Ayurvedic Treatment in the Rehabilitation of Ischemic Stroke Patients in India: A Randomized Controlled Trial Study Protocol.

In patients with ischemic stroke, motor and sensory impairments are common and are associated with functional disability. Conventional physiotherapy (CP) is the primary modality of rehabilitation for post-stroke sensorimotor dysfunction. Ayurveda is a commonly practiced alternative system of medicine that offers unique rehabilitative measures for post-stroke recovery. We hypothesize that Ayurvedic rehabilitative treatment (ART) is superior to similar duration CP in improving the sensorimotor recovery of patients with ischemic stroke at 90 days after enrollment. AyuRvedic TrEatment in the Rehabilitation of Ischemic STrOke Patients in India: A Randomized controllEd trial (RESTORE) is an investigator-initiated, multicenter, prospective, randomized, controlled, parallel-arm, blinded outcome assessment trial being conducted under the Indian Stroke Clinical Trial (INSTRuCT) Network across the four comprehensive stroke centers in India. Consecutive hemodynamically stable adult patients with their first acute ischemic stroke between 1 and 3 months from stroke onset are being randomized (1:1) into two treatment groups to receive either 1 month of ART or 1 month of CP. The primary outcome measure is the Fugl Meyer Assessment-upper extremity for physical performance at 90 days. The secondary outcomes are the modified Rankin Scale, Barthel Index, Berg Balance, and SF-36 at 90 days. The safety outcomes include a composite of irreversible morbidity and mortality. A sample size of 140 (70 in each group) patients with ischemic stroke will allow us to detect a minimal clinical important difference of 9.4 (standard deviation) with superiority margin of 5, an attrition rate of 10%, alpha of 5%, and power of 80%. This randomized trial will systematically assess the efficacy and safety of traditional ART compared to CP. The trial has been registered in the Clinical Trial Registry India (CTRI/2018/04/013379).

INSTRuCT: Protocol, Infrastructure, and Governance.

Background and Purpose: Very few large scale multicentric stroke clinical trials have been done in India. The Indian Council of Medical Research funded INSTRuCT (Indian Stroke Clinical Trial Network) as a task force project with the objectives to establish a state-of-the-art stroke clinical trial network and to conduct pharmacological and nonpharmacological stroke clinical trials relevant to the nation and globally. The purpose of the article is to enumerate the structure of multicentric stroke network, with emphasis on its scope, challenges and expectations in India. Methods: Multiple expert group meetings were conducted by Indian Council of Medical Research to understand the scope of network to perform stroke clinical trials in the country. Established stroke centers with annual volume of 200 patients with stroke with prior experience of conducting clinical trials were included. Central coordinating center, standard operating procedures, data and safety monitoring board were formed. Discussion: In first phase, 2 trials were initiated namely, SPRINT (Secondary Prevention by Structured Semi-Interactive Stroke Prevention Package in India) and Ayurveda treatment in the rehabilitation of patients with ischemic stroke in India (RESTORE [Rehabilitation of Ischemic stroke Patients in India: A Randomized controlled trial]). In second phase, 4 trials have been approved. SPRINT trial was the first to be initiated. SPRINT trial randomized first patient on April 28, 2018; recruited 3048 patients with an average of 128.5 per month so far. The first follow-up was completed on May 27, 2019. RESTORE trial randomized first patient on May 22, 2019; recruited 49 patients with an average of 3.7 per month so far. The first follow-up was completed on August 30, 2019. Conclusions: In next 5 years, INSTRuCT will be able to complete high-quality large scale stroke trials which are relevant globally. REGISTRATION: URL: http://www.ctri.nic.in/; Unique Identifier: CTRI/2017/05/008507.

Ischemic Stroke Profile, Risk Factors, and Outcomes in India: The Indo-US Collaborative Stroke Project.

BACKGROUND AND PURPOSE: The Indo-US Collaborative Stroke Project was designed to characterize ischemic stroke across 5 high-volume academic tertiary hospitals in India. METHODS: From January 2012 to August 2014, research coordinators and physician coinvestigators prospectively collected data on 2066 patients with ischemic stroke admitted <2 weeks after onset. Investigator training and supervision and data monitoring were conducted by the US site (Massachusetts General Hospital, Boston). RESULTS: The mean age was 58.3±14.7 years, 67.2% men. The median admission National Institutes of Health Stroke Scale score was 10 (interquartile range, 5-15) and 24.5% had National Institutes of Health Stroke Scale ≥16. Hypertension (60.8%), diabetes mellitus (35.7%), and tobacco use (32.2%, including bidi/smokeless tobacco) were common risk factors. Only 4% had atrial fibrillation. All patients underwent computed tomography or magnetic resonance imaging; 81% had cerebrovascular imaging. Stroke etiologic subtypes were large artery (29.9%), cardiac (24.9%), small artery (14.2%), other definite (3.4%), and undetermined (27.6%, including 6.7% with incomplete evaluation). Intravenous or intra-arterial thrombolysis was administered in 13%. In-hospital mortality was 7.9%, and 48% achieved modified Rankin Scale score 0 to 2 at 90 days. On multivariate analysis, diabetes mellitus predicted poor 3-month outcome and younger age, lower admission National Institutes of Health Stroke Scale and small-artery etiology predicted excellent 3-month outcome. CONCLUSIONS: These comprehensive and novel clinical imaging data will prove useful in refining stroke guidelines and advancing stroke care in India.

Determining the feasibility and preliminary efficacy of a stroke instructional and educational DVD in a multinational context: a randomized controlled pilot study.

OBJECTIVE: To assess the feasibility of conducting a randomized controlled trial of an instructional and educational stroke DVD and determine the feasibility and preliminary efficacy of this intervention in a multinational context. DESIGN: Non-funded, pilot randomized controlled trial of intervention versus usual care. SETTING: International, multicentre, community-based. PARTICIPANTS: Community-living adults up to three years post stroke with moderate to severe disability and their nominated informal caregivers. INTERVENTIONS: Intervention patients viewed and practised rehabilitation techniques demonstrated in the DVD over six weeks. MAIN MEASURES: Trial feasibility by number of active recruitment sites, recruitment efficiency, randomization and follow-up. Intervention feasibility by patient and caregiver impressions. Preliminary efficacy by the quality of life - 5-level EuroQol-5D (EQ-5D) health status measure, General Health Questionnaire and Centre for Epidemiological Studies-Depression at two months. RESULTS: In total, 14 recruitment sites were established across eight countries. Recruitment was achieved at nine (64%) sites. Over 16 months, 66 participants were recruited (mean (SD) age = 63.5 (12.47) years) and randomized to intervention ( n = 34) and control ( n = 32) groups. In total, 54 (82%) completed a follow-up assessment. Patient and/or caregiver comments about the benefits and barriers to accessing the intervention were mixed. There were no significant between-group differences in outcomes at two months ( P > 0.05). CONCLUSION: Conducting a multinational trial of a stroke DVD requires full funding. The intervention was acceptable to some patients and their caregivers, yet a generalized education approach did not fully meet their needs and/or expectations. A more individualized method may be required to meet peoples' changing needs during stroke recovery.

STENOSIS: Long-term single versus dual antiplatelet therapy in patients with ischaemic stroke due to intracranial atherosclerotic disease - a randomised trial.

Rationale: Intracranial atherosclerotic disease (ICAD) is a pathological process that causes progressive stenosis and cerebral hypoperfusion, leading to stroke occurrence and recurrence around the world. The exact duration of dual antiplatelet therapy (DAPT) for ICAD is unclear in view of long-term risk of bleeding complications. Aim: The current study aims to study the efficacy and safety of long-term DAPT (up to 12 months) in patients with ICAD. Sample size: Using 80% power and an alpha error of 5 %, presuming a 10%-15% drop-out rate, a total of 2200 patients will be recruited for the study. Methodology: This is a prospective, randomised, double-blind, placebo controlled trial. Study outcomes: The primary outcomes include recurrent ischaemic stroke (IS) or transient ischaemic attack and any intracranial haemorrhage (ICH), major or minor systemic bleeding at the end of 12 months. Secondary outcomes include composite of any stroke, myocardial infarction or death at the end of 12 months. The safety outcomes include any ICH, major or minor bleeding as defined using GUSTO (Global Use of Streptokinase and tPA for occluded Coronary Arteries) classification at the end of 12 months and 1 month after completion of the drug treatment phase. Discussion: The study will provide level I evidence on the duration of DAPT among patients with IS due to ICAD of more than or equal to 50%.

RE-OPEN: Randomised trial of biosimilar TNK versus TPA during endovascular therapy for acute ischaemic stroke due to large vessel occlusions.

Rationale: Rapid and timely treatment with intravenous thrombolysis and endovascular treatment (EVT) in patients with acute ischaemic stroke (AIS) and large vessel occlusion (LVO) significantly improves patient outcomes. Bridging therapy is the current standard of care in these patients. However, an incompletely answered question is whether one thrombolytic agent is better than another during bridging therapy. Aim: The current study aims to understand if one thrombolytic agent is superior to the other during bridging therapy in the treatment of AIS and LVO. Sample size estimates: Using 80% power and an alpha error of 5 %, presuming a 10% drop out rate, a total of 372 patients will be recruited for the study. Methods and design: This study is a prospective, randomised, multicentre, open-label trial with blinded outcome analysis design. Study outcomes: The primary outcomes include proportion of patients who will be independent at 3 months (modified Rankin score (mRS) ≤2 as good outcome) and proportion of patients who achieve recanalisation modified thrombolysis in cerebral infarction grade 2b/3 at first angiography run at the end of EVT. Secondary outcomes include proportion of patients with early neurological improvement, rate of symptomatic intracerebral haemorrhage (ICH), rate of any ICH, rate of any systemic major or minor bleeding and duration of hospital stay. Safety outcomes include any intracranial bleeding or symptomatic ICH. Discussion: This trial is envisioned to confirm the theoretical advantages and increase the strength and quality of evidence for use of tenecteplase (TNK) in practice. Also, it will help to generate data on the efficacy and safety of biosimilar TNK. Trial registration number: CTRI/2022/01/039473.

Secondary prevention by structured semi-interactive stroke prevention package in INDIA (SPRINT INDIA): Findings from the process evaluation of a randomized controlled trial.

INTRODUCTION: Secondary Prevention by Structured Semi-Interactive Stroke Prevention Package in INDIA Trial delivered secondary stroke awareness intervention to sub-acute stroke patients in form of workbook, videos and SMS across 31 centres in 12 languages. Trial was stopped for futility due to fewer vascular outcomes than anticipated. Trial results indicated that trial intervention, did not lead to reduction in vascular events. We carried out process evaluation, to evaluate trial implementation and participant's perspectives, to comprehend the trial's futile outcomes. MATERIALS AND METHODS: Using mixed methods approach, qualitative interviews and quantitative data from case report forms, workbooks and questionnaires were analysed to measure intervention fidelity and contamination. Using purposive sampling, 115 interviews of patient-caregiver dyads and health professionals at 11 centres and 2 focus group discussions were held. RESULTS AND DISCUSSION: Iterative thematic analysis of qualitative data was done with RE-AIM and realist models. There was good fidelity to intervention and adherence to protocol; however, there was dilution of inclusion criteria by randomly enrolling uneducated and caregiver-dependent patients. Centre coordinators provided counselling to both arms, not specified by protocol, causing bias. Coordinators found it difficult to keep patients motivated to view intervention which was corroborated by fidelity questionnaire showing decreased viewing of intervention for a year. Cardiovascular protection improved in routine care by virtue of participating in trial. No contamination of intervention was reported. CONCLUSION: The intervention was acceptable by patients and caregivers, which could be made a community-based programme. Reasons identified for decreased viewing were repetitive content and non-availability of personal cellular device.

Impact of revascularization therapies on outcome of posterior circulation ischemic stroke: The Indo-US stroke project.

INTRODUCTION: Posterior circulation strokes (PCS) have been less extensively studied than anterior circulation strokes (ACS), especially regarding revascularization therapies. We analyzed the differences in baseline stroke characteristics, revascularization therapy and 3-month outcomes between PCS and ACS in a large prospective multicentre Indian stroke registry. METHODS: Patients with acute ischemic stroke recruited in the Indo-US collaborative stroke project from January 2012 to August 2014 were classified into PCS and ACS based on imaging-confirmed infarct location. Demographics, stroke severity, risk factors, and mechanisms were compared. We further compared these parameters in the subgroups who received revascularization therapies (RT) and no revascularization therapies (NRT). The primary outcome was 3-month modified Rankin scale (mRS). RESULTS: Of 1889 patients (1270 males), 1478 (78.2%) had ACS and 411 (21.8%) PCS. The median NIHSS was lower in PCS (7 vs 11, p < 0.001). Diabetes mellitus and hypertension were more common in PCS and rheumatic heart disease in ACS. Small artery occlusion was higher in PCS (23.8% vs 12.9%, p < 0.001). Only 28 (6.8%) PCS received RT compared to 213 (14.4%) ACS. At 90 days, a good functional outcome (mRS 0-2) was more common in PCS (56.4% vs 45.9%, p < 0.001) in NRT group, while no significant difference was noted in RT group. Stroke territory was not an independent predictor of 3-month outcome in regression analysis. In-hospital mortality was not different between the groups. CONCLUSIONS: The 3-month functional outcome and in-hospital mortality were not different between ACS and PCS. Compared to ACS, PCS received revascularization therapies less often.

Impact of Pre-Stroke Antiplatelet Use on 3-Month Outcome After Ischemic Stroke.

BACKGROUND: Pre-stroke anti-platelet (PAP) therapy can potentially influence the severity and outcome after ischemic stroke. METHODS: We analyzed data from the prospective multicenter Indo-US collaborative stroke project for the impact of PAP therapy. Outcome measures included the admission National Institute of Health Stroke Scale (NIHSS) score, 3-month modified Rankin scale (mRS) score, and rates of in-hospital mortality and post-ischemic intracerebral hemorrhage. RESULTS: Among 2048 of 2066 patients (M:F = 2:1) with known pre-stroke medication status, 336 (16.3%) were on PAP therapy. As compared to the non-PAP group, the PAP group had significantly higher mean age (62.2 vs 57.4 years, P < 0.001) and significantly more men, vascular risk factors, cerebral microbleeds (12.8% vs 6.2%, P = 0.001) and intravenous thrombolysis treatment (17% vs. 10.6%, P = 0.001). Cardioembolic strokes were significantly more in the PAP group (P < 0.001), but not large artery atherosclerosis. No significant differences were observed in the median NIHSS score (9 vs. 10, P = 0.274), 3-month mRS (score 0-2,51.4% vs. 49.0%, P = 0.428), in-hospital mortality (8.6% vs. 7.8%, P = 0.592), or symptomatic post ischemic intracerebral haemorrhage (12.2% vs. 10.6%, P = 0.382). The PAP group had more stroke recurrence (6.6% vs. 2.9%, P = 0.002) which was not significant (P = 0.065) after multivariate regression analysis adjusting for age, sex and vascular risk factors. PAP therapy was not an independent predictor of initial stroke severity or stroke outcome. CONCLUSION: PAP therapy has no significant effect on initial stroke severity, rates of post-ischemic hemorrhage with or without thrombolysis, in-hospital mortality, stroke recurrence, and 3-month outcome after ischemic stroke.

Secondary Prevention by Structured Semi-Interactive Stroke Prevention Package in India (SPRINT INDIA) study protocol.

RATIONALE: Recurrent stroke, cardiovascular morbidity, and mortality are important causes of poor outcome in patients with index stroke. Despite the availability of best medical management recurrent stroke occur in up to 15-20% of patients with stroke in India. Education for stroke prevention could be a strategy to prevent recurrent strokes. HYPOTHESIS: We hypothesize that a structured semi-interactive stroke prevention package can reduce the risk of recurrent strokes, acute coronary artery syndrome, and death in patients with sub-acute stroke at the end of one year. DESIGN: Secondary Prevention by Structured Semi-Interactive Stroke Prevention Package in INDIA (SPRINT INDIA) is a multi-center stroke trial involving 25 centers under the Indian Stroke Clinical Trial Network. Patients with first ever sub-acute stroke within two days to three months of onset, age 18-85 years, mRS <5, showing recent stroke in imaging are included. Participants or caregivers able to read and complete tasks suggested in a stroke prevention workbook and have a cellular device for receiving short message service and watching videos. A total of 5830 stroke patients speaking 11 different languages are being randomized to intervention or control arm. Patients in the intervention arm are receiving a stroke prevention workbook, regular educational short messages, and videos. All patients in the control arm are receiving standard of care management. SUMMARY: Structured semi-interactive stroke prevention package may reduce the risk of recurrent strokes, acute coronary artery syndrome, and death in patients with sub-acute stroke. TRIAL REGISTRATION: This trial is registered with clinicaltrials.gov (NCT03228979) and CTRI (Clinical Trial Registry India; CTRI/2017/09/009600).

Systematic Development of Structured Semi-interactive Stroke Prevention Package for Secondary Stroke Prevention.

BACKGROUND: Lack of compliance to medication and uncontrolled risk factors are associated with increased risk of recurrent stroke and acute coronary syndrome in patients with recent stroke. Multimodal patient education may be a strategy to improve the compliance to medication and early adoption of nonpharmacological measures to reduce the vascular risk factor burden in patients with stroke. We thus aim to develop multilingual short messaging services (SMS), print, and audio-visual secondary stroke prevention patient education package. The efficacy of the package will be tested in a randomized control trial to prevent major cardiovascular and cerebrovascular events. METHODS: In the formative stage, intervention materials (SMS, video, and workbook) were developed. In the acceptability stage, the package was independently assessed and modified by the stakeholders involved in the stroke patient care and local language experts. The modified stroke prevention package was tested for implementation issues (implementation stage). RESULTS: Sixty-nine SMS, six videos, and workbook with 11 chapters with 15 activities were developed in English language with a mean ± SD SMOG index of 9.1 ± 0.4. A total of 355 stakeholders including patients (24.8%), caregivers (24.8%), doctors (10.4%), nurses (14.1%), local language experts (2.8%), physiotherapists (13.2%), and research coordinators (9.8%) participated in 10 acceptability stage meetings. The mean Patient Education Material Assessment Tool understandability score in all languages for SMS, video scripts, and workbook was 95.2 ± 2.6%, 95.2 ± 4.4%, and 95.3 ± 3.6%, respectively. The patients [n = 20, mean age of 70.3 ± 10.6 years and median interquartile range (IQR) baseline NIHSS 1 (0-3)] or the research coordinators (n = 2) noted no implementation issues at the end of 1 month. CONCLUSION: An implementable complex multilingual patient education material could be developed in a stepwise manner. The efficacy of the package to prevent major adverse cardiovascular events is being tested in the SPRINT INDIA study.

Regional differences in ischemic stroke in India (north vs. south).

BACKGROUND: India is a large country with geographically diverse populations and varying risk factors. Identification of regional differences can improve healthcare policy decisions. AIM: To study regional differences in stroke between North and South India. METHODS: We analyzed data from the Indo-US Collaborative Stroke Project, a National Institute of Health-funded multicentre prospective study conducted in five academic centers in India with a US-based coordinating center. Risk factors, severity, mechanisms, management, complications, and outcomes among ischemic stroke patients were compared between North and South Indian centers. RESULTS: Of the 2066 patients enrolled from North (n = 1060) and South India (n = 1006), North Indian patients were significantly older with fewer men and had lower rates of diabetes (32.8% vs. 38.7%, p < 0.01), dyslipidemia (3.5% vs. 25.7%, p < 0.01), tobacco use (27% vs. 38%, p < 0.001), and alcohol use (30.1% vs. 38.6%, p < 0.01). North Indian patients had higher median National Institute of Health stroke scale scores (10 vs. 9, p < 0.01), more frequent large-artery atherosclerosis mechanism (34% vs. 25.6%, p < 0.001), intravenous thrombolysis (14.0% vs. 6.1%, p < 0.001), and lower rates of pneumonia (10.5% vs. 15.1%, p = 0.02). The three-month outcome (modified Rankin Scale score 0-2, 45.8% vs. 50.3%, p = 0.08) did not differ; however, North Indian patients had higher 90-day mortality (23.5% vs. 13.5%, p < 0.0001). CONCLUSIONS: The substantial regional differences in stroke risk factors and mechanisms may be partly explained by factors such as differing dietary habits and lifestyle, which can be addressed at a national level. Differences in acute and inpatient stroke care suggest a need for better adoption of national stroke management guidelines.

Quality of care for ischemic stroke in China vs India: Findings from national clinical registries.

OBJECTIVE: To understand stroke risk factors, status of stroke care, and opportunities for improvement as China and India develop national strategies to address their disproportionate and growing burden of stroke. METHODS: We compared stroke risk factors, acute management, adherence to quality performance measures, and clinical outcomes among hospitalized ischemic stroke patients using data from the Indo-US Collaborative Stroke Project (IUCSP) and China National Stroke Registry-II (CNSR-II). The IUCSP included 5 academic stroke centers from different geographic regions (n = 2,066). For comparison, the CNSR-II dataset was restricted to 31 academic hospitals among 219 participating sites from 31 provinces (n = 1,973). RESULTS: Indian patients were significantly younger, had health insurance less often, and had significantly different risk factors (more often diabetes mellitus, dyslipidemia, and coronary heart disease; less often prior stroke, hypertension, atrial fibrillation, and smoking). Hospitalized Indian patients had greater stroke severity (median NIH Stroke Scale score 10 vs 4), higher rates of IV thrombolysis within 3 hours (7.5% vs 2.4%), greater in-hospital mortality (7.9% vs 1.2%), and worse outcome (3-month modified Rankin Scale score 0-2, 49.3% vs 78.1%) (all p < 0.001). The poorer clinical outcomes were attributable mainly to greater stroke severity in IUCSP patients. Chinese patients more often received antithrombotics, stroke education, and dysphagia screening during hospitalization. CONCLUSION: These data provide insights into the status of ischemic stroke care in academic urban centers within 2 large Asian countries. Further research is needed to determine whether these patterns are representative of care across the countries, to explain differences in observed severity, and to drive improvements.