Endovascular Thrombectomy for Large Core Ischemic Stroke—Age Matters

Six recent phase 3 randomized clinical trials (RCTs) and current aggregate-data meta-analyses have provided robust evidence that endovascular thrombectomy (EVT) in addition to best medical treatment (BMT) compared with best BMT alone is associated with improved functional outcomes among patients with large vessel occlusion (LVO) with large core Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 0 to 5 acute ischemic stroke (AIS).^1-5 More specifically, a recent meta-analysis of 6 RCTs⁵ documented that EVT compared with BMT increased the likelihood of good functional outcome (modified Rankin Scale [mRS] score of 0-2) and excellent functional outcome (mRS score of 0-1) by more than 2-fold at 3 months. EVT was also independently associated with increased rates of independent ambulation (mRS score of 0-3) and the odds of reduced disability (mRS shift analysis).⁵ There was an independent increase in the risk of symptomatic intracranial hemorrhage (sICH) with EVT, while mortality tended to be lower in the EVT-treated subgroup, although the result was not statistically significant (16% relative risk reduction; P = .06).⁵

However in these RCTs, patients older than 80 years were underrepresented (in TENSION, SELECT 2, and TESLA), selected more stringently (in LASTE), or even fully excluded (in ANGEL-ASPECT). The treatment effect of EVT in older patients (>80 years) with AIS, LVO, and ASPECTS 6 to 10 has been previously established in an individual patient–data meta-analysis conducted by Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES) investigators.⁶ Moreover, predefined subgroup analyses of these 6 pivotal RCTs did not provide evidence that age represents an effect modifier of the efficacy of EVT (compared with BMT) in patients with AIS with large ischemic core.^1-5 On the other hand, data on EVT safety and efficacy in the oldest-old patients with established large infarct remain scarce, despite the fact that this subgroup is frequently encountered in acute stroke treatment.

In view of the former considerations, the German Stroke Registry–Endovascular Treatment (GSR-ET) investigators conducted a retrospective analysis of prospectively collected (during a 7-year period) observational data in patients with anterior circulation LVO (isolated occlusion of intracranial internal carotid artery and M1 middle cerebral artery) with established large infarct (ASPECTS 0-5).⁷ They compared safety and efficacy outcomes in 126 patients older than 80 years and 282 patients aged 80 years and younger.⁷ The rate of independent ambulation decreased from 56.4% in patients 60 years and younger to 15.1% in patients older than 80 years (P < .001), while mortality increased from 15.4% to 64.3% (P < .001). Consistent with most other stroke studies, being older than 80 years was associated with lower rates of independent ambulation (adjusted odds ratio, 0.44; 95% CI, 0.23-0.82) and higher mortality (adjusted odds ratio, 2.75; 95% CI, 1.61-4.72). However, successful reperfusion (SR), defined as a final modified Thrombolysis in Cerebral Infarction grade of 2b or 3, was associated with higher rates of independent ambulation (adjusted odds ratio, 4.95; 95% CI, 2.14-11.43), independent of age and without significant interaction (P = .27).

The highest and lowest predicted probability of independent ambulation at 3 months in older patients with large ischemic core was 46% (in patients with SR, baseline National Institutes of Health Stroke Scale [NIHSS] score of 0-14 points, and prestroke mRS score of 0) and 1% (in patients without SR, baseline NIHSS score of 29-42 points, and prestroke mRS score of 2-3), respectively. In addition, the lowest and highest predicted probability of 3-month mortality in older patients with large ischemic core was 25% (in patients with SR, baseline NIHSS score of 0-14 points, and prestroke mRS score of 0) and 96% (in patients without SR, baseline NIHSS score of 29-42 points, and prestroke mRS score of 3), respectively. Finally, a difference in the rate of sICH was not observed between patients older than 80 years and those aged 80 years and younger (8.3% vs 4.0%; P = .12).

These findings indicate that age is associated with functional outcomes and survival at 3 months in patients with AIS with large infarct receiving EVT in clinical settings. While functional outcomes are generally exceptionally poor (15% independent ambulation and 64% mortality rates at 3 months) in patients older than 80 years with ASPECTS of 0 to 5, outcomes differed substantially after stratification for baseline stroke severity, prestroke disability, and SR following EVT.

Certain methodological shortcomings of this study need to be considered when interpreting the reported observations. First, this was a retrospective analysis of registry data and propensity score matching was not used to control for potential imbalances in baseline characteristics in the different age subgroups. Age and frailty are correlated, and it is likely, given the data were derived from a registry of clinical practice, that physician judgement regarding frailty in older patients was applied such that patients who received EVT may not be fully representative of their peers. Second, there was no official sample size estimation. Third, patients with tandem (extracranial and intracranial) occlusions were excluded. Fourth, patients with very low ASPECTS (0-3) were severely underrepresented (<25%) in all age subgroups. Fifth, information on baseline ischemic core volume was not collected, and this essential neuroimaging parameter was not included in the multivariable analyses aiming to identify factors independently associated with 3-month mortality and independent ambulation. ASPECTS has limited volumetric correlation, and it is possible that physician preferences led to smaller than average ischemic core volume among those who received EVT compared with the overall population of patients with ASPECTS 0 to 5. Additionally, there was no central adjudication of SR and sICH, and the reported rates may be subject to significant interrater variability. Last and most important, the reported findings are primarily valid for AIS management within the German health care system and may not be reproducible in other countries with less developed health care systems.

In conclusion, this timely study adds to the mounting evidence indicating that swift SR following EVT appears to be the strongest predictor of good clinical outcomes and improved survival in patients with large-core AIS, even in the oldest-old (>80 years) subgroup. Age seems to represent an important prognostic indicator but not an effect modifier of EVT safety and efficacy in patients with large-core AIS. Given the available randomized and observational evidence, the findings of GSR-ET investigators reinforce the existing notion that EVT for AIS with large infarct should not be withheld based on an upper age limit. Nevertheless, age needs to be integrated within a multimodal prognostic approach to individualize treatment decisions in these patients with the worst prognosis in terms of AIS natural history.

Published: August 12, 2024. doi:10.1001/jamanetworkopen.2024.25958

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2024 Tsivgoulis G et al. JAMA Network Open.

Corresponding Author: Georgios Tsivgoulis, MD, Second Department of Neurology, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens, Rimini 1, Chaidari, Athens, Greece 12462 (tsivgoulisgiorg@yahoo.gr).

Conflict of Interest Disclosures: None reported.