Mortality after large artery occlusion acute ischemic stroke

Despite randomized trials showing a functional outcome benefit in favor of endovascular therapy (EVT), large artery occlusion acute ischemic stroke is associated with high mortality. We performed a retrospective analysis from a prospectively collected code stroke registry and included patients presenting between November 2016 and April 2019 with internal carotid artery and/or proximal middle cerebral artery occlusions. Ninety-day mortality status from registry follow-up was corroborated with the Social Security Death Index. A multivariable logistic regression model was fitted to determine demographic and clinical characteristics associated with 90-day mortality. Among 764 patients, mortality rate was 26%. Increasing age (per 10 years, OR 1.48, 95% CI 1.25–1.76; p < 0.0001), higher presenting NIHSS (per 1 point, OR 1.05, 95% CI 1.01–1.09, p = 0.01), and higher discharge modified Rankin Score (per 1 point, OR 4.27, 95% CI 3.25–5.59, p < 0.0001) were independently associated with higher odds of mortality. Good revascularization therapy, compared to no EVT, was independently associated with a survival benefit (OR 0.61, 95% CI 0.35–1.00, p = 0.048). We identified factors independently associated with mortality in a highly lethal form of stroke which can be used in clinical decision-making, prognostication, and in planning future studies.

All patient characteristics were de-identified. Study approval was obtained from the Atrium Health, Carolinas Medical Center Institutional Review Board (IRB, File #07-19-21E). Carolinas Medical Center is a certified Comprehensive Stroke Center. Due to the study design and use of de-identified data, the requirement for informed consent was waived by the IRB.
Statistical analysis. Descriptive statistics were reported for demographic and clinical characteristics.
Baseline clinical characteristics included comorbidities, presenting glucose level, time from LKW to Computed Tomography (CT) imaging, CT image completion, National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), thrombolysis in cerebral infarction (TICI) score (good defined as 2b-3), type of treatment (no EVT, EVT only, or IV alteplase and EVT), and revascularization therapy (interaction term for treatment type and baseline TICI score good/poor). Ninety-day mortality was calculated from admission date and confirmed using the Social Security Death Index Masterfile. Univariate analysis was performed to examine risk factors associated with 90-day mortality. A multivariable logistic regression model was fitted to determine demographic and clinical characteristics associated with 90-day mortality. A p value of < 0.05 was considered statistically significant.
Ethical approval. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Results
Demographic and clinical characteristics are listed in Table 2. In 764 total subjects, mean age was 68 years, 52% were women, and mean NIHSS was 14. Fourteen percent of patients presented with an ICA occlusion, 76% with an MCA occlusion, and 10% had tandem ICA and MCA occlusions.
Seventy-two percent of patients presented in the 0-6 h time window, while approximately 28% presented in the 6-24 h time window. Nearly 40% were treated with IV alteplase. Twenty-five percent were treated with IV alteplase and EVT, and 26% received EVT only.
Mortality rate for the entire cohort was 26% (Table 3). Substantial differences between the survival and mortality groups were seen with respect to age, gender, race, presenting glucose, presence of ICA occlusion, presenting NIHSS, history of hypertension, history of atrial fibrillation, CT perfusion (CTP) core infarction volume (cerebral blood flow, CBF < 30%, IschemaView RAPID), CTP delayed perfusion volume (Time to maximum greater than 6 s, Tmax > 6 s, IschemaView RAPID), treatment with EVT, revascularization therapy, and discharge mRS (Table 3).

Discussion
Our retrospective analysis from prospectively collected data on 764 subjects showed an independent association between age, NIHSS, and discharge mRS with 90-day mortality in patients with ICA and/or proximal MCA occlusions. Good revascularization therapy, compared to no EVT, improved 90-day survival.
Numbers-needed to treat for functional independence in the Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke (HERMES) trial, DEFUSE 3, and DAWN cohorts were 2.6, 2, and 2.8, respectively 1-3 . While a meta-analysis suggests that EVT improves 3-month survival compared to best medical therapy 5 , EVT has demonstrated a statistically significant mortality benefit in only a single randomized trial 6 . Identifying subsets of www.nature.com/scientificreports/ patients at higher risk of death is thus especially important, as this can guide clinical management, assist family discussions and prognostication, and help plan future clinical trials. Modifiable risk factors may be targeted in future studies, additional relevant clinical endpoints for studies can be elucidated, and evidence-based therapies for improvement in functional outcome, such as EVT, may be refined in order to reduce mortality risk.
Among the common mortality associations in other studies include age 7-10,14,16 , initial stroke severity 7-9,13-16 presenting glucose 8,16 , pre-morbid function [7][8][9] , and history of atrial fibrillation [8][9][10]15 . We similarly found that age, initial stroke severity, presenting glucose, and history of atrial fibrillation were significant univariate associations with mortality risk, though among these factors, the multivariable model demonstrated independent mortality associations with increasing age, presenting NIHSS, and discharge mRS. These differences may be explained by the heterogeneity of the patient cohorts and treatment algorithms.
While age [17][18][19][20][21][22] and stroke severity [17][18][19][20][21] have previously been incorporated into functional outcome prediction models for LAO patients, as well as into prognostic models for non-selected ischemic stroke patients 7-10,15 , our findings of an independent association with mortality in strictly the LAO population is novel. In addition, to our knowledge, discharge functional outcome has not previously been demonstrated to predict mortality, though we have recently shown its importance in predicting 90-day outcome in basilar artery occlusion patients treated with EVT 23 .
Moreover, while good revascularization may improve survival in the thrombectomy population [24][25][26] , our study demonstrated that TICI 2b-3 revascularization, compared to no EVT, produced a survival benefit. This may seem intuitive, as patients receiving no EVT may be categorized into the "no revascularization" or "poor revascularization" group of a thrombectomy-only study. However, we believe this is still significant in that this was shown in a cohort of patients that included exclusively medically managed LAO patients, indicating that the treatment effect of only medical therapy did not modify this benefit. Future studies may build on our findings to develop mortality prediction models specifically in this subset of patients, as other groups have done for functional outcome [17][18][19][20][21][22] .
The logistic regression model showed that each increasing decade of life elevated odds of 90-day mortality by nearly 1.5 times. While age is a non-modifiable risk factor, quantification of its contribution to mortality risk is helpful during hospital management and prognostication. It should be emphasized that thrombectomy should still be offered to older patients, as the clinical benefit in favor of treatment for functional improvement has been demonstrated across the spectrum of age ranges in randomized trials 1-3 . Subgroup analyses from early www.nature.com/scientificreports/ and late-window thrombectomy trials demonstrate a trend for higher likelihood of functional independence in older patients than younger patients treated with EVT, compared to similar age patients treated with best medical therapy 1-3 . Further studies may focus specifically on the impact of age on risk of mortality in this population. One might also hypothesize that discharge mRS impacts risk of 90-day mortality. In our study, an over fourfold odds of death were found with each increasing point on the mRS at discharge. Discharge mRS may be impacted by multiple factors, including pre-morbid mRS, presenting NIHSS, treatment with EVT, and medical co-morbidities, all of which were investigated in our study. Another factor that may influence discharge mRS is   www.nature.com/scientificreports/ the institution of early rehabilitation. Trials conducted thus far instituting very early rehabilitation after stroke have shown mixed results, though initiation of rehabilitation within 2 weeks appears to be beneficial 27 . Targeting specific therapies with more defined time windows may be a focus of future studies impacting post-stroke mortality. Elevated presenting NIHSS was associated with increased mortality risk in our study, and while presenting NIHSS may not be able to be specifically impacted, it can be used in risk assessments for prognosis. In addition, targeting primary and secondary prevention may reduce not only risk of incident stroke, but may impact collateral blood flow status 28 , and thereby presenting stroke severity. This specific clinical question requires additional study.
Good reperfusion, defined as achieving TICI 2b-3, has been associated with improved functional outcome after LAO stroke 29,30 and may improve survival in the subset of LAO patients that are treated with EVT [24][25][26] . Our study demonstrated that compared to no EVT, good revascularization improved odds of survival. This further emphasizes the importance of achieving good reperfusion with EVT, and is an example of reinforcing an existing, evidence-based treatment for functional improvement for a potential survival benefit. TICI 2b-3 revascularization was achieved in 86% of patients receiving EVT in our study, and in 76% and 84% of patients in DEFUSE 3 and DAWN, respectively 2, 3 . In HERMES, TICI 2b-3 revascularization was achieved in a low of 59% of patients in MR CLEAN 31 up to a high of 88% of subjects in SWIFT-PRIME 32 .
The mortality rate for our entire cohort was 26%, higher than that reported in the medical and EVT arms of prior thrombectomy trials [1][2][3]5 . However, elevated in-hospital mortality has been reported for EVT patients treated outside of clinical trials 33 . In addition, subjects who met inclusion criteria for DEFUSE 3 and DAWN were required to have a mismatch between infarcted brain tissue and salvageable brain tissue, or a mismatch between infarcted tissue and clinical exam findings. As such, most patients in DEFUSE 3 or DAWN likely had "slow-growing" infarcts by meeting inclusion criteria for the trials. Accordingly, subjects randomized to the medical therapy arms of the trials might be expected to have better outcomes than subjects who did not meet trial criteria. An extension of this so-called "late-window paradox" 34 for good outcome may also apply to mortality, such that meeting trial enrollment criteria may offer a protective survival benefit. In our study, late window (6-24 h) patients comprised 28% of all subjects and just over 50% of all subjects were treated with EVT.
Moreover, the elevated number of M2 branch occlusions in our study (over 30% of total subjects, compared to 8 total patients in DEFUSE 3 and DAWN and 8% in HERMES), higher ischemic core volume (mean of 27 cc, compared to 10 cc in DEFUSE 3 and 8 cc in DAWN), and inclusion of subjects with mRS 0-2 (rather than 0-1) for EVT may have contributed to our higher mortality as well.
Our study had several limitations. Pre-morbid mRS scores were not consistently available and could not be analyzed, though discharge mRS scores were captured. While obtained in over three-quarters of patients, CTP was not routinely performed on every LAO patient, limiting the conclusions that may be drawn from these data. The focus of our study was on mortality, though some might consider an mRS score of 5 to be an equally bad or worse outcome than death. The sub-category of patients with mRS 5 was not quantified at 3 months, as outcome data on patients not treated with alteplase or EVT was not routinely captured at 90 days. Some patients died as a direct result of stroke, while others died after withdrawal of care when meaningful neurological recovery appeared exceedingly unlikely. Patients who died as a result of withdrawal of care were not independently analyzed.

Conclusion
Increasing age, higher presenting NIHSS, and worse discharge functional outcome were associated with 90-day mortality after LAO AIS in our study. Good revascularization after EVT, compared to no EVT, improved survival. These factors may be used in clinical settings to assist in treatment, prognostication, resource allocation, financial planning, and in future trials.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.