A 2025 meta-analysis systematically evaluated the efficacy and safety of intravenous thrombolysis (IVT) administered beyond 4.5 hours of ischemic stroke onset in adult patients who did not undergo mechanical thrombectomy. The analysis included data from eight randomized controlled trials (RCTs), encompassing a pooled cohort of 1,742 patients across 263 centers globally. Selection criteria included RCTs comparing IVT (using either alteplase or tenecteplase [TNK]) with standard medical care or placebo beyond the traditional 4.5-hour time window, with primary endpoints focused on functional outcomes measured by the modified Rankin Scale (mRS 0–1 and mRS 0–2) at 90 days, as well as rates of symptomatic intracerebral hemorrhage (sICH) and all-cause mortality. Patient populations were derived from diverse regions, including China, Europe, and Australia, and eligibility was determined using advanced imaging modalities such as diffusion-weighted imaging–fluid-attenuated inversion recovery (DWI-FLAIR) mismatch or perfusion-based imaging. Of note, three RCTs specifically evaluated TNK (EXIT-BT - last known well to intervention 5.5 (5.2–5.7) hrs, ROSE-TNK - 11.47±4.70 hrs, and TRACE-III - 12.4 (8.8–16.3) hrs), enrolling a total of 706 patients (353 in the TNK group and 353 in the control group; all conducted in China). [1]
The analysis demonstrated that IVT administered beyond 4.5 hours was associated with significantly improved functional outcomes compared to standard medical care. Specifically, patients receiving IVT had higher odds of achieving excellent (mRS 0–1: odds ratio [OR] 1.43, 95% confidence interval [CI] 1.17–1.75; p= 0.0005) and good (mRS 0–2: OR 1.36, 95% CI 1.12–1.66; p= 0.002) recovery at 90 days, with negligible heterogeneity across studies (I² = 0%). However, IVT recipients experienced increased rates of sICH (OR 4.25, 95% CI 1.67–10.84; p= 0.002), although mortality at 90 days did not differ significantly between IVT and control groups (OR 1.28, 95% CI 0.87–1.89; p= 0.21). Subgroup analyses revealed that patients selected with perfusion imaging had marginally higher odds of excellent outcomes (OR 1.45, 95% CI 1.08–1.94) compared to those selected using a DWI-FLAIR mismatch approach (OR 1.34, 95% CI 0.94–1.91). Additionally, subanalysis showed the use of TNK (OR 1.47, 95% CI 1.06–2.04) yielded a comparable benefit to alteplase (OR 1.38, 95% CI 1.08–1.78) in the extended window. These findings underscore the efficacy of imaging-guided IVT beyond 4.5 hours and suggest a potential role for broader thrombolytic use in settings lacking access to endovascular therapy. [1]
A 2024 systematic review and meta-analysis synthesized data from three RCTs evaluating the efficacy and safety of IV TNK 0.25 mg/kg in patients with acute ischemic stroke (AIS) presenting in the extended time window, defined as beyond 4.5 hours from last-seen-well up to 24 hours. The included trials, TWIST, TIMELESS, and ROSE-TNK, enrolled a total of 1,116 patients (556 receiving TNK and 560 controls). The eligibility was based on neuroimaging and clinical selection criteria varying across trials. Primary efficacy was defined as the achievement of an excellent functional outcome (mRS score ≤1) at 3 months. Secondary endpoints encompassed good outcome (mRS ≤2), reduced disability (≥1-point reduction on mRS), sICH, any ICH, and 3-month mortality. A random-effects model was employed to generate pooled estimates, with risk ratios (RR) and common odds ratios (cOR) accompanied by 95% CIs. The meta-analysis demonstrated that TNK administration was associated with a statistically significant improvement in the likelihood of excellent 3-month functional outcome compared to controls (RR 1.17; 95% CI 1.01–1.36; I²=0%). However, the differences for good outcome (RR 1.05; 95% CI 0.94–1.17) and reduced disability (adjusted cOR 1.14; 95% CI 0.92–1.40) were not statistically significant. Importantly, safety outcomes indicated comparable risks between TNK and control groups: sICH (RR 1.67; 95% CI 0.70–4.00), any ICH (RR 1.08; 95% CI 0.90–1.29), and 3-month mortality (RR 1.10; 95% CI 0.81–1.49), with no detected heterogeneity across trials. Subgroup analyses stratified by endovascular therapy (EVT) administration revealed consistent outcomes in reduced disability, regardless of EVT status. Interpretation is supported by a low pooled sICH rate in the TNK group (2%), aligning with previous reports of favorable hemorrhagic profiles for TNK at this dose. These findings reinforce the potential utility of TNK 0.25 mg/kg as a thrombolytic agent in selected AIS patients beyond the standard treatment window, pending further evidence from ongoing phase III trials. [2]
A 2025 systematic review and meta-analysis of randomized clinical trials investigated the efficacy and safety of administering TNK in AIS patients who presented within a 4.5 to 24-hour window from the last known well (LKW) time. The analysis included three RCTs, encompassing a total of 1,054 patients, with 532 receiving TNK and 522 receiving standard medical therapy. The pooled data demonstrated that TNK treatment was associated with a 33% higher likelihood of achieving functional independence (mRS 0–2) at 90 days, as evidenced by an odds ratio of 1.33, with a 95% confidence interval of 1.04–1.70 and a p-value of 0.023. However, no significant difference was observed in the ordinal mRS shift. Safety analysis indicated no statistically significant increase in sICH rates or 90-day mortality among patients treated with TNK compared to standard medical therapy. The analysis further detailed the inclusion criteria and methodologies of the RCTs, highlighting that patient selection varied slightly in terms of pre-stroke mRS scores and imaging criteria, such as computed tomography perfusion (CTP) and magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI). The trials utilized different definitions for outcome measures, such as early neurological improvement and sICH, contributing to the heterogeneity observed in the pooled results. Despite these variations, the comprehensive data synthesis suggested that TNK might offer an effective treatment option for AIS patients beyond the traditional 4.5-hour window, particularly in settings with limited access to endovascular thrombectomy (EVT). This expansion of the therapeutic window could significantly increase the number of patients eligible for treatment, potentially reducing the global burden of stroke-related disability. However, the analysis also called for larger, well-powered studies to confirm these findings and address the limitations of the current data regarding patient selection and heterogeneity. [3]
A 2021 meta-analysis evaluated the use of IV alteplase in patients who presented with a stroke of unknown time of onset, particularly in those with perfusion-diffusion MRI, perfusion computed tomography (CT), or MRI with DWI-FLAIR mismatch. Results from four randomized controlled trials (N= 843; alteplase n= 429) demonstrated that favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS] = no disability) at 90 days occurred more in the alteplase group vs. placebo (47% vs. 39%; adjusted odds ratio [aOR] 1.49, 95% confidence interval [CI] 1.10 to 2.03, p= 0.011). Additionally, patients who received alteplase had a significant shift towards a better functional outcome (adjusted common odds ratio 1.38, 95% CI 1.05 to 1.80, p= 0.019) and a higher odds of independent outcome as defined as score 0-2 on the mRS (aOR 1.50, 95% CI 1.06 to 2.12). Numerically, more patients in the placebo group (25%) were severely disabled or dead (mRS 4–6) compared to the alteplase group (21%). Death occurred in 6% patients with alteplase and 3% patients among controls (aOR 2.06, 95% CI 1.03 to 4.09, p= 0.040). Symptomatic intracerebral hemorrhage (sICH) occurred more frequently in alteplase-treated patients than the controls (3% vs. 1%, aOR 5.58, 95% CI 1.22 to 25.50, p= 0.024). Pre-defined subgroup analysis did not reveal a significant heterogeneity of the treatment effect across different variables, including dose of alteplase (0.9 vs. 0.6 mg/kg body weight), age (≤60 vs >60 years), sex, and baseline stroke severity (NIHSS ≤10 vs.>10). On the other hand, patients with a history of stroke and transient ischemic attack experienced a larger benefit with IV alteplase (OR 4.5, 95% CI 1.58 to 12.8, p= 0.02). Although the overall rate of sICH in this analysis was higher compared to the placebo, it was similar to the rate (3.5%) based on a previous pooled analysis of patients with known onset of ischemic stroke receiving thrombolysis. [4]
As the patients included in this meta-analysis had mild to moderate strokes (median NIHSS score of 7), results may not be applicable to patients with severe stroke and large core. A dose-effect of alteplase (0.6 mg/kg vs. 0.9 mg/kg) could not be definitively concluded, as only one of the four trials used the lower dose. Despite the fact that 60% of the patients were from the WAKE-UP trial, it’s concluded that in stroke patients with unknown time of onset with a DWI-FLAIR or perfusion mismatch, IV alteplase resulted in better functional outcomes at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes regardless of the increased risk of sICH. [4]
A 2025 meta-analysis included 6 randomized controlled trials (N= 1,955 patients) to assess use of tenecteplase in AIS patients presenting after 4.5 hours of symptom onset or wake up AIS. A pooled analysis found treatment with tenecteplase was associated with a significantly improved excellent functional outcome on 90 days (OR 1.35, 95% CI 1.12 to 1.64) compared to control. However, no significant association was found between tenecteplase and control for good functional outcome, all-cause death, sICH, or any ICH. Ultimately, administration of tenecteplase even in an extended time window for AIS patients resulted in more favorable neurological outcomes. [5]