Outcomes of young patients following mechanical thrombectomy for stroke: A systematic review and meta-analysis

Abstract

Background

Young patients experience acute ischemic stroke (AIS) at much lower rates than their older counterparts. We performed a systematic review and meta-analysis to assess the question regarding outcomes and clinical characteristics of young stroke patients who underwent mechanical thrombectomy for AIS.

Methods

Following PRISMA guidelines, a systematic review of the literature was conducted using the databases PubMed, MEDLINE, and Embase. The primary outcome of interest was 90-day modified Rankin Scale (mRS) 0–2. Secondary outcome variables included rate of successful reperfusion (TICI 2b/3), symptomatic intracerebral hemorrhage (sICH), and mortality. Using R software version 4.1.2, we calculated pooled event rates and their corresponding 95% confidence intervals (CI) for all outcomes.

Results

Our analysis included eight studies with a total of 1903 patients. Definitions of young patients included age ranges of 18–49/50 years, 18–54/55 years, and 18–64/65 years. Functional independence was achieved in 62.0% of the patients, with an overall mortality of 9.0%. Moreover, successful reperfusion was achieved in 82.0% of the patients with sICH rates of 5.7%. There was significant heterogeneity among different analyses, which could not be attributed to the differences of the definition of young patients.

Conclusions

Following mechanical thrombectomy for AIS, patients aged 18–65 years achieved relatively high rates of functional independence and successful reperfusion and low rates of mortality and sICH.

Clinical Perspective

In this systematic review and meta-analysis of eight studies, we examined outcomes in young stroke patients, aged 18–65 years old, following mechanical thrombectomy for acute ischemic stroke. We found that young patients achieved high rates of functional independence, high rates of successful reperfusion, and low rates of mortality and symptomatic intracerebral hemorrhage.

While there have been several papers examining outcomes following mechanical thrombectomy for acute ischemic stroke in young patients, the results of these studies have yet to be pooled together in a meta-analysis. Our results indicate that young patients have good outcomes following mechanical thrombectomy. Further studies that examine these outcomes are warranted so that a higher-powered analysis can be performed to better informed clinicians regarding outcomes in this patient age-group cohort.

Keywords

Stroke thrombectomy young ischemic

Introduction

The global incidence of ischemic stroke is approximately 101.3 events per 100,000 people. In the United States, approximately 795,000 people experienced a new or recurrent stroke and an estimated 87% of those strokes were ischemic in nature.¹ Stroke in young adults aged 18 to 50 years was estimated to account for 10%–20% of these strokes.² Patients who develop stroke are often left with significant disability and mortality, and young stroke patients in particular are left with a disproportionately large socio-economic impact.³

Large vessel occlusions account for upwards of 30% of all ischemic strokes.⁴ With the advent of mechanical thrombectomy, endovascular therapy has been shown to be one of the most efficacious options in improving morbidity and reducing mortality in these select patients.^5–11 The HERMES study, a pooled study, showed that mechanical thrombectomy was efficacious and showed better outcomes in treatment of large vessel occlusion. Interestingly, older age, particularly over 80 years, was found to be a significant contributor to increased benefit of mechanical thrombectomy over control. 158 patients aged 18–49 years included in this study were found to have a non-significant reduction in disability over 90 days.¹² Despite these differences in outcomes, to date, no randomized control trials have been done with a focus on mechanical thrombectomy and young adult patients. Furthermore, retrospective and subgroup analysis of previous trials have shown varying results.

The objective of this study is to further examine the functional and mortality benefit of mechanical thrombectomy in young adult patients. In this paper, we performed a systematic review and meta-analysis of studies that have examined outcomes of young adults who have undergone mechanical thrombectomy for AIS.

Methods

Search strategy

On 22nd February 2022, following the PRISMA guidelines for performing systematic reviews, a systematic literature review of the English language literature was conducted in the AutoLit (Nested Knowledge, MN) software, from inception, using: PubMed, Embase, Web of science, and Scopus.¹³ Based on each database, different combinations of possible keywords and/or MeSH terms were used for that purpose. Keywords and MeSH terms included: “stroke”, “cerebral infarction”, “endovascular”, “thrombectomy”, “young”, “young adult”, “young people”, “stent”, and several others. Moreover, we did an extensive manual search through the references of the included articles to retrieve any missed papers.

Screening process

We included all original studies fulfilling our pre-determined Population/Intervention/Control group/Outcome (PICO). Population was young patients treated for AIS; Intervention was mechanical thrombectomy; there was no Control group; Outcomes of interest were the modified Rankin Scale (mRS) 0–2, mortality, symptomatic intracerebral hemorrhage (sICH), and thrombolysis in cerebral infarction (TICI) scale 2b/3. We excluded papers that focused on pediatric patients or elderly individuals, review articles, duplicate studies including the same patients presented in other included papers, case reports, case series with less than five patients, and conference abstracts. We did not pose any further limitations regarding study design or patients” characteristics.

Two authors (S.G and H.K.) completed the title and abstract screening against the pre-defined criteria. This was followed by a full text screening of any retained studies of the first screening step. In both stages, the senior author was consulted to resolve any conflicts in the decisions.

Data extraction

Following a pilot extraction, an extraction sheet was produced, and the extraction was performed by two authors (S.G and H.K.). The extracted data included study characteristics, baseline data of the included patients, and the previously mentioned outcomes of interest (mRS 0–2, sICH, mortality, TICI2b/3). “Good functional outcome” was defined as mRS 0–2 at 90-days post-treatment. “Successful reperfusion” was defined as TICI2b/3. After performing the extraction, a third author (M.L.) did an extensive revision of the extracted data to avoid any prior mistakes. The data that support the findings of this study are available from the corresponding author on reasonable request

Risk of bias

We assessed the risk of bias using the Newcastle-Ottawa Scale (NOS) for assessing the quality of cohort studies.¹⁴ Two authors evaluated the quality of each study (S.G and H.K.) and adjudicated by a third one, whenever needed.

Statistical analysis

Using R software version 4.1.2, we calculated pooled event rates and their corresponding 95% confidence intervals (CI). Random model was adopted to pool all data due to heterogeneity among the included. Heterogeneity was assessed using Q statistics and the I² test, where I² > 50% or p-value < 0.05 were considered significant.¹⁵ We performed subgroup analyses, based on the age of the included patients, to show possible differences and explore sources of heterogeneity. Among the performed analysis, the number of studies was less than ten, so publication bias (Egger's regression test) and the impact of sample size (meta-regression) were not tested.^{16, 17}

Results

Literature search results

Our literature search identified 861 studies. After screening for variables of interest A total of eight studies were included in our final meta-analysis (Figure 1). Four of the studies were retrospective in nature. Three studies used data acquired from a prospectively collected cohort. One study was based on sub-group analysis of the MR CLEAN registry.⁶

Figure 1.

PRISMA flow diagram showing the review process.

Risk of bias assessment

Following the risk of bias assessment, five of the included studies were given a “good” quality rating, while the other three studies were found to be of a “fair” quality. Supplementary Table S1 shows further details regarding our risk of bias assessment.

Study patient demographic data

From the eight studies included in our systematic review, a total of 1903 patients were included. Three studies included patients from the ages of 18–54/55 years,^18–20 three studies included patients from 18–49/50 years,^21–23 and two studies included patients from 18–64/65 years.^{24, 25} Mean follow-up duration was 3 months for all trials. The sample size of the studies included in the analysis ranged from 34–565 patients. Table 1 and Supplementary Table S2 show details regarding demographic review, patient outcomes, and procedural characteristics for each of the eight studies.

Table 1.

Patient characteristics and outcomes of the studies included in the meta-analysis.

Study	Sample size	Age range (years)	Baseline NIHSS, median (IQR)	Baseline NIHSS, mean (SD)	Age, years, median (IQR)	Age, years, mean (SD)	mRS 0–2, (%)	TICI 2b/3, (%)	Mortality, (%)	sICH, (%)
Singer, 2013	90	18–54/55					60	87
Deb-Chatterji, 2021	526	18–54/55	12 (8–17)		50 (46–54)		64.3	85	11.8
Chalouhi, 2014	45	18–54/55	13.5	14.1 (5)		45 (9.6)	77.8	93	7.5	2.2
Brouwer, 2022	310	18–49/50	14 (10–18)		44 (39–47)		61	64.2	6.8	2.9
Szmygin, 2021	34	18–49/50		16 (5.9)		41 (7.5)	65	79.4	12	15
Yeo, 2021	275	18–49/50	14 (10–19)			41.4 (7.3)	66.2	85.1	4.7	6.5
Roland, 2022	565	18–64/65	14 (9–18)		56 (48–61)		46.2	81.2	6.9	5.5
Hyte, 2015	58	18–64/65					64	N/A	21

NIHSS indicates National Institutes of Health Stroke Scale; mRS: modified Rankin Scale; TICI: thrombolysis in cerebral infarction; sICH: symptomatic intracerebral hemorrhage; IQR: interquartile range; SD: standard deviation.

Good functional outcome

Good functional outcome (mRS 0–2) was achieved in 1118 (59%) patients. Pooled random effects model of all age subgroups showed an event rate of 62.0% (95% CI 55.59–69.21) of achieving good functional outcome. Heterogeneity and variability between studies showed substantial heterogeneity (I² = 87%, t² = 0.020, p < 0.001) (Figure 2). In the 18–49/50 year age group (n = 619), good functional outcome was achieved at an event rate of 63.7% (95% CI 60.04–67.63). In the 18–54/55 year age group (n = 661), good functional outcome was achieved at an event rate of 66.6% (95% CI 58.68–75.68). In the 18–64/65 year age group (n = 623), good functional outcome was achieved at an event rate of 53.6% (95% CI 39.13–73.53). A test for subgroup differences indicated that there was not significant difference between the previously mentioned age groups (χ₂² = 1.61, df = 2, p = 0.447). Analysis of individual subgroups can be seen in Figure 2.

Figure 2.

Forest plot of modified Rankin Scale score (mRS) of 0–2 at 90 days. Results were stratified by definition of age group.

Mortality

1808 patients were included in mortality analysis. A total of 154 (8.5%) of patients died in the first 90 days. Pooled random effects model showed an event rate of 9.0% (95% CI 6.27–12.89) of mortality in the first 90 days after mechanical thrombectomy. Heterogeneity and variability between studies not attributed to sampling error was again substantial (I² = 76%, t² = 0.144, p < 0.001). Analysis of individual age subgroups can be seen in Figure 3.

Figure 3.

Forest plot of mortality at 90 days. Results were stratified by definition of age group.

Successful reperfusion

A total of 7 studies reported TICI outcomes and a total of 1834 patients were included in analysis. 1477 (81%) of patients achieved ≥ TICI 2b reperfusion. The rate that this occurred was 82.0% (95% CI 76.62–87.67). There was substantial variability and heterogeneity between studies (I² = 88%, t² = 0.007, p < 0.001). Analysis of subgroups can be seen in Figure 4.

Figure 4.

Forest plot of successful reperfusion (TICI 2b/3). Results were stratified by definition of age group.

Symptomatic intracerebral hemorrhage

5 studies reported data regarding sICH for a total of 1229 patients. 64 (5.2%) patients were reported to have sICH. Pooled random effects modeling showed that sICH occurred at a rate of 5.7%. Substantial heterogeneity was again noted (I² = 63%, t² = 0.151, p < 0.029). Analysis of subgroups can be seen in Figure 5.

Figure 5.

Forest plot of symptomatic intracerebral hemorrhage. Results were stratified by definition of age group.

Subgroup analysis for patients under 55 years of age

When examining the subgroup of patients between 18–55 years, we report good functional outcomes (mRS 0–2) with an event rate of 64.8% in a pooled random effects model. Mortality at 90 days occurred at a rate of 8.1%, sICH at a rate of 5.6%, and successful reperfusion at a rate of 82.0% in our pooled random effects models (Supplementary Figure S1-S4).

Discussion

We have performed, to our knowledge, the first systematic review and meta-analysis examining mechanical thrombectomy outcomes in young adult patients. Our study has shown that young adult patients aged 18–65 years who received mechanical thrombectomy achieved relatively high rates of good clinical outcome and remarkably low rates of mortality, even in the setting of modestly high rates of sICH. Subgroup analysis of patients from 18–55 showed similar results as well. While this study did not carry out a formal comparison between “young” and “old” cohorts of patients undergoing mechanical thrombectomy for AIS, it does provide important clinical data for young patients that not only can inform clinicians in discussions with patients and families, but also assist researchers in designing future trials of stroke interventions in young patient cohorts.

The current literature on mechanical thrombectomy outcomes focused on young adult patients is limited, and our literature search did not return any meta-analyses or randomized controlled trial data with a dedicated focus on young adult stroke patients. The current literature largely consists of retrospective and prospective studies which mostly conclude that younger patients achieve good functional outcomes.^18–25 Our study adds the perspective of a large cohort reporting favorable outcomes in young adults undergoing mechanical thrombectomy. When compared to literature focusing on treatment of AIS in young patients, there has been much more literature published detailing the etiology of AIS in young patients. It is interesting to note that of all strokes in young patients, a much higher proportion are due to hemorrhage when compared to their older counterparts.²⁶ Still, stroke of undetermined etiology was the most common etiology in this demographic.³

Previously, a direct comparison through a subgroup analysis between young and older patients of the MR CLEAN randomized controlled trial was conducted. The study showed that young adult patients had higher rates of functional outcome and lower mortality when compared to older patients.²¹ The HERMES study subgroup analysis of young adult patients, however, showed no significant differences favoring intervention when comparing against medical intervention alone.¹² What has been demonstrated, subsequently, is that while older patients (octogenarians, nonagenarians) benefit from mechanical thrombectomy, outcomes become worse when compared to their younger counterparts.^{27, 28} Interestingly, it was also shown that significantly lower number of attempts were used for elderly patients compared to younger patients.²⁷ This relationship may explain the increased incidence of sICH in the young adult population despite high rates of good clinical outcomes, but this is far from certain and many other variables are in play.²⁹ A more recent and robust cohort, the ARISE II study, has shown good functional outcome in upwards of two-thirds of patients which was favorable when compared with older studies. The rates of good functional outcomes and mortality in the ARISE II study are similar to those seen in our study, though no direct comparison can be made.³⁰

Though better outcomes in young stroke patients are evident, the reasons for this remains unclear. Current literature suggests that rates of lower recanalization in the elderly may be due to anatomic differences, such as an increased frequency in combination of extracranial and intracranial vessels and higher rates of tortuous vessel anatomy.¹⁸ Additionally, elderly patients may experience worse functional outcomes due to higher rates of co-morbidities. Specifically, there is lower medication compliance, altered metabolism, and higher drug interactions due to polypharmacy.^{31, 32}

Limitations of our meta-analysis include the quality of the papers in our study. No randomized controlled trials that fit our clinical question was available. We were also unable to definitively compare outcomes and measure significance between groups as a direct comparison arm was unavailable in the majority of studies. Additionally, the studies included in the meta-analysis heavily favored anterior circulation large vessel occlusion. Significant heterogeneity was noted between the studies. A test for residual heterogeneity indicated that the heterogeneity observed between studies cannot be attributed to differences in the age groups (I² = 70%, p = 0.005). Based on this, we can conclude that although there are differences in the definition of “young” patients, the better outcomes were not dependent on these different definitions. The heterogeneity seen could be attributed to multiple factors such as advancements in devices, technology, and techniques that has occurred through time. Despite these limitations, we were able to show that young adult patients undergoing mechanical thrombectomy for AIS, regardless of the definition of “young”, have excellent outcomes.

Further studies are recommended examining mechanical thrombectomy in a young adult cohort. This would allow for further clarification and estimation of the true effect size and benefits of mechanical thrombectomy in this cohort. Another area of interest includes the development of more aggressive selection criteria for mechanical thrombectomy in young patients. Finally, the etiology of ischemic stroke in young patients should be further studied.

Conclusion

In this meta-analysis examining functional outcomes of mechanical thrombectomy in young adult patients, we have found that young adults achieve excellent rates of good functional outcome and successful reperfusion and low rates of sICH and mortality.

Supplemental Material

sj-docx-1-ine-10.1177_15910199221121378 - Supplemental material for Outcomes of young patients following mechanical thrombectomy for stroke: A systematic review and meta-analysis

Supplemental material, sj-docx-1-ine-10.1177_15910199221121378 for Outcomes of young patients following mechanical thrombectomy for stroke: A systematic review and meta-analysis by Hassan Kobeissi, Michael Liu, Sherief Ghozy, Ramanathan Kadirvel and David F Kallmes in Interventional Neuroradiology

Supplemental Material

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Supplemental material, sj-xlsx-2-ine-10.1177_15910199221121378 for Outcomes of young patients following mechanical thrombectomy for stroke: A systematic review and meta-analysis by Hassan Kobeissi, Michael Liu, Sherief Ghozy, Ramanathan Kadirvel and David F Kallmes in Interventional Neuroradiology

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Supplemental material, sj-xlsx-3-ine-10.1177_15910199221121378 for Outcomes of young patients following mechanical thrombectomy for stroke: A systematic review and meta-analysis by Hassan Kobeissi, Michael Liu, Sherief Ghozy, Ramanathan Kadirvel and David F Kallmes in Interventional Neuroradiology

Footnotes

Acknowledgements

The authors acknowledge Karl Holub, Stephen Mead, Jeffrey Johnson, and Darian Lehmann-Plantenberg for their design, development, and support of the Nested Knowledge meta-analytical software.

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. D.F.K. holds equity in Nested Knowledge, Superior Medical Editors, and Conway Medical, Marblehead Medical; a consultant for MicroVention, Medtronic, Balt, and Insera Therapeutics; Data Safety Monitoring Board for Vesalio; and receiving royalties from Medtronic.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R01NS076491. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

ORCID iDs

Hassan Kobeissi

Michael Liu

Sherief Ghozy

Ramanathan Kadirvel

David F Kallmes

Supplemental material

Supplemental material for this article is available online.

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