Neurointerventional Advances in 2023

Notice very specifically NOTHING ON 100% RECOVERY! It's like stroke researchers don't listen to survivor's only goal in stroke: 100% recovery! You'll also notice they are still using the milquetoast  term of neuroprotection instead of the neuronal cascade of death  which at least signifies urgency to get it solved!

Neurointerventional Advances in 2023

Amol Mehta,

Ashutosh P. Jadhav and

Sunil A. Sheth

Originally published16 Feb 2024https://doi.org/10.1161/SVIN.123.001251Stroke: Vascular and Interventional Neurology. 2024;0:e001251

This past year did not disappoint with major advancements in acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) care across multiple domains. As we had anticipated in our previous annual summary,¹ the headliners in 2023 were a suite of trials examining the benefit of endovascular stroke therapy (EVT) in patients with large and established infarcts, building on the RESCUE JAPAN LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra‐Acute Embolism–Japan Large Ischemic Core Trial) of 2022.² These trials included SELECT2 (Randomized Controlled Trial to Optimize Patient's Selection for Endovascular Treatment in AIS),³ ANGEL‐ASPECT (Study of Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core),⁴ and TENSION (Efficacy and Safety of Thrombectomy in Stroke With Extended Lesion and Extended Time Window).⁵ Two other studies that have presented their results with publication pending are TESLA (Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke)⁶ and LASTE (Large Stroke Therapy Evaluation).⁷ SELECT2 randomized 352 patients across 31 centers to either EVT or medical management in patients with anterior vessel large‐vessel occlusion and Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 3 to 5 or computed tomography (CT) perfusion core estimate >50 mL. The trial was stopped early, as the rate of functional independence [modified Rankin scale (mRS) score of 0–2] at 90 days in the EVT arm was 20% compared with 7% in the medical management arm. Rates of symptomatic intracerebral hemorrhage (sICH) were extremely low in both groups (1% versus 1%, EVT versus medical management). ANGEL‐ASPECT (Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core), conducted across 46 centers in China, enrolled 456 patients with anterior circulation large‐vessel occlusion and ASPECTS of 3 to 5. This trial also included participants who had ASPECTS of 0 to 2 if the CT perfusion core estimate was 70 to 100 mL. Significantly greater proportions of patients in the EVT arm achieved functional independence at 90 days (30% versus 12%, EVT versus medical management), and the odds ratio for treatment effect using shift analysis across the mRS range was 1.4 (95% CI, 1.1–1.7). The rate of sICH in the EVT arm was 6.1%. The TENSION (Efficacy and Safety of Thrombectomy in Stroke With Extended Lesion and Extended Time Window) trial was conducted across 40 centers in 8 countries throughout Europe and Canada. A total of 253 patients with ASPECTS of 3 to 5 on primarily noncontrast head CT were randomly assigned to EVT versus medical management. It was stopped early for efficacy after EVT was associated with a shift in mRS scores toward better outcome at 90 days (odds ratio [OR], 2.58 [95% CI, 1.60–4.15]; P = 0.0001). Although high mortality rates were seen at 90 days both in the medical (63/123 [51%]) and EVT arms (49/122 [40%]), EVT was associated with a lower mortality rate (hazard ratio, 0.67 [95% CI, 0.46–0.98]; P = 0.038). There remained considerable morbidity, however, in the EVT‐treated group, with a median mRS score of 4. sICH rates were 6% in the EVT arm and 5% in the medical management arm. The TESLA (Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke) trial, which was the first large‐core trial to identify patients on solely noncontrast head CT, randomly assigned 300 participants with anterior circulation large vessel occlusion patients with ASPECTS of 2 to 5 to EVT versus medical management. This trial failed to meet its primary end point of 90‐day utility weighted Rankin differences between the 2 groups with a Bayesian posterior probability of 0.96 (prespecified threshold, 0.975). Dichotomized mRS outcomes at 90 days were similarly nonsignificant for mRS of 0 to 2 versus 3 to 6 but were significantly different for mRS of 0 to 3 versus 4 to 6 (30% versus 20%, EVT versus medical management; P<0.05). The mortality rate was 35%, and the sICH rate was 4% in the EVT arm. Finally, the LASTE (Large Stroke Therapy Evaluation) trial was a randomized trial of 324 patients that addressed EVT in large‐core trials (ASPECTS of 0–5) with predominantly magnetic resonance imaging. Ordinal shift analysis demonstrated an increased odds of good outcome in EVT compared with medical management (OR, 1.63 [95% CI, 1.29–2.06]; P < 0.0001) with a number needed to treat of 4.2. sICH rates were close to 10% in the EVT arm. The LASTE and TENSION trials are the first large‐core trials to demonstrate a mortality benefit in patients undergoing EVT.

With the results of the trials, the question of EVT eligibility has shifted concretely from “who should we treat” to “who should we not treat.” Several open questions remain, particularly with respect to the optimal imaging selection definitions, as there was considerable heterogeneity across all the trials in terms of acquisition methods (noncontrast head CT versus CT perfusion versus magnetic resonance imaging) and definitions of infarct volume. Time also seems to play an important role in treatment outcomes, with better results in patients undergoing EVT in the first 6 to 10 hours, independent of size of infarct at presentation. Some of these questions were addressed in the recently published MR CLEAN LATE (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands for Late Arrivals) trial,⁸ which was a phase 3 randomized controlled trial across 18 centers across the Netherlands. A total of 535 patients who were eligible for late‐window EVT were randomly assigned to either EVT or medical management on the basis of the presence or absence of collateral flow on CT angiogram. The EVT group had a shift toward lower mRS (OR, 1.67 [95% CI, 1.20–2.32]). Undoubtedly, we will see updates to guidelines from multiple societies in the coming year, and given the variability in study designs and conduct and high rates of considerable morbidity in the EVT‐treated groups, there will likely be variable interpretation when it comes to defining eligibility in this large‐core population.

Additional data emerged on the optimal blood pressure management following EVT. The OPTIMAL‐BP (Outcome in Patients Treated With Intra‐arterial Thrombectomy–Optimal Blood Pressure Control)⁹ randomized clinical trial took place in South Korea across 19 centers and enrolled 302 participants. Groups were randomly assigned to intensive systolic blood pressure (SBP) lowering (<140 mm Hg SBP) compared with a conventional goal (140–180 mm Hg SBP) for the initial 24 hours following EVT. The trial was stopped early, as the rates of functional independence (mRS score of 0–2) at 90 days were significantly lower in the intensive arm (OR, 0.56 [95% CI, 0.33–0.96]; P = 0.03). There were no differences in the safety outcomes of sICH or index stroke‐related death at 90 days. The BEST‐II (Blood Pressure After Endovascular Stroke Therapy II) trial was a futility designed randomized clinical trial that included 120 participants. In this study, participants were randomly assigned to either <140, 160, or 180 mm Hg SBP. Although the lower SBP targets did not meet the prespecified futility criteria, the authors concluded that a future larger clinical trial would be unlikely to demonstrate a benefit of intensive SBP control after EVT.

This year also heralded renewed optimism for neuroprotection(Why are you still using this milquetoast term? The Rockefeller University in 2008 coined the term, cascade of death; which at least means urgency.) . Two trials built on the results of the prior ESCAPE‐NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischaemic Stroke)¹⁰ trial and evaluated the eicosapeptide nerinetide in AIS. ESCAPE‐NEXT (Efficacy and Safety of Neerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular thrombectomy Excluding Thrombolysis)¹¹ enrolled 850 patients who did not receive alteplase across 77 sites in the United States, Canada, Europe, Australia, and Singapore and randomly assigned them to nerinetide versus placebo. While this study found no difference in primary outcome (mRS score of 0–2) between the placebo arm (45.7%) compared with the nerinetide arm (45.4%), the FRONTIER (Field Randomization of NA‐1 Treatment in Early Responders) study,¹² which studied this same drug administered in the prehospital phase, found evidence of benefit. Among the 532 randomized patients, who were treated on average 60 minutes after AIS onset, there was an improvement in the shift analysis of mRS (OR, 1.72 [95% CI, 1.13–2.6]; P = 0.011). This improvement was even greater in patients who received reperfusion. Another molecule, the aptamer ApTOLL, studied in Spain also showed benefit. The APRIL (Phase Ib/IIa Clinical Study of ApTOLL for theTreatment of Acute Ischemic Stroke) trial¹³ was a double‐blind, placebo‐controlled, randomized study investigating the potential neuroprotective effects of ApTOLL, through its mechanism of TOLL‐like receptor 4 antagonism. In this trial, >150 adults were randomly assigned to receive placebo or either 0.05 or 0.02 mg/kg ApTOLL after which they received EVT. In the higher‐dose ApTOLL group, 64% of participants reached functional independence (mRS score of 0–2) compared with 47% in the placebo group. Additionally, a 40% decrease in final infarct volume was observed in the higher‐dose ApTOLL group. Larger trials are in the planning stages.

Finally, 2023 witnessed at last a successful result for hematoma evacuation for ICH. The ENRICH (Early MiNimally invasive Removal of Intracerebral Hemorrhage [ICH]) trial¹⁴ was a multicenter randomized adaptive clinical trial that enrolled 300 participants and compared standard medical management to early (<24 hours) surgical hematoma evacuation using minimally invasive parafascicular surgery in the treatment of acute spontaneous supratentorial ICH. The trial demonstrated a Bayesian posterior probability of superiority of 0.9813 for improved 90‐day mRS outcomes. Hematoma evacuation was highly successful with nearly 90% hematoma removal in study participants. The number needed to treat to prevent an mRS score of 3 to 6 was 8. Study publication is still pending.

One of the substantial regulatory changes that occurred this past year was the expansion of Centers for Medicare and Medicaid Services coverage for carotid artery stenting. This change was the first major revision since 2009.¹⁵ The Centers for Medicare and Medicaid Services determined that angioplasty with concurrent carotid artery stenting was reasonable and necessary for Medicare beneficiaries in patients with symptomatic carotid artery stenosis ≥50% and patients with asymptomatic carotid artery stenosis ≥70%. This decision expands coverage to those who were previously eligible for coverage only in clinical trials, removes the limitation of coverage to only high‐surgical‐risk individuals, and removes facility standards and approval requirements.

Looking ahead, we can expect the invigorating pace of discovery in vascular and interventional neurology to continue through 2024. The CREST‐2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) has completed the carotid endarterectomy arm, and the carotid artery stenting arm is nearly complete.¹⁶ The highly anticipated results will play a large role in informing the management of asymptomatic carotid disease. We will also likely have the first set of data on embolization for subdural hematoma, through the conclusion of ongoing trials including EMBOLISE (Embolization of the Middle Meningeal Artery with ONYX Liquid Embolic System for Subacute and Chronic Subdural Hematoma),¹⁷ STEM (The SQUID Trial for the Embolization of the Middle Meningeal Artery for Treatment of Chronic Subdural Hematoma),¹⁸ MEMBRANE (Middle Meningeal Artery Embolization for the Treatment of Subdural Hematomas With TRUFILL n‐BCA)¹⁹ and MAGIC‐MT (Managing Nonacute Subdural Hematoma Using Liquid Materials: A Chinese Randomized Trial of MMA Treatment),²⁰ as well as the commencement of the CHESS (Chronic Subdural Hematoma Treatment With Embolization Versus Surgery Study).²¹ Results from the RESILIENT‐EXTEND (Randomization of Endovascular Treatment in Acute Ischemic Stroke in the Extended Time Window) trial²² are also anticipated, which will shed some light on selecting patients for EVT in the extended window using only noncontrast CT ASPECTS and CT Angiogram (CTA). In 2024, we may also see the presentation of study results for medium‐ and distal‐vessel EVT through ESCAPE‐MeVO (Endovascular Treatment to Improve Outcomes for Medium Vessel Occlusions) trial,²³ the DISTALS (Distal Ischemic Stroke Treatment With Adjustable Low‐Profile Stentriever) trial,²⁴ and DISCOUNT (Evaluation of Mechanical Thrombectomy in Acute Ischemic Stroke Related to a Distal Arterial Occlusion) trial.²⁵ Finally, the GOLDEN‐BRIDGE (Intervention to Bridge the Evidence‐Based Gap in Stroke Care Quality) trial will further investigate the growing relationship between artificial intelligence and the medical decision making in the management of cerebrovascular disease.²⁶

In summary, new science in 2023 demonstrated that neurointerventional techniques can benefit a broader array of patients with AIS, and the Centers for Medicare and Medicaid Services acknowledged the safety and efficacy of carotid artery stenting. In the next year, we look forward to learning whether similar expansions will occur for both AIS and subdural hemorrhage.

Sources of Funding

Dr Sheth reports grant funding from the National Institutes of Health (5R01NS121154).