Intravenous Thrombolysis in Acute Ischaemic Stroke Two Years into the COVID-19 Pandemic: A Retrospective Study

The COVID-19 pandemic impacted healthcare systems Worldwide, affecting the delivery of various medical interventions. Stroke, a life-threatening event that requires prompt medical treatment, was particularly affected (Hurford, Sekhar, Hughes, & Muir, 2020). The provision of intravenous thrombolysis (IVT), a well-established treatment for acute ischaemic stroke (AIS) (Wardlaw et al., 2012), was challenging during this unprecedented time (Jala et al., 2022). Of note there was a reduction in the number of patients receiving IVT and delay in the initiation of thrombolysis reported internationally (Cadilhac et al., 2021; Ishaque et al., 2022; Jala et al., 2022; Mag Uidhir et al., 2020; Xu et al., 2022).

Disruptions in healthcare systems due to the COVID-19 pandemic led to a number of changes in protocols including personal protective equipment and infection control requirements, resource allocation, and patient management (Filip, Gheorghita Puscaselu, Anchidin-Norocel, Dimian, & Savage, 2022). The pandemic posed unique challenges to patients resulting in altered healthcare-seeking behaviour and changes in stroke presentations (Padmanabhan, Natarajan, Gunston, Raseta, & Roffe, 2021). These factors may have influenced the diagnosis and treatment of AIS, potentially leading to variations in thrombolysis utilisation and outcomes. As we have reached the two-year mark of the COVID-19 pandemic, it is crucial to assess the impact of this global health crisis on the administration and outcomes of IVT in stroke patients and the implications on hospital policy, clinical practice guidelines, and quality of essential care, to intervene and improve at a systems level if required. Thus, we examined the differences in the provision of IVT in acute stroke two years into the COVID-19 pandemic in our acute stroke service. Officially, the World Health Organisation declared on the 5th of May 2023, that COVID-19 is no longer a global public health emergency (Rahman, Cronmiller, Victoros, Shanjana, & Islam, 2023).

Descriptive statistics were performed to summarise data and determine distribution. The Mann-Whitney U-test was used to explore differences in continuous outcomes and ordinal variables. Differences in categorical variables were assessed using Pearson’s chisquare test or Fisher’s exact test. A value of p<0.05 was considered statistically significant. All analyses were conducted using IBM SPSS Statistics v.27.

This study adhered to the National Health and Medical Research Council definition of quality assurance and evaluation and was reviewed and approved by the Northern Sydney Local Health District Human Research and Ethics Committee.

This retrospective study showed that the demographics of the groups were similar: mostly non-indigenous (98.7%, pre-COVID-19 and 98.9% during COVID-19), almost half were females (pre-COVID-19 = 49.3% and during COVID-19 = 44.6%), with a median age of 77 (pre-COVID-19) and 76 (during COVID-19) years. During the COVID-19 pandemic, there was an increase of 4.4% in stroke presentations (Pre-COVID-19 = 1041 vs during COVID-19 = 1087). Although both groups had mild to moderate symptoms at baseline, there were fewer patients with severe symptoms (NIHHS >20) in the COVID-19 group (pre-COVID-19 = 12.2% vs during COVID-19 = 4.8%; p = 0.009).

During the COVID-19 pandemic, the IVT rate of ischaemic stroke significantly decreased (pre-COVID-19, 19.2% [n = 200/1041]; during COVID-19, 13.9% [n = 151/1087], p<.001). There was a delay in the administration of IVT treatment, with an increase of 6 minutes in the median door-to-needle time (DNT) during the same period (DTN: Pre-COVID-19 = 59 minutes and during COVID-19=65 minutes p=0.002), which was significant. Further, the number of stroke mimics treated with IVT increased during the COVID-19 pandemic (pre-COVID-19 = 8.3% [n = 19/229] vs during COVID-19 = 15.6% [n = 29/186]; p = 0.021).

In terms of post-thrombolysis outcome, both groups had a similar median NIHSS score that is,1. At hospital discharge, half of the patients from both groups had a discharge modified ranking score (mRS) of < 2, and a mean length of hospital stay of 5 days (p=0.095).

This single-centre, retrospective observational study found a significant reduction (30%) in patients receiving IVT during the COVID-19 pandemic. This finding is consistent with results from studies conducted at other stroke centres (Cadilhac et al., 2021; Filip et al., 2022; Ishaque et al., 2022; Khunte et al., 2023; Xu et al., 2022). A recent meta-analysis reported a reduction in the rate of IVT administration of 27.2% during the COVID-19 pandemic (95% CI, 22.7 to 32.0%) for acute ischaemic stroke worldwide (Ishaque et al., 2022). The decline was highest in Asia (40.3%; 95% CI, 27.8 to 53.3), followed by North America (26.9%; 95% CI, 12.7 to 43.9), and Europe (25.7%; 95% CI, 19.7 to 32.1) (Ishaque et al., 2022).

The decrease in IVT administration during the COVID-19 pandemic could be attributed to several factors. Delay in stroke patients’ presentation to hospitals could have resulted in an overall lower number of patients eligible for thrombolysis (Gu et al., 2022). On top of the delay presentation, the added COVID-19 infection control protocol / requirements contributed to the delay of assessment and diagnosis. A study reported that during the pandemic, the number of patients seeking urgent medical attention decreased as many feared contracting COVID-19 and were concerned about overwhelming the healthcare system (Padmanabhan et al., 2021). However, in our case, we had an increase in patient presentations with stroke symptoms. In addition, the pandemic may have overwhelmed and compromised healthcare systems, leading to delays in stroke recognition and treatment initiation. Healthcare resources and personnel may have been redirected to managing patients with COVID-19, causing delays in stroke evaluations and the administration of IVT. Further, the pandemic may have introduced additional challenges in accurately diagnosing acute ischaemic stroke. The presentation of stroke symptoms may have been confounded by COVID-19 and vaccination-related complications, such as respiratory distress or neurological manifestations (Alam et al., 2021; Patone et al., 2021). This could have led to diagnostic uncertainty and increased caution in initiating IVT because of potential adverse events. It is worth noting that the decrease in IVT during the COVID-19 pandemic does not necessarily indicate a decline in the overall quality of stroke care. For example endovascular thrombectomy was used more in some centres during the COVID-19 pandemic (Khunte et al., 2023).

In the current study we found a significant delay in providing IVT for stroke patients from arrival at the ED (6 minutes, p=0.002). The median door to needle time (DNT) during the COVID-19 period was 65 minutes compared to 59 minutes pre-COVID-19. A decrease in DNT was reported in a similar observational study conducted in China during the pandemic but the delay was lower (51.60 minutes, p=0.026) (Xu et al., 2022). During the pandemic delays in treatment initiation were attributed to various factors including increased infection prevention measures; changes in hospital workflows; reduced healthcare resources; and difficulty in clinical decisionmaking as COVID-19 and vaccination reaction signs and symptoms sometimes mimic stroke.

Further, we found more stroke mimics were treated with IVT during the COVID-19 period. Stroke mimics are patients who present with stroke symptoms, not caused by a cerebrovascular event. The administration of IVT to stroke mimics can be attributed to the challenges in accurately differentiating between stroke and stroke mimics based solely on initial emergency department clinical presentation. Time is of the essence in stroke treatment, and clinicians may err on the side of caution and initiate thrombolysis if there is uncertainty about the diagnosis. Moreover, the concern for potential underdiagnosis or failure to correctly diagnose stroke due to the fear of overwhelming the healthcare system during the pandemic may result to a more liberal approach towards IVT.

Interestingly, during the COVID-19 pandemic, an upward trend in stroke mimic presentations was noted. For example an observational study exploring stroke mimic patterns in Lithuania, demonstrated an increase in hospital presentation of severe symptoms for stroke mimics (Melaika et al., 2021). In contrast, summary data for many studies suggests there was a decline in the rates of stroke mimics, which was demonstrated in a recent meta-analysis (2022). Nonetheless, there are limited reports for the thrombolysis treatment and outcomes of stroke mimics.

In this current study the sample was relatively small and from a single site. Thus, the findings might not be generalisable. The findings may not be representative of healthcare settings in other states of Australia or countries. As this is an observational study, there may be some confounding variables thus we could not demonstrate causality.

The study identified a significant difference in IVT administration before and during the COVID-19 outbreak which highlights the impact of the pandemic on stroke management practices. These findings emphasise the need for continuing evaluation and adjustment of stroke care protocols to ensure that timely and appropriate treatment is provided to all eligible acute ischaemic stroke patients, particularly during health challenges such as a pandemic.

This study highlighted the need for further research to explore the underlying reasons for reduced thrombolysis rates and delayed IVT during the COVID-19 pandemic. This research could focus on understanding clinicians’ clinical decision-making, patient preferences, biases, and system-level factors that contributed to the observed trends. Moreover, future studies and analysis are required to understand the long-term implications of the decrease in thrombolysis rate and delays in IVT treatment so as to identify strategies to mitigate their potential negative consequences on stroke outcomes.