Remote ischaemic conditioning: individual patient data meta-analysis of acute stroke trials and prospective MRI evaluation in healthy adults

Background: Remote ischaemic conditioning (RIC) is a promising neuroprotective method, with preclinical studies showing improved neurological outcome following acute stroke. However, early phase randomised controlled trials (RCTs) have given rise to conflicting results. Furthermore, the optimal strategy to apply RIC in humans is unknown. Clinical studies have utilised a variety of doses and methods, ranging from a single ‘dose’ using one limb, to daily application for 300 days using two limbs, decisions that are not based on meaningful pre-clinical data. A reliable way to directly measure end-organ effects of RIC would allow optimal methods of application and ‘dose’ to be determined, thereby informing clinical trial design. Aims: To prospectively pool and analyse individual patient data (IPD) from RCTs on the effects of RIC on safety and outcomes in acute stroke. The aim was to also test a small group of healthy young adults to establish the feasibility and tolerability of administering RIC during a non-invasive magnetic resonance imaging (MRI) scan, and to collect preliminary data on using Phase-contrast (PC) and Arterial Spin Labelling (ASL) for detecting RIC-induced cerebral haemodynamic changes. Methods: For the individual patient data meta-analysis, we systematically searched electronic databases up to December 2020, including PubMed/MEDLINE, EMBASE, Cochrane, and clinical trial registries using pre-specified keywords. RCTs were included when RIC (intervention) and sham therapy (control) were administered within 24 hours of stroke. We extracted individual patient data obtained from the invited trial investigators. The primary functional outcome (mRS) was assessed by ordinal analysis at the end of the trials. The secondary outcomes included early and late neurological deterioration based on the National Institute of Health Stroke Severity (NIHSS) scores, adverse vascular events, death at 90 days, and changes in infarct volume, NIHSS scores (between baseline and end-of-trial) and serum biomarkers. Unadjusted and multivariable regression analysis adjusted for age, sex, baseline NIHSS and systolic blood pressure, and time-to-treatment were conducted. For the healthy human volunteer feasibility study, we recruited 6 young (18-40 years) healthy males to undergo a single ‘dose’ of 4 cycles of intermittent arm ischaemia - alternating 5 minutes inflation (200 mmHg) followed by 5 minutes deflation of an upper arm blood pressure cuff during an MRI scan. ASL & Phase contrast MRI of the brain were performed before and after RIC, as well as 24 hours later. Measurements of blood flow and perfusion were compared to baseline pre-RIC values. Results: Seven RCTs from four countries comprising 556 patients (281 RIC, 275 sham) were included: age 66.3years (SD 13.9), 61% male, NIHSS 7 (IQR 5-12) and 43% randomised ≤3 hours. Final NIHSS scores significantly improved following RIC therapy (OR=-0.85, 95%CI -1.55 to -0.16, p=0.01), but there was no statistical difference in the mRS scores (OR=0.97, 95%CI 0.71-1.31,p=0.83), overall major cardiovascular adverse events (OR=0.76, 95%CI 0.42-1.39,p=0.38), or mortality (OR=1.44, 95%CI 0.69-2.98,p=0.33). A possible treatment interaction (p=0.08) occurred with time-to-treatment (mRS: ≤3 hours, OR 0.71, 95%CI 0.44-1.16; >3 hours, OR 1.23, 95%CI 0.82-1.85). Study heterogeneity and risk of bias (except one study) were low. In the healthy human volunteer pilot study, RIC administration during the MRI scan appeared feasible, safe, and was well tolerated by the study participants. There were no significant changes observed in the blood flow velocity of the major intracranial vessels (bilateral internal carotid arteries and basilar artery). Although ASL analysis was planned in this cohort, due to extenuating circumstances caused by the COVID-19 pandemic, no formal analysis could be performed by the time of the thesis submission. Conclusions: RIC appeared safe and significantly improved the final NIHSS, but did not improve the functional outcome (mRS) in acute stroke. RIC therapy may be beneficial when administered ≤3 hours from stroke onset. The preliminary findings of the human volunteer pilot study showed RIC administration during MRI scanning appeared to be feasible, safe, and well tolerated. It also allowed quantitative haemodynamic measurements during RIC, though no significant change in blood flow velocity was demonstrated in this small study sample. Future work could exploit this method further, in a larger sample size, and potentially assess the treatment ‘dose’ and administration parameters in target populations

Perfusion imaging in acute ischaemic stroke - the beginning of the end?

Endovascular thrombectomy (EVT) for large vessel occlusion in acute ischaemic stroke is the standard of care when initiated within 6 hours of stroke onset, and is performed between 6-24 hours using advanced neuroimaging (CT perfusion or MR imaging) for patients who meet the strict imaging selection criteria. However, adherence to the restrictive imaging criteria recommended by current guidelines is impeded in many parts of the world, including the UK, by resource constraints and limited access to advanced neuroimaging in the emergency setting. Furthermore, recent randomised and non-randomised studies have demonstrated that patients selected without advanced neuroimaging (with non-contrast CT and CT angiography only) using less restrictive imaging criteria for EVT eligibility beyond 6 hours from onset still benefited from EVT treatment, thereby increasing the proportion of patients eligible for EVT and widening the potential treatment impact at a population level. Hence, current guidelines should be updated expeditiously to reflect the level I evidence in support of more liberal imaging selection criteria for patients presenting with acute ischaemic stroke due to a large vessel occlusion.Copyright © Royal College of Physicians 2023. All rights reserved.https://doi.org/10.7861/clinmed.2022-055

Direct mechanical thrombectomy without intravenous thrombolysis versus bridging therapy for acute ischemic stroke:A meta-analysis of randomized controlled trials

Background: Direct mechanical thrombectomy may result in similar outcomes compared to a bridging approach with intravenous thrombolysis (IVT + MT) in acute ischemic stroke. Recent randomized controlled trials have varied in their design and noninferiority margin. Aim: We sought to meta-analyze accumulated trial data to assess the difference and non-inferiority in clinical and procedural outcomes between direct mechanical thrombectomy and bridging therapy. Summary of review: We conducted a systematic review of electronic databases following the preferred reporting items for systematic reviews and meta-analyses guidelines. Random effects meta-analyses were conducted for the pooled data. The primary outcome was good functional outcome at 90 days (modified Rankin scale (mRS) ≤ 2). Secondary outcomes included excellent functional outcome (mRS ≤ 1), mortality, any intracranial hemorrhage, symptomatic intracranial hemorrhage, successful reperfusion (thrombolysis in cerebral infarction ≥ 2 b), and procedure-related complications. Four randomized controlled trials comprising 1633 patients (817 direct mechanical thrombectomy, 816 bridging therapy) were included. There were no statistical differences for the 90-day good functional outcome (OR = 1.02, 95% CI 0.84–1.25, p = 0.54, I2= 0%), and the absolute risk difference was 1% (95% CI: −4% to 5%). The lower 95% CI falls within the strictest noninferiority margin of −10% among included randomized control trials. Direct mechanical thrombectomy reduced the odds of successful reperfusion (OR = 0.76, 95% CI: 0.60–0.97, p = 0.03, I2= 0%) and any intracranial hemorrhage (OR = 0.65, 95% CI: 0.49–0.86, p = 0.003, I2= 38%). There was no difference in the remaining secondary outcomes. The risk of bias for all studies was low. Conclusion: The combined trial data assessing direct mechanical thrombectomy versus bridging therapy showed no difference in improving good functional outcome. The wide noninferiority thresholds set by individual trials are in contrast with the clinical consensus on minimally important differences. However, our pooled analysis indicates noninferiority of direct mechanical thrombectomy with a 4% margin of confidence. The application of these findings is limited to patients presenting directly to mechanical thrombectomy-capable centers and real-world workflow times may differ against those achieved in a trial setting

To bridge or not to bridge:summary of the new evidence in endovascular stroke treatment

Recently published summaries and meta-analyses of four randomised controlled trials (RCTs)1-5 comparing direct mechanical thrombectomy (dMT) and bridging therapy with intravenous (IV) thrombolytics (alteplase) suggested that dMT is non-inferior to bridging therapy to achieve good functional outcome 3 months after stroke (modified Rankin Score 0-2) with the non-inferiority margin (NIM) &lt;-5%.5-7 However, there were considerable limitations in generalisability as three of the RCTs were performed in the Asian population, and the alteplase dose was different between studies (0.6 mg/kg or 0.9 mg/kg). Recently, preliminary results of two further RCTs (SWIFT-DIRECT8 and DIRECT-SAFE9) were presented at the 2021 World Stroke Congress and other conferences. Both RCTs (SWIFT-DIRECT and DIRECT-SAFE) compared dMT with bridging therapy, assuming a NIM of 12% and 10%, respectively. Both failed to confirm the non-inferiority of dMT approach, although it is worth noting that DIRECT-SAFE was terminated early in June 2021, with only 293 out of planned 780 participants recruited, following the publications of the other RCTs' results.9</p

Left atrial enlargement on non-gated CT is associated with large vessel occlusion in acute ischaemic stroke

BACKGROUND: Recent reports have suggested that atrial fibrillation (AF) is more prevalent in the large vessel occlusion (LVO) subgroup of acute ischaemic stroke patients. Given the association between left atrial enlargement (LAE) and AF, we sought to evaluate the feasibility of assessing LAE on non-gated CT and its association with LVO in the hyperacute stroke setting. METHODS: We analysed our prospectively collected database that included all stroke patients referred for consideration of endovascular treatment between April 14, 2020, and May 21, 2020. During this period, a CT chest was included in our regional stroke protocol to aid triage of patients suspected for COVID-19 from which cardiac measurements were obtained. Patients were dichotomized into LVO and no-LVO groups, and LA measurements were trichotomized into normal, borderline, and enlarged. Univariate analyses were performed between groups. RESULTS: Of the included 38 patients, 21 were categorized as LVO and 17 as no LVO. There was a statistically significant association between LAE and LVO (p = 0.028). No significant difference was demonstrated between groups for the baseline AF and other clinical characteristics, except for baseline NIHSS (p = 0.0005). There was excellent inter- and intra-rater reliability (ICC = 0.969) for LA measurements. CONCLUSION: Our study provides preliminary data to suggest LAE is more prevalent in the LVO stroke subgroup at presentation and can be reliably assessed on non-gated CT in the hyperacute setting. These findings have potential implications for stratifying secondary management and may prompt a more rigorous pursuit of occult AF or other cardiac causes of stroke. Copyright © 2021 The Author(s) Published by S. Karger AG, Basel.https://doi.org/10.1159/00051912

Endovascular thrombectomy vs best medical management for late presentation acute ischaemic stroke with large vessel occlusion without CT perfusion or MR imaging selection: A systematic review and meta-analysis

Background: The efficacy and safety of endovascular thrombectomy (EVT) beyond 6 hours from stroke onset for patients with large vessel occlusion (LVO) selected without CT perfusion(CTP) or MR imaging(MRI) is undetermined. We conducted a systematic review and meta-analysis of the current literature comparing outcomes for late presenting patients with LVO treated by best medical management (BMM) with those selected for EVT based only on non-contrast CT(NCCT)/CT angiography(CTA) (without CTP or MRI). Method(s): PRISMA guidelines were employed. The primary outcome was functional independence (modified Rankin Scale 0-2) at 3 months. Secondary outcomes were symptomatic intracranial haemorrhage (sICH) and mortality at 3 months. Data were analysed using the random-effects model. Result(s): Six studies of 2083 patients, including three randomised controlled trials, were included; 1271 patients were treated with EVT and 812 patients with BMM. Compared to BMM, patients treated with EVT demonstrated higher odds of achieving functional independence (39.0 % EVT vs 22.0 % BMM; OR = 2.55, 95 %CI 1.61-4.05,p Result(s): Six studies of 2083 patients, including three randomised controlled trials, were included; 1271 patients were treated with EVT and 812 patients with BMM. Compared to BMM, patients treated with EVT demonstrated higher odds of achieving functional independence (39.0 % EVT vs 22.0 % BMM; OR = 2.55, 95 %CI 1.61-4.05,p 2 = 74 %). The rates of sICH (OR = 2.09, 95 %CI 0.86-5.04,p = 0.10) and mortality (OR = 0.62, 95 %CI 0.35-1.10,p = 0.10) were not significantly different between each cohort. Conclusion(s): Compared to BMM, late presenting stroke patients selected for EVT eligibility with NCCT/CTA only and treated with EVT achieved significantly higher rates of functional independence at 90 days, without increasing the incidence of sICH or mortality. Whilst these findings indicate that NCCT/CTA only may be used for EVT eligibility selection for patients who present beyond 6 hours from stroke onset, the results should be interpreted with caution due to the substantial heterogeneity between studies.Copyright © 2024 The Authorshttps://doi.org/10.1016/j.jstrokecerebrovasdis.2024.10800

Incidence and predictors of poor functional outcome despite complete recanalisation following endovascular thrombectomy for acute ischaemic stroke

Background: Numerous ischaemic stroke patients experience poor functional outcome despite successful recanalisation following endovascular thrombectomy (EVT). We aimed to identify the incidence and predictors of futile complete recanalisation (FCR) in a national stroke registry. Method(s): Patients who achieved complete recanalisation (mTICI 3) following EVT, between October 2015 and March 2020, were included from a United Kingdom national stroke registry. Modified Rankin Scale of 4-6 at discharge was defined as a 'poor/futile outcome'. Backward stepwise multivariable logistic regression analysis was performed with FCR as the dependent variable, incorporating all baseline characteristics, procedural time metrics and post-procedural events. Result(s): We included 2132 of 4383 patients (48.8%) with complete recanalisation post-EVT, of which 948 patients (44.4%) developed FCR. Following multivariable regression analysis adjusted for potential confounders, patients with FCR were associated with multiple baseline patient, imaging and procedural factors: age (p=0.0001), admission NIHSS scores (p=0.0001), pre-stroke disability (p=0.007), onset-to-puncture (p=0.0001) and procedural times (p=0.0001), presence of diabetes (p=0.005), and use of general anaesthesia (p=0.0001). Although not predictive of outcome, post-procedural events including development of any intracranial haemorrhage (ICH) (p=0.0001), symptomatic ICH (sICH) (p=0.0001) and early neurological deterioration (END) (p=0.007) were associated with FCR. Conclusion(s): Nearly half of patients in this national registry experienced FCR following EVT. Significant predictors of FCR included increasing age, admission NIHSS scores, pre-stroke disability, onset-to-puncture and procedural times, presence of diabetes, atrial fibrillation, and use of general anaesthesia. Post procedural development of any ICH, sICH, and END were associated with FCR.Copyright © 2023 The Authorshttps://doi.org/10.1016/j.jstrokecerebrovasdis.2023.10708

Local anaesthesia as a distinct comparator versus conscious sedation and 1 general anaesthesia in endovascular stroke treatment: a systematic review and meta-analysis

Background: The optimal anesthetic modality for endovascular treatment (EVT) in acute ischemic stroke (AIS) is undetermined. Comparisons of general anesthesia (GA) with composite non-GA cohorts of conscious sedation (CS) and local anesthesia (LA) without sedation have provided conflicting results. There has been emerging interest in assessing whether LA alone may be associated with improved outcomes. We conducted a systematic review and meta-analysis to evaluate clinical and procedural outcomes comparing LA with CS and GA.Methods: We reviewed the literature for studies reporting outcome variables in LA versus CS and LA versus GA comparisons. The primary outcome was 90 day good functional outcome (modified Rankin Scale (mRS) score of ?2). Secondary outcomes included mortality, symptomatic intracerebral hemorrhage, excellent functional outcome (mRS score ?1), successful reperfusion (Thrombolysis in Cerebral Infarction (TICI) >2b), procedural time metrics, and procedural complications. Random effects meta-analysis was performed on unadjusted and adjusted data.Results: Eight non-randomized studies of 7797 patients (2797 LA, 2218 CS, and 2782 GA) were identified. In the LA versus GA comparison, no statistically significant differences were found in unadjusted analyses for 90 day good functional outcome or mortality (OR=1.22, 95%?CI 0.84 to 1.76, p=0.3?and OR=0.83, 95%?CI 0.64 to 1.07, p=0.15, respectively) or in the LA versus CS comparison (OR=1.14, 95%?CI 0.76 to 1.71, p=0.53?and OR=0.88, 95%?CI 0.62 to 1.24, p=0.47, respectively). There was a tendency towards achieving excellent functional outcome (mRS ?1) in the LA group versus the GA group (OR=1.44, 95%?CI 1.00 to 2.08, p=0.05, I2=70%). Analysis of adjusted data demonstrated a tendency towards higher odds of death at 90 days in the GA versus the LA group (OR=1.24, 95%?CI 1.00 to 1.54, p=0.05, I2=0%).Conclusion: LA without sedation was not significantly superior to CS or GA in improving outcomes when performing EVT for AIS. However, the quality of the included studies impaired interpretation, and inclusion of an LA arm in future well designed multicenter, randomized controlled trials is warranted

Effect of proximal blood flow arrest during endovascular thrombectomy (ProFATE): Study protocol for a multicentre randomised controlled trial

Background: Observational studies have demonstrated improved outcomes with the adjunctive use of balloon guide catheters (BGC) during endovascular thrombectomy (EVT) for anterior circulation acute ischaemic stroke (AIS). However, the lack of high-level evidence and global practice heterogeneity justifies a randomised controlled trial (RCT) to investigate the effect of transient proximal blood flow arrest on the procedural and clinical outcomes of patients with AIS following EVT. Hypothesis: Proximal blood flow arrest in the cervical internal carotid artery during EVT for proximal large vessel occlusion is superior to no flow arrest in achieving complete vessel recanalisation. Method(s): ProFATE is an investigator-initiated, pragmatic, multicentre RCT with blinding of participants and outcome assessment. An estimated 124 participants with an anterior circulation AIS due to large vessel occlusion, an NIHSS of 2, ASPECTS 5 and eligible for EVT using a first-line combined technique (contact aspiration and stent retriever) or contact aspiration only will be randomised (1:1) to receive BGC balloon inflation or no inflation during EVT. Outcome(s): The primary outcome is the proportion of patients achieving near-complete/complete vessel recanalisation (eTICI 2c-3) at the end of the EVT procedure. Secondary outcomes include the functional outcome (modified Rankin Scale at 90 days), new or distal vascular territory clot embolisation rate, near-complete/complete recanalisation after the first pass, symptomatic intracranial haemorrhage, procedure-related complications and death at 90 days. Discussion(s): This is the first RCT to investigate the effect of proximal blood flow arrest during EVT using a BGC on the procedural and clinical outcomes of patients with AIS due to large vessel occlusion.Copyright © European Stroke Organisation 2023.https://doi.org/10.1177/2396987323116619

Effect of proximal blood flow arrest during endovascular thrombectomy (ProFATE): A multicenter, blinded-end point, randomized clinical trial

BACKGROUND: The effect of temporary blood flow arrest during endovascular thrombectomy for acute ischemic stroke is uncertain due to the lack of evidence from randomized controlled trials. We aimed to investigate whether temporary blood flow arrest during endovascular thrombectomy using a balloon guide catheter improves intracranial vessel recanalization compared with nonflow arrest. METHOD(S): The ProFATE trial (Proximal Blood Flow Arrest During Endovascular Thrombectomy) was a multicenter, randomized, participant- and outcome-blinded trial at 4 thrombectomy centers in the United Kingdom. Adults with acute ischemic stroke due to anterior circulation large vessel occlusion were randomly assigned (1:1) by a central, Web-based program with a minimization algorithm to undergo thrombectomy with temporary proximal blood flow arrest or nonflow arrest during each attempt. The primary outcome was the proportion of participants achieving near-complete/complete vessel recanalization (expanded Thrombolysis in Cerebral Infarction score of 2c or 3) at the end of the thrombectomy procedure, adjudicated by a blinded independent imaging core laboratory. Analyses were performed on the intention-to-treat population, adjusted for age, IV thrombolysis, onset-to-randomization time, Alberta Stroke Program Early CT Score, occlusion site, randomization site, and National Institutes of Health Stroke Scale. RESULT(S): Between October 10, 2021, and June 27, 2023, we recruited 134 participants, of whom 131 participants (mean age, 75 years; 62 47%] women and 69 53%] men) were included in the final analysis. Sixty-six participants were allocated to the temporary blood flow arrest group and 65 to the nonflow arrest group. The proportion of participants with an expanded Thrombolysis in Cerebral Infarction 2c/3 score at the end of the endovascular procedure was 74.4% (49/66) in the flow arrest group and 70.8% (46/65) in the nonflow arrest group (adjusted odds ratio, 1.07 95% CI, 0.45-2.55]; P=0.88). Among the prespecified secondary efficacy outcomes, a lower rate of emboli to a new vascular territory occurred in the blood flow arrest group compared with the nonflow arrest group (1.5% versus 12.3%; adjusted odds ratio, =0.04 95% CI, 0.01-0.53]; P=0.014) and a higher rate of complete recanalization (expanded Thrombolysis in Cerebral Infarction score, 3) after the first attempt in the flow arrest group versus the nonflow arrest group (33.0% versus 15.3%; adjusted odds ratio, =3.80 95% CI, 1.40-10.01]; P=0.007). No between-group differences were identified for the remaining procedural or clinical efficacy (modified Rankin Scale at 90 days) or safety outcomes (worsening of the stroke severity at 24 hours, adverse events, symptomatic intracranial hemorrhage, or mortality). CONCLUSION(S): Among patients presenting with anterior circulation large vessel occlusion acute ischemic stroke, temporary proximal blood flow arrest during endovascular thrombectomy, compared with nonflow arrest, did not significantly improve the near-complete/complete vessel recanalization (expanded Thrombolysis in Cerebral Infarction score, 2c-3) at the end of the procedure. Larger randomized controlled trials are warranted to confirm or refute a clinically significant treatment effect of temporary flow arrest on the functional outcome following endovascular thrombectomy.Copyright © 2024 The Authors.https://doi.org/10.1161/strokeaha.124.04971