Trial Oversight

The DEFUSE 3 trial was funded by the National Institutes of Health (NIH) through StrokeNet, a network of more than 300 U.S. hospitals. The trial was approved by the StrokeNet central institutional review board and the Food and Drug Administration (FDA) for an investigational device exemption (IDE G150028). The trial was designed by the first three authors and the last author. A steering committee provided guidance during monthly telephone conferences. Data management, oversight of site monitoring, and interim statistical analysis were performed by the NIH StrokeNet National Data Management Center at the Medical University of South Carolina. The trial was monitored by an NIH-appointed independent data and safety monitoring board. All the authors attest to the trial integrity and the completeness and accuracy of the reported data and adverse events. The first draft of the manuscript was written by the first author.

Patients and Participating Centers

The trial was performed at 38 centers in the United States. Neurointerventionalists were preapproved to participate on the basis of training and experience. (For approval requirements, see the Supplementary Appendix, available with the full text of this article at NEJM.org.) Enrolled patients or their surrogates provided written informed consent. Patients were enrolled if they met clinical and imaging eligibility requirements and could undergo initiation of endovascular therapy between 6 and 16 hours after the time that they had last been known to be well, including if they had awakened from sleep with symptoms of a stroke. Perfusion imaging had to be performed at the trial-site hospital in which endovascular therapy was planned.

Figure 1. Figure 1. Example of Perfusion Imaging Showing a Disproportionately Large Region of Hypoperfusion as Compared with the Size of Early Infarction. A 59-year-old man presented with a “wake-up stroke” (having awakened with symptoms of stroke) 13 hours after he was last known to be well. The score on the National Institutes of Health Stroke Scale (NIHSS; range, 0 to 42, with higher scores indicating a greater deficit) was 23. A baseline CT perfusion scan that was obtained with the use of RAPID software shows a region of severely reduced cerebral blood flow (<30% of that in normal tissue), which represents the early infarct (ischemic core), of 23 ml (pink) and a region of perfusion delay of more than 6 seconds, which represents hypoperfused tissue, of 128 ml (green).

Patients were eligible if they had an initial infarct volume (ischemic core) of less than 70 ml, a ratio of volume of ischemic tissue to initial infarct volume of 1.8 or more, and an absolute volume of potentially reversible ischemia (penumbra) of 15 ml or more. Estimates of the volume of the ischemic core and penumbral regions from CT perfusion or MRI diffusion and perfusion scans were calculated with the use of RAPID software (iSchemaView), an automated image postprocessing system. The size of the penumbra was estimated from the volume of tissue for which there was delayed arrival of an injected tracer agent (time to maximum of the residue function [Tmax]) exceeding 6 seconds.8 (An example is given in Figure 1.) Patients were required to have an occlusion of the cervical or intracranial internal carotid artery or the proximal middle cerebral artery on CT angiography (CTA) or magnetic resonance angiography (MRA). Detailed inclusion and exclusion criteria for the trial are provided in the Supplementary Appendix.

Trial Design and Randomization

The DEFUSE 3 trial was a randomized, open-label trial, with blinded outcome assessment, that compared endovascular therapy plus standard medical therapy with standard medical therapy alone in patients with acute ischemic stroke. The trial design has been published,9 and the protocol and statistical analysis plan are available at NEJM.org. Patients who met all eligibility criteria were randomly assigned in a 1:1 ratio to endovascular therapy plus medical therapy or medical therapy alone with the use of a Web-based dynamic randomization system (Table S1 in the Supplementary Appendix). Randomization was stratified according to age, core infarct volume, time from symptom onset to enrollment, baseline score on the National Institutes of Health Stroke Scale (NIHSS; range, 0 to 42, with higher scores indicating a greater deficit), and trial site.

Endovascular Thrombectomy and Medical Therapy

Thrombectomy was performed with any FDA-approved thrombectomy device, at the discretion of the neurointerventionalist. For patients with stenosis or occlusion of the cervical internal carotid artery due to atherosclerosis, carotid angioplasty with or without stenting was permitted as part of the intervention. The protocol required that femoral puncture occur within 90 minutes after the end of qualifying imaging. The use of general anesthesia was discouraged, and intraarterial tissue plasminogen activator (t-PA) was not allowed (intravenous t-PA was allowed if begun within 4.5 hours after symptom onset). The protocol specified that standard medical therapy, based on current American Heart Association guidelines, would be administered to patients in both groups of the trial.10

Outcomes

The primary efficacy outcome was the ordinal score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at day 90; the score was assessed in person, or by telephone if an in-person visit was not feasible, by a certified rater who was not aware of the trial-group assignments. The secondary efficacy outcome was functional independence (defined as a score on the modified Rankin scale of 0 to 2) at day 90. The primary safety outcomes were death within 90 days and the occurrence of symptomatic intracranial hemorrhage within 36 hours, defined as an increase of at least 4 points in the NIHSS score that was associated with brain hemorrhage on imaging within 36 hours after symptom onset.

Imaging outcomes were infarct volume measured at 24 hours (with a window of ±6 hours) after randomization; lesion growth (increase in volume of the infarct) between baseline imaging and 24 hours; reperfusion, defined as a greater than 90% reduction in the region of perfusion delay (Tmax of >6 seconds) between baseline and 24 hours; and complete recanalization of the primary arterial occlusive lesion at 24 hours on CTA or MRA. The technical efficacy of the endovascular procedure in establishing reperfusion was defined in the endovascular-therapy group by a modified Thrombolysis in Cerebral Infarction (TICI) score of 2b (50 to 99% reperfusion) or 3 (complete reperfusion).11

Clinical and Radiologic Assessment

Clinical assessments were performed at baseline, 24 hours after randomization, at hospital discharge, and at 30 and 90 days; assessments included the score on the modified Rankin scale and the NIHSS score, both determined by certified assessors who were unaware of the trial-group assignments at 30 and 90 days. Baseline and follow-up MRI and CT images were assessed independent of each other at the core imaging laboratory at Stanford University by assessors who were unaware of the trial-group assignments. Angiographic studies from the endovascular procedure were assessed for reperfusion by two independent raters, who were unaware of any other imaging and clinical data, and a consensus was reached in cases of disagreement.

Statistical Analysis

We planned for this trial to use an adaptive enrichment design.12 The maximal sample size was calculated to be 476, with two planned interim analyses after 200 and 350 patients had data on 90-day outcomes that could be evaluated. The plan was modified in June 2017 to accommodate the results of the DAWN trial, which involved patients and treatments similar to those in our trial and which showed clinical benefit of endovascular thrombectomy over medical therapy when treatment was initiated 6 to 24 hours after the onset of stroke symptoms. Enrollment in the DEFUSE 3 trial was placed on hold, and an early interim analysis, including subgroup analysis of the primary and secondary efficacy outcomes in patients who would have been eligible for the DAWN trial, was requested by the sponsor (the NIH).

As a result of that interim analysis, the trial was halted because the prespecified efficacy boundary (P<0.0025) had been exceeded. The statistical analysis plan specified one-sided hypothesis testing for the Wilcoxon rank-sum test and a P value of less than 0.025 as a measure of statistical significance, but we report two-sided results and use a P value of less than 0.05 as a measure of statistical significance. Adjusted treatment effects and P values for the primary efficacy outcome were calculated with the use of ordinal regression on the full modified Rankin scale and stratified Cochran–Mantel–Haenszel tests, with the randomization stratification variables split at their medians as the covariates. For patients lost to follow-up at 90 days, the missing 90-day score on the modified Rankin scale was imputed from the 30-day score by the last-observation-carried-forward method.