Medium and distal vessel occlusion stroke: Redefining the role of thrombectomy through technology, timing, and patient selection

Dear Editor,

Growing evidence on the use of endovascular thrombectomy (EVT) for medium and distal vessel occlusions (MDVOs) has sparked important debate about how mechanical reperfusion should be applied beyond the setting of large vessel occlusion (LVO) stroke. Recent observational and randomized data have raised concerns regarding the efficacy and safety of EVT in MDVO. In the large SITS International Stroke Register (SITS-ISTR) analysis by Keselman et al., the addition of EVT to intravenous thrombolysis (IVT) was associated with lower rates of functional independence and higher mortality compared with IVT alone after propensity-score matching.[6] Together with randomized trials reporting neutral or negative results, these findings have intensified the debate regarding whether EVT is intrinsically limited in MDVO stroke or whether current outcomes reflect limitations in patient selection, technology, and procedural implementation.[2,3,9]

However, interpretation of these findings requires caution. The SITS-ISTR analysis is an important contribution from a large international registry, but, as with all nonrandomized studies, treatment allocation was determined by clinical judgment rather than randomization. Propensity-score matching can balance only recorded variables, and several factors that may critically influence outcome – including device characteristics, vessel diameter, number of thrombectomy passes, reperfusion success, and procedural strategy – were not available.[6] These missing variables are particularly important for MDVO stroke, as the field has undergone rapid evolution during the study period.

The experience gained from LVO thrombectomy offers valuable insight into the challenges currently facing the MDVO field. Before the widespread adoption of modern stent retrievers and refined selection criteria, several early studies failed to demonstrate clear benefit. The subsequent success of EVT was not due to a change in the underlying biological principle but rather due to improvements in technology, procedural strategy, and patient identification. A similar process may now be occurring in the MDVO field.

A major limitation of the current evidence base is that many early MDVO procedures relied on devices developed for larger arteries rather than dedicated distal technologies. Stent retrievers designed for proximal vessels were frequently delivered through 0.021- or 0.027-inch microcatheters, whereas newer low-profile systems compatible with 0.017-inch microcatheters, such as the Catch Mini (Balt) or Tigertriever 13 (Rapid Medical), allow a more tailored approach to smaller vessels.[1] Device-vessel mismatch is unlikely to be clinically irrelevant. In M2 occlusions, excessive oversizing of the retriever relative to vessel diameter has been associated with increased symptomatic hemorrhage and higher rates of futile outcome.[13] In smaller distal vessels, particularly perforator-rich territories, similar mechanical forces may carry even greater consequences.

Therefore, outcomes reported from studies spanning several years may represent a mixture of different technological eras rather than a uniform assessment of EVT efficacy. Without detailed information regarding device type, sizing strategy, number of passes, and procedural technique, it remains difficult to distinguish the limitations of thrombectomy itself from the limitations of the tools used to perform it.

Timing represents another important determinant of outcome. The added value of IVT before thrombectomy is not constant throughout the treatment window. In an individual patient data meta-analysis of six randomized trials, Kaesmacher et al. demonstrated that adding IVT to thrombectomy improved functional outcome compared with thrombectomy alone when thrombolysis was expected to be delivered early after onset, with no clear benefit once the anticipated onset-to-IVT time exceeded approximately 2 h and 20 min.[5] Registry and trial populations, however, span the full range of these intervals, so any combined IVT-plus-thrombectomy group inevitably blends patients in whom thrombolysis still added value with those in whom it did not – a distinction that outcome comparisons such as SITS-ISTR cannot capture. Future MDVO studies should incorporate not only onset-to-treatment times but also the interval between thrombolysis and thrombectomy and the treatment pathway leading to intervention.

The potential consequences of these factors are particularly relevant for hemorrhagic complications. In the SITS-ISTR analysis, combined treatment was associated with a substantial increase in symptomatic hemorrhage according to ECASS II criteria.[6] In distal circulation stroke, even relatively small hemorrhages may result in clinically significant deterioration because of eloquent cortical or perforator-rich anatomy. Excess symptomatic hemorrhage without a corresponding increase in large parenchymal hematoma rates may therefore reflect a combination of mechanical manipulation, vessel caliber, device characteristics, and ongoing thrombolytic effect rather than an inherent inability to treat distal occlusions safely.

Another unresolved issue is the relationship between procedural success and functional outcome. Reperfusion grading, including modified thrombolysis in cerebral infarction (mTICI) scores, is essential for interpreting negative clinical results. The SITS-ISTR analysis collected mTICI grades in the combined-treatment group but did not include these data in the outcome analysis because a comparator was unavailable.[6] Nevertheless, reporting reperfusion quality would provide valuable context and help distinguish poor outcomes after unsuccessful or incomplete recanalization from outcomes following technically successful reperfusion.

Patient selection remains equally important. MDVO is not a single clinical entity but a heterogeneous group encompassing different vessels, territories, neurological deficits, and stroke mechanisms. In contrast to the neutral trials, which enrolled predominantly mild-to-moderate deficits, ORIENTAL-MeVO was positive in patients with more substantial impairment (National Institutes of Health Stroke Scale ≥6), meeting its primary outcome and increasing functional independence (58.6% vs. 46.6%) – indicating that trial results may hinge on patient selection rather than an intrinsic absence of benefit.[4] The concept of treating MDVO should therefore not be evaluated as a binary question of “EVT versus no EVT,” but rather as a question of which patients, vessels, and clinical circumstances justify intervention.

The anatomical distribution of treated occlusions is another major determinant of generalizability. In SITS-ISTR, posterior circulation occlusions, particularly posterior cerebral artery occlusions, represented a substantial proportion of the EVT-treated population, and the mortality signal was concentrated in this subgroup.[6] Against an already complex evidence base for posterior circulation thrombectomy, including data from PLATO and TOPMOST, these findings may therefore reflect a predominantly posterior circulation population rather than MDVO stroke as a whole.[7,8]

The future direction of MDVO thrombectomy will likely depend on refinement rather than abandonment. Dedicated low-profile devices, improved procedural techniques, and more selective patient identification may substantially alter the balance between benefit and harm. The recently reported DISTALS trial, evaluating a dedicated distal thrombectomy device, demonstrated that favorable reperfusion rates with acceptable safety profiles can be achieved when technology is appropriately matched to vascular anatomy.[12]

Device innovation is unlikely to be the only route to progress. Pharmacological reperfusion could be evaluated as a primary strategy for very distal occlusions, as rescue therapy after failed or incomplete thrombectomy, or as an adjunct after angiographic reperfusion. In ORIENTAL-MeVO, operator-selected endovascular approaches included intra-arterial thrombolytic agents in 20.2% of treated patients, although their contribution to the overall trial benefit cannot be isolated.[4] A recent propensity-matched DMVO registry analysis found similar functional outcomes with primary intra-arterial urokinase and mechanical thrombectomy, with numerically fewer safety events but lower successful reperfusion; only 19 patients received thrombolysis, making the findings preliminary.[11] Randomized LVO evidence from CHOICE-2 further supports the biological plausibility of adjunctive intra-arterial alteplase after successful thrombectomy but cannot be directly extrapolated to MDVO and included a mortality imbalance requiring caution.[10] Beyond thrombolysis, concepts in the pipeline include adjunctive platelet inhibition or other microvascular-targeted therapies and catheter-based neuroprotection, such as selective intra-arterial hypothermia; however, these remain investigational and are supported predominantly by LVO rather than MDVO-specific evidence. Future MDVO trials should therefore distinguish pharmacological-first, rescue, and adjunctive strategies and standardize the drug, dose, catheter position, prior IVT, tissue-level reperfusion endpoints, and hemorrhagic safety.

The central question in MDVO stroke is therefore not simply whether thrombectomy works or does not work. Rather, it is how to define the patients in whom mechanical reperfusion provides meaningful benefit while avoiding situations in which device characteristics, timing, or anatomical factors increase risk without sufficient therapeutic gain.

Future trials should prioritize detailed reporting of device characteristics, vessel anatomy, reperfusion success, procedural metrics, thrombolysis-to-thrombectomy intervals, and clinically relevant subgroups. Such data will be essential to determine whether current negative signals represent the limits of the concept or merely the limitations of its earliest implementation.

Ethical approval:

Institutional Review Board approval is not required.

Declaration of patient consent:

Patient’s consent is not required as there are no patients in this study.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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