Abstract
Few studies have reported the clinical outcomes of older adult patients with acute anterior circulation large-vessel occlusion (LVO) who underwent mechanical thrombectomy (MT). Therefore, we investigated the safety, functional outcomes, and predictors of MT for anterior circulation LVO in older adults. We enrolled patients with acute anterior circulation LVO from May 2018 to October 2021 in this retrospective study. Patients were divided into older (≥80 years) and young (<80 years) groups. Multivariable logistic regression analyses determined the safety, functional outcomes, and predictors of MT for anterior circulation LVO. We divided 1182 patients with acute ischemic stroke into young (18-79 years; 1028 patients) and older (≥80 years; 154 patients) groups. Compared with the young group, the older group had more unfavorable functional outcomes and increased mortality (P = .003). In the older adult patients, lower initial NIHSS score and higher ASPECTS were correlated with good outcomes. On the contrary, higher initial NIHSS score and lower ASPECTS were related to increased mortality. No difference was detected in symptomatic intracranial hemorrhage within 48 h between two groups. Increasing age was associated with lower rates of favorable functional outcomes and higher mortality rates. The lower initial NIHSS score combined with the higher ASPECTS may predict functional outcomes post-thrombectomy in older adults.
Introduction
Emergent large-vessel occlusion (LVO) is a major cause of disability and death worldwide. 1 Several international randomized control trials have shown the clinical benefits of mechanical thrombectomy (MT) for anterior circulation LVO in patients with acute ischemic stroke (AIS), even up to 24 h after onset.2-7 Approximately 30% of AIS cases occur in patients aged >80 years.8,9 Compared to younger patients, older adult stroke patients have higher mortality and severe disability at discharge. 9 Several studies have shown that advanced age is an independent predictor of adverse outcomes. 10 The utility of endovascular treatment (EVT) for LVO has been questioned in older adult stroke patients, owing to poor outcomes and high mortality. 11 On the contrary, several studies reported good outcomes in older adult patients after strict screening. 12 Outcomes of EVT among older adults are better than among the older adults received general supportive measures. The lower NIHSS score at the admission, shorter duration of EVT, and better thrombolysis in cerebral infarction (TICI) score could be the predictors of good outcome. Better patient selection and more studies of EVT in the older adult patients are needed. 13
Patient demographics are characterized by a marked aging due to the increase in life expectancy and improvements in medical care. The ever-growing elderly population is much more vulnerable to cerebral ischemia than the younger population, leading to a higher incidence of AIS in this group. In addition, this patient population become disabled after stroke more often than the younger population. However, older patients (>80 years) are commonly excluded from large randomized controlled stroke studies because this age group was found to be associated with significantly poorer clinical outcome and increased mortality compared to younger patients. Older patients with LVO should not be excluded from EVT even if prognosis for good clinical outcome in this age group remains low and the procedure is more challenging. 14
We aim to assess the safety, functional outcomes, and predictors of MT for anterior circulation LVO in older adult patients. With this study, we might obtain the following new observations. Good functional outcome rates declined and mortality rates increased with an increase in the initial NIHSS score among older adult patients. However, a high proportion of patients treated with endovascular therapy for LVO can achieve good functional recovery. We expect all these results to provide novel ideas for MT in older adults, thus providing some ideas and reference for further study.
Methods
Study Population
The data in this retrospective study were obtained from the Endovascular Treatment With versus Without Tirofiban for Stroke Patients with LVO (RESCUE BT) trial and the Direct Endovascular Thrombectomy versus Combined intravenous thrombolysis and Endovascular Thrombectomy for Patients With Acute Large Vessel Occlusion in the Anterior Circulation (DEVT) trial.15,16 The RESCUE BT and DEVT trials are multicenter, prospective, randomized, double-blind, placebo-controlled clinical trials. The two trials were designed in compliance with the Declaration of Helsinki and were registered at www.chictr.org.cn (identifiers ChiCTR-INR-17014167 and ChiCTR-IOR-17013568). The recruitment of patients for research and clinical observation in this trial was regulated by the Patients and Medical Volunteers Welfare Act 2001 of (the People's Republic of China), and all practices and procedures were performed in this trial only when approval was granted by the ethics committee of Xinqiao Hospital, Army Medical University, and all participating hospitals. All participants provided written informed consent, and the inclusion and exclusion criteria were based on the RESCUE BT and DEVT trials.15,16
The RESCUE BT trial aimed to assess whether additional intravenous tirofiban therapy can improve the clinical outcomes in LVO stroke patients who underwent EVT within 24 h of symptom onset. The DEVT trial was to investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with LVO stroke.15,16
The American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) ranked the cerebral collateral status in five grades as follows: grade 0, no collaterals visible to the ischemic site; grade 1, slow collaterals to the periphery of the ischemic site with persistence of some of the defect; grade 2, rapid collaterals to the periphery of ischemic site with persistence of some of the defect and to only a portion of the ischemic territory; grade 3, collaterals with slow but complete angiographic blood flow of the ischemic bed by the late venous phase; and grade 4, collaterals with slow but complete angiographic blood flow of the ischemic bed by the late venous phase. 17
All assessments and procedures listed above were performed by neurologists and interventionists working at our institutions, including the collection of clinical data, evaluation of neurological function, assessment of angiography findings, and appraisal of the interventional results. To be eligible for participation, each center had to perform more than 50 MTs per year and each neurointerventionist had to have performed at least ten thrombectomies per year. To ensure the quality of the trial, training in the study protocol and EVT technique was performed every 6 months in Chongqing.
Technical Procedure
We performed MT for patients with AIS under conscious sedation or general anesthesia according to the level of cooperation and medical conditions of the patients. Rescue treatment with balloon angioplasty and stenting may be required in patients undergoing MT. The research process and criteria are listed in the RESCUE BT and DEVT trial protocols.15,16
Outcome Variables
The primary endpoint was the distribution of global disability on the modified Rankin Scale (mRS) 90 days after randomization. mRS 0-2 was considered as functional outcomes in this study. Successful recanalization was defined as an expanded thrombolysis in cerebral infarction (eTICI) score of 2b-3. The safety endpoints were either the symptomatic intracranial hemorrhage (SICH) rate within 48 h, mortality at 90 days, procedure-related complications, or incidence of serious adverse events.
Statistical Analyses
SPSS (IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.) and STATA version 15.2 (Stata Corp LLC, TX, USA) were used for statistical analysis, and the chi-squared test was used to further examine categorical variables. Continuous variables are described as medians (interquartile ranges). Standard statistical measures (Mann–Whitney U test) were used for non-normally distributed continuous variables. Multivariate logistic regression analysis was performed to assess clinically significant predictors of favorable functional outcomes. The adjusted common odds ratios (cOR), beta coefficients, and ORs were adjusted for the following main prognostic variables: sex, age, baseline National Institutes of Health Stroke Scale (NIHSS) score, baseline Alberta Stroke Program Early Computed Tomography score (ASPECTS), time from onset to randomization, and occlusion location. Adjusted and unadjusted ORs are reported with 95% confidence intervals (CIs) to indicate statistical precision.
In this study, the missing values of key variables were excluded from the analysis; thus, imputation was not required. All significant differences were set at P < .05, and all P values were two-sided. Percentage bar plots were drawn using the Microsoft Excel 2020 software (Microsoft Corporation). Distribution surfaces representing changes in the predicted outcome probabilities were generated using SigmaPlot 12.5, with models assessed using the R2 correlation metric.
Results
Baseline Characteristics of the RESCUE BT Trial Full Cohort
We included 1182 patients, including 948 and 234 patients from the RESCUE BT and DEVT trials, respectively. Of these, 1028 were <80 years old and 154 were ≥80 years old. The median (interquartile range [IQR]) age of the entire cohort was 68 (57-75) years.
Univariate Analysis: Clinical Outcomes in Young and Older Patients with EVT
There were 154 patients aged ≥80 years (38.3% male; median [IQR] age, 82 [81-85] years; age range, 80-92 years). There were 1028 patients aged <80 years (61.3% male, median [IQR] age, 66 [56-72] years). The baseline characteristics of the entire cohort are presented in Table 1.
Patients’ Baseline Characteristics.
Abbreviations: ASPECTS, Alberta Stroke Program Early Computed Tomography Score; CE, cardiogenic embolism; DBP, diastolic blood pressure; ICA, internal carotid artery; IQR, interquartile range; LAA, large artery atherosclerosis; MCA, middle carotid artery; NIHSS, National Institutes of Health Stroke Scale.
In the univariate analysis, compared with the group aged <80 years, the group aged ≥80 years had a lower rate of favorable functional outcome when defined by different mRS scores (mRS 0-2: 26.0 vs 51.1%, P < .001; mRS 0-1: 14.9 vs 37.3%, P < .001), and increased mortality (26.0 vs 16.2%; P = .003; Figure 1). Without adjustment, differences were observed in the proportion of patients in the first pass (39.6 vs 28.9%, P = .007). The main stroke etiology in the group aged ≥80 years was cardiogenic embolism (CE) and large artery atherosclerosis (LAA) in the group aged <80 years, respectively (P < .001). No differences were detected in the overall rates of SICH (8.6 vs 7.6%, P = .69) and eTICI 2b-3 (90.8 vs 90.6%, P = .93) between the two groups. After adjusting for sex, NIHSS, ASPECTS, AF, smoking, Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification, occlusion site, onset to randomization, and ASITN/SIR grade, univariate analysis showed that differences were detected in mRS scores (mRS 0-2: OR, 0.362; CI, 0.239-0.547; P < .001 and mRS 0-1: OR, 0.326; CI, 0.198-0.536; P < .001) and mortality within 90 days (OR, 1.549; CI, 1.009-2.379; P = .046). The probability of good functional outcomes decreased and mortality increased with age (Table 2). The distribution of the mRS scores at 90 days is shown (Figure 1). The distribution showed that, compared with patients aged <80 years, older adult patients aged ≥80 years had a higher mortality rate. The overall prognosis tends to become poorer with increasing age.
Distribution of mRS scores at 90 days.
Clinical Outcomes in Young Patients and Older Adults with EVT.
To identify the predictors of outcomes, the 154 older adult patients aged ≥80 years were dichotomized by mortality (alive vs deceased) and functional outcome (favorable vs poor) to determine the variables to be adjusted. The variables were calculated using multiple logistic regression, considering the following: sex, systolic blood pressure on admission, NIHSS score, ASPECTS, hypertension, diabetes mellitus, dyslipidemia, AF, smoking, ASITN/SIR grade, stroke etiology, occlusion sites, tirofiban, onset to randomization, onset to puncture, and onset to recanalization. Adjusting for NIHSS, ASPECTS, sex, occlusion site, and onset to randomization, multivariate analysis demonstrated that male sex (OR, 3.820; CI, 1.632-8.946; P = .002), NIHSS scores (OR, 0.846; CI, 0.768-0.931; P = .001), ASPECTS (OR, 1.431; CI, 1.032-1.984; P = .03), and onset to recanalization (OR, 0.991; CI, 0.982-1.000; P = .04) were predictors of good outcome. Dyslipidemia (OR, 0.104; CI, 0.012-0.897; P = .04) was a risk factor of good outcome. NIHSS score (OR, 1.122; CI, 1.029-1.224; P = .01) and occlusion site MCA-M2 (OR, 0.168; CI, 0.036-0.775; P = .02) were predictors of mortality (Table 3). The predicted probability of good outcomes and mortality with the baseline NIHSS score and ASPECTS are shown via distribution surfaces (Figures 2 and 3).
Predicted probability of good outcomes and mortality by baseline NIHSS scores and ASPECTS in older adult patients.
Predicted probability of good outcomes by baseline NIHSS score and ASPECTS in older adult patients.
Multivariate Analysis: Predictors of Outcome in Patients ≥80 Years old.
For all patients aged ≥80 years, the curves showed decreases in the predicted probabilities of good outcomes and increases in the predicted probabilities of mortality with baseline NIHSS score and ASPECTS.
For patients aged ≥80 years, the three-dimensional diagram illustrated a decrease in the predicted probabilities of good outcomes with baseline NIHSS score and ASPECTS.
The Subgroup Analysis Outcome
The forest plot shows the differences in odds ratios for favorable outcomes (defined as mRS score of 0-2) at 3months in the subgroups. Adjusted variables: sex, baseline NIHSS score, ASITN/SIR grade, baseline ASPECTS, and stroke etiology. These results were relatively stable. Among patients with different characteristics, the functional outcomes of older adult patients aged ≥80 years were worse (Figure 4).
Subgroup analyses of primary outcomes. The forest plot shows the differences in odds ratios for favorable outcomes (defined as mRS score of 0-2) at 3 months in the subgroups. Adjusted variables: sex, baseline National Institutes of Health Stroke Scale (NIHSS), the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grade, baseline Alberta Stroke Program Early Computed Tomography score (ASPECTS), and stroke etiology.
Discussion
This multicenter study represents the real-world experience of patients aged ≥80 years with acute anterior circulation LVO who were treated with MT. The main finding of the present study was that nearly half of the patients who underwent MT had good functional outcomes at 90 days. However, this effect declines with age. Compared with the group aged <80 years, the probability of a good functional outcome at 90 days was reduced by 25.1% in the group aged ≥80 years (P < .001). This finding underscores the need to provide MT to patients aged ≥80 years with acute anterior circulation LVO only after strict screening.
Compared with conservative treatment, outcomes following MT in older adult patients with acute anterior circulation LVO have been reported in several published studies. Among the randomized thrombectomy trials of anterior circulation LVO, the overall functional outcomes of older adult patients following MT were significantly more beneficial than those following conservative treatment in the subgroups of the ESCAPE, DAWN, and SWIFT-PRIME trials. 18 However, few studies have focused solely on older adult stroke patients and reported outcomes following MT in older adult patients with acute anterior circulation LVO. Our results clearly showed the real-life outcomes of MT, with special reference to patients aged ≥80 years. Thus, our study may shed light on the treatment of older adult patients with acute anterior circulation LVO.
The present study showed that increasing age was associated with a lower rate of good outcomes and a higher mortality rate (Table 2, Figure 1). The mortality rate of older adult patients within 90 days was 26% in our study, which is consistent with the data from STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke; 27.5%) and HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials; 28%) Registry. Older patients evidently experienced overall worse outcomes and higher rates of mortality than younger patients did. Although the mechanisms remain unclear, frailty, and comorbidities, which are more common in older adult patients, may be important predictors of poor outcomes in patients with stroke. Compared with conservative treatment, good functional outcomes were more often achieved among older adult patients with independent premorbid function in a study by McDonough et al. 19
Probably due to the use of advanced devices and techniques, our study showed a high rate of successful recanalization in patients (90.7%) following thrombectomy (Table 2). In a series of 157 patients, Jayaraman et al 20 demonstrated that worse outcomes in older patients following thrombectomy for acute anterior circulation LVO were associated with partial and incomplete recanalization. However, in our study, no significant difference was detected in the overall rate of successful recanalization (adjusted OR, 1.054; 95% CI: 0.566-1.963; P = .87).
In our study, the onset-to-recanalization time was a predictor of good outcomes in patients aged ≥80 years (Table 3). Komatsubara et al 21 demonstrated that reducing the time from onset to recanalization can improve thrombectomy results in older adults. Aoki et al 22 reported that recanalization was relatively more difficult in patients with severe stroke than in those with mild stroke, and that the initial NIHSS score may predict successful recanalization. In our study, the initial NIHSS score predicted good outcomes and mortality rates. Good functional outcome rates declined and mortality rates increased with an increase in the initial NIHSS score among older adult patients.
The ASPECTS was a predictor of good outcomes in older adult patients in our study (Table 4). Danière et al 23 demonstrated that predicted ASPECTS values vary by age subgroup. When the core infarct size was small and the initial ASPECTS was high, older adult patients with acute anterior circulation LVO were more likely to benefit from thrombectomy. When the ischemic core is large, good outcomes are far less likely to be achieved in older adults. However, good outcomes may be achieved in younger patients with lesions of similar severity.
Consequently, the initial NIHSS score and ASPECTS may be selective tools for older adult patients when deciding on the treatment (Figure 2). Furthermore, no specific baseline comorbidities predicted good outcomes in the multivariate analysis. Mokin et al 24 reported that age >80 years was not a predictor of poor outcomes in patients with M2 segment occlusion. Among patients with different characteristics, the functional outcomes of older adult patients aged ≥80 years were worse in this study. Good outcomes can be achieved using selective tools in older adults, age should not be a discriminator. 13
In our study, the occlusion site in the MCA-M2 segment was a good predictor of mortality in patients aged ≥80 years (Table 5). Several studies have reported that thrombectomy for the MCA-M2 segment may be safe and effective in patients of all ages. 25 The functional outcomes of thrombectomy of the MCA-M2 segment were associated with the dominant M2 branch, collateral compensation, and ischemic core. Dyslipidemia was a risk factor for good outcome in the study (Table 5). Also, dyslipidemia was a strong risk factor for ischemic stroke. 26
Our study had some limitations. Although the RESCUE BT and DEVT trials were multicenter, prospective, randomized, double-blind, placebo-controlled clinical trials, this study was retrospective and had the inherent weakness of being a nonrandomized clinical trial. Our study may suffer from confounding bias because neurologists and interventionists at our institutions obtained the NIHSS and ASPECTS scores. The number of older adult patients included in this study was relatively small. Due to the lack of older adult cases, the study could not determine the upper age limit above which endovascular therapy was no longer effective. Moreover, confounding factors that might have affected our results were not fully controlled for between the two groups.
Conclusions
In summary, increasing age is associated with a low rate of favorable functional outcomes and high mortality rates. Older adult patients are more likely to achieve favorable outcomes through selection. The initial lower NIHSS score combined with the higher ASPECTS may predict functional outcomes after thrombectomy, which may be regarded as a selective tool for older adult patients.
Footnotes
Acknowledgments
We would like to thank the RESCUE BT (the Endovascular Treatment With vs Without Tirofiban for Stroke Patients with Large-Vessel Occlusion trial) and the DEVT collaboration (the direct endovascular thrombectomy vs combined IVT and endovascular thrombectomy for patients with acute LVO in the anterior circulation trial) investigators.
Author Contributions
ZGJ, SJX, HZ, YNZ, and GCW contributed to the concept and rationale for the study.LS, YCS, and YDH were responsible for the first draft. XDJ contributed to statistical analyses. XDJ and LX performed the data collection. XGD and LL contributed to the first revision. All authors read and approved the final manuscript.
Data Availability Statement
The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (grant number 82071323), Chongqing Natural Science Foundation (grant number cstc2020jcyj-msxmX0926), and Clinical Medical Research Talent Training Program of the Army Medical University (grant numbers 2019XLC2008 and 2019XLC3016).
