Effects of Remote Ischemic Preconditioning on Restenosis Post Lower Limb Revascularization Angioplasty
NCT ID: NCT02406131
Last Updated: 2017-09-26
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
SUSPENDED
Clinical Phase
NA
Total Enrollment
40 participants
Study Classification
INTERVENTIONAL
Study Start Date
2018-04-30
Study Completion Date
2019-12-31
Brief Summary
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The investigators will established relation between restenosis and inflammatory response to shearing stress caused by angioplasty suggest that any mechanism that affect inflammatory response can consequently affect the restenosis rate. There is accumulated evidence that remote ischemic precondition has modifying suppressive effect on inflammatory response and the investigators hypothesized that RIPC may lead to reduction in post angioplasty restenosis rate.
Detailed Description
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Rationale:
The father of interventional radiology Charles Dotter (1920-1985) performed the first percutaneous transluminal angioplasty in university of Oregon hospital on Laura Shaw in 16th of January 1964. She presented with typical rest pain and foot gangrene on left leg and her angiogram show distal superficial femoral artery focal stenosis. He saved her leg and she was walking for the next 3 years of her life using his experimental dilating catheter Later in 1977 Zurich witnessed the first coronary angioplasty by German cardiologist Andreas Gruentzig (1939-1985) using same technique .
The angioplasty utilized gradually in the next years after Dotter to provide less invasive option for the growing number of peripheral vascular disease patients estimated to be in the range of 3% to 10%, increasing to 15% to 20% in persons over 70 years. Early diagnosis remains difficult because patients tends to be asymptomatic up to 50% or more of vessel narrowing. the strong association between prevalence of peripheral vascular disease and age increase the demand with world population ageing specially in western Europe and USA. The lower extremity revascularization USA statistics in year 2000 was 40/100,000 and increasing.
Restenosis or the gradual narrowing of the re vascularized vessel remains one of the main problems usually it occurs within 6 months of angioplasty . Restenosis percentages varies between 12% up to 63 % in different studies largely depends on the lesion type and site with below knee interventions being more liable for restenosis.
The restenosis phenomena can be explained by the physiological response to the trauma caused by the balloon when inflated to compress the atheroma. Many factors can influence the process e.g. patient , procedure and vessel condition before intervention.it can be considered as hypertrophic wound healing from the interaction between monocyte-derived macrophages , T cells and arterial wall .the inflammatory response lead to Neointimal Hyperplasia the terminology uses to describe the proliferation and migration of vascular smooth muscle cells . Elevated inflammatory and coagulation factors markers levels after angioplasty has been suggested as predictors for the possibility of restenosis . The inflammatory theory was more supported when using immunosuppressive drugs like Sirolimus shows positive effects on reducing restenosis rate.
Ischemic precondition introduced first as mechanism to reduced subsequent myocardium injury after applying intermittent periods of sub-lethal ischemia . Subsequently the concept examined on other body organs . The mechanisms through which remote ischemic preconditioning (RIPC) work was the subject for many studies suggesting neural, humoral and anti-Inflammatory pathways . Animal studies suggest powerful anti-inflammatory effect for RIPC . other studies shows endothelial protections by decrease formation of reactive oxygen species (ROS) and upregulates endothelial nitric oxide (eNOS) synthase which responsible for most of vasculature Nitric Oxide a very important protective molecule in reperfusion and shearing stress injuries . In human studies Ischaemic, preconditioning show endothelial protective effect and altered Neutrophils function including reduced adhesion, exocytosis, phagocytosis, and modified cytokine secretion. . In one study, RIPC stimulates modified leukocyte inflammatory gene expression in correlations with the first and second windows of the RIPC, which is 1-2 hours and 12-24 respectively.
Sampling Frame the peripheral vascular disease patients with medical profiles, which match trial criteria who are waiting for or admitted from emergency department for lower limb revascularization angioplasty in Galway university hospital, will be identified. Recruitment will be stopped at 10 months of 16 months of the trial period.
Trial Design Patients who need revascularization angioplasty classically had history of symptomatic peripheral vascular disease usually assessed in OPD using ABI and send for duplex ultrasound scan after which some get CT angiogram or Magnetic Resonance Angiography (MRA). Furthermore, intra operative images are the common practice. the investigators will be recruiting from this group in accordance with trial protocol.
The target number will be 40 patients divided into 2 groups. All groups candidates will undergo base line assessment which include history, examination, duplex, ABI and blood sample for inflammatory and coagulation markers.
The candidates will randomly allocated to:
Randomisation Age and DM are associated with many comorbidities. Randomization will be stratified for these two confounders using Minimpy computer software.
All trial candidates will have unique numbers to identify them and conceal their identity. Patients files will be locked in trial office with one-person access and each candidate will get their numbers in sequential way according to their allocation.
Projected recruitment. Galway University hospital provides vascular services for a population of approximately 750000 served by the West-North West Hospitals Group. The patients for the trial will be actively recruited from out patient's clinics, in patients and theatre booking database. Information about the trial will be given to all vascular team including criteria for selection and exclusion. Those who qualified will be counselled by the trial team and consented if the agree to join. The target of 40 patients should be achievable within the recruitment window.
Patient recruitment \& consent Eligible candidates will get all the information about the trial in written and verbal explanation for all the steps. Patients who are willing to take part will asked to provide written informed consent. Three copies of the consent form will be signed: one for the patient, one for the patient's clinical notes file and a one copy for the patient's trial folder.
Data collection Demographic and clinical data of eligible candidates who agree to participate will be collected. The candidates will be assign a trial number identifier after informed consent is signed and no personal information will be available on the data entry sheets. The original data-entry preform will be retained together with a copy of the consent form in the trial office with other trial documents in the trial office in CSI building. The code key for the trial numbers will be limited to the Chief Investigator. Encrypted back up copy will be prepared at the end of each data entry and will be kept looked separately. All data will be retained in the care of the principal investigator for a period of five years from the closure of the trial.
Statistical analysis A trial team member blinded to trial allocation will perform the statistical analysis with respect to the primary and secondary outcomes. This is a pilot study the results will be used to identify if there is a need for larger trial.
Trial monitoring Day-to-day management of the trial will be the responsibility of the trial manager, supervised by the principal investigator. A meeting will be held every two weeks between the trial manager and the principal investigator to monitor recruitment, data collection etc.
The father of interventional radiology Charles Dotter (1920-1985) performed the first percutaneous transluminal angioplasty in university of Oregon hospital on Laura Shaw in 16th of January 1964. She presented with typical rest pain and foot gangrene on left leg and her angiogram show distal superficial femoral artery focal stenosis. He saved her leg and she was walking for the next 3 years of her life using his experimental dilating catheter Later in 1977 Zurich witnessed the first coronary angioplasty by German cardiologist Andreas Gruentzig (1939-1985) using same technique .
The angioplasty utilized gradually in the next years after Dotter to provide less invasive option for the growing number of peripheral vascular disease patients estimated to be in the range of 3% to 10%, increasing to 15% to 20% in persons over 70 years. Early diagnosis remains difficult because patients tends to be asymptomatic up to 50% or more of vessel narrowing. the strong association between prevalence of peripheral vascular disease and age increase the demand with world population ageing specially in western Europe and USA. The lower extremity revascularization USA statistics in year 2000 was 40/100,000 and increasing.
Restenosis or the gradual narrowing of the re vascularized vessel remains one of the main problems usually it occurs within 6 months of angioplasty . Restenosis percentages varies between 12% up to 63 % in different studies largely depends on the lesion type and site with below knee interventions being more liable for restenosis.
The restenosis phenomena can be explained by the physiological response to the trauma caused by the balloon when inflated to compress the atheroma. Many factors can influence the process e.g. patient , procedure and vessel condition before intervention.it can be considered as hypertrophic wound healing from the interaction between monocyte-derived macrophages , T cells and arterial wall .the inflammatory response lead to Neointimal Hyperplasia the terminology uses to describe the proliferation and migration of vascular smooth muscle cells . Elevated inflammatory and coagulation factors markers levels after angioplasty has been suggested as predictors for the possibility of restenosis . The inflammatory theory was more supported when using immunosuppressive drugs like Sirolimus shows positive effects on reducing restenosis rate.
Ischemic precondition introduced first as mechanism to reduced subsequent myocardium injury after applying intermittent periods of sub-lethal ischemia . Subsequently the concept examined on other body organs . The mechanisms through which remote ischemic preconditioning (RIPC) work was the subject for many studies suggesting neural, humoral and anti-Inflammatory pathways . Animal studies suggest powerful anti-inflammatory effect for RIPC . other studies shows endothelial protections by decrease formation of reactive oxygen species (ROS) and upregulates endothelial nitric oxide (eNOS) synthase which responsible for most of vasculature Nitric Oxide a very important protective molecule in reperfusion and shearing stress injuries . In human studies Ischaemic, preconditioning show endothelial protective effect and altered Neutrophils function including reduced adhesion, exocytosis, phagocytosis, and modified cytokine secretion. . In one study, RIPC stimulates modified leukocyte inflammatory gene expression in correlations with the first and second windows of the RIPC, which is 1-2 hours and 12-24 respectively.
Sampling Frame the peripheral vascular disease patients with medical profiles, which match trial criteria who are waiting for or admitted from emergency department for lower limb revascularization angioplasty in Galway university hospital, will be identified. Recruitment will be stopped at 10 months of 16 months of the trial period.
Trial Design Patients who need revascularization angioplasty classically had history of symptomatic peripheral vascular disease usually assessed in OPD using ABI and send for duplex ultrasound scan after which some get CT angiogram or Magnetic Resonance Angiography (MRA). Furthermore, intra operative images are the common practice. the investigators will be recruiting from this group in accordance with trial protocol.
The target number will be 40 patients divided into 2 groups. All groups candidates will undergo base line assessment which include history, examination, duplex, ABI and blood sample for inflammatory and coagulation markers.
The candidates will randomly allocated to:
Randomisation Age and DM are associated with many comorbidities. Randomization will be stratified for these two confounders using Minimpy computer software.
All trial candidates will have unique numbers to identify them and conceal their identity. Patients files will be locked in trial office with one-person access and each candidate will get their numbers in sequential way according to their allocation.
Projected recruitment. Galway University hospital provides vascular services for a population of approximately 750000 served by the West-North West Hospitals Group. The patients for the trial will be actively recruited from out patient's clinics, in patients and theatre booking database. Information about the trial will be given to all vascular team including criteria for selection and exclusion. Those who qualified will be counselled by the trial team and consented if the agree to join. The target of 40 patients should be achievable within the recruitment window.
Patient recruitment \& consent Eligible candidates will get all the information about the trial in written and verbal explanation for all the steps. Patients who are willing to take part will asked to provide written informed consent. Three copies of the consent form will be signed: one for the patient, one for the patient's clinical notes file and a one copy for the patient's trial folder.
Data collection Demographic and clinical data of eligible candidates who agree to participate will be collected. The candidates will be assign a trial number identifier after informed consent is signed and no personal information will be available on the data entry sheets. The original data-entry preform will be retained together with a copy of the consent form in the trial office with other trial documents in the trial office in CSI building. The code key for the trial numbers will be limited to the Chief Investigator. Encrypted back up copy will be prepared at the end of each data entry and will be kept looked separately. All data will be retained in the care of the principal investigator for a period of five years from the closure of the trial.
Statistical analysis A trial team member blinded to trial allocation will perform the statistical analysis with respect to the primary and secondary outcomes. This is a pilot study the results will be used to identify if there is a need for larger trial.
Trial monitoring Day-to-day management of the trial will be the responsibility of the trial manager, supervised by the principal investigator. A meeting will be held every two weeks between the trial manager and the principal investigator to monitor recruitment, data collection etc.
Conditions
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Peripheral Vascular Diseases
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
DOUBLE
Caregivers
Outcome Assessors
Study Groups
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Control Group:
This group will be getting all the routine work up including Duplex scan . we will add request for inflammatory and coagulation markers in their blood samples before and after intervention . The pre-op blood sample will be collected within the 24 hours before intervention and the post intervention in the 24 hrs after (second RIPC window). The repeated duplex scan will be schedule after 6 months.
Group Type
NO_INTERVENTION
No interventions assigned to this group
RIPC Group
Remote Ischemic Preconditioning Group (RIPC):This group will have all the tests as for the control group with the additional component will be preconditioning. One hour prior to procedure candidates in this group will have structured intermittent periods of induced remote ischaemic preconditioning using standard blood pressure cuffs. The cuff will be inflated to 200 mmHg applied for 5 minutes alternating with 5 minutes rest to the total of 4 cycles, which needs 40 minutes.
Group Type
ACTIVE_COMPARATOR
Remote Ischemic Preconditioning
Intervention Type
OTHER
standard blood pressure cuffs applied to upper limb . The cuff will be inflated to 200 mmHg applied for 5 minutes alternating with 5 minutes rest to the total of 4 cycles
Interventions
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Remote Ischemic Preconditioning
standard blood pressure cuffs applied to upper limb . The cuff will be inflated to 200 mmHg applied for 5 minutes alternating with 5 minutes rest to the total of 4 cycles
Intervention Type
OTHER
Eligibility Criteria
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Inclusion Criteria
1\. Patients planned for lower limb Angioplasty
Exclusion Criteria
1. Known upper limb PVD
2. Previous history of upper limb deep vein thrombosis
3. Patients on glibenclamide or nicorandil- May affect RIPC
4. Raynaud's Disease
5. Intra operative decision to use graft - will be documented
2. Previous history of upper limb deep vein thrombosis
3. Patients on glibenclamide or nicorandil- May affect RIPC
4. Raynaud's Disease
5. Intra operative decision to use graft - will be documented
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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University College Hospital Galway
OTHER
Sponsor Role
collaborator
University Hospital of Limerick
OTHER
Sponsor Role
collaborator
National University of Ireland, Galway, Ireland
OTHER
Sponsor Role
lead
Responsible Party
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KHALID AHMED
Mr
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Stewart Walsh, Professor
Role: PRINCIPAL_INVESTIGATOR
NUIGalway - UCHG
Locations
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University Collage Hospital Galway
Galway, Co Galway, Ireland
Site Status
Limerick University Hospital
Limerick, , Ireland
Site Status
Countries
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Ireland
References
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Reference Type
DERIVED
Other Identifiers
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C.A. 1238
Identifier Type: -
Identifier Source: org_study_id