Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging

Abstract

Background: Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms.

Methods: We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90.

Results: The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18).

Conclusions: Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .).

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).

Figure 2.. Scores on the Modified Rankin Scale at 90 Days.

Patients in the endovascular-therapy group received endovascular therapy plus standard medical therapy. Patients in the medical-therapy group received standard medical therapy alone. Scores on the modified Rankin scale range from 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability, and 6 death. There was a significant difference favoring the endovascular-therapy group over the medical-therapy group in the overall distribution of scores (unadjusted common odds ratio, 2.77; 95% CI, 1.63 to 4.70; P<0.001).

Figure 3 (facing page).. Subgroup Analyses.

The forest plot shows that the difference in the risk ratio for functional independence (defined as a score on the modified Rankin scale of 0 to 2) at 90 days favored the endovascular-therapy group across all prespecified subgroups. The size of the squares is proportional to the number of patients in the subgroup. Arrows indicate that the limits of the confidence interval are not shown. The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a tool that is used to estimate the volume of infarcted tissue. Scores range from 0 to 10, with lower scores indicating a larger area. Race and ethnic group were reported by the patient or a family member. Patients who were considered to be ineligible for the DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) trial had one or more of the following characteristics: a prestroke score on the modified Rankin scale of 2 (13 patients); a baseline NIHSS score of less than 10 (31 patients); a baseline volume of the ischemic core of 51 ml or more (13 patients); an age of 80 years or older with a baseline volume of the ischemic core of 21 ml or more (14 patients); and an age of less than 80 years, an NIHSS score of less than 20, and a baseline volume of the ischemic core of 31 ml or more (14 patients) (some patients met multiple criteria). All other patients were considered to be eligible for the DAWN trial. A risk ratio was not calculated for a baseline NIHSS score of more than 18 because of zero outcomes in the medical-therapy group.