Mechanical thrombectomy for medium vessel ischaemic stroke – results of recent trials and potential future directions

Recent research efforts in the field of stroke interventional treatment have focused on efficacy and safety of mechanical thrombectomy (MT) in medium vessel occlusions (MeVO)-acute ischaemic stroke (AIS). A second individual patient data HERMES (Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials) Collaboration meta-analysis identified all middle cerebral artery (MCA) M2 segment occlusions, after re-analysis of pre-procedural images of 7 randomized controlled trials (RCT).  In total, 130 patients fit the imaging criteria, with results particularly favoring MT for proximal M2 occlusions (aOR 2.39 95%CI 1.08 to 5.28) and dominant M2 occlusions (aOR 4.08 95%CI 1.08 to 15.48) over best medical treatment (BMT).¹

Efficacy of intravenous alteplase is associated with more distal intracranial occlusion sites, with successful recanalization achieved in 37% of M2 occlusions in a prospective cohort study.² However, in the HERMES Collaboration meta-analysis, despite almost 90% of patients in the control group having received intravenous thrombolysis, a good functional outcome (defined as mRS score of 0-2) was documented in around 40% of patients.¹ Furthermore, the advent of more specialized MT devices such as low-profile stent retrievers and smaller aspiration catheters would facilitate access to more distal occlusions without excess harm to the patient.

Consequently, recent RCTs were designed and conducted to determine if MT would lead to a better clinical outcome in more distal cerebral vessel occlusions. Contrary to a widespread empiric impression that MT is clinically beneficial in MeVO, the results of 3 negative RCTs were presented at the International Stroke Conference this year.

The DISCOUNT trial (ClinicalTrials.gov: NCT05030142), led by Prof. Frederic Clarencon, was conducted in 22 centers in France and included patients with MeVO-AIS as late as 24 hours after last time seen well with compatible advanced imaging, with a NIHSS ≥ 5 points or disabling aphasia and vessel occlusion distal to the mid-height of the insula for the MCA and all anterior cerebral (A1-A3) and posterior cerebral (P1-P3) arteries occlusions. The study was stopped following the first interim analysis, having had randomized 163 patients. The primary clinical outcome, mRS 0-2 at months, occurred in 60% of patients treated with MT + BMT vs. in 77% of patients treated with BMT solely (OR 0.42, 95%CI 0.2-0.88, after multiple imputations). Moreover, symptomatic intracranial hemorrhage (sICH) and mortality were higher in the experimental group. Similarly, the ESCAPE-MeVO trial co-led by Prof. Goyal and Prof. Hill was a multicenter study conducted in North America and Europe that randomized 529 patients with MeVO-AIS with onset within 12 hours, with NIHSS criteria similar to the previous trial. In contrast, the ESCAPE-MeVO trial included proximal M2 occlusions (amounting >20% of occlusions in each group) and evaluated pre-stroke independence by targeted questions regarding activities of daily living, and not on the mRS scale. No benefit of EVT was documented at 3-months follow-up, with more than 50% of patients having a mRS of 0-2 in each group. Similarly, sICH was higher in the experimental group. Interestingly, infarct volume measured at 2 days from onset did not differ between groups.³ Lastly, the DISTAL trial co-led by Prof. Psychogios and Prof. Fischer, included 460 patients with MeVO-AIS randomised within the first 24 hours after onset, with similar clinical eligibility criteria. Trial design utilized the concept of co-dominant or non-dominant M2 segments (based on CT angiography aspect or CTP lesion volume measurement), thus excluding patients with dominant M2 segment occlusions. The primary outcome of mRS 0-2 at 3 months was similar between groups, with a common OR for improvement in mRS score of 0.9 (95%CI 0.67-1.22).⁴

For the present time, the results of these 3 trials do not support the routine use of MT for MeVO strokes. However, several avenues of improvement for future research and trial design in MeVO-AIS were suggested by the principal investigators.

A better patient selection would be paramount. Firstly, deciding on a common M2 segment and subsegment definition would lead to a more homogenous patient population. Secondly, a higher NIHSS threshold would target patients who may benefit most from MT. Subgroup analysis from the DISTAL trial revealed a trend favoring MT with increasing NIHSS.⁴ This is in line with the findings of a population-based study on M2 occlusions, documenting an optimal NIHSS cut-off of 9 points for predicting a poor outcome (22% vs. 78% of patients with NIHSS score > 9 vs. < 9, respectively).⁵

An improvement in MT devices and techniques should parallel patient selection. In the ESCAPE-MeVO trial, only 75% of recanalizations were deemed successful (adapted mTICI 2b-3 scores).³ Moreover, operators should strive to obtain a complete recanalization following the first MT pass, as the first pass effect was associated with favourable outcome.⁶ In addition, a subgroup analysis from the DISTAL trial found that hemorrhagic complications occurred less upon utilizing aspirations catheters versus stent retrievers or their combination.⁴ Lastly, operator experience might influence recanalization and complication rates, as distal vessels are more tortuous, fragile and difficult to navigate.

Changing how post-stroke disability in patients with mild neurological deficit is evaluated may detect subtle differences between patients. These differences might otherwise not be captured by a not sufficiently ‘granular’ scale, such as the mRS.

In conclusion, combining the data from all MeVO RCTs will identify potential subgroups which could benefit from MT (either stemming from patient selection or from intra-procedural device selection). These analyses will be hypothesis generating and thus facilitate the design of better RCTs of MeVO-AIS.

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References

1. Menon BK, Hill MD, Davalos A, et al. Efficacy of endovascular thrombectomy in patients with M2 segment middle cerebral artery occlusions: Meta-analysis of data from the HERMES Collaboration. J Neurointerv Surg. 2019;11(11):1065-1069. doi:10.1136/neurintsurg-2018-014678
2. Menon BK, Al-Ajlan FS, Najm M, et al. Association of clinical, imaging, and thrombus characteristics with recanalization of visible intracranial occlusion in patients with acute ischemic stroke. JAMA – Journal of the American Medical Association. 2018;320(10):1017-1026. doi:10.1001/jama.2018.12498
3. Goyal M, Ospel JM, Ganesh A, et al. Endovascular Treatment of Stroke Due to Medium-Vessel Occlusion. New England Journal of Medicine. Published online February 5, 2025. doi:10.1056/NEJMoa2411668
4. Psychogios M, Brehm A, Ribo M, et al. Endovascular Treatment for Stroke Due to Occlusion of Medium or Distal Vessels. New England Journal of Medicine. Published online February 5, 2025. doi:10.1056/NEJMoa2408954
5. Rai AT, Domico JR, Buseman C, et al. A population-based incidence of M2 strokes indicates potential expansion of large vessel occlusions amenable to endovascular therapy. J Neurointerv Surg. 2018;10(6):510-515. doi:10.1136/neurintsurg-2017-013371
6. Radu RA, Costalat V, Fahed R, et al. First pass effect as an independent predictor of functional outcomes in medium vessel occlusions: An analysis of an international multicenter study. Eur Stroke J. 2024;9(1):114-123. doi:10.1177/23969873231208276