Remote Ischemic Conditioning for Acute Stroke

Abstract

ImportanceDespite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke.ObjectiveTo evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke.Design, Setting, and ParticipantsThis was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023).InterventionThe intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants.Main Outcomes and MeasuresThe primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke.ResultsAmong 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, −1; −1.7 to −0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group.Conclusions and RelevanceRIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke.Trial RegistrationClinicalTrials.gov Identifier: NCT03481777

Effect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST Trial

“…The RESIST was an investigator-initiated, multicenter, randomized, patient and outcome-assessor-blinded, sham-controlled clinical trial. 9 , 10 The trial was approved by Danish regional research ethics committees (ID: 1–10-72–97-17), Data Protection Agency (ID: 1–16-02–16-18), and Danish Medicines Agency (ID: 2017114177; EUDAMED: CIV-17–11-022324) as an acute study, and consent was waived in the acute prehospital phase. Consent was obtained from all patients or relatives and trial guardians as soon as possible after arrival at the hospital.…”

“…The analysis was performed using the entire range (shift analysis) of the mRS (ordinal logistic regression), with a random effect on the stratification groups as previously described in the target population group. 9 To investigate the effect of stroke cause and treatment effect on the primary end point, we used an ordinal logistic regression model, relating the odds of the primary outcome with the covariate of interest and the randomization group (RIC/sham) in patients with an acceptable treatment adherence of at least 80%.…”

“…Overall, RIC was not associated with a beneficial improvement in 90-day functional outcome, but whether there is heterogeneity in treatment effect according to stroke cause and adherence is unknown. 9 …”

Remote Ischemic Conditioning for Acute Ischemic Stroke: Does Stroke Etiology Matter?

“…The primary efficacy end point of shift toward better functional outcome measured by the modified Rankin Scale score at 90 days was similar in the RIC and sham groups (odds ratio, 0.95 [95% CI, 0.75-1.20]). 8 These results may be contrasted with the RICAMIS trial (Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke), a large randomizedcontrolled trial of RIC performed in China that included 1776 patients with acute ischemic stroke, which found rates of excellent functional outcome, defined by a modified Rankin Scale score at 90 days of 0 to 1 (the primary study outcome), of 67.4% in the RIC group versus 62.0% in the control group (P=0.02). 9 However, RICAMIS was not focused on the prehospital setting and suffered from key methodological limitations including an open-label design without a sham control group.…”