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

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

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

Pressor therapy in acute ischaemic stroke: an updated systematic review

Background Low blood pressure (BP) in acute ischaemic stroke (AIS) is associated with poor functional outcome, death, or severe disability. Increasing BP might benefit patients with post-stroke hypotension including those with potentially salvageable ischaemic penumbra. This updated systematic review considers the present evidence regarding the use of vasopressors in AIS. Methods We searched the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE and trial databases using a structured search strategy. We examined reference lists of relevant publications for additional studies examining BP elevation in AIS. Results We included 27 studies involving 1886 patients. Nine studies assessed increasing BP during acute reperfusion therapy (intravenous thrombolysis, mechanical thrombectomy, intra-arterial thrombolysis or combined). Eighteen studies tested BP elevation alone. Phenylephrine was the most commonly used agent to increase BP (n = 16 studies), followed by norepinephrine (n = 6), epinephrine (n = 3) and dopamine (n = 2). Because of small patient numbers and study heterogeneity, a meta-analysis was not possible. Overall, BP elevation was feasible in patients with fluctuating or worsening neurological symptoms, large vessel occlusion with labile BP, sustained post-stroke hypotension and ineligible for intravenous thrombolysis or after acute reperfusion therapy. The effects on functional outcomes were largely unknown and close monitoring is advised if such intervention is undertaken. Conclusion Although theoretical arguments support increasing BP to improve cerebral blood flow and sustain the ischaemic penumbra in selected AIS patients, the data are limited and results largely inconclusive. Large, randomised controlled trials are needed to identify the optimal BP target, agent, duration of treatment and effects on clinical outcomes.acceptedVersio

Perfusion Imaging for Endovascular Thrombectomy in Acute Ischemic Stroke Is Associated With Improved Functional Outcomes in the Early and Late Time Windows

Background: The impact on clinical outcomes of patient selection using perfusion imaging for endovascular thrombectomy (EVT) in patients with acute ischemic stroke presenting beyond 6 hours from onset remains undetermined in routine clinical practice. Methods: Patients from a national stroke registry that underwent EVT selected with or without perfusion imaging (noncontrast computed tomography/computed tomography angiography) in the early (&lt;6 hours) and late (6-24 hours) time windows, between October 2015 and March 2020, were compared. The primary outcome was the ordinal shift in the modified Rankin Scale score at hospital discharge. Other outcomes included functional independence (modified Rankin Scale score ≤2) and in-hospital mortality, symptomatic intracerebral hemorrhage, successful reperfusion (Thrombolysis in Cerebral Infarction score 2b-3), early neurological deterioration, futile recanalization (modified Rankin Scale score 4-6 despite successful reperfusion) and procedural time metrics. Multivariable analyses were performed, adjusted for age, sex, baseline stroke severity, prestroke disability, intravenous thrombolysis, mode of anesthesia (Model 1) and including EVT technique, balloon guide catheter, and center (Model 2). Results: We included 4249 patients, 3203 in the early window (593 with perfusion versus 2610 without perfusion) and 1046 in the late window (378 with perfusion versus 668 without perfusion). Within the late window, patients with perfusion imaging had a shift towards better functional outcome at discharge compared with those without perfusion imaging (adjusted common odds ratio [OR], 1.45 [95% CI, 1.16-1.83]; P=0.001). There was no significant difference in functional independence (29.3% with perfusion versus 24.8% without; P=0.210) or in the safety outcome measures of symptomatic intracerebral hemorrhage (P=0.53) and in-hospital mortality (10.6% with perfusion versus 14.3% without; P=0.053). In the early time window, patients with perfusion imaging had significantly improved odds of functional outcome (adjusted common OR, 1.51 [95% CI, 1.28-1.78]; P=0.0001) and functional independence (41.6% versus 33.6%, adjusted OR, 1.31 [95% CI, 1.08-1.59]; P=0.006). Perfusion imaging was associated with lower odds of futile recanalization in both time windows (late: adjusted OR, 0.70 [95% CI, 0.50-0.97]; P=0.034; early: adjusted OR, 0.80 [95% CI, 0.65-0.99]; P=0.047). Conclusions: In this real-world study, acquisition of perfusion imaging for EVT was associated with improvement in functional disability in the early and late time windows compared with nonperfusion neuroimaging. These indirect comparisons should be interpreted with caution while awaiting confirmatory data from prospective randomized trials.</p

Perfusion Imaging for Endovascular Thrombectomy in Acute Ischemic Stroke Is Associated With Improved Functional Outcomes in the Early and Late Time Windows

Background: The impact on clinical outcomes of patient selection using perfusion imaging for endovascular thrombectomy (EVT) in patients with acute ischemic stroke presenting beyond 6 hours from onset remains undetermined in routine clinical practice. Methods: Patients from a national stroke registry that underwent EVT selected with or without perfusion imaging (noncontrast computed tomography/computed tomography angiography) in the early (&lt;6 hours) and late (6-24 hours) time windows, between October 2015 and March 2020, were compared. The primary outcome was the ordinal shift in the modified Rankin Scale score at hospital discharge. Other outcomes included functional independence (modified Rankin Scale score ≤2) and in-hospital mortality, symptomatic intracerebral hemorrhage, successful reperfusion (Thrombolysis in Cerebral Infarction score 2b-3), early neurological deterioration, futile recanalization (modified Rankin Scale score 4-6 despite successful reperfusion) and procedural time metrics. Multivariable analyses were performed, adjusted for age, sex, baseline stroke severity, prestroke disability, intravenous thrombolysis, mode of anesthesia (Model 1) and including EVT technique, balloon guide catheter, and center (Model 2). Results: We included 4249 patients, 3203 in the early window (593 with perfusion versus 2610 without perfusion) and 1046 in the late window (378 with perfusion versus 668 without perfusion). Within the late window, patients with perfusion imaging had a shift towards better functional outcome at discharge compared with those without perfusion imaging (adjusted common odds ratio [OR], 1.45 [95% CI, 1.16-1.83]; P=0.001). There was no significant difference in functional independence (29.3% with perfusion versus 24.8% without; P=0.210) or in the safety outcome measures of symptomatic intracerebral hemorrhage (P=0.53) and in-hospital mortality (10.6% with perfusion versus 14.3% without; P=0.053). In the early time window, patients with perfusion imaging had significantly improved odds of functional outcome (adjusted common OR, 1.51 [95% CI, 1.28-1.78]; P=0.0001) and functional independence (41.6% versus 33.6%, adjusted OR, 1.31 [95% CI, 1.08-1.59]; P=0.006). Perfusion imaging was associated with lower odds of futile recanalization in both time windows (late: adjusted OR, 0.70 [95% CI, 0.50-0.97]; P=0.034; early: adjusted OR, 0.80 [95% CI, 0.65-0.99]; P=0.047). Conclusions: In this real-world study, acquisition of perfusion imaging for EVT was associated with improvement in functional disability in the early and late time windows compared with nonperfusion neuroimaging. These indirect comparisons should be interpreted with caution while awaiting confirmatory data from prospective randomized trials.</p

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