Introduction
The effectiveness of mechanical thrombectomy (MT) for acute ischemic stroke (AIS) in octogenarians and nonagenarians remains debated. The Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials meta-analysis of individual patient-level data from five randomized controlled trials (RCTs) showed that AIS patients aged ≥ 80 years benefit from MT compared to standard medical therapy. Reference Goyal, Menon and van Zwam1 However, this meta-analysis included only 198 (15%) patients aged ≥ 80 years from a pooled total of 1278 patients, as elderly patients were either excluded from RCTs or under-represented. Indeed, three of the six major trials excluded older patients. Reference Jovin, Chamorro and Cobo2–Reference Bracard, Ducrocq and Mas4 Data on clinical outcome, intracranial hemorrhage (ICH), and procedural complications following MT in patients aged ≥ 85 years remain limited, while the proportion of stroke patients in this age group is increasing. Reference Jayaraman and Mc Taggart5–Reference Meyer, Alexandrou and Flottmann8 We hypothesized that MT achieves good outcomes in patients aged ≥ 85 years and aimed to identify predictors of outcome at 3 months in this patient population, using a large two-center cohort.
Methods
Patient Selection
This observational study retrospectively analyzed clinical and imaging data prospectively gathered from two comprehensive academic stroke centers (Centre Hospitalier de l’Université de Montréal, Québec, Canada; Neurological Hospital, Hospices Civils de Lyon, France) between January 2016 and November 2019. We included all patients aged ≥ 85 years treated by MT for an AIS with large vessel occlusion. This age cutoff was used since patients aged > 85 years were excluded from several MT trials and therefore data on MT in elderly patients derived from these trials include few patients over 85. Reference Goyal, Menon and van Zwam1
There were no systematic exclusion criteria based on pre-stroke modified Rankin scale (mRS) and National Institute of Health Stroke Scale (NIHSS) scores or extent of infarction on baseline imaging.
Neurovascular Imaging and Interventional Procedure
All patients underwent either computed tomography (CT) and CT-angiography or magnetic resonance imaging (MRI) and MR-angiography before MT. Repeat brain imaging using CT or MRI was performed 24–36 hours after MT or earlier in cases of clinical deterioration. On follow-up imaging, ICH was classified according to the European Cooperative Acute Stroke Study II criteria. Reference Larrue, von Kummer and Müller9 Symptomatic hemorrhage was defined as any ICH associated with neurological deterioration (NIHSS score increase of ≥ 4 points). An experienced neuroradiologist reviewed pre-treatment CT or diffusion-weighted MRI images and recorded the Alberta Stroke Program Early CT (ASPECT) score. Reference Barber, Hill and Eliasziw10 The occlusion site was assessed on the initial angiogram before MT. Patients were treated with aspiration catheters, stent retrievers, or a combination of both techniques. The choice of device was left to operator discretion. Embolism in a new territory was defined as a thromboembolic migration in a previously unaffected artery during the endovascular procedure. At the end of the procedure, the neuro-interventionalist determined a final modified thrombolysis in cerebral ischemia (mTICI) score. Successful recanalization was defined as an mTICI grade of 2b (perfusion with incomplete [≥ 50%] distal branch filling) or 3 (full perfusion with filling of all distal branches) on the final angiogram.
Data Collected
Baseline data on demographic characteristics (age, sex) and stroke risk factors (current smoking, hypertension, hyperlipidemia, atrial fibrillation, and diabetes mellitus) were collected at hospital admission. Neurological status was assessed using NIHSS score at admission. Pre-stroke functional status was assessed with the mRS score. Time from admission to initiation of intravenous thrombolysis with recombinant tissue-type plasminogen activator, to groin puncture, and to recanalization was recorded. Clinical outcome was assessed by the 90-day mRS score during a face-to-face neurological follow-up visit or via a structured telephone interview performed by an mRS-certified stroke research nurse.
Outcome Definitions
The 90-day mRS was used as the primary clinical outcome and was dichotomized into good outcome (mRS score ≤ 3 or equal to pre-stroke value) and poor outcome (mRS score 4–6). This outcome is aligned with other studies of elderly patients undergoing MT that have also defined a good outcome as an mRS of 0–3, given the higher levels of baseline disability in this population. Reference Drouard-de-Rousiers, Lucas and Richard7,Reference Meyer, Alexandrou and Flottmann8 The more conventional outcome of mRS score ≤ 2 or equal to pre-stroke value, termed favorable, was analyzed as a secondary outcome.
Other descriptive secondary outcomes were the proportion of patients with any ICH, symptomatic ICH, procedural complications (including intracranial arterial perforation, iatrogenic dissection, embolic event in a new territory, and groin hematoma), and death.
Statistical Analysis
Statistics were performed using SAS software 9.4 version (SAS Institute Inc., Cary, NC, USA). Categorical variables are displayed as the number and percentage of patients (n, %), and quantitative variables are presented as the median and interquartile range.
We explored factors associated with good outcome using univariate and multivariate stepwise logistic regression. Crude and adjusted odds ratios (aOR) are given with their 95% confidence interval (95% CI). We used a structured approach to select variables to be included in the multivariate model, associating literature search and exchange between experts in order to identify the relationships between the variables and include relevant factors in the model (patient and stroke characteristics). We entered in the multivariate model baseline demographic, clinical, and radiological characteristics (age, sex, center, pre-stroke mRS, NIHSS and ASPECT scores, and occlusion site), stroke risk factors, procedural variables (intravenous thrombolysis, successful recanalization, and time from admission to groin puncture), and ICH as explanatory variables. Interactions were tested and multicollinearity was screened using the COLLIN option on SAS. Significance level was set at α = 0.05.
Results
From January 2016 to November 2019, 151 patients aged ≥ 85 years (median age 88 years) were consecutively treated by MT at the two participating centers. Main patient and treatment characteristics are reported in Table 1. Intravenous thrombolysis was administered before MT in 55% (83 of 151) of patients.
Table 1 Baseline characteristics, procedural times, and 3-month outcome of all patients
ASPECTS = Alberta Stroke Program Early CT Score; ICA = internal carotid artery; IQR = interquartile range; IV r-tPA = intravenous recombinant tissue-type plasminogen activator; MCA = middle cerebral artery; mRS = modified Rankin scale; NIHSS = National Institutes of Health Stroke Scale.
Values expressed as n/total n (%) unless otherwise indicated.
* 1 missing data (n = 150).
** 5 missing data (n = 146).
Procedural Outcomes
Successful recanalization (mTICI ≥ 2b) was achieved in 74.2% (112 of 151). Baseline characteristics (age, sex, NIHSS and ASPECT scores, occlusion site, rate of intravenous thrombolysis) were not different according to successful recanalization status, apart from pre-stroke mRS score, which was higher in patients with successful recanalization (median [Q1–Q3], 1 [0–2] vs 2 [0–3] in patients with successful recanalization, p = 0.049).
Procedural complications occurred in 14.5% (17 of 117) of patients: there was 1 intracranial arterial perforation, 2 embolic events in a new territory, 5 iatrogenic dissections, and 11 groin hematomas.
On follow-up imaging, any ICH and symptomatic ICH occurred in 20.3% (28 of 138) and 3.6% (5 of 138) of patients, respectively.
Functional Outcome and Death
Ten patients were lost to follow-up despite several telephone attempts and were therefore excluded from the final functional outcome analysis. These patients had similar baseline characteristics (age, sex, pre-stroke mRS, NIHSS and ASPECT scores) as included patients (data not shown).
At 90 days, 33.3% (47 of 141) of all patients had a favorable functional outcome (mRS score ≤ 2 or equal to pre-stroke value), 44.7% (63 of 141) had a good functional outcome (mRS score ≤ 3 or equal to pre-stroke value), and 39.0% (55 of 141) had died.
Figure 1 provides an overview of mRS distribution at 90 days for the overall cohort and according to final recanalization status. Patients with successful recanalization had a significantly higher rate of good functional outcome (p = 0.013) (45.3% [48 of 106] vs 34.3% [12 of 35]) and a significantly lower mortality rate at 90 days (p = 0.006) (35.8% [38 of 106] vs 48.6% [17 of 35]) as compared to patients with failed recanalization (mTICI ≤ 2a). Notably, 54.7% (58 of 106) of patients had an unfavorable outcome despite successful recanalization (so-called “futile recanalization”).
Figure 1: Distribution of 3-month modified Rankin scale (mRS) score according to successful recanalization status. Successful recanalization was defined as modified TICI 2b/3 at the end of the endovascular procedure. *Adjusted p value for good outcome (3-month mRS score 0–3 or equal to pre-stroke value) is reported, multivariate stepwise regression model (Table 2).
In univariate analysis, lower NIHSS score at admission (p < 0.001), lower pre-stroke mRS score (p < 0.001), middle cerebral artery M1 segment occlusion site as opposed to other occlusion sites (p = 0.043), shorter time from admission to groin puncture (p = 0.046), and absence of ICH on follow-up imaging (p = 0.007) were predictors of good functional outcome (mRS ≤ 3 or equal to pre-stroke value) at 90 days. After multivariate analysis, lower NIHSS score at admission (aOR, 0.90; 95% CI, 0.83–0.97; p = 0.013), lower pre-stroke mRS score (aOR, 0.52; 95% CI, 0.36–0.76; p < 0.001), successful recanalization (aOR, 3.65; 95% CI, 1.32–10.09; p = 0.013), and absence of ICH on follow-up imaging (aOR, 0.42; 95% CI, 0.08–0.75; p = 0.013) remained as independent predictors of good functional outcome (Table 2). For favorable outcome (mRS ≤ 2 or equal to pre-stroke value), multivariate analysis yielded similar results, with the exception of successful recanalization, which was not associated with outcome (Supplementary Data).
Table 2 Univariate and multivariate logistic regression of factors associated with good outcome (3-month modified Rankin scale score ≤ 3 or equal to pre-stroke value)
ASPECTS = Alberta Stroke Program Early CT Score; ICA = internal carotid artery; IQR = interquartile range; IV r-tPA = intravenous recombinant tissue-type plasminogen activator; MCA = middle cerebral artery; mRS = modified Rankin scale; NIHSS = National Institutes of Health Stroke Scale; NS = not significant, p > 0.05, variables not retained in the stepwise logistic regression model.
* Multivariate logistic regression model using stepwise selection process including (n = 119) age, gender, pre-stroke mRS, NIHSS, ASPECTS, hypertension, diabetes mellitus, hypercholesterolemia, current smoking, atrial fibrillation, site of occlusion, IV r-tPA, recanalization, admission to groin puncture time, and ICH.
** 1missing data (n = 140).
Discussion
In this large cohort of consecutive AIS patients aged ≥ 85 years treated with MT, we found that successful recanalization is associated with a higher rate of good outcome and a lower rate of mortality at 90 days. This suggests that attempting to achieve recanalization in elderly patients using MT is worthwhile. A recent analysis of the MR CLEAN Registry has shown that successful recanalization was more strongly associated with a shift toward good functional outcome in older adults than in younger patients. Reference Groot, Treurniet and Jansen11
With a sample size of 151 patients aged ≥ 85 years, our study is one of the largest in the field. Most patients were women (75.5%), related to the higher life expectancy of women, and a majority had atrial fibrillation. Regarding the risk of symptomatic ICH and procedural complications, our results are in line with the results of previously published RCTs. Reference Goyal, Menon and van Zwam1,Reference Papanagiotou and White12
Good functional outcome at 90 days was observed in 44.7% of patients. This is less than what was observed in most major MT RCTs, further suggesting that the rate of good outcome after MT declines with increasing age, Reference Alawieh, Starke and Chatterjee6,Reference Groot, Treurniet and Jansen11,Reference Hilditch, Nicholson and Murad13 particularly in a “real-world setting”. Like others, Reference Drouard-de-Rousiers, Lucas and Richard7,Reference Meyer, Alexandrou and Flottmann8 we defined good functional outcome as an mRS score ≤ 3 or equal to pre-stroke value as it represents a reasonable outcome in an elderly population (24% of our patients had a pre-stroke mRS score ≥ 3). In elderly patients, a preserved ability to walk without the help of another person is an important determinant of relative functional independence and both mRS 2 and 3 have been found to be associated with similar health-related quality of life. Reference Rangaraju, Haussen, Nogueira, Nahab and Frankel14 A high 90-day mortality rate (39%) was also observed in our study, while large cohorts of younger patients treated by MT have shown mortality rates closer to 20%. Reference Goyal, Menon and van Zwam1 This high mortality likely reflects the frailty of the elderly population, with its higher burden of pre-stroke medical comorbidities and its increased susceptibility to developing post-stroke complications, Reference Meyer, Alexandrou and Flottmann8 but may also be related to higher rates of early limitation of care orders as compared to younger patients. Consequently, and somewhat reassuringly, we observed a relatively low rate (18.4%) of patients surviving at 3 months with moderately severe or severe disability (mRS score 4–5), fear of which might drive some physicians to withhold MT from elderly patients.
In our analysis, most predictors of good outcome, including pre-stroke mRS and NIHSS scores, were readily available at admission, emphasizing that decision-making for MT in this age group should be made on an individual basis, with particular consideration of patient’s pre-stroke level of disability. The influence of baseline clinical severity on functional outcome after MT in octogenarians has been suggested by others as well. Reference Kurre, Aguilar-Pérez and Niehaus15
Importantly, our data show that successful recanalization is an independent predictor of good functional outcome and is associated with a significant reduction of mortality at 90 days. A recent retrospective analysis of 124 nonagenarians treated with MT highlighted that only patients with successful recanalization after the first thrombectomy device pass had an increased rate of good outcome and a reduced 90-day mortality. Reference Drouard-de-Rousiers, Lucas and Richard7 In our series, successful recanalization was achieved in 74.2% of cases. A similar relatively low rate of recanalization (78.2%) was observed among nonagenarians, Reference Drouard-de-Rousiers, Lucas and Richard7 while recent series of younger patients have reported recanalization rates of up to 95%. Reference Schramm, Navia and Papa16 These lower rates of recanalization among patients aged ≥ 85 years may be explained by difficult thrombus access related to age-associated vessel tortuosity, failed thrombus retrieval, Reference Meyer, Alexandrou and Flottmann8,Reference Kastrup, Brunner and Hildebrandt17 or earlier procedural abandonment in cases of initial failure of recanalization. These findings suggest that alternative access approaches and the use of new thrombectomy devices should be evaluated in elderly patients in the hope of improving the rates of recanalization and consequently, good outcome. However, futile recanalization was common in our cohort (54.7%), suggesting that factors other than artery reopening, such as baseline functional status and comorbidities, delays in recanalization, age-dependent infarct core thresholds, Reference Nogueira, Jadhav and Haussen18 poor recruitment of collaterals, Reference Lin, Brott and Liebeskind19 and post-stroke complications are likely to influence outcome in elderly patients.
The presence of any ICH complicating reperfusion therapy was a significant predictor of poor outcome in our cohort, 55% of which received intravenous thrombolysis. Whether MT alone is superior to combined intravenous thrombolysis and MT with regard to functional outcome and hemorrhagic complications is not yet settled, Reference Yang, Zhang and Zhang20 but is of particular interest in elderly patients who may be at higher risk for ICH with thrombolysis. Reference Mazya, Egido and Ford21 However, current recommendations are to combine intravenous thrombolysis and MT, with no exception given for patient age. Reference Boulanger, Lindsay and Gubitz22
Our study has several limitations. First, it is a retrospective study of selected patients treated in high-volume MT centers. Our population had a high median NIHSS score (19), a low median pre-stroke mRS score (1), and a high median ASPECT score (9), pointing to a likely selection bias. Second, no control arm of elderly patients (only treated with intravenous thrombolysis or not treated with any reperfusion therapy) was available for comparison. Third, the potential role of a first-pass-effect, found by others to be associated with favorable outcome in the elderly, Reference Drouard-de-Rousiers, Lucas and Richard7 was not analyzed. Fourth, our approach was exploratory in that we may not exclude residual confounding factors and the effect estimates in our results may not reflect total effects of the variables on outcome. Finally, the association of early limitation of care orders with mortality could not be evaluated.
In conclusion, our data suggest that MT is relatively safe in selected AIS patients aged ≥ 85 years with procedural complications and symptomatic ICH, in line with those of previously published cohorts having a younger median patient age. Successful recanalization is achievable in about three-quarters of patients and is a predictor of good functional outcome and lower mortality at 90 days, supporting the utility of attempting to achieve recanalization in this population using MT. Importantly, only a minority of patients survived at 3 months with moderately severe or severe disability. However, lower rates of recanalization, higher mortality, and less frequent favorable functional outcomes can be expected at 90 days as compared to younger patients studied in the major MT trials. Withholding MT based on age alone does not seem justified, and therapeutic decision-making for elderly patients should be made on an individual basis with particular consideration of pre-stroke disability.
Disclosures
The authors report no disclosures.
Statement of Authorship
LD and AYP conceptualized and designed the study, collected the data, and drafted the manuscript. MB and ML collected the data and reviewed the manuscript for intellectual content. JH analyzed the data and reviewed the manuscript for intellectual content. CO conceptualized the study and reviewed the manuscript for intellectual content. WA, YB, ND, YD, OFE, LG, DI, GJ, FK, NN, JR, DR, CS and AW reviewed the manuscript for intellectual content.
Supplementary Material
To view supplementary material for this article, please visit https://doi.org/10.1017/cjn.2021.37.
