Direct Thrombectomy vs. Combined Treatment With Intravenous Thrombolysis in the Extended Time Window: A Target Trial Emulation

Background In the early time window, direct mechanical thrombectomy (MT) is not non-inferior to combined treatment with intravenous thrombolysis (IVT) for patients with large vessel occlusion (LVO) stroke, while its non-inferiority in the extended time window remains uncertain. This study assessed whether direct MT is non-inferior to IVT + MT beyond 4.5 h or at wake-up. Methods We emulated a non-inferiority trial, comparing direct MT vs. IVT + MT, including patients with anterior circulation LVO between 4.5 and 24 h from symptom onset or at wake-up, without contraindications to IVT and with target perfusion mismatch. We used inverse probability weighting (IPW) adjusted for pre-specified covariates. The primary outcome was 90-day mRS 0–2, with non-inferiority defined by a lower 95% CI boundary of the Risk Difference (RD) ≥ −1.3%. Results Among 347 patients, 212 received direct MT and 135 received IVT + MT. After IPW, patients treated with direct MT and IVT + MT had a similar likelihood of achieving a 90-day mRS of 0–2 (adjRD –2.90 [95% CI –6.64 to 0.84]) with the lower boundary of the RD 95% CI crossing the non-inferiority margin. Additionally, direct MT was associated with a shift toward a higher score on the 90-day mRS (adjusted Common OR 1.59 [95% CI 1.05–2.39]), not confirmed after IPW, and with lower odds of successful recanalization (adjOR 0.38 [95% CI 0.18–0.78]). Rates of 90-day mRS 0–1, sICH, and mortality were similar between groups. Conclusions In our target trial emulation, direct MT was not non-inferior to IVT + MT treatment beyond 4.5 h from symptom onset or at wake-up, with IVT before MT yielding higher successful recanalization rates.