Remote Ischemic Conditioning for Acute Ischemic Stroke: Does Stroke Etiology Matter?

HomeStrokeVol. 55, No. 4Remote Ischemic Conditioning for Acute Ischemic Stroke: Does Stroke Etiology Matter? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBRemote Ischemic Conditioning for Acute Ischemic Stroke: Does Stroke Etiology Matter? Aravind Ganesh and Fernando D. Testai Aravind GaneshAravind Ganesh Correspondence to: Aravind Ganesh, MD, DPhil, Calgary Stroke Program, Departments of Clinical Neurosciences and Community Health Sciences, the Hotchkiss Brain Institute, the Matheson Centre for Mental Health Research and Education, and the O'Brien Institute for Public Health, University of Calgary Cumming School of Medicine, HMRB Room 103, 3280 Hospital Dr NW Calgary, AB T2N 4Z6. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5520-2070 Calgary Stroke Program, Departments of Clinical Neurosciences and Community Health Sciences, the Hotchkiss Brain Institute, the Matheson Centre for Mental Health Research and Education, and the O'Brien Institute for Public Health, University of Calgary Cumming School of Medicine, Alberta, Canada (A.G.). and Fernando D. TestaiFernando D. Testai https://orcid.org/0000-0002-7355-4915 Department of Neurology and Rehabilitation, University of Illinois Chicago (F.D.T.). Originally published25 Mar 2024https://doi.org/10.1161/STROKEAHA.124.046615Stroke. 2024;55:880–882This article is a commentary on the followingEffect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST TrialSee related article, p 874It is well recognized that early initiation of treatment is an important predictor of stroke outcome. However, many patients incur prehospital delays in their transport to stroke centers even under the best of circumstances due to geographic realities.1,2 Thus, the prehospital setting is a key untamed frontier for therapeutic development in neurovascular research. Unfortunately, there are no proven prehospital treatments for stroke, besides thrombolysis for ischemic stroke in mobile stroke units.3 Remote ischemic conditioning (RIC) is a safe and simple treatment that is being studied as a promising strategy to mitigate infarct growth and promote recovery in ischemic stroke, and to reduce hematoma expansion or accelerate hematoma resolution in intracerebral hemorrhage.4RIC consists of brief periods of ischemia reperfusion in a limb which are thought to protect a remote organ such as the brain from injury through humoral and neuronal-mediated responses that enhance cell survival and repair, whereas inhibiting apoptosis and inflammation.5 Results from a previous open-label blinded outcome proof-of-concept trial that included 443 patients with suspected acute stroke demonstrated the safety of RIC administered in the ambulance, even for patients with intracranial hemorrhage.6 The primary efficacy outcome of the study, defined as penumbral salvage, was comparable in the RIC and control groups. However, the study was confounded by a higher proportion of transient ischemic attacks and less severe strokes in the RIC group and relatively short ambulance transport times which interfered with the application of RIC. After adjustment for baseline perfusion and diffusion lesion severity, however, post hoc voxel-wise analyses suggested that RIC lowered the tissue risk of infarction.The RESIST (Remote Ischemic Conditioning in Patients With Acute Stroke) built on this work.7 This investigator-initiated, multicenter, randomized, patient and outcome-assessor blinded, sham-controlled clinical trial randomized 1500 patients with suspected stroke within 4 hours of onset, in the ambulance setting to either RIC—each session consisting of 5 cycles, each with 5 minutes of cuff inflation to 200 mm Hg (or 35 mm Hg above systolic blood pressure, to maximum cuff pressure of 285 mm Hg, whether the blood pressure was >175 mm Hg) followed by 5 minutes of deflation—or sham control, in which case the sham device would only inflate to a pressure of 20 mm Hg. Treatment was started immediately after randomization in the ground ambulance or helicopter, and in those with ischemic stroke or intracerebral hemorrhage admitted to the study hospital, RIC was continued twice daily for 7 days. The primary efficacy end point of shift toward better functional outcome measured by the modified Rankin Scale score at 90 days was similar in the RIC and sham groups (odds ratio, 0.95 [95% CI, 0.75–1.20]).8 These results may be contrasted with the RICAMIS trial (Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke), a large randomized-controlled trial of RIC performed in China that included 1776 patients with acute ischemic stroke, which found rates of excellent functional outcome, defined by a modified Rankin Scale score at 90 days of 0 to 1 (the primary study outcome), of 67.4% in the RIC group versus 62.0% in the control group (P=0.02).9 However, RICAMIS was not focused on the prehospital setting and suffered from key methodological limitations including an open-label design without a sham control group.One intriguing question that might arise in the aftermath of such results is whether the efficacy of RIC in acute ischemic stroke differs based on stroke etiology. Evidence from secondary stroke prevention studies suggests that patients with large artery atherosclerosis may benefit from RIC in particular.10 For example, a small open-label randomized-controlled trial with blinded end point assessment of bilateral arm RIC in 68 patients with symptomatic intracranial atherosclerotic disease found that patients receiving RIC were less likely to have recurrent stroke at 90 and 300 days.11 The double-blind RICA trial (Chronic Remote Ischemic Conditioning in Patients With Symptomatic Intracranial Atherosclerotic Stenosis) of 3033 patients—which focused on secondary stroke prevention and was neutral for the primary outcome of time to first recurrent stroke–found a significant reduction in the secondary composite outcome of any stroke, transient ischemic attack, or myocardial infarction with RIC.12 As for evidence in acute ischemic stroke, the RICAMIS investigators recently published a post hoc subgroup analysis reporting a significant treatment effect of RIC with respect to 90-day modified Rankin Scale score 0 to 1 in patients attributed to large artery atherosclerosis (n=516) but not in those with the nonlarge artery atherosclerosis subtype (n=1257); however, there was no significant interaction between RIC effect and stroke subtype.13Now in this issue of Stroke, the RESIST investigators report a post hoc subgroup analysis investigating the effect of RIC by stroke subtype and treatment adherence. Among the 698 patients with a final diagnosis of acute ischemic stroke in the trial, 93 (13.3%) patients were classified, based on discharge diagnosis, as having cerebral small vessel disease (CSVD) stroke, as determined using the Trial of ORG 10172 in Acute Stroke Treatment criteria.14 A total of 452 (64.8%) of patients with ischemic stroke were deemed to have acceptable treatment adherence, defined as completing at least 80% of planned RIC cycles. In patients with a stroke due to CSVD who were adherent to treatment (34 RIC, 31 sham), RIC was associated with improved functional outcome, including after adjusting for potential confounders (adjusted common odds ratio for shift to lower modified Rankin Scale score, 3.58 [95% CI, 1.30–9.88]).A direct comparison between RESIST and previous studies that investigated RIC for patients with CSVD is confounded by the fact that such studies used white matter hyperintensity volume and cognitive scores rather than functional recovery as primary outcomes.15,16 Having a treatment that is safe and could help acute stroke patients with CSVD would be useful, given that these patients are by definition not eligible for thrombectomy. Key limitations of the RESIST study include the small number of cases with CSVD and the etiologic classification that was based solely on the clinical impression at discharge by the treating physician, without any trial-specific protocols to adjudicate the stroke etiology. The post hoc nature of the analysis also means that the results should only be considered hypothesis generating. It is important to highlight that whereas analysis by stroke subtype and per-protocol analysis (based on treatment adherence) were each predefined in the statistical analysis plan, the combination of the 2—which necessarily involves splitting the data further into smaller groups and increases the risk of spurious findings from multiple comparisons—was not clearly predefined. In this regard, it is again noteworthy that, as in the RICAMIS analysis, the overall test for interaction between treatment assignment and stroke subtype was not significant—further underscoring the highly exploratory nature of splitting the data by etiology.Equipoise remains in relation to the beneficial effect of RIC in stroke. In addition, although provocative, the biologic mechanism by which RIC would benefit a particular stroke subtype, as suggested by the findings of RESIST, are still to be determined. Trials of RIC specifically in patients with CSVD are currently ongoing (NCT04109963, NCT05225948), although these trials remain primarily concerned with preventing stroke or CSVD progression as opposed to improving recovery after acute ischemic stroke.17Disclosures Dr Ganesh reports membership in the editorial boards of Neurology, Neurology: Clinical Practice, and Stroke; services as a review editor for stroke for Frontiers in Neurology; consulting fees from Atheneum, Canadian Association of Neuroscience Nurses, Creative Research Designs, DeepBench, MD Analytics, Figure 1, Alexion, Biogen, Servier Canada, MyMedicalPanel, AlphaSights, and CTC Communications Corporation; research support from Alberta Innovates, Alzheimer Society of Canada, Brain Canada, Canadian Cardiovascular Society, Canadian Cardiovascular Society, Canadian Institutes of Health Research, Campus Alberta Neuroscience, the Heart and Stroke Foundation of Canada, the Government of Canada INOVAIT program (Sunnybrook Research Institute) and New Frontiers in Research Fund, the France-Canada Research Fund, MicroVention, Inc, Panmure House, and the Rhodes Scholarships; travel support from the American Academy of Neurology, American Heart Association; stock/stock options from SnapDx and Let's Get Proof (Collavidence, Inc); has a patent application (US 17/317771) for a system for remote ischemic conditioning; and is co-leading ongoing/planned trials of remote ischemic conditioning in patients with small vessel disease (NCT04109963 and NCT05967728). The other author reports no conflicts.FootnotesFor Disclosures, see page 881.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Aravind Ganesh, MD, DPhil, Calgary Stroke Program, Departments of Clinical Neurosciences and Community Health Sciences, the Hotchkiss Brain Institute, the Matheson Centre for Mental Health Research and Education, and the O'Brien Institute for Public Health, University of Calgary Cumming School of Medicine, HMRB Room 103, 3280 Hospital Dr NW Calgary, AB T2N 4Z6. Email aganesh@ucalgary.caREFERENCES1. Holodinsky JK, Williamson TS, Demchuk AM, Zhao H, Zhu L, Francis MJ, Goyal M, Hill MD, Kamal N. Modeling stroke patient transport for all patients with suspected large-vessel occlusion.JAMA Neurol. 2018; 75:1477–1486. doi: 10.1001/jamaneurol.2018.2424CrossrefMedlineGoogle Scholar2. Fassbender K, Walter S, Grunwald IQ, Merzou F, Mathur S, Lesmeister M, Liu Y, Bertsch T, Grotta JC. Prehospital stroke management in the thrombectomy era.Lancet Neurol. 2020; 19:601–610. doi: 10.1016/S1474-4422(20)30102-2CrossrefGoogle Scholar3. Kate MP, Jeerakathil T, Buck BH, Khan K, Nomani AZ, Butt A, Thirunavukkarasu S, Nowacki T, Kalashyan H, Lloret-Villas MI, et al. Pre-hospital triage of suspected acute stroke patients in a mobile stroke unit in the rural Alberta.Sci Rep. 2021; 11:4988. doi: 10.1038/s41598-021-84441-0CrossrefGoogle Scholar4. Chen CH, Ganesh A. Remote ischemic conditioning in stroke recovery.Phys Med Rehabil Clin N Am. 2023; doi: 10.1016/j.pmr.2023.06.006CrossrefGoogle Scholar5. Stokfisz K, Ledakowicz-Polak A, Zagorski M, Zielinska M. Ischaemic preconditioning: current knowledge and potential future applications after 30 years of experience.Adv Med Sci. 2017; 62:307–316. doi: 10.1016/j.advms.2016.11.006CrossrefGoogle Scholar6. Hougaard KD, Hjort N, Zeidler D, Sorensen L, Norgaard A, Hansen TM, von Weitzel-Mudersbach P, Simonsen CZ, Damgaard D, Gottrup H, et al. Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial.Stroke. 2014; 45:159–167. doi: 10.1161/STROKEAHA.113.001346LinkGoogle Scholar7. Blauenfeldt RA, Mortensen JK, Hjort N, Valentin JB, Homburg AM, Modrau B, Sandal BF, Gude MF, Berhndtz AB, Johnsen SP, et al. Effect of remote ischemic conditioning in ischemic stroke subtypes: a post hoc subgroup analysis from the RESIST trial.Stroke. 2024; 55:874–879. doi: 10.1161/STROKEAHA.123.046144LinkGoogle Scholar8. Blauenfeldt RA, Hjort N, Valentin JB, Homburg AM, Modrau B, Sandal BF, Gude MF, Hougaard KD, Damgaard D, Poulsen M, et al. Remote ischemic conditioning for acute stroke: The RESIST randomized clinical trial.JAMA. 2023; 330:1236–1246. doi: 10.1001/jama.2023.16893CrossrefGoogle Scholar9. Chen HS, Cui Y, Li XQ, Wang XH, Ma YT, Zhao Y, Han J, Deng C-Q, Hong M, Bao Y, et al; RICAMIS Investigators. Effect of remote ischemic conditioning vs usual care on neurologic function in patients with acute moderate ischemic stroke: The RICAMIS randomized clinical trial.JAMA. 2022; 328:627–636. doi: 10.1001/jama.2022.13123CrossrefMedlineGoogle Scholar10. Ganesh A, Smith EE, Hill MD. Remote ischaemic conditioning for stroke prevention.Lancet Neurol. 2022; 21:1062–1063. doi: 10.1016/S1474-4422(22)00438-0CrossrefGoogle Scholar11. Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, Li G, Ren C, Luo Y, Ling F, et al. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis.Neurology. 2012; 79:1853–1861. doi: 10.1212/WNL.0b013e318271f76aCrossrefMedlineGoogle Scholar12. Hou C, Lan J, Lin Y, Song H, Wang Y, Zhao W, Li S, Meng R, Hao J, Ding Y, et al; RICA investigators. Chronic remote ischaemic conditioning in patients with symptomatic intracranial atherosclerotic stenosis (the RICA trial): a multicentre, randomised, double-blind sham-controlled trial in china.Lancet Neurol. 2022; 21:1089–1098. doi: 10.1016/S1474-4422(22)00335-0CrossrefMedlineGoogle Scholar13. Cui Y, Yuan ZM, Liu QY, Wang YJ, Chen HS. Remote ischemic conditioning and outcomes in acute ischemic stroke with versus without large artery atherosclerosis.Stroke. 2023; 54:3165–3168. doi: 10.1161/STROKEAHA.123.045040LinkGoogle Scholar14. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment.Stroke. 1993; 24:35–41. doi: 10.1161/01.str.24.1.35LinkGoogle Scholar15. Mi T, Yu F, Ji X, Sun Y, Qu D. The interventional effect of remote ischemic preconditioning on cerebral small vessel disease: a pilot randomized clinical trial.Eur Neurol. 2016; 76:28–34. doi: 10.1159/000447536CrossrefMedlineGoogle Scholar16. Wang Y, Meng R, Song H, Liu G, Hua Y, Cui D, Zheng L, Feng W, Liebeskind DS, Fisher M, et al. Remote ischemic conditioning may improve outcomes of patients with cerebral small-vessel disease.Stroke. 2017; 48:3064–3072. doi: 10.1161/STROKEAHA.117.017691LinkGoogle Scholar17. Ganesh A, Barber P, Black SE, Corbett D, Field TS, Frayne R, Hachinski V, Ismail Z, Mai LM, McCreary CR, et al. Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol.BMJ Open. 2020; 10:e040466. doi: 10.1136/bmjopen-2020-040466CrossrefGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. 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Stroke. 2024;55:874-879 April 2024Vol 55, Issue 4 Advertisement Article InformationMetrics © 2024 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.124.046615PMID: 38527151 Originally publishedMarch 25, 2024 KeywordsEditorialshematomahemorrhageischemic preconditioningischemic postconditioningischemic strokestrokePDF download Advertisement SubjectsCerebrovascular Disease/StrokeIschemic StrokeNeuroprotectantsTreatment