BALTIMORE—Data from five large trials, including the MR CLEAN trial, published in the New England Journal of Medicine have greatly improved understanding of endovascular therapy for acute stroke. They have indicated that the therapy is effective if initiated within six hours of onset and suggested that baseline collateral flow predicts successful reperfusion and response to therapy. Research currently under way could address several questions that remain unanswered, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.
Defining the Treatment Window
The most important of these questions is whether thrombectomy is effective in appropriately selected patients if administered at more than six hours from onset, said Joseph P. Broderick, MD, Professor of Neurology and Rehabilitation Medicine at the University of Cincinnati College of Medicine. “We are going away from chronological measures of infarction to physiological measures of brain ischemia. That is how we are going to try to appropriately select patients.”
The DEFUSE 3 trial is based on the premise that after six hours from onset, many patients with stroke still have salvageable tissue. The investigators are examining whether imaging can identify these patients and whether devices cleared by the FDA can benefit them. Eligible patients have an occlusion of the internal carotid artery or an M1 occlusion and a target mismatch profile. The inclusion criteria are similar to those of other endovascular trials, except that baseline NIH Stroke Scale (NIHSS) score must be 6 or higher. Patients with a contraindication to MRI or CT perfusion are excluded from the trial, as are patients with an Alberta Stroke Program Early CT Score (ASPECTS) of less than 6 on a noncontrast CT.
Patients are randomized to thrombectomy plus standard medical therapy or standard medical therapy alone. Treatment is delivered within 16 hours of stroke onset using any device that has been cleared for thrombectomy by the FDA (eg, the Solitaire device or the Penumbra aspiration system). Intra-arterial t-PA is not allowed in the trial, and the investigators strongly recommend conscious sedation rather than general anesthesia. The trial’s adaptive design will identify, at interim analyses, the group with the best prospect for showing benefit from endovascular treatment, based on baseline core lesion volumes and the times since stroke onset. The investigators plan to enroll a maximum sample size of 476 and to perform interim analyses when enrollment reaches 200 patients and 340 patients.
The DAWN trial will test endovascular therapy when administered at six to 24 hours after onset. Its primary objective is to evaluate the hypothesis that Trevo thrombectomy plus medical management provides superior clinical outcome at 90 days, compared with medical management alone, in appropriately selected patients. The primary end point is modified Rankin scale (mRS) score at 90 days. Participants will be randomized in a 1:1 ratio at as many as 50 sites. Unlike in DEFUSE 3, the DAWN investigators will be examining patients with a clinical–imaging mismatch. “It will end up having a different but overlapping population of patients, as compared to DEFUSE 3,” said Dr. Broderick. “My prediction is that patients, no matter which arm they are randomized to, will have better outcomes in this particular trial because their core volumes will be smaller than in DEFUSE III.”
In addition, the POSITIVE trial will examine whether patients with acute ischemic stroke who are refractory to or ineligible for t-PA have less stroke-related disability and better functional outcomes if they receive thrombectomy, compared with best medical therapy, at six to 12 hours after onset. Patients without an associated large penumbra, as defined by physiologic imaging, will be excluded from the trial. Disability will be assessed by mRS.
Finally, the MR CLEAN LATE trial will compare endovascular therapy and best medical therapy with endovascular therapy alone in patients with acute stroke and moderate to good collateral flow. Treatment will be administered at six to 12 hours after stroke onset. The trial has not begun, but will enroll 500 patients, including some with wake-up stoke. The investigators will examine whether the two groups’ outcomes differ by 10%.
Triaging Patients With Suspected Large Artery Occlusions
Another unanswered question is how emergency physicians can best triage patients with acute stroke who are most likely to have large artery occlusions. Mobile stroke units, for example, can identify large right occlusion on a baseline thin-slice CT or on CT angiography. Or emergency medical responders can use brief prehospital scales (eg, the Cincinnati Stroke Triage Assessment Tool), which take less time to administer than CT. Identifying the best method of triage could greatly reduce time to reperfusion, said Dr. Broderick.
The RACECAT trial, which has not yet been initiated, may provide evidence to address this question. Emergency responders in Catalonia, Spain, will use the Rapid Arterial Occlusion Evaluation (RACE) scale, which has more items than some of the other triage scales, to identify patients with acute stroke and suspected large vessel occlusion. After the responders contact the stroke neurologists on call using a telestroke system, eligible participants will be randomized according to a predetermined sequence to either transfer to the closest local stroke center or direct transfer to an endovascular stroke center. The study allocations will allow for three additional comparisons: between two groups of 12 hours, between metropolitan and provincial areas, and between workdays and weekends. The primary end point is the mRS at 90 days.
Identifying the Best Level of Anesthesia
Other trials will seek to determine whether general anesthesia or planned conscious sedation is more cost-effective in patients who are eligible for either procedure. Researchers previously examined this question in the IMS III trial. Setting aside patients who underwent medically indicated general anesthesia (who had large strokes and many comorbidities and tended to have poor outcomes), the researchers found a trend toward better outcomes among patients who underwent conscious sedation, compared with patients who received general anesthesia. In addition, general anesthesia cost approximately $16,000 more than conscious sedation did.
In the prospective SIESTA trial, patients with acute ischemic stroke were randomized in a 1:1 ratio to a nonintubated state or to an intubated state for endovascular stroke treatment. The primary outcome measure was NIHSS at 24 hours after the intervention. Secondary outcome measures included mRS at three months and inpatient mortality. Conscious sedation was not associated with any advantage over general anesthesia in this small randomized trial, according to the researchers.
In addition, investigators are recruiting patients for the GOLIATH trial, in which patients will be randomized to general anesthesia or local anesthesia. The primary outcome measure will be growth of the ischemic lesion on diffusion-weighted imaging (DWI). Secondary outcome measures will include time from arrival to groin puncture and recanalization, blood pressure during intervention, and mRS.
Thrombectomy With or Without Thrombolysis
Another unanswered question is whether thrombectomy alone provides greater benefit than IV t-PA followed by thrombectomy for patients with acute ischemic stroke. Investigators in the Netherlands are conducting the MR CLEAN NO IV trial to answer this question. They plan to include 500 patients who are taken directly to a comprehensive stroke center. One group will receive IV t-PA plus endovascular treatment, and the other group will receive endovascular treatment alone.
—Erik Greb
Suggested Reading
Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731.
Lansberg MG, Cereda CW, Mlynash M, et al. Response to endovascular reperfusion is not time-dependent in patients with salvageable tissue. Neurology. 2015;85(8):708-714.
Schönenberger S, Uhlmann L, Hacke W, et al. Effect of conscious sedation vs general anesthesia on early neurological improvement among patients with ischemic stroke undergoing endovascular thrombectomy: a randomized clinical trial. JAMA. 2016;316(19):1986-1996.
