Endovascular Treatment Beyond the 24-Hour Mark

Mechanical thrombectomy for anterior circulation-acute ischemic stroke (AIS) with large vessel occlusion (LVO) can be performed in the extended time window (defined as 6-24 hours from time last known well (TLKW) for endovascular treatment (EVT)) by using advanced imaging, as per the most recent ESO mechanical thrombectomy guidelines¹. This indication mostly relies on inclusion criteria from the DAWN² and DEFUSE-3³ trials (clinical/radiological mismatch and perfusion mismatch, respectively). These studies were among the first to shift the time-based paradigm unto a tissue-clock based paradigm for patient selection in LVO-AIS treatment.

Both DAWN and DEFUSE 3 trials demonstrated a superior rate of functional independence (mRS 0-2) at 3 months in the thrombectomy group compared to the control group.^2,3 More recently, the results of a meta-analysis published by the AURORA collaboration, comprising 6 randomized trials of EVT performed more than 6 hours from last time seen well in acute ischemic stroke (n=505 patients), confirmed these findings⁴. Mechanical thrombectomy was associated with higher rates of independence in activities of daily living at 90 days, with no difference between groups regarding symptomatic intracerebral hemorrhage or mortality. Moreover, treatment effect was stronger in patients who received EVT within 12-24 hours versus within 6-12 hours after last time known well (TLKW) (OR 5.86 95% CI [3.14-10.94] and OR 1.76 95% CI [1.18-2.62], respectively).⁴ This phenomenon was named the ‘late-window paradox’ and is considered to result from the slow growth of the ischemic core for up to 12 hours or more in some patients (the same late-arriving patients with the favorable clinical and radiological inclusion criteria who eventually received EVT) and from the presence of a good collateral vessels status.⁵ Furthermore, these findings were also replicated in a pooled analysis of functional outcome reported by randomized clinical trials of EVT in large core LVO-AIS (ANGEL-ASPECT, SELECT-2 and RESCUE JAPAN), with patients receiving EVT later than 6 hours faring proportionately better than patients treated earlier (compared with controls).⁶

Both the favorable results of performing extended time-window EVT, as well the occurrence of a “late-window paradox” demonstrated that in a certain set of patients, mechanical thrombectomy is associated with a robust effect on functional outcome; these tissue-clock derived ischemic core behavior might potentially further expand the time window for EVT, provided that patients retain a favorable target mismatch profile.

Shortly after the publication of the DAWN trial, a retrospective analysis was performed on patients fulfilling the DAWN clinical/radiological mismatch criteria, but receiving EVT beyond 24 hours from TLKW.⁷ This case series included 21 patients with a median time from TLKW to groin puncture of 48 hours and with rates of recanalization and favorable outcome comparable to the interventional arm of the DAWN trial (mRS 0-2 of 43% versus 48%, p 0.68) and without an increased risk of symptomatic intracerebral hemorrhage;⁷ the authors suggested that EVT appears safe and feasible if performed beyond 24 hours with the right selection criteria.

A more recent retrospective case-control study encompassed 150 patients with LVO-AIS presenting later than 16 hours from LKW, with 109 patients presenting later than 24 hours.⁸ At least a third of patients met the inclusion requirements for both the DAWN and DEFUSE 3 trials. EVT was performed in 24/150 patients (with clinical profiles similar to the untreated population). Patients were treated at a median of 26.3 hours from TLKW . In a subgroup analysis of the 109 patients arriving later than 24 hours from TLKW and receiving EVT, mechanical thrombectomy was associated with increased odds of functional independence at 3 months follow-up (common adjusted OR, 10.54 [95% CI, 2.18-59.34]). According to the study, the favorable effect of EVT on outcome was maintained throughout the inclusion period (16 hours – 240 hours).⁸

Finally, the tissue-clock selection paradigm is further supported and simplified by the multicentric cohort CT for Late Endovascular Reperfusion (CLEAR) study, aiming to compare outcomes of patients treated by mechanical thrombectomy in the extended time window (6-24 hours after TLKW) an selected by either non-contrast CT (ASPECTS of > 5 in most centers) , CTP or MRI. The results showed no significant difference in clinical outcomes between non-contrast CT and more advanced imaging methods.⁹ This finding potentially expands the indication for performing EVT, by facilitating decision making based on an easily accessible imaging technique. Furthermore, one can envision further widening of this selection paradigm to very-late presentations (>24 hours).

In conclusion, despite being limited by the small number of published cases, the sustained favorable clinical and radiological profile as well as the treatment effect in selected patients beyond the 24-hour mark warrants further research.

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 References:

1. Turc G, Bhogal P, Fischer U, et al. European Stroke Organisation (ESO)- European Society for Minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in acute ischemic stroke. J Neurointerv Surg. 2019;11(6):535-538. doi:10.1136/neurintsurg-2018-014568
2. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018;378(1):11-21. doi:10.1056/nejmoa1706442
3. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018;378(8):708-718. doi:10.1056/nejmoa1713973
4. Jovin TG, Nogueira RG, Lansberg MG, et al. Thrombectomy for anterior circulation stroke beyond 6 h from time last known well (AURORA): a systematic review and individual patient data meta-analysis. Lancet. 2022;399(10321):249-258. doi:10.1016/S0140-6736(21)01341-6
5. Albers GW. Late window paradox. Stroke. 2018;49(3):768 771. doi:10.1161/STROKEAHA.117.020200
6. Al-Mufti F, Elfil M, Ghaith HS, et al. Time-to-treatment with endovascular thrombectomy in patients with large core ischemic stroke: the ‘late window paradox.’ J Neurointerv Surg. 2023;15(8):733 LP – 734. doi:10.1136/jnis-2023-020493
7. Desai SM, Haussen DC, Aghaebrahim A, et al. Thrombectomy 24 hours after stroke: Beyond DAWN. J Neurointerv Surg. 2018;10(11):1039-1042. doi:10.1136/neurintsurg-2018-013923
8. Kim BJ, Menon BK, Kim JY, et al. Endovascular Treatment after Stroke Due to Large Vessel Occlusion for Patients Presenting Very Late from Time Last Known Well. JAMA Neurol. 2021;78(1):21-29. doi:10.1001/jamaneurol.2020.2804
9. Nguyen TN, Abdalkader M, Nagel S, et al. Noncontrast Computed Tomography vs Computed Tomography Perfusion or Magnetic Resonance Imaging Selection in Late Presentation of Stroke with Large-Vessel Occlusion. JAMA Neurol. 2022;79(1):22-31. doi:10.1001/jamaneurol.2021.4082