Chronic remote ischemic conditioning for symptomatic internal carotid or middle cerebral artery occlusion: A prospective cohort study

Abstract Aims Remote ischemic conditioning (RIC) has been demonstrated to reduce recurrent stroke in patients with intracranial artery stenosis. This study aimed to evaluate the effects of RIC in patients with the symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion. Methods This study is based on a high‐volume single‐center prospective cohort study in China, which included patients with symptomatic ICA or MCA occlusion with impaired hemodynamics and receiving chronic RIC. Clinical follow‐up visits were performed regularly, and cardio‐cerebrovascular events were assessed. Results In total, 131 patients (68 with ICA occlusion and 63 with MCA occlusion; mean age, 52.6 ± 13.7 years; stroke, 73.5%; transient ischemic attack TIA, 26.5%) qualified for the analysis; the mean follow‐up period was 8.8 years (range, 3–14 years). The compliance of RIC was 95.6 ± 3.7%, and no associated severe adverse events happened. The annual risk of ischemic stroke and ischemic cerebrovascular events was 2.4% and 3.3%, respectively. The cumulative probabilities of ischemic cerebrovascular events and major adverse cardiovascular and cerebrovascular events were 32.8% and 44.8% at 14 years, respectively. Conclusion In patients with symptomatic ICA or MCA occlusion with impaired hemodynamics, chronic RIC is well‐tolerated, and it appears to be associated with a low annual risk of ischemic stroke and cardio‐cerebrovascular events.


| INTRODUC TI ON
The internal carotid artery (ICA) is the most common artery involved in atherosclerosis, followed by the middle cerebral artery (MCA). 1 Occlusion of the ICA and MCA reduces cerebral blood perfusion and increases the risk of ischemic stroke, which accounts for more than one-fourth of cases of ischemic stroke in the carotid territory. [2][3][4] Improvement of regional cerebral blood flow (rCBF) has been considered a therapeutic option for patients with intracranial atherosclerosis. However, large trials investigating extracranial-intracranial bypass surgery in patients with symptomatic ICA or MCA atherosclerosis have failed to demonstrate its clinical benefits, [5][6][7] leading to the standard management of symptomatic ICA or MCA occlusion mainly involving antithrombotic medication and vascular risk factor modification. 8 However, the annual risk of stroke in patients with symptomatic ICA or MCA occlusion remains to be 5%-6% in general and up to 35.6% for those with decreased rCBF and regional cerebrovascular reactivity to acetazolamide, 9,10 which causes significant challenges in clinical practice.
Remote ischemic conditioning (RIC) is a systematic protective strategy in which one or more cycles of brief, nonlethal limb ischemia confers protection against prolonged, severe ischemia in distant organs. 11 Recently, it has been suggested that RIC is a promising strategy in reducing recurrent stroke or transient ischemic attacks (TIAs) in patients with symptomatic intracranial atherosclerosis. RIC also improves cerebral perfusion and promotes arterial collateral opening and reconstruction. 12,13 As the protective period of one session of RIC persists for approximately 96 h with a 12-24 h unprotected period, adjunctive chronic RIC has been proposed to treat ischemic cerebrovascular diseases and proven safe and effective in this patient population. [14][15][16] However, it remains unknown whether adjunctive chronic RIC is safe and effective in patients with symptomatic ICA or MCA occlusion.
In this prospective cohort study with long-term follow-up (8.8 years), we aimed to assess the safety and potential clinical benefits of chronic RIC as adjunctive therapy for the treatment of symptomatic ICA or MCA occlusion.

| Study design and patients
This study was an observational study of a high-volume singlecenter cohort in which a prospectively designed follow-up schedule was used for the follow-up of all patients by experienced stroke neurologists. Since 2007, RIC has been used for the treatment of ischemic cerebrovascular disease in Xuanwu Hospital of Capital Medical University, and all patients who received adjunctive RIC were enrolled in this prospective cohort study. Herein, patients aged≥18 years at the first visit who had ischemic stroke or TIA secondary to ICA or MCA occlusion (i.e., occlusion of the extracranial and intracranial segments of the ICA occlusion or M1 segment of the MCA) within 6 months of ictus along with impaired hemodynamics in the territory of the MCA were recruited. Meanwhile, patients diagnosed with moyamoya disease; patients who underwent extracranial-intracranial bypass surgery during follow up; patients with occlusion secondary to non-atherosclerotic disease, including artery dissection, arteritis, and fibromuscular dysplasia; and patients who received RIC irregularly were excluded. Cerebral hemodynamics were evaluated using single-photon emission computed tomography (SPECT) and semiquantitative analyses; impaired hemodynamics were defined as an rCBF of the affected side/unaffected side (or the affected side/cerebellum in cases of moderate-to-severe contralateral ICA or MCA stenosis or occlusion) of <0.9.

| Interventions
All enrolled patients were managed in accordance with guidelines [17][18][19] and received the best medical therapies, including modifiable risk factor management, antiplatelet or anticoagulant medication, and statin therapy. Antihypertensive, antidiabetic, and homocysteinelowering agents were administered as required, depending on the presence of comorbidities. In addition, all patients received RIC once or twice a day, consisting of five cycles of simultaneous bilateral upper arm ischemia for 5 min, followed by reperfusion for another 5 min. RIC was performed using an electric autocontrol device with cuffs inflated to a pressure of 200 mmHg during the ischemic period and deflated to a pressure of 0 mmHg during the reperfusion period.
The procedure was performed by the patients themselves or with the help of their caregivers at home.
All electric autocontrol devices were equipped with subscriber identification module cards carrying patient-unique identification numbers and recording dates of RIC implementation and connected to a background monitoring platform. To ensure compliance to RIC, the patients were automatically remined by the background monitoring platform when the treatment had been interrupted for four consecutive days, and the investigators were alerted when it had been interrupted for seven consecutive days; all this information was documented in the background monitoring platform.

| Follow-up
All enrolled patients were required to undergo clinical follow-up visits every 6 months or when necessary in the initial two years, and every 12 months or when necessary thereafter. During the visits, the patients were interviewed regarding recurrent stroke and TIAs, cardiovascular events, symptoms of heart failure, bleeding, new hospitalizations (and their causes), RIC, current medications, control of cerebrovascular disease risk factors, and any other discomfort that they may have complained of. This information was documented in the database of the cohort study.
In addition, a systematic telephone call was conducted for every patient to confirm their medical history between January and February 2021. During the telephone interviews, all patients were also asked regarding recurrences of TIAs and stroke; angina, acute myocardial infarction, or heart failure; new hospitalizations (and causes); bleeding; current medical therapies and RIC; and cerebrovascular risk factor status.

| SPECT examination
The cerebral perfusion status was assessed using SPECT (Siemens E. Cam SPECT Workstation, Siemens Healthineers,) prior to enrollment into this study and post RIC treatment. The rCBF was evaluated using technetium-99 m ethylene cysteine dimer ( 99m Tc-ECD) and a dual-headed rotating γ camera at 30 min after intravenous 99m Tc-ECD (25 mCi) bolus injection. Qualitative and semiquantitative analyses of the rCBF were performed using an automated region of interest (ROI) analysis. The ROI was classified according to the territory of the major blood vessels supplying the brain, including the ICA and vertebral arteries. The activity of each signal was compared to the maximal signal uptake in the cerebellum. The heterogeneity of brain perfusion was measured as the coefficient of variation, which was defined as the ratio of the standard deviation to the mean. All SPECT images were evaluated by two independent nuclear medicine physicians.

| Data collection
This study included the following patients variables from the database: age, sex, medical history, clinical manifestation of ICA or MCA occlusion, concomitant cerebral artery occlusion or stenosis, combined therapies, baseline cerebral hemodynamics assessed using SPECT, cerebrovascular events, cardiovascular events, and any other clinical events reported by the patients themselves. To ensure accuracy, two independent reviewers matched all patient data with the medical records, and any inconsistent or vague information was clarified after confirmation with the patients.

| Outcome assessment
The primary outcome was the proportion of patients who experienced recurrent ischemic cerebrovascular events, including ischemic stroke, TIAs, and amaurosis fugax. The secondary outcomes included the rate of compliance RIC and proportion of patients who experienced cardiovascular events (e.g., angina and myocardial infarction), major adverse cardiovascular and cerebrovascular events (MACCEs), and those who died. The rate of compliance RIC was calculated using the following formula: months of regular RIC/total months of follow-up; regular RIC was defined as no interruption of RIC or interrupted RIC for ≤4 consecutive days.
MACCEs were defined as all-cause death, stroke or TIAs, acute coronary syndrome (e.g., myocardial infarction and angina), and heart failure requiring hospitalization.

| Statistical analysis
Categorical variables were reported as n (%) and continuous variables as means ± standard deviations or medians [25th to 75th interquartile ranges (IQRs)] depending on the variable distribution.

| Baseline characteristics
The baseline characteristics of all recruited patients are summarized in

| Cerebrovascular risk factor control
The medical therapies and cerebrovascular risk factor control status at the latest follow-up visit are summarized in Table 2

| DISCUSS ION
In this study, patients with symptomatic ICA or MCA occlusion who had impaired hemodynamics and received chronic (>10 years) RIC as adjunctive therapy exhibited lower annual risks of stroke (2.4%) and ischemic cerebrovascular events (3.3%). In addition, rates of 4.6% for mortality and 4.6% for the occurrence of cardiovascular events were Previous studies have demonstrated that among with ICA or MCA occlusion, the annual risk of stroke is 12.5% in those with any impaired hemodynamics, and is much higher at 35.6%-41.4% in patients with severely impaired hemodynamics, the annual risk of stroke. [22][23][24] In our study, we recruited patients with symptomatic ICA or MCA occlusion who had impaired hemodynamics, as measured using SPECT, and the annual risk of all-cause stroke was 2.4%, which was notably lower than previously reported. The discrepancy in the annual risk of stroke between this study and previous studies may have been attributable to several reasons. First, chronic RIC is associated with an improved cerebral perfusion status in the ischemic territory, as shown by the SPECT results, and an improved cerebral tissue tolerance to ischemic injury, both of which may improve brain tissue tolerance to ischemic insults. Second, the modification of risk factors of cerebrovascular diseases and antiplatelet therapy have been advancing greatly over the past few decades, which might have also contributed to the low risk of recurrent ischemic cerebrovascular events. In addition, stroke is more likely to recur within the first few months after ischemic stroke. In this study, the median time interval from symptom onset to enrollment was approximately 2 months, which might have led to missing the high stage of recurrent stroke. In previous studies that investigated RIC in patients with moyamoya disease and symptomatic intracranial atherosclerosis, RIC was found to reduce ischemic cerebrovascular events and improve the cerebral perfusion status, as evaluated using SPECT or positron emission tomography. 12,25 However, these studies mainly included patients with cerebrovascular stenosis, and the follow-up period for most patients was less than 2 years. To the best of our knowledge, this study is the first to reveal the potential effects of RIC in pa- Furthermore, all the patients tolerated the procedure with few complaints of pain. This may confirm that pain tolerance can also be adapted, which is in line with the findings of previous studies that showed that 20 min of painful stimulation once daily for eight consecutive days may substantially decrease pain ratings in response to a constant pain stimulus 29 and that the pain threshold gradually increases in the ischemic arm over the course of each cycle of RIC. 30 This study had limitations. First, this study has a prospective single-center cohort study design, whose inherent limitation is related to certain biases. However, it is difficult to conduct a randomized controlled trial with such a long-term follow-up, and a long-term cohort study might be a better substitute. Second, the number of patients in this study was relatively small, which might have influenced the study results. Therefore, the findings should be further verified in larger trials and interpreted with caution. Furthermore, considering the longterm follow-up, the number of patients lost to follow-up was relatively small; however, the possibility of missing adverse events cannot be completely ruled out, especially considering the incidence of TIA and amaurosis fugax related to the inherent characteristics of the disease.
In conclusion, chronic RIC is well tolerated with high compliance and may be associated with low rates of ischemic cerebrovascular events and MACCEs in long-term follow-ups among patients with symptomatic ICA or MCA occlusion with impaired hemodynamics.
As it is difficult to conduct randomized controlled trials investigating the effects of chronic RIC in patients with symptomatic ICA or MCA occlusion with such a long-term follow-up, larger cohort studies are needed to confirm the results, so that a meta-analysis may be conducted to clarify the overall clinical benefits of chronic RIC in this patient population.

CO N FLI C O F I NTE R E S T
Dr. Xunming Ji is one of the inventors of the electric autocontrol device that has been patented in China. The other authors report no disclosures.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data, analytic methods, and study materials of this study are available from the corresponding author on reasonable request and detailed protocol is provide.