of a favorable outcome was also performed using the per-protocol analysis set, which excluded patients with mRS scores prior to stroke higher than 2 and a large volume infarct (ASPECTS of 0-5 or DWI-ASPECTS of 0-4) from the primary analysis set.

In the prespecified secondary efficacy analysis, the mRS scores were compared between groups to test for the noninferiority of mechanical thrombectomy compared with combined intravenous thrombolysis plus mechanical thrombectomy, using ordinal logistic regression (shift analysis). The proportional odds assumption of the shift analysis was validated by a Brant test. Furthermore, mortality at 90 days; reperfusion rate of the occluded arteries; mRS score of 5 to 6, 0 to 1, or 0 to 3 at 90 days; and recanalization of modified Mori grade of 2 or 3 at 72 hours after stroke onset were compared between the 2 groups using unadjusted logistic regression analysis.

As prespecified adverse events, any and symptomatic intracerebral hemorrhage and other bleeding events were assessed for superiority of mechanical thrombectomy alone compared with combined therapy. In the post hoc analysis, mixed-effect logistic regression analysis of the primary outcome was performed with study site as a random effect. In addition, association between any intracerebral hemorrhage and clinical outcome at 90 days, and subgroup plot–adjusted treatment effect for favorable outcome were assessed.

The primary noninferiority analysis used a 1-sided significance threshold of .025, as did all other noninferiority analyses. Superiority analyses used a 2-sided significance threshold of .05. The heterogeneity of treatment effects on the primary outcome across subgroups was examined using an interaction test for the treatment × subgroup interaction. Because of the potential for type I error due to multiple comparisons, findings for analyses of secondary end points and subgroup analyses should be interpreted as exploratory.

All data analyses were performed with JMP version 11 software (SAS Institute) and Stata version 14 software (StataCorp).

Results
Characteristics of the Patients

From January 2017 through July 2019, 204 patients were enrolled. The median age was 74 years, 128 (62.7%) were men, and the median NIHSS score was 18 (interquartile range [IQR], 12-23) (Table 1). At admission, 181 (88.7%) and 23 (11.3%) patients were assessed by MRI/MRA and CT/CTA, respectively. The median ASPECTS was 8 (IQR, 6-9) and the occluded vessel site was ICA in 77 patients (37.7%), M1 proximal in 37 (18.1%), and M1 distal in 90 (44.1%). Patients were randomized into 2 groups: 101 (49.5%) in the mechanical thrombectomy alone group and 103 (50.5%) in the combined intravenous thrombolysis plus mechanical thrombectomy group. Ten patients did not fulfill the inclusion criteria (2 patients had a poor mRS score and 8 had a low ASPECTS. Therefore, 194 patients (97 in each group) were included in the per-protocol analysis (Figure 1). No baseline covariate or outcome data were missing, except for 12 cases (5.9%) for modified Mori grade. Table 1 shows the demographic and clinical characteristics at baseline according to group.

Endovascular Therapy

Five patients did not undergo mechanical thrombectomy because of aortic dissection (n = 2) and impossibility of approach (n = 1) in the mechanical thrombectomy alone group and because of spontaneous recanalization (n = 1) and impossibility of approach (n = 1) in the combined group. Therefore, 199 patients (97.5%) underwent mechanical thrombectomy. The median door-to-randomization time was 33 minutes (IQR, 23-48), randomization-to-puncture time was 18 minutes (IQR, 11-25), and puncture-to-reperfusion time was 34 minutes (IQR, 22-55). The randomization-to-puncture time was not statistically significantly different between the 2 groups (mechanical thrombectomy alone vs intravenous thrombolysis plus mechanical thrombectomy: 16 minutes [IQR, 11-24] vs 19 minutes [13-27], P = .38). In the combined group, the puncture was performed before the administration of rt-PA in 22 patients (21.4%). The rate of clot migration was not significantly different between the 2 groups (25/100 [25%] vs 28/103 [27%], P > .99).

Primary Outcome

In the primary analysis set, a favorable outcome was observed in 60 of 101 patients (59.4%) in the mechanical thrombectomy alone group and in 59 of 103 (57.3%) in the combined group (difference, 2.1% [1-sided 97.5% CI, –11.4% to ∞]; odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ∞]; 1-sided noninferiority P = .18). Therefore, noninferiority of mechanical thrombectomy alone to combined intravenous thrombolysis plus mechanical thrombectomy was not proven (Table 2 and Figure 2). In the per-protocol analysis, a favorable outcome was observed in 59 of 97 patients (60.8%) in the mechanical thrombectomy alone group and in 57 of 97 (58.8%) in the combined group, and noninferiority of the primary outcome measure was not proven (difference, 2.1% [1-sided 97.5% CI, –13.7% to ∞]; odds ratio, 1.06 [1-sided 97.5% CI, 0.60 to ∞]; P = .22).

Secondary Outcome

In the primary analysis set, we analyzed the overall distribution of the mRS score at 90 days (shift analysis of the disability level). Mechanical thrombectomy alone was not associated with a favorable shift in the distribution of the mRS score at 90 days (odds ratio, 0.97 [1-sided 97.5% CI, 0.60 to ∞]; noninferiority P = .37), without any violation of the proportional odds assumption (Brant test P = .90). The number of deaths within 90 days after onset was 8 (7.9%) in the mechanical thrombectomy alone group and 9 (8.7%) in the combined group (difference, –0.8% [95% CI, –9.5% to 7.8%]; odds ratio, 0.90 [95% CI, 0.33 to 2.43]; P > .99). The 2 groups did not significantly differ in rates of successful reperfusion after mechanical thrombectomy, defined as eTICI grade of 2b or greater (91 [90.1%] vs 96 [93.2%]; difference, –3.1% [95% CI, –11.8% to 5.6%]; odds ratio, 0.66 [95% CI, 0.24 to 1.82]; P = .46) (Table 2). Other prespecified secondary outcome data are described in the eTable in Supplement 3.

Adverse Events

Intracerebral hemorrhage was assessed by only CT at 36 hours from onset. Of 86 patients with intracerebral hemorrhage, 16 patients showed parenchymal hematoma 2 defined by European Cooperative Acute Stroke Study criteria. The rate of any intracerebral hemorrhage at 36 hours from onset was lower 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). However, the rate of symptomatic intracerebral hemorrhage was not significantly different between the 2 groups, based on the NINDS criteria (8 [7.9%] vs 12 [11.7%]; difference, –3.7% [ 95% CI, –13.0% to 5.6%]; odds ratio, 0.65 [95% CI, 0.25 to 1.67]; P = .48) and the SIT-MOST criteria (6 [5.9%] vs 8 [7.8%]; difference, –1.8% [95% CI, –9.7% to 6.1%]; odds ratio, 0.75 [95% CI, 0.25 to 2.24]; P = .78). In the post hoc analysis, patients with any intracerebral hemorrhage (symptomatic [n = 14] and asymptomatic [n = 72]) had less frequently favorable outcomes than those without intracerebral hemorrhage (41.9% [36/86] vs 70.3% [83/118], P < .001). The incidence of other hemorrhagic events was not significantly different (1/101 [1%] and 4/103 [4%], P = .37) (1 [1.0%] vs 4 [3.9%]; difference, –2.9% [95% CI, –0.08 to 0.02]; odds ratio, 0.25 [95% CI, 0.03 to 2.25]; P = .37) between the 2 groups.

Subgroup Analysis and Post Hoc Analyses

There was no significant heterogeneity of effect on the primary outcome across the post hoc subgroups: age, sex, atrial fibrillation, blood glucose, antithrombotic agent, NIHSS score, ASPECTS, occluded artery at admission, and onset randomization time (Figure 3).

The results for the primary outcome of the post hoc mixed-effect logistic regression analysis with study site as a random effect were similar (odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ∞]; noninferiority P = .17).

Discussion

Quiz Ref IDThis clinical trial of patients with acute large vessel occlusion stroke failed to demonstrate noninferiority of mechanical thrombectomy alone compared with combined intravenous thrombolysis plus mechanical thrombectomy with regard to favorable functional outcome. Although this study hypothesis could not be proved, the point estimates of treatment effect for mechanical thrombectomy alone was nominally slightly better, not worse, compared with combined therapy. Accordingly, a larger trial or meta-analysis of trials is needed to conclusively assess noninferiority.

Recent studies have evaluated the effectiveness of mechanical thrombectomy therapy compared with that for combined intravenous thrombolysis plus mechanical thrombectomy therapy in patients with acute large vessel occlusion stroke.1,5,12,13,22,24-31 A meta-analysis demonstrated that combined intravenous thrombolysis plus mechanical thrombectomy therapy was associated with a higher likelihood of functional independence compared with that for mechanical thrombectomy alone therapy (odds ratio, 1.52 [95% CI, 1.32 to 1.76]).32 However, these results were obtained from retrospective cohort studies, in which mechanical thrombectomy alone was performed on many rt-PA–ineligible patients.33 In contrast, Kaesmacher et al34 reported that a meta-analysis using only rt-PA–eligible patients could not conclude that mechanical thrombectomy alone had more favorable outcome compared with combined intravenous thrombolysis plus mechanical thrombectomy.

This study demonstrated that any intracerebral hemorrhage within 36 hours from onset was significantly lower in the mechanical thrombectomy alone group than in the combined group. However, symptomatic intracerebral hemorrhage did not significantly differ between the 2 groups. Intracerebral hemorrhage is associated with high morbidity and mortality after mechanical thrombectomy therapy.35 Administration of rt-PA alone is known to increase the rate of symptomatic intracerebral hemorrhage 3- to 10-fold vs that with controls, though absolute numbers were low.14,20 In this trial, the incidence of any intracerebral hemorrhage was significantly higher in the combined group than in the mechanical thrombectomy alone group. The higher frequency of any intracerebral hemorrhage may be caused by the administration of rt-PA. Many reports have shown that symptomatic, but not asymptomatic, intracerebral hemorrhage is associated with poor outcomes.36-38 Van Kranendonk et al39 reported that any intracerebral hemorrhage has a potential for poor outcome. In the post hoc analysis of this study, favorable outcomes were significantly less frequent in patients with any intracerebral hemorrhage than in those without intracerebral hemorrhage. Further studies are needed to clarify the relationship between any intracerebral hemorrhage and patient outcome.

The combined intravenous thrombolysis plus mechanical thrombectomy therapy might be considered to be disadvantaged by the delayed start of mechanical thrombectomy due to the preparation of rt-PA administration. However, the randomization-to-puncture time was not statistically significantly different between the 2 groups. In 22 cases (21.4%) in the combined group, groin puncture occurred before the start of intravenous thrombolysis. Therefore, rt-PA administration might be not a disadvantage to the starting of mechanical thrombectomy therapy.

Limitations

Quiz Ref IDThis study has several limitations. First, this was an open-label study regarding the use of rt-PA. Second, the sample size and the noninferiority margin of 0.74 were calculated from previous studies using a dose of 0.9 mg/kg of alteplase. In addition, the noninferiority margin was selected using the fixed-margin method rather than the minimal clinically important difference. Third, favorable outcomes were more frequent than expected, which may have resulted in a reduction of study power. Recently, the Direct-MT trial40 in China, which was a similar randomized clinical trial to this trial, demonstrated noninferiority for mechanical thrombectomy alone compared with combined intravenous thrombolysis and mechanical thrombectomy with regard to functional outcome. In addition, 3 randomized clinical trials (MR CLEAN-NO IV [ISRCTN80619088], SWIFT DIRECT [NCT03192332], and DIRECT-SAFE [NCT03494920]) similar to this trial are ongoing. Meta-analyses that include these trials may provide greater clarity.

Conclusions

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.

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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.

Data Sharing Statement: See Supplement 4.

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