Trial Design

The DAWN trial was a multicenter, prospective, randomized, open-label trial with a Bayesian adaptive–enrichment design and with blinded assessment of end points.12 The trial protocol was approved by the institutional review board at each participating site. Enrolled patients or their surrogates provided written informed consent. The trial was designed and conducted by a steering committee, which was composed of independent academic investigators and statisticians, in collaboration with the sponsor, Stryker Neurovascular, which provided funding and the thrombectomy devices for the trial and performed regulatory monitoring at each site and central database maintenance. The first drafts of the manuscript were written by the first and last authors, with input from all the authors and with no writing assistance from the sponsor. The authors had unrestricted access to the data. The data analysis was performed by a data-management staff from Stryker Neurovascular, with oversight from independent statisticians. All the authors vouch for the completeness and accuracy of the reported data and the fidelity of the trial to the protocol. Decisions related to safety, adaptive–enrichment techniques, and trial discontinuation were made at the recommendation of an independent data and safety monitoring board.

Information on the inclusion and exclusion criteria, interventions, and assessments has been published previously.12 The trial protocol and statistical analysis plan are available at NEJM.org.

Patients

Patients were eligible for inclusion in the trial if they had evidence of occlusion of the intracranial internal carotid artery, the first segment of the middle cerebral artery, or both on computed tomographic (CT) angiography or magnetic resonance angiography. In addition, patients had to have a mismatch between the severity of the clinical deficit and the infarct volume, which was defined according to the following criteria: those in Group A were 80 years of age or older, had a score of 10 or higher on the National Institutes of Health Stroke Scale (NIHSS; scores range from 0 to 42, with higher scores indicating a more severe deficit), and had an infarct volume of less than 21 ml; those in Group B were younger than 80 years of age, had a score of 10 or higher on the NIHSS, and had an infarct volume of less than 31 ml; and those in Group C were younger than 80 years of age, had a score of 20 or higher on the NIHSS, and had an infarct volume of 31 to less than 51 ml. Infarct volume was assessed with the use of diffusion-weighted magnetic resonance imaging (MRI) or perfusion CT and was measured with the use of automated software (RAPID, iSchemaView).

Other inclusion criteria were an age of 18 years or older, an interval between the time that the patient was last known to be well and randomization of 6 to 24 hours, a prestroke score of 0 or 1 on the modified Rankin scale (which ranges from 0 to 6, with a score of 0 indicating no disability and higher scores indicating more severe disability), no evidence of intracranial hemorrhage on CT or MRI, and no evidence of an infarct involving more than one third of the territory of the middle cerebral artery on CT or MRI at baseline. Patients either did not meet the usual criteria for treatment with intravenous alteplase because of a late presentation or received treatment with intravenous alteplase and had persistent occlusion of the vessel at the time that they were eligible for enrollment in the trial.

Treatment

Patients were randomly assigned, in a 1:1 ratio, to thrombectomy plus standard medical care (the thrombectomy group) or to standard medical care alone (the control group). Randomization was performed with the use of a central, Web-based procedure, with block minimization processes to balance the two treatment groups, and was stratified according to mismatch criteria (Group A, Group B, or Group C), the interval between the time that the patient was last known to be well and randomization (6 to 12 hours or >12 to 24 hours), and the occlusion site (intracranial internal carotid artery or the first segment of the middle cerebral artery).

The trial was conducted at 26 centers in the United States, Canada, Europe, and Australia; at least 40 mechanical thrombectomy procedures had been performed at each center annually. Enrolled patients were admitted to stroke units or intensive care units. Patients who had not received intravenous alteplase could receive therapy with antiplatelet agents, which could be started within 24 hours after randomization. Standard medical care was provided in accordance with local guidelines (see Section S6 in the Supplementary Appendix).12 Thrombectomy was performed with the use of the Trevo device (Stryker Neurovascular), a retrievable self-expanding stent that is used to remove occlusive thrombi and restore blood flow. Rescue reperfusion therapy with other devices or pharmacologic agents was not permitted. Concomitant stenting of the cervical internal carotid artery at the time of thrombectomy was not permitted, but carotid angioplasty was permitted if necessary to allow for intracranial access for the catheter to deploy the retriever device.

End Points

For the coprimary end points, scores on the modified Rankin scale were obtained through in-person, formal, structured interviews with patients and caregivers that were performed by local certified assessors13,14 who were unaware of the treatment assignments.15 For the 43 patients for whom in-person assessment was not possible, telephone interviews with patients, caregivers, or both were performed.

The first primary end point was the mean score for disability on the utility-weighted modified Rankin scale at 90 days. To determine the utility-weighted score, the score on the modified Rankin scale is weighted according to average values calculated from patient-centered and clinician-centered studies.16-18 The following weights are assigned to scores 0 through 6 on the modified Rankin scale: 10.0, 9.1, 7.6, 6.5, 3.3, 0, and 0, respectively. The utility-weighted modified Rankin scale ranges from 0 (death) to 10 (no symptoms or disability).

The second primary end point was the rate of functional independence (defined as a score of 0, 1, or 2 on the modified Rankin scale) at 90 days. This end point was changed from a secondary end point to a coprimary end point at the request of the Food and Drug Administration at 30 months after the start of the trial, when the trial was still blinded.

Prespecified secondary end points were an early therapeutic response (defined as a decrease in the NIHSS score of ≥10 from baseline or an NIHSS score of 0 or 1 on day 5, 6, or 7 of hospitalization or at discharge if it occurred before day 5), death from any cause at 90 days, centrally adjudicated infarct volume and change from baseline in the infarct volume at 24 hours, and evidence of recanalization of the occluded vessel on CT angiography or magnetic resonance angiography at 24 hours (see Section S3 in the Supplementary Appendix). In the thrombectomy group, a secondary end point was centrally adjudicated successful recanalization (on the basis of findings on postprocedural conventional angiography), which was defined as a grade of 2b or 3 on the modified Thrombolysis in Cerebral Infarction scale (which ranges from 0 to 3, with a grade of 2b or 3 indicating reperfusion of >50% of the affected territory). A prespecified subgroup analysis for heterogeneity of treatment effect was performed, with subgroups defined according to mismatch criteria (Group A, Group B, or Group C), the interval between the time that the patient was last known to be well and randomization (6 to 12 hours or >12 to 24 hours), occlusion site (intracranial internal carotid artery or the first segment of the middle cerebral artery), sex, age (<80 years or ≥80 years), baseline NIHSS score (10 to 17 or >17), type of stroke onset (on awakening, unwitnessed stroke, or witnessed stroke), and time from the first observation of symptoms to randomization (0 to 6 hours or >6 hours).

The main safety end point was stroke-related death at 90 days. Other safety end points included neurologic deterioration (defined as an increase in the NIHSS score of ≥4 points within 5 days after stroke that was not attributed to intracranial hemorrhage or malignant cerebral edema) and symptomatic intracranial hemorrhage (defined according to European Cooperative Acute Stroke Study III criteria as the presence of extravascular blood in the cranium that was associated with an increase in the NIHSS score of ≥4 points or death and was judged to be the predominant cause of neurologic deterioration) within 24 hours after randomization.19 Safety end points, procedure-related complications, and serious adverse events were adjudicated by an independent clinical-events committee.

Statistical Analysis

The adaptive trial design allowed for a sample size ranging from 150 to 500 patients. During interim analyses, the decision to stop or continue enrollment was based on a prespecified calculation of the probability that thrombectomy plus standard care would be superior to standard care alone with respect to the first primary end point. The enrichment trial design gave us the flexibility to identify whether the benefit of the trial intervention was restricted to a subgroup of patients with relatively small infarct volumes at baseline. The interim analyses, which included patients with available follow-up data at the time of the analysis, were prespecified to test for the futility, enrichment, and success of the trial.

The first primary analysis, which evaluated the posterior probability that thrombectomy plus standard care would be superior to standard care alone with respect to the mean score for disability on the utility-weighted modified Rankin scale at 90 days, was conducted with the use of a Bayesian statistical model with adjustment for infarct volume at baseline. The threshold for significance was a one-sided posterior probability of superiority of at least 0.986, which was increased from 0.975 to account for the potential for enrichment and different final sample sizes. The second primary analysis, which evaluated the posterior probability that thrombectomy plus standard care would be superior to standard care alone with respect to the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale) at 90 days, was conducted with the use of the same statistical model (with an assumption of normal distribution) and was carried out in a nested hierarchical fashion. The trial had 86% power to detect an adjusted difference between the two treatment groups in the mean score on the utility-weighted modified Rankin scale of 1.0. No additional adjustments for multiplicity were made for analyses of the secondary end points. Bayesian multiple imputations were used for patients who had missing values for the primary analyses. Descriptive statistics were calculated with the use of the last-observation-carried-forward method for patients who had missing values for the subgroup analyses.

Enrollment in the trial was stopped at 31 months, because the results of an interim analysis met the prespecified criterion for trial discontinuation, which was a predictive probability of superiority of thrombectomy of at least 95% for the first primary end point. This was the first prespecified interim analysis that permitted stopping for this reason, and it was based on the enrollment of 200 patients. Because enrichment thresholds had not been crossed, the analysis included the full population of patients enrolled in the trial, regardless of infarct volume. (For details about the statistical analysis, see Section S4 in the Supplementary Appendix.)