Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial

Abstract

Importance: Despite 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.

Objective: To 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 participants: This 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).

Intervention: The 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 measures: The 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.

Results: Among 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 relevance: RIC 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 registration: ClinicalTrials.gov Identifier: NCT03481777.

Figure 1.. Flow of Patients in the Trial of Remote Ischemic Conditioning in Patients With Acute Ischemic Stroke or Intracerebral Hemorrhage

^aEligibility assessment and randomization was performed by the stroke neurologists on call. Some screened patients had multiple reasons for not meeting study criteria, accounting for more reasons than the number excluded. Patients underwent randomization using a Web-based procedure with a permuted-block design (random blocks of 4, 6, and 8) according to site. Randomization was stratified by the receiving stroke center, age (strata of age: ≥18 to 65, 66 to 80, and >80 years) and prehospital stroke severity (strata of PreSS: 1–2, 3–4, and 5–6 present symptoms/deficits). ^bScore range, 0 [no symptoms] to 6 [death]. ^cThe entire population included all the patients who were randomly assigned to a group and who consented to study participation, disregarding the final diagnosis. ^dIn the sham group, 3 patients refused to participate due to pain and 19 patients in the target population experienced pain or discomfort to sham treatment. In the sham group, pain and/or discomfort was typically elicited by agitated arm movement during the 20 mm Hg cuff inflation period. ^eIn total, 10 patients were excluded for not fulfilling the prehospital study criteria: 4 patients had symptoms lasting longer than 4 hours, 1 patient presented as a wake-up stroke, 2 patients’ symptoms or history were incorrectly communicated to the stroke neurologist, and 3 patients were not independent in daily activities of living before their stroke. ^fPatients could be included without motor deficit, which may partially explain the high stroke mimic rate. ^gThe target population included all the patients who were randomly assigned to a group, consented to study participation, and who had a target diagnosis of acute stroke. No patients were lost to follow-up for the primary end point. ^hThe per-protocol population included all the patients who had undergone randomization, who had a target diagnosis of acute stroke, and who had acceptable treatment adherence with at least 80% of allocated cycles. ⁱSome screened patients had multiple reasons for not meeting study criteria, accounting for more reasons than the number excluded. ^jThe reasons for “no adherence data from device” besides from lost device, were not registered specifically, but the most frequent causes were that the device was erroneously reset by study personnel before adherence data was downloaded or that the USB-port did not function.

Figure 2.. Distribution of Modified Rankin Scale Score Between Remote Ischemic Conditioning and Sham in the Target Population Group

Differences in the scores on the modified Rankin Scale (mRS) between groups at 90 days are shown. Each stratum is presented in percentage. The raw distribution of scores is shown. Scores range from 0 to 6 (0, no symptoms; 1, symptoms without clinically significant disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death).

Figure 3.. Aalen-Johansen Cumulative Incidence Curves of Mortality, MACCE, and Recurrent Ischemic Events

A, Ninety days major adverse cardiac and cerebral events (MACCE) (cardiovascular death, acute myocardial infarction, stroke) in the target population. B, Ninety days recurrent ischemic events (acute ischemic stroke, transient ischemic attack, myocardial infarction, or other vascular events) in the target population. C, Ninety days all-cause mortality in the target population. D, Ninety days cardiovascular mortality in the target population (post hoc). For all analysis the median observation times were 90 days (IQR, 90-90) in both groups. The reference is the sham treatment.