Current State and Future for Emerging Stroke Therapies: Reflections and Reactions
2022; Lippincott Williams & Wilkins; Volume: 53; Issue: 6 Linguagem: Inglês
10.1161/strokeaha.122.039796
ISSN1524-4628
AutoresKeith W. Muir, Gustavo Saposnik,
Tópico(s)Acute Ischemic Stroke Management
ResumoHomeStrokeVol. 53, No. 6Current State and Future for Emerging Stroke Therapies: Reflections and Reactions Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCurrent State and Future for Emerging Stroke Therapies: Reflections and Reactions Keith W. Muir, MD and Gustavo Saposnik, PhD Keith W. MuirKeith W. Muir Correspondence to: Keith W. Muir, MD, School of Psychology and Neuroscience, Queen Elizabeth University Hospital, University of Glasgow, G51 4TF, Scotland, United Kingdom. Email E-mail Address: [email protected] https://orcid.org/0000-0001-9535-022X School of Psychology and Neuroscience, Queen Elizabeth University Hospital, University of Glasgow, Scotland, United Kingdom (K.W.M.). and Gustavo SaposnikGustavo Saposnik https://orcid.org/0000-0002-5950-9886 Stroke Outcomes and Decision Neuroscience Unit, Li Ka Shing Institute, University of Toronto, Canada (G.S.). Division of Neurology, Department of Medicine, St. Michael's Hospital, University of Toronto, Canada (G.S.). Originally published10 May 2022https://doi.org/10.1161/STROKEAHA.122.039796Stroke. 2022;53:2082–2084Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 10, 2022: Ahead of Print Surveying the potential emerging therapies for stroke over recent years prompts us to offer some reflections and to consider the challenges faced by researchers developing new treatments. We choose to focus on acute therapies and rehabilitation/recovery treatments as the 2 main areas that demand stroke-specific solutions, rather than the more clearly defined primary and secondary prevention approaches.Acute stroke treatment has enjoyed 2 major successes over the past 30 years, both involving early reperfusion of the ischemic brain. Both thrombolytic drug treatment and endovascular thrombectomy, after some initial stutters, hit upon successful strategies for patient selection and trial design that yielded a large treatment effect compared with control groups. The key design elements included a combination of clinical and imaging criteria, specific technologies, and crucially, short onset to treatment time intervals. The large treatment effects meant that sample size for these trials was accordingly small—624 participants in the NINDS trial (National Institute of Neurological Disorders and Stroke)1 and 500 in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands)2 were sufficient to provide highly significant results for clinically robust disability end points and thus compelling evidence of benefit. The current and future challenge for emerging acute therapies is to develop an effective trial strategy in the face of highly effective reperfusion therapies being widely available as standard of care, effect sizes likely to be much smaller, and in light of the consequences of higher life expectancy and the population aging (eg, higher burden of comorbidities also leading to higher frailty3,4). How might this be achieved?Trials can pursue either patients receiving reperfusion therapies or target those currently ineligible. Pursuing the reperfusion-eligible population faces the prospect of any new treatment being likely to yield only small incremental effects, with attendant substantially increased sample size compared with what has become typical in the stroke field. While cardiology successfully and rapidly evolved networks capable of delivering acute trials including tens of thousands of patients, this relied on simple end points and selection criteria, and it is unclear whether stroke, reliant on advanced imaging to select cases, and complex disability outcomes, will be able to expand capacity in a similar manner. Limited access to specialist stroke care necessitates cooperative networks of centers, but resources at spoke sites are limited, particularly the capacity to prosecute complex research protocols. Recruiting large numbers of patients through a network model is challenging. Acute trials that target those who present via transfer from spoke sites to endovascular centers have hypothesized incremental benefit based on retarding ischemic tissue damage or enhancing nonendovascular reperfusion rates.5 However, recent experience from direct-to-endovascular treatment trials has highlighted the vulnerability of such studies to ever-shortening workflow time intervals and improved field triage of thrombectomy-eligible patients that redirects them to a comprehensive treatment center, with smaller than anticipated differences in the interval to endovascular treatment6 and consequently small magnitude of effect size.Prehospital trials represent another potential target for early prereperfusion interventions, but even for safe and widely available established treatments, the poor sensitivity of clinical criteria for separating ischemic stroke from hemorrhage from mimics introduces further limitations,7 and the need to match field patient selection and treatment initiation with adherence to trial protocols across all destination hospital services is logistically complex. Mobile stroke units that include brain imaging facilities or in-field medical expertise have limited population coverage even where local infrastructure exists.The great majority of patients with stroke remain ineligible for reperfusion treatments; therefore, targeting this group for future trials is superficially attractive. The interventional field is already pushing beyond the criteria used in the definitive clinical trials, however, to argue for treatment of groups with lower ASPECTS (Alberta Stroke Program Early CT Scores), more distal occlusion sites, larger ischemic core volumes, and frail patients with prior disability. It is likely that trial-capable centers will have increasing difficulty in finding thrombectomy-ineligible patients as techniques and devices advance, and clinical practice runs ahead of trial evidence to embrace wider populations. In other words, this new standard of care will include more patients eligible for reperfusion therapies but also narrows their future scope by selecting subgroups with smaller therapeutic margins. The impact on trial recruitment and outcomes is uncertain but is potentially detrimental as the assumptions regarding severity and outcomes may be modified by practice drift.8 An alternative strategy is to target less severe stroke, clinically minor, or those without intracranial occlusion amenable to endovascular approaches.9 Less severe stroke represents a majority of patients presenting to hospital, so numbers are hypothetically plentiful. Whether current outcome measures are suited to this group is questionable. Already, successive thrombolytic drug trials have witnessed decrementing severity of stroke, and the modified Rankin Scale as the most widely used functional outcome measure offers little discriminatory power when the great majority of trial participants experience excellent recovery (eg, as seen in NOR-TEST [Randomized Trial of Tenecteplase vs Alteplase for Recanalization in Acute Ischemic Stroke]).10 There is a lack of a universally accepted measure that discriminates different grades of outcome in this situation, although tools that are more meaningful for patients such as the EuroQOL visual analogue scale are promising. Regulatory and general clinical acceptance of an intervention will be anchored in changes in clinically meaningful outcomes.Imaging will remain a key element of patient selection. The large number of physiologically relevant imaging prognostic measures, including core and penumbra volume, collaterals, occlusion site, indices of tissue damage such as ASPECTS, clot burden score, intracranial hemorrhage volume and location, points toward mandatory minimum imaging to characterize populations and ensure that modest-sized trials can adjust for random variation in disease severity among groups but carries requirements that include standardization of selection-critical interpretation and minimum site competencies and technical capacity. For reperfusion therapies, angiographic recanalization/reperfusion grade has already become a technical end point, but given the high proportion of patients significantly disabled at day 90 despite optimal endovascular reperfusion being achieved,11 this alone cannot be a viable surrogate. It is unclear whether other imaging end points offer biomarkers for functional outcomes. Follow-up infarct volume is widely used in trials but mediates only a small part of the variation in day 90 outcome,12 and it is unclear whether addressing potentially correctable factors such as variable timing or modality of imaging will improve performance. If instead an imaging biomarker needs to reflect more complex factors such as lesion location or disruption of functional networks,13,14 then substantial investment in newer technologies may be necessary. At present, widely available imaging biomarkers may not reduce sample size compared with clinical measures and are vulnerable to variation in patient selection strategy.15 The minimum clinically important difference for an imaging biomarker remains undefined.Trials in the subacute or recovery stages that investigate restorative or rehabilitation strategies require innovation in trial design to similarly address patient selection strategies and biomarkers but with some specific added issues and with few exemplars of successful trial strategies to suggest a solution. Vagus nerve stimulation exemplifies several of these.16 Physical interventions—be they devices, implants, cell injections, or human interactions of one kind or another—are often difficult to blind effectively. Implanted devices may limit imaging options or necessitate surgical removal at the end of a trial. The mode of action is often complex, ill-defined, and multidimensional, making it more difficult to identify relevant biomarkers. Using specific functional impairment end points, such as upper limb motor function, imposes specific selection criteria that may narrow patient eligibility and, therefore, recruitment, markedly. Any intervention that requires repeated visits, or sustained treatment, is vulnerable to loss of participants, more likely when perceived to be ineffective or tiresome, and causes particular difficulty in interpreting longitudinal performance data when the participants at each time point are not the same individuals.17 General functional outcomes such as the modified Rankin Scale are still viewed as suboptimal by rehabilitation specialists,18 at least for early phase explanatory studies, and trials that target specific neurological impairments remain common, with consequent narrowed eligibility criteria, difficulty in generalizing findings to other deficits, and underrepresentation of patient groups (eg, visual field loss, visuospatial neglect, and frailty) in trials. Identifying a universally agreed minimally important difference and finding a large enough effect to be detected with a modest sample size remain elusive goals.In conclusion, the major advances in acute reperfusion therapies are of major clinical benefit and inform the design of future trials. Continued innovation in trial design is of critical importance to the success of emerging therapies, since the very large effect sizes for reperfusion are unlikely to be replicated and new therapies will be tested on the background of ever-expanding indications for reperfusion. Solutions that may only be amenable for small groups of patients will not necessarily accomplish the main goal: improving the quality of life and clinical outcomes that are meaningful for stroke survivors.Article InformationSources of FundingNone.Disclosures Dr Muir declares grants from the British Heart Foundation, Innovate UK, Chief Scientist Office, the Stroke Association, and the National Institute of Health Research; consultancy agreements with Boehringer Ingelheim and Abbvie; advisory boards for Boehringer Ingelheim, Abbvie, and Biogen; and speaker's fees from Boehringer Ingelheim. Dr Saposnik received financial support from the World Stroke Organization as the Editor-in-Chief of the World Stroke Academy and declares grants from the Hoffmann Laroche and consultancy agreements with Roche Canada.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 2084.Correspondence to: Keith W. Muir, MD, School of Psychology and Neuroscience, Queen Elizabeth University Hospital, University of Glasgow, G51 4TF, Scotland, United Kingdom. Email keith.[email protected]ac.ukReferences1. The National Institute of Neurological Disorders & Stroke Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995; 333:1581–1587.Google Scholar2. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, et al; MR CLEAN Investigators. 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Standardized measurement of sensorimotor recovery in stroke trials: consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable.Int J Stroke. 2017; 12:451–461. doi: 10.1177/1747493017711813CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails June 2022Vol 53, Issue 6 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.122.039796PMID: 35535598 Originally publishedMay 10, 2022 Keywordsfrailtystrokesecondary preventionsample sizereperfusionPDF download Advertisement
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