Edited by: Xinyi Leng, The Chinese University of Hong Kong, China
Reviewed by: Tao Wang, Capital Medical University, China
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The recent results of large core trials in acute ischemic stroke prompt the most influential paradigm shift in over a decade since endovascular therapy (EVT) was proven as the mainstay of acute stroke treatment. Six randomized, controlled trials (RCTs) of EVT in patients with more extensive ischemia on imaging than prior approved treatment indications revealed a consistent benefit of EVT, despite different imaging criteria and ischemic core definitions across the individual trials. These findings unfolded sequentially, akin to the acts of a drama, with the story evolving until perhaps the most conclusive results on extensive ischemia treatment about to be published. At this juncture, it is important to summarize the collective findings of these 6 RCTs, consider the potential expansion in the use of EVT, outline the penultimate or next steps during the encore of this drama and ponder the broad implications of these recent findings on the entire stroke field for many years to come. This logical rationale and perspective form the basis of Establishing Neuroimaging Criteria of Revascularization Efficacy (ENCORE), the proposed pooled, subject-level, meta-analysis of the recent large core trials, leveraging imaging re-adjudication by a collaborative, imaging core lab with documented expertise. Expansion of the treatment indications for EVT will likely ensue, yet numerous questions persist regarding other confounding variables that we normally use in routine clinical practice. Precision medicine for large core ischemic stroke mandates a more detailed investigation of the numerous clinical, imaging and angiographic variables that each trial dataset collected. In a simple pooled meta-analysis, these varying definitions, methodology and analytic approaches preclude anything beyond current summary results showing that EVT is favored, in general, over medical treatment. The epilog of the large core trials can be written by ENCORE, using the imaging and statistical methods and relevant expertise of the prior Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration.
The six recent large core trials include: Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism–Japan Large Ischemic Core Trial (RESCUE-Japan LIMIT) (Yoshimura et al.,
Unlike other pooling of individual RCT results, the primary outcomes were consistent across all individual studies, demonstrating the clear benefit of EVT over medical treatment alone in large core strokes. However, the heterogeneous use and combinations of basic to advanced imaging modalities for trial selection criteria and imaging methods regarding treatment outcomes, including hemorrhagic transformation (HT), complicate the broader implementation of EVT around the world for ischemic strokes of any size, compounded by discrepant time windows for potential intervention used in each of the RCTs. Expansion of the treatment indications for EVT will likely ensue, yet numerous questions persist regarding other confounding variables that we normally use in routine clinical practice. Precision medicine for large core ischemic stroke mandates a more detailed investigation of the numerous clinical, imaging and angiographic variables that each trial dataset collected. In a simple pooled meta-analysis, these varying definitions, methodology and analytic approaches preclude anything beyond current summary results showing that EVT is favored, in general, over medical treatment. The associated complications and impact on workflow, resource utilization or costs also remain unknown.
The epilog of the large core trials can be written by ENCORE, using the imaging and statistical methods and relevant expertise of the prior HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration (Goyal et al.,
The insights derived from ENCORE will have broad implications. For clinical practice, it will provide important estimates of treatment effect based on standardized imaging characteristics in combination with clinical factors such as time window and age. It will yield a better understanding of the pathophysiology of large core stroke by analyzing the imaging evolution of infarcts under prolonged ischemia (medical treatment alone) and after endovascular reperfusion. This may help to identify targets for edema-reducing therapies and neuroprotection. The role of automated imaging pipelines, diverse software packages and even novel analyses, such as mapping of net water uptake in these edematous brains, may be investigated and correlated with age or sex differences, duration of ischemia, concomitant use of thrombolytics, hemicraniectomy and the subtypes of HT in this distinct population of stroke patients previously unstudied with EVT, controlling for medical treatment alone. Such pooling and re-adjudication of 1,890 cases with serial imaging and angiography during EVT in almost a thousand cases is feasible via the imaging core lab used in HERMES. Limitations undoubtedly exist with use of some current imaging core lab services. In clinical practice, the timeliness of imaging interpretation at a core lab, the process of interpretation verification and the management of data transmission need attention. Standardization and optimization of imaging and angiography core lab services is critical for use in future clinical trials, registries and post-marketing surveillance.
The precision medicine of how to optimally treat specific stroke cases with EVT and the future use of adjunctive drugs will be outlined by the course of these relatively large subsets of cases. Such large strokes undergoing thrombectomy are the ideal population to study and ultimately prove the role of neuro- or cytoprotection. Until then, much can be learned about how to organize stroke care (e.g., personnel, timing, imaging resources, expertise) for this rapidly evolving entity of large core strokes around the globe.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
DL: Conceptualization, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing. SB: Data curation, Investigation, Methodology, Writing – review & editing. AY: Conceptualization, Investigation, Writing – review & editing.
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
DL was Consultant as Imaging Core Lab to Cerenovus, Genentech, Medtronic, Rapid Medical, Stryker. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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