Remote ischemic conditioning in the thrombectomy era: The first step toward clinical neuroprotection?

Over the past decade, the widespread introduction of endovascular thrombectomy (EVT) has revolutionized the treatment of acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Yet, even among patients achieving complete reperfusion, many remain disabled at 90 days.[1] This persistent “treatment gap” reflects the underlying complex pathophysiology behind an ischemic stroke: excitotoxicity, inflammation, injury to the blood–brain barrier, oxidative stress, and reperfusion injury.[2,3] The success of EVT in restoring macrovascular patency does not fully prevent downstream microvascular failure damage and save the entire penumbra.[4] To enhance microvascular protection in patients with LVO stroke, there is a renewed interest in neuroprotective strategies that could complement current reperfusion therapies. Remote ischemic conditioning (RIC) has emerged as one of the most promising candidates.[5] By applying brief, intermittent limb ischemia with a blood pressure cuff, RIC activates endogenous protective pathways with systemic and neural signaling effects. Preclinical models demonstrate reduced infarct volumes, better collateral perfusion, and attenuated reperfusion injury.[5] The first safety data on RIC in patients treated with EVT were reported in 2018 in a pilot study by Zhao et al., which also underscored its translational potential based on safety, low cost, and scalability.[6] Although results in AIS have been mixed, two recent studies, including a newly published trial, are starting to clarify whether these benefits extend to patients undergoing endovascular therapy (EVT). The recently published Chinese SERIC-EVT (The safety and efficacy of RIC combined with EVT for AIS due to large vessel occlusion of the anterior circulation) trial is the first adequately powered randomized controlled trial to test RIC in patients undergoing EVT.[7] Conducted across 25 hospitals in China, it enrolled 498 patients with AIS treated with EVT within 24 h from symptom onset. Participants were randomized to RIC (4 cycles of 5 min of cuff inflation to 200 mmHg and 5 min with a deflated cuff, twice daily for 7 days) or a sham procedure (60 mmHg cuff inflation). At 90 days, 61.1% of patients in the RIC group achieved functional independence (modified Rankin scale [mRS] 0–2) compared to 48.9% in the sham group, risk ratio: 1.25, 95% confidence interval (CI): 1.06–1.47, P = 0.009. RIC was well tolerated, with no increase in hemorrhagic transformation or other safety concerns. The 12% absolute difference in functional independence (mRS 0–2) is remarkably high, exceeding the expected effect size for a neuroprotective intervention. Moreover, no significant differences were detected in early neurological outcomes, including the National Institutes of Health Stroke Scale (NIHSS) and Barthel Index, at 24 h or 7 days. This raises an important mechanistic question: does RIC exert its primary effects by facilitating long-term recovery and plasticity processes between 7 and 90 days, rather than by producing immediate neuroprotection detectable in the acute phase? While the sample size is larger than in previous trials, it remains relatively modest for a neuroprotection study, and although the results are encouraging, the possibility of a false-positive finding should be kept in mind. The other study is a post hoc analysis from the Danish RESIST trial (Remote Ischemic Conditioning in Stroke), which was a multicenter, randomized, sham-controlled study, tested combined prehospital and in-hospital RIC initiated within 4 h of stroke onset.[8] The main results were neutral, with no benefit of RIC in the general cohort of patients with AIS or in those treated with intravenous thrombolysis. In patients treated with EVT (n = 134, median NIHSS 16), RIC did not significantly lead to a better functional outcome, odds ratio (OR; 95% CI) of 1.26 (0.68–2.32), but the direction favored RIC treatment. However, in the subset who received both intravenous thrombolysis (IVT) and EVT, RIC was associated with a more than twofold improvement in functional outcome (adjusted OR: 2.46, 95% CI: 1.05–5.78, P = 0.038). The effect was mainly present in patients achieving complete reperfusion during EVT treatment. This study was limited by its post hoc nature and was not powered to investigate the effect in any specific subgroups. What about the Effect of Remote Ischemic Conditioning in Other Trials with EVT Patients? Only a few studies included patients treated with EVT or presented functional outcomes in patients treated with EVT. In the French RESCUE-BRAIN (The Remote Ischemic Conditioning in Acute Brain Infarction), 64 out of 188 included patients underwent mechanical thrombectomy within 6 h from symptom onset.[9] No treatment heterogeneity was found in the subgroup of RIC-treated EVT patients on change in brain infarct volume, and data on functional outcome in the EVT group were not presented. In the Dutch REPOST trial (The effect of repeated ripostc on infarct size in patients with an ischemic STroke), 25 patient out of 88 were treated with EVT, but no subgroup analysis or results for the EVT treated patients were presented.[10] The Spanish REMOTE-CAT trial (Remote Ischemic Perconditioning Among Acute Ischemic Stroke Patients in Catalonia) enrolled 200 prehospital-randomized patients, of whom 122 had a confirmed diagnosis of AIS.[11] A good functional outcome (mRS ≤ 2 at 90 days) was numerically higher in the RIC group (64.9%) than the sham group (47.3%), though not reaching statistical significance, OR: 2.03 (95% CI: 0.98–4.21). A total of 51 patients were treated with EVT; in this subgroup, RIC was not associated with a higher likelihood of good functional outcome (OR: 0.92, 95% CI: 0.32–2.76). Finally, in the Chinese SERIC-IVT (Safety and Efficacy of Remote Ischemic Conditioning Combined With Intravenous Thrombolysis for Acute Ischemic Stroke), 558 IVT patients were randomized to RIC or sham RIC.[12] At 90 days, 62.7% of patients in the RIC group and 56.8% in the sham RIC group had an excellent functional outcome, mRS 0–1 (OR: 1.10 [95% CI, 0.96–1.27]). Only 5 out of 558 patients were treated with EVT, which prevented subgroup analysis. Returning to the recently published SERIC-EVT trial: It provides the strongest clinical evidence to date that RIC may improve outcomes in EVT-treated AIS and is supported by a post hoc subgroup analysis from the RESIST trial. SERIC-EVT did not identify any treatment interactions with IVT or reperfusion status. Why EVT and Remote Ischemic Conditioning May Be Synergistic Several mechanisms are plausible: First, humoral mediators released by RIC may require restored blood flow to reach ischemic brain tissue, and without reperfusion, their delivery is probably limited. Candidate molecules that may include nitric oxide/nitrite, cytokines, extracellular vesicles, and microRNAs have been implicated in vasodilation, angiogenesis, and modulation of inflammation and cellular stress responses.[5,13,14] These circulating factors are unlikely to reach the ischemic penumbra in sufficient concentrations unless macrovascular reperfusion is achieved. Second, while preclinical studies suggest that RIC may exert neuroprotective effects in transient occlusion models in animals, we are only now beginning to see results when applying it to the clinical situation that mimics this paradigm of “occlusion followed by complete reperfusion,” namely EVT. Third, EVT largely addresses the macrovascular occlusion but does not always resolve downstream microvascular problems, such as distal microthrombosis, capillary no-reflow, that can persist after the large vessel is opened.[4] RIC may help protect the microvasculature or preserve collateral perfusion, possibly by modulating endothelial response, cell aggregation, or enhancing endogenous fibrinolysis.[15,16] A dual effect of IVT and RIC on the microcirculation could explain the findings from a recent post hoc analysis of the RESIST trial, in which RIC in EVT-treated patients had no significant overall effect on functional outcome but a significant effect in those receiving IVT who achieved complete reperfusion (modified Thrombolysis in Cerebral Infarction 3).[17] Fourth, stroke severity may be another consideration. In the SERIC-EVT, the median NIHSS was between 14–15 and 16 in the RESIST EVT subgroup, whereas it was between 4 and 5 in the overall AIS group of RESIST, 6 in the SERIC-IVT trial, 10 in the RESCUE BRAIN trial, and 9 in the REMOTE-CAT trial. Patients with more severe strokes (higher NIHSS) may have greater brain areas at risk (greater penumbra and more salvable tissue) and thus more potential for benefit from adjunctive therapies like RIC. Next Step? An important next step could be a pooled individual patient data meta-analysis of all randomized trials of RIC, with particular attention to patients who have undergone EVT. Such analyses could help clarify the overall treatment effect and identify treatment modifiers that may explain the heterogeneity observed to date. Importantly, replication of the current findings in non-Asian populations will also be needed, given the substantial differences in stroke etiology across ethnic groups. Further, defining the optimal RIC regimen remains a key question for its clinical translation and current protocols has considerable variations in its application (unilateral or bilateral upper extremity?), duration (only acute, extended to 1, or 2 weeks?), number of cycles (4 or 5 cycles?), and timing (acute, subacute, chronic phase only, or combinations?). At present, the large Chinese remote ischemic conditioning for acute ischemic stroke treated with mechanical thrombectomy (RECAST-MT) trial (ClinicalTrials.gov identifier: NCT06559241) is ongoing, with a planned enrollment of 2100 EVT-treated patients. Its results are eagerly awaited, and the trial is expected to provide clear insights into the role of RIC in EVT-treated patients and is also likely to inform on the impact of concurrent IVT use, the degree of reperfusion achieved, and stroke etiology. Ethical policy and institutional review board statement Not applicable. Data availability statement Data sharing is not applicable to this article as no datasets were generated and/or analyzed during the current study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.