Precision Reperfusion Therapy for Disabling Minor Stroke With Large Vessel Occlusion Beyond Time Window

Stroke is a leading cause of death and disability. Minor stroke (NIHSS ≤5) accounts for 48% of ischemic strokes, with its "mild symptom" presentation masking the potential risk of disability. About 30% of patients have poor 90-day outcomes (mRS ≥2) due to disabling deficits (e.g., unilateral limb weakness ≥2, aphasia, or hemianopia), resulting not only in loss of personal independence but also a surge in family and social medical expenses. Notably, up to 55% of patients present beyond the standard time window (4.5-24 hours). Having missed the golden window for thrombolysis, they are often relegated to conservative treatment. When complicated by large vessel occlusion (LVO), the recanalization rate with dual antiplatelet therapy (DAPT) alone is less than 5%, creating a "silent epidemic" of accumulating disability risk.

The PRISMS trial showed no benefit of thrombolysis within 4.5 hours in non-disabling stroke, but due to the exclusion of the LVO subgroup and early termination (actual enrollment only 313), the potential benefit for disabling patients remains an open question. The TEMPO-2 trial found increased mortality (5% vs 1%) in patients receiving tenecteplase (TNK) without selecting for ischemic penumbra, potentially masking recanalization benefits in certain subgroups (e.g., those with mismatch ratio ≥1.8). A subgroup analysis of TEMPO-2 for onset 4.5-12h, minor disabling stroke (median NIHSS 4), showed a 3-month mRS 0-1 rate of 61.7% in the tenecteplase group vs. 47.2% in the standard care group, but this was not statistically significant due to the small subgroup size. While CHANCE series studies confirmed that DAPT reduces the risk of stroke recurrence by 33%, it is ineffective for LVO recanalization, leaving disability rates high.

The 2023 "Chinese Guidelines for Clinical Management of Cerebrovascular Diseases" and the European Stroke Organisation (ESO) guidelines explicitly state that treatment for disabling minor stroke with LVO beyond the time window (4.5-24 hours) lacks a Class I recommendation (Evidence Level C), leaving clinical decision-making in a dilemma without evidence-based guidance.

DAWN/DEFUSE-3/TRACE Ⅲ studies validated the value of imaging selection in thrombectomy, but they excluded patients with NIHSS ≤5, leaving a gap in penumbra assessment criteria for minor stroke.

Therefore, the investigators designed the TIME-MINOR trial to evaluate whether intravenous tenecteplase, guided by multimodal imaging, can improve outcomes in patients with NIHSS ≤5 and LVO presenting 4.5-24 hours after onset.

• Proportion of patients with mRS 0-2 at 90 days. [Time frame: 3 months after randomization]
• Distribution of mRS score at 90 days. [Time frame: 3 months after randomization]
• Rate of vessel recanalization. [Time frame: 3 months after randomization]
• Proportion of patients undergoing rescue mechanical thrombectomy. [Time frame: cerebral infarction within 24 hours of onset]
• Proportion of patients with NIHSS score 0-1 or an improvement of ≥4 points from baseline at 24 hours, 7 days, or discharge (whichever occurs first). [Time frame: 24 hours, 7 days, or discharge after randomization]
• Proportion of patients with neurological deterioration at 90 days (increase in NIHSS score ≥4 points from baseline at the 90-day follow-up). [Time frame: 3 months after randomization]
• New vascular events within 90 days (including ischemic stroke, hemorrhagic stroke, myocardial infarction, and vascular death), with independent evaluation of each event. [Time frame: 3 months after randomization]