Each year, over five million people die worldwide from stroke. One out of four strokes is recurrent placing huge burden on health care system. Despite new evidences on how to best treat patients with ischemic stroke, stroke recurrence remains unacceptably high. Therefore, there is a great need for novel thechnologies and markers to prevent hospital readmissions due to recurrent stroke. This paper attempts to list possible options in the areas of prevention, early detection, monitoring, and personalised therapy.
As reported by the Stroke Alliance For Europe (SAFE) summary [1], the number of people aged 65 or over is estimated to increase by 45 per cent and, aged 85 or over by 89 per cent between 2017 and 2040 across the EU member states [1]. Consequently, the number of people with disabilities related to stroke will probably increase. In paralel,the number of people of working age will fall over the same period [1]. Despite advances in diagnostics and current evidences on how to treat patients with acute ischemic stroke, there is still an unacceptably high risk for recurrent stroke[2]. As society ages, this places a huge burden on the entire health care system. All this is happening in challenging times such as the COVID-19 pandemic, when the fair distribution of health resources can be a source of conflict. Consequently, a paradigm shift in organisations of the health care systemis inevitabledictated by needs of improvement in both performance and accountability.To achieve these, it is of paramount importance to get more value from the available resources, treating “the right people, at the right time, in the right place”.Importantly, the hospital readmission of stroke patients is associated with higher mortality rates, greater levels of disability and increased costs as compared with initial stroke events[3]. Therefore, there is a great need for novel markers (not only molecules, but neuroimaging) and therapeutic measures: (i) to explore clusters with increased vascular risk; (ii) to implement novel translational findings into clinical setting; (iii) to identify patients who may benefit most from interventions; (iv) to predict risk of recurrent stroke, and (v) to recognise short-term avoidable complications optimising better long-term outcomes [4].
Hospital readmission rate
Identifying factors that contribute to early readmission after stroke is pivotal. The rate of readmissions varied widely ranging from 20 per cent to 59 per cent within one year after the initial stroke depending on patient characteristics and the length of follow-up[5,6]. The three major causes of 30-day hospital readmissions were infection (20 per cent), coronary artery disease (18 per cent) and recurrent stroke (16 per cent) successively[7]. During 1-year follow-up,the three major causes were recurrent stroke (19.4 per cent), infection (19.3 per cent) and CAD (16.3 per cent) [7]. Therefore, patients with coronary artery disease, longer length of index admission and higher National Institute of Health Stroke Scale (NIHSS) reflecting the severity deserve extensive attention after hospital discharge. A post-stroke care coordination program in the first year after a stroke should be welcomed [8]. This complex program must contain at least the followings:
(i) scoring to identify critical patients with an increased risk of readmission after hospital discharge;
(ii) AI processed registry data to cluster patients into phenotypes, which will allow the activation of smart services for the prediction of the clinical outcomes;
(iii) generation of prevention alarms and linking of phenotypes with intervention efficacy;
(iv) a personalised clinical pathway to ensure that patients receive treatment and care remotely after discharge with appropriate interventions;
(v) providing personalised health monitoring based on AI solutions (wearable smart devices etc.);
(vi) personalised antiplatelet regimens based on genetic information, clinical and platelet characteristics.
Scoring systems
Beside currently used scores, development of novel and innovative in-hospital scoring would be critical to predict a discharge failure for patients with acute stroke. On the other hand, selecting ischemic stroke patients with large vessel occlusion (LVO) based on prehospital stroke scales could provide a faster triage and transportation to a comprehensive stroke center resulting in a favorable outcome[9].
Telemedicine
The COVID-19 pandemic is facilitatinga digital health revolution, compelling healthcare professionals to quickly adopt new tools and technologies, and has highlighted the enormous potential of telemedicine in stroke care.Readmission due to stroke recurrence might also be prevented by using health monitoring based on AI solution to ensure remote monitoring and tele-assistance to patients [10]. Telestroke can also identify people who are eligible for urgentneurointervention (e.g. mechanical thrombectomy) resulting in a measurable impact on outcomes[11]. Ideally, the improved process times (e.g. onset to door, door to needle or groin, onset to recanalisation) associated with telestroke program add to its public health impact. Assessment by skilled neurologists and experts in neuroimaging is known to increase thrombolysis rates. This approach will also facilitate national capacity building in stroke expertise, eventually bringing the specialist closer to the patient [11].
Stroke Registry
In general, there has been significant advancement in acute stroke care during the last 50 years. This stemmed from debunking common practices and the development of more reliant tools and strategies. Advancement in neurocritical care overall has had a significant impact on the management of patients with cerebrovascular disease. Inpatient stroke units were developed providing dedicated care to stroke patients. These units typically have multidisciplinary care teams including skilled neurointerventionists, neurologists, nurses and rehabilitation specialists. Patients who receive such focused care are more likely to be alive, independent and living at home within a year after their stroke.
Today, stroke care teams assess the impact of new strategies and techniques on brain physiology, meanwhile generating a huge volume of physiological data. Such large amounts of data cannot be processed and analysed without registers [12].
Personlaised antiplatelet therapy
Post ischemic stroke patients are commonly on antiplatelet therapy (aspirin, clopidogrel monotherapy or dual antiplatelet treatment, DAPT). Despite such interventions, the treatment failure leading to recurrent stroke is often explained by the phenomenon called high-on-treatment platelet reactivity (HTPR).Data on the risk of ischemic stroke (IS) and transient ischemic attack (TIA) recurrence was recently reported in a meta-analysis, indicating that patients with HTPR had a significantly higher risk for IS/TIA recurrence (RR = 1.81, 95 per centCI: 1.30–2.52; p<0.001)[13].Personalised antiplatelet medication would be one of the cornerstone of preventive measures of a recurrent stroke. However, the interindividual variability in response to antiplatelet agents resulting from gene polymorphism and other platelet specific factors may cause limitation in their efficacy. There are many attempts currently being made around the world to make translational research findings usable in clinical settings to achieve individualised antiplatelet therapy [14,15,16].Although a great body of evidence suggests the increased rate of recurrent cerebrovascular ischemic events among patients presenting with HTPR, the recognition of HTPR remained unsolved [13,17].Measurement of ex vivo platelet function in patients on antiplatelet therapy would potentially enable physicians to tailor antiplatelet strategies to an individual. As such a new and innovative modification of Electric Impedance Aggregometry measurementwas recently published. The ex vivo platelet aggregation induced by an agonist is expressed by the area under the curve (AUC) detected by Multiplate impedance aggregometer.The measurement was performed not only in the whole blood, butas a novelty from the lower and upper blood fractions separated after 1-hour gravity sedimentation by the analogy with erythrocyte sedimentation rate (ESR) [15].Importantly, a greater AUC (≥70 as a cut-off value) from the separated upper blood sample after 1-hour gravity sedimentation emerged as a novel independent predictor of future stroke episodes, while clopidogrel resistance based solely on Multiplate electrode aggregometry from the whole blood was not able to predict recurrent stroke in a prospective, but small study. Based on atomic force microscopy, the more reactive, ascending platelets (presumably detected with greater AUC by Multiplate) were found to be larger in volume, suggesting a link between the function and size of platelets[4]. In accordance, platelets with a higher mean volume showed association with high residual platelet reactivity after conventional dual antiplatelet therapy in patients with coronary artery disease[18].
Future perspectives
Overall, numerous promising preclinical and clinical research tackling the current barriers is going on through out the world. Without wishing to be exhaustive, some novel clinical modalities should be mentioned here: (i) borderzone infarcts and impaired collateral flow were able to identify a cluster of patients with intracranial stenosis who were at particularly high risk of recurrent stroke on medical treatment [19]; (ii) the Stroke Imaging Package Study of Intracranial Atherosclerosis (SIPS-ICAS) study group identified specific imaging markers for risk stratification and prognosis prediction by high-resolution magnetic resonance imaging in patients with intracranial atherosclerosis [20]; and (iii) considering potential overlap among subjects with cardio- and cerebrovascular pathology, a special combination of a pharmacological stress agent (dipyridamole) and post-stress/rest neuroimaging along with assessment of systemic markers were used as a precise identification technique of patients at risk for myocardial and/or cerebral ischemia [21,22]. In another innovative study, enhanced platelet production reflected by higher platelet count, secretion accompanied by increased CD62P and CD63 expression, and activation indicated by more neutrophil-platelet and monocyte-platelet complexes were observed in recently symptomatic (≤4 weeks of TIA or ischaemic stroke) carotid stenosis patients with echodense plaques compared with their asymptomatic counterparts, suggesting that simultaneous assessment of neurovascular imaging and platelet biomarkers may aid risk-stratification in carotid stenosis[23].
Conclusion
It is expected that more rapid and less technologically heavy modalities will be used in the future that would help identify patients at risk for stroke recurrence. Stroke care specialists would continue to improve their understanding of the physiologic changes associated with acute brain injury to prevent and treat secondary brain injuries (e.g. ischemia, inflammation and edema). Overall, the goals of enhanced prognosis, recovery and outcome will still be pursued.
Efforts of better stroke prevention and care will continue with involvement of recent technical advances such as telemedicine services (telestroke, telepharmacy, tele-emergency medicine) providing care even for rural and underserved areas.
References
1. At what cost- The economic impact of Stroke in Europe- A summary. https://www.safestroke.eu/At_What_Cost_EIOS_Summary_Report.pdf (accessed on April 18th, 2021).
2. Norvving B, Barrick J, Davalos A. Action Plan for Stroke in Europe 2018-2030. European Stroke Journal 2018, Vol. 3(4) 309–336.
3. Wissel J, Olver J, Sunnerhagen KS. Navigating the poststroke continuum of care. J Stroke Cerebrovasc Dis. 2011;22(1):1–8.
4. Molnar T, Csecsei P: Prevention of Non-Cardiogenic Ischemic Stroke: Towards Personalized Stroke Care. In: Seena Dehkharghani, (Editor) STROKE ISBN: 978-0-6450017-6-1 Pages 133-147, Exon Publications, Brisbane, Australia
5. Sloan FA, Taylor DH, Jr Picone G. Costs and outcomes of hip fracture and stroke, 1984 to 1994. Am J Public Health. 1999 Jun; 89(6): 935–937. doi: 10.2105/ajph.89.6.935.
6. Moloney E, Bennett K, Silke B. Patient and disease profile of emergency medical re-admissions to an Irish teaching hospital. Postgrad Med J. 2004 Aug; 80(946): 470–474. doi: 10.1136/pgmj.2003.017624.
7. Zhong W, Geng N, Wang P, et al. Prevalence, causes and risk factors of hospital re-admissions after acute stroke and transient ischemic attack: a systematic review and meta-analysis. Neurol Sci. 2016;37(8):1195–1202.
8. Deutschbein J, Grittner U, Schneider A, et al. Community care coordination for stroke survivors: results of a complex intervention study. BMC Health Serv Res. 2020 Dec 19;20(1):1143.
9. Tarkanyi G, Csecsei P, Szegedi I, et al. Detailed severity assessment of Cincinnati Prehospital Stroke Scale to detect large vessel occlusion in acute ischemic stroke. BMC Emerg Med. 2020;20(1):64.
10. Markus HS, Brainin M. COVID-19 and stroke-A global World Stroke Organization perspective. Int J Stroke. 2020 Jun;15(4):361-364.
11. Bladin C, Kim J, Bagot KL, et al. Improving acute stroke care in regional hospitals: clinical evaluation of the Victorian Stroke Telemedicine program. Med J Aust 2020; 212: 371–376.
12. Shahraki AD, Safdari R, Shahmoradi L, et al. Acute Stroke Registry Planning Experiences. J Registry Manag. 2018 Spring;45(1):37-42.
13. Fiolaki A, Katsanos AH, Kyritsis AP, et al. High on treatment platelet reactivity to aspirin and clopidogrel in ischemic stroke: A systematic review and meta-analysis. J Neurol Sci. 2017;376:112–16.
14. Zhang XG, Zhu XQ, Xue J, et al. Personalised antiplatelet therapy based on pharmacogenomics in acute ischaemic minor stroke and transient ischaemic attack: study protocol for a randomised controlled trial. BMJ Open. 2019 May 22;9(5):e028595.
15. Ezer E, Schrick D, Tőkés-Füzesi M, et al. A novel approach of platelet function test for prediction of attenuated response to clopidogrel. Clin Hemorheol Microcirc. 2019;73(2):359-369.
16. Schrick D, Ezer E, Tokes-Fuzesi M, et al. Novel Predictors of Future Vascular Events in Post-stroke Patients-A Pilot Study. Front Neurol. 2021 Jun 18;12:666994.
17. Yan AR, Naunton M, Peterson GM, et al. Effectiveness of Platelet Function Analysis-Guided Aspirin and/or Clopidogrel Therapy in Preventing Secondary Stroke: A Systematic Review and Meta-Analysis. J Clin Med. 2020;9(12):3907.
18. Kim YG, Suh JW, Yoon CH, et al. Platelet volume indices are associated with high residual platelet reactivity after antiplatelet therapy in patients undergoing percutaneous coronary intervention. J Atheroscler Thromb. 2014;21(5):445–53.
19. Wabnitz AM, Derdeyn CP, Fiorella DJ, et al. SAMMPRIS Investigators. Hemodynamic Markers in the Anterior Circulation as Predictors of Recurrent Stroke in Patients With Intracranial Stenosis. Stroke. 2018:STROKEAHA118020840.
20. Lin Q, Liu X, Chen B, et al. Stroke Imaging Package Study of Intracranial Atherosclerosis (SIPS-ICAS) study group. Design of stroke imaging package study of intracranial atherosclerosis: a multicenter, prospective, cohort study. Ann Transl Med. 2020;8(1):13.
21. Molnar T, Zambo K, Scmidt E, et al. Dipyridamole stress test in the early evaluation of cerebral circulatory disorders? Orv Hetil, 2000, 141:2717-2722.
22. Molnar T, Horvath A, Szabo Z, et al. Detection of silent cerebral microcirculatory abnormalities in patients with manifest ischemic coronary disease: a perfusion brain MRI study combined with dipyridamole stress. Scand Cardiovasc J. 2020:1–5.
23. Murphy SJ, Lim ST, Kinsella JA, et al. Simultaneous assessment of plaque morphology, cerebral micro-embolic signal status and platelet biomarkers in patients with recently symptomatic and asymptomatic carotid stenosis. J Cereb Blood Flow Metab. 2020;40(11):2201–14.
Keywords: ischemic stroke; telemedicine; antiplatelet therapy; personalized medicine; outcome.
Conflict of interest: The author declare no potential conflict of interest with respect to research, authorship and/or publication of this article.
