Thrombolysis Versus Nonthrombolyzed in Patients With Mild Strokes and Large Vessel Occlusions

Abstract

Background

The safety and efficacy of intravenous thrombolysis (IVT) in acute ischemic stroke patients with large vessel occlusions and mild neurological deficits are controversial.

Methods:

Data of stroke patients presenting with mild initial stroke, which was defined as the National Institutes of Health Stroke Scale score (NIHSS) ≤5 and large vessel occlusion, were extracted from a large provincewide stroke registry.

Results:

A total of 619 IVT and 2170 non-IVT patients were identified in this study. IVT patients had higher rates of favorable functional outcome Modified Rankin Scale(mRS) ≤1 (74.6% vs. 70.6%; P=0.047), lower mRS scores (1 vs. 1, P=0.001), and higher NIHSS score decreased (1 vs. 0, P<0.001) at discharge compared with the non-IVT patients. The rates were similar in symptomatic intracranial hemorrhage (2.1% vs. 2.0%, P=0.853), severe systemic bleeding (0.8% vs. 0.6%, P=0.474), and mortality at discharge (0.2% vs. 0.2%, P=0.906) between the 2 groups. A multiple Logistic regression model found that age above 80 years [adjusted OR (aOR) 2.056 (95% CI, 1.125 to 3.756)], history of stroke [aOR 1.577 (95% CI, 1.303 to 1.910)], hyperlipidemia [aOR 2.156 (95% CI, 1.059 to 4.388)], high admission NIHSS score [aOR 1.564 (95% CI, 1.473 to 1.611)], and non-IVT [aOR 1.667 (95% CI, 1.337 to 2.077)] were independent risk factors for mRS >1.

Conclusions:

IVT administration is safe and effective in eligible acute ischemic stroke patients. Age above 80 years, with a history of stroke and hyperlipidemia, high admission NIHSS score, and non-IVT were independent risk factors for mRS >1 at discharge in these patients.

Approximately 30% of all acute ischemic stroke (AIS) present with mild neurological deficits [defined as National Institutes of Health Stroke Scale score (NIHSS) ≤5] on hospital admission in Chinese population.¹ The proportion is as high as 50% in the United States,² but up to one third of these patients fail to make a favorable prognosis as it was anticipated,³ especially when a large vessel is occluded.⁴ It is fairly common in large vessel occlusions (LVO) strokes that presenting with mild symptoms, nearly a third of patients with ischemic stroke with NIHSS score of ≤5.⁵

Although IVT is the mainstay therapy for eligible patients with AIS, the efficacy of IVT in AIS patients with mild neurological deficits and LVO is also not well verified.⁶ There is an ongoing debate that IVT may be futile or even dangerous in those patients, especially when nondisabling neurological deficits are present.⁷

In this study, we compared the natural course, as well as the safety and outcome of patients with mild neurological deficits (NIHSS score ≤5) and LVO who were treated with or without IVT.

METHODS

Patient Selection

The study was carried out from March 2019 to June 2021. A total of 15,732 patients with stroke were admitted from 143 stroke centers, which were distributed in 11 cities of Hebei Province of China. We eliminated the Transient ischemic attack(TIA) (n=1161), hematencephalon (n=887), stroke mimics (n=121), nonlarge vessel (n=6575), admission NIHSS >5 (n=2249), urokinase thrombolytic (n=198) does not meet the entry criteria or lacked follow-up data (n=1752) patients. Finally, 2789 patients were enrolled in this study, among them 619 patients received IVT, and the remaining 2170 patients did not receive IVT.

Patients were selected using the following criteria: (1) aged more than 18 years; (2) diagnosed with AIS according to computed tomography, MR imaging, or clinical symptoms; (3) symptom presented within 24 hours from onset; (4) admission NIHSS 0 to 5; (5) with LVO (defined as occlusions at the following locations: (internal carotid artery, M1 and M2 segments of middle cerebral artery, A1 segment of the anterior cerebral artery, V4 segment of the vertebral artery, basilar artery, and P1 segment of the posterior cerebral artery⁸) determined by reviewing each initial computed tomography angiography or magnetic resonance angiography report that is neurologically relevant to the presenting symptoms and signs; (6) without systemic or endovascular reperfusion therapies; (7) prestroke estimated modified Barthel Index of ≥90 and premorbid mRS 0 to 1. IVT was defined as administering 0.9 mg/kg IV tPA within 4.5 hours after the onset of symptoms. Patients were subsequently dichotomized into 2 groups according to the treatment history with IVT.

The following baseline characteristics were recorded: age, sex, hypertension, diabetes, hyperlipidemia, coronary artery disease, atrial fibrillation, prior stroke or TIA, family history of stroke, smoking status, drinking status, admission and discharge NIHSS scores, and mRS at discharge.

The safety outcomes included (1) all-cause mortality at discharge, (2) symptomatic intracranial hemorrhage (sICH) defined as presence of a parenchymal hematoma type 2 on follow-up neuroimaging associated with an increase in NIHSS score ≥4 points within 36 hours from treatment,⁹ (3) severe systemic bleeding, defined as any fatal systemic bleeding or any bleeding in a critical area or organ or any bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells.¹⁰

Statistical Analyses

Continuous variables were expressed as mean values ± SD for normally distributed data or median with interquartile ranges for skewed data. Between-group comparisons were assessed using the Student t test or Mann-Whitney U test for continuous variables and the χ² test or Fisher exact test for categorical variables. Significance was set at P<0.05, and P were 2 sided. All baseline characteristics that contributed to the corresponding outcome of interest in the initial univariable ordinal at P<0.1 were included in the multivariable logistic regression analysis for predictors of mRS >1 point as candidate variables. All statistics were performed using IBM SPSS Statistics 22.

RESULTS

A total of 2789 patients had an LVO with baseline NIHSS scores ≤5 were identified in this study, IVT was administered in 619 patients, and 2170 patients were treated without IVT. Baseline characteristics in these 2 subgroups are shown in Table 1. Patients treated with IVT had a higher prevalence of hyperlipidemia (P=0.012), coronary artery disease (P=0.002), and family history of stroke (P<0.001). Compared with non-IVT patients, IVT patients were more often smoking (P=0.021) and drinking (P=0.016). The baseline NIHSS score in non-IVT was lower than in the IVT group (3 vs. 2, P<0.001). As for age, there were more IVT patients between 46 and 65 years old (P=0.049), while the proportion of non-IVT patients over 80 years old was higher (P=0.002).

TABLE 1.

Baseline Characteristics of Included Patients

Baseline characteristics	IVT (n=619)	Non-IVT (n=2170)	P
Age (y)	63.7±22.4	64.3±11.4	0.440
Age group (%)
18-45	5	4.1	0.301
46-65	50.9	46.4	0.049
66-80	40.5	42.6	0.356
>80	3.6	6.9	0.002
Females	33.0	35.9	0.177
History of stroke	25.2	28.1	0.153
Hypertension	57.2	61.2	0.069
Diabetes mellitus	20.0	20.6	0.777
Hyperlipidemia	2.6	1.2	0.012
Atrial fibrillation	3.2	2.2	0.147
Coronary artery disease	15.0	10.6	0.002
Smoking	31.8	27.1	0.021
Drinking	28.4	23.7	0.016
Family history of stroke	5	2.2	<0.001
NIHSS score on Admission (median, IQR)	3 (2-4)	2 (1-3)	<0.001

IQR indicates interquartile range; IVT, intravenous thrombolysis; NIHSS, National Institutes of Health Stroke Scale score.

IVT patients had higher rates of discharge favorable functional outcome (mRS≤1) (74.6% vs. 70.6%; P=0.047) and lower mRS scores at discharge (1 vs. 1, P<0.001) compared with the non-IVT patients (shown in Fig. 1), but the functionally independent (mRS≤2) at discharge was similar between the 2 groups (89.2% vs. 88.2%; P=0.524). Despite there was no statistical significance found in the discharge NIHSS score (1 vs. 1, P=0.781), the NIHSS score decreased was significantly higher in IVT than in non-IVT (1 vs. 0, P<0.001) (Table 2).

FIGURE 1.

Distribution of modified Rankin Scale scores at discharge of acute ischemic stroke patients with large vessel occlusions and mild neurological severity on admission treated with and without IVT. IVT indicates intravenous thrombolysis; mRS, modified Rankin Scale.

TABLE 2.

Outcomes of Included Patients

Variables	IVT (n=619)	Non-IVT (n=2170)	P
Symptomatic ICH, n (%)	13 (2.1)	43 (2.0)	0.853
Severe systemic Bleeding, n (%)	5 (0.8)	12 (0.6)	0.474
Discharge mRS score	1 (1-2)	1 (1-2)	0.001
mRS≤1 at discharge, n (%)	462 (74.6)	1531 (70.6)	0.047
mRS≤2 at discharge n (%)	552 (89.2)	1915 (88.2)	0.524
Mortality at discharge n (%)	1 (0.2)	4 (0.2)	0.906
Discharge NIHSS score (median, IQR)	1 (0-2.75)	1 (0-2)	0.781
NIHSS score decrease (median, IQR)	1 (0-3)	0 (0-1)	<0.001

ICH indicates intracranial hemorrhage; IQR, interquartile range; IVT, intravenous thrombolysis; NIHSS, National Institutes of Health Stroke Scale score.

The rates were similar in safety outcomes between the 2 groups in terms of symptomatic ICH (2.1% vs. 2.0%, P=0.853), severe systemic bleeding (0.8% vs. 0.6%, P=0.474), and mortality at discharge (0.2% vs. 0.2%, P=0.906) (Table 2).

A multiple Logistic regression model found that age >80 years [adjusted OR (aOR) 2.056 (95% CI, 1.125 to 3.756)], history of stroke [aOR 1.577 (95% CI, 1.303 to 1.910)], hyperlipidemia [aOR 2.156 (95% CI, 1.059 to 4.388)], admission NIHSS score [aOR 1.564 (95% CI, 1.473 to 1.611)], and non-IVT [aOR 1.667 (95% CI, 1.337 to 2.077)] were independent risk factors for mRS >1 at discharge (Table 3 and Fig. 2).

TABLE 3.

Multiple Logistic Regression for Prediction of Discharge Favorable Functional Outcome(mRS >1)

Characteristics	P	aOR	95% CI
Male vs. female	0.053	1.223	0.997-1.499
Age groups
46-65 vs. 18-45	0.081	1.577	0.946-2.631
66-80 vs. 18-45	0.062	1.636	0.975-2.745
>80 vs. 18-45	0.019	2.056	1.125-3.756
History of stroke	<0.001	1.577	1.303-1.910
Hypertension	0.700	0.965	0.805-1.157
Diabetes mellitus	0.557	0.937	0.753-1.165
Hyperlipidemia	0.034	2.156	1.059-4.388
Atrial fibrillation	0.585	0.846	0.464-1.541
Coronary artery disease	0.295	0.860	0.648-1.141
Smoking	0.167	0.845	0.666-1.073
Drinking	0.763	1.038	0.814-1.325
Family history of stroke	0.870	0.956	0.561-1.632
NIHSS score on admission	<0.001	1.564	1.473-1.661
Treatment type (non-IVT vs. IVT)	<0.001	1.667	1.337-2.077

IVT indicates intravenous thrombolysis; NIHSS, National Institutes of Health Stroke Scale score.

FIGURE 2.

A forest tree to elucidate the multivariable logistic regression analysis for predictors of mRS 1 at discharge. IVT indicates intravenous thrombolysis; NIHSS, National Institutes of Health Stroke Scale score; mRS, modified Rankin Scale.

DISCUSSION

Our study indicated that AIS patients with LVO and mild stroke had better functional outcome and improved NIHSS scores at discharge with IVT compared with patients without IVT, and there was no significant difference in safety and discharge mortality. In addition, age above 80 years, history of stroke, hyperlipidemia, high admission NIHSS score, and non-IVT were independent risk factors for mRS >1 at discharge.

The findings of our study are in accordance with previous reports, suggesting IVT is beneficial despite the mild neurological deficits and large vessel stenosis.^11–14 Patients with mild stroke symptoms are traditionally excluded from IVT due to safety concerns. The PRISMS study showed that IVT was ineffective on the functional outcomes in patients with mild, nondisabling neurological deficits stroke, in light of a trend toward increased incidence of sICH.¹⁵ According to the results of our study, the probability of sICH was 2.1%, which is lower than in PRISMS (3.2%); however, in line with the GWTG-Stroke registry (1.8%)¹⁶ and the study on the Chinese population (1.9%).¹³ Moreover, it should be noted that, IVT did not increase the risk of sICH (2.1% vs. 2.0%) and serious bleeding complications (0.8% vs. 0.6%) in our study population, which is consistent with earlier researches.^11,14,17 Rha et al¹⁸ also hold the same opinion with us that the incidence of sICH (1.7%) after IVT in Asians is similar to that in Europeans, and even has better functional outcomes.

In acute stroke patients with large vessel stenosis, endovascular therapy has been demonstrated to be superior to IVT. However, in these trials, the patients were highly selected, and those with minor strokes were either excluded or under-represented.¹⁹ A trial of 305 patients with mild stroke and large vessel stenosis showed that compared with IVT, the routine use of endovascular therapy did not significantly improve the early clinical or radiologic outcome in these patients.²⁰ Wardlaw et al²¹ also reported that IVT efficacy is more pronounced in AIS patients affected by mild stroke than in those enrolled in regulatory randomized controlled trials, in which patients with minor symptoms were largely under-represented. Previous meta-analysis shows that, after IVT, the overall incidence of early recanalization was 33%, and it varied according to different occlusion sites. Among them, the recanalization rate of the distal middle cerebral artery was the highest, and the partial and total recanalization rates were 52% and 38%.²² According to the data of our center, the early revascularization rate was 31% in patients receiving intravenous thrombolysis and 12.1% in patients not receiving intravenous thrombolysis. The beneficial effect of tPA may be related to increased rates of complete or partial recanalization in AIS with large vessel or distal occlusions and improved collateral circulation due to the improvement of downstream microvascular thrombosis. So, we believe that IVT is a safe, effective, and active treatment for mild stroke patients with large vessel stenosis.

We also detected that hyperlipidemia was the predictor of mRS >1 at discharge. Hypertriglyceridemia and hypercholesterolemia are both included in hyperlipidemia; previous studies have suggested that hyperlipidemia may be the predictor of early neurological deterioration and poor functional capacity at discharge.^5,23 However, the impact of hypertriglyceridemia in acute stroke is not well defined, the possible mechanisms may be that hypertriglyceridemia could induce a prothrombotic state and eventually disturb microcirculation, especially for the vulnerable small-caliber penetrating arteries. Finally, it could lead to the extension of infarct or acceleration of neuronal death.²⁴

Disabling symptoms are closely related to thrombolytic decisions. IVT in stroke with minor and nondisabling symptoms remains thus highly controversial. The disabling symptoms were defined as a deficit that would prevent the patient from performing basic activities of daily living or returning to work if unchanged.¹⁵ As we all know, NIHSS is not able to detect symptoms of posterior circulation stroke, such as postural instability, gait disturbance, and dysphagia that can cause very severe disability. In fact, the Barthel Index covers all activities considered part of any assessment of activities of daily living and has excellent reliability and validity, which can reflect whether symptoms cause disability or not to some extent.²⁵ According to the data of our center, 60 of 143 IVT patients had Barthel Index ≥90 at the onset of thrombolysis, and 150 of 368 non-IVT patients had Barthel Index ≥90 at the onset of thrombolysis. However, we lack data from other subcenter, so the safety and effectiveness of IVT in disabling mild stroke need to be confirmed by further experiments.

Several limitations of the present study need to be acknowledged. First, similar to other large registries, the data in our study, while having the benefit of being broadly representative, are collected with no independent adjudication. And the presence of unmeasured confounding factors in the report cannot be ruled out. Second, the treatment plan was at the discretion of the physician of each attending subcenter thus the bias cannot be completely eliminated. Moreover, it should be noted that we can not being able to assess the subitems of the NIHSS score (consciousness, aphasia, hemianopsia, motor, etc.) and their relevance to the disability of a patient, which may result in heterogeneity in the study population in terms of functional outcome. Therefore, further randomized clinical trials are needed to ensure the safety and efficacy of IVT in different subtypes of neurological deficits. Third, nearly 40% of patients with mild stroke complicated with LVO were excluded from the experiment due to incomplete data or other reasons, which may cause analysis bias. Fourth, we lack relevant records of stroke localization and etiology, so we cannot further analyze the effects of treatment on different subgroups of patients and their functional outcome. Further clinical trials are needed to prove this. Fifth, due to the limitations of equipment and technology, revascularization rate after IVT was not evaluated in all subcenters, which may result in heterogeneity in the IVT effect in the study population.

Finally, though no significant differences were discovered in sICH between groups, our study is presumably underpowered to uncover a statistically significant association for the outcome of sICH, as it is an expectedly uncommon event in patients with minor strokes. Therefore, the presence of higher intracranial bleeding risk with IVT cannot be excluded with certainty.

CONCLUSIONS

Our study suggests that prompt IVT administration is safe and effective in eligible AIS patients with mild stroke and LVO. And that age above 80 years, with a history of stroke and hyperlipidemia, high admission NIHSS score, and non-IVT were independent risk factors for mRS >1 in these patients. But these observations require independent confirmation from RCTs and larger prospective multicenter real-world evidence studies.