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Original research
Endovascular therapy versus thrombolysis in patients with large vessel occlusions within the anterior circulation aged ≥80 years
  1. Andreas Kastrup1,
  2. Freimuth Brunner1,
  3. Helmut Hildebrandt1,
  4. Christian Roth2,
  5. Michael Winterhalter3,
  6. Panagiotis Papanagiotou2
  1. 1 Department of Neurology, Klinikum Bremen-Mitte gGmbH, Bremen, Germany
  2. 2 Department of Neuroradiology, Klinikum Bremen-Mitte gGmbH, Bremen, Germany
  3. 3 Department of Anesthesiology, Klinikum Bremen-Mitte gGmbH, Bremen, Germany
  1. Correspondence to Professor Andreas Kastrup, Department of Neurology, Klinikum Bremen-Mitte, Bremen 28205, Germany; akastrup06{at}gmail.com

Abstract

Background and purpose In patients with large vessel occlusions, endovascular treatment (ET) has been shown to be superior to intravenous thrombolysis (IVT) in recent trials. However, the effectiveness of ET in elderly patients is uncertain.

Methods Using our stroke database, we compared the rates of good outcome (modified Rankin scale (mRS) ≤2), excellent outcome (mRS 0–1), poor outcome (mRS 5–6) at discharge, in-hospital death, infarct size, and symptomatic intracranial hemorrhage (SICH) in patients aged ≥80 years with distal intracranial carotid artery, M1 and M2 occlusions during two time periods.

Results From January 2008 to October 2012, 217 patients were treated with IVT and, from November 2012 to October 2017, 209 patients received ET with stent retrievers (with or without IVT). Significantly more patients in the ET group than in the IVT group had a good outcome (25% vs 16%, P<0.05), as well as an excellent outcome (12% vs 4%, P<0.01). Significantly fewer patients in the ET group than in the IVT group died (14% vs 22%, P<0.05) or had a poor outcome (35% vs 52%, P<001). The SICH rates were lower after ET than after IVT (1% vs 6%, P<0.01), and the infarct sizes were smaller after ET than after IVT.

Conclusions Compared with IVT, the routine use of ET significantly improved the early clinical and radiological outcome in patients with anterior circulation large vessel occlusions aged ≥80 years. Nevertheless, poor outcome rates were high so the role of ET needs to be defined further in this population.

  • stroke
  • thrombolysis
  • thrombectomy

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Introduction

In the past few years, endovascular treatment (ET) (with the use of third-generation retrievable stents in the majority of patients) in addition to intravenous thrombolysis (IVT) has become the treatment of choice in patients with proximal intracranial occlusions of the anterior circulation based on the results of several landmark trials.1 In these trials, the benefit of ET in addition to IVT on outcome was principally observed across all age groups, including octogenarians.2 However, advanced age was an exclusion criterion in two trials3 4 and the number of older patients included in the other trials was rather small, likely reflecting a selection bias (in the MR CLEAN trial, for instance, only 16% of the patients were aged ≥80 years).2 In addition, several case series and registries have clearly shown that older patients have a poorer clinical outcome after ET than younger patients, even despite adequate recanalization rates.5–9 Notably, ET was not compared with IVT in these case series.5–9

Against the background of an ageing population, the question therefore arises whether ET is superior to IVT in older patients. Using our prospectively obtained database of a high-volume stroke center, we compared the early clinical and radiological outcome in older patients (≥80 years) with anterior circulation large vessel occlusions during two time periods. During the first time period all patients had been treated with systemic thrombolysis whereas ET with stent retrievers (with or without systemic thrombolysis) was routinely used during the second time period.

Methods

Study population

We retrospectively analyzed prospectively collected clinical and imaging data of patients with distal intracranial carotid artery (ICA) and/or M1 and/or M2 segments of the middle cerebral artery and an admission National Institutes of Health Stroke Scale (NIHSS) aged ≥80 years, who had been treated from January 2008 through October 2017. Patients with distal occlusions beyond the M2 segment were excluded. In addition, patients with posterior circulation strokes and with bilateral strokes were excluded from the current analysis. Before November 2012 all patients were treated with systemic thrombolysis within 4.5 hours. After November 2012 a systematic approach (using no upper age limit or specific imaging exclusion criteria) comprising ET with and without systemic thrombolysis was implemented in patients who presented within 6 hours (within 4.5 hours in patients additionally treated with recombinant tissue plasminogen activator) of symptom onset. These patients were treated with retrievable stents: Solitaire FR (Covidien); pREset (Phenox); Catch+ (Balt).

Demographic data (age, gender) and stroke risk factors (arterial hypertension, diabetes, hyperlipidemia, atrial fibrillation) were collected. The time to thrombolysis (or to thrombectomy in patients without prior systemic thrombolysis) from stroke onset was also noted.

The protocol of our stroke registry had been approved by our local ethics committee. Because of the retrospective character of this study, the lack of treatment influence, and the clinical data having been collected as part of a national quality control program, the study was exempt from informed consent. Using our stroke database, the clinical outcomes of patients treated before December 2014 as well as a subgroup analysis have been published previously.10 11

Imaging techniques

Non-enhanced CT (NCT) and CT angiographic (CTA) acquisitions before treatment were performed on a four-row multisection CT scanner (Siemens Volume Zoom, Siemens Medical Solutions, Forchheim, Germany).

NCT was performed with the patient in a head holder in the transverse plane. Using the following parameters, incremental CT acquisitions of the brain were obtained: 120 kVp, 250 mA, 2 s scan time, and 5 mm section thickness.

To allow visualization of the vascular tree from the distal common carotid artery to the intracranial vessels, the CTA covered the region from the fifth vertebral body up to the vertex. The following parameters were used: 120 kVp, 200 mAs, 4×1 mm collimation, 5.5 mm/rotation table feed, and 0.5 s rotation time. A total of 100 mL of contrast material was injected intravenously at a flow rate of 4 mL/s using a power injector. For follow-up studies, repeated CT or MR scans were obtained after 1–3 days of treatment or immediately in case of clinical worsening.

Image analysis

CT and MRI analyses were performed jointly by a board-certified neuroradiologist (PP, 18 years of neuroimaging review experience) and a stroke neurologist (AK, 16 years of neuroimaging review experience) on a high-resolution monitor. Except for the side of involvement, the readers were blinded to the clinical data whereas they were not blinded to the treatment modality. The CT scans without contrast were analysed first, followed by the CTA source images. At this stage the readers were blinded to the follow-up images. The CTA source images were used to determine the Alberta Stroke Program Early CT score (CTA-SI-ASPECTS).12 The follow-up CT or MR scans were used to determine the final ASPECTS as a marker of infarct extent, as well as the incidence of symptomatic intracranial hemorrhages (SICH) using the ECASS III definition.

End points

Functional outcome was assessed by a senior vascular neurologist who was certified for NIHSS and modified Rankin Scale (mRS) scoring (AK, FB). The mRS at the time of hospital discharge was used for early clinical outcome analysis. A favorable early clinical outcome (mRS 0–2 at the time of discharge) was the primary outcome measure. Secondary outcome measures included excellent clinical outcome (mRS 0–1 at the time of discharge), poor clinical outcome (discharge mRS 5–6), in-hospital death, and shifts in disability levels over the entire range of mRS scores at the time of discharge. Imaging outcome measures included the extents of the infarcts and SICH rates.

Statistical analysis

Continuous values were expressed as mean±SD or as median (IQR). Nominal variables were expressed as counts and percentages. For comparisons of categorical data, two-tailed χ2 statistics with Yates correction and univariate Fisher’s exact test were used. The Fisher’s exact test was used when the predicted contingency table cell values were less than five. Analyses of continuous variables were performed with an unpaired Student’s t-test or, in case of abnormally distributed data, with a Mann–Whitney U test. A Cochran–Mantel–Haenszel test was used for the shift analysis.

A stepwise forward multiple regression analysis (P in. 05, P out. 1) was applied to determine the independent predictors of a good early clinical outcome (mRS ≤2). Results are presented as odds ratios (ORs) with 95% CI.

A value of P<0.05 was considered to indicate a statistically significant difference. All statistical analyses were performed with SPSS Version 22.

Results

Demographic data

From January 2008 to November 2017 a total of 1198 patients with distal intracranial carotid artery, M1 and M2 occlusions had been treated with IVT or ET at our institution. The study group comprised 426 patients (36%) aged ≥80 years. There were 134 men (31%) and 292 women (69%) with a mean age of 85±5 years. Among these, 217 patients had been treated with systemic thrombolysis (IVT group) and a total of 209 patients had received ET (ET group). In the ET group, 64 patients (31%) had had contraindications for a systemic thrombolysis and thus were solely treated with ET. Table 1 summarizes the baseline characteristics of both treatment groups. Notably, patients in the ET group more often had had hypertension, hyperlipidemia and ICA and/or M1 occlusions than patients in the IVT group. In addition, early signs of ischemia were more often present in the ET group than in the IVT group, likely reflecting the fact that several patients in the ET group were treated beyond 4.5 hours or had unknown times of symptom onset.

Table 1

Patient characteristics according to treatment

Clinical outcome

Overall, 87/426 patients (20%) had a favorable early clinical outcome (mRS 0–2), 34/426 patients (8%) had an excellent early clinical outcome (mRS 0–1), and 186/426 patients (44%) had a poor clinical outcome (mRS 5–6), respectively. 18% of the patients died within the hospital. Significantly more patients in the ET group than in the IVT group had a good outcome (25% vs 16%, P<0.05), as well as an excellent outcome (12% vs 4%, P<0.01). Significantly fewer patients in the ET group than in the IVT group died (14% vs 22%, P<0.05) or had a poor outcome (35% vs 52%, P<0.001)(table 2).

Table 2

Clinical and radiological outcomes according to treatment

In the subgroup of ET patients who had had contraindications for a systemic thrombolysis and thus were solely treated with ET, 11/64 patients (17%) had a favorable early clinical outcome (mRS 0–2), 6/64 patients (9%) had an excellent early clinical outcome (mRS 0–1), and 26/64 patients (41%) had a poor clinical outcome (mRS 5–6).

The shift analysis demonstrated that there was a significant difference between the two treatment modalities in the overall distribution of the discharge mRS scores (figure 1).

Figure 1

Distribution of modified Rankin Scale (mRS) scores at the time of discharge in the two treatment groups.

In the multivariate regression analysis the presence of a favorable SI-ASPECTS (OR 1.4, 95% CI 1.17 to 1.63, P<0.001), admission NIHSS (OR 0.84, 95% CI 0.8 to 0.9; P<0.001), age (OR 0.94, 95% CI 0.89 to 0.99; P<0.05), and ET (OR 2.88; 95% CI 1.6 to 5.1, P<0.001) were significantly associated with a good early clinical outcome.

Radiological outcome

In the ET group, good recanalization (defined as Thrombolysis in Cerebral Infarction (TICI) 2b and 3) was achieved in 127 (61%) of the patients.

The follow-up ASPECT scores were used as a marker of infarct extent. Follow-up imaging was not available in 37 patients. In good agreement with the clinical results, the infarct sizes were smaller after ET than after IVT in both treatment groups (follow-up ASPECTS 6 (IQR 3–8) in the IVT group vs follow-up ASPECTS 7 (IQR 4–8) in the ET group; P<0.05).

For the entire cohort, the overall incidence of SICH (using the ECASS III definition) was 15/426 (3%). The SICH rates were significantly lower after ET than after IVT (13/217 in the IVT group vs 2/209 in the ET group, P<0.05).

Discussion

Based on a large prospectively recorded database of a high-volume academic stroke center and two time periods of treatment, the goal of this study was to compare the clinical and radiological outcome in older patients (≥80 years) with large vessel intracranial occlusions within the anterior circulation after IVT or ET with modern stent retrievers. Compared with IVT, the routine use of ET significantly improved the early clinical and radiological outcome in these patients. However, after IVT every second patient had a very poor early clinical outcome compared with every third patient after ET. Irrespective of the treatment modality, the prognosis was even poorer in the subgroup of nonagenarians.

One third of the patients with a large vessel occlusion within the anterior circulation who had been treated at our institution during the study period were aged ≥80 years, which fits well with a previous report showing that approximately 30% of all first-ever stroke patients are aged ≥80 years.13 These numbers stress the importance of finding the optimal treatment in these patients, all the more considering the fact that the elderly population will grow substantially in the coming years.

To date, only a few randomized trials comparing ET with IVT have incorporated older patients (≥80 years).14–16 In the MR CLEAN trial, ET was superior to IVT in 81 patients aged ≥80 years.14 In the ESCAPE trial a favorable good clinical outcome after 3 months was observed in 37% of the patients aged >80 years after ET compared with 18% after IVT.16 In principle, our results are in good agreement with these trial data and show that ET is also superior to IVT in older patients under daily routine conditions.

Although it was not the objective of this study to compare the outcome between younger and older patients, we could show that, for our entire study population, age was negatively associated with a good clinical outcome irrespective of the treatment modality.10 In contrast, the effect of ET on clinical outcome was not influenced by age in the three interventional trials, which also included older patients.2 However, only 16% of the patients included in the MR CLEAN trial were ≥80 years, so this finding could at least partially also be attributed to a selection bias.14 In good agreement with our results, rather low rates of good clinical outcome and high rates of poor outcome after ET in patients aged ≥80 years have also been reported in other series.5 7 9 In the recently published STRATIS registry the percentage of patients achieving a good clinical outcome at 90 days (mRS 0–2) decreased from 52% in patients aged 80–84 years to 38% and 26% in those aged 85–89 years and ≥90 years, respectively.7 In that registry, the mortality rates were 24%, 28%, and 35% at 90 days in the three age groups. In the MR CLEAN pretrial registry only 23% of the patients aged 71–93 years who were treated with ET achieved a mRS of 0–2 after 3 months and 20% of the patients had died.5 As in these case series, the low rates of good clinical outcome or rather high rates of poor clinical outcome in patients aged ≥80 years in this study were not attributable to increased rates of hemorrhagic complications. In fact, it is noteworthy that the SICH rates were extremely low in the ET group.

In the ET group good recanalization (TICI 2b and 3) was achieved in 61% of the patients, which is lower than the recanalization rates of approximately 75% found in our entire case series (data not shown).10 In our series, this finding likely reflects the increasing number of patients with no recanalization (TICI 0) due to aortic and supra-aortic vessel tortuosity leading to a failure to reach the intracranial vessels with the stent retrievers with advanced age.

While the rather low recanalization rates could have contributed to our clinical results in the ET group, a poor prognosis after ET in older stroke patients has been repeatedly observed despite good angiographic recanalization rates.7 17 Aside from lower recanalization rates and irrespective of the treatment modality, several factors could therefore also account for the rather poor prognosis in our older stroke patients with acute large vessel occlusions in the anterior circulation. Among others, these likely include pre-existing medical or cognitive comorbidities, a higher burden of decreased neuronal plasticity with a poorer potential for neurologic rehabilitation, and withdrawal of care.18

The strengths of our study include the large sample size as well as the homogeneity of the sample from a single institution and having been evaluated and treated by the same stroke team. However, certain limitations of the present report need to be acknowledged. First, although we used a prospectively collected cohort, the impact of ET or IVT on early clinical and radiological outcome was determined in a non-randomized and retrospective fashion. Hence, the study holds all the drawbacks of observational design. Second, the discharge mRS scores served as markers of early clinical outcome while the time point generally recognized as most appropriate to assess functional outcome after ischemic stroke is 3 months. On the other hand, a recent reanalysis of the NINDS tPA stroke trial has indicated that the day 7 mRS can serve as a good proxy for the 90-day mRS.19 Third, the status of recanalization was not determined routinely in the IVT group so this important variable was not considered in our analyses. Fourth, we did not systematically assess the patients' prestroke cognitive functions, which clearly have a potential impact on outcome, especially in older patients.

In conclusion, we extend previous trial data and show that ET improves clinical outcome in patients aged ≥80 years compared with IVT in everyday clinical practice. However, many patients still had a poor outcome so there is an ongoing need to further define the role of ET in this patient group.

References

Footnotes

  • Contributors AK, FB, PP: study design, data acquisition, critical data review, interpretation of data. HH, CR, MW: data acquisition and interpretation of data. AK, FB: primary manuscript writing, tables, and figure. AK, FB, HH, CR, MW, PP: critical revision and final approval of the manuscript.

  • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval Local Ethics Committee of the Ärztekammer Bremen.

  • Provenance and peer review Not commissioned; externally peer reviewed.