Thrombectomy for Large Core Infarcts: Redefining the Limits

For years, patients with large ischemic cores were systematically excluded from thrombectomy trials and clinical practice. The landmark studies that established endovascular therapy—MR CLEAN, DAWN, and DEFUSE 3—required favorable imaging profiles, typically ASPECTS ≥6 or ischemic core volumes <70 mL. This left a substantial proportion of LVO patients without access to reperfusion therapy. Beginning in 2022, a series of pivotal trials challenged this paradigm, demonstrating that thrombectomy can benefit carefully selected patients even with extensive established infarction.

The Prior Standard: Why Large Cores Were Excluded

MR RESCUE (2013)

The MR RESCUE trial was an early attempt to use penumbral imaging to select patients for endovascular therapy within 8 hours of onset. Using first-generation devices (Merci Retriever, Penumbra system), the trial found no benefit of mechanical embolectomy over standard care—mean 90-day mRS was 3.9 in both groups. This neutral result, combined with suboptimal recanalization rates, contributed to initial skepticism about thrombectomy and reinforced conservative patient selection.

DAWN and DEFUSE 3 (2018)

The paradigm-shifting DAWN and DEFUSE 3 trials extended the thrombectomy window to 24 hours but explicitly excluded patients with large cores. DAWN required infarct core <21–51 mL depending on age and NIHSS, while DEFUSE 3 mandated core <70 mL with target mismatch. Both trials used ASPECTS ≥6 as a general threshold. While these criteria ensured robust treatment effects, they left uncertainty about whether patients with larger infarcts could also benefit.

Clinical Context: Prior to 2022, patients presenting with ASPECTS 3–5 or core volumes >70 mL were generally offered supportive care only, with thrombectomy considered futile or potentially harmful due to concerns about hemorrhagic transformation and poor functional outcomes.

The Large Core Trials: A New Era

RESCUE-Japan LIMIT (2022)

RESCUE-Japan LIMIT was the first randomized trial to demonstrate thrombectomy benefit in large core infarcts. The trial enrolled 202 patients with ASPECTS 3–5 and ICA or M1 occlusion within 6 hours (or 6–24 hours with DWI-FLAIR mismatch).

• mRS 0–3 at 90 days: 31.0% vs. 12.7% (RR 2.43; P=0.002)
• Early neurological improvement (NIHSS ≥8 points at 48h): 31.0% vs. 8.8%
• Symptomatic ICH: 9.0% vs. 4.9%
• 90-day mortality: 18.0% vs. 23.5%

Clinical Pearl: RESCUE-Japan LIMIT used the Japanese IV alteplase dose (0.6 mg/kg) and allowed treatment up to 24 hours with imaging selection. The trial established that thrombectomy could more than double the rate of favorable outcomes in large core patients.

SELECT2 (2023)

SELECT2 was a multicenter trial enrolling 352 patients with large core infarcts defined by ASPECTS 3–5 on NCCT or ischemic core ≥50 mL on CT perfusion. Patients with ICA or M1/M2 occlusion were randomized within 24 hours of last known well.

• mRS 0–2 at 90 days: 20.3% vs. 7.0%
• Utility-weighted mRS (primary endpoint): significantly favored thrombectomy
• Symptomatic ICH: ~5% vs. ~2%
• Mortality at 90 days: similar between groups

Clinical Pearl: SELECT2 introduced CT perfusion-based core volume (≥50 mL) as an alternative to ASPECTS for defining large core, allowing greater precision in patient selection.

ANGEL-ASPECT (2023)

ANGEL-ASPECT enrolled 456 patients in China with ASPECTS 3–5 and anterior circulation LVO within 24 hours. The trial compared thrombectomy plus medical management to medical management alone.

• mRS 0–2 at 90 days: 30.0% vs. 11.6% (RR 2.62; P<0.001)
• mRS 0–3 at 90 days: 47.0% vs. 33.1%
• Symptomatic ICH: 6.1% vs. 2.7%
• 90-day mortality: 27.4% vs. 38.1%

Clinical Pearl: ANGEL-ASPECT showed the largest absolute benefit in functional independence among the large core trials, with an NNT of approximately 5.4 for mRS 0–2.

TESLA (2023)

TESLA pushed the boundaries further by including patients with ASPECTS 2–5 (even lower than other trials). The trial enrolled patients with ICA or M1 occlusion, NIHSS >6, and pre-stroke mRS 0–1 within 24 hours.

• 90-day mean mRS: 2.93 (thrombectomy) vs. 2.27 (medical therapy)
• 1-year mRS 0–2: 22% vs. 6%
• 1-year mortality: 43% vs. 47%
• 1-year EQ-5D-5L quality of life: 60.3 vs. 49.3

Clinical Pearl: TESLA demonstrated that even patients with ASPECTS as low as 2 can achieve functional independence with thrombectomy, though overall outcomes remain guarded.

SELECT2 — 1-Year Follow-Up (2024)

Long-term outcomes from SELECT2 confirmed that the benefit of thrombectomy in large core infarcts persists at 1 year:

• 1-year mRS 0–2: 24% vs. 6%
• 1-year mRS 0–3: 37% vs. 18%
• 1-year mortality: 45% vs. 52%

Clinical Pearl: The 1-year data show that early thrombectomy benefit is not only maintained but may increase over time, with continued separation in functional independence rates. This addresses concerns that large core patients might have delayed deterioration.

LASTE (2024)

LASTE examined the most extreme end of the spectrum—patients with ASPECTS 0–5 (age <80) or ASPECTS 4–5 (age ≥80) presenting within 6.5 hours. The trial enrolled 333 patients with ICA or M1 occlusion.

• 90-day median mRS: 4 (thrombectomy) vs. 5 (control)
• mRS 0–2 at 90 days: 23.9% vs. 13.3%
• mRS 0–3 at 90 days: 26.9% vs. 33.5%
• 90-day mortality: 36% vs. 55.5%
• Symptomatic ICH: 3.2% vs. 2.5%
• Need for decompressive craniectomy: 8.8% vs. 11.5%

Subgroup analyses showed particular benefit in patients <70 years (OR 2.03), those with core volume >150 mL (OR 1.58), and MRI-selected patients (OR 1.71).

Clinical Pearl: LASTE demonstrated that even with ASPECTS ≤2 or infarct volumes >150 mL, thrombectomy significantly reduces mortality and improves the chance of a favorable outcome. The mortality reduction from 55.5% to 36% represents a major benefit even in this severely affected population.

Conclusion: A Paradigm Shift

The large core trials have fundamentally changed the treatment landscape for acute ischemic stroke. Patients previously deemed untreatable now have evidence-based options for reperfusion therapy. While outcomes in large core patients remain more guarded than in traditional candidates, the consistent benefit across multiple trials—including reduced mortality and increased functional independence—supports offering thrombectomy to carefully selected patients with extensive infarction.