Endovascular thrombectomy with versus without intravenous thrombolysis for acute ischaemic stroke.

Rationale: Acute ischaemic stroke is a major cause of death and disability worldwide. Once diagnosed, treatment is generally limited to intravenous thrombolysis (IVT), endovascular thrombectomy, or both. Intravenous thrombolysis has theoretical benefits (enhancing reperfusion, dissolving smaller thrombi) and harms (delaying time to endovascular intervention, allergic reaction, increased bleeding risk).

Objectives: To assess the effects of endovascular thrombectomy with IVT versus without IVT on functional independence (defined as a modified Rankin Scale score (mRS) < 3) within 90 days in people with acute ischaemic stroke.

Search methods: We searched CENTRAL, MEDLINE, Embase, Scopus, LILACS, Google Scholar, the International HTA database, and two trial registries to November 2023.

Eligibility criteria: We included randomised controlled trials of adults with acute ischaemic stroke who received endovascular therapy and were randomised to either intravenous thrombolysis within 4.5 hours or a control.

Outcomes: Outcomes were: functional independence (mRS score < 3), excellent functional outcome (mRS score < 2), mortality, asymptomatic intracranial haemorrhage, symptomatic intracranial haemorrhage, successful revascularisation (thrombolysis in cerebral infarction (TICI) grades 2b to 3), and complete revascularisation (TICI grade 3 only), within 90 days.

Risk of bias: We used the Cochrane RoB 2 tool to assess the following potential sources of bias for each outcome: bias arising from the randomisation process; bias due to deviations from intended interventions; bias due to missing outcome data; bias in measurement of the outcome; and bias in selection of the reported result.

Synthesis methods: We pooled outcome data using the random-effects model and performed meta-analyses using the Mantel-Haenszel method. We assessed the statistical heterogeneity of pooled data by visually inspecting forest plots to consider the direction and magnitude of effects, and used the Chi² test and I² statistic to quantify the heterogeneity. We used GRADE to assess the certainty of evidence.

Included studies: We included six studies, with a total of 2336 participants (1166 control and 1170 intervention). The mean age was 71 years. There were 1034 women and 1302 men. Four studies used alteplase 0.9 mg/kg, one study used alteplase 0.6 mg/kg, and one study used either alteplase 0.9 mg/kg or tenecteplase 0.25 mg/kg. There were no important variations in the outcomes reported across studies.

Synthesis of results: All six studies were at overall low risk of bias for each outcome. There was probably little to no difference in functional independence between the IVT and control groups (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.92 to 1.14; P = 0.62; 6 studies, 2336 participants; moderate-certainty evidence). There was no evidence of a difference in excellent functional outcome between the IVT and control groups (RR 0.99, 95% CI 0.92 to 1.05; P = 0.67; 6 studies, 2336 participants; high-certainty evidence). There was no evidence of a difference in mortality between the IVT and control groups (RR 0.94, 95% CI 0.78 to 1.14; P = 0.54; 6 studies, 2336 participants; high-certainty evidence). There was no evidence of a difference in asymptomatic intracranial haemorrhage between the IVT and control groups (RR 1.13, 95% CI 1.00 to 1.29; P = 0.06; 6 studies, 2334 participants; high-certainty evidence). There was probably little to no difference in symptomatic intracranial haemorrhage between the IVT and control groups (RR 1.20, 95% CI 0.84 to 1.70; P = 0.31; 6 studies, 2336 participants; moderate-certainty evidence). There was a higher rate of successful revascularisation with IVT over control (RR 1.04, 95% CI 1.01 to 1.08; P = 0.008; 6 studies, 2326 participants; high-certainty evidence). There was a higher rate of complete revascularisation with IVT over control (RR 1.14, 95% CI 1.02 to 1.28; P = 0.02; 5 studies, 2037 participants; high-certainty evidence). Limitations included: differences in inclusion and exclusion criteria between studies (e.g. age thresholds, pre-existing comorbidities or baseline functional status, time periods, diagnostic imaging, specific vessels); specific endovascular device used; thrombolysis medication and dose; and potential conflict of interest, as multiple study authors reported receiving funding or fees from pharmaceutical companies. For functional independence, assessed as an mRS score < 3 within 90 days, we downgraded the certainty of evidence by one level due to a high I² value, indicating that heterogeneity may be substantial for this outcome. For symptomatic intracranial haemorrhage within 90 days, we downgraded the certainty of evidence by one level because the 95% CI included both important benefits and important harms.

Authors' conclusions: The evidence does not currently support a clear benefit or harm for routine intravenous thrombolysis amongst people receiving endovascular thrombectomy. Amongst participants receiving endovascular thrombectomy, IVT did not demonstrate evidence of a difference in functional independence, excellent functional outcome, mortality, and asymptomatic intracranial haemorrhage, or symptomatic intracranial haemorrhage, when compared with no IVT. However, IVT did result in a higher rate of successful and complete revascularisation when compared with no IVT. Future research should include more high-quality trials to further evaluate the role of intravenous thrombolysis in people receiving endovascular thrombectomy to provide more robust data and further narrow the confidence intervals. Future research should also identify whether time- and person-specific factors influence the effect of IVT amongst those receiving endovascular thrombectomy.

Funding: None REGISTRATION: Gottlieb M, Carlson JN, Westrick J, Peksa GD. Endovascular thrombectomy with versus without intravascular thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews. 2024;2:1465-1858.