DOI: https://doi.org/10.21203/rs.3.rs-1337645/v1
Background： We aimed to investigate the risk factors of early neurological deterioration (END) after intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and the relationship between END and poor 3-month functional outcomes.
Methods: Patients who accepted intravenous recombinant rt-PA were enrolled continuously. END was defined as an increase of National Institute of Health Stroke (NIHSS) score ≥ 4 points or death within 24 hours after intravenous thrombolysis. The modified Rankin Scale (mRS) score was recorded to evaluate the functional prognosis of stroke, and the poor 3-month prognosis was defined as an mRS score ≥ of 3. Univariate and multivariate analyses were used to analyze the risk factors of END. The relation between END and 3-month functional outcome was analyzed by multivariate logistic regression analysis.
Results: A total of 1107 patients (mean age, 63.42±11.33 years; 673 males) were included in the final analysis, and 81(7.32%) patients had END. In multivariate analysis, the serum glucose level was significantly associated with END; the odds ratio was 1.10 (95% CI 1.03 to 1.18, p =0.004). The multivariate logistic analysis showed END has a notable association with the poor 3-month functional recovery even after adjusting for confounding factors; the adjusted OR was 8.25 (95% CI 3.77 to 18.03, p<0.0001).
Conclusions: The initial serum glucose level might be an independent risk factor of END, and END might predict a poor 3-month prognosis.
Stroke has become one of the leading causes of death and disability of humans(1), and there has been a high incidence of stroke in China(2). It has been confirmed that target-vessel revascularization is the most effective method to reduce the disability and mortality of patients. Meanwhile, intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) has been the most economical and convenient treatment(3). However, some studies have found that some patients still suffered severe neurological deterioration after receiving intravenous thrombolysis, which resulted in prolonged hospitalization and severe adverse prognosis(4). This study explored the risk factors of early neurological deterioration (END) and the correlation between END and 3-month functional prognosis.
Study Population
The data were obtained from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-CHINA) database - a multicenter prospective stroke registry program that enrolled patients who received intravenous tPA within 4.5hours after symptom onset from May 2007 to July 2012 in China(5). Some previous pieces of literature have reported the trial design and some results of the study(6, 7). The ethics committee approved the study protocol of Beijing Tiantan Hospital with the Helsinki Declaration. The quality monitoring committee of TIMS-China and the Contract Research Organization independently have been regularly monitoring the registry. All participants had signed written consent.
Definition of END and Clinical outcome measurement
END was defined as an increase of NIHSS (National Institute of Health Stroke) score ≥ 4 points or death within 24 hours after intravenous thrombolysis(8). The primary outcome was poor 3-month functional recovery, expressed as a modified Rankin Scale (mRS) score ≥3. The secondary outcomes were sICH (symptomatic intracranial hemorrhage) and mortality at seven days and 90 days. We used the definitions of sICH in the following three studies: Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST)(8), National Institute of Neurological Disorders and Stroke (NINDS)(9), and European Cooperative Acute Stroke Study Ⅱ (ECASS Ⅱ)(10).
Statistical analysis
Continuous variables were described by means (standard deviations [SDs]) or medians (interquartile ranges [IQRs]). Categorical variables were presented as frequencies and percentages. The baseline characteristics of patients between the END group and the non-END group were compared by Wilcoxon rank-sum tests for continuous variables and X2 test for categorical variables. Univariate and multivariate logistic regression was used to estimate the odds ratios (ORs), the corresponding 95% confidence intervals (CIs), and the adjusted ORs with their 95% CI. The multiple ordinal regression was used to test the distribution of mRS at 3-month of patients. SAS software performed all statistical analyses, version 9.4 (SAS Institute Inc., Cary, NC, USA). All P values were two-sided, with P < 0.05 considered statistically significant.
Baseline Characteristics
A total of 1107 consecutive patients (mean age, 63.42±11.33 years; 673 males) were included in the final analysis, among which 81(7.32%) patients occurred END (Figure 1). Between the END group and the non-END group, there were statistical differences in the history of prior stroke/TIA (2.47% vs.9.75%, p=0.029), initial serum glucose level (9.00±4.35 mmol/L vs.7.58±2.87 mmol/L, p=0.001), fibrinogen (3.47±1.24 g/L vs. 3.23±1.23 g/L, p=0.040), low-density lipoprotein (3.20±0.90 mmol/L vs. 2.92±0.96 mmol/L, p=0.003), cholesterol (5.08±1.16 mmol/L vs. 4.85±1.20 mmol/L, p=0.021), SBP (systolic blood pressure) on admission (152.30 ±18.56 mmHg vs. 147.57±21.09 mmHg, p=0.039), DBP (diastolic blood pressure) on admission (88.35±11.86 mmHg vs. 85.70±12.68 mmHg, p=0.038), taking aspirin within seven days before thrombolysis (38.27% vs. 65.20, p<0.0001), and taking clopidogrel within seven days before thrombolysis(13.58% vs. 23.59%, p=0.039). There was no significant statistical difference in the neurological deficit on admission between the two groups. Concerning TOAST types, although the proportion of CE in the END group was higher than in the non-END group (28.21% vs. 18.69%), there was no difference in the etiology distribution between the two groups. In multivariate analysis, END has a significant correlation with the initial serum glucose level (OR,1.10, 95%CI 1.03-1.18; p=0.004), taking aspirin within seven days before thrombolysis (OR, 0.25, 95%CI 0.14-0.44; p<0.0001), and taking clopidogrel within seven days before thrombolysis (OR,0.39, 95%CI 0.19-0.82; p=0.013). The demographics and clinical characteristics at the baseline of subjects in this study were demonstrated in Table 1, and multivariate logistic regression analysis for risk factors of END was shown in Table 2.
Clinical outcomes
During the follow-up, 23 patients were excluded because of missing, and there were 1084 patients (97.92%) who had a 3-month mRS score. The proportion of poor function outcomes is 83.54% in the END group and 37.41% in the non-END group (crude OR 8.49; 95%CI 4.62 to 15.60; P<0.0001). After adjusting the baseline variables as the history of prior stroke/TIA, initial serum glucose level, fibrinogen, low-density lipoprotein, cholesterol, SBP on admission, DBP on admission, taking aspirin within seven days before thrombolysis, taking clopidogrel within seven days before thrombolysis, and TOAST types, END has a statistical correlation with poor 3-month functional outcomes, the adjusted OR was 8.25(95%CI 3.77 -18.03; P<0.0001; Table 3). There was a numerical difference in the distribution of 3-month mRS among patients in the two groups (crude p <0.0001), and this difference was still significant after adjusting compound factors (adjusted OR 11.74, 95%CI 7.58 to 18.18; P<0.0001; Figure 2). Regarding the secondary outcomes, END has a prominent correlation with SICH (NINDS), the adjusted OR was 12.53 (95%CI 5.15 -30.49; P<0.0001; Table 3). Meanwhile, END has a significant correlation with mortality at seven days and mortality at 90 days, the adjusted OR was 20.92(95%CI 7.45 -58.72; P<0.0001; Table 3) and 8.06(95%CI 3.91 -16.62; P<0.0001; Table 3).
Our study aimed to explore the risk factors of END and the relationship between END and poor 3-month functional outcomes. In some studies, the incidence of END was significantly different due to the lack of a unified definition of END, which was from 5.8% to 34.9%(11-14). At present, most studies have defined END as an increasing NIHSS score ≥ 4 points or death within 24 hours after intravenous thrombolysis(8, 15), which was the exact definition of END in our study. Our study enrolled a total of 1107 patients accepting intravenous thrombolysis, and 81 (7.32%) patients occurred END. Simonsen et al. studied a total of 569 patients who received reperfusion therapy and found the incidence of END was 5.8%(13).
Concerning the risk factors of END, although some experts generally believe that elderly patients are more prone to END, it has not been confirmed in some studies(9, 14). Some studies also have demonstrated the predictors of END as follows: diabetes(16), neurological functional deficits on admission(17), and systolic BP(18-20).
There was no statistical difference in age between the END group and the non- END group in our study. Still, there were statistical differences in the history of prior stroke/TIA, initial serum glucose level, fibrinogen, low-density lipoprotein, cholesterol, SBP on admission, and DBP on admission between the two groups. However, in the multivariate analysis, our study found the initial serum glucose level was an independent risk factor of END; the odds ratio was 1.10 (95%CI 1.03 to 1.18, p =0.004).
We have an exciting discovery that taking antiplatelets (aspirin or clopidogrel) within seven days might be the protective factor of END. The incidence of END in patients taking aspirin could be 0.25 times lower than patients without aspirin, similar to patients taking clopidogrel within seven days. Due to the limitation of our research, we had no further study on this result, and it would be a meaningful research focus in the future.
The series of pathophysiological reactions of the brain after intravenous thrombolysis such as intracranial hemorrhage (ICH)(21, 22), malignant edema(23), early recurrent ischemic stroke(11), and early seizures(24) resulted in the aggravation of neurological deficit(18, 19). Meanwhile, SICH had been the leading cause of END. Our study confirmed that the patients in the END group had a higher incidence of ICH than in the non-END group. The incidence of SICH(NINDS) in the END group patients could be 12.53 times higher than patients in the non-END group. Furthermore, END was significantly correlated with mortality at seven days and mortality at three months. Compared the patients with non- END, the mortality at seven days of patients with END could be 20.92 times higher, and the mortality at three months could be 8.06 times higher.
Early neurological deterioration has a high incidence after intravenous thrombolysis and the initial serum glucose level might be an independent risk factor of END. END might predict a poor 3-month prognosis. It might be essential to understand the underlying mechanism of END.
TIA, transient ischemic attack; SBP, systolic blood pressure; DBP, diastolic blood pressure; WBC, white blood cell; PLT, platelet; INR, international normalized ratio; PT, prothrombin time; APTT, activated partial thromboplastin time; FBG, fibrinogen; NIHSS, National Institute of Health Stroke; LDL, low-density lipoprotein; TC, cholesterol; IQR, interquartile ranges; TOAST, Trial of Org 10172 in Acute Stroke Treatment; LAA, large-artery atherosclerosis; Scale; SAO, small-artery occlusion; CE, cardioembolism; OR, odds ratio; CI, confidence interval; TIA, transient ischemic attack; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fibrinogen; LDL, low-density lipoprotein; TC, cholesterol; mRS, modified Rankin Scale; SICH, symptomatic intracranial hemorrhage; SITS-MOST, safe implementation of treatments in stroke-monitoring; ECASS II, second European–Australasian acute stroke study; NINDS, National Institute of Neurological Disorders and Stroke.
Acknowledgements
We gratefully appreciate all the participants and staff for their contributions.
Authors’ contributions
Concept and design: FC, XZ, XG, and YJ. Drafting of the manuscript: FC, YL, and XG. Critical revision of the manuscript for important intellectual content: HD, YD, and JJ. Provision of study material or patients: YL and YJ. Collection and assembly of data: FC, YL, JJ, AW, HD, YJ, YD, and XG. Check and approve of clinical definition: XG and XZ. Data analysis: FC and AW. Data interpretation: FC, AW, HD, JJ, YD, and XG. Administrative, technical or material support: XZ and YJ. Supervision: XG and XZ. Final approval of manuscript: all authors.
Funding
The study was supported by grants from the Beijing Natural Science Foundation (Z200016).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The ethics committee of Beijing Tiantan Hospital approved this study. All study subjects had signed informed consent. We confirm that all methods in our study were performed in accordance with the relevant guidelines and regulations.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Table 1 Demographic and clinical characteristics in patients
|
Variables
|
END (n =81) |
non-END (n = 1026) |
P-Value |
|
Gender, male, n (%) |
49(60.49) |
624(60.82) |
0.954 |
|
Age, mean ±SD (years) |
64.47±9.34 |
63.34±11.48 |
0.636 |
|
Hypertension, n (%) |
54(66.67) |
598(58.34) |
0.143 |
|
Diabetes mellitus, n (%) |
17(20.99) |
174(16.96) |
0.356 |
|
Atrial fibrillation, n (%) |
15(18.52) |
182(17.74) |
0.860 |
|
Hyperlipidemia, n (%) |
3(3.70) |
69(6.73) |
0.288 |
|
prior stroke/TIA, n (%) |
2(2.47) |
100(9.75) |
0.029 |
|
Current smoking, n (%) |
20(24.69) |
361(35.19) |
0.056 |
|
Glucose, mean (SD), mmol/L |
9.00±4.35 |
7.58±2.87 |
0.001 |
|
WBC, mean (SD), ×109/L |
8.32±2.85 |
7.87±2.70 |
0.216 |
|
FBG, mean (SD), g/L |
3.47±1.24 |
3.23±1.23 |
0.040 |
|
LDL, mean (SD), mmol/L |
3.20±0.90 |
2.92±0.96 |
0.003 |
|
TC, mean (SD), mmol/L |
5.08±1.16 |
4.85±1.20 |
0.021 |
|
SBP on admission, mean (SD), mmHg |
152.30±18.56 |
147.57±21.09 |
0.039 |
|
DBP on admission, mean (SD), mmHg |
88.35±11.86 |
85.70±12.68 |
0.038 |
|
SBP at 2 hours after thrombolysis, mean (SD), mmHg |
150.05 ±22.31 |
143.03±19.80 |
0.002 |
|
DBP at 2 hours after thrombolysis, mean (SD), mmHg |
87.19±14.28 |
83.42±12.38 |
0.015 |
|
NIHSS on admission, IQR |
12(3-28) |
11(0-40) |
0.559 |
|
Pre-admission mRS 0–2, n (%) |
80(100) |
1002(92.75) |
0.398 |
|
Baseline medication within seven days before thrombolysis |
|
|
|
|
Taking aspirin, n (%) |
31(38.27) |
669(65.20) |
<0.0001 |
|
Taking clopidogrel, n (%) |
11(13.58) |
242(23.59) |
0.039 |
|
Taking other antiplatelets, n (%) |
11(13.58) |
156(15.20) |
0.694 |
|
Taking hypoglycemic drugs , n (%) |
0(0.00） |
9(0.88) |
1.000 |
|
Median door-to-needle time, IQR, h |
1.82±0.95 |
2.60±9.90 |
0.971 |
|
TOAST subtypes |
|
|
0.080 |
|
LAA, n (%) |
43(55.13) |
553(54.11) |
|
|
SAO, n (%) |
4(5.13) |
113(11.06) |
|
|
CE, n (%) |
22(28.21) |
191(18.69) |
|
|
Other, n (%) |
9(11.54) |
165(16.14) |
|
Abbreviation: TIA, transient ischemic attack; SBP, systolic blood pressure; DBP, diastolic blood pressure; WBC, white blood cell; PLT, platelet; INR, international normalized ratio; PT, prothrombin time; APTT, activated partial thromboplastin time; FBG, fibrinogen; NIHSS, National Institute of Health Stroke; LDL, low-density lipoprotein; TC, cholesterol; IQR, interquartile ranges; TOAST, Trial of Org 10172 in Acute Stroke Treatment; LAA, large-artery atherosclerosis; Scale; SAO, small-artery occlusion; CE, cardioembolism.
Table 2 Multivariate logistic regression analysis for risk factors of END
|
Variables |
OR |
95%CI |
P-value |
|
prior stroke/TIA |
3.14 |
0.74-13.38 |
0.123 |
|
Glucose |
1.10 |
1.03-1.18 |
0.004 |
|
FBG |
1.07 |
0.91-1.26 |
0.426 |
|
LDL |
1.24 |
0.79-1.95 |
0.361 |
|
TC |
0.93 |
0.66-1.32 |
0.685 |
|
SBP on admission |
1.00 |
0.98-1.02 |
0.748 |
|
DBP on admission |
1.01 |
0.98-1.04 |
0.555 |
|
SBP at 2 hours after thrombolysis |
1.02 |
1.00-1.04 |
0.107 |
|
DBP at 2 hours after thrombolysis |
1.00 |
0.97-1.03 |
0.960 |
|
Taking aspirin within seven days before thrombolysis |
0.25 |
0.14-0.44 |
<0.0001 |
|
Taking clopidogrel used within seven days before thrombolysis |
0.39 |
0.19-0.82 |
0.013 |
Abbreviation: OR, odds ratio; CI, confidence interval; TIA, transient ischemic attack; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fibrinogen; LDL, low-density lipoprotein; TC, cholesterol.
Table 3 Outcomes after intravenous thrombolysis in END group versus non-END group
|
Outcomes |
No. (%) of patients |
Unadjusted OR (95% CI) |
P value |
Adjusted OR (95% CI) * |
P value |
|
|
END group (n=81) |
non-END group (n=1026) |
|||||
|
Primary outcome |
|
|
|
|
|
|
|
mRS 3–6 at three months |
66(83.54) |
376(37.41) |
8.49 (4.62-15.60) |
<0.0001 |
8.25 (3.77-18.03) |
<0.0001 |
|
Safety outcomes |
|
|
|
|
|
|
|
SICH(SITS-MOST) |
15(18.52) |
1(0.10) |
232.83(-) |
<0.0001 |
109.77(-） |
0.001 |
|
SICH (ECASS II) |
30(37.04) |
5(0.49) |
120.12 (44.74-322.50) |
<0.0001 |
90.46 (19.84-412.44) |
<0.0001 |
|
SICH (NINDS) |
30(37.04) |
22(2.14) |
26.84 (14.47-49.79) |
<0.0001 |
12.53 (5.15-30.49) |
<0.0001 |
|
Mortality at seven days |
26(32.50) |
16(1.56) |
30.39 (15.39-60.01) |
<0.0001 |
20.92 (7.45-58.72) |
<0.0001 |
|
Mortality at three months |
36(45.00) |
59(5.86) |
13.13 (7.86-21.94) |
<0.0001 |
8.06 (3.91-16.62) |
<0.0001 |
*Adjusted baseline variables: prior stroke/TIA, Systolic BP before thrombolysis, Diastolic BP before thrombolysis, glucose before thrombolysis, FBG before thrombolysis, Systolic BP at 2 hours after thrombolysis, Diastolic BP at 2 hours after thrombolysis, LDL after thrombolysis, TC after thrombolysis, Aspirin use within seven days after thrombolysis, clopidogrel use within seven days after thrombolysis, OCSP subtypes.
Abbreviation: mRS, modified Rankin Scale; SICH, symptomatic intracranial hemorrhage; SITS-MOST, safe implementation of treatments in stroke-monitoring; ECASS II, second European–Australasian acute stroke study; NINDS, National Institute of Neurological Disorders and Stroke.