Frailty outperforms chronological age as a predictor of improved outcomes: a retrospective multinational cohort thrombectomy study of stroke patients aged above 70 with anterior circulation stroke

Introduction

Mechanical thrombectomy (MT) has become the standard of care in the treatment of acute ischemic stroke. Despite numerous technical advances, there is a rapidly growing incidence of stroke in an increasingly aged global population (1). While the initial studies established guidelines for patient selection and eligibility (2-4), there have been numerous trials extending the eligibility of patients who present with acute ischaemic stroke (IS), such as patients who were previously deemed ineligible due to large-core infarcts (5-7) or in extended time windows. However, pre-existing disability remains a key consideration in patient selection, as pre-morbid functional dependence is often an exclusion criterion in randomised trials (8,9). Given this backdrop, understanding the impact of frailty on patient outcomes post-thrombectomy is crucial for optimizing care strategies.

Frailty, as measured by the Clinical Frailty Scale (CFS), is an important predictor of various health outcomes in older adult patients (10,11). It reflects the patient’s underlying physiological reserve and ability to maintain homeostasis under periods of stress regardless of their chronological age (12). Frailty may thus be a valuable predictor in the outcome of older adult patients undergoing MT. This study therefore aims to evaluate the influence of the CFS on functional outcomes in older adult patients following MT. We present this article in accordance with the STROBE reporting checklist (available at https://jni.amegroups.com/article/view/10.21037/jni-25-2/rc).

Methods

Data collection

Our multi-center study involved six comprehensive stroke centers, each with an annual MT volume of at least 100 cases. Patients aged 70 years and above who underwent MT for IS with large vessel occlusion (LVO) of the anterior circulation from January 2017 to December 2021 were included. Patients deemed eligible for MT were selected according to the American Heart Association/American Stroke Association guidelines (3). Patient data was collected including clinical and demographic data such as co-morbidities, National Institutes of Health Stroke Scale (NIHSS), administration of intravenous thrombolysis and CFS as scored by a geriatrician. A CFS of >3 signified frailty, while scores ≤3 indicated robust health status (13). The primary outcome measure was functional independence (FI), defined as a Modified Rankin Scale (mRS) score of 0–2 at 90 days post-stroke in line with extant studies in the literature (4-6), while an excellent mRS score of 0–1, mortality and symptomatic intracranial haemorrhage (sICH) according to the ECASS-2 trial definitions (14) were analyzed as secondary outcome measures. Successful recanalization was defined as TICI2B or greater. A multiphase CT angiogram collateral score of less than 3 was considered to be poor collaterals (15). A full description of CFS and mRS can be found in the Supplementary file (Appendix 1 and Appendix 2 respectively).

Statistical analysis

Statistical analysis was performed using SPSS version 26 for both the primary and secondary outcomes. Missing data was excluded. Summary statistics were presented as means or medians along with the relevant percentages. Continuous variables were analyzed using the Student’s t-test, ordinal data were analyzed using the Mann-Whitney U test, and categorical variables were compared using Fisher’s exact test in the univariate analysis. Multivariate binary logistic regression models were developed using baseline covariates that showed statistically significant associations (P<0.05) to identify independent predictors of the primary and secondary outcomes. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) and P values were reported for all analyses. Significance was defined as a two-sided P value <0.05.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional ethics committee and research board (NHG Domain Specific Review Board Reference Number 2024/00227). The study design was retrospective, using de-identified patient data that was anonymized prior to extraction by the study teams. Written informed consent was not required following waiver by the Institutional Review Board.

Results

Patient demographics

From an initial cohort of 855 patients, 181 patients were excluded as they were below the age of 70 years (Figure 1). A further 55 patients were excluded as they had LVO of the posterior circulation. This cohort comprised of 619 patients from various centres, with an average age of 79.6 years [standard deviation (SD) =6.37]. Of this cohort, 225 (36.3%) were considered frail on arrival, while 537 (87.2%) were functionally independent prior to admission with an mRS of 2 or better. 48 patients were lost to their subsequent 90-day follow-up, yielding 571 included participants. At 3 months post-stroke, 189 patients (33.2%) achieved FI. In-hospital mortality was observed in 85 patients (13.7%), and 22 patients (3.5%) developed sICH following MT (Table 1).

Figure 1 Included patients. mRS, Modified Rankin Scale.

The univariate analysis identified several factors significantly associated with FI at 90 days, including age (P<0.001), race (P<0.001), male sex (P=0.049), diabetes mellitus (P=0.041), albumin (P<0.001), NIHSS on arrival (P<0.001), ASPECTS (P<0.001), number of attempts ≥3 at thrombectomy (P<0.001), recanalization ≥ TICI 2B (P<0.001), and frailty (P<0.001). In the multivariate logistic regression model, low NIHSS (aOR 0.876 95% CI: 0.807–0.951, P=0.002) was independently associated with FI at 90 days while TICI <2B was independently associated with significantly lower odds of FI at 90 days (aOR 0.079, 95% CI: 0.008–0.793, P=0.03) (Table 2). Frailty (aOR 0.067, 95% CI: 0.012–0.370, P=0.002) was negatively associated with FI at 90 days.

Secondary outcomes

Among our secondary outcomes, frailty emerged as a statistically significant predictor for both mRS 0–1 at 90 days (aOR 0.053, 95% CI: 0.006–0.516, P=0.01) and mortality (aOR 2.39, 95% CI: 1.33–4.28, P=0.004) within our cohort. A higher serum albumin was also independently found to be associated with excellent functional outcome at 90 days (aOR 1.13, 95% CI: 1.00–1.28, P=0.048). It is noteworthy that age was not found to be significant in the multivariate analysis (Table 3). Multiple attempts at thrombectomy (3 or more) were also independently associated with mortality (aOR 2.78, 95% CI: 1.55–4.98, P=0.001) and risk of SICH (aOR 5.73, 95% CI: 1.12–29.3, P=0.04). Other factors associated with increased risk of mortality included a greater NIHSS (aOR 1.05, 95% CI: 1.01–1.09, P=0.02) and unsuccessful recanalization (aOR 0.420, 95% CI: 0.225–0.782, P=0.006). Lower ASPECTs was a predictor of sICH (aOR 0.713, 95% CI: 0.537–0.949, P=0.02). The full list of variables studied are available in the Tables S1-S3.

In accordance with STROBE guidelines, participants with missing data in variables of interest are reflected in Table S4.

Discussion

In this study, frailty was found to be an important predictor of functional outcomes in a multinational cohort of patients aged above 70 years. This was true after adjustment for co-morbidities such as age, presence of diabetes and NIHSS.

Our findings suggest that in a geriatric population, holistic assessments by means of a measurable frailty score may more closely reflect physiological reserve and vulnerability over chronological age. Incorporating such measures into clinicians’ assessments of an older adult patient presenting with acute IS would allow clinicians to identify patients that would benefit from MT who would otherwise be considered too elderly or unsuitable for intervention. Conversely, there may be patients who are in the ‘old’ rather than ‘oldest-old’ range (16) but who are identified to be frail and would benefit from closer monitoring but may not benefit from aggressive recanalization therapies.

Of note, in this cohort of elderly patients, chronological age was not found to be a statistically significant predictor of FI on multivariate analysis. This finding suggests that within an older population, frailty may provide greater prognostic value than age alone when evaluating candidacy for interventions such as MT. While initial studies in MT mainly included patients under the age of 80 years or applied more stringent selection to older adult patients (2,4), there is increasing recognition that age alone should not be a hard contraindication (17,18) with more centres offering MT even to the ‘oldest-old’. Instead, frailty and other markers of biological reserve, such as functional status and imaging biomarkers, have emerged as more relevant predictors of outcomes (17-19). This shift underscores the importance of individualized patient assessments over arbitrary age cut-offs, ensuring that treatment decisions are equitable and evidence-based. By moving beyond age as a primary determinant, clinicians can focus on optimizing outcomes and aligning interventions with the goals and needs of older adult patients.

The effect of frailty on functional outcomes was clear across the two main ethnicities represented in our multi-national cohort taken from various centres in Asia, Europe and Oceania. This suggests that frailty is an important predictor after considering variability in practice patterns and outcomes across healthcare systems, and our findings are more likely to be generalizable. The utility of a standardized tool like the CFS lies in its ability to provide a consistent, objective measure of frailty, ensuring that assessments are not swayed by cultural perceptions or local practice norms. By embedding frailty evaluations into global stroke care protocols, clinicians can make more equitable and informed decisions about MT, even in resource-limited settings.

Limitations

While our study is of a moderate sample size, it is non-randomised and retrospective which implies an inherent risk of bias and inability to establish causality. In addition, not all centres included their data on relevant serum laboratory results such as haemoglobin and creatinine levels, which may limit the generalisability of our results. This highlights the need for future efforts to study the importance of basic serum laboratory results in patients with acute IS. Despite the use of CFS as a standardised tool, there is still potential subjectivity in interpretation by assessors leading to inter-rate variability. This is particularly so in a multi-centre, multi-national study that may have differences in training and familiarity with the CFS exacerbating variability. Future efforts should focus on standardized training programs to ensure consistent and accurate frailty assessments across diverse clinical settings. Other subsequent studies may explore how frailty interacts with other emerging biomarkers of interest to refine patient selection further, ensuring optimal outcomes across diverse populations.

An important limitation is the wide confidence intervals observed for the adjusted odds ratios associated with frailty and successful recanalization. While the associations are statistically significant, the broad intervals reflect uncertainty regarding the exact effect size. This may reflect the moderate sample size and number of events, as well as the semi-quantitative nature of the CFS and TICI score despite efforts to standardize training. While the influence of the CFS and TICI on functional outcomes remains important consistent with prior literature, the uncertainty regarding the effect size emphasize the need for larger, prospective studies with standardized assessments.

Conclusions

In conclusion, the CFS is a valuable tool in predicting patient outcomes after MT and individualizing care in older adult populations. Frailty significantly influences FI, mortality rates, and complication rates, underscoring the importance of incorporating frailty assessments into clinical practice. In doing so, patients would be evaluated based on their biological resilience rather than chronological age alone, allowing for equitable access to function- or life-preserving interventions.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jni.amegroups.com/article/view/10.21037/jni-25-2/rc

Data Sharing Statement: Available at https://jni.amegroups.com/article/view/10.21037/jni-25-2/dss

Peer Review File: Available at https://jni.amegroups.com/article/view/10.21037/jni-25-2/prf

Funding: This work was supported by a grant from the National Medical Research Council (MOH-001461, to L.L.L.Y.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jni.amegroups.com/article/view/10.21037/jni-25-2/coif). L.L.L.Y. serves as an unpaid editorial board member of Journal of Neurointervention from November 2024 to December 2026. L.L.L.Y. was supported by a grant from the National Medical Research Council (MOH-001461). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional ethics committee and research board (NHG Domain Specific Review Board Reference Number 2024/00227). The study design was retrospective, using de-identified patient data that was anonymized prior to extraction by the study teams. Written informed consent was not required following waiver by the Institutional Review Board.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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