key: cord-0970759-a6hta6ve
authors: Sobolewski, Piotr; Antecki, Jacek; Brola, Waldemar; Fudala, Małgorzata; Bieniaszewski, Leszek; Kozera, Grzegorz
title: Systemic thrombolysis in ischaemic stroke patients with COVID‐19
date: 2021-08-20
journal: Acta Neurol Scand
DOI: 10.1111/ane.13520
sha: efd532318b6a1a2ae3a75a18e75c8577cc1b33c9
doc_id: 970759
cord_uid: a6hta6ve

OBJECTIVE: Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator is the core medical therapy of acute ischaemic stroke (AIS). COVID‐19 infection negatively modifies acute stroke procedures and, due to its pro‐coagulative effect, may potentially impact on IVT outcome. Thus, short‐term efficacy and safety of IVT were compared in patients with and without evidence of SARS‐CoV‐2. METHODS: An observational, retrospective study included 70 patients with AIS, including 22 subjects (31%) with evidence of acute COVID‐19 infection, consecutively treated with IVT in 4 stroke centres between 15 September and 30 November 2020. RESULTS: Patients infected with COVID‐19 were characterized by higher median of National Institute of Health Stroke Scale (NIHSS) score (11.0 vs. 6.5; p < .01) and D‐dimers (870 vs. 570; p = .03) on admission, higher presence of pneumonia (47.8% vs. 12%; p < .01) and lower percentage of ‘minor stroke symptoms’ (NIHSS 1–5 pts.) (2% vs., 18%; p < .01). Hospitalizations were longer in patients with COVID‐19 than in those without it (17 vs. 9 days, p < .01), but impact of COVID‐19 infection on patients’ in‐hospital mortality or functional status on dismission has been confirmed neither in uni‐ or multivariate analysis. CONCLUSION: SARS‐CoV‐2 infection prolongs length of stay in hospital after IVT, but does not influence in‐hospital outcome.

The COVID-19 pandemic is associated with a variety of neurological symptoms. In the course of COVID-19 infection, hypercoagulability occurs that is likely a 'sepsis-induced coagulopathy' and may predispose to stroke. 1 The clinical course of COVID-19 is most severe in elderly patients, in men, and in patients with comorbidities as diabetes mellitus, obesity, hypertension and most cardiovascular risk factors. 2 The data from the 'first wave' of SARS-CoV-2 pandemic show that the rates of stroke in hospitalized patients with COVID-19 range from 1% to 3% and up to 6% of critically ill patients. 2, 3 Strokes course in patients with COVID-19 may be more severe and associated with higher in-hospital mortality and disability on discharge. 4 Intravenous thrombolysis (IVT) with the use of recombinant tissue plasminogen activator is an effective and universally recommended method of treatment in the acute ischaemic stroke (AIS). 5, 6 Unfortunately, COVID-19 resulted in a global decline in the volume of stroke hospitalizations and IVT treatments. [7] [8] [9] [10] Moreover, inflammatory processes predict poor outcomes in ischaemic stroke treated with IVT, 11 and pneumonia especially predicts increasing mortality in these patients. 12 However, only a few reports associated the impact of SARS-CoV-2 infection on the outcome of patients treated with IVT. 9, 10, [13] [14] [15] [16] Therefore, our objectives were to determine short time safety and efficacy of IVT in patients with AIS and COVID-19.

We conducted a retrospective observational study based on 

Study population consisted of 70 Caucasian adults (51.4% of males, mean age 72, 7 ± 12 years)-all of those patients who were treated only with IVT between 15 September 2020 and 30 November 2020 (14.8% of 473 subjects with AIS consecutively hospitalized in study stroke units in recruitment period).

The severity of stroke symptoms was assessed using the National Institute of Health Stroke Scale (NIHSS) by stroke physician at admission to Emergency Departments. 18 Stroke onset was defined as the last occasion on which the patient was known to be without neurological deficit. Brain computed tomography (CT) and/or magnetic resonance were performed upon admission to hospitals in order to establish the indication for treatment and between 22 and 36 h after treatment. Examinations to evaluate the inflammatory processes and the coagulation status and also chest X-ray and/or chest CT in all patients were performed. To evaluate the aetiology of the stroke transcranial doppler, carotid duplex ultrasonography, Holter electrocardiography and transthoracic echocardiography were performed.

The stroke outcomes were measured using the modified Rankin scale (mRS). 19 A favourable outcome was defined as an mRS score ≤2 points, whilst an unfavourable outcome was defined as an mRS score of 3-6 points. Symptomatic intracerebral haemorrhage rates were assessed according to the ECASS II (European Cooperative Acute Stroke Study II) and III criteria. 20 To determine the type of ischaemic strokes, the TOAST (trial of ORG 10172 in acute stroke treatment) classification was also taken from the discharge summary. 21 

All patients were tested for COVID-19 with the reverse transcriptasepolymerase chain reaction tests. For SARS-CoV-2-infected group, we included patients with positive test performed within 3 days of admission.

This study was based on a retrospective database analysis. Data gathering, characteristics and univariate analysis were performed using Microsoft Excel 2017; statistical analysis was performed with STATISTICA v. 9.1. All continuous variables were tested for a normal distribution and equality of variances. Because of the nonnormality of the variables, non-parametric Mann-Whitney U tests were used to perform the univariate analysis of the continuous variables. Categorical data were compared using chi-square tests; p values <.05 were considered statistically significant. The multivariate analysis was performed using multiple logistic regression models.

Three separate models, each excluding correlating variables, were done. Factors identified in the univariate analysis with a p value <.01

were then examined using a multivariate models. Each model was created taking into account the correlation between the individual continuous variables.

Patients infected COVID-19 were characterized by higher median of baseline NIHSS, lower percentage of diagnosis 'minor stroke' (NIHSS 1-5 pts.) and higher presence of pneumonia. Patients with COVID-19 stayed in the hospital longer. There was no difference between pre-and in-hospital delays, risk factors profile, presence of fever at admission and complications rate between the two groups.

Median of D-dimers was higher in COVID than in non-COVID patients; no other differences of biochemical parameters between patients with and without COVID infection existed. Proportion of patients functionally independent (mRS 0-2) on discharge tended to be lower in patients with COVID infection; in-hospital mortality did not differ between both groups (Table 1) vs. 11.4%, p =.04) or body mass index (BMI) ≥26 kg/m 2 (57.1% vs.

28.6%, p =.01) and a higher baseline percentage of saturation on admission than patients with mRS 3-6 pts (96, 81-99 vs. 93, 60%-98%, p <.01). Initial saturation was also higher amongst stroke survivors than those who died during hospitalization (96, 81-99 vs. 90, 60%-96%, p <.01). No other differences between patients with and without favourable clinical outcome were found; significant correlations between CRP and saturation or NIHSS score on admission and between saturation and door-to-needle time or NIHSS score on admission in studied group existed (Table 2) .

Multivariate logistic regression models showed that only baseline NIHSS, higher age and presence of carotid stenosis had an impact on patients' outcome on discharge ( Table 2 ). Amongst patients with COVID-19 treated with IVT during the first wave of pandemic in Italy, the median NIHSS score was 12 and was similar to our patients, 14 and in patients from 9 stroke centres in the United States, the median NIHSS score was higher (14.5 pts.). 15 In both studies, there were no control groups or no consecutive data collection. The results of many studies and meta-analyses showed that initial stroke severity is known to be the strongest predictor of functional outcome and mortality for ischaemic stroke patients. 25 In the group of Italian patients mentioned above, baseline NIHSS score was higher in patients who died. 14 In our group of thrombolytic patients, high NIHSS score was a predictor of unfavourable outcome on discharge and inpatient mortality.

We showed that SARS-CoV-2 infection prolongs length of stay 1.01-1.16) .02

NIHSS score on admission a (pts) Differences in the results of routine inflammatory markers or fever on admission between patients with and without COVID-19

were not found in our cohort. However, similarly to previous authors, we found higher levels of D-dimers in patients with COVID-.

Formerly, lower platelet counts and higher level of D-dimers in the group of infected patients with AIS from Wuhan were reported. 22 Also majority of the patients treated with IVT from United States Stroke-associated pneumonia often negatively influences the prognosis of stroke patients. 11 Pneumonia occurred more frequently in our patients with COVID-19. 26 In patients with stroke and pneumonia, the saturation decreases more often than in patients without pneumonia. Almost 20% patients with COVID-19 have hypoxic respiratory failure. 27 We showed that stroke survivors functionally independent on discharge were characterized a higher baseline percentage of saturation on admission than patients with mRS 3-6 pts. However, similarly to the group from Wuhan, blood oxygen saturation was significantly lower in those patients who died. 28 The severity of the neurological condition and the accompanying lung infection prolonged the patients' stay in the hospital, which was pointed out in previous publications. 29, 30 First of all, this was an observational study of only four regional stroke centres and, consequently, the group of analysed patients was not large. Thus, small size of the study may mask the results and lack of statistical significance. Although the data collection was conducted in a prospective manner and included all patients admitted within the observation period. Second, the treatment results were only limited to the in-hospital period, and long-term outcome has not been assessed. However, as it has been recently reported, independence on discharge may predict 90-Day Outcome after Thrombolysis. 31 

Based on our results, we suggest that patients with AIS infected COVID-19 may be safely treated with IVT in routine practise.

However, when treating patients with COVID, one should strive to achieve the improvement in blood saturation, whose decrease can adversely affect the in-hospital outcome. SARS-CoV-2 infection prolongs length of stay in hospital after IVT. 

PS and GK conceived the study. PS and GK wrote and distributed the protocol, designed the case report form and registration log, received the case report forms and uploaded them into the database.

PS, JA, WB and MF extracted data from clinical records and completed case report forms. GK and LB performed statistical analyses.

PS and GK wrote the manuscript. JA, WB, MF and LB were the members of the Core Writing Group and critically reviewed the protocol, case report form and manuscript. All authors critically reviewed the manuscript and approved the final version.

The ethics committee approved all data of analysis (Ethics Committee of Jan Kochanowski University in Kielce).

Data are available on reasonable request, subject to restrictions imposed by patient confidentiality.

Piotr Sobolewski https://orcid.org/0000-0003-4646-1702

Jacek Antecki https://orcid.org/0000-0002-8667-7615

Waldemar Brola https://orcid.org/0000-0002-7955-3454

Małgorzata Fudala https://orcid.org/0000-0002-0884-8175

Leszek Bieniaszewski https://orcid.org/0000-0001-6237-521X

Grzegorz Kozera https://orcid.org/0000-0001-7704-2434

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