Francesco Andrea Pedrazzini

BACKGROUND: Remote ischemic conditioning (RIC) has shown neuroprotective potential in preclinical stroke models. In patients with acute ischemic stroke, trials report heterogeneous results, supporting ongoing debate about clinical efficacy, especially in those ineligible for recanalization. This trial assessed RIC benefit in this population and evaluated HSP27 (heat shock protein 27) and HIF-1α (hypoxia-inducible factor 1-alpha) as biomarkers of RIC-related biological activity. METHODS: This was a multicenter, phase II, proof-of-concept, block-randomized, controlled, parallel-arm, PROBE (Prospective Randomized Open Blinded End Point)-designed clinical trial. Patients with acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 5–25) who were ineligible for recanalization therapies were randomized 1:1 within 9 hours of symptom onset to RIC (4 5-minute cycles of upper-arm ischemia/reperfusion) plus standard medical therapy or standard therapy alone. The primary outcome was the percentage change in NIHSS score at 72 hours. Secondary outcomes included NIHSS score changes at 24 and 48 hours, 90-day modified Rankin Scale, tolerability, and changes in plasma HSP27 and HIF-1α concentrations from 24 to 72 hours. RESULTS: Eighty patients (40 per group) were enrolled across 4 centers from August 2021 to March 2024. Although slightly in favor of RIC treatment, median NIHSS score percentage change at 72 hours did not differ between the RIC and control groups (23.6% versus 29.9%; adjusted coefficient, −3.8 [95% CI, −19.7 to 12.1]; P =0.635). No significant differences in NIHSS score percentage change were observed at 24 or 48 hours. Ninety-day poor functional outcome (modified Rankin Scale score, 3–6) was similar between groups (57.5% versus 65.0%; adjusted odds ratio, 0.79 [95% CI, 0.21–2.97]; P =0.732). RIC was completed by 97.5% of patients with minimal treatment-related discomfort. No major adverse events occurred. No between-group differences were detected in HIF-1α or HSP27 changes from 24 to 72 hours. CONCLUSIONS: In patients with acute ischemic stroke ineligible for recanalization therapies, early RIC was safe, feasible, and well tolerated but did not improve neurological outcomes or modify HIF-1α and HSP27 levels. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04400981.

Recent randomised trials have questioned the benefit of endovascular therapy (EVT) for MeVO stroke, but data from clinical practice are limited. This study aimed to assess the effectiveness and safety of EVT, with or without intravenous thrombolysis (IVT), vs IVT alone in MeVO stroke using registry-based real-world data. This retrospective multicentre study included patients from 82 Italian centres in the Safe Implementation of Treatments in Stroke (SITS) registry (January 2020–December 2023). Adults with acute ischaemic stroke due to MeVO (ACA A1/A2, MCA M2/M3 or more distal or PCA P1/P2), treated with IVT or EVT ± IVT, and with available 90-day mRS scores were included. Patients with tandem occlusions were excluded. Propensity score matching (1:1) was used to balance baseline variables. Primary outcome was functional independence (mRS 0–2) at 90 days. Secondary outcomes included in-hospital mortality, intracranial haemorrhage incidence and recanalisation status. Among 1375 total patients, 780 were included and matched (390 per group) by propensity score. Baseline characteristics were balanced. Functional independence at 90 days was achieved in 60.6% of EVT ± IVT patients vs 60.9% in the IVT-only group (odds ratio [OR] 0.99; 95% CI, 0.73–1.34; P = .939). When restricted to patients with baseline mRS < 2, functional independence rates remained comparable between groups, confirming the primary findings. In-hospital mortality was non-significantly lower in the EVT ± IVT group (5.4% vs 8.7%, P = .069). Symptomatic intracranial haemorrhage rates were comparable between groups, although overall haemorrhagic complications were higher with EVT (18.4% vs 11.2%, P < .0001). Stratified analyses by stroke severity and treatment timing showed consistent lack of benefit across all subgroups (all interaction P-values > .05). The absence of functional benefit from EVT observed in this real-world cohort is consistent with the results of the ESCAPE-MeVO and DISTAL randomized trials. Notably, the higher rate of any intracranial haemorrhage in the EVT group (18.4% vs 11.2%), driven primarily by minor haemorrhagic events, represents a clinically meaningful safety concern that must be weighed against the lack of demonstrated efficacy. A hypothesis-generating signal was observed in patients treated within 180 minutes (OR 2.16, 95% CI 1.06–4.38), warranting prospective investigation. The retrospective design and the limitations inherent to registry-based data, including incomplete procedural data and anatomical heterogeneity in MeVO classification, should be considered when interpreting these findings. Endovascular therapy did not improve long-term functional outcomes compared to IVT alone in MeVO stroke but was associated with higher haemorrhagic risk. These findings support a cautious approach to EVT in this setting, in line with recent trial evidence.

BACKGROUND: Collateral blood flow is a critical determinant of successful recanalization in acute ischemic stroke caused by large vessel occlusion. Head down tilt −15° (HDT15), similar to Trendelenburg positioning, is a simple, low-cost positional therapy that may augment cerebral collateral blood flow and penumbral survival. The aim of the study is to assess the safety, feasibility, and efficacy of HDT15 in improving cerebral collateral circulation and clinical outcomes in patients with large vessel occlusion–acute ischemic stroke treated with mechanical thrombectomy (MT). METHODS: The DOWN-SUITE trial (Head Down Tilt 15° to Increase Collateral Flow in Acute Ischemic Stroke) is a multicenter, randomized, open-label, phase 2a/b clinical trial with blinded outcome assessment, conducted across 7 Italian stroke centers. A total of 118 patients with acute ischemic stroke due to M1 segment middle cerebral artery occlusion will be randomized 1:1 in the emergency department to receive HDT15 or standard positioning (head-of-bed 0° to +30°) before and during MT. RESULTS: The primary end point is good collateral status (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology grade 3–4), assessed on the first angiographic sequence during MT by a blinded imaging core laboratory. Secondary end points include feasibility (proportion maintaining HDT15, admission-to-MT time), safety (symptomatic intracranial hemorrhage, pneumonia, vomiting, neurological deterioration, vital signs), and efficacy (neurological improvement before MT, at 24 hours, and at 7 days or discharge, modified Rankin Scale score at 90 days). CONCLUSIONS: The DOWN-SUITE trial will provide evidence on the acute cerebrovascular effect of HDT15 in large vessel occlusion–acute ischemic stroke, potentially establishing a cost-effective, practice-changing intervention to improve collaterals for global stroke care. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06297863.

BACKGROUND: Basic science studies have reported remote ischemic conditioning (RIC) as neuroprotective in acute ischemic stroke, although clinical evidence remains conflicting. The TRICS BASIC study (Multicenter Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke) investigated the efficacy and safety of RIC in experimental ischemic stroke using a rigorous clinical trial methodology. METHODS: Multicenter, multispecies, parallel group, randomized, controlled, preclinical trial of transient femoral artery clipping to induce RIC in female and male rats and mice subjected to transient endovascular occlusion of the middle cerebral artery. Animals were randomized to receive RIC, or sham surgery, after reperfusion. The primary end point was a good functional outcome at 48 hours, assessed using a composite functional neuroscore. Secondary end points were infarct volume at 48 hours and safety, assessed using a standardized health report at 24 and 48 hours. Preenrollment harmonization, centralized monitoring, allocation concealment, blinded outcome assessment, and intention-to-treat analysis were applied. RESULTS: The trial enrolled 164 rodents (82 mice and 82 rats) of both sexes (53% females), across 7 laboratories. A greater proportion of RIC-treated rodents achieved a favorable functional outcome compared with controls, at 48 hours postischemia (55% versus 36%; odds ratio, 2.2 [95% CI, 1.23–4.4]; P =0.009). RIC was associated with a small reduction in infarct volume (standardized mean difference, −0.38 [95% CI, −0.70 to −0.05]; P =0.024). Health monitoring indicated no major safety concerns, and postoperative analgesia requirements were lower in RIC-treated mice. CONCLUSIONS: Surgically induced RIC provided a modest but evident neuroprotective effect in experimental ischemic stroke, underscoring the potential of this strategy as an adjunctive treatment in stroke care. The findings of the TRICS BASIC study highlighted the importance of multicenter preclinical trials in addressing variability and enhancing translational validity. REGISTRATION: URL: https://www.preclinicaltrials.eu ; Unique identifier: PCTE0000177.

Background: Recent randomized trials have questioned the benefit of endovascular therapy (EVT) for medium vessel occlusion (MeVO) stroke, but data from clinical practice are limited. This study aimed to assess the effectiveness and safety of EVT, with or without intravenous thrombolysis (IVT), versus IVT alone in MeVO stroke using registry-based real-world data. Methods: This retrospective multicenter study included patients from 82 Italian centers in the SITS registry (January 2020–December 2023). Adults with acute ischemic stroke due to MeVO (ACA A1/A2, MCA M2/M3 or more distal, or PCA P1/P2), treated with IVT or EVT±IVT, and with available 90-day modified Rankin Scale (mRS) scores were included. Patients with tandem occlusions were excluded. Propensity score matching (1:1) was used to balance baseline variables. Primary outcome was functional independence (mRS 0–2) at 90 days. Secondary outcomes included in-hospital mortality, intracranial hemorrhage incidence, and recanalization status. Results: Among 1375 total patients, 780 were included and matched (390 per group) by propensity score. Baseline characteristics were balanced. Functional independence at 90 days was achieved in 57.7% of EVT±IVT patients versus 59.2% in the IVT-only group (OR 0.939, 95% CI 0.706–1.248, p=0.663). In-hospital mortality was non significantly lower in the EVT±IVT group (5.4% vs 8.7%, p=0.069). Symptomatic intracranial hemorrhage rates were comparable between groups, although overall hemorrhagic complications were higher with EVT (18.4% vs 11.2%, p0.05). Conclusions: EVT did not improve long-term functional outcomes compared to IVT alone in MeVO stroke but was associated with higher hemorrhagic risk. These findings support a cautious approach to EVT in this setting, in line with recent trial evidence.

We investigated the therapeutic effect of head down positioning at −15° (head down tilt; HDT15) on cerebral collateral flow and infarct growth in a rat model of large vessel occlusion (LVO) stroke, using multi-modal MRI. Twenty-eight Wistar rats were randomly assigned to HDT15 or flat position for 60 minutes, starting 30 minutes after occlusion of the middle cerebral artery, followed by reperfusion. The perfusion shift analysis, comparing post- versus pre-treatment voxel-level changes in time-to-peak perfusion maps, showed a significant increase in cerebral perfusion in the HDT15 group (common odds ratio 1.50; 95% CI 1.41-1.60; p < 0.0001), but not in the flat group (common odds ratio 0.97; 95% CI 0.92-1.03; p = 0.3503). Infarct growth at 24 hours was + 31.4% in the flat group (343 versus 250 mm ³ ; 95% CI 2.4 to 165.1; p = 0.0447) and + 15.4% in the HDT15 group (224 versus 192 mm ³ ; 95% CI -26.9 to 85.9; p = 0.2272). Our findings indicate that HDT15 acutely increases cerebral perfusion in LVO acute ischemic stroke and provides a tissue-saving effect before recanalization. Further research is needed to develop HDT15 as an emergency therapy to acutely increase collateral flow in ischemic stroke prior to recanalization therapy.