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Remote Ischemic Conditioning in Patients With Acute Ischemic Stroke Ineligible for Recanalization Therapies: A Phase
Susanna Diamanti1, Mauro Tettamanti2, Raffaele Ornello3,4
1Department of Neurology, Fondazione San Gerardo dei Tintori, Istituto di Ricovero e Cura a Carattere Scientifico, Monza, Italy (S.D., C.F., S.B.).
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.
