Abstract
Introduction:
Sex-specific differences in ischemic stroke outcomes are prevalent. We sought to investigate sex differences in the determinants of reperfusion and functional outcomes after endovascular thrombectomy (EVT) for emergent large-vessel occlusion ischemic stroke (ELVO).
Methods:
Patients presenting to a single referral center with an anterior circulation ELVO that underwent EVT from 2011 to 2019 were included in this retrospective analysis. Sex differences in history, presentation, adequate reperfusion (TICI 2b-3), and 90-day good outcome (delta modified Rankin Scale [mRS]≤2 from pre-stroke) were examined. Multivariable logistic regression analyses were performed to assess sex-specific associations with outcomes.
Results:
381 consecutive ELVO patients were identified. Women (N=193) were older (75 vs 64, p<0.0001), had more pre-stroke disability (17% vs 9%, p=0.032), more atrial fibrillation (41% vs 30%, p=0.033), but less carotid atherosclerosis (8% vs 16%, p=0.027). Rates of TICI 2b-3 and good outcome were similar between sexes. Carotid atherosclerosis (OR=0.315, 95%CI=0.130,0.762) and dissection (OR=0.124, 95%CI= 0.027,0.569) independently decreased the odds of TICI 2b-3 among men but not women. Older age, more severe stroke, and not achieving TICI 2b-3 independently decreased the odds of good outcome among both sexes, while prior stroke (OR=0.258, 95%CI=0.083,0.797) and hemorrhagic transformation (OR=0.111, 0.021,0.592) were determinants exclusive to men.
Conclusion:
In a real-world analysis of ELVO stroke patients treated with EVT, we found that despite advanced age and more pre-stroke disability, women have comparable reperfusion rates and functional outcomes compared to men. Sex-specific determinants of reperfusion and functional outcome were identified that require further study.
Keywords: ischemic stroke, sex differences, large vessel occlusion, endovascular thrombectomy
Introduction:
Endovascular thrombectomy (EVT) has revolutionized the care of patients with acute ischemic stroke secondary to anterior circulation emergent large vessel occlusion (ELVO).[1] While the benefit of EVT has been proven in clinical trial patient populations, understanding real-world outcomes and identifying potential disparities is crucial to optimizing this treatment for all patient subsets.[2,3] Given rigid randomized trial inclusion criteria, analyses of routine clinical practice are essential for advancing disparities research.[4] Sex-specific differences in stroke presentation and outcomes have been reported, with trends toward women having more severe strokes with higher mortality and worse functional outcome.[5–7] Disparities in stroke treatments have also been reported, with women having a lower likelihood of receiving treatments at a stroke unit[8] and worse outcomes following thrombolytic treatment.[9] Understanding the factors that contribute to sex differences in stroke care represents an important area of investigation.
Regarding sex-specific differences in EVT outcomes, however, the results are mixed. Analyses of several of the EVT clinical trial databases have reported women have worse outcomes compared to men, while other studies have shown no sex-specific differences.[10,11] A Japanese registry-based study of EVT selection and outcomes demonstrated that women were less likely to receive EVT and more likely to have worse outcomes.[12] Because of these mixed results from the EVT trials, an investigation in a real-world setting holds potential to advance our understanding of sex-specific differences. We conducted a retrospective, observational study to understand sex differences in stroke presentations for EVT and to illuminate specific determinants of EVT reperfusion rates and 90-day clinical outcomes.
Patients and Methods:
This study was approved by the local institutional review board. The data that support the findings of this study will be made available from the corresponding author upon reasonable request and pending approval of local institutional review board. Informed consent was waived based on minimal patient risk and practical inability to perform the study without the waiver.
We retrospectively identified acute anterior circulation ELVO stroke patients who underwent EVT from a prospectively maintained database at a single referral center from January 2011 to September 2019 to include a wide breadth of patients as protocols changed in response to EVT evidence over the last decade.[13–15] This database includes demographics, medical history, presentations, treatments, and outcomes for consecutive patients. Admission NIH Stroke Scale (NIHSS) score was determined as described.[16] Cervical internal carotid artery (ICA) disease was defined as severe stenosis (>70%) by NASCET criteria or occlusion.[17] Cervical ICA disease could be related to atherosclerosis or dissection, defined by the presence or absence of calcium on CT and vessel appearance on angiography.[18] Alteplase treatment decisions were guideline-based at the discretion of a vascular neurologist.[19] EVT treatment decisions were at the discretion of a team comprised of vascular neurologists and neurointerventionalists.
Thrombolysis in Cerebral Infarction (TICI) scores were determined by a neurointerventionalist using the modified scale: 2a partial filling <50%, 2b partial filling ≥50%, 3 complete perfusion.[20] Adequate reperfusion was considered TICI 2b-3. Intracerebral hemorrhage (ICH) was defined as any symptomatic or asymptomatic PH1 or PH2 by ECASS criteria during the hospitalization.[21] Modified Rankin Scale (mRS) scores were determined as described, with 0 representing no symptoms and 6 representing death.[22] Pre-stroke mRS was prospectively recorded for 83% of patients and the remaining by chart review blinded to outcome. 90-day mRS score was obtained by telephone call and available for 89% of patients. Pre-stroke disability was defined as mRS ≥2 as described by others (no patients with mRS 5 were treated with EVT).[23,24] Good outcome was defined as a ≤2 point change in 90-day mRS from pre-stroke mRS score; this outcome was chosen given our inclusion of patients with pre-stroke disability.[23] Functional independence, defined as 90-day mRS ≤2, was also included as an outcome in analyses of a cohort excluding patients with pre-stroke disability.
Median values with interquartile range were reported for continuous variables. Percent and count were reported for categorical variables. Differences were assessed using nonparametric Wilcoxon rank-sum for continuous variables and Fisher’s Exact tests for categorical variables. Logistic regression analyses were performed to assess associations with adequate reperfusion, good outcome, and functional independence. Variables with pre-specified significance of p<0.10 in univariable analysis were subsequently included in multivariable models. Two-tailed p-values <0.05 were interpreted as statistically significant. Analyses were performed with SPSS version 23.0 (IBM Corp).
Results:
381 consecutive patients were identified, including 193 women and 188 men. Women were older with median age 75 years (IQR 62–82) compared to 64 (IQR 56–75, p<0.0001). Women also had more pre-stroke disability (17% vs 9%, p=0.032). Atrial fibrillation was more common in women (41% vs 30%, p=0.033). In contrast, cervical ICA atherosclerosis (8% vs 16%, p=0.027), coronary artery disease (18% vs 27%, p=0.038), and smoking (15% vs 23%, p=0.036) were all less common in women. There was no difference comparing sexes in the proportion treated before the 2015 EVT trials. There were no other differences in demographics, medical history, or risk factors (Table 1).
Table 1.
Demographics, medical history, clinical presentations, and outcomes of men and women presenting with acute large vessel occlusion stroke and treated with endovascular thrombectomy.
| Men (188) | Women (193) | ||||
|---|---|---|---|---|---|
| Median/Count | IQR/Percent | Median/Count | IQR/Percent | P | |
| Age, Years | 64 | 56,75 | 75 | 62,82 | <0.0001 |
| Pre-stroke mRS 2–4 | 17 | 9% | 32 | 17% | 0.032 |
| Hypertension | 122 | 65% | 134 | 69% | 0.383 |
| Diabetes | 40 | 21% | 39 | 20% | 0.802 |
| Atrial Fibrillation | 57 | 30% | 79 | 41% | 0.033 |
| Coronary Disease | 51 | 27% | 35 | 18% | 0.038 |
| Stroke/TIA | 33 | 18% | 35 | 18% | 0.894 |
| Smoking | 44 | 23% | 28 | 15% | 0.036 |
| Cervical ICA Atherosclerosis | 30 | 16% | 16 | 8% | 0.027 |
| Cervical ICA Dissection | 8 | 4% | 8 | 4% | 1.000 |
| ICA Terminus Occlusion | 34 | 18% | 36 | 19% | 0.896 |
| M1 Occlusion | 126 | 67% | 136 | 71% | 0.508 |
| M2 Occlusion | 28 | 15% | 20 | 10% | 0.217 |
| Left Side Infarct | 103 | 59% | 99 | 54% | 0.456 |
| NIHSS | 17 | 13,20 | 16.5 | 13,20 | 0.485 |
| Alteplase treatment | 110 | 59% | 103 | 53% | 0.353 |
| LKW-Alteplase, Min | 116 | 86,165 | 112 | 85,155 | 0.735 |
| LKW-Groin, Min | 283 | 190,378 | 270 | 180,368 | 0.450 |
| Groin-Recanalization, Min | 39 | 20,66 | 50 | 27,81 | 0.095 |
| TICI 2b-3 | 147 | 78% | 151 | 78% | 1.000 |
| TICI 3 | 40 | 21% | 41 | 21% | 1.000 |
| Treated Before 2015 Trials | 65 | 35% | 74 | 38% | 0.458 |
| ICH | 15 | 8% | 9 | 5% | 0.210 |
| 90-Day mRS ≤2 (N=338) | 73 | 44% | 66 | 39% | 0.377 |
| 90-Day Good Outcomes (N=338) | 84 | 50% | 83 | 49% | 0.828 |
| 90-Day Mortality (N=338) | 30 | 18% | 46 | 27% | 0.052 |
Abbreviations: mRS modified Rankin Scale, TIA transient ischemic attack, ICA internal carotid artery, M1 first segment of middle cerebral artery, M2 second segment, NIHSS NIH Stroke Scale, LKW last known well, TICI Thrombolysis in Cerebral Infarction, ICH intracerebral hemorrhage, IQR interquartile range.
Clinical presentations, treatments, and outcomes were similar comparing sexes. Median NIHSS was 17 (IQR 13–20) for both sexes. 53% of women and 59% of men were treated with IV alteplase (p=0.353). Median last known well (LKW)-to-alteplase (112 vs 116 min, p=0.735) and LKW-to-groin (270 vs 283 min, p=0.450) times were also similar between sexes. Women had a non-significantly longer groin-to-recanalization time (50 vs 39 min, p=0.095). Both sexes achieved adequate reperfusion in 78%. ICH occurred in 5% of women and 8% of men (p=0.210). Rates of both 90-day functional independence (39% vs 44%, p=0.377) and 90-day good outcomes (49% vs 50%, p=0.828) were similar between sexes, however there was a strong trend for women to have higher mortality (27% vs 18%, p=0.052) (Table 1).
We subsequently explored sex-specific determinants of adequate reperfusion. Among women, smoking history and cervical ICA atherosclerosis decreased the odds of adequate reperfusion. When both were entered in a multivariable model, neither reached statistical significance. Among men, cervical ICA atherosclerosis, cervical ICA dissection, ICA terminus occlusion location, and longer LKW-to-groin time decreased the odds of adequate reperfusion. When all were entered in a multivariable model, cervical ICA atherosclerosis (OR 0.315, 95%CI 0.130,0.762) and cervical ICA dissection (OR 0.124, 95%CI 0.027,0.569) were significant determinants of inadequate reperfusion (Table 2).
Table 2.
Associations with adequate reperfusion (Thrombolysis in Cerebral Infarction, TICI 2b-3) among men and women presenting with large vessel occlusion stroke and treated with endovascular thrombectomy.
| Univariate, Men | Multivariate, Men | |||
|---|---|---|---|---|
| OR (95% CI) | P | OR (95% CI) | P | |
| Age, Years | 1.012 (0.988,1.036) | 0.342 | ||
| Pre-stroke mRS, Ordinal | 0.788 (0.533,1.165) | 0.232 | ||
| Hypertension | 0.947 (0.457,1.963) | 0.884 | ||
| Diabetes | 1.406 (0.571,3.462) | 0.459 | ||
| Atrial Fibrillation | 0.920 (0.436,1.941) | 0.827 | ||
| Coronary Disease | 1.199 (0.539,2.665) | 0.656 | ||
| Stroke/TIA | 0.575 (0.248,1.332) | 0.197 | ||
| Smoking | 1.111 (0.484,2.551) | 0.804 | ||
| Cervical ICA Atherosclerosis | 0.337 (0.146,0.777) | 0.011 | 0.315 (0.130,0.762) | 0.010 |
| Cervical ICA Dissection | 0.150 (0.034,0.657) | 0.012 | 0.124 (0.027,0.569) | 0.007 |
| ICA Terminus Occlusion | 0.425 (0.189,0.957) | 0.039 | 0.494 (0.205,1.188) | 0.115 |
| M1 Occlusion | 1.606 (0.787,3.277) | 0.193 | ||
| M2 Occlusion | 1.335 (0.474,3.763) | 0.584 | ||
| Left Side Infarct | 0.851 (0.411,1.764) | 0.665 | ||
| NIHSS | 1.001 (0.936,1.071) | 0.968 | ||
| Alteplase | 1.288 (0.642,2.586) | 0.476 | ||
| LKW-Groin, Min | 0.999 (0.998,1.000) | 0.098 | 0.999 (0.998,1.000) | 0.138 |
| Univariate, Women | Multivariate, Women | |||
| OR (95% CI) | P | OR (95% CI) | P | |
| Age, Years | 0.995 (0.973,1.017) | 0.641 | ||
| Pre-stroke mRS, Ordinal | 1.006 (0.722,1.402) | 0.973 | ||
| Hypertension | 0.761 (0.353,1.642) | 0.487 | ||
| Diabetes | 1.678 (0.651,4.324) | 0.284 | ||
| Atrial Fibrillation | 1.512 (0.737,3.099) | 0.259 | ||
| Coronary Disease | 0.925 (0.386,2.221) | 0.862 | ||
| Stroke/TIA | 1.835 (0.664,5.067) | 0.242 | ||
| Smoking | 0.433 (0.183,1.028) | 0.058 | 0.484 (0.200,1.173) | 0.108 |
| Cervical ICA Atherosclerosis | 0.317 (0.110,0.910) | 0.033 | 0.357 (0.122,1.048) | 0.061 |
| Cervical ICA Dissection | 0.445 (0.102,1.945) | 0.282 | ||
| ICA Terminus Occlusion | 0.798 (0.342,1.861) | 0.602 | ||
| M1 Occlusion | 1.651 (0.805,3.387) | 0.171 | ||
| M2 Occlusion | 0.471 (0.175,1.269) | 0.136 | ||
| Left Side Infarct | 1.094 (0.548,2.181) | 0.799 | ||
| NIHSS | 1.008 (0.938,1.084) | 0.819 | ||
| Alteplase | 1.717 (0.861,3.425) | 0.125 | ||
| LKW-Groin, Min | 0.999 (0.998,1.000) | 0.224 | ||
Abbreviations: mRS modified Rankin Scale, TIA transient ischemic attack, ICA internal carotid artery, M1 first segment of middle cerebral artery, M2 second segment, NIHSS NIH Stroke Scale, LKW last known well, OR odds ratio.
Sex-specific determinants of 90-day good outcome were also investigated. In women, the odds of 90-day good outcome were increased by alteplase administration and adequate reperfusion after EVT, but reduced by advanced age, higher NIHSS, longer groin-to-recanalization time, and ICH. In a multivariable model, adequate reperfusion (OR 6.465, 95%CI 1.717,24.35) increased the odds of good outcomes, while advanced age (OR 0.968, 95%CI 0.942,0.995) and greater NIHSS (OR 0.884, 95%CI 0.809,0.966) reduced them. The odds of 90-day good outcome in men were increased by adequate reperfusion, but reduced by advanced age, coronary artery disease, stroke/TIA history, cervical ICA atherosclerosis, left-sided infarcts, higher NIHSS, longer LKW-to-groin time, longer groin-to-recanalization time, and ICH. In a multivariable model, adequate reperfusion (OR 4.920, 95%CI 1.204,20.10) increased the odds of good outcome, while advanced age (OR 0.968, 95%CI 0.938,0.998), history of prior stroke/TIA (OR 0.258, 95%CI 0.083,0.797), higher NIHSS (OR 0.912, 95%CI 0.831,1.000), and ICH (OR 0.111, 95%CI 0.021,0.592) reduced the odds of 90-day good outcome in men (Table 3). Importantly, analyses excluding those with pre-stroke disability were performed to assess associations with absolute 90-day functional independence, which showed similar results (Table 4); pre-stroke disability was not found to independently decrease the odds of good outcome or adequate reperfusion.
Table 3.
Associations with 90-day good outcomes (change in modified Rankin Scale score, Δ mRS ≤2) among men and women presenting with large vessel occlusion stroke and treated with endovascular thrombectomy.
| Univariate, Men | Multivariate, Men | |||
|---|---|---|---|---|
| OR (95% CI) | P | OR (95% CI) | P | |
| Age, Years | 0.981 (0.960,1.002) | 0.069 | 0.968 (0.938,0.998) | 0.035 |
| Pre-stroke mRS, Ordinal | 1.089 (0.745,1.593) | 0.660 | ||
| Hypertension | 0.865 (0.453,1.651) | 0.660 | ||
| Diabetes | 0.749 (0.362,1.549) | 0.436 | ||
| Atrial Fibrillation | 0.881 (0.460,1.685) | 0.701 | ||
| Coronary Disease | 0.552 (0.282,1.082) | 0.084 | 0.814 (0.330,2.003) | 0.653 |
| Stroke/TIA | 0.275 (0.115,0.657) | 0.004 | 0.258 (0.083,0.797) | 0.019 |
| Smoking | 0.859 (0.416,1.773) | 0.681 | ||
| Cervical ICA Atherosclerosis | 0.409 (0.166,1.008) | 0.052 | 0.863 (0.240,3.096) | 0.821 |
| Cervical ICA Dissection | 0.578 (0.134,2.500) | 0.463 | ||
| Left Side Infarct | 0.565 (0.297,1.073) | 0.081 | 0.832 (0.357,1.936) | 0.669 |
| NIHSS | 0.915 (0.856,0.978) | 0.009 | 0.912 (0.831,1.000) | 0.049 |
| Alteplase | 1.312 (0.703,2.449) | 0.393 | ||
| LKW-Groin, Min | 0.998 (0.997,1.000) | 0.017 | 0.999 (0.997,1.000) | 0.133 |
| Groin-Recanalization, Min | 0.993 (0.985,1.001) | 0.071 | 0.998 (0.988,1.009) | 0.757 |
| TICI 2b-3 | 7.750 (3.021,19.88) | <0.0001 | 4.920 (1.204,20.10) | 0.026 |
| ICH | 0.131 (0.029,0.602) | 0.009 | 0.111 (0.021,0.592) | 0.010 |
| Univariate, Women | Multivariate, Women | |||
| OR (95% CI) | P | OR (95% CI) | P | |
| Age, Years | 0.963 (0.941,0.984) | 0.001 | 0.968 (0.942,0.995) | 0.021 |
| Pre-stroke mRS, Ordinal | 1.111 (0.824,1.499) | 0.488 | ||
| Hypertension | 0.655 (0.337,1.271) | 0.211 | ||
| Diabetes | 0.789 (0.364,1.710) | 0.548 | ||
| Atrial Fibrillation | 0.719 (0.391,1.322) | 0.289 | ||
| Coronary Disease | 0.801 (0.376,1.705) | 0.565 | ||
| Stroke/TIA | 1.348 (0.629,2.889) | 0.443 | ||
| Smoking | 1.071 (0.465,2.469) | 0.871 | ||
| Cervical ICA Atherosclerosis | 0.608 (0.211,1.754) | 0.357 | ||
| Cervical ICA Dissection | 0.519 (0.092,2.909) | 0.455 | ||
| Left Side Infarct | 1.257 (0.679,2.329) | 0.467 | ||
| NIHSS | 0.908 (0.848,0.971) | 0.005 | 0.884 (0.809,0.966) | 0.006 |
| Alteplase | 1.811 (0.987,3.322) | 0.055 | 1.651 (0.772,3.529) | 0.196 |
| LKW-Groin, Min | 1.000 (0.999,1.001) | 0.733 | ||
| Groin-Recanalization, Min | 0.987 (0.979,0.996) | 0.004 | 0.993 (0.983,1.003) | 0.174 |
| TICI 2b-3 | 5.357 (2.293,12.52) | <0.0001 | 6.465 (1.717,24.35) | 0.006 |
| ICH | 0.122 (0.015,0.997) | 0.050 | 0.168 (0.014,2.044) | 0.162 |
Abbreviations: TIA transient ischemic attack, ICA internal carotid artery, NIHSS NIH Stroke Scale, LKW last known well, TICI Thrombolysis in Cerebral Infarction, ICH intracerebral hemorrhage, OR odds ratio.
Table 4.
Associations with 90-day functional independence (modified Rankin Scale score, mRS ≤2) among men and women presenting with large vessel occlusion stroke and treated with endovascular thrombectomy, excluding those with pre-stroke disability (pre-stroke mRS ≥2).
| Univariate, Men | Multivariate, Men | |||
|---|---|---|---|---|
| OR (95% CI) | P | OR (95% CI) | P | |
| Age, Years | 0.977 (0.954,0.999) | 0.043 | 0.967 (0.938,0.996) | 0.027 |
| Pre-stroke mRS, Ordinal | 0.640 (0.294,1.397) | 0.263 | ||
| Hypertension | 0.686 (0.347,1.359) | 0.280 | ||
| Diabetes | 0.462 (0.207,1.033) | 0.060 | 0.441 (0.156,1.248) | 0.123 |
| Atrial Fibrillation | 0.703 (0.353,1.400) | 0.316 | ||
| Coronary Disease | 0.507 (0.244,1.053) | 0.069 | 1.028 (0.374,2.827) | 0.957 |
| Stroke/TIA | 0.160 (0.052,0.491) | 0.001 | 0.235 (0.057,0.974) | 0.046 |
| Smoking | 0.702 (0.326,1.512) | 0.366 | ||
| Cervical ICA Atherosclerosis | 0.412 (0.160,1.060) | 0.066 | 0.887 (0.227,3.459) | 0.863 |
| Cervical ICA Dissection | 0.671 (0.154,2.912) | 0.594 | ||
| Left Side Infarct | 0.569 (0.291,1.116) | 0.101 | ||
| NIHSS | 0.898 (0.835,0.965) | 0.004 | 0.850 (0.766,0.942) | 0.002 |
| Alteplase | 1.812 (0.924,3.551) | 0.084 | 1.454 (0.542,3.902) | 0.457 |
| LKW-Groin, Min | 0.997 (0.996,0.999) | 0.005 | 0.997 (0.995,1.000) | 0.025 |
| Groin-Recanalization, Min | 0.993 (0.985,1.002) | 0.120 | ||
| TICI 2b-3 | 13.33 (3.854,46.13) | <0.0001 | 24.78 (5.433, 113.0) | <0.0001 |
| ICH | 0.167 (0.036,0.773) | 0.022 | 0.142 (0.024,0.853) | 0.033 |
| Univariate, Women | Multivariate, Women | |||
| Age, Years | 0.951 (0.927,0.975) | <0.0001 | 0.955 (0.919,0.993) | 0.020 |
| Pre-stroke mRS, Ordinal | 0.392 (0.173,0.888) | 0.025 | 0.389 (0.124,1.218) | 0.105 |
| Hypertension | 0.477 (0.234,0.976) | 0.043 | 0.943 (0.311,2.858) | 0.917 |
| Diabetes | 0.527 (0.212,1.306) | 0.167 | ||
| Atrial Fibrillation | 0.606 (0.308,1.194) | 0.148 | ||
| Coronary Disease | 0.312 (0.109,0.894) | 0.030 | 0.445 (0.110,1.807) | 0.258 |
| Stroke/TIA | 0.934 (0.384,2.270) | 0.880 | ||
| Smoking | 1.241 (0.491,3.140) | 0.648 | ||
| Cervical ICA Atherosclerosis | 0.991 (0.325,3.019) | 0.987 | ||
| Cervical ICA Dissection | 0.650 (0.115,3.668) | 0.626 | ||
| Left Side Infarct | 1.133 (0.578,2.221) | 0.717 | ||
| NIHSS | 0.893 (0.828,0.963) | 0.003 | 0.817 (0.729,0.914) | <0.0001 |
| Alteplase | 1.963 (1.001,3.851) | 0.050 | 1.398 (0.539,3.629) | 0.491 |
| LKW-Groin, Min | 1.000 (0.999,1.002) | 0.677 | ||
| Groin-Recanalization, Min | 0.988 (0.978,0.997) | 0.011 | 0.992 (0.981,1.004) | 0.196 |
| TICI 2b-3 | 8.814 (2.913,26.67) | <0.0001 | 21.71 (3.448,136.7) | 0.001 |
| ICH | 0.176 (0.021,1.467) | 0.108 | ||
Abbreviations: TIA transient ischemic attack, ICA internal carotid artery, NIHSS NIH Stroke Scale, LKW last known well, TICI Thrombolysis in Cerebral Infarction, ICH intracerebral hemorrhage, OR odds ratio.
Discussion:
Among our cohort of 381 patients who underwent EVT, we found no differences in reperfusion rates or 90-day good outcome between men and women, despite women being significantly older with more pre-stroke disability. However, sex-specific determinants of EVT outcomes were identified. In men but not women, cervical ICA atherosclerosis and dissection significantly decreased the odds of adequate reperfusion. In both men and women, age, NIHSS, and adequate reperfusion were independent determinants of good outcome, however, prior stroke/TIA and ICH decreased the odds of good outcome in men only.
While determinants of adequate reperfusion have been described after EVT, no prior study has separately examined determinants for men and women. Cervical ICA atherosclerosis and dissection independently decreased the odds of adequate reperfusion in men but not women. This may be related in part to increased prevalence and severity of cervical ICA atherosclerosis in men.[25] Cervical ICA stenosis has been shown to be independently associated with failure of reperfusion.[26] Additional factors reported to be associated with inadequate reperfusion among combined sexes include technical obstacles and off-hour treatment,[27,28] however these variables were unavailable in our dataset. Increased time to treatment has also been associated with decreased adequate reperfusion,[27] however we did not observe this association for either sex in our analyses.
Similarly, no prior studies have examined sex-specific determinants of 90-day outcomes. Recovery after stroke is difficult to predict, and understanding determinants of outcomes is key.[29,30] Older age, higher NIHSS, and not achieving TICI 2b-3 independently decreased the odds of good outcome among both sexes, while prior stroke and ICH, both PH1 and PH2, were determinants exclusive to men. These findings concord with prior combined-sex reports demonstrating strong associations between 90-day outcome and age, NIHSS, and adequate reperfusion.[31,32] Other factors associated with 90-day outcomes in combined-sex reports but unavailable in our study, include core volume and collateral grade.[33,34]
We also observed several notable differences in demographics and clinical presentations between sexes. As stated, women were older (75 vs 64 years), had more pre-stroke disability, and more atrial fibrillation. In contrast, men had a higher prevalence of cervical ICA atherosclerosis, coronary artery disease, and smoking history. These findings are concordant with other reports describing men presenting for EVT as younger with more cardiovascular risk factors and women with more atrial fibrillation.[10,12] In contrast to our study, others have reported women present with higher NIHSS.[35] Furthermore, we did not observe any sex-specific differences in alteplase treatment rates. Prior studies have shown that women presenting with any acute ischemic stroke are less likely to receive alteplase.[36] Our findings in this EVT-treated cohort may be explained by severe stroke syndromes with less ambiguity in alteplase treatment selection.
Despite our observed differences in determinants of outcome, we found no sex-specific differences with respect to 90-day functional independence (mRS ≤2) and 90-day good outcome (change from pre-stroke mRS ≤2), however there was a strong trend for women to have higher mortality which nearly reached statistical significance (p=0.052). Our observed lack of difference is consistent with previous analyses of EVT trial populations supporting sex is not a significant treatment-effect modifier.[10,11,37] This is in contrast to other data that suggest women may have worse functional outcomes after any acute ischemic stroke (not limited to those undergoing EVT).[35,36] Furthermore, an analysis of another real-world Japanese EVT registry reported worse 90-day outcomes for women (OR 0.47, 95% CI 0.40–0.56).[12] However, women in this cohort had comparatively higher NIHSS at presentation and there may have been inter-site treatment selection variability. One potential explanation for our findings showing no differences is that our institutional guidelines for EVT are based strictly on clinical and radiographic criteria including NIHSS, LKW, pre-stroke disability, and ASPECTS.
Our study is unique in that real-world cases were analyzed. Previous studies investigating sex differences in EVT outcomes have primarily been post-hoc analyses of randomized controlled trials, possibly limiting their generalizability.[10,11] Furthermore, previous studies of sex differences included only early time window patients.[38] While there was no significant difference comparing sexes in the proportion treated before the 2015 EVT trials, our study includes a wide breadth of patients as protocols changed in response to subsequent published randomized controlled EVT trials. Another strength of our study is that several baseline characteristics were included in our analyses, allowing for novel investigation and testing of modifiers and confounders. There were, however, several limitations important to consider. First, our study was conducted at a single center with a predominantly Caucasian population, which may limit generalizability. Since our data only include patients who underwent EVT, we are unable to assess sex-specific differences in the determination of EVT eligibility for all patients presenting with ELVO. Future studies examining sex-specific differences in EVT patient selection as well as those that include other outcome measures beyond mRS are warranted.
Conclusion:
In summary, we demonstrate in a real-world, single-center analysis of ELVO stroke patients treated with EVT that despite advanced age and greater rates of pre-stroke disability, women have comparable reperfusion and functional outcomes after EVT. These findings support those of the major EVT clinical trials demonstrating that EVT is an efficacious therapeutic strategy in both men and women. Sex-specific determinants of EVT outcomes were identified; among men, cervical ICA disease is a determinant of reperfusion, while prior stroke history and hemorrhagic transformation are determinants of 90-day functional outcomes.
Acknowledgements:
We would like to thank Joyce A. McIntyre for her work maintaining the prospective Massachusetts General Hospital stroke database. This work was supported by the National Institute of Neurological Disorders and Stroke [grant number R25 NS065743].
Footnotes
Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.
Competing interests: None relevant.
Ethics approval: The ethics committee of Massachusetts General Hospital approved this study (Protocol Number: 2014P002789)
Consent: Waived based on minimal patient risk and practical inability to perform the study without the waiver.
Data availability:
The data that support the findings of this study will be made available from the corresponding author upon reasonable request and pending approval of local institutional review board.
References:
- 1.Albers GW, Marks MP, Kemp S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med 2018;378:708–18. doi: 10.1056/NEJMoa1713973 [doi] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Regenhardt RW, Young MJ, Leslie-Mazwi TM. Is the COVID-19 pandemic magnifying disparities in stroke treatment? J Neurointerv Surg 2021;:neurintsurg-2021–017292. doi: 10.1136/neurintsurg-2021-017292 [DOI] [PubMed] [Google Scholar]
- 3.Regenhardt RW, Biseko MR, Shayo AF, et al. Opportunities for intervention: stroke treatments, disability and mortality in urban Tanzania. Int J Qual Heal Care 2019;31:385–92. doi: 10.1093/intqhc/mzy188 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Blonde L, Khunti K, Harris SB, et al. Interpretation and Impact of Real-World Clinical Data for the Practicing Clinician. Adv Ther 2018;35:1763–74. doi: 10.1007/s12325-018-0805-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Dehlendorff C, Andersen KK, Olsen TS. Sex Disparities in Stroke: Women Have More Severe Strokes but Better Survival Than Men. J Am Heart Assoc 2015;4. doi: 10.1161/JAHA.115.001967 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update a report from the American Heart Association. Circulation 2016;133:e38–48. doi: 10.1161/CIR.0000000000000350 [DOI] [PubMed] [Google Scholar]
- 7.Lisabeth LD, Reeves MJ, Baek J, et al. Factors influencing sex differences in poststroke functional outcome. Stroke 2015;46:860–3. doi: 10.1161/STROKEAHA.114.007985 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Weber R, Krogias C, Eyding J, et al. Age and sex differences in ischemic stroke treatment in a nationwide analysis of 1.11 million hospitalized cases. Stroke 2019;50:3494–502. doi: 10.1161/STROKEAHA.119.026723 [DOI] [PubMed] [Google Scholar]
- 9.Liu M, Li G, Tang J, et al. The influence of sex in stroke thrombolysis: A systematic review and meta-analysis. J Clin Neurol 2018;14:141–52. doi: 10.3988/jcn.2018.14.2.141 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sheth SA, Lee S, Warach SJ, et al. Sex Differences in Outcome after Endovascular Stroke Therapy for Acute Ischemic Stroke. Stroke 2019;50:2420–7. doi: 10.1161/STROKEAHA.118.023867 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Chalos V, De Ridder IR, Lingsma HF, et al. Does Sex Modify the Effect of Endovascular Treatment for Ischemic Stroke?: A Subgroup Analysis of 7 Randomized Trials. Stroke 2019;50:2413–9. doi: 10.1161/STROKEAHA.118.023743 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Uchida K, Yoshimura S, Sakai N, et al. Sex Differences in Management and Outcomes of Acute Ischemic Stroke with Large Vessel Occlusion. Stroke 2019;50:1915–8. doi: 10.1161/STROKEAHA.119.025344 [DOI] [PubMed] [Google Scholar]
- 13.Yu AT, Regenhardt RW, Whitney C, et al. CTA Protocols in a Telestroke Network Improve Efficiency for Both Spoke and Hub Hospitals. Am J Neuroradiol Published Online First: 4 February 2021. doi: 10.3174/ajnr.A6950 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Regenhardt RW, Etherton MR, Das AS, et al. White Matter Acute Infarct Volume After Thrombectomy for Anterior Circulation Large Vessel Occlusion Stroke is Associated with Long Term Outcomes. J Stroke Cerebrovasc Dis 2021;30. doi: 10.1016/J.JSTROKECEREBROVASDIS.2020.105567 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Boulouis G, Siddiqui K-A, Lauer A, et al. Immediate Vascular Imaging Needed for Efficient Triage of Patients With Acute Ischemic Stroke Initially Admitted to Nonthrombectomy Centers. Stroke Published Online First: 2017. doi: 10.1161/STROKEAHA.117.017607 [DOI] [PubMed] [Google Scholar]
- 16.Zachrison KS, Leslie-Mazwi TM, Boulouis G, et al. Frequency of early rapid improvement in stroke severity during interfacility transfer. Neurol Clin Pract 2019;9:373–80. doi: 10.1212/CPJ.0000000000000667 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Collaborators NASCET, Barnett HJM, Taylor DW, et al. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445–53. doi: 10.1056/NEJM199108153250701 [doi] [DOI] [PubMed] [Google Scholar]
- 18.Nolan NM, Regenhardt RW, Koch MJ, et al. Treatment Approaches and Outcomes for Acute Anterior Circulation Stroke Patients with Tandem Lesions. J Stroke Cerebrovasc Dis 2021;30:105478. doi: 10.1016/j.jstrokecerebrovasdis.2020.105478 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke. Stroke 2019;50:e344–418. doi: 10.1161/STR.0000000000000211 [DOI] [PubMed] [Google Scholar]
- 20.Regenhardt RW, Etherton MR, Das AS, et al. Infarct Growth despite Endovascular Thrombectomy Recanalization in Large Vessel Occlusive Stroke. J Neuroimaging Published Online First: 2020. doi: 10.1111/jon.12796 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017–25. doi: 10.1001/jama.1995.03530130023023 [DOI] [PubMed] [Google Scholar]
- 22.Young MJ, Regenhardt RW, Leslie-Mazwi TM, et al. Disabling stroke in persons already with a disability: Ethical dimensions and directives. Neurology 2020;94:306–10. doi: 10.1212/WNL.0000000000008964 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Regenhardt RW, Young MJ, Etherton MR, et al. Toward a more inclusive paradigm: thrombectomy for stroke patients with pre-existing disabilities. J Neurointerv Surg 2020;:neurintsurg-2020–016783. doi: 10.1136/neurintsurg-2020-016783 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Salwi S, Cutting S, Salgado AD, et al. Mechanical Thrombectomy in Patients with Ischemic Stroke with Prestroke Disability. Stroke 2020;51:1539–45. doi: 10.1161/STROKEAHA.119.028246 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Gory B, Piotin M, Haussen DC, et al. Thrombectomy in acute stroke with tandem occlusions from dissection versus atherosclerotic cause. Stroke 2017;48:3145–8. doi: 10.1161/STROKEAHA.117.018264 [DOI] [PubMed] [Google Scholar]
- 26.Flottmann F, Broocks G, Faizy TD, et al. Factors Associated with Failure of Reperfusion in Endovascular Therapy for Acute Ischemic Stroke: A Multicenter Analysis. Clin Neuroradiol Published Online First: 2020. doi: 10.1007/s00062-020-00880-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Kaesmacher J, Gralla J, Mosimann PJ, et al. Reasons for reperfusion failures in stent-retriever-based thrombectomy: Registry analysis and proposal of a classification system. Am J Neuroradiol 2018;39:1848–53. doi: 10.3174/ajnr.A5759 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Leischner H, Flottmann F, Hanning U, et al. Reasons for failed endovascular recanalization attempts in stroke patients. J Neurointerv Surg 2019;11:439–42. doi: 10.1136/neurintsurg-2018-014060 [DOI] [PubMed] [Google Scholar]
- 29.Regenhardt RW, Takase H, Lo EH, et al. Translating concepts of neural repair after stroke: Structural and functional targets for recovery. Restor Neurol Neurosci 2020;38:67–92. doi: 10.3233/rnn-190978 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Takase H, Regenhardt R. Motor tract reorganization after acute central nervous system injury: A translational perspective. Neural Regen. Res 2021;16:1144–9. doi: 10.4103/1673-5374.300330 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Rizvi A, Seyedsaadat SM, Murad MH, et al. Redefining success’: A systematic review and meta-analysis comparing outcomes between incomplete and complete revascularization. J Neurointerv Surg 2019;11:9–13. doi: 10.1136/neurintsurg-2018-013950 [DOI] [PubMed] [Google Scholar]
- 32.Adams HP, Davis PH, Leira EC, et al. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 1999;53:126–31. doi: 10.1212/wnl.53.1.126 [DOI] [PubMed] [Google Scholar]
- 33.Luo G, Mo D, Tong X, et al. Factors Associated with 90-Day Outcomes of Patients with Acute Posterior Circulation Stroke Treated By Mechanical Thrombectomy. World Neurosurg 2018;109:e318–28. doi: 10.1016/j.wneu.2017.09.171 [DOI] [PubMed] [Google Scholar]
- 34.Danière F, Lobotesis K, Machi P, et al. Patient selection for stroke endovascular therapy-DWI-ASPECTS thresholds should vary among age groups:Insights from the RECOST study. Am J Neuroradiol 2015;36:32–9. doi: 10.3174/ajnr.A4104 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Madsen TE, Decroce-Movson E, Hemendinger M, et al. Sex differences in 90-day outcomes after mechanical thrombectomy for acute ischemic stroke. J Neurointerv Surg 2019;11:221–5. doi: 10.1136/neurintsurg-2018-014050 [DOI] [PubMed] [Google Scholar]
- 36.Reeves MJ, Bushnell CD, Howard G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. The LancetNeurology 2008;7:915–26. doi: 10.1016/S1474-4422(08)70193-5 [doi] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.de Ridder IR, Fransen PSS, Beumer D, et al. Is Intra-Arterial Treatment for Acute Ischemic Stroke Less Effective in Women than in Men. Interv Neurol 2016;5:174–8. doi: 10.1159/000447331 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Desai SM, Haussen DC, Aghaebrahim A, et al. Thrombectomy 24 hours after stroke: Beyond DAWN. J Neurointerv Surg 2018;10:1039–42. doi: 10.1136/neurintsurg-2018-013923 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study will be made available from the corresponding author upon reasonable request and pending approval of local institutional review board.