Breaking New Ground in Stroke Care: The Evolution and Future of Mechanical Thrombectomy

The importance of rapidly advancing technology in interventional stroke therapy became clear early in its history. Before 2015, clinical trials failed to demonstrate significant recanalization or clinical benefit of mechanical thrombectomy (MT) compared with medical management alone.¹ This failure was due in no small part to the relative inferiority of first-generation devices, as well as to the enrollment of individuals without large vessel occlusions (LVOs) and other factors related to trial design.² Pivotal trials published in 2015^1,3 revolutionized stroke care by combining imaging for selection of participants with confirmed LVOs with next-generation stent retrievers capable of efficient and safer clot removal. These advancements resulted in significantly greater functional independence (modified Rankin Scale [mRS] score 0–2) and reduced rates of symptomatic intracerebral hemorrhage, establishing both the efficacy and safety of the procedure. 

In 2018, the Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo (DAWN, NCT02142283) and Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE-3, NCT02586415) trials demonstrated that MT could be safely and effectively performed up to 24 hours after symptom onset in carefully selected individuals with small infarct cores and comparatively large, salvageable ischemic penumbras.^4,5 These findings extended the treatment window and shifted selection criteria from rigid time cutoffs to imaging-based tissue viability.

Expanding Indications for Current Technology
More recently, there has been considerable effort to expand MT eligibility by challenging the paradigm of how ischemic tissue is salvaged. Both animal models and human studies have demonstrated that ischemia does not occur as a uniform process within the oligemic penumbra. Instead, ischemia results from a progressive evolution of microsatellite ischemic regions within a radiographic core.^6,7 These findings highlight the potential to maximize stroke recovery by targeting both penumbra and core for intervention.^8,9 To this end, it was hypothesized that even individuals with large stroke cores could benefit from MT, with the aim to continue to minimize infarct conversion while maximizing the potential for recovery of the core itself and minimizing potential complications of continued core maturation (such as hemorrhagic transformation and edema).

Six major trials conducted between 2022 and 2024—Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism–Japan Large Ischemic Core Trial (RESCUE-Japan LIMIT, NCT03702413), Randomized Controlled Trial to Optimize Patient Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT2, NCT03876457), Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT, NCT04551664), The Efficacy and Safety of Thrombectomy in Stroke With Extended Lesion and Extended Time Window (TENSION, NCT03094715), Large Stroke Therapy Evaluation (LASTE, NCT03811769), and Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke (TESLA, NCT03805308)—were conducted to evaluate the efficacy of MT in individuals with large-core ischemic strokes. Significantly improved outcomes were reported among individuals with large cores (typically defined as Alberta Stroke Program Early CT Scores of 3 through 5) despite an increased risk of hemorrhage.^10–13 Despite these positive results, some controversy remains: TESLA did not meet its primary end point,¹⁴ LASTE demonstrated a median mRS of 4 despite its favorable 90-day mRS shift,¹⁵ and questions persist regarding whether treatment benefits are sustained at 12 months.¹⁰

A similar attempt to expand treatment indications was made to evaluate the applicability of current procedural techniques to smaller and more distal target occlusions. Recently, data from the Endovascular Therapy Plus Best Medical Treatment (BMT) versus BMT Alone for Medium Vessel Occlusion Stroke (DISTAL, NCT05029414),¹⁶ Evaluation of Mechanical Thrombectomy in Acute Ischemic Stroke Related to a Distal Arterial Occlusion (DISCOUNT, NCT05030142),¹⁷ and Endovascular Treatment to Improve Outcomes for Medium Vessel Occlusions (ESCAPE-MeVO, NCT05151172)¹⁸ trials have been reported, with notably different overall outcomes. When considering individuals with anterior or posterior circulation strokes with moderate average deficits (median National Institutes of Health Stroke Scale score 6–8) from singular more distal occlusions (eg, distal M2 and beyond, A1–A2, P1–P2), the data did not support procedural intervention. Understanding these results within the greater context of this rapidly maturing field is key, as they highlight the challenge of measuring a clinically significant effect size in less disabled individuals at presentation within the inherent confines of current technology and its use in distal vessels givent their unique anatomy.

Taken together, the results of studies assessing large core and distal medium vessel occlusions represent important turning points for the advancement of interventional stroke treatments. Trials assessing individuals with LVOs indicate that current interventional techniques have a role in providing improvement in quality of life and reducing mortality rates for the sickest individuals with LVO, whereas trials assessing individuals with smaller and more distal occlusions indicate that patients who are less sick but require more technically challenging procedures may not have a similar benefit to gain. Ultimately, the field may need to shift its approach to expanding access through more personalized, hypothesis-driven selection of cases at the boundaries of current (and forthcoming) guidelines. Advanced imaging,¹⁹ new integrated risk scores,^20,21 and artificial intelligence²² may provide valuable information in such cases. However, as the next round of more carefully tailored and selective trials are designed to better identify individuals who may benefit from current interventional stroke treatments, the development of new technologies may be integral in pushing the boundaries further.

Implementing New Technologies and Techniques
Beyond the classically used approach of MT with medium-bore aspiration catheters and current-generation stent retrieval devices, the past decade has seen a variety of market-ready and in-development advances (Table). 

Following the establishment of aspiration-only MT as a viable option in the 2014 ADAPT FAST study,²³ which demonstrated that aspiration alone could achieve up to 78% Thrombolysis in Cerebral Infarction grade 2b/3 reperfusion, there has been growing interest in the optimization of this technique. Early efforts to refine the application of aspiration, such as the Contact Aspiration vs Stent Retriever for Successful Revascularization (ASTER, NCT02523261)²⁴ and COMPASS Trial: A Direct Aspiration First Pass Technique (COMPASS, NCT02466893)²⁵ trial protocols, ultimately led to the implementation of combined techniques with stent retrieval in the Combined Use of Contact Aspiration and the Stent Retriever Technique versus Stent Retriever Alone for Recanalisation in Acute Cerebral Infarction (ASTER2, NCT03290885) trial.²⁶ Building on published data from the Stent-Retriever Assisted Vacuum-Locked Extraction (SAVE) study, the combination aspiration–stentriever approach is now seen as a viable intervention option, particularly in more challenging cases.²⁷

There has also been motivation to optimize aspiration itself by pushing the envelope of the largest “superbore” catheters. Recent work using ≥.088-inch catheters, such as the MonoPoint reperfusion system (Route 92 Medical; San Mateo, CA) in the Prospective, Randomized, Controlled, Interventional Clinical Trial to Evaluate the Safety and Effectiveness of the Route 92 Medical MonoPoint Reperfusion System for Aspiration Embolectomy in Acute Ischemic Stroke Patients (SUMMIT MAX, NCT05018650)²⁸ and the Millipede system (Perfuze; San Mateo, CA) in Millipede Aspiration for Revascularization in Stroke (MARRS, NCT05714501) trial, combined with retrospective analyses,²⁹ demonstrated particularly improved first-pass effect in early reported data. When combined with recent advances in cyclic and modulated aspiration, such as developments from RapidPulse (Miami, FL) and Penumbra (Alameda, CA) to further enhance the first-pass effect,³⁰ novel aspiration technology is likely to become increasingly utilized.

Analogous to the iteration of aspiration technologies, retrieval devices have come a long way from the original Merci Retriever device. Indeed, next-generation stent retrievers, such as Solitaire (Medtronic; Minneapolis, MN) and Trevo (Stryker; Portage, MI), were seen as crucial in the efficacy of MT in the 2015 trials.^30a Building on data from the Analysis of Revascularization in Ischemic Stroke With EmboTrap (ARISE II, NCT02488915) trial,³¹ a better understanding of the molecular makeup of clots helped refine the design of Embotrap III (Cerenovus; Johnson & Johnson Medical Devices, Irvine, CA), which was found by the PREMIER study to have an effective design to remove harder, fibrin-rich clots.³² Medtronic modified the Solitaire X to optimize visualization and increase the safety of device deployment,³³ and newer technologies, such as the Tigertriever (Rapid Medical; New York, NY), go one step further in giving manual radial adjustment control to the operator.³⁴ Beyond stent retrieval, novel devices, such as the milli-spinner device, may allow for more elegant approaches to remove large clot burdens, with the ability to compress up to 90% of extensive proximal vessel thrombus before retrieval.³⁵

In addition to devices optimizing aspiration and retrieval, a number of other complementary technologies are under investigation. Application of optical coherence tomography, a technology of increasing interest in the field of interventional cardiology, has been evaluated for assessing complex intracranial lesions for burden of atherosclerotic disease and for procedural planning.³⁶ More readily available catheter delivery devices, such as Tenzing (Route 92 Medical), Carrier (Balt; Irvine, CA), and SENDit (Penumbra; Alameda, CA), are tapered flexible inserts that reduce the ledge effect at the catheter tip to further aid in trackability through tortuosity. Furthermore, new catheters and guide wires to better navigate complex anatomy, such as those utilizing magnetic forces^36a or flow guidance,³⁷ may enhance the ability to maneuver through areas of extreme tortuosity in older or sicker individuals. Tandem lesions involving both cervical carotid and intracranial lesions remain a unique challenge to navigate and treat, and intra-arterial ultrasonic lithotripsy³⁸ may have a role in their management. Robotic-assisted techniques³⁹ that enhance operator ability to navigate challenging proximal anatomy and improve precision and stability in distal anatomy may similarly maximize the safe and effective application of current technology, particularly with the increasing fidelity of preoperative 3-dimensional imaging for planning.

Adjunctive Technologies for Improved Outcomes and Neurorecovery
A number of new avenues for technologic development are being actively investigated to improve outcomes for candidates for endovascular intervention. Early detection technologies are being developed for use before the patient enters the angiography suite. These include deploying existing imaging in mobile stroke units,⁴⁰ identifying LVO in the prehospital setting with transcranial Doppler or EEG,⁴¹ and using novel point-of-care blood tests⁴² that can help identify candidates faster. Adjunctive systemic drug administration, inspired by the long-standing use of alteplase (Activase; Genentech, South San Francisco, CA), is another promising point of progress. As tenecteplase (TNKase; Genentech, South San Francisco, CA) use becomes increasingly common, recent studies such as Tenecteplase versus Alteplase Before Endovascular Therapy for Ischemic Stroke (EXTEND IA-TNK, NCT02388061),⁴³ have broadly supported the continued use of systemic treatment with newer thrombolytics. Whereas the debate as to whether thrombolytics are needed in thrombectomy candidates continues, modern trials, including Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN–NO IV, ISRCTN76741621),⁴⁴ Randomized Study of Endovascular Therapy With vs Without Intravenous Tissue Plasminogen Activator in Acute Stroke With ICA and M1 Occlusion (SKIP, UMIN000021488),⁴⁵ Solitaire With the Intention for Thrombectomy Plus Intravenous t-PA vs DIRECT Solitaire Stent-Retriever Thrombectomy in Acute Anterior Circulation Stroke (SWIFT DIRECT, NCT03192332),⁴⁶ and A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval (DIRECT-SAFE, NCT03494920),⁴⁷ support continuation of the practice overall. Beyond standard intravenous thrombolysis, the Intravenous Tirofiban for Patients With Large Vessel Occlusion Stroke (RESCUE BT, ChiCTR-IOR-17014167)⁴⁸ trial opened the door to the consideration of tirofiban as an adjunctive agent that may enhance the first-pass effect. An additional consideration is the intra-arterial administration of thrombolytics during MT. Building on the Intraarterial Alteplase versus Placebo After Mechanical Thrombectomy (CHOICE, NCT03876119) trial,⁴⁹ recent data from Intra-arterial Alteplase for Acute Ischemic Stroke After Mechanical Thrombectomy (PEARL, NCT05856851) and Intra-Arterial Recombinant Human TNK Tissue-Type Plasminogen Activator (rhTNK-tPA) Thrombolysis for Acute Large Vascular Occlusion After Successful Mechanical Thrombectomy Recanalization (ANGEL-TNK, NCT05624190),⁵⁰ as well as Adjunctive Intra‐Arterial Urokinase After Successful Endovascular Thrombectomy in Patients With Large Vessel Occlusion Stroke (POST-UK, ChiCTR2200065617)⁵¹ and Adjunctive Intra-Arterial Tenecteplase Following Near-Complete to Complete Reperfusion for Large Vessel Occlusion Stroke (POST-TNK, ChiCTR2200064809), suggest that this approach is likely safe and possibly effective when used after successful MT (ie, Thrombolysis in Cerebral Infarction grade 2b/3) to target distal microvascular thrombi. 

Adjunctive neuroprotection alongside reperfusion methods is an equally exciting frontier for improving patient outcomes. Nerinetide (NoNO Inc., Toronto, ON, Canada), a PSD-95 inhibitor with strong preclinical data, was recently investigated in the Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis (ESCAPE-NEXT, NCT04462536)⁵² trial alongside standard of care MT in participants who did not receive thrombolytic therapy. Additional studies are needed to determine the ideal timing of treatment and if certain patient subgroups may be more likely to benefit. Neuroinflammatory modulation via the TLR-4 antagonist ApTOLL (AptaTargets, Madrid, Spain) has been studied in early phase 1/2 trials and was shown to lower 90-day mortality rates in individuals with severe strokes.⁵³ The Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following Large Hemispheric Infarction (CHARM, NCT028664953) investigating glibenclamide did not meet its primary end point of decreased symptomatic edema⁵⁴ but suggested promising results for individuals with large-core infarctions. There is also potential for direct drug delivery in situ, with results of the First-in-Man Trial Evaluating the Safety and Efficacy of the NOVA Intracranial Stent (NOVA, NCT02578069) suggesting benefit in individuals undergoing intracranial stenting with sirolimus-eluting stents for direct delivery of drugs targeting atherosclerotic disease to optimize outcomes and decrease in-stent restenosis.⁵⁵

As a final point of discussion, moving beyond thromboembolic causes of LVO to more targeted technologies for occlusion from in situ intracranial stenosis is another point of active investigation. Although the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS, NCT00576693) trial demonstrated that the risk of intracranial stenting likely outweighs the benefit in individuals with minor strokes,⁵⁶ acutely stenting critically stenotic or occluded lesions in severe strokes is not an uncommon rescue strategy if MT is unsuccessful, particularly with the positive results of the Registry of Emergent Large Vessel Occlusion due to Intracranial Stenosis (RESCUE-ICAS, NCT05403593) study⁵⁷ and the expanded safety data implied by the China Angioplasty & Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS, NCT01763320) trial⁵⁸ and WEAVE and WOVEN registries.^59,60 Newer stents mirroring the balloon-mounted drug-eluting coronary stents or the intracranial balloon-expandable Apollo stent (MicroPort, Shanghai, China) may have a role to play in moving beyond self-expanding bare-metal stents for these complex cases.⁶¹ The success of balloon angioplasty in the Balloon Angioplasty for Symptomatic Intracranial Artery Stenosis (BASIS, NCT03703635) trial⁶² may also open the door for nonimplantable technologies to augment acute interventional stroke management with removable intracranial dilation devices such as TG dilators⁶³ and drug-coated balloons.^64,65

Conclusion
The field of interventional stroke has a remarkable history, characterized by technologic innovation and advances. A decade after the 2015 trials that revolutionized stroke care with MT, the field continues to evolve rapidly. MT has proven to be one of the most impactful interventions in modern medicine, with dramatic expansion in its indications. However, recent data provide reminders of the limitations of MT, with risk outweighing benefit for many distal occlusions and the fact that more than half of individuals with early-window, small-core infarcts remain functionally disabled or die despite treatment. Teams from clinical, academic, and industry settings continue to push these boundaries, improve utilization of existing technology, and develop new technology. The decade ahead promises to be equally transformative.