Expanding horizons in the endovascular treatment of stroke: larger cores and adjunct thrombolytics

Endovascular thrombectomy (EVT) has been firmly established as the gold standard of treatment in emergent large vessel occlusion (ELVO) acute ischaemic stroke. As of 2015, efficacy of EVT has been corroborated by randomized clinical trials and subsequent meta-analyses1 confirmed by ongoing real-world registry data. The emphasis has been on preventing viable but ischaemic brain tissue (penumbra) from becoming irreversibly infarcted and therefore recruited to the ‘core’ by recanalizing the affected large vessel and restoring microvascular reperfusion. As such, the patient selection criteria have focused on those with small core infarcts, often defined as Alberta Stroke Programme Early CT Score2 (ASPECTS; Figure 1) ≥6 on non-contrast computed tomography (NCCT) based on the initial clinical trial criteria. Alternative approaches, derived from the late-window EVT trials, have included a mismatch between core volume and clinical severity on the National Institutes of Health Stroke Scale (NIHSS) with small absolute core volumes or a penumbra-core ratio of >1.8 and absolute core volume <70 mL based on perfusion imaging thresholds.3 In addition to maximizing treatment benefit, restricting treatment to small cores is thought to reduce the risk of symptomatic intracranial hemorrhage (sICH). Illustrative examples of ASPECTS on CT. (A and B) Supraganglionic and basal ganglionic slices showing ASPECTS = 10 (no ischaemic changes). (C and D) Equivalent slices showing ASPECTS = 2 (severe right hemisphere tissue damage involving all 10 regions: 6 cortical areas, insula and internal capsule; the lentiform and caudate nuclei are intact). C, caudate nucleus; L, lentiform nucleus; IC, internal capsule; I, insula; M1, M2, M3, M4, M5, M6, cortical regions. There have been comparatively little data on those patients with large cores as they were largely excluded from the initial trials and remain under-represented in registries. Meta-analysis of seven EVT trials found that in patients with ASPECTS 0–4, EVT was associated with an overall favorable odds ratio for functional independence, defined as modified Rankin scale (mRS) 0–2; however, this was limited by small sample sizes and wide confidence intervals and a four-fold increase in sICH.4 A further meta-analysis including randomized controlled trials, prospective, and retrospective cohort studies further supported the efficacy of EVT in low ASPECTS patients, with increased odds of functional independence and reduced mortality after EVT despite a large infarct core.5 RESCUE-Japan LIMIT was a randomized clinical trial of thrombectomy in 203 patients with ELVO stroke and a large core infarct, with ASPECTS 3–5 on NCCT or MRI.6 The study did not include ASPECTS 0–2 patients, as they were presumed to have very poor outcomes regardless of treatment. The odds ratio of achieving mRS 0–3 with EVT compared to medical management was 2.43 (31% vs. 12.7%), and there was an overall significant beneficial shift on the mRS scale. EVT patients were also more likely to exhibit early improvement in NIHSS, with a comparable safety profile. It is worth noting that the primary functional outcome in RESCUE-Japan LIMIT included mRS 3 (moderate disability requiring help but independently mobile), in contrast to the typical cut-off of mRS 0–2; their secondary analyses for mRS 0–1 and 0–2 did not reach statistical significance. However, this is to be expected given the severity of strokes on initial presentation and still reflects a clinically meaningful effect as further supported by their post-hoc utility-weighted mRS analyses. These findings challenge certain assumptions about clinicopathological and radiological correlations in the core infarct. First, in the case of ASPECTS, we are classifying relatively large regions of brain on a binary system, which does not consider the volume of ischaemic changes within a region. Second, our ability to classify the severity of ischaemia is limited, and it is likely that a region considered as infarct on ASPECTS will have heterogenous degrees of neuronal and glial death between patients. Even with perfusion imaging, the commonly used threshold of <30% relative cerebral blood flow does not necessarily equate to irreversible pan-necrosis.7 As such, there may be salvageable tissue within the areas that we would radiologically consider as core. We expect that there will be heterogeneity in the viability thresholds and mechanisms of cell death affecting different cell populations—not only neurons but also the broader neurovascular unit including astrocytes, pericytes, microglia, and others—but our understanding of how to optimize reperfusion based on these remains very limited. A major limitation of RESCUE-Japan LIMIT is its use of diffusion-weighted magnetic resonance imaging (DWI) in >85% of included patients. DWI is significantly more sensitive to ischaemic changes, particularly at early time points,8 and it is worth noting that >55% of patients in the trial were randomized within 4.5 hours of onset with a median onset to imaging time of approximately 3 hours. It is therefore plausible that many of the patients included in this study would have qualified as ASPECTS ≥6 on NCCT, which limits its external validity as most centres use on CT-based approaches. Further data are now required to validate these initial findings, especially with low ASPECTS on NCCT, and to this end there are ongoing trials including SELECT-2 (NCT03876457), TENSION (NCT03094715), TESLA (NCT03805308), and LASTE (NCT03811769). Nonetheless, this result is a promising step forward for the management of larger infarcts and the associated enormous morbidity and mortality. Even with a small core, EVT outcomes remain highly variable. In the HERMES meta-analysis, 46% of patients treated with EVT achieved mRS 0–2 at 90 days, and only 26.9% achieved mRS 0–1.1 There is considerable scope for improvement, including through more rapid access to treatment, improved EVT devices and methodology, and post-procedural care. There is therefore an imperative for adjunct treatments, including neuroprotectants/cytoprotectants and thrombolytic drugs. The argument for thrombolysis is that there is a risk of distal embolization, due to intrinsic fragmentation of the clot or an iatrogenic effect of clot manipulation in EVT, resulting in impaired microvascular reperfusion despite large vessel recanalization. However, as these thrombi are much smaller, they should be more amenable to thrombolysis. The role of intravenous thrombolysis (IVT) in EVT is controversial despite multiple trials and reviewed in greater depth elsewhere.9 However, there has been little evidence on intra-arterial thrombolysis (IAT) in EVT to date. CHOICE was a phase IIb randomized clinical trial of intra-arterial alteplase compared with vehicle in patients undergoing EVT.10 The trial found that IAT was associated with significantly higher odds of mRS 0–1 at 90 days compared to vehicle (59% vs. 40.4%). Intriguingly, there was also no difference in angiographic scores, suggesting that this was either not sensitive to microvascular clot burden or the effects of IAT were not directly mediated through improved reperfusion. IAT was not associated with any cases of sICH in their study population. There were however significant limitations to CHOICE. The sample size was 121 patients in total, relating to challenges posed by the pandemic, and the authors acknowledged that further validation is required with the planned CHOICE-2 trial. Indeed, the fact that there was no overall shift in mRS distribution, and other functional outcomes including Barthel index and EQ-5D-3L showed no difference, further emphasize the need for more prospective randomized data. The trial used alteplase as their thrombolytic; while this remains the most popular agent for IVT worldwide, there is growing evidence that tenecteplase is more efficacious11 and might therefore provide a greater IAT effect as well. Finally, the vehicle used in CHOICE contains significant amounts of arginine, itself a vasoactive agent, and it would be of interest to know whether the outstanding rates of mRS 0–1 (40.4%) and 0–2 (63.5%) seen in the placebo group represent a potential vasodilatory effect from arginine.12 EVT represented a giant leap in the management of ELVO stroke in 2015, and it is unlikely that we will see revolutions of a similar magnitude in the foreseeable future. However, RESCUE-Japan LIMIT and CHOICE both illustrate that ongoing work to further improve EVT outcomes and expand patient eligibility is still needed. While both trials need validating, they nonetheless show the exciting prospects in store for the field of interventional stroke care. Biography: Dr Ain Neuhaus is a Specialty Registrar (Resident) in Radiology at Oxford University Hospitals and Lecturer in Medicine at Somerville College, University of Oxford. He completed his undergraduate and clinical medical education at the University of Oxford and intercalated a DPhil in Medical Sciences under the supervision of Prof. Buchan and Prof. Daniel Anthony, investigating microvascular blood flow regulation following ischaemia and reperfusion. His ongoing research focuses on patient selection criteria for endovascular thrombectomy and the development of novel prognostication methods. Biography: Prof Alastair Buchan is currently Professor of Stroke Medicine in the Radcliffe Department of Medicine at the John Radcliffe Hospital where he is an Honorary Consultant Neurologist. From 2008 to 2018, he was Dean of Medicine and a Pro-Vice-Chancellor at the University of Oxford. A Neurologist and Neuroscientist in Stroke Medicine and Neurology since 1988, he is a Professorial Fellow in Medicine at Corpus Christi College, Oxford. He was educated at Repton School, Cambridge, Oxford and Harvard. He undertook clinical medical training at Oxford and Neurology Specialist training in Oxford, London, Ontario, and Cornell University Medical College in New York. Since completing his training, he has worked at the University of Western Ontario, University of Ottawa, and University of Calgary. He has been a Consultant Neurologist at University Hospital in London, the Civic Hospital in Ottawa, and the Foothills Hospital in Calgary where he held the Heart and Stroke Foundation Professorship in Stroke. In Oxford since 2005, he has established the Acute Stroke Programme and has been the Translational Research Director for the UK Stroke Research Network. He was the founding Director of the Acute Vascular Imaging Centre, and the Director of the Oxford NIHR Biomedical Research Centre. He was appointed Head of the Medical Sciences Division of the University of Oxford in December 2007 and served as Dean of Medicine from October 2008. He is a Fellow of the Academy of Medical Sciences (FMedSci), a Senior Investigator of the NIHR and holds a DSc from the University of Oxford.

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