Study Design
This study was designed as a retrospective study evaluating the efficacy and safety of IVT administered within 4.5 hours of symptom onset.
This study was approved by the First Affiliated Hospital of Soochow University Institutional Review Board. And the need for patient informed consent was waived by the same ethics committee. Consecutive acute ischemic stroke (AIS) patients with minor-to-mild stroke symptoms (NIHSS score≤5) were enrolled from our hospital between August 2016 and May 2018.
Patients Selection
Eligible cases were collected using the following inclusion criteria: (1) Clinical diagnosis of AIS or transient ischemic stroke (TIA) with NIHSS score 0 to 5; (2) Age 18 years or older; (3) Time from symptom onset within 4.5h for rt-PA group, however, it could be administered up to 24 hours after symptom onset in non-rt-PA group; (4) Available for a telephone interview at 90 days. The exclusion criteria were as follows: (1) Pre-stroke mRS score of ≥2; (2) ICH on baseline computed tomography, and other contraindications to IVT and antithrombotic therapy.
Patient Management
Participants were divided into two groups according to different approaches about the management of mild stroke patients: (1) rt-PA group: Intravenous rt-PA within 4.5 hours of AIS onset or last known well time (0.9 mg/kg, maximum dose 90 mg with initial 10% of total dose given as bolus during 1 minute), followed by appropriate secondary stroke prevention strategies; (2) Non-rt-PA group: Optimal secondary stroke prevention strategies within 24h from AIS onset: including initiation of dual antiplatelets among patients with NIHSS≤3 (clopidogrel 75 mg per day for 90 days + aspirin 100 mg per day for the first 3 weeks); clopidogrel 75mg/ aspirin 100mg per day; or anticoagulation agents in the event of cardioembolism, and other measures such as statins and antihypertensive medication, etc.
Patient Data Collection
Baseline demographic and clinical information were collected by experienced stroke neurologists: including age, gender, previous history (hypertension, diabetes mellitus, atrial fibrillation, coronary heart disease, previous stroke or TIA and current smoking), medication history, stroke severity (measured by NIHSS score at admission and 7d) , time from symptom onset, blood pressure at baseline, ABCD2 score, stroke subtype (assessed using TOAST classification [Trial of Org 10172 in Acute Stroke Treatment])[15], and neurological imaging (collected at baseline, 24-36h, 7d or discharge if sooner in stroke unit). The 90d-mRS was assessed by telephone follow-up.
Definition of Clinical Information
All participants were hospitalized in the stroke unit assessed by neurologic specialists. (1) Efficacy outcomes: The achievement of an mRS of 0 to 1 at 90 days was defined as excellent outcome, and an mRS of 0 as perfect outcome. Significant improvement was referred as complete resolution of the neurologic deficit or an improvement of at least 4 points over baseline NIHSS score[16]. (2) Adverse outcomes: Early neurological deterioration (END) was defied as a NIHSS score increase of 2 or more within 7d after symptom onset excluding any CT- or MRI-documented ICH[17]. sICH was defined as CT-based ICH within 7 days with a NIHSS score increase of at least 4 or death[18]. The recurrent ischemic stroke within 3 months was assessed by stroke specialists via face-to-face interviews or telephone follow-up.
Statistical Analysis
Categorical variables are expressed as numbers (%). Continuous variables are expressed as mean (standard deviation [SD]) in the case of normal distribution, otherwise as median (interquartile range [IQR]), and the normality of distributions was evaluated by histograms and the Shapiro–Wilk test. The between-group differences in baseline characteristics were assessed as follows: continuous variables were compared with the Student t test or Mann-Whitney test as appropriate, while categorical variables were compared with chi-square test (Pearson’s χ2 or continuity correction). ORs with their CIs for efficacy and adverse outcomes were estimated respectively using multivariable binary logistic regression analyses in the whole study group. Moreover, we intended to estimate the heterogeneity of therapeutic effect magnitude for excellent outcome stratified by baseline NIHSS score (<3 versus≥3), stroke subtype (large artery atherosclerosis, cardioembolism, small vessel occlusion and other/undetermined etiology), disabling neurologic deficits (yes versus no), and baseline ABCD2 score (<4 versus≥4).
The α-level of significance was P<0.05 two-tailed. All analyses were performed using the SPSS software version 25.0.
Results
Population and Baseline Characteristics
Between August 2016 and May 2018, a total of 327 patients with AIS were treated with intravenous rt-PA in stroke unit within 4.5h, among which 111 (33.9%) with mild neurologic deficit (baseline NIHSS score ≤5). And 3 were excluded for lost during follow-up, resulting in 108 patients in the rt-PA group. Meanwhile, 2994 patients were admitted to the unit with AIS not receiving intravenous rt-PA. Among these 119 participants responding to inclusion criteria were enrolled in the non-rt-PA group (Figure 1).
The median age of rt-PA treated patients was 65.5 (IQR, 59-74), and 66 (IQR, 59-74) in rt-PA untreated patients. There were 30 patients (27.8%) in rt-PA group and 45 patients (37.8%) in non-rt-PA group were female. The median baseline NIHSS score in different medical approaches was both 3 (IQR, 2-4; P=0.09). And the median baseline ABCD2 score among two groups was also matched (5 versus 5; IQR, 4-6 versus 5-6; P=0.58). Study groups were generally balanced as shown in Table 1, with the most common medical risk factors being hypertension (71.8%) and current smoking (34.8%). However, patients in rt-PA group had a significantly higher proportion of history of atrial fibrillation (18.5% versus. 7.6%, P=0.01). Among patients with mild stroke, the most common stroke subtype was small vessel occlusion (37.9%) followed by large artery atherosclerosis (32.6%), with other/undetermined etiology (15.4%) and cardioembolism (14.1%) less frequent.
Efficacy outcomes
Figure 2 showed the comparisons in efficacy and adverse outcomes between different medical approaches. And multivariable-adjusted associations between covariates and efficacy/adverse outcomes were showed in Table 2. Excellent outcome at 90 days was achieved in 85 (78.7%) patients treated with rt-PA compared with 78 (65.5%) patients without rt-PA treatment (Figure 2), with an adjusted OR of 2.95 (95% CI, 1.44-6.03; P=0.003) after controlling for the effects of male (OR, 3.2; 95%CI, 1.60-6.28; P=0.001), history of diabetes mellitus (OR, 0.34; 95%CI, 0.16-0.70; P=0.004) and worse baseline NIHSS score (OR, 0.51; 95%CI, 0.38-0.69; P<0.001) (Table 2). Meanwhile, excellent outcome at 90 days achieved by intravenous rt-PA therapy was both observed in different time window from symptom onset (0-3h versus 3-4.5h, 83.9% versus 73.1%, P=0.17) (data not shown). Similar result was found considering perfect outcome (OR, 2.08; 95%CI, 1.17-3.70; P=0.013). Besides, worse stroke severity (OR, 0.66; 95%CI, 0.52-0.83; P<0.001) and history of diabetes mellitus (OR, 0.48; 95%CI, 0.24-0.97; P=0.039) were associated with lower rate of perfect outcome. Moreover, we detected significant improvement in 32 (29.6%) patients receiving rt-PA treatment (OR, 2.57; 95%CI, 1.29-5.12; P=0.007), with control for the effects of male (OR, 4.52; 95%CI, 1.78-11.49; P=0.002) and wore baseline NIHSS score (OR, 0.69; 95%CI, 0.53-0.91; P=0.009).
Adverse outcomes
The rate of END within 7 days was 13.0% in patients treated with rt-PA, whereas 10.1% in patients without rt-PA treatment, with no statistically significant difference between two groups (OR, 1.33; 95%CI, 0.59-3.01; P=0.497). History of diabetes mellitus was strongly associated with END at 7 days (OR, 3.37; 95%CI, 1.46-7.78; P=0.004). Any ICH within 7 days, occurred more frequently in patients treated with rt-PA compared with patients without rt-PA treatment (6.5% versus 1.7%; OR, 4.05; 95%CI, 0.82-19.96; P=0.085). However, only 1 (0.9%) was sICH in rt-PA group. Older age, high level of systolic blood pressure at admission and worse stroke severity were associated with any ICH. While the recurrent ischemic stroke in 90 days was less frequent in patients treated with rt-PA compared with the other group (2.8% versus 4.2%; OR, 0.65; 95%CI, 0.15-2.79; P=0.564). Only male was strongly associated with lower incidence of recurrent ischemic stroke (OR, 0.064; 95%CI, 0.01-0.53; P=0.011).
Association Between Subgroups and Excellent Outcome
In the subgroup analysis stratified by ABCD2 score (Figure 3), excellent outcome was achieved in 80 patients (78.4%) receiving intravenous rt-PA with ABCD2 score ≥4, compared with 73 (64.6%) patients not receiving intravenous rt-PA with ABCD2 score ≥4 (OR, 2.81; 95%CI, 1.31-6.03; P=0.008). For patients with ABCD2 score<4, no significant of treatment effect was observed between two groups. Excellent outcome was achieved in both subgroups of baseline NIHSS score with significant difference. However, we detected no significant heterogeneity of therapeutic effect magnitude for excellent outcome stratified by stroke subtype and disabling neurologic deficits.