Abstract
Background
Postoperative stroke can undermine the benefits of endovascular stenting for cerebrovascular stenosis. This trial investigated whether adjunctive remote ischemic conditioning (RIC) improves cerebral blood flow (CBF) regulation and reduces the risk of postoperative stroke.
Methods
A total of 104 patients with intracranial or extracranial cerebrovascular stenosis who underwent endovascular stenting were enrolled and randomized to receive either RIC or sham-RIC (1:1). The intervention was administered twice daily for 7 consecutive days postoperatively. CBF regulation was assessed bilaterally using transfer function analysis of spontaneous blood pressure and CBF oscillations at baseline and on day 7 or at discharge. The primary outcomes were phase difference (PD) and gain, whereas the secondary outcomes were 90-day stroke incidence and safety.
Results
Significantly higher PD values were observed in the RIC group than in the sham-RIC group on the affected side (40.67° [26.76°–58.28°] vs. 20.51° [10.90°–41.73°], P < 0.001) and the unaffected side (36.04° [21.66°–54.53°] vs. 26.80° [11.94°–44.83°], P = 0.022), indicating improved CBF regulation. Intragroup comparisons revealed significant PD improvement from baseline to day 7 or discharge in the RIC group (affected side: 20.57° [8.70°–34.24°] vs. 40.67° [26.76°–58.28°], P < 0.001; unaffected side: 26.06° [8.70°–44.37°] vs. 36.04° [27.66°–54.53°], P = 0.001). The 90-day stroke incidence was significantly lower in the RIC group (0.00% vs. 9.62%, P = 0.022).
Conclusions
Adjunctive RIC safely enhanced CBF regulation and substantially reduced postoperative stroke in patients after cerebrovascular stenting, suggesting a promising non-pharmacological strategy to improve outcomes.
Trial registration
This trial was registered at ClinicalTrials.gov (NCT05970653).
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12916-026-05038-w.
Keywords: Remote ischemic conditioning, Cerebral blood flow regulation, Cerebrovascular stenosis, Endovascular stenting, Randomized controlled trial, Secondary prevention
Background
Cerebrovascular stenosis is a major cause of ischemic stroke. Intracranial atherosclerotic stenosis accounts for 10%–15% of cases of ischemic stroke in Western populations and 30%–50% in Asian populations [1–4]. In patients with cerebrovascular stenosis, the risk of experiencing a stroke and its recurrence rises in proportion to the severity of the stenosis [5, 6]. Endovascular stenting has emerged as a significant therapeutic advancement, effectively restoring cerebral perfusion. The inclusion of stenting was linked to a reduced risk of the combined outcome of perioperative stroke, death, or ipsilateral stroke compared with intensive medical management alone [7]. This finding is further supported by the CREST-2 trial, which demonstrated the superior efficacy of stenting over medical therapy alone [8]. This suggests that stent therapy has a significantly broader therapeutic prospect. However, the procedure itself carries an inherent risk of perioperative ischemic events, primarily because of the dislodgement of emboli and procedural hemodynamic instability [9–11]. Despite the implementation of standardized periprocedural regimens involving dual antiplatelet therapy (DAPT) and anticoagulation [12, 13], postoperative stroke continues to occur [7, 14, 15] or recur [16] in a considerable proportion of patients with cerebrovascular stenosis following endovascular stenting [17]. Accordingly, the identification of effective adjunctive interventions aimed at reducing the incidence of postoperative stroke in this population remains a critical clinical priority.
Hemodynamic instability is a well-recognized contributor to postoperative complications after endovascular stenting [18]. The procedure inherently induces substantial blood pressure fluctuations, posing a significant risk to patients [19]. Cerebral blood flow (CBF) regulation, an intrinsic neurovascular mechanism that maintains stable perfusion despite fluctuations in systemic blood pressure, is critical for withstanding the hemodynamic stress induced by stenting. When this regulatory capacity is impaired, the brain loses its ability to buffer procedural blood pressure fluctuations and clear emboli, thereby heightening its susceptibility to hypoperfusion injury [20]. Notably, impaired CBF regulation is not only a consequence of stroke but also an independent predictor of unfavorable functional outcomes [21–26]. Therefore, we hypothesized that a therapeutic strategy aimed at enhancing CBF regulation could attenuate periprocedural hemodynamic instability and, by preserving cerebral perfusion, ultimately improve clinical outcomes in patients undergoing endovascular stenting.
Remote ischemic conditioning (RIC) is a systemic protective intervention in which brief, non-lethal limb ischemia induces tolerance to subsequent prolonged ischemic insults in remote organs [27–29]. Accumulating evidence has demonstrated the safety and efficacy of RIC in managing various neurological disorders [30, 31]. Our previous research demonstrated that RIC enhances CBF regulatory function in healthy adults [32]. Given the pivotal role of impaired CBF regulation in post-stenting stroke and the demonstrated ability of RIC to improve CBF regulation, we hypothesized that adjunctive RIC would improve CBF autoregulation and consequently reduce the incidence of postoperative stroke in patients undergoing endovascular stenting for cerebrovascular stenosis.
To evaluate this hypothesis, we conducted a randomized, single-blind, parallel-controlled trial aimed at determining whether RIC can enhance CBF regulation and reduce the occurrence and recurrence of postoperative stroke in patients with cerebrovascular stenosis following endovascular stenting.
Methods
This randomized, single-blind, parallel-controlled trial was registered at ClinicalTrials.gov (NCT05970653). This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Hospital of Jilin University (23K126-001). Written informed consent was obtained from all participants.
Participants
Patients with cerebrovascular stenosis admitted to the First Bethune Hospital of Jilin University and scheduled for endovascular stenting between August 2023 and March 2024 were enrolled. Individuals (1) aged ≥ 18 years, regardless of sex; (2) with symptomatic or asymptomatic cerebral vascular stenosis (including internal carotid artery system and vertebrobasilar system) suitable for elective cerebrovascular stenting; and (3) who were able or had immediate family members able and willing to provide informed consent were included in the analysis. In contrast, patients who satisfied any of the following criteria were excluded: (1) presence of progressive stroke; (2) a pre-admission Modified Rankin Scale (mRS) of ≥ 2 points; (3) requirement for other surgical treatments; (4) presence of severe comorbid diseases or a life expectancy of < 3 months; (5) contraindications to RIC, including severe soft tissue injury, fracture, or vascular injury in the upper extremities, or venous thrombosis in the acute or subacute stage of the upper extremities; (6) abnormal laboratory test results, which include aspartate aminotransferase or alanine aminotransferase levels that exceed three times the upper limit of normal; a blood creatinine level of > 265 umol/L (> 3 mg/dl); a platelet count of < 100 × 109/L; or international normalized ratio, activated partial thromboplastin time, prothrombin time exceeding the upper limit of normal; (7) pregnancy or lactation; (8) participation in other clinical studies or in such studies within 3 months before enrollment; (9) unwillingness undergo follow-up or poor treatment adherence; or (10) any other condition that the investigator considers inappropriate for enrollment.
Study design
The patients were randomly assigned (1:1) to either the RIC or sham-RIC group. The RIC group received RIC at a pressure of 200 mmHg twice daily for 7 consecutive days in conjunction with cerebrovascular stenting treatment. In contrast, the sham-RIC group received RIC at a pressure of 60 mmHg. To ensure that the intervention encompassed the preoperative and postoperative periods, at least two RIC sessions were required to be completed before stenting. CBF regulation was assessed at baseline and after treatment (following the final RIC or on the day of discharge) in all participants. A 90-day follow-up was conducted in both groups to assess long-term outcomes. This study follows the CONSORT statement, with the corresponding checklist provided in Additional file 1: CONSORT checklist. The study protocol is available in Additional file 2: Study protocol.
Background pharmacological therapy
All patients received standardized guideline-directed medical therapy throughout the trial [33]. For antiplatelet management, DAPT (aspirin 100 mg and clopidogrel 75 mg daily) was administered for at least 3 days before the procedure and continued for 90 days post-stenting, followed by lifelong aspirin monotherapy. All eligible patients received atorvastatin 40 mg or rosuvastatin 20 mg post-enrollment (target LDL-C < 1.8 mmol/L), with no adjunctive ezetimibe or use of PCSK9 inhibitor in either group. Uniform standardized management was applied for all other vascular risk factors, including blood pressure (≤ 140/90 mmHg), glycemic control (HbA1c < 7.0%), and lifestyle modification.
Endovascular intervention procedure
All endovascular procedures were performed by the same certified senior neurointerventional team in accordance with relevant Chinese guidelines [34]. All patients underwent target vessel stent implantation, with no isolated balloon angioplasty performed in any case. All procedures were conducted via femoral artery access under DSA guidance, with standardized perioperative heparinization applied uniformly.
All devices used in the procedures, including cerebrovascular-specific stents, balloons, and accessories, were approved by the National Medical Products Administration: the Xact Carotid System (Abbott Laboratories Trading (Shanghai) Co., Ltd.) for carotid artery stenting (CAS), the intracranial stent system (Stryker (Beijing) Medical Devices Co., Ltd.) for intracranial artery stenting, and the vertebral artery stent system (MicroPort NeuroTech (Shanghai) Co., Ltd.) for vertebral artery stenting (VAS).
Territory-specific standardized protocols were implemented [35]: (1) CAS: self-expanding stents with routine distal embolic protection; (2) intracranial atherosclerotic stenosis stenting: intracranial stent system, roadmap-guided micro guidewire navigation, and submaximal angioplasty for full lesion coverage; (3) VAS: vertebral artery stent system with balloon-expandable stents precisely positioned and deployed.
Uniform perioperative management was applied to all patients, including continuous blood pressure monitoring intraoperatively and for 24 h post-procedure (target systolic blood pressure: 100–140 mmHg). Perioperative adverse events (AEs) were recorded in real time, with no significant between-group difference observed.
Randomization and blinding
In this randomized, single-blind, parallel-group controlled trial, patients scheduled for cerebrovascular stenting were randomly assigned into either the RIC or sham-RIC group. The allocation sequence was concealed in sequentially numbered, opaque, sealed envelopes. An on-call physician, who was not involved in data analysis or clinical assessments, opened the envelopes after obtaining written informed consent. Nurses administering the RIC procedures and physicians responsible for opening the envelopes were instructed to refrain from disclosing allocation information to patients under any circumstances. To minimize cross-contamination, patients enrolled at the same center during the same period were accommodated in separate wards but managed by the same medical team. All participants remained blinded to their group assignments.
Outcomes
The main outcome measure was the difference in CBF regulation on the affected side between the two groups after receiving RIC or sham-RIC treatment. The secondary outcome measures included the 90-day stroke incidence or recurrence rates. The exploratory outcome measures included the difference in CBF regulation on the unaffected side and the 90-day mRS. Safety outcomes included AEs and serious AEs within 90 days. Additionally, comprehensive patient data, including demographic and clinical characteristics, laboratory findings, complete trial records, and follow-up data, were collected.
Sample size calculation
The primary outcomes were phase difference (PD) and gain values following RIC or sham-RIC treatment. Based on previous data, a superiority test was performed with a non-inferiority margin of 4° for PD. Previous studies indicated a standard deviation (SD) of 6.5° in the control group, and this same SD was assumed for the RIC group at the 7-day mark. The sample size calculation indicated that 86 participants (43 per group) would provide 80% statistical power at a one-sided significance level of α = 0.025. Based on clinical experience, approximately 20% of eligible patients were expected to decline interventional therapy after evaluation and consultation. To account for an anticipated dropout rate of 20%, we enrolled 104 participants (52 per group) in the study.
Intervention
All patients were provided with standard medical care in accordance with established clinical guidelines. Additionally, patients in the RIC group underwent RIC at a pressure of 200 mmHg twice daily for 7 consecutive days in conjunction with cerebrovascular stenting, whereas those in the sham-RIC group underwent the procedure at a pressure of 60 mmHg. All RIC sessions were conducted with the BB-RIC-D1 device from LAPUL Medical Devices Co. (LAPUL Medical Devices, Beijing, China) under the supervision of trained medical personnel.
CBF regulation assessment
All measurements were conducted in a dedicated examination room with controlled visual, acoustic, and thermal stimuli. All CBF regulation assessments were performed by a physician specializing in neurovascular ultrasonography. Before each assessment, blood pressure and heart rate were measured at the left brachial artery using an automated monitor. CBF regulation was assessed concurrently through transcranial Doppler (Multi-Dop X4; DWL, Sipplingen, Germany) and continuous monitoring of finger arterial pressure (Finometer Model 1, FMS, Amsterdam, Netherlands). Real-time CBF velocity (CBFV) and arterial blood pressure (ABP) signals were continuously recorded over 5 min. End-tidal CO₂ was monitored using a nasal cannula capnograph (MultiDop X4; DWL, Sipplingen, Germany). Throughout the procedure, the patients were instructed to remain awake, breathe normally, and minimize movement.
The data were analyzed offline using MATLAB (MathWorks, Natick, MA, USA). The ABP and CBFV signals were temporally aligned using a cross-correlation function and subsequently down-sampled to 1 Hz following anti-alias filtering with a cutoff frequency of 0.5 Hz. Welch’s method was utilized to estimate the auto spectrum of ABP, Sxx(ƒ), and the cross-spectrum of ABP and CBFV, Sxy(ƒ), by applying 90-s Hamming windows with a 50% overlap. The transfer function H(ƒ) was then derived as follows:
 |
1 |
Subsequently, the gain and PD were calculated using Eqs. (2) and (3):
 |
2 |
 |
3 |
where HR(ƒ) and HI(ƒ) denote the real and imaginary components of H(ƒ), respectively. Finally, PD, gain, and coherence values were averaged within the low-frequency range of 0.06–0.12 Hz.
Blood sampling and measurement of serum brain injury biomarkers
Venous blood samples were collected from the cubital vein of each patient at baseline, on day 7, or at discharge, whichever occurred first. The serum was promptly isolated by centrifugation and stored at -80 °C until it was analyzed in batches. Human specimens were supplied by the Department of Biobank at the Division of Clinical Research, First Hospital of Jilin University, China. Serum concentrations of S100β were determined by means of an automated magnetic particle-based chemiluminescent enzyme immunoassay system (MS-Fast/Aceso 80 A; Sophonix, Beijing, China). The assay employed a sandwich format consisting of biotinylated capture antibodies and alkaline phosphatase-conjugated detection antibodies specific to each analyte. Immune complexes were captured using streptavidin-coated magnetic particles and subsequently isolated via magnetic separation to enhance analytical sensitivity. The detection limit for all biomarkers was 0.8 pg/mL, with an intra-assay coefficient of variation of < 8.0%.
Statistical analysis
Descriptive statistical methods were employed to summarize the demographic and baseline characteristics of the study cohort, leading to the establishment of three analytical sets. The full analysis set comprised all randomized patients (n = 104) and was utilized for the primary efficacy analysis. The safety analysis set included all patients who underwent at least one session of RIC or sham-RIC (n = 104) and was used for all safety evaluations. As only two pieces of data were missing, simple interpolation was applied. The per-protocol analysis set (n = 102) was applied for the supportive efficacy analyses. All statistical analyses were performed using the SPSS software (version 26.0; IBM Corp., Armonk, NY, USA). Data were expressed as mean ± SD or median (interquartile range) depending on the data distribution, assessed using the Shapiro-Wilk test. Independent samples were analyzed using the t-test or Mann–Whitney U test, as appropriate. Paired data were analyzed using the paired t-test or Wilcoxon signed-rank test. Categorical variables were expressed as frequencies and percentages, and comparisons between the groups were performed using the 2 test or Fisher’s exact test. Safety outcomes were also compared using the 2 test or Fisher’s exact test.
To address confounding from baseline coronary artery disease (CAD) imbalance, prespecified adjusted analyses were conducted for all efficacy outcomes with baseline CAD as the sole covariate: linear regression for continuous outcomes, and Firth’s bias-corrected logistic regression for the binary 90-day stroke outcome.
Prespecified exploratory subgroup analyses were performed based on stenting type, with patients stratified into three subgroups: CAS, intracranial atherosclerotic disease (ICAD) interventions, and VAS. For the primary outcome, between-subgroup heterogeneity was assessed using the interaction P value.
A two-tailed P value of < 0.05 was considered statistically significant. The statistical analysis plan is available in Additional file 3: Statistical analysis plan.
Results
Participant characteristics
A total of 104 patients were enrolled between August 2023 and March 2024 (Fig. 1). Of these, 52 patients were assigned to the RIC group and 52 to the sham-RIC group. All patients were included in the full analysis set. Two patients who underwent endovascular stenting but did not complete the cerebral autoregulation monitoring were excluded. Consequently, 102 patients completed the final follow-up and were included in the per-protocol analysis (50 in the RIC group and 52 in the sham-RIC group). All 104 patients successfully underwent endovascular stenting procedures.
Fig. 1.
Enrollment and randomization of the patients. The figure shows the overall flow of the trial, including full and per-protocol analysis
The baseline characteristics of patients in the RIC group were comparable to those in the sham-RIC group (Table 1). In the full analysis set, the RIC group included 52 patients with a mean age of 61.40 ± 8.83 years, of whom 51 (98.08%) were men. The sham-RIC group consisted of 52 patients with a mean age of 59.98 ± 8.06 years, including 50 (96.15%) male patients. Baseline laboratory parameters—including biochemical indices, blood glucose, lipid profiles, and homocysteine levels—did not differ significantly between the two groups (Table 1).
Table 1.
Characteristics of the patients between the two groups
| Baseline Characteristic |
Full analysis set (N = 104) | Per-protocol population (N = 102) | ||||
|---|---|---|---|---|---|---|
| Sham-RIC Group (n = 52) | RIC Group (n = 52) | P | Sham-RIC Group (n = 52) | RIC Group (n = 50) | P | |
| Age, mean (SD), year | 59.98 ± 8.06 | 61.40 ± 8.83 | 0.393 | 59.98 ± 8.06 | 61.54 ± 8.98 | 0.358 |
| Sex, male, n (%) | 50 (96.15) | 51 (98.08) | 0.562 | 50 (96.15) | 49 (98.00) | 0.581 |
| Smoking, n (%) | 26 (50.00) | 28 (53.85) | 0.695 | 26 (50.00) | 27 (54.00) | 0.686 |
| Drinking, n (%) | 22 (42.31) | 15 (28.85) | 0.152 | 22 (42.31) | 14 (28.00) | 0.131 |
| Hypertension, n (%) | 30 (57.69) | 33 (63.46) | 0.547 | 30 (57.69) | 31 (62.00) | 0.657 |
| Diabetes, n (%) | 10 (19.23) | 14 (26.92) | 0.352 | 10 (19.23) | 14 (28.00) | 0.297 |
| Stroke, n (%) | 10 (19.23) | 17 (32.69) | 0.117 | 10 (19.23) | 17 (34.00) | 0.091 |
| Coronary Heart Disease, n (%) | 8 (15.38) | 3 (5.77) | 0.202* | 8 (15.38) | 3 (6.00) | 0.227* |
| SBP, mean (SD), mmHg | 140.88 ± 22.30 | 145.87 ± 19.02 | 0.223 | 140.88 ± 22.30 | 146.20 ± 19.00 | 0.199 |
| DBP, median (IQR), mmHg |
83.00 (78.00-94.75) |
85.50 (79.00-93.50) |
0.338 |
83.00 (78.00-94.75) |
84.50 (78.75-94.00) |
0.372 |
| Admission HR, median (IQR), times/minute |
78.00 (78.00-87.50) |
78.00 (72.25-80.00) |
0.075 |
78.00 (78.00-87.50) |
78.00 (72.00-80.50) |
0.081 |
| NIHSS, median (IQR) |
0.00 (0.00–1.00) |
0.00 (0.00–1.00) | 0.861 | 0.00 (0.00–1.00) | 0.00 (0.00–1.00) | 0.981 |
| mRS, median (IQR) |
1.00 (1.00–1.00) |
1.00 (1.00–1.00) | 0.842 | 1.00 (1.00–1.00) | 1.00 (1.00–1.00) | 0.717 |
|
Affected Side (Left), n (%) |
29 (55.77) | 32 (61.54) | 0.550 | 29 (55.77) | 32 (64.00) | 0.366 |
| CAS, n (%) | 28 (53.85) | 37 (71.15) | 0.291 | 28 (53.85) | 35 (70.00) | 0.357 |
| ICAD intervention, n(%) | 10 (19.23) | 7 (13.46) | 0.288 | 10 (19.23) | 7 (14.00) | 0.353 |
| VAS, n (%) | 14 (26.92) | 8 (15.38) | 0.119 | 14 (26.92) | 8 (16.00) | 0.156 |
| Baseline Characteristic |
Full analysis set (N = 104) | Per-protocol population (N = 102) | ||||
|---|---|---|---|---|---|---|
| Sham-RIC Group (n = 52) | RIC Group (n = 52) | P | Sham-RIC Group (n = 52) | RIC Group (n = 50) | P | |
| Fasting blood glucose, median (IQR), mmol/L | 5.20 (4.74–6.49) | 5.48 (5.00-6.32) | 0.105 | 5.20 (4.74–6.49) | 5.53 (4.99–6.38) | 0.092 |
| Glycosylated hemoglobin, median (IQR), (%) | 5.95 (5.58–6.60) | 6.20 (5.70–7.15) | 0.172 | 5.95 (5.58–6.60) | 6.25 (5.70–7.23) | 0.118 |
| Creatinine, median (IQR), µmol/L |
69.15 (59.70-82.35) |
67.50 (55.03–82.90) |
0.375 |
69.15 (59.70-82.35) |
66.70 (54.58–81.78) |
0.219 |
| Homocysteine, median (IQR), µmol/L |
12.27 (9.63–14.87) |
11.56 (9.29–14.36) |
0.581 |
12.27 (9.63–14.87) |
11.44 (9.19–14.33) |
0.395 |
| Cholesterol, median (IQR), mmol/L | 3.91 (3.28–4.87) | 3.57 (2.97–4.47) | 0.090 | 3.91 (3.28–4.87) | 3.60 (2.98–4.55) | 0.160 |
| Triglycerides, median (IQR), mmol/L | 1.30 (1.00-1.77) | 1.18 (0.80–1.71) | 0.254 | 1.30 (1.00-1.77) | 1.23 (0.79–1.78) | 0.317 |
| Low-density lipoprotein cholesterol, median (IQR), mmol/L | 2.45 (1.87–3.18) | 2.16 (1.73–2.97) | 0.112 | 2.45 (1.87–3.18) | 2.24 (1.75–3.02) | 0.195 |
| DAPT, n (%) | 52 (100.00) | 52 (100.00) | 1.000 | 52 (100.00) | 50 (100.00) | 1.000 |
| SAPT, n (%) | 0(0) | 0(0) | 1.000 | 0(0) | 0(0) | 1.000 |
| Statin therapy, n (%) | 52 (100.00) | 52 (100.00) | 1.000 | 52 (100.00) | 50 (100.00) | 1.000 |
| Other lipid-lowering therapy, n (%) | 0(0) | 0(0) | 1.000 | 0(0) | 0(0) | 1.000 |
| PD of affected side, median (IQR), degree |
24.14 (12.12–40.81) |
20.57 (8.70-34.24) | 0.333 |
24.14 (12.12–40.81) |
20.57 (8.75–32.75) | 0.332 |
| PD of unaffected side, median (IQR), degree |
33.98 (15.18–50.68) |
26.06 (8.70- 44.37) |
0.269 |
33.98 (15.18–50.68) |
26.06 (8.33–45.38) | 0.239 |
SD: standard deviation; IQR: interquartile range; SBP: systolic blood pressure; DBP: diastolic blood pressure; PP: pulse pressure; MAP: mean arterial pressure; HR: heart rate. NIHSS: National Institutes of Health Stroke Scale; mRS: Modified Rankin Scale; PD: phase difference; *: Continuity Correction Chi-square Test;
CAS: carotid artery stenting; ICAD: intracranial atherosclerotic disease; VAS: vertebral artery stenting
IQR: interquartile range; DAPT: Dual antiplatelet therapy; SAPT: Single antiplatelet therapy
Primary outcome
In the full analysis set, the RIC group demonstrated a significantly higher PD on the affected side compared with the sham-RIC group (40.67° [26.76°–58.28°] vs. 20.51° [10.90°–41.73°], P < 0.001) (Fig. 2). Similar findings were observed in the per-protocol analysis (Table 2). This significant difference remained after adjustment for baseline CAD history (adjusted P = 0.001, Table 3).
Fig. 2.
Phase difference in the Sham-RIC and RIC groups. A Phase difference at the baseline and 7 days/discharge between the Sham-RIC group and the RIC group after randomization. B Comparison of the phase difference phase in the Sham-RIC and RIC groups at 7 days/discharge. C Comparison of the phase difference before and after RIC in the RIC group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001
Table 2.
Efficacy outcomes
| Indicators | Full analysis set (N = 104) | Per-protocol population (N = 102) | |||||
|---|---|---|---|---|---|---|---|
| Sham-RIC Group (n = 52) | RIC Group (n = 52) | P | Sham-RIC Group (n = 52) | RIC Group (n = 50) | P | ||
| Primary outcome | |||||||
| PD of affected side at 7 days/discharge, median (IQR), degree |
20.51 (10.90- 41.37) |
40.67 (26.76–58.28) |
< 0.001 |
20.51 (10.90- 41.37) |
40.67 (25.59–58.76) |
< 0.001 | |
| Secondary outcome | |||||||
| Stroke within 90 days, n (%) | 5 (9.62) | 0 (0) | 0.022 | 5 (9.62) | 0 (0) | 0.025 | |
| Exploratory outcomes | |||||||
| PD of unaffected side at 7 days/discharge, mean (SD), degree |
26.80 (11.94–44.83) |
36.04 (21.66–54.53) |
0.022 |
26.80 (11.94–44.83) |
34.90 (21.24–55.03) |
0.031 | |
| Gain of unaffected side at 7 days/discharge, mean (SD), cm/s/mmHg | 1.06 ± 0.48 | 1.05 ± 0.39 | 0.869 | 1.06 ± 0.48 | 1.04 ± 0.39 | 0.794 | |
| Gain of affected side at 7 days/discharge, mean (SD), cm/s/mmHg | 1.12 ± 0.62 | 1.06 ± 0.34 | 0.526 | 1.12 ± 0.62 | 1.05 ± 0.35 | 0.500 | |
| mRS, median (IQR) | 1.00 (0.00–1.00) | 1.00 (0.00–1.00) | 0.844 | 1.00 (1.00–1.00) | 1.00 (1.00–1.00) | 0.821 | |
| Death (%) | 0 (0) | 0 (0) | - | 0 (0) | 0 (0) | - | |
PD: phase difference; SD: standard deviation; IQR: interquartile range
Table 3.
Unadjusted and CAD-adjusted efficacy outcomes in the full analysis set
| Indicators | Full analysis set (N = 104) | |||
|---|---|---|---|---|
| Sham-RIC Group (n = 52) |
RIC Group (n = 52) |
Unadjusted P | Adjusted P (for CAD) |
|
| Primary outcome | ||||
| PD of affected side at 7 days/discharge, median (IQR), degree |
20.51 (10.90- 41.37) |
40.67 (26.76–58.28) |
< 0.001 | 0.001 |
| Secondary outcome | ||||
| Stroke within 90 days, n (%) | 5 (9.62) | 0 (0) | 0.022 | 0.023 |
| Exploratory outcomes | ||||
| PD of unaffected side at 7 days/discharge, mean (SD), degree |
26.80 (11.94–44.83) |
36.04 (21.66–54.53) |
0.022 | 0.013 |
| Gain of unaffected side at 7 days/discharge, mean (SD), cm/s/mmHg | 1.06 ± 0.48 | 1.05 ± 0.39 | 0.869 | 0.904 |
| Gain of affected side at 7 days/discharge, mean (SD), cm/s/mmHg | 1.12 ± 0.62 | 1.06 ± 0.34 | 0.526 | 0.571 |
| mRS, median (IQR) | 1.00 (0.00–1.00) | 1.00 (0.00–1.00) | 0.844 | 0.839 |
| Death (%) | 0 (0) | 0 (0) | - | - |
Secondary outcome
In the full analysis set, during the 90-day follow-up period, five patients (9.62%) in the sham-RIC group experienced cerebrovascular events, including two who had a stroke and three who had a transient ischemic attack. Meanwhile, no stroke events occurred in the RIC group. The 90-day stroke incidence was significantly lower in the RIC group than in the sham-RIC group (0.0% vs. 9.6%, P = 0.022). This significant difference remained statistically significant after adjustment for baseline CAD history (adjusted P = 0.023, Table 3). No deaths occurred in either group during the 90-day follow-up period (Table 2). Similar results were observed in the per-protocol analysis set.
Exploratory outcomes
In the full analysis set, the PD on the unaffected side at day 7 or at discharge was significantly higher in the RIC group than in the sham-RIC group (36.04° [21.66°–54.53°] vs. 26.80° [11.94°–44.83°], P = 0.022). This significant difference remained robust after adjusting for baseline CAD history (adjusted P = 0.013, Table 3). No significant differences in gain values were observed between the RIC and sham-RIC groups on either the affected or unaffected sides (Table 2), and the results remained non-significant before and after CAD adjustment (Table 3). The above adjusted results were fully validated in the analysis of the PP population (Table 4). The 90-day mRS showed no statistically significant difference between the two groups (1.00 [0.00–1.00] vs. 1.00 [0.00–1.00], P = 0.844) (Table 2).
Table 4.
Sensitivity analysis of CAD-adjusted outcomes in the per-protocol population
| Indicators | Per-protocol population (N = 102) | |||
|---|---|---|---|---|
| Sham-RIC Group (n = 52) |
RIC Group (n = 50) |
Unadjusted P | Adjusted P (for CAD) |
|
| Primary outcome | ||||
| PD of affected side at 7 days/discharge, median (IQR), degree |
20.51 (10.90- 41.37) |
40.67 (25.59–58.76) |
< 0.001 | 0.001 |
| Secondary outcome | ||||
| Stroke within 90 days, n (%) | 5 (9.62) | 0 (0) | 0.025 | 0.026 |
| Exploratory outcomes | ||||
| PD of unaffected side at 7 days/discharge, mean (SD), degree |
26.80 (11.94–44.83) |
34.90 (21.24–55.03) |
0.031 | 0.016 |
| Gain of unaffected side at 7 days/discharge, mean (SD), cm/s/mmHg | 1.06 ± 0.48 | 1.04 ± 0.39 | 0.794 | 0.829 |
| Gain of affected side at 7 days/discharge, mean (SD), cm/s/mmHg | 1.12 ± 0.62 | 1.05 ± 0.35 | 0.500 | 0.548 |
| mRS, median (IQR) | 1.00 (0.00–1.00) | 1.00 (0.00–1.00) | 0.821 | 0.807 |
| Death (%) | 0 (0) | 0 (0) | - | - |
Furthermore, within the RIC group, comparison of CBF regulation before and after treatment demonstrated a significant increase in PD on the affected and unaffected sides following RIC treatment (affected side: 20.57° [8.70°–34.24°] vs. 40.67° [26.76°–58.28°], P < 0.001; unaffected side: 26.06° [8.70°–44.37°] vs. 36.04° [27.66°–54.53°], P = 0.001) (Fig. 2). In contrast, no significant differences were noted in CBF regulation on either side in the sham-RIC group (Table 5).
Table 5.
Intra-group comparison of CBF regulation
| PD median (IQR)/ mean (SD), degree | Sham-RIC Group | RIC Group | |||||
|---|---|---|---|---|---|---|---|
| Baseline | 7 days/discharge | P | Baseline | 7 days/discharge | P | ||
| Full analysis set (N = 104) | Sham-RIC Group (n = 52) | RIC Group (n = 52) | |||||
| Affected side |
24.14 (12.12–40.81) |
20.51 (10.90- 41.37) |
0.423 |
20.57 (8.70- 34.24) |
40.67 (26.76–58.28) |
< 0.001 | |
| Unaffected side |
33.98 (15.18–50.68) |
26.80 (11.94–44.83) |
0.101 |
26.06 (8.70- 44.37) |
36.04 (27.66–54.53) |
0.001 | |
| Per-protocol population (N = 102) | Sham-RIC Group (n = 52) | RIC Group (n = 50) | |||||
| Affected side |
24.14 (12.12–40.81) |
20.51 (10.90- 41.37) |
0.423 |
20.57 (8.70- 32.75) |
40.67 (26.76–58.28) |
< 0.001 | |
| Unaffected side |
33.98 (15.18–50.68) |
26.80 (11.94–44.83) |
0.101 |
25.21 (8.33–45.38) |
34.90 (21.24–55.03) |
0.001 | |
CBF: cerebral blood flow; PD: phase difference
In this study, serum brain injury biomarkers were analyzed in 53 patients, including 30 in the sham-RIC group and 23 in the RIC group. Baseline serum concentrations of brain injury biomarkers did not differ significantly between the groups, indicating comparable initial levels of neuronal and glial injury before the intervention. Notably, in the sham-RIC group, serum S100β levels exhibited a significant post-intervention increase compared with baseline values (0.03 [0.01–0.06] µg/L vs. 0.06 [0.03–0.13] µg/L, P = 0.001). By contrast, no significant change in serum S100β levels was observed in the RIC group following treatment (0.03 [0.02–0.07] µg/L vs. 0.05 [0.02–0.08] µg/L, P = 0.184). No significant differences were observed in the remaining indicators (Table 6).
Table 6.
Brain injury biomarkers of the patients between the two groups
| Indicators | Time | Sham-RIC Group (n = 30) | RIC Group (n = 23) | P |
|---|---|---|---|---|
| S100β | Baseline | 0.03 (0.01, 0.63) | 0.03 (0.02, 0.07) | 0.928 |
| 7 days/discharge | 0.06 (0.03, 0.13) | 0.05 (0.02, 0.08) | 0.382 | |
| P | 0.001 | 0.184 |
S100B: S100 calcium-binding protein B
Safety outcomes
During hospitalization, five patients in the RIC group developed AEs. Among these, three patients (5.77%) presented with digestive tract symptoms, whereas two (3.85%) reported dizziness and headache following the procedure. In the sham-RIC group, nine patients developed AEs: 5 (9.62%) with digestive tract symptoms, 3 (5.77%) with dizziness and headache, and 1 (1.62%) with postoperative hemorrhage transformation. No significant difference was found in the incidence of AEs between the two groups (Table 7).
Table 7.
Safety outcomes within 90 days
| Safety outcomes | Safety analysis set (N = 104) | ||
|---|---|---|---|
| Sham-RIC Group (n = 52) | RIC Group (n = 52) | P | |
| Electrolyte disorder n (%) | |||
| Constipation | 5 (9.62) | 3 (5.77) | 0.358* |
| Dizziness and headache | 3 (5.77) | 2 (3.85) | 0.500* |
| Hemorrhagic transformation | 1 (1.92) | 0 (0) | 0.500* |
| Serious adverse event- n (%) | 0 (0) | 0 (0) | - |
*: Continuity correction Chi-square test
Subgroup analyses
The beneficial effect of RIC on improving CBF regulation showed a consistent trend across all three prespecified subgroups (CAS, ICAD interventions, VAS), with no significant between-subgroup heterogeneity (interaction P = 0.263 in the full analysis set; P = 0.269 in the per-protocol population). Specifically, RIC significantly improved PD in the CAS subgroup (P = 0.001, adjusted P = 0.002) and in the ICAD interventions subgroup (P = 0.028, adjusted P = 0.028) A consistent directional benefit of RIC on PD was observed in the VAS subgroup, although no statistical significance was found between the two groups (Tables 8 and 9).
Table 8.
Subgroup analysis of outcomes in the full analysis set
| Subgroups | PD of affected side at 7 days/discharge, median (IQR), degree |
P | Adjusted P (for CAD) |
Interaction P | |
|---|---|---|---|---|---|
| Sham-RIC Group (n = 52) |
RIC Group (n = 52) |
||||
| Overall population |
20.51 (10.90-41.37) |
40.67 (26.76–58.28) |
< 0.001 | 0.001 | 0.263 |
| CAS |
21.14 (4.27–40.55) |
40.81 (29.47–58.76) |
0.001 | 0.002 | |
| ICAD intervention |
17.48 (7.14–40.29) |
43.75 (30.10-79.25) |
0.028 | 0.028 | |
| VAS |
22.86 (14.44–58.62) |
29.11 (18.89–44.04) |
0.482 | 0.700 | |
CAS: carotid artery stenting; ICAD: intracranial atherosclerotic disease; VAS: vertebral artery stenting; CAD: coronary artery disease
Table 9.
Subgroup analysis of outcomes in the per-protocol population
| Subgroups | PD of affected side at 7 days/discharge, median (IQR), degree |
P | Adjusted P (for CAD) |
Interaction P | |
|---|---|---|---|---|---|
| Sham-RIC Group (n = 52) |
RIC Group (n = 50) |
||||
| Overall population |
20.51 (10.90-41.37) |
40.67 (26.76–58.28) |
< 0.001 | 0.001 | 0.269 |
| CAS |
21.14 (4.27–40.55) |
40.82 (28.00-58.76) |
0.001 | 0.002 | |
| ICAD intervention |
17.48 (7.14–40.29) |
43.75 (30.10-79.25) |
0.028 | 0.028 | |
| VAS |
22.86 (14.44–58.62) |
29.11 (18.89–44.04) |
0.482 | 0.700 | |
CAS: carotid artery stenting; ICAD: intracranial atherosclerotic disease; VAS: vertebral artery stenting;
CAD: coronary artery disease
Discussion
This randomized controlled trial demonstrated that RIC significantly enhanced CBF regulation and reduced the occurrence or recurrence of postoperative stroke in patients with cerebrovascular stenosis following endovascular stenting, without increasing the risk of adverse effects. These findings suggest that RIC is a safe and effective adjunctive therapy for improving hemodynamic function and clinical outcomes in this patient population.
Although endovascular stenting is recognized as a critical therapeutic strategy in current clinical guidelines [36], the procedure itself carries a persistent risk of ischemic events, largely attributable to hemodynamic impairment [18]. Substantial evidence has identified impaired CBF regulation as an independent predictor of adverse stroke outcomes [37–39]. Impaired CBF regulation compromises the capacity of cerebral vessels to maintain stable perfusion under conditions of hyperperfusion or hypoperfusion and to facilitate the clearance of emboli [40]. These findings underscore the critical role of CBF regulation in influencing the incidence and recurrence of stroke among patients with cerebrovascular stenosis following endovascular stenting. In the present study, RIC significantly improved bilateral CBF regulation, thereby increasing the resilience of cerebral vessels to stenting-induced hemodynamic fluctuations, improving microcirculatory perfusion, and promoting embolus clearance. This physiological improvement translated into a marked clinical benefit. No stroke events occurred in the RIC group during the 90-day follow-up compared with five events in the sham-RIC group. This finding aligns with the established neuroprotective effects of RIC [41] and underscores its therapeutic potential, thereby validating the initial hypothesis of the study.
These compelling clinical benefits raise the question of the underlying mechanisms through which RIC exerts its protective effects. Based on previous preclinical and clinical studies, RIC is proposed to enhance endothelial function and microvascular reactivity through a synergistic interplay among humoral, neural, and immunomodulatory pathways [42]. This improvement is believed to enhance cerebrovascular microcirculation and strengthen CBF regulation, thereby increasing resilience in patients with hemodynamic instability. The bilateral improvement in CBF regulation observed in the present study indicates a systemic protective effect. The humoral pathway appears to play a fundamental role in this mechanism. The transient limb ischemia-reperfusion cycles induced by RIC trigger the release of circulating mediators, including adenosine [43], bradykinin [44], nitric oxide, and vascular endothelial growth factor [45]. These mediators are pivotal in enhancing endothelial function and microvascular reactivity. Neural pathways are also essential for the systemic propagation of these protective signals [45–47]. Meanwhile, immunomodulation constitutes a critical component of the overall response. Endovascular stenting induces microglial activation and peripheral immune cell infiltration. RIC suppresses microglial activation [48], reduces neutrophil abundance and activity [49], and modulates the proinflammatory state [42]. Combined with the existing literature, our findings suggest that RIC enhances endothelial cell function, improves cerebral microcirculation, and ultimately strengthens CBF regulation in patients with stents through adenosine-mediated synergistic neural signal transduction while concurrently mitigating stent-induced inflammation. Therefore, RIC is considered a multi-pathway, multi-target therapeutic strategy that may enhance CBF regulation by improving microcirculatory perfusion, thereby promoting embolus clearance and reducing the risk or recurrence of postoperative stroke in patients with stents.
Further corroboration of the neuroprotective effect of RIC was provided by biomarker evidence. Serum biomarkers reflect various aspects of brain injury and serve as established clinical indicators of neuronal and glial damage [50–57]. Post-intervention, the levels of S100β—an astrocyte-derived damage-associated molecular pattern protein—were significantly elevated in the sham-RIC group but remained unchanged in the RIC group [51, 53, 56]. The result indicates that RIC attenuated subclinical brain injury associated with the stenting procedure [58]. This attenuation of biomarker release strengthens the conclusion that RIC confers tangible protection at the tissue level, further supporting the neuroprotective role of RIC.
From the baseline data, we can observe that the lipid levels of many included patients did not reach the recommended targets. Two main reasons can explain this. First, among the included patients, most were newly diagnosed with atherosclerotic cerebrovascular stenosis, with limited duration of lipid-lowering therapy before admission and surgery. Second, some patients who were previously diagnosed with atherosclerotic cerebrovascular stenosis had relatively poor long-term medication adherence in prior outpatient management. After the patients entered this study, we provided them with education on medication compliance and detailed instructions on post-discharge medication use. We believe that these patients will be able to better control their blood levels. However, as the intensity of lipid-lowering therapy, baseline LDL-C levels, and post-procedure medical management were well balanced between the two groups, this did not introduce significant confounding bias.
Our study has some limitations. First, the sample size was relatively modest; therefore, multicenter, large-sample randomized controlled trials are required to validate the long-term efficacy and generalizability of RIC in patients undergoing cerebrovascular stenting. Second, all participants were recruited from a single center. Although no significant differences were observed across stent locations, future multicenter trials incorporating stent site and number would allow for a more detailed evaluation of potential effect modifiers. Third, our study cohort consisted predominantly of male patients, reflecting the real-world clinical population treated at our center in northern China, but this may limit the generalizability of the results to female patients with cerebrovascular stenosis. Fourth, our study did not perform targeted detection of circulating humoral mediators, neural signaling markers, or inflammatory biomarkers related to the proposed mechanisms. Therefore, we cannot directly verify the specific biological pathways through which RIC improves CBF regulation in this cohort, and the proposed mechanisms remain hypothetical. Further studies integrating multi-omics and serial mechanistic biomarker measurements are needed to elucidate the underlying pathways.
In conclusion, this trial provides compelling evidence that RIC safely enhances CBF regulation and reduces the risk of stroke in patients undergoing endovascular stenting for cerebrovascular stenosis. These benefits, coupled with the attenuated biomarker evidence of injury, suggest that RIC plays a potential role in improving clinical outcomes in this patient population.
Conclusions
RIC appears to be a safe and promising non-pharmacological intervention that enhances CBF regulation and reduces the occurrence or recurrence of postoperative strokes in patients with cerebrovascular stenosis following endovascular stenting.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary Material 1: Additional file 1: CONSORT checklist
Supplementary Material 2: Additional file 2: Study protocol
Supplementary Material 3: Additional file 3: Statistical analysis plan
Acknowledgements
The authors express gratitude to all those who have cooperated and contributed to this research.
Abbreviations
- ABP
Arterial blood pressure
- AEs
Adverse events
- CAD
Coronary artery disease
- CAS
Carotid artery stenting
- CBF
Cerebral blood flow
- CBFV
Cerebral blood flow velocity
- DAPT
Dual antiplatelet therapy
- DBP
Diastolic blood pressure
- HR
Heart rate
- ICAD
Intracranial atherosclerotic disease
- IQR
Interquartile range
- MAP
Mean arterial pressure
- mRS
Modified Rankin Scale
- NIHSS
National Institutes of Health Stroke
- PD
Phase difference
- PP
Pulse pressure
- RIC
Remote ischemic conditioning
- SAPT
Single antiplatelet therapy
- SBP
Systolic blood pressure
- SD
Standard deviation
- VAS
Vertebral artery stenting
Author contributions
Conception and design: ZW, YY and ZNG. Collection of data: YTH, BFX JL, PDZ and HMZ Data analysis: PZ, YTH, SQ and YQ. Manuscript writing: YTH, ZNG, BFX and QYH. Critical and intellectual revision of manuscript: all authors. Final approval of manuscript: all authors. All authors read and approved the final manuscript.
Funding
This project was supported by the National Natural Science Foundation of China (U24A20686), Science and Technology Department of Jilin Province (20250601002RC) and the Development Center for Medical Science & Technology, National Health commission of the People’s Republic of China (WKZX2023CZ0101) to YY, the Fundamental Research Funds for the Central Universities (45124031D051) to ZNG, Science and Technology Department of Jilin Province (YDZJ202302CXJD061), Jilin Provincial Key Laboratory (YDZJ202302CXJD017) and the Norman Bethune Health Science Center of Jilin University (2025JBGS02) to YY. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request. Due to privacy, the data are not publicly accessible and are stored in the database of the First Hospital of Jilin University.
Declarations
Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Hospital of Jilin University (23K126-001). Written informed consent was obtained from all participants or their immediate legal guardians before enrollment.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yi-Ting Hou and Bao-Feng Xu contributed equally to this work.
Contributor Information
Wang Zan, Email: wangzan@jlu.edu.cn.
Yi Yang, Email: yang_yi@jlu.edu.cn.
Zhen-Ni Guo, Email: zhen1ni2@jlu.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material 1: Additional file 1: CONSORT checklist
Supplementary Material 2: Additional file 2: Study protocol
Supplementary Material 3: Additional file 3: Statistical analysis plan
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request. Due to privacy, the data are not publicly accessible and are stored in the database of the First Hospital of Jilin University.