Evidence Table and Reference List 5 (Acute Ischemic Stroke Treatment – Thrombolytic Therapy)

Evidence Table and Reference List 5b (Acute Ischemic Stroke Treatment – Endovascular Therapy)

Sex and Gender Considerations Reference List

The weight of evidence from many large, international trials over a time frame of 20 years clearly indicate that treatment with intravenous alteplase reduces the risk of death or disability following ischemic stroke, at 3 to 6 months post-treatment. The NINDS trial (1995) was one of the earliest, large trials conducted in the USA. Patients were randomized to receive alteplase or placebo within three hours of symptom onset. At 3 months, significantly more patients in the t-PA group had experienced a good outcome (using any one of the study’s four metrics), with no difference in 90-day mortality between groups. In contrast, patients who received alteplase within 3 to 5 hours in the ATLANTIS trial (1999) were no more likely to have a good neurological or functional outcome at 90 days than patients in the placebo group. 

In the first ECASS trial (1995) 620 patients received alteplase or placebo within 6 hours of the stroke event. Using intention-to-treat analysis and including the data from 109 patients with major protocol violations, the authors did not report a significant benefit of treatment. The median Barthel Index and modified Rankin scores at 90 days did not differ between groups. In an analysis restricted to patients in the target population, there were differences favouring patients in the alteplase group. In the ECASS II trial (1998), there was again no significant difference on any of the primary outcomes. The percentages of patients with a good outcome at day 90 (mRS<2) treated with alteplase and placebo were 40.3% vs. 36.6% respectively, absolute difference=3.7%, p=0.277. In subgroup analysis of patients treated <3 hours and 3 to 6 hours, there were no between-group differences on any of the outcomes. The authors suggested that the reason for the null result may have been that the study was underpowered, since it was powered to detect a 10% difference in the primary outcome, but the observed difference between groups in previous trials was only 8.3%. Finally, in the ECASS III trial (2008) 821 patients were randomized within 3 and 4.5 hours of symptom onset. In this trial, a higher percentage of patients in the alteplase group experienced a favourable outcome, defined as mRS scores <2 (52.4% vs. 45.2%, adjusted OR=1.34, 95% CI 1.02 to 1.76, p=0.04). A higher percentage of patients in the alteplase group also had NIHSS scores of 0 or 1, (50.2% vs. 43.2%, adjusted OR=1.33, 95% CI 1.01 to 1.75, p=0.04). Secondary outcomes of the ECASS III trial were reported by Bluhmki et al. (2009). At 90 days, there were no between-group differences in the percentages of patients with mRS score of 0-2 (59% vs. 53%, p=0.097) or BI score ≥85 (60% vs. 56%, p=0.249, but a significantly greater percentage of patients had improved NIHSS scores of ≥8 points (58% vs. 51%, p=0.031). In all of the trials described above there was an increased risk of symptomatic intracerebral hemorrhage (ICH) associated with treatment with alteplase and in some cases, increased short-term mortality; however, there were no differences between treatment and placebo groups in 90-day mortality. 

The Third International Stroke Trial (IST-3, 2012) is the largest (n=3,035) and most recent trial of alteplase, in which patients were randomized to receive a standard dose of alteplase (0.9 mg/kg) or placebo. Investigators aimed to assess the risks and benefits of treatment among a broader group of patients, and determine if particular subgroups of patients might benefit preferentially from treatment. In this trial, 95% of patients did not meet the strict licensing criteria, due to advanced age or time to treatment. Unlike all previous large trials, which excluded them, IST-3 included patients >80 years of age. In fact, the majority of patients (53%) were >80 years of age. Approximately one-third of all patients were treated within 0-3 hours, 3.0-4.5 hours, and 4.5-6.0 hours of onset of symptoms. Overall, there was an increase in the risk of death within 7 days in patients who had received alteplase, although there was no difference in 6-month mortality in both crude and adjusted analyses. There was no significant difference in the percentage of patients who were treated with alteplase who were alive and independent (defined as an Oxford Handicap Score of 0-1) at 6 months (37% vs. 35%, adjusted OR=1.13, 95% CI 0.95 to 1.35, p=0.181, although a secondary ordinal analysis suggested a significant, favourable shift in the distribution of OHS scores at 6 months. Significantly improved odds of a good outcome at 6 months were associated with the subgroups of older patients (≥80 years), higher NIHSS scores, higher baseline probability of good outcome and treatment within 3 hours. Fatal or non-fatal symptomatic intracranial hemorrhage within 7 days occurred more frequently in patients in the t-PA group (7% vs. 1%, adjusted OR=6.94, 95% CI 4.07 to 11.8, p<0.0001). The 3-year risk of mortality (2016) was similar between groups (47% vs. 47%, 95% CI 3.6%, 95% CI -0.8 to 8.1); however, patients who received rt-PA had a significantly lower risk of death between 8 days and 3 years (41% vs. 47%; HR= 0.78, 95% CI 0·68–0·90, p=0·007).

Although it is known that the optimal timing of administration of intravenous alteplase is <3 hours, debate continues as to the safety and efficacy of treatment provided between 3 and 6 hours post stroke. The results from a few studies suggest that treatment is still beneficial if provided beyond the three-hour window. The Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) includes patients who were treated with intravenous alteplase under strict licensing criteria and also those who were thought to be good candidates based on clinical/imaging assessment of the treating facility. Wahlgren et al. (2008) used data from a cohort of patients collected from 2002–2007 to compare the outcomes of patients who had been treated with alteplase within 3 hours of symptom onset (n=11,865) and those treated within 3 to 4.5 hours (n=644). The primary focus of this analysis was to assess treatment safety beyond the three-hour treatment window. Patients in the <3-hour group had significantly lower initial median NIHSS scores (11 vs. 12, p<0.0001). There were no significant between-group differences on any of the outcomes (symptomatic ICH within 24-36 hours, mortality within 3 months, or percentage of patients who were independent at 3 months); however, there was a trend towards increased number of patients treated from 3 to 4.5 hours who died (12.7% vs. 12.2%, adjusted OR=1.15, 95% CI 1.00-1.33, p=0.053) and who experienced symptomatic ICH (2.2% vs. 1.6%, adjusted OR=1.32, 95% CI 1.00-1.75, p=0.052). Additional analysis from the SITS-ISTR cohort was conducted to further explore the timing of alteplase treatment (Ahmed et al. 2010). In this study, patients treated within 3 hours (n=21,566) and 3 to 4.5 hours (n=2,376) of symptom onset between 2007 and 2010, were again compared. Significantly more patients treated from 3-4.5 hours experienced a symptomatic ICH (2.2% vs.1.7%, adjusted OR=1.44, 95% CI 1.05-1.97, p=0.02), and were dead at 3 months (12.0% vs. 12.3%, adjusted OR=1.26, 95% CI 1.07-1.49, p=0.005). Significantly fewer patients treated from 3-4.5 hours were independent at 3 months: (57.5% vs. 60.3%, adjusted OR=0.84, 95% CI 0.75-0.95, p=0.005). 

Emberson et al. (2014) used data from 6,756 patients from 9 major t-PA trials (NINDs a/b, ECASS I/II, III, ATLANTIS a/b, EPITHET, IST-3) to examine the effect of timing of administration more closely. Earlier treatment was associated with the increased odds of a good outcome, defined as an (mRS score of 0-1 (≤3.0 h: OR=1.75, 95% CI 1.35-2.27 vs. >3 to ≤4.5 h: OR=1.26, 95% CI 1.05-1051 vs. >4.5 h: OR=1.15, 95% CI 0.95-1.40). Framed slightly differently, when patient-level data from the same 9 major randomized controlled trials (RCTs) were recently pooled, Lees et al. (2016) reported that for each patient treated within 3 hours, significantly more would have a better outcome (122/1,000, 95% CI 16-171), whereas for each patient treated >4.5 hours, only 20/1,000 (95% CI -31-75, p=0.45) would have a better outcome. Wardlaw et al. (2013), including the results from 12 RCTs (7,012 patients), concluded that for every 1,000 patients treated up to 6 hours following stroke, 42 more patients were alive and independent (mRS<2) at the end of follow-up, despite an increase in early ICH and mortality. The authors also suggested that patients who did not meet strict licensing criteria due to age and timing of treatment (i.e., patients from the IST-3) trial were just as likely to benefit; however, early treatment, within 3 hours of stroke onset, was more effective. 

Results from several recent trials indicate that thrombolysis with t-PA can be used for patients outside of the previously established therapeutic window. In the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial (Ma et al., 2019), 225 patients with an ischemic stroke were included, where symptom onset was estimated to be 4.5 to ≤9 hours previously. Recruitment was suspended after the results of the WAKE-UP trial became available. The primary outcome (mRS 0-1 at 90 days) occurred in 35.4% of the patients in the alteplase group and 29.5% in the control (placebo) group. After adjustment for age and baseline severity, the likelihood of the primary outcome significantly increased in the alteplase group (RR=1.44, 95% CI 1.01–2.06), as did the proportion of patients who attained a mRS score of 0-2 at 90 days (49.6% vs. 42.9%; adjusted RR=1.36, 95% CI, 1.06 to 1.76); however there was no significant difference between groups in functional improvement at 90 days (i.e., shift in mRS scores; RR=1.55, 95% CI 0.96 to 2.49). The results from the Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke (WAKE-Up) trial (Thomalla et al., 2018) also suggest that highly selected patients with mild to moderate ischemic strokes and an unknown time of symptom onset, treated with alteplase may also benefit from treatment. Patients in this trial were not eligible for treatment with mechanical thrombectomy and were selected based on a pattern of DWI-FLAIR-mismatch. A significantly higher proportion of patients in the alteplase group had a favourable clinical outcome (mRS 0-1) at 90 days (53.3% vs. 41.8%, adj OR=1.61, 95% CI 1.06-2.36, p=0.02), although the risk of type 2 parenchymal hemorrhage was significantly higher compared with placebo (4% vs. 0.4%, adj OR=10.46, 95% CI 1.32 to 82.77, p=0.03).

The standard treatment dose of rt-PA is established to be 0.9 mg/kg, with a maximum dose of 90 mg. The non-inferiority of a lower dose (0.6 mg/kg) was recently examined in the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial (Anderson et al., 2016). The primary outcome (death or disability at 90 days) occurred in 53.2% of low-dose patients and 51.1% in standard-dose patients (OR=1.09, 95% CI 0.95-1.25, p for non-inferiority=0.51), which exceeded the upper boundary set for non-inferiority of 1.14. The risks of death within 90 days or serious adverse events did not differ significantly between groups (low dose vs. standard dose: 8.5% vs. 10.3%; OR=0.80, 95% CI 0.63-1.01, p=0.07 and 25.1% vs. 27.3%; OR=0.89, 95% CI 0.76-1.04, p=0.16, respectively), although the risk of symptomatic ICH was significantly higher in patients that received the standard dose of rt-PA.

Earlier treatment with thrombolytic agents is associated with better stroke outcomes. Using data from 61,426 Medicare patients aged ≥65 years admitted to Get With The Guidelines (GWTG)–stroke participating hospitals between January 1, 2006, and December 31, 2016, Man et al. (2020) found that among patients treated with intravenous alteplase, all-cause mortality was significantly higher in those that with door-to-needle times (DTN) of <45 minutes (vs. ≥45 minutes) and <60 minutes (vs. ≥60 minutes). The authors estimated that every 15-minute increase in DTN time was associated with a 4% increase in all-cause mortality within 90 minutes after hospital arrival, but not after 90 minutes, and a 2% increase in all-cause readmission. Analyzing data from the alteplase arm of seven major trials, the HEREMES Collaborators (Goyal et al., 2019) reported the common odds of a better outcome were decreased by each 60-minute delay in onset-to- treatment time (OTT) (OR=0.80, 95% CI 0.68–0.95). The odds of an excellent outcome (mRS 0-1) were also decreased by each 60-minute delay in OTT (OR=0.76, 95% CI 0.58–0.99).

Strategies to improve guideline adherence have been shown to help improve thrombolysis uptake and shorten thrombolysis process times. In Canada, following the initiation of an Improvement Collaborative intervention during 2016–2017, the number of patients receiving thrombolysis increased from 9.35% in the pre-period to 15.73% in the post-period, the median DTN time was reduced significantly from 70 to 39 minutes, and a significantly higher number of patients were discharged home in the post-period (46.5% to 59.5%) (Kamal et al., 2020). Using data from 71,169 patients admitted to 1,030 GWTG-participating hospitals, the outcomes and process times of patients admitted before and after the initiation of a quality improvement initiative (Target:Stroke) were examined (Fonarow et al., 2014). During that time the median DTN were reduced significantly from pre- to post- intervention (77 vs. 67 minutes, p<0.001), the percentage of patients treated within 60 minutes of stroke onset increased significantly from 26.5% to 41.3%, and in-hospital mortality decreased significantly from 9.93% to 8.25%. The percentage of patients discharged home also increased significantly from 37.6% to 42.7%.

The results from several studies indicate that tenecteplase, which has some pharmacokinetic advantages over alteplase, may be non-inferior to alteplase. Several clinical trials are ongoing and the results are not yet available. In these trials tenecteplase was compared with either alteplase (ATTEST2 NCT0281440) or placebo, or best medical management (TIMELESS NCT03785678, TWIST NCT03181360, and TEMPO-2 NCT02398656). Among completed trials comparing tenecteplase with alteplase, all were used as a potential bridging treatment prior to thrombectomy. The Alteplase Compared to Tenecteplase in Patients with Acute Ischemic Stroke (AcT) Trial (Mennon et al., 2022) was the first trial to report that tenecteplase is non-inferior to alteplase for 90-day functional outcomes. In this trial, 1,600 patients recruited from 22 centres who were eligible for treatment with alteplase (+/-thrombectomy) were randomized to receive intravenous tenecteplase (0.25mg/kg, maximum 25m) or 0.9 mg/kg alteplase. At a median of 97 days 36.9% of patients in the tenecteplase group achieved the primary outcome (mRS score of 0-1) vs.34.8% in the alteplase group (unadjusted difference=2.1%, 95% CI -2.6% to 6.9%; adjusted RR=1·1, 95% CI 1·0 to 1·2), meeting the non-inferiority threshold, (the lower bound 95% CI of which was set at >-5%). There was no significant difference between groups in mortality at 90 days (15.3% vs. 15.4%), or in the proportion with symptomatic ICH at 24 hours (3.4% vs. 3.2%). In contrast to these findings, the NOR-TEST 2 (Kvistad et al., 2022) was halted early due to safety concerns, which included an increased risk of intracranial hemorrhage and mortality; however, the dose in the tenecteplase group was higher (0.4 mg/kg) than is currently recommended (0.25 mg/kg). In the EXTEND-IA TNK (Campbell et al., 2018), which compared 0.25mg/kg tenecteplase vs. 0.9 mg/kg alteplase, at initial angiographic assessment, a significantly higher number of patients in the tenecteplase group achieved substantial reperfusion (22% vs. 10%, p=0.02 for superiority), although the percentage of patients who were functionally independent at 90 days or who had achieved an excellent outcome, did not differ between groups. 

The evidence base for the safety and effectiveness of the use of thrombolysis during pregnancy and the puerperium is derived from a series of case reports. The results from a total of 15 previous cases (10 intravenous and 5 intra-arterial), in addition to the presentation of their own case were summarized by Tversky et al. (2016). The neurological outcomes of these women were described as similar to non-pregnant patients who met the eligibility criteria. Most of the women who experienced significant recovery went on to deliver healthy babies. The evidence in terms of thrombolytic treatment for patients <18 years comes primarily from the International Pediatric Stroke Study (IPSS), an observational study (n=687) in which the outcomes of 15 children, aged 2 months to 18 years, who received thrombolytic therapy (9 with intravenous Alteplase, 6 with intra-arterial alteplase). Overall, at the time of hospital discharge, 7 patients were reported having no or mild neurological deficits, 2 had died, and the remainder had moderate or severe neurological deficits. The Thrombolysis in Pediatric Stroke (TIPS) study (Amlie-Lefond et al., 2009) is currently recruiting subjects for a five-year, prospective cohort, open-label, dose-finding trial of the safety and feasibility of intravenous and intra-arterial t-PA to treat acute childhood stroke (within 4.5 hours of symptoms). The TIPS investigators are aiming to include 48 subjects.

Sex and Gender Considerations

Possible interactions (treatment group x sex) were not analyzed in the initial reports of early trials of alteplase including NINDS (1995), ATLANTIS (1995), or ECASS (1995, 1998, 2008). The IST-III examined this relationship and reported there were no significant interactions based on sex, as did the authors of the ENCHANTED trial (2016) that examined low vs. standard dose alteplase. In more recent trials of late window treatment, including WAKE-UP (2018) and EXTEND (2019), the results of subgroup analyses based on sex were not conducted or reported. In the RCTs of tenecteplase including NOR-TEST 2 (2022), EXTEND-IA TNK (2018), and NOR-TEST (2017), the effect of treatment based on sex was not reported in subgroup analyses in the initial publications. Subgroup analysis for interactions based on sex for the AcT trial (2022) were conducted and no interactions were found.

Endovascular Thrombectomy

Over the past decade, the use of endovascular thrombectomy (EVT) for acute ischemic stroke has evolved, particularly in terms of patient selection criteria. Initially, EVT was limited to individuals with anterior circulation large vessel occlusion (LVO), small infarct core (ASPECTS ≥6), and treatment within a narrow time window (typically up to 6 hours from symptom onset). Compared with best medical management, the efficacy of EVT was established in landmark trials such as MR CLEAN, (Berkhemer et al. 2015) ESCAPE,(Goyal et al. 2015) and SWIFT PRIME. (Saver et al. 2015) Subsequent studies, including DAWN (Nogueira et al. 2018) and DEFUSE 3, (Albers et al. 2018) expanded eligibility to patients presenting up to 24 hours since last known well, provided there was a mismatch between clinical deficit and infarct core identified through advanced imaging. More recently, trials such as SELECT-2, (Albers et al. 2018) ANGEL-ASPECT, (Huo et al. 2023) and TENSION (Bendszus et al. 2023) have further broadened inclusion criteria by demonstrating the benefit of EVT in patients with large infarct cores (e.g., ASPECTS 3–5 or core volumes up to 100–150 mL). Treatment with EVT has been explored for the treatment of posterior artery infarctions (ATTENTION,(Hu et al. 2025) BAOCHE (Jovin et al. 2022) and BASICS (Langezaal et al. 2021)) and for medium and distal occlusions (ESCAPE-MeVO, (Goyal et al. 2025) DISTAL,(Psychogios et al. 2025) and DISCOUNT [NCT05030142]).

Several recent trials evaluated EVT in patients with medium-to-large core infarcts (ASPECTs 2-5) or high infarct core volumes. Traditionally these patients were considered poor candidates for reperfusion therapies. LASTE, (Costalat et al. 2024) TENSION, (Bendszus et al. 2023) ANGEL-ASPECT, (Huo et al. 2023) and SELECT-2, (Sarraj et al. 2023) trials all enrolled patients with anterior circulation LVO and low ASPECTS scores or large infarct volumes. LASTE included 333 patients with ASPECTS 0–5 (if less than 80 years old) identified on non-contrast CT, randomized within 6.5 hours of symptom onset. TENSION enrolled 253 patients with ASPECTS 3–5, on baseline computed tomography (CT) or diffusion-weighted imaging – magnetic resonance imaging (DWI-MRI) and occlusion defined by computed tomography angiography (CTA) or magnetic resonance angiography (MRA), treated within 12 hours. SELECT-2 (Sarraj et al. 2023) included 352 patients with ASPECTS 3–5 or infarct core measuring 50-100 mL using CT perfusion or diffusion-weighted MRI, with a treatment window of up to 24 hours. ANGEL-ASPECTS (Huo et al. 2023) included 456 patients with either an ASPECTS of 3–5 (regardless of core volume) or an ASPECTS of 0–2 with an infarct core volume of 70–100 mL, assessed within 24 hours of symptom onset. Additionally, patients with ASPECTS > 5 were included only if they had a core volume between 70–100 mL and presented between 6 and 24 hours after onset. All four of the trials were stopped early due to demonstrated efficacy of EVT at interim analysis, whereby EVT was associated with significantly improved functional outcomes (favourable shift in the distribution of mRS scores) at 90 days compared to best medical management alone. The benefit was consistent across subgroups, including those with ASPECTS as low as 3 and large core volumes. While symptomatic intracranial hemorrhage (sICH) occurred more frequently in the EVT group, overall mortality was either unchanged or reduced. The results were similar in RESCUE-Japan LIMIT, (Yoshimura et al. 2022) although the benefit was not as pronounced. The TESLA trial,(Yoo et al. 2024) included 300 patients with ASPECTS 2–5 up to 24 hours from last known well.  The mean average utility weighted mRS score at 90 days was not significantly different between the groups, nor was the percentage of patients with an mRS score of 0-2 at 90 days significantly higher in the EVT group (14.5% vs. 8.9%, RR=1.64, 95% CI 0.86-3.12); however, the percentage of patients with an mRS score of 0-3 at 90 days was significantly higher in the EVT group. Across all trials, the majority of patients (61%-69%) were dead or severely disabled at 90 days, despite EVT.

The use of EVT for medium vessel occlusions (MeVOs), including occlusions in the M2/M3 segments of the middle cerebral artery (MCA), anterior cerebral artery (ACA), and posterior cerebral artery (PCA) is a new area of interest.  While EVT is well established for anterior LVOs, its role in MeVOs remains under investigation. In the ESCAPE-MeVO trial, (Goyal et al. 2025) EVT in addition to best medical management was not associated with benefit compared with best medical management only, in 530 patients with occlusions located in the M2 segment of the proximal MCA (23.3%), M2 segment of the distal MCA (20.3%) and the M3 segment of MCA (41.4%). The median mRS score at 90 days was 2 in both groups. The likelihood of the primary outcome (mRS 0-1 at 90 days) was not significantly higher in the EVT group (adjusted common RR=0.95, 95% CI 0.79 to 1.15), nor was the likelihood of an mRS score of 0 -2 at 90 days (adjusted RR=0.92, 95% CI 0.80 to 1.05). Ninety-day mortality was significantly higher in the EVT group (13.3% vs. 8.4%, HR=1.82, 95% CI 1.06 to 3.12). The incidence of serious adverse events was higher in the EVT group (33.9% [in 87 patients]) than in the usual-care group (25.7% [in 70 patients]). In the DISTAL trial, (Psychogios et al. 2025) which included 543 patients with an isolated occlusion of medium or distal vessels (M2 [44.0%], M3 [26.9%], M1 [13.4%], P2 [13.4%], and P1 [5.5%] segments), there was no significant difference between groups in the distribution of mRS scores at 90 days (median mRS score was 2 vs. 2; common OR=0.90; 95% CI 0.67 to 1.22). Preliminary results from the DISCOUNT trial (NCT05030142), which was terminated early following the first interim analysis also suggests potential harm associated with EVT treatment. The primary outcome (mRS 0-2 at 90 days) occurred in 45/75 patient (60%) in the EVT group vs. 59/77 (77%) in the usual care group (adjusted OR=0.42, 95% CI 0.2-0.88). Additionally, sICH occurred in 12% of the patients in the EVT group vs. 6% in the usual care group.

Intra-arterial thrombolysis administered following EVT may help to dissolve residual thrombus in distal vessels, potentially improving microvascular reperfusion and functional outcomes, without significantly increasing the risk of sICH. However, in the POST-UK(Liu et al. 2025) and POST-TNK (Huang et al. 2025) trials, patients with anterior circulation LVO infarcts, who achieved near complete or complete reperfusion following EVT and who received intra-arterial thrombolysis post procedure, with either tenecteplase or urokinase, did not have a higher likelihood of achieving an mRS score of 0-1 at 90 days compared with patients who did not receive thrombolysis, nor did thrombolysis reduce the risk of 90-day mortality. In contrast, preliminary results presented at the International Stroke Conference in 2025, from the PEARL trial (NCT05856851) indicated that patients with anterior circulation LVO infarcts who achieved near complete or complete reperfusion (expanded Thrombolysis in Cerebral Infarction score of 3 or 2b50) following EVT, and received thrombolysis with either tenecteplase or alteplase post EVT had higher likelihood of having an mRS score of 0-1 at 90 days (44.8% vs 30.2%; RR=1.45, 95% CI 1.08-1.96), with no increased risk of sICH within 36 hours or 48 hours. Intra-arterial thrombolysis post EVT did not increase the likelihood of freedom from disability at 90 days in patients with posterior circulation strokes in the ATTENION-IA trial.(Hu et al. 2025) 

For large artery occlusions in the posterior circulation, 4 RCTs have compared EVT with best medical management only, with conflicting results. In the ATTENTION trial (Tao et al. 2022) which included 342 patients, recruited  <12 hours from onset with NIHSS ≥10, a significantly higher percentage of patients in the EVT group achieved an mRS score of 0-3 compared with those in the medical management group (46.0% vs. 22.8%; adjusted RR= 2.06, 95% CI 1.46 to 2.91, NNT=4). Ninety-day mortality was also lower (36.7% vs. 55.3%: adj RR= 0.7,95% CI 0.5 to 0.8, NNT=5.4). A benefit of EVT was also demonstrated in the BAOCHE trial, (Jovin et al. 2022) which included 217 patients enrolled within 6–24 hours after symptom onset and NIHSS ≥6. In contrast, Liu et al. (Liu et al. 2020) included 131 adult patients presenting within 8 hours of vertebrobasilar occlusion to 28 centres in China in the BEST trial. The trial was terminated early due to excessive crossovers and low enrollment. In the intention-to-treat analysis, the percentage of patients with a favourable outcome (mRS 0-3) at 90 days was not significantly higher in the intervention group (42% vs. 32%; adjusted [age and baseline NIHSS] OR=1.74, 95% CI 0.81–3.74, p=0.23), nor was the percentage of patients who were functionally independent; however, in both the per protocol and as treated analyses, the percentage of patients with a favourable outcome was significantly higher in the EVT group. There was no significant difference between groups in 90-day mortality or in sICH. The BASICS trial recruited 300 patients with basilar artery occlusion. (Langezaal et al. 2021) Intravenous alteplase was used in close to 80% of patients in both the EVT and control groups. The percentage of patients in the EVT group who experienced a favourable (mRS 0-3) or excellent (mRS 0-2) outcome at 90 days was not significantly higher in the EVT group. The results of these two RCTs and three observational studies were pooled in a systematic review by Katsanos et al. (Katsanos et al. 2021) With low certainty of evidence, there was no significant difference found between the groups for the primary outcome of mRS score 0–3 at 90 days (RR= 0.97, 95% CI: 0.64-1.47). There were no significant differences between groups for the proportion of patients with mRS scores of 0-2 at 3 months, all-cause mortality or functional outcome (ordinal shift analysis of mRS scores), with significant heterogeneity. The risk of sICH was significantly higher in the EVT group (RR=5.42, 95% CI 2.74-10.71).

To date, 6 RCTs have been published comparing direct EVT with intravenous alteplase prior to EVT for LVO infarcts (i.e., bridging), with conflicting results. The most recent trials, DIRECT SAFE (Mitchell et al. 2022) and SWIFT DIRECT (Fischer et al. 2022) both reported that EVT alone was not shown to be non inferior to EVT plus thrombolysis. For the primary outcome of mRS score of 0-2 at 90 days, the adjusted differences in proportions between groups were −7.3% (95% CI −16.6 to 2.1, p=0·12) in the SWIFT-DIRECT trial and −5.1% (95% CI −16 to 5.9, p=0.19) in the DIRECT SAFE trial, which crossed the lower boundaries of the two-sided 95% confidence interval set for non-inferiority at 12% and 10%, respectively. Two previously published trials, the SKIP trial (Suzuki et al. 2021) and MR CLEAN–NO IV trial, (LeCouffe et al. 2021) also did not demonstrate the non-inferiority of EVT alone. In the MR CLEAN–NO IV trial, the adjusted common odds ratio (OR) for shift in mRS score at 90 days was 0.84 (95% CI 0.62 to 1.15), which showed neither superiority nor noninferiority of EVT alone. In the SKIP trial, (Suzuki et al. 2021) mechanical thrombectomy alone was not associated with a favorable shift in the distribution of the mRS score at 90 days (OR=0.97, 1-sided 97.5% CI 0.60 to ∞; noninferiority p =0.27, which crossed the 0.74 threshold). In contrast, DIRECT-MT (Yang et al. 2020) and DEVT (Zi et al. 2021) reported that EVT alone was non-inferior to alteplase followed by EVT. In the DEVT trial, 54.3% of patients in the EVT group achieved functional independence vs. 46.6% in the bridging group (difference= 7.7%; 1-sided 97.5% CI −5.1% to ∞; p = .003 for noninferiority, threshold for non-inferiority was -10%). Finally, EVT alone was noninferior to bridging in an ordinal shift analysis of mRS scores at 90 days (adjusted common OR=1.07; 95% CI 0.81 to 1.40; p=0.04 for noninferiority) in the DIRECT-MT trial. (Yang et al. 2020) In a systematic review and patient-level meta-analysis including the results from all 6 RCTs described above, (Majoie et al. 2023) non-inferiority of EVT alone was not established. For an average patient, the estimated difference in probability of reaching functional independence (mRS 0-2) at 90 days when omitting intravenous thrombolysis was –2.5% (95% CI –6.5% to 1.0%). Thrombolysis prior to EVT using tenecteplase has also been evaluated. In the BRIDGE-TNK trial, (Qiu et al. 2025) the likelihood of achieving an mRS score of 0-2 at 90 days was significantly higher in patients who received tenecteplase (0.25 mg/kg) prior to EVT compared with those who did not (52.9% vs. 44.1%; adjusted RR=1.18, 95% CI 1.01–1.39).

Sedation
There have been a limited number of RCTs specifically comparing the use of general anesthesia versus conscious sedation for EVT procedure. The results are conflicting. Results from the AMETIS trial, (Chabanne et al. 2023) indicated that conscious sedation increased the probability of a good outcome (mRS 0-2) at 90 days by 29%, while 10.9% of the conscious sedation patients converted to general anesthesia. Previous single-centre trials including GOLIATH, (Simonsen et al. 2018) AnStroke Trial, (Löwhagen Hendén et al. 2017) and SIESTA (Schönenberger et al. 2016) trials, reported that general anesthesia was associated with better outcome (mRS 0-2) at 90 days. The conversion from conscious sedation to general anesthesia in these trials occurred in 6.3%, 14.3% and 15.5% of patients. Preliminary results from the SEdation Versus General Anesthesia for Endovascular Therapy in Acute Ischemic Stroke (SEGA, NCT03263117), also suggest that general anaesthesia was associated with a significantly higher likelihood of functional independence measured by mRS at 90 days (OR=1.22).

A systematic review (Campbell et al. 2021) including the results of 3 RCTs (GOLIATH, AnStroke and SIESTA) in addition to data from a pilot study of 40 patients, (Sun et al. 2020) found the odds of successful recanalization and good functional outcome were significantly higher in the general anesthesia group (OR=2.14, 95% CI 1.26-3.62, p=0.005 and OR=1.71, 95% CI: 1.13-2.59; P=0.01, respectively), with no significant differences between groups in the risk of mortality or intracerebral hemorrhage. A Cochrane review (Tosello et al. 2022) included the results from 7 RCTs and reported on both short and long-term outcomes. In the short-term, general anesthesia was not associated with better early neurological recovery or stroke related mortality, but was associated with a decreased risk of adverse events and greater likelihood of artery revascularisation. The likelihood of having a good functional outcome (mRS ≤2) at 90 days was not significantly higher in the general anesthesia group.

The outcomes of patients who received general anesthesia or conscious sedation has also been examined within the landmark EVT trials. Using the results from 7 RCTs including MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, PISTE and THRACE,  Campbell et al. (Campbell et al. 2018) performed a patient-level meta-analysis comparing the outcomes of patients randomized to the EVT groups who had received general anesthesia or non-general anesthesia.  The odds of improved outcome using non-general anesthesia were significantly higher in ordinal analysis of mRS scores. The authors estimated for every 100 patients treated under general anesthesia (compared with non-general anesthesia), 18 patients would have worse functional outcome, including 10 who would not achieve functional independence. There was no increased risk of 90-day mortality associated with general anesthesia.

Sex and Gender Considerations

In a patient-level meta-analysis using data from 5 RCTs, conducted by the HERMES Collaborators, (Goyal et al. 2016) there were no significant treatment effects of EVT based on pre-specified subgroups including age, sex, NIHSS, site of intracranial occlusion, intravenous alteplase received or ineligible, ASPECTS, time from onset to randomization, or the presence of tandem cervical carotid occlusion. The same finding was reported in another Hermes Collaboration, using data from 7 RCTs, (Chalos et al. 2019) which was confined to an examination of sex differences. No evidence of heterogeneity of treatment effect based on sex was detected in prespecified subgroups in the DEFUSE 3 trial, (Albers et al. 2018) DAWN trial, (Nogueira et al. 2018) ESCAPE, (Goyal et al. 2015) or THRACE(Bracard et al. 2016) trials, where subgroup analysis was performed. In the two, most recent trials examining  EVT with bridging therapy, (DIRECT SAFE, (Mitchell et al. 2022)  and SWIFT DIRECT (Fischer et al. 2022)), differences in sexes between treatment groups were examined in prespecified subgroup analyses; none were found. Sex differences were examined specifically in 3,422 patients included in the IRETAs database who had undergone EVT treatment since 2011.(Casetta et al. 2022) The outcomes of women vs. men were compared in the original cohort (1,621 men and 1,801 women) and in a propensity-matched cohort of 1,150 men and women. In both the whole cohort and matched-pair cohort, the odds of functional independence at 90 days given EVT treatment were significantly higher in women (OR= 1.19, 95% CI 1.02–1.38 and OR=1.25, 95% CI 1.04-1.51, respectively). Time metrics (e.g., onset to groin puncture) were similar for men and women. Kobeissi et al.(Kobeissi et al. 2023) included 10 studies (10,209 patients) treated with EVT. There was no significant difference between the sexes in the odds of achieving the primary outcome (mRS 0-2 at 90 days: OR= 1.16, 95% CI 0.87-1.56), nor were there any differences between groups on any of the secondary outcomes (mRS 0-1, sICH, thrombolysis in cerebral infarction (TICI) score of 2b-3, and mortality).

Note: The CSBPR Acute Stroke Management writing group and the National Advisory Committee strongly endorse all of the recommendations in Section 5, based on available research evidence, clinical expertise, and international consensus. A recent technology assessment report provided a focused assessment of some of these data and suggested there is “substantial uncertainty” regarding the effectiveness of alteplase; however, this technology report did not synthesize all the available evidence and their conclusions differ from most other international guideline organizations as well as the CSBPR writing group. Refer to evidence table (CADTH, 2022).