“Few procedures have gone through a decade of practice-changing clinical trials as impressive as thrombectomy for stroke… It seemed that no corner of the cerebrovasculature would not benefit substantially from a proper clot removal—until now.” This quote from J Mocco, MD, an endovascular neurosurgeon from Mount Sinai Health System in New York, in a recent New England Journal of Medicine editorial accurately captures the surprise of the neurointerventional community at the equivocal results of three recent thrombectomy trials.¹

Unlike medications such as tissue plasminogen activator (tPA)—which dissolves clots blocking a brain artery—thrombectomy uses image guidance to direct a small catheter to a blocked artery. The clot is either removed with a stent (mechanical thrombectomy) or suctioned (aspiration thrombectomy). Throughout the past decade, the use of thrombectomy to treat ischemic stroke has rapidly expanded.

The spark that ignited this expansion was the simultaneous publication of the “Big Five” thrombectomy trials in 2015, all of which demonstrated that thrombectomy provided a substantial clinical benefit for patients with ischemic stroke due to large vessel occlusions (LVO) with small infarct cores—areas of dead brain tissue—who present within six hours of symptom onset.² Undoubtedly, thrombectomy for eligible patients with LVO has saved millions from disability, dependency, and death. But the key word is “eligible”: the inclusion criteria in the 2015 trials restricted thrombectomy use to a fraction of stroke patients.

Recognizing this restriction, many neurointerventionalists sought to broaden the indications for thrombectomy beyond the inclusion criteria of the Big Five. Consequently, several subsequent trials with broader inclusion criteria have been undertaken and have demonstrated a clinical benefit for thrombectomy in additional contexts, including in stroke patients who present past the six-hour window^3,4 and with large infarct cores.⁵

But one question has remained unanswered: Could thrombectomy be beneficial for acute stroke patients with occlusions of smaller brain arteries—commonly known as “distal” or “medium-sized” vessel occlusions (D/MeVO)? Such occlusions are far from rare, as an estimated 20-40% of patients with ischemic stroke experience an obstruction in a distal or medium-sized artery.⁶

Thanks to the extensive thrombectomy data produced by trials starting with the Big Five in 2015, neurointerventionalists can swiftly identify which patients with LVO should receive a thrombectomy procedure. In patients with D/MeVO, however, the decision is less straightforward due to the insufficient clinical trial data available to inform decision-making in this area. Consequently, three clinical trials were conducted to help resolve this issue, and the findings were presented at the International Stroke Conference in Los Angeles in February 2025.

Despite much anticipation from the neurointerventional community, the data are sobering.

Let’s dive into the findings of each trial and what their results mean for the future of D/MeVO.

The trials and what they found

DISTAL

The EnDovascular Therapy Plus Best Medical Treatment (BMT) Versus BMT Alone for MedIum VeSsel Occlusion sTroke (DISTAL) was a randomized, open-label trial that investigated whether thrombectomy in addition to medical management—typically a clot-busting medication like tPA —reduced disability in patients with acute stroke due to D/MeVO compared to medical management alone.⁷ Across 55 European centers, the trial enrolled 543 patients who were randomized to receive either thrombectomy in addition to medical management or medical management alone. The primary outcome was the level of dependency and disability—as measured by the modified Rankin Scale (mRS)—at 90 days, while secondary outcomes included death rates and rates of symptomatic brain bleeding.

DISTAL found no significant difference in the distribution of mRS scores between groups at 90 days, indicating that thrombectomy and medical management did not improve dependency and disability compared to medical management alone. Furthermore, both groups experienced similar rates of all-cause mortality, although the incidence of symptomatic brain bleeding was slightly higher in the thrombectomy group compared to the medical management group (5.9% vs 2.6%, respectively), though this difference was not statistically significant.

ESCAPE-MeVO

Taking place at multiple centers throughout the U.S., Canada, and several European countries, Endovascular Treatment to Improve Outcomes for Medium Vessel Occlusions (ESCAPE-MeVO) was a randomized, open-label trial that sought to determine the effect of mechanical thrombectomy on improving outcomes in patients with medium vessel occlusion (MeVO).⁸ The trial allocated 530 patients with MeVO to receive either thrombectomy in addition to medical management or medical management alone. In contrast to DISTAL, however, ESCAPE-MeVO utilized the proportion of patients in each treatment arm with mRS of 0-1—indicating functional independence—at 90 days as the primary outcome. Regarding secondary outcomes, the authors evaluated mortality rates, serious adverse events, and rates of procedural complications, among a handful of other outcomes.

Similar to DISTAL, ESCAPE-MeVO found no significant difference between the groups concerning the primary outcome, with 41.6% of patients in the thrombectomy group achieving an mRS of 0-1 at 90 days, compared to 43.1% of patients in the medical management group. Mortality rates at the same time point were slightly higher in the thrombectomy group (13.3%) compared to the medical management group (8.4%), although these differences were not statistically significant. Serious adverse events were also more frequent in the thrombectomy group (33.9% vs. 25.7%), as were rates of procedure-related complications, including recurrent stroke (5.4% vs. 3.7%), stroke progression (5.4% vs. 1.8%), and symptomatic brain bleeding (5.4% vs. 2.2%).

DISCOUNT

The Evaluation of Mechanical Thrombectomy in Acute Ischemic Stroke Related to a Distal Arterial Occlusion (DISCOUNT) trial was a randomized, open-label study that sought to enroll 488 D/MeVO patients across 22 French centers. Like DISTAL and ESCAPE-MeVO, DISCOUNT allocated patients to receive either thrombectomy plus medical or medical management alone. In contrast to ESCAPE-MeVO, however, DISCOUNT used an mRS of 0-2 to indicate a “good” functional outcome at 90 days.

After randomizing the first 163 patients with an available three-month follow-up visit, a planned interim analysis indicated a “disfavorable” outcome for mechanical thrombectomy, leading to the halting of the study. Early data revealed that 60% of patients in the thrombectomy group had an mRS score of 0-2, compared to 77% of patients receiving medical management. Furthermore, patients treated with thrombectomy had higher rates of at least one serious adverse event (39% versus 31%) and symptomatic brain bleeding (12% vs 6%) compared to those receiving medical management. However, the mortality rate was slightly lower in the thrombectomy group than in the medical management group (3% vs 7%).

In Totality…

While all three studies had slightly different primary outcomes, none showed a clinical benefit of thrombectomy in reducing disability or dependency in patients with D/MeVO. In the DISCOUNT study, patients who underwent thrombectomy had worse functional outcomes compared to those who received only medical management. Additionally, thrombectomy patients experienced slightly higher rates of several secondary outcomes across studies, including recurrent stroke, brain bleeding, and other adverse events, though not all of these differences reached statistical significance.

These findings suggest that mechanical thrombectomy for patients with acute ischemic stroke caused by D/MeVO does not appear to offer a clinical benefit. In contrast to LVO, thrombectomy should not be routinely applied in these patients without carefully considering individual patient factors.

Indeed, Dr. Mocco was correct in his NEJM editorial when he said these trials represent “ground zero” for mechanical thrombectomy for treating D/MeVO.

But Why?

Prior studies have indicated that thrombectomy for D/MeVO is safe and associated with improved clinical outcomes when performed in appropriately selected patients.⁹ Given the substantial findings from over a dozen trials since 2015, many expected the DISTAL, ESCAPE-MeVO, and DISCOUNT trials to expand the indications for thrombectomy to patients with stroke caused by D/MeVO. The data, however, suggest otherwise.

We are still waiting for the final data from all studies to be published, but many neurointerventionalists have offered explanations for these findings.

Technology. First, many have opined that limitations on current endovascular technology likely played a role. Existing equipment—wires, catheters, and stent retrievers—is primarily manufactured to remove clots of the larger diameter vessels of the brain involved in an LVO. More recently, device companies have begun designing microcatheters that can better access the smaller arteries involved in D/MeVO—and existing data has indicated their effectiveness.¹⁰ These more specific catheters were commercially available only toward the end of the three trials, meaning that a small proportion of patients with D/MeVO were treated with more advanced technology. It may be that devices more specific to D/MeVO could result in more effective clot removal and, therefore, a larger treatment effect.

Anatomical Heterogeneity. Second, there was great heterogeneity among the types of occluded vessels involved in this study and the corresponding areas of the brain supplied by distal or medium-sized vessels: Some provide blood to eloquent portions of the brain crucial for daily functioning, while others may provide blood to more “minor” areas. With this in mind, all patients diagnosed as having D/MeVO likely comprise a heterogeneous group of strokes, meaning that not all patients may benefit equally from having a thrombectomy. For example, a patient with an occlusion of a large branch of the middle cerebral artery that supplies a portion of the brain involved in the function of their dominant hand is going to benefit more from clot removal than a patient with an occlusion of a smaller vessel that supplies an area involved in the sensation of their left foot. So, including both kinds of patients in the same group might dilute the treatment effect.

Outcome Measures. These three trials—and most mechanical thrombectomy studies—use the mRS at a specified follow-up period as the primary outcome. The mRS is well-validated, easy to use, and provides a broad measure of a stroke patient’s functionality following an intervention. But because it is so broad, it is a poor measure of capturing minor differences in improvement. Patients with D/MeVO may not have massive, debilitating strokes, and therefore, performing thrombectomy in such patients may not result in a large clinical improvement compared to patients with LVO. As such, more precise outcome measures other than mRS may capture minute clinical differences between treatment groups and, therefore, demonstrate a clinical benefit for thrombectomy for D/MeVO.

Looking up from Ground Zero

In his editorial, Dr. Mocco emphasized that the data brought about by these three studies are clear and represent a sort of “limit” in how far neurointervention can reach at this point.¹ Certainly, these data are disappointing. Yet, instead of discouragement, these findings can serve as an impetus for finding better ways to treat patients’ strokes caused by D/MeVO. In fact, a large proportion of patients in the control groups of each study had deficits at follow-up—for example, 57% of the control arm of the DISTAL study had an mRS greater than one at follow-up. Together, these data indicate that D/MeVO, regardless of the artery involved, is not a benign disease and more effective treatment options are needed.

So, how do we start moving up if we are at ground zero?

More Data. So far, only the DISTAL trial has been published,⁷ and two additional D/MeVO trials are currently enrolling patients. Following their completion, a meta-analysis similar to that following the completion of the 2015 trials is likely to be undertaken.² By combining sample sizes from all trials, we can detect smaller clinical effect sizes, and while it is unlikely that a clinical benefit will be evident from such a meta-analysis, we can use the larger sample size to derive more concrete conclusions about which patients and are more likely to benefit from thrombectomy for D/MeVO, and in which clinical contexts thrombectomy is most effective.

The LVO trials of 2015 and beyond included patients who had severe strokes with substantial clinical deficits. Consequently, such patients stood to benefit from thrombectomy regardless of the procedure’s inherent risks. In contrast, patients with ischemic stroke caused by D/MeVO are likely to have less severe clinical deficits, meaning the clinical benefit they receive from thrombectomy may not be as obvious. It is, therefore, likely that patients with more severe clinical symptoms from D/MeVO will demonstrate a benefit from thrombectomy during an analysis of such patients in a meta-analysis.

More Devices. Strokes occurring in the brain's smaller arteries present a technological challenge, as the distant, slender, and fragile arteries involved in D/MeVO require longer catheters and more navigable, smaller devices to reach and remove clots. While some D/MeVO-specific devices are already being tested, the outcomes of these three trials will act as a catalyst for device companies to collaborate more closely with neurointerventionalists in designing devices tailored for D/MeVO.

Once these devices become commercially available, future trials may demonstrate a clinical benefit for patients with D/MeVO. Many experts, including Dr. Mocco, have indicated that these three trials may be similar to two LVO trials completed in 2013, both of which failed to show a clinical benefit for thrombectomy. Those two trials used a primitive, first-generation thrombectomy device that wasn’t adequately suited to remove clots in LVO. But the wildly successful 2015 trials utilized more advanced thrombectomy devices, resulting in more successful clot removal and, therefore, better clinical outcomes. It may be, then, that more sophisticated devices explicitly designed for D/MeVO may result in better outcomes in future trials.

Better Designs. The DISTAL, ESCAPE-MeVO, and DISCOUNT trials were well-designed, multi-center randomized trials. Yet, based on the results, future trials may have different designs in two key areas. First, future trials will likely limit inclusion criteria to patients with more severe clinical deficits or patients with occlusion of specific arteries. As mentioned, patients with more severe strokes—caused by D/MeVO involving specific arteries—are more likely to demonstrate a clinical benefit from thrombectomy.

Second, future trials may use different primary outcome measures beyond mRS. Although validated, easy to use, and generalizable, mRS is a crude measure of functional status. Since D/MeVO results in less severe strokes, a more granular outcome measure will likely be able to detect more subtle clinical benefits that are patient-specific: A violinist who regains the use of her right hand after thrombectomy for D/MeVO should be considered an “excellent” clinical outcome, despite little change in her mRS.

Undoubtedly, the findings of the DISTAL, ESCAPE-MeVO, and DISCOUNT trials are disappointing. This doesn’t mean, however, that thrombectomy has no role to play for patients with acute stroke caused by D/MeVO—we must remember that a large proportion of patients in the control groups across studies still had significant deficits, meaning that there is a clinical need. Furthermore, there did not appear to be any safety concerns, as indicated by several secondary outcomes, and indeed, the safety of these procedures will continue to improve as device technology advances. Together, these findings suggest that thrombectomy is still a viable option for patients with D/MeVO.

Certainly, better technology could improve outcomes in this population, and once more data is available, we can ascertain which patient populations—and in which contexts—will benefit the most from thrombectomy. As many neurointerventionalists have indicated, it is unlikely that the results of these trials are going to stop them from performing thrombectomy in appropriate patients with D/MeVO. But, in contrast to LVO, physicians will likely need to be more selective of which D/MeVO cases they take to the endovascular suite.

As we look up from ground zero, instead of seeing a limit that has been reached, we can instead see how much potential room there is for growth. As Dr. Mocco has indicated, these trials provide an impetus for more work to be done to help patients affected by D/MeVO.

References

1. Mocco J. Medium-and Distal-Vessel Occlusion—The Limit of Thrombectomy? : New Engl J Med; 2025.

2. Goyal M, Menon BK, Van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. The Lancet. 2016;387(10029):1723-1731.

3. Jovin TG, Nogueira RG, Investigators D. Thrombectomy 6 to 24 hours after stroke. N Engl J Med. 2018;378(12):1161-1162.

4. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. New Engl J Med. 2018;378(1):11-21.

5. Chen H, Lee JS, Michel P, Yan B, Chaturvedi S. Endovascular stroke thrombectomy for patients with large ischemic core: a review. JAMA neurology. 2024;

6. Ospel JM, Nguyen TN, Jadhav AP, et al. Endovascular treatment of medium vessel occlusion stroke. Stroke. 2024;55(3):769-778.

7. Psychogios M, Brehm A, Ribo M, et al. Endovascular Treatment for Stroke Due to Occlusion of Medium or Distal Vessels. New Engl J Med. 2025;

8. Ospel JM, Dowlatshahi D, Demchuk A, et al. Endovascular treatment to improve outcomes for medium vessel occlusions: The ESCAPE-MeVO trial. Int J of Stroke. 2024;19(9):1064-1070.

9. Loh EDW, Toh KZX, Kwok GYR, et al. Endovascular therapy for acute ischemic stroke with distal medium vessel occlusion: a systematic review and meta-analysis. J of NeuroInt Surg. 2023;15(e3):e452-e459.

10. Monteiro A, Makalanda HLD, Wareham J, et al. Mechanical thrombectomy in medium vessel occlusions using the novel aspiration Q catheters: an international multicenter experience. J of Neuroint Surg. 2024;16(6):603-607.