Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke: The DEVT Randomized Clinical Trial

Question  Among patients with ischemic stroke secondary to large vessel occlusion and eligible for thrombolysis, is endovascular treatment alone noninferior to intravenous alteplase plus endovascular treatment with regard to functional independence?

Findings  In this randomized clinical trial that included 234 patients with acute ischemic stroke, the proportion who achieved functional independence at 90 days was 54.3% in the endovascular treatment alone group vs 46.6% in the intravenous alteplase plus endovascular treatment group, a difference that met the prespecified noninferiority margin of 10%.

Meaning  Among patients with acute ischemic stroke due to large vessel occlusion and eligible for thrombolysis, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence, although the clinical acceptability of the threshold for noninferiority should be considered when interpreting the results.

Importance  For patients with large vessel occlusion strokes, it is unknown whether endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes.

Objective  To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with large vessel occlusion stroke.

Design, Setting, and Participants  Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020).

Interventions  A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group.

Main Outcomes and Measures  The primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was −10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality.

Results  The trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% CI, −5.1% to ∞)P for noninferiority = .003). No significant between-group differences were detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, −0.8%; 95% CI, −7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, −0.5%; 95% CI, −10.3% to 9.2%).

Conclusions and Relevance  Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold.

Trial Registration  Chinese Clinical Trial Registry: ChiCTR-IOR-17013568

Quiz Ref IDSeven randomized clinical trials have consistently demonstrated that patients with a large vessel occlusion in the anterior circulation benefit from endovascular treatment following intravenous thrombolysis (IVT).^1-7 However, IVT prior to endovascular treatment has potential benefits and risks. Intravenous thrombolysis may sometimes contribute to reperfusion, averting the need for endovascular treatment.⁵ Intravenous thrombolysis may facilitate endovascular reperfusion and promote dissolution of downstream microemboli improving distal perfusion.^8,9 Conversely, IVT may increase the risk of intracranial or systemic hemorrhage, lead to thrombus fragmentation and worsening distal perfusion, and delay the start of the endovascular treatment.^10,11 Furthermore, IVT limits the use of antithrombotic therapy within 24-hour, and increases health care costs.¹²

The recently reported randomized clinical trial of Endovascular Thrombectomy With or without Intravenous Alteplase in Acute Stroke (DIRECT-MT) showed that endovascular thrombectomy alone was noninferior to thrombectomy after IVT.¹³ Similar effect directions were seen in the SKIP trial,¹⁴ although this study was underpowered and, as such, was unable to demonstrate significance for noninferiority. The aim of the Direct Endovascular Thrombectomy vs Combined IVT and Endovascular Thrombectomy for Patients With Acute Large Vessel Occlusion in the Anterior Circulation (DEVT) trial was to test the hypothesis that endovascular thrombectomy alone was noninferior to combined IVT and endovascular thrombectomy in patients with proximal anterior circulation occlusions treated within 4.5 hours of onset.

This trial was a multicenter, randomized, open-label, clinical trial with blinded central evaluation of outcomes in patients with stroke. The trial protocol was approved by medical ethics committee of the Second Affiliated Hospital of the Army Medical University and all participating centers. Written informed consent was obtained from all enrolled patients or their legal representatives before randomization. The trial protocol is available in Supplement 2, the statistical analysis plan, in Supplement 3.

The trial was monitored by an independent data and safety monitoring board. An independent clinical events committee validated adverse events, procedural-related complications, and serious adverse events. All images were assessed in a blinded manner by a core laboratory. The methods of this trial have been published previously.¹⁵ eFigure 1 in Supplement 4 shows planned trial assessments and interventions.

The study was conducted at 33 stroke centers in China. To qualify for participation, each center had to perform more than 50 mechanical thrombectomies annually and each neurointerventionist, at least 10 thrombectomies per year. To ensure the quality of the trial, training of study protocol and endovascular treatment technique was held every 6 months in Chongqing (eMethods 4 in Supplement 4).

Quiz Ref IDStudy candidates were 18 years or older with acute ischemic stroke, eligible for IV alteplase treatment within 4.5 hours of onset, and had occlusion of the intracranial internal carotid artery or the first segment of the middle cerebral artery confirmed by computed tomographic (CT) angiography or magnetic resonance (MR) angiography. Time of stroke onset was defined as when the patient was last known to be well. Randomization was performed no later than 4 hours 15 minutes from onset (Figure 1). The main exclusion criteria were imaging evidence of intracranial hemorrhage and premorbidity with a modified Rankin Scale score of 2 or more (mRS; range, 0 [no symptoms] to 6 [death]). Additional detailed study criteria are provided in eMethods 1 in Supplement 4. Central blinded readers assigned a collateral score using the 5-point American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral flow grading scale (range, 0 [no collaterals visible] to 4 [complete or rapid collaterals to entire ischemic territory]).

Patients were randomized in a 1:1 ratio to either the endovascular thrombectomy alone group or combined IV thrombolysis and endovascular thrombectomy group. The randomization procedure was web-based, and competitive recruitment was applied in this trial. Randomization allocations were created by an independent statistician with the use of SAS version 9.3 (SAS Institute Inc) to keep the study group blind. Four-block randomization was used. Personnel conducting clinical examinations were qualified assessors who had not participated in the study procedures.

Patients in both groups received rapid endovascular treatment. In the endovascular thrombectomy alone group, patients underwent endovascular treatment only, which included thrombectomy with stent retrievers, thromboaspiration, intraarterial thrombolysis, balloon angioplasty, stenting, or a combination of these approaches at the discretion of the treatment team.

Patients in the combined treatment group underwent the endovascular procedure after receiving a standard dose of IV alteplase (0.9 mg/kg of body weight; 10% administered as a bolus followed by 1-hour infusion of the remaining dose). Endovascular treatment was initiated as soon as possible without waiting for clinical response from IV alteplase. The full alteplase dose was infused even if successful reperfusion had already been established.

Quiz Ref IDThe primary outcome was the proportion of patients achieving functional independence (mRS score, 0-2) at 90 days (+/− 14 days), with central evaluation by 2 blinded independent mRS-certified neurologists based on video or voice recordings taken at the outpatient clinic, during a telephone or video call, or by the patient’s family. If video or voice recordings were unavailable, the outcomes were determined in person by local investigators blinded to the treatment assignments. Disagreements were resolved through consensus (eMethods 3 in Supplement 4).

Secondary outcomes included the distribution of 90-day mRS scores and the rates of excellent functional outcome (mRS score, 0-1), successful reperfusion on postprocedural angiography ( grade 2b-3 on the expanded Thrombolysis in Cerebral Infarction [eTICI] scale , indicating reperfusion of ≥50% of the affected territory),¹⁶ vessel reperfusion on CT or MR angiography within 48 hours after treatment (successful recanalization was defined by a core laboratory–adjudicated modified Arterial Occlusive Lesion score of 2 or 3 on CT or MR angiography, indicating partial or complete recanalization of the occluded artery), the change of the National Institutes of Health Stroke Scale (NIHSS) score (range, 0 to 42, with higher values indicating more severe deficit) from baseline to 24 hours and 5 to 7 days (or discharge if earlier), and score of European Quality of Life 5-Dimension 5-level scale (EQ-5D-5L; range, −0.39 to 1, higher scores indicate a better quality of life) at 90 days. The NIHSS assessment was based on central evaluation through video recording or, if recording was unavailable, by blinded local investigators. A post hoc analysis evaluated the rates of successful reperfusion before endovascular treatment (defined as an eTICI score of 2b, 2c, or 3 on the initial intracranial angiogram).

Adverse events, including incidence of symptomatic intracranial hemorrhage within 48 hours, 90-day mortality, procedure-associated complications, and serious adverse events, were adjudicated by an independent clinical events committee unaware of treatment assignment. Assessment of intracranial hemorrhage was based on the Heidelberg classification.¹⁷ A post hoc analysis investigated the rates of asymptomatic and symptomatic intracranial hemorrhage using the European Cooperative Acute Stroke Study III (ECASS III), ECASS II, the Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS-MOST), and the National Institute of Neurological Disorders and Stroke (NINDS) definitions.

The primary hypothesis was that the rate of 90-day functional independence with endovascular treatment alone would be noninferior to IV alteplase plus endovascular treatment, the primary aim of the statistical analysis. Sample size calculation was made assuming that 43% of patients in both groups would achieve functional independence at the 90-day follow-up according to previous studies.^18-20 Among the recent high-quality randomized clinical trials, the endovascular group in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN)⁶ trial had the lowest proportion (about 33%) of 90-day functional independence. We assumed that the proportion of patients achieving 90-day functional independence of the endovascular thrombectomy alone group could not be lower than 33%. Therefore, the noninferiority margin was set at −10.0% as the clinically relevant limit for the outside bound of the CI.

A sample size of 918 patients (459 patients per group) would provide 80% statistical power to show noninferiority of endovascular thrombectomy alone group compared with combined treatment group including a 5-interim group-sequential analysis plan, using a 1-sided significance level of .025 and a noninferiority margin of 10% of the functional independence proportion in the combined treatment group. To adjust for a 5% attrition rate, the total sample size increased to 970. The evaluable sample size was 194 at each interim analysis (97 patients in each group). The termination rule for efficacy was defined by using the Pocock analog boundaries on the binary outcome of functional independence.²¹

The primary outcome was analyzed using a noninferiority test for the difference of 2 proportions. The adjusted odds ratio was estimated using a logistic regression model by taking the following variables into account: age, baseline NIHSS score, baseline Alberta Stroke Program Early Computed Tomography Score (ASPECTS), onset to randomization time, and occlusion site. Secondary outcomes were analyzed using a logistic, ordinal logistic, or linear regression model as appropriate. The Kaplan-Meier method was used to assess the mortality. The log-rank test was applied to compare the 2 treatment groups. Moreover, the death data of each treatment group were reported as 90-day binary deaths. The post hoc hierarchical modeling and sensitivity analyses were performed to assess site effects.

The missing values of baseline variables were imputed with multiple imputation. Subgroup analyses were conducted for the primary effect variable, and the Wald χ² test was used to test the interaction. All enrolled patients were analyzed according to their randomization group. Patients who actually received the assigned treatment and did not have major protocol violations were included in the per-protocol analysis. The rates of successful reperfusion before endovascular treatment was analyzed post hoc. All statistical tests were 2-sided with a significance level at .05 unless otherwise noted. Because of the potential for type I error due to multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory. Statistical analyses were performed using SAS version 9.4. Figures were drawn using Excel software 2019 (Microsoft).

The first interim analysis was performed as planned after 194 patients (20% of the maximum sample size) had completed their 90-day follow-up on May 12, 2020. The proportion of patients achieving functional independence for the endovascular thrombectomy alone group (54.64%) exceeded that of the combined treatment group (47.42%) by 7.2% (1-sided 97.5% CI, −6.8% to ∞). The noninferiority test demonstrated that endovascular thrombectomy alone was noninferior to combined treatment (z = 2.4042, P for noninferiority = .008). Because this crossed the prespecified efficacy boundary (z = 2.35826, P for noninferiority = .009) that was prespecified for early termination, the steering committee accepted the recommendation from the data and safety monitoring board of concluding the trial on May 14, 2020 (eMethods 2 and eFigure 2 in Supplement 4).

From May 20, 2018, to May 2, 2020, a total of 509 patients across 33 stroke centers in China were screened. Among them, 235 qualified and were randomly enrolled in the trial. One patient enrolled into the endovascular thrombectomy alone group could not be included in the analysis because the legal representative withdrew consent immediately after randomization. The median age of the 234 patients was 70 years (interquartile range [IQR], 60-78 years); 132 patients (56.4%) were men. Of 234 patients, 116 were randomized to the endovascular thrombectomy alone group and 118 to combined treatment group. No crossovers occurred, and no one was lost to the 90-day follow-up. Baseline characteristics were similar in both groups (Table 1; eTable 1 in Supplement 4). The distribution of participating centers is illustrated on the map of China (eFigure 3), another map shows the number of patients recruited at each center (eFigure 4), and the third map shows the enrollment and follow-up of patients (eFigure 5 in Supplement 4).

Among the patients who survived and were followed up to 90 days, video materials were acquired from 186 patients and voice recordings from 6 patients. One patient’s assessment was determined by local investigators blinded to the treatment assignments because video or voice recording technology was unavailable. Sixty-three patients (54.3%) in the endovascular thrombectomy alone group achieved functional independence vs 55 patients (46.6%) in the combined treatment group (difference, 7.7%; 1-sided 97.5% CI, −5.1% to ∞; Table 2). The lower boundary of the CI of −5.1% and was greater than the prespecified noninferiority margin of −10%. In addition, the noninferiority test demonstrated that the endovascular thrombectomy alone was noninferior to the combined IV thrombolysis and endovascular thrombectomy group (z = 2.7157, P for noninferiority = .003) since it crossed the efficacy boundary (z = 2.35826, Pfor noninferiority = .009) that was prespecified for early termination. The per-protocol analysis indicated that results were consistent with the primary analysis (eTable 3 and eTable 4 in Supplement 4). Prespecified subgroup analyses are shown in eFigures 6 and 7 (Supplement 4), and the post hoc hierarchical modeling and sensitivity analyses indicate that the site effects were not significant (eTable 5 in Supplement 4).

The median of 90-day mRS scores for endovascular thrombectomy alone was 2 (IQR, 1-4) and for the combined treatment, 3 (IQR, 1-4). The unadjusted difference was 0 (95% CI, −1 to 0). The adjusted common odds ratio was 1.13 (95% CI, 0.71-1.79). There were no significant differences in other secondary efficacy outcomes (Table 2). In a post hoc analysis, successful reperfusion before endovascular treatment assessed on initial angiography was observed for 2 patients in the endovascular thrombectomy alone and 3 in the combined IV thrombolysis and endovascular thrombectomy group (1.7% vs 2.6%). Further details are provided in the Table 2 and Figure 2.

The proportion of patients who died within 90 days was 17.2% among those in the endovascular thrombectomy alone group vs 17.8% among those in the combined treatment group (difference, −0.5%; 95% CI, −10.3% to 9.2%). According to the Heidelberg bleeding classification, the symptomatic intracerebral hemorrhage in the 2 groups was 6.1% vs 6.8% (difference, −0.8%; 95% CI, −7.1% to 5.6%), respectively. Furthermore, in post hoc analyses, based on other definitions, the rate of symptomatic intracranial hemorrhage did not differ significantly between the 2 groups (Table 3). In a post hoc analysis, asymptomatic intracerebral hemorrhage occurred in 15.7% vs 25.6% (difference, −10.0%; 95% CI, −20.3% to 0.3%), respectively. Clot migration occurred in 20 patients (17.7%) of 113 in the endovascular thrombectomy alone group vs 28 of 117 (23.9%) in combined treatment group. There were no significant differences in proportions of procedures associated complications or serious adverse events (Table 3). Kaplan-Meier estimates of the probability of death are provided in eFigure 5 in Supplement 4.

Quiz Ref IDIn this randomized clinical trial involving patients with ischemic stroke who presented within 4.5 hours from onset, had proximal anterior circulation occlusion, and were eligible for intravenous alteplase, endovascular thrombectomy alone, compared with combined IV alteplase and endovascular thrombectomy, met the prespecified statistical threshold for noninferiority for achieving 90-day functional independence. Different from the prior trials, this present trial excluded participants with middle cerebral artery M2 segment occlusion and used a full dose of alteplase.

The rate of 90-day functional independence with combined IV thrombolysis and endovascular thrombectomy in this trial was 46.6%, which is similar to the 46.4% observed in the Highly Effective Reperfusion Using Multiple Endovascular Devices (HERMES) meta-analysis.²³ However, the overall frequency of 90-day functional independence in this study was higher (50.4%) than that observed in the Direct Intraarterial Thrombectomy in Order to Revascularize Acute Ischemic Stroke Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals (DIRECT-MT) trial (36.6%).¹³ The potential explanations for these differences include that the intracranial internal carotid artery occlusions occurred more frequently in the DIRECT-MT trial (35%) than in either this trial (15%) or the HERMES trial (21%), whereas the patients with favorable collateral status (defined as grade 2-3 on the ASITN/SIR scale) had fewer in the DIRECT-MT trial (24%) than patients in either this trial (68.4%) or the HERMES trial (85%).^13,24

More patients participating in both groups in this study achieved 90-day functional independence than patients in the DIRECT-MT trial. This provided an important supplement of noninferiority despite the early termination and consequent smaller sample size in the current study. That middle cerebral artery M2 occlusions were excluded from this trial, which are known to have a better response to IVT,²⁵ may have contributed to the differences across the 2 trials. Indeed, higher rates of successful reperfusion prior to thrombectomy were seen with combined IVT and endovascular thrombectomy in the DIRECT-MT trial but not in this trial. Some other factors that may have theoretically favored endovascular thrombectomy alone in this trial include the lower proportions of both clot migration (17.7% vs 23.9%) and asymptomatic intracranial hemorrhage (15.7% vs 25.6%) over combined IV thrombolysis and endovascular thrombectomy because both these factors appear to be associated with worse functional outcomes after endovascular stroke treatment.^10,26

A cohort study that used data from 2017 to 2019 and included 1526 patients showed that patients with asymptomatic intracranial hemorrhage have a worse functional outcome at 3 months than do those without it after endovascular treatment for acute ischemic stroke.²⁷ This observation may be attributed to the cytotoxic effect of the contrast agent and the mass effect caused by the destruction of the blood-brain barrier, compressing the adjacent healthy parenchyma with subsequent impairment of the functional recovery.²⁷

In comparing the results of this trial with those of the SKIP and DIRECT-MT trials, the rate of intracranial hemorrhage was similarly higher among patients in the combined treatment group this trial and in the SKIP trial (34% vs 50%, P = .02), even though patients in the SKIP trial received a lower dose of alteplase (0.6 mg/km) than did the patients in this study. Conversely, patients in the DIRECT-MT trial had similar rates of asymptomatic intracranial hemorrhage between treatment groups (33.3% vs 36.2%). This could be partially because in the DIRECT-MT trial’s combined IV thrombolysis and endovascular thrombectomy group, 30 patients (9.1%) did not receive either the full dose (n = 20) or any dose (n = 10) of alteplase, and 37 patients (11.2%) did not undergo thrombectomy. Moreover, eTable 6 lists other important factors—including trial design, inclusion criteria, primary end point—used in the DIRECT-MT and SKIP trials alongside those used in this trial (Supplement 4).

Quiz Ref IDThis study has several limitations. First, the noninferiority margin used in this trial was not selected using the minimal clinically important difference or fixed margin methods. The noninferior margin of 10% is broad, reaching no consensus in the clinical community, which may lead to concerns about the robustness of study results. Second, the early termination of the trial does create potential for overestimation of the effect size. However, it followed a highly conservative prespecified statistical stopping rule.

Third, the median time from hospital arrival to the start of IV alteplase of 61 minutes (IQR, 49-81 minutes) in this trial was similar to the 59 minutes (IQR, 45-78 minutes) in the DIRECT-MT trial but was longer than what has been reported in the other recent thrombectomy trials.^2-7 The main reason for these differences is that alteplase could not be administrated immediately after standard clinical and neuroimaging screening as they were in the previous trials because additional time was required for study screening, obtaining patient consent, and randomization in this and the DIRECT-MT trials. This explanation is supported by the findings of a recent multinational neuroprotection randomized trial. Despite having one of most efficient workflows for IVT and thrombectomy reported to date, the median time from hospital arrival to the initiation of the experimental drug in the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE NA-1) trial was 64 minutes (IQR, 48-86 minutes).²⁸ This highlights that achieving hospital arrival to initiate IV alteplase times as short as those in the previous trials with the absence of waiver of informed consent is unlikely.

In China, informed consent is required even before the standard administration of IVT because patients or their families often have to pay in advance before receiving alteplase. Relatedly, the median door-to-needle time was 62 minutes (IQR, 40-94 minutes) among 24 542 patients treated with IV alteplase in a recent analysis of the Chinese Stroke Center Alliance Program,²⁹ a finding that is fully consistent with the times seen in this and the DIRECT-MT trials. Nevertheless, given the relatively long times from hospital arrival to alteplase initiation in this trial, it remains possible that IV alteplase might still be beneficial in the presence of faster delivery times. Moreover, as bridging with tenecteplase vs alteplase was associated with higher rates of prethrombectomy reperfusion and better 90-day functional outcomes in the Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke (EXTEND-IA-TNK) trial,³⁰ it is possible that tenecteplase bridging might yield better results than thrombectomy alone.

Fourth, because this, the DIRECT-MT, and the SKIP trials only included Asian patients, the generalizability of their findings is somewhat limited due to the significantly higher incidence of intracranial atherosclerotic disease in Asian than in Western populations.

Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with IV alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold.

Corresponding Authors: Qingwu Yang, MD, PhD, Department of Neurology, Xinqiao Hospital and The Second Affiliated Hospital, Army Medical University (Third Military Medical University), No. 183 Xinqiao Main St, Shapingba District, Chongqing 400037, China (yangqwmlys@163.com); Raul G. Nogueira, MD, Department of Neurology, Marcus Stroke & Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine, 80 Jesse Hill Jr Dr SE, Room 8D108A, Atlanta, GA 30303 (raul.g.nogueira@emory.edu).

Accepted for Publication: December 3, 2020.

Author Contributions: Drs Q. Yang and Nogueira 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. Drs Zi and Z. Qiu are co–first authors. Drs Q. Yang and Nogueira are co–corresponding authors.

Concept and design: Zi, Z. Qiu, F. Li, Sang, D. Wu, W. Liu, Shuai, Nogueira, Q. Yang.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Zi, Z. Qiu, F. Li, Sang, D. Wu, W. Luo, W. Liu, Z. Zhou, Bai, Q. Yang.

Statistical analysis: W. Luo, Shuai Liu, X. Huang.

 Obtained funding: Zi, Z. Qiu, F. Li, Sang, Q. Yang.

Administrative, technical, or material support: Zi, Z. Qiu, F. Li, Sang, D. Wu, W. Luo, Shuai Liu, Yuan, Song, Z. Shi, W. Huang, Min Zhang, W. Liu, Z. Guo, T. Qiu, Q. Shi, P. Zhou, L. Wang, Fu, Shudong Liu, S. Yang, S. Zhang, Z. Zhou, X. Huang, Y. Wang, J. Luo, Bai, Min Zhang, Y. Wu, Zeng, Wan, C. Wen, H. Wen, Ling, Z. Chen, Peng, Ai, F. Guo, H. Li, J. Guo, Guan, Zhiyi Wang, Y. Liu, Pu, Zhen Wang, H. Liu, L. Chen, J. Huang, G. Yang, Gong, Shuai, Q. Yang.

Supervision: Zi, Z. Qiu, F. Li, Sang, D. Wu, Shuai, Nogueira, Q. Yang.

Conflict of Interest Disclosures: Dr Nogueira reported receiving consulting fees for advisory roles with Anaconda, Biogen, Cerenovus, Genentech, Imperative Care, Medtronic, Phenox, Prolong Pharmaceuticals, and Stryker Neurovascular and having stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, Vesalio, Viz-AI, and Perfuze. No other disclosures were reported.

Funding/Support: The study was supported by grants 81525008, 81901236, 81801157 from the National Natural Science Foundation of China, 2019ZX001 from the Chongqing Major Disease Prevention and Control Technology Research Project, 2019XLC2008 2019XLC3016 from the Clinical Medical Research Talent Training Program of Army Medical University, and 2018JSLC0017 from the Major Clinical Innovation Technology Project of the Second Affiliated Hospital of Army Medical University.

Role of the Funder/Sponsor: The sponsors 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 DEVT Trial members are listed in Supplement 1.

Data Sharing Statement: See Supplement 5.