Stroke SPECIAL REPORT Characteristics and Outcomes in Patients With COVID-19 and Acute Ischemic Stroke The Global COVID-19 Stroke Registry George Ntaios , MD, MSc, PhD; Patrik Michel, MD; Georgios Georgiopoulos, MD; Yutao Guo, MD; Wencheng Li, MD; Jing Xiong, MD; Patricia Calleja, MD; Fernando Ostos, MD; Guillermo González-Ortega, MD; Blanca Fuentes, MD, PhD; María Alonso de Leciñana, MD, PhD; Exuperio Díez-Tejedor, MD, PhD; Sebastian García-Madrona, MD; Jaime Masjuan, MD, PhD; Alicia DeFelipe, MD; Guillaume Turc, MD; Bruno Gonçalves, MD; Valerie Domigo, MD; Gheorghe-Andrei Dan, MD; Roxana Vezeteu, MD; Hanne Christensen, MD; Louisa Marguerite Christensen, MD, PhD; Per Meden, MD; Lejla Hajdarevic, MD; Angela Rodriguez-Lopez, MD; Fernando Díaz-Otero, MD; Andrés García-Pastor, MD, PhD; Antonio Gil-Nuñez, MD, PhD; Errikos Maslias, MD; Davide Strambo, MD; David J. Werring, MD, PhD; Arvind Chandratheva, MD; Laura Benjamin, MD; Robert Simister, MD, PhD; Richard Perry, MD; Rahma Beyrouti, MD; Pascal Jabbour, MD, PhD; Ahmad Sweid, MD; Stavropoula Tjoumakaris, MD; Elisa Cuadrado-Godia, MD; Ana Rodríguez Campello, MD; Jaume Roquer, MD; Tiago Moreira, MD; Michael V. Mazya, MD; Fabio Bandini, MD; Karl Matz, MD; Helle K. Iversen, MD; Alejandra González-Duarte, MD; Cristina Tiu, MD, PhD; Julia Ferrari, MD; Milan R. Vosko, MD; Helmut J.F. Salzer, MD; Bernd Lamprecht, MD; Martin W. Dünser, MD; Carlo W. Cereda, MD; Ángel Basilio Corredor Quintero, MD; Eleni Korompoki, MD, PhD; Eduardo Soriano-Navarro, MD; Luis Enrique Soto-Ramírez, MD; Paulo F. Castañeda-Méndez, MD; Daniela Bay-Sansores, MD; Antonio Arauz, MD; Vanessa Cano-Nigenda, MD; Espen Saxhaug Kristoffersen, MD, PhD; Marjaana Tiainen, MD; Daniel Strbian, MD; Jukka Putaala, MD; Gregory Y.H. Lip, MD ABSTRACT: Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institute of Health Stroke Scale was 10 (interquartile range [IQR], 4–18). In the 1:1 matched sample of 336 patients with COVID-19 and non- COVID-19, the median National Institute of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4–18] versus 6 [IQR, 3–14]), P=0.03; (odds ratio, 1.69 [95% CI, 1.08–2.65] for higher National Institute of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2–6] versus 2 [IQR, 1–4], P<0.001) and death (odds ratio, 4.3 [95% CI, 2.22–8.30]) compared with patients without COVID-19. Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes. Key Words: coronavirus ◼ COVID-19 ◼ prognosis ◼ propensity score ◼ survivors Correspondence to: George Ntaios, MD, MSc, PhD, Department of Internal Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece. Email gntaios@med.uth.gr The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.031208. For Sources of Funding and Disclosures, see page xxx. © 2020 American Heart Association, Inc. Stroke is available at www.ahajournals.org/journal/str Stroke. 2020;51:00–00. DOI: 10.1161/STROKEAHA.120.031208 September 2020   1 Ntaios et al COVID-19 and Acute Ischemic Stroke Between January 27, 2020, and May 19, 2020, 174 Nonstandard Abbreviations and Acronyms patients (median age 71.2 years; 37.9% females) with Special Report COVID-19 and AIS were hospitalized (median of 12 AIS acute ischemic stroke patients per site). There were 45 patients aged >80 COVID-19 coronavirus disease 2019 years and 41 aged <64 years. IQR interquartile range In 96% of the cases, COVID-19 was confirmed with PCR and in the others by serology. The most prevalent stroke risk factors and comorbidities were hyperten- C oronavirus disease 2019 (COVID-19), a viral disease sion (68.4%), obesity (37.4%), and diabetes mellitus caused by the severe acute respiratory syndrome (31.03%). Previous stroke was reported in 20 (11.5%) coronavirus 2, may predispose patients to arterial patients. The median delay between the initiation of thrombotic complications mediated by inflammation, COVID-19 symptoms and stroke onset was 7 days endothelial dysfunction, thrombin generation, and platelet (interquartile range [IQR]: 2–15). The most prevalent activation.f Three recent case-series of small size implied COVID symptoms were fever (55.2%,), cough (53.5%), a pathophysiological association between COVID-19 and dyspnoea (43.7%). and severe large-vessel acute ischemic stroke (AIS).2–4 The main stroke symptoms were motor (67.8%), dys- Given that severe strokes are typically associated with arthria (46%), and sensory (42%). The median National poor prognosis and can be very efficiently treated with Institute of Health Stroke Scale was 10 (IQR: 4–18). In recanalization techniques, confirmation of this putative the 1:1 matched sample of 336 patients with and with- association is urgently warranted in a large representa- out COVID-19, the median National Institute of Health tive patient cohort to alert stroke clinicians and inform Stroke Scale was higher in patients with COVID-19 (10 pre- and in-hospital acute stroke patient pathways. [IQR: 4–18] versus 6 [IQR: 3–14], P=0.03; odds ratio, We pooled all consecutive patients hospitalized with 1.69 [95% CI, 1.08–2.65] for higher National Institute of laboratory-confirmed COVID-19 and AIS in 28 sites from Health Stroke Scale score; Figure). 16 countries. We excluded patients who were infected The vascular territory most frequently affected was after the onset of stroke. Nineteen (70.4%) sites were the middle cerebral artery (in 93 out of 163 patients reference hospitals for patients with COVID-19. A pre- with available information). In the matched database specified form was used to register anonymized patient (n=366), 132 of 168 patients with COVID-19 had data. To assess whether stroke severity (estimated by the a complete diagnostic workup towards stroke cause. National Institute of Health Stroke Scale) and outcomes Among those 132 patients, 30 (22.7%) and 10 (7.6%) (assessed by the modified Rankin Scale, at discharge or had a large-artery or a lacunar stroke, respectively. In at the latest assessment for those patients still hospital- the non-COVID-19 matched cohort, we recorded 22 ized) in patients with AIS are different between patients (13.1%) patients with large-artery atherosclerosis and with and without COVID-19, we performed 1:1 propen- 17 (10.2%) with lacunar stroke. Overall, we did not sity score matching analyses of our COVID-19 patients find a difference in the prevalence of large-artery and with non-COVID-19 patients registered in the Acute lacunar stroke between the 2 populations (nonpara- Stroke Registry and Analysis of Lausanne5 between metric χ2 test P=0.082). 2003 and 2019. For the propensity score matching In the overall population of the patients with COVID- analysis of stroke severity, patients were matched with- 19, alteplase was administered in 34 (19.7%) of patients out replacement on a set of prespecified covariates, and endovascular thrombectomy was performed in 21 including demographics (age, sex), stroke risk factors, (12.1%) patients (33 and 20 among the patients with and comorbidities (hypertension, diabetes mellitus, atrial COVID-19who were included in the matched analy- fibrillation, coronary artery disease, heart failure, cancer, sis, respectively). The outcomes per intervention in the previous stroke, smoking, obesity, dyslipidemia). For the matched cohort of patients with stroke with and without propensity score matching analysis of outcomes, the COVID-19 are presented in the Data Supplement. Any type of intervention and main stroke symptoms (motor hemorrhagic transformation of the infarct was diagnosed symptoms, sensory symptoms, dysarthria, and aphasia) in 22 patients, of whom 5 had been treated with intrave- were additionally matched (further details on statistical nous alteplase. Malignant brain edema was present in 4 methods are available in the supplementary material). (5.1%) patients and 3 of these patients were treated with The Global COVID-19 Stroke registry was approved hemicraniectomy. by the Institutional Review Board of the co-ordinating Among 112 patients who had pulmonary imaging site (Larissa University Hospital). Informed consent was with chest CT, 89.3% had lung opacities. Twenty- waived as this was an observational study on pseudony- seven patients (15.5%) were intubated, 40 (23%) mized data. Requests to access the data set from quali- were transferred to an intensive care unit, and 110 fied researchers trained in human subject confidentiality (63.2%) were discharged from the hospital. There protocols may be sent to the first author. were 48 (27.6%) deaths, of which 22 were attributed 2   September 2020 Stroke. 2020;51:00–00. DOI: 10.1161/STROKEAHA.120.031208 Ntaios et al COVID-19 and Acute Ischemic Stroke Special Report Figure. Matched populations of patients with coronavirus disease 2019 (COVID-19) from the Global COVID-19 Stroke Registry and patients without COVID-19 from the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) registry. The upper panel presents the distribution of the modified Rankin Scale scores. The lower panel presents the histogram and Kernel Density Estimates of the National Institute of Health Stroke Scale (NIHSS) scores. to COVID-19 and 26 to stroke. Among 96 survivors classification to the case or control group by up to with available information about disability status, 49 130% and in parallel was totally unrelated to all of the (51%) had severe disability at discharge. In the pro- variables taken into consideration (demographic char- pensity score matched population (n=330), patients acteristics, risk factors, comorbidities, stroke symptoms, with COVID-19 had higher risk for severe disability and treatment), still our results of increased mortality (median modified Rankin Scale 4 [IQR: 2–6] versus 2 and disability in patients with COVID-19 would not [IQR: 1–4], P<0.001) and death (odds ratio, 4.3 [95% substantially change. CI, 2.22–8.30]) compared with patients with non- There are several potential explanations for the rela- COVID-19 (Figure). tion between COVID-19 associated ischemic strokes The strengths of this analysis are the large patient and increased stroke severity, which may co-exist. It cohort, the multicentre international design, the inclu- was proposed that viral infections may cause a direct sion of all consecutive known COVID-19 AIS patients vasculopathic effect (endotheliopathy) or potenti- treated in each site, and the propensity score matching ate the prothrombotic milieu via several mechanisms comparison with a non-COVID-19 AIS cohort. A limi- including immune-mediated platelet activation, dehy- tation of the study is that the propensity score match dration, and infection-induced cardiac arrhythmias.6 It cohort was from a single site; however, as described is unclear whether the finding of increased severity in in the supplemental material, our sensitivity analy- COVID-19 associated ischemic strokes applies to all sis for potential hidden bias in the matched database ischemic stroke types or is mainly driven by an increase confirmed the robustness of the main findings. Even in large-vessel occlusion strokes, as implied by recent if this extra, unobserved indicator (ie, site of recruit- findings.2 Finally, it may be possible that the stay-at- ment) could affect the odds of a patient’s conditional home recommendations/orders and the general fear of Stroke. 2020;51:00–00. DOI: 10.1161/STROKEAHA.120.031208 September 2020   3 Ntaios et al COVID-19 and Acute Ischemic Stroke the hospital during the COVID-19 pandemic may have (A.G.-D.). Carol Davila University of Medicine and Pharmacy, Bucharest, Romania (C.T.). University Emergency Hospital, Bucharest, Romania (C.T.). Department of prevented patients with acute stroke with smaller defi- Neurology, Krankenhaus Barmherzige Brüder, Vienna, Austria (J.F.). Department Special Report cits from presenting to the hospital, although a recent of Neurology 2 (M.R.V.) and Department of Pulmonary Medicine (H.J.F.S., B.L.), study in Barcelona reported that initial stroke severity Kepler University Hospital, Linz, Austria. Department of Anesthesiology and In- tensive Care Medicine, Johannes Kepler University, Linz, Austria (M.W.D.). Stroke was not different between patients with stroke admit- Center EOC, Neurocenter of Southern Switzerland, Lugano (C.W.C.). Department ted in March 2019 and March 2020.7 of Neurology, Hospital Departamental Universitario del Quindío San Juan de The increased stroke severity at admission in COVID- DiosArmenia, Colombia (Á.B.C.Q.). Department of Clinical Therapeutics, National 19 associated stroke patients compared with the non- and Kapodistrian University of Athens, Alexandra Hospital, Greece (E.K.). Internal Medicine, Fundación Clínica Médica Sur, Mexico City (E.S.-N., L.E.S.-R., P.F.C.-M., COVID-19 cohort may explain the worse outcomes. The D.B.-S.). Stroke Clinic, Instituto Nacional de Neurologıa y Neurocirugıa Manuel broad multi-system complications of COVID-19 including Velasco Suarez, Mexico City (A.A., V.C.-N.). Department of Neurology, Akershus acute respiratory distress syndrome, cardiac arrhythmias, University Hospital, Norway (E.S.K.). Department of General Practice, HELSAM, University of Oslo (E.S.K.). Department of Neurology, Helsinki University Hospi- acute cardiac injury, shock, pulmonary embolism, cyto- tal, Finland (M.T., D. Strbian, J.P.). Liverpool Centre for Cardiovascular Science, kine release syndrome and secondary infection,8 prob- University of Liverpool and Liverpool Heart & Chest Hospital, United Kingdom ably contribute further to the worse outcomes including (G.Y.H.L.). Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Denmark (G.Y.H.L.). higher mortality in these patients. Our findings suggest that COVID-19 associated isch- Sources of Funding emic strokes are more severe with worse functional out- None. come and higher mortality than non-COVID-19 ischemic Disclosures strokes. The association between COVID-19 and severe Dr Michel reports grants from Swiss National Science Foundation, grants stroke highlights the urgent need for studies aiming to from Swiss Heart Foundation, during the conduct of the study; grants from uncover the underlying mechanisms and is relevant for European Thrombosis Investigator-Initiated Research Program (Bristol-Myers Squibb/Pfizer), personal fees from Medtronic (used for research), outside the prehospital stroke awareness and in-hospital acute stroke submitted work. Dr Gonçalves reports grants from Coordenação de Aper- pathways during the current and future pandemics, since feiçoamento de Pessoal de Nível Superior—Brasil outside the submitted work. severe strokes have typically poor prognosis and can Dr Dan reports personal fees from Boehringer Ingelheim, personal fees from Bayer, and personal fees from Pfizer outside the submitted work. Dr Strambo potentially be treated with recanalization techniques. reports grants from Swiss Heart Foundation and grants from University of Lausanne outside the submitted work. Dr Werring reports personal fees from Bayer, personal fees from Alnylam, and personal fees from Portola outside ARTICLE INFORMATION the submitted work. Dr Simister is part funded by the UCLH/UCL Biomedical Research Centre. Dr Benjamin reports grants from GlaxoSmithKline outside Affiliations the submitted work. Dr Jabbour reports grants from Medtronic, other from Department of Internal Medicine, Faculty of Medicine, School of Health Sci- Microvention, and other from Balt outside the submitted work. Dr Korompoki ences, University of Thessaly, Larissa, Greece (G.N.). Stroke Center, Neurology reports personal fees from Pfizer, nonfinancial support from Bayer, and per- Service, Department of Clinical Neurosciences, Lausanne University Hospital, sonal fees from Amgen outside the submitted work. Dr Lip reports other from Switzerland (P.M., E.M., D. Strambo). School of Biomedical Engineering and Im- Consultant for Bayer/Janssen, Bristol-Myers Squibb/Pfizer, Medtronic, Boeh- aging Sciences, King’s College, London, United Kingdom (G.G.). Department of ringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo. Speaker for Bayer, Cardiology, Chinese PLA General Hospital, Beijing, China (Y.G.). Department of Bristol-Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi- Urology (W.L.) and Department of Nephrology (J.X.), Union Hospital, Tongji Medi- Sankyo. The other authors report no conflicts. cal College, Huazhong University of Science & Technology, China. Department of Neurology and Stroke Center, Doce de Octubre University Hospital, Instituto de Supplemental Materials Investigación Hospital 12 de Octubre (i+12), Madrid, Spain (P.C., F.O., G.G.-O.). Supplementary Methods. Department of Neurology and Stroke Center, La Paz University Hospital, IdiPAZ Supplementary Tables. Health Research Institute, Madrid, Spain (B.F., M.A.d.L., E.D.-T.). Department of Neurology and Stroke Centre, Ramón y Cajal University Hospital, IRYCIS Health Research Institute, Madrid, Spain (S.G.-M., J.M., A.D.). Department of Neurology, GHU Paris Psychiatrie et Neurosciences, Université de Paris, INSERM U1266, REFERENCES and FHU Neurovasc, France (G.T., B.G., V.D.). 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