Table 1.

Large hemispheric infarct management: endovascular treatment

Trials (chronological)	Patient sample and intervention	Major findings	Reported limitations
Intravenous (IV) rt-plasminogen activator (tPA)
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995)4	Part 1: 291 patients (n = 144 t-PA group vs. n = 147 placebo group. Assessed clinical outcome of t-PA within 24 h of the onset of stroke Part 2: 333 patients (n = 168 t-PA group vs. n = 165 placebo group). Assessed clinical outcome at 3 mo	Part 1: No significant difference between the patients in the t-PA group and the patients given placebo Benefit was observed for the t-PA group at 3 mo for all four outcome measures Part 2: Patients treated with t-PA were at least 30% more likely to have minimal or no disability at 3 mo compared with patients in placebo group Symptomatic ICH within 36 h after stroke onset occurred in 6.4% of patients treated with t-PA and in 0.6% of patients given placebo (p = 0.001) Mortality at 3 mo was 17% in the t-PA group and 21% in the placebo group (p = 0.30)	Some patients with transient ischemic attacks whose symptoms rapidly improved were enrolled A small percentage (2%) of patients who received a placebo showed no neurological deficits after 24 h based on NIHSS, which is unlikely to be attributed to the t-PA treatment
Hacke et al (2008)5	821 patients (418 alteplase group vs. 403 placebo) and were able to receive the study drug within 3–4h after onset	Alteplase had more favorable outcomes than (52.4 vs. 45.2%; OR, 1.34; 95% CI, 1.02–1.76; p = 0.04) The incidence of ICrH was higher with alteplase than with placebo for any ICrH (27.0 vs. 17.6%; p = 0.001) and for symptomatic ICrH (2.4 vs. 0.2%; p = 0.008) Mortality did not differ between groups (7.7 and 8.4%, respectively; p = 0.68)	Modification of the ECASS criteria for hemorrhage could have led to lower incidence of ICH in the alteplase treated Mortality rate (8%) was lower than previous trials, probably due to inclusion of patients with less severe strokes
Schwamm et al (2018)7	80 patients were enrolled who were between 4.5 and 24 h since last known well and could receive be treated with alteplase (0.9 mg/kg) within 4.5 h of symptom discovery	At 90 d, 39% of subjects achieved mRS 0–1 compared with 48% of patients with imaging confirming no LVO IV thrombolysis within 4.5 h of symptom discovery in patients with unwitnessed stroke selected by DWI-FLAIR MRI mismatch, who are beyond the recommended time windows, is safe	Small sample size No pre- and posttreatment angiography, limiting data on recanalization rates No perfusion imaging to assess potential candidates for late time window MT
Ma et al (2019)6	225 patients (113 alteplase group vs. 112 placebo group) between 4.5 and 9.0 h after the onset compared the proportion of patients that scored of 0 or 1 on the mRS at 90 d	At 90 d, 40 patients (35.4%) in the alteplase group had mRS 0–1 vs. 33 patients (29.5%) in the placebo group (adjusted RR, 1.44; 95% CI, 1.01–2.06; p = 0.04) ICH occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97–53.5; p = 0.05)	The study was stopped early The “door-to-needle time” 2 h longer than recommend
IV tenecteplase (TNK)
Tong et al (2012)9	413,147 patients with acute ischemic stroke from 1287 hospitals whose data were submitted data via a web-based patient management tool 47.0% had a documented time of stroke onset	No substantial change in onset-to-door time over the 6-y study period Extension of the alteplase treatment time window from 3 to 4.5 h after stroke onset increases the number of potential patients as candidate for alteplase treatment by 6.3% (30.1% relative increase)	Data accuracy and completeness of depends on the individual hospitals. NIHSS was missing in many patients, reflecting inconsistent use of the score in practice
Menon et al (2022)8	1,600 patients (n = 816 TNK group vs. n = 784 alteplase group) presenting within 4.5 h of symptom onset 1,577 were the intention-to-treat population (n = 806 TNK vs. n = 771 alteplase)	296 (36.9%) of 802 patients in the TNK group and 266 (34.8%) of 765 in the alteplase group had mRS of 0–1 at 90–120 d (unadjusted RR difference 2.1%; 95% CI, 2.6–6.9) 27 (3.4%) of 800 in TNK group and 24 (3.2%) of 763 in alteplase group had symptomatic ICH within 24 h 122 (15.3%) of 796 in TNK and 117 (15.4%) of 763 in alteplase died within 90 d	Only 6.3% of the patients in the intention-to-treat population had ischemic stroke symptomatic intracerebral hemorrhage used in the trial was broader than that used for symptomatic intracranial hemorrhage COVID19 pandemic might have affected the trial
Mechanical thrombectomy (MT)
First wave of studies with negative results
Furlan et al (1999)10	Randomized, controlled, multicenter, open-label clinical trial with blinded follow-up 180 patients (n = 121 intra-arterial r-proUK plus heparin vs. n = 59 heparin only) with acute ischemic stroke with onset within 6 h proven with angiography	40% treated with r-proUK patients and 25% in the heparin only group had a mRS ≤ 2 respectively (p = 0.04) Mortality was 25% for the r-proUK group and 27% for the control group	Small sample size
Ciccone et al (2013)12	362 patients with acute stroke (n = 181 endovascular therapy group vs. n = 181 alteplase group) underwent randomization within 4.5 h after symptom onset	At 3 mo, 55 patients in the endovascular-therapy group (30.4%) and 63 in the IV t-PA group (34.8%) were alive without disability (adjusted OR 0.71; 95% CI, 0.44–1.14; p = 0.16) No significant differences between groups in the rates of other serious adverse events or the case fatality rate	12 patients were excluded due to enrollment from one center for failure to comply with the treatment assignments 8 other patients with major protocol deviations from six centers
Kidwell et al (2013)13	118 patients, the mean time to enrollment was 5.5 h, and 58% had a favorable penumbral pattern	Mean mRS did not differ between MT and standard medical treatment (3.9 vs. 3.9; p = 0.99) MT was not superior to standard care in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; p = 0.23)	During the 8 y needed for the trial to be completed, advances in techniques and clinical practices Baseline neuroimaging prediction maps may have changed by the time of recanalization with thrombectomy Time-to-groin puncture was > 6h after symptom onset (longer than previous trials) Follow-up imaging was not available for all patients
Broderick et al (2013)11	656 participants had undergone randomization (434 patients to endovascular therapy and 222 to IV t-PA alone)	Findings in the endovascular-therapy and IV t-PA groups were similar for mortality at 90 d (19.1 and 21.6%, respectively; p = 0.52) and the proportion of patients with symptomatic ICH within 30 h after initiation of t-PA (6.2 and 5.9%, respectively; p = 0.83)	The study was stopped early
Second wave of studies with positive results
Berkhemer et al (2015)14	500 patients at 16 medical centers in the Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). Of them, 445 patients (89.0%) were treated with IV alteplase before randomization. MT with retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment	Adjusted OR was 1.67 (95% CI, 1.21–2.30). There was an absolute difference of 13.5% points (95% CI, 5.9–21.2) in the rate of functional independence (mRS, 0–2) in favor of the MT (32.6 vs. 19.1%) No significant differences in mortality or ICH	Unbalanced randomization (more patients in control group) Lower reperfusion rate (58.7%) than other case series 9% of the patients in intervention group had embolization into new vascular territories Broad inclusion criteria resulted in low proportion of patients in the control group had a mRS of 0 to 2 at the 90 d
Campbell et al (2015)16	70 patients had undergone randomization (35 patients in each group)	Increased early neurological improvement at 3 d (80% in MT group vs. 37% in control group (p = 0.002) At 90 dmRS 0–2 was 71% in MT group vs. 40% in control (p = 0.01)	The trial was stopped early
Goyal et al (2015)17	316 patients from 22 hospitals worldwide were enrolled, of whom 238 received IV tPA (120 in the intervention group and 118 in the control group)	90-day mRS 0–2 was 53.0% in MT group vs. 29.3% in the control group (p < 0.001) MT was associated with reduced mortality (10.4%, vs. 19.0% in the control group; p = 0.04). Symptomatic ICH occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (p = 0.75)	The trial was stopped early
Saver et al (2015)21	196 patients in 39 centers underwent randomization (98 patients in both group)	There were no significant between-group differences in 90-day mortality (9 vs. 12%; p = 0.50) or symptomatic ICrH (0 vs. 3%; p = 0.12)	The study was stopped early
Bracard et al (2016)15	414 patients were randomly assigned to the IV alteplase group (0·9 mg/kg, max. 90 mg, initial bolus of 10% of the total dose followed by infusion of the remaining dose over 60 min, n = 208) or the IV alteplase plus MT group (n = 204)	Functional independence at 3 mo was achieved by 85 (42%) patients in the alteplase group vs. 106 (53%) in the alteplase plus MT group (OR, 1·55; 95% CI, 1·05–2·30; p = 0·028) No significant differences in mortality at 3 mo (12% deaths in alteplase plus MT vs 13% in ; p = 0·70) or symptomatic intracranial hemorrhage at 24 h (four [2%] of 185 vs three [2%] of 192; p = 0·71)	Treating physicians were not blinded to mRS Protocol changes occurred while 80 were already enrolled in the study by extending the alteplase time window from 3h to 4h and MT initiation at 5h after onset Results apply only to patients with anterior circulation stroke Initial design was occlusion of the superior third of basilar artery with ultimately only 2 only two patients available for inclusion
Muir et al (2017)20	65 patients (n = 32 IV thrombolysis and n = 35 IV thrombolysis and adjunctive MT) enrolled in a multicentre, randomized, controlled trial with acute supratentorial ischemic stroke with onset of 4.5 h with imaging showing ICA, M1, or a single M2 artery occlusion	No significant difference in disability-free survival at day 90 with MT (absolute difference 11%, adjusted OR, 2.12; 95% CI, 0.65–6.94; p = 0.20) Greater likelihood of full neurological recovery (mRS 0–1) at day 90 (OR, 7.6; 95% CI, 1.6–37.2; p = 0.010) In the per-protocol population (n = 58), the primary and most secondary clinical outcomes significantly favored MT (absolute difference in mRS 0–2 of 22% and adjusted OR, 4.9; 95% CI, 1.2–19.7; p = 0.021)	Small sample size
Jovin et al (2022)28	217 patients with stroke due to basilar-artery occlusion who presented 6 to 24 h after symptom onset (110 in the MT group and 107 in the control group) were included in the analysis	51 patients (46%) in the MT group had mRS of 0 to 3 occurred in and in 26 (24%) in the control group (adjusted RR, 1.81; 95% CI, 1.26–2.60; p < 0.001) The results for the original primary outcome of a mRS of 0 to 4 were 55 and 43%, respectively (adjusted RR, 1.21; 95% CI, 0.95–1.54) Symptomatic ICrH occurred in 6 of 102 patients (6%) in the MT group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64–42.18) Mortality at 90 d was 31% in the MT group and 42% in the control group (adjusted RR, 0.75; 95% CI, 0.54–1.04)	Enrollment was stopped at a prespecified interim analysis because of the superiority of MT
Studies on MT with extended time window from onset
Nogueira et al (2018)23	206 patients were enrolled; 107 were assigned to the MT group and 99 to the control group	The rate of symptomatic IcrH did not differ between the two groups (6% in the MT group and 3% in the control group; p = 0.50), nor did 90-day mortality (19 and 18%, respectively; p = 1.00)	At 31 mo, enrollment in the trial was stopped because of the results of a prespecified interim analysis
Albers et al (2018)22	182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical therapy group)	Endovascular therapy plus medical therapy was associated with a favorable mRS at 90 d (OR, 2.77; p < 0.001) Higher % of patients in the endovascular-therapy group with mRS of 0 to 2 (45 vs. 17%; p < 0.001) 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical therapy group (p = 0.05)	The study was stopped early
Studies on MT and large ischemic core
Yoshimura et al (2022)27	203 patients in Japan underwent randomization (101 patients in endovascular treatment vs. 102 patients in medical treatment group) 27% of patients in each group received alteplase	At 90 d, 31.0% in the endovascular therapy group vs 12.7% in the medical-care group had mRS 0 to 3 (RR 2.43; 95% CI, 1.35–4.37; p = 0.002 All-type IcrH occurred in 58.0 and 31.4%, respectively (p < 0.001)	Limited generalizability beyond the Japanese population Standard dose of rt-PA in Japan is lower than in other countries No data were collected on the causes of death, no association of adverse events with endovascular therapy or thrombolysis
Huo et al (2023)25	456 patients (n = 231 MT group vs, n = 225 medical therapy alone group) in China who had stroke within 24 h	At 90 d, MT group had better mRS compared with medical therapy alone (generalized OR, 1.37; 95% CI, 1.11–1.69; p = 0.004) Symptomatic IcrH occurred in 14 of 230 patients (6.1%) in the MT group and in 6 of 225 patients (2.7%) in the medical-management group; any IcrH occurred in 113 (49.1%) and 39 (17.3%), respectively	The trial was stopped early
Sarraj et al (2023)26	178 patients had been assigned to MT and 174 to medical care	Mortality was similar between the two groups MT resulted in better functional outcomes than medical therapy alone but was associated with vascular complications	The trial was stopped early
Bendszus et al (2023)24	125 patients assigned to endovascular MT vs. 128 to medical treatment alone	At 90 d, MT was associated better outcome (adjusted OR, 2.58; 95% CI, 1·60–4·15; p = 0·0001) and with lower mortality (HR, 0.67; 95% CI, 0.46–0.98; p = 0·038)	The trial was stopped early
Studies on MT and basilar artery infarction
Liu et al (2020)30	131 patients (n = 66 patients in MT group and 65 in medical therapy alone group)	No difference in outcomes of patients receiving endovascular therapy compared with those receiving standard medical therapy alone	The trial was stopped early Results might have been confounded by loss of equipoise over the course of the trial
Langezaal et al (2021)29	300 patients (n = 154 MT group vs. n = 146medical therapy only) with basilar-artery occlusion, within 6 h after stroke onset in a multicenter, open-label, international, randomized, controlled trial	Good functional outcomes occurred in 68 of 154 patients (44.2%) in the MT group and 55 of 146 patients (37.7%) in the medical care group (RR, 1.18; 95% CI, 0.92–1.50) Symptomatic ICrH occurred in 4.5% of the MT patients and in 0.7% of the medical therapy alone (RR, 6.9; 95% CI, 0.9–53.0) Mortality at 90 d was 38.3% in MT group and 43.2% in medical therapy alone group respectively (RR, 0.87; 95% CI, 0.68–1.12)	29.2% of eligible patients were treated outside the trial and that 79.0% NIHSS, used for stratification in randomization, is less sensitive to posterior-circulation stroke Low than anticipated, our trial was underpowered for some analyses, including subgroup analyses
Jovin et al (2015)19	Multicenter, prospective, randomized, sequential, open-label phase 3 study with blinded evaluation with random assignment of 206 patients who could be treated within 8 h of stroke onset Patients were divided into thrombectomy ± IV alteplase (when appropriate) or medical therapy alone	MT reduced the severity of disability over the range of the mRS (adjusted OR for improvement of 1 point, 1.7; 95% CI, 1.05–2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 d (43.7 vs. 28.2%; adjusted OR, 2.1; 95% CI, 1.1–4.0) At 90 d, the rates of symptomatic ICrH were 1.9% in both the MT group and the control group (p = 1.00), and rates of death were 18.4 and 15.5%, respectively (p = 0.60)	The trial was stopped early
Tao et al (2022)31	507 patients in China with basilar artery occlusion within 12 h after stroke onset 340 were in the intention-to-treat population, (226 MT group vs. 114 control group)	At 90 d, 104 patients (46%) in the MT group and in 26 (23%) in the control group had good functional outcomes (adjusted RR, 2.06; 95% CI, 1.46–2.91; p < 0.001) Mortality at 90 d was 37% in the MT group and 55% in the control group (adjusted RR, 0.66; 95% CI, 0.52–0.82)	Higher prevalence of intracranial large-artery atherosclerosis is known in Chinese population Results are not generalizable to patients with milder stroke NIHSS score < 10 or onset beyond 12-h occlusion

Abbreviations: CI, confidence interval; DWI, diffusion-weighted image; FLAIR, fluid-attenuated inversion recover; HR, hazard ratio; ICH, intracerebral hemorrhage; ICrH, intracranial hemorrhage; LHI, large hemispheric infraction; LVO, large vessel occlusion; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; MT, mechanical thrombectomy; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; RR, risk ratio.