ACHAIKI IATRIKI | 2023; 42(3):127–129
Neurointerventional Department, Ahepa University Hospital, Thessaloniki, Greece
Received: 29 Apr 2023; Accepted: 07 Jul 2023
Corresponding author: Stefanos Finitsis, Neurointerventional Department, Ahepa University Hospital, Kiriakidi 1, T.K. 546 36, Thessaloniki, Greece, Tel.: 231303417, E-mail: email@example.com
Key words: Stroke, ischaemic, large vessel, thrombectomy, large core, extended time window
Mechanical Thrombectomy (MT) is a safe and effective treatment for patients with acute ischaemic stroke (AIS) due to large vessel occlusion (LVO) in the anterior circulation since the appearance of six randomised trials in 2015 [1–6]. These trials established MT in the “early time window” (i.e., within six hours from symptom onset) but included very few patients beyond the 6-hour cutoff [3,7]. In 2018, treatment was further extended in the “late time window” (i.e., 6 to 24 hours from symptom onset) by two additional randomised trials, DAWN and DEFUSE 3 (Table 1) [8,9].
These trials, which provide the backbone for current AHA guidelines  in the extended time window, used a combination of clinical criteria and advanced imaging to select patients most likely to benefit from thrombectomy. According to these guidelines, CT perfusion (in addition to nonenhanced CT and CT angiography), or MRI (DWI and MRI perfusion), establish eligibility for thrombectomy (Evidence Level I, AHA guidelines). Central to the selection of patients is the evaluation of the volume of the infarct core, defined as the brain volume with a Cerebral Blood Flow (CBF) < 30% or an Apparent Diffusion Coefficient (ADC) < 620-3 x 10 mm2/sec on MRI. The penumbral volume is defined as a Tmax > 6 sec on CT Perfusion or MRI [8,9]. The cutoff for these volumes is further adapted for the age and clinical deficit of the patient.
According to the DAWN trial criteria, which are applicable for patients from 6 to 24 hours after symptom onset  , patients younger than 80 years are further subdivided into patients with an NIHSS score > 20, in which case only patients with a core ≤ 50 ml are eligible for thrombectomy and patients with an NIHSS 10-20, in which case only patients with a core ≤ 30 ml are eligible, while patients with an NIHSS < 10 should not receive thrombectomy. For patients older than 80, thrombectomy is indicated only for those with a core ≤ 20 ml. According to the DEFFUSE 3 criteria , which are applicable for patients from 6 to 16 hours after symptom onset, thrombectomy is indicated in patients with a core ≤ 70 ml and a penumbra ≥15 ml or a mismatch ratio ≥1.8. Compared to medical therapy, the DAWN trial demonstrated an overall benefit of good functional outcome (mRS score 0-2) of 49% versus 13%, while the DEFUSE 3 trial showed a benefit of 44.6% vs. 16.7%. However, the imaging criteria used are restrictive, and there is growing evidence that several patients outside the DAWN and DEFUSE 3 eligibility criteria may still benefit from MT.
New randomised trials for the extended time window – A shift of perspective
Three new randomised trials (RESCUE Japan, SELECT-2 and ANGEL-ASPECTS) [11–13] on patients in the extended time window from 6 to 24 hours were concluded recently and present a shift in perspective in both imaging selection criteria and patient outcomes (Table 1). These trials enrolled patients presenting with large ischaemic strokes with ASPECTS as low as three and set the bar for a successful clinical outcome to an mRS of 0-3.
RESCUE-Japan  focused on Japanese patients presenting with ASPECTS 3-5 (CT or MR) 6-24 hours from symptom onset or patients with no MR FLAIR changes up to 24 hours. Compared to medical therapy, patients undergoing thrombectomy demonstrated an overall benefit of independent ambulation of 31% vs. 12.7% (OR 2.43 95%CI 1.35-4.37, p=0.002), a higher rate of functional independence (OR 1.79, 95%CI 1.46-4.01) without an increased risk of symptomatic haemorrhage (9% vs 4.9%, RR 1.84, 95%CI 0.44-1.32, p=0.33). Rates of any intracranial haemorrhage were significantly higher in the thrombectomy group (58% vs 31.4%, RR 1.85 95% CI 1.33-2.58, p<0.001). The treatment effect persisted across all subgroups, signaling an even greater benefit in elderly patients.
SELECT-2  was an international trial that focused on patients with a CT ASPECTS 3-5 or MRI 50 ml < ADC < 620 ml or core > 50 ml (CBF < 30%) within 24 hours of symptom onset. Compared to medical therapy, patients undergoing thrombectomy demonstrated an overall benefit of independent ambulation of 37.9% vs. 18.7% (OR 2.06 95%CI 1.43-2.96), a higher rate of functional independence (20.3% vs 7%, OR 1.79, 95%CI 1.46-4.01) without an increased risk of symptomatic haemorrhage (0.6% vs. 1.1%, OR 0.49, 95%CI 0.04-5.36). Of note, MT reduced the number of mRS 5 patients by more than half. The treatment effect persisted across all subgroups, especially in patients with very large ischaemic core volumes ≥ 150 ml, patients with large penumbras, and patients with small penumbras as 10 ml.
ANGEL-ASPECTS  was a randomised trial focusing on Chinese patients with a CT ASPECTS of 3-5 or a CBF<30% core of 70-100 ml within 24 hours of symptom onset. Compared to medical therapy, patients undergoing thrombectomy demonstrated an overall benefit of independent ambulation of 47% vs. 33.3% (OR 1.5 95%CI 1.17-1.91) and a higher rate of functional independence (30% vs. 11.6%, OR 2.62 95%CI 1.69-4.06) without an increased risk of symptomatic haemorrhage (6.1% VS 2.7%, p=0.21). In addition, MT reduced the number of mRS 5 patients by nearly half.
Implications of the new trials
The results of the three published large core trials provide preliminary evidence that infarction volume, even large, does not negatively modify the treatment effect of MT with no additional risk of symptomatic intracerebral haemorrhage. Furthermore, this effect is not modified by age or NIHSS. However, one could envision extreme scenarios, like elderly patients with very large cores where there may be no benefit from MT. Nevertheless, the treatment effect demonstrated in patients with ASPECTS ≥ 3 will likely render perfusion imaging unnecessary or reserved for extended-window patients with ASPECTS < 3.
The present trials also corroborate earlier concerns that ASPECTS and CT perfusion volumes are imperfect measures of the salvageable brain even with automated quantification . ASPECTS has high interrater variability and does not consider the location of the infarcted regions and their weight in the final prognosis. Thus, the present results stress the need for more efficient methods to correlate CT hypodensities with the final functional outcome.
Other logistical questions include the need to repeat a head CT at the hub hospital after a transfer, the role of time windows in patient selections, and for which patient MT may be declared futile. A broader question pertains to the patients who do not reach ambulatory independence. In the present studies, only 2-3 out of 10 large core patients with MT get to be functionally independent, while 7-8 of 10 large core patients die or will need full-time nursing, adding to a high up-front cost. A cost-effectiveness analysis of the RESCUE-JAPAN trial found MT cost-effective with a cost-effectiveness ratio of $16 239/QALY . The trials also denote a change in therapeutic perspective, reflecting the goal to avoid mRS 5, that is, avoid the outcome of a bedridden patient, which represents a dramatic increase in the cost of care and burden for the family and society.
The remaining additional large core trials, including LASTE (NCT03811769), TESLA (NCT03805308), and TENSION (NCT03094715), should provide further data to elucidate these questions.
The three published large core trials demonstrated a significant benefit of MT for large vessel occlusion in anterior circulation stroke in the extended time window. In addition, the treatment effect remained across all studied subgroups. Following these results and the results of other ongoing trials, a shift will likely occur regarding patient imaging triage resulting in an enlargement of the pool of patients who may benefit from MT.
Conflict of interest: None to declare
Declaration of funding sources: None to declare
Author Contributions: SF is responsible for conception, writing, data interpretation and review of the final draft of the article.
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