Advances in Acute Stroke Treatment 2020

Joseph P. Broderick, MD; Michael D. Hill, MD, MSc, FRCPC


Stroke. 2021;52(2):729-734. 

Acute Ischemic Stroke Thrombolysis and EVT

For a quarter century, thrombolysis has been a standard of care treatment for acute ischemic stroke. The withholding of intravenous alteplase seems anathema, but has now been challenged in patients with large artery occlusions arriving first at thrombectomy centers. The SKIP trial (Randomised Study of Endovascular Therapy With Versus Without Intravenous Tissue Plasminogen Activator in Acute Stroke With ICA and M1 Occlusion),[4] examined 204 Japanese patients with middle cerebral artery or internal carotid artery occlusions, half of whom were randomized to treatment with intravenous alteplase (0.6 mg/kg) before EVT and half to EVT alone. The trial did not meet its primary outcome of noninferiority. The DIRECT-MT (Direct Intraarterial Thrombectomy to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicentre Clinical Trial)[5] enrolled 656 patients of whom half were randomized to intravenous alteplase (0.9 mg/kg) before EVT and half to EVT alone. The median time from randomization to groin puncture was 33.5 minutes. The trial met its noninferiority margin (A, 1.07 [0.81–1.40]) with 36.4% in the EVT only group and 36.8% in the alteplase plus EVT group achieving modified Rankin Scale score of 0 to 2 at 90 days. Participants treated with EVT alone had lower percentages of successful reperfusion before thrombectomy (2.4% versus 7.0%) and overall successful reperfusion (79.4% versus 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy groups. In both trials, however, the noninferiority margin was much larger than the minimal clinically important difference and so the trials were underpowered. Additional trials, MR-CLEAN-NoIV (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands No IV Thrombolysis Study), SWIFT-DIRECT (Solitaire™ With the Intention For Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire™ Stent-Retriever Thrombectomy in Acute Anterior Circulation Stroke), and DIRECT-SAFE (Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval Within 4.5 Hours of Stroke Onset) are ongoing.

A quarter of patients with internal carotid artery or M1-middle cerebral artery occlusions in the INTERRSeCT study (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography) had thrombus migration into a distal segment resulting in poorer outcomes compared with complete recanalization or no change in recanalization. Registry data from California identified the challenge of distal embolization occurring in a quarter of patients resulting in distal emboli that were not possible to address with EVT.[6] Both studies confirm data from the MR-CLEAN registry.[7] Similarly, data from the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times Study) showed early recanalization rates of only 6% in the EVT arm at a median of 50 minutes after the start of IV alteplase infusion. In the control arm, recanalization was observed, on computed tomography angiography completed a median of ≈4.5 hours after the start of intravenous alteplase infusion, in 37% of patients.[8] The EXTEND-IA TNK (Extending the Time for Thrombolysis in Emergency Neurological Deficits—IntraArterial Using Intravenous Tenecteplase study) part 2 study compared 2 doses of tenecteplase, 0.25 versus 0.4 mg/kg, among patients with large vessel occlusion (LVO), eligible for EVT.[9] The primary outcome was early recanalization (not reperfusion) defined at the first angiographic run of the EVT procedure. There was no difference in outcome between the two doses but the study confirmed prior results from EXTEND-IA TNK part 1,[10] of an early recanalization rate of 20% at an average of 46.5 minutes from treatment with tenecteplase to imaging. Finally, a pooled individual patient meta-analysis of trials examining patients with stroke-with-unknown-onset, who were selected by magnetic resonance imaging (either diffusion weighted imaging fluid attenuated inversion recovery) mismatch or magnetic resonance perfusion imaging, showed that intravenous alteplase treatment was superior to placebo when assessed at 90 days.[11]

Together these data provide empirical evidence and quantitative understanding of the in vivo mechanisms of intravenous thrombolysis, further demonstrating that patient selection is increasingly based on imaging and not time, and that thrombolytic agents require time to work. In a majority of patients with large vessel occlusion, thrombolysis alone will be unsuccessful during the critical time window when reperfusion will effectively salvage the ischemic tissue. In addition, thrombolysis can, in a minority of patients with LVOs, make the situation worse due to thrombus migration. Very rapid EVT possibly obviates any additional benefit of combined intravenous thrombolysis and EVT, but it remains unknown if an incremental benefit of combined therapy may emerge due to thrombolytic action on distal emboli, on incomplete reperfusion, on the microcirculation, or in situations where EVT proves to be unsuccessful. In contrast, a 20% target vessel recanalization rate within 45 minutes after thrombolysis is clinically meaningful, particularly in the drip and ship paradigm. Treatment with tenecteplase at 0.25 mg/kg (the dose seems settled now[9,12–14]) is not ready for widespread usage at present but more evidence will accrue from ongoing trials (TASTE [Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation], TEMPO-2 (Multicentre, Prospective Randomized Open Label, Blinded-End Point (PROBE) Controlled Trial of Thrombolysis With Low Dose Tenecteplase (TNK-tPA) Versus Standard of Care in Minor Ischemic Stroke With Proven Acute Symptomatic Occlusion), NORTEST-2 [Norwegian Tenecteplase Stroke Trial 2: A Randomised Trial of Tenecteplase versus Alteplase in Acute Ischemic Stroke], ACT [Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke: QuICR & OPTIMISE Registry Based Pragmatic Randomized Controlled Trial], and TWIST [Tenecteplase in Wake-up Ischaemic Stroke Trial]) over the next 2 years. The issue of withholding thrombolysis, is much less relevant when patients arrive at hospitals which do not perform EVT and so far the data do not justify withholding thrombolysis generally. At the end of 2020, it remains clear that the goal of acute ischemic stroke treatment is reperfusion as quickly as possible, whether that is achieved by going directly to EVT in selected patients or with combined thrombolysis and EVT in most patients.