Background
Grade | Category | Clinical description | Objective criteria |
---|---|---|---|
0 | 0 | Asymptomatic - no hemodynamically significant occlusive disease | Normal treadmill test and ABI ≥0.9 |
1 | Mild claudication | Completes treadmill test. AP after exercise >50 mmHg, but at least 20 mmHg lower than resting value | |
I | 2 | Moderate claudication | Between categories 1 and 3 |
3 | Severe claudication | Cannot complete treadmill test and AP after exercise <50 mmHg | |
II | 4 | Ischemic rest pain | Resting AP <40 mmHg, flat or barely pulsatile ankle or metatarsal PVR, TP <30 mmHg |
III | 5 | Minor tissue loss - nonhealing ulcer, focal gangrene with diffuse pedal ischemia | Resting AP <60 mmHg, ankle or metatarsal PVR flat or barely pulsatile, TP <40 mmHg |
6 | Major tissue loss - extending above TM level, functional foot no longer salvageable | Same as category 5 |
Epidemiology
Endovascular treatment
TASC guidelines
PTA or PTA with stenting for iliac obstructions
Distal outflow after endovascular repair
Balloon-expandable or self-expanding stents for iliac obstructions
Bare or covered stents for iliac obstructions
Author, year | Type of study | Number | Type of stent | Freedom of binary restenosis | |
---|---|---|---|---|---|
Covered | Uncovered | ||||
Sabri, 2010 [54] | Retrospective, comparative | 26 covered | Balloon-expandable | 1 year: 92% | 1 year:78%, |
28 uncovered | 2 year:92%, | 2 year: 62% | |||
Lammer, 2000 [61] | Prospective | 61 | Self-expanding | 6 month: 98%, | |
1 year: 91% | |||||
Wiesinger, 2005 [62] | Prospective | 60 | Self-expanding | 6 month: 94%, | |
1 year: 91% | |||||
Bosiers, 2007 [63] | Prospective | 91 | Balloon-expandable | 1 year: 91% | |
Chang, 2008 [53] | Retrospective, comparative | 71 covered | Mostly self-expanding | 5 year: 87% | 5 year: 53% |
122 uncovered | |||||
Mwipatayi, 2011 | Randomized controlled trial | 83 covered | Both | 18 month: 92% | 18 month: 75% |
84 uncovered |
Conclusion and rationale of this study
Methods/Design
Objectives
Primary objective
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To assess the absence of binary restenosis rate of advanced atherosclerotic lesions of the common iliac artery with a balloon-expandable PTFE-covered stent (Advanta V12, Atrium Medical Inc., Hudson, NH, USA), when compared to selected balloon-expandable uncovered stents, in a 2-year follow-up period.
Secondary objectives
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To assess the reocclusion rate and target-lesion revascularization rate after endovascular treatment of advanced atherosclerotic lesions of the common iliac artery with a balloon- expandable PTFE-covered stent (Advanta V12, Atrium Medical Inc., Hudson, NH, USA), when compared to selected balloon-expandable uncovered stents, in a 2-year follow-up period.
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To assess morphological outcome after endovascular treatment of advanced atherosclerotic lesions of the common iliac artery with a balloon-expandable PTFE-covered stent (Advanta V12, Atrium Medical Inc., Hudson, NH, USA), when compared to selected balloon-expandable uncovered stents, in a 2-year follow-up period.
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To assess hemodynamic outcome after endovascular treatment of advanced atherosclerotic lesions of the common iliac artery with a balloon expandable PTFE-covered stent (Advanta V12, Atrium Medical Inc., Hudson, NH, USA), when compared to selected balloon- expandable uncovered stents, in a 2-year follow-up period.
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To assess the complication rate, mortality rate and amputation rate after endovascular treatment of advanced atherosclerotic lesions of the common iliac artery with a balloon-expandable PTFE-covered stent (Advanta V12, Atrium Medical Inc., Hudson, NH, USA), when compared to selected balloon-expandable uncovered stents, in a 2-year follow-up period.
Study Design
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Maasstad Hospital, Rotterdam, The Netherlands
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Sint Antonius Hospital, Nieuwegein, The Netherlands
Study population
Inclusion criteria
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Age over 18;
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Symptomatic, atherosclerotic lesion of the common iliac artery, either a hemodynamically significant stenosis with a length of more than 3 cm, or an occlusion. This will be measured on the pre-dilation DSA-images, where a diameter reduction of >50% is considered significant. A hemodynamically significant stenosis is confirmed with an intra-arterial translesional systolic blood pressure gradient measurement, where >10 mmHg pressure gradient is considered significant. Serial lesions less than 2 cm apart will be regarded as one long stenosis;
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Signed informed consent form.
Exclusion criteria
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Stenosis with a length of less than 3 cm;
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Presence of a metastatic malignancy, or other disease that limits life expectancy to less than 2 years;
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Previous endovascular or surgical treatment of the common iliac artery on the affected side;
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Inability or unwillingness to comply with the follow-up schedule;
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Mental disability or language barrier that hinders the ability to understand and comply with the informed consent;
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Pregnancy or breast-feeding;
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Severe renal failure (e-GFR <30 mL/min/1.73 m2);
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Known allergy to iodinated contrast agents or to PTFE;
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Contra-indication for anti-coagulation;
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Acute limb ischemia;
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Occlusion of the abdominal aorta;
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Aneurysm of the abdominal aorta that is not amenable to endograft placement.
Sample size calculation
Treatment of subjects
Treatment of the common iliac artery
Treatment of the aorta
Treatment of the external iliac artery
Treatment of the common femoral artery
Medication
Investigational product
Name and description of investigational product
Name and description of control group products
Endpoints/parameters
Primary endpoint
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Absence of binary restenosis rate. Defined as the percentage of limbs with absence of hemodynamically significant obstruction in the target-lesion after endovascular treatment.
Secondary endpoints
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Reocclusion rate. Defined as complete occlusion of the initially treated target-lesion.
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Target-lesion revascularization (TLR) rate. Defined as the rate and frequency of the need for repeated procedures (endovascular or open surgical) due to a problem arising from the target-lesion (+1 cm proximally and distally to include edge phenomena) in surviving patients with preserved limb.
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Immediate outcome:
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Procedural success. Defined as the combination of technical success, device success and absence of procedural complications.
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Technical success. Defined as successful vascular access and completion of the endovascular procedure and immediate morphological success with less than 30% residual diameter reduction of the treated lesion on completion and a systolic pressure gradient of less than 5 mmHg.
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Device success. Defined as exact deployment of the device, according to the instructions for use, using the assigned device only.
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Clinical outcome: – Distribution of Rutherford stages during follow-up as compared to baseline.
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Functional outcome:
▪ In patients with IC: Improvement in claudication onset time (COT) and absolute claudicating time (ACT) on standardized treadmill test.-
Improvement in disease-related health status, functioning and quality of life. As defined by the Walking Impairment Questionnaire (WIQ) and RAND-36 questionnaire.
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Hemodynamic outcome: – Mean and median ABI during follow-up as compared to baseline.
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Morphological outcome: – Acute diameter gain (change in minimal luminal diameter from base-line to post-intervention.
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Target-extremity revascularization (TER) rate. Defined as the rate and frequency of the need for repeated procedures (endovascular or open surgical) due to a problem arising remote from the target-lesion in surviving patients with preserved limb.
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Mortality rate. Mortality rate associated with the endovascular procedure (that is, mortality within 30 days post-procedure or mortality during a hospitalization >30 days due to the procedure) will be reported separately, as well as overall mortality.
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Complication rate. In contrast with AE’s and SAE’s, which do not need to be related to the treatment, only complications that are (likely) related to the treatment will be reported. This is at the discretion of the investigator.– Complications will be scored as ‘major’ or minor’. A major complication is a complication that:▪ Leads to death;▪ Results in a life-threatening illness or injury;▪ Results in permanent impairment of a body structure or bodily function;▪ Requires inpatient hospitalization or prolongation of existing hospitalization;▪ Results in medical or surgical intervention to prevent permanent impairment to body structure or bodily function.
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Complications will be classified in to four complication categories:
▪ Access site complication (access site including distal to the site): Hematoma/bleeding, arterial/venous occlusion/thrombosis, severe vasospasm, intimal injury/dissection, pseudoaneurysm, arteriovenous fistula, vascular perforation or rupture, arterial embolization distal to puncture site.▪ Treatment site complication (treatment site including distal to the site): Hematoma/bleeding, arterial/venous occlusion/thrombosis, severe vasospasm, intimal injury/dissection, pseudoaneurysm, arteriovenous fistula, vascular perforation or rupture, arterial embolization distal to treatment site.▪ Organ-specific complication:∘ Neurological: TIA, minor and major stroke, seizure;∘ Cardiovascular: Hypotension or hypertension requiring treatment, arrhythmia requiring treatment, myocardial ischemia/infarction, chronic heart failure;∘ Respiratory: Profound hypoxia, pulmonary edema, respiratory arrest, pulmonary embolism, pneumothorax;∘ Gastrointestinal: Gastric bleeding, pancreatitis, peritonitis, abscess, perforation of hollow viscus.▪ Systemic complication: Allergic/anaphylactic reaction, renal failure, idiosyncratic reaction to drug, fluid/electrolyte imbalance. -
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Amputation rate. Divided in to minor (below the ankle) and major (above the ankle). Major amputation is sub-divided in to below-the-knee and above-the-knee. Planned and unplanned amputations will be reported separately. Planned amputations are defined as amputations that were planned prior to the revascularization procedure, that is, when the revascularization procedure is performed to improve the vascularization (and thereby healing potential) of the planned amputation wound.
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Rate of device-specific problems, for example, stent fracture, stent migration.
Baseline characteristics
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Risk factors and comorbidities: – Age;
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Gender;
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Hypertension: Systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, or if the patient is on antihypertensieve therapy for the indication of hypertension;
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Hyperlipidemia: LDL-cholesterol >4.4 mmol/L (>170 mg/dL) or triglycerides >2.0 mmol/L (>177 mg/dL), or if the patient is taking lipid-lowering medication for the indication of hyperlipidemia;
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Diabetes mellitus: HbA1c >7% or if the patient consumes oral hypoglycemic agents or uses insulin;
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Smoking: Current smoking status (active/previous/never), number of pack years, number of years since last smoked;
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Ischemic heart disease: History of myocardial infarction, angina pectoris, previous percutaneous or surgical coronary revascularization, positive exercise test, anti-anginal therapy;
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Congestive heart failure: Ejection fraction <40%;
Renal insufficiency: e-GFR <60 mL/min/1.73 m2;-
Cerebrovascular disease: Known carotid artery disease and history of minor or major stroke or transient ischemic attack (TIA).
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Medication, pre-, peri- and post-procedural, (including dose, frequency and duration of use): – Anticoagulants (Acenocoumarol, Fenprocoumon, unfractioned or low molecular weight heparins, and so on);
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Antithrombotic agents (Acetyl salicylic acid, Clopidrogel, Dipyridamol, and so on);
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Statins or other lipid-lowering agents;
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Beta-blockers;
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Angiotensin converting enzyme inhibitors;
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Angiotensin-II receptor antagonists;
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Insulin and oral hypoglycaemic agents;
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Medications for the treatment of IC (Pentoxifylline, Buflomedil).
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Baseline anatomic characteristics of the target lesion in the common iliac artery, as determined by DSA and pre-operative CT-angiography or MR-angiography: – Arterial inflow: Impaired inflow is defined as presence of hemodynamically significant obstruction in the aorta;
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Arterial outflow: Impaired outflow is defined as presence of hemodynamically significant obstruction in the external iliac artery, common femoral artery or both superficial and deep femoral arteries. Isolated hemodynamically significant obstruction in either the superficial or deep femoral artery will not be considered impaired outflow;
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Reference vessel diameter, obtained from averaging 5mm segments proximal and distal to the lesion;
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Involvement of origin/ostium;
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Lesion length, documented in centimeters and classified as follows:
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Cerebrovascular disease: Known carotid artery disease and history of minor or major stroke or transient ischemic attack (TIA).
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Medication, pre-, peri- and post-procedural, (including dose, frequency and duration of use): – Anticoagulants (Acenocoumarol, Fenprocoumon, unfractioned or low molecular weight heparins, and so on);
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Antithrombotic agents (Acetyl salicylic acid, Clopidrogel, Dipyridamol, and so on);
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Statins or other lipid-lowering agents;
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Beta-blockers;
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Angiotensin converting enzyme inhibitors;
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Angiotensin-II receptor antagonists;
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Insulin and oral hypoglycaemic agents;
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Medications for the treatment of IC (Pentoxifylline, Buflomedil).
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Baseline anatomic characteristics of the target lesion in the common iliac artery, as determined by DSA and pre-operative CT-angiography or MR-angiography: – Arterial inflow: Impaired inflow is defined as presence of hemodynamically significant obstruction in the aorta;
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Arterial outflow: Impaired outflow is defined as presence of hemodynamically significant obstruction in the external iliac artery, common femoral artery or both superficial and deep femoral arteries. Isolated hemodynamically significant obstruction in either the superficial or deep femoral artery will not be considered impaired outflow;
Reference vessel diameter, obtained from averaging 5mm segments proximal and distal to the lesion;Involvement of origin/ostium;Lesion length, documented in centimeters and classified as follows:▪ Focal: ≤1 cm;▪ Short: >1 and <3 cm;▪ Intermediate: ≥ 3 and < 5 cm;▪ Long: ≥ 5 cm;▪ In case of vessel occlusion with a stenosed segment, both the length of the stenosed segment and the length of the occluded segment should be reported.-
Occlusion or stenosis
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In case of stenosis
▪ Minimal luminal diameter;▪ Percent diameter stenosis;▪ Systolic pressure gradient, measured as described previously.-
Calcification: Semi-quantitative distinction between no, moderate, and heavy calcification at the site of the lesion.
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TASC-classification.
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Baseline anatomic characteristics of other hemodynamically significant lesions at the aortoiliac and femoropopliteal level: – Arterial segment(s):▪ Infra-renal abdominal aorta;▪ Internal iliac artery;▪ External iliac artery;▪ Common femoral artery;▪ Deep femoral artery;▪ Superficial femoral artery;▪ Popliteal artery.
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Lesion length, documented in centimeters and classified as follows:
▪ Focal: ≤1 cm;▪ Short: >1 and <5 cm;▪ Intermediate: ≥ 5 and < 15 cm;▪ Long: ≥ 15 cm;▪ In case of vessel occlusion with a stenosed segment, both the length of the stenosed segment and the length of the occluded segment should be reported.-
Occlusion or stenosis
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Crural outflow: Each of the crural arteries with patency directly to the foot will score 1 point. A patent dorsal and plantar pedal arch will each score 1 point. This will lead to a score of 0 to 5, indicating crural outflow. As it is not standard procedure to make a DSA of the crural arteries during iliac interventions, pre-operative CT-A or MR-A will be used to score this.
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Presence of multilevel disease: Defined as presence of significant obstructive lesions at more than one level in the same limb (aortoiliac, femoropopliteal and crural). When patients are included with both limbs, one limb can have multilevel disease, while the other limb does not.
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Disease-related health status and quality of life: As defined by the Walking Impairment Questionnaire (WIQ) and RAND-36 questionnaire.
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Rutherford stage.
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Functional status: – In patients with IC: Claudication onset time (COT) and absolute claudication time (ACT) on a standardized treadmill test (3.2 km/h at a 12% grade for a maximum of 5 minutes).
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Hemodynamic status: – In patients with IC: ABI at rest and after standardized treadmill test;
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In patients with CLI: Systolic ankle pressure and ABI.
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Degree of stenosis and peak systolic velocity ratio on DUS.
Procedure-related parameters
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Grams of intravenous iodine used for contrast. The amount of millilitres used will be scored during the procedure, and post-hoc the amount of iodine will be calculated. In our centre, we use Visipaque®, which contains 320mg of Iodine per ml
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Radiation time and dosage, as is measured by the fluoroscopy device
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Amount and type of materials used (guidewires, sheaths, balloons, catheters)
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Type, diameter, number and length of stents used
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Lesion characteristics after treatment: – Arterial inflow: Impaired inflow is defined as presence of hemodynamically significant obstruction in the aorta;
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Arterial outflow: Impaired outflow is defined as presence of hemodynamically significant obstruction in the external iliac artery, common femoral artery or both superficial and deep femoral arteries. Isolated hemodynamically significant obstruction in either the superficial or deep femoral artery will not be considered impaired outflow;
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Minimal luminal diameter (MLD);
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Percent diameter stenosis;
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Systolic pressure gradient.
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Peri-procedural complications.
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Technical success
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Device success
Parameters scored during regular follow-up
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Disease-related health status and quality of life: As defined by the Walking Impairment Questionnaire (WIQ) and RAND-36 questionnaire.
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Rutherford stage.
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Functional status: – In patients with IC: Claudication onset time (COT) and absolute claudication time (ACT) on a standardized treadmill test (3.2 km/h at a 12% grade for a maximum of 5 minutes).
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Hemodynamic status: – In patients with IC: ABI at rest and after standardized treadmill test;
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In patients with CLI: Systolic ankle pressure and ABI.
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Degree of stenosis and peak systolic velocity ratio on DUS.
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Occurrence of amputation.
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Mortality.
Parameters scored in case of restenosis or reocclusion
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Anatomic characteristics of the restenosis or occlusion in the stent in the common iliac artery: – Arterial inflow: Impaired inflow is defined as presence of hemodynamically significant obstruction in the aorta.
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Arterial outflow: Impaired outflow is defined as presence of hemodynamically significant obstruction in the external iliac artery, common femoral artery or both superficial and deep femoral arteries. Isolated hemodynamically significant obstruction in either the superficial or deep femoral artery will not be considered impaired outflow.
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Relation of stenosis or occlusion to the stent:
▪ Proximal edge, defined as 1 cm proximal and distal to the proximal edge of the stent;▪ In-stent, defined as 1 cm distal from the proximal to 1 cm proximal from the distal end;▪ Distal edge, defined as 1 cm proximal and distal to the distal edge of the stent.-
Lesion length, documented in centimeters and classified as follows:
▪ Focal: ≤1 cm;▪ Short: >1 and <3 cm;▪ Intermediate: ≥ 3 and < 5 cm;▪ Long: ≥ 5 cm;▪ In case of vessel occlusion with a stenosed segment, both the length of the stenosed segment and the length of the occluded segment should be reported.-
Occlusion or stenosis;
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In case of stenosis:
▪ Minimal luminal diameter;▪ Percent diameter stenosis;▪ Systolic pressure gradient. -
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Procedural success rate of re-intervention.
Randomization, blinding and treatment allocation
Study procedures
Digital Subtraction Angiography (DSA)
Duplex Ultrasonography
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Grayscale: Uses ultrasound to directly visualize the structure of the vessel. No motion or bloodflow is assessed. In this way, stenosis or occlusion can be directly visualized
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Color-doppler: Uses ultrasound to visualize the flow in the vessel. This is expressed as peak-systolic velocity (PSV), the highest velocity of the blood, during the systolic phase, in cm/sec. In a stenosis, the PSV will increase. When a stenosis is suspected, the peak-systolic velocity ratio is calculated. This is defined as the ratio of intra-stenotic PSV to pre-stenotic PSV. A ratio of >2.4 will be defined as a significant stenosis. When the vessel is occluded, no flow will be measured.
ABI measurement
Standardized treadmill test
Walking Impairment Questionnaire (WIQ)
RAND-36 questionnaire
Follow up scheme
Pre-operative
Per-operative
1 month postoperative
6, 12 and 24 months postoperative
Pre-ope-rative | Per-ope-rative | 1 month | 6 months | 12 months | 24 months | In case of restenosis | |
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DUS | X | X | X | X | X | ||
ABI (with or with-out treadmill test) | X | X | X | X | X | X | |
DSA | X | X | |||||
WIQ/RAND-36 | X | X | X | X | X |
Unplanned visits
Withdrawal of individual subjects
Replacement of individual subjects after withdrawal
Follow-up of subjects withdrawn from treatment
Premature termination of the study
Safety reporting
Section 10 WMO event
Adverse and serious adverse events
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Causes death, or is life threatening (at the time of the event);
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Requires hospitalization or prolongation of existing inpatients’ hospitalization;
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Results in persistent or significant disability or incapacity.
Follow-up of adverse events
Data safety monitoring board
Statistical analysis
Descriptives
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Continuous data (age, BMI, length, and so on): Averages with standard deviation (parametric data) or medians with percentiles (non-parametric data) will be calculated for both groups.
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Categorical data (TASC type, co-morbidities, and so on): Frequencies will be calculated for both groups.
Comparative statistics
Actuarial analysis
Univariate analysis
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Target lesion revascularization rate and target extremity revascularization rate;
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Procedural, technical and device success rate;
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Rate of device-specific problems.