Carotid Artery Stenosis
Conditions
Keywords
Remote ischemic preconditioning, Stroke secondary prevention, Carotid artery stenting, Carotid stenosis, Inflammation
Brief summary
Remote limb ischemic preconditioning (RIPC) has neuro-protective and anti-inflammatory effects on ischemia- reperfusion injury. As the extent of its effect is unknown, the investigators will use clinical outcome, serum biochemical markers and brain magnetic resonance imaging (MRI) to determine whether RIPC has neuro-protective and anti-inflammatory effects on patients undergoing carotid artery stenting.
Detailed description
BACKGROUND: Brain ischemia and injury contributed to perioperative morbidity and mortality in Carotid Artery Stenting. Remote ischemic preconditioning (RIPC), brief periods of ischemia followed by reperfusion, can provide systemic protection for prolonged ischemia. Our previous study found no significant protection to the patients who received once RIPC before Carotid Artery Stenting. In order to investigate whether long-term RIPC before Carotid Artery Stenting can protect these patients from the perioperative and long-term complications, a prospective randomized controlled trial will be performed in the current study. DESIGNING: About 189 patients who are eligible for carotid artery stenting will be randomly assigned in 1:1:1 ratio to RIPC group, sham RIPC group and conventional Carotid Artery Stenting group (control). Remote limb ischemic preconditioning (RIPC) is consisted of five 5-min cycles of bilateral arm ischemia/reperfusion, it is induced by an automated cuff-inflator placed on bilateral arm and inflated to 200 mmHg for 5-min followed by deflating the cuff for 5-min, patients in the RIPC group will do it twice a day for at least two weeks before carotid artery stenting. Patients in the sham RIPC group receive sham RIPC treatment, which is consisted of five 5-min cycles of bilateral arm ischemia/reperfusion, induced by an automated cuff-inflator placed on bilateral arm and inflated to 60 mmHg for 5-min followed by deflating the cuff for 5-min, they will do it twice a day for at least two weeks before carotid artery stenting. Patients in the control group receive conventional carotid artery stenting without RIPC or sham RIPC treatment. Cerebral injury is assessed by serum S-100B and Neuron specific enolase (NSE), systematic inflammation is assessed by serum high-sensitivity C-reactive protein (hs-CRP). Post-treatment infarctions, both symptomatic and asymptomatic, are detected by diffusion-weighted imaging (DWI) and clinical outcomes are determined by cerebrovascular events, cardiac events or death.
Interventions
PROCEDURERemote ischemic preconditioning
Remote ischemic preconditioning consisted of five 5-min cycles of bilateral arm ischemia/reperfusion, which is induced by an automated cuff-inflator placed on bilateral arm and inflated to 200 mmHg for 5-min followed by deflating the cuff for 5-min.
PROCEDURESham remote ischemic preconditioning
Sham remote ischemic preconditioning consisted of five 5-min cycles of bilateral arm ischemia/reperfusion, which is induced by an automated cuff-inflator placed on bilateral arm and inflated to 60 mmHg for 5-min followed by deflating the cuff for 5-min.
PROCEDURECarotid Artery Stenting
Carotid Artery Stenting is an invasive therapy of carotid artery stenosis.
Sponsors
Ji Xunming
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Symptomatic or asymptomatic carotid artery stenosis. In symptomatic patients the degree of stenosis should more than 60% (Based on NASCET Criteria), in asymptomatic patients the degree of stenosis should more than 70% (Based on NASCET Criteria); 2. Tolerance to any of the study medications, including clopidogrel, aspirin and statins; 3. Can cooperate with and complete brain MRI examination; 4. Has a negative pregnancy test within 7 days before randomization and no childbearing potential; 5. Vascular ultrasound excluded intravascular thrombosis and unstable plaques in blood vessels of the bilateral upper limbs; 6. No hemorrhagic tendency; 7. Stable vital sign, normal renal and hepatic functions; 8. Informed consent.
Exclusion criteria
1. Evolving stroke; 2. Prior major ipsilateral stroke, if likely to confound study endpoints; 3. Severe dementia; 4. Hemorrhagic conversion of an ischemic stroke within the past 60 days; 5. Chronic atrial fibrillation; 6. Myocardial infarction within previous 30 days; 7. Inability to understand and cooperate with study procedures or provide informed consent; 8. Participating in other device or drug trial that has not completed the required protocol follow-up period; 9. Any conditions that hampers proper angiographic assessment or makes percutaneous arterial access unsafe; 10. High risk candidates defined as the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST); 11. Any vascular, extremity soft tissue or orthopedic injury that may contraindicate bilateral arm ischemic preconditioning (e.g. superficial wounds and fractures of the arm); 12. Blood pressure cannot be controlled lower than 200 mmHg by medications; 13. Peripheral blood vessel disease (especially subclavian arterial and upper limb artery stenosis or occlusion).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | Within six months after carotid artery stenting | Cerebrovascular events included ischemic stroke, transient ischemic attack (TIA), cerebral hemorrhage and hyperperfusion syndrome. Cardiovascular events included angina and myocardial infarction.Death included any reason caused death. |
| Participants Who Got New Diffusion-weighted Imaging (DWI) Lesions on Post-treatment Magnetic Resonance Imaging (MRI) Scans. | Within 48 hours after carotid artery stenting. | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum High-sensitive C-reactive Protein (Hs-CRP). | Baseline, on admission, and 1 and 24 hours after carotid artery stenting. | — |
| Number of Patients With Any Side Effects of Remote Ischemic Preconditioning (RIPC) Treatment. | From baseline to 6 months after treatment. | The side effects referred to any side effects of RIPC or sham RIPC treatment, not including the sides effect of medications and CAS. |
| Serum Neuron Specific Enolase (NSE) Levels. | Baseline, on admission, and 1 and 24 hours after carotid artery stenting. | — |
| Serum S-100B Levels. | Baseline, on admission, and 1 and 24 hours after carotid artery stenting. | — |
Countries
China
Participant flow
Recruitment details
Symptomatic and asymptomatic subjects with carotid artery stenosis which was more than 70% by angiography , duplex ultrasound, Computed Tomography Angiography or Magnetic Resonance Angiography (NASCET criteria), who could undergo carotid artery stenting and all follow-ups, were recruited starting from August 2012.
Participants by arm
| Arm | Count |
|---|---|
| RIPC Group Treatment:Patients in this group received standard medical therapy and remote ischemic preconditioning (RIPC) treatment for at least 2 weeks before carotid artery stenting.
Remote ischemic preconditioning: Remote ischemic preconditioning consisted of five 5-min cycles of bilateral arm ischemia/reperfusion, which is induced by an automated cuff-inflator placed on bilateral arm and inflated to 200 mmHg for 5-min followed by deflating the cuff for 5-min.
Carotid Artery Stenting: Carotid Artery Stenting is an invasive therapy of carotid artery stenosis. | 63 |
| Control Group Treatment:Patients in this group received standard medical therapy alone for at least 2 weeks before carotid artery stenting.
Carotid Artery Stenting: Carotid Artery Stenting is an invasive therapy of carotid artery stenosis. | 63 |
| Sham RIPC Group Treatment:Patients in this group received standard medical therapy and sham RIPC treatment for at least 2 weeks before carotid artery stenting.
Sham remote ischemic preconditioning: Sham remote ischemic preconditioning consisted of five 5-min cycles of bilateral arm ischemia/reperfusion, which is induced by an automated cuff-inflator placed on bilateral arm and inflated to 60 mmHg for 5-min followed by deflating the cuff for 5-min.
Carotid Artery Stenting: Carotid Artery Stenting is an invasive therapy of carotid artery stenosis. | 63 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 4 | 5 | 5 |
| Overall Study | Protocol Violation | 7 | 4 | 8 |
| Overall Study | Withdrawal by Subject | 4 | 4 | 1 |
Baseline characteristics
| Characteristic | Total | Sham RIPC Group | RIPC Group | Control Group |
|---|---|---|---|---|
| Age, Continuous | 66.56 years STANDARD_DEVIATION 8.58 | 65.71 years STANDARD_DEVIATION 8.61 | 67.49 years STANDARD_DEVIATION 8.63 | 66.47 years STANDARD_DEVIATION 8.54 |
| Clinical manifestation Asymptomatic | 61 participants | 21 participants | 22 participants | 18 participants |
| Clinical manifestation Symptomatic | 128 participants | 42 participants | 41 participants | 45 participants |
| Contralateral carotid condition Occlusion | 5 participants | 2 participants | 2 participants | 1 participants |
| Contralateral carotid condition Other | 170 participants | 57 participants | 56 participants | 57 participants |
| Contralateral carotid condition Severe stenosis | 14 participants | 4 participants | 5 participants | 5 participants |
| Pre-treatment scans New DWI lesions | 5 participants | 1 participants | 2 participants | 2 participants |
| Pre-treatment scans No new DWI lesions | 184 participants | 62 participants | 61 participants | 61 participants |
| Race/Ethnicity, Customized Han race | 189 participants | 63 participants | 63 participants | 63 participants |
| Sex: Female, Male Female | 54 Participants | 19 Participants | 17 Participants | 18 Participants |
| Sex: Female, Male Male | 135 Participants | 44 Participants | 46 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 52 | 26 / 56 | 23 / 54 |
| serious Total, serious adverse events | 1 / 52 | 3 / 56 | 3 / 54 |
Outcome results
Primary
Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death.
Cerebrovascular events included ischemic stroke, transient ischemic attack (TIA), cerebral hemorrhage and hyperperfusion syndrome. Cardiovascular events included angina and myocardial infarction.Death included any reason caused death.
Time frame: Within six months after carotid artery stenting
Population: The analysis population only included participants who fully completed the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | No Cardiovascular Events | 47 participants |
| RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | No cerebrovascular event within 6 months | 47 participants |
| RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | Ischemic stroke within 6 months | 0 participants |
| RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | TIA within 6 months | 1 participants |
| RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | No Deaths | 47 participants |
| Control Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | No cerebrovascular event within 6 months | 48 participants |
| Control Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | Ischemic stroke within 6 months | 2 participants |
| Control Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | TIA within 6 months | 0 participants |
| Control Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | No Cardiovascular Events | 48 participants |
| Control Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | No Deaths | 48 participants |
| Sham RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | No Deaths | 46 participants |
| Sham RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | No Cardiovascular Events | 46 participants |
| Sham RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | Ischemic stroke within 6 months | 2 participants |
| Sham RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | No cerebrovascular event within 6 months | 46 participants |
| Sham RIPC Group | Number of Patients With Cerebrovascular Events, Cardiovascular Events or Death. | TIA within 6 months | 1 participants |
Primary
Participants Who Got New Diffusion-weighted Imaging (DWI) Lesions on Post-treatment Magnetic Resonance Imaging (MRI) Scans.
Time frame: Within 48 hours after carotid artery stenting.
Population: The analysed population only included participants who finished carotid artery stenting, post-treatment MRI scans and blood drawn.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RIPC Group | Participants Who Got New Diffusion-weighted Imaging (DWI) Lesions on Post-treatment Magnetic Resonance Imaging (MRI) Scans. | With new lesions on post-treatment scans | 10 participants |
| RIPC Group | Participants Who Got New Diffusion-weighted Imaging (DWI) Lesions on Post-treatment Magnetic Resonance Imaging (MRI) Scans. | Without new lesions on post-treatment scans | 42 participants |
| Control Group | Participants Who Got New Diffusion-weighted Imaging (DWI) Lesions on Post-treatment Magnetic Resonance Imaging (MRI) Scans. | With new lesions on post-treatment scans | 26 participants |
| Control Group | Participants Who Got New Diffusion-weighted Imaging (DWI) Lesions on Post-treatment Magnetic Resonance Imaging (MRI) Scans. | Without new lesions on post-treatment scans | 30 participants |
| Sham RIPC Group | Participants Who Got New Diffusion-weighted Imaging (DWI) Lesions on Post-treatment Magnetic Resonance Imaging (MRI) Scans. | With new lesions on post-treatment scans | 23 participants |
| Sham RIPC Group | Participants Who Got New Diffusion-weighted Imaging (DWI) Lesions on Post-treatment Magnetic Resonance Imaging (MRI) Scans. | Without new lesions on post-treatment scans | 31 participants |
Secondary
Number of Patients With Any Side Effects of Remote Ischemic Preconditioning (RIPC) Treatment.
The side effects referred to any side effects of RIPC or sham RIPC treatment, not including the sides effect of medications and CAS.
Time frame: From baseline to 6 months after treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIPC Group | Number of Patients With Any Side Effects of Remote Ischemic Preconditioning (RIPC) Treatment. | 0 participants |
| Control Group | Number of Patients With Any Side Effects of Remote Ischemic Preconditioning (RIPC) Treatment. | 0 participants |
| Sham RIPC Group | Number of Patients With Any Side Effects of Remote Ischemic Preconditioning (RIPC) Treatment. | 0 participants |
Secondary
Serum High-sensitive C-reactive Protein (Hs-CRP).
Time frame: Baseline, on admission, and 1 and 24 hours after carotid artery stenting.
Population: The analysed population only included participants who finished carotid artery stenting, post-treatment MRI scans and blood drawn.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RIPC Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | Baseline | 1.23 mg/L |
| RIPC Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | On admission | 0.99 mg/L |
| RIPC Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | 1 hour after CAS | 1.31 mg/L |
| RIPC Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | 24 hours after CAS | 5.09 mg/L |
| Control Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | 24 hours after CAS | 7.90 mg/L |
| Control Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | Baseline | 1.22 mg/L |
| Control Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | 1 hour after CAS | 1.46 mg/L |
| Control Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | On admission | 1.09 mg/L |
| Sham RIPC Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | 24 hours after CAS | 6.90 mg/L |
| Sham RIPC Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | On admission | 1.35 mg/L |
| Sham RIPC Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | 1 hour after CAS | 1.55 mg/L |
| Sham RIPC Group | Serum High-sensitive C-reactive Protein (Hs-CRP). | Baseline | 1.37 mg/L |
Secondary
Serum Neuron Specific Enolase (NSE) Levels.
Time frame: Baseline, on admission, and 1 and 24 hours after carotid artery stenting.
Population: The analysed population only included participants who finished carotid artery stenting, post-treatment MRI scans and blood drawn.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RIPC Group | Serum Neuron Specific Enolase (NSE) Levels. | Baseline | 12.83 ng/L | Standard Deviation 3.07 |
| RIPC Group | Serum Neuron Specific Enolase (NSE) Levels. | On admission | 12.63 ng/L | Standard Deviation 3.77 |
| RIPC Group | Serum Neuron Specific Enolase (NSE) Levels. | 1 hour after CAS | 13.00 ng/L | Standard Deviation 2.85 |
| RIPC Group | Serum Neuron Specific Enolase (NSE) Levels. | 24 hours after CAS | 12.65 ng/L | Standard Deviation 2.78 |
| Control Group | Serum Neuron Specific Enolase (NSE) Levels. | 24 hours after CAS | 12.97 ng/L | Standard Deviation 4.28 |
| Control Group | Serum Neuron Specific Enolase (NSE) Levels. | Baseline | 12.51 ng/L | Standard Deviation 2.92 |
| Control Group | Serum Neuron Specific Enolase (NSE) Levels. | 1 hour after CAS | 13.18 ng/L | Standard Deviation 3.98 |
| Control Group | Serum Neuron Specific Enolase (NSE) Levels. | On admission | 12.85 ng/L | Standard Deviation 3.59 |
| Sham RIPC Group | Serum Neuron Specific Enolase (NSE) Levels. | 24 hours after CAS | 12.77 ng/L | Standard Deviation 3.05 |
| Sham RIPC Group | Serum Neuron Specific Enolase (NSE) Levels. | On admission | 12.56 ng/L | Standard Deviation 2.71 |
| Sham RIPC Group | Serum Neuron Specific Enolase (NSE) Levels. | 1 hour after CAS | 13.01 ng/L | Standard Deviation 4.32 |
| Sham RIPC Group | Serum Neuron Specific Enolase (NSE) Levels. | Baseline | 12.12 ng/L | Standard Deviation 2.76 |
Secondary
Serum S-100B Levels.
Time frame: Baseline, on admission, and 1 and 24 hours after carotid artery stenting.
Population: The analysed population only included participants who finished carotid artery stenting, post-treatment MRI scans and blood drawn.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RIPC Group | Serum S-100B Levels. | On admission | 49.70 pg/mL | Standard Deviation 16.25 |
| RIPC Group | Serum S-100B Levels. | 24 hours after CAS | 51.40 pg/mL | Standard Deviation 16.16 |
| RIPC Group | Serum S-100B Levels. | 1 hour after CAS | 50.99 pg/mL | Standard Deviation 20.21 |
| RIPC Group | Serum S-100B Levels. | Baseline | 49.64 pg/mL | Standard Deviation 15.74 |
| Control Group | Serum S-100B Levels. | 1 hour after CAS | 51.19 pg/mL | Standard Deviation 22.4 |
| Control Group | Serum S-100B Levels. | 24 hours after CAS | 52.94 pg/mL | Standard Deviation 24.34 |
| Control Group | Serum S-100B Levels. | On admission | 50.75 pg/mL | Standard Deviation 16.79 |
| Control Group | Serum S-100B Levels. | Baseline | 50.14 pg/mL | Standard Deviation 17.04 |
| Sham RIPC Group | Serum S-100B Levels. | 24 hours after CAS | 52.02 pg/mL | Standard Deviation 19.71 |
| Sham RIPC Group | Serum S-100B Levels. | Baseline | 50.42 pg/mL | Standard Deviation 13.62 |
| Sham RIPC Group | Serum S-100B Levels. | 1 hour after CAS | 51.79 pg/mL | Standard Deviation 19.42 |
| Sham RIPC Group | Serum S-100B Levels. | On admission | 51.24 pg/mL | Standard Deviation 13.3 |