Sex-related difference in outcomes of remote ischemic conditioning for symptomatic intracranial atherosclerotic stenosis

Stroke remains a leading cause of death and disability globally, with sICAS—narrowing of major intracranial arteries by 50–99%—being a primary culprit. Even with aggressive medical therapy, sICAS patients face high recurrent stroke risks. RIC, a non-invasive intervention involving repetitive transient limb ischemia, has emerged as a neuroprotective strategy, but its effectiveness across sexes remained unclear. “Sex differences in stroke outcomes and treatment responses are well-documented, yet few studies have focused on RIC in sICAS,” explained first author Yuanyuan Liu. “Our goal was to fill this gap by analyzing data from the largest randomized controlled trial of RIC for sICAS to date.”

The RICA trial (2015–2019) enrolled patients aged 40–80 years who had experienced a transient ischemic attack (TIA) within 15 days or ischemic stroke within 30 days of sICAS diagnosis. Participants were randomly assigned 1:1 to receive daily RIC (200 mmHg limb inflation) or sham RIC (60 mmHg) for 12 months, alongside standard stroke prevention therapy (antiplatelet drugs, blood pressure/lipid/sugar control). Key baseline differences emerged between sexes: Female patients (35.6% of the cohort, n=1,079) were older (mean age 62.9 vs. 60.0 years) and had higher rates of hypertension (86.4% vs. 81.4%), diabetes (38.7% vs. 34.8%), and higher BMI and lipid levels than males (n=1,954); Males were far more likely to be current or former smokers (75.6% vs. 38.5%). Two populations were analyzed: the intention-to-treat (ITT) group (all 3,033 patients) and the per-protocol (PP) group (1,409 patients with ≥50% intervention adherence).

In the ITT population, unadjusted rates of ischemic stroke recurrence were higher in women (20.5%) than men (16.6%). However, after accounting for baseline confounders (age, BMI, comorbidities), this difference became non-significant (adjusted HR=1.18; 95% CI, 0.97–1.42; P=0.092). No sex-based disparities were observed for other endpoints (hemorrhagic stroke, TIA, myocardial infarction, or all-cause death). In the PP group (patients who consistently followed the RIC protocol): Males receiving RIC had a 32% lower risk of ischemic stroke recurrence compared to sham (adjusted HR=0.68; 95% CI, 0.48–0.95; P=0.025). Females showed no significant benefit from RIC (adjusted HR=0.88; 95% CI, 0.58–1.32; P=0.539). No significant interaction between sex and treatment was detected (P=0.379), but subgroup analyses revealed stronger RIC effects in younger males (<65 years; adjusted HR=0.62) and those with severe stenosis (≥70%; adjusted HR=0.58). RIC also reduced the composite endpoint (stroke, TIA, or myocardial infarction) in males (adjusted HR=0.62; P=0.001) but not in females (adjusted HR=0.85; P=0.410).

The study’s findings challenge the one-size-fits-all approach to RIC for sICAS, suggesting personalized application based on sex and adherence. “For male patients with good compliance, RIC is a valuable addition to standard therapy,” noted senior author Dr. Xunming Ji. “For females, however, our results do not support routine RIC use—further research is needed to understand why benefits are absent.” The results align with some prior studies (e.g., CICAS trial) that found no overall sex differences in sICAS outcomes but contrast with others (e.g., WASID trial) that reported worse female outcomes—likely due to improvements in stroke care over the past decade narrowing sex gaps.

This secondary analysis of the RICA trial confirms that while sICAS-related stroke recurrence risk does not differ significantly between sexes after adjusting for confounders, RIC provides meaningful protection against recurrent ischemic stroke in adherent male patients. The findings underscore the importance of sex-aware precision medicine in stroke prevention and call for further research to refine RIC’s role in female sICAS patients.

Authors of the paper include Yuanyuan Liu, Chengbei Hou, Xiao Dong, Di Wu, Xuehong Chu, Jiaqi Luo, Wanwan Zhang, Erlan Yu, Chuanhui Li, Chen Zhou, Chuanjie Wu, and Xunming Ji

This work was supported by the National Natural Science Foundation of China (82027802 and 82271507), Noncommunicable Chronic Diseases—National Science and Technology Major Project (2023ZD0505403), Beijing Science Foundation for Distinguished Young Scholars (JQ24041), and Beijing Physician Scientist Training Project (BJPSTP-2024-04).

The paper, “Sex-Related Difference in Outcomes of Remote Ischemic Conditioning for Symptomatic Intracranial Atherosclerotic Stenosis” was published in the journal Cyborg and Bionic Systems on Jun 6, 2025, at DOI: 10.34133/cbsystems.0275.