Endovascular Thrombectomy Eligibility in the 0-24-Hour Time Window at a Large Academic Center in India
Keywords: Acute ischemic stroke, eligibility, endovascular treatment, extended time window, thrombectomy
Stroke is one of the leading causes of disability and the second most common cause of death worldwide. Acute ischemic stroke (AIS) is the major stroke type contributing to over 85% of all strokes. The patients presenting within the first few hours have the highest chance of benefit with definitive treatment in the form of thrombolysis or thrombectomy. The updated AHA/ASA AIS guidelines have extended the window of opportunity for endovascular thrombectomy (EVT) for patients with anterior circulation large-vessel occlusion (ACLVO) to up to 24 h. This has been based on the results of the Diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake up and late presenting strokes undergoing neurointervention with Trevo (DAWN) and Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE)-3 trials., However, data regarding the proportion of patients who are eligible for thrombectomy, especially in the developing world, are lacking. Such data are required to prioritize the allocation of healthcare budget, training, and infrastructure development. Also, in the 'real world,' the benefits may be different from the strict inclusion of patients in the clinical trials., This is of special relevance in the developing world, with the increasing incidence of stroke and under-developed stroke systems of care.,
While estimates in the developed world have been previously explored,[11–13] the variability in the stroke etiology and demographics between the regions highlights the importance of data specific to the developing world. The aim of our study was to determine the proportion of patients who are eligible for EVT in the 0–24-h time window.
The study included patients with AIS presenting to the emergency room (ER) of a tertiary care teaching hospital in North India. The patients within 24 h of symptom onset were included in the study. The data were collected retrospectively from the charts and records drafted prospectively. The patients presenting to the ER between July 2017 and September 2019, who were under the care of the team of co-investigators (DV, KP, AKS, MT, RKS, and AKP), were enrolled in the study. Our center is a tertiary care hospital with 1,500 beds spread across multiple facilities and is the only government-funded institution capable of performing EVT in New Delhi. Written informed consent was taken for data collection. The study was approved by the Institute Ethics Committee (IEC-337/08.05.20).
Inclusion and exclusion criteria
All patients ≥18 years of age with the clinical diagnosis of AIS confirmed by non-contrast computerized tomography (NCCT) head/magnetic resonance imaging (MRI) brain were included in the study. In cases of wake-up stroke, the last seen well (LSW) time was determined as the onset time. The patients with pre-existing metabolic or psychiatric conditions which would confound the neurological function evaluation were excluded. The patients with intracerebral hemorrhage, cerebral venous sinus thrombosis (CVST), stroke mimics, and strokes presenting beyond 24 h were excluded.
The diagnosis of AIS was made by the clinical history and examination with supporting NCCT head and Computerized Tomography (CT) angiography (CTA). In cases of diagnostic uncertainty, MRI brain was performed. The demographic characteristics including age, sex, and time taken to reach the ER were noted. Risk factors such as diabetes, hypertension, smoking, dyslipidemia, coronary artery disease (CAD), underlying rheumatic heart disease (RHD), and atrial fibrillation (AF) were recorded. Details of pre-morbid functionality were registered in the form of modified Rankin Scale (mRS) score. The stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). The details of the investigations in the form of NCCT head, Alberta stroke program early CT score (ASPECTS), CTA findings, presence of large-vessel occlusion (LVO), and MRI findings were recorded. Management in the form of thrombolysis (and the agent used), thrombectomy, and surgical decompressive hemicraniectomy was noted.
EVT eligibility for AIS in the 0–6-h time window was based on the following criteria: NIHSS score >= six, presence of ACLVO (internal carotid or middle cerebral artery M1 occlusion), ASPECTS >=six, and baseline mRS zero to two. In the 6–24-h time window, as per the guidelines, the clinical trial-specific selection criteria included specific radiological imaging criteria (DAWN trial: clinical-core mismatch, DEFUSE-3 trial- target mismatch). At our center, all AIS patients did not undergo advanced imaging (CT perfusion or MRI). The CT perfusion imaging capability was not available during the study period and MRI brain was performed in only selected cases. Hence, we explored the eligibility for EVT based on non-contrast CT head imaging data (ASPECTS ≥6) using modified DAWN/DEFUSE-3 criteria (ACLVO, LSW 6–24 h, NIHSS at admission ≥ 10, ASPECTS ≥ 6). The hospital course, mRS at discharge, and in-hospital mortality were recorded.
A descriptive analysis of the results was carried out using the SPSS version 22.0 statistical package for MS Windows (SPSS Inc., Chicago, IL, USA). Continuous variables were reported as the mean and standard deviation (SD) in the presence of a normal sample distribution as confirmed by the Kolmogorov–Smirnov test. The median and interquartile range (IQR) were calculated in the presence of a non-normal distribution. The categorical variables were reported as absolute and relative frequencies. We chose the denominators based on (1) patients with AIS within 0–6-h window (with and without ACLVO), (2) patients with AIS in the 6–24-h window (with and without ACLVO).
In the study period between July 2017 and September 2019 (27 months), there were 221 patients with AIS, who presented within 24 h and 61.5% (136/221) arrived within 6 h [Figure 1]. Therefore, approximately five patients per month presented within 0–6 h and three patients per month presented within 6–24 h of LSW. The mean age of the patients was 54.4 (16.0) years and 33.9% (75) were females.
The stroke risk factors included dyslipidemia (69.7) and hypertension (63.3%), followed by CAD (37.6%), smoking (34.8%), and diabetes (29.0%). Non-valvular atrial fibrillation (NVAF) was present in 12.7% (28) of the patients while 87.0% (20/23) of the patients with RHD had AF [Table 1].
Zero to six hours (n = 136)
The median time to the LSW was 2.0 (1.5; 3.8) h. Most patients in this cohort arrived within 3 h of the onset of the symptoms (71.3% [97/136]). The mean age was 56.0 (15.8) years and the median NIHSS was 10 (6;17). Most of the patients were males (83 [61.0%]) and had a pre-morbid mRS of 0 (77.2% (105)). The patients with NIHSS ≥6 and ACLVO constituted 43.4% of this group. More than half of the patients with ACLVO (52.5%) were eligible for EVT.
More than half of the patients (55.9% [76/136]) received thrombolytic therapy. Of these, 78.9% (60/76) were in the 0–3 h window and the remainder (16/76) in the 3–4.5 h window. More than half (56.7% (34/60) were thrombolyzed with tenecteplase. However, not all patients in the window period of 0–4.5 h (111) received thrombolysis (68.5% [97/111]). The reasons for not receiving thrombolysis included patients on anticoagulation (3 [2.7%]), established infarct in more than one-third of the hemisphere (6 [5.4%]), or they were taken directly for thrombectomy (5 [4.5%]). Twenty patients presented within 4.5 h of the symptom onset but were outside of the treatment time window period once the diagnosis of stroke was ascertained.
LVO was present in 44.9% (61) of the patients. Posterior circulation LVO was present in two patients. Half the patients received thrombolysis (50.8% [31/61]) and about one-third (32.8% [20/61]) underwent thrombectomy. Decompressive hemicraniectomy was performed in 30.0% (6/20) of the patients who underwent thrombectomy. In the total cohort, decompressive hemicraniectomies were performed in 11.8% (16/136) of the patients and in 27.1% (16/59) of the patients with anterior circulation LVO (ACLVO). Favorable ASPECTS was present in 52.5% (31/59) of ACLVO. There were 32.3% (10/31) with ASPECTS ≥ 6 who did not undergo thrombectomy. These were patients with either chronic occlusion or carotid dissections (five patients). Other causes of non-intervention were non-affordability (four patients) and consent refusal (one patient). The overall in-hospital mortality was 7.4% (10/136), and 13.1% (8/61) with LVO. Thus, LVO constituted 80% of the stroke patients with in-hospital mortality among the patients in 0–6 h.
Six to twenty-four h (N = 85)
The median time to reach the hospital in the 6–24 h time window was 10.5 (8.0;16.3) h. The mean age of the patients was 51.8 ± 16 years and 74.1% (63) of the patients were males. There was a higher proportion of males in this window as compared to the 0–6 h (61% vs. 74% [P-value: 0.05]). The median ASPECTS was 7 (IQR 5–9) and ACLVO was present in 41.2% (35) of the patients. Among the patients with LVO, most were males (80%; 28/35). In the LVO patients, the median NIHSS was 16 (IQR 11–21) and median ASPECTS was 5 (IQR 3–6); 74.3% (26) of the patients had M1 occlusion. Among the patients with ACLVO (35), 65.7% (23) did not meet modified DAWN and/or DEFUSE-3 criteria. Of these patients, the reasons for not meeting the modified DAWN/DEFUSE-3 criteria included ASPECTS <6 (91% ), NIHSS <6 (13% ), and baseline mRS score >2 (4% ). Only 1 of the 12 eligible patients underwent thrombectomy. The causes of non-intervention were non-affordability in six patients, dissection in two patients, consent refusal in two patients, and tandem occlusion with unfavorable access in one patient.
Zero to six h versus six to twenty-four h
The clinico-radiological characteristics of the patients who presented in 0–6 h versus 6–24 h were similar in most aspects [Table 1]. The males were more in the 6–24 h (0–6 h: 61.0% vs. 6–24 h: 74.1%; P value: 0.05) which showed a trend toward statistical significance. Also, as expected, the later time window had worse median ASPECTS score (0–6 h: 8 [5;10] vs. 6–24 h: 7 [5;9]; P value: 0.05). The occurrence of ACLVO was similar (0–6 h: 43.4% vs. 6–24 h: 41.2%; P value: 0.75). The proportion of patients with NIHSS ≥ 6 with ACLVO eligible for EVT were also similar in the early versus late time window (0–6 h: 52.5% vs. 6–24 h: 37.5%; P value: 0.17).
The main finding of our study is that 19.5% (43/221) of the AIS presenting within 24 h is eligible for EVT. Of these, 14.0% (31/221) presented in the 0–6-h time window and 5.4% (12/221) presented in the 6–24-h time window. In the AIS patients with LVO, 47.3% meet EVT criteria in the 0–24-h time window (52.5% in the 0–6 h; 37.5% in the 6–24 h).
The current American Heart Association (AHA) and European Stroke Organization (ESO) guidelines recommend that all AIS within 0–6 h with NIHSS score >= 6, ACLVO, and an ASPECTS of ≥6, and AIS within 6–24 h with NIHSS >= 6, ACLVO, and sufficient clinical-core mismatch or target mismatch profile, should undergo EVT. Our results are similar to the EVT eligibility estimates performed in the previous studies. In an analysis of a single North American CSC, Jadhav et al. found that 30% of the patients with AIS were present within the 6–24-h time window. Tsivgoulis et al. found 2.9–12.8% of the patients were eligible for mechanical thrombectomy via various criteria within 5–8 h from LSW.
However, the 'real world,' non-trial settings have not looked at the proportion who get excluded due to various stroke and non-stroke-related factors. The stroke-related factors in our study were NIHSS <5, poor pre-stroke mRS, while the non-stroke-related factors were consent refusal by family and unaffordability.
Our study is the first to estimate the early and late-window EVT eligibility at a large academic center in India. Since 2015, the EVT has become the standard of care for LVO stroke and the time window for treatment now extends up to 24 h., The RESILIENT trial in Brazil has demonstrated that EVT has the capability to significantly improve outcomes even in resource-limited environments. Our study shows that there is an immense potential for thrombectomy in India in the 0–6 h as well as in the 6–24-h time window.
Our study highlights the following key findings: first, the lower mean age of the patients compared to the data from other countries,,, would translate into better functional outcomes and cost-effectiveness of EVT. Second, the differences in stroke etiology and the presence of unique mechanisms of stroke including RHD (10.4% of our patients) is an important potential consideration in the stroke diagnosis and treatment. Third, the proportion of patients presenting within 24 h and patients with LVO are comparable to those with other studies.,
Approximately, 1.8 million Indians suffer a stroke every year., Extrapolating results of this study, about 280,000 strokes in India would meet the criteria for thrombectomy in 24 h. This represents a large expansion opportunity for EVT in the late time window in India. Reaching this potential and offering EVT to more patients will involve a multi-faced approach involving raising awareness and education, developing better systems of care, training specialized stroke physicians and neuro-interventionalists, and optimizing the cost of stroke care. It has been shown that EVT initiated beyond 6 h of onset is equally effective and safe as EVT within 6 h.
This study is limited by its retrospective design. A major constraint of this study was the lack of advanced imaging. DAWN and DEFUSE-3 trial criteria were modified and the EVT eligibility was determined using an ASPECTS ≥6 cut-off. While studies comparing CT perfusion and ASPECTS have shown CT perfusion as a better predictor of clinical outcome,, another limitation of the study may be the inclusion of only those patients who were admitted from the emergency under the care of the co-investigators. While this provided reliable and complete data, this might not be truly representative of all the patients coming to the emergency.
ASPECTS is likely to be the only available tool for EVT patient selection in resource-limited environments and may be a reasonable alternative to advanced neuroimaging.[28–30] The costs of intervention is prohibitive for the patients who have no insurance cover (approximately USD 1500–$2000) which would be almost equal to the average annual income (USD 1800).
In summary, our study suggests that a significant population of AIS patients in India may be eligible for EVT, comparable to the developed world. Given the incorporation of EVT into the stroke guidelines, we anticipate a significant increase in the treatment rates in eligible patients. The outcomes and cost-effectiveness of such interventions in a resource-limited setting should be further investigated.
Dr Vibha was the recipient of the Indian Academy of Neurology- Association of Indian Neurologists in America (IAN-AINA) observership programme in 2019.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.