Effects of time delays on the therapeutic outcomes of intravenous thrombolysis for acute ischemic stroke in the posterior circulation: An observational study

Abstract Objectives We aim to demonstrate the effects of time delays on the therapeutic outcomes of intravenous thrombolysis (IVT) in acute posterior circulation stroke (PCS) patients. Methods Consecutive PCS cases treated with IVT alone were retrospectively examined. The primary end point was set to be a favorable outcome (modified Rankin Scale [mRS] ≤2) at 3 months, and angiographic recanalization was set to be the secondary outcome. Results A total of 95 PCS cases with IVT were recruited. The patients with favorable outcomes and those without favorable outcomes had similar baseline characteristics, except for significantly lower National Institute of Health Stroke Scale (NIHSS) scores (5 vs. 12, respectively; p < 0.001) and less hyperdense basilar artery signs in head CTs (26.5% vs. 70.4%, respectively; p < 0.001) for those with favorable outcomes. For patients with an onset‐to‐treatment time (OTT) of 0–90 min (n = 5), 91–180 min (n = 38), 181–270 min (n = 37), or ≧271 min (n = 15), the rate of favorable outcome was 100.0%, 71.1%, 67.6%, or 73.3%, respectively, and the Cochran–Armitage trend test showed no linear trend between the OTT and the clinical prognosis of IVT in PCS (p = 0.501) patients. In addition, the rates of recanalization were 100.0%, 68.4%, 64.9%, and 46.7%, and the Cochran–Armitage trend test suggested a linear trend between the OTT and recanalization (p = 0.046); that is, the proportion of PCS patients who underwent recanalization decreased with increasing OTTs. In the multivariate logistic regression analysis, after adjusting for confounding factors with p ≦ 0.20 in the univariate analysis, baseline NIHSS scores and hyperdense basilar artery signs were negatively associated with favorable outcomes, with odds ratios (OR) of 0.884 (95% confidence interval [CI], 0.804–0.971; p = 0.010) and 0.208 (95% CI, 0.062–0.693; p = 0.011), respectively. In addition, there was a negative association between recanalization, OTTs (OR, 0.993, 95% CI, 0.987–0.999; p = 0.029), and baseline NIHSS scores (OR, 0.881, 95% CI, 0.802–0.967; p = 0.008). Conclusion Irrespective of stroke severity, the therapeutic effects of recanalization after IVT decreased significantly with longer time delays in PCS patients.

Conclusion: Irrespective of stroke severity, the therapeutic effects of recanalization after IVT decreased significantly with longer time delays in PCS patients.

| INTRODUC TI ON
Although the clinical characteristics between posterior circulation stroke (PCS) and anterior circulation stroke (ACS) are more similar than dissimilar, which makes differentiation between the two using clinical neurological deficits in the absence of the neuroimaging unreliable (Tao et al., 2012), there tends to be different profiles for the response to reperfusion therapy between ACS and PCS patients (Pagola et al., 2011). On the one hand, statistically significant differences were found between PCS and ACS patients treated with intravenous thrombolysis (IVT), including more favorable outcomes (Sarikaya et al., 2011) and a reduced risk of intracranial hemorrhage (ICH) in PCS patients (Dornak et al., 2015;Sarikaya et al., 2011).
Moreover, compared with ACS patients, PCS patients also experienced longer time delays before receiving a neurology evaluation after the initial emergency department evaluation and longer delays before the administration of IVT (Sarraj et al., 2015). It is worth noting, however, that differences between PCS and ACS in regard to the efficacy and safety of IVT have not been previously investigated using randomized controlled trials (RCTs; Hacke et al., 2008;the NINDS trial., 1995). On the other hand, although endovascular therapy with stent retrievers has been shown to have increased efficacy compared with IVT in several RCTs (Sardar et al., 2015), as mentioned in the American Heart Association/American Stroke Association guidelines, the analyzed studies included so few PCS patients (8%) that the superiority of endovascular therapy over IVT for PCS is still uncertain (Powers et al., 2015). Therefore, although earlier treatment has been strongly associated with increased proportional IVT benefits for all ischemic stroke patients (Emberson et al., 2014), the effects of time delays on the therapeutic outcomes of IVT in PCS patients must be further evaluated.

| ME THODS
A standard stroke pathway was available for 7 days a week and 24 hr a day in two tertiary teaching hospitals, which were described in detail in our previous study (Huang et al., 2016). Consecutive AIS patients treated with IVT in these two hospitals were collected by the same team from March 2011 to December 2017 and were enrolled in this analysis. We retrospectively identified consecutive PCS cases treated with IVT from the two databases. The detailed inclusion process for IVT cases was mentioned in previous studies (Huang et al., 2015(Huang et al., , 2016. The primary inclusions and exclusions for IVT followed published Chinese guidelines (Liu et al., 2010). Briefly, the following guidelines were used: (a) a definite and persistent neurological deficit (as measured by National Institute of Health Stroke Scale (NIHSS) score), (b) age ≥18 years, (c) onset-to-treatment time (OTT) ≤4.5 hr, (d) no intracranial hemorrhage (ICH) in the screening head CT and no other known contraindications of IVT therapy, and (e) written informed consents were received from the patients or their proxies.
Recombinant tissue-type plasminogen activator (rt-PA), at a standard dose of 0.9 mg/kg (maximum 90 mg), was using as the thrombolytic agent, which was applied as recommended in the guidelines (Liu et al., 2010). Routine head imaging (CT or MR) was performed within 24 hr to identify responsible cerebral infarction lesions and to ex-

| Explanatory and outcome variables
All PCS patient information was collected on a standard case report form. Demographic data (sex and age), medical history (hypertension, diabetes, dyslipidemia, coronary heart disease, atrial fibrillation, and prior stroke), smoking and drinking status, baseline variables (body mass index, OTT, blood pressure, blood glucose, The mRS score (with a cutoff ≤2 as a favorable outcome) at 3 month and vascular recanalization were taken as the primary and secondary therapeutic end points, respectively. Recanalization of the responsible cerebral vessel after IVT was first detected by a 24hr TCD with a preset criteria (e.g., a moderate to severe degree of stenosis in the basilar artery was defined as ≥50%, which was assessed as a peak systolic velocity ≥100 cm/s and featured spectrum or audio frequency; Hua, Gao, Wu, Pan, & Qian, 2008) and further confirmed by CT or MR angiography. Other outcomes included sICH (defined as any decline in the NIHSS score accompanied by a hemorrhage observed in the head CT imaging within 36 hr after the treatment) and mortality at 3 months.

K E Y W O R D S
intravenous thrombolysis, outcome, posterior circulation stroke, recanalization, time delay

| Ethics approval and consent to participate
The study protocol and data analysis were approved by the Ethical Committee of Beijing Tsinghua Changgung Hospital and by the Ethical Committee of Xuanwu Hospital, and conform to the principles outlined in the Declaration of Helsinki. Written informed consent for IVT was obtained from all patients.

| Statistical analysis
SPSS 19.0 software was used for statistical calculations, with a twotailed p < 0.05 defined as being statistically significant. A Mann-Whitney U test and a Pearson chi-squared test were used for group comparisons of related variables. A Cochran-Armitage trend test was conducted to detect the potential linear trend between OTT subgroups and therapeutic outcomes. Multivariate logistic regression analysis, adjusted by confounding factors with p ≤ 0.20 in the univariate analysis, was performed to identify the predictors of favorable outcome and recanalization. Effect sizes were presented as odds ratios (ORs), and statistical uncertainty was presented as the 95% confidence interval (CI).

| RE SULTS
A total of 95 PCS cases with IVT therapy (69 cases were enrolled be-  Notes. If not otherwise stated, continuous data are presented as median (IQR). DBP, diastolic blood pressure; IQR, interquartile range; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OTT, onset-totreatment time; SBP, systolic blood pressure.

| D ISCUSS I ON
Our results showed that, irrespective of stroke severity, a linear trend existed between OTT and recanalization (p = 0.046 in the Cochran-Armitage trend test), with an OR of 0.993 per minute (95% CI, 0.987-0.999; p = 0.029), but not between OTT and favorable outcomes (p = 0.501 in the Cochran-Armitage trend test) in PCS patients treated with IVT. That is, despite a greater ischemic tolerance (Pagola et al., 2007) and a safer profile in bleeding complications (Sarikaya et al., 2011) when compared with ACS patients, recanalization after IVT was still time-dependent for PCS patients, which was consistent with the results reported for ACS

patients.
Given to the fact that PCS cases, especially those with basilar artery occlusion (BAO), may naturally follow a dismal course (Schonewille, Algra, Serena, Molina, & Kappelle, 2005), timely recanalization may represent the only solution (Kumar, Shahripour, & Alexandrov, 2014). As shown in our study, the differences between PCS and ACS in regard to ischemic tolerance and the response to hemorrhagic complication do not appear to change the time-dependent nature of vascular recanalization. This result was also supported by the strong association between AIS treated with IVT within the first hour (the golden hour) and the substantially higher chance of complete recanalization and the early reversal of neurological deficits reported in the results of the Safe Implementation of Treatments in Stroke-East registry (Tsivgoulis et al., 2017). Moreover, a strong association between late recanalization (˃6 hr) and unfavorable outcomes for BAO patients after endovascular therapy was also observed in the Basilar Artery International Cooperation Study (BASICS; Vergouwen et al., 2012). These results may be due to the benefits of a higher rate of recanalization after endovascular therapy being offset by longer time delays in OTT. Therefore, efforts made to reduce time delays for IVT and to increase the rate of patients treated in the "golden hour," such as with the application of treatment in novel settings with a mobile stroke unit and the optimization of work flows in traditional hospital settings, deserve increased attention and should be generalized (Huang, Zhang, Xu, & Wu, 2018). It is noteworthy that there were no significant differences in the safety and efficacy of ultra-early IVT between the two settings (Tsivgoulis, Geisler, et al., 2018;, highlighting the key role of prompt IVT initiation, regardless of treatment location.
High morbidity (28.4%) and mortality (8.4%) were observed in PCS patients in our study, even after standard IVT, which was consistent with the results of previous studies (Kumar et al., 2014;Lindsberg et al., 2004). However, the optimal interventions for PCS are still uncertain (Powers et al., 2015) and could include IVT, IVT bridging therapy, or advanced endovascular therapy (with stent retrievers (Mordasini et al., 2013) or endovascular sonolysis (Kuliha et al., 2013)). A recent meta-analysis showed that pretreatment with IVT in patients with large vessel occlusions only resulted in a successful recanalization rate of approximately 10%, with patients requiring additional endovascular therapy (Tsivgoulis, Geisler, et al., 2018;. The advanced endovascular therapy with the highest rate of recanalization is the most likely to become the best treatment for PCS, according to the similar history of reperfusion therapy for acute myocardial infarction (Widimsky, Coram, & Abou-Chebl, 2014) and for ACS (Sardar et al., 2015;Tsivgoulis, Geisler, et al., 2018;.

Inspired by the rapid progress being made in endovascular therapy
techniques, the overall recanalization rate of BAO patients using novel stent retrievers (Mordasini et al., 2013) or endovascular sonolysis (Kuliha et al., 2013) could reach as high as 100%, and the rate of ICH has been relatively low, which demonstrates the greatly improved benefits and reduced complications of endovascular therapy.
However, it is still worth mentioning that a streamlined organization with reduced time delays in stroke care plays a key role in delivering the benefits of reperfusion therapies for both PCS and ACS patients. shown in a previous study (Goldmakher et al., 2009), HDBA signs can be utilized to detect thrombosis in the basilar artery and to predict poor outcomes in patients presenting PCS symptoms. HDBA signs were also a negative predictor for favorable outcomes of PCS cases in our study, which was consistent with the results of a previous study (Goldmakher et al., 2009). However, the low incidence (38.9% in our study) of HDBA signs in the admission CT could restrict its utility, and the accuracy must be further validated.
The limitations of this study primarily result from the small sample size and the retrospective study design. Moreover, severe PCS cases were more likely to receive endovascular therapy, which could have induced a selective bias. In addition, the clinical outcome follow-up being conducted through telephone interviews could have resulted in the subjective bias of the patients. Finally, our study has the same limits faced by all non-RCTs.

| CON CLUS ION
Our study demonstrated a significant association and linear trend between OTT and vascular recanalization in PCS cases after IVT, in which the concept of "time is brain" was further highlighted for PCS, with greater ischemic tolerance than ACS.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

AUTH O R CO NTR I B UTI O N S
Qiang Huang, Xiao-wei Song, Qing-feng Ma, Hai-qing Song, contributed to data curation. Qiang Huang, wrote the original draft. Qiang Huang, contributed to methodology. Jian Wu, contributed to writing-review and editing. Qiang Huang, performed formal analysis.
Jian, Wu involved in project administration.