The INTRECIS is a nationwide, multi-center, prospective, and registry study of consecutive adult AIS patients who received intravenous thrombolysis within 4.5 h of the onset of symptoms. The details of the study design have been reported recently (23). From the INTRECIS cohort, patients were included in the current study with the following criteria: (1) consecutive adult AIS patients who received 0.9 mg/kg intravenous alteplase within 4.5 h of a definite time of onset of symptoms; (2) the complete clinical data including SBP at baseline, 1, and 24 h after alteplase. Patients were excluded if they met the following criteria: (1) patients who received urokinase; (2) patients who received a non-standard dose of alteplase; (3) patients who lacked complete clinical data; (4) age > 80 years; (5) patients treated with mechanical thrombectomy. All patients and/or their legally authorized surrogates gave written informed consent.

We collected baseline characteristics of patients including age, sex, current smoker, current drinker, hypertension, diabetes mellitus, history of stroke, coronary heart disease, atrial fibrillation, body mass index, baseline heart rate, symptom onset-to-thrombolysis time (OTT), door-to-needle time (DNT), National Institute of Health Stroke Scale (NIHSS) score, blood pressure data including diastolic blood pressure, baseline SBP (SBP01), immediate SBP after the end of alteplase (SBP02), SBP 24 h after alteplase (SBP03), maximum SBP among three timepoints (SBP max), minimum SBP among three timepoints (SBP min), and average SBP among three timepoints (SBP mean), and mRS at 90 days. Blood pressure was measured using a validated electronic sphygmomanometer while the patient was supine.

In parallel with the INTRECIS study (23), the poor outcome was defined as a mRS score of 2–6 points at 90 days, whereas the good outcome was defined as a mRS score of 0–1 points at 90 days.

We performed descriptive statistics for baseline characteristics. Baseline information was compared between favorable and poor outcome groups using the t-test or U-test for continuous variables and the chi-square test or Fisher's exact test for categorical variables. First, we performed the univariate logistic regression analysis to identify the associated variables with poor outcomes. In the multivariate logistic regression analysis, BMI, baseline NIHSS score, baseline heart rate, current drinker, previous stroke, and atrial fibrillation were further adjusted to determine whether different SBP metrics were associated with patient outcomes after thrombolysis. Results are reported as odds ratios (OR) and 95% confidence intervals (CI). Differences with P-values < 0.05 were considered statistically significant in the relevant analytical tests. Second, we used a receiver operating characteristic (ROC) curve to explore the predictive value of SBP via areas under the curve (AUCs). The statistical software SPSS version 26.0 was used for analysis.

From 4,550 patients enrolled in the INTRECIS cohort between October 2016 and September 2019, 1,593 eligible patients were included in this study: 1,159 (72.8%) in the good outcome group and 434 (27.2%) in the poor outcome group (Figure 1). Table 1 presents baseline characteristics in two groups. Patients with poor outcomes were older (65 years vs. 62 years, P < 0.000), had higher NIHSS score at admission (11 vs. 5, P < 0.000), and higher SBP indicators such as median SBP02 (145 mmHg vs. 141 mmHg, P = 0.010), median SBP03 (142 mmHg vs. 140 mmHg, P < 0.000), median SBP max (156 mmHg vs. 154 mmHg, P = 0.012), and median SBP min (137.5 mmHg vs. 135 mmHg, P = 0.008), and median SBP mean (146.7 mmHg vs. 143.7 mmHg, P = 0.004) (Table 1).

In the univariate logistic regression analysis, age, body mass index, current drinker, history of stroke, atrial fibrillation, baseline heart rate, NIHSS score at baseline, SBP02, SBP03, SBP max, SBP min, and SBP mean were statistically significant (P < 0.05, Table 2). In multivariate logistic regression analysis (Table 2), SBP02, SBP03, SBP max, SBP min, and SBP mean after IVT were associated with a higher likelihood of good outcomes after adjusting for variables with P < 0.05 in univariate regression analysis (per 10 mm Hg higher SBP indicator, adjusted OR 0.87–0.94, all P < 0.05). Furthermore, ROC curve analysis showed these SBP indicators had good prediction power for functional outcomes: SBP02 with an AUC of 0.764 (95% CI = 0.737–0.790), SBP03 with an AUC of 0.766 (95% CI = 0.739–0.792), SBP max with an AUC of 0.762 (95% CI = 0.735–0.789), SBP min with an AUC of 0.764 (95% CI = 0.737–0.790), and SBP mean with an AUC of 0.763 (95% CI = 0.736–0.790) (Figure 2).

Based on sex, patients were divided into two groups: 1113 in the men group and 480 in the women group. After adjusting for BMI, baseline NIHSS score, baseline heart rate, current drinker, previous stroke, and atrial fibrillation, the multivariate logistic regression analysis showed that all SBP indicators after IVT except SBP max were associated with outcome in women, while only SBP03 in men (Table 3).

According to the age, patients were classified into two groups: 962 in the ≥ 60-year-old group and 631 in the < 60-year-old group. After adjusting for BMI, baseline NIHSS score, baseline heart rate, current drinker, previous stroke, and atrial fibrillation, the multivariate logistic regression analysis showed that all SBP indicators after IVT were associated with outcomes in the ≥ 60 years group, but none were associated in the < 60 years group (Table 4). Furthermore, ROC curve analysis showed age had moderate prediction power for functional outcomes: ≥ 60 years with an AUC of 0.572 (95% CI = 0.532–0.611) and < 60 years with an AUC of 0.515 (95% CI = 0.461–0.569) (Figure 3).

Based on age and sex, we further divided the patients into four subgroups: men ≥60 years, women ≥60 years, men <60 years, and women <60 years. After adjusting for BMI, baseline NIHSS score, baseline heart rate, current drinker, previous stroke, and atrial fibrillation, the multivariate logistic regression analysis showed that all SBP indicators after IVT were associated with outcomes in the ≥60 years women group, while only SBP 03 were associated in the ≥60 years men group (Table 5, Figure 4).

Given the close association of SBP indicators with outcomes in the women subgroup with ≥ 60 years, ROC curve analysis was performed. The results showed SBP02 with an AUC of 0.777 (95% CI = 0.725–0.829), SBP03 with an AUC of 0.782 (95% CI = 0.731–0.883), SBP max with an AUC of 0.775 (95% CI = 0.723–0.827), SBP min with an AUC of 0.778 (95% CI = 0.727–0.829), and SBP mean with an AUC of 0.779 (95% CI = 0.727–0.839) (Figure 5).

In this post hoc analysis, we identified several findings: (1) Among AIS patients who received intravenous alteplase, SBP indicators after IVT, but not baseline SBP were associated with clinical outcomes; (2) more SBP indicators were associated with clinical outcomes in women but only SBP 03 in men; (3) the association of SBP indicators with clinical outcome was found in the ≥ 60 years group but not the < 60 years group; (4) in the ≥ 60 years group, more SBP indicators were associated with clinical outcomes in women but only SBP 03 in men. Collectively, these findings suggest that age and sex should influence the relationship between SBP and outcomes in thrombolysed patients, and the closer association of SBP with outcomes may be in the subgroup of women aged ≥ 60 years.

Prior studies have investigated the relationship between SBP levels and functional outcomes in thrombolysed AIS patients (24), but the results were inconsistent. In our study, there was no difference in SBP at baseline between good and poor outcome groups, but SBP at 1 h and 24 h after IVT was found to be significantly associated with clinical outcomes. The finding was in agreement with a previous study (7), but not with other studies reporting the close association of SBP at the baseline and up to 24 h after thrombolysis with poor prognosis (6, 8, 25). This conflicting reason was not clear. Given the potential effect of stress, bladder pressure, or other transient stimuli on SBP at the stroke onset, the association of baseline SBP with clinical outcomes should be complex. In summary, the current results suggested that increasing SBP after thrombolysis may reduce the likelihood of 3-month good functional outcomes.

The pathophysiological mechanism underlying their associations may be attributed to impaired cerebral autoregulation (CA) function following stroke. Under normal conditions, CA can maintain relatively constant cerebral blood flow (CBF) when arterial blood pressure or cerebral perfusion pressure fluctuates (26, 27). However, CA may be impaired or even vanish after ischemic stroke (28), which may partially explain the association of increased SBP with poor outcomes because impaired CA leads to ischemia-reperfusion injury or reduced cerebral perfusion (29, 30).

In the present study, we found the significant effect of age and sex on the relationship with SBP and functional outcomes in patients with AIS after IVT, and more closer association was identified in old women patients, which was never reported previously. These findings should be plausible. Compared to pre-menopausal women and age-matched men, post-menopausal women were found to have reduced vasomotor reserve, poorer cerebrovascular reactivity, and reduced cerebral blood flow autoregulation (31). Mechanisms underlying these changes may be related to estrogen. For example, estrogen can bind to estrogen receptors on the endothelium of cerebral arteries, which would cause vasodilatation in response to the deficit in cerebral perfusion (32). However, the protective effect of estrogen is lost in post-menopausal women, which makes them more susceptible to changes in blood pressure. As a non-modifiable risk factor for cerebrovascular diseases (33), aging would impair cerebral autoregulation (34). Collectively, these results suggest that aging and estrogen decrease in a synergistic manner cause the impairment of cerebral autoregulation, resulting in poor outcomes in this population.

The main strength of this study was the first attempt to determine the effect of sex and age on the association of SBP indicators with outcomes in patients with AIS after IVT. The results suggested that higher SBP indicators after IVT were associated with poor 3-month functional outcomes, especially in older women patients. However, we recognize several limitations. The main limitation was the retrospective analysis nature, which was subject to selection bias and unexpected confounding factors. Second, the current study was only performed in Chinese ischemic stroke patients, and patients over 80 years old were excluded due to too small sample size, which should limit the generalizability of the results. Third, the detailed data on antihypertensive drugs were not available, which may make it impossible to investigate their effects on the current findings. Fourth, given the sex difference in the distribution of risk factors, stroke severity, functional outcomes (12), the difference in the pathophysiology, prognosis, and clinical features of lacunar vs. non-lacunar stroke (35), and the relationship between SBP, sex, age, and outcomes warrants investigation in patients with lacunar vs. non-lacunar ischemic stroke. Fifth, patients with mild-to-moderate neurologic deficit (median NIHSS score of 6) were enrolled in this study, which limited the generalization in moderate and severe stroke. Sixth, the small absolute difference in SBP indicators in different groups would affect the practical implementation of this finding. Finally, these findings need to be explained with caution due to the exploratory nature of this secondary analysis.

In summary, among Chinese acute ischemic stroke patients, SBP indicators after intravenous thrombolysis were independently associated with outcomes at 3 months, which may be affected by age and sex. The relationship will be worth exploring in different stroke subtypes.