Abstract
Background and Purpose
Sex differences in acute ischemic stroke have been widely investigated, but the difference in acute ischemic stroke patients who received intravenous thrombolysis is not well understood. The current study was to investigate the issue based on a prospective cohort.
Methods
From the Intravenous Thrombolysis Registry for Chinese Ischemic Stroke within 4.5h onset (INTRECIS) cohort, a total of 953 eligible patients with acute ischemic stroke were enrolled in final analysis. Based on 3-month modified Rankin scale score (mRS), patients were classified into good outcome group (mRS 0–1) and poor outcome group (mRS 2–6). Univariate and multivariate logistic regression analyses were used to identify predictive factors for clinical outcome in male or female patients.
Results
Of the 953 patients treated with intravenous thrombolysis, 314 (32.9 %) were women. At day 90, we found no significant gender differences in good outcome (72.5 % vs 65.6 %, adjusted p = 0.414). We got the same results after propensity score matching (69.5 % vs 63.4 %, adjusted p = 0.637). Furthermore, we found that initial National Institute of Health Stroke Scale (NIHSS) score (odd ratio [OR] 0.877; 95 % CI 0.847–0.909, p < 0.001) and serum creatinine (OR 0.993; 95 % CI 0.986–1.000, p = 0 0.043) were found to be independent risk factors for poor outcome in male patients, while initial NIHSS score (OR 0.879; 95 % CI 0.839–0.920, p < 0.001), age (OR 0.970; 95 % CI 0.946–0.995, p = 0.017), systolic blood pressure (OR 0.984; 95 % CI 0.972–0.996, p = 0.007) and small artery occlusion (OR 2.718; 95 % CI 1.065–6.936, p = 0.036) in female patients.
Conclusions
In this study, we found no gender difference in clinical outcome of thrombolysed stroke patients, but a difference in risk factors predicting outcome in male vs female patients was identified for the first time.
Keywords: Gender, Thrombolysis, Acute ischemic stroke, Outcome
1. Introduction
Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) has been recommended to treat acute ischemic stroke (AIS) by guidelines [[1], [2], [3]]. A lot of studies have found the gender difference in etiology, risk factors, clinical manifestations, delay in prehospital and in-hospital treatment, implementation of thrombolytic therapy, complications related to thrombolytic therapy, and prognosis of AIS patients [[4], [5], [6], [7], [8]]. It is of clinical importance to determine the gender difference in AIS, which will be helpful to improve the individualized management including the implementation of thrombolytic therapy in male vs female AIS patients.
However, the effect of gender on outcome of thromblysed AIS patients is still controversial [5,9]. Therefore, the current study was designed to investigate whether the gender has effect on outcome of AIS patients who received intravenous rt-PA, and made the first attempt to analyze the predictive factors of outcome in male vs female patients.
2. Methods
2.1. Study population
Intravenous Thrombolysis Registry for Chinese Ischemic Stroke within 4.5h onset (INTRECIS) [10] is a prospective, multicenter cohort study. From this cohort, we consecutively enrolled eligible AIS participants with over 18 years who received 0.9 mg/kg rt-PA. The inclusion criteria were (1) age ≥18 years; (2) diagnosis of AIS; (3) treatment with standard dose of rt-PA (alteplase, 0.9 mg/kg up to a maximum of 90 mg/kg) within 4.5h of symptom onset; (4) complete clinical data. Patients with any of the following conditions were excluded: (1) receiving endovascular therapy; (2) lack of complete clinical data. The INTRECIS study was centrally approved by General Hospital of the Northern Theater Command (the former General Hospital of ShenYang Military Region), and was registered at Clinicaltrials.gov (NCT 02854592). Signed informed consents were obtained from the patients or their legally authorized representative.
2.2. Data collection
From electronic data capture system, we collected demographic and clinical data, including sex, age, smoking history, drinking history, time of onset, onset-to-needle time (ONT), National Institute of Health Stroke Scale (NIHSS) scores, Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification, past medical history, and laboratory indexes. All patients were assessed at 3-month using modified Rankin Scale (mRS). Good outcome was defined as a mRS score of 0 or 1 at 90 days, while poor outcome as a score of 2 or greater on the mRS at 90 days. The safety outcome was symptomatic intracranial hemorrhage (sICH) within 48h, defined as an increase in the NIHSS score of ≥4 points as a result of intracranial hemorrhage according to the ECASS-3 study [11].
2.3. Statistical analysis
Continuous variables were shown as mean ± standard deviation and median (interquartile range) in normal and non-normal distributions, respectively, and categorical variables were shown as frequency (proportion). Differences in normally and nonnormally distributed continuous variables were identified using the Student t tests and Mann-Whitney U test, respectively, while the chi-squared test was used for categorical variables. The demographic and clinical characteristics between male and female patients with ischemic stroke, including age, smoking history, drinking history, initial NIHSS scores, ONT, TOAST classification, past medical history, and laboratory indexes, were compared. Univariate and multivariate logistic regression analyses were applied to calculate the odds ratio (OR) and relative 95 % confidence interval (CI) to assess the association between gender and outcome. Potential variables that may be related to outcomes and those with a P-value <0.1 in the univariate regression analysis were further validated by multivariate regression analysis. As the sensitivity analysis, propensity score matching (PSM) was used to balance the baseline characteristics between male and female. We used 1:1 propensity score matching with a caliper width of 0.1, matching for variables with a P-value <0.05. In addition, we apply logistic regression analyses to compared the differences in factors predictive of outcome after intravenous thrombolysis in male and female patients. A P-value of <0.05 was considered to reflect statistical significance, and all data were analyzed using IBM SPSS version 25.0 (SPSS Inc., Chicago, IL, USA).
3. Results
As shown in Fig. 1, a total of 953 eligible patients were enrolled in the current study after excluding 3597 patients with different reasons. The median age of all participants was 64 (interquartile range, 55, 73) years, and 314 patients (32.9 %) were women. Demographic and baseline characteristics according to gender were presented in Table 1. Many baseline characteristics were not balanced between male and female, but only several variables were imbalanced after PSM (Table 1). After adjusting these imbalanced variables, multivariate logistic regression analysis showed that gender was not associated with good functional outcome (Before PSM: 72.5 % vs 65.6 %; adjusted OR 0.834, 95 % CI 0.540–1.288, p = 0.414, Fig. 2A; After PSM: 69.5 % vs 63.4 %, adjusted OR 1.118, 95 % CI 0.703–1.777; p = 0.637, Fig. 2B) or sICH (Before PSM: adjusted OR 1.879, 95 % CI 0.681–5.184, p = 0.294; After PSM: adjusted OR 1.457, 95%CI 0.377–5.631, p = 0.586).
Fig. 1.
The flow diagram.
Table 1.
Baseline characteristics and clinical characteristics after intravenous thrombolysis in AIS patients according to gender.
| Before PSM |
After PSM |
|||||
|---|---|---|---|---|---|---|
| Male (n = 639) | Female (n = 314) | P value | Male (n = 243) | Female (n = 243) | P value | |
| Age, y (IQR) | 62 (54–70) | 69 (59–78) | <0.001 | 66 (59–73) | 65 (56–74) | 0.363 |
| Smoking history, n (%) | 338 (52.9) | 18 (5.7) | <0.001 | 130 (53.5) | 15 (6.2) | <0.001 |
| Drinking history, n (%) | 242 (37.9) | 2 (0.6) | <0.001 | 80 (32.9) | 2 (0.8) | <0.001 |
| Previous stroke, n (%) | 118 (18.5) | 57 (18.2) | 0.906 | 44 (18.1) | 40 (16.5) | 0.631 |
| Hypertension, n (%) | 349 (54.6) | 198 (63.1) | 0.013 | 135 (55.6) | 146 (60.1) | 0.312 |
| Diabetes mellitus, n (%) | 98 (15.3) | 71 (22.6) | 0.006 | 43 (17.7) | 54 (22.2) | 0.212 |
| Coronary artery disease, n (%) | 88 (13.8) | 66 (21) | 0.004 | 36 (14.8) | 43 (17.7) | 0.389 |
| Atrial fibrillation, n (%) | 40 (6.3) | 60 (19.1) | <0.001 | 23 (9.5) | 32 (13.2) | 0.198 |
| Body mass index, kg/m2 (IQR/mean ± SD) | 24.2 (22–26.1) | 23.4 (20–26.33) | 0.008 | 23.67 ± 0.21 | 23.93 ± 0.26 | 0.449 |
| Heart rate, bpm (IQR) | 76 (70–84) | 78 (70–87) | 0.117 | 76 (68–84) | 78 (70–88) | 0.012 |
| Systolic blood pressure, mmHg (IQR/mean ± SD) | 150 (137–166) | 155 (138–170) | 0.071 | 152.47 ± 1.43 | 155.38 ± 1.54 | 0.167 |
| Diastolic blood pressure, mmHg (IQR) | 90 (80–100) | 87 (79–96) | 0.006 | 88 (80–98) | 89 (80–98) | 0.851 |
| TOAST, n (%) | <0.001 | 0.909 | ||||
| Large artery atherosclerosis | 308 (48.2) | 141 (45) | 110 (45.3) | 113 (46.5) | ||
| Cardioembolism | 61 (9.5) | 63 (20.1) | 33 (13.6) | 39 (16) | ||
| Small artery occlusion | 217 (34) | 87 (27.8) | 81 (33.3) | 74 (20.5) | ||
| Other determined | 15 (2.3) | 4 (1.3) | 5 (2.1) | 4 (1.6) | ||
| Undetermined | 38 (5.9) | 18 (5.8) | 14 (5.8) | 13 (5.3) | ||
| Median NIHSS on admission | 5 (3–10) | 7 (3–13) | 0.001 | 6 (3–10) | 7 (3–13) | 0.123 |
| Onset-to-needle time, m (IQR) | 171 (130–212) | 170 (130–202) | 0.647 | 161 (120–203) | 171 (135–210) | 0.133 |
| Random blood sugar, mmol/L (IQR) | 6.65 (5.76–8.31) | 7.1 (5.9–8.95) | 0.004 | 6.76 (5.8–8.7) | 7.1 (5.84–9.3) | 0.122 |
| White blood cell, ⅹ10^9/L (IQR) | 7.51 (6.11–9.38) | 7.15 (5.75–8.83) | 0.010 | 7.11 (5.76–9.18) | 7.17 (5.76–9.2) | 0.969 |
| Hemoglobin, g/L (IQR) | 147 (136–157) | 130 (123–139) | <0.001 | 141 (129–150) | 132 (125–141) | <0.001 |
| Albumin, mg/L (IQR) | 39.5 (36–42.2) | 38.7 (35.5–42) | 0.049 | 39 (35.8–41.7) | 38.8 (36–42.1) | 0.907 |
| Blood urea nitrogen, mmol/L (IQR) | 5.5 (4.55–6.71) | 5.49 (4.6–6.53) | 0.655 | 5.4 (4.5–6.46) | 5.45 (4.6–6.59) | 0.538 |
| Creatinine, μmol/L (IQR) | 73 (63–86.4) | 59.65 (49–71) | <0.001 | 67 (58–79.3) | 60 (49–72) | <0.001 |
| Urate, μmol/L (IQR) | 312 (239–393) | 263 (200–336) | <0.001 | 291 (226–357) | 265 (201–341) | 0.015 |
| C-reactive protein, mg/L (IQR) | 1.6 (0.4–5) | 1.7 (0.5–5) | 0.482 | 1.7 (0.5–5) | 1.4 (0.49–5) | 0.638 |
| Cholesterol, mmol/L (IQR) | 4.39 (3.8–5.09) | 4.6 (3.99–5.27) | 0.002 | 4.44 (3.89–5.32) | 4.63 (4–5.24) | 0.105 |
| Triglyceride, mmol/L (IQR) | 1.4 (0.96–1.96) | 1.28 (0.87–1.85) | 0.048 | 1.24 (0.84–1.88) | 1.34 (0.89–1.88) | 0.479 |
| Low density lipoprotein, mmol/L (mean ± SD) | 2.68 ± 0.36 | 2.82 ± 0.52 | 0.029 | 2.72 ± 0.06 | 2.83 ± 0.06 | 0.191 |
| High density lipoprotein, mmol/L (IQR) | 1.09 (0.92–1.31) | 1.21 (1.04–1.40) | <0.001 | 1.12 (0.96–1.39) | 1.21 (1.04–1.42) | 0.003 |
| mRS≤1 at 3months, n (%) | 463 (72.5) | 206 (65.6) | 0.03 | 169 (69.5) | 154 (63.4) | 0.150 |
| Symptomatic intracranial hemorrhage | 19(3) | 5(1.6) | 0.201 | 9(3.7) | 5(2.1) | 0.278 |
AIS, acute ischemic stroke; IQR, interquartile range; TOAST, trial of org 10,172 in acute stroke treatment; NIHSS, national institute of health stroke scale; mRS, modified Rankin scale.
Fig. 2.
Distribution of modified Rankin scale (mRS) score.
Table 2 exhibited baseline and clinical characteristics according to outcome in male vs female patients. Among men, poor outcome was associated with older age, larger artery atherosclerosis (LAA) etiology, more history of previous drinking, and atrial fibrillation, higher initial NIHSS score, white blood cells (WBC), body mass index (BMI), serum hemoglobin, albumin and random blood glucose (RBG). Among women, poor outcome was associated with older age, previous stroke, more LAA etiology, atrial fibrillation, higher systolic blood pressure, heart rate, NIHSS on admission, RBG, serum creatinine, and blood urea nitrogen (p < 0.05).
Table 2.
Baseline characteristics and clinical characteristics after intravenous thrombolysis in AIS patients.
| Male (n = 639) | Female (n = 314) | |||||
|---|---|---|---|---|---|---|
| mRS 0–1 (n = 463) | mRS ≥2 (n = 176) | P value | mRS 0–1 (n = 206) | mRS ≥2 (n = 108) | P value | |
| Age, y (IQR) | 62 (53–70) | 65 (56–73) | 0.002 | 66 (56–77) | 74 (66–81) | <0.001 |
| Smoking history, n (%) | 211 (45.6) | 90 (51.1) | 0.208 | 11 (5.3) | 7 (6.5) | 0.679 |
| Drinking history, n (%) | 190 (41) | 52 (29.5) | 0.007 | 1 (0.5) | 1 (0.9) | 0.641 |
| Previous stroke, n (%) | 83 (17.9) | 35 (19.9) | 0.568 | 31 (15) | 26 (24.1) | 0.049 |
| Hypertension, n (%) | 245 (52.9) | 104 (59.1) | 0.161 | 130 (63.1) | 68 (63) | 0.980 |
| Diabetes mellitus, n (%) | 71 (15.3) | 27 (15.3) | 0.998 | 42 (20.4) | 29 (26.9) | 0.193 |
| Coronary artery disease, n (%) | 62 (13.4) | 26 (14.8) | 0.651 | 40 (19.4) | 26 (24.1) | 0.366 |
| Atrial fibrillation, n (%) | 22 (4.8) | 18 (10.2) | 0.011 | 30 (14.6) | 30 (27.8) | 0.005 |
| Body mass index, kg/m2 (IQR) | 24.2 (22.5–26.3) | 23.7 (21.5–25.95) | 0.018 | 23.4 (21–26.7) | 22.85 (20.3–25.85) | 0.151 |
| Heart rate, bpm (IQR) | 76 (70–84) | 76 (68–86) | 0.771 | 76 (69–85) | 80 (71–91) | 0.029 |
| Systolic blood pressure, mmHg (IQR) | 150 (136–166) | 153 (138–168) | 0.361 | 150 (136–167) | 160 (142–177) | 0.016 |
| Diastolic blood pressure, mmHg (IQR) | 90 (80–100) | 90 (80–99) | 0.906 | 85 (78–95) | 89 (80–98) | 0.098 |
| TOAST, n (%) | <0.001 | <0.001 | ||||
| Large artery atherosclerosis | 204 (44.1) | 104 (59.1) | 85 (41.5) | 56 (51.9) | ||
| Cardioembolism | 39 (8.4) | 22 (12.5) | 26 (12.7) | 37 (34.3) | ||
| Small artery occlusion | 180 (38.9) | 37 (21) | 75 (36.6) | 12 (11.1) | ||
| Other determined | 10 (2.2) | 5 (2.8) | 3 (1.5) | 1 (0.9) | ||
| Undetermined | 30 (6.5) | 8 (4.5) | 16 (7.8) | 2 (1.9) | ||
| Median NIHSS on admission | 5 (3–7) | 10 (5–15) | <0.001 | 5 (3–9) | 12 (9–17) | <0.001 |
| Onset-to-needle time, m (IQR) | 175 (130–213) | 165 (122–208) | 0.348 | 165 (125–200) | 174 (145–215) | 0.114 |
| Random blood sugar, mmol/L (IQR) | 6.55 (5.62–8.05) | 6.8 (6.0–8.9) | 0.029 | 6.9 (5.8–8.61) | 7.44 (6.2–10.1) | 0.026 |
| White blood cell, ⅹ10^9/L (IQR) | 7.47 (6.1–9.2) | 7.91 (6.45–9.99) | 0.057 | 7.07 (5.7–8.79) | 7.2 (5.96–9.40) | 0.220 |
| Hemoglobin, g/L (IQR) | 148 (137–158) | 144 (132–154) | 0.003 | 130 (123–139) | 131 (122–141) | 0.843 |
| Albumin, mg/L (IQR) | 40 (36.5–42.4) | 38.25 (35.33–41.96) | 0.006 | 38.85 (35.48–41.7) | 38.55 (35.68–42.2) | 0.887 |
| Blood urea nitrogen, mmol/L (IQR) | 5.48 (4.5–6.55) | 5.7 (4.68–7.06) | 0.057 | 5.27 (4.39–6.35) | 5.82 (4.95–7.1) | 0.002 |
| Creatinine, μmol/L (IQR) | 72.3 (63–85) | 74 (62.63–90.98) | 0.116 | 58 (48–69) | 63 (52–73) | 0.036 |
| Urate, μmol/L (IQR) | 319 (247.8–394) | 300.5 (227.5–385) | 0.349 | 264.8 (201.75–340.88) | 252.2 (191.68–334.7) | 0.354 |
AIS, acute ischemic stroke; IQR, interquartile range; TOAST, trial of org 10,172 in acute stroke treatment; NIHSS, national institute of health stroke scale; mRS, modified Rankin scale.
In Table 3, univariate analysis found that age, drinking, atrial fibrillation, LAA, small artery occlusion (SAO), initial NIHSS score, WBC, hemoglobin, and creatinine were significant predictors of poor outcome in male patients, while age, LAA, SAO, atrial fibrillation, heart rate, systolic blood pressure, initial NIHSS score and RBG in female patients. Multivariate analysis showed that initial NIHSS score (OR 0.877; 95 % CI 0.847–0.909, p < 0.001) and serum creatinine (OR 0.993; 95 % CI 0.986–1.000, p = 0 0.043) were independent risk factors for poor outcome in male patients (Table 4), while initial NIHSS score (OR 0.879; 95 % CI 0.839–0.920, p < 0.001), age (OR 0.970; 95 % CI 0.946–0.995, p = 0.017), systolic blood pressure (OR 0.984; 95 % CI 0.972–0.996, p = 0.007) and SAO (OR 2.718; 95 % CI 1.065–6.936, p = 0.036) for poor outcome in female patients (Table 5).
Table 3.
Univariate logistic regression analysis of the 90-day outcome after intravenous thrombolysis in AIS patients.
| Parameter | mRS≤1 at 3months |
|||||
|---|---|---|---|---|---|---|
| Male (n = 639) |
Female (n = 314) |
|||||
| OR | 95%CI | P value | OR | 95%CI | P value | |
| Age | 0.976 | (0.961–0.991) | 0.001 | 0.957 | (0.937–0.977) | <0.001 |
| Smoking history | 1.250 | (0.883–1.769) | 0.208 | 0.814 | (0.306–2.163) | 0.680 |
| Drinking history | 0.603 | (0.415–0.875) | 0.008 | 1.916 | (0.119–30.933) | 0.647 |
| Previous stroke | 1.136 | (0.732–1.764) | 0.569 | 1.790 | (0.999–3.208) | 0.051 |
| Hypertension | 1.285 | (0.904–1.827) | 0.162 | 0.994 | (0.614–1.610) | 0.980 |
| Diabetes mellitus | 1.000 | (0.618–1.619) | 0.998 | 1.433 | (0.832–2.470) | 0.195 |
| Coronary artery disease | 1.121 | (0.683–1.839) | 0.651 | 1.316 | (0.752 2.304) | 0.337 |
| Atrial fibrillation | 2.284 | (1.194–4.370) | 0.013 | 2.256 | (1.274–3.998) | 0.005 |
| Body mass index | 1.060 | (1.007–1.115) | 0.025 | 1.050 | (0.990–1.113) | 0.106 |
| Heart rate | 0.996 | (0.984–1.009) | 0.576 | 0.984 | (0.969–0.999) | 0.036 |
| Systolic blood pressure | 0.997 | (0.989–1.005) | 0.416 | 0.990 | (0.980–1.000) | 0.048 |
| Diastolic blood pressure | 1.003 | (0.990–1.016) | 0.702 | 0.989 | (0.973–1.006) | 0.210 |
| Large artery atherosclerosis | 0.545 | (0.383–0.775) | 0.001 | 0.658 | (0.412–1.051) | 0.080 |
| Small artery occlusion | 2.389 | (1.589–3.593) | <0.001 | 4.615 | (2.376–8.966) | <0.001 |
| NIHSS on admission | 0.862 | (0.833–0.893) | <0.001 | 0.860 | (0.823–0.897) | <0.001 |
| Onset-to-needle time | 1.001 | (0.998–1.004) | 0.420 | 0.999 | (0.996–1.002) | 0.456 |
| Random blood sugar | 0.961 | (0.910–1.015) | 0.153 | 0.932 | (0.875–0.992) | 0.027 |
| White blood cell | 0.944 | (0.889–1.002) | 0.056 | 0.942 | (0.864–1.028) | 0.182 |
| Hemoglobin | 1.011 | (1.003–1.020) | 0.012 | 1.001 | (0.987–1.016) | 0.896 |
| Albumin | 1.005 | (0.992–1.018) | 0.421 | 0.997 | (0.982–1.012) | 0.657 |
| Blood urea nitrogen | 0.942 | (0.871–1.019) | 0.139 | 0.977 | (0.913–1.044) | 0.487 |
| Creatinine | 0.990 | (0.984–0.997) | 0.004 | 0.993 | (0.982–1.005) | 0.241 |
| Urate | 1.000 | (0.999–1.002) | 0.524 | 1.001 | (0.999–1.003) | 0.226 |
AIS, acute ischemic stroke; NIHSS, national institute of health stroke scale; mRS, modified Rankin scale; OR, odds ratio; CI, confidence interval.
Table 4.
Multivariate logistic regression analysis of the 90-day outcome after intravenous thrombolysis in male patients.
| Parameter | mRS≤1 at 3months |
||
|---|---|---|---|
| OR | 95%CI | P value | |
| Age | 0.994 | (0.976–1.012) | 0.500 |
| Drinking history | 0.742 | (0.419–1.123) | 0.158 |
| Atrial fibrillation | 1.495 | (0.672–3.325) | 0.324 |
| Body mass index | 1.048 | (0.989–1.110) | 0.112 |
| Large artery atherosclerosis | 0.781 | (0.446–1.368) | 0.387 |
| Small artery occlusion | 1.384 | (0.740–2.592) | 0.309 |
| NIHSS on admission | 0.877 | (0.847–0.909) | <0.001 |
| White blood cell | 0.953 | (0.890–1.020) | 0.167 |
| Hemoglobin | 1.007 | (0.997–1.018) | 0.157 |
| Creatinine | 0.993 | (0.986–1.000) | 0.043 |
NIHSS, national institute of health stroke scale; mRS, modified Rankin scale; OR, odds ratio; CI, confidence interval.
Table 5.
Multivariate logistic regression analysis of the 90-day outcome after intravenous thrombolysis in female patients.
| Parameter | mRS≤1 at 3months |
||
|---|---|---|---|
| OR | 95%CI | P value | |
| Age | 0.970 | (0.946–0.995) | 0.017 |
| Previous stroke | 1.682 | (0.842–3.360) | 0.141 |
| Atrial fibrillation | 1.015 | (0.460–2.240) | 0.970 |
| Systolic blood pressure | 0.984 | (0.972–0.996) | 0.007 |
| Heart rate | 0.993 | (0.976–1.012) | 0.481 |
| Large artery atherosclerosis | 0.779 | (0.380–1.600) | 0.497 |
| Small artery occlusion | 2.718 | (1.065–6.936) | 0.036 |
| NIHSS on admission | 0.879 | (0.839–0.920) | <0.001 |
| Random blood sugar | 0.966 | (0.897–1.040) | 0.362 |
NIHSS, national institute of health stroke scale; mRS, modified Rankin scale; OR, odds ratio; CI, confidence interval.
As the sensitivity analysis, we further analyzed the association of gender with outcome of thrombolysed stroke in patients with 18–80 years old. Similar results were observed (sTable 1–5).
4. Discussion
Previous studies have investigated the relationship between gender and functional outcome after IVT, but the results are conflicting. For example, in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR), gender was not found to show influence on the functional outcome after IVT, though there was a higher bleeding risk among men [5]. A pooled analysis of randomized IVT trials also found no appreciable effect of gender on outcome after IVT [12]. However, in the study of IVT registries of 12 European tertiary hospitals, women more often had poor functional outcome compared with men [5]. Our study found no effect of gender on outcome in AIS patients who received intravenous thrombolysis. Collectively, these conflicting results suggest that the association of gender with outcome of AIS was complex and warrant further investigation [13]. Furthermore, we found a difference in dependent risk factors predicting poor outcome in male vs female patients.
A lot of studies have investigated the risk factors for predicting outcomes after IVT in AIS patients [14,15]. This is the first to investigate whether there is a difference in dependent risk factors predicting outcome in male vs female patients. We unexpectedly found that serum creatinine was a dependent risk factor of predicting outcome in only male patients who received IVT. The reason for the difference remains elusive. Creatinine is one of components contributing to the total antioxidant capacity [16]. We have not identified a study on the effect of creatinine on gender-related prognosis of acute ischemic stroke. However, the impact of creatinine has been studied in patients with traumatic brain injury and sex-related differences have been observed, in accordance with what we have discovered [17]. One possible explanation may be due to the mild effect of oxidative stress for women with brain injury, which need further exploration.
Unlike male patients, age, systolic blood pressure, and small vessel occlusion were found to be independently associated with only female patients. One possible explanation is a difference in endogenous fibrinolysis because of differences in gender hormones between men and women. Estrogen has an indirect influence on the controlling of the fibrinolytic system, as well as a direct neuroprotective activity [[18], [19], [20], [21]]. In humans, studies showed that the sooner the hormone replacement therapy was started after menopause or at younger age, the lower was the incidence of vascular events, suggesting a neuroprotective effect from higher estrogen levels [22]. Thus, with the increase of age, the protective effect of estrogen in women gradually disappears, so it is more likely to affect the prognosis in female patients. More basic studies have also provided evidence that age affects gender not only in hormonal changes, but also in systemic inflammation, metabolism, and age-related gene expression [23]. These may further explain more cardiovascular involvement in high blood pressure, worse arteriosclerosis, and larger impairment of automatic regulation of cerebral blood flow in women, compared with men [24]. Therefore, this may explain the association of systolic blood pressure and small artery occlusion with the outcome of female stroke patients. Collectively, the gender differences in predicting factors for functional outcomes after intravenous thrombolysis warrant to be confirmed in prospective, big sample, clinical trials.
Our study has some limitations. First of all, this is retrospective study, which is prone to bias, although our data were collected based on a prospective cohort. Second, there is some missing clinical data and laboratory indicators, which would produce selection bias. Third, this finding would be of limited applicability to younger populations given the included patients with median age over 60 years old in this study. Finally, the sample size of male and female patients was significantly different, which could have influenced the conclusions.
5. Conclusions
In this study, gender was not found to have effect on outcome in AIS patients who received intravenous thrombolysis. Furthermore, we found a difference in dependent risk factors predicting outcome in male vs female patients.
Statement of ethics
This study was approved by the Institutional Review Board of General Hospital of Northern Theater Command (IRB: k2016-11).
Funding sources
The study was funded by grants from National Key R&D Program of China (2017YFC1308200), and the Project on Research and Application of Effective Intervention Techniques for Chinese Stroke Guidelines from the National Health and Family Planning Commission in China (GN-2016R0008).
Data availability statement
The data underlying this article will be shared upon reasonable request to the corresponding author.
CRediT authorship contribution statement
Tong Chen: Writing – original draft, Formal analysis, Data curation. Yu Cui: Formal analysis, Data curation. Hui-Sheng Chen: Writing – review & editing, Supervision, Funding acquisition, Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Associated Data
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Data Availability Statement
The data underlying this article will be shared upon reasonable request to the corresponding author.