Expanding boundaries in stroke treatment: New horizons in revascularization strategies and critical decision-making

Ischemic stroke is one of the leading causes of mortality and long-term disability worldwide, emphasizing the need for rapid and effective acute management. Revascularization therapies are critical to this strategy, demanding swift intervention. Intravenous thrombolysis (IVT) with alteplase (ALT) was traditionally recommended within 4.5 h from symptom onset for acute ischemic stroke (AIS) patients. However, landmark studies, such as ECASS IV, EXTEND, and EPITHET have demonstrated that IVT may be extended up to 9 h in select patients, identified through perfusion imaging with computed tomography or magnetic resonance imaging, enabling differentiation of viable, at-risk brain tissue in the ischemic penumbra from the infarct core. This allows treatment in cases with favorable “mismatch” profiles, Similarly, endovascular procedures for large vessel occlusions (LVOs) were initially recommended within 6 h, but trials, such as DEFUSE-3 and DAWN have established efficacy for thrombectomy up to 16 – 24 h from the last known well time, using perfusion imaging to guide patient selection. These advancements prioritize tissue viability over rigid temporal thresholds. Despite significant progress, optimal revascularization strategies for AIS remain uncertain in complex clinical contexts, such as posterior circulation strokes, large infarct core AIS, distal vascular occlusions, and mild clinical deficit LVO-related AIS. Recent research aims to address these gaps, expanding reperfusion criteria and exploring new thrombolytic agents with potential benefits over ALT. Collectively, these studies aim to refine and broaden therapeutic criteria, improving outcomes for a wider AIS patient population.
- Boysen G, ECASS Study Group. European Cooperative Acute Stroke Study (ECASS): (rt-PA-Thrombolysis in acute stroke) study design and progress report. Eur J Neurol. 1995;1(3):213-219. doi: 10.1111/j.1468-1331.1995.tb00074.x
- Amiri H, Bluhmki E, Bendszus M, et al. European cooperative acute stroke study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND. Int J Stroke. 2016;11(2):260-267. doi: 10.1177/1747493015620805
- Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): A placebo-controlled randomised trial. Lancet Neurol. 2008;7(4):299-309. doi: 10.1016/S1474-4422(08)70044-9
- Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708-718. doi: 10.1056/NEJMoa1713973
- Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11-21. doi: 10.1056/NEJMoa1706442
- Haley EC Jr., Thompson JL, Grotta JC, et al., Phase IIB/III trial of tenecteplase in acute ischemic stroke: Results of a prematurely terminated randomized clinical trial. Stroke. 2010;41(4):707-711. doi: 10.1161/STROKEAHA.109.572040
- Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366(12):1099-1107. doi: 10.1056/NEJMoa1109842
- Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): A phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol. 2015;14(4):368-376. doi: 10.1016/S1474-4422(15)70017-7
- Campbell BC, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before endovascular thrombectomy (EXTEND-IA TNK): A multicenter, randomized, controlled study. Int J Stroke. 2018;13(3):328-334. doi: 10.1177/1747493017733935
- Xiong Y, Campbell BCV, Fisher M, et al. Rationale and design of tenecteplase reperfusion therapy in acute ischaemic cerebrovascular Events III (TRACE III): A randomised, phase III, open-label, controlled trial. Stroke Vasc Neurol. 2024;9(1):82-89. doi: 10.1136/svn-2023-002310
- Bivard A, Zhao H, Churilov L, et al. Comparison of tenecteplase with alteplase for the early treatment of ischaemic stroke in the melbourne mobile stroke unit (TASTE-A): A phase 2, randomised, open-label trial. Lancet Neurol. 2022;21(6):520-527. doi: 10.1016/S1474-4422(22)00171-5
- Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): A pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022;400(10347):161-169. doi: 10.1016/S0140-6736(22)01054-6
- Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): A phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017;16(10):781-788. doi: 10.1016/S1474-4422(17)30253-3
- Del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: A phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in acute cerebral thromboembolism. Stroke. 1998;29(1):4-11. doi: 10.1161/01.str.29.1.4
- Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: A randomized controlled trial. Prolyse in acute cerebral thromboembolism. JAMA. 1999;282(21):2003-2011. doi: 10.1001/jama.282.21.2003
- Li S, Gu HQ, Feng B, et al. Safety and efficacy of intravenous recombinant human prourokinase for acute ischaemic stroke within 4·5 h after stroke onset (PROST-2): A phase 3, open-label, non-inferiority, randomised controlled trial. Lancet Neurol. 2025;24(1):33-41. doi: 10.1016/S1474-4422(24)00436-8
- Xiong Y, Hao M, Pan Y, et al. Rationale and design of ProUrokinase in Mild IsChemic strokE (PUMICE): A multicentre, prospective, randomised, open-label, blinded-endpoint controlled trial. Stroke Vasc Neurol. 2024;9(6):715-722. doi: 10.1136/svn-2023-002673
- Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20. doi: 10.1056/NEJMoa1411587
- Liu X, Dai Q, Ye R, et al. Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): An open-label, randomised controlled trial. Lancet Neurol. 2020;19(2):115-122. doi: 10.1016/S1474-4422(19)30395-3
- Drumm B, Banerjee S, Qureshi MM, et al. Current opinions on optimal management of basilar artery occlusion: After the BEST of BASICS survey. Stroke Vasc Intervent Neurol. 2022;2:e000538. doi: 10.1161/SVIN.122.000538
- Edwards C, Drumm B, Siegler JE, et al. Basilar artery occlusion management: Specialist perspectives from an international survey. J Neuroimaging. 2023;33:422-433. doi: 10.1111/jon.13084
- Tao C, Nogueira RG, Zhu Y, et al. Trial of endovascular treatment of acute basilar-artery occlusion. N Engl J Med. 2022;387(15):1361-1372. doi: 10.1056/NEJMoa2206317
- Jovin TG, Li C, Wu L, et al. Trial of thrombectomy 6 to 24 hours after stroke due to basilar-artery occlusion. N Engl J Med. 2022;387(15):1373-1384. doi: 10.1056/NEJMoa2207576
- Yoshimura S, Sakai N, Yamagami H, et al. Endovascular therapy for acute stroke with a large ischemic region. N Engl J Med. 2022;386(14):1303-1313.doi: 10.1056/NEJMoa2118191
- Sarraj A, Hassan AE, Abraham MG, et al. Trial of endovascular thrombectomy for large ischemic strokes. N Engl J Med. 2023;388(14):1259-1271. doi: 10.1056/NEJMoa2214403
- Huo X, Ma G, Tong X, et al. Trial of endovascular therapy for acute ischemic stroke with large infarct. N Engl J Med. 2023;388(14):1272-1283. doi: 10.1056/NEJMoa2213379
- Writing Committee for the TESLA Investigators, Yoo AJ, Zaidat OO, et al. Thrombectomy for stroke with large infarct on noncontrast CT: The TESLA randomized clinical trial. JAMA. 2024;332(16):1355-1366. doi: 10.1001/jama.2024.13933
- Bendszus M, Fiehler J, Subtil F, et al. Endovascular thrombectomy for acute ischaemic stroke with established large infarct: Multicentre, open-label, randomised trial. Lancet. 2023;402(10414):1753-1763. doi: 10.1016/S0140-6736(23)02032-9
- Costalat V, Lapergue B, Albucher JF, et al. Evaluation of acute mechanical revascularization in large stroke (ASPECTS <5) and large vessel occlusion within 7 h of last-seen-well: The LASTE multicenter, randomized, clinical trial protocol. Int J Stroke. 2024;19(1):114-119. doi: 10.1177/17474930231191033
- Marchal A, Bretzner M, Casolla B, et al. Endovascular thrombectomy for distal medium vessel occlusions of the middle cerebral artery: A safe and effective procedure. World Neurosurg. 2022;160:e234-e241. doi: 10.1016/j.wneu.2021.12.113
- Rikhtegar R, Mosimann PJ, Weber R, et al. Effectiveness of very low profile thrombectomy device in primary distal medium vessel occlusion, as rescue therapy after incomplete proximal recanalization or following iatrogenic thromboembolic events. J Neurointerv Surg. 2021;13(12):1067-1072. doi: 10.1136/neurintsurg-2020-017035
- Ospel JM, Dowlatshahi D, Demchuk A, et al. Endovascular treatment to improve outcomes for medium vessel occlusions: The ESCAPE-MeVO trial. Int J Stroke. 2024;19(9):1064-1070. doi: 10.1177/17474930241262642
- Marios-Nikos P, Alex B, Jens F, et al. Endovascular therapy plus best medical treatment (BMT) versus BMT alone for medium distal vessel occlusion stroke (DISTAL): An international, multicentre, randomized-controlled, two-arm, assessor-blinded trial. Eur Stroke J. 2024;9(4):1083-1092. doi: 10.1177/23969873241250212
- Renú A, Millán M, San Román L, et al. Effect of intra-arterial alteplase versus placebo following successful thrombectomy on functional outcomes in patients with large vessel occlusion acute ischemic stroke: The CHOICE randomized clinical trial. JAMA. 2022;327(9):826-835. doi: 10.1001/jama.2022.1645
- Tao C, Li R, Sun J, et al. Intra-arterial tenecteplase following endovascular therapy in patients with acute posterior circulation arterial occlusion: Study protocol and rationale. J Neurointerv Surg. 2024;17(e1):e68-e73. doi: 10.1136/jnis-2023-021076
- Raynald, Sun D, Huo X, et al. The safety and efficacy of endovascular treatment in acute ischemic stroke patients caused by large-vessel occlusion with different etiologies of stroke: Data from ANGEL-ACT registry. Neurotherapeutics. 2022;19(2):501-512. doi: 10.1007/s13311-022-01189-9
- 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. doi: 10.1016/S0140-6736(16)00163-X
- Bai X, Li Z, Cai Z, Yao M, Chen L, Wang Y. Gender differences in risk factors for ischemic stroke: A longitudinal cohort study in East China. BMC Neurol. 2024;24(1):171. doi: 10.1186/s12883-024-03678-0
- Choi JW, Ryoo IW, Hong JY, et al. Clinical impact of estradiol/testosterone ratio in patients with acute ischemic stroke. BMC Neurol. 2021;21(1):91. doi: 10.1186/s12883-021-02116-9
- Ospel J, Singh N, Ganesh A, Goyal M. Sex and gender differences in stroke and their practical implications in acute care. J Stroke. 2023;25(1):16-25. doi: 10.5853/jos.2022.04077
- Kremer C, Gdovinova Z, Bejot Y, et al. European Stroke Organization Guidelines on stroke in women: Management of menopause, pregnancy and postpartum. Eur Stroke J. 2022;7(2):I-XIX. doi: 10.1177/23969873221078696