Tenecteplase versus alteplase for large vessel occlusion recanalization (T-FLAVOR): Trial protocol

Background Tenecteplase has higher fibrin specificity with a longer half-life and the potential to achieve higher rates of recanalization than alteplase. A critical limitation of tenecteplase is no commercial use in Japan and no experience with its administration to Japanese patients. Hypothesis Tenecteplase is superior to alteplase in achieving recanalization on the initial angiogram when administered ≤4.5-hour of stroke onset in patients planned for mechanical thrombectomy (MT) in Japan where alteplase at the unique dose of 0.6mg/kg is officially used. Methods The Tenecteplase versus alteplase For LArge Vessel Occlusion Recanalization (T-FLAVOR) trial is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, masked-endpoint, superiority study. Eligibility criteria include acute ischemic stroke with pre-stroke modified Rankin Scale score ≤3 and large vessel occlusion (internal carotid artery, middle cerebral artery, or basilar artery) eligible for intravenous thrombolysis ≤4.5-hour and MT ≤6-hour of stroke onset. After completing the safety confirmation phase involving three patients who received non-masked tenecteplase (0.25 mg/kg), 220 patients will be randomized to two groups (1:1), intravenous alteplase (0.6mg/kg, n = 110) or tenecteplase (0.25mg/kg, n = 110), prior to MT. Outcomes In the safety confirmation phase, the primary outcome is symptomatic intracranial hemorrhage (sICH) ≤24-36-hour. In the randomized, comparative phase, the primary efficacy outcome is substantial angiographic reperfusion (mTICI grade 2b/2c/3) or absence of retrievable thrombus on the initial angiogram. The primary safety outcome is sICH ≤24-36-hour and 90-day mortality. Discussion T-FLAVOR may help determine if tenecteplase should be recommended as a routine clinical strategy before MT for Japanese stroke patients. Trial registration jRCTs051210055

Long-term mortality and recurrent vascular events in lacunar versus non-lacunar ischaemic stroke: A cohort study

Introduction Studies of differences in very long-term outcomes between people with lacunar/small vessel disease (SVD) versus other types of ischaemic stroke report mixed findings, with limited data on myocardial infarction (MI). We investigated whether long-term mortality, recurrent stroke and MI risks differ in people with versus without lacunar/SVD ischaemic stroke. Patients and methods We included first-ever strokes from a hospital-based stroke cohort study recruited in 2002–2005. We compared risks of death, recurrent stroke and MI during follow-up among lacunar/SVD versus other ischaemic stroke subtypes using Cox regression, adjusting for confounding factors. Results We included 812 participants, 283 with lacunar/SVD ischaemic stroke and 529 with other stroke. During a median of 9.2 years (interquartile range 3.1–11.8), there were 519 deaths, 181 recurrent strokes and 79 MIs. Lacunar/SVD stroke was associated with lower mortality (adjusted HR 0.79, 95% CI 0.65 to 0.95), largely due to markedly lower all-cause mortality in the first year. From one year onwards this difference attenuated, with all-cause mortality only slightly and not statistically significantly lower in the lacunar/SVD group (0.86, 95% CI 0.70 to 1.05). There was no clear difference in risk of recurrent stroke (HR 0.84, 95% CI 0.61–1.15) or MI (HR 0.83, 95% CI 0.52–1.34). Conclusion Long-term risks of all-cause mortality, recurrent stroke and MI are similar, or only slightly lower, in patients with lacunar/SVD as compared to other ischaemic stroke. Patients and physicians should be as vigilant in optimising short- and long-term secondary prevention of vascular events in lacunar/SVD as for other stroke types.

National implementation of reperfusion for acute ischaemic stroke in England: How should services be configured? A modelling study

Objectives To guide policy when planning thrombolysis (IVT) and thrombectomy (MT) services for acute stroke in England, focussing on the choice between ‘mothership’ (direct conveyance to an MT centre) and ‘drip-and-ship’ (secondary transfer) provision and the impact of bypassing local acute stroke centres. Design Outcome-based modelling study. Setting 107 acute stroke centres in England, 24 of which provide IVT and MT (IVT/MT centres) and 83 provide only IVT (IVT-only units). Participants 242,874 emergency admissions with acute stroke over 3 years (2015–2017). Intervention Reperfusion delivered by drip-and-ship, mothership or ‘hybrid’ models; impact of additional travel time to directly access an IVT/MT centre by bypassing a more local IVT-only unit; effect of pre-hospital selection for large artery occlusion (LAO). Main outcome measures Population benefit from reperfusion, time to IVT and MT, admission numbers to IVT-only units and IVT/MT centres. Results Without pre-hospital selection for LAO, 94% of the population of England live in areas where the greatest clinical benefit, assuming unknown patient status, accrues from direct conveyance to an IVT/MT centre. However, this policy produces unsustainable admission numbers at these centres, with 78 out of 83 IVT-only units receiving fewer than 300 admissions per year (compared to 3 with drip-and-ship). Implementing a maximum permitted additional travel time to bypass an IVT-only unit, using a pre-hospital test for LAO, and selecting patients based on stroke onset time, all help to mitigate the destabilising effect but there is still some significant disruption to admission numbers, and improved selection of patients suitable for MT selectively reduces the number of patients who would receive IVT at IVT-only centres, challenging the sustainability of IVT expertise in IVT-only centres. Conclusions Implementation of reperfusion for acute stroke based solely on achieving the maximum population benefit potentially leads to destabilisation of the emergency stroke care system. Careful planning is required to create a sustainable system, and modelling may be used to help planners maximise benefit from reperfusion while creating a sustainable emergency stroke care system.

Rationale, Design and Methods of the Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) Study

Background The optimal timing of anticoagulation following acute ischaemic stroke or TIA in patients with atrial fibrillation (AF) is a frequent challenge. Early initiation of anticoagulation can reduce the risk for recurrent ischaemic events, but may lead to an increased risk for intracerebral haemorrhage. Aim The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study was initiated to investigate outcome events under antithrombotic therapy after ischaemic stroke or TIA in patients with AF. The main objective is to compare the three-month rates of major haemorrhagic events between early (≤ 7 days) versus late (> 7 days) administration of dabigatran or treatment with vitamin-K antagonists started at any time. Occurrences of ischaemic and major haemorrhagic events will be evaluated to determine the optimal time point for initiation or resumption of anticoagulation. Design and Methods PRODAST is a prospective, multicenter, observational, non-interventional post-authorization safety study. 10,000 patients with recent (≤ 1 week from index event) ischaemic stroke or TIA and non-valvular AF were recruited at 86 German sites starting in July 2015. The observational plan includes a baseline visit, documentation of data during hospitalization and a telephone-based, central follow-up at three months after the index event. The primary endpoint is the major bleeding rate within three months. Secondary endpoints include rates of recurrent ischaemic or haemorrhagic stroke, TIA, systemic embolism, myocardial infarction and death. Summary PRODAST will provide important real-world data on safety and efficacy of antithrombotic therapy after acute stroke and TIA in patients with AF.

Updating estimates of the number of UK stroke patients eligible for endovascular thrombectomy: incorporating recent evidence to facilitate service planning

Introduction Endovascular thrombectomy (EVT) is a highly effective treatment for acute ischaemic stroke due to large arterial occlusion (LAO). To support decisions about service provision, we previously estimated the annual UK population eligible for EVT as ∼10% of stroke admissions. Since then, several trials have produced evidence that could alter these figures. We update our estimates considering information from studies and trials reporting 2018–2021 on incidence, presentation time and stroke severity and consider the possible impact of predicted demographic changes in the next 10–20 years. Patients and Methods We produce an updated decision tree describing the EVT eligible population for UK stroke admissions. One-way sensitivity analyses (using upper and lower confidence intervals for estimates at each branch of our decision tree) were used to identify where further research evidence is necessary to increase certainty around estimates for numbers of EVT eligible patients. Results The updated estimate for the number of UK stroke patients eligible for EVT annually was between 10,020 (no advanced imaging in early presenting patients) and 9,580 (advanced imaging in all early presenting patients), which compared with our estimates in 2017 is a minimal reduction. One-way sensitivity analyses established that enhanced evidence about eligibility for milder strokes, ASPECTS scores and pre-stroke disability are offset by evidence regarding a lower incidence of LAO. Importantly, predicted increases in life expectancy by 2040 may increase thrombectomy need by 40%. Discussion Information from additional randomised trials published during 2018–2020 with updated estimates of LAO prevalence had a minimal impact on overall estimates of stroke patients eligible for EVT in the UK. Ongoing research into the benefits of EVT for patients with mild stroke or European Stroke Journal For Peer Review lower ASPECTS scores has the potential to increase the estimates of the eligible population; future need for EVT will increase with the ageing population. Conclusion Our updated analyses show overall numbers eligible little changed, but evidence from ongoing trials and demographic changes have the potential to increase the need for EVT significantly.

Patient and proxies’ attitudes towards deferred consent in randomised trials of acute treatment for stroke: A qualitative survey

Introduction Deferral of consent for participation in a clinical study is a relatively novel procedure, in which informed consent is obtained after randomisation and study treatment. Deferred consent can be used in emergency situations, where small therapeutic time windows limit possibilities for patients to provide informed consent. We aimed to investigate patients’ or their proxies’ experiences and opinions regarding deferred consent in acute stroke randomised trials. Patients and methods For this qualitative study, Dutch Collaboration for New Treatments of Acute Stroke (CONTRAST) trial participants were selected. Study participants were either patients or their proxies who provided consent and were selected with theoretical sampling based on patient characteristics. Semi-structured interviews were conducted face-to-face or by telephone. Themes and subthemes were iteratively defined. Results Twenty of the 23 interviewed participants (16 patients and 7 proxies) considered deferred consent acceptable. The received study treatment and consent conversation were remembered by 18 participations, although the concept of randomisation and treatment comparison were generally not well understood. Sixteen participants felt capable of overseeing the decision to give deferred consent. Distress in the first days after stroke, lack of understanding and neurological deficits were reasons for feeling incapable of providing consent. Four participants would have preferred a different timing of the consent conversation, of whom two prior to treatment. Conclusion Our study found that deferred consent was considered acceptable by most study participants who provided consent for acute stroke randomised trials. Though they felt capable, the recall and comprehension of consent were overall limited.

Micro-embolic signal monitoring in stroke subtypes: A systematic review and meta-analysis of 58 studies

Introduction Micro-embolic signals (MESs) detected using transcranial Doppler (TCD) help in risk stratification in stroke patients. A systematic review and meta-analysis were performed to estimate the prevalence of MES and its association with stroke recurrence, functional outcome, and mortality in different stroke subtypes. Methods A comprehensive literature search was conducted before 26th January 2021 in PubMed, Embase, Google Scholar, Cochrane Library, and ClinicalTrials.gov . Studies were identified that used TCD to detect MES in stroke/TIA patients. Pooled prevalence and odds ratio (OR) along with 95% confidence interval (95% CI) were calculated for different outcome measures. The entire statistical analysis was conducted in R version 3.6.2. Findings Fifty-eight studies involving 5123 patients (1329 MES+, 3794 MES−) were included in our meta-analysis. The pooled prevalence of MES among all acute stroke/TIA patients was 30% (95% CI 25-34%). The pooled prevalence adjusted after the trim-and-fill analysis among all acute stroke/TIA patients was 18% (95% CI 14-23%). The prevalence of MES was high among all stroke subtypes except in patients with small vessel disease (SVD). In patients with new-onset stroke/TIA, the presence of MES was associated with a high risk of recurrence of cerebral ischemia (OR 4.03; 95% CI 2.38-6.82). Although no significant association was observed for the presence of MES with increased mortality (OR 2.37; 95% CI 0.75-7.50) and poor functional outcome (OR 2.11; 95% CI 0.20-22.50) among patients with new-onset stroke/TIA, this could only be determined in a smaller sample size of 477 patients. Conclusions Our meta-analysis showed a 30% prevalence of MES following acute stroke/TIA. The presence of MES increased the chance of recurrence of cerebral ischemia but was not associated with poor functional outcomes and mortality in the studied subgroup.

A case series of cerebral venous thrombosis as the first manifestation of homocystinuria

Background Cerebral venous thrombosis (CVT) is an important cause of stroke particularly in younger patients and potentially fatal if diagnosis is delayed. The presentation of symptoms is highly variable and consequently the diagnosis and underlying cause is often delayed or overlooked. Homocystinuria, a rare autosomal recessive disorder is an identified risk factor for CVT. Purpose A timely diagnosis and treatment of the underlying cause of CVT could result in improved outcome and prevent further events. This case series describes the clinical course of six adults presented with unprovoked CVT, in whom the diagnosis of underlying homocystinuria was delayed with adverse consequences. We aim to highlight the importance of recognising homocystinuria as an underlying cause of CVT and offer a practical approach to the diagnosis and management. Methods This is a retrospective case series of a cohort of 30 consecutive patients seen in a UK tertiary referral centre. Result Six out of 30 patients presented with CVT prior to homocystinuria diagnosis. The mean and range of age at the time of the first CVT episode was 22.6 (range 11–31) years. The mean ±SD age at diagnosis of homocystinuria as the underlying cause was 26 ± 4.2 years. The time between first CVT and diagnosis of homocystinuria ranged from 1.6 to 11 years resulting in a delay to introduction of effective treatment and, in some cases, a further large vessels thrombotic event. Conclusion Physician awareness of homocystinuria as an underlying cause for an unprovoked CVT will facilitate timely introduction of effective treatment to prevent a further event.

Accuracy of CTA evaluations in daily clinical practice for large and medium vessel occlusion detection in suspected stroke patients

Introduction: Early detection of large vessel occlusion (LVO) is essential to facilitate fast endovascular treatment. CT angiography (CTA) is used to detect LVO in suspected stroke patients. We aimed to assess the accuracy of CTA evaluations in daily clinical practice in a large cohort of suspected stroke patients. Patients and methods: We used data from the PRESTO study, a multicenter prospective observational cohort study that included suspected stroke patients between August 2018 and September 2019. Baseline CTAs were re-evaluated by an imaging core laboratory and compared to the local assessment. LVO was defined as an occlusion of the intracranial internal carotid artery, M1 segment, or basilar artery. Medium vessel occlusion (MeVO) was defined as an A1, A2, or M2 occlusion. We calculated the accuracy, sensitivity, and specificity to detect LVO and LVO+MeVO, using the core laboratory evaluation as reference standard. Results: We included 656 patients. The core laboratory detected 89 LVOs and 74 MeVOs in 155 patients. Local observers missed 6 LVOs (7%) and 28 MeVOs (38%), of which 23 M2 occlusions. Accuracy of LVO detection was 99% (95% CI: 98–100%), sensitivity 93% (95% CI: 86–97%), and specificity 100% (95% CI: 99–100%). Accuracy of LVO+MeVO detection was 95% (95% CI: 93–96%), sensitivity 79% (95% CI: 72–85%), and specificity 99% (95% CI: 98–100%). Discussion and Conclusion: CTA evaluations in daily clinical practice are highly accurate and LVOs are adequately recognized. The detection of MeVOs seems more challenging. The evolving EVT possibilities emphasize the need to improve CTA evaluations in the acute setting.