How Far Can We Go in the Early Management of Acute Ischemic Stroke?
(In anticipation of the International Stroke Conference 2019 – ISC19)
Not so long ago, the benefit of endovascular thrombectomy beyond six hours of ischemic stroke onset was uncertain, particularly among patients with ischemic brain tissue that has not yet undergone infarction. The volume of irreversibly injured ischemic tissue and the volume of brain tissue that is ischemic, but not yet infarcted, could be assessed by computed tomographic perfusion imaging or a combination of diffusion and perfusion magnetic resonance imaging.1,2
Early last year, the DAWN3 and DEFUSE 34 trials’ investigators presented findings at ISC18 that lead to immediate change in the guidelines5 with substantial implications for prevention of functional dependence among stroke survivors.
The DAWN trial was a multicentre, prospective, randomized, open labelled trial conducted at 26 centers in the United States, Canada, Europe and Australia, with at least 40 mechanical thrombectomy procedures performed annually. Patients were enrolled if they were last known to be well within 6 to 24 hours earlier and had occlusion of the intracranial internal carotid artery or proximal middle cerebral artery with a mismatch between the severity of clinical deficit and the infarct volume. The mismatch criteria were defined according to age, stroke severity, occlusion site, time to treatment and type of stroke onset. Primary end points included mean score for disability and functional independence at 90 days.
The mean score on the utility-weight modified Rankin scale and rate of functional independence at 90 days were 5.5 and 49% in the thrombectomy group, compared to 3.4 and 13% in the control group. The rate of symptomatic intracranial haemorrhage and death at 90 days did not differ between the two groups.
The DEFUSE 3 trial was a multicentre, randomized, open labelled trial that included 38 centers in the United States. Patients were enrolled if they were last known to be well within 6 to 16 hours and 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 70ml and ratio of ischemic tissue to infarct volume of 1.8 or more were randomly assigned to thrombectomy plus standard medical therapy or standard medical therapy alone. The primary outcome was the ordinal score on the modified Rankin scale at 90 days.
The 90-days mortality rate was 14% in the endovascular therapy group compared to 26% in the medical therapy group. The absolute difference in functional independence between groups was 28% points, indicating a better 90 day functional outcomes compared to patients who had standard medical therapy alone. This mainly applies to patients who had evidence of salvageable tissue determined on the basis of a formula that incorporates early infarct size and the volume of hypoperfused tissue on perfusion imaging.
The incidence of symptomatic cerebral haemorrhage was not statistically different, yet numerically higher in the endovascular compared to the medical therapy group. Mortality was numerically lower in the endovascular therapy group. In between group differences of 24-hour infarct volume and growth after thrombectomy were not significant. Further, patients treated within six hours after stroke onset had favourable outcomes compared to other trials. This difference could be attributed to the favourable collateral circulation and slower infarct growth in patients recruited in the DEFUSE 3 trial.
Enrollment in the DAWN 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. Similarly, the DEFUSE 3 trial was terminated early for efficacy after 182 patients had undergone randomization, given the interim analysis results exceeded the prespecified efficacy boundary (P<0.0025). Both the DAWN and DEFUSE 3 trials used the same automated perfusion software (RAPID) to measure the volume of early infarct and hypoperfused volume.
Further advancements are anticipated at ISC19, with key questions on benefits beyond those time points and among the broader population of ischemic stroke survivors.
- Albers GW, Goyal M, Jahan R, et al. Ischemic core and hypoperfusion volumes predict infarct size in SWIFT PRIME. Ann Neurol 2016. 79: 76-89.
- Wheeler HM, Mlynash M, Inoue M, et al. Early diffusion-weighted imaging and perfusion-weighted imaging lesion volumes forecast final infarct size in DEFUSE2. Stroke 2013. 44: 681
- Nogueira, Raul G., et al. “Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct.” New England Journal of Medicine 2018. 378:11-21.
- Albers, Gregory W., et al. “Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging.” New England Journal of Medicine 378: 708-718.
- Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018. 39:46-99.