Five-Year Outcomes After Endovascular Treatment for Large Vessel Occlusion Stroke

Background The long-term outcomes of acute large vessel occlusion (LVO) in anterior circulation treated by endovascular treatment (EVT) remains to be determined. The aim of this study was to assess the 5-year outcomes of patients with LVO who underwent EVT. Methods This study was an observational, nationwide registry of consecutive patients with acute LVO who received EVT in 28 comprehensive stroke centers in China. The primary outcome was the proportion of favorable outcome [modified Rankin Scale score (mRS) 0–2] at 5 years. Secondary outcomes included proportions of patients with excellent outcome (mRS 0–1), all-cause mortality and risk of stroke recurrence at 5 years. Results A total of 807 patients were included into the study and had 90-day follow-up data, 657 patients had 5-year follow-up data. At 90 days, 218 patients (27.0%) had an excellent outcome, 349 patients (43.2%) had a favorable functional outcome. 199 patients (24.7%) died. At 5 years, 190 patients (28.9%) had an excellent outcome, 261 patients (39.7%) had a favorable functional outcome, 317 patients (48.2%) died and 129 (28.2%) had stroke recurrence. Because of missing 5-year follow-up data, among available 269 patients who achieved functional independence at 90 days, 208 (77.3%) maintained favorable outcome, 19 (7.1%) had disability (mRS 3–5) and 42 (15.6%) died at 5 years. Furthermore, among available 189 patients with mRS 3–5 at 90 days, 53 (28.0%) patients achieved favorable functional outcome, 60 (31.7%) patients maintained unfavorable functional outcome and 76 (40.2%) patients died within 5 years. Multivariate analyses identified that younger age [odds ratio (OR): 0.96; 95% CI, 0.93–0.99; P = 0.009], lower mRS at 90 days (OR: 0.15; 95% CI, 0.10–0.23; P < 0.001) and absence of stroke recurrence (OR: 0.001; 95% CI, 0.000–0.006; P < 0.001) were significantly associated with favorable outcome at 5 years. Advanced age (OR: 1.06, 95% CI, 1.04–1.08; P < 0.001), higher mRS at 90 days (OR: 0.84; 95% CI, 0.73–0.98; P = 0.021) and atrial fibrillation (OR: 1.63; 95% CI, 1.02–2.60; P = 0.04) were independent factors for stroke recurrence. Conclusion Our results indicated that the beneficial effect of EVT in patients with acute LVO can be sustained during the course of at least 5 years. Reducing the risk of stroke recurrence by anticoagulation for atrial fibrillation may be a crucial strategy to improve long-term outcome.


Introduction
Stroke is one of the leading causes of disability and death worldwide 1  With improvements in acute care, longer term outcomes will impact the organization of stroke care systems and the allocation of health care resources. This may be particularly true for stroke care organization in developing countries which have a higher stroke burden, but more limited health care resources. 9,10 Therefore, we conducted this nationwide, observational study (SUSTAIN study) to assess the long-term outcomes after EVT for AIS due to LVO in the anterior circulation. This study has been registered on the website, Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) (Registration No. ChiCTR1900020671).

Study design
The SUSTAIN study was an observational, nationwide registry of consecutive patients presented with acute anterior circulation stroke in whom an EVT procedure

Inclusion criteria
Patients can be enrolled in the study if they fulfilled the following criteria: 1) age 18 years or older; 2) were diagnosed with AIS; 3) a LVO in anterior circulation confirmed by computed tomographic angiography, magnetic resonance angiography, or digital subtraction angiography; 4) initiation of intravenous recombinant tissue plasminogen activator (rt-PA) within 4.5 hours or intravenous urokinase within 6 hours of LVO; 5) underwent endovascular recanalization treatment; 6) informed consent.

Exclusion criteria
Patients will be excluded from the study in case of: 1) pre-existing dependency with a modified Rankin Scale (mRS) ≥ 2; 2) neuroimaging evidence of cerebral hemorrhage on presentation; 3) patients without follow-up information; 4) incomplete baseline critical data (e.g., imaging and time points) 5) currently in pregnant or lactating; 6) serious, advanced or terminal illness.

Participating center eligibility
To avoid selection bias, all centers were obliged to enter all consecutive patients in the study. To be fully eligible for participation in the cohort study, study site selection had to meet the following minimum criteria: all study centers were required to have performed at least 30 endovascular procedures annually, including at least 15 thrombectomy procedures; all intervention teams were certified interventionists for EVT on large artery occlusion.

Treatments
Patients underwent EVT which comprised mechanical thrombectomy, thromboaspiration, balloon dilation, stenting, intra-arterial thrombolysis, or various combinations of these approaches. The mechanical thrombectomy may consist of thrombus retraction, aspiration or use of a stent retriever device. Generally, solitaire Re-occlusion often occurred after thrombectomy in atherosclerotic disease, therefore, rescue therapy including balloon dilation, stenting, intra-arterial thrombolysis, and glycoprotein IIb/IIIa inhibitor (GPI) might be utilized to retrieve recanalization. After recanalization of the target artery, most of the patients were transferred to the neuro-intensive care unit for at least 24 hours with their systolic blood pressure maintained at 120-140mmHg. Additionally, the patients who underwent extracranial or intracranial stent implantation were prescribed antithrombotic medication to prevent acute stent thrombosis. For the patients without prior intravenous thrombolysis (IVT), loading doses of clopidogrel (300 mg) and aspirin (300 mg) were given, or a low dose of GPI was bolus-injected intra-arterially and maintained for at least 24 hours, while for those with prior IVT, clopidogrel (75 mg) and aspirin (100 mg) were given after 24 hours of IVT, then all the patients were given clopidogrel (75 mg/d) and aspirin (100 mg/d) for 1-3 months.
Patients received medical treatment, e.g. intravenous IVT with rt-PA or urokinase, antiplatelet drugs, systematic anticoagulation, or combinations of these medical treatments, as described in the guidelines for the management of AIS 11 .

Data collection
We

Follow-up
At 24 hours, a clinical examination including the National nstitutes of Health Stroke Scale (NIHSS) will be carried out. At 48 hours, patients will undergo CTA or MRA imaging to evaluate the recanalization rate and CT to assess the cerebral hemorrhage.
At one-week, clinical status, NIHSS score, and adverse events will be reported. At 90 days, 1 year, 2 years, 3 years, 4 years and 5 years, mRS and stroke recurrence will be recorded.

Primary efficacy outcome
The primary outcome measure was the proportion of patients with good clinical outcome (mRS 0-2) at 5 years after stroke as assessed by trained local neurologists who were blinded to all clinical data. The mRS is a 7-level scale (range, 0 [no symptoms] to 6 [death]) for the assessment of neurologic functional disability.

Secondary efficacy outcomes
Secondary outcomes included the proportion of patients with good clinical outcome (mRS 0-2) at 90 days, excellent clinical outcome (mRS 0-1) at 90 days, excellent clinical outcome (mRS 0-1) at 5 years; death from any cause during the study period after stroke; risk of stroke recurrence that occurred at 90 days and 5 years after stroke.
Symptomatic intracerebral hemorrhage (sICH) at 48 hours, procedure-related complications (e.g., arterial perforation, arterial dissection, and embolization in a previously uninvolved vascular territory), and serious adverse events. The technical efficacy outcomes regarding recanalization were substantial reperfusion, as assessed by means of catheter angiography in the EVT group and defined as a modified Treatment in Cerebral Infarction score of 2b (50 to 99% reperfusion) or 3 (complete reperfusion). Stroke was defined according to the World Health Organization criteria as "rapidly developing symptoms and/or signs of focal, and at times global, loss of cerebral function, with symptoms lasting more than 24 hours or leading to death with no apparent cause other than that of vascular origin." 16 Although the definition of recurrent stroke was not strictly identical in each study, in practice, we used the above definition to define recurrent stroke as stroke and met the following criteria: there was clinical evidence of the sudden onset of a new focal neurological deficit with no apparent cause other than that of vascular origin (i.e., the deficit could not be ascribed to an inter-current acute illness, epileptic seizure, or toxic effect) occurring at any time after the index stroke; or there was clinical evidence of the sudden onset of an exacerbation of a previous focal neurological deficit with no apparent cause other than that of vascular origin. [17][18][19] Blinding All those involved in the subsequent clinical and imaging assessment of outcomes will be blinded to treatment allocation.

Imaging core laboratory
Centralized imaging core labs will be used in this study to provide consistent evaluation of images. The imaging core laboratory evaluated the findings on baseline non-contrast CT for the posterior circulation-Alberta Stroke Program Early CT Score

Clinical events committee
The clinical events committee will be comprised of three expert physicians who are independent of the investigational sites. This committee will be responsible for the review and validation of all complications that occur over the course of the study and the subsequent classification of these complications as related to the device or procedure.
Members of the clinical events committee will review all complications and adjudicate them as defined in the adverse event section in the clinical events committee manual of operations. The clinical events committee can request additional source documentation and any imaging obtained in support of the adverse event to assist with adjudication.

Statistical analysis
Statistical analyses were performed using SPSS method) was used to identify independent predictors for poor functional outcome.
Kaplan-Meier analysis was used to reflect the long-term survival and stroke recurrence probability of LVO patients treated with EVT. As stated earlier, patients who did not consent to the extended follow-up may introduce an important selection bias. To gain as much information as (legally) possible on the clinical status of these patients, a waiver from the Institutional Review Board was obtained to assess the vital status of these patients at five years of follow-up. This information will be used for the survival analysis as well as for the sensitivity analyses of the outcome.  23 However, few studies have investigated 5 or more years outcomes for AIS treated with EVT. In the current study we extend the follow-up duration to five years after stroke to estimate the effect of EVT on functional outcome over the longer term. Secondary objectives include the effect of EVT on stroke recurrence and mortality during five years.

Discussion
During longer term follow-up studies, loss to follow-up is a well-known phenomenon, resulting in smaller sample sizes. Furthermore, loss to follow-up may cause serious attrition bias. Both these problems may play an important role in our study. Therefore, we will provide clear information on the flow of patients through the study and differences in baseline and measured variables, and we will perform additional sensitivity analyses for different scenarios.
The results of our study will provide information on the five-year clinical effectiveness of EVT for patients with AIS due to large vessel occlusion in the anterior circulation. The benefit of EVT on short-term disability might translate into longer term improvements in survival and functional status, which may be useful for individual treatment decisions and estimates of cost-effectiveness. Subsequently, it will have important additional value concerning implementation of EVT all over the world.