Nonatrial Fibrillation was Associated With Early Neurological Improvement After Intravenous Thrombolysis With rt-PA in Patients With Acute Ischemic Stroke

Background: Intravenous thrombolysis is the only approved pharmacological treatment for acute ischemic stroke (AIS) patients, but the immediate response to thrombolysis varies by patient. Objective: To investigate the factors associated with early neurological improvement (ENI) after the administration of intravenous recombinant tissue plasminogen activator (rt-PA) treatment to AIS patients within 4.5 hours of onset. Methods: Demographics, onset to treatment time, risk factors, and clinical and laboratory data of 209 AIS patients undergoing intravenous rt-PA therapy at a Chinese hospital between January 2013 and August 2016 were retrospectively analyzed. The National Institutes of Health Stroke Scale (NIHSS) score was recorded before thrombolytic therapy, 24 hours after the treatment, and 7 days after the treatment to evaluate the recovery of neurological function. ENI was defined as a ≥4-point decrease in NIHSS score compared with baseline or a score of 0 or 1 at 24 hours and 7 days. A multivariate logistic regression analysis was performed to assess the outcomes. Results: Of the 209 AIS patients treated by intravenous thrombolysis with rt-PA, low-density lipoprotein (LDL) levels were significantly lower (P<0.05) in patients with ENI. The multivariable analysis showed that non-atrial fibrillation (AF) was independently associated with ENI at 24 hours and 7 days after thrombolysis. An overall 40.3% non-AF patients had ENI 24 hours after thrombolysis (odds ratio=2.501, 95% confidence interval: 1.204-5.198; P=0.014), and 65.9% non-AF patients had ENI 7 days after thrombolysis (odds ratio=2.953, 95% confidence interval: 1.434-6.081; P=0.003). Onset to treatment time was an independent predictor (P<0.05) for ENI at 7 days after thrombolysis. The NIHSS score and diastolic blood pressure on admission were associated with symptomatic intracerebral hemorrhagic transformation. Conclusions: Non-AF was independently associated with ENI after intravenous thrombolysis in AIS patients, but non-AF was not associated with the occurrence of symptomatic intracerebral hemorrhage. Onset to treatment time was an independent predictor of ENI at 7 days after thrombolysis in AIS patients.


BACKGROUND
Stroke is the leading cause of death in the world, and > 80% of strokes are ischemic. 1,2 Stroke has become a huge economic burden for both the families of the victims and society. Intravenous thrombolysis is the only approved pharmacological treatment for acute ischemic stroke (AIS) patients. The benefit of recombinant tissue plasminogen activator (rt-PA) was thought to be due to vessel recanalization, resulting in restitution of blood flow to ischemic regions of the brain, which improves neurological outcomes of stroke patients treated with intravenous rt-PA within 4.5 hours from symptom onset 3 ; however, only ∼50% of AIS patients show significant improvement after thrombolytic therapy. 4,5 Some studies have shown that early improvement of neurological function after intravenous thrombolysis was an independent predictor of better prognosis at 90 days, [6][7][8] whereas other studies have identified diverse predictors of major neurological improvement 24 hours after thrombolysis. [9][10][11] The immediate response to thrombolysis varies by patient. Although some have shown significant improvement after treatment, others have derived fewer benefits. In this study, we chose 24 hours and 7 days as our endpoints for investigation of the multiple clinical data associated with early neurological improvement (ENI) of intravenous rt-PA treatment in AIS patients.

METHODS Participants
A total of 236 AIS patients who were given rt-PA thrombolytic therapy (dose of 0.9 mg/kg, but not > 90 mg, of which 10% was given by intravenous injection, leaving 90% to be delivered by intravenous drip over a period of 60 min) in the emergency room of Second Affiliated Hospital, Zhejiang University School of Medicine, from January 2013 to August 2016, were enrolled. AIS patients were confirmed by computed tomography or magnetic resonance imaging of the brain within 4.5 hours from symptom onset. This study was approved by the hospital's institutional ethics committee. Because of the retrospective nature of the study, informed consent was waived. thrombolysis with rt-PA treatment within 4.5 hours of stroke onset; (3) having a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 25; posterior circulation stroke is not subject to this limitation; and (4) no evidence of intracerebral or subarachnoid hemorrhage by CT.

Risk Factors
Data for baseline assessment were collected from hospital discharge reports, including age, sex, weight, previous history of hyperlipidemia, hypertension, diabetes, and alcohol abuse. Alcohol abuse was considered as drinking ≥ 20 g per day on average. Clinical data included SBP and DBP, blood glucose, fibrinogen, glycosylated hemoglobin, low-density lipoprotein (LDL) cholesterol, total cholesterol (TC), high-density lipoprotein cholesterol, triglycerides, homocysteic acid levels, time from onset to thrombolysis, and intravenous rt-PA dose. All laboratory determinations were performed at admission. Atrial fibrillation (AF) was diagnosed when its presence was documented in medical records, or when it was diagnosed at stroke by conventional electrocardiogram, dynamic electrocardiogram, or electrocardiogram monitoring; hence, the rest were defined as non-AF. Hemorrhagic transformation and symptomatic intracranial hemorrhage 24 hours after thrombolysis assessment referred to the European Cooperative Acute Stroke Study (ECASS) II standard. 12

Stroke Severity and Outcome Measures
Stroke severity was assessed with NIHSS score by neurologists before intravenous thrombolysis. Neurological impairment was evaluated using the NIHSS score at 24 hours and 7 days after intravenous thrombolysis. ENI was defined as a ≥ 4-point decrease in NIHSS score compared with a baseline or a score of 0 or 1 at 24 hours and 7 days [13][14][15] ; other scores were considered invalid.

Statistical Analysis
SPSS (version 19.0; SPSS Inc., Chicago, IL) was used for all statistical analyses. The risk factors for ENI were separately tested. Significant variables (P < 0.1) identified in univariate analyses were entered in a multivariate logistic regression model for further analysis. AF, DBP, TC, LDL cholesterol, triglyceride, C-reactive protein (CRP), and treatment to onset time were included in the multivariate model. Odds ratios (ORs) and 95% confidence intervals (CIs) were presented. P-value <0.05 was considered statistically significant.

RESULTS
A total of 236 patients with AIS received intravenous rt-PA thrombolysis, of whom 11 patients had an NIHSS score <4 on admission, 10 patients had arterial embolectomy, and there were 6 patients with incomplete data. The remaining 209 patients were enrolled, of whom 84 were female individuals. The average age of the patients was 65.2 13.1 years old. The average NIHSS score was 10.7 5.5 at baseline, and the average treatment time was 170 59.4 minutes.
A total of 74 patients showed ENI 24 hours after intravenous thrombolysis with rt-PA, and 127 patients showed ENI 7 days after intravenous thrombolysis with rt-PA. Patients with poor outcomes had higher levels of blood lipids (including TC, LDL), inflammatory A total of 7 patients (3.35%) had spontaneous intracerebral hemorrhage (sICH) after thrombolysis. These patients had higher SBP and DBP, higher baseline NIHSS scores, and higher rates of AF. Baseline NIHSS score and DBP were independently associated with sICH (Table 3).

DISCUSSION
Non-AF was independently associated with ENI at both 24 hours and 7 days after intravenous thrombolysis in our study. The group with the best outcome had fewer patients with a previous history of AF or a diagnosis of AF at stroke. Our results are consistent with previous studies showing poorer outcomes among AIS patients with AF receiving thrombolysis. [16][17][18][19] Others have found that AF patients show no observable benefit after thrombolysis, even if their thrombolytic therapy was similar when compared with non-AF patients. 20 The adverse impact of AF is likely attributable to larger areas of hypoperfusion and lower recanalization, leading to larger infarct volumes, more severe hemorrhagic transformation, and worse stroke outcome. 21 However, another trial showed that AF patients had a similar outcome after thrombolysis when compared with non-AF patients. 22 Some research even indicates that AF is a good predictor of 3 months' outcome after thrombolysis in patients with severe stroke. 23 One possible reason is that AIS patients with AF often form red thrombi in the intracranial arteries, which are composed of red blood cells and fibrous proteins. Animal studies have shown that red thrombi show increased sensitivity to rt-PA and are more likely to be dissolved. 24,25 Whether AIS patients with AF benefit from thrombolytic therapy or not is controversial, and more research is needed.
We found that treatment to onset time was independently associated with ENI at 7 days. The benefit of rt-PA was thought to be due to vessel recanalization, resulting in the restitution of blood flow to ischemic regions of the brain. The improvement of early neurological dysfunction indicated recanalization of the occlusive vessels, which is highly correlated with a good long-term prognosis. 26,27 In our study, patients who showed ENI had shorter onset to treatment time compared with those without ENI.
Patients without ENI had higher levels of blood lipids (including TC, LDL) and inflammatory factor (CRP). However, they showed no significant difference in the multiplicity analysis, possibly due to other confounding factors. There have been reports that blood lipids and CRP are factors associated with stroke and stroke outcome, 28-30 but whether they are independently associated with ENI needs further exploration.
In our study, there were 7 patients (3.35%) with hemorrhage after thrombolytic therapy. After a single-factor analysis, it was found that the baseline NIHSS and DBP were risk factors for sICH after thrombolysis. We did not do a multiplicity analysis due to the sample size (N = 7). A study with a total of 31,627 patients treated with intravenous rt-PA has shown that baseline NIHSS is an independent risk factor for sICH and that the overall rate of SICH is 1.8%. 31 AIS patients with high baseline NIHSS score had a greater risk of sICH and a worse outcome. A study from Germany and Slovakia indicated that significantly increased blood pressure (SBP > 185 mm Hg or  DBP > 110 mm Hg) was common in stroke patients before and during intravenous thrombolysis, but could not predict cerebral hemorrhage or sICH. 32 The current study demonstrated that SBP was independently associated with sICH 33 ; however, due to the sample size, whether DBP was associated with sICH could not be determined and needs further study.
This study has several limitations. First, our small sample size may lower the power enough to impact our ability to detect predictive relationships between ENI and other factors; a larger number of patients will be used in future research. Second, we did not follow-up at 90 days. Instead, we chose 24 hours and 7 days as our endpoints because 7 days' NIHSS is a sensitive outcome measure for exploratory clinical trials in acute stroke. 34 Third, we did not use prolonged noninvasive cardiac rhythm monitoring, which may increase AF detection among AIS patients. Finally, we did not carry out additional analyses for patients with AF who received intravenous tissue plasminogen activator and who also had ENI. Identifying predictors of ENI may help to improve patient selection for interventional therapy and allow for a more accurate estimation of the prognosis.

CONCLUSIONS
Non-AF was independently associated with ENI after intravenous thrombolysis in AIS patients, but non-AF was not associated with the occurrence of sICH. Onset to treatment time was a predictive independent factor for ENI at 7 days after thrombolysis in AIS patients.