Turning Point of Acute Stroke Therapy: Mechanical Thrombectomy as a Standard of Care Keith G. DeSousa1,2, Matthew B. Potts1,3, Eytan Raz1, Erez Nossek1,3, Howard A. Riina1,3

In the December 17, 2014 and February 11, 2015 editions of the New England Journal of Medicine, the highly anticipated results of 3 multicenter, randomized controlled trials comparing standard medical care with or without endovascular treatment for acute ischemic stroke were published. Together, these trials (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands [MR CLEAN], Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke [ESCAPE], and Extending the Time for Thrombolysis in Emergency Neurological DeficitseIntra-Arterial [EXTEND IA]; Table 1) (1, 3, 5), provide data to show benefit for patients treated with mechanical thrombectomy versus intravenous tissue plasminogen activator (IV tPA) alone for the subset of patients with large vessel occlusions. Although IV tPA is the current mainstay of treatment for acute ischemic stroke (10), mechanical thrombectomy has been a promising adjunctive strategy for the subset of patients with large vessel occlusions since the development of the Merci retrieval device (8, 9). Data from this and subsequent mechanical thrombectomy devices has supported improved recanalization rates with mechanical thrombectomy and the possibility of extending treatment time beyond the standard 3e4.5 hour window used for IV tPA (7-9). The advantage of mechanical thrombectomy, however, was put into question by 3 randomized trials published in 2013 that compared medical treatment to medical plus endovascular treatment (Interventional Management of Stroke [IMS III] and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy [MR RESCUE]) (2, 6) or to endovascular treatment alone (SYNTHESIS EXPANSION) (4). Collectively, these trials failed to show a benefit of endovascular therapy for acute ischemic stroke. However, their trial designs and the generalizability of their results were called into question for their use of older generation clot retrieval devices with lower recanalization rates than newer devices, treatment delays, and no requirement for confirming large vessel occlusion on imaging (11). The MR CLEAN (1), ESCAPE (5), and EXTEND IA (3) trials were therefore designed to address these specific issues, applying rapid diagnostic techniques to select patients with large vessel occlusions, salvageable penumbra, or sufficient collaterals, and

WORLD NEUROSURGERY - [-]: ---, - 2015

using the most up-to-date thrombectomy devices for most treatments (mainly stent retrievers). MR CLEAN (1) (Table 1) randomized 500 patients to either standard medical treatment or standard medical treatment plus endovascular treatment. Patients were required to have evidence of an internal carotid, middle cerebral (M1 or M2 branches), or anterior cerebral artery (A1 or A2 branches) occlusion based on angiographic imaging. Overall 89% were treated with IV tPA and although there were no requirements as to the type of endovascular therapy used, 81.5% of the endovascular group were treated with stent retrievers. The primary outcome was the modified Rankin Scale (mRS) at 90 days with functional independence (mRS 0-2) seen in 32.6% and 19.1% of patients in the endovascular and medical treatment groups, respectively (95% confidence interval 5.9e21.2). The EXTEND-IA trial (3) (Table 1) randomized patients to receive either IV tPA or IV tPA plus endovascular therapy using the Solitaire FR (Flow Restoration) device (ev3/Covidien, Irvine, CA, USA). All patients had an occlusion of either the internal carotid or proximal middle cerebral (M1 or M2 branches) artery based on computed tomography angiography and an estimated ischemic core of less than 70 mL using computed tomography perfusion imaging. The trial was stopped early after enrolling 70 patients when interim analysis in response to the MR CLEAN (1) results found efficacy favoring the endovascular treatment arm. The amount of ischemic territory that was reperfused at 24 hours was higher in the endovascular group (median 100% vs. 37%; P ¼ 0.002). In addition, the functional outcomes were improved by endovascular treatment, with functional independence (mRS 0e2) achieved in 71% and 40% of the endovascular and control groups, respectively (P ¼ 0.01). The ESCAPE trial (5) (Table 1) also randomized patients to receive standard care or standard care plus endovascular therapy. This trial differed from MR CLEAN (1) and EXTEND-IA (3) in that patients with a proximal anterior circulation occlusion were included up to 12 hours from symptom onset. In addition, the presence of “moderate-to-good” collaterals based on multiphase computed tomography angiography was also required for inclusion. This meant that included patients had evidence of collateral filling distal to the occluded vessel, suggesting that these tissues still had some perfusion to

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1

Table 1. Summary of 2015 Randomized Stroke Intervention Trials MR CLEAN Berkhemer et al., 2015 (1)

EXTEND-IA Campbell et al., 2015 (3)

ESCAPE Goyal et al., 2015 (5)

Comparison

Medical þ endovascular vs. medical alone

IV tPA þ endovascular vs. IV tPA alone

Endovascular þ “guidelinebased care” vs. “guideline-based care alone”

No. of patients

233/267

35/35

165/150

Main inclusion criteria Age (years)

18

18

Adults

Timing

Treatment within 6 hour of symptom onset

IV tPA within 4.5 hour of symptom onset; able to start endovascular therapy within 6 hour

Enrollment within 12 hour of symptom onset

NIHSS

2

All

All

Imaging

large vessel occlusion (ICA, M1, M2, A1, or A2) confirmed on vascular imaging

CTA: ICA, M1, or M2 occlusion and CTP: mismatch >10 mL and ischemic core