Early arrival did not ensure the early acquisition of intravenous thrombosis for acute ischemic stroke during the COVID‐19 pandemic

Abstract Background Intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) is a time‐dependent treatment with a narrow therapeutic time window, in which the time delay could result from the deadline effect. Methods One hospital‐based cohort was recruited to detect the factors contributing to the deadline effect, where patients with the deadline effect were defined as those who were presented with the onset‐to‐door time (ODT) in the first 50%, while the door‐to‐needle time (DNT) was in the last quartile. DNT (in‐hospital delay) was further subdivided into several time intervals [door‐to‐examination time (DET), door‐to‐imaging time (DIT), door‐to‐laboratory time (DLT), and decision‐making time (DMT) of the patients or their proxies. Results A total of 186 IVT cases were enrolled, of which 17.2% (32/186) suffered a delay of the deadline effect. The median age was 66 years, and 35.5% were female. Baseline characteristics were similar between the two groups (all p > .05). For the comparisons of the time intervals, DIT (26 versus 15 min, p = .001) was significantly longer in the group with deadline effect, while the differences of DET, DLT, DMT, and ONT did not reach statistical significance (all p > .05). Upon multivariable adjustment in the binary logistic regression model, longer DIT [odds ratio (OR), 1.076; 95% confidence interval (CI), 1.036–1.118; p < .001], and history of coronary heart disease (OR, 3.898; 95%CI, 1.415–10.735; p = .008) were independently associated with deadline effect in the binary logistic regression model, while admitted in the working day (OR, 0.674; 95%CI, 0.096–0.907; p = .033), and having medical insurance (OR, 0.350; 95% CI, 0.132–0.931; p = .035) were negatively associated with the deadline effect. Conclusions A speed‐safety tradeoff phenomenon from the deadline effect was observed in 17.2% of IVT cases during the COVID‐19 pandemic, where longer DIT contributed a lot to this time delay. Patients without medical insurance, or admitted in official holidays were more likely to experience a delay of the deadline effect.


BACKGROUND
Acute ischemic stroke (AIS) is the leading cause of death in China in 2017 (Wu et al., 2019) and its prevalence continues to increase (Tu et al., 2022), in which intravenous thrombolysis (IVT) still serves as the mainstream drug therapy. According to several recent studies, the COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, intravenous thrombolysis (IVT), and interfacility IVT transfers (Velilla-Alonso et al., 2021;Xu et al., 2022). It was believed that the pandemic mainly affected postadmission treatment procedures, where prolonged time of the green channel for stroke during the COVID-19 pandemic was the leading cause (Xu et al., 2022).
Since the effectiveness and safety of IVT were high time-dependent (Lees et al., 2010), where in-hospital delay, also known as the door-toneedle time (DNT), consisted of a major component of the total time delay. Deadline effect, when physicians expect idle time following a task or just be occupied on other minor tasks (e.g., tasks for pandemic prevention), their work pace declines, and task completion time increases.
It was estimated to have occurred in more than 20% of IVT patients after the extension of the time window from 3 to 4.5 h in European countries (Pitt et al., 2012). Deadline effect during the pandemic in such a time-dependent urgency would have contributed a lot to the inhospital delay of IVT and counteracted the benefits of early arrival in saving the brain (known as "time is brain"; Saver, 2006). However, little was known about the deadline effect on Chinese doctors and there are significant variations in the Chinese health care system (Blumenthal & Hsiao, 2015), doctors' situations (No Authors, 2014Sun et al., 2017), and policies for the prevention of the pandemic to those in western countries. And workplace violence was more severer in Chinese hospitals than that western countries (Sun et al., 2017), which might bring into a different profile in the deadline effect of IVT. We are aiming at exploring the potential factors of deadline effect in IVT during the pandemic and illustrated how it worked through a hospital-based cohort.

Participants' eligibility and enrollment
Consecutive AIS patients who were treated with IVT in our hospital between January 2020 and December 2021 were recruited retrospectively to detect factors that contributed to the deadline effect of IVT. A similar stroke pathway was fully available for 7 days a week and 24 h a day in our hospital with the help of doctor Huang and other colleagues (Huang et al., 2021), which was described in detail in previous studies (Huang et al., 2016;Huang et al., 2015).

Statistical analysis
Statistical calculations were using SPSS19.0 software, with two-tailed p < .05 as statistically significant.

Patients' characteristics
As shown in the research flow chart in Figure 1

DISCUSSION
There was a speed-safety tradeoff phenomenon between integrating The time delay from deadline effect could have been partly due to a run on public medical resources during the COVID-19 pandemic.
That is because individuals run on medical resources for the pandemic, leading to inefficient usage and many unavoidable delays in acute stroke treatment, which could have included treatments for other time-dependent conditions, such as myocardial infarction, pulmonary embolism, and so on. There was no significant association between deadline effect and mortality, which was greatly due to the small sample size. However, as showed in another nationwide study in China, during the COVID-19 pandemic lockdown, patients hospitalized for stroke fell by 12.6%, and there were substantial increases in TA B L E 1 Baseline characteristics of cases included in this study. Note. Unless otherwise stated, continuous and categorical data are presented as median (IQR) and percentage (%), respectively, with p values calculated using Mann-Whitney U and χ 2 tests, respectively. a Neurological improvement was defined as NIHSS equaled to 0 or improved by four points than baseline NIHSS at 24 h after intravenous thrombolysis.
NIHSS, National Institutes of Health Stroke Scale; EMS, emergency medical system; mRS, modified ranking scale.
out-of-pocket rates (9.3%) and in-hospital case fatality rates (18.0%) (Tu et al., 2023). Fair allocation of public medical resources in the time of COVID-19 remains a huge challenge, since the COVID-19 pandemic has led to an absolute scarcity of public medical resources, which could have affected all patients. Operationalizing the value of maximizing benefits in front-line medical care workers, as well as policy makers, should be paramount during the pandemic.
Safety concerns rather than the efficacy of IVT were more focused on by Chinese doctors. On the one hand, although IVT was a proven efficient therapy with only a relatively increased risk of symptomatic intracranial hemorrhage, especially for those CHD patients who have usually taken antithrombotic agents, many emergency physicians (especially for nonneurologist physicians) were reluctant to take on the risk performing this therapy in clinical practice (Leira et al., 2007), and the decision-making process for IVT could be much more time-   (Xu et al., 2022). Worth to note, limitations in physicians' knowledge regarding IVT (Ma et al., 2017) and the strict time pressure of urgent decision-making also accounted for the lack of confidence in performing timely IVT. However, how it works in collecting more information for safety concerns at the cost of sacrificing time as the deadline approaches, and improving the quality of thrombolytic therapy during the pandemic needs further study.
The absence of medical insurance might have contributed to the time delay of the deadline effect. One reason for this phenomenon was that the personal financial burden of stroke treatment could have been a large expense for most people in China, especially for those who did not have on-site medical insurance in Beijing (Yong et al., 2018).
Since a real-time settlement of off-site medical insurance could not be achieved for most of the non-Beijing patients at present time. Another reason was that, although the therapeutic time window of IVT has been extended to 4.5 h after stroke onset in the guidelines (Jauch et al., 2013), the administration of IV rt-PA to patients presenting within the 3-4.5 h window after the stroke onset was still not adopted by the FDA (Daou et al., 2015) and CFDA. This off-label thrombolysis was not covered by the present medical insurance policy in Beijing yet and needed a time-consuming explanation in the decision-making of IVT.
Given the large population suffering from AIS and the low rate of IVT for AIS (mainly due to time delay) in China (Xu et al., 2015), great progress seen in the TARGET-Stroke program of the United States (Fonarow et al., 2014) was also ungently expected in China. Reducing the time delay of intravenous thrombosis played a key role, as the saying goes, time is brain, and 1.9 million neurons are dying per minute in AIS (Saver, 2006).
In this study, to the best of our knowledge, we first explored the time delay due to the deadline effect during the COVID-19 pandemic, which may have indicated the importance of improving the organizational workflow and real-time settlement of off-site medical insurance to facilitate IVT in AIS. However, the main shortness of our study was the limited generalizability of the findings due to the small sample of a hospital-based cohort and the retrospective study design, which thus needs further validation.

CONCLUSION
In a word, early arrival did not ensure the early acquisition of IVT during the COVID-19 pandemic, where patients without medical insurance or admitted on official holidays were more likely to experience the time delay due to the deadline effect.

ACKNOWLEDGMENTS
We are thankful to all of the participants.

CONFLICT OF INTEREST STATEMENT
The authors declare that they have no competing interests.

DATA AVAILABILITY STATEMENT
The data sets used during the current study would be available from the corresponding author upon reasonable request.

INFORMED CONSENT
Informed consent was obtained from every participant.