Beyond the Clock: Expanding the Thrombectomy Window in Acute Stroke

Mechanical thrombectomy has revolutionized the treatment of acute ischemic stroke due to large vessel occlusion (LVO). What began as a 6-hour treatment window has progressively expanded—first to 24 hours for anterior circulation strokes, then to posterior circulation, and now emerging evidence suggests benefit even beyond 24 hours in select patients.

The Initial 6-Hour Window: 2015 Trials

The modern era of thrombectomy was established in 2015 with five landmark trials demonstrating the benefit of endovascular therapy within 6 hours of stroke onset.

MR CLEAN (2015)

MR CLEAN was the first positive thrombectomy trial, enrolling 500 patients with anterior circulation LVO within 6 hours of onset. Thrombectomy plus standard care showed improved functional outcomes compared to standard care alone: mRS 0–2 at 90 days in 32.6% vs. 19.1% (adjusted OR 1.67). No significant difference in mortality or symptomatic ICH was observed.

EXTEND-IA (2015)

EXTEND-IA used perfusion imaging to select patients with salvageable tissue. Thrombectomy after IV alteplase achieved dramatic results: mRS 0–2 at 90 days in 71% vs. 40% (P=0.01), with 0% sICH in the intervention arm. The trial pioneered the use of automated perfusion software (RAPID) for patient selection.

Clinical Pearl: The 2015 trials (MR CLEAN, EXTEND-IA, ESCAPE, SWIFT PRIME, REVASCAT) collectively established thrombectomy as standard of care for anterior LVO within 6 hours, with NNT of approximately 2.6 for functional independence.

Extending to 24 Hours: DAWN (2018)

The DAWN trial fundamentally changed the treatment paradigm by demonstrating that the "clock" could be extended when imaging showed favorable tissue status.

DAWN Trial

DAWN enrolled 206 patients with anterior circulation LVO presenting 6–24 hours from last known well. Eligibility required a mismatch between clinical deficit (NIHSS) and infarct volume on MRI or CT perfusion:

• Age ≥80: infarct core <21 mL
• Age <80 with NIHSS ≥10: infarct core <31 mL
• Age <80 with NIHSS ≥20: infarct core <51 mL

Results were striking: mRS 0–2 at 90 days was 49% vs. 13% (adjusted difference 33%; P<0.001). The trial was stopped early for efficacy. Mortality was similar between groups (19% vs. 18%), and sICH was 6% vs. 3% (P=0.50).

Clinical Pearl: DAWN demonstrated that tissue viability, not time alone, determines candidacy for thrombectomy. The "clinical–imaging mismatch" concept became central to late-window patient selection.

The 16-Hour Window: DEFUSE 3 (2018)

Published the same year as DAWN, DEFUSE 3 used perfusion imaging to identify patients with salvageable tissue 6–16 hours from last known well.

DEFUSE 3 Trial

DEFUSE 3 enrolled 182 patients with ICA or proximal MCA occlusion and a target mismatch profile on CT or MRI perfusion:

• Ischemic core volume <70 mL
• Mismatch ratio ≥1.8
• Mismatch volume ≥15 mL

Thrombectomy achieved mRS 0–2 at 90 days in 45% vs. 17% (P<0.001). Mortality was lower with thrombectomy (14% vs. 26%; P=0.05). Symptomatic ICH was 7% vs. 4% (P=0.75). Like DAWN, the trial was stopped early for efficacy.

Clinical Pearl: Together, DAWN and DEFUSE 3 established perfusion imaging–guided thrombectomy up to 24 hours as standard of care, with current guidelines recommending treatment when imaging criteria are met.

Posterior Circulation: BAOCHE (2022)

While anterior circulation trials dominated, posterior circulation strokes remained a therapeutic challenge. BAOCHE addressed the critical question of thrombectomy for basilar artery occlusion (BAO) in the extended window.

BAOCHE Trial

BAOCHE randomized 217 patients with basilar or bilateral vertebral artery occlusion presenting 6–24 hours from symptom onset to thrombectomy plus medical therapy vs. medical therapy alone. Key inclusion criteria included:

• Age 18–80 years
• NIHSS ≥6
• PC-ASPECTS ≥6
• Pre-stroke mRS 0–1

Results demonstrated clear benefit: mRS 0–3 at 90 days in 46% vs. 24% (adjusted RR 1.81; P<0.001). Functional independence (mRS 0–2) was achieved in 39% vs. 14%. Successful revascularization (TICI ≥2b) occurred in 88%. Mortality trended lower with thrombectomy (31% vs. 42%), though sICH was higher (6% vs. 1%).

Clinical Pearl: BAOCHE established that posterior circulation LVO can be treated up to 24 hours with thrombectomy. Given the devastating natural history of BAO, the benefit is substantial despite increased hemorrhagic risk.

Beyond 24 Hours: SELECT Late (2023)

The next frontier in thrombectomy is treatment beyond the 24-hour window. SELECT Late provided the first robust evidence for this ultra-late cohort.

SELECT Late Trial

SELECT Late was a prospective registry study of 301 patients with ICA or M1/M2 MCA occlusion treated beyond 24 hours from last known well. Patients were compared using propensity score matching: 185 received thrombectomy and 116 received medical management.

Results showed substantial benefit for thrombectomy:

• Functional independence (mRS 0–2) at 90 days: 38% vs. 10% (adjusted OR 4.56; P<0.001)
• Mortality: 26% vs. 41% (adjusted OR 0.49; P=0.02)
• Symptomatic ICH: 10.1% vs. 1.7% (adjusted OR 10.65; P=0.003)

Despite increased sICH, the net clinical benefit strongly favored thrombectomy, with an NNT of approximately 3.6 for functional independence.

Clinical Pearl: SELECT Late suggests that the 24-hour cutoff may be arbitrary for some patients. However, given the observational design and increased hemorrhagic risk, thrombectomy beyond 24 hours remains selective and is not yet widely adopted.

Ongoing Research: Late-MT Trial

The Late-MT trial is an ongoing prospective randomized controlled trial specifically designed to evaluate thrombectomy in patients presenting beyond 24 hours from last known well. This trial will provide the definitive evidence needed to establish or refute the role of ultra-late thrombectomy in clinical practice.

Key features of the Late-MT trial include rigorous imaging selection criteria and prospective randomization, which will address the limitations of observational studies like SELECT Late.

Conclusion: From Clock to Core

The evolution of thrombectomy has shifted from a time-based to a tissue-based paradigm. While the original 6-hour window served as a practical starting point, advanced imaging now enables individualized patient selection far beyond traditional time limits. For anterior and posterior circulation LVO, thrombectomy up to 24 hours is now standard when imaging criteria are met. Emerging evidence supports cautious consideration of thrombectomy even beyond 24 hours in highly selected patients, though prospective RCT data from Late-MT will be crucial for establishing firm recommendations.