Ongoing Advances in Medical And Interventional Treatments Of Large Vessel Occlusion Stroke

While the pandemic cast a long shadow on the whole of the healthcare system in 2020, progress in multiple aspects of medicine continued, including in the realm of neurovascular medicine. Specifically, in interventional neurology, several ground-breaking studies advanced the field from the perspective of triage, neuroprotection, reperfusion therapy, and public policy. The well-recognized mantra time is the brain has heightened awareness regarding the importance of early and efficient triage and increased prehospital decision-making and patient engagement. 

Click to cistanche tubulosa extract for neuroprotection

Several stroke severity scales have reasonable sensitivity and specificity for identifying large vessel occlusion (LVO). One such scale (RACE [Rapid Arterial Occlusion Evaluation]) was used in the RACECAR trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion)1 to prospectively identify suspected LVO patients and triage them to the closest primary stroke center (PSC, prioritizing intravenous alteplase administration) versus directly to the comprehensive stroke center (CSC, prioritizing endovascular therapy [EVT]). 

Of 1401 patients randomized, the modified intention-to-treat analysis focused on 949 (67%) with ischemic stroke or transient ischemic attack, of whom 67% had LVO. PSC patients received alteplase more frequently than CSC patients (60% versus 48%, P<0.001). Time from onset to thrombolysis was shorter for PSC patients (median 120 minutes versus 155 minutes, P<0.001). Conversely, more CSC than PSC patients received EVT (50% versus 41%, P=0.003) with a shorter time from onset to arterial puncture (median 214 minutes versus 270 minutes, P<0.001).

Importantly, the 90-day modified Rankin Scale (mRS) was comparable between groups (adjusted odds ratio, 1.02 [95% CI, 0.8–1.2]). These results suggest that in a highly efficient transfer system, as in Catalonia with < 1-hour delay in EVT between PSC versus CSC, bypass of potential LVO patients to a CSC may not be beneficial. However, RACECAT included patients with prolonged transfer times and further analysis will explore whether a subgroup, perhaps with a shorter transfer time difference between PSC and CSC, would benefit from direct triage to the CSC. 

Ongoing trials are also addressing this issue (TRIAGE; Treatment Strategy in Acute Ischemic Large Vessel STROKE: Prioritize Thrombolysis or Endovascular Treatment; URL: https://www. clinicaltrials.gov; Unique identifier: NCT03542188). Several studies have investigated the need for thrombolysis before EVT. Some observational analyses have reported comparable results in patients receiving EVTalone versus bridging thrombolysis. Although a meta-analysis favored bridging thrombolysis,2 reasons for thrombolysis-ineligibility confound interpretation.

 Two recently completed studies randomized thrombolysis-eligible patients presenting directly to a CSC with proximal anterior circulation occlusions (middle cerebral artery, segment 1; internal carotid artery) to receive IV thrombolysis followed by EVT versus EVT-alone. The SKIP trial (The Randomized Study of Endovascular Therapy With Versus Without Intravenous Tissue Plasminogen Activator in Acute Stroke With ICA and M1 Occlusion; n=204) found similar rates of mRS score 0 to 2 at 90 days between the 2 groups (EVT: 59.4% versus EVT/ IV thrombolysis: 57.3%) but did not meet noninferiority criteria.3 

Total intracranial hemorrhages were lower in patients treated with EVT-alone versus EVT/IV thrombolysis (33.7% versus 50.5%, P=0.02) but symptomatic intracranial hemorrhage did not differ (5.9% versus 7.8%, P=0.78). The MT-DIRECT trial (Direct Intraarterial Thrombectomy to Revascularise Acute Ischaemic Stroke Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: A Multicentre Randomised Clinical Trial; n=656) met noninferiority criteria (adjusted common odds ratio, 1.07), although the noninferiority margin chosen has been criticized as too broad.4 Symptomatic intracerebral hemorrhage occurred in 4.3% direct versus 6.1% bridging (P=0.30). 

The MR CLEAN-NO IV (Intravenous Treatment Followed by IntraArterial Treatment Versus Direct Intra-Arterial Treatment for Acute Ischemic Stroke Caused by a Proximal Intracranial Occlusion; ISRCTN80619088), DIRECT-SAFE (A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval; NCT03494920), and SWIFT-DIRECT (Bridging Thrombolysis Versus Direct Mechanical Thrombectomy in Acute Ischemic Stroke; NCT03192332) trials are ongoing. Rates of functional independence after EVT remain in the range of 40% to 50%. 

The ESCAPE-NA1 trial (Safety and Efficacy of Nerinetide [NA-1] in Subjects Undergoing Endovascular Thrombectomy for Stroke) tested whether intravenous nerine tide, a putative neuroprotectant peptide, could improve this benchmark in patients undergoing EVT 0 to 12 hours after symptom onset.5 While overall neutral, the prespecified subgroup analysis of alteplase-ineligible patients had significantly increased functional independence with nerine tide versus placebo (59.3% versus 49.8%). 

Pharmacokinetics revealed lower levels of nerine tide in alteplase-treated patients, consistent with preclinical data showing that plasmin activated by alteplase degrades nerine tide. The ESCAPE-NEXT trial (Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis; NCT04462536) is underway specifically in alteplase ineligible LVO patients. 

While the majority of patients with IV thrombolysiseligible stroke receive alteplase, tenecteplase affords several theoretical advantages over alteplase, including higher fibrin-specificity, resistance to inhibitors, longer half-life permitting bolus administration, and potentially higher efficacy. The EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Thrombectomy for Ischemic Stroke) demonstrated higher rates of recanalization in patients with LVO receiving 0.25 mg/kg tenecteplase versus alteplase,6 and EXTEND-IA TNK part 2 demonstrated no advantage in increasing the dose to 0.40 mg/ kg.7 While tenecteplase is the drug of choice for myocardial infarction, use for ischemic stroke remains an American Heart Association/American Stroke Association class 2B recommendation.8 

Two recent meta-analyses both suggested the noninferiority of tenecteplase versus alteplase.9,10 Multiple ongoing trials are investigating the benefit of tenecteplase, including in the late time window (eg, TIMELESS [Tenecteplase in Stroke Patients Between 4.5 and 24 Hours], NCT03785678; TWIST [Tissue Window in Stroke Thrombolysis Study], NCT03181360; and ETERNAL [Extending the Time Window for Tenecteplase by Effective Reperfusion in Patients With Large Vessel Occlusion], NCT04454788). Previous randomized controlled trials that demonstrated the benefit of EVT for anterior circulation LVO stroke were conducted in developed countries with high-quality postprocedural care and rehabilitation. 

The RESILIENT trial (Endovascular Treatment With StentRetriever and/or Thromboaspiration vs Best Medical Therapy in Acute Ischemic Stroke) demonstrated that the strong benefit of thrombectomy over medical therapy for functional independence persisted in the Brazilian public health care system (common odds ratio of 2.28), with the commendable system-wide organization from prehospital triage, trial enrollment, in-hospital work-flow, and post-stroke care.11 The trial was funded by the Brazilian government and importantly demonstrated cost-effectiveness, leading to thrombectomy approval in the Brazilian public health system. 

The benefit of EVT over medical therapy in posterior circulation stroke remains unproven. The BEST trial (Endovascular Treatment Versus Standard Medical Treatment for Vertebrobasilar Artery Occlusion) randomized 131 patients within 8 hours of basilar artery occlusion to EVT versus medical therapy.12 The trial was halted prematurely due to poor enrollment and high crossover. In the intention-to-treat analysis, rates of 90-day mRS scores of 0 to 3 were not significantly better in the EVT group versus medical therapy (42% versus 32%, P=0.23). However, in the per-protocol analysis, EVT increased the mRS score from 0 to 3 (44% versus 25%; adjusted odds ratio, 2.90 [95% CI, 1.20−7.03]). 

The BASICS study (The Basilar Artery International Cooperation Study) randomized 300 patients 0 to 6 hours after the onset of basilar artery occlusion (mild initial symptoms were not considered in determining the onset time). EVT did not significantly improve the mRS score of 0 to 3 (44.2% versus control 37.7%). Details remain unpublished, including rates of successful revascularization, but EVT appeared effective in patients with higher National Institutes of Health Stroke Scale (≥10 points).13 Further analysis is necessary to understand the role of EVT in posterior circulation. 

The Chinese BAOCHE trial (Basilar Artery Occlusion Chinese Endovascular Trial; NCT02737189) results are awaited. While coronavirus disease 2019 (COVID-19) introduced new challenges in stroke care, multiple clinical trials were published and presented with important implications for the care of LVO stroke including optimal triage and treatment strategy. 

Ongoing trials will clarify many remaining questions including the management of patients with LVO and low National Institutes of Health Stroke Scale or large baseline ischemic core, the role of EVT in the posterior circulation, the role of thrombolysis in patients receiving EVT in both early and late time windows, and novel therapies that may improve outcome through mechanisms other than reperfusion.

the mechanism of the Cistanche neuroprotective effect

Cistanche is a plant that has been traditionally used in Chinese medicine for its various health benefits, including neuroprotection. Although the exact mechanism of Cistanche's neuroprotective effect is not fully understood, several studies have investigated its potential mechanisms of action. One proposed mechanism suggests that Cistanche may act as an antioxidant by increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) to reduce oxidative stress in the brain. Additionally, Cistanche may increase the levels of intracellular antioxidants like glutathione which can help to protect neurons from oxidative damage.

Another suggested mechanism is related to the regulation of inflammation. Chronic inflammation has been linked to various neurological disorders, and Cistanche has been shown to possess anti-inflammatory properties in several studies. It can inhibit the release of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), which contribute to neuroinflammation. Furthermore, recent studies have highlighted the potential of Cistanche for promoting neuroplasticity and neurogenesis. For instance, Cistanche extract has been found to enhance nerve growth factor (NGF) production and activate the brain-derived neurotrophic factor (BDNF) pathway, both of which are essential for neurogenesis and neuronal survival.

Overall, findings suggest that Cistanche's neuroprotective effect may be due to its antioxidant, anti-inflammatory, and neurotrophic properties.

Reference

1 Abilleira S, Pérez de la Ossa N, Jiménez X, Cardona P, Cocho D, Purroy F, Serena J, Román LS, Urra X, Vilaró M, et al. Transfer to the local stroke center versus direct transfer to the endovascular center of acute stroke patients with suspected large vessel occlusion in the Catalan territory (RACECAT): study protocol of a cluster randomized within a cohort trial. Int J Stroke. 2019;14:734–744. doi: 10.1177/1747493019852176 

2. Mistry EA, Mistry AM, Nakawah MO, Chitale RV, James RF, Volpi JJ, Fusco MR. Mechanical thrombectomy outcomes with and without intravenous thrombolysis in stroke patients: a meta-analysis. Stroke. 2017;48:2450– 2456. doi: 10.1161/STROKEAHA.117.017320 

3. Suzuki K, Kimura K, Takeuchi M, Morimoto M, Kanazawa R, Kamiya Y, Shigeta K, Ishii N, Takayama Y, Koguchi Y, et al. The randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ICA and M1 occlusion (SKIP study). Int J Stroke. 2019;14:752–755. doi: 10.1177/1747493019840932 

4. Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, Peng Y, Han H, Wang J, Wang S, et al; DIRECT-MT Investigators. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med. 2020;382:1981–1993. doi: 10.1056/NEJMoa2001123 5. Hill MD, Goyal M, Menon BK, Nogueira RG, McTaggart RA, Demchuk AM, Poppe AY, Buck BH, Field TS, Dowlatshahi D, et al; ESCAPE-NA1 Investigators. Efficacy and safety of nerine tide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomized controlled trial. Lancet. 2020;395:878–887. doi: 10.1016/S0140-6736(20)30258-0 

6. Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, Yan B, Bush SJ, Dewey HM, Thijs V, et al; EXTEND-IA TNK Investigators. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018;378:1573–1582. doi: 10.1056/NEJMoa1716405 

7. Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, Yan B, Bush SJ, Thijs V, Scroop R, et al; EXTEND-IA TNK Part 2 investigators. Effect of intravenous tenecteplase dose on cerebral reperfusion before thrombectomy in patients with large vessel occlusion ischemic stroke: the EXTEND-IA TNK part 2 randomized clinical trial. JAMA. 2020;323:1257– 1265. doi: 10.1001/jama.2020.1511 

8. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50:e344–e418. doi: 10.1161/STR.0000000000000211 

9. Kheiri B, Osman M, Abdalla A, Haykal T, Ahmed S, Hassan M, Bachuwa G, Al Qasmi M, Bhatt DL. Tenecteplase versus alteplase for management of acute ischemic stroke: a pairwise and network meta-analysis of randomized clinical trials. J Thromb Thrombolysis. 2018;46:440–450. doi: 10.1007/ s11239-018-1721-3 10. Burgos AM, Saver JL. Evidence that tenecteplase is non-inferior to alteplase for acute ischemic stroke: a meta-analysis of 5 randomized trials. Stroke. 2019;50:2156–2162. doi: 10.1161/STROKEAHA.119.025080 

11. Martins SO, Mont’Alverne F, Rebello LC, Abud DG, Silva GS, Lima FO, Parente BSM, Nakiri GS, Faria MB, Frudit ME, et al; RESILIENT Investigators. Thrombectomy for stroke in the public health care system of Brazil. N Engl J Med. 2020;382:2316–2326. doi: 10.1056/ NEJMoa2000120 12. Liu X, Dai Q, Ye R, Zi W, Liu Y, Wang H, Zhu W, Ma M, Yin Q, Li M, et al; BEST Trial Investigators. Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomized controlled trial. Lancet Neurol. 2020;19:115–122. doi: 10.1016/S1474-4422(19)30395-3 

13. Endovascular therapy fails to outperform best medical management in basilar artery occlusion stroke. https://neuronewsinternational.com/basicsstudy-basilar-artery-occlusion/. Accessed Jan 3, 2021.

Ashutosh P. Jadhav, MD, Ph.D.; Bruce C.V. Campbell, MBBS, PhD